Current Pharmaceutical Design

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.