Current Pharmaceutical Design

Worldwide rate of prevalence of diabetes is around 9% and is increasing at a rapid pace. According to the WHO, every year, there is a significant increase in the number of people diagnosed with the disease. Moreover, it is considered that diabetes, due to micro and macrovascular complications, is one of the ten leading causes of death [1]. Cardiovascular disease is the underlying cause of more than 55% of death in these patients [2-5]. Hyperglycemia-induced inflammation and oxidative stress provoke endothelial dysfunction, arterial stiffness and thrombogenicity leading to serious complications such as diabetic foot, diabetic nephropathy and diabetic retinopathy thus, aggravating life quality and expectancy in these patients [6, 7]. Considering that, patients with diabetes may develop premature atherosclerosis, they are at greater risk of cardiovascular and cerebrovascular disease [8, 9]. Based on epidemiological data, coronary artery disease, stroke and peripheral artery disease occur from 2 to 6 times more frequently in patients with diabetes and even at a younger age compared to the general population. In the context of this evidence, we will highlight the link between diabetes and different manifestations of cardiovascular disease, emphasizing heart failure and peripheral artery disease, and will also discuss all the current data concerning the role of novel molecular mechanisms in the development and progression of the disease, as well the role of novel antidiabetic agents in the management of these patients. More specifically, this special issue under the topic “Diabetes and Cardiovascular Disease” contains 5 review articles. The first review article focuses on the role of novel antidiabetic agents, especially, DPP-4is on cardiovascular parameters such as endothelial function and arterial stiffness. The next two review articles focus on the cardiovascular comorbidities in patients with diabetes, including peripheral artery disease and heart failure, while the last two reviews discuss the role of microRNAS in the pathogenesis of diabetic complications and the well-promising effects of novel antidiabetic agents on cardiovascular parameters, respectively. Furthermore, supplementary figures and tables are also provided. Approximately 70% of patients with diabetes will develop cardiovascular complications [10]. Therefore, the optimal treatment against the disease should include not only the regulation of blood glucose levels but also the improvement of endothelial function and arterial stiffness, which are early strong indicators of microvascular and macrovascular complications [11, 12]. DPP-4 inhibitors are a new class of antidiabetic agents, which have gained an FDA approval, as well as market authorization. Interestingly, in patients with diabetes, impaired production of GLP-1 has been observed, leading to insulin resistance and hyperglycemia. Furthermore, DPP-4 enzyme is responsible for the degradation and cleavage of these incretins. Consequently, DPP-4is prolong GLP-1 activity [13], which stimulates insulin secretion from pancreas and reduces glucagon secretion, thus lowering blood glucose levels. Due to the existing gap in the literature regarding the effect of novel antidiabetic agents on cardiovascular parameters and molecular pathways, this systematic review of randomized, double-blinded clinical trials will examine the current data for possible cardioprotection of DPP-4 inhibitors and summarize their effects on endothelial function and arterial stiffness in patients with type 2 diabetes [14]. Patients with peripheral artery disease are at high risk of lower extremity amputations, deteriorating both their life expectancy and quality [15]. So far, it is well known that patients with diabetes present a greater risk of developing peripheral artery disease when compared to healthy subjects [16]. In these patients, the disease occurs at the early stages with a rapid progression, and it is usually asymptomatic, making it difficult to diagnose. Many pathophysiological pathways that have been described in diabetes such as thrombogenicity, inflammation and oxidative stress seem to contribute to the development and progression of peripheral artery disease [17]. This review will focus on therapeutical management in patients with diabetes and peripheral artery disease, summarizing all the novel pharmacological agents and nonpharmacological measures such as lifestyle, as well as revascularization therapy [18]. Diabetes has been a major health problem leading to cardiovascular disease, despite the advance in the prevention and treatment of the disease. More specifically, patients with diabetes present higher risk of developing heart failure, with greater mortality and poorer prognosis. As a consequence, both hospitalization in Europe and economic burden on the health system increase [19]. Hyperglycemia and insulin resistance affect plenty of molecular pathways, thus leading to impaired systolic and diastolic function [20, 21]. Considering the fact that almost 50% of patients with diabetes will develop heart failure, European Society of Cardiology in collaboration with the European Association for the Study of Diabetes have announced specific recommendations for the treatment of the disease based on novel anti-diabetic agents, so as to delay the development and progression of heart failure in these patients [22]. So far, only SGLT-2 inhibitors have proven cardiovascular benefit regarding heart failure, and thus they are highly indicated in patients with diabetes and established heart failure. As far as DPP-4 inhibitors are concerned, saxagliptin is strongly contradicted in patients with diabetes, who are at high risk of developing heart failure. This review article summarizes all the recent data about the pathophysiology and management of patients with diabetes and heart failure, emphasizing on the role of all current available antidiabetic agents on HF clinical outcomes [23]. MicroRNAs are endogenous, non-coding RNAs, consisting of only 20-22 nucleotides [24]. More than 1,800 human microRNAs have been discovered and they seem to play a major role in regulation of homeostasis. In more details, each microRNA targets the 3’ untranslated region of mRNAs, thus modulating the expression of many proteins [25]. So far, microRNAs have gained much popularity, considering that they seem to participate in many molecular pathways of atherosclerosis and vascular remodeling, such as monocyte stimulation and arterial wall adhesion, vascular smooth muscle cell activation and platelet aggregation [26-28]. Moreover, microRNAs may modify insulin secretion or insulin action, as they can alter pancreatic beta cell development, insulin production and signaling. The aim of this review is to discuss the role of microRNAs in the development of diabetic complications [29]. Concerns of elevated cardiovascular risk with some anti-diabetic medications such as rosiglitazone, a peroxisome proliferator-activated receptor (PPAR) agonist, warranted pre- and post-approval cardiovascular outcome trials to demonstrate cardiovascular safety of newly marketed anti-diabetic drugs [30, 31]. Only these anti-diabetic agents would be eligible to apply for marketing authorization by the United States FDA, as well as EMA. Although these trials were initially designed to evaluate the safety, some of these demonstrated impressive cardiovascular benefit [32]. More specifically, although DPP-4is were non-inferior to placebo [33, 34], SGLT-2is and most of GLP-1RAs have shown significant cardioprotective properties in patients with diabetes and established cardiovascular disease or with multiple risk factors [35-38]. These favorable effects of novel antidiabetic agents on cardiovascular parameters discussed in this review will signify new perspectives in medical management, risk stratification and prevention, as well making the future brighter for these patients [39].

Novel materials from nano to bulk scale level are consistently introduced in various sectors. Like other fields, the pharmaceutical, medical and environmental areas have also been significantly advanced by recently emerging materials [1-4]. The most effective innovation has been witnessed in natural products, nanomaterials, polymers and their composites. Nanomaterials having at least a dimension less than 100 nm have been effectively utilized in controlled drug delivery system development. Additionally, the antimicrobial features developed from their extremely small size, high surface area and enhanced number of interaction points has been consistently reported [5-8]. Similarly, polymers due to their multiple synthetic routes, easy handling, surface modification, molding, and combination with other materials have led to advance applications in medical, and environmental fields [9-13]. Natural products including bioactive plant extracts, biopolymers and their composites are reported to have applications in wound healing, tissue regeneration, drug delivery, pollutant absorption, organic matter degradation etc. [10]. The increasing microbial resistance to the antibiotics has grasped attention of researchers to explore efficient alternatives. Advancement in nanotechnology has acknowledged emergence of certain novel antibiotics exhibiting excellent performance against pathogens. Various metal and metal oxides with multiple mode of antimicrobial action have been reported emerging antibiotic materials [Antimicrobial activities of metal containing compounds and hybrids]. Besides nanomaterial, numerous natural and synthetic compounds with potential therapeutic applications including anti-cancer, cardioprotective, antidiabetic, antiosteoporosis, anti-ageing have been explored. Nanoformulation of natural compounds e.g. curcumin has shown improved anticancer effects compared to conventional curcumin formulations [Therapeutic Potential of Equol: A Comprehensive Review; Nanocurcumin: A double-edged sword for microcancers]. The dilemma associated with these materials and drugs is their conventional practices of synthesis, manufacturing, processing and side effects that leads to severe adverse consequences for living beings and the environment. The development of green synthetic technologies seems as a potential alternate for preparation of various sizes and shapes of nanomaterials as well as diseases diagnosis and treatment [Assessing the Significance of Green Synthetic Chemistry from a Pharmaceutical Perspective; Pharmaceutical and Biomedical Applications of Green Synthesized Metal and Metal Oxide Nanoparticles]. The green synthesis approaches use living biotemplates, including plants and different microorganisms such as viruses, bacteria, fungi, algae, and actinomycetes. The presence of various metabolites in different parts of the plants such as leaves, fruits, seeds, flower, and others serve as the reducing and stabilizing agents [Biotemplate-mediated green synthesis and applications of nanomaterials]. Aerogels represent another class of advanced materials having the lowest density known with extraordinary characteristics of high surface area, extreme porosity, lowest thermal conductivity, and tunable surface chemistry. Aerogels of silica, alumina, carbon, metals, metal oxides, clay, cellulose, gelatin, chitosan, synthetic polymers and many others have attracted much interest for different potential applications. Pure and composite aerogels have been magnificently utilized in biomedical and environmental applications [Composite Aerogels for Biomedical and Environmental Applications]. Bacterial cellulose has emerged an impressive biopolymer with potential environmental and biomedical applications.Additionally, it has been combined with nanomaterials, polymers, and natural products through numerous composites syntheses strategiesfor further advanced applications. Its stability, nontoxicity, environment friendliness, biocompatibility and cost effectiveness have led to impressive applications including filtration, pollutant degradation, enzymes immobilization, tissue engineering, artificial blood vessels and heart valve prosthesis, bone and cartilage regeneration, corneal replacement, skin tissues repair. Importantly its production from waste materials have posed economic and environmental benefits simultaneously [Potential applications of bacterial cellulose in environmental and pharmaceutical sectors; Bacterial Cellulose Based Metallic Green Nanocomposites for Biomedical and Pharmaceutical Applications]. The last review article is about the use of hydrogels in the pharmaceutical sector [Hydrogel: A Promising Material in Pharmaceutics]. Hydrogels are high content water absorbed crosslinked polymeric materials. This review encircles various biopolymer-based hydrogel uses in the biomedical, bio-separation, wound healing, tissue engineering and drug delivery applications. In this special issue, the journal aims to provide information about the green synthesis approaches of newly emerging nanomaterials, natural products and polymeric composites and their consequent therapeutic and environmental impacts.

Remarkable progress has been made both in computer science and in the development of new experimental chemical and biological procedures. In silico predictions could be an efficient way of providing useful information in supporting experimental data and thus accelerate drug discovery research. The development of new routes combining in silico and experimental methodologies represents a highly important goal for medicinal chemistry to find new drugs and reverse the “Eroom’s Law” trend (Scannell JW, Blanckley A, Boldon H, Warrington B. Diagnosing the decline in pharmaceutical R&D efficiency. Nat Rev Drug Discov. 2012;11(3):191-200). Overall, future developments will greatly benefit from the integration of computational and experimental technologies’ platforms: these can represent powerful synergies to quickly assess whether a new molecule binds with high affinity to its target/s and/or has a proper PK (PharmacoKinetic) profile, increasing the degree of certainty involved in the initial stages of the drug pipeline and therefore reducing the failures and costs during development so that it’s faster and risk free. Fundamental for the acceleration of drug discovery research is the development of new organic synthesis methods which obtain new lead compounds, especially when they are carried out by chemical products and processes that reduce or eliminate the generation of hazardous substances. In this special issue we browse through different steps in the drug discovery pipeline through a collection of papers (5) by different wellknown research groups from across the world: first the characterization of the target and the design of new ligands (chapters 1,2), then the exploration of the chemistry comprehensive of ADME (Administration, Distribution, Metabolism, Excretion)(chapters 3,5) predictions with the biology (chapter 4) as an intermediate step.

This special issue of “Current Pharmaceutical Design” is dedicated to endocrine diseases that are associated with increased risk of cardiovascular (CV) disease (CVD). In relation to Reproductive Endocrinology, Bosdou et al. [1] consider the association between female infertility and CVD. In general, current data do not support a clear association, although common pathways may lead to both entities, with a contributory role attributed to the ageing process [1]. The inconsistency of evidence also extends to the association between female infertility and the prevalence of CV risk factors, such as dyslipidaemia, arterial hypertension (AH) and type 2 diabetes mellitus (T2DM) [1]. However, some causes of infertility, such as polycystic ovarian syndrome (PCOS) and endometriosis, may be associated with increased CV risk [1]. Whether female infertility is an indicator of early CVD needs to be confirmed in well-designed, large population-based studies [1]. In this context, some indices of ovarian reserve, such as the anti-Müllerian hormone concentrations, which are negatively associated with subclinical atherosclerosis markers (carotid intima-media thickness) [2], may serve this purpose. The association of specific infertility states (such as PCOS) with increased risk of CVD events and mortality also needs to be established in future studies. Of note, a recent meta-analysis showed an increased risk of nonfatal cerebrovascular disease events [relative risk (RR) 1.41, 95% confidence interval (CI) 1.02-1.94], but not coronary heart disease (CHD), in patients with PCOS compared with non-PCOS women [3]. Kostopoulou et al. [28] provide an updated approach to Turner’s syndrome (TS) in the context of CVD. Structural CV defects (aortic coarctation, dilatation and dissection), endothelial dysfunction and increased prevalence of cardiometabolic risk factors (AH, T2DM, central obesity, atherogenic dyslipidaemia) increase CV risk in these patients [28]. The decline in estrogen reserve, as in women with early menopause [5-7] constitutes the main mechanism for this association. Menopausal hormone therapy (MHT) is the mainstay of treatment, combined with growth hormone (GH). MHT improves the CV risk profile, although its effect on CVD mortality has not been proven [28]. However, the exact effect of GH on CV risk in patients with TS is currently unknown. Moving to the male reproductive system, Sesti et al. [8] refer to CV complications in patients with Klinefelter’s syndrome (KS). These patients demonstrate high CV mortality rates, mainly due to the increased prevalence of CHD and thromboembolic disease. The main mechanisms include severe CV structural defects, such as transposition of the great arteries, patent ductus arteriosus, partial atrioventricular canal defect, tetralogy of Fallot and hypertrophic cardiomyopathy, as well as increased prevalence of T2DM, atherogenic dyslipidaemia and central adiposity, due to hypogonadism [8]. Testosterone is the mainstay of treatment in these patients [8], although its contribution to reducing CVD risk needs to be proven in future studies. Fourth, the long-term metabolic consequences of gestational diabetes mellitus (GDM) are discussed by Kousta et al. [9]. The evolution of screening tests for GDM and relevant guidelines are described, as well as a brief overview of the authors’ own experience as a singlecentre is presented. Except for a 7-fold higher risk of T2DM, a higher prevalence of CV risk factors, such as atherogenic dyslipidaemia, visceral obesity, metabolic syndrome, AH, systemic inflammation and endothelial function have been reported in women with a history of GDM [9]. The authors also underscore that more than one-third of patients with GDM, even those who were normoglycaemic postpartum, may display metabolic abnormalities in the long-term [9]. For example, a recent meta-analysis showed that women with GDM are at 2-fold higher risk of future CVD compared with those of normal carbohydrate metabolism during pregnancy (RR 1.98, 95% CI 1.57-2.50). This risk was independent of the development of T2DM in later life (RR 1.56 in those who did not develop T2DM, 95% CI 1.04-2.32) [10]. Moreover, poor glycaemic control during pregnancy seems to augment CVD risk in the future [11]. Further research is needed to delineate the effect of therapeutic interventions, such as diet, metformin or insulin, on the reduction in CVD risk in patients with GDM. In the field of pituitary diseases, Gogakos et al. [12] discuss the effects of pituitary hormone excess and deficiency on the CV system. According to their review, GH excess (acromegaly) is associated with an increased risk of CVD events. GH has direct effects on the heart and peripheral vasculature, and an indirect effect on the deterioration of glucose and lipid homeostasis, blood pressure (BP) and fatty-liver disease [12]. Restoration of the GH axis seems to avert the progression of atherosclerotic and structural changes of the myocardium [12]. However, it remains to be proven whether the type of intervention (surgical or pharmacological) determines the decrease in CVD risk. An older meta-analysis showed that treatment with somatostatin analogues might lead to structural improvements of the heart (although without effect on BP and left ventricular end-systolic dimension) [13] and apnoea-hypopnoea index [14]. Limited data exist concerning the association between hyperprolactinaemia and CVD risk factors and events. Hyperprolactinaemiainduced hypogonadism appears to be the main mechanism [12]. Of note, the potential association of cabergoline use (a dopamine agonist used as first-line treatment in these patients) with increased risk of tricuspid regurgitation, as shown in a recent meta-analysis, should be taken under consideration [15]. Concerning Cushing’s disease (CD), the association with increased CVD risk is more straightforward due to the well-established cluster of CVD risk factors in these patients. Of utmost importance is the remaining increased mortality seen in these patients despite optimal biochemical disease control [pooled standardized mortality ratio (SMR) 2.5, 95% CI 1.4-4.2] [16]. Any differential effect of phrarmacological or surgical intervention in patients with CD needs to be demonstrated in future studies. Hypopituitarism and its independent association with CVD risk should also be considered in these patients as they are considered in this review [12]. Apart from CD, a review on subclinical Cushing’s syndrome (SCS) is provided by Ivovic et al. [17]. They consider the optimal diagnostic approach and clinical manifestations in patients with SCS. In addition to the higher prevalence of CV risk factors, an overall increased risk or CVD morbidity and mortality also exists in these patients, which is dependent on the degree of impairment of glucose and lipid metabolism, BP and abdominal fat [17]. In the largest cohort published so far (n=198; mean follow-up 7.5 years), the incidence of CVD events was higher in patients with SCS compared with those with non-secreting adrenal incidentalomas (16.7% vs. 6.7%; p=0.04) and in those with worsening hypercortisolaemia during follow-up (28.4% vs. 6.7%; p=0.02) [18]. However, the optimal diagnostic method and the specific thresholds need to be established as well as the superiority adrenalectomy over conservative management. The former approach decreases the prevalence of CV risk factors (mostly DM and AH) to a greater extent than the latter. Whether it is also associated with a reduction in CVD event rates, needs to be proven. Nonetheless, adrenalectomy may be considered in young patients (<50 years), with a recent onset of CV risk factors, which are difficult to be controlled with medication or which show progression over time [19]. In addition to SCS, two more papers in the field of adrenal disorders are included. The first, by Kotanidou et al. [20], covers the wide spectrum of endocrine hypertension in children. The authors provide an overview of catecholamine, glucocorticosteroid and mineralocorticosteroid excess syndromes, as well as congenital adrenal hyperplasia and other rare syndromes with specific genetic defects focusing on optimal diagnostic and therapeutic approach. Specific interest is paid to paediatric obesity, which is independently associated with AH [20]. Paediatric obesity necessitates early dietary and lifestyle intervention in order to reduce CVD risk in later life. Obese or overweight children display a >5-fold higher risk of developing T2DM and 2- to 3-fold increased risk of AH, atherogenic dyslipidaemia and carotid-artery atherosclerosis in adult life, compared with non-obese children and irrespective of adult body mass index [21]. It remains to be established whether prompt intervention in childhood is associated with a reduction in CVD risk in adulthood. Livadas et al. [22] discuss the association between premature adrenarche (PA) and CVD risk. In general, limited evidence exists on this issue, emerging mainly from studies with small sample size conducted in prepubertal girls [22]. Available data indicate an increased prevalence of abdominal obesity, insulin resistance (IR), atherogenic dyslipidaemia and, potentially, higher BP in the prepubertal PA population compared with their age-matched controls. However, these risks seem to be mitigated in adolescents with PA [22]. Therefore, a clear association between PA and the CVD risk cannot be established and prospective studies with long-term follow-up data are needed. This topic becomes even more complicated if one considers the diversity in terms of diagnosis and overlapping with other syndromes, such as PCOS and non-classical congenital adrenal hyperplasia. The impact of increased dehydroepiandrosterone sulphate (DHEAS) concentrations on CVD risk has not been proven. In contrast, recent meta-analyses have shown a negative association between DHEAS concentrations and CVD (mainly CHD) risk [23, 24]. Stojkovic et al. [25] address the issue of subclinical thyroid dysfunction in the context of CVD. A mounting body of evidence from observational studies has shown that both subclinical hypo- (SHypo) and hyperthyroidism (SHyper) are associated with increased CVD risk. SHypo doubles the risk of CHD events, heart failure (HF) and mortality. This is evident in cases with TSH concentrations >10 mIU/l, especially in patients <65 years old [25]. On the other hand, SHyper increases the risk of HF and atrial fibrillation, especially for TSH concentrations <0.1 mIU/l [25]. However, whether restoration of subclinical thyroid dysfunction also reduces the risk of CVD events and mortality remains to be established. Tournis et al. [26] consider the evidence regarding the association between primary hyperparathyroidism (PHPT) and CVD. In addition to the direct actions of parathyroid hormone on the CV system (vasodilatation, positive inotropic and chronotropic effects), there is evidence for an independent association between PHPT and CVD. This is indicated by the increased prevalence of T2DM, dyslipidaemia, AH, endothelial dysfunction, arrhythmias and left ventricular hypertrophy in these patients [26]. The association with an increased incidence of CVD events is prominent in severe cases [26]. It remains to be established whether parathyroidectomy is associated with a decrease in CV risk in patients with PHPT. Finally, with respect to glucose metabolism, particular interest is paid to the association between hypoglycaemia and CV risk, an underestimated aspect in patients with either type 1 DM and T2DM. This topic is covered by Katsiki et al. [27]. Briefly, severe hypoglycaemia (defined as those episodes during which the patient requires the assistance of another person in order to be corrected [4]) increases the risk of CVD morbidity and mortality, mainly due to CHD and increased incidence of arrhythmias leading to sudden death [27]. Limited data exist about the association with stroke, carotid and peripheral artery disease [27]. Therefore, precision medicine, setting less stringent glycaemic goals, especially in older patients, is suggested. The degree of reduction in CV risk after the restoration of hypoglycaemic episodes also needs to be defined in future studies. Another aspect that should be taken under consideration is glycaemic variability which may further augment CV risk in patients with DM [29].

This special issue of Current Pharmaceutical Design is dedicated to Professor Suresh P. Vyas, as a tribute to his exceptionally illustrious and remarkable research career in the area of drug delivery applications of nano-colloidal systems. It is to celebrate and honour this extraordinary and iconic scientist who dedicated his teaching career to his passion and gave his energy, imagination, and intellect to the scientific community in general, and pharmaceutical scientists in particular. This dedicated issue comprises a total of fourteen articles, including Editorial, Biosketch, Minireview and eleven Reviews contributed by the former students and scientists associated with Prof. Vyas. Nanocarriers present a novel platform for the effective delivery of drug molecules to the various diseased tissues. Advanced nanocarriers based on organic materials (e.g. polymeric micelles, liposomes, niosomes, dendrimers, hydrogels, etc.) and inorganic materials (e.g. quantum dots, metallic and mesoporous silica nanoparticles, etc.) have found various drug delivery applications. These carriers are reported to reduce sensitive toxicity and/or adverse reactions associated with actives. Nano drug delivery systems are reported to improve pharmacokinetics & biodistribution, solubility and stability as well as decrease toxicities due to controlled release and site-specific delivery of therapeutic agents. The biodegradability of the components makes these delivery systems an attractive core and results in the production of minimal amounts of toxic metabolites. The advantages derived from the use of such systems are manifold. The physiochemical profile of the nano-constructs can be manipulated by changing their composition, size, shape, surface charge, functional groups, and tagging of targeting moieties. The use of biodegradable nanocarriers as molecule transporters is one of the most promising strategies for controlled-release systems. The fundamental requirement for a biomaterial to be used in this sense is its biocompatibility; that is, the ability to be metabolised without any harmful effects. Systems of this type must have properties such as the ability to cross the body's anatomical barriers, controlling the concentration of the drug over time and the release of the active molecule at the site of action. The nanotherapeutic agents may be modified with target specific molecules or ligands for delivering the active therapeutics via receptor-mediated transcytosis to the desired sites. Lipid coated vesicles with a polymer core have been shown to act as stable drug carriers where polylactide (PLA), poly-lactide-coglycolide (PLGA), poly-alkyl cyanoacrylate (PACA), and many other polymers can be used as core materials. These biodegradable polymers are more suited since they break down into molecules physiologically and so they do not pose any threat to the body. Polymeric nanocarriers have also emerged as a potential and efficient, targeted drug delivery system for clinical applications. Hyaluronic acid (HA) -based soft nanosystems have garnered considerable attention owing to the biodegradability, biocompatibility and nonimmunogenic profile of HA. Additionally, since surface receptors can recognise HA on the tumour cells, they may be an ideal candidate for targeted delivery of anticancer drugs. A number of soft nanocarriers based on HA conjugated or complexed polymer systems like micelles, nanogels, nanoparticles and polymerosomes have been reported. Magnetic liposomes (ML) that combine magnetic nanoparticles with liposomes are reported to offer cumulative benefits for cancer therapy. The MLs may be utilised for various types of cancer treatments for triggering drug/gene release, photothermal/ photodynamic therapy, among others. Glyconanoparticles (GNPs) have been reported for drug targeting potential of actives for diseases localised in macrophages owing to their inbuilt ability to interact with macrophage lectins. The carbohydrates are key components in several biological events like inflammation, cellular migration, immune reactions, cellular communication, infection, enzyme trafficking and cancer metastasis. These features, coupled with their hydrophilicity, biodegradability, biocompatibility and highly specific interaction of targeting cell-surface receptors have expanded the horizon of their utility in drug delivery applications. The GNPs also hold immense promise in antimicrobial drug carrier for the treatment of HIV/AIDS, candidiasis, leishmaniasis, salmonellosis and tuberculosis. This thematic issue aims to provide an update on the various facets of biocompatible nano-carriers, including their design, fabrication, characterization, fate, toxicity, challenges, applications and translational potentials. It also intends to provide insight into the versatile role of the vesicular carriers in delivering various drugs and bioactives that may provide future directions for innovations in this field.

Currently, individuals are aware of the COVID-19 pandemic, its origin and global impact on health and finance. What is the solution for management? The novel coronavirus (SARS-CoV-2/ COVID-19) infection has become a pandemic at the beginning of 2020, and on April 25th, the official death toll crossed 200,000, and the total affected counts near three million. Original figures might be much higher as many developing countries could not determine an accurate account of the number of affected individuals due to the lack of testing facilities. The world health organization warns that the situation might worsen if there is no control of the virus spreading without the development of drugs or vaccines. Natural products or medicinal plant extracts have been used to treat infectious diseases for hundreds of years. For example, the Arabian traditional medicine, sub-continental Ayurvedic medicine or traditional Chinese medicine are still being used locally for many viral and bacterial diseases. SARS-CoV-2/ COVID-19 infection is indeed new, and it will take time to develop drugs or vaccines. However, there are tremendous efforts from scientists all over the world to develop effective treatment strategies against this deadly pandemic disease, and several pre-print articles are coming out with their findings. This thematic issue on “Viral disease and natural products, with a special focus on COVID-19” consists of two current research articles and five reviews, which are helpful in the recent crisis perspectives. The current challenge is to develop a vaccine for COVID-19, and currently, several scientists are working on this challenging project worldwide. The aim of this special issue of Current Pharmaceutical Design (CPD) is to publish with most recent articles on natural products against viral diseases, with a particular focus on the Covid-19. On the other hand, the dengue virus is a potential source of propagating dengue hemorrhagic fever [6]. This virus leads to dengue hemorrhagic fever/dengue shock syndrome, benign syndrome, and severe syndrome, and due to its infection, their alterations occur at multiple levels such as gene expression and the pathway levels. Therefore, it is critical to understand the pathogenesis of dengue infection in terms of gene expression and the associated functions. For this purpose, Warsi et al. analyzed the temporal gene expression profiling for the dengue hemorrhagic fever dataset at 12, 24, and 48 hrs. The outcome appeared that the dengue hemorrhagic fever evolves differently at different time periods or stages. The change in gene expression pattern increases exponentially from 12 to 48 hrs, and the number of altered functions (pathways) also increased. Wnt, apoptosis, transcription signalling was among the critical pathways dominantly altered. In the initial phase (first 12 hrs), only two pathways are altered due to dengue infection while in the next 12 hrs, eight pathways were altered, and finally, in the next 24 hrs, 11 pathways were altered, and most of these 11 pathways are very critical in terms of biological pathways and functions [6]. While the latest SARS COV2 coronavirus contributes to a pandemic of millions of COVID-19 [1], because there is no defensive immunity in humans and a virus can overcome inborn immune reaction, it can propagate unhindered, mostly in tissues contaminated. No unique therapies for COVID-19 contaminated patients are available at this time. The insights learned from previous respiratory viral infection control have given guidance into COVID-19 therapy. Several complementary treatments have been tentatively introduced in hospital environments, such as immune-modulators, antiviral, convalescent plasma transfusions and natural products. In COVID-19 patients, some of these therapies have provided substantial curative benefits. Moreover, numerous studies and clinical trials are being carried out in order to determine the efficacy of current pharmaceutical and natural products and establish possible therapeutic strategies for producing novel COVID-19 medicines. Rahman et al. summarized and defined the modes of mechanism, protection and efficacy on existing therapeutic strategies for diseases linked to COVID-19 infection [1]. Previously, human society has faced various unprecedented pandemics in history, and viruses have majorly held the responsibilities of those outbreaks [7]. Furthermore, due to amplified global connection and speedy modernization, epidemic outbreaks caused by novel and reemerging viruses signify potential risks to community health. Despite great advancements in immunization and drug discovery processes, various viruses still lack prophylactic vaccines and efficient antiviral therapies. Although the vaccine is a prophylaxes option, it cannot be applied to infected patients, hence therapeutic interventions are urgently needed to control the ongoing global SARS-CoV-2 pandemic condition. To spot the novel antiviral therapy is of decisive importance and Mother Nature is an excellent source for such discoveries. Dhasmana et al. implemented prompt high through-put virtual screening for vetting the best possible drug candidates from natural compounds' databases [7]. They applied time tested, rigorous multi-layered drug screening process to narrow down 66,969 natural compounds for the identification of potential lead(s). Drug ability parameters, different docking approaches, and neutralization tendency of the natural products were employed in their study to screen the best possible natural compounds from the digital libraries. The compounds PALA and HMCA are potential inhibitors of SARS-CoV-2 spike protein and can be further explored for experimental validation. Overall, the methodological approach reported can be suitably used to find the potential drug candidates against SARS-CoV-2 in the hot situation of COVID-19 with less expenditure and a very short span of time [7]. The SARS-CoV-2 is a coronavirus, of which infection-causing COVID-19 was first reported in Wuhan, China, at the end of 2019, and the outbreak became pandemic in February of 2020 [2]. Till now, there is no effective drug or vaccine against this virus that can make a complete cure. However, a number of drugs are in trials. Shawon et al. focused on an alternative therapeutic approach using natural products utilizing host anti-viral responses for resolving COVID-19 pathogenesis in their review. They searched databases like Pubmed, Scopus, Web of science and Google Scholar for articles related to natural products and viral diseases, with a specific focus on coronaviruses, as well as RNA viruses and recent updates on COVID-19 pandemic, and collected articles and reviewed comprehensively. Scientific studies clarified the viral pathogenesis that involved viral entrance into host cells, and antiviral response inside the cells, which can be effectively targeted by numerous natural compounds from different sources. Many of these compounds can potentially target viral genomic material or protein machinery. Natural products, which were found effective against other coronaviruses, especially SARS-CoV or MERS-CoV (which emerged in 2002 and 2012, respectively) might be effective against SARS-CoV-2 due to structural similarities. However, it needs time to establish the clinical success of these drugs. COVID-19 pandemic is a global emergency problem, and urgent drug development is necessary. Natural products can be the biggest source of drugs, as they have been found effective in other coronaviruses previously; however, it needs time to establish these drugs for clinical application [2]. The World Health Organisation (WHO) announced on the 11th March 2020, a pandemic caused by a novel beta-coronavirus SARS-CoV- 2, a virus first observed in Wuhan, China, in December 2019 [3]. It emerged that this virus has spread across the entire world. The traditional usage of medicines from plants can be traced back to 60,000 years. Global interest in the development of drugs from natural products has magnificently risen during the last few decades. Essential oils (EOs) have been studied through the centuries and are known to possess different pharmaceutical properties. Wilkin et al. tried to enlighten about current biology, epidemiology, various clinical aspects, different diagnostics techniques, clinical symptoms, and management of COVID-19 in their review article. Moreover, a detailed account of antiviral action of EOs along with their proposed mechanisms and in silico studies conducted have been concluded. The reported studies of EOs antiviral activity highlight the baseline data about the additive, and/or synergistic effects among primary or secondary phytoconstituents found in individual oils, combinations or blends of oils and between EOs and antiviral drugs. It is hoped that further research would provide a better insight into EOs potential to limit viral infection and aid in providing solution through natural therapeutically active agents [3]. The COVID-19 is an ongoing, rapidly spreading pandemic disease caused by Severe Acute Respiratory Syndrome Coronavirus2 (SARSCoV2) [4]. Among all the infected countries around the globe, as of June 15th, 2020, the total reported confirmed positive cases are 7,805,148, with the death of 431,192. At present, no specialized treatments evolved to cure COVID-19. Treatment is symptomatic. Though huge effects are being made to produce potential therapies to scuffle this COVID-19, no drug has been discovered so far. Natural products play a significant role in disease control since ancient days. These products are serving as templates for designing new anti-microbial agents with a different mechanism of action and also open a door for the investigation of effective anti-viral drugs to combat COVID-19. Pamuru et al. narrated the basic structure, infection, and pathogenesis of SARS-CoV2 virus in humans and also reported various natural products or plant-based extracts/bioactive compounds tested against coronaviruses like SARS and MERS as these viruses are structurally similar to SARS-CoV2 and can be used in designing novel drug against this virus. The natural products that show activity against SARS, MERS, and other viruses reviewed in their review article might be having anti-viral activities against the SARS-CoV2 virus and can be used directly for further preclinical studies [4]. Generally, human coronaviruses (HCoV) are common viruses and known to be associated with respiratory diseases, including pneumonia [5]. Currently, seven human coronaviruses have been identified and known to cause upper and lower respiratory infections as well as nosocomial viral infections in humans. The bats, palm civets and camels are identified as the reservoir of human coronaviruses. In 2002-2003, the emergence of SARS-CoV resulted in an outbreak and led towards more awareness and importance of scientific research and medical urgency. The recently identified SARS-CoV-2 was identified from the seafood market of the city Wuhan, China, in December 2019 and caused a global pandemic. This virus has now spread to more than 213 countries. This is the third highly pathogenic human coronavirus after SARS and MERS-CoV. The coronaviruses have RNA as genetic material and are known to have frequent recombination and mutations in their genome, which led to the emergence and re-emergence of new virus strains and isolates with novel properties and their extended hosts. The genetic mutations and suitable environmental conditions result in the emergence and re-emergence of pathogenic coronaviruses and pose a serious issue for human health and the economy globally. Lectins are the ubiquitous group of proteins, which bind to glycosylated molecules. The plant lectins are known to have significant antiviral activities against coronaviruses. Additionally, the plant lectins can be used as a potential therapeutics against bacteria, fungus, yeast and protozoa. Sohrab et al. discussed the current status of human pathogenic coronavirus emergence and the use of plant lectins as antivirals against SARS-CoV-2 in their review [5]. We would like to acknowledge all authors who submitted their articles in this Special Issue and reviewers, who secured their time in providing valued feedback to improve the submitted manuscripts. Last but not least, GEs are also thankful to Prof. William A. Banks (former EiC) and the management of Current Pharmaceutical Design for their cooperation throughout the processing of the manuscripts.

Lysosomal storage diseases (LSDs) are a large group of disorders caused by a deficiency of specific enzymes responsible for the degradation of substances present in lysosomes. In the past few years, treatments for LSDs were non specific and could only cope with signs and symptoms of the diseases. A successful therapeutic approach to LSDs should instead address to the underlying causes of the diseases, thus helping the degradation of the accumulated metabolites in the various organs, and at the same time preventing their further deposition. One way is to see to an available source of the deficient enzyme: bone marrow transplantation, enzyme replacement therapy and gene therapy are based on this rationale. The purpose of substrate reduction therapy is to down regulate the formation of the lysosomal substance to a rate at which the residual enzyme activity can catabolize the stored and de novo produced lysosomal substrate. Chemical chaperone therapy is based on small molecules able to bind and stabilize the misfolded enzymes. This paper offers a historical overview on the therapeutic strategies for LSDs. Lysosomal storage diseases (LSDs) are a series of complex disorders caused by a deficiency of specific enzymes involved in the degradation of substances at a lysosome level [1]. Lysosomes are present in the whole series of human cells, except for red blood cells, therefore, LSDs may affect different organs and systems simultaneously. The clinical signs characterizing different diseases depend on the quantity and type of accumulated substance; in general, any disease is named after the type of undegraded substrate. Most LSDs have an autosomal recessive inheritance pattern. Mucopolysaccharidosis type II, Fabry disease and Danon disease are X-linked [1]. Nevertheless, LSDs prognosis is usually very serious and great effort has always been made to address effective treatment strategy able to correct underlying causes. A successful therapeutic approach to LSDs should ensure an available source of the deficient enzyme, thus helping the degradation of the accumulated metabolites in the various organs, and at the same time preventing their further deposition [2-6]. This special issue of Current Pharmaceutical Design will offer an overview on the therapeutic strategies for two types of LSDs such as Anderson-Fabry Disease and Hunter Disease, and, in a more general review article across the wide clinical entities of LSDS. In the first review by Simonetta and coworkers [7], the authors examined the treatment of Anderson-Fabry disease. Fabry disease is a rare lysosomal storage disorder that is caused by an X- linked recessive inborn error of glycosphingolipid metabolism because of mutations in GLA gene, thus resulting in a deficiency of α-galactosidase A activity. Although the causative role of the accumulation of globotriaosylceramide (Gb3) is known in determining the damaging effects on numerous cells such as endothelial cells, smooth muscle cells, glomerular cells, and cardiomyocytes, the detailed pathophysiological mechanisms leading to early multi-organ involvement are still not entirely understood. The progressive damage to multiple organ systems leads to the main complications of Fabry disease, including cerebrovascular events, endstage renal disease, and heart failure causing a reduced life expectancy [8, 9]. Definitive diagnosis requires genetic testing, biochemical dosage of enzymatic activity, and tissue exam showing intracellular Gb3 deposits. After the detection of a known, causative established mutation, diagnosis is made. A wide screening of high-risk population from several specialty settings as cardiology, internal medicine, nephrology, neurology, and dermatology is required. A multidisciplinary approach may allow to improve and extend the yield of diagnosis of Fabry disease. To date, therapies such as enzyme replacement therapy (ERT) and oral pharmacological chaperone are available. Next-generation lysosomal storage disorder treatment is based on new strategic approaches as stem cell-based therapy, pharmacological approaches chaperones, and viral gene therapy. Great efforts have been made and are still required in this field in order to make available a more effective, safer, advantageous therapeutic strategy for patients with Fabry disease [10]. In the second review article, Giugliani and coworkers [11] examined the therapeutic options for Mucopolysaccharidosis II (Hunter Disease). Hunter syndrome, also known as mucopolysaccharidosis II (MPS II), is an MPS lysosomal storage disorder. Hunter syndrome is an Xlinked- recessive Hunter syndrome that appears in children as young as two years and it nearly always occurs in males. In the past, the treatment of Hunter syndrome was limited to the relief of symptoms and complications. Enzyme replacement therapy with idursulfase aims to replace iduronate-2-sulfatase, the enzyme that is deficient or absent in people with Hunter syndrome. Authors reviewed new therapeutic strategies in this clinical setting. In the last review article by Sheth et al. [12], new therapeutic options in Treatment for Lysosomal storage disorders. Authors evaluated the considerable development in therapeutic strategies for LSDs in past few years owing to the incentives given to pharmaceutical companies through the implementation of orphan drug regulation. Authors will evaluate the widely used approaches in the treatment of LSDs involve Enzyme replacement therapy (ERT), Bone marrow transplantation (BMT), Substrate reduction therapy, use of molecular chaperones and Gene therapy They also reviewed numerous studies over the decade that have shown that inflammasomes playing a role in mediating inflammatory reactions post cellular injury occurring after stroke or a rupture of an atherosclerotic plaque. They also reviewed the mechanisms by which inflammasomes drive the pathogenesis of stroke and atherosclerosis and possible treatment strategies available for inhibiting inflammasomes or their up-stream/down-stream mediators. Nevertheless in several LSDs, other pathogenetic mechanisms in vascular and tissue damage such as the role of oxidative stress and inflammation similarly to classical vascular complications due to atherosclerosis and arteriolosclerosis such as diabetic foot and ischemic stroke [13-15] play an ancillary role

Metabolic syndrome (MetS) which is caused by poor dietary habits and sedentary behavior is a serious global health problem. MetS is a cluster of risk factors, represented by central obesity, hyperglycemia, dyslipidemia, and hypertension. In the 21st century, MetS and associated comorbidities, including obesity, diabetes and cardiovascular diseases, are the major threats to human health. Practical dietary strategies, nutritional bioactive compounds and a healthy lifestyle are claimed to be efficient in the management of one or more components of MetS. Nevertheless successful management of MetS and commodities is still a major concern. Since hyperglycemia, inflammation and redox imbalance are intrinsically involved in the progression of MetS comorbidities, finding effective strategies that precisely target these systems is highly warranted. In this scenario, pharmacological and non-pharmacological approaches with or without dietary patterns, phytochemicals or exercise interventions are the practical strategies to combat MetS and associated diseases. However, designing and prescribing of optimal nutritional patterns and exercise regimens remains a big challenge to achieve the maximum beneficial effects. This thematic issue addressed the concerns and provided practical strategies to overcome the malady of MetS in the modern world.

Current Advances in Design, Development and Characterization of New Solid Forms of Active Pharmaceutical Ingredients

Today, global humanity is suffering from many physical, intellectual, emotional and spiritual disorders. There are numerous aspects to discuss in each issue to understand the underlying causes, diagnosis and management strategies. There are many advancements into the health sector such as nanotechnology, stem cells and vaccines development. The current challenge is to develop a vaccine for COVID-19 and currently, several scientists are working on this challenging project worldwide. The aim of this special issue of Current Pharmaceutical Design (CPD) was to aid pharmaceutical research in this exertion by providing articles for an overview of current progress and future perspectives focused towards management strategies for neurological disorders. Authors of this special issue (Part-II) were requested to provide a review/ meta-analysis for motivation to identify guidelines for in vitro to clinically translatable research that will enhance the right treatment for public health globally. Uddin et al. shed light on the topic of Alzheimer's disease (AD), which is a chronic, age-related, and irreversible brain disorder that typically develops slowly and gets worse over time [1]. They reported that the simultaneous modulation of several targets linked to AD by one potent molecule is the auspicious drug candidate for the treatment of AD. The new therapeutic approach involves drug candidates that are designed to act on multiple targets and have various pharmacological properties. This trend has triggered the development of various multimodal drugs including TV-3326 (i.e. ladostigil) and M-30 (i.e. a new multitarget iron chelator). TV-3326 combines the neurorestorative/ neuroprotective actions of the cholinesterase (ChE) inhibitory activity of rivastigmine with rasagiline (a selective monoamine oxidase-B inhibitor and novel antiparkinsonian agent) in a single molecule. M-30, the second derivative of rasagiline, was developed by combining the propargyl moiety of rasagiline into the skeleton of VK-28 (i.e. a novel brain permeable neuroprotective iron chelator). It has been revealed that both the compounds possess anti-AD effects and therefore, the clinical development is directed to the treatment of this type of neurodegenerative diseases. They have reviewed the neuroprotective molecular mechanisms and multimodal actions of TV-3326 and M-30 [1]. AD is the most well-known reason for disability in persons aged greater than 65 years worldwide. AD influences the part of the brain that controls cognitive and noncognitive functions. Therefore, Liu et al. studied the screening of natural compounds for the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) using a computational methodology [11]. They performed a docking-based virtual screening utilizing the 3D structure of AChE and BuChE to search for potential inhibitors for AD. In this work, a screened inhibitor Ajmalicine similarity search was carried out against a natural products database (Super Natural II). Lipinski rule of five was carried out and docking studies were performed between ligands and enzyme using 'Autodock4.2'. Two phytochemical compounds SN00288228 and SN00226692 were predicted for the inhibition of AChE and BuChE, respectively. The docking results revealed Ajmalicine, a prominent natural alkaloid, showing promising inhibitory potential against AChE and BuChE with the binding energy of - 9.02 and -8.89 kcal/mole respectively. However, SN00288228- AChE, and SN00226692-BuChE were found to have binding energy -9.88 and -9.54 kcal/mole, respectively. These selected phytochemical compounds showed better interactions in comparison to Ajmalicine with the target molecule. The study of Liu et al. verified that SN00288228 and SN00226692 are more capable inhibitors of human AChE and BuChE as compared to Ajmalicine with reference to ΔG values [11]. The AD, characterized by the accumulation of amyloid-β (Aβ), hyperphosphorylated tau, PHFs, NFTs, and mTOR hyperactivity, is a neurodegenerative disorder affecting people across the globe [2]. Osmolytes are small, compatible organic molecules that not only osmoregulate but also cytoprotective through their role in folding function and stability of proteins, preventing proteins aggregation, and counteracting effects of denaturing solutes on proteins. Osmolytes such as sorbitol, inositol, and betaine play an important role in maintaining homeostasis during hyperosmotic stress. The selective advantage of utilizing osmolytes over inorganic ions by cells is in maintaining cell volume without compromising cell function, which is important for organs such as the brain. Osmolytes have been documented both as neuroprotector as well as to have neurodegenerative effects. Betaine, sucrose and trehalose supplementation has been seen to induce autophagy thereby inhibiting the accumulation of Aβ. In contrast, sucrose has also been associated with mTOR hyperactivity, a hallmark of AD pathology. The neuroprotective action of taurine is revealed when taurine supplementation is seen to inhibit neural damage, apoptosis and oxidative damage. Inositol stereoisomer's namely, scylloinositol and Myo-inositol, have also been seen to inhibit Aβ production and plaque accumulation in the brain, inhibiting AD pathogenesis. However, TMAO affects the aging process adversely by de-regulating the mTOR signalling pathway and then inducing cognitive dysfunction via degradation of chemical synapses and synaptic plasticity. Mueed et al. concluded that osmolytes may act as a potential therapeutic approach for neurodevelopmental disorders in their review. They have focussed upon the impact of osmolytes on mTOR signalling pathway and thereby its role in AD pathogenesis [2]. Nuts hold prime significance throughout the world as they offer multiple health benefits owing to their highly nutritious profile [3]. A number of scientific studies have demonstrated their actions against inflammation, oxidative damage, the aging process, as well as dementia or memory loss according to report of Arslan et al. [3]. However, only walnuts, followed by almonds, hazelnuts and pistachios, have shown promising results in empirical studies for memory improvements. So, their review focused on presenting hypotheses regarding anti-dementia property of nine different nuts: almond, walnut, pistachio, Brazil nut, peanut, pecans, cashew, hazelnut, and chestnut. The nutritious profile of nuts contains essential fats (mostly mono- and poly-unsaturated fatty acids), proteins (source for arginine, lysine and tryptophan), vitamins (riboflavin, folate, and various tocopherols), fibres, minerals (calcium, sodium, magnesium, phosphorus and potassium) and trace elements (copper, zinc, and selenium). Interestingly, the constituents of natural products, nuts being an excellent example, work synergistically and/or in a side-effect neutralizing manner. These latter properties can make nuts an alternate therapy against humankind's fight against memory loss [3]. Kumar et al. discussed the Parkinson's disease (PD), which is one of the most severe progressive neurodegenerative diseases having a mortifying effect on the health of almost hundreds of millions of people around the globe [4]. The neural cells producing dopamine in the substantia nigra of the brain die out which leads to symptoms like hypokinesia, rigidity, bradykinesia and rest tremor. Parkinsonism cannot be cured but the symptoms can be reduced with the intervention of medicinal drugs, surgical treatments and physical therapies. Delivering drugs to the brain for treating PD is very challenging, the blood-brain barrier act as a highly selective semi-permeable barrier which refrains the drug from reaching the brain. Conventional drug delivery systems used for PD does not easily cross the blood barrier and further leads to a number of side effects. Recent advancements in drug delivery technologies have facilitated the drug delivery to the brain without flooding the bloodstream and by directly targeting the neurons. In the era of Nanotherapeutics, liposomes can be an efficient drug delivery option for brain targeting. Liposomes can facilitate the passage of drugs across the blood-brain barrier, enhances the efficacy of the drugs and minimises the side effects related to it. The review of Kumar et al. aims at providing a broad updated view of the liposomes, which can be used for targeting PD [4]. Ghanta et al. also highlighted on the treatment of PD through dopamine replacement strategies, which may provide improvement in early stages and this treatment response related to dopaminergic neuronal mass which decreases in advanced stages [5]. This treatment failure was revealed by many studies and levodopa treatment becomes ineffective or toxic in chronic stages of PD. Early diagnosis and neuroprotective agents may be a suitable approach for the treatment of PD. The essentials required for early diagnosis are biomarkers. Characterising the striatal neurons, understanding the status of dopaminergic pathways in different PD stages may reveal the effects of drugs used in the treatment. Ghanta et al. described the update on the characterisation of striatal neurons, electrophysiology of dopaminergic pathways in PD, biomarkers of PD, approaches for the success of neuroprotective agents in clinical trials [5]. On the other hand, despite gigantic advances in medical research and development, chemotherapeutic resistance remains a major challenge for CNS tumours [6]. The failure of complete eradication of CNS tumours has been correlated with the existence of several factors including overexpression of transporter proteins reported by Asif et al. [6]. To date, 49 ABC-transporter proteins (ABC-TPs) are reported in humans, and the evidence of their strong association with chemotherapeutics' influx, dissemination, and efflux in CNS tumours, is growing. Research studies in CNS tumour are implicating ABC-TPs as diagnostic, prognostic and therapeutic biomarkers that may be utilised in preclinical and clinical studies. With the current advancements in cell biology, molecular analysis of genomic and transcriptomic interplay, and protein homology-based drug-transporters' interaction, research approaches are streamlining the ABC-TPs' roles in cancers and multidrug resistance. Potential ABC-TPs' inhibitors for better clinical outcomes in CNS tumours have emerged. These include members of EZH2 inhibitors, which exhibit a disparate level of selectivity for being a substrate for ABCB1 and ABCG2. Elacridar was shown to enhance the chemosensitivity of Dasatinib and Imatinib in various glioma models. Tariquidar has improved Temozolomide's effectiveness in CNS tumours. Although these inhibitors were shown to be effective in preclinical settings, their significant clinical outcomes have not been promising in clinical trials. Molecular evaluations of ABC-TPs and their drug-interactions are being pursued in various research labs, including ours, in an effort to better comprehend their biological mechanisms that are utilised for drug resistance, and to develop novel strategies to upsurge the clinical effectiveness of anticancer chemotherapeutics, which will ultimately improve the clinical outcomes [6]. Sumoylation is the Posttranslational modification gaining most of the research interest recently [7]. Sumoylation is involved in various crucial functions of the cell such as regulation of cell cycle, DNA damage repair and apoptosis. Oncology is advancing in radiotherapy, targeted chemotherapy, various forms of immunotherapy and targeted gene therapy. Researches are being conducted to prove its connotation with a variety of cancers and inhibitors are being developed to obstruct the fatal effect caused by misbalance of the SUMO-catalytic cycle. It has been shown that upregulation of certain enzymes of Sumoylation correlates with cancer incidence in most of the cases. But, in some cases, down-regulation also associates with cancer invasion such as under-expression of UBC9 in initial stage breast cancer. This can aid in future study, treatment and diagnosis of a variety of cancers including breast cancer, prostate cancer, lung adenocarcinoma, melanoma and multiple myeloma. Various mechanistic assays are being developed and used to identify potential inhibitors against the dysregulated proteins of Sumoylation. Liu et al summarized the normal roles of the enzymes involved in the SUMO catalytic cycle, their misbalanced regulation leading to tumorigenesis and nearly all the potent inhibitors identified till now [7]. As the most popular intrinsic neoplasm throughout the brain, glioblastoma multiforme (GBM) is resistant to existing therapies [8]. Due to its invasive nature, GBM shows a poor prognosis despite aggressive surgery and chemoradiation. Therefore, identifying and understanding the critical molecules of GBM can develop new therapeutic strategies. Glutamatergic signaling dysfunction has been well documented in neurodegenerative diseases as well as GBM. Inhibition of glutamate receptor activation or extracellular glutamate release by specific antagonists inhibits cell development, invasion, and migration and contributes to apoptosis and autophagy in GBM cells. Mollazadeh et al. outlined the current knowledge of glutamate signaling involvement and current therapeutic modalities for the treatment of GBM [8]. Out of the box, Chen et al. presented the language development via FOXP2 in autism spectrum disorder in their review article in this special issue [9]. An expanding number of newborn children and toddlers in numerous nations are enrolled in early childhood education programs, and instructors in this way assume a focal job in invigorating language improvement in these youthful kids. Kids with language issues are found to have a higher risk for future scholarly challenges and learning inabilities. Language advancement among kids is an intricate procedure and vital for correspondence. The shortcomings in the utilization of grammatical structures may lessen the useful utilization of language for verbally expressive kids with autism spectrum disorder and exacerbate troubles with academic and social expertise advancement. FOXP2, the principal single gene connected to a speech and language issue is significant for the right execution of complex motor behaviours used for speech. In any case, while changes in FOXP2 lead to a speech/language issue portrayed by childhood apraxia of speech. These days language learning is fundamentally required for kids who need to move to different nations to pursue the instructive frameworks and to end up helpful individuals or residents of those nations. A great teaching idea is to gather valuable assets of toys, manikins, pictures, maps, schedules and sparing them for use in each other’s classes [9]. Cerebral palsy (CP) is a brain disorder that affects the development of movement and posture leading to limitation of Range of Movement (ROM) in the growing children [10]. CP leads to deformities as equinus foot deformity. Fathi et al investigated the efficacy of different botulinum toxin (BTX) products with or without serial casting in reducing the muscle spasticity in equinus foot deformity in patients with CP [10]. A systematic review of the literature was performed by searching for different electronic databases. They analyzed the extracted data by network meta-analysis method using the R software package. Regarding Modified Ashworth score (MAS), BTX-A was superior compared to placebo and BTX-A plus immediate casting and respectively. Concerning growth motor function movement Classification System (GMFM), Neuronox ranked above at 3 months and at six months compared to BTX-A. Regarding the Modified Tardieu Scale (MTS) with knee flexion, BTX-A was superior to BTX-A plus immediate casting. Concerning passive range of movement (PROM) with Knee flexion or extension at 3 months, BTX-A showed a significant improvement compared to BTX-A plus immediate casting. BTX-A ranked best on a physician rating scale (PRS), MAS, MTS with knee flexion and PROM (Knee flexion and extension) compared to Neuronox and Botulax. BTX-A alone was also better than BTX-A plus immediate casting [10]. We would like to acknowledge all authors who submitted their articles in this Special Issue and reviewers, who secured their time in providing valued feedback to improve the submitted manuscripts. Last but not least, GEs are also thankful to Prof. William A. Banks (EiC) and management of Current Pharmaceutical Design for their cooperation throughout the processing of the manuscripts.

Skin diseases affect nearly 30-70 % of the population worldwide. These can range from acute to chronic or benign to life-threatening ailments. According to the Global Burden of Disease survey conducted in 2013 and the recently published 2015 iterations of the project, skin diseases were the 4th leading cause of the non-fatal disease burden and contributed 1.79 % to the global burden measured in disability adjusted life years. The skin disorders which contributed the most were dermatitis, acne vulgaris, urticaria, psoriasis and viral/fungal skin diseases [1]. Multiple available therapies exist such as oral, parenteral or topical therapies. Still, several skin diseases remain untreated. Oral and parenteral therapies for the treatment of superficial skin diseases may not prove efficient due to variable amount of drug concentration at the site of action however, these therapies prove beneficial in case of chronic invasive skin diseases. Moreover, these routes may show off-target side effects and organ toxicities [2]. The most preferred route in case of skin diseases is the topical route. The stratum corneum layer of the skin behaves as a major hurdle for the permeation of drug molecules through the skin. Permeation enhancement techniques either make use of sound waves, electric current, or chemical permeation enhancers improve the permeation of drugs into deeper layers of skin however pose safety issues. Ointment, cream, gel, lotion, spray applied topically improve efficacy and patient compliance but have certain limitations like poor permeation of drug, high dose requirement and multiple applications in a day that lead to poor adherence to the therapy [3]. In order to overcome the challenges of conventional therapies, nanotechnology has gained much attention in the last few decades. Nanoparticles exist in the size range 1-1000 nm. The drug can be encapsulated inside the diverse nanocarrier based systems like nanoemulsions, micelles, nanocapsules, liposomes, solid lipid nanoparticles, nanostructured lipid carriers, liquid crystalline nanoparticles, dendrimers, microneedles and many more. Encapsulating the drug in these nanosystems provide advantages like improved drug solubility, protection of drug from degradation, improved permeation and retention, controlled drug release, reduced dose and reduced application frequency. These nanocarriers can be further incorporated into gels, creams or sprays for topical application suitability. On application on the skin, these nanocarriers can follow intercellular or follicular pathway for transport into the skin layers. Nanocarriers have also been investigated for as vehicles for active phytoconstituents. These will provide a future scope for emerging phytopharmaceuticals in skin diseases [4-6]. These nanoparticles generally consist of lipids, polymers and surfactants. The safety and toxicity of these have been evaluated using cell culture studies and different animal models. Human clinical trials have proved the potential of these nanosystems in effectively treating skin diseases. Further, a few nanoparticle based products like NanoLipid Restore CLR®, Cutanova Cream NanoRepair Q10, Celandrin® Topical liposome lotion, Lipo CTM have successfully gained entry into the market for the treatment of skin diseases. The major challenge is the translation of these nanoformulations from lab to production scale. Nanoformulation preparation involves multiple steps like evaporation, homogenization, sonication, centrifugation, sterilization, and lyophilization. These steps can be optimized and reproduced at lab scale but may face challenges during large scale production in the industry. During scale-up, the parameters like size, surface functionality, drug loading may alter significantly. Changes in these parameters can affect the final therapeutic outcomes like cell-uptake, permeation, circulation time and biodistribution. Development of newer technologies provides further opportunities for faster translation of nanomedicine from lab scale to clinics. The preparation process selected should produce consistent and reproducible large scale batches without altering the final critical parameters of the end product. Manufacturing processes like high pressure homogenization and microfluidics have shown great potential in large scale production of nanoparticles. Further, application of Quality by Design (QbD) and Process analytical techniques (PAT) can be utilized for a better understanding of different formulation and process parameters and thus aid faster regulatory acceptance and translation of nanoformulations. Minimizing the steps involved in the preparation may save the time and cost involved in nanoformulation production [7-8].

The search for new compounds from natural sources or the chemical modifications of known structures enhancing drug pharmacokinetics while decreasing unwanted secondary effects has been the goal of a high number of researchers. In this thematic issue, we have 13 contributions, 11 reviews, one original contribution, and one perspective on COVID19 treatment. In general, the issue has dealt with a wide variety of structures, diseases, and proposals for new research and clinical trials. The first manuscript by Bracegirdle and Keyzers [1] reviews the importance of chemical structures obtained from marine invertebrates, in particular the isolation, synthesis, and biological activities of butenolide natural products, rubrolides, cadiolides, and prunolides. Butenolides have a four-carbon heterocyclic ring structure, lactone structure. Therefore, several of the compounds with similar chemical structures have antibacterial or antimycotic properties. Some structures obtained from natural products may also have other interesting biological effects as anti-parasitic or antineoplastic. The second manuscript by Miller and Das [2] is devoted to microtubule inhibitors as prominent compounds to treat neurodegenerative diseases. The high incidence of neurodegenerative diseases has prompted the researchers to analyze several therapeutic options to decrease disease incidence and progression. Piperazines are organic compounds with unique six-member rings that contain two nitrogen atoms on the opposite sides of the structure. Based on this basic scaffold, Sharma and coworkers [3] evaluated the wide variety of compounds with a broad biological effect form inhibition of viral replication to antitumour effects. A high number of structures have been synthesized with promising pharmacological perspectives. Dengue is one of the most prevalent viral infection in humans. According to the World Health Organization, WHO (https://www.who.int/news-room/fact-sheets/detail/dengue-and-severe-dengue), half of the world population is at risk, and around 400 million people are infected per year. There is a need for useful antivirals to decrease viral infection and protect the susceptible population from being infected. Maddipati et al. [4] concentrated on antiviral compounds that inhibit RNA-dependent RNA polymerase of flavivirus and other viruses. Moreover, they reviewed the structure-activity relationship as well as the use of plant metabolites as potential inhibitors. Cardiovascular diseases are the first cause of death globally (https://www.who.int/health-topics/cardiovascular-diseases/#tab=tab_1). The use of simple and effective therapies in underdeveloped countries has been very difficult. One option is nutrition and phytotherapy to decrease the incidence and aid in the management of these diseases. Chávez-Castillo approached two important issues of phytotherapy. In the first manuscript [5], they reviewed the most important pieces of evidence that have been analyzed in phytotherapy, which were shown to modulate dyslipidemia, atherosclerosis, and hypertension. In the second review [6], the authors focused on the phytotherapeutic alternatives for obesity, insulin resistance, and diabetes mellitus. An interesting approach was also devoted to metabolic syndrome. Salazar and associates [7] revised the effect of dietary polyphenols on the signal transduction mechanism of white and brown adipose tissue, mainly, in the murine model. Polyphenols can modulate thermogenesis by activating mitochondrial metabolism and activating the α subunit of PPARγ. The review provides a general analysis of the probable mechanisms in white and brown adipose tissue. The effect of pro-oxidant therapy against cancer was studied by Rieber [8]. The review focuses on the Copper chelating activities of ammonium tetrathiomolybdate and disulfiram metabolites. Moreover, the report illustrates the proposed mechanism of action of both compounds as tumoral. He recommends the use of chelators in cancer patients with high serum levels of Copper. Since Platinum and Copper share the same transport mechanisms, the synergy among both metals could be significant in cancer. The role of chloroquine and hydroxychloroquine as anti-inflammatory drugs is revised by Martínez et al. [9]. Most of the analysis is devoted to the use of the drugs and different modified structures not only for autoimmune disease but also as essential compounds to induce cytotoxicity to tumour cells and cell differentiation. The use of these compounds as antivirals has been demonstrated, primarily, in vitro. Unfortunately, in vivo studies have been limited due to the unwanted secondary effects of the compounds. Manzo Atencio et al. [10] analyzed the role of histamine as a peripheral neuro mediator. Histamine’s role in the central and peripheral nervous system has drawn the attention of researchers since the pharmacological modulation of the receptors can be crucial in several diseases. Metformin, one of the most commonly used drugs, has been shown to decrease cell ageing [11]. Different signal pathways seem to be involved in this new protective effect of the drug. New research has been proposed in this complex issue of ageing, especially in inflammatory diseases. De Franciscis P and coworkers [12] studied the effect of non-hormonal treatments in menopausal women. The used pollen extract, which they showed could be more advantageous than isoflavones in reducing menopause-related disturbances. Finally, the last contribution to this thematic issue is the proposal to use pentoxifylline for the treatment of SARS-CoV-2 infected patients [13]. The rationale is based on the use of the drug to decrease the cytokine storm produced upon viral infection and activation of the innate immune system. Pentoxifylline is an old drug that may be able to aid complicated patients. In summary, this thematic issue has dealt with a wide variety of very important human diseases ranging from cancer, viral disease, cardiovascular disease, diabetes, inflammation, and ageing. We consider that the aim of the thematic issue has been achieved by highlighting the most important compounds and general mechanisms involved. Several interesting areas of research have been proposed, which hopefully will be developed in the near future.

Stroke is an heterogenous disease and within the broad large category of brain ischemia and its subtypes vary dramatically in cause: from systemic hypoperfusion to atherosclerotic large artery disease, from penetrating artery disease to carotid dissection, from emboli arising from the heart valves or atria to emboli arising from the aorta, from paradoxical emboli to occlusion of cerebral and dural sinus veins, from hypercoagulability to genetic syndromes. With its large network of different subtypes, stroke represents a paradigmatic example of vascular disease. In this special issue of Current Pharmaceutical Design (CPD) entitled “Ischemic stroke pathogenesis: genetics, epigenetics and inflammation” some authors reviewed the role of genetic and epigenetic determinants in stroke pathogenesis and the influence of inflammatory networks in ischemic stroke pathogenesis and its clinical consequences. Tuttolomondo et al. [1] will examine the role of endothelial dysfunction and inflammation in ischemic stroke Endothelium is able to regulate the vascular homeostasis by modulating processes of vascular dilation and constriction by producing and secreting cytokines and chemical mediators; one of the most important factors that contribute to alteration in vessel structure and function is certainly the inflammation that leads to a dysregulation of this fine balance and to endothelial dysfunction. Cerebral ischemia acts like the trigger of a complex cascade of events at genomic, molecular, and cellular levels, and inflammation is important in this cascade, both in the Central Nervous System (CNS) and in the periphery. The entire spectrum of inflammatory processes is likely to act in concert and cytokines are important mediators of stroke induced immunological/inflammatory reactions, which contribute to brain infarct progression as well as to the disease severity and outcome; clinical studies suggest that the strength of this acute response is important in early and late clinical outcomes, early clinical worsening, and extent of brain damage. Endothelial dysfunction represents a basic determinant of the vascular damage which can be identified in all different clinical subtypes of stroke. It is viewed today as an attractive intermediate phenotype of cardiovascular risk and, as reported in several studies, it is associated with a great variety of different diseases such as arterial hypertension, atherosclerosis, coronary artery diseases (CAD) [2, 3] and also in cardiovascular risk associated to viral chronic liver diseases [4-6]. Thus many authors have investigated the role of endothelial dysfunction not only as a surrogate marker of risk but, because of its role in regulating key pathways of the vessel homeostasis, even as an important pathogenetic actor of the diseases, an index of progression and a determinant of severity. In the second review article of this special issue of CPD Jiang and coworkers [7] will examine the role of proinflammatory and antiinflammatory genes in stroke pathogenesis. The brain's response to ischemic injury may represent and acute and long-term inflammatory process. Authors will show as several processes involve activation of resident cells (mainly microglia, hematogenous macrophages), production of proinflammatory mediators and infiltration of various proinflammatory cells (mainly neutrophils and lymphocytes). These cells play an essential role in ischemic brain tissue by releasing either proinflammatory or anti-inflammatory mediators at different time points. Authors also will investigate the inflammatory process of stroke, especially the role of proinflammatory and anti-inflammatory genes in the pathogenesis of strokeand they will sumarize the current clinical trials of drugs that target the inflammatory mechanism for intervention. In the third review Sarmah et al. [8] will examine the role of Inflammasomes in sroke and atherosclerosis pathogenesis. These authors will review the numerous studies over the decade that have shown that inflammasomes play a role in mediating inflammatory reactions post cellular injury occurring after stroke or a rupture of an atherosclerotic plaque. They also will review the mechanisms by which inflammasomes drive the pathogenesis of stroke and atherosclerosis. Also discussed here are the possible treatment strategies available for inhibiting inflammasomes or their up-stream/down-stream mediators. In another review of the issue article Rodrigo et al. [9] will review the role of oxidative stress in stroke pathogenesis. Oxidative stress is an imbalance between pro-oxidants and antioxidants with increased production of reactive oxygen species. Reactive oxygen species have a possible dual role, playing a role in normal physiological processes but they have been also reported as involved in pathologic processes, whereby they mediate damage to cell structures, including lipids, membranes, proteins, and DNA. The cerebral vasculature represent a major target of oxidative stress that is consecutively involved in the pathogenesis of ischaemic brain injury following a ischemic stroke. In the last review article [10] Keat Wei et al. examined the role of Lipid metabolism genes in stroke pathogenesis and atherosclerosis in a more wide conception. Although dyslipidemia is a well stablished risk factor for coronary artery disease, its relationship to ischemic cerebrovascular disease has remained unclear, perhaps because of the heterogeneous nature of strokes. The “ so called” stroke paradox” remains a uncertain issue for several decades. Authors will review several research articles in order to better clarify this concept and consequent issues. In the modern world acute cerebrovascular accidents (strokes) are one of the most important sociomedical problems due to its high degree of related invalidization and mortality of the population. Ischemic stroke is a complex (multifactorial) polygenic disease due as a result of interactions between risk factors and genetic components due to independently acting or interacting polymorphic genes [11-15]. Thus only a complex and multilevel genetic and epigenetic approach concerning the several pathogenetic possible pathways possibly involved in ischemic stroke pathogenetic determinants will allow to define a possible genetic risk profile of ischemic stroke.

Natural products are important sources of bioactive compounds and the prospect of these compounds from plant, marine and animal species has been the main research aim in health area [1-4]. The discovery of these products with medicinal potential is due to the richness existing mainly in the biomes present in the fauna and flora of a region, which are responsible for the discovery of many bioactive compounds, such as morphine, atropine, spirofornabuxine and vinblastine among others [5, 6]. If we evaluate the large existing biodiversity on the planet, few molecules were discovered and studied for their phytochemical and biological aspects. And this discovery can be motivated by ethnopharmacological studies and the identification of secondary metabolites. One of the most important properties of secondary metabolites is associated with its ability to produce a wide variety of bioactive compounds. The search for these compounds is a priority for many countries, due to the need to find new compounds that can combat immunosuppressive, antibacterial, antidepressant diseases, among others. In the last decades, it has been observed that the developed countries have invested in research in this area, in order to find bioactive compounds that can be used in the technological prospection of new products by the pharmaceutical and food industries [7, 8]. Thus, in this special issue, we approach the chemical, pharmacological, biological, and technological aspects of known compounds and other unpublished studies to boost their technological development (R&D).

This second part of the single-topic issue entitled “NAFLD in the 20’s. From epidemiology to management” concludes this special issue of CPD. Nonalcoholic fatty liver disease (NAFLD) is an “umbrella” definition, which describes the whole range of pathological liver changes spanning from simple steatosis to nonalcoholic steatohepatitis (NASH). NASH may be associated with fibrosis, which carries an increased risk of progressing to either cirrhosis or hepatocellular carcinoma (HCC), which, in this case, is defined as NAFLD-related HCC. Given that NAFLD affects up to a quarter of the general adult population in Europe and USA and owing to the global decline of other causes of chronic liver disease, such as viral hepatitis, NAFLD is rapidly becoming the leading cause of HCC worldwide. In addition to its liver-related burden, NAFLD is also associated with an increased risk of adverse cardiovascular events and other extra-hepatic diseases. Therefore, the prediction of the natural history of this common and burdensome liver disease is key in implementing personalized management and follow-up strategies. On this background, Tovoli et al. from the group led by Professor Piscaglia in Bologna, Italy, have examined published studies pertinent to characterizing those features of NAFLD-related HCC useful in distinguishing this specific etiology of HCC from cases of HCC owing to other non-NAFLD etiologies in humans [1]. In their systematic review, these authors were able to retrieve a total of 244 eligible original papers. Data have shown that NAFLD-related HCC may often escape the surveillance programs given that it is difficult to precisely identify the population at high-risk, and that NAFLD-related HCC may also occur amongst patients with non-cirrhotic NASH. These specific features will result in delayed diagnoses, more limited access to radical management options and, eventually, in a reduced life expectancy which is not due to inherently more aggressive behavior of HCC. On these grounds, it is expected that additional efforts to further improve prevention, surveillance protocols and identification of drugs modifying the course of NAFLD will beneficially impact healthcare expenditures and clinical outcomes of patients with NAFLD-related HCC [1]. Dr. Ballestri et al. from Modena, Italy, have highlighted the importance of diagnosing NAFLD through non-invasive imaging techniques [2]. In their extensive review of the literature, the authors examined the added value of conventional liver ultrasonography when performed with semi-quantitative scores. These simple ultrasonographic scores can effectively rate the severity of steatosis and its progression over time (indicating those subjects, who should undergo second-line imaging techniques or liver biopsy), while also acting as accurate sensors of cardio- metabolic health [2]. Along the same line, Dr Pennisi et al. from the group led by Prof. Petta, Palermo, Italy, have extensively discussed the main limitations of liver biopsy for the diagnosis of NAFLD. These include the invasiveness and potentially life-threatening, albeit rare complications of this method, as well as its poor acceptability, sampling variability and costs [3]. On these grounds, the authors have critically discussed the clinical importance of differentiating simple steatosis from NASH as well as of non-invasively assessing liver fibrosis [3]. We are grateful to the CPD Editorial Team for granting us the honor to serve as Guest Editors of this single-topic issue. We also thank all those Colleagues who accepted to contribute their outstanding articles to the present monography to which we wish great success.

This special issue in Current Pharmaceutical Design 2020; 26(31) entitled “Targeted Drug Delivery and Theragnostics “ celebrates The World Theragnostics Day on the 31st of March because the first radioiodine dose was given on that day in 1941. Theragnostics utilizes same active pharmaceutical in the patient selection both in in vivo diagnosis and in active therapy. This is an essential part of novel precision medicine which identifies new subclasses of disease and guides individual treatments. Multi-omics approaches include the use of genomics, transcriptomics, proteomics, metabolomics, epigenomics and phenomics data to explore the complexity of a disease-associated biological network (Fig. 1), to predict prognostic biomarkers, and to identify new targeted drugs for individual cancer patients; this is reviewed by Assadi et al. [1] in the framework of systems biology in the era of precision medicine, emphasising the combination of molecular imaging modalities with high-throughput screening techniques and the new targeted treatments in prostate cancer. In the second review by Harvey Turner from Australia [2], the shortcomings of short-term randomised controlled trials of new anticancer agents are presented as published in high impact publications. As an example of global harmonisation in theragnostics, a prostate cancer study protocol will establish real-world evidence of overall survival and quality of life in patients undergoing routine 177Lu-PSMA-radioligand therapy. This theragnostics agent widely used on harmonised compassionate patient treatments throughout the world. For example, the real-time monitoring of quality of life in this study is independent of questionnaires, language differences, or oncologist bias, and relies upon individual patient self-assessment by choice of one of five emoji which best reflects their mood each day [2]. In nuclear medicine, theragnostics is developing a strategy which can be used to implement accepted tools for individual molecular targeting, including diagnostics, and advances in genomic molecular knowledge. This has resulted in identifying theragnostic radiopharmaceuticals that have the potency to diagnose and treat malignancies. In the third review by Jokar et al. [3], the most important radiotheragnostic agents are presented: MIBG, FAPI, PRRT, PSMA, radioiodine. Molecular targeted radionuclide treatment methods based on theragnostics is an excellent paradigm of the relationship between molecular imaging and therapy that has been used to provide individualised or personalised patient care [3]. The fourth review by Einat Slonimsky and Mark Tulchinsky [4] has radioiodine, the oldest radiotheragnostic pharmaceutical in focus: radioactive iodide treatment extends from historical origins to its modern utilization in differentiated thyroid cancer. This review discusses post-thyroidectomy thyroglobulin level and diagnostic radioiodine uptake in the neck as the decision-making tool that can be used in the majority of patients for radionuclide therapy consideration. Case examples demonstrate application of the method for logical selection of the specific radioiodine treatment category, identification and management of radioiodine-avid versus nonavid thyroid cancer [4]. Nanoparticle imaging and the imaging of the release of the loaded material from a nanoparticle system have attracted great attention in recent years. If the release of loaded molecules from delivery vehicles could be monitored reliably in vivo, it would speed up the development of drug delivery systems remarkably. A system that uses indocyanine green (ICG) as a fluorescent agent for studying release kinetics in vitro and in vivo of a lipid iron nanoparticle delivery system has been described in [5]. The spectroscopical properties of ICG are characterized in detail for real-time nanoparticle release quantification in vitro and in vivo in imaging in [5]. It has also been shown here that ICG containing liposomal nanoparticles can be traced under a surgical camera in vivo in orthotopic SCC xenografts in mice. The indocyanine green (ICG) has been used in novel sentinel lymph node approach in oral squamous cell carcinoma in a study by Åsa Kågedal et al. [6] from Karolinska Institute, Stockholm, Sweden. They present a novel protocol for identification of sentinel node in the head and neck region in 14 consecutive patients with T1-T2 N0 oral cancer scheduled for elective neck dissection and for sentinel lymph node biopsy in head and neck cancer. After evaluation, a combination of techniques was found to constitute a reliable, clinically adaptable work concept. The procedure started with the pre-surgical injection of radioactive technetium 99m Tc carried on tilmanocept nanoparticle at the tumour site. The radioactivity in the lymph node was then visualized preoperatively with Single Photon Emission Computed Tomography (SPECT/CT) imaging. Intraoperatively, indocyanine green (ICG) was injected and a sentinel node was visualized with near infrared light. To support the sentinel node detection, the surgeon used a hand held gamma detection probe. This approach resulted in a reproducible and reliable detection of sentinel nodes [6]. The last research work [7] in this special issue describes a novel targeted imaging and drug delivery vehicle for clinical use. The utility of targeted drug delivery has been tested in inflammatory bowel disease model. Alpha(α)-MSH, endogenous anti-inflammatory tridecapeptide, was used as targeting agent and it has an anti-inflammatory and immunomodulating effects and it bounds to its receptor, melanocortin-1 receptor (MC1-R). which are found on macrophages, neutrophils and renal tubules. Nanoliposomes were targeted with fluorescein labelled α- MSH and loaded with ICG for tracking. Liposome targeting to inflammatory disease models correlated with the macrophage concentration of the disease supporting the active targeting of the liposomes with αMSH. The liposomal αMSH was well tolerated by animals. On the basis of these preliminary findings, the αMSH targeted delivery may open towards clinically relevant theragnostic applications in inflammation and cancer.

For a long time, the cells of the inner vascular layer were considered only a physical, passive and inert barrier between blood and vascular smooth muscle. However, since the pioneering studies of the 1970’s and 1980’s, major advances in the understanding of the functions of this cell monolayer, i.e. the vascular endothelium, led to the recognition of its central role in the cardiovascular homeostasis. Currently, the vascular endothelium is considered a vital organ with multiple endocrine, paracrine and autocrine functions, regulating not only the vascular tone but also angiogenesis, inflammation, platelet aggregation and leukocyte adhesion, vascular cell proliferation and oxidative stress. In addition, several reports have demonstrated clear evidence between the biochemical or structural damages of the endothelium and the genesis and maintenance of pathological events related to inflammation, thrombosis, and atherosclerosis, as well as changes in the vascular resistance and blood pressure. Consequently, clinical and experimental evidence place the endothelial dysfunction as the pivot of the pathophysiological mechanisms in diseases of great morbidity and mortality today, such as hypertension, myocardial infarction, stroke, diabetes and metabolic syndrome, rheumatic diseases, renal failure, neurodegenerative diseases, cancer, inflammatory diseases, and others. Therefore, it is of significant interest that strategies are developed with the aim of not only warding off aggressive agents or risk factors, thereby preventing the onset of endothelial dysfunction, but also therapies that can reverse or mitigate the harmful effects generated by this condition. Due to the complexity of the mechanisms involved in the responses of the endothelium to physical and biochemical stimuli to carry out its functions, it is understandable that numerous therapeutic targets will be listed for the treatment of endothelial dysfunction, and that they are designed for each related disease. Furthermore, although the current literature shows a number of studies with pharmacological and nonpharmacological therapeutic approaches for endothelial dysfunction, the clinical applicability and translational nature of the studies do not appear to be evident. The present issue collects reviews covering basic, translational and clinical aspects, addressing potential molecular targets and/or promising pharmacological strategies for endothelial dysfunction in its different aspects (e.g. vascular tone control and hypertension, leukocyte/platelet adhesion and inflammation, atherogenesis and thrombogenesis, proliferation and neovascularization, et cetera). A critical point in the investigation of therapeutic targets and the development of therapies is an adequate characterization of the endothelial dysfunction status. In this regard, since the first experiment reported by Furchgott and Zawadaski in 1980, vascular relaxation to acetylcholine has been a widely used pharmacological tool to assess endothelial function integrity in isolated arteries. Almost simultaneously, acetylcholine- induced contractions were noted in pathological conditions such as vascular inflammation and hypertension. In their mini-review, Edwards et al. critically examine the historical and current literature on this phenomenon, and also address the potential underlying mechanism involving arachidonic acid signaling, questioning whether the resolution of inflammation would actually interfere [1]. In fact, inflammation is recognized as an important factor in the development of several diseases, including those in which the pathogenesis involves morphofunctional impairment of the vascular endothelium. At the same time, endothelial dysfunction per se is accompanied by localized inflammation, which subsequently amplifies vascular and tissue injury. In this regard, in their mini-review Ferreira-Duarte et al. present the relationship between these factors focusing on the role of endothelial dysfunction in inflammatory bowel disease, as well as the current knowledge and possible gaps for therapeutic approaches [2]. There is a consensus that nitric oxide (NO) is the major endothelial-derived bioactive agent, mediating numerous regulatory processes operated by these cells. Thus, both the L-arginine-NO-synthase and NO-cGMP-PKG signaling pathways are frequent subjects of studies to discover promising therapies for vascular dysfunction. Because endothelial dysfunction is well characterized by reduced NO bioavailability, either by its impaired synthesis or elevated destruction, Paulo et al. review the theoretical bases for the rational design of NO donor molecules, as well as issues related to the applicability, tolerance and therapeutic limitations of these NO donor drugs in patients [3]. The reduction in the effects of NO, present in many vascular diseases related to endothelial dysfunction, is characterized by impairment in cGMP production and/or signaling. Because phosphodiesterases (PDE) are able to catalyze cGMP hydrolysis, Blanco-Rivero & Xavier supply, in their review article, the current evidence of the potential benefits of selective PDE inhibitors (PDE1-5) in improving of endothelial function for the treatment of atherosclerosis, diabetes mellitus, arterial hypertension, stroke, aging and cirrhosis [4]. In addition, the authors provide critical analysis of the usefulness and interest of these drugs for the research, clinical and pharmaceutical industries. Notably, the integrity of the endothelium is also important for controlling the flow of molecules such as insulin and, thus, Luse et al. in their mini-review critically analyze the relationship between the endothelial dysfunction identified in type-2 diabetes and the molecular and cellular aspects of insulin-based therapies and exercise practice [5]. Similar to non-pharmacological therapies such as exercise, changes in lifestyle and diet, the use of plant extracts and dietary supplements has been shown to be useful and potential subjects for the pharmaceutics. For example, in this special issue Professor Kazuo Yamagata reviews the biochemical and physiological aspects of using polyunsaturated fatty acids in the prevention and treatment of endothelial dysfunction present in cardiovascular diseases such as hypertension, atherosclerosis, heart failure, myocardial infarction and stroke, and also examines the main clinical and epidemiological evidence on the benefits of using n-3 fatty acids, fish oil concentrate and fish consumption for endothelial dysfunction and oxidative stress [6]. As reported by repeated studies over the past decades and in several diverse pathological conditions, in their review-article Almenara et al. demonstrate that oxidative stress plays a key role on endothelial dysfunction and, in fact, should be an interesting therapeutic target in the harmful effects induced by cadmium intoxication [7]. This is also proposed by Miguel et al., offering a critical review on the promising utility of dietary supplementation with bioactive egg protein hydrolysates on cardiometabolic diseases associated with oxidative stress, which highlights the importance of the pharmaceutical design of nutritionally improved food products [8]. In addition, foods and natural products with higher concentrations of antioxidant polyphenols have the potential for excellent results in countering the harmful effects from oxidative stress, as presented by Delgado et al. on their review about the antihypertensive, antiatherogenic, antihyperglycemic and anti-inflammatory properties of pomegranate (Punica granatum L.) [9]. Endothelial dysfunction is also common in postmenopausal women and in animal models after ovariectomy, which explains, at least in part, why the cardiovascular risk in women has been lower than in men, but becomes comparable to men after menopause. In this regard, Oliveira et al. in their review article, analyze the literature supporting innovative potential therapeutic approaches for endothelial dysfunction in estrogen-deficient states and address the potential underlying mechanisms [10]. Additionally, these authors report their preliminary data on the potential antioxidant effects of probiotic kefir in ovariectomized female rats. This promising bioprospecting target for identifying bioactive peptides is also aptly discussed by Vasquez et al. in another article of this special issue, revising the role of gut microbiota dysbiosis on the cardiovascular (Arterial Hypertension) and neurodegenerative (Azheimer`s dementia) diseases and presenting translational researches focused on the use of probiotic kefir [11]. Finally, in addition to the vascular endothelium, a standing of perivascular adipose tissue (PVAT) has recently also been recognized for cardiovascular homeostasis, as able to release a variety of vasomotor substances. Yet similar to the endothelium, Victorio et al. complete this special issue analyzing in-depth several studies that reveal sex differences in PVAT morphology and function, which has implications not only with regard to sex-specific mechanisms of dysfunction, but also sex-specific therapeutic targets for cardiovascular protection [12]. CONCLUSION Although more than 40 years have passed since the first descriptions of its functions, the vascular endothelium remains a subject of research in many areas today, and a leading player in the search for therapeutic targets in the current pharmaceutical design, whether experimenting strategies with our ancestral relationship with natural and plant products, or envisioning new molecular and genetic mediators.

Chitin is a β-1,4-linked homopolymer of N-acetylglucosamine (GlcNAc), and widely distributed in living organisms, such as crustacean shell, insect cuticle, and fungal cell wall. The polysaccharide and the deacetylated derivatives, chitosan, are mainly produced from marine products, crab and shrimp, and utilized as functional materials in food and textile industries, as well as for medical and pharmaceutical materials. However, chitin is not fully utilized as cellulose, because it is relatively expensive and its application is still limited to some areas. Recent studies on the chitin oligosaccharides have provided novel strategies for efficiently utilizing chitin. Various biological functions of chitin/ chitosan oligosaccharides have been recently identified in plants, and applications of the oligosaccharides have produced economic and social benefits in agriculture [1]. Furthermore, chemical and enzymatic synthesis of novel oligosaccharides with biological functions have provided new opportunities for utilizing chitin. Heat-induced transformation of GlcNAc produced furanodictine A and B with neuronaldifferentiation activity toward PC12 cells from the fruiting body of the cellular slime mold [2]. Enzymatic transglycosylation reaction using chitin oligosaccharides produced a novel inhibitor and substrate for lysozyme, which will be potentially applied for pharmaceutical use [2]. All of these works may facilitate the application of chitin in various fields, enhancing the chitin utilization. On the other hand, in insects, chitin contributes to the rigidity of the cuticle and serves as an attachment matrix for other cuticular proteins. Many of the genes involved in chitin metabolism are critical for the structural integrity of the exoskeleton. Interestingly, cuticular chitin was found to be partially deacetylated. Chitin and chitin deacetylases strongly influence the shape and functions of the exoskeleton as well as locomotion of insects [3]. One of the unexplored areas is how the exoskeleton is tied to muscle function. Based on these findings on insect cuticle stabilization, drugs targeting the enzymes for chitin synthesis and degradation have been developed for controlling insect pests. The molecular knowledge of the chitin synthesis and organization pathways and chitin degrading enzyme chitinases may offer new opportunities to design novel insecticides that are environmentally harmless at the same time being specific to a pest species. The fruit fly Drosophila melanogaster may serve as an excellent model insect in order to better understand their mode of action [4]. The red flour beetle, Tribolium castaneum, is a powerful model organism for developmental, physiological and applied entomological research on coleopteran species. As T. castaneum develops resistance rapidly to many classes of insecticides including organophosphates, methyl carbamates, pyrethroids, neonicotinoids and insect growth regulators such as chitin synthesis inhibitors, it is a suitable pest model for studying resistance mechanisms and the mode of action of insecticides [5]. In this special issue on “Chitin Biology and Beyond”, the journal aims at providing the information on chemical and biological strategies for enhancing chitin utilization and insect pest control.

Transplantation of solid organs has presented enormous progress over the last four decades. Success of transplantation is largely attributed to advances in four areas: immunosuppression, organ preservation, surgical technique and intensive medical care. Immunosuppression is divided in two steps: induction and maintenance. Induction therapy is immunosuppressive therapy administered at the time of transplantation to reduce the risk of allograft rejection. Induction therapy is not always administered: low-risk organ recipients in general do not receive induction therapy. Maintenance immunosuppression is administered to transplant recipients to help prevent acute rejection and the loss of the allograft. Both induction therapy and immunosuppression are able to prevent the occurrence of cellular rejection episodes in the large majority of recipients of transplants of solid organs. In this thematic issue, worldwide transplantation authorities review the standard of care in solid organ transplantation. Kidney, pancreas, liver, heart, lung, intestinal and multivisceral transplantation current protocols are reviewed here. Protocols of transplant services from eight different countries: Unites States, Canada, Sweden, Italy, Spain, Czech Republic, Brazil and Taiwan are included in this same issue. This diversity certainly will provide a variety of clinical experiences that will enable a broad understanding of the current practice of organ transplantation around the World. Acute cellular rejection (ACR) still triggers immnune damage to the allograft sometimes leading to organ failure. Thus, still there is room for improvement both in induction and in maintenance immunosupression protocols. Each of the review articles in this thematic issue provides insights to the reader regarding future directions in immunosupression protocols. In the late 1960’s, the development of the cytotoxic crossmatch (CDCXM) by Paul Terasaki and colleagues lead to better understanding of the risks of early allograft loss secondary to humoral damage. Specifically, the concept of antibody-mediated acute humoral rejection (AMR) was established. Moreover, AMR was divided in its two early subtypes hyperacute and acute humoral rejection types. Following worldwide adoption of the CDCXM, the occurrence of hyperacute AMR became a rare phenomenon. However, AMR including cases of severe acute allograft damage (sometimes leading to graft loss) still occurred because low levels of reactivity against the donor were not usually detected by the CDCXM. In other words, the test was not sensitive enough to detect all cases of humoral reactivity against the donor. Recently, the matching process has evolved into safer sideways. More modern assays such as the flow cytometric crossmatch (FXM) are able to detect low levels of antidonor humoral reactivity. In other words, FXM is a more sensitive test. In order to be performed, FXM still needs that tissue from the donor (lymph nodes or serum) be obtained and tested against donor serum. A more modern assay was developed more recently: the single antigen beads assay (SAB). In this test, a large variety of anti-HLA microspheres is utilized. Each of the miscrospheres reacts against one of the of HLA subtypes that are present in the donor serum. The SAB can be performed pretransplant by only testing donor and recipient blood. Moreover, there is no need for testing the serum reactivity of each recipient against the potential donor. SAB only demands individual HLA subtyping of the donor and the potential recipients. Thus, this test may be performed when the donor and its potential recipients are far away from each other. Although there have been important developments in the field of transplantation of solid organs, there still is room for improvement. Complete prevention of the occurrence of AMR and ACR is the mainstay of transplantation research. The main player of the process of AMR is the plasma cell. Currently, the plasma cell has not yet received a pharmacologic agent to completely block it. The plasma cell and AMR still are the Achilles’ heel of solid organ transplantation (except for liver transplantation though). In this thematic issue of Current Pharmaceutiacal Design, the review article of Mustian and Locke on positive crossmatch kidney transplantation explores the standard of this practice and its current pitfalls. Most of the protocols adopted at the University of Alabama for this practice also are suitable for the practice of ABOincompatible kidney transplantation. The article by Rodrigo et al. “Acute Rejection Following Kidney Transplantation: State of Art and Future Perspectives” properly addresses the current knowledge in the subject of treatment of AMR and ACR. Mostly due to its immunologic barriers, Intestinal and Multivisceral transplantation are not widely performed worldwide. In this issue, the article “Immunosuppression in Visceral Transplantation: Current Trends and Future Perspectives” Backes et al. address the standard of care of this practice. The authors also discuss the current practice of the group of the University of Miami, the USA leading group in number of transplants in the year of 2019. The future directions of intestinal and multivisceral transplantation also are discussed. Tolerance with complete withdrawal of all immunosuppressive agents would be the main goal of transplant practice. The liver is a unique organ in terms of tissue pool and resistance to autoimmunity. In the review article “Immunosuppression in Liver Transplantation: State of the Art and Future Perspectives” of this issue of Current Pharmaceutical Design, the collaboration article between Norwegian and Brazilians specialists including myself addresses the standard of care and the future directions of immunosuppression in liver transplantation. Tolerance currently has been achieved in few liver transplant recipients worldwide and this subject is explored in the article. I am honored to be the Guest Editor of the Thematic Issue “IMMUNOSUPRESSION IN SOLID ORGAN TRANSPLANTATION: STANDARD OF CARE AND FUTURE DIRECTIONS”. I faithfully believe that the exceptionally qualified group of transplant experts from eight Countries and four continents who wrote the twelve review articles of this issue after accepting my invitation was able to deliver an outstanding overview of the worldwide standard-of-care practice of transplantation of solid organs. I also would like to thank the anonymous reviewers for the thorough fully task of performing the peer review of this thematic issue.

Nano-lipoidal Carriers for Delivery of Systemic and Bioactive Compounds: Strategies, Advances and Opportunities

The development of the next-generation sequencing technologies makes it more easy for us to reveal the structure and function of molecules in the wet lab. In recent years, the accumulation of data and findings regarding single molecule has been growing fast. Despite current progress and successes, the genetic cause of many human complex diseases still remains unknown, due to the fact that complex diseases are often caused by the combined dysregulations of a large number of molecules and phenotypes. The lack of comprehensive understanding of complex diseases has greatly limited the identification and design of novel drugs for curing human diseases. In the post-genome era, the major challenge for drug development and design is to identify novel casual genes and phenotypes of diseases and drug targets based on multilevel omics data using system biology approaches, which can also extend our knowledge of the disease genetics, and could then improve the exploring of novel drugs for diseases. Here, I propose a Special Issue of Current Pharmaceutical Design around the topic 'System Biology Methods and Tools for Pharmaceutical Design'. A Total of seven review papers are presented in this thematic issue. Zhao et al. [6] viewed the methods of identifying drug side effects. They not only elaborated the importance and progress of this field, but also categorized the methods and summarized the general framework to explain the advantages and disadvantages of each type of method. In addition, the commonly used databases are given to help researchers find the resource easily. As a review article, it discusses the related knowledge of the field in detail, summarizes it, and looks forward to future developments. It is very useful for researchers who want to obtain knowledge about the identification of side effects. Peng et al. [4] summarizes the recent methods for link prediction in the biological network and discusses the application and significance of network representation learning in link prediction task. The paper first introduces the widely used link prediction algorithms and discusses the advantages and disadvantages of these methods. Then, the recently proposed network representation methods and its applications on the link prediction task in the biological network are reviewed. The existing research shows that compared with traditional methods, the network embedding methods have achieved better results in the downstream tasks for biological network link prediction. At last, the possible future directions of link prediction tasks are discussed. Bioluminescent proteins (BLPs) are special proteins which could convert chemical energy into light emission. Bioluminescence has wide applications, such as camouflage, finding food, attraction of prey and so on. Thus, the correct identification of BLPs could provide important clues for designing new applications. With the accumulation of protein data, some machine learning methods have been proposed in this field. Tang et al. [1] reviewed the progress of machine learning method application in bioluminescent proteins identification from benchmark dataset construction, feature extraction and optimization, clarifiers to publications. Finally, how to improve the prediction accuracy for identifying bioluminescent proteins was suggested. This review will provide more guidance to related scholars for computational analysis of bioluminescent proteins. Plasmodium falciparum (P. falciparum) could infect humans and result in about 500,000 deaths according to the report of the World Health Organization (WHO). The study on the proteomics of P. falciparum could provide important clues for anti-malarial drug-target discovery. As the mitochondrial proteins in malaria parasite are different from human mitochondrial proteins, it is possible to develop anti-malarial drugs and vaccines based on malarial mitochondrial proteins. In the past two decades, scholars have developed several kinds of computational methods to identify malaria mitochondria proteins. To summarize the development of machine learning methods in the field, Liu et al. [7] reviewed the published benchmark datasets, sequence description methods, machine learning methods and models’ performances. From the review, readers could get important information to study the malarial mitochondrial proteins. Deng et al. [2] comprehensively reviewed recent developments and progress in computational drug repositioning. They demonstrated the available data sources in detail, which are conducive to identifying novel indications. They also provided a summary of current computing approaches and described techniques, case studies, and evaluation criteria for each method. They finally discussed the limitations of existing computing approaches. This review will be beneficial for researchers interested in developing new drug repositioning approaches to have a good overview of the field. With the continuous development of artificial intelligence (AI) technology, big data-supported AI technology with considerable computing and learning capacity has been applied in diagnosing different types of diseases. Zou et al. [3] reviews the systems used by AI technology in disease diagnosis and briefly expounds the intelligent diagnosis and treatment of digestive system diseases, respiratory system diseases, and osteoporosis by AI technology. Stimulator of interferon genes is an important innate immune signaling molecules in the body and is involved in the innate immune signal transduction pathway induced by pathogen-associated molecular patterns or damage-associated molecular patterns. Stimulator of interferon genes promotes the production of type I interferon and thus plays an important role in the innate immune response to infection. In addition, according to a recent study, the Stimulator of interferon genes pathway also contributes to anti-inflammatory and antitumor reactions. He et al. [5] reviewed current researches on the Stimulator of interferon genes signaling pathway and its relationship with tumor immunity. Each paper in this special issue was extensively peer-reviewed by two external reviewers. I would like to thank all the authors for contributing their work to our hot thematic issue and all the reviewers for their time and efforts. At last, I would like to thank the Editor-in-Chief of Current Pharmaceutical Design, and Editorial Office of Bentham Science Publishers, for their support during the whole process.

The gastrointestinal tract (GI-tract) is constantly exposed to a variety of strong irritants, toxins, poisoning liquids, drugs and deleterious microbial organisms. Thus, the maintenance of the GI-tract integrity is of great importance for the normal functioning of the physiological processes including proper food intake control, gastrointestinal digestion and absorption. This special issue of Current Pharmaceutical Design was created to provide an update on the crucial mechanisms of GI-tract integrity, protection and ulcer healing of the upper and lower GI-tract, in addition to being enriched with quite recent aspects such as the physiology and pharmacology of brain-gut axis and microbiota. As Guest Editors of this Special Issue, we are truly convinced that despite the extensive and multidisciplinary research presented in these articles, more basic and clinical research is still required for better understanding of the central and peripheral mechanisms of the mucosal protection, as well as repair and healing of the GI-tract mucosa injured by various damaging agents. Future trends in research related to this field of medicine should consider the search for the plethora of molecular regulators, first and second messenger systems for a discussion on novel concepts resulting in better implementation of modes of treatment, and the introduction of a variety of prevention/management modalities with the application of new agents. Therefore, our attempt was to provide an overview of a large frame of pertinent scientific research by eminent experts in the field, providing their most updated experimental and clinical evidence, including the development of new medical products, pro-drugs and new approaches. In their review, Bilski and colleagues [1] presented the epidemiology of inflammatory bowel disease (IBD), the clinical entity of intestinal bowel disorders comprising of Crohn’s disease and ulcerative colitis, which is nowadays characterized by increased prevalence. Among other risk factors of these disorders, the link between obesity and IBD is now rapidly increasing along with the global prevalence of obesity. Bilski et al. presented the potential therapeutic interventions against experimental and clinical IBD, with a focus addressed to novel roles of alternative therapeutics such as exercise, intestinal alkaline phosphatase treatment and supplementation therapies with probiotics and herbal products, effective in the attenuation of IBD and obesity pathogenesis [1]. In line with risk factors for IBD, De Musis and collaborators [2] have presented the extensive and interesting overview of gut microbiota contribution to the development of these chronic multifactorial diseases. The authors presented evidence that commensal microbiota may drive the intestinal inflammatory process and that the intestinal inflammation may result from an impaired equilibrium in microbiota composition [2]. It is now evident that the development of colonic inflammation requires the presence of commensal enteric bacteria in genetically-susceptible hosts [2]. This review tried to answer the question of whether dysbiosis (i.e. alteration of intestinal microbiota) represents a cause or rather a consequence of IBD. The authors point out the beneficial probiotic role of gut microbiota, which might serve as a therapeutic target in IBD. The evidence is provided that the restoration of the intestinal flora composition using prebiotics, probiotics, synbiotics, and fecal microbiota transplantation (FMT), has become a complementary medical strategy for intestinal inflammation. It is well known that in addition to NSAIDs, experimental and clinical therapy with glucocorticoids has also been associated with the increased risk of bleeding and sometimes even perforations of the GI-tract. The mechanism of these side effects requires further studies, but it has been shown that glucocorticoids injected at high doses inhibit prostaglandin biosynthesis, which can promote severe gastric injury. In their review, Filaretova, Podvigina and Yarushkina [3] pertained to the physiological and pharmacological effects of glucocorticoids on the gastrointestinal tract. The authors focused on the gastric mucosal ulcerogenic properties of these steroids in relation to the emerging findings, suggesting the gastroprotective role of stress-produced glucocorticoids. Based on the long term experimental experience of these authors, their convincing literature evidence is provided on the adaptive gastroprotective nature of glucocorticoids produced during acute stress-caused activation of the hypothalamic-pituitary-adrenocortical (HPA) axis [3]. Furthermore, glucocorticoids have been shown to exhibit a permissive role in gastroprotection caused by other protective factors such as prostaglandins, sulfhydryl’s, cimetidine or interleukin-1. This experimental evidence has definitely changed the traditional and general point of view on the ulcerogenic nature of glucocorticoids produced during stress and should be considered by general practitioners [3]. Besides the intestinal compartment, the oral cavity is considered as the proximal section of the GI-tract serving as the reservoir of diverse microbiota strains responsible for maintaining the neutral environment of the mouth. Keremi et al. [9] refer in their overview of the microbial manifestation of oral cavity pathogenesis, which includes herpes zoster (HZ), an infection with the varicella-zoster virus in the sensory ganglia causing an infection of the skin. The clinical manifestation of HZ is defined by a painful and unilateral erythematous maculopapular rash, which normally involves 1-2 dermatomes. These authors provide the mechanism of the pathogenesis of this disease at the cellular level attributed to the upregulation of receptors associated with pain, such as the transient receptor potential vanilloid 1 (TRPV1), the increasing proportion of voltage-gated sodium channels and potassium voltage-gated channels and the evident loss of γ-aminobutyric acid (GABA) inhibitory interneurons in the dorsal horn [9]. These alterations in the oral microbiome and the pathological outcome of this disease could be attenuated by mouth rinsing. In their systematic review and meta-analysis, Keremi et al. [9] presented an overview on the efficacy of chlorine dioxidecontaining mouthwashes, compared to other established mouthwashes in healthy adults. Similarly to other routinely used oral rinses, it seems that chlorine dioxide reduces plaque index as well as gingival and bacterial counts in the oral cavity. Interestingly, the administration of GABA and its derivatives could be a good alternative to reduce the incidence of HZ-associated pain in the first month after the onset of the rash, but well-designed randomized clinical trials are definitely needed to prove this strategy [9]. Nakamura and collaborators [11] have demonstrated that Helicobacter heilmannii (H. heilmannii) in mice is capable of inducing not only gastric but also hepatic and pulmonary MALT lymphoma, the supporting important hypothesis about the extragastric manifestations of gastric Helicobacters, such as H. pylori and H. heilmanii. In their study, Nakamura et al. [11] recall previous evidence that infections with certain Helicobacter strains, so called enterohepatic Helicobacters including H. hepaticus, H. billis, H. rodentium and H. canis, have been described to reside in the liver. The bacteriological characteristics of these strains differ from the Helicobacters residing in the stomach, i.e. gastric Helicobacters. Consequently, this group of investigators led by Nakamura [11] suggested that infection with this non-Helicobacter pylori- Helicobacter strain may induce not only gastric- but also non-gastric- or generalized MALT lymphoma. Their observation implies some similarities between the Helicobacter strains and possibly the direct bacterial H. heilmanii and/or H. hepaticus strain’s interaction with target organs in the development of stomach and liver diseases, such as gastritis and hepatitis. Of particular therapeutic importance might be the evidence that administration of antibiotics and lansoprazole significantly reduced the H. heilmannii-induced liver and lung damage [11]. Park and collaborators [4] presented an interesting review on the cytoprotective activity of the body protection compound (BPC) 157 against the cytotoxicity of non-steroidal anti-inflammatory drugs (NSAIDs), due to this peptide's induction of cytoprotective strengthening of the intestinal epithelial barrier as well as prevention of the leaky gut syndrome. It is well known that NSAIDs ingestion can be associated with serious bleedings and the formation of mucosal damage, but stabilizing gut permeability by BPC 157 can be both an essential and attractive strategy for prevention of the troublesome NSAIDs-induced gastroenteropathy. The authors highlighted the novel therapeutic intervention with BPC 157 to prevent the leaky gut syndrome and characterized the molecular background of BPC 157-induced cytoprotection against NSAID-induced gastroenteropathy [4]. Interestingly, BPC 157 can exert its cytoprotective action against NSAID-induced mucosal damage via the preservation of endothelial injury, known to precede the subsequent gastrointestinal epithelial damage caused by administration of these drugs [11]. Stress of different origins can induce gastric lesions frequently called “gastric ulcers”, but the pathogenesis of these lesions is complex and not fully understood. In their review, Ray, Gulati and Henke [5] presented the perspectives and trends in cytoprotective strategies against stress-induced gastric lesions, with a major focus on alterations in the central nervous system (CNS) and brain-gut axis. The authors pointed out that the amygdala and its links with other limbic areas of CNS and the brain structures play a crucial role in stress ulcer formation. This presents many aspects of experimental research based on the manipulation of specific brain areas and neuro-immune interactions [5]. The pathogenesis of stress ulcers observed mainly in the upper GI-tract involves the enhanced biosynthesis of CNS neurotransmitters like biogenic amines (dopamine), and their interactions with neuropeptides (opioids) and gaseous molecules such as nitric oxide (NO) and hydrogen sulfide (H2S) [5]. Besides being a gas transmitter, NO and its signaling pathways can interact with the immune system and the brain-immune axis [5]. The modulation at the central and peripheral levels by cytoprotective agents, play an essential role in both stress ulcerogenesis and the mechanism of mucosal protection against these lesions [5]. This seems to constitute the novel but not yet fully elucidated concept, now underlined by these authors [5]. In view of the above and the lack of consistent therapeutic modalities, pharmacological strategies targeting the above mentioned hypotheses could be developed in the future for a better understanding of stress protection and prophylaxis of stress ulcers. Sadaeng and collaborators [10] presented in their meta-analysis and systematic review the effectiveness of γ-aminobutyric acid (GABA) and its derivatives in the reduction of acute pain in individuals who suffer from herpes zoster (HZ). After a careful analysis of exclusion criteria, the authors could include three randomized trials involving 297 participants from Slovenia, Korea and China, yielding an inhomogeneous patient population. The results showed that the treatment with the GABA agonist gabapentin significantly reduced the pain sensation in patients with acute HZ. The mechanism of action of the GABA agonist to prevent or decrease HZ-associated pain is not fully understood. However, the authors refer to the modulation by GABA and its derivatives to influence neuronal transport because the descending GABA-ergic neuronal nerve fibers were reported to inhibit the peripheral nociceptive signals [10]. In line with this concept, the loss of GABA-ergic neurotransmission has been reported to play an important role in the development of acute HZ-associated pain. Furthermore, the experimental evidence provided by the authors [10] suggests that these changes can be blocked by both the GABA-like compounds and sodium channel blockers. Thus, one of the proposed strategies beneficial in attenuation of acute HZ-induced pain resulting from the virus activation affecting nerve axonal transport and causing nerve inflammation is the pharmacological modulation of the GABA receptors [10]. In their review on the possible clinical importance of therapy with pentadecapeptide BPC 157, Sikiric and collaborators [6] emphasized the remarkable efficacy of this peptide to heal various types of experimentally evoked fistulas i.e. esophagocutaneous, gastrocutaneous, duodenocutaneous, colovesical, and rectovaginal. Based on the mechanism of tissue and organ wound healing process accelerated by the application of the BPC 157 described in their review, they intend to implement BPC 157 in clinical settings as the useful and common protective and wound healing enhancer [6]. Despite modern pharmacological and biological therapies in IBD which include anti-tumor necrosis factoralpha agents, the major complications of fistulas and strictures healing in Crohn’s disease is of great importance. Strictures as a complication remain a significant cause of surgery as well as disability, and have been shown to impair the quality of life of IBD patients [6]. The summarized arguments and the ultimate effectiveness of the given BPC 157 experimental treatments encourage the practical applicability of this peptide in the therapy of GI-disorders. The reason and mechanism of why the morbidity of ulcers is statistically higher in males than females remains unknown. In their overview, Takeuchi, Ohashi and Amagase [7], attempted to resolve several dilemmas related to this topic. These authors provide the arguments that the protective duodenal HCO3 - response to mucosal acidification is higher in females than males, and this may be a factor responsible for the sex difference in the mucosal protection [7]. The authors provide evidence that this response was inhibited by indomethacin and sensory deafferentation, suggesting the involvement of endogenous PG and neuropeptides released from sensory nerves in this protection. The HCO3 - response to acid disappeared on ovariectomy, and it was restored by the repeated supplementation with estrogen. Interestingly, the gene expression of acid-sensing ionic channel (ASIC3) involved in the duodenal HCO3 - response mechanism induced by mucosal acidification was greater in female rats than in male rats, and down-regulated by ovariectomy. This review provides an insight into the mechanism of gender dependency of acid-induced HCO3 - response crucial for the sex-related course of ulcerogenesis, involving estrogen availability and mediated by increased expression of ASIC3 on sensory neurons in females [7]. In the exclusive and comprehensive review, Jackie D. Wood has described the key signaling molecules serotonin and substance P in the integrated physiology and pathophysiology of the GI-tract [8]. Serotonin is synthesized and released from three types of intestinal mucosal cells, namely enterochromaffin cells, enteric mast cells and the spinal sensory afferent nerves. Substance P has been recognized as a primary mediator in the chain of events leading to C. difficile toxin-A-induced mast cell degranulation and release of chemoattractant factors for circulating leucocytes [8]. This mediator which is expressed by interneurons, secretomotor neurons and musculomotor neurons in the enteric nervous system (ENS), as well as by intestinal spinal afferents, is also a secretagogue for histamine and cytokine release from mast cells. This overview provides an insight into the essential role of brain-gut axis and the interaction between particular cells releasing serotonin i.e. mast cells and afferent nerves in the pathogenesis of various disorders, and intestinal protection against various stressors. We believe that the evidence presented by experts in the field of experimental and clinical gastroenterology in this Special Issue may contribute not only to the scientific value of the entire journal volume but also to the translation of this information into medical practice for the benefit of patients suffering from gastrointestinal disorders.

Natural products have a major impact on drug discovery and have been used as medical remedies since ancient times. The therapeutic properties of plants are well recognized and their use in medicines is widespread. Moreover, isolated natural products are also a unique source of leads in medicinal chemistry and drug discovery, mostly because of their wide range of structural diversity, with multidimensional chemical structures. The main aim of this thematic issue is to illustrate the strong influence of Nature to find new lead structures of pharmaceutical relevance. According to the World Health Organization, the world population is largely dependent on traditional and folk medicines for the treatment of diseases. In addition, the utility of natural products as modulators of biological functions is also recognized. Integration of traditional knowledge with modern molecular technologies is a current challenge that could lead to the development of new drugs. Drug discovery based on natural sources includes the phytochemical analysis, characterization and pharmacological analysis of active principles and their biological effects. Lead molecules might also emerge from medium- to high-throughput screening and could be developed up to drug candidates through structural elucidation and identification using several techniques such as GC-MS, NMR and HPLC. Computational tools can also play an important role in the design and optimization of efficacy drug candidates. The use of natural products with green chemistry concerns, using more environmentally sustainable, economical, and effective drug discovery processes, is also desirable. Thus, this issue will collect recent advances in the above fields, and set the state of the art in techniques and approaches used to exploit natural sources in drug discovery. This thematic issue focuses on the confirmation of the success of natural resources to find new and effective drugs. The long tradition of natural products as a source for therapeutic agents is currently living a revitalization of interest thanks to the inclusion of these chemotypes in screenings libraries and achieving selective target modulation. This issue contributes to discuss natural product-inspired drug discovery with a focus on recent advances to the design of small synthetic molecules that mimic nature's chemistry. Natural products chemistry together with the new technologies such as computational tools and biological/biochemical evaluations has the potential to open up unexplored areas to search new and effective treatments. The discovery of new natural products continues to record significant advances not only in chemistry but also in biochemistry, pharmacology and medicine. Overall, this thematic issue covers different natural products compounds such as: 1. Mosolygó et al. manuscript reviewed articles published in the last decade in order to summarize the current understanding of AMR in correlation with biofilm formation and the evidence of phytotherapeutic agents against bacterial biofilms and their mechanisms of action [1]. 2. Sitarek et al. cover the literature over the past five years and examine the role and utilities of plant extracts in treating various skin diseases such as atopic dermatitis, acne or melanoma with various potential mechanisms of action [2]. 3. Dr. Leitão provides a mini-review of chalcones as a privileged scaffold in medicinal chemistry that aims to highlight the synthetic methodologies used in the preparation of these compounds [3]. 4. Skała et al. review the recent advances in the use in vitro cultures of various plant species for the alternative system for the production of bioactive caffeoylquinic acid derivatives (CQAs) [4]. 5. Wieczfinska et al. provide an overview of the anti-inflammatory effects of some of the natural agents and illustrates their great potential as sources of drugs to cover an extensive range of pharmacological effects [5]. 6. Hussein et al. summarize the published data during the period 2005-2018 on the biological importance of abietane diterpenes in the prevention and management of type 2 diabetes and closely related diseases [6]. 7. Patrícia Rijo et al. collect, organize, select and discuss the existing knowledge about the different uses of Artemia salina spp. as a bench-top bioassay for the discovery and purification of bioactive natural products [7]. 8. Kadidiatou O. Ndjoubi et al. review the literature from 1994-2018, and 158 diterpenoids from medicinal plants, as well as 40 diterpenoids from marines, are alluded to have anti-tuberculosis properties [8]. In conclusion, in this issue, a team of international experts that work with natural products overviewed the most novel topics and approaches towards Natural Products as an important source in drug discovery.

Antithrombotic therapy has a wide spectrum of applications in every day therapeutical approach as arterial and venous thrombosis is a major cause of morbidity and mortality. It is important to understand that arterial thrombi form under high shear conditions and they usually consist of platelet aggregates held together by small amounts of fibrin. So, strategies to inhibit arterial thrombogenesis focus mainly on antiplatelets but include anticoagulants as well, for the prevention of cardioembolic events in patients with atrial fibrillation or mechanical heart valves. On the other hand, venous thrombi form under low shear. They are mainly composed of fibrin and trapped red blood cells and contain relatively few platelets [1]. Anticoagulants are the mainstay for the prevention and treatment of venous thromboembolism. A new generation of direct oral anticoagulants (DOAC) directly inhibit thrombin or factor Xa. DOACs have greatly expanded oral antithrombotic therapy, which was previously limited to vitamin K antagonists (VKA). VKA target several coagulation factors and can be difficult to manage, they have a narrow therapeutic window, significant interactions, and high variability, all of which necessitate frequent monitoring of blood clotting (prothrombin time and INR). The DOAC, including dabigatran, rivaroxaban, apixaban, and edoxaban, target a specific coagulation factor and do not require routine coagulation monitoring. DOAC is in most situations, as effective as VKA in the prevention and treatment of thromboembolic events and seem to be more convenient [2-4]. As far as oral antiplatelet agents, from the commonly used aspirin to the P2Y12 antagonists (clopidogrel, prasugrel, and ticagrelor), exhibit interindividual variability that may be influenced by genetics. Indeed, patients treated with P2Y12 inhibitors show variable degrees of platelet reactivity associated with risk of thrombosis or bleeding [5, 6]. Therefore, this special issue contains 10 articles reviewing the role of antithrombotic therapy in various disease stated, beyond coronary artery disease, and provide clinical useful assumptions based on review of the literature. The first 2 articles [7, 8] focus on the treatment of acute venous thromboembolism and deep venous thrombosis. Antithrombotic treatment after atrial fibrillation ablation [9], antithrombotic treatment in patients with recent stroke and atrial fibrillation [10] and antithrombotic therapy in carotid artery disease [11] are discussed in the 3 following reviews. The next 2 reviews are focusing on the role of antithrombotic treatment in heart failure [12] and cardiomyopathies [13], following by 3 articles analyzing treatment approaches in more specific entities, such as in patients with diabetes mellitus, Transcatheter Aortic Valve Implantation (TAVI), patent foramen oval and atrial septal defect closure [14-16]. Venous thromboembolism (VTE) includes Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE). PE is the most important and potentially fatal complication of DVT with a three-month mortality rate as high as 17%, while the 6-month fatality rate has been reported 14.7%. As far as for patients suffered from DVT 6-month fatality is 10.5%. VTE is associated with a 3.6% risk of hospital-documented recurrence and a 7.1% risk of post-thrombotic syndrome up to 1 year after index VTE [17-19]. Anticoagulation is the cornerstone of treatment for DVT and it aims to reduce clinical manifestations, complications and eventually mortality. The first-line therapy in the antithrombotic treatment of DVT are DOACs, although there are specific populations such as patients with renal failure or patients with an active malignancy that they must be used under consideration. Other anticoagulant agents such as LMWHs (low molecular weight heparin) remain the standard care of treatment for pregnant women and patients with cancer. Results from several ongoing studies in the field of antithrombotic treatment in cancer patients and renal failure patients are expected to give more data about the most appropriate anticoagulation management in the era of DOACs [8]. Giannakoulas et al. summarized evidence about DOACs in patients with PE. They identified the lack of randomized controlled trials exclusively in patients with PE, cancer-associated thrombosis and antiphospholipid syndrome. Their bibliographic research ended up that DOACs seem to be more effective, and probably safer than a dual-drug approach with LMWH-VKA in patients with acute pulmonary embolism [7]. In Antoniou’s et al. review of literature about antithrombotic treatment in patients with atrial fibrillation (AF), it is highlighted that both DOACs and VKAs are acceptable choices, with a clear preference towards the former, while in any case treatment should remain uninterrupted throughout the periprocedural phase. They discuss the need of modifications in thromboembolic risk assessment in AF, as currently available and recommended grading scores lack accuracy and are unable to evaluate the effects of novel interventions, such as ablation of arrhythmia. They also point out the need for an individualized approach as to both minimize catastrophic thrombotic events and iatrogenic major bleeding [9]. Papageorgiou et al. pointed out the management of acute stroke in AF. In haemorrhagic stroke, both antiplatelet and antithrombotic therapy should be withheld in the acute phase, with the administration of reversal agents where appropriate. Oral anticoagulation (OAC) should then be restarted after 8 weeks to avoid further bleeding complications. In treatment naïve ischaemic stroke, anti-platelet therapy may be acutely initiated and converted to an OAC after 14 days. Early initiation of OAC may be considered in cases of minor stroke. Oral anticoagulant therapy could be in the form of VKA or DOACs, with DOACs having emerging evidence to be superior to VKAs and long term continuation would be based on patients' risk profile [10]. Doctor Antonopoulos et al. have reviewed the aspects of antithrombotic treatment in patients with carotid artery disease which remains a major cause of stroke. Antiplatelet therapy reduces not only the risk of stroke but of total cardiovascular events and is currently recommended in patients with known vascular disease including carotid artery stenosis. The role of additional antithrombotic treatment with anticoagulants in patients with carotid artery stenosis and no other compelling indication for anticoagulation (e.g. atrial fibrillation) is unknown. Recent studies suggest a possible benefit with low-dose rivaroxaban on top of low-dose aspirin in patients with vascular disease and high ischemic risk. More studies are required to confirm the role of other anticoagulants in patients with carotid artery disease [11]. Heart failure (HF) is a global public health problem affecting approximately 1-2% of adults in developed countries, mounting to over 10% in individuals aged >70 years old. Although there is little doubt that a prothrombotic state is present in HF, especially in HFrEF, the exact role of antithrombotic therapy is not fully elucidated. Antiplatelet agents should be used in case of concomitant vascular disease or presence of bioprosthetic valve, but they have shown no benefit in isolated HF, thus, they should be avoided in such patients. NOACs, have shown a favorable safety and efficacy profile in HF patients with AF. Vitamin K antagonists should be reserved for patients with severely impaired kidney function and in patients already in VKAs. As for HF patients in sinus rhythm, anticoagulation with VKAs does not improve outcomes. More suitable candidates for anticoagulation therapy might be HF patients with intracardiac thrombus. Identification of HF patients at higher risk for thromboembolism, perhaps with the assistance of a variation of already known or new scores could also contribute to better design of future trials assessing the role of antithrombotic therapy in HF in order to reduce the morbidity and mortality burden that accompanies this disease [12]. There are no guidelines regarding the use of prophylactic anticoagulation in cardiomyopathies although they are associated with many complications such as arrhythmias and thromboembolism. Patients at high risk for thromboembolic events should be considered for antithrombotic therapy. However, there are no data for antithrombotic therapy in patients without predisposing factors. Randomized controlled trials will hopefully lead to a comprehensive understanding of the underlying mechanisms and the natural course of thrombogenesis in cardiomyopathies and help resolve the question of antithrombotic therapy in uncomplicated clinical conditions associated with cardiomyopathies [13]. Siasos et al. reviewed antithrombotic treatment in diabetes mellitus (DM). Proper antithrombotic strategies to reduce cardiovascular disease (CVD) risk in DM is required. It should be taken into consideration that DM is a prothrombotic state with various changes in platelet reactivity and antiplatelet treatment failure has been described. Interestingly, in patients with DM resistance to both aspirin and clopidogrel can observe and combination therapies may be used to overcome resistance and reduce morbidity and mortality attributed to CVD [15]. One more interesting topic is antithrombotic therapy after percutaneous intervention for inter-atrial shunts closure. During these procedures, the delicate balance between thrombotic risk, device sealing process and bleeding risk is crucial. Appropriate anticoagulation/ antiplatelet therapy after device placement remains controversial. Prospective and adequately powered, randomized trials are needed in order to determine the most appropriate antithrombotic therapy for the prevention of device thrombosis and/or recurrent cerebrovascular events [14]. Last but not least, Toutouzas et al. review the literature on the underlying pathogenetic mechanisms contributing in periprocedural TAVI thrombotic complications and the efficacy of current antithrombotic strategies as evaluated in randomized trial. They underline that there is a lack of evidence-based data regarding the optimal antithrombotic regimen in TAVI, so current guidelines and antithrombotic strategies are mainly based on small studies and expert-consensus. The need for further randomized controlled trials investigating the appropriate combination and the duration of antithrombotic treatment after TAVI is undeniable [16].

Molecular Mechanisms and Therapeutic Targets of Inflammatory-Related Disease

sun exposure and, to a lesser degree, obtained from foods. Although it has traditionally been linked to calcium homeostasis, bone health and prevention of osteoporosis, recent evidence have found a pleiotropic effect of this compound [1]. Vitamin D receptors (VDR) and vitamin D metabolizing enzymes are common in the central nervous system and Vitamin D is considered a neurosteroid that modulates multiple brain functions. It is now well known that vitamin D plays a pivotal role in brain development (neuronal differentiation, maturation and growth), neurotransmission, neuroprotection and immunomodulation. Like other neurosteroids, vitamin D exerts both genomic and non-genomic actions, regulating thus short term effects (non genomic action) and long term effects (through a genomic action) [2]. Vitamin D has demonstrated to promote gamma-glutamyltranspeptidase gene expression, thereby stimulating the formation of glutathione (GSH), the most important antioxidant in brain, exerting thus a neuroprotective role. Indeed, treatments of primary cortical neuronal cultures with the active form of vitamin D(1,25(OH)2D3), against the induced oxidative stress, give better protection to neurons [3]. Moreover, the administration of vitamin D or its metabolites reduced neurological injury and/or neurotoxicity in a variety of animal systems, by activating the expression of VDR and downregulating NADPH oxidase, inhibiting the progression of apoptosis [2]. This monographic issue tries to cover the most recent literature evaluating the role of Vitamin D in several neurodegenerative diseases, focusing on the influence of vitamin D on neurodegeneration, and proposing a rationale for its physio-pathological actions. The deficiency in vitamin D seems to increase the risk for neurodegenerative pathologies, including Parkinson's disease. A neuroprotective role of Vitamin D has also been recently demonstrated in dopaminergic neurons of hemiparkinsonian rats against neuroinflammation and oxidative stress [4]. The issue contains recent advances relative to gender differences, considering that sex and gender in biomedical research are acknowledged as important determinants of the susceptibility to develop neurodegenerative diseases, such as Alzheimer’s Disease. It is now well known that Vitamin D deficiency is associated with impaired cognition [5]. Vitamin D regulates tyrosine and tryptophan hydroxylases, which are the rate-limiting enzymes responsible for catalyzing the conversion of tyrosine to dihydroxyphenylalanine (DOPA), precursor of the neurotransmitters such as dopamine, adrenaline, nor-adrenaline and serotonin. Therefore, Vitamin D plays a crucial role in neurotransmission and in synaptic plasticity by regulating these rate-limiting enzymes and its deficit may lead to an alteration of the cited neurotransmitters resulting in a variety of emotional and behavioral problems [5]. Interestingly, Vitamin D status exhibits a seasonal variation [6], which is similar to the seasonal variation of serotonin. It is well known that even mood disorders often show a seasonal presentation and the serotonin hypothesis for the pathophysiology of depression is one of the most accredited [7]. Moreover, VDR and the enzymes that control Vitamin D activation and degradation are expressed in several areas of the brain involved in sleep regulation. Therefore, Vitamin D seems to have a pivotal role in pathways of production of melatonin, hormone involved in the regulation of human circadian rhythms and sleep. Here, the work of dr. Romano et al., (Dept Endocrinology, Federico II University, Naples) focuses on the delicate interplay between vitamin D and sleep regulation, explaining the main regulatory mechanisms underlying it. Several sleep disorders, including Restless legs syndrome and Obstructive sleep apnea syndrome are taken into account and a complete review of the literature is presented. Besides, vitamin D, by interacting with aggregates of the extracellular matrix, perineuronal nets, seems to regulate brain plasticity, and cell differentiation, indeed the incidence of some neurodevelopmental disorders, including autism, increases hand in hand with vitamin D deficiency [8]. Here the work by Siracusano et al., (Department of Child Neuropsychiatry, Tor Vergata University, Rome) focuses on the latest hypothesis on autism and vitamin D, with special attention to the contributing role of prenatal and early post natal vitamin D deficiency in autism ethiopathogenesis, at both genetic and environmental level, and the potential effect of vitamin D supplementation in autistic children. Interestingly, another primary role of Vitamin D is taking part in the immune responses of the organisms by modulating the innate immunity and autoimmunity. Indeed, Vitamin D deficiency appears to affect the mechanism of immune cells, though the impact of reduced cytokine response in vitamin malnutrition is not clear. Vitamin D is involved in many medical conditions, such as infections and inflammation, and mediates innate immunity. Deficiency of vitamin D increases the risk of infectious and inflammatory diseases [9]. Moreover, low levels of vitamin D have been associated with several autoimmune diseases, such as autoimmune thyroiditis, psoriasis, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease, etc. [9]. Vitamin D analog 1, 25-dihydroxyvitamin D(3) exerts a biologic role acting as antiinflammatory agent, reducing cytokine production by T cells, and stimulating immunoglobulin production by B cells. It has been shown that Vitamin D(3) acts on dendritic cells in a manner similar to corticosteroids. Furthermore, combined dexametasone and D(3) analog treatment of dendritic cells results in significant additive inhibition of pro-inflammatory cytokines, T-cell stimulation, chemokines, chemokine receptors, and NF-kappa B components . Therefore, Vitamin D is considered an immunomodulatory and immunosuppressive agent. On the other hand, it is well known that the immune system can influence the brain and behavior. In the context of inflammation, proinflammatory cytokines can access the central nervous system and interact with a cytokine network in the brain to influence neurotransmitter metabolism, neuroendocrine function, synaptic plasticity, and neurocircuits that regulate mood, motor activity, motivation, anxiety and alarm. The consequences of these effects of the immune system on the brain may include depression, anxiety, fatigue, psychomotor slowing, anorexia, cognitive dysfunction and sleep impairment; all these symptoms overlap with those which characterize neuropsychiatric disorders, especially depression [10]. Thus, hypovitaminosis D may play a key role in the pathophysiology of psychiatric diseases where inflammatory pathways are altered. A potential link between inflammation and mood disorders was first described in the past century by Wagner-Juaregg, and a strong correlation among these has been recently reviewed by various authors [11]. A very recent study carried out on treatment-resistant depression (TRD) demonstrates a unique pattern of increased inflammatory mediators and chemokines in these patients reinforcing the immune hypothesis of TRD [12]. Moreover, Magnetic Resonance Spectroscopy findings in bipolar depression indicate that inflammatory cytokines may contribute to glutamate alterations in patients with mood disorders and increased inflammation [13]. There is evidence that low vitamin D status may be associated with mood disorders, including major depressive disorder, seasonal affective disorder and premenstrual syndrome. Several observational studies found a strong positive link between vitamin D status and depression status or subclinical depressive symptoms. Recent studies on depressed patients showing a deficiency of Vitamin D demonstrated that the association of a vitamin D supplement and an antidepressant had a favorable effect on the severity of depression [14, 15]. Therefore, in this issue we remark the role of vitamin D in Treatment Resistant Depression, reviewing the latest literature and focusing on the potential pharmacological effect of vitamin D supplementation. In conclusion, we suggest that Vitamin D supplementation in patients with mood disorders and reported vitamin D baseline deficiency might be useful for improving symptoms, especially in those patients where the inflammatory component is evident and plays an important role in sustaining the mood alteration. Analogously to mood disorders, it is conceivable that a Vitamin D deficiency may play a key role in the pathophysiology of Obsessive- Compulsive Disorder, by determining a reduction in the brain formation of GSH, by increasing the vulnerability for an autoimmune diathesis and through alteration of dopamine and serotonin levels. Indeed, it is well known the role of the oxidative stress and excitotoxicity caused by glutamate abnormalities in the pathophysiology of OCD. Besides, an autoimmune diathesis has been evidenced in a subgroup of OCD patients [16]. Interestingly, the studies carried out on OCD patients associated with Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcical (PANDAS) infection, concluded with the hypothesis of an association between vitamin D and OC symptoms associated with streptococcal infection, suggesting an etiological role of vitamin D-related immune processes. Overall, it might be possible that low vitamin D levels represent an underlying biological vulnerability for immune-related neuropsychiatric symptoms such as those present in PANDAS and in a subgroup of adult OCD. This is in line with the hypothesis of heterogeneous nature of OCD neurobiology and therefore vitamin D deficiency may help to identify different subtypes of the pathology [16]. Neuroinflammation may also disrupt the development of mesolimbic dopaminergic systems that are critical for optimal functioning of social reward processing systems. This neuroinflammation-induced disturbance of mesolimbic dopaminergic functioning has been substantiated using maternal immune activation rodent models whose offspring show aberrant dopaminergic corticostriatal function, as well as behavioral characteristics of autism model systems. Preclinical findings are in turn supported by clinical evidence of increased mesolimbic neuroinflammatory responses in individuals with autism [17]. On the other hand, emerging evidence suggests that maternal or developmental vitamin D deficiency is a risk factor for Autism Spectrum Disorders. The placenta is considered a significant source of vitamin D and locally produced vitamin D is an essential regulator of immune function during pregnancy. The placenta has as well the role of mediator of the maternal immune response in respect to the foetus. It has been shown that developing vitamin D-deficient male foetus may be particularly vulnerable to maternal viral exposures and this increases incidence of developmental conditions such as autism [18]. Gestational vitamin D deficiency was associated with autism-related traits in a large population-based sample. Here, a complete review of the literature entitled “Maternal Vitamin D and its role in determining fetal origins of mental health” has been carried out from the group of Dr. Lisi et al., (Dept of Systems Medicine, Tor Vergata University, Rome). In particular, the hypothesis on Vitamin D deficiency and maternal stress during pregnancy, including perinatal depression, that may both contribute to alter the efficacy of the immune system and modulate its activity is well illustrated. From all the above studies, the potential benefit of Vitamin D supplementation for brain health and mental well-being is becoming increasingly evident. In conclusion, in this monographic issue, the role of the steroid hormone Vitamin D in different neuropsychiatric populations is described, referring to the major studies carried out in the last decade. Moreover, the opportunity to routinely monitor the hormonal status of vitamin D on plasma levels and supplementing this nutraceutical to pharmacological treatment is remarked, focusing on its potential benefits reported. Finally, the neurocircuitry alterations and the neuroimmune abnormalities found in the neurodegenerative and psychiatric diseases targeted by the Vitamin D treatment are well illustrated. Therefore, the use of complementary therapies, such as vitamin D, may constitute a challenge for designing more specific therapeutic approaches to treat neuropsychiatric pathologies. Indeed, the lack of undesirable side effects of Vitamin D represents an optimal profile especially considering the frequent need of a polytherapy, or the need to treat special populations such as elders or patients with internist comorbidities. Vitamin D dietary supplements may provide an efficacious and accessible treatment strategy for these pathologies. Both the guest editors and all the authors hope that the thematic issue will help the readers know the recent advances in this field. Moreover, the critical visions from the contributors in this special issue would motivate other scientists to think about alternate but effective treatments for neuropsychiatric disorders in the next future.

There is a steady increase in the incidence of obesity in developed countries, attributable, among other reasons to the consumption of fast and processed food. This shift in the eating habits of the population makes it very necessary to study how nutritional and metabolic factors influence cognition, mental health and substance use [1]. Nutritional status is an important factor in the development of addiction, and research has highlighted behavioral and biological similarities between fast food intake and addiction [2]. For instance, the brain’s reward circuit, constituted by the mesocorticolimbic dopaminergic pathway, regulates motivation to seek or consume rewarding stimuli such as drugs of abuse or palatable foods [3]. The aim of this special issue was to compile a number of works that have explored the relations among diet, nutritional status, cognitive consequences and vulnerability to drugs of abuse in both animals and humans, an area of research of great interest that does not cease to grow. Therefore, we herein present a series of reviews by experts on this subject focusing on the most important aspects known to date, with the hope of encouraging researchers to continue exploring the complex relationship between nutrition and drugs of abuse. This special issue will explore different aspects related to nutritional habits, such as homeostatic adaptations, vulnerability to drug addiction, and binge eating disorders and their similarities with substance abuse and cognitive consequences. In addition, we present an optimist approach to treating mental health and alcohol disorders through nutrition and microbiota. Nutrition has a great impact on metabolism and homeostasis, and directly increases vulnerability to reward, something observed after exposure to highly palatable food, but also, somewhat surprisingly, after food restriction. Homeostasis and metabolism directly affect motivation for reward, including that provided by food and drugs [9]. When homeostatic control is modified the aforementioned motivational processes undergo a series of changes. Three of the reviews in this issue explain in detail how both animal models and human studies have shown that nutritional factors, such as high-fat diets [10], omega-3 deficiencies [11] and hedonic eating, [4] ultimately affect vulnerability to drugs such as alcohol and cocaine. Another review focuses on how humans use and abuse nicotine with the purpose of controlling body weight and food intake [5]. Numerous studies indicate similarities and differences between eating disorders and binge drinking, both of which induce changes in the brain reward circuit. We provide an exhaustive comparison of binge eating and binge drinking [12] and take a close look at how binge eating modifies the brain mechanisms and structures implicated in the reward system, producing a homeostatic dysfunction and, as a consequence, increasing sensitivity to drugs and food [6]. Nutritional factors have a considerable impact on the hippocampus and cognition. For example, circadian rhythms and the hippocampus are severely affected after exposure to highly palatable food [13]. This dysregulation of circadian rhythms directly affects cognitive processes such as memory and learning. An important role of the hippocampus is the regulation of contextual stimuli as an inhibitory mechanism that regulates food and drug satiety. It would seem that both drugs and palatable food inflict damage on this mechanism, leading to a vicious cycle of impairment in the behavioral inhibition of these processes [7]. Finally, we explore the role of nutrition and intestinal microbiota in alcohol [14] and mood disorders, such as bipolar disorder and depression [8], which points to an infinite number of new lines of promising research. Today, there is an imperative need for more research in this field, and we hope that this special issue will serve to increase knowledge and awareness about the relevance of nutritional habits in cognitive function and their role in the multifactorial disorder of drug addiction. We trust that the various contributions will facilitate a comprehensive understanding of the impact of food on cognitive processes, mental health and drug addiction. To conclude, we would like to encourage a moment of reflection by posing the question “are we taking our diet seriously?”

In today’s world there is a tremendous rise in various neurological disorders due to stress, anxiety, prolonged ageing, oxidative stress, etc. The various diseases that come under the umbrella of neurological disorders including depression, stroke, schizophrenia, brain tumours, and neurodegenerative diseases like Alzheimer’s, Parkinson’s, Huntington, amyotrophic lateral sclerosis to name a few. To tackle these disorders, there has been a rapid spurt in the demand for drugs for treating and managing them. Efficacy obtained by the use of conventional dosage forms of these neurological drugs is limited due to their inability to reach the site of therapeutic action i.e. the brain. Blood Brain Barrier (BBB) is the major hurdle and it restricts the access of drugs to the brain on oral as well as intravenous administration. Thus brain targeting can increase the concentration of the drug with better therapeutic action and concomitant reduction in dose and peripheral side effects. Nanotechnology has been proposed to play a promising role in reversing the progression of various neurological disorders by overcoming the above major challenges, by crossing or bypassing the BBB. Nanotechnology also provides added advantages of targeted and sustained release along with improvement in bioavailability with a subsequent decrease in the dose and dose-related side effects. Various nanocarriers like metallic, inorganic, polymeric nanoparticles, lipid nanocarriers like solid lipid nanoparticles, nanostructured lipid carriers, liposomes, nanoemulsions, self-nanoemulsifying drug delivery system, nanomicelles, dendrimers, nanoconjugates, etc. have been studied to modulate the fate of drugs inside human body in maintaining therapeutically effective concentration at the targeted site i.e. CNS. The collaboration of nanotechnology with oral and intranasal route of administration can result in a more acceptable method for the delivery of CNS drugs thereby improving the state of disease progression. In case of Alzheimer’s disease (AD), a disease characterized by impairment of learning and memory, researchers worldwide are formulating nanoformulations for the successful and effective delivery of drugs for its treatment. Besides the therapeutic application of these nanoformulations, they have also been used as diagnostic tools for easy and early detection like superparamagnetic iron oxide nanoparticles, nanoscale optical based localized surface plasmon resonance, Gold (Au) nanoparticles, etc. Their toxicity issues need to be addressed in order to have commercial formulations for treatment and diagnosis [6]. Another major issue being focussed widely by researchers is the treatment of dementia associated with AD which is on the rise due to an increase in the life span both in the developed as well as the developing nations. There is a growing interest of the researchers and the pharmaceutical industry to combat this disorder using nanotechnology-based formulations via intranasal route but the clinical application of these nanocarrier-based deliveries to the brain is yet to be established to bring a new era in the treatment of demented patients [4]. Recent advancements in the intranasal administration of nanocarriers have further strengthened the prospect of nano-deliveries in the treatment of dementia. Several nanocarrier mediated preclinical approaches via nose-to-brain have depicted enhanced targeting potential of therapeutics to the brain [5]. The advent of nanotechnology has offered plenty of opportunities in exploring the oral route of administration for efficient drug delivery for the treatment of Parkinson’s disease (PD) which is considered to be a common neurodegenerative disorder. Recent advancements in nanobased therapeutics have received considerable popularity owing to targeting the specific site (brain) by circumventing constraints associated with oral drug delivery. To decelerate the progression of PD and to provide symptomatic relief, various nanosystems loaded with antiparkinson agents have been investigated. Owing to the capability of reverting the signs and symptoms of the disease, the oral route has been exploited for its role in enhancing cell targeting and selectivity, bioavailability and in developing a patient compliant therapy. Although, more clinical trials need to be directed for nanoformulations that can make the reality to be available in clinical usage [7]. Rotigotine, a drug indicated as the first line therapy for Parkinson’s disease (PD) and Restless Leg Syndrome (RLS) is available as a transdermal formulation to provide 24-hour continuous dopaminergic stimulation and research is in progress to develop a nanotechnology-based product of it [3]. The use of cold atmospheric plasma (CAP) has been reported for enhancing neural cell differentiation into neurons both in vitro and in vivo, which is of great interest for medical treatment of neurodegenerative diseases like Alzheimer's disease and traumatic injuries of the central nervous system. CAP and its derivatives (Plasma activated water/media) also may have a promising potential for future treatment of brain cancers or neurological diseases when used alone or along with a combination of different nanoparticles i.e., iron, gold, copper, etc. Therefore, CAP represents a favourable method for future neurological disease therapy [1]. Carbon dots are showing promise as vehicle transporters for neurotherapeutics across the BBB and proof of concept results by researchers are reported for them as a novel diagnostic tool for the early detection of neurodegenerative diseases [2]. Another approach which is being widely researched is the use of ligands, for site specific delivery of drug across the brain. Conjugation of ligand, to the drug or excipient moiety in the formulation, is important to exploit the targeted action provided by ligands. Ligands such as transferrin, lactoferrin, apolipoprotein, glutathione, etc. can bind to specific receptors present on the surface of endothelial cells and provide a site-specific targeted action, which can be exploited to reduce the dose of the drug also and improving the efficacy of drugs [8]. In this issue, the focus has been to highlight various advancements which have been made in the past few years to improve the efficacy of these neurological drugs using nanoparticulate drug delivery systems in the respective neurological disease manifestation. I hope the readers will find it useful.

Pharmacological Scenarios in Translational Research: A Current Multidisciplinary Overview and Possible Developments

Cancer stem cells (CSCs), also known as tumor-initiating cells, are a subpopulation of tumor cells found in many human cancers, which are endowed with self-renewal and pluripotency. Cancer stem cells may be more resistant and less accessible to conventional anticancer therapies than the average cancer cell. They can easily escape the cytotoxic effects of standard chemotherapy, thereby resulting in tumor relapse. Despite significant progress in related research, effective elimination of cancer stem cells remains an unmet clinical need. This thematic issue presents recent advances in the field of cancer stem cells, including the various phenotypes of CSCs, plasticity of CSCs, the relationship between CSCs and therapeutic resistance, CSCs and tumor microenviroment, immunological properties of CSCs and immunotherapy, and therapeutic strategies targeting CSCs, etc. These topics not only provide a new theoretical basis for in-depth discussion of tumor occurrence, development, and prognosis evaluation but also bring new ideas for the targeted treatment of cancer. Now, the focus of CSC research has shifted from traditional signal pathways to novel ones. G protein-coupled receptors (GPCRs) are highly expressed on a variety of tumor tissues while several GPCR exogenous ligands become marketed pharmaceuticals since they can target GPCRs to modulate plenty of cancer cell functions. Cancer stem cells (CSCs) become widely investigated drug targets for cancer therapy but its underlying mechanism is still not fully elucidated. Dr. Jiang summarizes and provides sufficient evidence on the regulation of GPCR signalling in the maintenance, differentiation and pluripotency of CSCs, linking GPCRs with CSCs, and suggesting targeting GPCRs on the surface of CSCs as potential therapeutic strategies for cancer therapy [1]. Also, CSCs can be used as a therapeutic target to treat tumor relapse. In order to reduce such patient relapse, therefore, a series of CSCs derived from many tumors were targeted by liposomes, nanoparticles, carbon nanotubes, exosomes and viral formulations [6, 8]. Lin et al. outlined the targeting strategies and challenges in CSC-based treatment of renal cell carcinoma (RCC) patients [2]. Zhang et al. describe another advanced therapeutic approach targeting breast cancer stem cells to eradicate the roots [5]. CSCs are also a very common target in urological cancers, including prostate, bladder and renal [7]. These CSCs may cause multi-drug resistance, drug efflux, quiescence and ionizing radiation tolerance, protect them from most traditional chemotherapeutics. As a result, this small subpopulation of persistent cells leads to more aggressive and chemoresistant cancers, causing failure in target to tumors [8]. Thus, the new target strategies to their niche were developed gradually. CSCs reside in a “CSC niche” which maintains them in a stem-like state, controls their self-renewal and differentiation [3]. This makes the CSC niche a potential target for novel therapies. On the other hand, to further eradicate CSCs, combination therapies including photothermal therapy, gene therapy and chemotherapy are of great help to eliminate tumors [4]. Taken together, an increasing number of investigators have recognized that target strategy is the key to inhibit the existence of CSC, which have been introduced as a novel concept and hold tremendous potential for the treatment of malignant diseases due to the ability to eliminate tumor-initiating cells towards complete eradication of minimal residual disease in patients. It is becoming an emerging area in cancer targeted drug design.

The worldwide people's lifestyle is unbalanced, being itself an important triggering factor for health disorders [1]. The use and consumption of medicinal plants is a worldwide practice, being even so old as the human history, and several botanical preparations have demonstrated a high potential in the control of several diseases. Most of the medicinal research aims to evaluate the therapeutic value of plants and identify the related active ingredients [2, 3]. During the past years, reactive oxygen species (ROS), reactive nitrogen species (RNS) and reactive sulfur species (RSS) have been implicated in the oxidative deterioration of food products, as well as in the pathogenesis of several human diseases such as atherosclerosis, diabetes mellitus, chronic inflammation, neurodegenerative disorders and certain types of cancer. Interest has increased considerably in finding naturally occurring antioxidants to be used in foods or pharmaceutical applications, which can protect the human body from free radicals and retard the progress of many chronic diseases as well as retard lipid oxidative rancidity in foods [1, 3]. In fact, many natural products from plants, algae and mushrooms are between the most important targets to search for natural antioxidants, which might serve as leads in the development of novel drugs and food ingredients [2, 3]. Nevertheless, more information regarding their mechanisms of action involved in each antioxidant process is scarce and should be further described. This special issue “Natural antioxidants and human health effects” includes eleven review articles, revising all the mentioned aspects presented above. The review article presented by Vieira et al. deals with an interesting theme about the antioxidant activity of oligosaccharides, considering in vivo and in vitro assays. The authors also described the influence of phytochemical characteristics of these compounds on their bioactivity [4]. The review carried out by Seoane et al. summarizes the use of lactose in food and pharmaceutical products and its effects on health, considering four different categories of intolerance to lactose in human metabolism [5]. Cásedas et al. reviewed the anthocyanin effects on central nervous system achieved using clinical trials and preclinical experiments [6]. Furthermore, Mirkov et al. reviewed recent data on the effect of treatment with different plant extracts and their isolated compounds on heavy metal induced oxidative stress in animal models [7]. The review performed by Petropoulos et al. presents the chemical composition of the main plants of wild Allium genus, focusing on main compounds. The authors also reported the health benefits of these species [8]. While, Graça et al. carried out a systematic research considering current data on the biological activities of the Geranium genus of interest for therapeutic application for several ailments [9]. Dridi and Bordenave described the typical polyphenolics found in a pine bark phenolic extract. These authors also discussed current medical uses, extraction methods and explored the food applications of this extract [10]. Ciudad-Murelo et al. reviewed the phytochemical characteristics of some pulses (beans, fava beans, lentils, chickpeas, peas and lupins) in terms of their hydro- and liposoluble antioxidant compounds. They also reviewed the effects of processing on these compounds [11]. Amarowicz and Pegg revised the antioxidant potential of tree nuts and peanuts. The authors reported the polyphenolic composition of different species of these fruits, the effects of thermal processing on the stability of antioxidant compounds found in them, and the impact of their consumption on biomarkers of human health arising from randomized clinical trials [12]. The chemical composition, bioactive proprieties, health effects and industrial applications of Vaccinium myrtillus L. fruit and its by-products were reviewed by Ferreira et al. [13]. Finally, the nutritional and phytochemical compositions of microalgae were reviewed by Pereira et al. They also researched and discussed different extraction techniques to obtain their bioactive compounds [14]. Overall, this special issue includes research regarding natural sources of bioactive compounds, such as antioxidants. It is known that dietary antioxidants are thought to have a great biological capacity to avert oxidative stress that induces diseases. Therefore, the reviews included in this special issue contribute as high scientific content in the possible development of products, such as functional, nutraceutical and therapeutic foods that can promote human health.

The computational tools in drug discovery are based on an examination of the chemical structure of compounds, identifying features responsible for specific biological activity, thus enabling the estimation of theoretical data and the validation of any statistical model of a large set of compounds before they are synthesized, contributing significantly to accelerating the design/discovery process and reducing the need for expensive lab work and clinical trials. Technological advances in the areas of structural characterization, computational science, and molecular biology have contributed to faster planning of new feasible molecules; showing that a large fraction of compounds are “drug-like” or at least, “lead-like” having structural and physicochemical properties that render them as potential drugs or leads.

Bioinformatics and cheminformatics can rapidly propose new molecular structures as potential bioactive compounds to support the treatment. Drug repurposing or drug repositioning is an interesting approach that shows advantages over developing an entirely new potential drug. Among them, the compounds are safer in preclinical models and humans having lower probability to fail in efficacy trials, time for drug development because several steps as preclinical testing, safety assessment and, in some cases, formulation development will already have been completed and, less investment is needed. Another interesting approach is the use of natural products that have molecular structures rich in pharmacophore groups, with a high degree of stereochemistry, and the property of “metabolite-likeness”.

In this thematic issue we reported recent studies in computational research of different methodologies, such as QSAR, docking, chemometric tools, artificial intelligence and others focused on drug development for the cure and treatment of several diseases.

Among various areas nano-technology has contributed a lot in the field of medical science. The smart drug delivery vectors along with stimuli-based characteristics are gaining importance. The external and internal stimulating factors have enormous benefits and act as well defined nano-platforms for increasing target efficiency. pH of tumor vascular tissues is acidic, leading to better payload, specific targeting of anticancer drug from drug delivery vector. Nanopolymers are smart drug delivery vectors; recently recommended by scientists. The potential targeting, non-toxicity, biocompatibility, and their use in personalized drugs make them perfect nano-carriers. Our review [1] deals with the state-of-the-art of the advances in nano-particles as anticancer drug delivery vectors. It was written comprising molecular basis for personalized medicine, personalized therapy, emerging vista in anticancer therapy, target of nano-polymers, passive and active targeting transports, pH responsive drug carriers, biobarriers, computer aided drugs design, future challenges and perspectives, biodegradable and safety.

The synthetic heterocyclic compounds have their importance due to their wide applications in various fields of science. The heterocyclic compounds have been reported for their anticancer, antitubercular, insecticides, analeptics, analgesic, anti-bacterial, anti-viral, anti-fungal, and weedicidal activity. Researchers have tried various newer targets for search of better antimicrobials acting via novel mechanisms. Glucosamine- 6-Phosphate synthase is an enzyme present in microbial cells. The inactivation of G-6-P synthase may serve as a novel approach to find better antimicrobial. The increasing demands development of newer and effective antimicrobial drugs has reported for the search of newer techniques for the generation of new drugs. Hence, the molecular docking technique shall be explored to find or investigate the newer target to find the novel compounds which can be an active antimicrobial compound. The review of Lather et al. [2] focused on the reported heterocyclic compounds which have been evaluated for their antimicrobial potential using G-6-P synthase as target. The results of in silico methods and in vitro methods have been compared and critically discussed.

Recently, in the medical and pharmaceutical fields, biopolymers are extensively used for chemical and mechanical modifications of Pharmaceutical dosage forms, which add novel properties, functions, and applications. Structural modification of dosage by polymers along with redesigning in pharmaceutical and tissue engineering fields, presently being the center of analysis for the modern research world, utilizes the subtle instruments, precise research strategies and most significantly the excipients. The polymer, chitosan, which is a natural linear polysaccharide composed of randomly distributed β-(1-4)-linked D-Glucosamine and N-acetyl-D-Glucosamine units. It is already proved that the chitosan-drug conjugated nanoparticles CDNP facilitate the more drugs uptaking or cytotoxicity to cancerous cell. This overcomes the dosage form designing problems of complexity in the biological mechanism and cell specificity. A computer-aided pharmacokinetic study with model fitting can provide the possible finding related to target selectivity and interaction. Till today, insufficient research has been reported, such as PyRx with AutoDock, response surface methodology and molecular dynamic simulation for drug delivery by chitosan-drug conjugated nanoparticles. Therefore, cancer cell target-specific drug delivery using natural biopolymer conjugate with a computer-aided pharmacokinetic model will be the thirst area of future research. To get successful anticancer drug formulation, in-silico pharmacokinetic modeling would minimize time, labor and expenses, during and prior to the experiment that has been extensively discussed in the review of Roy et al. [3].

Tuberculosis (TB) ranks among the diseases with the highest morbidity rate with significantly high prevalence in developing countries. Globally, tuberculosis poses the most substantial burden of mortality. Further, partially treated tuberculosis patient is worse than an untreated; they may lead to stand out as a critical obstacle to global tuberculosis control. The emergence of multi-drug resistant (MDR) and extremely drug-resistant (XDR) strains, and co-infection of HIV further worsen the situation. The present review article discusses validated targets of the bacterial enzyme thymidine monophosphate kinase (TMPK). TMPKMTB enzyme belongs to the nucleoside monophosphate kinases (NMPKs) family. It is involved in phosphorylation of TMP to TDP, and TDP is phosphorylated to TTP. The review of Gul et al. [4] highlights structure elucidation of TMP enzymes and their inhibitors study on TMP scaffold, and it also discusses different techniques, including molecular docking, virtual screening, 3D-Pharmacophore, QSAR for finding anti-tubercular agents.

Much research in Alzheimer’s disease (AD) related to disease-modifying agents is concentrated on pharmacological approaches related to diagnostic markers, neurofibrillary tangles and amyloid plaques. Although most studies focus on anti-amyloid strategies, investigations of tau protein have produced significant advances in the modulation of the pathophysiology of several neurodegenerative diseases. Since the discovery of phenothiazines as tau protein aggregation inhibitors (TAGIs) many additional small molecule inhibitors have been discovered and characterized in biological model systems, with exerting their interaction effects for covalent and non-covalent means. The paper of Monteiro et al. [5] summarizes the latest advances in the discovery and development of tau aggregation inhibitors using a specialized approach in their chemical classes. The design of new TAGIs and their encouraging use in in vivo and clinical trials support their potential therapeutic use in AD.

Epilepsy is a chronic neurological disorder characterized by irregular, excessive neuronal excitability, and recurrent seizures that affect millions of patients worldwide. Currently accessible antiepileptic drugs (AEDs) do not adequately support all epilepsy patients, with around 30% patients of them not responding to existing therapies. Numerous medicinal compounds with concurrent anticonvulsant, procognitive, antioxidant effects, modulating effects on several brain neurotransmitters in rodents, and various several newly developed classes of compounds applying computer-aided drug design (CADD) have been under development as potential AEDs. The article of Alachkar et al. [6] elaborates details on the in-silico approach following CADD, which can be utilized in for generating libraries of novel compounds and novel mode of action of AEDs for further clinical development.

We, the Guest-Editors, would like to express our gratitude to the many authors who contributed to this special issue, reporting investigations in various aspects of Recent Advancement in Computer-Aided Drug Design.

The therapeutic arsenal of approved antifungal drugs is restricted to a few drugs, and most of them have limitations such as low effectiveness and high toxicity. These limitations are more serious by the fact that some species of fungi are resistant to the available medicines.

This special issue selected seven manuscripts containing reviews and original articles on the following topics as drug resistance; therapeutical activity: new targets and pharmaceutical innovations; strategies of medical treatments: natural, conventional and advanced pharmacology; natural products: biological activity and pharmacological studies.

Silva et al. [1] discussed the recent advances on the area of new antifungal development from the discovery of promising natural products that have shown to be effective as antifungal, such as peptides, lectins and secondary metabolites from plants and their additive effects when tested with well-known and well-established antifungal drugs and beyond that, some proteins, enzymes and metabolic pathways that could be targets for the discovery of efficient inhibitor compounds. Finally, the advances of high-throughput techniques, such as transcriptomics and proteomics, regarding some pathogenic fungi species are highlighted and finally we discuss how computational biology has helped in the search of more effective approaches and early antifungal drug discovery.

The mini-review presented by Wasan et al. [2] showed how they were able to develop a novel oral amphotericin B formulation that was indeed effective in treating systemic fungal infections without the side effects associated with the drug in a variety of fungal animal models.

Pereira et al. [3] demonstrated that metal-azole complexes containing Au(I) and Zn(II) are effective against mature biofilms of Candida albicans and Candida glabrata formed in human nail fragments in vitro, with increased efficacy than their respective standard antifungal alone.

Maximino et al. [4] demonstrated the synthesis of eugenol derivatives conjugated to 1,2,3-triazoles where one of them was more active against F. solani f. sp. piperis with acceptable cytotoxicity being more effective than tebuconazole in an antifungal assay and presented similar cytotoxicity in macrophages. The results suggest that 2-(4-allyl-2-methoxyphenoxy)-3-chloronaphthalene-1,4-dione is a potential candidate for use in the design of new and effective compounds that could control this pathogen.

Kılıç et al. [5] reported the optimization of Posaconazole loaded micellar formulations in the treatment of ocular fungal infections. The results revealed that the optimized micellar formulation of posaconazole offers a potential approach for topical ocular administration.

Lima et al. [6] evaluated the antifungal activity of Syngonanthus nitens Bong. (Ruhland) derivatives and employed a lipid nanoemulsion as a delivery system. The authors concluded that S. nitens derivatives were important sources of active molecules against C. parapsilosis. In addition, the use of a lipid nanoemulsion was shown to be an important tool to promote more effective F2 release and to improve the antifungal activity of these compounds and make them suitable for use in studies aimed at the control of C. parapsilosis infections.

Noronha et al. [7] reported the development of an emulgel containing itraconazole and clotrimazole to ensure therapeutic effectiveness against Sporothrix brasiliensis. The topical use of a formulation that combines both drugs represents an interesting option for the complementary treatment of sporotrichosis. The results showed that the newly developed emulgel displayed promising physicochemical characteristics, as well as a good in vitro inhibitory activity against S. brasiliensis yeasts. These results also suggested that the emulgel containing itraconazole and clotrimazole might be highly efficient and a complementary therapy to oral administration in the treatment of sporotrichosis.

We hope that the selected articles for this special issue will motivate, inspire and promote the research for the development of new prototypes of drugs for antifungal therapy.

At the end of the 19th-century the famous German physician and “microbe hunter” Paul Ehrlich observed that water-soluble dyes injected into the circulation do not stain the brain and spinal cord. Based on Ehrlich's work a few years later, Lewandowsky concluded that the brain capillaries stopped specific molecules from entering the brain and Stern and Gautier introduced the term “barrière hémato-encéphalique”, Blood-Brain Barrier (BBB). The first detailed anatomical characterization of the BBB at the ultrastructural level was published more than half a century later in 1967 when Reese and Karnowski showed that brain endothelial cells connected with tight junctions are different than endothelium in the periphery. Over the years, researchers discovered that BBB is a unique and specialized interface between the brain and periphery that is necessary for the proper function of the central nervous system. Nowadays, it is becoming clear that the endothelial cells are only part of this highly dynamic system called the neurovascular unit, consisting of vascular cells including brain pericytes, glial cells, and neurons. Despite an intensive research in the field of drug delivery to the brain, the present knowledge is still limited on the intracellular transport mechnisms at the level of brain endothelial cells. Most of the current understanding about the vesicular transport machinery and the endolysosomal system is based on epithelial cells, although recent observations indicate that the endothelial trafficking system differs from the epithelial ones. In their very timely review, Tóth AE et al. [1] summarize recent findings on the trafficking machinery in brain endothelial cells and highlight opportunities for further studies. Many different pathologies involve BBB dysfunction. These include tumors, diabetes mellitus, hyperlipidemia causing damage in the cardio- and the cerebrovascular systems, and neurodegenerative diseases, such as tauopathies. Understanding BBB changes in diseases is a key step in the development of any brain therapeutics. Breast cancer is among those types of malignancies which give brain metastases. The role of extracellular vesicles and the microRNA they contain emerges as an important factor in the development of tumor growth and metastasis formation in both the periphery and the central nervous system. The paper of Curtaz et al. [2] focuses on how microRNA modifies breast cancer development and metastasis, as well as the function of the BBB. Efflux pumps, including P-glycoprotein, are present in tumors and also in biological barriers. P-glycoprotein at the BBB protects the brain from toxic chemical substances, however its expression by tumors prevents efficient therapy and contributes to the high mortality of brain malignancies. In their interesting work de Trizio et al. [3] describes the developmental expression of P-glycoprotein in different cells of the human fetal brain, especially in radial glial cells, and how these new data can help to better understand P-glycoprotein-mediated chemoresistance in glioblastoma, the most common primary brain tumor in adults. Vascular and especially BBB dysfunction are associated with the development of neurodegenerative diseases and dementia. The mini-review of Tóth EM et al. presents a transgenic mouse line overexpressing the human apolipoprotein B-100, a preclinical model of human atherosclerosis and cerebrovascular dysfunction [7]. In the last decade, this mouse model helped to reveal how hyperlipidemia is linked to BBB damage, neurodegeneration and memory impairment and can be a helpful tool to test neuroprotective agents. The BBB is disrupted in both types of diabetes. The brain regions with disruption, however vary between Type I and Type II, suggesting the involvement of different mechanisms and pathways. The paper of Banks [4] focuses on the role of BBB in diabetes mellitus. The BBB not only prevents harmful substances from entering the brain however, due to specific anatomical and functional features also represent a significant bottleneck in the delivery of therapeutics. In fact, more than 98% of small-molecule therapeutics and almost 100% biotherapeutics do not enter the brain effectively. The different strategies such as 1) physiological approaches, 2) pharmacological methods, or 3) invasive approaches, have demonstrated the potential to bypass the BBB. The review of Hanes et al. [5] summarized their limitations and benefits for the therapy of different neurological diseases such as tauopathies. The fully validated in-vitro BBB models based on primary cells are widely accepted as powerful tools in drug development. The review of Morofuji et al. [6] focuses on the recent progress of in-vitro BBB models and their use in alternative approaches such as drug repositioning projects. One of the most promising approaches for delivering drugs across the BBB is the use of short cell-penetrating peptides. In their work Cavaco et al. [8] showed that proteolysis stable DPepH3 peptide is effectively transported across the BBB. In this special issue on Brain Barriers as Targets in Pathologies and Therapy, the journal aims at providing information about the latest research in the field of BBB and the development of brain delivery systems. We believe that a better understanding of the role of the BBB in a course of different human diseases will greatly help to develop more efficient therapeutic approaches.

Currently, it is necessary to improve and develop therapeutic strategies for the treatment of neurological disorders. These include Alzheimer's disease, the most important worldwide neurodegenerative disorder. Likewise, the development of blood markers is very important for an early diagnosis of this disease. An interesting approach in the treatment of neurological diseases is the use of nanoparticles to increase the levels of drugs in the brain, favoring the passage through the blood-brain barrier. In this special issue the therapeutic potential of drug nanoparticles is evaluated by Sánchez-López and colleagues in models of neuronal affectation [1]. Specifically, is this paper is discussed the link to the delivery of solid lipid nanoparticles and second generation nanostructured lipid carriers for Alzheimer’s disease (AD) and glaucoma. These lipid nanoparticles shown high potential as strategies to induce neuroprotective effects being, in most cases, more effective than traditional drugs since they improve brain bioavailability and efficacy. Cano and colleagues also describe advances on anti-glioblastoma drug development associated to polymeric and lipid based nanocarriers [7]. In another interesting manuscript, Bahadur and colleagues reported how the use of nanotechnology-based intranasal drug delivery was effective for the treatment of AD [8]. Glutamate, the main excitatory amino acid in the brain, plays a key role in neurological disorders. There are two articles related to the role of the excitatory neurotransmitter glutamate and neurodegenerative processes. Binvignat and Olloquequi reported on therapeutic strategies and molecular mechanisms related to neuronal excitotoxic cell death [2]. In addition, research preclinical and clinical studies targeting glutamate pathways as treatment against neurological diseases are discussed. Related to ionotropic glutamate receptors, Montiel and colleagues investigated the neuroprotective effects of the D-isomer of β-hydroxybutyrate against N-methyl-D-aspartate administration in the rat brain [12]. The potential neuroprotective properties of natural compounds is evaluated by Vega-Garcia and colleagues, which reported the antiinflammatory and neuroprotective effects of a treatment with compounds derived of Magnolia officinalis, in post status epilepticus in rats [13]. They observed a neuronal preservation on the cornu ammonis 1 (CA1), CA3, dentate gyrus (DG) and hilus of the hippocampus, and lower expression of gliosis on CA3 and hippocampal DG after kainic acid administration. Likewise, Jara-Moreno and colleagues reported the neuroprotective effects of ethyl acetate and ethanolic extracts obtained from Ugni molinae leaves against neurotoxic actions of β-amyloid aggregates [11]. The therapeutic potential of L-carnitine (LCAR) and acetyl-L-carnitine (ALCAR) in neurological and neurodegenerative disorders are revised by Maldonado et al. [4]. These compounds shown a multiplicity of pharmacological effects as antioxidants, neuromodulators and neuroprotectors. Ettcheto et al. also reported on the effectiveness of a combinatory treatment with several drugs such as anti-inflammatory compounds, antidiabetic drugs, anti-Tau or antI- amyloid beta for the prevention of AD [5]. Additionally, Casadesus et al. discuss the role of amylin and its receptor’s signalling pathways in the neurodegenerative process in AD pathogenesis [9]. Ureña-Guerrero et al. discuss the neuroprotective effects of Epo and vascular endothelial growth factor (VEGF) in neurological disorders such as stroke, epilepsy and AD [3]. Both molecules exerts neuroprotective effects through the inhibition of neuroinflammation, excitotoxicity, oxidative stress and the prevention of neuronal apoptosis. The neuroprotective role of erythropoietin and its receptor activation is reviewed by Auzmendi and colleagues [10]. The neuroprotective role of the EPO/EPO-R system in both brain and heart under hypoxic conditions, such as epilepsy and sudden death constitutes a therapeutic research strategy for the epilepsy treatment and the prevention of sudden death. Apart from the pharmacological treatment of neurodegenerative disorders when they are already causing consequences, it is mandatory to find biomarkers for the diagnosis of these pathologies so that early preventive treatments can be carried out. As an example, Manzine and colleagues report on a blood-based AD tester [6]

Cancer is a leading cause of death worldwide. However, the efficacy of current treatment approaches for a variety of cancers is considered to be suboptimal. A majority of the drugs used for the treatment of cancers lack specificity for discrimination between the normal cells and the cancer cells [1, 2]. Besides, the biopharmaceutical challenges associated with the cytotoxic agents including poor aqueous solubility and poor permeability limit their therapeutic effectiveness in cancer treatment [3, 4]. As a result of these challenges, the application of nanotechnology- based carriers has provided enhanced benefits for improving the efficacy of anticancer agents. Nanomedicines primarily constituted of polymer and lipid-based composites nanoparticles have shown to be quite effective in exhibiting diverse biopharmaceutical advantages like the ability to improve the selectivity of cancer chemotherapeutic agents, lowering the cytotoxicity of anticancer drugs on normal tissues, and their toxic side-effects [5, 6]. In the last decade, several literature reports have been demonstrated the efficacy of lipidic and polymeric nanotherapeutics for cancer treatment. In this context, the thematic issue compiled has covered articles on current progress in the development of polymeric and lipidic nanoparticulate systems for tumor targeting applications and next generation challenges in evaluating clinical translation of such carriers for regulatory approval and benefits.

Some of the key areas the review has covered include application of nanoparticles in nose to brain delivery of anticancer drug. The high potential of lipidic and polymeric nanoparticles for crossing the blood-brain barrier through nasal route has been extensively explored otherwise. In case of solid tumors of brain and even in cerebral glioblastoma, the drug-loaded nanosystems have shown significant improvement in the therapeutic performance along with reduction in the tumor recurrence. Besides, the application of lipidic systems and polymer-lipid hybrid nanosystems has also been covered in the special issue for their role in drug delivery to solid tumors. Nevertheless, the use of nanoemulsion as versatile systems for delivering the anticancer agents has significant potential for improving biopharmaceutical attributes of the drugs. The idea of surface engineering of the aforesaid nanocarriers in reducing off-target side effects of the drugs is very valuable for the purpose.

Overall, the special issue shows that current innovation shifting more towards designing cancer vaccination strategies using the benefits of nanotherapeutic systems [7, 8]. A significant gap still exists in the domain of cancer treatment and reducing their challenges, thus require greater attention in improving therapeutic efficacy of the drugs against cancer modalities.

First named as nonalcoholic fatty liver disease (NAFLD) by Dr. Ludwig, from Mayo Clinic, USA in 1980 [1], and recently renamed as metabolic associated fatty liver disease (MAFLD) [2], NAFLD is an increasingly recognized public health problem and a leading cause of morbidity and mortality worldwide [3]. To date, owing to its epidemiological and clinical burden, which spans from hepatic to systemic manifestations, NAFLD is an intensively investigated pathologic condition. Aimed at envisaging the lines of research which may possibly be developed in the near future, the Current Pharmacological Design (CPD) journal has promoted a collection of invited review articles, the first section of which has now been published. We strongly believe that the topics addressed here are clinically relevant as much as they cover the most recent advances in epidemiology, genetics, pathophysiology, natural course and management of NAFLD in both adults and the motherand- child dyad. Epidemiology - The group led by Prof. Younossi, from Inova Health System and Medical Campus, Virginia, USA, has achieved impressive results in the epidemiology of NAFLD over the last 5-6 years. In this CPD issue, Dr. Golabi and colleagues specifically focus on the epidemiology of NAFLD in North America. The USA is a privileged observatory owing to a multi-ethnic population being exposed to an “obesogenic” milieu. It is, therefore, of interest that an ethnic gradient in the prevalence of NAFLD has been observed, with Hispanic Americans showing the highest prevalence and African Americans the lowest prevalence of NAFLD, thus suggesting an important [as yet incompletely defined] role of genetics [4]. Genetics - The groups belonging to the Medical School of Milan, Italy, have particular expertise in the role of genetics and epigenetics in NAFLD. In this single-topic CPD issue, Dr. Cespiati and colleagues suggest that genetics could be exploited to develop useful risk scores for identifying liver-related complications and predicting individual response to drug treatment for NAFLD [5]. Along the same line, Dr. Lombardi and colleagues provide us with an innovative paradigm of how genetic polymorphisms might be fruitfully used in clinical practice for diagnosing NAFLD and predicting its clinical outcomes, i.e. by combining some genetic polymorphisms with quantitative elastography methods [6]. These are two excellent examples of personalized care of NAFLD that are expected to receive scientific validation and increasing diffusion in hepatological clinical practice in the near future. Pathophysiology - The role of dysregulated iron homeostasis remains to date one of the most controversial areas in NAFLD research. On the one hand, there are robust pathophysiological grounds supporting the view that dysmetabolic iron overload, which is commonly associated with both NAFLD and the metabolic syndrome, has the potential to worsen the severity of NAFLD mostly by increasing oxidative stress. On the other hand, these notions have not been yet translated into principles of NAFLD management. Two eminent groups of investigators analyze the current literature on this intriguing topic in the present CPD issue: Prof. Athyros and colleagues from the Aristotle University of Thessaloniki, Greece; and Dr. Rametta and colleagues from the University of Milan, Italy [7,8]. Their contributions strongly support the need for further mechanistic studies in this intriguing NAFLD research area. Two review articles also bridge the gap between the pathophysiology and natural course of this burdensome liver disease. In the first article, Dr. Spinosa and Dr. Stine, from Pennsylvania State University, USA [9], address the most relevant disorders in hemostasis, which can be found in NAFLD independent of hemostatic disorders secondary to cirrhosis per se or other recognized risk factors for venous thromboembolism, such as obesity [9]. Clearly, this is a complex research area, which will undoubtedly benefit from additional studies. Similarly, the increased risk of chronic kidney disease in patients with NAFLD deserves additional investigations. This topic has been extensively reviewed in the second article by Dr. Mantovani and colleagues from the Universities of Verona and Modena-Reggio Emilia, Italy [10], who showed that NAFLD patients are exposed to an increased risk of developing chronic kidney dysfunction and should, therefore, be monitored for the development of this complication. Conversely, NAFLD should also be actively investigated among patients with chronic kidney disease, particularly in the presence of the so-called “diabesity” (i.e., a common condition characterized by co-existing obesity and diabetes) [10]. Natural Course - Our understanding of the natural course of NAFLD is key to the rational management of this disease. Two elegant review articles in the present CPD issue address the role of the most important modifiers of NAFLD [11] and the major causes of mortality [12], respectively. In the first review article, Dr. Nasr and colleagues, from Linköping University, Sweden, critically discuss the role of dysglycaemia (mainly type 2 diabetes and insulin resistance), overweight/obesity, alcohol consumption, genetics and histological hallmarks of NAFLD as important predictors for the progression of NAFLD [11]. In the second review article, Dr. Johnston and colleagues, from the University of Southampton, UK, provide a comprehensive overview of the major causes of mortality in NAFLD as compared to those in alcoholic liver disease [12]. Moving further along this comparison, Dr. Craciun et al. from the Universities of Lisbona, Portugal, and Graz, Austria, extensively discuss differences and similarities between alcoholic and nonalcoholic fatty liver disease [13]. These authors conclude that similarities between these two conditions outnumber the possible differences. This finding may have important future important clinical and research implications [13]. Management - Owing to the paucity of drug options currently available to treat NAFLD, the most important international guidelines now recommend that long-standing lifestyle modifications aimed at losing body weight (mainly through diet and physical exercise) should be the first treatment option in NAFLD. Consistent with this background, Dr. Petroni et al. from the Universities of Bologna and Palermo, Italy, accurately review the most recent publications on this topic [14]. These authors emphasize that progress in the field of information technology, bypassing job and time constraints, and maintaining long-term follow-up of NAFLD population, may facilitate the treatment of patients with NAFLD [14]. Pediatric NAFLD - Clinicians have become increasingly more able to diagnose NAFLD both in children and adolescents. Studies have shown that the manipulation of diet in the mother-infant dyad may affect the development of NAFLD. In this CPD issue, Dr. Bertrando and Vajro from the University of Salerno, Italy, show that an accurate control of gestational “diabesity” is expected to result in a healthier metabolic reprogramming of the fetus via the interaction of both genetic/epigenetic factors and changes in intestinal microbiota. In addition, the beneficial role of prolonged breast-feeding towards the prevention of NAFLD in the newborn, in his/her adult life and also towards the health of the mother may also represent advances of great clinical impact [15]. In conclusion, we cordially wish to manifest here our sincere gratitude to all those eminent researchers and young investigators who, by contributing their knowledge to this CPD special issue on NAFLD, will guarantee the success of this timely editorial initiative. Along the same line, we are also grateful to the Editorial board of CPD. Upon our suggestion, they were willing to expand the boundaries of their journal, primarily devoted to the evaluation of innovative drug treatment so as to embrace the most recent aspects of the epidemiology, pathogenesis and management of NAFLD. This editorial policy faithfully mirrors the importance of NAFLD as an important priority for public health and a considerable clinical and economic burden worldwide.

Chronic non-resolving inflammation is a critical condition found in many incident diseases such as obesity, cancer, type 1 and 2 diabetes, and cardiovascular diseases. However, the mechanism that links the perpetuation of the inflammatory response, same as in low grade and the impaired inflammation resolution phase is still not completely elucidated. Several lines of evidence indicate the existence of a complex interrelationship between inflammatory processes and metabolism. In this sense, changes in metabolism as found in overnutrition or undernutrition were demonstrated to modulate leukocyte function and induce inflammatory processes. Indeed, changes in the activity of the nutrient sensors mTOR and PPARs, for example, are associated with important alterations in inflammatory processes. Vice versa, inflammation and inflammatory mediators are associated with major changes in cell and tissue metabolism. In our Special Issue, 1 original and 6 review papers are exhibited. Furtado et al. [1] found that adoption of moderate long-term exercise (chair multimodal exercise) as therapy leads for a better equilibrium between pro- and anti-inflammatory profiles in frail older women with cognitive impairment. In this sense, Inoue et al. [2] discussed the role of regular resistance and/or aerobic training that may be able to improve pathophysiological obesity condition and cognitive performance through the improvement of the inflammatory profile, decreased insulin resistance and higher BDNF production. Biondo et al. [3] explored the potential effects of thiazolidinediones and metformin for insulin resistance associated with obesity and cancer, leads your eyes for PPAR-gamma and AMPK pathway. Moser et al. [4] discussed in detail the role of physical exercise in improving clinical outcomes, physiological responses to exercise and different nutrition and therapy strategies around exercise in type 1 diabetes, while Walsh et al. [5] showed potential effects of exogenous ketone supplementation for type 2 diabetes, specially on metabolic, inflammation, oxidative stress, and cardiovascular function in humans and highlight the potential application for breaking the vicious cycle of T2D pathophysiology. Soares et al. [6] enlightened the effects of dietary protein in cancer-induced sarcopenia as anti-catabolic strategy, different protein sources were discussed for mitigate as cancer-induced sarcopenia. Finally, Dorneles et al. [7] claim the role of exercise training on the metabolism and function of Treg cell in the diseases and health status. This Special Issue brings new concepts about immunometabolism approach, and pharmacological and nonpharmacological treatment might be adopted to decrease chronic inflammation status and restores energetic homeostasis in physiological and cellular environment.

The special issue: Current reviews, perspectives and future trends in synthetic medicinal chemistry for pharmaceutical applications, contains contemporary research and reviews on this hot topic. The issue contains four articles, one research paper and three review articles. Synthetic medicinal chemistry is one of the most promising and contemporary approaches to treat different diseases. The molecules and compounds are synthesized in order to discover active compounds that might have future applications in the treatment of life-threatening diseases, with special emphasis that is given to antibacterial, antifungal and antiviral compounds. Promising potential of novel chalcones as anti-HIV-protease agents has been described in the research article of this issue and gives insight and perspectives of the compounds with promising potential [1]. Synthetic antibiotics of the last generation were reviewed and their harmful and beneficial effects were discussed, as well as recent trends in this field [2]. Structure and activity studies on lipophilic guanylhydrazone analogues, as promising trypanocidal agents, were discussed and recent studies were reviewed, highlighting promising effects [3]. Heterocycle compounds as antimicrobial agents were discussed with literature covering recent findings and potential applications of novel synthetic heterocycles [4].

There are various health issues worldwide such as osteoporosis, cancer, obesity, infectious diseases, neurological disorders (Alzheimer’s disease, Parkinson’s disease) and neuropsychiatric disorders. There are many topics to discuss about each disease such as pathology, causes, symptoms, risk factors, diagnosis, current management as well as new research to discover best treatment strategies. There are many advanced researches to manage health issues via nanotechnological, nanomedicines, stem cells and vaccines. The vaccines stimulate the production of long-lived memory cells/plasma cells to produce antibodies to defend the body against viral or bacterial (antigens) attacks. The aim of this special issue of Current Pharmaceutical Design was to aid pharmaceutical research in this exertion by providing articles for an overview of current progress and future perspectives focused towards management strategies for neurological disorders. Particular challenges facing numerous laboratories are those that involve laboratory bench to clinical bedside in the path of successful drug discovery. Authors of this special issue (Part-I) were requested to provide a review (Table 1), sufficient for an inspiration to identify guidelines for in vitro to clinically translatable research that will enhance the rate treatment can reach its public health goals globally.

Active Ingredients of Natural Sources and their Applications (Part II)

Nature is a precious source of substances useful in the pharmaceutical, nutraceutical, diet supplement and cosmetic fields. Active ingredients of natural source therefore have high potential and applications that can contribute to improving human health. They can perform both a preventive action against many diseases and a strengthening and optimization of medical therapies. Natural products could have an excellent impact on the market due to patient (user) acceptability and because the correct use of natural products can also solve the problems of environmental pollution, linked to the activity of chemical synthesis. Today, however, traditional medicine is no longer valid and the use of natural products must be rationalized. The active ingredients of natural source must be well studied and well formulated to guarantee quality, safety and efficacy. The interest for natural ingredients focuses both on the active ingredients and excipients to prepare a final product (PART I). Essential oils from natural sources e.g. families of Lamiaceae, Myrtaceae, Apiaceae, Cupressacae, and Asteraceae are good sources of several bioactive compounds having different activities, the most common are the antioxidant and antimicrobial. The extraction procedure is very important in terms of yield and quality of the final product. The most important technologies used for essential oil extraction are deeply described by Ferrentino et al. [1]. Edible South American Prosopis is rich of many compounds such as flavonoids, ellagic acid derivatives, catechin and simple phenolics. These are responsible for the bioactivity (antioxidant, anti-inflammatory, and enzyme inhibition associated with metabolic syndrome) making this source interesting in health field [2]. Some products as natural polymers, penetration enhancers and remineralizing agents are particularly useful in the treatment of nail diseases as effective alternative to chemical-based formulations [3]. Biodegradable polymers are the future of green materials having innumerable uses in biomedicine, particularly in the fields of tissue engineering and drug delivery. Among them it is possible to find naturally occurring proteins which are constituted of one of the most important α-amino acids [4]. Several natural compounds as monoterpenoid, triterpenoid saponin, sesquiterpenoid alkaloid and polyphenols have demonstrated potential for the treatment of central nervous system disorders due to their well-known antioxidant, anti-inflammatory, neuroprotective, anti-tumor, anti-ischemic and analgesic properties. However many of them have poor aqueous solubility, low bioavailability and extensive gastrointestinal and/or hepatic first-pass metabolism, leading to a quick elimination as well as low serum and tissue concentrations. Thus, the intranasal route emerged as a viable alternative to oral or parenteral administration [5]. Together to organic natural sources, the use of inorganic natural ingredients represents an interesting tool in health field (PART II). Natural inorganic ingredients, especially clays, act as multitasking agents able to improve physical (mechanical resistance and water vapor transmission), chemical (release of drugs, hemostasis and/or adsorption of exudates and moisture) and biological (antimicrobial effects and improvement of healing) properties of wound dressings [6]. Clays (anionic) can also be used as carrier for natural active ingredients showing limited solubility, and thus low bioavailability. Together to the improvement of such property the use of the clays improves the performances of the final formulation [9]. Also cationic clays represent promising materials for therapeutic purposes. Numerous publications in fact document extensive their applications as an alternative and complementary treatment for numerous health conditions and as detoxifying agent and for the preparation of several bionanocomposites [7]. Inorganic clays are also widely used as alternative adsorbents of carboxylic acids produced in plants, animals and also as products from biotechnological processes, from liquid media. The proposal to use hydroxide particles is based on its affinity to adsorb or intercalate carboxylic acids. The use of inorganic clays is helpful as allows to reduce the number of separations steps, costs and reduce or eliminate solvents, thus encouraging the design of industrial processes of separation [8].

Defects in the molecular signaling pathways can lead to the development of communicable and non-communicable diseases. Various pathogenic organisms such as viruses or bacteria, coming in contact with bodily fluids and blood products, interfere with signaling events and lead to defects in the functioning of cell signaling pathways. Signaling pathways are an important means of communication from the exterior of cells to intracellular mediators, as well as intracellular-interactions that govern diverse cellular processes. Cell biology takes advantage of identifying diverse cellular signaling pathways that are disrupted in these diseases. The major population of the modern world is suffering from obesity, diabetes, cardiovascular problems, respiratory and neurological diseases and cancer. As reflected in recent publications, these diseases share a common pathophysiological and mechanistic background. Mitochondrial alterations, oxidative stress and inflammation are inextricably linked and play a major role in the onset and development of these diseases. Genetic modifications occurring due to somatic and germline mutations are also responsible for the pathogenesis of various diseases. Although management protocols for both communicable and non-communicable diseases are available, various side effects and complexities are reported to be associated with them. Therefore, a deeper knowledge of molecular mechanisms will lead us towards the development of a completely new realm of drug designing. The current issue presents a collection of original research studies with the aim of summarizing recent investigations relevant to the most current herbal and synthetic treatment approaches for early-stage, advanced and recurrent diseases, while recognizing the importance of oxidative stress, inflammation and microRNA therapy. All ten original review research papers have been included in this manuscript. The first one deals with the “Viral MicroRNAs: Interfering the Interferon Signaling”, which are the secreted cytokines with potent antiviral, antitumor and immunomodulatory functions. The paper presents new insights into our understanding of how v-miRs promote viral evasion of host immunity and likely provide novel antiviral therapeutic targets. Second article presents results on the “Critical View on the Usage of Ribavirin in Already Existing Psychostimulant-Use Disorder”, which represents a frequently hidden non-communicable chronic disease. The review focuses on the current knowledge about neurochemical/neurobiological changes that exist in the psychostimulant drug-addicted brain per se and the antipsychotic-like efficiency of adenosine agonists. Particular attention has been paid to the potential side effects of ribavirin therapy, and the opportunities and challenges related to its application in already existing psychostimulant- use disorder. The emerging role of angiotensin AT2 receptor in anti-inflammation: an update article presenting information on the collective effects promoting cell survival and tissue function, as hyperactive RAS and inflammation are closely associated. This manuscript is followed by a paper on the “evolution of molecular targets in melanoma treatment”. This paper discusses the fact that there is still an unmet need for melanoma treatment. As per the results, a significant population of patients has not responded to either BRAF inhibitors or immune checkpoint inhibitors. Those who gained an initial response from the therapies, a remarkable percentage developed drug resistance even when MEK inhibitors were added to the treatment, some possible targets for melanoma treatment are presented. Another manuscript included here presents information on the “Glucagon and Glucagon-like Peptide-1 Receptors: Emerging Therapeutic Targets in the Management of Diabetes Mellitus”. In general structural diversity of glucagon and GLP-1 receptors along with their signaling pathways, site-directed mutations and significance in drug discovery against type-2 diabetes have been addressed. It also discusses the promising non-peptide antagonists of glucagon receptors and agonists of the GLP-1 receptor for the management of diabetes as well as their structure-activity relationship (SAR). In the manuscript titled “Some neuroprotective approaches in drug design for the treatment of CNS Diseases” with the clinical outcomes, the rationale behind the design of molecules is reviewed together with representative drug candidates of each group. This manuscript is followed by a study on the “Chemosensitisation of Therapy Resistant Tumors: Targeting Multiple cell Signaling pathways by Lupeol, A Pentacyclic Triterpene” with the aim of reviewing the current literature on chemosensitization of therapy resistance tumor by Lupeol through targeting different cell signaling pathways and biomolecules. The mini-review discusses how Lupeol modulates different signaling pathways responsible for chemoresistance in various types of cancer and possible use of Lupeol as an adjuvant molecule along with clinically approved drugs to reduce the toxicity and increase the effectiveness. In the article titled “Exploring Dysregulated Signaling Pathways in Cancer”, the authors are discussing different signaling pathways and how their dysregulation contributes to the development of tumors. This is followed by a paper titled “Role of miRNA and Long Non-Coding RNA in Hepatocellular Carcinoma”, summarising the relationship between ncRNAs and hepatocellular carcinoma. The last article in this issue is about the “Emerging role of Mitophagy in inflammatory diseases: Cellular and Molecular Episodes”. The aim behind this review was to enquire about the possible role of mitophagy and its associated mechanism in inflammation-mediated diseases at both cellular and molecular levels. We are sure that the readers of Current Pharmaceutical Design will appreciate this collection, which will provide a useful reference for additional studies as well as new techniques related to the management of communicable and non-communicable diseases. Maryam Sarwat is currently an associate professor at Amity Institute of Pharmacy, Amity University. Her research interests focus on the anti-cancer and neuroprotective activity of biologically active molecules. She has published more than 50 articles in peer-reviewed journals and a very informative and comprehensive book with Elsevier titled “Saffron, An Age Old Panacea In New Light”. Munir Ozturk is an emeritus professor from Ege University, Izmir, Turkey. His research interests cover studies on the medicinal plants, mainly anticancer and antidiabetic herbal as well as general herbal treatments. He has published three volumes with Springer on “Herbals and Human Health” and several other books together with more than 200 papers in international journals.

Translational research is the process of applying knowledge from basic biology and clinical trials to techniques and tools to improve medical needs and outcomes. Basic scientific research, if translated into the current clinical surgical practice, allows for innovative therapies, medical procedures and diagnostics. Pharmacology makes full use of medicine and translational research, since, starting from animal models or from cell cultures, one can obtain a lot of useful data to produce drugs or medical devices that can then be used either in clinical-surgical practice or in meaningful health outcomes. Indeed, the translational research applies findings from basic science to enhance human health and well-being. Pharmacological translational research, from laboratory experiments to clinical studies to patient applications, uses the knowledge of basic sciences to produce new drugs, devices and treatment options for patients. The final point is the production of promising new treatments that can be used with practical applications, which can be used in medical practice. In this special issue, some aspects of pharmacological research to be translated into clinical practice are discussed. Fibroids’ pharmacological treatments: innovative therapeutic options. In the uterine fibroid topic, research on fibroids has developed new drug therapies, including Vilaprisan and Ulipristal Acetate. Both molecules were very effective in controlling fibroid growth, limiting symptoms in women with uterine fibroma and allowing the patient to be operated on with blood chemistry parameters suitable for myomectomy. Vilaprisan (VPR) is a new orally available selective progesterone receptor modulator (SPRM), a class of progesteron receptor (PR) ligands with clinical applications in many gynecological conditions, with anti-proliferative activity against uterine fibroids. The SPRMs have direct effects on the pituitary gland, the uterine fibroids, and the endometrium. Amenorrhea is induced by means of the direct effect on the pituitary gland, by inhibiting ovulation (in approximately 80% of patients) and simultaneously maintaining the estradiol level in the midfollicular range. The SPRMs produce also a reduction in the uterine fibroids by inhibiting the cell proliferation and by inducing apoptosis, since progesteron plays a vital role in the regulation of uterine fibroid growth by modulating cell proliferation and apoptosis induction. VPR definitively causes suppression of ovulation and inhibition of proliferation of endometrial, myometrial and uterine fibroids’ cells. The review on VPR [1] summarized current knowledge on VPR from all studies, including clinical trials, conducted to date and to contextualize the potential role of VPR in future medical regimens for the treatment of uterine fibroids. VPR was shown to be effective in ameliorating uterine fibroids-related clinical symptoms, especially abnormal or excessive uterine bleeding and in shrinking uterine fibroids. The tolerability of VPR is roughly like that of ulipristal acetate (UPA) and it tends to be more favorable than that of GnRH-agonists. The other drug, the UPA, another SPRM, have demonstrated its clinical benefits by reducing tumor growth and extracellular matrix (ECM) deposition. The UPA modestly inhibits cell proliferation, induces a temporary phase of apoptosis and reduces ECM content. The review on UPA [2] summarized drug effects on signaling pathways frequently upregulated in uterine fibroids, exploring biological changes in the expression levels of proteins related to cell cycle regulation, cytoskeleton remodeling, and drug resistance after ex vivo on cultured myoma cells treated by UPA administration. This research showed that the UPA administration on fibroid reduced, ex vivo, cofilin, Erk and Src phosphorylation, p27 and ezrin protein levels (all markers of tissue remodeling), but not Akt phosphorylation and cyclin D1 and β-catenin levels. Uterine fibroids morcellation: analysis of critical biological issues and drawbacks from a medical-legal prospective. In November 2014, the Food and Drug Administration (FDA) discouraged the power morcellation during laparoscopy in all pre-menopausal and post-menopausal women with leiomyomas, for the risk of cancerous cell dissemination in undiagnosed uterine leiomyosarcomas (ULMs). This banning has thus created a series of major medical, administrative, insurance and legal problems, with the sudden decrease in laparoscopic procedures and increase in laparotomies, with the abandonment of the use of power morcellation and with the sudden emergence of containing devices, in which to morcellate or crush myomas. The most important step in the surgical choice, in open or in minimally invasive surgery, is to balance the risks (complications) and benefits of different interventions. Obviously, all this chaos has generated many doubts about the real opportunity of this sudden change in the American scientific community and especially in countries that are not influenced by FDA recommendations, since there are no unique data on the real incidence of ULMs in women (they are quite rare) and there are no reliable data on the effectiveness of these containing devices. Another unsolved question is whether the power morcellation should worsen the prognosis and the overall survival of patients with an occult ULM. The review on uterine fibroid morcellation [3] has highlighted all the problems related to the choices of many doctors and some scientific societies, that criticized fibroids morcellation after myomectomy by power morcellation, potentially disseminating occult tumor cells. In fact, the unsolved biological issues have raised concerns about FDA banning, as the "myometrial spillage" during myoma enucleation (which may result in upstaged ULM), the fast-growing fibroid (which is often not an ULM at all), the lack of accurate preoperative diagnostics and adequate markers, the problem of the spread by contact and by CO2 of the hypothetic cancer (after its removal from uterus), and so on. New techniques to overcome the issue of uterine tissue spreading, as the in-bag morcellation, is proving to be a promising, safe and feasible technique, even if it may prolong the operative times. Presently the available data are still preliminary and not enough to provide strong evidence to recommend the in-bag morcellation as a general tool in laparoscopic surgery. From a medical legal prospective, the FDA statement and the above-mentioned concerns raise several considerations and raise many drawbacks, all discussed and analyzed in this review. The problem of HPV infection in the world: analysis of epidemiological spreading and vaccination. The HPV nowadays represent the most common worldwide sexually transmitted diseases, with an estimated prevalence of approximately 12%, in a population of over one million asymptomatic women [4] and around 90% of infected individuals are asymptomatic and clear the infection within two years [5]. Carcinogenic types are responsible for up to 4.5% (630,000 cases) of all new cases (8.6% in females; 0.9% in males) and cause 29.5% of all HPV-related cancers. In particular, HPV 16 and 18 cause 70% of the cervical cancers, and a relevant proportion of vaginal (78%) and anal (88%), as well as some vulvar (25%) and penile (50%) cancers and, together with HPV types 31/33/45/52/58, are responsible for about 90% of HPV-related cancers worldwide [6]. Cervical cancer remains the fourth most common female cancer globally, with an estimated 570,000 cases and 311,000 deaths yearly [7]. Despite all these enormous problems that also involve the oncological sphere, recognized effective and safe preventive strategies, knowledge, attitudes and awareness on HPV are considerably low. Health education programs aimed at increasing knowledge, attitudes and awareness on HPV are needed to implement the outcomes of HPV immunization programs, especially if supported by the physicians involved in counselling and recommendation processes. Balmagambetova et al. [8] in their review discussed a current point of view regarding the HPV as a causative factor in tumorigenesis, highlighting the role of the most problematic property of these virus’s fam-ily, its ability to continuous evolution. Present trends in HPV infection diagnostics throughout the human fluids and tissues are also reported, including the latest novelties in this field, such as HPV assay/self-sample device combinations. Concerned actual issues of current cervical cancer prevention are summarized in this review. Icardi et al. [9] analyzed the evolution of preventive tools, the complexity of the vaccine choice process, and the challenges posed by HPV vaccine hesitancy and refusal among pre-adolescents and their parents and assessed knowledge, practices and attitudes toward HPV infection and vaccination in a sample of Italian pre-adolescents and their parents. They highlighted a significant increase in HPV vaccination awareness was observed among pre-adolescents after the educational sessions. Thus, the inclusion of parents in the evaluation of knowledge gaps and attitudes about HPV should be encouraged in order to obtain an exhaustive list of the factors that influence the decision-making process. Moreover, the role of physicians in providing counselling and recommendations for HPV vaccine target populations plays a crucial role together with school-based vaccination programs and social media in the case of preadolescents. Guido et al. [10] reviewed the utility of HPV vaccination, that has globally leading to a significant reduction of vaccine-targeted HPV infections, cross-protective genotypes, precancerous lesions and anal-genital warts. They realized a review of the most recent literature to evaluate the effects after vaccine introduction on effectiveness of vaccine-targeted and cross-protected HPV genotypes. Moreover, they evaluated the progress of HPV infection in southeast Italian region, as an ideal territorial study model, by an epidemiological investigation on the vaccination impact on genotype and on the prevalence and distribution of HPV during last 12 years (2006-2017) in the Local Health Unit. The problem of infections in pregnancy: rational, safety and effectiveness of pertussis immunization. Pertussis remains a serious public health problem, as the coverage is not optimal, due to increasing vaccine hesitancy. The pertussis is a highly contagious respiratory tract infection, commonly known as whooping cough, caused by a type of bacteria called Bordetella pertussis. This Gram-negative bacterium. B. pertussis adheres to the cilia of the epithelium of the upper respiratory tract, damaging it through the production of toxins [11]. Generally, pertussis affects patients by a severe hacking cough followed by a high-pitched intake of breath, that sounds like "whoop" [12]. The highest risk in terms of cases, severity and mortality is greater in the neonatal period and in the first months of life, when children have not yet started vaccination cycles [11]. Before the vaccine was developed, whooping cough was considered a childhood disease. Maternal immunization in pregnancy allows for the transplacental passage of maternal antibodies to the fetus, guaranteeing its protection already at birth [13]. Gabutti et al. [14] reviewed the rational, safety and effectiveness of pertussis immunization in pregnancy, starting from the 2012, when the Advisory Committee on Immunization Practices (ACIP) recommended a dTap dose for each pregnancy, especially between the 27th and 36th gestational week. Several observational studies supported maternal vaccination, as it is effective in protecting newborns in their first months of life and pertussis vaccine in pregnancy has proven to be safe, effective and well tolerated. This vaccination approach has demonstrated the safety, immunogenicity and efficacy in preventing pertussis in new-borns, resulting in substantial reduction in pertussis incidence and mortality. Maternal immunization, therefore, offers the best opportunity to prevent pertussis-related incidence and deaths in newborns/infants and is therefore an important and undelayable priority. Reproduction in advanced age. uterine innervation and premature ovarian failure. Nowadays, the number of aged patients and in peri/post-menopause wishing pregnancy is increasing, and it increases obstetrical and neonatal related problems. This is because the physiology of reproduction changes with advancing age, with ovarian and myometrial changes that cause many problems. Normally, the human uterus is richly innerved and modified especially during pregnancy and labor, and it is endowed with different sensory, parasympathetic, sympathetic and peptidergic neurofibers. They are differently distributed in uterine fundus, body and cervix, and they are mainly observed in the stroma and around arterial vessel walls in the myometrial and endometrial layers [15]. Many neurotransmitters playing important roles in reproductive physiology are released after stimulation by adrenergic or cholinergic nerve fibers (the so called sympathetic/parasympathetic co-transmission). Adrenergic and cholinergic effects of the autonomous nervous system are the most implicated in the uterine functionality [16]. Kosmas et al. [17] evaluated, in aged women, the Adrenergic and AChE neurofibers distribution in the fundus, body and cervix is progressively reduced by increasing age. Adrenergic and AChE neurotransmitters were closely associated with the uterine arteries and myometrial smooth muscles, and they reduced markedly by ageing, with a dramatic and negative impact on uterine physiology, as for conception and uterine growth, with the increase risk of spontaneous abortion and prematurity. To this problem is added another problem in older women, the premature ovarian failure (POF), with the loss of ovarian functionality around 40 years. When this happens, your ovaries don't produce normal amounts of the hormone estrogen or release eggs regularly, and this condition often leads to infertility and several negative effects on overall health [18]. Kosmas et al. [19] reviewed the pathways involved in POF by a systematic review to understand the impact of various pathways on the follicular growth. They analyzed experimental studies on the stage-specific function of PTEN/PI3K-AKT-mTOR signaling, the VeGF gene and one of its receptors, the KDR, the expression of TGFβ, FOXL2 and FOXO3A proteins, autoimmunity disease, the Xp18 gene and chemotherapy for cancer. Most of the analyzed studies were experimental, using mostly mice and rats, but there were also various case reports studying women suffering from POF or having an autoimmune disease. Certain experimental studies combined both in vivo and in vitro experiments. A wide spectrum of techniques has been performed in the above studies, including histological analysis, microarray analysis, Western Blotting, histological analysis as well as statistical analysis. The epithelial mesenchymal transition program and alterations of large proteome-based networks. Several physiological and pathological processes in human beings are characterized by proteome modifications including alterations of protein abundance, subcellular protein localization, and alterations of protein-protein interactions (PPIs) networks. These networks are involved in several processes including cancer, tissue regeneration, and differentiation. The epithelial to mesenchymal transition (EMT) is a multistep process that transforms an epithelial cell with well-characterized morphological features into a mesenchymal model [20]. Several studies profiled this transition at the mRNA, protein, and metabolomic level in order to obtain a system-level understanding of the process [20]. Molecular changes associated with the initiation of the EMT program involve alterations of large proteome-based networks, but the role of protein products mapping to non-coding genomic regions is still unexplored. Millithaler et al. [24] studied the identification of an alternative protein signature in breast cancer cellular models with a distinct expression of EMT markers. They profiled MCF-7 and MDA-MB-231 cells using liquid-chromatography mass/spectrometry (LC-MS/MS) and interrogated the OpenProt database to identify novel predicted isoforms and novel predicted proteins from alternative open reading frames (AltProts). The analysis revealed an AltProt and isoform protein signature capable of classifying the two breast cancer cell lines. Among the most highly expressed alternative proteins, authors observed proteins potentially associated with inflammation, metabolism and EMT. The data support the presence of a specific alternative protein signature associated with the epithelial and mesenchymal features of the breast cancer models. Aptamers use in the lab and clinical research: a translation to diagnosis and therapy. Aptamers, small fragments of ssDNA or RNA, artificially assembled to achieve high binding affinity to their targets, as proteins to simple ions, are relevant for diagnosis in macular degeneration, cancer, thrombosis and many inflammatory diseases, and promising in drug discovery and development [22]. Their low dimension, short half-time, low immunogenicity and production cost, coupled with their high affinity and specificity, make them formidable competitors to antibodies in both diagnosis and therapy [23]. Many aptamers have reached therapeutic clinical trials, diagnostic markets, or that have immediate translational potential for therapeutics and diagnostics applications [23]. Vergara et al. [21] briefly review the literature, discussing if and how general network parameters in the framework of Proteotronics and graph theory (such as electrical features, link number, free energy change, and assortativity), are important in characterizing the complexes, anticipating some features of the biomolecules. Authors described a case study to better explain this complex topic. The study constituted by a set of anti-angiopoietin (Ang2) aptamers, whose performances are known from the experiments, and for which two different types of conformers were predicted. A topological indicator was proposed, named Möbius (M), which combined local and global information, and seemed able to discriminate between the two possible types of conformers, so that it can be considered as a useful complement to the in vitro screening for pharmaceutical aims. The calcium-activated potassium channel KCa3.1: new features and possible use in the structuring of new drugs. The human intermediate conductance calcium activated potassium channel, Kca3.1, is involved in several pathophysiological conditions playing a critical role in cell secretory machinery and calcium signalling. The recent cryo-EM analysis opens new insights in the understanding of the modulation led by both endogenous and pharmacological agents. A typical feature of this channel is the low open probability in saturating calcium concentrations and its modulation by potassium channel openers (KCOs, such as benzoimidazolone 1-EBIO) without changing calcium-dependent activation. The calcium-activated potassium channel KCa3.1 regulates membrane potential and calcium signaling in erythrocytes, activated T and B cells, macrophages, microglia, vascular endothelium, epithelia, and proliferating vascular smooth muscle cells and fibroblasts [25]. Besides its role in cell volume regulation, the KCa3.1 channel modulates other cellular processes such as cell proliferation and endotheliumdependent. KCa3.1 has therefore been suggested as a potential therapeutic target for diseases such as sickle cell anemia, asthma, coronary restenosis after angioplasty, atherosclerosis, kidney fibrosis and autoimmunity, where activation and excessive proliferation of one or more of these cell types is involved in the pathology [26]. The review "New insights on KCa3.1 channel modulation" [27] present an accurate and wide review about the human intermediate conductance calcium activated potassium channel KCa3.1 that is widely expressed by many types of cells in normal and even cancer conditions (e.g. glioblastoma). The importance of this potassium channel, in influencing the ion exchanges regulating the cell membrane potential and under the functional modulation by Ca++ levels and variations, is well documented and described. Particularly intriguing the part discussing the modulators of the channel opening/blocking and how a same chemical class, like benzimidazolone molecules, can furnish possible opposite derivatives. The hypothesis proposed are also a useful point for critical discussion about the importance of KCa3.1 channel in the cell physiology, behavior and cytopathology, opening perspectives for new approaches also in anticancer treatments. The anticancer property of resveratrol: the possible use in cerebral cancer. Natural product compounds have recently attracted significant attention from the scientific community for their potent effects against inflammation-driven diseases, including cancer. Resveratrol (3,4′,5-trihydroxy-trans-stilbene) is a dietary polyphenol derived from grapes, berries, peanuts, and other plant sources. Resveratrol is a phytoestrogen, a natural stilbene and a non-flavonoid polyphenol, that possesses anti-oxidant, anti-inflammatory, cardioprotective, and anticancer properties [28]. It has been reported that resveratrol can reverse multidrug resistance in cancer cells, and, when used in combination with clinically used drugs, it can sensitize cancer cells to standard chemotherapeutic agents [29]. Resveratrol affects all three discrete stages of carcinogenesis (initiation, promotion, and progression) by modulating signal transduction pathways that control cell division and growth, apoptosis, inflammation, angiogenesis, and metastasis. The anticancer property of resveratrol has been supported by its ability to inhibit proliferation of a wide variety of human tumor cells in vitro. These in vitro data have led to numerous preclinical animal studies to evaluate the potential of this drug for cancer chemoprevention and chemotherapy [30]. Authors reviewed these resveratrol anti-tumor effects and evaluated them on glioblastoma (GBM) [31], the most frequent and malignant form of glioma cancer, with a general high chemo and radioresistance and patients’ very poor prognosis, with a median overall survival of about of 14.6 months. They evaluated data especially from preclinical studies conducted with resveratrol as a possible adjuvant during standard protocol of GBM. Resveratrol can reach brain parenchyma at submicromolar concentrations when administrated through convention routes. In this contest, resveratrol reduces cell invasion and increases the efficacy of radiotherapy (radio sensitizer effects) and of temozolamide. The molecular mechanism of the adjuvant action of resveratrol may depend upon the reduction of PI3K/AKT/NF-Kb axis and downstream targets O-6-methylguanine-DNA methyltransferase (MGMT) and metalloproteinase-2 (MMP-2). The involvement of redox status is also discussed as regulator of the autophagy process. Resveratrol administration through intra carotid external (ECA) or lumbar puncture (LP) can reach micromolar concentrations in tumor mass and is able to reduce the tumor growth by STAT-3 dependent mechanisms. Anticoagulant therapy and bleeding problems: a computational systems biology models analysis. Anticoagulant therapy is often refrained from due to the fear of hemorrhagic complications. The problem of correct antithrombotic targeting is critical for this system because, although several anticoagulants is currently available, all of them are associated with bleeding risks. The most frequent type of major bleeding is gastrointestinal but intracranial hemorrhage has the worst prognosis. In addition, for life-threatening or massive hemorrhages reversal of the anticoagulant effect is also crucial [32]. Moreover, situations that ordinarily necessitate consideration of anticoagulation, such as arterial and venous thrombotic events and prevention of stroke in atrial fibrillation, become challenging in patients with inherited bleeding disorders such as hemophilia A, hemophilia B, and von Willebrand disease. There are no evidence-based guidelines to direct therapy in these patients, and management strategies that incorporate anticoagulation must weigh a treatment that carries a risk of hemorrhage in a patient who is already at heightened risk against the potential consequences of not treating the thrombotic event [33]. Panteleev et al. [34] have faced this problem, reviewing and discussing the application of the computational systems biology models to address this problem using the blood coagulation cascade as an example. The advantages and the drawbacks of different sensitivity analysis strategies are considered, focusing on the approaches that emphasize: 1) the functional modularity and the multi-tasking nature of this biological network; 2) the need to normalize hemostasis during the anticoagulation therapy rather than completely suppress it. To illustrate this effect, Panteleev et al showed the possibility of the differential regulation of lag time and endogenous thrombin potential in the thrombin generation. These methods allowed to identify of the elements in the blood coagulation cascade, that may serve as the targets for the differential regulation of this system.

Novel Biomarkers and Treatments for Mental Disorders

Atherosclerosis-related diseases start long before the overt clinical manifestations occur. The time lapse for progression of pathological process may take many years, and the persons at risk remain unaware of the already existing premorbidic conditions. Therefore, preventive measures are not undertaken to reduce the risk of the development of the overt disease. By now, many basic and clinical studies have unraveled the number of vascular biology pathways and established reliable mechanistic and diagnostic biomarkers of atherosclerosis, atherothrombosis and atherosclerosis-related diseases [1, 2]. The impact of these findings on potential and perspective molecular targets for the development of novel therapeutic approaches should be further evaluated. The omics technologies and advantages in genetic diagnostics provide the great field for future developments. Emerging biomarkers, including chemical, imaging, molecular and genomic biomarkers hold great promise for early diagnosis of atherosclerosis and related diseases [3-5]. For the past few decades, a great progress has been achieved in the reduction of cardiovascular mortality. This was mainly due to the successes of cardiovascular surgery, the improvements of healthy lifestyle, and wide use of hypolipidemic and antithrombotic medications. However, within the global aspect, atherosclerosis and related diseases remain the leading killer [6]. The additional years of life due to surgery and lipid-lowering medications do not imply the radical treatment of atherosclerosis. Further studies of precise cellular and molecular mechanisms of atherogenesis, especially in the field of vascular biology, are clearly needed for the development of targeted pathogenetic strategies in the development of anti-atherosclerotic treatment. The introduction of novel research strategies, like NGS, GWAS and systems biology, atop of conventional research approaches, may provide the translation of “big data” to general plausible solutions for the prevention and treatment of atherosclerotic and atherothrombotic disease [7,8]. In this Thematic Issue, we present a selection of reviews on the promising achievements and current expert views in the field. Frigerio et al. (Italian team of authors) in the review paper entitled “Traditional risk factors are causally related to carotid intima-media thickness progression: Inferences from observational cohort studies and interventional trials” discussed various associations between traditional vascular risk factors (VRFs) and carotid intima-medial thickness progression (C-IMTp) as well as the effects of therapies for VRFs control on C-IMTp were appraised to infer causality between each VRF and C-IMTp well in detail [9]. In the paper “Radix Stephaniae Tetrandrine: An emerging role for management of breast cancer” authors from China (Guo et al.) reviewed the role of Radix Stephaniae tetrandrine in the management of breast cancer. Additionally, they discussed the application of this product of traditional Chinese medicine in the treatment of cardiovascular diseases [10]. Melnikov et al. (Russian research team) in their review article “Current position on the role of monomeric C-reactive protein in vascular pathology and atherothrombosis” focused on the role of monomeric C-reactive protein (mCRP) in vascular pathology and atherosclerosis and also discussed several pathophysiological mechanisms of atherothrombosis in which mCRP is involved and plays a crucial role [11]. The review paper entitled “Citrus species: A review of traditional uses, phytochemistry and pharmacology” by Zibaee et al. presented data on the application of Citrus plants in the treatment of immune, reproductive, cardiovascular and central nervous system disorders; traditional and modern studies were referred to in this review [12]. One more Russian research group (Varaeva et al.) in the review entitled “Characteristics of blood lipid profiles of professional athletes: literature review” summarized very interesting topic of the influence of sports activities on lipoprotein metabolism and plasma lipids. They question on different relevant factors contributing to the observed differences in lipid and lipoprotein levels in sport-prone subjects from physically non-active population [13]. The review paper entitled “Neurodegenerative diseases associated with mitochondrial DNA mutations” written by international research team (Zhunina et al.) is focused on the current knowledge on the distribution and possible roles of mtDNA mutations in the onset and development of various neurodegenerative diseases, with special focus on Parkinson’s and Alzheimer’s diseases [14]. Ramezani et al. (Iranian team) gave us an opportunity to know more about the Islamic traditional medicine from their paper “A review on the phytochemistry, ethnobotanical uses and pharmacology of Borago species”. Ethnobotanical, phytochemical, pharmacological, and clinical data about Borago sp. were observed [15]. The international team from China and Japan (Tian et al.) has presented the meta-analysis on atrial fibrillation in Brugada syndrome in the review entitled “A pooled analysis of the prognostic significance of Brugada syndrome with atrial fibrillation”. This review seems to be very innovative like the first article in this field. The authors overviewed the risk of arrhythmic events in patients with Brugada syndrome in different populations [16]. Ban et al. (Chinese team of authors) in their review paper “Vitex diterpenoids: structural diversity and pharmacological activity” performed a comprehensive review on the chemical diversity and biological activities of diterpene metabolites isolated from Vitex plants. The manuscript is presented in a way useful for facilitating further investigations on this kind of secondary metabolites [17]. One more international research team from UK and China (Chen et al.) in the paper “Scutellaria barbata: A review of chemical constituents, pharmacological activities and clinical application” reviewed current data on chemical constituents, pharmacological activities and clinical application of Scutellaria barbata. Anti-cancer, bacteriostasis, anti-oxidation, anti-inflammation, anti-virus, and immunity enhancement properties were discussed [18]. The authors from Brazil (Mendes et al.) in the review paper “Cellular and molecular mechanisms of anti-thrombogenic plants: A narrative review” provided an overview of current knowledge on the major molecular and cellular mechanisms of anti-thrombogenic plants and their main components. They shed light on the importance of natural products as anti-thrombogenic agents. Cellular mechanisms of various medicinal plants and compounds as anti-thrombogenic candidates were thoroughly observed [19]. Upon the compiling of this Special Issue of Current Pharmaceutical Design, we have noticed that rather little attention was given to the molecular and genetic factors involved in atherogenesis. For example, mitochondrial genetics of atherosclerosis is the evolving and rapidly developing field of research [14, 20-22]. Therefore, we tried to fill in this gap in the present editorial with our own considerations. Atherosclerosis as the main cause of coronary heart disease, myocardial infarction and stroke, occurs as a result of multiple interactions of genetic and environmental factors. Genetic and epidemiological studies have revealed a surprisingly extensive list of genetic and non-genetic risk factors attributable to the development of atherosclerosis. In these studies, it was found that family history is one of the most significant independent risk factors and accounts for about 15% of the variability of diseases of atherosclerotic origin. Several Mendelian diseases associated with atherosclerosis (for example, familial hypercholesterolemia) were characterized, but it was concluded that they account for only a small fraction of cases of hereditary predisposition. Moreover, the entire set of known nuclear genome polymorphisms associated with atherosclerosis can explain no more than 7% of cases of coronary heart disease, and no more than 5% of cases of myocardial infarction. At the same time, the contribution of damage to the mitochondrial genome as a genetic factor affecting the formation of a predisposition to atherosclerosis remained out of focus in the vast majority of studies. Atherosclerosis should be regarded as a typical age-related degenerative pathology characterized by signs of aging of cells in the artery wall, including decreased cell proliferation, irreversible growth retardation and apoptosis, increased DNA damage, the presence of epigenetic modifications, shortened telomere repeat lengths and mitochondrial dysfunction. The most prominent characteristics of mitochondrial aging are structural changes in mitochondria and damage to mitochondrial DNA (mtDNA). There is increasing evidence supporting the role of mitochondrial factors in the pathogenesis of atherosclerosis. Impaired mitochondrial function and qualitative changes in mitochondrial components, such as mtDNA, can be directly involved in the mechanisms of atherogenesis, including progressive oxidative stress, impaired glucose and lipid metabolism, and changes in energy homeostasis. Recent studies have shown that some mtDNA mutations are associated with coronary and carotid atherosclerosis, as well as its clinical manifestations - coronary heart disease and myocardial infarction. Undoubtedly, this area of research should be further developed, since mutations and variants of mtDNA can represent a new promising molecular biomarker and pathogenetic factor of genetic predisposition to atherosclerosis, atherothrombosis and related pathological conditions and diseases. Several clinical and experimental studies have defined some mtDNA mutations as the potential therapeutic targets amendable for further interventions, even employing the instruments of genetic engineering. However, the main problem in creating approaches to mtDNA editing and regulating its functioning is the complexity of targeted delivery of macromolecular complexes to mitochondria. In general, gene therapy of atherosclerosis is only a potential treatment option, and it is currently under research [23]. To prevent or to treat atherosclerosis, important role can be played by gene therapy, which makes it possible to correct defects in genes or suppress genes associated with atherosclerosis [24]. There are known gene targets for this therapy, including IL1b [25], PCSK9 [26], ApoE [27], LDR [28], and also lncRNAs [29] and miRNAs [30]. Using gene therapy, these genes can be edited, silenced or deleted both throughout the body and selectively in certain types of cells or tissues. There are also mitochondrial DNA point mutations associated with atherosclerosis. To date, there are no animal models of these mutations, only the cybrid models were described [31, 32]. Mitochondrial DNA (mtDNA) editing is still a challenging task nowadays despite advances in nuclear genome modification, due to numerous limitations [33]. Only one of those limitations, namely, nuclease delivery into mitochondrial matrix, was rather successfully overcome by fusion of endonuclease protein with mitochondrial target signal [34]. However, DNA template delivery, homology recombination in mitochondria, sgRNA delivery, without which Cas9 is not able to cleave, are currently under research. The nuclear genome editing techniques were tested to modify mtDNA, but those applications are still very restricted and only used to eliminate mutant mtDNA haplotype. Mitochondria- targeted PstI, SmaI restriction enzymes were historically first nucleases that were used to shift the human mtDNA heteroplasmy ratios from mutant to wild-type [35, 36]. Their application was very limited because only three restrictases (PstI, SmaI and XmaI, the last being an isoschizomer of SmaI) are known to be applied to target only in two human diseases associated with mtDNA mutations [35-37]. Mitochondrial zinc-finger nucleases (ZFNs) were engineered to circumvent limitation of naturally occurring restriction enzymes, because it is possible to design ZFNs that can potentially bind and cleave any predetermined mtDNA sequence [38]. MitoTALEN is another type of endonuclease that was successfully used to shift down the heteroplasmy level for mtDNA mutation [39]. The CRISPR/Cas9 is an alternative to ZFNs and mitoTALEN for DNA manipulation approaches as it uses single guide RNA (sgRNA) instead of amino acid sequence to recognize target DNA [40, 41]. Upto date, there are only two papers, in which researchers demonstrated that mitoCas9 causes functional defects of mitochondria, which, in turn, lead to subsequent elimination of mitochondria [28, 42]. Unfortunately, there are practically no approaches for creating model animals, since all existing approaches are aimed only to removal of defective mtDNA. A prerequisite for the success of mtDNA editing should be a solution to the challenge of the simultaneous delivery of DNA template for homology-directed repair (HDR), single guide RNA (sgRNA), which is necessary to target Cas9 to the specific DNA site, and Cas9 protein itself. Recently, the import of RNA into human mitochondria was critically reviewed [43]. It was shown that tRNA import pathway may exist in human cells, and RNA import mechanisms were partly described. This data makes sgRNA import quite possible. Moreover, Verechshagina et al. have confirmed the possibility of sgRNA creation, which can be imported into human mitochondria (mitosgRNA). They combined this modified sgRNA with their version of mitoCas9 and successfully digested mtDNA [33]. This approach is an initial and very promising step towards the creation of CRISPR/Cas9 mitochondrial genome editing system. After all, CRISPR/Cas9 editing technology implicates the reparation of a double-strand breaks by homology recombination using homological DNA template [44]. Using biochemical assays, it has been shown that homologous recombination plays an important role in the maintenance of mitochondrial genome stability [45]. Based on this fact, it can be assumed that the DNA template delivery will be sufficient for mtDNA editing after mtDNA is cut by mitoCas9. Nowadays, there are physical, chemical and biological approaches to deliver DNA template into mitochondria [46]. The physical approaches compromise hydrodynamic injection [47] and biolistics [48]. Chemical delivery techniques include formation cationic micelle-like structure with DNA [49], precipitation of DNA using lipophilic molecule with delocalized positive charge [50], transport of DNA by amphiphilic and cationic lipid-based vesicle (DQAsomes) [51, 52], liposome transfection [53-55], dendrimer-based nanocarrier formation [56] and peptide-based carbon nanotubes construction [57]. The adeno-associated virus vector with MTS [58] and DNA-binding peptide conjugated with MTS [59] are promising biological approaches to delivering DNA into human mitochondria. Liposome combined with MTS despite cytotoxicity [60] may be the most promising delivering approach because it can be used for simultaneous delivery of Cas9 protein, sgRNA and template DNA for HDR into mitochondria. However, it remains unclear if this machinery will work properly in mitochondria to edit mtDNA. Also, there are CRISPR/Cas9 modifications that are able to edit DNA base without incorporating double-srand breaks and using DNA template by producing C>T and A>G substitutions [61]. These base editors may be used as an alternative strategy to modify mtDNA. MtDNA mutations are one of the important causes of atherosclerosis, but no relevant animal models still exist. The development of mice with mtDNA mutations, related to any disease, remains a challenge, because there is no approach how to transfect a mammalian mitochondrion. Until recently, the main strategy was to introduce mutations existed in cell lines into mouse embryos [62-64]. Later, the novel phenotype- based strategy that is based on detecting clonal expansion of pathogenic mtDNA mutations in colonic crypts of founder mice derived from PolgA+/MUT mtDNA mutator mice was described. Using this approach, the mouse line transmitting a heteroplasmic pathogenic mutation in the mitochondrial alanine tRNA gene was created [65]. To date, this method remains one of the easiest approaches to create animal model with mitochondrial mutations. The downside of this approach is the ability to apply only in mice, without the ability to use on other model animals. Another disadvantage of this approach is the impossibility of obtaining mice with mtDNA mutations that do not have an obvious phenotypic manifestation; such mutations can only be found by chance. For this reason, creating an approach that allows editing mtDNA directly remains relevant. Finalizing this introduction to the Special Issue, we should conclude that the contributors - several teams of international experts - have successfully represented the most novel topics related to the problem of vascular biology and atherothrombosis, and their views and opinions will provide the panel for further discussions and research activities. With very best regards to all contributors and readers.

Executive Guest Editor: Zhiqin Yuan

Nanomaterials with small size and unusual electronic structure make them distinctly different from bulk materials. With the ever-increasing nanotechnology, the generation of numerous functional nanomaterials and their applications in sensing, imaging, catalysis and pharmaceutics attract growing attention in recent decades. So far, many nanomaterials have been widely utilized for the development of sensing platform with satisfying sensitivity and specificity, including metal nanoparticles/nanoclusters, metal oxide/sulfide nanomaterials, carbon nanomaterials, and rare earth nanoparticles. They also show great potential in imaging, catalysis and antimicrobials. Alternatively, nanomaterials have also become one of the most attractive new drugs and antibacterial reagents.

Among these nanomaterials, biocompatible gold and carbon nanomaterials have been widely investigated due to their easy preparation, tunable optical/chemical properties, and high stability. Interestingly, the performances of nanomaterials could be altered by controlling their shapes and compositions, as well as surface functionalization. To achieve various purposes, much effort has been devoted to the exploration of facile approaches for the preparation of gold or carbon nanomaterials with different morphologies and compositions.

The generation of function programmable gold and carbon nanomaterials inspires researchers to fabricate diverse nanostructures with favorable performance and activity. Hybrid nanomaterials with multilevel structures provide synergistic effects, promoting their functionality.

Since the wide use of these functional nanomaterials in various fields, deep understanding of the working principle of nanomaterials will lead to a completely new realm of design of nanoprobe, nanodevice and nanodrug. Thus, the understanding of the working fundamentals of functional nanomaterials is beneficial to the betterment of nanotechnology.

This collection aims to summarize recent works in sensing and therapeutic applications using gold and carbon nanomaterials and collect the use of new concepts to develop novel analytical or antibacterial formats for homogeneous assays and the treatment of targets efficiently. Other contributions present a fundamental illustration of designed optical probes and nanodrugs. Another aspect addressed by this collection is the discussion of new directions using gold and carbon nanomaterials, which guides the future research of junior scientists.

We are sure that the readers of Current Pharmaceutical Design will appreciate this collection, which will provide a useful reference for additional studies as well as inspiring new techniques based nanomaterials. Zhiqin Yuan is currently an Associate Professor of the State Key Laboratory of Chemical Resource Engineering, College of Chemistry, Beijing University of Chemical Technology. He is an Editorial Board member of Current Chinese Chemistry from Bentham Science Publishers. His research interests focus on the synthesis and analytical application of small organic probes, metal nanoparticles and metal nanoclusters. He has published more than 50 articles in peer-reviewed journals.

Executive Guest Editors: Matilde Otero-Losada and Francisco Capani

Traumatic brain injury (TBI), a complex injury with a broad spectrum of symptoms and disabilities, not only pertains to adults but also newborns. Nearly one-third of the world population suffers from neurological diseases including Parkinson’s and Alzheimer’s diseases, multiple sclerosis, epilepsy, and spinal cord injury. Sometimes, deficits are seen in childhood and in others, they are delayed, arising in adolescence or young adulthood. Understanding brain injury pathophysiology contributes to identifying new neuroprotective agents.. While oxidative stress affects brain tissue and function, the other way round is also true. Oxidative stress and its foregone vicious epigenetic regulation follow traumatic brain injury and hemorrhagic stroke in the vascular neural network. Whether cause or effect, oxidative stress is a double-edged sword. It may help in fighting bacteria, but it may destroy the host too. This latent phase susceptible to an incidental and secondary injury brings about a therapeutic window and sets the grounds for neuroprotection. The aim of this special issue is bringing together the ac- crued research addressing the role of the reactive oxygen species (ROS) in the pathophysiology of brain injury and possible therapeutic strategies.

This special issue is focused on neuroprotective strategies for the brain, their possible pathways, and pharmacological analogs’ use. The topics include:

New insights on oxidative damage and iron associated impairment in Traumatic Brain Injury. This chapter is focused on the hem- orrhage caused by trauma and the ongoing oxidative process generated by biochemical disturbances in brain tissue which increase the level of iron and reactive oxygen species. The relationship between oxidative damage and the traumatic brain injury is well-known, for that reason, diminishing of the factors that potentiate the production of reactive oxygen species has promissory therapeutic uses. Iron chelators scavenge oxidative damage. The authors show an updated overview of the underlying mechanisms of oxidative damage in TBI, introducing the potential use of iron chelators as neuroprotective compounds [1, 2].

Copper and neurotoxicity in autism spectrum disorder. The authors discuss the role of metals, like copper, and the amyloid precursor protein (APP) derivative (s-APP-alpha) as an antioxidant and a possible adjuvant in the treatment of some autistic spectrum disorder symptoms (ASD) [3].

Neuroinflammation in demyelinating diseases: oxidative stress as a modulator of glial cross-talk. A preserved hallmark of this neuroinflammatory scenario is a local increase of oxidative stress, where several cytokines and chemokines are released by glial and other cells generating an environment that determine cell interaction and the outcome of oligodendrocyte maturity and ability to neosynthesize myelin. The authors review the main features of the regulatory aspect of these molecules and propose new putative signal molecules involved in remyelination, focused in the etiology of Multiple Sclerosis [4, 5].

Energy-sensing pathways in ischemia: The counterbalance between AMPK and mTORC. Stroke is an important cause of death and disability, and it is the second leading cause of death worldwide. In humans, middle cerebral artery occlusion (MCAO) is the most common cause of ischemic stroke. This review analyzes to what extent the lack of each of the elements of the system produces damage and which mechanisms are unchained by this deficiency [6, 7].

β-amyloid and oxidative stress: perspectives in drug development. This chapter is focused on the reciprocal regulation of β-amyloid protein (Aβ), that causes oxidative stress, and oxidative stress, that favors Aβ aggregation and toxicity and negatively affects the peptide clearance. Analysis of this strict interaction may offer novel opportunities for therapeutic intervention. Molecules endowed with antioxidant properties deserve attention in this regard [8, 9].

Oxidative Stress-Induced Brain Damage Triggered by Voluntary Ethanol Consumption during Adolescence: a Potential Target for Neuroprotection? The mechanisms involved in alcohol-induced brain damage in developing individuals and the effect of different potential neuroprotectants which prevent alcohol-induced oxidative stress are reviewed. A selective inhibitor of the endocannabinoi anandamide, a flavonol present in different fruits (quercetin), an antibiotic with known neuroprotective properties (minocycline), a SOD/catalase mimetic, a potent antioxidant and anti-inflammatory molecule (resveratrol), the female hormone estradiol known to have antioxidant properties, a powerful scavenger of ROS (melatonin) or an isoquinoline alkaloid (berberine) may be relevant to treating alcoholism [10, 11].

Long-term effects of hypoxia-reoxygenation on thioredoxins in rat central nervous system. Oxidative stress induced by the oxidative pathway dysregulation following ischemia/reperfusion has been proposed as an important cause of neuronal death and brain damage. The proteins of the thioredoxin (Trx) family are crucial mediators of protein function regulating the intracellular hydrogen peroxide levels and redox-sensitive post-translational protein changes. The authors evaluated the long-term effects of common carotid artery ligation-induced ischemia/reperfusion on the protein expression and distribution of fourteen members of the Trx family and related proteins in cerebellum, corpus striatum, and the hippocampus. The thioredoxin proteins displayed a complex, cell-type, and tissue-specific expression pattern following ischemia/reperfusion [12-14].

Activation of Melanocortin-4 Receptor by a Synthetic Agonist Inhibits Ethanol-induced Neuroinflammation in Rats. The activation of melanocortin-4 receptor (MC4R) in the brain decreases the neuroinflammatory response in models of brain damage. The authors discuss whether MC4R activation by a synthetic MC4R-agonist peptide prevents ethanol-induced neuroinflammation, and if alcohol consumption produces changes in MC4R expression in the hippocampus and hypothalamus. The administration of a synthetic MC4R- agonist peptide prevents neuroinflammation induced by excessive alcohol consumption in the hippocampus, hypothalamus and prefrontal cortex. The results could explain the effect of α-MSH and other synthetic MC4R agonists in decreasing alcohol intake, through the reduction of the ethanol-induced inflammatory response in the brain [15, 16].

Executive Guest Editor: Nikolaos Patelis

Since the first use of x-rays, it became necessary to enhance the angiographic image of different tissues and organs in order to separate them from their surrounding anatomic structures, depict in detail the area of interest and ease the diagnosis through the enhanced final image. Iodinated contrast (IC) solutions were both safe and effective in delineating the vascular bed and in the early 20th century, Brooks first reported on the use of such an IC to produce a clear image of lower extremity arteries of patients with severe peripheral arterial disease, in order to determine the proper level of lower extremity amputation.

Despite the advances in medical imaging, fluoroscopy with an IC agent is still considered the gold standard for performing endovascular vascular procedures and angiography with IC is still routinely used to diagnose vascular pathology.

In a number of cases, the intravascular administration of IC is linked to potential risks of adverse reactions. These adverse reactions can be general or renal and their severity varies significantly from minor to life-threatening. The onset of an adverse reaction can be acute (within an hour of administration) or delayed. Minor adverse reactions include self-limiting symptoms such as flushing, nausea, vomiting, pruritus, and mild urticaria. IC-related life-threatening reactions are anaphylactic shock and acute kidney injury (AKI) due to IC nephrotoxicity. The pathophysiological mechanism of the injury to the renal parenchyma is described in detail by Georgalis et al. Special attention should also be given to the interference of IC and other medications, especially if the latter is eliminated through the kidneys.

In order to avoid IC-induced AKI, a number of methods are employed. The volume of IC necessary for angiography of different vascular beds varies significantly, as well as the rate of injection. Therefore, the first method to reduce the risk of AKI during a vascular procedure is to reduce the total dosage and the per injection volumes of IC. This reduction of IC volumes comes to a cost: the reduction of imaging quality. The vascular surgeon or the interventional specialist should employ proper techniques to reduce the use of IC while maintaining the quality of the vascular imaging, especially when it comes to finer structures below the infrainguinal ligament. In the endovascular repair of aneurysms of the infrarenal aorta (EVAR) or more complex aortic procedures, the volume of IC is significantly higher and it is injected at the level of the renal arteries or more proximal. Therefore, these procedures need additional caution and effort in order to lower the risk of AKI. If post-procedural IC-AKI is suspected, then a decrease in glomerular filtration rate should be expected, but other biomarkers indicating that the renal function is impaired exist.

A different approach to reducing the risk of AKI in patients undergoing an endovascular procedure is to eliminate the use of IC and perform angiographies using an alternative contrast material, such as carbon dioxide (CO2). The properties and the physiology of CO2 are substantially different from those of IC, therefore, the technique of CO2 angiography and the image produced are not similar to IC angiography. CO2 angiography is a “new” method of vascular imaging during an endovascular procedure, but novel automatic delivery systems make this method safer and more efficient compared to the old manual administration. This could be the revival of this old method of avoiding IC-related AKI.

In this special issue on AKI after endovascular therapy, the journal aims at providing the information that a vascular surgeon or an interventional specialist needs in order to minimize the risk of this life-threatening condition in their patients.

Executive Guest Editor: Hsiuying Wang

NEUROLOGICAL DISEASES

Neurological disorders are diseases that affect the brain, spine and nervous systems. There are more than several hundreds of neurological disorders including Huntington's disease, muscular dystrophy, spina bifida, Parkinson's disease, Alzheimer's disease, stroke, epilepsy, brain tumors, and meningitis. Some of them are not easily diagnosed at an early stage. To accurately diagnose these disorders, in addition to diag- nosis based on clinical symptoms, molecules biomarkers are useful tools to help determine these diseases in an early stage. Therefore, explor- ing biological biomarkers is an important issue in recognizing diseases and understanding the mechanism of these diseases.

VACCINES AND ADVERSE EVENTS

Vaccines are one of the most preventive measures against certain diseases. However, many clinical reports revealed that neurological disorders are associated with various vaccinations, including tetanus, diphtheria, pertussis, and poliomyelitis, H1N1 influenza and Japanese encephalitis vaccinations. The neurological syndrome associated with vaccinations includes encephalitis, Guillain-Barre syndrome, febrile convulsion, poliomyelitis, etc. [1-5]. Adverse neurologic events have raised concern about vaccine safety. Vaccination has a known risk, of- ten in people with an immune deficiency. The safety of vaccines has been disputed for a long time. In this thematic issue, clinical cases and the association between vaccinations and neurological disorders are discussed. In addition, related topics such as molecules biomarkers for neurological disorders, and bioinformatics methods for exploring neurological disorders are included in this issue. Pharmaceutical research and vaccine development are closely related. This thematic issue collects papers for contributing to pharmaceutical research and vaccine development.

ESSAYS WITHIN THIS SPECIAL EDITION: TOPIC SUMMARIES

Dr. Tatsuya Akutsu and his student Shogo Nakashima at Bioinformatics Center, Institute for Chemical Research, Kyoto University, and Dr. Jose C. Nacher at Department of Information Science, Faculty of Science, Toho University, along with Dr. Jiangning Song at Monash Biomedicine Discovery Institute, Monash University, review bioinformatics methods for analyzing Autism Spectrum Disorders data with the focus on computational aspects [6]. Dr. Taguchi at Department of Physics, Chuo University, and Dr. Turki at Department of Computer Science, King Abdulaziz University, propose a strategy to screen differentially expressed genes in Alzheimer's disease model mouse brain, and this method is useful to screen drug candidate compounds using scRNA-seq data set [10]. Dr. Bak-Sau Yip and his colleagues Yichen Lee and Pingchen Chou at Department of Neurology, National Taiwan University Hospital, Bo Hahn Lee at Department of Geriatrics, Northern Beaches Hospital and Mr. William Yip at Department of Pathology and Laboratory Medicine, University of British Columbia, review neuro-filament protein as a biomarker in different neurological disorders [7]. Drs Maoqiang Tian, Jing Yang, Lei Li, Juan Li, Wenting Lei and Xiaomei Shu, at Department of Pediatrics, Affiliated Hospital of Zunyi Medical University review vaccine-associated neurological adverse advents and report a child with acute flaccid paralysis that may be caused by poliovirus vaccine [8]. Dr. Hsiuying Wang at Institute of Statistics, National Chiao Tung University, reviews the vaccines associated with anti-NMDA receptor encephalitis. Also, anti-NMDA receptor encephalitis cases that were induced by virus infection are reviewed.

ACKNOWLEDGEMENTS

Organization of this special edition was supported by the grant from Ministry of Science and Technology 107-2118-M-009-002-MY2, Taiwan. In recognition of the participation of contributors to this editorial, we express our gratitude to Professor W.A. Banks, the Editor-in-Chief of the Journal, and his team Mr. Kazim Baig and Mr. Aamer M. Khan for their help and support. This body of work reflects the high standards of Current Pharmaceutical Design and will stand as a valuable resource for years to come.

Executive Guest Editor: Ling-Qing Yuan

Exosomes are extracellular vesicles ranging in diameter from 30 to 150 nm that contain miRNA, mRNA, protein, lipid and so on. Exosomes act as biological mediators that mediate different physiological and biological functions through cell–cell communication, such as participating in the immune response and facilitating antigen presentation. Exosomes play a pivotal role in the diseases of the nervous system, inflammatory diseases, nephropathy, metabolic bone diseases, tumorigenesis and so on. Exosomes can deliver various agents, such as RNAs or proteins, from donor cells to target cells or tissue, contributing to various aspects of physiological functions and the pathogenesis of various diseases. Moreover, many methods have been introduced to load therapeutic agents into exosomes, especially using exosomes to transfer mRNA or protein. Recently, lots of interesting studies have evaluated natural nanoparti- cles as therapeutic strategies in treating cancer, cardiovascular disease, kidney disease, neurodegenerative disease and so on. Moreover, exosomes are also proposed to be disease biomarkers. The thematic issue collected reviews from several high reputation experts in exosomes, exploring the current progress of exosomes in pre- clinical and clinical usage in sepsis, fibrotic diseases, Parkinson’s disease, musculoskeletal diseases and bone disease. Dr. Kluszczyńska K et al. [1] outlined the generation, composition and biological function of exosomes. They also described and evalu- ated the various methods used for the isolation of small vesicles,and give the assessment of advantage and disadvantage of various methods. Then, the authors also compared the quality of exosomes based on different protocols. Park EJ et al. [2] analyzed the role of exosomes in sepsis, which mediates communications between homeostasis and multiple organ fail- ure. In particular, exosomes could act as nanocarriers for drug delivery in the treatment of patients with sepsis or inflammatory tissue injury. Furthermore, Li M et al. [3] described that exosomes could carry the profibrotic signals involved in the pathogenesis of fibrotic diseases. Moreover, serving as the potential biomarkers, exosomes might be initially used for the treatment of fibrotic diseases. In addition, Longoni B et al. [4] outlined the function of exosomes in the pathogenesis of Parkinson’s disease, providing the potential application of exosomes as biomarkers or drug delivery in Parkinson’s disease. Besides, Tu C et al. [5] summarized the recent progress of exosome-derived from ncRNA in the musculoskeletal diseases including os- teoarthritis, rheumatoid arthritis, osteoporosis, muscular dystrophies, osteosarcoma, and other diseases. Finally, Shan SK et al. [6] summarized the pathophysiological mechanism, clinical significance, and therapeutic effects of exosomes in bone metabolism.

Executive Guest Editor: George Anderson

The growing incidence in the levels of people classed on the autism spectrum disorders (ASD) is accelerating exponentially, making ASD pathophysiology and targeted treatment cutting edge areas of research. People classed with ASD show a wide range of biological alterations, including genetic and epigenetic, with an etiology that is generally accepted to arise via changes occuring prenatally and early postnatally. Much of the research on ASD pathophysiology has focussed on systemic processes, including alterations in the immune system and immune modulators, such as gut dysbiosis and increased gut permeability. Biological treatments are currently limited, often restricted to the use of antipsychotics in order to dampen agitation and irritability. However, there is a slowly growing body of data looking at biological treatments based on measured alterations in subgroups of people classed with ASD. This themed edition of Current Pharmaceutical Design focuses on the pathophysiological underpinnings of ASD from an early develop- mental etiology to the changes occuring in later life. The authors of these articles are widely regarded as leading experts in their fields and have been gathered from countries worldwide. The article by Anderson and Medina [1] looks at the role of antenatal and prenatal factors, including genetic and epigenetic, in driving alterations in the development of the foetal immune system, especially on the role that gammaDelta (γδ) t cells may play in this. The conse- quences of this are proposed to alter the mucosal immune system's regulation of the development and functioning of the postnatal gut. The role of prenatal stress and maternal immune dysregulation in the etiology of ASD are detailed by the work of Beversdorf and col- leagues [2], with potential points for intervention. These authors highlight the role of maternal stress susceptibility interactions with prenatal stress exposure and highlight the recent work implicating a role for specific fetal brain proteins targeted by maternal autoantibodies, and the identification of unique mid-gestational maternal immune profiles. This is followed by the article by Seo and Anderson [3] looking at the role of alterations in gut functioning that drive changes in central development, especially via gut-driven modulation of amygdala development, with consequences for how the amygdala influences the early regulation of cortex development and wider brain inter-area connectivity. The article by Alzghoul [4] highlights the role that vitamin D may play in the early developmental etiology of ASD, including via its modulation of the developing immune system and the interactions of the mother and foetus. The relevance of vitamin D in the treatment of childhood and adult ASD is also reviewed in this article. The role of microRNAs in mediating the interactions of genetic, epigenetic and environmental factors in the pathophysiology of ASD is reviewed by Mahesh and colleagues [5]. These authors summarize our current knowledge on microRNAs and their complex roles in ASD, as well as on their therapeutic applications. A growing body of data has highlighted the role of circadian factors in the pathophysiology of ASD, including in the interactions of be- haviors problems, immune-inflammation, sleep disorders, and reduced circadian neuroendocrine responses. This is reviewed by Pinato and colleagues [6], with the authors proposing that the low levels of melatonin in ASD are a significant treatment target. A proportion of people with classic ASD symptomatology have a specific mutation leading to a diagnosis of Fragile X syndrome. The pathophysiology of this condition is strongly associated with alterations in synaptic functioning, with treatment and wider ASD implications. This work is reviewed by Telias [7]. The article by Maes and colleagues [8] looks to integrate ASD pathophysiology via alterations in mitochondrial function and the putative role of the mitochondrial melatonergic pathways. This incorporates wider bodies of data pertinent to ASD, including alterations in vitamin A, CD38, oxytocin, and serotonin, with particular relevance to early developmental processes in the placenta and gut as well as to how these have treatment implications across the lifespan. The wide array of physiological alterations in ASD, including in neurotransmitters, antioxidants and neuroinflammation provide the basis for looking at the potential of herbal medicines in the management of ASD symptomatology. This work is reviewed by Kardani and col- leagues [9], who propose a number of herbal medicines that may be useful in ASD treatment, including Zingiber officinale, Astragalus membranaceu, Ginkgo biloba, Centella asiatica and Acorus calamus. Pacheva and Ivanov [10] provide a wider overview of biologically based treatments in the management of ASD. These authors detail an extensive collection of data on the range of treatment options and highlight the need for the treatment of targed subgroups that have been defined by specific pathophysiological alterations at baseline. Finally, the article by Ruggieri and colleagues [11] overviews the available data on ageing in ASD, and the implications that this has for treatment and quality of life. On the basis of this overview the authors detail the need for treatment and service options that will be necessary to manage ageing in ASD.

ACKNOWLEDGEMENTS

As the guest editor of this thematic issue, I am grateful to the contributors and reviewers for their time, consideration and insight. It is hoped this themed edition will provide insights and inspiration for the development of treatments that are based on a better understanding of the biological underpinnings of this poorly defined spectrum of medical conditions.

Executive Guest Editor: Bing Niu

Precision Medicine is a medical concept and medical model based on personalized medicine, developed with the rapid advancement of genome sequencing technology and the cross-application of bioinformation and big data science. Essentially, through the genomics, pro- teomics and other omics technologies and medical frontier technologies, the analysis, identification, verification and application of biomark- ers for a specific disease are performed to accurately reveal the cause of the disease, the target of treatment as well as accurately sub- categorize different states and processes of disease. Finally, it is possible to achieve the purpose of personalized and precise treatment for diseases and specific patients, and improve the effectiveness of disease diagnosis and treatment.

Despite novel approaches being an attractive strategy in treatment, persistent gaps do exist between published research and clinical application. Thus, there is a need to fundamentally address all the above-mentioned issues in this issue.

Following are the seven interesting researches in this special issue:

• An insightful 10-year recollection since the emergence of the 5-steps rule,

• Prediction of K562 cells functional inhibitors based on machine learning approaches,

• Recent Development of Computational Predicting Bioluminescent Proteins,

• Advances in the detection, mechanism and therapy studies of chronic kidney disease,

• Oncolytic virotherapy for malignant tumor: current clinical status,

• Study of mechanism on binding between Neratinib and MAD2L1 based on molecule simulation and multi-spectroscopy methods,

• Application of Genome-Wide Association Analysis in the Study of Coronary Artery Disease.

Since the 5-steps rule was proposed in 2011, it has been widely and increasingly used as the guidelines to develop new prediction meth- ods or predictors for various proteome or genome analysis. Chou et al introduced this rule because it has the following notable merits: (1) crystal clear in logic development, (2) completely transparent in operation, (3) easy to repeat the reported results by other investigators, (4) have high potential in stimulating other sequence-analyzing methods, and (5) very convenient to be used by the majority of experimental scientists [1].....

Executive Guest Editors: Anna Aiello and Giulia Accardi

1. INTRODUCTION

Aging is one of the main health-related challenges in the world. The average life expectancy of the global population at birth is increasing up to 72 years, in 2016 and it increases about two years every decade. The healthcare costs in many countries are very high because of the increased number of unhealthy populations, and the consequent increase of severe age-related disabilities [1]. Therefore, the goal of the future should be the achievement of the so-called “health-span” (healthy-life-span), more than the treatment of age-related disease to prevent the collapse of the health system. In order to achieve this objective, it is necessary to identify new targets and biomarkers and to address key is- sues of aging to delay or prevent the onset of pathologies and disorders. This would allow to develop or to identify anti-aging therapies, modulating aging rate, or tested known drugs for different uses (i.e. to reduce systemic or local inflammation). Aging is an ineluctable process, which affects all cells, tissues, organs, and organisms, narrowing the homeodynamic space and increasing organism vulnerability, although it has demonstrated in model organisms the possibility to modulate some pathways related to aging proc- esses. Systemic aging causes a reduction in the response to environmental stimuli and, in general, is associated with an increased predisposi- tion to disease and death. However, there are two ways to become old: without success (unsuccessful aging, UA) and with success (successful aging, SA) [2, 3]. UA is manifested by people that develop one or more age-related diseases, such as neurodegenerative (Alzheimer’s or Park- inson’s disease), metabolic (metabolic syndrome and type 2 diabetes mellitus), cardiovascular, and cancer [2]. Regarding SA, the World Health Organization defines it as “the process of developing and maintaining the functional ability, which enables well-being in older age”, and defines healthy aging as “the process of developing and maintaining the functional ability, which enables wellbeing in older age” [3, 4]. Thus, promoting healthy and successfully aging is a key priority, taking into account that this trait is heterogeneous and is influenced by ge- netic, epigenetic, and environmental factors. In adulthood, the heritability of age of death is approximately 25%, but it can reach even 48% in males who achieve exceptional longevity. Many of the genetic aspects of longevity include mutations or polymorphisms, which can occur at different frequencies within a population. Indeed, longevity genes affect a vast spectrum of biological functions that improve the feature of repair mechanisms, increase the resistance to stressors like virus and injury, and slow the age-related changes in cells and tissues. The remain- ing part is due to the environmental exposure, chance, stochastic events, access to health care, and lack of trivial accidents [5, 6]. The correlation between genetic background and the environment in determining the individual chance of delayed aging or SA is an emerging topic in gerontology. Therefore, the proven and significant correlation between the effects of environment and molecular pathways may be used as preventive measures to increase the chance to attain longevity or health-span.

2. THE SERIES

This series collects eight reviews focusing on some genetic aspects of aging and interesting target and strategies to counteract diseases and disabilities. Caruso et al. [7], reviewed the genetic aspect of longevity to debate about the way of achieving successful aging. In particular, they re- ported data on the main polymorphisms associated with longevity -APOE, FOXO3A and BPIFB4- suggesting some possible targets for achieving successful aging and highlighting the value of the use of centenarians as a model to identify new strategies and therapies. Guarasci et al. [8], considered epigenetic, aging and longevity and focused on on DNA methylation profile. They paid particular attention on the modification in both nuclear and mitochondrial genomes, made by endogenous and exogenous causes. Moreover, they focussed on the importance of personalized methylation-medicine, using epigenetic biomarkers as therapeutic outcomes. Cammarata et al. [9], focused on a new interesting topic: miRNA in aging and longevity. They covered the main aspects of this field, reporting personal observation of unpublished data. In particular, they illustrated variations between circulating miRNAs at different ages, highlighting the importance of environmental influence on different miRNA expression profiles and their use as biomarkers. Witkowski et al. [10], examined the evolution of the immune system. They described the evolutionary changes over the years, in the story of human beings, leading to the onset of immunesenescence and inflammaging, as a consequence of population aging. They reported the main features of these two processes, analyzing their pros and cons and offering possible solutions for their modulation. Zareian et al. [11], described Toll-like receptors (TLRs) and vaccination. Starting from their expertise, they described the role of dendritic cells and TLRs in immunity, reported the novel data related to the use of TLRs agonist in the vaccine. Firstly, they described the evidence on model organisms, concluding with interesting preliminary data on humans about new strategies for vaccination in elderly people. Gambino et al. [12], addressed the issue of the neuroinflammatory disorders in UA. The aim of their review was to analyze the deep con- nection between these age-related diseases and the state of inflammation associated with them. The identification of the peripheral biomark- ers, as therapeutic targets, commonly involved in the pathophysiologic development of neuroinflammatory processes, could be helpful to identify high-risk individuals at the early stage of the disease, thereby, improving the efficiency of treatment. Mangoni et al. [13], discussed the potential therapeutic applications of methotrexate in the vasculoprotection, whereas, the old age is characterized by cardiovascular risk. The authors reviewed the in vitro and in vivo studies investigating the effects of methotrexate on the cardiovascular system, and the potential mechanisms of action on it. The available evidence suggests that this drug might exert beneficial effects on vascular homeostasis and blood pressure control by specific inflammatory pathways. Scuderi et al. [14], illustrated the potential and therapeutic role of melatonin in ocular disease both in age-related and unrelated diseases, such as uveitis, glaucoma, age-related macular degeneration, and diabetic retinopathy. Literature data suggest that the neurohormone could potentially protect ocular tissues by scavenging free radicals and reducing inflammatory mediators, concluding that melatonin, as a single agent or in combination with other drugs, is an attractive pharmacological candidate for age-related ocular diseases.

CONCLUSION

Aging and anti-aging therapies are emerging fields involving different branches of medicine and biology. In the last decades, one of the aims within the scientific community is to slow down the aging process and avoid main age-related diseases, an approach called as positive biology. The genotype can influence lifespan: changes in the duration are observed as a result of variation of a single allele. But studies in model organisms have shown that aging is not an immutable process. Despite being ineluctable, its rate can be modified by exogenous interventions, influencing molecular patterns. This special issue collected a selection of invited original reviews from experts in the aging field, covering molecular and clinical ap- proaches as strategies to counteract age-related diseases and disabilities.

Executive Guest Editor: Manasa K. Nayak

Cardiovascular disease (CVD) is the leading cause of deaths globally. It accounted for more than 17.6 million deaths in 2016 and the number is expected to reach 23.6 million by 2030 [1, 2]. In the USA, CVDs were responsible for 840,678 deaths in 2016, which accounts for 1 in every 3 deaths [3]. The CVDs that contributed to this mortality included coronary heart disease (CHD) (43.2%), stroke (16.9%), hyper- tension (9.8%), heart failure (9.3%), diseases of the arteries (3.0%), and other CVDs (17.7%). In the UK, CVDs accounts for nearly 34% of all deaths each year [4]. This figure rises to reach approximately 40% in the European Union. Besides this, CVDs also accounted for ap- proximately 14% of the total health expenditures in 2014-2015, which is more than any other major diagnostic group. Total direct medical costs of CVD are projected to increase to $749 billion by 2035, which would lead to a significantly high socio-economic loss [5]. The prevalence of CVDs is predicted to increase worldwide because of the rise in associated risk factors, even in countries that were pre- viously categorized as low-risk countries. Presently, more than 80% of the global burden of CVDs occurs in low-income and middle-income countries. By 2020, CVDs are expected to surpass infectious diseases to become the major cause of mortality in most developing nations [6]. Not only CVD is a leading cause of mortality, but it is the foremost cause of loss of disability-adjusted life years globally [7]. According to the World Health Organization (WHO), 75% of premature CVDs are preventable by ameliorating risk factors [8]. This can significantly re- duce the overall rise in CVD burden on both individuals and healthcare providers. While aging is one of the principal risk factors for the progression of CVDs, autopsy evidence has shown that the process of developing CVD in later years is not unavoidable, which provides risk reduction fundamental importance [8]. The INTERHEART study elucidated the causative effects of CVD risk factors such as dyslipidemia, smoking, hypertension, diabetes and abdominal obesity. These risk factors exist consistently across all the population and socioeconomic levels, which suggests the viability of uniform approaches towards the prevention of CVDs globally [9].

Executive Guest Editor: Martín Desimone

The scientific community admits in a general way that nanomaterials (NMs) are those made up of materials with at least one of their spa- tial dimensions less than 100 nm. Thus, it is possible develop nanomaterial with only one dimension in the nanoscale (i.e.: nanosheets), two nanoscale dimensions (i.e.: nanotubes) and three nanoscale dimensions (i.e.: nanoparticles). At these sizes, the materials show very special physical-chemical properties due mainly to their high specific surface area, which means that they can possess high reactivity and a very high number of possible interaction points. These would be more complex considering that nanomaterials would be solid, porous or hallow, crys- talline or amorphous, organic or inorganic and any combination of them. Moreover, nanomaterials can be subjected to various surface func- tionalization. Nanomaterials has a long history. Indeed, they were found in structures obtained more than one thousand years ago. Although, the con- tinue growing interest and development experienced nowadays is mainly due to the ability to engineer, manipulate and image systems in the nanoscale. The synthesis of nanoparticles is generally carried out under controlled thermodynamic conditions and from atoms or molecules. In this way, nanoparticles especially designed for applications in a wide range of technologies that affect the electronics, telecommunications, medi- cal, pharmaceutical, chemical, automotive, aerospace and energy industries, among many others, can be obtained. Unlike, there are nanoparti- cles that are unintentionally produced, such as productions during combustion processes. In all cases, the physical and chemical properties are extremely important, since they will determine the correct function of the nanoparticles or the products that contain them as well as their de- gree of toxicity or safety. As a result, these NPs possesses new properties not completely known yet. For example, they can cause toxicity through mechanisms not described so far, ranging from the simple physical union to the cells to the triggering of complex processes that lead to an elevation of oxida- tive stress. On the other hand, the properties of these NPs will generate new advances in science and technology. For example, they can inter- act with therapeutic molecules, reach specific organs or penetrate cells by various mechanisms. Thus, study the fate and effect nanomaterials is important not only from the point of view of toxicology but also from the possible use of NPs in therapeutic formulations. This thematic issue gathers information from the Fate and Effects of Nanomaterials with and emphasis in the potential therapeutic uses. Moreover, it also generates a forum for discussion of nanotoxicological effects, including the effect in different biological systems (i.e.: in- sect, fish and cells). The review of Dusica Maysinger and Jeff Ji, highlights the effect of some nanostructures that can alter the state of activation of microglia and astrocytes in different biological models. The focus is on some “hard” nanoparticles (e.g. gold nanoparticles and gold nanoclusters) and some “soft” (e.g. dendritic polyglycerol nanostructures). They present effects of these nanostructured materials in dissociated neural cells, cells in 3D and in vivo models [1]. The article of Sajjad Molavipordanjani and Seyed Jalal Hosseinimehr summarizes and integrates the current state of knowledge on differ- ent strategies for conjugation of biomolecules to nanoparticles and their application in tumour targeting [2]. Cazenave et al., describe the current state-of-the-art on nanotoxicity using fish as models. This review gives a current overview of the main effects and toxicity mechanisms of nanoparticles and highlights the knowledge gaps, which still are needed to be further investigated [3]. Kuldeep Rajpoot outlines the enormous promise that SLNs have as promising nanomaterials for efficient delivery of various Active Pharmaceutical Ingredients (APIs) for healthcare improvements [4]. Mauricio De Marzi and co-authors present different studies that have been carried out to evaluate the response of immune cells in the presence of nanoparticles and its possible applications in the biomedical field [5]. Regarding the use of nanoparticle-mediated drug delivery systems to treat infectious diseases in CNS, an interesting article by Marcos Vinicius da Silva and collaborators, summarizes the use of nanoparticles as an extremely applicable alternative. It is highlighted that the transport of drugs with chemical and physical characteristics that prevent them from reaching the CNS at therapeutic concentrations can pro- vide stability, restricted release and increased bioavailability in specific areas [6]. The review of Professor Lúcio R. Cançado Castellano group highlights current applications of biopolymer-based nanofibers as drug de- livery systems and scaffolds. Important techniques employed to produce natural nanofibers are presented. Moreover, some evidences regard- ing toxicology and cell interactions using natural nanofibers are discussed [7]. The topics developed by Ratiram Chaudhary et al., are emerging technologies on metal/metal oxide nanoparticles and their characteristics such as size, shape, particle dissolution on their induced toxicity. The focus is on the toxicity and current and future issues and applications [8]. Finally, Santo Orihuela et al., summarized the state of knowledge on silica nanoparticles (SiNPs) used in pest insect management. Be- sides, aspects of their synthesis, mode of action, and toxic effects on non-target organisms and environment are reviewed [9].

Executive Guest Editor: Semanur Kuyucu

It is my great pleasure to be a guest editor for this special thematic issue of the Current Pharmaceutical Design entitled “Current Status and Advances in Severe Drug Hypersensitivity Reactions” contributed by distinguished authors who are highly experienced and cited in the scientific area of drug hypersensitivity reactions.

1. “PRIMUM NON NOCERE”

The so-called Hippocratic warning “first do no harm” has been an axiom central to the education of medical and graduate students for centuries [1]. In the last decades we have been witnessing a global ever-increasing production and consumption of pharmaceuticals [2]. With the increasing knowledge of the nature and magnitude of adverse reactions to drugs, this maxim remains a potent reminder that every medical and pharmacological decision carries the potential for harm. A physician should always balance the risks of harm and the potential for benefit during drug prescription to his/her patients. In the emerging era of precision medicine, any health care provider should be familiar with the expected and unexpected adverse drug reactions, some of which, may be fatal [3]. Drug hypersensitivity reactions (DHR) are defined as type B adverse drug reactions, among which those with an immunological mecha- nism are termed drug allergies. They constitute approximately 15% of all adverse drug reactions and affect more than 7% of the general popu- lation [4]. Among DHRs severe adverse cutaneous drug reactions (SCAR) such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome and severe organ-specific reactions such as drug-induced liver injury, result in considerable morbidity and mortality and will probably remain to be so in the future when one considers the exponen- tially increasing introduction of new drugs [5]. Physicians need to be able to understand the mechanisms, know the risk factors and high-risk medications, be aware of early biomarkers and immediately recognise the phenotypes of severe DHRs to enable immediate drug withdrawal and appropriate management. In spite of their rarity, severe DHRs have a huge impact on public health due to high mortality rates [6]. Hence, the avoidance of these reactions should also be considered a public health and drug policy issue of high-priority. In this context, approaches such as pharmacogenetic tests to select patients at risk for severe DHRs, epidemiological studies and pharmacovigilance algorithms should be implemented. The recent pharmacoge- nomic discoveries about severe delayed DHRs have created the promise of prevention and they are rapidly evolving from different parts of the world [7]. Alongside, accurate diagnostic tools which can predict potential DHRs in the pre-clinical phase of drug development are also a critical expectation. Our knowledge on severe DHRs increasingly accumulates every year and therefore, what we know so far, should be fre- quently updated, which is the major aim of this issue.

2. ESSAYS WITHIN THIS SPECIAL EDITION: TOPIC SUMMARIES

In this issue the current status and recent developments in severe DHRs are extensively reviewed in seven sections. First; epidemiology and risk factors for severe delayed drug hypersensitivity reactions are discussed in depth by the leadership of an expe- rienced author from Porto University of Portugal, Dr Eva Rebelo Gomes together with Dr. Maria Luís Marques from the Allergy and Clinical Immunology Department of Centro Hospitalar e Universitário do Porto,and Dr. Frederico S. Regateiro from the Allergy and Clinical Immu- nology Department of Centro Hospitalar e Universitário de Coimbra [8]. A group of authors from the Allergy Research Group of Instituto de Investigación Biomédica de Málaga-IBIMA-ARADyAL, and Universidad de Málaga led by Prof. Cristobalina Mayorga provided state-of- the-art insight into the immunological, metabolic and genetic mechanisms in drug hypersensitivity reactions which are strongly related to phenotypes and severity of reactions [9]. Another team of authors from Spain from the Allergy Unit of Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga, and Andalusian Center for Nanomedicine and Biotechnology-BIONAND led by the director Prof. Dr. Maria J. Torres, discussed the evolving early biomarkers for severe DHRs, such as human leukocyte antigen (HLA), in- flammatory and lipid mediators in serum, or cytokines, chemokines, and cytotoxic markers in skin biopsies, which may hold the promise of early detection and prevention of these hazardous reactions [10]. The clinical presentations, findings and complications of severe cutaneous adverse reactions (SCAR) to drugs such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and sys- temic symptoms (DRESS) syndrome, acute generalized exanthematous pustulosis and other phenotypes and danger signs for these reactions are reviewed in detail by a group of authors specialized in Pediatric Allergy and Clinical Immunology from Turkey under the senior author- ship of Prof. Dr. Emine Mısırlıoglu [11]. A different and often underdiagnosed/underdiscussed presentation of severe DHRs is drug-induced liver injury (DILI). The criteria used for DILI recognition among SCARS, the drugs most commonly involved in these syndromes as well as the outcome, prognostic factors and the need for a multidisciplinary approach to improve the management of DILI in the context of SCARs is discussed in depth by a very experienced multidisciplinary team including researchers from departments of clinical pharmacology, immunol- ogy and gastroenterology/hepatology led by Prof. M. Isabel Lucena, Head of Clinical Pharmacology and Founding Director of Malaga Bio- medical Research Institute and Prof. Raúl J. Andrade, the Director of the Service of Gastroenterology and Hepatology of University Hospital of Málaga (Spain) and the Director of the Spanish DILI Registry network (www.spanishdili.uma.es) and of the Spanish Latin-American DILI Network (www.slatindili.uma.es) [12]. Diagnosis of a causative underlying drug hypersensitivity and confirmation or exclusion of the role of incriminated drug(s) by tests is mandatory due to the high morbidity and mortality upon re-exposure with that agent, although the utility of some tests are limited. Relevant to diagnostic testing of severe DHRs, Prof. Jean-Christoph Caubet from Pediatric Allergology unit of Uni- versity Hospitals of Geneva, Switzerland and Dr. Marcel Bergmann from Centro Pediatrico del Mendrisiotto, Switzerland gave updated and detailed information about the test types, predictive values and algorithms of in vivo and in vitro test procedures in the diagnosis of SCARs [13]. Lastly, the current supportive and targeted treatment options and advances in the management of SCARs are discussed systematically by experienced authors from Turkey; Prof. Dr. Aslı Gelincik from Division of Immunology and Allergy of Istanbul University, Faculty of Medi- cine, Assoc. Prof. Dr. Ozlem Cavkaytar from Pediatric Allergy and Immunology Department of Istanbul Medeniyet University and Prof. Dr. Semanur Kuyucu from Pediatric Allergy and Immunology Department of Mersin University, Faculty of Medicine [14].

I want to express my gratitude to Professor W.A. Banks, the Editor-in-Chief of the Journal, and his team Mr. Kazim Baig and Mr. Aamer M. Khan for their help and support in production of this large-scale work in high standards. I do believe that this issue will provide a valuable contribution to the existing literature and be helpful to many physicians in order to understand, prevent and manage these “iatrogenic” haz- ardous diseases.

Executive Guest Editors: Hao Jiang and Aijun Sun

Challenge of pharmacotherapies in Cardiovascular diseases: With the acceleration of population aging and urbanization, the global preva- lence of cardiovascular risk factors led to the continuous increase in the incidence of cardiovascular diseases (CVDs). Moreover, cardiovascu- lar death has become the leading cause of urban and rural deaths in low- and middle-income countries [1]. With the growing application of percutaneous intervention in acute myocardial infarction (AMI), the need for rescuing heart from reperfusion injury led to numerous re- searches. Although basic research has been carried out to explore signalling transduction and related mechanisms, while few of them are proved to improve clinical outcomes so far [2]. As the end stage of various cardiovascular diseases, heart failure remains to be a challenge to physicians. Although current medications as angiotensin-converting enzyme inhibitors (ACEI) / angiotensin receptor blockers (ARB), β- receptor blockers, aldosterone antagonist reduced mortality and symptoms to some extent, we are still unable to reverse or halt the progres- sion of HF. The emerging treatments that improve the function of the failing heart by targeting mitochondria and metabolism [3] are currently recognized as a potential pharmacotherapy target which is worthy of attention.

Essays within this special edition: This thematic issue contains decades of novel findings in anatomic, cellular, molecular, and genetic changes during the pathophysiological process of CVD. Dr. Dragana Nikolic (University of Palermo, Italy) discussed the mechanisms re- sponsible for aging-associated changes in cardiovascular system, which was complemented by evaluation of evidence-based approaches for lifestyle modifications toward cardiovascular risk reduction, particularly nutritional interventions [4]. Dr. Esma R. Isenovic mainly focused on the data regarding the role of IGF-1 in cardiovascular system in the physiological and pathophysiological condition [5]. Dr. Li presented an overview of the state of cardioprotection today and provide a roadmap for how we might progress towards successful clinical use of car- dioprotective therapies following AMI, focusing on the rational combination of judiciously selected, multitarget therapies [6]. Dr. Wong summarized the cardioprotective effects of oleanolic acid and its bioactive analogues as cardioprotective agents and highlighted their thera- peutic perspectives of CVD [7]. Dr. Sun focused on the result of clinical findings and possible mechanisms of chronic exercise on cardiovas- cular system [8]. The introduction to novel therapeutic targets in this thematic issue will provide new insights for developing cardioprotective agents aiming at different stages of CVD and extend the application of known drugs in the field of CVD. The main content of this special issue focuses on new findings of signaling pathway possible for designing drugs and newly discovered agents that are available for cardiopro- tection. This special issue will contribute to the improvement of translation from research bench to clinical practice.

ACKNOWLEDGEMENTS

We thank all authors who contributed their valuable work to this special issue. We express our gratitude to Professor W.A. Banks, the Editor- in-Chief of the journal, and his team Mr. Kazim Baig and Mr. Aamer M. Khan for their help and support in organizing this special issue.

It is really a great pleasure as the Guest Editor of the journal Current Pharmaceutical Design to present the special issue on “Bionanocomposite and nanomaterials for medical and environmental applications”. The pharmaceutical industry has been significantly benefitted by recent innovative discoveries in nanotechnology, polymer sciences and composites materials. Nanomaterials having at least a dimension less than 100nm have been effectively utilized in controlled drug delivery system development. Additionally, the antimicrobial features developed from their extremely small size, high surface area and enhanced number of interaction points have been consistently reported [1-5]. With the advent of time, researchers are focused on to design nanoformulation of drugs for controlled delivery and sensitive site treatments. Furthermore, the recent discoveries attained in the synthesis of biopolymers with bactericidal and biocompatible features have added values to pharmaceutical industries. Biopolymers have been extensively applied in medical fields for wound dressing/ healing, drug carrying, artificial organs development, and so many other applications. Recently, the focused is extended to the composite development where certain shortcoming of the parental materials is addressed by additives before subjecting them to practical applications. Several important features including biocompatibility, antimicrobial activities, conducting and magnetic properties, transparency etc. of virgin polymers have been remarkably upgraded by corresponding additives in the form of composites. It is worth mentioning that structural features of biopolymers, as well as their synthesis techniques provide an ideal scenario for in-situ and exsitu composite synthesis. Pure nanomaterials, biopolymers as well as their composites have depicted impressive applications in medical, environmental and pharmaceutical fields owning to their structural features and multiple interaction mechanisms with animal cells and tissues [6- 12]. This thematic issue has been comprised of research and review articles, addressing the synthesis of nanoparticle and biopolymer composites systems, as well as newly extracted or synthesized biological compounds for potential applications in the medical and pharmaceutical fields. First (review) paper summarizes the recent approaches developed so far for three-dimensional (3D) cell culturing and their relevancies to the practical in-vivo cell culture systems. Unlike two dimensional in-vitro cultures, the 3D culture system provides a similar physiologically relevant in-vivo model for studying various diseases including cancer. Besides, various factors causing resistance to anticancer drugs in the forms of spheroids in 3D in-vitro cell culture systems and the challenges and possible solutions for the future development of these systems have been discussed [13]. Arif et al., were asked to review the biomedical applications of biocompatible polymers. Biocompatible polymers work in intimacy with living cells and are used to gauge, treat, boost, or substitute any tissue, organ or function of the body. It encompasses advances in tissue culture, tissue scaffolds, implantation, artificial grafts, wound fabrication, controlled drug delivery, bone filler material, etc. Their review provides an insight into the remarkable contribution made by some well-known biopolymers, such as polylactic-co-glycolic acid, poly(ε- caprolactone), polylactic acid, poly(3-hydroxybutyrate-co-3-hydroxyvalerate), chitosan and cellulose in the therapeutic measure for a number of biomedical applications [14]. Another key topic of developing a medically important biopolymer from waste materials was addressed by Ul-Islam. Several food and agriculture waste contribute to economic losses and environmental hazards. Ul-Islam in his work attempted to utilize waste and cheaply available local resources including; waste (expired) orange juice, sugarcane juice and coconut water as alternative media for bacterial cellulose (BC) production in comparison to the synthetic media (control). The successful synthesis, high production, and potential applications in pharmaceutical fields augment the reported process for scaling up and industrialization [15]. Lee et al., were asked to review the development made in developing drug systems linked to nanoformulations. Nanotechnology has played a vital role in providing new directions for diagnosis, prevention, and treatment of different disorders, and of cancer in particular. Their review details the therapeutic effectiveness, mode of action, and pharmacokinetic limitations of resveratrol, as well as discusses the successes and challenges of resveratrol nanoformulations. Emphasis has been given to the modern nanotechnology techniques which enhance the encapsulation of resveratrol within nanoparticles and which in turn enhance its therapeutic effectiveness [16]. In another review article, Shah et al. summarized the molecularly imprinted polymer nanocomposites development for medical applications. Core shell molecularly imprinting polymers (CSMIPs) could develop the ability of identifying template molecules, increase the relative adsorption selectivity and offer higher adsorption capacity. This review covers the approaches of developing the CSMIPs synthetic schemes, and their application with special emphasis on their uses in biomedical field, food care subjects, plant extracts analysis and in the environmental studies [17]. The last review article by Ismail et al. presents the recent trends involved in the water treatment by nanomaterials. Recent research articles from different sources about the treatment of polluted water have been gathered and shortly described. This review mainly concerns the treatment of dye, heavy metal ions and microorganisms polluted water [18]. The research article by Shah et al., illustrates the development of agar based biocomposites for potential applications in drug delivery and biomedical applications. The biocomposites were developed via a single step ex-situ impregnation of additives in agar matrix. Characterization of composites through conventional physico-chemical approaches successfully confirmed the homogenous structure and effective anti-microbial activities against various pathogenic bacterial strains including Escherichia coli, Staphylococcus aureus and Klebsiella pneumonia [19]. Another research article by Rehan et al., confer an effort to extract a new anticancer compound from Ocimum basilicum (O. basilicum) plant extract for potential application in triggering the apoptosis pathway. The plant extract was fractioned and analyzed through modern chromatographic techniques. It was noteworthy that fractions of O. basilicum extract were found to kill cells following JNK pathway activation. The excellent results were obtained with BF2 and BF3 fractions probably due to predominantly Epicatechin and Cinnamic acid derivatives in these fractions [20]. Connected to the successful BC synthesis, another study by Ullah et al., evaluated the feasibility of BC as a drug carrier in microparticulate form for potential pharmaceutical and biomedical applications. BC microparticles were prepared by injection moulding method through regeneration. Model drugs, i.e., cloxacillin (CLX) and cefuroxime (CEF) sodium salts were loaded in these microparticles to assess their drug loading and release properties. Various formulations prepared showed immediate drug release, wherein more than 85% drug was released in the initial 30 min. Moreover, such microparticles exhibited good antibacterial activity [21]. We would like to thank all the authors who contributed high quality research and review articles. We are also thankful to the reviewers who provided valuable comments for further improvement of the articles. We believe the issue will gain the attention of the readers.

It was really a great opportunity to work as Guest Editor of “Current Pharmaceutical Design” journal for this special issue on “New drug treatment paradigms for metabolic and neurological disorders”. The metabolic and neurological disorders are the major health concerns witnessed globally and we still lack effective drug treatment strategies to halt such devastating diseases. Especially, neurodegenerative diseases such as Alzheimer’s and Parkinson’s are very challenging and lack precise therapeutic drugs to date, although some of them could only provide symptomatic relief. They implicate a huge financial burden and especially in the form of care-givers. It also affects the social stigma as well as the family members of the affected individuals. Hence, new and viable treatment strategies are the welcoming features in the present condition to efficiently treat the patients. The first review article by Dr. Upadhya et al. tries to show how exosomes can be employed as therapeutic molecules to overcome brain injuries and neurological diseases [1]. The application of Extracellular vesicles (EVs) in drug delivery of the central nervous system (CNS) as well as their functions in treating neurological disorders is well emphasized in this article. The EVs easily cross the blood-brain barrier and reach the target organs effectively in conditions such as brain injury and disease. The authors substantiated how the EVs isolated from mesenchymal stem cells and neural stem cells could be employed for managing the brain dysfunctions especially during CNS injury and disease. The second review article by Ghulam Ashraf et al. highlighted the importance of NMDA receptors antagonists as potential therapeutic agents for treating Alzheimer’s disease (AD) [2]. This work emphasized the importance of repositioning of memantine as a novel and multitargeted therapeutic approach for AD. Alzheimer’s disease (AD) is the leading neurodegenerative disease associated with memory loss, and problems with thinking, and behavior. Currently, no drug exists that can cure the disease although there are drugs which are widely used for only symptomatic relief. N-methyl-D-aspartate (NMDA) receptors play a critical role for synaptic plasticity as well as transmission. NMDA receptor antagonists such as memantine block the NMDA receptor, thereby reducing the calcium (Ca2+) ions influx into neurons to ameliorate the toxic functions. The third review article by Sahab et al. entitled “Cholinesterase Inhibitors for Alzheimer Disease: Multitargeting Strategy based on Anti- Alzheimer's Drugs Repositioning” deals with the research works focused on targeted therapies towards AD based on Cholinesterase Inhibitors (ChEIs) used for symptomatic AD treatment [3]. AChE inhibitors (AChEIs) increase the levels of acetylcholine in the synaptic cleft to improve cognitive functions and hence considered as one of the important strategies in AD treatment. Moreover, this article reveals how the current studies on the repositioning of the Food and Drug Administration (FDA)-approved ChEIs as multitargeting anti-AD drugs could have pharmacological importance in drug development. A narrative review by Yusuf Öztürk’s addressed the importance of plant- and nutraceutical-based treatment approaches to overcome diabetes and its neurological complications [4]. Metabolic disease such as diabetes affects many organs and systems in the body including the nervous system. The consequences of neuropathic complications seen in diabetic patients are high with adverse effects. Through this research article, the authors try to address the importance of treatment with an integrative approach (consisting of nutraceuticals e.g., prebiotics and probiotics and plant products), to overcome diabetes and diabetic complications. Being complementary, prebiotics, probiotics, and plants could be used as an additive/adjuvant for the prevention and drug therapy of diabetes. I would like to thank all the authors who contributed interesting review articles. I am also grateful to the expert reviewers for their valuable comments and questions for the critical revision and further improvement of the articles. I hope the issue will get a wider audience and readers in the relevant field.

The metabolic syndrome is associated with obesity and predisposing factors for cardiometabolic diseases (type 2 diabetes and cardiovascular disease), which are the major causes of death worldwide. These diseases can be prevented and treated with medicinal foods. Other diseases associated with metabolic errors, such as phenylketonuria, can also be managed with medical foods for people with special dietary needs. Medicinal foods are also used in the treatment of conditions, such as Alzheimer’s disease [1] and autism [2]. Besides naturally functional foods, medicinal foods are obtained through the modification of edible biological macromolecules, thus reducing the effects of the diseases indicated above. This special issue aims to summarize the current knowledge on some preventive issues of medicinal foods providing basis for their potential application in future pharmaceutical design. The articles in the dossier put emphasis on phenolic-rich edible sources, which reflects the increasing attention paid to these compounds in the recent years [3]. The first review article of this special issue was presented by Pico and Martínez [4], in which the inhibition of intestinal glucose transport from dietary phenolic compounds is illustrated. These compounds are frequently found in fruits and vegetables. These findings are interesting since polyphenol-rich foods can be used as medicinal foods in the intervention against type 2 diabetes and obesity, as well as all diseases associated with metabolic syndrome. Keeping this in view, Mercado-Mercado et al. [5] and Angulo-Bejarano et al. [6] provide comprehensive reviews of how some traditional foods acting as polyphenol-rich medicinal foods can, for example, inhibit the enzymatic activity of lipases, thus, reducing lipid absorption and the subsequent accumulation of adipose tissue. The article written by Ballard et al. [7] provides a review and meta-analysis related to the pharmacological effects of polyphenol-rich fruit extracts on the reduction of obesity in rodent models, while Hernandez-Hernandez [8] reviewed the important aspects of in vitro gastrointestinal models for the evaluation of the bioactivity of prebiotic carbohydrates. In this way, digestion-resistant carbohydrates, such as fibers and resistant starches have been shown to have a positive effect on health and can also be used as components of medicinal foods for intervention measures in diabetic, obese, and hypertensive patients. We, as guest editors, appreciate the invitation to this prestigious journal and thanks Dr. Octavio Paredes-López (editor-in-chief for the journal ‘Plant Foods for Human Nutrition’) and his group for valuable contribution to this special issue. Our gratitude also to the selected group of highly qualified reviewers that took part in the editorial process; their input was crucial for the quality of the final publication. “Let food be thy medicine and medicine be thy food.” -Hippocrates, the father of modern medicine.

In earlier days; the finding and establishment of the lead drug molecule and pharmaceutical product need plenty of time, manpower and expenditure. The increasing demand for personalized dosage form necessitates the production of easily customizable with less cost, affordable and scientific approach. But recently in early twenty-first century drug discovery and evolution of novel dosage form has witnessed the implementation of scientific tools and mathematical models for a compound or product development likely to be successful, and also conversely enable identification of associated liabilities at an earlier stage of development. These concepts need the integration of mathematical modeling and in-silico designs from large available theoretical and web database as well as informatics tools to find out the desired candidate and results. Hence, a mathematical description of an in-silico approach of these systems is the only feasible way to manage such diverse properties of different products or pharmaceutical dosage formulations. The proposed thematic issue will keep a focus on the involvement and implementation of in-silico models and design in pharmaceutical dosage and drug design. It will explore the application of computational tools that can be utilized for theoretical background and methodologies of a pharmaceutical properties, compositions, formulation techniques, ADME, drug interactions and network modeling and discuss the various applied strategies to systematically retrieve, integrate and analyze datasets from the diverse sources. This thematic issue aims at featuring the latest design and developments of drug research utilizing informatics tools and to encourage design, prediction, and development of leads and new drug formulations. This special thematic issue is an effort to provide the recent updates through goodquality review papers including most recent patents filed in the relevant areas.

This Special Issue of the Current Pharmaceutical Design is devoted to the role of opioid analgesics in the management of patients with severe pain. In spite of “opioid epidemy” opioid analgesics have prominent and indispensable role in the management of severe pain. This refers to both acute and chronic pain conditions, and in the latter, especially in patients with pain in the course of cancer [1]. Two review articles deal with important issues in the judicial use of opioids. Prof. Sebastiano Mercadante discussed current knowledge on pathophysiology and recent advances of therapeutic approach to management of opioid-induced adverse effects [2]. The first report is devoted to the pathophysiology and management of opioid-induced adverse effects. This is still a main problem in the optimal management of patients who require opioid analgesics administration. It is quite interesting that our knowledge of adverse effects induced by opioids is still limited. This especially refers to long-term effects of chronic opioid administration which is now discussed among clinicians and basic scientists. Issues such as impact of opioids on immune system and potential cancer progression is one of the most hot topics that may have also practical implications, for example in looking for opioids devoted of such effects. Author demonstrates pathophysiology and possible management strategies in common opioid-induced adverse effects such as nausea and vomiting, constipation, drowsiness, sleep disorders, cognitive dysfunction, myoclonus, pruritus, dry mouth, dysuria, respiratory depression, and long-term complications such as physical dependence, aberrant use, endocrinopathy and impact on immune system. The next manuscript written by Prof. Mike Bennett and Dr. Helen Edwards is very important from a practical point of view [3]. Authors discuss current problems in appropriate access to opioid analgesics. This is of paramount importance for patients who suffer from chronic illness and require opioid administration for the effective management of severe pain. The “opioid epidemy” in the USA even increased a gloomy picture of opioids and encourage administrative authorities to more restriction on opioids availability. Along an increased mortality observed in the U.S.A. and significant increase in opioid consumption, it should be also noted that at least partially this might be an effect of illicit use or inappropriate prescription of opioids and concurrent use of benzodiazepines in many patients. It should also be noted that apart from strict law regulations directed at limited risk of opioid misuse and abuse, patients who require opioid therapy should have appropriate access to opioids, which are indispensable drugs in chronic pain and dyspnea management, especially in cancer patients. Authors discussed numerous barriers for effective management of chronic pain including those from professionals such as inappropriate pain assessment, insufficient knowledge, fear of inducing adverse effects, especially respiratory depression, which also refer to many patients who may be reluctant to take opioids. To strict law regulations may lead to inadequate access to opioid analgesics for patients as well as insufficient access to palliative care. Authors suggest that complex interventions combining a number of different approaches are most effective in optimizing pain outcomes for patients with advanced diseases. The next part of this Special Issue contains two original reports. Dr. Barbara Kościelniak-Merak, Dr. Ilona Batko, Dr. Krzysztof Kobylarz, Dr. Krystyna Sztefko, Dr. Magdalena Kocot-Kępska, and Prof. Przemysław Tomasik report on a study with the perioperative use of opioids, in which serum levels of endogenous opioids were measured [4]. Authors compared patients treated with opioids alone (morphine, fentanyl) with those who additionally received lidocaine intravenously. In the group treated with a combination of opioids and lidocaine better analgesia and less rescue analgesic consumption were noted which could be expected. Interestingly, a group of children treated with addition of lidocaine to opioids, apart from aforementioned better analgesic effects, displayed a higher level of endogenous opioids, which may be a new target for more effective management of postoperative pain. This suggests also a new mode of analgesic action of lidocaine, not only associated with sodium channels, but also an interaction with endogenous opioid system. Wojciech Leppert and Dr. Krzysztof Nosek in a clinical study demonstrated a successful use of opioids in the management of chronic pain and compared quality of life (QoL) of cancer patients treated with four commonly used opioid analgesics: oral controlled-release morphine, oral controlled-release oxycodone, transdermal buprenorphine and transdermal fentanyl [5]. Although a large multicenter study conducted in Italy demonstrated satisfactory and comparable analgesic efficacy and beneficial profile of all 4 opioids studied, QoL was not evaluated in this large multicenter trial [6]. Interestingly, in the presented, randomized, multicenter study, which compared the same 4 opioids, some significant advantages of morphine compared to oral oxycodone, and transdermal buprenorphine and fentanyl were found: less consumption of rescue analgesics, less negative impact of pain on ability to walk, work and activity (tendency) and a clear tendency of a better improvement in mood. These observations confirm that morphine still remains a first line opioid in the management of moderate to severe pain [7]. As an improvement of QoL remains one of ultimate goals of holistic medical care, an effective pain management greatly contributes to its improvement in patients and their caregivers, especially those suffering from chronic pain. It was a great pleasure working with the Director Kazim Baig, Editorial Assistant Aamer M. Khan and Editor-in-Chief Prof. William A. Banks for the opportunity to publish in an outstanding journal Current Pharmaceutical Design. I would like to acknowledge the contributions of others who took care of editing and processing the manuscripts to obtain the best final quality at the time of publication.

Executive Guest Editors: Federico Carbone and Fabrizio Montecucco

Since the early 2000s, inflammation has been recognized as the paradigm for explaining atherosclerotic plaque development, vulnerabil- ity, and finally the rupture with consequent atherothrombotic events [1]. The growing awareness of underlying inflammatory pathways has prompted a step forward not only in disease pathophysiology but also in identifying biomarkers of disease [2] and potential therapeutic strate- gies [3]. However, inflammatory response is a very complex phenomenon characterized by cross talks between several pathways each one with pleiotropic activity. In this context, the results of CANTOS trial were looked at with great interest, as they first demonstrated a signifi- cant role of interleukin-1β in inhibition in secondary prevention of cardiovascular (CV) events [4]. The search for further therapeutic strategy for CV prevention is then a trend topic that deserves great attention. This issue summarizes the most important lines of research in this field of research by including the following reviews: Luca Liberale and Camici GG [5] from the center for molecular cardiology of Zurich University (Switzerland) focused their review on the role of aging as promoter of atherosclerosis. They illustrate the current knowledge about the pathophysiology of aging genes and potential therapeutic application. Vecchiè and colleagues [6] reviewed the multiple mechanisms by which diabetes promote atherosclerosis development and progression. They also described the beneficial effects of new anti-diabetic drugs in CV prevention. Satta et al. [7] from the University of Geneva (Switzerland) extensively overviewed the protective role of the high-density lipoproteins and explained how humoral immunity against those particles may be involved in atheroprogression. Piscitelli and Silvestri [8] reviewed the role of cannabinoids in atherosclerosis by describing endocannabinoidome and its relationship with circulating lipids and gut microbiota. Taghizadeh et al. [9] from Iran described potential benefits of targeting macrophage. Recruitment, polarization, oxidative stress, choles- terol metabolism, efferocytosis are some of the mechanisms currently under investigation for macrophage inhibition. Veloso et al. [10] from the University of Coimbra (Portugal) proposed a mitochondrial approach to prevention of atherosclerosis and related complications. Once summarized mitochondrial alteration in cardio-metabolic diseases, they reported how the beneficial effects of lifestyle and pharmacological interventions on CV disease are strongly related with an improved mitochondrial function. Although this field of research is extremely wide and dynamic, the aim of this issue is to provide an overview of novel perspective in 2019. We hope that the reader will find a number of inputs for updating knowledge and suggestions for researches.

Cancer is becoming the leading cause of mortality in some parts of the world and its incidence is increasing. Mortality from cancer usually results from recurrence or metastases, rather than the primary tumour itself. Surgical removal of the primary tumour is the basis of treatment, but despite optimum surgical technique, some minimal residural cancer remains, including Circulating Tumour Cells which may be inadvertently dispersed into the blood and lymphatic systems. In addition, surgery itself induces a systemic stress response and transiently inhibits the immune system [1]. The fate of the minimal residual cancer cells depends on the balance of a number of perioperative factors promoting or resisting tumour survival and growth, including surgery itself, some anaesthetic drugs themselves, acute postoperative pain and opioid analgesics and the perioperative immune status of the patient [2]. Preclinical and clinical studies suggest that the anaesthetics and adjuvants given in the perioperative period might affect cancer recurrence and survival, perhaps tipping the balance in some instances to determine whether cancer progresses or regresses [3-5]. These reviews, written by members of Euro-Periscope, an EU-funded COST Action (15204) network of clinicians and scientists working in this field, summarise available evidence from experimental cell culture studies, live animal data and clinical retrospective studies. Taken together, current data are sufficient only to generate a hypothesis that anaesthetic or analgesic and the first and largest such trial (NCT00418457) will be published this autumn. Meanwhile, clinicians should continue to choose the optimum anaesthetic and analgesic technique in discussion with their cancer patients, based on their own expertise and current best practice.

Both central and peripheral immune tolerance mechanisms are crucial in maintaining the non-self-reactivity of T and B-cells and in eliminating self-reactive T and B-cells, respectively. Failure of such immune tolerance mechanisms results in autoimmunity leading to the development of autoimmune diseases (ADs). ADs are a heterogeneous set of chronic diseases with shared aetiology in which the immune system may mistakenly attack an individual’s own organ or affect the whole body. The increasing incidence and prevalence make ADs as one of the leading causes of disability and mortality worldwide. To date, there are more than 100 ADs collectively reported, affecting almost 4.5% individuals globally [1, 2]. Genetic and environmental factors are believed to play important roles in the development of Ads [3, 4]. Shared immunogenic pathogenesis are frequently observed making the differentiation of two unlike ADs a challenge. Different cytokines, pro-inflammatory cytokines, chemokines, enzymes, eicosanoids, immune cells and inflammatory mediators take part in the inflammatory pathogenesis of ADs, ultimately leading to devastating and life-threatening clinical manifestations [5, 6]. The main therapeutic goals in treating ADs are to maintain autoimmunity-derived different clinical manifestations and to sustain immunological homeostasis. Using the current knowledge of immune-mediated pathogenesis of ADs, several novel strategies for the therapeutic intervention of the said disease have been conducted. Administration of immunosuppressive drugs is one of such strategies. Specific-targeted treatments involving administration of inflammatory mediator-specific monoclonal antibodies have also been tested and found to be potentially promising in both preclinical and clinical applications. Recently, researches on immunosuppressive or regulatory immune cell-based therapy and exploration of new biomarkers including autoantibodies in ADs have gained much attention [7-9]. In this special issue of Current Pharmaceutical Design (CPD), Giemza-Stokłosa et al. [10] represented an update on the role of ferritin in inflammatory and autoimmune diseases including adult onset Still’s diseases, macrophage activation syndrome, catastrophic antiphospholipid syndrome and sepsis with an emphasis to hyperferritinaemic syndrome. Cavestro et al. [11] provided an insightful review focusing on pathogenesis of migraine from the origin of the neuro-inflammatory theory, to the modern pathophysiological model and the latest therapies. In an interesting review, Khan et al. [12] summarized the role of chemokines and their receptors in pathogenesis of rheumatoid arthritis (RA) and also indicated the possible interactions of chemokines or receptors with various synthetic and natural compounds that might be used as potential therapeutic targets in treatment of RA. Kechida [13] critically reviewed the common factors in the pathogenesis of autoimmune diseases aiming towards developing better treatment strategies. To sum up, we would like to complete this editorial by thanking Dr. William A. Banks, the Editor-in-Chief, as well as Mr. Kazim Baig, the director of CPD, along with all the contributing authors who have enthusiastically responded to our request by contributing to this special issue of CPD. In addition, we would like to thank all the reviewers who evaluated the submitted manuscripts for this special issue and provided their evaluation based on novelty and scientific contribution in the fields of autoimmunity.

Executive Guest Editor: Pran Kishore Deb

The endogenous purine nucleoside adenosine is an integral component of ATP which regulates various pathophysiological functions of the body [1]. The synthesis of adenosine mainly depends on the metabolic conditions of a cell. In normal physiological conditions, the con- centration of extracellular adenosine remains low (20-300 nM), whereas its concentration increases to micromolar levels (up to 30 μM) under various metabolic stress/demand such as exercise, hypoxia, inflammation, including various disease states like epilepsy and cancer among others [1, 2]. Earlier, adenosine was recognised as a hormone or secondary metabolite, but its ability to restore the imbalance between energy demand and availability under several pathophysiological conditions has earned it a new term “retaliatory metabolite” [3]. Adenosine also prevents ischaemic damage by preconditioning of cells and promotes anti-inflammatory response and angiogenesis [4]. In physiological conditions, adenosine is mainly produced intracellularly through the hydrolysis of adenosine monophosphate (AMP) and/or S-adenosyl-homocysteine (SAH) by endo-5’-nucleotidase and/or SAH hydrolase, respectively [5]. Extracellularly, adenosine is re- leased with micromolar concentration by different types of cells under metabolic stress/demand through dephosphorylation of ATP, ADP and AMP by hydrolysing enzymes viz. ectonucleosidase triphosphate diphosphohydrolase (CD39) and ecto-5’-nucleotidase (CD73), respectively [6]. Transport of adenosine across the cell membrane takes place either via three isoforms of energy-dependent cation-linked (Na + ) concentra- tive nucleoside transporters (CNTs 1-3) or by four isoforms of energy-independent equilibrative nucleoside transporters (ENTs 1-4). Nor- mally the transport of adenosine takes place from extracellular to intracellular region, except during hypoxia where the flux is reversed [7-9]. Intracellularly, adenosine undergoes biotransformation either by phosphorylation to AMP via adenosine kinase (AK) and/ or deamination to inosine through adenosine deaminase (ADA). It should be noted that AK is the main mechanism of adenosine biotransformation under physiological conditions, while its clearance via ADA preferentially takes place under pathological conditions. Adenosine clearance from extracellular region mainly occurs either by ecto-ADA or influx through ENTs [10, 11].

The endogenous purine nucleoside adenosine is ubiquitously present throughout the body; where it is implicated in mediating various physiological functions by interactions with four G-protein coupled receptors (GPCRs) denoted as A1, A2A, A2B and A3 adenosine receptors (ARs) [1-3]. Biological actions of A1 and A3 ARs are mainly mediated by the inhibition of adenylyl cyclase (AC) activity followed by reduction of cyclic AMP (cAMP). In contrast, A2A and A2B ARs mediated physiological actions are linked to the activation of AC activity and a consequent increase of cAMP [4-6]. Agonists of A1 AR have been found to be useful as neuro- and cardio-protective agents for the treatment of cardiac arrhythmias, type-2 diabetes (T2D), and glaucoma, pain, epilepsy, Huntington’s disease, and acute renal injury, whereas A1 AR antagonists are envisioned to be beneficial for the treatment of asthma, chronic obstructive pulmonary disease (COPD), acute heart failure and as diuretics [7-11]. However, off-target tissue activation, tachyphylaxis and cardiovascular side effects related to the chronic use of A1 AR agonists paved the way to the design and discovery of various potential partial agonists and allosteric modulators of A1 AR to overcome the unintentional side effects [8]. Partial agonists like capadenoson, neladenoson, and its prodrug neladenoson bialanate (BAY 1067197) are under various stages of clinical trial investigations for the treatment of various diseases like T2D, and heart failure [12]; whereas allosteric modulators like T-62 has been investigated as a potential anti-nociceptive agent [13]. It is interesting to note that both agonists and antagonist have been found to be useful for the treatment of cancer based on the type of tumor and metastasis [14]. In recent years, much effort have been paid towards developing novel non-dopaminergic therapeutic approaches to cure neurodegenerative movement disorders such as Parkinson’s disease (PD) and Huntington’s disease to overcome the adverse reactions associated with the classical dopaminergic drugs. Among various non-dopaminergic strategies, the selective antagonism of A2A AR is found to be highly beneficial for not only enhancing dopamine D2 receptor-dependent signalling and improving motor disabilities but also reducing dyskinesia from long-term use of neuroleptic and dopaminergic drugs [15, 16]. The A2B AR antagonists on the other hand are being investigated for the treatment of T2D, asthma and gastrointestinal disorders [17-19]. Similarly, agonists selective for A3 AR are currently under investigation for the treatment of autoimmune inflammatory disorders (rheumatoid arthritis, psoriasis), liver cancer, dry eye disease including cardioprotection, whereas A3 AR antagonists are being developed for the treatment of asthma, inflammatory bowel disease, glaucoma as well as cerebroprotective agent [20, 21]. It is worth mentioning that in past two decades, numerous innovative ligand-based and structure-based computer aided drug design (CADD) strategies have been employed in the pursuit of discovery and design of high affinity AR-specific ligands [22-30]. In this regard, the discovery of 3D X-ray crystal structures of A2A AR followed by A1 AR has not only enhanced researchers’ understanding about these receptors but also greatly facilitated structure-based CADD approaches towards the discovery of various novel potential ligands [31-33]. This thematic issue highlights the various aspects of recent advances made in the area of design, discovery and development of agonists, partial agonists, antagonists and allosteric modulators of all the four subtypes of adenosine receptors (A1, A2A, A2B and A3 ARs) as potential therapeutic agents. In particular, the medicinal chemistry and therapeutic potential of agonists/partial agonists, antagonists and allosteric modulators of A1 AR have been thoroughly discussed with special emphasis on their current status and future perspectives in clinical settings [34]. Omar et al., discussed the recent developments of various ligands targeting A2A AR, including their structure-activity relationship (SAR) and therapeutic potentials. Also, molecular modeling approaches utilized in the design of A2AAR ligands have been highlighted with various recent examples [35]. Balakumar et al. (2019), elaborated the recent advancement made in the development of agonists and antagonists of A2B AR with particular emphasis on the therapeutic potentials of selective A2B AR ligands in the management of airway inflammatory conditions and cancer [36]. Finally, Raghuprasad et al. (2019), discussed the progress in the pursuit of discovery and development of novel potential ligands belonging to diverse chemical classes selectively targeting A3 AR as a potential drug target for the treatment of various pathological conditions such as cardiovascular disorders, inflammation, cancer and pain [37]. Recent updates given in this thematic issue might augment the understanding of the researchers from academia and industries for the design and development of high affinity ligands specifically targeting ARs as novel potential therapeutic agents.

In the continuation of our previous issue emerging trends on Nanoparticles and Nano-materials in biomedical applications -I [1], this mini-thematic issue consists of six different review articles from the young and expert’s researchers in the field across the world. These articles highlights the advantages, limitations and prospects related to drug delivery system, importance of actino-bacteria in the nanoparticles fabrication, multimodal imaging, and biomedical applications of silver nanoparticles (AgNPs) and application of nanoparticles enzyme immobilization. At first review, Saravaranakumar et al., [2] depicted that emerging strategies in tailored ligand functionalized stimuli-responsive nanocarriers as the drug delivery system DDS for cancer therapies. As the conventional DDS has the several limitations such as leakage of the drug and toxicity to normal cells, loss of drug efficiency, while the smart stimuli responsive DDS is non-toxic to cells, prevent the leakage and degradation of drug because of its targeted drug delivery in pathological site. Thus, nanomaterial chemistry enabled to the development of smart stimuli responsive DDS over the conventional DDS. Stimuli responsive DDS are ensured the spatial or temporal, on demand drug delivery in targeted cancer cells. These are engineered using the organic (synthetic polymers, liposomes, peptides, aptamer, micelles, dendrimers) and inorganic (zinc oxide, gold, magnetic, quantum dots, metal oxides) material. Principally, these nanocarriers are releasing the drug at targeted cells in response to external and internal stimuli’s (temperature, light, ultrasound and magnetic field, pH value, redox potential (glutathione), enzyme). The most recent findings are indicated that multi-stimuli responsive DDS is better than the single stimuli responsive DDS, which extensively increasing the drug release and accumulation in the targeted cancer cells resulting the better tumor cell ablation. These investigations are demonstrating that the multi-stimuli responsive DDS is more promising in cancer therapy. In addition, a handful of multistimuli responsive DDS are in clinical trial for further approval. However, the comprehensive review is addressing the existing knowledge about multi-stimuli responsive DDS. Sivasankar et al., [3] described that comprehensive review, which will spotlight the potential of actinobacteria-mediated nanoparticles in the field of Nanomedicine. Nanoparticles have gained significant consideration in the past two decades, due to their multifaceted applications in the field of nanomedicine. As our ecosystem and habitats changed due to the global warming, many new diseases are emerging. Treating those costs a lot and mostly ended up in failure. In addition, the frequent use of antibiotics to control the emerging diseases led the pathogens develop resistance to the antibiotics. Hence, the nanoparticles are targeted to treat such diseases instead of the costly antibiotics, where the make resistant strains. In particular, the biosynthesized nanoparticles have considerable attention due to their simple, eco-friendly, and promising activity. To highlight, microbial mediated nanoparticles were found to possess higher antimicrobial activity and thus have promising role in the antimicrobial therapy to fight against the emerging drug resistant pathogens. In this context, this review article was aimed to provide the role of nanoparticles in the field of nanomedicine and importance of actinobacteria in the nanoparticle fabrication and their need in antimicrobial therapy. Pan et al., [4] comprehensively illustrated the application of different form nanoparticles in various medical imaging techniques. Multimodal imaging plays an important role in the diagnosis of brain disorders. Neurological disorders need to be diagnosed at an early stage for their effective treatment as later, it is very difficult to treat them. If possible, diagnosing at an early stage can be much helpful in curing the disease with less harm to the body. There is a need for advanced and multimodal imaging techniques for the same. This paper provides an overview of conventional as well as modern imaging techniques for brain diseases, specifically for tumor imaging. In this paper, different imaging modalities are discussed for tumor detection in the brain along with their advantages and disadvantages. Conjugation of two and more than two modalities provides information that is more accurate rather than a single modality. They can monitor and differentiate the cellular processes of normal and diseased condition with more clarity. The advent of molecular imaging, including reporter gene imaging, has opened the door of more advanced noninvasive detection of brain tumors. Due to specific optical properties, semiconducting polymer-based nanoparticles also play a pivotal role in imaging tumors. The objective of this paper is to review nanoparticles mediated brain imaging and disease prognosis by conventional as well as modern modal imaging techniques. Shanmuganathan et al., [5] depicted that emphasizes the synthesis methods, modes of action under dissipative conditions and the various biomedical applications of AgNPs. Generally, silver is considered as a noble metal used for treating burn wound infections, open wounds and cuts. However, the emerging nanotechnology has made a remarkable impact by converting metallic silver into AgNPs for better applications. The advancement in technology has improved the synthesis of nanoparticles using a biological method instead of physical and chemical methods. Nonetheless, synthesizing AgNPs using biological sources is eco-friendly and cost effective. Until date, AgNPs are widely used as antibacterial agents; therefore, a novel idea is needed for the successful use of AgNPs as therapeutic agents to uncertain diseases and infections. In biomedicine, AgNPs possess significant advantages due to their physical and chemical versatility. Indeed, the toxicity concerns regarding AgNPs have created the need for non-toxic and ecofriendly approaches to produce AgNPs. The applications of AgNPs in nanogels, nanosolutions, silver-based dressings and coating over medical devices are under progress. Still, an improvised version of AgNPs for extended applications in an eco-friendly manner is the need of the hour. Bhavaniramya et al., [6] comprehensively reviewed different form of nanoparticles on enzyme immobilization. Enzymes possess a great potential on catalytic activity of several physiological process. Utilization of immobilized enzymes has great attention in several food industries due to their excellent functional properties, simple processing and cost effectiveness during past decades. Though it possesses several applications, still have some challenges. To overcome the challenges, nanoparticles with their unique physicochemical properties act as very attractive carriers for enzyme immobilization. Enzyme immobilization method is not only widely used in food industry and a component methodology in pharmaceutical industry. Compared to free enzymes immobilized form shows more robust and more resistant to environmental changes. In this method, the mobility of enzymes is artificially restricted to change their structure and properties. Due to the sensitive nature, the classical immobilization methods are still limited because of reduction of enzyme activity. In order to improve the enzyme activity and their properties, nanomaterials are used as carrier for enzyme immobilization. Recently, much attention has been directed towards the research on potentiality of the immobilized enzymes in the food industry. Hence, the present review, emphasizeon the different types of immobilization methods, which are presently used in food industry and other applications. Various types of nanomaterials such as nanofibers, nanoflowers and magnetic nanoparticles are significantly used as a support material in the immobilization methods. However, several numbers of immobilized enzymes are used in food industries to improve the processing methods, which not only reduces the production cost but also the effluents from the industry. Finally, Baskaran et al., [7] briefly described about antioxidant, antidiabetic, anti-inflammatory and anticancer properties of biocompatible nanoparticles. Nano-pharmaceuticals have rapidly emerged to cure several diseases. There are numerous reports describing the development and application of nano-pharmaceuticals. Here, we discuss nanoparticles synthesis and the mechanisms to scavenge free radicals. We also discuss their major properties and list several commercially available nano-medicines. Reactive oxygen and hydrogen species are formed during normal metabolism, and excessive reactive species can damage proteins, lipids and DNA and cause disease. Plant and microbe-based nanoparticles, which can protect tissues from free radical damage, have recently gained research momentum because they are inexpensive and safe. We hope multidisciplinary topics on nanomaterials discussed with the theme issue will promote further discussion among researchers in nano-therapeutics and drug delivery. As the guest editors, we would like to thank all the authors and co-authors for their excellent contributions. Besides, we would like to thank a group of scientific experts in computation and cancer drug delivery who offered their strong comments and suggestions to improve the quality of this special issue. Finally, we would like to express our sincere appreciation to the Director Kazim Baig, Editorial Assistant Aamer M. Khan, copy-editors and all the editorial staffs in Current Pharmaceutical Design, Bentham Science Publishers for the excellent opportunity, experience while working with this thematic issue.

Diabetes is known as the major worldwide problem currently. Insulin deficiency, insulin resistance, obesity etc. are major pathologies contributing factors. Diabetes causing a high rate of mortality and morbidity worldwide and currently affected more than 1/4 world’s adult population. Diabetes also associated with several diabetic complications which are difficult to treat. Treatment of diabetes includes lifestyle alterations, insulin therapy and oral hypoglycemic agents besides that now needed to develop new medications or formulations to combat the toxicities associated with the existing drugs. In current thematic issue entitled as “Current pharmaceutical interventions and drug design in the management of diabetes and diabetic complications”, we have been enclosed valued articles which discuss the inventions and exploration carried out on the management of diabetes and its complications. Six exhaustive reviews were included from the expert in the field of drug design, formulations and pharmacology covering the recent updates on the drug development, formulation and pharmacological interventions in the treatment of diabetes. Dua K. and colleagues [1] have been focused their discussion on alpha-glucosidase and its inhibitor in the management of diabetes. They described the role of this pancreatic enzyme which involves in the anabolism of carbohydrate and converting into glucose along with its inhibitors interestingly helps to prevent postprandial hyperglycemia, particularly in type 2 diabetes. Sivakumar & Prabhakar [2] have been describing the protein tyrosine phosphatase-1B (PTP1B) and its inhibitors which govern the insulin signaling pathways. PTP1B supposed to works by dephosphorylating the tyrosine of insulin receptor and suppress the insulin signaling cascade and currently emerging therapeutic strategy for the diabetes management. Peroxisome proliferator-activated receptors (PPARs) involved in lipid and glucose metabolism and thus its agonists have a significant role in the management of diabetes as extensively described by Ahsan W. [3], A critical analysis on recently reported thiazolidinone derivatives as PPAR- γ agonist has been also elaborated. Taliyan R. & co-workers [4] exhaustively covered the fibroblast growth factor 21 (FGF21) which found to be efficacious in the treatment of diabetes mellitus and obesity. It is a circulating endocrine hormone shows its effect after binding with FGFR1 and co-receptor. Its role as a neuroprotectant and potential metabolic regulator has been a major focus of their review. An important contribution by Giri N. and co-workers [5] includes the dendrimer as nanocarrier containing hypoglycaemic drugs. They described how these provide improved diabetes management with minimum risk of associated side effects due to better drug delivery via nanosized structures like dendrimers. Another important inclusion in this issue is from Kumar A. and co-workers [6] who described the ATP dependent and independent proteases involved in the regulation of mitochondrial function which is found to be important in the management of diabetes and diabetic complications. They emphasize on anterograde pathways as well as on retrograde pathways helpful in mitochondrial function via ATP dependent and independent proteases which are the keys for balancing anterograde to retrograde signalling. We had a great pleasure to work with the Director Kazim Baig and his team specially Editorial Assistant Aamer M. Khan. We express our sincere gratitude for them for providing us the opportunity to work as the Guest Editors in the journal Current Pharmaceutical Design. We wish that this thematic issue will be fruitful for the enormous readership and may assist the researcher as a good information source in the field of diabetes, and its management.

Dietary antioxidants have been the focus of major attention over the last decades due to their potential effects on human health. Several vitamins and phenolic compounds have been considered responsible for the benefits of plant-based dietary patterns and plant-derived beverages [1, 2]. Due to the impact on general population, it is imperative to define the mechanisms underlying these effects, providing a strong rationale and biological plausibility to the observational evidence from epidemiological studies. There are a variety of pathways through which antioxidants may act at cellular level depending on their chemical structure. Counteracting oxidative stress and inflammation represent the main targets of antioxidants activity and it is undoubtedly the most studied by far [3]. However, potentially beneficial effects have been hypothesized in a multitude of conditions, including cardiovascular disease, cancer, and neurodegenerative disorders, thus suggesting that specific pathways depending on the organ systems may exist [4-7]. Moreover, the impact of certain antioxidants (i.e., polyphenols) on the microbiome as well as the effect of the microbiome on the (bacterial) metabolites of polyphenols and their importance for the bioactivity of many phytochemicals may deserve certain attention [8]. Among others, vitamin D has been demonstrated to exert immunomodulatory effects leading to potentially metabolic benefits and cancer prevention [9]. In this special issue, we invited researchers to contribute with breaking through reviews on the most innovative discoveries regarding dietary antioxidants, including epidemiological evidence and mechanisms of action for individual outcomes. Specifically, Valer-Martinez et al. [10] and Giampaolino et al. [11] investigated the potential effects of vitamin D toward metabolic disorders, including gynecological complications, such as endometriosis. Among other potential benefits of antioxidants and antioxidant-rich foods, Dominguez et al. [12] reviewed the existing evidence on their potential association with cognitive decline, Machado et al. with coronary heart disease [13], Yamagata with vascular and endothelial health [14], Chisari et al. with bone health [15]. Finally, the studies of Cianci et al. and Reyes-Muñoz et al. provided a summary of dietary intervention and treatment approaches for specific clinical conditions, such as gestational diabetes [16] and sarcopenia in cervical cancer patients [17], respectively.

Many types of pathologies and disorders affect skin, spanning from dehydration, inflammation or itching to tumors, such as melanoma. The importance of skin as a barrier for body protection is well known, as well as the limits associated to the local administration of synthetic drugs, often resulting in poor efficacy or toxicity problems. In recent years research efforts have been devoted to the development of therapeutic strategies aimed at treating skin by “green” approaches. Particularly several studies have focused on the possibility of treating the skin by administering specialized delivery systems loaded with phytoconstituents and made of biodegradable excipients. In the second part of the present issue, Puglia and colleagues have summarized the innovative strategies for the delivery of skin cosmetics and cosmeceutics [1], particularly the authors focused on the novel association between nanoparticles and phytocompounds, demonstrating its suitability for the treatment of skin disorders. Concerning the possibility to treat skin pathologies by innovative drug delivery systems, Esposito and colleagues have reported researches on nanotechnological approaches based on the use of lipid nanoparticles for the delivery of plant-derived molecules, spanning from solid lipid nanoparticles to monoolein aqueous dispersions [2]. Moreover, the Touitou group has reported the use of ethosomes for dermal administration of natural active molecules. Interestingly, ethosome enables to treat many skin disorders, such as skin bacterial and fungal infections, skin inflammation, acne vulgaris, arthritis, and skin cancer, assuring good safety profile and lack of toxicity or irritation [3]. At last in this issue two contributes have been reported about the physical-chemical characterization of topical vehicles. Indeed, this kind of studies exerts a crucial role in the design of pharmaceutical and cosmetic formulations suitable for cutaneous administration. For instance, the skin permeation of the active molecules, as well as the vehicle stability, can be strongly influenced by viscosity and inner structure of the formulations. At this regard, the review by Huang has provided a practical understanding of key rheological concepts and parameters [4], while Carducci and colleagues have highlighted the importance of the structural characterization of nano-formulations by X-ray scattering techniques [5]. I would like to thank all the authors for their excellent contributions and the Current Pharmaceutical Design publishing team for their help.

The skin is the largest organ in the body and provides a barrier protecting the body from both physical and environmental threats. However, the skin is involved in many disorders and pathological conditions [1, 2]. Synthetic drugs to treat skin pathologies always imply multidrug resistance, with a consequent relatively low success rate. In this view it is particularly important the possibility to find safe and effective compounds and formulations [3]. Nature offers a tremendous potential in medicine, nutraceutical as well as cosmetic field. In the last few years researchers have been focusing on the health benefits of natural products, for instance algae, spice and citrus fruits. Innovative pharmaceutical forms and strategies can solubilize and deliver bioactive compounds from natural sources, protecting them for degradation and controlling their delivery onto the skin [4, 5]. This issue relies on new challenges to treat skin, based on the use of molecules of plant origin and on delivery systems suitable for cutaneous administration. Particularly, some technological aspects are emphasized, such as the skin structural changes after exposure to molecules of natural origin, as well as the production and characterization of semisolid systems for cutaneous administration and the use of nanotechnological devices based on components derived from natural sources. The issue is divided in two parts, assembling ten manuscripts from nine countries, describing research studies on the treatment of skin disorders by different approaches. In the first part, Svitina and colleagues have summarized in vitro and in vivo studies, demonstrating that the use of Aloe materials (i.e. gel, whole leaf, isolated polysaccharides and anthraquinones) has attractive potential for the treatment of skin related disorders and for cosmetic applications [6]. The review by Styrczewska and colleagues has outlined the suitability of oil seed plants in treatment of various inflammatory skin disease, such as actinic keratosis, skin barrier repair and wound healing. In addition, the mechanism of action for fatty acids, selected mono-, sesqui-, di-and triterpenes, carotenoids, tocopherol and polyphenols are described [7]. Notably Lim and colleagues have reported on the positive effects of ozonated oils on wound healing, underling the importance of the ozonated degree of the oil. Indeed, it has been demonstrated that ozonated oils possess bactericidal, antiviral, and antifungal properties [8]. Bruschi and his research group have presented the possibility to treat psoriasis by photodynamic therapy, using molecules from vegetable sources as photosensitizer agent. The authors outlined that, although photodynamic therapy is widely utilized for the treatment of psoriasis, few photosensitizers from plant sources have been utilized (i.e. chlorophyll derivatives and hypericin) representing a safe and cheap alternative for the successful photodynamic treatment of this pathology [9]. Concerning the cosmeceutical field, Zaid and Al Ramahi have summarized the actual state of the art about the antiaging treatment, UV protection and depigmentation by natural molecules. Indeed, many plant-derived molecules can influence melanin synthesis by different mechanisms (e.g. Arbutin, Licorice extract, Glabridin, Liquiritin and Kojic acid), furthermore natural antioxidants have anti-aging properties, due to their capability to counteract the effects of reactive oxygen species in skin cells [10]. The authors have underlined the importance of developing an appropriate vehicle to ensure suitable absorption of these natural products. I would like to thank all the authors for their excellent contributions and the Current Pharmaceutical Design publishing team for its help.

Pharmacologic innovation is an integral part of health care innovation and is continually changing the way we practice medicine. In the field of anesthesia, critical care and perioperative pain management, a solid understanding of the indications, mechanism of action, side effects, and contraindications of pharmacologic agents is essential for the safe and effective management of our patients. This issue titled “Pharmacologic Agents in the Perioperative Period: New Medications and New Indications” includes a review of pertinent topics to the perioperative physician and focuses on perioperative management topics where introduction of new pharmacologic agents (e.g.: sugammadex, angiotensin II) or the expansion in the indication of other agents (e.g.: liposomal bupivacaine for management of postoperative shoulder pain) has revolutionized our practice. This issue also has a dedicated review of direct oral anticoagulants (also called non vitamin K dependent oral anticoagulants) and the management of patients taking these classes of medications in the perioperative period, including reversal options for this class of medications. Furthermore, a separate review of advances in indications and types of prohemostatic agents in the perioperative period is presented including the management of direct oral anticoagulant induced bleeding in the perioperative period, an increasing challenge faced by anesthesiologists. In addition, this issue outlines perioperative management approaches in two specific patient populations, the pediatric population because of the increasing concern about the potential deleterious effects of anesthetic medications on the developing brain and the obese patient population undergoing bariatric surgery because of the different pharmacokinetic and pharmacodynamic properties of anesthetic medications that influence the choice of medications and drug dosing in this patient population. Ultimately, the goal of this issue is to further improve our surgical patient outcomes by advancing our knowledge of new pharmacologic agents in the perioperative period. Many thanks to all our authors for their contribution to this issue and to the editorial team at “Current Pharmaceutical design” for their diligence in ensuring a high quality product for the readers of this journal. Here is an introductory list to the authors and their review articles that are included in this special issue of journal Current Pharmaceutical Design. We hope the readers of this journal will find these reviews pertinent and useful. Alvarez A. et al. [1] from the Hospital Italiano in Buenos Aires, Argentina and his colleagues provide an in depth review of the choice of perioperative anesthetic medications in patients undergoing bariatric surgery [1]. The authors present a thorough overview of the influence of body weight on the pharmacokinetics and pharmacodynamics of anesthetic medications including recommendations on drug dosing in this patient population. Farag E. [2] and his colleagues from the Cleveland Clinic in Cleveland, USA present a review on multimodal analgesia for perioperative management of patients presenting for spine surgery [2] including opioid sparing strategies as essential components of enhanced recovery after surgery pathways. Knotzer H. et al. from the Klinikum Wels in Austria and his colleagues present a comprehensive review on “Pharmacologic Agents for the Treatment of Vasodilatory Shock” [3] including the newly introduced pharmacologic agent angiotensin II which showed promising results in recent trials. Maged Argalious M. and his colleagues [4] at the Cleveland Clinic in Cleveland, USA provide an in depth review of sugammadex, including its current indications, mechanism of action, limitations, side effects and contraindications. This review titled “Sugammadex for Reversal of Neuromuscular Blockade: Uses and Limitations” [4] also describes the use of sugammadex in special situations, including the dreaded “cannot intubate cannot oxygenate” scenario. Lamperti M. et al. [5] from the Cleveland Clinic in Abu Dhabi, United Arab Emirates and his coauthors provide an evidence based overview of the perioperative management of patients receiving new anticoagulants [5]. This timely topic provides guidance to the practicing perioperative physician on the most recent guidelines regarding the perioperative use of non-vitamin K dependent oral anticoagulants (also called direct oral anticoagulants) and perioperative management strategies of patients receiving these pharmacologic agents. Kietaibl and Kietaibl [6] from the Evangelical Hospital in Vienna, Austria and her coauthor present a comprehensive review of new prohemostatic agents, the indication for their use in the perioperative period, [6] including a review of targeted reversal agents specifically approved for the management of specific direct oral anticoagulants. Finally, Hansen T.G. et al. [7] from Odense University Hospital, Odense, Denmark, together with his coauthors from Aberdeen, Scotland in the United Kingdom present their review article on “Anesthesia for the Growing Brain” [7] including an evidence based approach with support from animal and human studies that tackle the effect of exposure to anesthetic agents and its impact on neurodevelopment in the pediatric population as well as measures to minimize harm to the pediatric patient undergoing anesthesia.

Obesity is defined as abnormal or excessive fat tissue accumulation that may impair health and well-being and also increases death risk. Obesity occurs as a result of physiological responses of the organism in situations when the caloric intake is greater than energy expenditure consumption over an extended period of time, resulting in energy conservation. According to the World Health Organization (WHO), overweight and obesity are the fifth of the leading risk factors for global deaths and they could be defined as a chronic metabolic disorder associated with cardiovascular diseases (CVD) and increased risk of morbidity and mortality. Today, it is accepted that obesity is closely related to Insulin Resistance (IR). Metabolic and hormonal changes occurring first of all with increased visceral obesity which is a characteristic of metabolic syndrome, lead to IR development in adipose, liver and muscle tissue. It is assumed that IR, which occurs due to obesity, represents the first step in CVD development. Partly, IR increases the risk for CVD development due to the presence of multiple risk factors as hypertension and dyslipidemia, and changes in adipocytokines lead to blood vessel inflammation. Besides that, obesity adversely affects hemodynamic, structure and function of the cardiovascular system (CVS). Cardiovascular complications associated with obesity greatly contribute to increased risk of morbidity and mortality. Due to the rising number of obese patients and also the presence of IR and CVD in these patients, the study of adipose tissue and its effects on the development of various pathophysiological states as IR and CVD represents a very important area of biomedical research which would lead to new therapeutic approaches in these conditions. Also, in order to prevent obesity development and associated disorders, prevention and education are of great importance. In this special edition of the journal Current Pharmaceutical Design, the following reviews are included: Ioanna Gouni-Berthold [1] from the Polyclinic for Endocrinology, Diabetes and Preventive Medicine, University Hospital of Cologne, (Cologne, Germany) and co-author, review the current options for the pharmacotherapy of obesity. They presented data on available therapies in detail. They pointed out that although the prevalence of obesity is now more than 30% in many industrialized countries, the number of pharmacological options for its treatment remains limited. Djordje Radak [2] from the Vascular Surgery Clinic, “Dedinje” Cardiovascular Institute (Belgrade, Serbia), with co-authors reviewed the Obesity-associated Risk in Open and Endovascular Repair of Abdominal Aortic Aneurysm. In this review, the authors provided evidence from the current literature concerning the outcomes of open and endovascular treatment of abdominal aneurysm in obese patients. In conclusion authors stated that associated comorbidities inevitably lead to a selection bias leaning towards endovascular abdominal aortic repair (EVAR), as a less invasive treatment option, which makes it hard to single out obesity as an independent risk factor. EVAR seems like a more feasible treatment option than OR for obese patients with AAA, due to lower overall morbidity and mortality rates, as well as reduced woundrelated complication rates. Manfredi Rizzo [3] from the PROMISE Department, the University of Palermo (Palermo. Italy) and co-authors presented up-to-date information about relationships between the microbiome and obesity. In this manuscript, authors tackle important topics related to the understanding of the impact of resident microorganisms on human physical health and present medical treatment to restore metabolic health. Moreover, this review discusses possible mechanisms linking gut microbiota dysbiosis and obesity, since there is a dual interaction between the two of them. Furthermore, comments on bariatric surgery, as a favorable model to understand the underlying metabolic and inflammatory effects, as well as its association with changes in the composition of the gut microbiota, are also included. Niki Katsiki [4] from the First Department of Internal Medicine, Division of Endocrinology and Metabolism, Diabetes Center, Medical School, AHEPA University Hospital ( Thessaloniki, Greece), and co-author review the relationship between the metabolic syndrome and the risk of microvascular complications in diabetic patients. Precisely, in their narrative review they discussed the associations of obesity and Mets (as well as NAFLD) with diabetic kidney disease (DKD), diabetic retinopathy (DR) and diabetic peripheral neuropathy (DPN) as well as cardiac autonomic neuropathy (CAN). The available data on the effects of lifestyle measures and bariatric surgery on these diabetic complications are also briefly considered. Ying Tan [5] from the Department of Emergency Medicine, Department of Burns, Nanfang Hospital, Southern Medical University, (Guangzhou, China) and co-authors summarize the recent experimental and clinical progress on myocardial mitochondrial morphology and function in sepsis and discuss possible underlying mechanisms, as well as the contemporary interventional options. In addition, the authors also review the research progress on changes of mitochondrial morphology and function during sepsis, assess its fundamental principles and generally discuss the present interventions. Gordana Jaksic [6] from the Institute Vinca, (Belgrade, Serbia) and co-authors review the potential of Gentiana lutea in Treatment of Obesity-Associated Diseases. Authors reported the effects of Gentiana lutea extract on molecular signaling altered in obesity, diabetes mellitus, and other diabetic complications. They concluded that GL extract has significant potential as a functional food in the prevention and treatment of obesity, diabetes and CVD complications. Jun Ren [7] from the Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, (Laramie, USA) and co-authors in their work aimed to identify the effects of trehalose on mTOR-independent autophagy in an Akt2 knockout- induced model of insulin resistance. This study was designed to examine the effect of the mTOR-independent autophagy inducer trehalose on kidney and skeletal muscle (Gastrocnemius) injury in an Akt2 knockout-induced model of insulin resistance. Akt2 knockout (Akt2-/-) and adult WT mice were treated with trehalose (1 mg/g/d) intraperitoneally for 2 days, followed by 2% trehalose in drinking water for 2 months. Intraperitoneal glucose tolerance test (IPGTT) and protein carbonyl content were examined. Apoptosis and autophagy protein markers were monitored using Western blot analysis. Akt2 ablation impaired glucose tolerance and protein carbonyl formation in the kidney and skeletal muscles, associated with pronounced apoptosis and overt autophagy, the effects of which, with the exception of IPGTT, were greatly ameliorated or negated by trehalose treatment. Moreover, phosphorylation of mTOR was downregulated in both kidney and skeletal muscles from Akt2-/- mice, the effect of which was attenuated by trehalose. Levels of Akt (pan and Akt2) were much lower in Akt2-/- mice, the effect of which was unaffected by trehalose treatment although trehalose itself upregulated pan Akt levels. Taken together, these data suggest that the autophagy inducer trehalose rescued against insulin resistance-induced kidney and skeletal muscle injury, apoptosis, and excessive autophagy, possibly in association with restored mTOR phosphorylation without affecting Akt.

Active nanotargeting is now one of the best approaches in many serious therapies such as cancer, inflammatory and gene disorders, with the advantage to specifically deliver active molecules to the target tissues or organs, improving the therapy efficiency and decreasing the exposure of patients to toxics. In this issue, we would highlight some of the more recent and advanced strategies for active nanotargeting, also trying to focus on those pathologies for which the current and conventional treatments still exhibit limited efficacy and safety. Alterations into the articular cartilage lead to osteoarthritis, a severe joint disease only currently treated for symptoms or with surgery. The first review article [1] presents an overview of the composition, the causes and treatments of osteoarthritis, with a special emphasis on nanomaterials as carriers of drugs and cells, which reduce inflammation, promote the activation of biochemical factors and ultimately contribute to the total restoration of articular cartilage. In particular, locally administered nanobiomaterials, such as hydrogels and nanohydrogels can promote in situ cartilage regeneration by in situ release cells, anti-inflammatory drugs, and growth factors. Targeting brain is one of the most unsolved challenges in therapy. Biochemical studies more recently revealed the effects of Lysosomal storage disorders (LSDs), a group of serious genetic diseases characterized by the accumulation of non-catabolized compounds in the lysosomes. LDs mainly affect the central nervous systems (CNS), which is difficult to reach with drugs and biological molecules due to the presence of the blood-brain barrier (BBB). A review [2] aims to examine the strategies successfully developed during the last decade for the treatment of LDs. Among the LD treatments, this review also analyzed the challenges of the study to design new drug delivery systems for the effective treatment of the LDs. Polymeric nanoparticles and liposomes are explored from their technological point of view and for the most relevant preclinical studies showing that they are excellent choices to protect active molecules and transport them through the BBB to target specific brain substrates for the treatment of LDs. Macrophages play a role in almost every disease such as cancer, infections, injuries, metabolic and inflammatory diseases and are becoming an attractive therapeutic target. However, understanding macrophage diversity, tissue distribution and plasticity will help in defining precise targeting strategies and effective therapies. Active targeting of macrophages using nanoparticles for therapeutic purposes is still at its infancy but holds promises since macrophages have shown high specific uptake of nanoparticles. Here we highlight recent progress in active nanotechnology-based systems gaining pivotal roles to target diverse macrophage subsets in diseased tissues [3]. In the last few years, immunotherapy has become a promising strategy to fight cancer, as its goal is to reprogram or activate anti-tumour immunity to kill tumour cells, without damaging the normal cells and provide long-lasting results where other therapies fail. However, the immune-related adverse events due to the low specificity in tumour cell targeting, strongly limit immunotherapy efficacy. In this regard, nanomedicine offers a platform for the delivery of different immunotherapeutic agents specifically to the tumour site, thus increasing efficacy and reducing toxicity [4]. Indeed, playing with different material types, several nanoparticles can be formulated with different shape, charge, size and surface chemical modifications making them the most promising platform for biomedical applications. In particular, leukocyte infiltration plays a role in controlling tumour development and is now considered as one of the hallmarks of cancer. In this review, we will summarize different types of cancer immunotherapy currently in clinical trials or already approved for cancer treatment. Then, we will focus on the most recent promising strategies to deliver immunotherapies directly to the tumour site using nanoparticles. Increasing evidence has suggested that extracellular vesicles (EV) mediated bidirectional transfer of functional molecules (such as proteins, different types of RNA, and lipids) between cancer cells and tumor stromal cells (immune cells, endothelial cells, fibroblasts, stem cells) and strongly contributed to the reinforcement of cancer progression. Thus, intercellular EV-mediated signaling in tumor microenvironment (TME) is essential in the modulation of all processes that support and promote tumor development like immune suppression, angiogenesis, invasion and metastasis, and resistance of tumor cells to anticancer treatments. Besides EV potential to revolutionize our understanding of the cancer cell-stromal cells crosstalk in TME, their ability to selectively transfer different cargos to recipient cells has created excitement in the field of tumor-targeted delivery of specific molecules for anticancer treatments. Therefore, in tight connection with previous findings, this review brought insight into the dual role of EV in modulation of TME. Thus, on one side EV create a favorable phenotype of tumor stromal cells for tumor progression; however, as future new class of anticancer drug delivery systems, EV could re-educate the TME to overcome the main supportive processes for malignancy progression [5]. Multifunctional nanocomposites have a controlled drug release property [6]. Interestingly, the upconversion emission intensity of the multifunctional carrier increases with the released amount of model drug, thus allowing the release process to be monitored and tracked by the change of photoluminescence intensity. This composite can act as a multifunctional drug carrier system, which can realize the targeting and monitoring of drugs simultaneously.

The first part of this Special Issue on redox active nutraceuticals and their impact on nutrition and health in modern society has considered some of the rather prominent nutritional components and supplements. It has provided evidence that certain diets, such as the famous Mediterranean diet, appear to be healthier than others. Still, such findings are not entirely uncontroversial. It is therefore worthwhile to consider such diets and nutritional strategies both, in more detail and also with a wider angle. This dual approach may, at first sight, appear paradoxical. Still, a more detailed consideration of the underlying biochemistry may, for instance, bestow us with information on why such diets may be superior to others. In contrast, a wider angle on nutrition and designer foods appears necessary, as such changing habits will also impact on society as a whole, from agriculture and farming to resources and the environment, social and cultural issues, personal preferences and even philosophy. These discussions are not always entirely uncontroversial and often require more research and debate. We will therefore highlight some of the studies of and approaches to these more difficult issues, such as antioxidants and causality, with the aim to raise awareness that nutrition is not just what we eat during the day. Indeed, sausages do not grow during the night in the local supermarket, they have a history, and also go somewhere after they have left us again. Please enjoy your meal and the second part of the Special Issue. ANTIOXIDANTS So far, a major section of the Special Issue has focussed on diets rich in fish, as these appear to be particularly beneficial to human health. Although such diets are widespread across Southern Europe, the Mediterranean and many other regions in the world featuring a coast, there are also places where fish is seen as exotic and a culinary niche product. There is, for instance, no “fish and Sauerkraut” in Germany, and any attempt of serving a healthy fish sausage with honey mustard at the Oktoberfest in Bavaria may have you stripped of(f) your Lederhosen, literally. Other culinary delights, mostly plants, have therefore become a focus of special interest - and not only for Bavarians or vegetarians. These include the pomegranate, reviewed here by Vesna Vučić and her colleagues from University of Belgrade and oils and extracts from oregano, a medicinal culinary herb and spice popular in many cuisines across the Globe, reviewed here by Armen Trchounian and his colleagues from Yerevan State University [1, 2]. In many of these studies, the focus resides on antioxidants, as these substances may counteract oxidative stress - in turn being considered as a prime cause of many age-related disorders, ranging from chronic inflammation to degenerative diseases. Essential aspects of antioxidant supplementation include a mechanistic study on the impact of antioxidant natural compounds on the thyroid gland and Keap1/Nrf2 signalling pathway by Gerasimos Sykiotis and colleagues from Lausanne University Hospital [3]. Rosario Pastor and Pep Tur subsequently consider adaptive responses to training, which may interplay with antioxidant supplementation [4]. Similarly, Izabela Koss from Gdansk University of Technology and her colleagues raise the essential question if and why fruits and vegetables may be superior to dietary supplements and isolated phytochemicals [5]. BEYOND BIOLOGY These aspects of nutraceuticals pave the way to more applied aspects of food and health and to philosophical, often bioethical and epistemological questions. A contribution by Armen Trchounian and colleagues considers in vitro culture in form of callus as a rich source of secondary metabolites, some of which may differ from the ones found in the corresponding intact plant and may also exhibit activity against antibiotic-resistant bacteria [6]. Moving into a different direction of “applied nutraceuticals”, a meta-analysis of biochemical interactions from the perspective of epistemology highlights just some of the less obvious investigations possible and certainly necessary in this field. The study by Barbara Osimani from Marche Polytechnic University and her colleagues on the concept of “mechanistic evidence” demarcates new interfaces of current nutraceutical design, with philosophy and also with psychology, sociology, economics, ecology, politics and other disciplines across the spectrum of natural and social sciences [7]. Oguz Bayraktar and collegues from Ege University focus on a more practical approach by providing valuable insights into drug delivery of natural products [8]. Together, these contributions, spanning various sections of this Special Issue, cover a vast range of topics from hyperbaric oxygen therapy and selenium on the one side to the ethics of adulterated German sausages and an epistemological view on mechanism on the other. They also underline the challenges and requirements - and especially the excitement and opportunities - associated with this emerging field of research. No doubt, there are many important topics in current pharmacological design, from antibiotic resistances to inflammation. Still, once we consider the prevention of diseases and maintaining quality of life for billions of ageing people, we are playing in a league where simple rules of pharmacy, such as administering effective drugs for a short time and ignoring some side-effects, give way to regular spiced and spiked diets assembled on an individual basis from the global food store, and considered for their ethical, social, cultural, economical and ecological acceptance. This Special Issue may therefore serve as an appetizer to raise interest and awareness of the field of nutraceuticals. In 2020, Bentham will launch a new journal of the Current series and with “Current Nutraceuticals” will stay firmly at the forefront of these developments [9].

As an outcome of globalisation and advances in modern medicine, the 21st Century is witnessing dramatic demographic changes in societies across the Globe. Whilst a sharp increase in populace in many developing countries raises the demand for more, and more advanced medications against common illnesses and epidemic outbreaks of infectious diseases, already developed societies are faced with - often rapidly - ageing and fragile populations. The average life expectancy in many European countries, for instance, has risen from around 52 years in 1900 to 80 years in 2000, and similar developments are seen in the US, Japan and many other countries [1, 2]. And although this situation of ageing is intrinsically positive, it is also accompanied by new challenges related to healthy ageing and age, and the quality of life in persons above 70 or 80 years old with their own age-specific biology and needs [3-8]. Indeed, countries or regions with large populations in this age group face numerous social, political, ecological and economical challenges, which culminate in the demand for comprehensive medical support [6, 8-10]. From a scientific perspective, solutions to these challenges are far from trivial. In Germany, for instance, a majority of persons above the age of 60 regularly take five to six different medications to maintain their health, often resulting in adverse interactions and side effect caused by poly-medication [11, 12]. At the same time, the demand for medications places a serious burden on the economy, and the pollution of the environment with disposed medications and excreted metabolites is also no longer entirely negligible. This situation is far from satisfactory and is likely to deteriorate further as more societies worldwide begin to age. Not surprisingly, there have been various attempts to provide alternatives to extensive over-medication of vast parts of the - elderly - population. One particularly promising approach involves the design and implementation of so-called “healthy diets” for individual sections of the population [13-15]. The idea of “healthy eating” has a long tradition, and besides being “natural” and therefore generally socially acceptable, also has certain advantages from a fairly practical, “pharmaceutical” perspective. First of all, food is consumed regularly and in considerable amounts of around two to three kilogrammes per adult a day. Any biologically active ingredients stowed away in such a quantity of tasty food are therefore also taken up regularly, in equally good quantities and even with pleasure, and without any issues regarding “compliance”. Secondly, plants harbour many biologically active secondary metabolites, and some of them have served as lead structures of modern medicines [16]. It is therefore not implausible to expect some health benefits from the substances found in our daily diets. Such notions are not new. Still, the challenges of ageing on the one side, and the opportunities arising from a global food marketplace on the other, have provided new impetus to consider more inclusive and perhaps exotic designer foods and diets based on ingredients harvested from different regions and corners across the Globe. At this point, a thorough scientific investigation of biologically active ingredients in food, so-called “nutraceuticals” clearly needs to be placed high on the menu and before any cross-continental mishmash is served. Here, the chemical composition of such foodstuff, from colourful herbs and spices to exotic and often smelly foods needs to be analysed, biologically active ingredients need to be identified, quantified and their biological activities and modes of action studied comprehensively. In parallel, biomarkers of disorders or diseases, for instance of oxidative stress, need to be defined and monitored in the sick and elderly - and also in response to diet and dietary changes. The awareness of these nutraceuticals, and their impact on human health, in prevention and also as a remedy, will then, and only then, enable us to propose and design diets adequate for healthy eating - and to support healthy ageing. These recommendations will be developed on an individual basis or for cohorts, rather than universally, as today still is commonly the case in popular medicine advertised by self-proclaimed “nutritionalists”. Besides “chemistry” and “biology”, such a scientifically sound and comprehensive approach will also need to address social and cultural aspects [17]. Just imagine the Queen faced with a tender sliced Durian laced with a rich garlic sauce at a State Banquet, or a vegetarian confronted with an equally healthy fishy Mediterranean Diet, and the message will be clear: Nutraceutics is a highly interdisciplinary field intertwined with pharmacy, spanning across disciplines from basic chemistry and cell biology to medicine, psychology, sociology and even philosophy, and always with considerable impact on the individual on one side and society on the other. It is therefore my great pleasure to welcome you to this Special Issue on “Redox active Nutraceuticals”, with contributions reflecting the current excitement in this multi-cultural and multi-disciplinary field of research. This Special Issue is authored by the many colleagues and close friends of the EU COST Action 16112 “Personalized Nutrition in aging society: redox control of major age-related diseases”, acronym “NutRedOx”, who have been essential for the success of this collection and to whom I am deeply indebted to for their many excellent contributions and reviews. The Special Issue is divided into two parts. In the first part, we will consider some of the rather prominent approaches to nutrition and health, from the “usual suspects”, such as vitamins and trace elements, to diets traditionally associated with “healthy eating”. Here, the Mediterranean diet stands out, as it goes easy on meat, animal fat, salt and carbohydrates and, as an interesting alternative, is rich in fish, unsaturated vegetable oils, spices and legumes. The second part of the Special Issue will then turn towards more controversial issues, such as the natural uptake or supplementation of antioxidants and wider issues surrounding nutrition. In this section, more applied aspects, from manufacture to philosophy are combined to illustrate that nutrition is not - just - great food, it is also a matter of society, ecology, agriculture, culture and economics. So welcome to the first part, and bon appétit!

Parasitic infections caused by helminths and protozoans are worldwide distributed, mainly in tropical and subtropical areas. They are strongly associated with high morbidity and mortality rates, in spite of continuous advances on traditional therapeutic approaches [1]. More recently, parasitic infections have been demanding even more attention due to their opportunistic pattern when associated with HIV/AIDS, organ transplantation or administration of prolonged regimens with immunosuppressive drugs. In such conditions the balance between the host and the parasites is enormously affected, culminating in worse prognosis or even in fatal outcomes. Traditional chemotherapeutic agents used to treat many infections present limited efficacy but high toxicity to the host, elevated costs and increasing parasitic resistance. In many cases, these drugs are intravenously administered with long cycles of treatment, resulting on low adherence and therapeutic failure [2]. For that reason, nanoscaled drug delivery systems (NDDS) have been denoted as novel therapeutic tools. Studies on NDDS have increased exponentially in last few years and demonstrated some noticeable advantages of these systems over classical drug formulations. For instance, biocompatible materials have been used with increased surface of contact and potential specific targeting to the site of infection. Despite of amazing advances in the nanomedicine field, many aspects regarding the development and the clinical implementation of the NDDS, such as the mechanisms of action, the immunomodulatory properties, the material stability and the optimization of potential nanodevices needs further investigation [3]. In this special edition of the journal Current Pharmaceutical Design, the development and the use of NDDS as novel therapeutic strategies against parasitic diseases are revised. For this Thematic Issue, leishmaniasis was chosen as a model parasitic disease due to its complex hostparasite interaction, outdated but still adopted therapeutic strategies, increasing reports of drug-resistant parasites and diverse spectrum of clinical forms distributed worldwide. Then, a final review about the recent advances of nano-delivery of plant extracts against a larger group of parasitic diseases serves as an indication about the future directions towards the treatment of parasitic diseases. In the first article of this series, Wagner et al. [4] discusses the potential application of nanoscale drug delivery systems (specifically lipid-, polymer- and metal-based systems) for treatment of leishmaniases, a complex parasitic disease which affects millions of people worldwide. Authors elegantly present how the advancement of the nanotechnology would solve the current pharmacological problems in leishmaniasis treatment: decreased bioavailability of drugs, elevated toxicity to patients and parasite resistance to existing chemotherapeutic regimens. Expanding the discussion over the drawback healthcare professionals face during the treatment of leishmaniasis, Rodríguez-Carlos et al. [5], revises the potential use of antimicrobial peptides-based NDDS as an approach for controlling Leishmania spp. infection. Authors demonstrate how human host defense peptides (HDP) can be included given their antimicrobial and immunomodulatory activities. Finally, Gondim et al. [6] discussed the use of plant extracts loaded in NDDS as an alternative to current therapies for treating parasitic diseases. Authors compile the most recent data on biological activities of these nanoscaled systems and discuss how the NDDS might interfere in the stability, solubility, bioavailability and release of the plant compounds when tested against models of parasitic infections in vitro and in vivo. Furthermore, Araújo et al. [7], developed an Amphotericin-B-containing nanoemulsion with exciting in vitro efficacy on the promastigote form of Leishmania chagasi. Their oil/water nanoemulsion efficiently encapsulated the drug resulting in a spherical morphology and nanometer- sized structure. This strategy would serve to exemplify the potentialities of NDDS to overcome systemic delivery and bioavailability of hydrophobic and toxic drugs currently used in the treatment of parasitic diseases. It was a great pleasure working with the Director Kazim Baig and Editorial Assistant Aamer M. Khan for the opportunity to publish in the journal Current Pharmaceutical Design. We would like to acknowledge the contributions of others who took care of editing and processing the manuscripts to obtain the best final quality at the time of publication.

Nanoparticles and Nano-materials are emerging resources involving in the various therapeutic applications including diagnosis, biomarker mapping, molecular imaging, and gene and drug delivery. The different form of nano-materials involves in the mentioned applications as the usage of nanoparticles, nanoemulsions, nanosensors, liposomes, polymeric nanoparticles, carbon nanotubes, quantum dots, dendrimers, and others. The special issue will cover a selection of invited original reviews from the young and expert’s researchers in the field across the world. Recently, several nanomaterials have proposed for the development of suitable platforms for mRNA delivery, such as lipids, polymers, peptides, and inorganic nanoparticles. However, lipid-based vectors are the most frequently used carriers for in vivo RNA delivery. In these issues, Guevara et al. [1] discussed the mRNA as a promising novel class of therapeutic molecule with prospective applications in cancer therapy. The most common classes of lipid-based nanocarriers such as lipoplexes (LPs), lipid nanoparticles (LNPs) and lipopolyplexes (LPPs) have been discussed for the mRNA cancer vaccine delivery. The authors also portrayed the various parameters that ought to be considered during the design of lipid-based vectors (LbVs) as delivery platforms for mRNA-based anti-cancer vaccines. The key factors include lipid composition, structural organization of LBVc, particle size, surface charges, and lipid bilayer fluidity respectively. In addition, it highlighted the current clinical trials and its overview of lipid-based vectors for the development of therapeutic mRNA-based anti-tumor vaccines. Carbon-based quantum dots (CQDs) with their zero-dimensional nanostructure have become the focus of intensive research based on their excellent luminescent properties, good solubility, and biocompatibility. These quasi-spherical nanoparticles (<10 nm) caught considerable attention based on their physicochemical properties along with their unique wavelength-dependent photoluminescence. Generally, CQDs are derived from chemical precursor materials, but recently researchers have focused their attention on the production of CQDs from waste biomass materials due to the economic and environmental exigency. In this review, Thangaraj et al. [2] discussed recent advances in the synthesis of CQDs by using the top-down and bottom-up approaches from waste biomass materials, functionalization, and modulation of CQDs. Also, the potential application of CQDs as biosensors for accurate and precise detection of tumors, pathogens, elevated blood glucose levels has been discussed. This review also brings out some challenges and future perspectives for developing smart biosensing gadgets based on CQDs. Metal nano-shells offer exciting perspectives to counteract tumor cells owing to their unique features. Matteis et al. [3] were described the current state-of-art of nanosystems embodying gold shells, regarding methods of synthesis, bio-conjugation, bio-distribution, imaging and photothermal effects (in vitro and in vivo). Moreover, this article discussed the significance of targeted AuNSs enhanced the quality of imaging contrast by their strong absorption of AuNSs; the diffuse optical tomography was used to localize cancerous site. Cancer is one of the biggest globally challenging diseases that revolt many lives every day. Notably, the magnetic liposomes (MLS) are the combination of magnetic nanoparticles (MNPs) with liposomes, which are endowed with advantages of both MNPs and liposomes for cancer therapy. Anilkumar et al. [4] reviewed the applicable synthesis methods of MNPs and MLS, followed by a comprehensive assessment of current strategies to apply MLS for different types of cancer treatments. The authors expanded their view on various applications of MLS in gene delivery, photothermal/photodynamic therapy or magneto-phototherapy, combined gene therapies, targeted photothermal/ photodynamic therapy, cancer imaging, and therapy. The high cost of a chemotherapeutics, devoid of early diagnosis, and insufficient awareness about screening programmes are responsible for the increased mortality and incidence rates of cancer. One of the recent trends in modern medicine is “Theranostics,” which is a combinatorial term of therapeutics and diagnosis, to reduce the mortality rate of cancer cases. The extensive interest on iron oxide nanoparticles in cancer theranostics has been increased due to their biocompatibility, superparamagnetism, less-toxicity, enhanced programmed cell death, and auto-phagocytosis of the cancer cells. Kaliamurthi et al. [5] highlight the mechanism of action of iron oxide nanoparticles in cancer therapy through passive and active targeting drug delivery. Also, the physical property and various route of synthesis of the magnetic nanoparticles has been provided. Besides, the theranostic application of the magnetic nanoparticles with a dual and multi-modal imaging system for earlier diagnosis and treatment of various cancer types includes breast, cervical, glioblastoma and lung cancer also conferred. Shortly, the theranostic potential of magnetic nanoparticles with the multimodality imaging techniques may enhance the acuity of personalized medicine in the diagnosis and treatment of individual patients. With the emergence of synthetic methods for new molecule synthesis in chemistry and better screening methods, the number of poorly water-soluble compounds has dramatically expanded in the last few years. In this review, Paudwal et al. [6] reported the manufacturing and characterization process of the most promising solid dispersion technology (SDT) to enhance the dissolution characteristics and bioavailability of poorly water-soluble drugs. The clinical success of SDT has been witnessed in the manuscript by various commercially available marketed products. Furthermore, the advantages, limitations, classification, various methods and carriers, and mechanism of drug release in stable dispersion have been illustrated. These advantages illustrate the present commitments and future capability of solid dispersion technology towards better treatments for an assortment of necessary therapeutic conditions being treated by poorly water-soluble drugs. The superiority of integrating nanotechnology into proteomics, including ultralow detection, high-throughput capability, real-time detection, and low sample consumption, can achieve rapid detection on low abundance biomarkers. Nano-assisted mass spectrometry (MS) remarkably enhanced detection efficiency of proteins or peptides and contributed to the precision diagnostics. Due to the quantitative and dynamic information provided for human proteome, MS-based quantitative proteomic technique has been a powerful tool for nanomedicine. Tang et al. [7] reported the recent trends of progress and development in the nanomedicine of proteomics from quantification techniques and publicly available resources or tools. Moreover, a variety of favorite protein quantification techniques including labeling and label-free strategies applied to nanomedicine studies are overviewed and systematically discussed. The authors depicted the numerous protein profiling tools for data processing and post-biological statistical analysis and publicly available data repositories for providing enrichment MS raw data information sources are also conferred. Mycobacterial infection is the etiology of several diseases, and each of the underlying species is having different antibiotic resistance status to negotiate by formulating an effective alternative therapeutic strategy. Minakshi et al. [8] provides a detailed account of multiple nanocarriers includes liposome, micelles, dendrimers, solid lipid NPs, niosomes, polymeric nanoparticles, nano-suspensions, nano-emulsion, mesoporous silica, and alginate-based drug delivery systems for the treatment of the mycobacterial infections was evidenced in vitro cell lines and in vivo experimental animal models. Besides, this review illustrated the mechanism of action, etiology of various mycobacterium species associated diseases, therapeutic drugs and reports of resistance. Further, the multi-faced benefits of the nano antimicrobials in nano-diagnostic platforms and nanoparticles-based vaccines are also growing in importance to negotiate mycobacterial infections. We hope multidisciplinary topics on nanomaterials discussed with the theme issue will promote further discussion among researchers in nano-therapeutics and theranostics applications in drug discovery. As the guest editors, we would like to thank all the authors and co-authors for their excellent contributions. Besides, we would like to thank a group of scientific experts in computation and cancer drug delivery who offered their strong comments and suggestions to improve the quality of this special issue. Finally, we would like to express our sincere appreciation to the Director Kazim Baig, Editorial Assistant Aamer M. Khan, copy-editors and all the editorial staffs in Current Pharmaceutical Design, Bentham Science Publishers for the excellent opportunity, experience while working with this thematic issue.

Resveratrol and Flavonoids: Therapeutic Studies

The biomedical industry is in constant need of innovative biomaterials. Natural polymers that are biocompatible, biodegradable and safe for human consumption are presently the high-demand materials. Seaweed industry has an estimated total annual production value of about 6 billion US$ with Asia alone contributing about 87% of the world production [1]. Algae or seaweeds are a diverse group of organisms that are ubiquitous to oceans and are considered a huge, underexplored reservoir of biomaterials including polysaccharides. These polysaccharides have traditionally been used as food additives viz. emulsifiers, stabilisers, gelling agents, and thickeners. However, in recent years, algal polysaccharides have received growing interest of scientific community for its health-related applications with 1 billion US$ market as of in 2010 [1]. Going by the recent number, 30% increase in seaweed market is reported by Food and Agriculture Organization (FAO) in 2016 [2]. Apart from being biocompatible and biodegradable, these polysaccharides do not have any terrestrial plants equivalent and resemble the chemical and biological properties of mammalian glycosaminoglycans [3]. This unique property of algal polysaccharides form basis for their recent biomedical applications in drug delivery, wound dressings, and tissue engineering. Their demand is increasing and they represent a potential, very inexpensive, resource for these applications. The present thematic issue is an honest endeavour of the editors to present before the readers a collection of carefully selected and written twelve reviews highlighting recent advances in therapeutic applications of algal polysaccharides. A first in the line is a review by Muhamad et al. [4] revisiting the general information existing on algal-derived polysaccharides including their source, the structural features, extraction/isolation methods, physicochemical properties, and their multi-functional biological activities. The next article by Geng et al. [5] discuss in detail about porphyrans, a sulfated polysaccharide derived from red alga Pyropia. This polysaccharide is consumed very commonly as food in asian countries and has diverse potential applications ranging from anticancer, neuroprotection, anti-aging, hypoglycemic and hypolipidemic effects. A review by Qureshi et al. [6] comprehensively summarizes the recent advancements in the use of one more sulfated polysaccharide, carrageenan, for designing targeted drug delivery systems. An article by Bouissil et al. [7] gives a view of the current therapeutic as well as agricultural applications (fertilizer, bio-elicitor, stimulators, signaling molecules and activators) of algal polysaccharides and/or their oligosaccharide derivatives obtained by chemical, physical and enzymatic processes. An article by Venkatesan et al. [8] highlights the applications of sulfated polysaccharides in bone tissue repair and regeneration. They conclude that sulfated polysaccharides have exceptional properties in terms of hydrogel forming ability, scaffold formation, and thus mimic the extracellular matrix required for stem cell differentiation during bone tissue regeneration. In the review by Sajadimajd et al. [9], the recent progress in therapeutic application of algal polysaccharide as anticancer agents, is outlined coupled with discussion on the underlying cellular and molecular mechanisms of their action. Further, the authors illustrate the role of structural chemistry of important polysaccharides like fucoidans, carageenans, and ulvan in their anticancer activities. Recent advances in wound healing dynamics suggest that preventing early infection, increasing blood flow, and providing nutrient/growth factors to the tissue can result in faster wound healing [10]. A comprehensive review by Kumar and Berthiaume [11] suggested that availability of a range of mechanical and physical properties along with excellent biocompatibility and biodegradability make algal polysaccharides a potential candidates for wound dressings or scaffolds for drug delivery. Authors emphasized that other beneficial properties like anti-viral, anti-bacterial, and anti-fungal activities; ability to modulate coagulation, oxidative stress, inflammatory and immune responses; favorable oxygen permeability; ability to stimulate local endogenous growth factors, cytokines, and pro-angiogenic factors further strengthen their candidature to be explored and studied vigorously for wound healing. A review by Gill et al. [12] discusses the technological advancement observed in the use of algal polysaccharides, especially alginates, as biomaterials in fabricating 3D scaffolds for drug delivery. Solid free forming (SFF) technique also called additive manufacturing (AM) fabrication process which is immensely popular owing to its high accuracy, precision and reproducibility has been discussed at length [13]. The review presents the recent advances in the use of alginate based bioinks for various SFF techniques (like stereolithography, selective laser sintering, laser direct write, electrodeposition and electrochemical lithography, extrusion printing, and inkjet printing) in creating 3D structures by its layer by layer processing. Next in the line is a review by Geskovski et al. [14] which presents the integrative approaches for the design of biomimetic drug delivery systems based on different algal polysaccharides that exert multiple biological functions and improved therapeutic and theranostic effects. The authors highlight the fact that although versatility in the polysaccharide chemical composition ensures it’s bioactive interactions with a variety of biomolecules and cells, however, the increase in bioactivity array is at the expense of the biomechanical and structural function of the polysaccharide. Therefore, in order to employ the algal polysaccharides both as drug delivery system building blocks and conveyor of the biomimicking properties, enhancement of either the structural capabilities or bioactivity are needed. An interesting contribution by Li et al. [15] describes the structural and biological features of functionally modified brown algal polysaccharides with special emphasis on recently developed approaches used to obtain the oligo- and polysaccharides with defined structures. They reemphasized the fact that functional modification of these polysaccharides can broaden their applications as biomedical materials for controlled release and targeted drug delivery as concluded by Geskovski et al. [14]. The last two article in the collection majorly discuss the pharmaceutical aspects of algal polysaccharides. A review by Severino et al. [16] discusses different aspects related to the use of alginate nanoparticles for drug delivery and targeting and how their toxicological profile determines the therapeutic outcome of the drug delivery system. The last article by Rahmati et al. [17] reviews possible applications of algalbased polysaccharides (especially alginate, agar, carrageenan, galactan, fucoidan, ulvan, and porphyran) in controlled drug delivery systems. In the end, I take this opportunity to most sincerely thank the contributors of this issue, both for complying with the journal instructions of submission and for providing their manuscripts in time. The intellectual and expert input of worthy reviewers is also highly appreciated. Hope the readers derive the same level of scientific pleasure that we derived while compiling this thematic issue.

Unique Approaches to Drug Development, Design, and Production

Unique Approaches to Drug Development, Design, and Production

Unique Therapeutic Approaches to Cancer

Adenosine receptors (ARs) belong to the G protein coupled receptors (GPCRs) and are classified into four subtypes viz. A1, A2A, A2B and A3 ARs [1]. These receptors show different tissue distribution and signalling pathways, and are considered as pivotal drug targets for developing potential therapeutic agents for modulating several physiological and pathological processes involving cardiovascular, respiratory, renal, immune and central nervous system [2]. Thus, it is essential to gain proper insight into the active site topology of these receptors along with the physicochemical properties of ligands required for effective binding and modulating the ARs. Several case studies from the failure of plenty of potential lead molecules at different stages of the development process of clinical trials suggested that major emphasis should be given at the early stages of rational drug design and discovery process for identifying new drug-like molecules in order to save time as well as to enhance the success rate of novel drug development [3]. In this regard, continuous advancement of computational techniques and algorithms have made computer-aided drug design (CADD) strategies as potential and reliable approach for rational discovery of new drugs, facilitating a deeper insight into the complex biological events that are experimentally difficult to comprehend [4]. Moreover, the discovery of the 3D X-ray crystal structure of the A2A AR (PDB:3EML) [5] has not only augmented researchers’ insight about this receptor but also facilitated the construction of improved homology models and understanding of other AR subtypes [6]. Several molecular docking and molecular dynamics (MD) simulation strategies [7] employing either the 3D crystal structure or homology models of ARs are mainly being used in the pursuit of rational structure-based drug design (SBDD) and discovery of molecules with novel chemotypes selectively targeting ARs [8-10]. In particular, MD simulation studies are considered as the most valuable in silico approach due to its diverse reliable applications such as evaluation of binding interactions, kinetics and affinities of agonists/antagonists and allosteric modulators of ARs, lead optimisation, and refinement of homology models among many others [11, 12]. Further, the recent discovery of 3D X-ray crystal structure of A1 AR [13, 14] has opened a new arena to computational medicinal chemists, anticipating more SBDD studies in near future. Ligand-based drug design (LBDD) strategies like 3D-QSAR [15, 16] and pharmacophore modelling have been extensively explored to gain insight into the physicochemical requirements as well as to predict the binding affinities of ligands particularly for A2B and A3 ARs as their crystal structures are not yet resolved (including A1 AR until the recent discovery of its 3D crystal structure) [17]. Various LBDD tools are also employed as part of virtual High Throughput Screening (vHTS) to predict the ADMET (absorption, distribution, metabolism, excretion and toxicity) properties of molecules in order to consider their drug-likeness as a measure reduce the rate of failure of drug development [18]. However, several studies revealed that the use of both SBDD and LBDD techniques together with each other [19, 20] increases the robustness of in silico modelling as compared to the use of either techniques alone. Pabitra et al. in their review illustrated the current use of both the SBDD and LBDD approaches, highlighting the importance of in silico-in vitro-in vivo correlation (Fig. 1) to rationally design, and develop novel drugs [21]. It is worth mentioning that advantages of such combined approaches are not being properly explored due to the lack of availability of various software tools including other required resources to researchers. Ligand-based in silico techniques including their robustness and limitations in search of novel and selective ligands for ARs have been discussed in details with specific examples by Pabitra et al. [21] and Nikhil et al. [22]. Extensive reviews by Nizar et al. [23] and Mohammed et al. [24] provide special emphasis on the several aspects of SBDD strategies that are currently being explored including homology modelling, molecular docking and MD studies of ARs. This thematic issue highlights the recent advancement, strengths and limitations of various in silico approaches towards ARs in order to facilitate the researchers to design and develop new strategies for the discovery of novel potential therapeutic agents selectively targeting AR subtypes.

Сancer and cardiovascular disease (CVD) are noncommunicable diseases and are the leading causes of global mortality and the major factors affecting life expectancy worldwide [1,2]. Correspondingly, these pathologies remain the focus of biomedical research, with thousands of studies published every year. In this part of the Thematic Issue, we present a collection of reviews on the latest achievements in the field. In addition to cancer and CVD, this issue includes two interesting reviews on depression therapy. Ya-Hui Hu, Lin Zhou, Shan-Shan Wang, Xia Jing, Hong-Li Guo, Fang Sun, Yong Zhang, Feng Chen, Jing Xu, and Xing Ji from China in their review “Genetic variants of drug transporters impacting methotrexate disposition in pediatric patients with acute lymphoblastic leukemia: what we have learn?” focus on genetic polymorphisms of methotrexate-disposition involved transporters and discuss the potential association between the genetic variants and methotrexate efficacy, toxicity, pharmacokinetics of methotrexate treatment [3]. Veronika A. Myasoedova, Vasily N. Sukhorukov, Andrey V. Grechko, Dongwei Zhang, Elena B. Romanenko, Varvara A. Orekhova, and Alexander N. Orekhov from Russia and China in their review “Inhibitors of DNA methylation and histone deacetylation as epigenetically active drugs for anticancer therapy” briefly discuss the mechanisms of cancer-associated epigenetic modifications as well as existing in clinical practice and prospective epigenetically-active anti-cancer agents [4]. Authors from Qatar and India Uzma Zaheer, Muhammed Faheem, Ishtiaq Qadri, Nargis Begum, and Shilu Mathew in their review “Expression profile of microRNA: an emerging hallmark of cancer” discuss the role of miRNAs in cancer biology and their potential as diagnostic and prognostic biomarkers and therapeutic tools [5]. Authors from China Lei Fang, Fengzhou Li, and Chundong Gu in their review “GDF-15 is a multifunctional modulator and potential therapeutic target in cancer” discuss the multifunctional roles of growth differentiation factor-15 (GDF-15) in tumor and its value in practical treatment. They postulate that GDF-15 can be used as a tool for the diagnosis and therapy of a wide range of cancers [6]. In a short review “Cellular and molecular basis of osteoblastic and vascular niches in the processes of hematopoiesis and bone remodeling (A short review of modern views)”, a group of Russian authors Yurova К.А, Khaziakhmatova О.G., Melaschenko Е.S., Malashchenko V.V., Shunkin E.O., Shupletsova V.V., Ivanov P.A., Khlusov I.А., and Litvinova L.S. present the ideas about the evolutionary formation of osteoblastic and hematopoietic niches that are rarely discussed in the literature. The authors discuss the molecular mechanisms of the regulation of these processes [7]. Priscila de Souza, Luisa Mota da Silva, Sérgio Faloni de Andrade, and Arquimedes Gasparotto Junior from Brazil in their review “Recent advances in knowledge of natural-derived bioactive as modulating agents of the renin-angiotensin-aldosterone system: therapeutic benefit in cardiovascular diseases” focus on medicinal properties of natural compounds as modulating agents of the renin-angiotensin-aldosterone system. The authors provide information that bioactive compounds isolated from natural products act either by inhibiting the angiotensinconverting enzyme or directly by modulating the AT1 receptors of angiotensin II, which consequently changes the entire classical axis of this system [8]. A Japanese team of Shunsuke Miyauchi, Michiaki Nagai, Keigo Dote, Masaya Kato, Noboru Oda, Eiji Kunita, Eisuke Kagawa, Aya Yamane, Tasuku Higashihara, Arinori Takeuchi, Akane Tsuchiya, and Kosuke Takahari dedicated their review article “Visit-to-visit blood pressure variability and arterial stiffness: which came first: the chicken or the egg?” to the analysis of the literature on the usefulness of visit-tovisit blood pressure variability in the relationship to arterial stiffness. The relationship between visit-to-visit blood pressure variability and coronary arterial remodeling was reviewed for the first time [9]. A Russian team of authors Margarita A. Sazonova, Anastasia I. Ryzhkova, Vasily V. Sinyov, Marina D. Sazonova, Zukhra B. Khasanova, Nadezhda A. Nikitina, and Igor A. Sobenin in their article “Creation of cultures containing mutations linked with cardiovascular diseases using transfection and genome editing” review the existing approaches to create cell cultures containing mutations associated with cardiovascular diseases [10]. Shuangshuang Zhang, Yong Wang, Jinsong Cheng, Ning Huangfu, Ruochi Zhao, Zhenyu Xu, Fuxing Zhang, Wenyuan Zheng, and Dandan Zhang from China in their review “Hyperuricemia and cardiovascular disease” focus on the physiology and epidemiology of hyperuricaemia and discuss its relationship with cardiovascular disease. They also discuss the treatment for reducing urate levels in cases of cardiovascular disease and hyperuricaemia [11]. E.V. Konstantinova, N.S. Chipigina, M.H. Shurdumova, E.I. Kovalenko, and A.M. Sapozhnikov from Russia in their review article “Heat shock protein 70 kDa as a target for diagnostics and therapy of cardiovascular and cerebrovascular diseases” summarize the latest findings on the protective role of HSP-70 chaperone in several cardiovascular diseases: myocardial and cerebral ischemia and atherosclerosis [12]. Hai-Yue Lan, Bin Zhao, Yu-Li Shen, Xiao-Qin Li, Su-Juan Wang, Li-Jun Zhang, and Hong Zhang from China in their review article “Phytochemistry, pharmacological activities, toxicity and clinical application of Momordica cochinchinensis” provide a comprehensive overview of Momordica cochinchinensis in phytochemistry, pharmacological activities, toxicity and clinical application [13]. The review article entitled, “The low molecular weight brain derived neurotrophic factor mimetics with antidepressant-like activity” by T.A. Gudasheva, P. Povarnina, A.V. Tarasiuk, and S.B. Seredenin from Russia is focused on several low molecular weight mimetics of brain derived neurotrophic factor and review their potential use as antidepressants. The current advances in the development of potential antidepressants are also considered [14]. International team of authors from Iran and UK Zohre Fathinezhad, Robert D.E Sewell, Zahra Lorigooini, and Mahmoud Rafieian-Kopaei in their review “Depression and treatment with effective herbs” revise the treatment of depression with the use of medicinal plants and discuss the possible mechanism of action, efficacy on depression and toxicity of herbs [15]. In this issue, several teams of international experts discussed the most novel topics relating to the problem of drug target discovery and treatment of cancer, CVD and depression which makes this special issue interesting for a wide range of potential readers.

Pharmacotherapy is a very powerful tool to improve medical outcome of pregnant women as well as their fetuses and infants. Unfortunately, only 5% of available drugs have been properly monitored, tested and labelled for use during pregnancy and lactation [1]. Pregnant or lactating women are usually excluded from trials, resulting in an unacceptable situation where pregnant women and their fetuses or infants are exposed to drugs that lack sufficient information about safe and effective use [1, 2]. Therapeutic misadventures such as the thalidomide disaster stimulated the development of pharmacovigilance systems, but these systems do not fully serve pregnant or lactating women. The same can be concluded for product specific pregnancy registries, commonly mandated to characterize and quantify maternal, fetal and neonatal risks post marketing. Six years after the Pregnancy and Lactation Labeling Rule was published, the Food and Drug Administration (FDA) reported that registries commonly fail to provide relevant information, usually caused by low enrollment. Only 7/59 (12%) registries resulted in a label update, while only 22/59 (37%) registries reported their observations in peerreviewed journals [3]. As a consequence, information to support decisions on pharmacotherapy during pregnancy or lactation remains very limited. Women of childbearing potential and their health care providers have to make poorly informed decisions because pregnant or lactating women get ill, and ill women get pregnant or prefer to breastfeed [2, 4]. In a first review, Ceulemans et al. explore perspectives of patients (women’s belief about medicines, adherence) and pharmacists (how to communicate) on this setting [5]. This issue subsequently focuses on various scientific approaches that can be tailored to pregnancy and lactation in order to generate more knowledge on drug exposure and effects. This includes pharmacokinetic (PK) modelling approaches during pregnancy and/or estimation of fetal exposure. Dallmann et al. discuss the relevance of pharmacometric tools, and highlight key elements to tailor these tools to improve pharmacotherapy [6]. Along the same line, Bouazza et al. provide an overview on PK approaches to evaluate fetal drug exposure, including in vitro placental transfer studies [7]. Such models are relevant, since PK studies in pregnant women - and especially when related to the fetal compartment - are very difficult to conduct because only scattered information is available. Moreover, the placenta has not only a barrier and transport function, but placental dysfunction in itself may result in maternal pre-eclampsia, caused by abnormal placentation and involving a cascade of dysregulated pathways in placental vasculature. Studies on human placental vascular reactivity, its variability and the mechanisms involved may therefore serve as an ex vivo model to learn more about pre-eclampsia, a disease typically confined to pregnancy, but potentially having cardiovascular consequences in later life for both the former pregnant woman and her offspring [8]. Similarly, pharmacometric models are developed to quantify and predict drug exposure during lactation. This emerging research field for infant drug exposure through human breast milk is discussed by Ito [9], while Ventrella et al. describe how to generate information on nonclinical models to determine drug transfer into human breast milk. This covers both in vitro tools like trans-epithelial mammary drug transport as well as in vivo studies in lactating animals [10]. These observations can subsequently be integrated in physiology-based (PB)-PK models. Since the infant ingests human milk, a subsequent link with neonatal PB-PK models is needed to turn these models into useful tools to predict exposure in the infant [11, 12]. The next section discusses pharmacotherapeutic aspects of maternal or fetal medical conditions during pregnancy or at delivery. This starts with a paper on novelties in postpartum hemorrhage. Data on tranexamic acid and fibrinogen concentrate in postpartum hemorrhage were summarized by Philips et al., highlighting strengths and limitations [13]. The full spectrum of PK, placental and breastmilk transfer of antiretroviral drugs in pregnant and lactating women living with Human Immunodeficiency Virus (HIV) and areas in need of additional research are discussed by Hodel et al. [14]. This is followed by two papers on preterm delivery prevention and long-term outcome following prenatal lung maturation, respectively. The safety and efficacy of tocolytic drugs to treat spontaneous preterm labor are reviewed by Lamont and Jørgensen. Since the authors conclude that the perfect tocolytic drug does not yet exist, this review subsequently covers currently explored research lines, including progesterone, prostaglandin F2α antagonists or statins, linking to another recent special issue of this journal [15, 16]. This is followed by an overview on antenatal corticosteroids for fetal maturity, with a call for long-term pharmacovigilance. It is well established that antenatal corticosteroids shortly before delivery reduce neonatal mortality and morbidity in neonates if born preterm. However, long term effects are poorly understood, particularly since about 50% of women who receive antenatal corticosteroids subsequently deliver at term [17]. The final paper of this section describes a repurposing drug development program of sildenafil for antenatal treatment of congenital diaphragmatic hernia. This program includes studies in animal models (rat, rabbit) and in vitro placental transfer studies to subsequently develop a PB-PK model to support studies during pregnancy [18]. Obviously, pharmacological research in pregnancy and during the postpartum period can only be performed within a regulatory framework. There is therefore an obvious need to facilitate therapeutic development by regulatory science [19]. Roca et al. discuss the most recent FDA guidance on scientific and ethical considerations for inclusion of pregnant women in clinical trials, and the recently initiated Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC) [20]. Finally, mobile health applications for prenatal assessment and maternal-fetal monitoring are emerging as valid tools to generate knowledge, and also can be used in clinical drug registration studies [21]. We should avoid that this population is again ‘forgotten’ in the product development of wearable devices as new tools of data collection in healthcare [22]. We hope that this special issue provides the reader with state-of-the-art reviews on various aspects of perinatal pharmacology. More relevant, we hope that this stimulates collaboration to take the steps to shift from best guess practices to evidence-based knowledge on pharmacotherapy for pregnant women, their fetuses and infants.

In addition to my teaching activities at the Euro Academy in Pößneck (Germany), I have been collaborating with Dr. Rafael Coveñas (Institute of Neurosciences of Castilla and León (INCYL), Salamanca, Spain) since 2002. Our collaboration has been focused on the neural networks involved in neurological and psychiatric diseases. In September 2004, I published my first abstract entitled “Theoretical reflections about the reciprocal influence of neurotransmitters upon each other” that was presented in the German congress on clinical neurophysiology (Jena). Because there is no laboratory technique to develop exactly neural networks, we use the therapeutic effects of CNS drugs exerting an agonistic or antagonistic effect, at a specific receptor, to develop these networks. In physiological brain function, classical neurotransmitters and neuropeptides show a transmitter balance with slight and short-time alterations of the transmitter levels. In psychiatric and neurological diseases, transmitter imbalance occurs, for example in generalized epilepsy, Parkinson’s disease and in two important psychiatric diseases: schizophrenia and major depression. In both latter diseases, the development of improved CNS drugs can be justified by the neural networks. Second-generation antipsychotic drugs have made progress in treating psychotic symptoms by minimizing movement disturbance, the extrapyramidal symptoms. Because one third of depressive patients cannot be successfully treated by available antidepressant drugs, multimodal antidepressant drugs can improve the antidepressant pharmacotherapy. In February 2013, I presented at the 5th ICDDT conference in Dubai an oral presentation about multimodal pharmacotherapy by examinig neural networks. Generalized epilepsy is not completely treated by available antiepileptic drugs. The derived neural network in the hippocampus, cerebral cortex, thalamus and hypothalamus was presented in meetings that were hold in Dubai, Salamanca and Munich. Our aim is to enlarge neural networks by considering all the involved classical neurotransmitters and neuropeptides, in order to improve the current pharmacotherapy by using CNS drugs. In 2018, we completely improved the neural network in the extrapyramidal system, because the anti-Parkinsonian pharmacotherapy is not yet satisfactory. As well in this neurodegenerative disease, we suggest a multimodal pharmacotherapy. In this special edition of the journal Current Pharmaceutical Design, the following reviews are included. Ana Velasco from the Institute of Neurosciences of Castilla and León (Salamanca, Spain) and co-workers review the current pharmacological treatment of multiple sclerosis [1]. They present the pharmaceutical preparation named GEMSP, which consists of fatty acids, antioxidants, free radical scavengers and amino acids. In first clinical studies, 72% of the patients with multiple sclerosis had a better outcome compared to patients who did not receive this treatment. In this review, the authors show a biochemical analysis of the constituents of GEMSP. Domenico de Beradis from the Department of Mental Health belonging to the Psychiatric Service of Diagnosis and Treatment (Teramo, Italy) and co-workers present the involvement of glutamatergic drugs in the treatment of major depression. Most antidepressant drugs are reuptake inhibitors of monoamines, such as serotonin, dopamine and noradrenaline. However, one third up to half of the depressive patients cannot be treated successfully with these available antidepressant drugs [2]. Domenico de Beradis presents NMDA (N-methyl-D-aspartate) antagonists, for example ketamine, which produce a rapid, long-lasting antidepressant effect. Besides, the authors review new glutamatergic drugs, which also show antidepressant properties. Felix-Martin Werner from the Euro Akademie Pößneck and Rafael Coveñas from the Institute of Neurosciences of Castilla and León update the alterations of neurotransmitters and neuropeptides in the brainstem and hippocampus involved in major depression [3]. They have previously published several reviews about the neural networks involved in major depressive disorder. They included not only monoamines such as serotonin, dopamine and noradrenaline, but also gamma-aminobutyric acid (GABA), glutamate and neuropeptides. The neural networks in the brain centers involved in major depression are up-dated. The mechanisms of action of new antidepressant drugs, for example NMDA and m5Glu (subtype 5 of the metabotropic glutamatergic receptor) antagonists, neurokinin-1 receptor antagonists and M1 mACh (muscarinic cholinergic receptor) antagonists are explained according to their therapeutic effects and to the neural networks. NMDA antagonists combined with M1 mACh antagonists can produce a rapid and long-lasting antidepressant effect. Felix-Martin Werner and Rafael Coveñas up-date the neural networks involved in generalized epilepsy and present novel antiepileptic drugs [4]. The neurotransmitter and neuropeptide alterations in the hippocampus, cerebral cortex, thalamus and hypothalamus are actualized. In a second step, neural networks are up-dated in these brain areas. Novel antiepileptic drugs, for example an allosteric positive modulator of the GABAB receptor, perampanel (an AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonist) and brivaracetam are described according to their mechanisms of action and therapeutic effects. It was a great pleasure working with the Director Kazim Baig and for the opportunity to publish in the journal Current Pharmaceutical Design. It was a wonderful experience working with Editorial Assistant Aamer M. Khan at the time of submission and processing of the manuscripts. I would like to acknowledge the contributions of others who took care of editing and processing the manuscripts to obtain the best final quality at the time of publication.

This Thematic Issue is focused on the current progress in genetic studies, drug discovery and drug application in non-communicable (chronic) diseases. Taken together, non-communicable diseases are the leading cause of morbidity and mortality worldwide. During the recent years, great advances in genetic studies and the accumulating pool of available data made possible the discovery of molecular mechanisms of a number of chronic human pathologies, investigation of genetic predispositions to various disorders, and identification of numerous potential therapeutic targets. This progress in turn was followed by a number of preclinical and clinical trials that collected important data on safety and efficacy of new drugs. Research articles provide numerous examples of successful development and application of drugs and gene therapies of cardiovascular diseases, cancer, and other human pathologies. Moreover, a significant amount of data is coming from clinical applications and molecular studies of traditional medicines. Part of these exciting findings were summarized in this Thematic Issue, which covers the following topics. International team of authors from Russia and China Victor G, et al. present a very interesting review “Transcriptional characteristics of activated macrophages” discussing the results of a macrophage transcriptome study. Transcriptome analysis might reveal the exact role of different genes in macrophage biology, which, in turn, might help in discovering new drug targets for treatment of inflammatory diseases [1]. In a non-systematic review “The role of genetic polymorphism in the formation of arterial hypertension, type 2 diabetes and their comorbidity” by a Ukrainian team of authors Shalimova A, et al. the role of genetic polymorphisms in the formation of type 2 diabetes mellitus, arterial hypertension and their comorbidity is discussed. Study of gene polymorphisms proved to be very important for diagnosis and treatment of arterial hypertension and type 2 diabetes mellitus, yet this problem requires further research [2]. Accardi G, et al. (Italian group) in their review “Genotypic and phenotypic aspects of longevity: results from a Sicilian survey and implication for the prevention and the treatment of age-related diseases” provided a detailed description of the phenomenon of longevity in the island of Sicily and described different aspects of Sicilian population. The authors discussed social and physiological features linked to longevity and pointed the aspects that can represent the most valuable targets for prevention and treatment of age-related diseases [3]. A Chinese team of authors Liu C, Sun Y, and Shao Z. in their review “Current concepts of the pathogenesis of aplastic anemia” focused on recent research of abnormal activation of the immune system in the pathogenesis of aplastic anemia. The authors hypothesized that such factors as genetic background, viral infection and abnormal bone marrow hematopoietic microenvironment play a role in the pathogenesis of aplastic anemia [4]. A Japanise team of Shibata K, et al. in their review “Thrombolytic therapy for acute ischemic stroke: Past and future” highlighted the pathophysiologic features of ischemic stroke, described the future of thromboembolic ischemia stroke research, and the available therapies. The authors reviewed the current thrombolytic drugs and the available historical background [5]. Russian authors Gusev E. Yu and Zotova NV. made an impressive work on the analysis of hundreds of papers. In their review entitled “Cellular stress and general pathological processes” authors discussed the involvement of cellular and tissue stress in the majority of the human diseases through the participation in the inflammation. They elaborated on different aspects of cellular stress and discussed the possible ways of cell and tissue stress therapy [6]. Kim DV, Makarova AV, Miftakhova RR, and Zharkov DO. (a Russian group) in their review “Base excision DNA repair deficient cells: From disease models to genotoxicity sensors” discussed the current knowledge on the base excision DNA repair pathway. Furthermore, the authors briefly described the current state of the ongoing study on BER-deficient cell lines and their use for genetic toxicology needs [7]. Yamagishi S, et al. (a Japanese team of authors) in their review “Therapeutic potential of pigment epithelium-derived factor in cancer” focused on pigment epithelium-derived factor and its role in the pathology of diverse types of cancer. Moreover, the authors discussed the therapeutic perspectives of using the pigment epithelium-derived factor for the treatment of cancer [8]. The review paper “Treatments for iron deficiency (ID): Prospective organic iron fortification” by D. Wan, Q. Wu, H. Ni, G. Liu, Z. Ruan, and Y. Yin from China focuses on the problem of iron deficiency and discusses iron bioavailability and iron supplement therapies [9]. Shahcheraghi SH, et al. from Iran present the review “Therapeutic potential of curcumin in the treatment of glioblastoma multiforme”. The authors focus on the problem of glioblastoma multiforme treatment. The recent observations on the therapeutic effects of curcumin against glioblastoma are considered, as well as the combination therapy with chemotherapeutics [10]. An international team of authors from China and the US Guo H-L, et al. in their review “Valproic acid and the liver injury in patients with epilepsy: an update” summarize the data regarding the side effects of valproic acid administration in epileptic patients. The valproic acid-induced hepatotoxicity mechanisms are also explained [11]. Sedighi M, et al. an international team of authors from Iran and the UK) in their review “A review of the most important medicinal plants effective on cardiac ischemia-reperfusion injury” discussed the current state of research and treatment of ischemic disease. Moreover, the authors give a broad overview of potential medicinal plants effective on ischemia [12]. Wang S-J, et al. from China and the UK in their review “Prunella vulgaris: A comprehensive review of chemical constituents, pharmacological effects and clinical applications” analyze the chemical constituents, clinical applications, and pharmacological activities of Prunella vulgaris [13]. Thus, in this special issue, several teams of international experts discussed the most novel topics relating to the problem of drug target discovery and treatment of non-communicable diseases. We would like to thank the contributors to this issue for their participation. We hope that this issue will be valuable for the readers.

Drug delivery systems are or increasing interest in medicine because can assure targeted, optimized release of the desired biological active agent and can reduce or even avoid systemic toxicity. In most of these cases, triggering factors can assure smart delivery at the desired situs and with the desired rate. For instance, pH, temperature, enzyme, magnetic field, light, etc. can act as triggering factors, these drug delivery systems being suitable for the treatment of cancer, infections, hepatitis C, neurodegenerative diseases, inflammations or other diseases. Drug delivery systems can be useful for the administration of various drugs, drug delivery systems are especially important for the administration of toxic drugs, such as cytostatics, antibiotics or when the drugs should be administered for a longer period of time and is important to maintain a certain concentration [1-11]. The current special issue is especially focused on presenting some of the most important and recent advances in the field of drug delivery systems based on organic and inorganic materials (such as metal nanoparticles, oxides, polymeric vesicles, carbon-based materials, composite and hybrid materials, etc.) with a focus on the treatment of cancer, diabetes, rheumatoid arthritis, diseases associated with colon (such as Crohn’s disease, ulcerative colitis, colon cancer), infections, thyroid disfunctions, etc. Certainly, the treatment of these diseases requires different biological active agents, both synthetic and natural agents being effective and highlighting advantages and disadvantages. Most of the manuscripts are mainly related to the treatment of certain diseases while two of them are focusing on the potential therapeutic activity of some extracellular vesicles and respectively to the exploiting of natural bioactive agents derived from walnut. Due to many reasons, cancer therapy by using drug delivery systems are of great importance and two papers are fully dedicated to this purpose while two of the papers are partially devoted to this topic. Also, it is important to mention that even topics such as drug delivery systems for diabetes or inflammation are presented, such topics being not so well reviewed in the scientific literature. Aruda et al. [12] present the potential benefits and highlights the necessity to use cardio-protective agents when doxorubicin is used in cancer treatment. It is important to mention that even if important improvements were obtained in the field cancer treatment, the survival rate increasing considerably in the last decades, especially after the development of cisplatin and its FDA approval nowadays a special attention is paid to a better administration and reduced toxicity [13, 14]. Croitoru et al. [15] made an overview of the biological active agents available in the walnut, their therapeutic activity as well as the current state of the art associated with the drug delivery systems developed starting from these agents. Organic, inorganic as well as composite support materials were considered in this review while the drug delivery systems became efficient for antioxidant, antibacterial, antitumor activity and many other pharmacological and medical applications. Surman et al. [16] focused their extensive review to highlight the importance of the extracellular vesicles as drug delivery systems for potentials biomedical applications such as: cancer, hepatitis C, neurodegenerative diseases, inflammations, etc. According to their manuscript, some of the main factors inducing the effectiveness of the drug delivery systems are related to the chemical stability in the circulation and intracellular space and the ability to reach and internalize into the target tissues/organs and cells. Also, many other advantages of using biomimetic vesicles are also highlighted but, certainly, numerous challenges are still to be undertaken. Stimuli responsive drug delivery systems are also applied in the treatment of different diseases, including rheumatoid arthritis [17]. According to this study, the need of developing new drug delivery systems should be considered, these new drug delivery systems should accomplish some general and specific criteria such as biocompatibility, safe, stable in blood circulation, bioaccumulation and targeted, fast delivery in arthritic tissue while the degradation products of the support could further support the cartilage and bone healing. Diabetes also attract the interest of the researchers because an increasing number of patients is diagnosed year by year. The conventional administration of insulin is problematic, and therefore new administration routes are desired, drug delivery systems conferring some important challenges for this purpose [11]. Zaric et al. [18] present the challenges in the field of diabetes treatment. Subcutaneous, buccal, ocular, pulmonary, ileum and colon, nasal, vaginal or rectal insulin delivery systems are described from the point of view of current state of the art but especially highlighting the new trends assured by the evolution of the nanotechnology.

Over the past years, Inflammatory Bowel Disease (IBD), has become one of the most innovative chapters in Gastroenterology. Not only because its frequency has been exponentially rising worldwide, but mainly due to a great improvement on the knowledge about the diversity of immunologic mechanisms, leading to multiple inflammatory pathways, involved in the physiopathology of the disease, thus, making it possible to develop novel drugs targeting several steps of this “spider web”. Moreover, IBD is of great interest because of its impact on the quality of life of affected individuals, as they are mostly at a young and productive age, requiring a global approach and close monitoring, intended to improve quality of life, prevent disease progression and disability, and disease-related costs. It is with great pleasure that we conclude this special team work, with collaboration of many dedicated professionals who made the effort to provide such a complete issue on the Novel Targets For Therapeutic Intervention in Inflammatory Bowel Disease. In this issue Argollo et al. [1] and Lakatos et al. [2], approach interesting topics on biosimilars in IBD. The first chapter describes, in a very academic manner, the equivalence in clinical efficacy of adalimumab-biosimilars questioning the importance of defining the ideal patient’s profile to receive or to be switched to a biosimilar, choosing one biosimilar vs. another, or cross-switching among biosimilars, which they considered the next challenge in IBD. The second chapter also describes available data on the efficacy and safety profile of infliximab biosimilars, and more, authors add that from a financial point of view, the use of biosimilars could lead to substantial cost savings and ultimately wider access to biological therapies. The review of D’amico and co-workers [3] analyses the mechanism of action of anti-adhesion molecules and nicely expose results from pivotal trials on the efficacy and safety profile of this class of drugs on the management of IBD. Authors suggest that gut specificity is pivotal to reduce adverse events and increase efficacy. An overview on interleukin (IL)-23 blockage for the treatment of CD by Argollo et al. [4] confirm the role of IL-23 as a key mediator in chronic intestinal inflammation and suggest the potential benefit of this class of drugs as promising alternatives in the treatment of Crohn’s disease and ulcerative colitis. Panes and co-workers [5] present a clear summary of all available data on the efficacy and safety of the novel class of small molecules inhibiting the Janus Kinase pathway, as a potential alternative approach for the treatment of IBD patients, in addition to their intrinsic characteristics making them an attractive option based on their oral administration, short plasma half-life, lack of immunogenicity and predictable pharmacokinetics. Kotze and colleagues [6] brilliantly discuss the management of complex perianal fistulas in Crohn’s with the use of mesenchymal stem cells (MSCs), as an emerging new therapeutic strategy, summarizing the evidence of MSCs in complex CD fistulas, exploring in detail the various types of cells that can be used and their modes of delivery. The review entitled “Anti-fibrotic drugs for Crohn’s disease: Ready for prime time?” [7] is focused on intestinal fibrosis in CD and gives a complete explanation on the mechanisms involved in intestinal inflammation vs. intestinal fibrosis, suggesting this topic as the novel potential target for future research in the IBD field. With the emergence of biologic therapies many adverse events have been detected. The article by Yzet et al. [8] review how to best assess the safety parameters of new IBD medications, from the earliest stage of development to population-based registries, with a focus on the special populations often excluded from the evaluation process. This review by Lindholm CR and Siegel CA [9] discuss biomarkers, current prognosticating tools, and tools that determine response to therapy and question if incorporating these into clinical trials will bring real benefit for the management of IBD patients. Last but not least, a key chapter in the IBD field is presented by Dan Turner [10] and express the importance of recruiting pediatric patients to participate in clinical trials and offers possible solutions to age-specific pitfalls in performing trials in this specific population. As executive guest editors, we had the honor to work with a great team of experts and young promising leaders in the IBD field and would like to thank all of them for their dedication and compromise to conclude an excellent work. In addition, we would kindly thank and acknowledge the group of experts and dear colleagues who offered their substantial reviewing efforts and suggestions. Finally, we would like to express our ad- miration to the Bentham Science Publishers for recognizing and honoring the importance of high level publication in the IBD field. The nice team of professionals, especially Director Kazim Baig and Editorial Assistant Aamer M. Khan, made this experience possible and turned initial ideas into a very special issue, giving us all the support provided. We would also like to express our gratitude to all the contributions that took care of editing and processing the manuscripts that resulted in high quality material at the time of publication.

Mineralocorticoid receptor antagonists (MRAs) were initially introduced six decades ago, when spironolactone, a first generation nonselective MRA was developed [1]. MRAs were immediately placed at the epicenter of cardiovascular medicine, mainly, due to their blood pressure lowering effects. Thereafter, a great scientific effort lead to a thorough evaluation of such agents, resulting in a stable evolve of this category of drugs, as well as in vast clinical experience. Recently, MRAs emerged at the epicenter of scientific interest after the approval of finerone (a third generation, non-steroidal MRA), and the development of novel hypokalemic agents [2-6]. Nowadays, all the abovementioned scientific efforts have provided three generations of MRAs, along with a well-established benefit in several crucial cardiovascular comorbidities and life expectancy, featuring a quite useful option in the armamentarium of physicians in everyday clinical practice. More specific, MRAs are currently considered as a second-line drug for the management of arterial hypertension, while they portrait the most efficacious add-on therapy for the management of drug resistant arterial hypertension [7-9]. Moreover, MRAs are the gold-standard therapy in patients with bilateral primary aldosteronism [10]. Accumulating data suggests that both spironolactone and eplerenone result in amelioration of mortality outcomes in patients with heart failure with reduced ejection fraction, and left ventricular dysfunction after myocardial infarction [11-16]. Furthermore, MRAs are indicated for the management of albuminuria in concomitant administration with renin-angiotensin system blockers [17, 18]. Altogether, MRAs are ascertained as a fundamental class of drugs for the multifactorial management of patients with cardiovascular disease; however, their usage remains quite restricted. The point behind this fact lies in the potential life-threatening side effects of such agents, as hyperkalemia and acute kidney injury. In this end, the recently developed third generation, more selective, and non-steroidal MRAs seem to offer a substantial cardiorenal protection with a parallel promising safety in terms of the abovementioned side effects [19-27]. In the current special issue published by the Current Pharmaceutical Design, we sought to: a) highlight the pleiotropic effects of MRAs in the management of cardiovascular risk, b) critically discuss clinically meaningful aspects and to conclude in useful tips for everyday clinical practice, c) present novel perspectives with the introduction of more selective agents, such as the lately approved finerenone, d) discuss new perspectives about the safety of these agents with the use of new hypokalemic agents, e) suggest clinically meaningful implications for physicians, and f) underline the major aspects for further evaluation in the upcoming randomized controlled clinical trials. In this end, Professor Lovic and co-authors drafted a review article to thoroughly present the impact of mineralocorticoid receptors on the progression of cardiovascular disease, as well as the pathophysiological role of MRAs in the management of such deterioration [28]. Professor Faselis et al discussed about the effects of MRAs in the management of essential hypertension, while they innovatively present data on the use of MRAs in resistant hypertension compared with other second-line antihypertensive agents, and of major interest versus renal sympathetic denervation [29]. Professor Doumas and colleagues highlight the most important clinical aspects and future perspectives in the management of primary aldosteronism with such agents [30]. Prof Papademetriou and co-authors provide state of the art evidence and summarize future perspectives of the MRAs in the management of heart failure with reduced ejection fraction [31]. Likewise, Professor Tziomalos et al present data assessing the impact of these agents on heart failure with preserved ejection fraction [32]. Moreover, Professor Sarafidis and associates conducted a very useful review article on the role of MRAs in the treatment of chronic kidney disease and albuminuria, focusing on the new advantages by the development of the third-generation MRAs and novel hypokalemic agents [33]. Prof Manolis and colleagues conducted an interesting review on the MRAs side effects, providing significant guidance for the prevention and management of such events [34]. Professor Karagiannis et al innovatively present all the new perspectives on the potential wider use of MRAs, secondary tothe development of new hypokalemic agents; namely zirconium, and patiromer [35]. Last but not least, Professor Tsioufis and colleagues investigated the future perspectives with the ongoing evaluation of the third generation, non-steroidal MRAs, unveiling significant aspects that need to be further investigated in future randomized controlled trials [36].

This Thematic Issue summarizes the current progress in the development of organ-on-chips for pre-clinical drug screening and personalized medicine research. In the past five decade, the advantages of organs-on-chips over conventional three-dimensional (2D) or threedimensional (3D) cell culture systems and animal models have attracted more and more interest of physicians and pharmaceutic scientists [1]. To make a precisely controlled and biomimetic microenvironment in vitro, an organ-on-a-chip technology showed the potential for recapitulating human physiological environment. Additionally, rapid development in tissue engineering and stem cell researches also advances the fabrication techniques of biomimetic organs and in vitro diseases chip models for use in drug screening and personalized medicine [2]. Organ-on-a-chip technology has been used to fabricate the minimized functional organ-based systems with the physical, cellular and biochemical microenvironments to mimic native organs such as lung, kidney, heart, blood vessels and others [3]. Therefore, an artificial bottomup approach is frequently used to build organ-on-a-chip with progressive complexity by exploitation of cellular differentiation, self-assembly or cell-cell interactions to recapitulate native physiological features [4]. Additionally, for disease modeling, patient-derived cells can bypass significant intra-species differences between humans and animals [5]. Based on these information, patient-tailored disease-on-a-chip models enables development of personalized medicine for the generation of more reliable efficient individual compound screening outcomes and therapeutic methods. Aizheng Chen and his co-workers emphasized the microfluidic models based organ-on-a-chip platforms [6]. They gave a brief overview of the limitations associated with the current drug development pipeline that include drug screening methods, in vitro molecular assays, cell culture platforms and in vivo models. Further, they discussed various organ-on-a-chip platforms, highlighting their benefits and performance in the preclinical stages. Next, they also emphasized their current applications toward pharmaceutical benefits including the drug screening as well as toxicity testing, and advances in personalized precision medicine as well as potential challenges for their commercialization. Yu Shrike Zhang et al. reviewed the current strategies, including the bioprinting and microfabrication technologies, that allow for fabrication of blood vessel-on-a-chip [7]. In addition, the diseased vascular states, such as thrombosis, may also be modeled by integrating cues that simulate the microenvironment of vascular disorders. These engineering technologies for development of biomimetic in vitro vascular structures will potentially offer a new strategy to study complex endovascular intervention problems which are hard to address via existing models. In Ning Hu and co-workers’ review, they introduced the heart-on-a-chip in the sensor-free or sensor-based strategy, and illustrated the advantages of sensor-based heart-on-a-chip in details by taking the examples of the recent studies [8]. They also provided a perspective on the integration of the organ-on-a-chip technology and biosensor platform. Ali A and his co-workers discussed lung-on-a-chip models that combine the technologies of bioengineering, microbiology, polymer science, and microfluidics disciplines to mimic physicochemical features, microenvironments, and cell-cell interfaces of a human lung [9]. Specifically, they further analyzed in detail the recent state of the construction steps, advantages, prospect of art technology for usage in lung-ona- chip models and diseases. Weitao Jia and his colleagues focus on the recent advances of microfluidic techniques that have been applied in the field of orthopedic tissue engineering [10]. After an extensive literature search, they discussed the culture of osteocyte cells and chondrocytes on the microfluidic platforms. Moreover, the incubation and studying of bone metastasis models in microfluidic platforms were also discussed in their review article. Lee I-Chi gave an overview of the innovations, development and limitations of tumor-on-a-chip [11]. They described the combination of 3D tumor-like organoid and microfluidic techniques to achieve in vitro models for mimicking tumor microenvironment and chemotherapy drug screening. Furthermore, they discussed the developmental directions and technical challenges in the tumor-on-a-chip field. They demonstrated that tumor-on-a-chip models could offer a better sufficient clinical predictive power and would bridge the gap between proof-ofconcept studies and a wider implementation within the drug development for pathophysiological applications. Yi-Chen Ethan Li and his co-workers reviewed the fundamental strategies adopted for brain-on-a-chip devices fabrication including photolithography, micromachining, and 3D printing technology [12]. Then, they discussed the state-of-the-art of brain-on-a-chip platforms including their role in the study of the functional brain architecture such as blood-brain barrier and neurodegenerative diseases like Alzheimer’s and Parkinson’s disease. Furthermore, they also discussed the current limitations and future perspectives of the brain-on-a-chip platforms for the development of new drugs and neurodegenerative diseases modeling. Ayca Bal Ozturk and her colleagues focused on the contribution of skin-on-chip platforms in fundamental and applied medical researches [13]. In addition, they also highlighted the technical and practical difficulties needed to be overcome for improving the current skin-on-chip platforms, for example, embedding electrical measurements or an improved modeling of human diseases as well as of new drug discovery and development. Junmok Seo and his colleagues reviewed current trends in screening platform such as a high-throughput system composed of engineered microarray devices for investigating cell-biomaterial interactions [14]. Furthermore, they provided versatile methods to achieve a continual monitoring of cell behaviors via integration of biosensors and high-throughput platforms. Consequently, the future perspectives of highthroughput screening platforms is also discussed. Su Ryon Shin et al. discussed the role of the body-on-chips in overall drug discovery process at preclinical and clinical stage, as well as outline remaining challenges [15]. They discussed the combination of multiple organs-on-chips to explore their crosstalk in the drug metabolism. In conclusion, in this special issue, a team consisted of the international experts from different research areas discuss the existing challenges and the most novel development of organ-on-a-chip. We would like to thank the contributors to this issue for their participation. We hope that this issue will be helpful for the development of novel drug screening and personalized medicine.

This thematic issue on redox regulation and cancer therapy summarizes current information on the role of redox regulation in cancer therapy. Although some important aspects of novel approaches to cancer therapy are covered, some of them such as development of resistance against certain drugs or generation of metastatic processes are missing. Redox regulation includes important mechanisms for cellular homeostasis that are involved in the treatment of many diseases and recent research in redox biology aims at manipulating the redox balance to increase its translational potential [1, 2]. However, in contrast to popular belief and early work done on the subject, recent knowledge suggests that reactive oxygen and nitrogen species (ROS and RNS) are not only harmful for the cell but also have important roles as signaling molecules [3]. Thus, our cells have different ways of coordinating and regulating ROS generation/elimination. This is essential for vitality of both cells and the organisms. When different approaches are used against a particular disease, targeting redox regulation and ROS at specific time points and locations is essential so that only diseased cells will be affected. This has recently been possible by use of targeted antioxidants which scavenge ROS at specific sites [4]. Thus, under physiological conditions redox homeostasis can be achieved by careful control of production and elimination. In cancer therapy, reactive species may influence redox homeostasis and promote tumor formation by initiating an aberrant induction of signaling networks causing tumorigenesis. One must not forget that although modulation of reactive species has promising anti-cancer therapy potential, redox regulation is at the same time a double-edged sword for cancer progression and therapy. In this aspect, ROS and RNS are important tools as signaling molecules but they can turn to be cytotoxic if present at wrong locations and in high amounts. Oxidative stress results from an imbalance in the production of reactive oxygen species (ROS) and antioxidant defenses of the cells, and is implicated in the etiology of cancer [5]. However, ROS may also deregulate the redox homeostasis and promote tumor formation by initiating an aberrant induction of signaling networks that cause tumorigenesis. Cancer stem cells may then take the advantage of the aberrant redox system and spontaneously proliferate. It has been shown that oxidative stress and gene-environment interactions play a significant role in the development of breast, prostate, pancreatic and colon cancer. Therefore, manipulating ROS metabolism and ROS dependent pathways may be an effective approach for supporting cancer treatment [6]. The authors of the reviews published in this issue have considered different aspects of the developments and problems encountered in redox regulation and cancer therapy. Some of the approaches presented in the reviews have already found application in clinical practice. But others need to be improved and more information is needed in the near future for their therapeutic use. In their review on the role of antioxidants in cancer, Poljsak and Milisav [7] indicate that antioxidants are able to decrease the risk of cancer formation by quenching ROS. But there is also evidence showing that antioxidants assist survival of cancer cells after malignant transformation. Antioxidants have roles in cancer initiation, they may interfere with cancer treatment and may also be beneficial during cancer treatment. In the second review, Schröter and Höhn [8] discussed the role of advanced glycation end-products (AGEs) in carcinogenesis and their therapeutic implications. They note that aging is one of the main risk factors for major prevalent diseases such as cardiovascular diseases, neurodegeneration and cancer. However, due to the complex and multifactorial nature of the aging process the molecular mechanisms underlying age-related diseases are not fully deciphered. AGEs significantly increase inflammation in the body which has long been associated with the development of cancer. The involvement of redox regulation in cancer therapy and use of proteasome inhibitors is reviewed by Kaplan, Okat, Sahin and Karademir [9]. As already discussed, redox homeostasis is an important process for the maintenance of cell survival. The redox system works in balance under physiological conditions and involves activation of many different signaling molecules. Proteasomal system is crucial in the regulation of these signaling molecules. Many proteasome targeting molecules have been developed over the years and some of them are already being used in the clinic for cancer treatment. In the final review of this mini-thematic issue, Manda et al. [10] have discussed redox networks in oncologic photodynamic therapy (PDT). PDT is a promising anti-cancer therapy modality that is based on a provoked singlet oxygen burst. It exhibits a better toxicological profile than chemo- and radiotherapy. Important gaps in the knowledge on molecular mechanisms underlining PDT impedes on its translation towards clinical applications in cancer. The authors have critically analyzed the present knowledge on redox networks underlining PDT and its outcome(s) related to cancer cell death as well as resistance to therapy. They have also presented the transcription factor NRF2 as a promising pharmacologic target for developing co-therapies designed to increase the efficacy of PDT.

Drug delivery deals with the methods or processes of administering drug(s) for enhanced efficacy and safety [1]. The science of drug delivery has revolutionized the healthcare system and a variety of nanotechnology-based products are now available in market all over the globe [2]. It is being estimated that the market for novel drug delivery systems would rise to $ 178 billion by the year 2019 [3]. Looking into the increasing research in this domain and numerous success stories, along with the commercial potential, the present thematic issue on Nanotechnology-based Drug Delivery Products: Need, Design, Pharmacokinetics and Regulations has been planned. This issue covers the vital aspects of the science of drug delivery in an updated manner. The historical aspects, need, classification, basic formulation approaches and success stories of drug delivery systems is presented in the first manuscript authored by Modgil et al. This manuscript beautifully also explains the pros and cons of various drug delivery carriers in a succinct manner [4]. Variety of topical drug delivery carriers with an emphasis on dermal pharmacokinetics specially designed for infectious diseases have been discussed by Katare et al. in the second manuscript of the issue [5]. The contribution by Chandasana et al., explores and explain the utility of nanocrystals as a tool in drug delivery [6]. The challenges and advancements in the ticklish protein and peptide drug delivery have been explained in the review article submitted by Babu et al. [7], whereas as the nanotechnology-based drug delivery of next generation peptide nucleic acids has been presented by Bahal et al. [8]. The concept and advances in the pharmacokinetic modeling with a special emphasis on the nanocarriers have been covered by Mukker and Singh [9]. Mahmood et al. contributed a manuscript dedicated to nanocosmetics and nanocosmeceuticals with a special consideration to gallic acid [10]. An advanced account on the material aspects of the nanodrug delivery, especially the materials from the biological origin has been presented by Singh et al. [11]. Grushevskaya and Krylova came up with a fascinating account on the carbon nanotubes, the inherited potentials and promises, and the usefulness of these inorganic nanoconstructs in the delivery of anticancer quinones [12]. The regulatory aspects of the nanomedicine in the present global perspective have been updated by Garg et al. [13]. This thematic issue will assist the formulation scientist and the researchers in the allied domains to advance the know-how and subsequent apply the same in the design and development of safer and effective nanocarriers in a federal compliant manner.

The introduction of three-dimensional (3D) printing technology to the pharmaceutical sector has the potential to cause a paradigm shift in how medicines are designed, formulated, manufactured and used by the end consumer. The interest in the 3D printing in pharmaceutical field has grown substantially since the Food and Drug Administration (FDA) approval of the first 3D printed drug Spritam® (levetiracetam) in 2015 [1]. 3D printing technique is an additive manufacturing method whereby successive layers of material deposited/solidified to form a 3D object. Three major 3D printing techniques (such as laser-based writing systems, printing-based inkjet systems and nozzle-based deposition systems) were exploited to design pharmaceutical product and its various applications in drug delivery [2]. Laser-based writing system, also termed stereolithography is a system, which utilizes laser and based on the technology of UV laser for photo-polymerization of liquid polymer plastic resin. Consequently, the resin is polymerized and superimposed layers of the solid resin are built by repeating the process over and again to obtain desired 3D structure. As there is a strict requirement of biocompatible resin for drug delivery system, the choices are limited. The most suitable choice is low molecular weight polyacrylate polymers. Inkjet printing is a digital system capable of controlling, generating and depositing small droplets on a selected substrate [3]. Inkjet technology can either be continuous (continuous inkjet printing or CIJ) having continuous jetstream of droplets or drop-on-demand (DOD) letting stream in response to a trigger signal. Here, the droplet behavior is affected by inertia, surface tension and viscosity of the liquid.In case of 3D printing, the powder-bed technologies have been mainly utilized for inkjet printing where droplets bind to a powder base to form layer over layer and give a 3D construct. The power bed technology delivers high resolution prints. However, the powder bed layers undergo rapid solidification that is a major disadvantage. Further, there is issue of compliance of entire formulation with jetted liquid. There is another technology based on nozzle extrusion of solid components to form 3D layered structure [4,5]. The nozzle system can have Fused Deposition Modeling (FDM) or Pressure- Assisted Microsyringe (PAM) also called semisolid extrusion (SSE) [2]. While the former extrudes filaments of melted solids, the latter uses pressure to extrude paste. FDM can only utilize thermoplastic components and there are chances of drug degradation at high temperatures. Even for the thermostable products, the high drug loading is challenge. Further, the biocompatible/biodegradable polymers that are printable with FDM for drug delivery are limitation. On the other hand, PAM technology is being increasingly utilized for the development of drug delivery systems. It has the advantage of compatibility with a variety of pharmaceutical excipients. It can provide a continuous flow of such excipients at room temperature. PAM-based 3D printing can serve as an important tool in design and development of high drug loaded formulation utilizing various pharmaceutical excipients. The advantages particularly with adaptability in the pharmaceutical field have enabled the development of 3D printed dosage forms with novel designs and geometries, multiple payloads, customized drug release as well as customized dose and personalized medicine [6-8]. Thus, this thematic issue presents a concise yet very focus discussion to guide the researchers to know about advancement in 3D printing technology based drug delivery and use of this novel technique in pharmaceutical product development. The inter-individual variability observed in population pharmacodynamics due to differing metabolic efficiencies and other factors is a global concern in the pharmacotherapy. In such cases, empirical methods are widely used for adjusting doses. However, there are high chances of undesirable side effects with empirical methods. The advent of 3D printed formulations as a tool for personalized therapy based on individual needs and requirements has been an important discovery. It can take into account not only pharmacogenetics and pharmacokinetic factors but also consider co-morbidity as well. Therefore, this pragmatic tool can be exploited for designing customized drug delivery systems to achieve personalized treatments. Indeed, an insight into the technical challenges facing the various 3D printing techniques (such as the formulation and processing parameters) is need to be identified and addressed. In addition, the different regulatory challenges that need to be surmounted for 3D printing to fulfill its real potential in the pharmaceutical manufacturing and drug delivery application. This special issue is dedicated to the use of 3D printing technology for pharmaceutical product development as well as drug delivery application. Warsi MH et al, have discussed in detail about the various 3D printing method for pharmaceuticals along with product development opportunity and related challenges [9]. Another author, El Aita I et al, have provided a comprehensive overview of the different 3D printing techniques for pharmaceutical applications, including information about the required material along with advantages and disadvantages of the respective technique [10]. Moreover, Jain A et al, have discussed about the various polymers utilized to fabricate 3D printed pharmaceuticals including their processing consideration, and challenges in fabrication of high throughput 3D printing based drug delivery systems [11]. Another contributor to this special issue, Algahtani MS et al, have highlighted specifically the extrusion-based 3D printing method to produce a novel dosage form with properties that are difficult to achieve using the conventional industrial methods [12]. However, Ameeduzzafar et al, have highlighted how product and process understanding can facilitate the development of a control strategy for various 3D printing techniques in design of various pharmaceutical products [13]. Similarly, Zeeshan F et al, have provided the in-depth discussion regarding the use of 3-D printing technology in the fabrication of tablets, polypills, implants, solutions, nanoparticles as well as targeted and topical dug delivery device [14]. Another author, Alam MS et al, have also provided a comprehensive overview of the use of 3D printing technology for the development of novel drug delivery system [15]. In the continuation, another contributor of this thematic issue, Kotta S et al, have highlighted the recent progress in 3D printing technology for various drug delivery application. Authors summarized the applications of 3D printing technology in personalized drug dosing, complex drug-release profiles, 3D printed polypills, personalized topical treatment devices, novel dosage forms as well as drug delivery devices [16]. Khan FA et al have discussed about the current state of the art of 3D printing in pharmaceuticals as well as highlighted the use of 3D printing technique to develop a truly customized drug delivery system [17]. In addition, Afsana et al, have highlighted the application of 3D printing technology to develop personalized medicines which could play vital role in treatment of life threatening diseases. Author further discussed about the 3D printing based personalized drug delivery system that could be investigated in chemotherapy of cancer patients with added advantage of reduction in adverse effects [18]. The contribution to this special issue by Haque S et al, have provided the detail applications of 3D printing technique in pulmonary drug delivery and treatment of various respiratory disorders. Authors have further extend their discussion on how 3D printing technique can be used to deconstruct the complex anatomy of the lungs and improve understanding of its physiological mechanisms, cell interactions and disease pathophysiology [19]. Mirza MA et al, have discussed about the regulatory perspective of 3D printing in pharmaceuticals. Author further highlighted that the current situation demands concerted and cautious efforts to bring in foolproof regulatory guidelines which would ultimately lead to the success of this revolutionary technology in pharmaceutical sector [20]. As a closing remark, we would like to thank Kazim Baig and complete Publications team of Bentham Science Publishers. Further, we would like to acknowledge the support of reviewers in conducting timely peer review. Thus, as a result of the collective efforts of all experts, we are able to bring up valuable scientific information in the area of 3D printing technology for pharmaceuticals.

A growing understanding of the roles of different chemical agents in treatment of retinal diseases has led to remarkable progress in ophthalmology in recent years. Retinal pharmacotherapies is an enlarging field covering distinct medicines and different disorders, including neovascular age-related macular degeneration (AMD), myopic choroidal neovascularization, central serous chorioretinopathy (CSC), choroidal neovascularization (CNV) due to uncommon causes, vitreomacular traction, diabetic retinopathy (DR), postsurgical cystoid macular edema (PCME), and pharmacological adjuncts to vitrectomy surgery. Nowadays many of these disorders, at least in some patients, are controllable with pharmacological treatment. Several therapeutic strategies for retinal diseases are based on vascular endothelial growth factor (VEGF) inhibitors, drugs well known and present in ophthalmology for about 15 years. Anti-VEGF therapy brought a breakthrough to the treatment of CNV in different diseases. Currently in the United States of America and in some European countries the number of annual anti- VEGF intravitreal injections has exceeded the number of cataract surgeries [1,2]. This theme issue provides an overview on the main developments in pharmacology of retinal diseases. Savastano et al. present pharmacological adjuncts to vitrectomy surgery, which may bring benefits before, during and after the surgery [3]. Isildak et al. discuss pharmacotherapy of myopic CNV, in which anti-VEGF agents the mainstay of treatment [4]. The review by Moisseiev and Loewenstein discusses novel pharmacotherapy for neovascular AMD beyond currently available anti-VEGF agents [5]. Iacono et al. present in detail the contemporary treatment approaches to chronic CSC [6]. Wan and associates discuss the pharmacotherapy of vitreomacular traction, which occurs due to incomplete or anomalous posterior vitreous detachment [7]. Ho and Lai review the pharmacotherapy for CNV due to uncommon causes, including uveitis, angioid streaks, intraocular tumors, hereditary chorioretinal dystrophies, or of idiopathic origin [8]. Grzybowski & Kanclerz analyze the role of corticosteroids and nonsteroidal anti-inflammatory drugs in the prevention and treatment of PCME, which remains one of the most common vision threatening complications of cataract surgery [9]. Villegas & Schwartz in their review present current and future pharmacologic therapies for DR, which is the leading cause of permanent visual loss in working-age adults in industrialized nations [10]. This issue seeks to review the current understanding of retinal pharmacotherapies and to provide some insights into future areas of research.

Our planet was formed as a condensed mass of cosmic debris about 4.5 billion years ago; it had a primitive ocean, an atmosphere, clime and a recurrent cataclysmic process. This cyclic and apparently endless inferno progressively became more suitable for life, albeit a life without oxygen. Oxygen imposed its presence on the Earth primarily as a result of the disruption of water (H2O) into hydrogen (H2) and oxygen (O2) mediated by solar radiation; later through a more sophisticated mechanism; oxygen became abundant as a byproduct of the photosynthetic process [1]. The presence of oxygen on earth implied a mass extinction of anaerobic species. The role of oxidative stress on biological systems; important organic functions, and the origin and developments of chronic diseases are discussed in this special issue of Current Pharmaceutical Design entitled “Oxidative Stress: an update on its controversial relationship with organic functions”. Galvez Cabezas et al. [2] focused their work on atherosclerosis, the major underlying mechanism driving the onset and maintenance of cardiovascular diseases; taking into consideration the role of oxidative stress in this process. This paper correlates cell damage caused by oxidative stress to atheromatous plaque formation, as well as an in-depth analysis of high-density lipoproteins. The paper also explores the role of enzymatic and non-enzymatic antioxidants on atherosclerosis prevention and their failure to reverse this process. Kumar et al. [3] have emphasized in aging and neurodegenerative diseases caused by excess of oxidative stress, explaining all the effects of telomere shortening and the pathways of neurodegeneration as well as neuropsychiatric diseases. This paper also reviews the effect of lifestyle change and activation of antioxidant pathways. Tangvarasittichai et al. [4] present the consequence of excessive oxidative stress in the physiology and function of the eyes. Oxidative stress induced ocular cells/tissues changes such as ECM accumulation, cell dysfunction, cell death, advanced senescence, disarrangement or rearrangement of the cytoskeleton and release of inflammatory cytokines. Increased inflammation may be a critical contributor of the development of Diabetic Retinopathy (DR). Gangaraju et al. [5] focused on the integrity of the blood retinal barrier (BRB) and its role on retinal cellular function and accurate vision. The paper reviews the effect of oxidative stress in relationship to endothelial activation in retinal diseases and BRB condition. Romá-Mateo et al. [6] have dedicated their work to the influence of oxidative stress at the epigenetic level, in the unleashing of progeroid syndromes in which cell senescence, oxidative stress and epigenetic mechanisms are severely impaired and the current pharmacological approaches that either target or use oxidative stress-related factors or epigenetic regulators as strategies for disease treatment. Cancer is a major cause death worldwide and their etiology of cancer is related in part by genetic inheritance, but mostly by environmental causes where oxidative stress plays a fundamental role. That is the topic developed by Klaunig [7] which discussed the importance of single nuclear polymorphisms for oxidative DNA repair and enzymatic antioxidants in determining potential human cancer risk role. Pinheiro Ferreira et al. [8] bring a study of the effects of sulforaphane on prostate cancer. This compound displays antioxidative, chemopreventive and antitumor properties; sulforaphene has been isolated from cruciferous plants. Often plants suffer from “excess respiration” and produce numerous compounds with similar properties like sulforaphane. The kidneys has a key function in organisms: to maintain plasma homeostasis by filtering plasma and reabsorbing other compounds essential for life maintenance in a highly active transmembrane consuming process. This process is presented by Coppolino et al. [9] were they highlight the link between kidney and oxidative stress accruing evidences that pints to the kidney as a fundamental organ in reactive oxygen species (ROS) production. Fritsch Neves et al. [10] paid attention to ROS as a common mechanism for endothelial dysfunction, vascular inflammation and arterial stiffness, resulting in early vascular aging and cardiovascular diseases as well as the importance of nutrition and active exercise in its prevention. Rosado-Pérez et al. [11] worke focuses on the powerful antioxidant naringenin, a flavonoid with a high antioxidant capacity present in the chayote plant (Chayota edulis (Jacq.)). The chayote plant is an example of edible fruits and vegetables with relevant antioxidant content. One of the reviews presents how known hepatoprotectors act as antioxidants and immune stimulators in animals. De la Riva et al. [12] used mice to develop a preventive treatment to be tested and used in livestock based on the hepatoprotective and antioxidative properties as well as the immune modulation effect of yeast β-glucans in animals. The study included perspectives on animal health care.

Gastrointestinal cancers are one of most common chronic diseases and are among the top three causes of mortality in the world. Despite extensive improvements in surgery, chemotherapy, radiotherapy and target therapy over the last decades, the outlook for patients remains miserable, with short survival in advanced cancer stages and recurrence. Long non-coding RNAs (lncRNAs) are non-protein coding RNA molecules more than 200 nucleotides which regulate gene expression.lncRNAs plays an important role in initiation, development and metastatic behavior of various tumors. MicroRNAs (miRNAs) are evolutionary conserved, short (~22 nucleotides in length), single-stranded RNA molecules that attributed to the big family of small non-coding RNAs. MiRNAs contribute in the tumorgenesis as either tumor suppressors (oncosuppressor) or oncogenes (oncomiR), lncRNAs may function as competing endogenous RNAs (ceRNAs) to attract miRNAs, therewith modulating the derepression of target miRNA. LncRNAs and micro-RNAs can be circulated in body fluid, suggesting their values as noninvasive predictor marker of cancer diagnosis, classification, prognosis, and response to treatment. The thematic issue provide the readers working in basic biomedical sciences as well as clinicians a comprehensive overview on diagnostic, prognostic significance and targeting lncRNAs and miRNAs in gastrointestinal cancers. In this issue, Garajová and co-workers [1] provide an overview about association of noncoding RNA in pancreatic cancer with respect to their application as diagnosis, prognosis and therapeutic target. Furthermore they discuss the influence of non-coding RNAs in the metastatic behavior of pancreatic cancer, and the role of diet in epigenetic regulation of non-coding RNAs, which can lead to the development of novel prevention approaches or targets for cancer therapy. The review entitled “Role of regulatory oncogenic or tumor suppressor miRNAs of PI3K/AKT signaling axis in the pathogenesis of colorectal cancer” explored the regulatory miRNAs of PI3K/AKT/mTOR signaling as represent novel biomarkers for new patient diagnosis and obtaining clinically invaluable information from post-treatment CRC patients for improving therapeutic strategies [2]. Moradi-Marjaneh and co-authors review TGF-β signaling pathway which plays an important role in normal intestinal tissue function and development of CRC. In this study, they summarized the data of interaction between TGF-β signaling pathway and miRNAs to better understand the molecular mechanisms in CRC [3]. Ghanaatgar-Kasbi et al., investigated the therapeutic potential of targeting c-mesenchymal-epithelial transition factor (c-MET) pathway via novel HGF/Met inhibitors in pancreatic cancer, since this pathway is among the key dysregulated pathway in pancreatic cancer and its overexpression is reported to be associated with poor prognosis and chemo-resistance [4]. Another study entitled “Phytosomal curcumin elicits anti-tumor properties through suppression of angiogenesis, cell proliferation and induction of oxidative stress in colorectal cancer” investigated the anticancer activity of phytosomal curcumin, in colorectal cancer [5]. Curcumin is a bioactive compound of the spice-herb turmeric or Curcuma longa and has been widely investigated for its anticancer activities in various types of cancer cell lines and in vivo tumor models. However, curcumin application in the clinic has been limited due to its poor solubility, low oral bioavailability and rapid metabolism which has resulted in attempts to improve curcumin formulations. Phytosomal curcumin is a novel formulation could overcome the limitations of conventional delivery systems, exerts sustained release and optimize the curcumin absorption and bioavailability. Moreover, phytosomal technology enhances absorption following oral administration and also has a liver protective effect due to phosphatidylcholine used to its preparation. Khazaei et al. showed that phytosomal curcumin has anti-tumor properties through suppression of VEGF signaling regulatory miRNAs, cell proliferation and induction of oxidative stress in colorectal cancer. Helicobacter pylori infection is considered as the most important risk factor for gastric cancer (GC). Although H. pylori is associated with acute and chronic inflammation of gastric epithelium, it has been recognized as an important carcinogen for GC. There is growing body of data showing that H. pylori is related with dysregulation of microRNAs expression. Parizadeh and co-workers provide an overview about recent studies investigated the different expression of tissues miRNAs depends on Helicobacter pylori infection and effect of these different expression on development and progression of Gastric cancer [6]. The review of Javadinia et al., summarized the current status on Phosphatidylinositol 3-kinase/AKT/Mammalian Target of Rapamycin (PI3K/AKT/mTOR) pathway and their cross regulation with a focused on the value of targeting this pathway as a potential therapeutic target in treatment of esophageal cancer, since overexpression of this pathway is associated in the development, and prognosis of esophageal cancer [7]. Asgharzadeh and colleagues investigated the therapeutic application of Angiotensin-converting enzyme and angiotensin receptor (ACEIs/ARIs) inhibitors in the treatment of colorectal cancer [8]. Fani et al. discussed the interaction of dysregulated miRNA by different viral infection, such as EBV, HSV1&2, KSHV, MHV68, CMV, Polyoma virus, Adeno Virus, HBV, HAV, EBOV [9]. Another study by Amerizadeh et al., explored discuss current circumstances and future outlooks of targeting angiogenesis using novel VEGF inhibitors and small noncoding microRNAs in gastrointestinal cancers [10]. Rezaei and colleagues present recent advances on electrochemical detection assays, which has strikingly gained the ultrahigh sensitivity and selectivity. This review summarizes the drawback of current detection methods and also highlights the recent advances on the biosensory methods as point-of-care devices which can able to measure the circulating miRNAs in various cancers [11]. Finally we hope these multidisciplinary topics discussed with the theme issue, promote further discussion among current status and future prospective of Long non-coding RNA and microRNAs as novel potential biomarker and therapeutic target in the treatment of gastrointestinal cancers. As the guest editors, we would like to thank all the authors and co-authors for their excellent contributions. furthermore, we would sincerely thank and acknowledge the diverse group of experts and colleagues who offered their substantial reviewing efforts and suggestions. Last but not least, we would like to express our gratitude to the Bentham Science Publishers for the wonderful experience on this thematic issue and Prof. William A. Banks, Editor-in-Chief of Current Pharmaceutical Design to give us this opportunity to publish this issue. Also It was a great pleasure working with the Director Kazim Baig, for the opportunity to publish in Current Pharmaceutical Design. It was a wonderful experience working with Editorial Assistant Aamer M. Khan at the time of submission and processing of the manuscripts. I would like to acknowledge the contributions of others who took care of editing and processing the manuscripts to obtain the best final quality at the time of publication.

Arterial and venous thrombosis affect a significantly underreported number of people worldwide, leading to million deaths per annum [1]. Cardiovascular disease is the leading cause of death, especially in low- and middle-income population [2]. Venous thromboembolism (VTE) is the cause for half a million deaths per year in the European Union, alone. A plethora of different mechanisms involving the coagulation cascade and platelets play various roles in thrombosis. The coagulation mechanism consists of activation, adhesion, and aggregation of platelets along with deposition and maturation of fibrin. For decades, acetylsalicylic acid, warfarin and heparin were the only available pharmaceutical agents to prevent arterial and venous thrombosis. Despite the fact that these medications saved millions of lives, they had – and still have - significant side effects; warfarin had a narrow therapeutic window, the need for regular monitoring, risk of bleeding and numerous interactions with other medication. Unfractionated heparin also requires continuous monitoring and had a short half-life. Acetylsalicylic acid is available for oral administration and its intravenous form is only a precursor molecule and not an active ingredient. The development of novel pharmaceutical agents answers to the clinical need for better control over the anti-thrombotic effect, improved hemodynamics and safer outcomes for patients. Novel oral anticoagulants (NOACs or DOACs from Direct Oral Anticoagulants) and novel antiplatelets (NAs) are new additions to the clinical armament for cardiac and vascular patients. These new drugs have been developed in order to address the limitations of the previous generation of anti-thrombotic medication. They do not need routine monitoring and interact less frequently with other medications. In 2010, the Food and Drug Administration (FDA) approved its first NOAC, dabigatran (Boehringer Ingelheim) [3]). By 2015, FDA had approved three more NOACs: rivaroxaban (Johnson & Johnson and Bayer Healthcare AG), apixaban (Bristol-Meyers Squibb & Pfizer Inc.), and edoxaban (Savaysa/Lixiana, Daiichi Sankyo). At present, clinical data and patients’ outcomes are being collected and the different NOACs and NAs are supported by different levels of evidence leading to fine differences in national guidelines on their use [4-7]. Despite the fact that the clinical use of most NOACs and a number of NAs is already regulated by the continuously updated guidelines, questions remain about the safety and the indication of their use on vascular patients presenting with peripheral arterial disease (PAD), VTE, and symptomatic or asymptomatic carotid disease. Vascular patients frequently present with various synchronous comorbidities and are often required to undergo more than one surgical or endovascular procedures in relatively short periods of time. As a result, the perioperative management of NOACs and NAs is still under careful assessment for this group of patients. Krasinski et al. [8] examine the administration of NOACs in patients with chronic kidney disease (CKD), a comorbidity frequently present in vascular patients. PAD affects approximately 10% of patients over 60 years of age [9]. Until recently, patients affected by PAD have traditionally been prescribed antiplatelets (acetylsalicylic acid and/or clopidogrel) and in cases of intermittent claudication cilostazol. Koutsoumpelis et al. [10] provide us with the latest updates on how the COMPASS and other trials are currently altering our existing knowledge on pharmaceutical treatment of PAD. The COMPASS trial mentions for the first time that adding a NOAC (rivaroxaban) to the established treatment of PAD improves patient outcomes, but it leaves some pending questions on which subgroup of patients are benefited the most [11]. Tsilimigras et al. [12] comment further on the clinico-economical impact of the COMPASS trial. It is essential for anaesthetists and vascular surgeons to know the properties of NOACs and NAs. The perioperative period is associated with significant prothrombotic and bleeding risks, both potentially leading to complications or death, if not efficiently and timely addressed. The peri-operative management of the NOACs in arterial surgery is discussed by Kouvelos et al. [13]. Regarding the peri-operative management of NOACs in venous procedures, Drebes et al. [14] focus on interventions for ilio-femoral deep vein thrombosis. As long as NOACs are concerned, peri-operative and post-traumatic bleeding is thought to be more complicated to control compared to traditional anticoagulants, although recent publications do not support this hypothesis [15]. Not all NOACs have a fully reversible effect or a direct inhibitor of their action. The management of post-traumatic or peri-operative bleeding is addressed in two publications by Zimmermann et al. [16] and Palaiodimos et al. [17]. Resistance to older antiplatelet agents is well known and recorded in previous publications [18]. Markel et al. [19] described how this resistance can be quantified and measured. NAs are capable of addressing this limitation of classic antiplatelet agents and providing better outcomes for vascular patients. Patelis et al. [20] provides an update on the use of already established NAs and also reports on experimental NAs.

Cardiovascular prevention strategies may consider that beyond treating hypertension per se, the benefit of evaluating subclinical organ damage and reverse these damage, is an important endpoint in the cardiovascular continuum from a risk factor to evident disease. The importance of subclinical organ damage lies on the reversible of the damage in many cases and this can be a protective factor for future CV health. As all human beings are in an atherosclerosis progress from birth to the end of life, it is important to have intermediate end points in this procedure that can predict future disease. prevent complications or delay the procedure. Different treatment approach of the hypertensive disease may relate to the regression or progression of subclinical organ damage. This special issue try to analyze the current evidence in treating hypertensive patients with organ damage. Treatment of hypertension induced target organ damage in children and adolescents is important because young patients that are already have cardiac or vessel disease are going to have more serious cardiovascular complications in the near future. The most prevalent subclinical hypertensive target organ damage in children and adolescents is left ventricular hypertrophy and adequate blood pressure control with antihypertensive therapy may result in the regression of the damage [1]. Arterial stiffness is a marker of cardiovascular disease associated with cardiovascular events. Increased vascular ageing is the acceleration of arterial damage for a given chronological age. Reduced progression of vascular ageing may include physical exercise, moderate alcohol consumption, reduced salt consumption, weight reduction and appropriate control of vascular damaging risk factors with antihypertensive, lipid lowering and anti-diabetic treatment [2]. Vascular factors contribute to the onset and progression of cognitive decline with advancing age. Hypertension is the most prevalent CV risk factor for cerebral macrovascular and microvascular complications factors for Alzheimer disease and vascular dementia. Evidence support that antihypertensive drug treatment may play a role in the prevention of cognitive impairment. Regression of hypertension-induced left ventricular hypertrophy reduces cardiovascular morbidity and mortality. Adequate blood pressure control reduces cardiac hypertrophy and future heart failure. Blockers of the renin-angiotensin-aldosterone system reduce cardiac remodeling beyond their blood pressure reduction. Such drugs are important in the regression of left ventricular hypertrophy but the most important factor is to reduce BP back to the normal levels [3]. Prevention of atrial fibrillation is important and hypertensions, a modifiable risk factor, may reduce new and recurrent atrial fibrillation. Renin-angiotensin system blockers prevent new-onset AF in patients at high cardiovascular risk, left ventricular hypertrophy or heart failure [4]. Finally, albuminuria is associated with cardiovascular and renal risk. Endothelial dysfunction of the renal vessels is increasing albumin excretion. Changes in albuminuria were considered to have moderate prognostic value. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers are the drug of choice, while mineralocorticoid receptor blockers can be considered in uncontrolled hypertensive patients with albuminuria. CCBs can be used in addition to the RAAS blockade as a second step and then all other drug classes if BP is not controlled. The effect of other antihypertensive drugs classes on the onset and reduction of albuminuria is driven from the BP reduction [5]. Subclinical organ damage is an evidence of a good or bad long term blood pressure control. Future research may focus in these patients to prevent disease and despite that we have many randomized clinical trials in hypertension, studies on long term effects on BP induced intermediate end points are lacking. Keywords: Hypertension, target organ damage, antihypertensive treatment, early vascular ageing, pulse wave velocity, left ventricular hypertrophy, microalbuminuria.

Plants have assured for centuries the treatment and prevention of several illnesses, and are still used on current days in traditional medicine. Phytochemical studies have disclosed the presence of bioactive secondary metabolites, some with cytotoxic properties, that prove the medicinal value of natural products. As such, their bioactivity and versatility have attracted researchers to perform all kinds of studies. The unmodified structures of cytotoxic natural products allowed the discovery and modulation of new cellular targets, and also the elucidation mechanisms of action, but their applications are limitless. The biological value of this type of molecules has inspired the modulation of their activity through structural modifications or the synthesis and design of new compounds with the aim of mimicking their properties. For this reason, this thematic issue focuses on recent discoveries related to cytotoxic natural products. Therefore, biological cancer-related targets, clarification of the signal transduction pathways of cell death, structural elucidation and drug design of new plant-derived natural products with proven activity cover the scope of this issue. Moreover, chemoprevention is the long-term pharmacological control on the risk of cancer. On this matter, several plants, together with their compounds, have been investigated for their antitumor potential. As it is well known, natural products represent a unique source of lead compounds for pharmaceutical drug design. In fact, several medicinal plants have been studied and their beneficial effects and have been rediscovered for the development of new drugs. Current research in drug discovery has been inspired by the vast ethnopharmacological applications of natural products, providing new and important leads against various pharmacological targets. Despite the recent interest in synthetic chemistry techniques by the pharmaceutical companies, the natural products and particularly medicinal plants, remains an important source of new drugs, new drug leads, and new chemical entities. At least one-third of the current top twenty drugs on the market are derived from a natural source, mainly plants, and approximately 50% of the marketed drugs are classified as naturally derived or designed on the basis of natural compounds [1]. Being that so, this special issue will cover current research articles on natural products from renowned researchers in the field of medicinal chemistry drug development. The works chosen in this proposal will evidence that natural products research can lead to advances in synthetic methodologies and to the possibility of making analogs of the original lead compound with improved pharmacological properties, which can prompted further pharmaceutical developments. The complex architectural scaffolds and densely deployed functional groups, affording the maximal number of interactions with molecular targets, often lead to exquisite selectivity against tumor cells. Considering all these facts, this thematic issue covers different natural products compounds such as: 1. Garcia et al. manuscript covers a vast range of Plectranthus-derived diterpenes and focusing on those that possess antiproliferative, antitumoral or cytotoxic potential. Previous studies have already proven the cytotoxic potential of diterpenes, some of which are herein reported, namely the abietane diterpene 6,7-dehydroroyleanone [2]. 2. Prieto and Silveira, reviewed the cytotoxic and/or antitumoral activities of diterpenes in melanoma. Many such compounds - particularly Phorbol esters- have been known for their activity against skin malignancies since ancient times, and have provided humans with one of the most potent anticancer drugs ever (Taxol). The recent approval of the diterpene ingenol mebutate for the chemoprevention of melanoma in actinic keratosis patients renews the interest in this megadiverse class of secondary compounds as potential sources of future melanoma chemotherapy [3]. 3. Mori et al. reviewed the use of natural products as a unique source of lead compounds in the identification of small molecule inhibitors of signaling pathways implicated in cancer stem cells proliferation, such as Notch and Hedgehog [4]. 4. Duarte et al. in their review “Cytotoxic Stilbenes and Derivatives as Promising Antimitotic Leads for Cancer Therapy” presents an overall overview regarding the discovery of natural stilbenes, its development as lead compounds and its mechanism of action. A global review about the synthetic methodologies and structure-activity relationships for the antimitotic cis-stilbenes combretastatins and derivatives is also referred. A special emphasis was made in the analysis of preclinical studies and clinical trials of the most promising candidates. In addition, recent nanotechnology procedures and particularly different types of nanocarriers for targeted delivery of combretastatins is extensively reviewed [5]. 5. Domínguez-Martín et al. in their review Anticancer Hybrid Combinations: Mechanisms of Actions, Implications and Future Perspectives” classify and analyze for the first time, the synergistic mode of action of the combinations between synthetic drugs and plants secondary metabolites from plants or their extracts. At this point, it should be emphasized that the study of synergy among the secondary metabolites of plants is one of the aims of the Medicine for the XXI century, which will have a huge relevance in rationalizing the use of Phytotherapy and Integrative Medicine as T. Efferth got an insight into his work [6]. 6. Milica Pesic: Inhibition of P-gp is very important characteristic of natural compounds with anticancer potential. Therefore, we conducted a comprehensive literature review of natural-based P-gp inhibitors that possesses great interest for the scientists in the field of cancer multidrug resistance (MDR) research and nature inspired chemical synthesis. An overview of traditional medicine contribution to the field is also included [7]. 7. Quintana and Estévez review about recent advances on cytotoxic sesquiterpene lactones against cancer cells. These plant-derived compounds may have therapeutic value in the development of new anticancer agents because they are better tolerated than synthetic chemotherapeutics, simultaneously target many key pathways and mechanisms and show higher affinity against cancer cells [8]. 8. Faustino et al., manuscript provides an updated overview on the cytotoxicity and chemotherapeutic potential of rosin abietane diterpenoids in cancer treatment. These compounds have been shown to execute their anticancer activity through targeting diverse oncogenic cell signaling pathways, promoting cell cycle arrest and apoptosis or oncosis, inhibiting tubulin polymerization and disrupting intracellular cholesterol transport, thus opening a new avenue for cancer treatment and chemoprevention [9]. In conclusion, in this issue, a team of international experts that works with natural products reviewed the most novel topics and approaches towards the development of therapeutic agents for precision medicine.

Cancer and chronic inflammatory diseases have a significant impact on quality of life, due to both disease progression and drugs’ adverse effect. On the other hand, complementary medicine, including supplements, herbs, probiotics and prebiotics, is a topic of growing interest in both preclinical and clinical studies. In particular, antioxidant phytochemicals have been suggested as complementary medicines able to reduce the adverse effects of drugs. In this context, Paz et al. [1] reported both hepatoprotective and cytotoxic effects for diterpenes. On the other hand, Ayati et al. [2] reviewed the traditional uses of Rosehip and the potential effects of its bioactive phytochemicals, including phenolic compounds. Marranzano et al. [3] suggested that polyphenols from residual sources could be used for increasing the stability of foods by preventing lipid peroxidation, potentially improving the effects on health of certain foods. However, polyphenols are metabolized by human body as drugs. Many genetic and epi-genetic factors affect the efficacy of conventional medicine, as well as of nutrients. Virgili et al. [4] reviewed the relationship between specific polymorphisms of genes encoding for metallothioneins and zinc transporters with zinc status, immune function and some non-communicable diseases. Concerning non-nutrient bioactive molecules, in addition to their metabolism by human body, which is affected by genetic polymorphisms of genes involved in the metabolisms and disposal of drugs, many phytochemicals are metabolized by gut microbiota. The latter can be affected by some phytochemicals, having anti-microbial activity, as well as by disease state and drug treatment. Vamanu [5] reviewed the prebiotic effects and the role of the polyphenolic component of wild edible mushrooms in the potential health effects of wild edible mushrooms as complementary medicine. Probiotics and prebiotics consumption can improve health by microbiota modulation. Korada et al. [6] reported that the potency of probiotic differs from strain to strain and that more comparison studies are needed in the direction of probiotic functionality and clinical efficacy of single strains versus multi-strain mixture for a disease prevention and management. Within mechanisms of probiotic protection on Inflammatory Bowel Disease there is the production of short chain fatty acids, such as the immunomodulatory molecule butyrate, by the gut microbiota [7]. On the other hand, hormones have significant roles in inflammatory and immune mediated diseases. Yang et al. [8] reviewed the influence of hormones on Sjögren’s syndrome, including adrenocorticotropic hormone, follicle-stimulating hormone, luteinizing hormone, thyroid- stimulating hormone and prolactin. Authors concluded that hormonal influence can account of the high prevalence in females and elderly people. Furthermore, being immune system primarily involved in Sjögren’s syndrome, also genetic polymorphisms in human leukocyte antigen play a role in disease pathogenesis [9]. Therefore, hormonal imbalance, genetic polymorphisms and microbiota diversity suggest that the concept of integrative medicine should be associated with that of personalized medicine. In this context, new trends in diagnosis and therapy include nanotechnology, having potential application in personalized health care. The latter, including personalized nutrition, physical activity and outdoor lifestyle, has been suggested for veterans with disabilities by Ciccotti et al. [10]. However, sunlight exposure may increase the incidence of eye diseases, including pterygium. In this context, Zein et al. [11] performed a meta-analysis of randomized controlled trials comparing the efficacy and complications of autologous blood versus using fibrin glue and surgical sutures for conjunctival autograft fixation in primary pterygium surgery. Patient satisfaction and postoperative symptoms are relatively better in the blood coagulum group than the other techniques [11]. In conclusion, we hope that this issue can add knowledge on the effects of bioactive molecules from foods and herbal extracts on chronic diseases and on the role of microbiota, genetic factors and hormones in diseases diagnosis and management. In closure, we end this editorial by thanking Dr. William A. Banks, the Editor-in-Chief, as well as Bentham Science Publishers, the Director Kazim Baig and the Editorial Assistant Aamer M. Khan. We extend our appreciation to contributing authors who have actively responded to our request by contributing to this special issue of Current Pharmaceutical Design and the peer reviewers for the time and expertise that each altruistically provided in reviewing the submitted manuscript.

Chronic disease such as has become the main killer of human health due to its difficult to early detection, diagnosis and treatment. The history of treatment of chronic diseases covered traditional herbal, medication, as well as new targeted drug therapy immunotherapy and even surgical anatomy. Through the above treatment, some diseases can be controlled, but some cannot be effectively cured, especially for cancer patients at advanced stage. In the past few decades, the developments in the biomedical technologies improve the diagnosis and treatment of disease. Despite novel approaches being an attractive strategy in treatment (and there is a great interest in the development of powerful approaches to be incorporated into clinical practice), persistent gaps do exist between published research and clinical application. Thus, there is a need to fundamentally address all the above-mentioned issues in this issue. There are six interesting papers in this special issue covering machine learning methods on handcrafted and deep learned features for ATC classification, machine learning in precision medicine and nitrotyrosine sites’ prediction in proteins, advances in antidiabetic drugs targeting insulin secretion, simulations of enzyme thermostability study and predict subcellular localization of plant proteins by general PseAAC and balancing training dataset Diabetes mellitus (DM) is a chronic, complex and multifactorial disease associated characteristically with hyperglycemia. Ding and coworkers [1] focused on antidiabetic drugs and antidiabetic drugs targets. In this article, some antidiabetic drugs were described, such as metformin (biguanide), sulfonylureas (Insulin secretagogues), thiazolidinediones (TZDs) and a-glucosidase inhibitors (AGI) and some antidiabetic drugs targeting insulin secretion including GLP-1R, KATP, GPR119 and FFAR1 were also introduced. At present, insulin therapy for diabetes mainly includes supplementation of exogenous insulin, improvement of insulin resistance, and protection of insulin beta cells. This article mainly introduces the drugs and targets related to improvement of insulin resistance. Meng and co-workers [2] provided an overview of how machine learning can help the scientific community of how to use machine learning algorithms for precision medicine. The review covered fundamentals of the machine learning methods, including the deep neural networks, as well as interesting case studies. The advantages and disadvantages are also discussed along with some computational tools. In this issue, Lumini and Nanni [3] described approaches for Anatomical Therapeutic Chemical (ATC) classification of unknown compound. The ATC classification system is a comprehensive drug classification scheme developed by the World Health Organization (WHO), in (Lumini and Nanni) the 14 main overlapping classes of the first level of ATC are used. A novel approach based on convolutional neural network is proposed, the authors reported state-of-the-art performance in a large dataset already used in the literature. Both code and dataset will be available at https://github.com/LorisNanni Information of protein subcellular localization is vitally important for both basic research and drug development. Cheng and co-workers [4] reviewed the protein subcellular localization and introduced a very powerful new predictor called “pLoc_bal-mPlant”. The new predictor is remarkably superior to the state-of-the-art method in predicting the subcellular localization of plant proteins.The new predictor’s webserver has been established by which users can easily obtain their desired results.It is anticipated that the new method will become a very useful tool for medical science. Li and co-workers [5] proposed Simulated Protein Thermal Detection (SPTD) to investigate the thermal stability of enzymes. The method was based on the evidences observed by conducting the MD (Molecular Dynamics) simulation for all the atoms of an enzyme vibrating from the velocity at a room temperature (e.g., 25°C) to a desired working temperature (e.g., 65°C). Some useful conclusions are summarized as follows. As a result, the SPTD method could provide the information of protein structures in dynamically thermal motion, which is very helpful for studying and improving protein thermal stability and enzyme bioactivity in the environment of higher temperature. The strategy of side-directed mutations for thermal stability improvement could be designed based on the interaction types between side chains of amino acids, such as hydrogen bond, cation-π interaction, polar hydrogen-π interaction, salt-bridge, and amide-bridge. And it is anticipated that the SPTD technique presented in this paper may become a very useful tool for pharmaceutical design and protein engineering. Ahmad and co-workers [6] proposed a new method for predicting the PTM sites for nitrotyrosine sites. They applied adaptive training algorithm i train a back propagation neural network for prediction purposes. Through verification and validation, a promising accuracy of 88%, a sensitivity of 85%, a specificity of 89.18% and Mathew’s Correlation Coefficient of 0.627 is achieved.

The spectrum of neurological disorders is extremely broad, and as we enter a super-aging society, the number of patients with age-related neurological disorders will rise rapidly. Therefore, the need to develop therapies and ways to prevent the progression of neurodegenerative diseases is highly important. For example, in Alzheimer's disease, the abnormal accumulation of the amyloid β peptide has been established as a fundamental pathology, and antibody therapies and vaccines targeting amyloid have been shown to improve cognitive function in animal models. However, even though some of these antibodies have been shown to suppress the accumulation of the amyloid β peptide, there is no vaccination/medication with a proven clinical effect available at the present time. Furthermore, true disease modifying medications are still needed for other neurological/ neurodegenerative diseases including epilepsy, Parkinson's disease, ALS (amyotrophic lateral sclerosis), SCD (spinocerebellar degeneration) etc. Thus, the importance of translational research aiming to develop concepts from basic research using an animal model to clinical application and incorporating the bench to bedside idea is more necessary than ever. By elucidating the pathogenic mechanisms of brain and neurological diseases, it may become possible to identify key molecules to develop prophylactic/therapeutic drugs and to target the mechanisms underlying these diseases. In the future, it is hoped that early detection of disease conditions will be achievable through the identification of biomarkers that can be used for early or specific diagnosis. Drug delivery methods also need to be developed through the use of appropriate animal models. In this special issue, leading international experts discuss the most relevant topics on novel potential targets for NAP [1], PACAP [2, 3], CGRP [4], ODN [5] and GALP [6]. We would like to thank all the contributors to this special issue for their efforts.

Recent decades, the development of computational tools and techniques has become a well-established research area, and it contributes to different applications in cancer research including genomics, proteomics, and epigenomics. Raising studies using computational techniques is constructing to the aggregation of big biological data, as well as the improvement of high-performance computing. Numerous techniques, such as Big data analysis, computer-aided drug design, cancer immuno-informatics, epigenomics, data science and medical computing, deep learning in precision medicine, gene regulatory networks, interactomics, molecular modeling and simulation techniques, machine learning in precision medicine, systems and synthetic biology, systems pharmacology and systems based precision medicines play a pivotal role in the field of computational biology. The developments and broader applications of these methods not only improve our standing of the mechanisms of biological processes but also facilitate the diagnosis and therapy. For instance, high throughput machine and deep learning is a rational drug design method that benefits the discovery and development of drugs targeting specific proteins. A computational perspective on the current state of the methods and challenges in cancer drug discovery looking for high-quality research related to interdisciplinary approaches to exploiting the power of drug discovery by applying new algorithms, tools and databases. The proposed articles in this special issue have a significant contribution to developing new ideas, machine learning, target identification, drug delivery system and rational drug discovery techniques to the cancer research through the esteemed researchers around the world. In this issue, Wang et al., [1] discussed the targeted therapy on personalized medicine in cancer. The authors describe a brief introduction on the advanced drug or drug-like therapy with genetics, epigenetics, and metagenomics respectively, from the viewpoint of personalized determinates. Then summarize the computational methods helpful to analyze the corresponding omics data under the consideration of personalized biological context; and mainly focus on the metagenomics to discuss current data, method, and opportunity for personalized medicine. This article indicates the targeted therapy has an important part in cancer individuals. Selvaraj and Singh [2] described the potential impact of DNA molecule on therapeutic application through selective recognition of molecular targets and pathways. The interaction mechanisms (intercalators and groove binders) of small molecules with DNA are a significant feature in target-based drug development. This article attempts to outline those interactions of drug target-DNA with both experimental and computational advances, including ultraviolet-visible spectroscopy, fluorescent spectroscopy, circular dichroism, nuclear magnetic resonance (NMR), molecular docking, dynamics, and quantum mechanical applications. Chien et al. [3] described the importance of computer-aided drug discovery (CADD) techniques on cancer drug development. CADD strategies like structure-based, ligand-based, and combined structure-based and ligand-based approaches have the advantage of identifying target sites and discovering candidate drugs with high affinity. In this article provide more details about the types of computational strategies, computational techniques to the modeling and drug discovery and scoring functions for evaluation protein-ligand complexes has been reviewed for future research. Rehman et al. [4] discussed the allosteric regulation of protein tyrosine phosphatase (Shp2) on the dysregulation of cell signaling cascades associated with cell differentiation and growth. The deletion, insertion or point mutation in specific amino acids, which alters the natural conformation of the Shp2, can ultimately lead to fatal cancer. Studies reported that the germline mutations in the interface of PTP and SH2 domain, Shp2 have a significant association with acute myeloid, juvenile myelomonocytic, and B-cell acute lymphoblastic leukemia, Noonan syndrome, and myelodysplastic. This review covers the last 10-year recap of Shp2 protein, their role in cancer, and regulation in allosteric regulation. Turanli et al. [5] described a complex framework of interacting partners including genetic, proteomic, and metabolic networks that cooperate to mediate specific functional phenotypes drives human biological processes. Pharmaco-omics analysis based on an integration of pharmacology and various “omics” data types can be employed to develop effective treatment strategies using particular drugs and doses that are tailored to each. Then, the authors provide an opening into precise medicine and drug targeting based on network approaches. Also, this article offers the current significant efforts as well as the accomplishments and limitations in precise drug targeting with the utility of network- based guided drug discovery methods for effective treatment of breast cancer. Kaliamuthi et al. [6] discussed the cancer immunoinformatics have new directions towards in vaccine design from predicted potential epitope candidates, able to stimulate correct cellular or humoral immune responses. In this review, the authors explained multiple computational tools including online and user-friendly immunological tools, servers and databases to identify the potential target epitopes for peptide vaccine design and development. Also, the mechanism of major histocompatibility (MHC) restricted peptide presentation and how these tools are supporting the vaccine development is presented. Human papillomavirus (HPV) has been taken as a model microbial strain for peptide vaccine design and discussed their sensitization against HPV induced cervical cancer significantly. Basharat et al. [7] discussed the cancer genome sequencing analysis and its application in diagnosis and personalized treatment. Analysis of the sequencing data involves the integration of computation, statistics, and system biology methods. The results of the analysis can improve the study about the interaction of cancer cells with the immune system, harnessing immune system for cancer therapy or its prevention through vaccines has led to the foundation of cancer immunomics. There has been a gradual increase in the establishment of cancer immune focused start-ups, research facilities and pharma-giants working on state-of-the-art methods for improving diagnostics, treatment, and prevention or minimizing side effects, applying immunomics. In this review, authors provide an overall picture and focused on immune biomarkers and relevant software that aid in the diagnostics and analysis of cancer. Loganathana and Muthusamy [8] described the current scenario in structure and ligand-based drug design on anti-colon cancer drugs. Recent molecular modeling approaches, driven by rapidly improving computational platforms, have led to many success stories for the use of computer-assisted drug design in the discovery of the structure and ligand-based drugs. This review provides information on how anti-cancer drugs were formulated and identified using computational power by the drug discovery society. Tang et al. [9] described the computational advances in the label-free quantification of cancer proteomics data. The label-free quantification (LFQ) is frequently employed to quantify cancer proteomics data. However, low precision, poor reproducibility, and inaccuracy of the LFQ of proteomics data have been recognized as the key “technical challenge” in the discovery of anticancer targets and drugs. The review article offers, a variety of favorite acquisition techniques and state-of-the-art quantification tools are systematically discussed and critically assessed. Then, many processing approaches including transformation, normalization, filtering, and imputation are subsequently discussed, and their impacts on improving the LFQ performance of cancer proteomics are evaluated. Finally, future directions for enhancing the computation- based quantification technique for cancer proteomics are also proposed. Kandasamy et al. [10] discussed the biopolymers-based nanocomposites for anticancer and antimicrobial drug delivery. Biopolymers based nanocomposites have gained more attention as a drug carrier, sensors, disease diagnosis, tissue engineering, wound healing and cancer therapy. This mini-review emphasized the source, extraction, and characterizations of the biopolymers and their use in the fabrication of various drug or metals based nanocomposites followed by its utilization as a drug carrier to treat cancer and microbial infections. We hope multidisciplinary topics discussed with the theme issue will promote further discussion among researchers in computational biology and cancer drug discovery. As the guest editors, we would like to thank all the authors and co-authors for their excellent contributions. In addition, we would like to thank a group of scientific experts in computation and cancer drug delivery who offered their strong comments and suggestions to improve the quality of this special issue. Finally, we would like to express our sincere appreciation to the Director Kazim Baig, Editorial Assistant Aamer M. Khan, copy-editors and all the editorial staffs in Current Pharmaceutical Design, Bentham Science Publishers for the excellent opportunity, and experience while working with this thematic issue.

This issue of Current Pharmaceutical Design covers several topics in the fields of prevalence, identification, scouting, and mainly treatment of Familial Hypercholesterolaemia (FH). Twelve experts with long-term personal experience in this field from both sides of the Atlantic had the courtesy to contribute significant papers that cover spherically the topic of FH. Prof. Viigimaa and colleagues [1] analyzed current data on the pathogenesis and on pathophysiology of FH. Prof. Elisaf and colleagues [2] reported the prevalence (the most common inherited disease), identification, and scouting for FH including FH Registries. Dr. Gossios and colleagues [3] investigated the multimodal treatment of homozygous FH (HoFH). Prof. Tselepis and colleagues [4] reported the current status and the future perspectives on the treatment of FH. Prof. Stefanutti and colleagues [5] reported recent data on the effect of lipoprotein apheresis plus PCSK9-inhibitors on low density lipoprotein cholesterol (LDL-C) and the anti-inflammatory mediators in HoFH and severe heterozygous FH (HeFH). Prof. Athyros and colleagues [6] reported on drugs that mimic the effect of gene mutations for the prevention or the treatment of atherosclerotic disease: from proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition to Angiopoietin-like protein 3 (ANGPTL3) inactivation. Prof. Papademetriou and colleagues [7] reported the main differences between the two commercially available PCSK9 inhibitors Evolocumab and Alirocumab. Dr. Theocharidou and colleagues [8] investigated the role of PCSK9 in the pathogenesis of non alcoholic disease (NAFLD) and reported the effect of PCSK9 inhibitors to ameliorate it. Prof. Faselis and colleagues [9] investigated whether very low LDL-C is harmful. Prof. Stevenson and colleagues [10] analyzed the data about the role of Lp(a) in Cardiovascular Disease (CVD) in patients with FH. Finally, Prof. Stabouli and colleagues [11] analyzed the existing data on the diagnosis and treatment of FH in children and adolescents. Familial hypercholesterolemia (FH), an autosomal dominant disorder, is the most common inherited disease (not only in lipid disorders) and it results in lifetime substantially increased levels of low-density lipoprotein cholesterol (LDL-C) leading to increased risk of premature Cardiovascular Disease (CVD), up to 13-fold increased risk of Coronary Heart Disease (CHD) or aortic stenosis in comparison to general population both in men and women [12]. The prevalence worldwide is 1/500 to 1/200 births; between 14 and 34 million individuals worldwide have FH [13]. The majority of cases are due to LDL receptor loss of function gene mutation, some to apolipoprotein B loss of function gene mutation and few to PCSK9 gain of function gene mutation [13]. From those, less than 1% are diagnosed and even less are treated, with only a few at LDL-C target, despite the fact that therapies (statins, ezetimibe, PCSK9 inhibitors, LDL apheresis, lomitapide, mipomersen [14]) are available [14]. However, early diagnosis and effective treatment diminish the excess risk of premature atherosclerotic CVD in FH [13-15]. The above underline the burden of this disease for the entire society, the necessity for effective efforts to treat it, and the enormous attempt of educating physicians and patients as well FH patient organizations to implement life-style changes and drug treatment for FH [13- 15]. The aim of the present special issue is to critically evaluate the extent to which FH is underdiagnosed and undertreated worldwide and to enlighten the identification and the effective treatment of this disease. Screening for FH is the most important aspect of the disease. Since, if you do not know that the patient is suffering from FH, how can you treat the disease? Most countries have no-screening strategy [16]. Roughly, there are two ways of screening: the clinical and the genetic one [17]. Both methods have three ways: One is to find a young adult with overt CVD and very high LDL-C and then proceeds to cascade screening of all blood relatives; the second is to investigate for FH all newborns and perform a reverse cascade screening of all blood relatives; the third is to screen the entire population (this is done only in Netherlands) [17-19]. One of the major issues in these methods is the cost. Recently, the general screening of children for FH followed by reverse cascade testing of blood relatives is viable and acceptable, although most countries use the adult cascade screening [17]. Homozygous FH (HoFH) is very rare. It requires treatment with LDL-C apheresis, or lomitapide, or mipomersen (approved only from FDA for use in US), or liver transplantation [20, 21]. All these treatments are very expensive. Some forms of HeFH respond positively to statin-ezetimibe-PCSK9 inhibitors (IgG human antibodies injected SQ every 14 days) regimen, which can substitute all very expensive measures stated above or can change the LDL-C apheresis cessions from once a week to once or twice a month, rendering the treatment less expensive [22, 23]. Heterozygous FH (HeFH) is the most prevalent genetic disease. Statins are the current primary treatment for all heterozygous FH patients, and have been shown to be effective in reducing the incidence of CVD in patients with FH [20, 21]. Nevertheless, many HeFH patients do not achieve their target LDL-C levels and they need additional lipid-lowering drugs, such as ezetimibe, and if the target was not achieved even then, the addition of PCSK9 inhibitors is necessary [24-29]. PCSK9 inhibitor administration further reduced CVD events on top of statin and ezetimibe treatment benefits [26-28]. Anti-DNA of PCSK9, small PCSK9 antibodies, microRNA, CRISPR/Cas9 are investigated in the pipeline of anti-LDL-C newer and less expensive agents; however, it will take some time until they become commercially available. We have the ways to screen for the disease; we have the ways to treat it; all we need is the knowledge and the willingness to do it. This is because, the timely treatment of FH, especially HeFH, with all available lipid lowering drugs can reduce the CVD risk to the same level of the normal population, practically eliminating the consequences of the disease. We hope that you will enjoy reading the reviews in this CPD issue.

Anti-inflammatories, Anti-coagulants and Anti-hypertensives

Unique Drugs and Drug Design

Unique Therapeutic Approaches to Cancer

Though there are numerous ongoing trials on gastro-intestinal (GIT) disorders, there is not much of reduction in mortality observed. On the other hand, the global epidemic of GIT continues to progress relentlessly. Yet existing drug classes for GIT disorders have substantial limitations. Majority of the reliability of drug discovery lies in medicinal chemistry. There are innumerable abrupt changes in the medicinal chemistry especially in 3D structure analysis, high throughput screening and various novel interventions. Utilization of chemical entities novel or modified can be targeted against the dreadful carcinomas via these modern techniques. In an instance, the majority of the colorectal cancers are targeted by virtue of chromosomal instability but some types like microsatellite unstable cancers which are drug-resistant do not respond to chemotherapy agents which is a huge challenge. This clearly shows that there is a high need for augmentation of therapeutics. Presently, alongside synthetic molecules peptides and proteins are contending to tackle cancers. The striking supremacy of proteins includes less intrinsic, tissue penetration and better targeting. It is a known fact that inhibition of apoptosis in the condition of cancers leads to an escalation in the aggression of metastasis. Thus, manipulation or promotion of apoptosis can lead to a reduction of metastasis and improve life expectancy. On the other hand, despite the advent of new drug classes, the global epidemic of the cardio-vascular and metabolic disease has not abated. Continuing unmet medical needs remain a major driver for new research. Drug discovery approaches in this field have mirrored industry trends, leading to a recent increase in the number of molecules entering development. Previously, we successfully published the issue “Novel interventions and therapeutic targets in gastro-intestinal (GI) and metabolic disorders” (Raj et al. 2017) in Current Pharmaceutical Design [1]. However, the issue was limited to a wide range of interventional targets for GI and metabolic diseases, but their biochemical pathways and molecular targets were not addressed. Thus, this special mini thematic issue would thus handle the novel interposing in GIT and metabolic disorder, their underlying mechanisms such as autophagy, anti-apoptotic pathways in intestinal cancers etc. The thematic issue would also focus on Biochemical pathways and the importance of interventions in designing a better and promising molecule. In this special issue, Dostie et al. demonstrated the importance of proper therapeutic targets for Inflammatory Bowel Disease (IBD). They suggested that Metallothionein (MT) could be the possible targets for the IBD. The release of MT results in activation of inflammatory responses leading to progressive inflammation and subsequent expansion of MT synthesis [2]. Rohini et al. discussed the causes of gastrointestinal diseases and the present state of various therapeutic strategies such as probiotics as live biotherapeutics and Fecal Microbial Transplants (FMT’s) [3]. The authors’ have recommended live biotherapeutics and FMT’s could be suitable and successful alternatives to conventional therapies in mitigating the gastrointestinal pathogens. Vinoth and colleagues in their review have discussed about Blastocystis sp., a protozoan parasite and its association with GIT disorders and possible therapeutic targets [4]. They suggested Metronidazole as is the first-line drug of choice. Another treatment option is the combination therapy with trimethoprim/sulfamethoxazole. Rohit et al. have reviewed the pathways of intrinsic cellular stress such as oxidative stress and autophagy, Endoplasmic Reticular Stress (ERS) and mitophagy and apoptosis as fate in cell stress. They indicated that the stress responses are a hallmark of numerous degenerative diseases including neurodegenerative diseases, diabetes, and cancer [5]. Understanding the cross-talk between different intrinsic cell stress responses will help to develop new therapeutic targets. Taken together, the special thematic issue aids in therapeutic and biochemical targets and focused nature of rational pharmaceutical design. I would like to thank all the authors and co-authors for their excellent contributions. Above all, I would like to acknowledge the support from Dr. Kazim Baig, and Aamer M. Khan from Current Pharmaceutical Design publishing team for their endorsements in compiling this issue. Considering specialized and superlative articles in the field of gastroenterology and pathophysiology, we hope that readers will find in this issue new broadways of research. As a guest editor(s), we would sincerely thank and acknowledge the diverse group of experts and colleagues who offered their substantial reviewing efforts and suggestions.

The Thematic Issue summarizes the current progress in the development of novel approaches to diagnostics and therapy with special focus on cell-based technologies. Identification of novel biomarkers and biologically active molecules is a rapidly developing and highly competitive field. During the recent years, generation of tremendous amounts of functional omics data and establishment of chemical libraries fueled the search for novel therapies for a wide range of human diseases. Screening and evaluation of potentially active substances and novel biomarkers requires reliable, versatile and relatively cheap test systems. In many cases, the systems of choice are cell-based models that are characterized by good reproducibility, fast operation time, relatively low cost and high flexibility. Recent literature provides numerous examples of successful development and application of cell-based test systems for developing diagnostics and therapies for various types of cancer, cardiovascular diseases, immune disorders and other pathologies. In addition, cell-based therapies and cell-based drug delivery systems are very promising approaches. This issue contains articles on various problems of translational medicine. Although a great number of promising therapeutic and diagnostic approaches has been proposed during the recent years, most of these developments did not reach clinical use, some due to economic reasons, the others due to the lack of proven effectiveness at different stages of clinical trials. In this regard, the important current task is validation of therapeutic targets, synthesis and testing of candidate drug compounds. Translational medicine is an interdisciplinary field of knowledge that determines the optimal mechanisms for introducing the most significant achievements of basic science into clinical practice. Personalized medicine is one of the emerging branches of modern medicine that opens interesting opportunities for improving the accuracy and clinical outcome of treatment of some of the most challenging human diseases [1-3]. The authors of the reviews published in this special issue consider the problems of translational medicine in different fields, focusing on cell diagnostics and therapy. Some of the developments presented in the reviews already find application in clinical practice, others will be in demand in the near future. Part of the review articles describe advances in the design of drugs and deliver them to the therapeutic target. Rui Lin, Shanshan Wang, and Wentian Liu (Chinese group) in their review “Protein-derived smart materials for medical applications: elastin-like polypeptides” discussed the physicochemical characteristics of the elastin-like polypeptides and their applications in biotechnology and medicine. Authors focused on the application of elastin-like polypeptides in drug delivery, protein purification, tissue engineering, removal of heavy metals and endoscopic submucosal injection solution [4]. Tabeshpour et al. (Iranian group) in their review “Computer-aided drug design and drug pharmacokinetic prediction: a mini-review” focused on computational drug design. “There are different types of software that can help predicting the pharmacokinetic profile of a drug. Quantitative structure-activity relationship (QSAR) modeling is used for drug design with less cost. Drug-excipient interactions are predicted by docking tools. Computerized drug target prediction and docking programs offer additional options to predict potential effects and adverse reactions of a given candidate as well as the best orientation of the compound on the receptor active site.” Drug design software can predict the pharmacokinetic profile of a drug and can help saving time and money [5]. T.A. Gudasheva, R.U. Ostrovskaya, and S.B. Seredenin (Russian group) in their review “Novel technologies for dipeptide drugs design and their implantation” focused on advantages of dipeptides in designing of nontoxic, orally available, highly effective drugs for the therapy of cognitive disorders. Two dipeptide drugs design approaches have been reviewed. “Both of them are based on the idea of a leading role of central dipeptide fragment of the peptide chain beta-turn in the peptide-receptor interaction. The first approach, named "peptide drug-based design" represents the transformation of known nonpeptide drug into its dipeptide topological analog. The latter usually corresponds to a betaturn of some regulatory peptide. The second approach represents the design of tripeptoide mimetic of the beta-turn of regulatory peptide or protein. The results of the studies, which led to the discovery of endogenous prototypes of the known non-peptide drugs piracetam and sulpiride, are presented in their review” [6]. The review paper “Research potential of metabolomics in vitamin status assessment” by Yu. R. Varaeva, E.N. Livantsova, I.V. Ukrainets, S.D. Kosyura, and A.V. Starodubova (Russian group) performs the potential usefulness of modern metabolomics methods in vitamin status assessment. The authors discussed applicability of a personalized approach in the appointment of vitamins using modern metabolomics methods [7]. I.A. Khlusov, L.S. Litvinova, M.Y. Khlusova, and K.A. Yurova (Russian group) in their review “Concept of hematopoietic and stromal niches for cell-based diagnostics and regenerative medicine (a Review)” focused on the niche concept for hematopoietic stem cells and multipotent mesenchymal stromal cells. Niche design is an approach to regenerative medicine and cell-based diagnostics. Authors speculated their definition of the stem cell niche, proposed and described certain stages (postulation; morphofunctional; topographical; quantitative; bioengineering) of the niche theory development [8]. Novel approaches to the treatment of diseases are discussed in several review articles. In two review papers from China authors discussed new treatment targets of atrial fibrillation. Li et al. in their review article “Mitochondria and the pathophysiological mechanism of atrial fibrillation” focused on elucidation the casual relationship between mitochondria and atrial fibrillation. Moreover authors discussed potential therapeutic target for the treatment and prevention of atrial fibrillation in clinical practice [9]. Ren et al. (Chinese group) in their review “The mechanisms of oxidative stress in atrial fibrillation” focused on discussion of the current literature on the use of new treatment targets of atrial fibrillation. New treatment targets were elucidated after analyzing the relationship between oxidative stress and Ca2+ [10]. International team from Qatar, Lebanon and USA have presented a review “Role of Methylglyoxal in Diabetic Cardiovascular and Kidney Diseases: Insights from Basic Science for Application into Clinical Practice” by S. Sankaralingam, A. Ahmed, M. Rahman, A.H. Eid, and S. Munusamy discussed potential of reducing methylglyoxal levels as a therapeutic strategy to counter the deleterious effects of methylglyoxal in patients with diabetes. Several studies have shown that the use of methylglyoxal scavengers (such as aminoguanidine, Nacetylcysteine, or metformin) or Nrf2/Glo1 activators (such as trans-resveratrol/hesperetin) to be useful in preventing methylglyoxal induced renal and cardiovascular complications in diabetes [11]. A. Gasparotto Junior and F.A. dos Reis Lívero (Brazilian team) in their review “Cell-based therapy for hypertension: challenges and perspectives” summarized data from research on cell-based therapy for hypertension and from relevant clinical trials. “Cell-based therapies may be used as replacement or complementary treatment strategies. The results of recent preclinical studies of cell-based therapies are promising.” Future perspectives of hypertension therapy and potent clinical applications were also briefly discussed [12]. Y.-L. Shen, X.-Q. Li, R.-R. Pan, W. Yue, L.-J. Zhang, and H. Zhang (Chinese group) in their review “Medicinal plants for the treatment of hair loss and the suggested mechanisms” summarized data from trials in which medicinal plants were used in the treatment of hair loss caused by androgenic alopecia. Alopecia can be treated with diverse hair loss strategies, including hair transplant, medication and cosmetics. Authors discussed opportunities of Traditional Chinese medicines in hair loss treatments and possible mechanism of action [13]. Selcuk Ozturk and Y. Murat Elçin (Turkish team) in their review “Cardiac Stem Cell Characteristics in Physiological and Pathological Conditions” discussed employment of cardiac stem cell for cardiac regenerative medicine therapies. There are two different types of cardiac stem cells for transplantation: allogeneic and autologous cardiac stem cells. For allogeneic cardiac stem cells there is a risk for immune rejection, whereas obtaining of autologous cardiac stem cells is time-consuming process. Cardiac stem cell have different characteristics in various physiological and pathological conditions and knowledge about these properties can help in choice of the most qualified cardiac stem cell populations for cardiac regenerative medicine therapies [14]. Aiello et al. (Italian group) in their review “Transcription of basic research into clinical practice: the case of killer immunoglobulin-like receptors genes in autoimmune and infectious diseases” discussed research data of the role of killer immunoglobulin-like receptors/ human leukocyte antigen interaction in human disease. Particularly, they assessed application of this knowledge in clinic trials. A growing body of evidence implying the influence of killer immunoglobulin-like receptor variants and their interaction with the ligand in the development of the main human viral and autoimmune diseases, highlighting the main applications in clinical practises was reviewed [15]. International team from Iran and UK in their review “Medicinal plants and atherosclerosis: A review on molecular aspects” by S. Gholipour, R.D. Sewell, and M. Rafieian-Kopaei discussed the molecular mechanisms of medicinal plants effective on atherosclerosis. Various molecular mechanisms include inflammation and other factors such as adiponectin, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, peroxisome proliferator-activated receptor, ATP-binding cassette transporters ABCA1 and ABCG1, and sterol regulatory element-binding proteins [16]. Konoplyannikov et al. (Russian team) in their review “Mesenchymal stem cell therapy for ischemic heart disease: advances and challenges” focused on preclinical and clinical studies on the application of mesenchymal stem cells in the therapy of ischemic heart disease. “The mesenchymal stem cell advantages, strategies of their modification for improvement of their regenerative potential, opportunities of the use of biomaterials as mesenchymal stem cell carriers are discussed in detail. The results of the most important preclinical and clinical studies on the mesenchymal stem cell application in the ischemic heart disease therapy are presented” [17]. Finally, Orekhov et al. (international team of authors from Russia, Japan, Germany and USA) presented their study of the key master regulator genes that control differentially expressed genes in macrophages exposed to modified LDL in the research article “Modified LDL particles activate inflammatory pathways in monocyte-derived macrophages”. The main identified master regulators (IL-7, IL-15, CXCL8, for example) participated in the inflammatory pathway and were not involved in the cholesterol metabolism pathway. The authors concluded that activation of the inflammatory pathway may be the primary effect of modified LDL, and inflammatory signaling may initiate changes in the expression of lipid metabolism genes [18]. Obviously, these results possess potential for further development diagnostics and therapies in the field of chronic inflammatory diseases. Thus, in this special issue, a team of international experts discuss the most novel topics relating to the problem of translational medicine. We would like to thank the contributors to this issue for their participation. We hope that this issue will be helpful for the development of novel cell-based diagnostics and therapy.

Abstract: This article summarizes several contributions on the coronary microcirculation. Many of the participant authors belong to the Working Group on Coronary Pathophysiology and Microcirculation of European Society of Cardiology. These contributions explored a variety of topics pertaining to coronary microvascular physiology and pathophysiology. The latest methodologies that are being used to investigate the coronary microvasculature, including myocardial contrast echocardiography, fractional flow reserve and and instantaneous wave free ratio, are discussed. Advances in the mechanisms of dysfunction of the coronary microcirculation - for example, enhanced arginase activity and production of free radicals by dyslipidemia or hyperhomocysteinemia and its myogenic and flow-dependent responses--are reported. The articles touched on the relation of the microcirculation to clinically important conditions, such as the coronary no reflow phenomenon and offered recommendations for future research in important areas, such as angiogenesis and restoration of the microvascular network. This research is providing new ways to explore abnormalities of myocardial perfusion and its relationship with post infarction myocardial damage, an area of inquiry that until recently has been limited to examination of coronary pressure-flow relationships using doppler wire-based measures. Keywords: Microcirculation, no reflow, vasospastic angina, myocardium, angiogenesis, dyslipidemia. THE MICROCIRCULATION AND THE HEART The coronary microcirculation has the significant function of maintaining the proper balance between oxygen supply and oxygen demands. To accomplish this task the resistance vessels of the heart integrate the input from many intrinsic vasodilator and vasoconstrictor signals. The goal is to discuss the innumerable outside inputs in the context of their actions on coronary blood flow and coronary resistance vessel. Many pathophysiological disturbances may alter the regulatory processes within the coronary microcirculation. Many are the clinical conditions that can be associated with microcirculatory disorders including ischemic heart disease. RECENT PHYSIOLOGICAL FINDINGS AND CLINICAL ASPECTS OF THE CORONARY MICROCIRCULATION We refer the reader first to the papers by Axel R. Pries et al. [1] and Lucian Calmac et al. [2] for a detailed discourse on regulation of microcirculation in patients with stable coronary artery disease. It has become increasingly apparent that microvascular dysfunction can aggravate tissue hypoxia and maintain a compromised state even after recanalization of the epicardial vessels. Single-photon emission computed tomography performed six months after Percutaneous Coronary Intervention (PCI) in normocholesterolemic patients shows reversible perfusion defects in 3% of patients treated with pravastatin and in 29% of those with placebo [3]. These data supports the hypothesis of a protective vascular action of statins on an otherwise compromised coronary microcirculation. Generally, small arterioles respond differently than larger arterioles and small arteries. However, there are neural interactions between small and large arteries, and arterioles which may account for some similarities in the development of coronary tone abnormalities in both the epicardial and endocardial segments. The epicardial and intramyocardial coronary arteries are densely innervated by postganglionic sympathetic and parasympathetic nerve fibers. Therefore, norepinephnne and acetylcholine released from these fibers interact with coronary adrenergic and muscarinic receptors to control coronary vascular resistance. The paper by Edina Cenko et al. clearly shows that the microcirculation is still the major culprit in patients having vasotonic angina or diffuse coronary epicardial artery spasm [4]. The primary cause of coronary vasospasm is coronary hyperreactivity that is commonly due to a deficiency in endothelial nitric oxide. Oxygen-derived free radicals scavenge and rapidly inactivate nitric oxide, thereby promoting coronary endothelial dysfunction and constriction of both the large and small coronary arteries even in myocardial sites remote from the ischemic region [5]. Further mechanisms that contribute to the regulation of coronary blood flow include the metabolic activity of the myocardium. The papers by Akos Koller et al. [6] and Teresa Padro et al. [7] show that hyperhomocysteinemia and dyslipidemia may affect myocardial cellular function of the resistive vessels. The pathogenic mechanisms underlying the relationship between microvascular dysfunction and dyslipidemia involve an enhanced arginase activity and production of free radicals with recruitment and accumulation of leukocytes through their diffusion in the post-capillary venules. Hyperhomocysteinemia dependent mechanisms seem to preferentially modulate tone in small arteries by increasing the uptake of glucose and lactate and decreasing the uptake of free fatty acid by the heart. Metabolic control mechanisms seem the most important, because they link flow to metabolism and are involved in ischemic vasodilation. CORONARY NO-REFLOW Many of the well-accepted risk factors for no-reflow are the traditional cardiovascular risk factors, such as hypertension, smoking, dyslipidemia, diabetes, and other inflammatory processes. The most important seems to be hypercholesterolemia [8]. As such, in individuals with hyperlipidemia, intensive statin therapy before PCI is beneficial in reducing no-reflow. In a meta-analysis of 7 studies that examined 3,086 patients treated with statins before PCI, there was a complete prevention of no-reflow in 4.2% of patients treated with high dose statins, compared with control patients receiving placebo, usual care, or lower dose statin therapy [9]. Coronary no-reflow phenomenon occurs when cardiac tissue fails to perfuse normally despite opening of the occluded vessel. The paper by Marialuisa Scarpone et al. [10] demonstrates that often after prolonged occlusion the cardiac tissue did not recuperate normal perfusion despite opening of the large epicardial coronary arteries, indicating that prolonged ischemia leads to damage of the microvasculature and precludes normal perfusion. The mechanism by which prolonged occlusion triggers the damage to the microcirculation is still unclear. Some recent work has suggested a role for the endothelial glycocalyx. The Endothelial Glycocalyx (EG) is an uneven soft polysaccharide coating over the vascular wall toward the vessel lumen. Changes in the glycocalyx lead to the alteration of the transendothelial permeability, thereby causing the swelling of the endothelial cells, which is one of the regulatory factors for functional capillary density. Rapid development of myocardial tissue edema may facilitate the impact of vasoactive peptides such as endothelin and angiotensin on the microcirculation, which, in turn, may deteriorate vessel diameter and flow, leading to the no reflow as illustrated by Evangelos Oikonomou et al. [11].MEASUREMENTS OF THE CORONARY MICROCIRCULATION Although the focus of this special issue of Current Pharmaceutical Design is on the regulatory mechanisms of the microcirculation and their translation to targets in clinical practice, it is important as well to highlight some methods that may be able to assess the distribution and regulation of resistance vessels across the wall of the left ventricle in clinical practice [12]. A number of noninvasive modalities are able to accurately assess microvascular dysfunction as shown by the paper by Danijela Trifunovic et al. [13]; however, these are not readily available in the catheterization laboratory and can be challenging to use in acutely ill patients, as those presenting with no reflow after PCI. For these reasons, there has been long-standing interest in developing invasive methods for assessing microvascular function in the catheterization laboratory. A number of Doppler wire-based measures are described by the paper of Sasko Kedev et al. [14]. The findings from this study confirm those of previous studies showing that Fractional Flow Reserve (FFR) and instantaneous wave Free Ratio (iFR) measured at the time of catheterization correlate with evidence of microvascular dysfunction on noninvasive imaging. FUTURE DIRECTIONS With this background in mind, it is interesting to read the reports by Davor Milicic et al. [15] and Zorana Vasiljevic et al. [16]. These papers focused on the role of microcirculation in congestive heart failure. Still, there is no solid proof to directly correlate coronary microvascular dysfunction to heart failure in human patients to date, which is probably due to the lack of proper models and the need for more advanced finer techniques. Much more importantly, there is no single drug regimen that could effectively reverse cardiac dysfunction after myocardial infarction. The paper by Lina Badimon et al. [17] offers an overview of the relationship between angiogenesis and the coronary microcirculation. The restoration of the microvascular network, which has been damaged during ischemia as well as upon reperfusion, appears a promising approach to refrain the deleterious effects of coronary obstruction. Monocytes can trans-differentiate into endothelial celllike promoting angiogenesis. In rodents, both growth factors and cell therapy can induce angiogenesis. However, uncertainties and controversies still remain. In this regard, the most common questions are: what type of cells can be primarily regenerated by angiogenesis: myocytes or endothelial cells? Are these cells able to strengthen cardiac performance? The answers to these questions may largely addresses our difficulty in understanding the mechanisms underlying the restoration of the microvascular network as well as myocardium after myocardial infarction. Human trials performed to stimulate angiogenesis in patients undergoing primary PCI have mostly failed. Investigating thoroughly the potential of different subsets of monocytes/macrophages in angiogenesis promotion, as well as the study of their receptors are needed to develop and optimize future therapies aimed to restore myocardial function after ischemia. In summary in this issue of Current Pharmaceutical Design, we summarized several aspects of control mechanisms that govern the level and the size of the coronary microcirculation: endothelial and myogenic control mechanisms in the coronary microcirculation and the translation in their clinical counterparts.

Current Approaches to Diagnostics and Therapies of Chronic Diseases: Focus on Molecular and Cell Biology Chronic diseases, also known as non-communicable diseases, are long-lasting complex disorders. Worldwide, millions of people die each year from chronic diseases including cardiovascular, neurological, lung diseases, type II diabetes mellitus and cancer. This cause of death increases in rate both in developed and developing countries [1-3]. Chronic diseases are often characterized by similar features, such as pathophysiological mechanisms and molecular alterations. Reactive oxygen species production causing oxidative stress, mitochondrial dysfunction, inflammation, accumulated DNA damage, dysregulation of autophagy are the common features of many chronic diseases [4-6]. During the recent years, the search for new therapeutic targets for the treatment and diagnosis of chronic diseases led to the discovery of novel biomarkers and therapeutic targets. Thus, current approaches to diagnosis and therapy of chronic diseases are based on the researches in the fields of cell and molecular biology. This special issue is focused on diagnosis and therapy of chronic diseases such as cancer, renal fibrosis, inflammatory bowel diseases, diabetes, atherosclerosis and others. The presented review papers authored by international experts in the field describe the current knowledge on therapy of chronic diseases and propose some unusual approaches such as traditional Chinese medicine. Fu et al. in their review “The anticancer effect of Sanguinarine, a review” discussed the anti-cancer properties of alkaloid sanguinarine. Sanguinarine possesses anti-inflammatory, proapoptotic, antioxidant and growth inhibitory activities on tumor cells. “This paper describes various anti-cancer mechanisms, such as inhibition of erroneously activated signal transduction pathways, apoptosis and inhibition of tumour cell proliferation, exhibited by sanguinarine” [7]. Sun et al. in their review “Individualized Tacrolimus Therapy for Children with Nephrotic Syndrome: Mind both the Ontogeny and Pharmacogenetics of CYP3A” have focused on individualized tacrolimus therapy for children with nephrotic syndrome. Authors discussed the role of ontogeny and genetics in the individual dosing regimen of tacrolimus, whereas current guideline has recommended that the tacrolimus dosage should be adjusted according to the Cytochrome P450 3A5 genotype (i.e. genetics) [8]. International team from UK and China have presented a rather unusual review “Chinese herbal formulas and renal fibrosis: An overview” by Shen et al. have focused on the therapy of renal fibrosis by Chinese herbal formulas of traditional Chinese medicine. It has been shown that Chinese herbal formulas can act as anti-fibrosis agents due to their anti-oxidant, anti-inflammatory and anti-proliferative properties. “Chinese herbal formulas are determined according to traditional Chinese Medicine theory and this review highlights these formulas and suggests a possible mechanism for their use in the treatment of renal fibrosis” [9]. International team from Saudi Arabia and China in the review paper “IRW and IQW attenuate induced-1 DSS inflammatory responses in colitis mice” by Ma et al. focused mainly on the antibiotics therapy of inflammatory bowel diseases and discussed alternative therapy with bioactive peptides (IRW and IQW). The effects of bioactive peptides on intestinal inflammation were described. “Intracolic administration of IRW and IQW might be a novel option for preventing inflammatory bowel disease via regulating the level of serum amino acid and enhancing the intestinal immune defense” [10]. International team of authors from UK and Iran have presented a review paper “Immunosuppression-lipid metabolism interplay and medicinal plants in atherosclerosis: a review” by Moradi et al. focused on medicinal herbs treatment of atherosclerosis. The authors described the most important medicinal herbs effective on atherosclerotic lesions through impact on the immune system. Effects of such medicinal herbs as garlic, Ginkgo biloba, Quercus infectoria, Astragalus mongholicus Bunge and others were discussed [11]. Diemberger et al. (Italian group) in their review “Meta-analysis of sinus rhythm restoration and maintenance by electrical cardioversion or catheter ablation in patients with chronic kidney disease: atrial fibrillation recurrences, thromboembolic events and modification of glomerular filtration rate.” discussed non-pharmacological treatments for sinus rhythm restoration/maintenance by electrical cardioversion and catheter ablation in Chronic kidney disease patients. Efficacy of such therapy for Chronic kidney disease patients and non-сhronic kidney disease patients was compared [12]. Yamagishi and Matsui from Japan in their review “Therapeutic potential of DNA-aptamers raised against AGE-RAGE axis in diabetesrelated complications” focused on discussion of the current literature on the therapeutic potential of DNA-aptamers raised against the advanced glycation end products - a receptor for advanced glycation end products (AGE-RAGE) in various diabetes- and aging-related disorders. Particular attention was paid to diabetes-associated complications, especially focusing on vascular complications of diabetes and cancer [13]. International team from the USA and Russia in the review paper “Approaches to the NK cell modification for anti-tumor immunotherapy” by M.A. Streltsova et al. focused on the therapy by the genetically modified natural killer cells. Authors compared the efficiency of recognizing and destroying tumor targets by the genetically modified natural killer cells in comparison with the therapeutic T cells. The perspectives and advantages of various approaches to modification of natural killer cells were discussed [14]. International team of authors from UK and China (Xiao-Qin Li et al.) in their review “Chemical constituents and pharmacological activities of Stellera Chamaeja” discussed anti-tumor effects of Stellera Chamaejasme. Authors mainly focused on the pharmacological properties and the chemical composition of S. Chamaejasme. The authors hypothesize that S. Chamaejasme has anti-tumor activity. They discussed antiliver cancer activity anti-lung cancer activity anti-leukemia activity and others [15]. International team from Pakistan, Saudi Arabia, Qatar and USA (Kaneez et al.) in their review “The dual specificity role of transcription factor FOXO in type 2-diabetes and cancer” summarized information about the biology of Forkhead box O transcription factors. “The Forkhead box O transcription factors are implicated in several signaling pathways and play a vital role in various cellular and physiological processes include, for instance, ROS (reactive oxygen species) response, cell proliferation, regulation of programmed cell death, longevity, metabolism and cancer and regulation of cell cycle.” These proteins can be used for elaborating on novel therapeutic approaches to treat cancer [16]. The review “Sulfur mustard-related ocular complications: a review of proteomic alterations and pathways involved” by Panahi et al. from Iran is focused on eye injuries caused by sulfur mustard. Sulfur mustard causes deficient of iron-dependent regulations and pathological changes in vascular endothelial growth factor expression. Furthermore, sulfur mustard related proteomic alterations and the association of the found proteins with other eye disorders and diseases were reviewed [17]. The remaining articles of this issue are devoted to current approaches to diagnostics of chronic diseases, new diagnostics targets were also discussed. Yuan et al. (Chinese group) in their review “The Mechanism of Exosomes Function in Neurological Diseases: a progressive review” discussed potential mechanisms of exosomes function in neurogenesis, angiogenesis and BBB delivery and differentiated various sources of exosomes in traumatic brain injury, Alzheimer’s disease, stroke and tumor. Moreover, authors focused on the potential application of exosomes in diagnostics and treatment of various diseases [18]. Hassan et al. (Iranian group) in their review article “The role of epigenetic alterations involved in sepsis: An overview” focused on the diagnosis of sepsis based on detection of epigenetic alterations (DNA methylation pattern, histone modification). Authors also discussed drug targets validation for the treatment of sepsis. “Epigenetic mechanisms can provide a highly sensitive and accurate method for sepsis diagnosis using blood and other body fluids” [19]. Karagodin et al. (Russian group) in their review “Diagnostics and Therapy of human diseases - Focus on sialidases” discussed diagnostics of sialidase-related disorders such as sialidosis, cancer, atherosclerosis and others. Therapeutic approaches by sialidase inhibition were also discussed. “Sialidases are involved in the pathogenesis of a whole range of diseases, so the knowledge and expertise gained from genetic defects leading to human sialidase inhibition can be used in the design of the drugs. In vitro studies suggest that some sialidase inhibitors might be useful therapeutics for treating sialidosis, cancer, infections, immune diseases, atherosclerosis and other pathologies” [20]. Prasad from Canada in his review “Does HbA1c Play a Role in the Development of Cardiovascular Diseases?” compared diagnosis of diabetes by hemoglobin A1c and advanced glycation end products. Hemoglobin A1c is considerate as a useful marker for the diagnosis and management of diabetes. Author concluded that advanced glycation end products cannot replace HbA1c in the diagnosis of diabetes because there is no correlation between advanced glycation end products with serum glucose [21]. A research article “Tumor necrosis factor-α and C-C motif chemokine ligand 18 associate with atherosclerotic lipid accumulation in situ and in vitro” by Orekhov et al. (Russian team) describes the expression of tumor necrosis factor-α and C-C motif chemokine ligand 18 under the accumulation of intracellular cholesterol in atherosclerosis. Authors assumed that the accumulation of intracellular lipid induces pro- and anti-inflammatory responses in the arterial cells. Authors did not discuss the direct clinical implementation of their results; however, perspective to use these results in the development of diagnostics of atherosclerosis and anti-atherosclerotic therapy is obvious [22]. We hope that the presented thematic issue will be of interest to our readers, as well as helpful for generalizing the current knowledge in various areas of clinical science.

Gene therapy is a promising approach to treat chronic and acquired diseases because it allows the regulation of a gene sequence that is identified as benefitial or detrimental to the proper functioning of the organism. By gene therapy it is possible to repair, replace, add or silence the target gene. In this special issue, gene therapy involving gene silencing by the RNA interference (siRNAi) mechanism will be presented and discussed as a promising therapeutic strategy for a wide variety of diseases; however it has not become clinically available yet because some shortcomings still need to be addressed for effective delivery, for instance, the instability and poor cellular uptake of RNAi molecules. Taking this into account, in our special issue, Kumavat et al. reviewed the nanotechnology aspects applied for the delivery of RNAi at the targeted site with fewer off-target effect and high stability. The manuscript also expounds on various types of nanoparticles, associated challenges and modalities to overcome the same with potential biomedical applications. A special emphasis ongoing clinical trials, regulatory and safety status has also been presented [1]. In addition, main challenges of topical delivery approaches mainly are related to the delivering of siRNA into skin due to the highly effective defensive skin barrier function, the high molecular weight of siRNA and also to the net siRNA negative charge under physiological conditions and the need to cross the negatively charged cell membrane. The development of siRNA delivery systems that overcome one or more of these limitations improves the efficiency of gene silencing. Thus, an update on the advances in topical siRNA-based non-viral delivery systems to prepared carrier molecules able to mask siRNA-negative charges, compress siRNA molecule to make it smaller and protect siRNA from degradation as a powerful therapeutic strategy for several skin diseases are deeply discuss by Rosa et al. [2]. The targeting liposomes containing siRNA to overexpressed receptors of cancer cells that represents a strategy for better therapeutic outcome, with improved efficacy and reduced toxicity were herein discuss by Eloy et al. [3]. Considering that efficient delivery of siRNA to the target tissue is a major challenge, the liposomes could be functionalized with several chemical moieties that can be recognized by cancer cells more than by normal cells. These ligands include folate, transferrin, peptides, oligosaccharides, monoclonal antibodies and aptamers. In this article, the authors describe chemical functionalization strategies and address the major in vitro and in vivo findings in the field of cancer treatment. Thereafter, Yoko Endo-Takahashi et al. summarize the Ultrasound-mediated nucleic acid delivery systems and discuss the possibility of combining liposome and ultrasound for RNAi-based therapies [4]. Emerging platform for siRNA delivery from hyaluronic acid (HA) is also discussed in this issue by Shah et al. [5]. This biopolymer offers a variety of properties such as biodegradability, biocompatibility, aqueous solubility, viscoelasticity, and non-immunogenicity. Numerous HA-based nano-vector delivery systems such as polymeric nanoparticles, liposomes, and others when hybridized with siRNA, have been delivering this genetic material safely and efficiently overcoming the stability problem. This review aimed to uncovers the HA and HA hybridized nanoplatforms for siRNA delivery systems with particular focus on the discussion of available reports with addressing the future potential of this combination. In the last article of this issue, Marinho et al. shows the use of gene therapy of RNAi targeting transcription factors involved in Ischaemia-reperfusion injury, the crucial choice of siRNA targets and the advantages and problems of the siRNA use for preventing liver Ischaemia-reperfusion injury during transplantation are also highlight [6]. Moreover, the authors discuss how the use of liposomes contributes to the improvement of siRNA therapy by increasing siRNA stability in vivo and avoiding siRNA off-target effects. Finally, we, the guest editors, would like to thank to Current Pharmaceutical Design publishing team, specially Dr. Kazim Baig for their help and patience, and to the authors for their excellent contributions, and to the guest-reviewers given your expertise in this area, they contributed to this special issue quality.

Abstract: Depressive disorders affect more than 300 million people all over the world and 16% of US population. Depression is also the leading cause of disability worldwide and a major contributor to the overall global burden of disease. The first antidepressant was approved in the 1950s. In 2013, antidepressants became the most commonly prescribed drugs in the United States. However, the diagnosis and treatment of depression is changeling since depression is a rather heterogeneous disorder with various co-occurring symptoms and divergent responses to treatment. In this theme issue, we brought together 12 papers written by the leading scientists from all over the world. The special issue was divided into 4 sections. The first set of papers explored topics in the precision medicine of depression. The next section was about the application of pharmacometabolomics on the discovery and development of new antidepressants. In the third section, we had a series of papers focusing on the status of current and future antidepressants. The final section described the alternative therapy for depression. This theme issue added our understanding of the diagnosis and treatment of depressive disorders. Keywords: Depression, neuroimaging, antidepressants, metabolomics, fast-onset, medicinal plants, nutrition, Ayurveda PRECISION MEDICINE IN DEPRESSION Precision medicine, the capacity to really tailor treatments to specific populations and individuals, is a novel approach for the treatment of depression. The effective treatment would only be achieved through the diagnosis and precise classification of depression subtypes. Magnetic Resonance Imaging (MRI) is an especially useful modality for depressive disorders due to its high resolution for soft tissues such as the brain. In the first 2 papers of this theme issue, Song, et al. [1] and Qiu, et al. [2] reviewed the recent advances for the diagnosis of depression and the evaluation of treatment response using MRI. The selection of antidepressant choices relies on the development of new techniques for measuring antidepressants. Mansour et al. [13] developed a simple, fast and sensitive method to determine venlafaxine in biological fluids and pharmaceutical formulations using just a pH meter and ion-selective electrodes. PHARMACOMETABOLOMICS IN THE DEVELOPMENT OF NEW ANTIDEPRESSANTS Pharmacometabolomics aims to assess the metabolic effects of the pharmaceutical treatment. With the technical advances in analytical instruments, metabolomics is entering into a “new generation”. Jian, et al. [3] summarized the broad applications of Next-Generation Metabolomics (NGM) in facilitating the discovery and development of antidepressants. Albiflorin was used as an example to illustrate how NGM improves our understanding of drug candidate actions and facilitates drug safety evaluation. CURRENT AND FUTURE ANTIDEPRESSANTS Pharmacotherapy is the main treatment approach for depression. Antidepressants have become the most prescribed drugs in the U.S. Amidfar and Kim reported the selective agonists and antagonists of 5-HT receptors in the treatment of major depression [4]. Sleep disorders are the core symptoms of depression. Satyanarayanan, et al. reviewed the pharmacologic interventions targeting on circadian rhythm and melatonin receptors [5]. The majority of current antidepressants are limited by their slow action. The conventional antidepressants can take as long as six weeks to have an effect. Potentially safe and fast-acting interventions would be invaluable. Jeff, et al. [6] and Kuo, et al. [7] discussed the molecular mechanisms of the promising fast-onset antidepressants. Depression is the most common neuropsychiatric illness associated with Parkinson disease (PD). Kabra and the co-authors reviewed the emerging and alternative therapies for the treatment of depressive patients with PD [8]. ALTERNATIVE THERAPY FOR DEPRESSION The current synthetic antidepressant drugs have limited efficacy and might undesirable side effects. Dietary improvement may provide an efficacious and accessible treatment strategy for depression. Xu, et al. [9] summarized the recent advances in nutrition for the treatment of depressive disorder. The use of complementary therapies is gaining popularity. Le, et al. [10] highlighted the psychotherapy of cancer patients with the secondary depressive disorder. Indian Ayurveda is one of the most ancient medicine in the world. Sharma and the co-authors [11] reviewed the herbal and holistic solutions of Ayurveda for depression. Ismail, et al. [12] described some important medicinal plants and their reported active constituents with antidepressant activity. This special issue covers all the major aspects related to the diagnosis and treatment of depression. Both the guest editors and all the authors hope that the special issue will help the readers quickly grab the recent advances in this field. Moreover, the critical visions from the contributors in this special issue would motivate other scientists to develop more effective treatments for major depressive disorders in the future.

Crystallization is defined as the process in which solid crystal is precipitated from a fluid media (i.e. vapor, solution or melt). It has been widely applied in many areas including pharmaceuticals, fine chemicals, functional materials, agrochemicals and foods. Generally, it can be used to prepare high quality crystal substance by crystallizing it from a fluid media or to concentrate substance in fluid media by precipitating unwanted crystals. In recent years, crystallization science and technology have received a lot of attention, especially in the field of development of new drugs and foods. The crystallization technology of drug products is common with that of food products (food additives, functional foods, etc) in many aspects. The works mainly focus on the molecular mechanisms of crystallization, new crystallization methods of active pharmaceutical ingredients and food ingredients, development of novel characterization technology of crystals and crystallization process, application of crystallization in the field of pharmaceutical and food science and industry. Thematic Issue “Crystallization for Pharmaceutical and Food Science” of Current Pharmaceutical Design is a platform to discuss the development and application of crystallization for pharmaceutical and food science. Marco Stoller et al. discuss process intensification techniques for the production of nano- and submicronic particles for food and medical applications [1]. Na Wang et al. introduce cocrystal and its application in the field of active pharmaceutical ingredients and food ingredients [2]. Nandi Chen et al. summarize the properties and the applications of existing soft biomaterial-based nanocrystal in pharmaceutical [3]. Hyerim Yang et al. review the pharmaceutical strategies for stabilizing drug nanocrystals [4]. Yanan Zhou et al. analyze the effects of polymorphism on physicochemical properties and pharmacodynamics of solid drugs [5]. Lek Wantha summarizes the kinetics of the solution-mediated polymorphic transformation of organic compounds [6]. Leming Sun et al. summarize the recent trends in nanocrystals for pharmaceutical applications [7]. Daisy Arora et al. introduce recent advances in nanosuspension technology for drug delivery [8]. Mingxue Fan et al. review nanocrystal technology as a strategy to improve drug bioavailability and antitumor efficacy for the cancer treatment [9]. Cao Wu et al. summarize the preparation, precise control, and application of nanocrystals toward the pharmaceutics and foods industry [10]. Qi Zhang et al. summarize recent advances in magnetic nanoparticle-based molecular probes for hepatocellular carcinoma diagnosis and therapy [11]. Preshita P. Desai et al. summarize crystal engineering approaches for the design of pulmonary delivery systems [12]. Chandrakant R. Malwade et al. introduce process analytical technology for crystallization of active pharmaceutical ingredients [13]. Jaleh Varshosaz et al. review crystal engineering techniques for enhanced solubility and bioavailability of poorly soluble drugs [14]. Zhongyao Cheng et al. provide a comprehensive review on nanocrystals technology in the field of pharmaceutical science and biochemical engineering [15]. J. R. Campos et al. analyze the phase behavior of polymorphic fats in drug delivery systems [16]. Editing this Thematic Issue for Current Pharmaceutical Design has been a great honor for us. We appreciate very much the invitation of Prof. William A. Banks, and kind support from the staff members of Current Pharmaceutical Design. Our special thanks goes to Director Kazim Baig for his continuous support during the whole process. In addition, we would also like to thank the authors for such grand writing and the reviewers for their careful and diligent peer-review.

Oxidative stress, antioxidants and disease. One of the most fundamental challenges to prevention and management of disease-associated tissue damage occurring as a result of oxidative stress, in particular, excessive activation of inflammatory processes, is the requirement to counteract the effects of highly reactive biomolecules, typically containing single unpaired electrons on oxygen atoms. These compounds, called reactive oxygen species (ROS), rapidly alter structure and chemistry of proteins, lipids, nucleic acids and other components of cells in ways that may severely disrupt cellular metabolism, causing oxidative damage to affected tissues, which manifest as symptoms of a disease [1]. Numerous antioxidant compounds, most often produced by plants, (phytochemicals), are capable of quenching ROS activity to levels that significantly augment health. Thus, aqueous-soluble antioxidants like vitamin C, and the lipid-soluble tocopherols (vitamin E), are necessary components of human diet [2] and may positively affect prognoses of some diseases [3], but lack the stand-alone potency to definitively safeguard against disease-associated oxidative tissue damage. This is due to the way such phytochemicals are utilized systemically. Such dietary supplements, distribute into the interstitium, but mostly fail to achieve sufficient levels inside cells, to thoroughly counteract whole-organism oxidative damage. As a consequence, endogenous defenses such as glutathione, and other antioxidant compounds active within cells, are often overwhelmed by elevated ROS levels, which are a prominent feature of many diseases [4]. For this reason, use of dietary supplements is ineffective as a primary preventive or therapeutic countermeasure against any disease at the time of this writing, with the exception of disorders such as scurvy, which develop as a result of deficiency of a dietary component (vitamin C) [5]. Current drug treatment doctrine: Major drawbacks. Current doctrine in pharmacotherapy for most disease states, has become reliant on small molecule compounds such as corticosteriods and Non-Steroidal Antiinflammatory Drugs (NSAIDs), which may act intracellularly to counteract a specific process – such as activity of a particular enzyme, critical for progress of a disease. Unfortunately, such interventions impose artificial alterations on normal physiology, which may interfere with cell signalling vital for healthy homeostasis, with significantly deleterious consequences. A well-known example of such an occurrence, was the case of Vioxx (Rofecoxib), that proved to be an excellent analgesic due to its ability to block activity of cyclooxygenase 2 (COX-2) and resulting pain-inducing prostaglandin synthesis, but resulted in cardiotoxic downstream effects that were occasionally fatal [6]. Heme oxygenases and novel approaches to pharmacotherapy. An emerging alternative strategy in current drug treatment approaches, is use of benign, Generally Regarded As Safe (GRAS) compounds (most often phytochemicals) that amplify the strength of endogenous cytoprotective mechanisms and mostly or completely avoid use of molecules that may interfere with normal cellular metabolism as an adverse side reaction. Modulation of Heme Oxygenases (HOs), a heat shock protein (hsp) enzyme which is a primary defense against oxidative stress, offers enormous promise for such an approach. HOs are produced by all animal cells studied at the time of this writing and are active in both extracellular (eHO) and intracellular spaces (iHO) [7]. The present special edition of Current Pharmaceutical Design (CPD) reviews the major structural and functional properties of these fascinating stress response proteins, in the context of their capacity to protect against a diverse range of pathological conditions in which particular diseases states may damage a host by imposing excessive oxidative stress on its component tissues. The topic material considered in the present review, examines the putative role played by heme oxgygenases in maintenance of normal homeostatic function and extends this insight to describe mechanisms by which their bioactivities constitute a core adaptive response to various forms of trauma. HO function is here illustrated for several disease states, with focus on cardiovascular, neurologic, neoplastic and immunoregulatory processes. This very exciting subject material is presented in the form of 11 essays by researchers and clinicians from around the globe, who have emerged as leaders in their respective branches of biomedical science and are providing unprecedented insight into the diverse means by which these enzymes may be exploited clinically. Essays within this special edition: topic summaries. Dr. Daniel Bereczki Sr. at Department of Neurology, Semmelweis University in Budapest, and Dr. Daniel Bereczki Jr, at the Department of Neurology, Hungarian Defence Forces Medical Center, along with Dr. Jozsef Balla at the Institute of Internal Medicine, University of Debrecen, in Hungary, describe the clinical relevance of heme oxygenase-1 (HO-1) in ischemic stroke [8]; a team of authors led by Prof. Vladislav Chernov at the Institute of Fundamental Medicine and Biology of Kazan Federal University in Russia analyze mechanisms by which membrane components of mycoplasmas, an important class of human pathogen, affect inflammation by modulating Nrf2 signaling – a pathway that includes hemе oxygenases [9]; Drs R. Clive Landis, Kim Quimby and André Greenidge at UWI’s Edmund Cohen Laboratory for Vascular Research in Barbados, describe how Nrf2/HO-1 signaling in macrophages influences differentiation of these cells to affect the pathogenesis of diabetic nephropathy [10]; Mark F. McCarty, founder and CEO of Catalytic Longevity, in San Diego, California, describes how the spirulina chromophore, phycocyanobilin (PhyCB) a structural analog of the HO degradation product biliverdin,and antioxidant potency in the same range as bilirubin may be combined with phase 2-inducer nutraceuticals for prevention of opiate tolerance [11] – and in a second essay, reporting on a research initiative led by Dr. Iloki Assanga Simon Bernard at University of Sonora in Hermosillo México, outlines a possible role for these enzymes in mitigating the severity of preeclampsia [12]; A U.S.- German team led by Harvard Medical School Professor Leo Otterbein provides a cautionary note to expectations over the past two decades, that strategies for inducing and regulating heme oxygenases will rapidly evolve into clinical tools with widespread use. Their essay outlines the enormous promise such methods hold for healthcare improvements, but emphasizes the limitations of this technology and the slow pace at which its implementation has proceeded [13]; Authors in the laboratory of Dr. Ana Lúcia S. Rodrigues at Brazil’s Federal University of Santa Catarina provide state-of-the-art insight into roles played by HO-1 in the underlying pathomechanisms of neuropsychiatric and neurodegenerative diseases [14]; Another team of Hungarian researchers, led by Professor Attila Szöllősi at University of Debrecen, Medical School, outline the participation of heme oxygenases on a wide range processes necessary for health of the skin, along with autoimmune, allergic and neoplastic dermatological disorders [15]; A second Brazilian team in the laboratory of Professor Leonardo Travassos, at the Federal University of Rio de Janeiro, describe the interplay of cellular signaling processes in which both HO-1 activity and autophagy are involved [16]; A team of collaborating researchers, with members in the USA, Russia, Mexico, Hungary and Kuwait, outline the role of heme oxygenases in the pathophysiology of Parkinson's disease (PD)– and a bold approach to treatment of the disorder by use of nanoparticles that potentially decrease alpha synuclein aggregation – a primary driver of PD pathogenesis [17]; Finally, Dr. David Haines and Dr. Arpad Tosaki at University of Debrecen, provide a description of the current understanding as to the role of heme oxygenases in maintenance of normal, healthy function of cardiovascular cells, tissues and organs, further describing how activity of these enzymes influence cardiovascular syndromes and co-morbidities

Plants are natural reservoirs of a diversity of compounds, many of which have pharmacological/nutraceutical activities towards a variety of diseases. One important class of plant bioactive compounds is polyphenols. The term phenol is used to describe a structure with at least one aromatic ring containing one or more hydroxyl groups attached and the flavonoids, with several aromatic rings, represent a well-known subgroup of bioactive polyphenols. Other compounds, including hydroxycinnamates and phenolic acids, with only one phenolic ring, are also referred to as polyphenols. These phytochemicals occur naturally in plants and epidemiological, pre-clinical and clinical studies have shown their importance for human health as they reduce the incidence and prevalence of cardiovascular diseases, cancer, diabetes, inflammation and age-related disorders. Modern pharmacopeia has received significant input from natural small molecules (such as polyphenols); however, the process of identifying novel bioactive compounds from biological sources has been a central challenge in the discovery of natural products. Moreover, the exploitation of polyphenols as sources of molecules with pharmacological/nutraceutical interest depends on effective methods for compounds extraction to be further tested as regards their chemical and biological activities. Additionally, the use of fractionation procedures coordinated with bioactivity/antimicrobial screenings – bio-guided fractionation – is required for the identification of single compounds with therapeutic potential. Once identified, the pharmacokinetics and modus operandi of compounds need to be gathered to support the rational design and synthesis of medicinal chemistry derivatives. Alternatively, large-scale production of potential bioactive polyphenols can be achieved by means of synthetic biology. At last, technologies of controlled delivery must ensure that the compounds are carried to the site of action. The ultimate goal of this pipeline is to discover and make available to society therapeutic alternatives for chronic diseases including cancer, neurodegenerative, cardiovascular, and metabolic diseases. The thematic issue is a journey in the field of polyphenols as bioactive compounds for health, exploring the current strategies for identification, characterization, improvement and production of these protective molecules. Foito et al. described the state of the art methodologies used for structural elucidation and annotation of novel bioactive compounds [1]. An overview of the metabolomics toolbox available, from hyphenated Mass Spectrometry (MS) and Nuclear Magnetic Resonance (NMR)- based analytical technologies, is described alongside with technical developments in instrumentation and data processing. In addition, the authors explore the importance of the integration of these tools in the bioprospection and drug discovery workflows. Overall, the review assesses the huge potential of metabolomics for application in the process of drug/bioactive discovery from plants. The degeneration of neurons in specific brain regions is one of the main causes of chronic Neurodegenerative Diseases (NDs) and the formation of aggregates of misfolded proteins has been considered a hallmark underlying the pathophysiology of these diseases. Kostelidou et al. discussed the available microbial (bacteria and yeast) genetic screens and selection systems targeting NDs-associated protein misfolding, which facilitate the identification of cellular factors and disease processes as well as the discovery of synthetic and natural compounds with protective activities [2]. The simplest eukaryotic organism yeast shares fundamental biological processes with mammalian cells, including some processes associated with human diseases. This feature allows the use of Saccharomyces cerevisiae as test-tubes to decipher the molecular mechanisms underlying disease pathology as well as to accelerate the discovery of protective molecules. In addition, mammalian cell models have been widely used in polyphenol research to identify/validate polyphenol bioactivity for chronic diseases. Rosado-Ramos et al. reviewed the use of eukaryotic cell models of NDs and their contribution for the identification of novel bioactivities as well as the benefits and limitations of their use as tools in the search for bioactive polyphenols [3]. The use of the nematode Caenorhabditis elegans has been largely explored in aging research and, more recently, to investigate the multifaceted properties of polyphenols as protective candidates for aging-related conditions. In this issue, Papaevgeniou & Chondrogianni compiled the studies addressing the anti-aging and neuroprotective potential of polyphenols using C. elegans as multicellular model organism [4]. Epidemiological evidence suggests that polyphenol-rich diets lower the risk of certain cancers whereas epidemiological, in vitro, in vivo and clinical studies point to the fact that natural polyphenols can be potentially used for the prevention and treatment of cancer. Momtazi et al. reviewed the effects of curcumin on nasopharyngeal cancer, a rare type of head and neck cancer that is mainly treated by radiotherapy [5]. Curcumin is a well-established polyphenol with chemosensitizing, chemotherapic and radiosensitizing effects and its chemopreventive potential has been studied in a variety of cancers. The authors highlight recent studies showing that curcumin has therapeutic and radio-sensitizing effects on cells as well their mechanism of action. Overall, the potential of using curcumin as co-adjuvant of chemotherapy without secondary systemic toxic effects in humans is discussed. Besides cancer, the therapeutic benefits of curcumin have also been described for inflammatory processes, immunological disorders, diabetes, and oxidative stress. The molecule has a unique molecular structure that easily interacts with biomolecules like protein and enzymes, thereby impacting their function/activity. Hatamipour et al. discussed the underlying mechanisms responsible for those chemical interactions of curcumin [6]. The cardiovascular system is another field where the protective activity of polyphenols is well documented, particularly for atherosclerosis, hypertension, myocardial infarction, anthracyclin-induced cardiomyopathy, angiogenesis and heart failure. Santos et al. reviewed the knowledge of the main pharmacological effects and mechanisms of cardioprotection mediated by polyphenols in the heart and vessels obtained, from in vitro, animal and human studies [7]. Hydroxytyrosol and its derivatives from virgin olive oil are important phytochemicals with proved activity for lifestyle-associated pathologies such as cancer, cardiovascular and neurodegenerative diseases, as indicated by the epidemiological evidence. Hazas et al. reviewed their natural occurrence, metabolic fate and bioavailability as well as their health beneficial effects together with newest perspectives on the mechanisms of action based on in vitro and animal studies [8]. The authors concluded that hydroxytyrosol, and its derivatives, could have potential clinical use in cardiovascular diseases. However, more epidemiological data is needed to evaluate their preventive effects for NDs and cancer. Diabetes is a chronic metabolic disorder associated with several comorbidities, including diabetic retinopathy (DR), and increased oxidative stress in the retina seems to trigger the damage of both neuronal and vascular cells. Ola et al. reviewed the evidence pointing out the potential metabolic sources and pathways related to the increase of oxidative stress in DR and the role of dietary flavonoids, particularly flavonones, flavanols, flavonols, isoflavones, flavones and anthocyanins, in the modulation of redox homeostasis in the diabetic retina [9]. Given the myriad of bioactivities described for polyphenols, these molecules have emerged as lead compounds for the design and synthesis of improved molecules with a therapeutic application for several diseases. Almeida et al. described how organic synthesis has been essential for the development of these new analogs, providing a wide range of structural modifications for structure-activity relationship studies and improving/modulating the biological activity of promising compounds [10]. The studies reviewed in this issue unequivocally show the potential of polyphenols to modify pathological processes associated with chronic diseases and the efforts of organic chemistry to develop novel molecules with improved activity. Nonetheless, the majority of these compounds are still obtained from plant material by means of costly and inefficient extraction procedures. Dudnik et al. reviewed the use of metabolic engineering and microbial cell factories (Escherichia coli, S. cerevisiae, Corynebacterium glutamicum and Lactococcus lactis) as emerging alternatives allowing efficient and sustainable production of protective polyphenols [11]. Overall, eleven outstanding international experts were invited to contribute to this thematic issue and to share their opinions, with perspectives of polyphenol research for the advance in therapy for chronic diseases. We hope that the multidisciplinary topics discussed with the theme issue will promote further discussion among pharmaceutical/nutraceutical industry and researchers.

As it is pointed out in this special issue of Current Pharmaceutical Design, despite the extensive and multidisciplinary research during the last years, a lot of basic and clinical research is still needed to better understand the manifestations, central and peripheral molecular regulators of new mechanisms of GI ulceration and healing, physiology, pharmacology and pathology, especially in relation to the classic modes of prevention/management of gastrointestinal ulceration and healing or their transformation into new concepts and the treatment of gastrointestinal ulceration and healing. This is particularly important for acquiring new vistas in the therapy of gastrointestinal tract disturbances. Therefore, “New mechanisms of GI ulceration & healing: Physiology, pharmacology & pathology” attempts to cover a huge area of the pertinent scientific research. Between various concepts, the Robert’s cytoprotection concept is still one of the most fascinating concepts in science development, particular with respect to conceptual disagreements, or on the other hand, novel agents, and attempts to improve concept, as well as to finally realize some or all of the concept postulates in gastrointestinal tract therapy. Therefore, it seems interesting to review again this issue, covering a huge area, by eminent experts, providing their most recent findings, including the development of new medicines and new approaches. Bilski et al. [1] in their review Exploiting significance of physical exercise in prevention of gastrointestinal disorders revealed the particular relationship between physical exercise with different intensity and alterations the morphology and function of the gut including its protective influence on the lipid metabolism and chronic systematic inflammation as well as the diversity, distribution and metabolite of the gut microbiota. Based on the evidence provided in this overview, the regular, moderate exercise can reduce the risk of colorectal cancer and exert a beneficial effect on upper and lower GI-tract disorders such as reflux esophagitis, peptic ulcers, cholelithiasis, constipation and IBD leading to the attenuation of the symptoms. On the other hand, the high-intensity training or prolonged endurance training can exert a negative influence on these same entities [1]. Olsen et al. [2] in the review New approaches for weight loss: experiments in animal models emphasized the interesting points such as animal models (i.e., VBLOC (implanted hunger-blocking device) and knockout of muscarinic acetylcholine M3 receptor) known to reduce food intake and body weight versus the expression of energy-balance regulating peptides in the hypothalamus as a drive for increased food intake. Finally, emphasizing that the brain-gut axis plays an important role in the regulation of body weight, they proposed that the brainstem may be more important in the regulation of food intake than hypothalamus in the context of the brain-vagus nerve-gut axis [2]. Review Similar and distinct mechanisms in the protective processes of upper and lower GI tract by Gyires et al. [3] is an excellent overview of the protective mechanisms of upper and lower gastrointestinal tract providing their own findings purposefully elaborated. This review analyzed many factors involved in various forms and levels of protection of mucosal tissues, mucosal protection in the periphery (barriers and mediators), intestinal defense mechanisms (mucosal barriers, bile acids), stimulation of gastrointestinal mucosal protection (pre-epithelial, epithelial, sub-epithelial possibilities) and central nervous system involvement [3]. The authors, Kang E.A. and collaborators [4] in review BPC 157 as potential agent rescuing from cancer cachexia summarized signaling pathways and promising drug candidates to treat cancer-associated cachexia and focused their review on the possible application of BPC 157 for cancer cachexia with the mode of action. They showed the significant relieving effects of BPC 157 on C-26 colon adenocarcinomainduced muscle degeneration and inflammation. The presented review is very informative and may provide support for the potential use of stable gastric pentadecapeptide BPC 157 as a cachexia-rescuing therapeutic agent [4]. The author, Gaetano Iaquinto [5] in his review, The several activities of 4-methypyrazole in animals and humans, reviews 4- methypyrazole (4-MP), a pyrazole derivative in animal and humans. 4-MP is a potent competitive inhibitor of ADH activity with an affinity about a 1000 times more than toxic alcohols. 4-MP was shown to reduce the formation of toxic metabolites in lethal methanol and ethylene glycol poisoning in animal models and in methanol poisoning in humans, and in particular, 4-MP provides significant protection of the human stomach against alcohol-induced acute mucosal injury [5]. Kodama et al. [6] in their review MALT lymphoma, stress ulcer and cholinergic nerves from the viewpoint of bilateral and unilateral truncal vagotomy and substance P follow the evidence that the vagal nerves play an important role in gastric function providing rich innervation to this area and that the vagal nerve activity was shown to be related to both gastric cancer development and progression, but its relation to the mesenchymal tumors such as MALT lymphoma is not known. Thereby, the authors were focused on the effect of vagotomy on gastric MALT lymphoma development by in the Helicobacter heilmannii-mouse infection model [6]. The review Role of formyl peptide receptors in gastrointestinal healing by Prevete and collaborators [7] assessed the role of a particular class of PRRs, the Formyl Peptide Receptors (FRP), in gut mucosa homeostasis. They report studies that strongly suggest the possibility that FRP activation is crucial for the maintenance of gut homeostasis. Furthermore, they provide indications for the potential clinical relevance of novel directions related to FPR modulation in various gastrointestinal disorders [7]. The authors, Seiwerth and collaborators [8], in review BPC 157 and standard angiogenic growth factors. Gastrointestinal tract healing, lessons from tendon, ligament, muscle and bone healing focused on gastric pentadecapeptide BPC 157, a peptide always given alone vs. standard peptidergic angiogenic growth factors such as EGF, FGF and VEGF, and numerous carriers. They also reviewed how the healing could happen involving angiogenic growth factors in the gastrointestinal tract and in extra-gastrointestinal tissues, such tendon, ligament, muscle and bone, providing a carrier, use (i.e., EGF, FGF and VEGF) or no use (BPC 157). The effects of EGF, FGF, VEGF, and BPC 157 were compared in various injuries, such as gastrointestinal ulcer, tendon, ligament, muscle and bone healing. They found that BPC 157 was the only factor being consistently effective in all of the models, given per-orally or locally, unlike FGF, EGF, and VEGF. The authors found that on the healing mechanism of BPC 157 is related to its own angiogenic effect in the healing [8]. The authors, Sikiric and collaborators [9], in review Novel cytoprotective mediator, stable gastric pentadecapeptide BPC 157. Vascular recruitment and gastrointestinal tract healing cover an intriguing story about the stable gastric pentadecapeptide BPC 157 and the whole story about the concept of the cytoprotection and possibly new insights. The basic concept providing the stomach cytoprotection as the most fundamental concept, stomach cell protection and endothelium protection was largely elaborated. Having managed these two points, stomach cell protection and endothelium protection, either one or together, even much more than standard cytoprotective agents do, BPC 157 employed large scale of its beneficial effects seen in various organs. This provides an additional realization of blood vessels controlling, described as “vessel recruitment depending on injury”, “bypassing vessel occlusion” or “running toward the defect”, leading to reestablishing blood flow. This was taken as a final implementation of the concept of cytoprotection. Obviously, the reestablished blood flow, and largely reversed injurious course may practically implement the cytoprotection concept [9]. The authors K. Takeuchi and K. Amagase [10] in their review Roles of cyclooxygenase, prostaglandin E2 and EP receptors in mucosal protection and ulcer healing in the gastrointestinal tract reviewed how the PGE2 prevents acid-reflux esophagitis and affords protection of the stomach against NSAIDs through the activation of EP1 receptors. Although CRS-induced gastric lesions were aggravated in IP but not EP1 KO mice, endogenous PGE2 may also be partly responsible for mucosal protection during CRS via the activation of EP4 receptors, in addition to that afforded by PGI1 /IP receptors. Similar observations were done in the other parts of GI tract (duodenum, small intestine, stomach, large bowel) [10]. Racz et al. [11] in their review Defense mechanisms against acid exposure by dental enamel formation, saliva and pancreatic juice production review defense mechanisms of different tissues. The similarities of enamel, salivary glands and pancreas are well emphasized and described. The authors highlight the importance of bicarbonate buffer system and highlight the possible failures as well. The intracellular transport and secretion mechanism are also reviewed [11]. Yanaka in his review Contribution of NRF2 in gastrointestinal protection from oxidative injury [12] reviews the evidence that dietary intake of sulforaphane, derived from broccoli sprouts, ameliorates H. pylori-induced gastritis, NSAIDs-induced small intestinal injury, and functional constipation. The additional focus was on many other compounds, which enhance the nuclear factor erythroid 2-related factor 2- mediated antioxidant system, and in particular on some reports, which have shown that excessive stimulation of nuclear factor erythroid 2- related factor 2 enhances chemoresistance and facilitates the growth of cancer cells [12]. The review Lifestyle and peptic ulcer disease from Yegen [13] extends a general point such as the risk of developing peptic ulcer disease shown to be associated with genetic inheritance, lifestyle and social status of the patients, to an extensive and very informative review providing particular chapters (Stress, NSAIDs, Diet and body weight, Alcohol, Smoking, Physical activity, Sleep) with a list of the references that seems to be quite extensive and well chosen [13]. We hope multidisciplinary topics discussed with the theme issue will promote further discussion among pharmaceutical industry and researchers. As the guest editor, I would like to thank all the authors and co-authors for their excellent contributions. Also, I would sincerely thank and acknowledge the diverse group of experts and colleagues who offered their substantial reviewing efforts and suggestions. Last but not least, I would like to express my gratitude to the Bentham Science Publishers for the wonderful experience while working with the journal on this thematic issue. It was a great pleasure working with the Director Kazim Baig and for the opportunity to publish in Current Pharmaceutical Design. It was a wonderful experience working with Editorial Assistant Aamer M. Khan at the time of submission and processing of the manuscripts. I would like to acknowledge the contributions of others who took care of editing and processing the manuscripts to obtain the best final quality at the time of publication.

CNS Therapeutics: Drugs and Peripheral Influences

Unique Approaches to Drug Delivery

It has been absolute honor to serve as a guest editor for this special issue of Current Pharmaceutical Design. Inflammation is the common pathological basis for age-related diseases such as cancer, neurodegenerative diseases, cardiovascular diseases, and diabetes. Life expectancy is estimated to dramatically increase in the upcoming decades, and despite it should be a great accomplishment for our societies, the increase of longevity is a significant challenge for the global economy because this increase leads to an enhance in the incidence of age-related diseases. There is great interest by pharmaceutical/biotechnology industries to focus on drug development strategies for inflammatory-related pathologies. Nowadays, anti-inflammatory therapeutics market is the major part of global pharmaceutical industries and is expected to grow. The pharmaceutical industries are benefiting of academic inflammation research, and are adopting novel approaches in drug designing as key strategies to gain additional market share. In fact, according with Allied Market Research report, the global anti-inflammatory market is expected to garner $106.1 billion by 2020. However, still the challenge is to design new anti- inflammatory drug with lesser side effects. This special issue will cover several inflammatory research areas. For example, a growing number of researchers have discovered various signaling pathways that are associated with the initiation and progression of inflammation. An excellent manuscript by Yeung and Colleagues [1] focus on classical inflammatory pathways: p38 MAPK, IL-6/JAK/STAT3 and PI3K; and a non-classical inflammatory pathway, the Hippo. The molecular mechanisms, associated pathologies, selected drugs of these signaling pathways and limitations and potential risks of anti-inflammatory drugs will be summarized. The central nervous system may be the target of several chronic inflammatory-related pathologies where the inflammatory component acts either as a primary cause of the disease or as a secondary outcome of the tissue damage. An outstanding manuscript by Degan and colleagues [2] summarize current data on Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic Lateral Sclerosis, stroke and traumatic brain diseases and discuss the potential anti-inflammatory therapeutic approaches acting at different levels and stages of the diseases. Alcohol consumption causes comprehensive liver disorders, designated as Alcoholic Liver Disease (ALD). In an interesting manuscript Lu and Cederbaum [3] summarize the consequences of liver damage, the relationship of CYP2E1/CYP2A5 and ALD development, the mechanisms involved and recent advances, some unpublished data of cytochrome P450 enzymes dysregulation in inflammatory disease states. Mucositis or inflammation of the mucosa that occurs throughout the alimentary tract from the mouth to anus, is a side effect associated with the use of chemotherapy. Mahendran and colleagues [4] in an excellent reviews focus the pathobiology of chemotherapy-induced oral and gastrointestinal mucositis and recent research examining the role of agents with anti-inflammatory activity in treatment and prevention of the condition. The skin is the largest organ in the human body which function is to protect the body from external hazards. Skin inflammation leads to skin aging that can eventually promote cellular damage and the development of cancer. An interesting manuscript by Kim and Lee [5] summarize some proteins and signaling pathways involving in skin inflammation, which can be modulated by phytochemicals with the purpose to attenuate skin inflammation. Considerable progress has been made in the understanding of inflammatory mechanisms which may open new avenues for preparation of novel anti-inflammatory drugs. Medicinal plants are promising sources for preparation of such novel drugs. Taking into consideration the anti-inflammatory activities of a large group of medicinal plants, Kazemi and colleagues [6] remarkably describe recent advances in progresses in understanding the molecular basis of inflammation, and presents the most important medicinal plants with anti-inflammatory activity. Melatonin is an indolamine synthesized and secreted by the pineal gland and other extrapineal sources including immune system cells, brain, skin and the gastrointestinal tract. Carrascal and colleagues [7] present very timely manuscript evaluating the use of melatonin in the control of inflammation underlying the Alzheimer, Amiotrophic lateral, Multiple Sclerosis, Huntigton´s disease and ulcerative colitis. The authors propose that these actions of melatonin are mediated through their receptors but also with their direct antioxidant action and melatonin's ability to break the vicious cycle of ROS-inflammation. The use of nanomedicine, nanoscale structures for drug delivery, exhibits a really high therapeutic potential in the field of neuroinflammation therapy. In an excellent manuscript Cayero-Otero and colleagues [8] analyzes a wide variety of compounds as possible candidates to cross the Blood-Brain Barrier (BBB) and reach the brain in sufficient concentration to be able to exert its effect. The authors also describe PLGA nanoparticles as one of the most versatile drug delivery nanosystems, and other strategies, as direct intranasal administration (nose-tobrain), novel viral vectors and novel implanted catheters. Computational biology approaches could be useful to design novel drugs for inflammation treatment. Virtual screening involves applying computational methods to discover new ligands for biological structures from the formation of large libraries composed of a large number of compounds. In an interesting manuscript Scotti and colleagues [9] illustrate different studies employing a variety of virtual screening approaches to find molecules that have actions on important, diverse targets implicated in inflammatory diseases.

Drug Delivery Systems and Drug Targeting

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Antibodies and Immunotherapeutics

In this special issue of Current Pharmaceutical Design, entitled: “Antimicrobial peptides as mediators of innate immunity”, the major features of Antimicrobial Peptides (AMPs) are outlined. In particular, their classification, cellular sources, and biological properties in health and disease are described. Finally, clinical applications of AMPs, as novel therapeutics in the course of infections caused by antibioticresistant bacteria, fungi, protozoa and viruses as well as in cancer, are discussed. Magrone et al. [1] at first review the phylogenic sources of AMPs as well as their anti-inflammatory and immunomodulating activities. Moreover, lantibiotics, as new potential anti-infective drugs, are described. Authors also point out the ability of dietary bioactive principles and food supplements to induce AMP production. Pizzo et al. [2] place emphasis on the exploitation of structure, function and mechanisms of action exerted by AMPs in drug targeting. In this review, cryptic AMPs are introduced as proteins hidden in their primary structure and, then, released by the host and/or bacterium proteases. Their discovery has enlarged the spectrum of known AMPs, also allowing investigation of new functions and applications. Drago-Serrano et al. [3] describe the role of Lactoferrin (LF) and lactoferricins (Lfcins) in the control of pathogens also in virtue of their immune regulatory properties. LF and Lfcins are molecules of pharmacological interest and native LF and its N-terminus peptides seem to have potential applications as adjunctive anti-infectious agents. Finally, these compounds have the property to retard tumor growth and attenuate endotoxin shock. Chieosilapatham et al. [4] review the role played by human cathelicidin LL-37 in the modulation of innate immune response. Particularly, LL-37 exerts pro- and anti-inflammatory activities, also inducing maturation, proliferation and regulation of apoptosis. Finally, according to its anatomical distribution, LL-37 seems to play different roles in the regulation of innate immunity. Kiatsurayanon et al. [5] illustrate the role of human beta-defensins (hBDs) in the maintenance of skin barriers. They exert a broad spectrum of microbicidal activities also displaying several immunoregulatory activities in the course of skin infections and inflammation. A better knowledge of hBD physiology may contribute to develop new therapeutic remedies in the course of skin barrier impairment, such as atopic dermatitis and psoriasis. Skovbakke et al. [6] outline the property of Formyl Peptide Receptors (FPRs) in mediating the immunomodulatory activities of AMPs and peptidomimetics. In this framework, for their function neutrophils express FPRs which behave as targets of AMPs. On these bases, peptidomimetics represent new molecules able to modulate neutrophil activities. Adolph et al. [7] describe the function of intestinal Paneth cells as producers of AMPs finalized to the homeostatic control of microbiota. Emphasis is placed on the alteration of Paneth cell function in inflammatory disease and, especially, in the course of ulcerative colitis and Crohn’s disease. Khurshid et al. [8] point out the unique structure of human defensins based on amino acid sequences bearing disulphide bridges which allow their synthesis or natural production with the help of bacteria. In particular, in this review, the role exerted by oral defensins in health and disease is stressed out. Rivas-Santiago and Torres-Juarez [9] highlight the ability of AMPs to kill mycobacteria both in vitro and in vivo. Then, AMPs can be used as an adjunctive therapy in the course of human tuberculosis. However, to avoid collateral effects depending on the multiple activities exerted by AMPs, Authors suggest that certain features, such as comorbidity, family history and risk factors in patients with tuberculosis should be taken into consideration prior to AMP therapy start. Magrone et al. [10] emphasize the concept that AMPs in comparison to antibiotics possess a larger spectrum of antimicrobial activities without inducing bacterial resistance. Therefore, their use in different clinical settings, even including septic shock is discussed. Finally, a series of novel compounds derived from AMPs for their potential capacity to reinforce the immune response are illustrated.

Approximately 15 million babies are born preterm each year and one million die of complications of prematurity. As of the close of 2016, the latest year for which data are available, the preterm birth rate rose for the second year in a row in the United States, and now stands at 9.8%. This setback in the US is likely tied to major lifestyle and environmental factors that have negatively impacted other health outcomes as well. Recent data indicate that increased obesity and oxidative stress lead to dysregulation of the immune response, which, in turn, leads to disease. Inflammation, resulting from immune dysregulation, has been linked to cardiovascular, neurodegenerative and oncologic disorders. Inflammation, in the absence or presence of microorganisms, is also the single most common driving force behind spontaneous preterm birth. In this second volume of our “hot topics” issue focused on emerging pharmacotherapy for preterm birth (PTB), we move into the realm of investigative approaches at the cutting edge of the field that target immune dysregulation. Recognizing that toll-like receptor 4 (TLR4) lies at the crossroads of both infectious and sterile inflammatory pathways, Sarah Robertson et al. review the evidence supporting the targeting of toll-like receptor 4 (TLR4) to prevent preterm labour [1]. The authors review the role of TLR4 in both normal parturition and preterm birth as well as how this receptor interacts with both pathogen-derived and endogenous ligands. Finally, the authors summarize recent exciting data supporting the use of specific TLR4 antagonists to prevent PTB, including (+)-naloxone. In a comprehensive review on the topic, Carlos Salomon et al. propose that preterm birth may be triggered by extracellular membrane vesicles involved in the regulation of signaling cascades during pregnancy and parturition, known as exosomes [2]. These highly stable nanovesicles, serving as transporters of mRNA, miRNA, DNA, lipid, cell-surface receptor and protein mediators, communicate between the maternal and fetal compartments in pregnancy. The authors present the provocative proposal that exosomes carry the signals for the initiation of parturition. Kiersten Giusto and Charles Ashby point to the role of the sphingosine kinase/endothelin-1 pathway as a novel putative target of prevent PTB [3]. The data summarized in their review provide solid evidence for the dual role of this pathway in PTB, which mediates both a proinflammatory response as well as uterine contraction. The fact that this pathway is regulated by positive feedback underlines its explosive role in inflammation-driven PTB. Samir Gorasiya et al. describe an exciting new class of cytokine suppressive anti-inflammatory drugs, based on the accidental discovery that N,N-dimethylacetamide, a common pharmaceutical excipient, rescues timed pregnant mice from lipopolysaccharide induced preterm birth [4]. These molecules represent a novel group of nuclear factor kappa B (NF-κB) inhibitors. As NF-κB is implicated in so many disorders, these new drugs may have broad clinical impact. Finally, Nicole Olgun of the Centers for Disease Control and Prevention reviews the special considerations related to viral infection in pregnancy and Ebola virus in particular [5]. Dr. Olgun reminds us of the devastating toll viral infections exert on neonatal health. Her review emphasizes the value of preparedness as unexpected epidemics emerge. The development of pharmacotherapy to prevent preterm birth presents a special challenge because of the vulnerability of the developing fetus. Even agents proven to be safe in other clinical settings that show potential tocolytic activity can not simply be repurposed for the prevention of preterm labor without being carefully vetted for teratogenic effects. The successful approach to this far-reaching clinical problem will come from collaborative efforts among investigators with different perspectives and expertise. This issue, the second of a two volume series on this topic, brings together insightful reviews written by experts from around the globe.

Infections caused by microorganisms are one of the most common issues and a serious threat to patients in the clinic. These microbial infections often result in disease progression and surgical failure. To address this problem, many efforts have been made to exploit various biomaterials and medical devices with antibacterial properties. Currently, various materials, namely antibiotics, inorganic nanomaterials, polymers, and Antimicrobial Peptides (AMPs), have been widely investigated and used as antimicrobial agents. The morphologies, molecular structures, or release behaviors of these materials may significantly affect their functionality. Meanwhile, the antibacterial mechanisms of these materials have also gained much attention and may direct the design of advanced antibacterial materials or medical devices. In this theme issue, ten reviews from researchers in differing fields were collected together with a primary focus on the design of antibacterial materials and their applications. Hydrogels, an important biomaterial, have been widely used in biomedical fields. Weiguo Xu et al. gave a review on the recent development of antimicrobial hydrogels and discussed their potential prospects [1]. Polymers with antibacterial functions have also been investigated. Cansu Ergene and Edmund F. Palermo introduced a wide range of antimicrobial polymers and gave a review on state-of-the-art methods employed to optimize macromolecular structures for high antibacterial activity [2]. Diego and his colleagues gave a comprehensive introduction on antibacterial coatings with different molecules, and the striking developments of chitosan-based functional coatings for pharmaceutical and biomedical applications were well reviewed [3]. Besides polymers, inorganic materials also made a significant impact in antibacterial fields. Zhou Chen et al. evaluated recent developments regarding bioactive glass, graphene-based antibacterial materials, as well as metal ion coatings [4]. The antibacterial mechanisms of nanoparticles have been well investigated by Scott and his colleagues as they summarized the challenges metal oxide antibacterial materials face and presented novel methods to evaluate the antibacterial potency and efficiency of these nanoparticles [5]. AMPs are another promising therapeutic agents to combat infectious diseases. However, the applications of AMP are limited due to insufficient sources, instability, toxicity, and bioavailability. In this theme issue, Huping Jiao’s group provided a review on the design and modification of AMPs, and summarized both chemical and biological methods to adjust the properties of AMPs [6]. The controlled release of antibiotics is an efficient method to prevent or treat implant-associated infections. Liqun Xu et al. provided a summary on the carrier platforms used for loading antibiotics and their drug release behaviors were also highlighted [7]. Layer-by-layer (LBL) is also a versatile method to construct functional surfaces and films. Lan Liao and coauthors gave a brief introduction and summarized the applications of LBL to construct antibacterial surfaces or films [8]. Antibacterial agents play an important role in the wound healing process. Zhengwen Li and Menno Knetsch gave a review on current antibacterial strategies of wound dressings, the wound infection process, antibacterial agents, and a controlled drug delivery system [9]. The real-time monitoring of bacterial infections and drug evaluation are also important topics. Xiwen Wang and his colleagues provide a review about bacterial luciferase gene cassette as a real-time bioreporter for infection model and drug evaluation [10]. This special issue covers various fields of antibacterial materials. The guest editors and all the authors hope this theme issue may help readers discover advanced ideas and guidance, while simultaneously motivating readers to contribute to researches on antibacterial materials.

Abstract: In the field of inflammation/infection imaging, nuclear medicine techniques offer non-invasive tools to detect early pathophysiological changes before the development of anatomical changes detected by radiological procedures and, often, before clinical onset of symptoms. This field has been recently developed with several new radiopharmaceuticals for SPECT and PET used to define new strategies for imaging immune cells as well as pathogens. In particular, we count now several dozens of new radiopharmaceuticals designed for bacterial imaging and new peptides and antibodies for imaging neutrophils, T-cells, B-cells and macrophages. These may have important applications not only for diagnostic purposes but also for prognostic purposes, therapy decision making and for early follow-up of therapy efficacy, thus allowing us to define specific therapies for each individual patient. Inflammatory disorders, infections and cancer, have a tangible impact for health and social costs. For this reason, it is advisable to establish, in each hospital, a multi-disciplinary team of experts for the management of patients with chronic inflammatory/infectious diseases, as well as for cancer patients, to optimize diagnostic protocols, therapy decision and follow-up. Nowadays, among the several imaging modalities available, nuclear medicine techniques play a secondary role after radiation-free methods such as ultrasound (US) and Magnetic Resonance Imaging (MRI). Nevertheless, a multidisciplinary approach combining radiology and nuclear medicine often represents a suitable diagnostic, prognostic, and monitoring tool in patient management. Nuclear medicine techniques, in particular, offer non-invasive tools to detect early pathophysiological changes before the development of anatomical changes detected by radiological procedures and often before clinical onset of symptoms. Hence, this monographic issue is well-timed for providing clinicians current knowledge on molecular imaging in inflammatory disorders and infections, since an early and accurate diagnosis represents an important step to prevent serious or long-lasting complications as well as to monitor therapeutic responses. Functional imaging with radiopharmaceuticals has been shown to detect inflammatory processes with high sensitivity and specificity and constitute the basis of molecular imaging with Positron Emission Tomography (PET) or Single-Photon Emission Computed Tomography (SPECT). These techniques are also of great importance for therapy decision making and in monitoring response to therapy. Thanks to the possibility of deeply understanding the nature of an inflammatory process and what cells or cytokines are present in the inflamed site we are now able to decide the most appropriate therapy and to verify its efficacy. As an example, I could mention the role of 99mTc-anti-TNFα antibodies [1-5] or 99mTc-anti-CD20 antibodies [6, 7] or 99mTc-octreotide [8, 9] in patients with rheumatic diseases, or the role of 99mTc-Interleukin-2 in patients with Type 1 diabetes [10, 11], or the role of 99mTc-labelled antibiotics in defining the nature of pathogen causative of an infection [12], or other radiopharmaceuticals in neuro-inflammation [13] and heart inflammation [14]. Along this line, many other radiopharmaceuticals have been developed and studied including those for targeting chemotaxis, cell recruitment, matrix metalloproteinase production, macrophage metabolism, angiogenesis, and several other specific against cells and soluble antigens involved in inflammatory and infective diseases as reviewed in this issue by Signore et al. [15] and Sollini et al. [16]. The approach of specific imaging of bacteria has been reviewed by Ebenhan et al. [17] whereas the new radiopharmaceuticals labelled with 68Ga for PET imaging have been reviewed by Vorster et al. [18]. It must be clarified, however, that in some pathological condition it is not so relevant to use a highly specific radiopharmaceutical, being more relevant its high sensitivity or even the strategy used for image acquisition that could improve the disease specificity of a non-highly specific radiopharmaceutical as clearly explained by S. Skehan and M. Peters in early 2000 [19, 20] and others [21]. The understanding of the properties of radiopharmaceuticals and of the most appropriate image acquisition modality, relies on the success of the use of radiolabelled neutrophils [22-24] and on the use of 18F-FDG is certain specific pathological conditions [25-27] as also reviewed by Ankrah et al. in case of fungal infections in children [28] or as described by Keidar in case of diabetic infections [29] or by Palestro et al. in case of fever of unknown origin [30].

Colchicine has been used for over two thousand years. Recently research studies have shed light on potential new indications. While colchicine is in fact an ancient drug, there is a lack of “big” data on its utilization in modern medicine. Tsoucalas et al. [1] searches back in ancient Greek and Byzantine sources for documentation of colchicine utilization. While initially considered as an effective poison to “kill a rebellious slave, or a rival nobleman”, later on Late Greek antiquity its potential therapeutic aspects were recognised [1]. Karamanou M et al. [2] unveils the modern historical course of colchicine from distribution through empiric physicians (charlatans) in the 15th century to the contemporary pharmacopeia of the 19th century. Colchicine exploits a plethora of pathophysophysiological pathways and is in general characterized by a relatively safe profile. Side effects are mainly of gastrointestinal origin, while toxicity is associated to doses multiple of the common therapeutic regimens. Angelidis C. et al. [3], review pharmacokinetics, mechanisms of action and side effects of colchicine. Drosos E. et al. [4] reviews potential indications of colchicine in the fields of low-back pain, gliomas and stroke from the viewpoint of neurosurgery. Tsivgoulis G. et al. [5] review available data and ongoing studies in utilization of colchicine’s anti-inflammatory properties for prevention cerebral atherosclerotic events. Marinaki S et al. [6] provide an overview of colchicine employment in a series of entities affecting the kidneys (fibrotic disorders, diabetic neuropathy, familial Mediterranean fever and amyloidosis, renal transplantation, hypertensive kidney disease, autosomal dominant polycystic kidney disease, focal segmental glomerulosclerosis). Colchicine as a treatment for gout, a classic indication, is comprehensively reviewed by Parcart T and Richette P [7]. Further, Lantinioti G. et al. [8] present current perspectives on indications of colchicine in autoinflammatory disorders (Familial Mediterranean Fever, Periodic fever with aphthous stomatitis, pharyngitis and adenitis, Behcet’s disease, Idiopathic recurrent acute pericarditis). Finally, colchicine has been suggested as a means of primary prevention for post-operative atrial fibrillation. A series of randomized studies and meta-analyses have lately been available and are presented in detail by Vrachatis D. et al. [9]. Last, but not least, a “traditional” indication of colchicine, pericardial syndromes, is thoroughly reviewed by Lazaros G. et al. [10].

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Heart diseases are the world’s leading cause of morbidity and mortality. For a broad spectrum of heart diseases, though each has its own unique features in pathogenesis and disease evolution, the inflammatory processes are commonly shared among them. The initial inflammatory reaction is a cardioprotective response to triggers such as ischemia, tissue injury and infection. However, prolonged inflammation, can damage normal tissue, cause cardiac dysfunction, result in adverse cardiac remodeling including myocyte hypertrophy and necrosis, fibrosis, and at last contribute to a poor prognosis. Recent findings suggest that regulation of inflammation is a potential target for development of therapies for heart diseases. In the purpose of facilitating further management of heart diseases, this issue will systemically review recent studies focusing inflammation in heart diseases. The issue contains 12 papers that summarize inflammatory pathways and potential therapeutic targets for heart diseases.

Lifestyle modifications and diet therapy are two of the most important tools in prevention and treatment of cardiovascular risk factors, cancer and other chronic diseases. In keeping to this, increasing epidemiological data support the concept that diet rich in fruit and vegetables promotes health and attenuate, or delay, the onset of various diseases, including heart disease, hypertension, cancer and certain age-related degenerative disorders. Over the past decades increasing research interest has been addressed to the potential health benefits of polyphenols. According to this, it has been suggested that the health benefits from fruit and vegetables can be partially linked to their content of a certain group of polyphenols, the flavonoids. A large body of evidence supports that dietary intake of polyphenols (particularly flavonoids and the specific class of flavonoids named flavanols largely contained in red wine, cocoa, tea, fruits and vegetables) might exert some beneficial vascular effects, reduce the risk of cardiovascular morbidity and mortality and contribute to the prevention of other chronic diseases. Among phytochemicals, polyphenols constitute one of the most numerous and widely distributed groups of substances in the plant kingdom, with more than 8000 phenolic structures. They occurred in a variety of fruits, vegetables, seeds, flowers, beverages and even some manufactured food as a component of the natural ingredients used. These bioactive compounds typically occur in small quantities in foods. They are being intensively studied to evaluate their effects on health. The impetus sparking this scientific inquiry was the result of many epidemiologic studies that have shown protective effects of plant-based diets on cardiovascular disease and cancer. According to this, growing interest has been addresed to many bioactive compounds. These compounds vary widely in chemical structure and function and are grouped accordingly. Plant polyphenols have drawn increasing attention due to their potent antioxidant properties and their marked effects in the prevention of various oxidative stress associated diseases. In the last few years, the identification and development of phenolic compounds or extracts from different plants has become a major area of health- and medical-related research. Adequate nutrition is one of the pillars of public health. Before developing and implementing effective intervention programmes to improve nutrition at the population level, it is important to know the nutritional situation of the target group. Therefore, the time lapse for hidden progression of pathological process may take years and even decades. During this time, both the person at risk and physician remain unaware of the existing premorbid pathological condition. As a result, no preventive measures are undertaken to reduce the individual risk of the development of the overt disease. Polyphenols are abundant nutraceutical micronutrients in our diet, and evidence for their role in the prevention of degenerative diseases is emerging. The WHO estimated that the costs of not engaging in prevention and therapy will be fastly growing in the next years, with a more severe impact in developing countries. Several natural nutraceutical from our diet and ingredients marketed for use in dietary supplements address such risk factors. The ability of nutraceuticals to favorably influence cardiovascular risk factors and atherosclerotic vascular disease as well as a number of different chronic disease should be recognized as an enormous opportunity for the prevention or treatment of this common condition.

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