Current Medicinal Chemistry

The aim and the scope of this special issue is to represent an exhaustive and comprehensive review on the current treatment of OCD, a quite common psychiatric disorder that has been recently considered a distinct nosological category. The pharmacological treatment of OCD is still mainly based on the serotonin hypothesis of the disorder that, although important, it is now evident that cannot fully explain the complexity of this condition. Therefore, there is an urgent need of novel pathophyiosological data, reliable animal models, still very limited, as well as innovative pharmacological targets. Emphasis will be given also to the problem of treatment resistance and chronicity of a large portion of OCD patient, as well as on current and new strategies to overcome this issue.

This thematic issue is dedicated to combine our current knowledge of mechanisms and molecular targets for photo-induced skin diseases and signs of premature cutaneous ageing as well as the discovery and development of effective targeted substances and compositions for the prevention and treatment of these diseases and age-related skin defects. Newly developed photosensitisers-drugs for photodynamic therapy is another key topic of the thematic issue where 7 full-length reviews from the leading groups in the field were collected. The first review by L. Marot [1] from L’Oreal Advanced Research, France speaks about a deleterious synergy between pollution and sun exposure and overviews the opportunities for cosmetological skin protection. The author underlines that an association of ultra-fine dust particles with toxic chemicals, heavy metals, polyaromatic hydrocarbons (PAH) or, especially, with photo-reactive PAH strongly aggravates oxidative stress associated with UVA exposure. The principle of cutaneous damage by pollutants from “outside” and “inside” is strongly supported by large epidemiological data showing a significant correlation between the exposure to pollutants/cigarette smoke and premature ageing signs/biological markers. Similar correlation was observed for atopic skin diseases and external hazards. The mechanisms of damaging synergy (f.e. oxidative stress, metabolic impairment, and inflammation) between pollution and sunlight, first of all, UVA radiation are discussed in detail. On these grounds, the author proposes combined protection strategies from outside (topical UVA absorbers and antioxidants-blockers of lipid peroxidation) and inside (mitochondria-targeting oral antioxidants and inducers of endogenous antioxidant and detox skin barriers via Nrf2 pathway). The next review by S.E. Dickinson & G.T. Wondrak [2] from Arizona University is focused on TLR4-directed molecular pathways underlying skin photodamage and photocarcinogenesis. In this comprehensive paper, improved molecular strategies for targeted photo-protection and photo-chemoprevention are suggested. The Toll-like receptor 4 (TLR4), which, since a long time, had been known as a key regulator of anti-bacterial defence, wound healing, and chronic inflammation in the skin, has been recently recognised as a molecular target for skin photoprotection and photo-chemoprevention. Both pharmacological and genetic suppression of TLR4 led to the impairment of UVinduced inflammatory signalling through NF-kappaB and AP-1 pathways. Several small molecules-antagonists of TLR4, such as eritoran, (+)-naloxone, ST 2825, and resatorvid were identified to modulate altered TLR4-dependent inflammatory signalling. The group of C.A. O’Neil [3] contributed the excellent overview on the impact of UV radiation on the barrier function of human skin: from molecular mechanisms to the development of topical therapeutics. A complex epidermal barrier includes the control of water content and temperature, mechanical protection, photochemical, toxicological, redox, immune, and metabolic defence systems to prevent the skin and underlying organisms against biotic and abiotic stresses and invaders. The effects of UV radiation (UVR) on barrier functions are still to be elucidated. Of importance, higher erythemal doses of UVR induce increased trans-epidermal water loss and reduction in tight junction functions in the granular layer, while sub-erythemal doses exert positive protective effects. According to the authors’ opinion, topical sunscreens should have double action: to block UV interaction with skin components and to prevent the water loss in order to provide a proper defence of barrier functions. Browsing the dedicated literature, the authors identified specific botanical extracts providing both UV protection and occlusive (moisturising) effects. The group of researchers from King’s College London, UK [4] presented a review dedicated to mycosporine-like amino acids for effective and safe photo-protection. The search for ecologically friendly and sustainable sunscreen has been going on for decades in an attempt to substitute synthetic sunscreens - pollutants for marine and terrestrial environment/ecosystems. In this review, the limited literature sources showing sun protective properties of mycoplasma- like amino acids are collected and thoroughly evaluated. These natural amino acids occurring in marine organisms as different as protozoa, algae, seaweed, corals, invertebrates, and fish are considered as a valuable and biocompatible alternative to synthetic sunscreens. There is an evidence that these amino acids have essential role of photoprotection of marine organisms against UVR, particularly in shallow clear waters. Due to specific chemical structure, they seem to act as broadband UV screens and antioxidants to interrupt free radical-driven chain reactions. Moreover, these amino acids are capable of inducing endogenous antioxidant defence systems through Nrf2 pathway like extracts of a number of terrestrial plants and plant cell cultures. The authors honestly admit that the current lack of pre-clinical and human studies does not allow these natural amino acids to be considered as substitutes of synthetic sunscreens. The second pool of review articles describes research and development of novel photo-sensitizers to be feasible for photo-dynamic therapy widely used in cancer, psoriasis, and vitiligo treatments. Thus, I. Bilkis and co-authors [5] and co-authors from Weizmann Institute (Rehovot, Israel) critically evaluate literature dedicated to the mechanisms, by which photo-sensitisers elicit chemical modifications in amino acid residues of proteins. They focus on singlet oxygen as a key player in the above modifications. The authors logically suggested three possibilities for singlet oxygen to specifically attack malignant cells while leaving normal cells intact. The first one involved photo-sensitiser methylene blue with high affinity to the protein acetylcholinesterase. The second one used hydrophobic photo-sensitiser hypericin with the capacity to interact selectively with partly unfolded proteins which are characteristic for rapidly growing cancer cells. In the third case, the photo-sensitiser emodin was coupled to a specific protein hormone GnRH, which recognises malignant cells via specific receptors to the hormone. This approach seems to be applicable in the search and optimisation of different photo-sensitisers for photodynamic therapy of cancer. The review by a group from Romania [6] is concentrated mainly on laboratory and clinical studies of photodynamic therapy in melanoma. Photo-dynamic therapy has been successfully used as the first line of therapy for the treatment of lung, esophageal, bladder, nonmelanoma skin, head, and neck cancers. At the same time, melanoma was resistant to classical photo-dynamic protocols. Melanoma resistance is thought to be dependent on melanosome trapping, presence of melanin, altered antioxidant defence, defects in the apoptotic pathways, immune evasion, and stimulation of angiogenesis. The review describes in detail: (a) the major signalling molecular pathways deregulated in melanoma cells, for example, RAS/RAF/MEK/ERK pathway, as targets for novel photo-dynamic therapy; (b) the clinical data on the efficacy of photodynamic therapy in metastasising melanoma; (c) the new designs of antimelanoma photo-sensitisers; (d) photo-sensitisers as new inhibitors of angiogenesis. There is a critical overview of the clinical results obtained in combinatory protocols consisting of photo-dynamic therapy plus conventional immune therapy. The authors conclude that up-to-now, photo-dynamic therapy of malignant melanoma at the advanced stages may be used as an adjuvant tool to improve the survival rate or as a palliative treatment. The researchers from the Netherlands-German group [7] contributed a review on the molecular mechanisms and therapeutic opportunities of visible blue light (UV-free part of the spectrum) therapy. In the review, the current knowledge of the molecular photo-acceptors (blue light sensors), signalling transmission, and future therapeutic applications of visible blue light in the treatment of chronic skin inflammatory conditions was collected and discussed. As the very first molecular event, blue light is absorbed by many bio-active molecules located in the skin, such as flavins, porphyrins, nitrosated proteins, etc. These activated photo-sensors transmit signals to induce ROS and RNS generation and the activation of G protein-coupled signalling pathway. Cellular mechanisms connected with these molecular pathways remain unknown so far. However, there is clear evidence that visible blue light has the potential to suppress chronic inflammatory conditions in the skin.

Parasitic infections represent a major challenge for global health and economy. Despite their high prevalence and clinical impact, treatment options are still incomplete. There are a limited number of effective medicines, many have serious side effects, and increasing drug resistance is also a real threat. Even if these diseases have been largely neglected for drug development because they affect poor people in poor regions of the world, in recent years, the search for antiparasitic drugs received a new impulse. Thus, this issue will focus on recent efforts to reinvigorate the drug development targeting major parasitic diseases. One interesting strategy recently used to fight these diseases is based on the inhibition of enzymes involved in metabolic pathways essential for parasite survival and/or infectivity and absent or sufficiently different at a structural level from those present in the host. In this context, the first paper of the issue [1] explores the possibility to target in trypanosomal diseases, the enzymes of the pentose phosphate pathway, which includes an oxidative branch, important in the maintenance of cell redox homeostasis, and a non-oxidative branch in which ribose 5- phosphate and erythrose 4-phosphate, precursors of nucleic acids and aromatic amino acids, are produced. In particular, the authors provide a comprehensive overview of the available chemotherapeutic options against trypanosomal diseases and discuss the potential of genetically validated enzymes from the pentose phosphate pathway of trypanosomatids to be explored as potential drug targets. The second paper [2] analyzes Carbonic Anhydrase (CA) metallo-enzymes as a new possible drug targets for parasitic diseases. CAs catalyze the reversible hydration of carbon dioxide to bicarbonate and protons. Compelling data in the literature strongly indicate that interference with CA activity in various parasites leads to an impairment of parasite growth and virulence, which in turn leads to a significant anti-infective effect. All the existing studies on CAs from protozoa responsible for the major human parasitic diseases, namely Malaria, Leishmaniasis and Chagas disease, are analyzed, and the emerging role of these enzymes as targets for the development of new anti-parasitic drugs is critically discussed. In the past, the lack of high-resolution structural information on parasitic proteins has been a big obstacle in structure based drug discovery programmes. However, the recent renaissance of electron microscopy (EM), which has seen a remarkable rise in the number of available structures, represents an important impulse in drug discovery for parasitic diseases. Thus, the third paper of the issue [3] addresses the challenges associated with the structural determination of parasitic proteins by EM and provides some examples of parasitic protein structures determined with this technique. Finally, limitations which need to be overcome before using EM as a mainstream technique in parasitic drug development are also discussed.

The resistance of common pathogens to first-choice drugs increased by up to 100% during the last decades. Moreover, the resistance of some strains to second- or third-choice drugs can be found. The development of crossresistant or multidrug-resistant strains is a serious global problem. The selection of resistant pathogens is especially caused by the irrational and unavailing application of anti-invasive agents in human, veterinary medicine, and in agriculture. Resistance may complicate the treatment regardless of how mild the disease was at the early stage. Increasing resistance refers to the urgency to design new effective anti-invasive drugs and develop strategies focused on overcoming drug resistance. The rational design of new entities from new chemical classes influencing new targets is considered as the most valuable approach. In addition, various combinations of existing drugs with other molecules, e.g., efflux pump inhibitors, are investigated. New effective anti-invasive agents or compounds mitigating resistance can be also designed based on the structures of natural products. Natural products are structurally diversified, and many of them have been reported to exhibit anti-invasive activity or have synergy effect with conventionally used drugs. The application of nanotechnology represents also an excellent alternative for improvement of existing anti-invasive drugs due to the fact that nanomaterials exert cytotoxicity through various mechanisms. The paper entitled “Design and discovery of new antibacterial agents: Advances, perspectives, challenges” is focused on recently reported new antibacterial chemotherapeutics approved for clinical practice, antibacterial chemotherapeutics in clinical trials and antibacterial agents under development. In addition, particular attention is given to agents decreasing bacterial resistance [1]. Tsang et al. [2] describe furano-naphthoquinones as potential candidates for new-generation lead compounds acting directly on cancer stem cells to overcome the chemotherapy resistance. Apart from natural plant sources, there are a number of synthetic furano-naphthoquinone derivatives that are effective in reducing the stemness of cancer cells and thus are anti-invasive. In the review, the anti-invasion mechanisms of the furano-naphthoquinones together with their natural origins, synthetic derivatives as well as their synthetic routes are discussed. The anti-invasive and anti-metastatic activities of some potential plant compounds with their sources of isolation and mechanistic pathways in different types of cancer cells and xenograft models are reviewed by Sarwar et al. [3]. Qing et al. [4] summarize isoquinoline-based alkaloids in relation to their cytotoxic and multidrug-resistant reversing activities against various cancer cells. Additionally, the structure-activity relationships of different types of isoquinoline alkaloids are discussed. Besides a severe upper respiratory illness, influenza viruses are able to cause pandemics with a significant loss of life in all age groups. Small molecule therapeutics are a critical part of antiviral strategies to control influenza virus. In the review written by Han et al. [5], the status of existing anti-influenza drugs, mechanisms of antiviral resistance, and novel antiviral drugs currently under development to target influenza viruses are discussed. Comprehensive data from in vitro and in vivo studies to elucidate the functional roles of natural compounds used in traditional Chinese medicine in reversing multidrug resistance during cancer therapy are summarized by Lou et al. [6]. Zitko and Doležal [7] devote their review to synthetic antitubercular drugs, discussing the recent research on the mechanism of action and molecular targets of first-line and second-line drugs and suggesting how this knowledge can be used to design simple derivatives with improved properties. In addition, they annotate old and known drugs from various pharmacodynamical groups as candidates for repurposing to become effective in combatting tuberculosis. Review of Luo et al. [8] examines the chemistry and antioxidant, anti-inflammatory, and cytotoxic activities of selected Gaultheria species that are used worldwide, especially as food and medicine in China, and their benefit for human health. In spite of the fact that Ebola virus is one of the most dangerous viruses, currently there are no FDA-approved therapeutics or vaccines to treat Ebola virus infections. Schafer et al. [9] summarize major findings on the Ebola virus replication cycle and explore therapeutic approaches to the treatment of this devastating disease. The major focus of this review is on small molecule inhibitors. Inflammatory bowel disease is an uncontrolled chronic inflammatory intestinal disorder, which requires medications for long-term therapy. The great potential of plant-sourced phenols for the treatment or prevention of inflammatory bowel disease and their mechanisms of actions are discussed by Xiao et al. [10]. Compounds with a benzothiazole scaffold show promising activities against Gram-positive and Gram-negative bacteria as well as Mycobacterium tuberculosis. Gjorgjieva et al. [11] assess the importance of the benzothiazole scaffold in the discovery of new antibacterial compounds, the potential of benzothiazole-based compounds against resistant bacterial strains, optimization of their antibacterial activity, and the future perspectives of benzothiazolebased antibacterials.

Phytochemicals for Human Diseases: From Kitchen to Clinic

Cancer, an abnormal division of cells, is one of leading causes of death worldwide. A large number of anti-cancer drugs, which have been approved commercially, are derived from plants. To meet the ever increasing demand for anti-cancer compounds, plants have been harvested ruthlessly from their natural habitat. Due to this, many plants have become extinct or are at the risk of becoming endangered. Production of anti-cancer drugs through chemical synthesis is not economically viable due to highly complex structures of compounds involved in biosynthesis pathways and high cost. Biotechnology by employing plant tissue and cell culture offers a valuable tool to produce compounds of interest for treating the cancer diseases. It is also possible to advantageously alter the biosynthesis pathway of plants to obtain the desired products in required amount as well as within shortest possible time. This method has successfully been employed for the large scale production of anti-cancer compounds e.g. vincristine, vinblastine, taxol and podophyllotoxin. We invite investigators to contribute original research as well as review articles that encourage the ongoing efforts on enhanced production of anti-cancer compounds from different plant species using various biotechnological means. A particular interest will be given to papers exploring or discussing the different strategies to produce anti-cancer compounds from plants in an environment friendly way.

Circulating progenitors cells (CPCs), including Endothelial progenitor cells (EPCs), are a heterogeneous population of cells in different states of maturation, originated from bone marrow (BM). Since their first identification in 1997 [1], great efforts are being made to explore the regenerative/reparative potential of EPCs, including their abilities of self-renewal, of starting reparative mechanisms, and of neoangiogenesis. The role of CPCs in vivo is still debated; however, the evidence of the involvement of CPCs in the pathophysiology of disease and their complications, as well as in aging and other physiological conditions, are growing [2-6]. There are many reports on associations between cell number, their activity and oxidoreductive status, and disease; growing evidence are being provided on the effects of different pharmacological treatments on CPCs, and also preliminary observations of the potential role of CPCs as therapy [7-11]. The mechanisms underlying cell mobilization into peripheral blood, circulation, and activities, and their relationships with medical therapy are far to be completely clarified [12]. The challenge of this special issue will be to bring together the leading experts in the field to add new insight into pathophysiological, drug-related and pharmacological aspects of CPCs, also to address the issue of why different subjects with similar risk profile could have a different outcome. This Thematic issue aims to provide a comprehensive literature review of the current knowledge, by different points of view. It is accepted that excessive inflammatory burden or imbalanced immune responses may underlie number or function alterations of EPC [13]. Rodriguez- Carrìo and coll. summarize the current knowledge regarding the cutting-edge area of the modulation of EPC levels and function by inflammatory cytokines in systemic diseases, suggesting these mediators as potential biomarkers for risk stratification in non-CV disease [14, 15]. Rigato and Fadini describe the prognostic role of CPCs/EPCs measurement on the development of cardiovascular disease and microangiopathy confirming that low CPCs/EPCs levels predict the onset or worsening of microalbuminuria and retinopathy in diabetic patients [16]. Autologous cell therapy represents a novel treatment option for vascular regeneration in different disease conditions. Bianconi, Pirro et al. report on therapeutic potential of different proangiogenic cells (PCs), including endothelial progenitor cells (EPCs), in the treatment of peripheral artery disease; however, despite a number of potential clinical applications of PCs are emerging, there is evidence that CV risk factors and chronic inflammation may induce PC dysfunction, rising possible limitations for the efficacy of autologous PC therapy [17]. In their article, Ruggeri and coworkers address another aspect: elevated CECs and EPCs levels have been reported in the peripheral blood of patients with different types of cancers and some other diseases, suggesting that these cells may be involved in disease progression and the neoplastic angiogenesis process. Moreover, abnormal CECs and EPCs are probably involved in endothelial damage that is a marker of several complications following allogeneic hematopoietic stem cell transplantation [18]. Last, another current challenge about EPCs as therapy regards the chronic kidney disease (CKD). Coppolino and coll. describe the potential role of EPC therapy in repairing injured renal tissue; strategies using EPCs to induce a reparative process with functional restoring of a diseased kidney or to delay CKD by direct stem cells infusion or stimulating endogenous release of EPCs are also described [19].

Nanomedicine is a growing field of medical research focused on the development of therapeutics and diagnostics tools in the nanoscale range (from 1 nm to 100 nm). Early diagnosis and effective cancer therapy are required to treat cancer, which causes approximately 14.1 million new cases and 8.2 million deaths in a year worldwide. “Nanomedicine uses nano-sized tools for the diagnosis, prevention and treatment of disease and to gain increased understanding of the complex underlying pathophysiology of disease. The ultimate goal is improved quality of life” as defined by the European Science Foundation. Nowadays, this new branch of science is a point of interest for many investigators, due to the important scientific and technological advances over the last few decades, in particular for cancer treatment. Cancer nanomedicine has been applied in different fields, such as drug delivery, nanoformulation and nanoanalytical contrast reagents. In the last two decades, nanotechnology has been rapidly developed allowing the incorporation of multiple therapeutics, sensing and targeting agents into nanoparticles in order to set up new nanodevices capable of detecting, preventing and treating complex diseases, such as cancer. The aim of this special issue is to highlight the state-of-art of diagnostic and therapeutic tools that nanomedicine is offering to fight cancer. In the first review, Mascheroni and Schrefler [1] take into consideration computational models that help in understanding biological mechanisms to provide quantitative analyses. To date, the use of mathematical modeling in cancer is a long-standing practice, covering several aspects such as tumor biology, cancer progression and tumor treatments. The authors report computational models based on in silico approaches, which address several aspects of tumor treatment through the use of nanoparticles. The authors also highlight four main topics related to nanoparticle formulations, namely the delivery to the tumor tissue, their uptake by tumor cells, drug release from the nanocarriers and their therapeutic use. In silico approaches constitute a valuable tool to aid clinical studies, guiding the rational design of new nanoparticle formulations and identifying the optimal strategies for existing treatments. Molinaro et al. [2] examine the role of inflammation in different steps of tumor development and the strategies based on the use of both conventional and biomimetic nanoparticles, which exploit the inflammatory pathways to selectively target the tumor-associated microenvironment for therapeutic and diagnostic purposes. In the review of Palazzolo et al. [3] the authors describe the main drug nanoformulations based on different types of organic nanoparticles (e.g. polymeric nanoparticles, liposomes, micelles and exosomes), including the advantages presented by the encapsulated drugs compared to their free form and how nanodrugs have improved the clinical care. Bayda et al. [4] illustrate the development of nanotechnology for diagnostic and therapeutic purposes of different types of inorganic nanoparticles, which are currently undergoing clinical development, and of those already approved by the FDA, which are being used in the market. In addition, the authors investigate the preclinical work and clinical trials to highlight the path of these NPs from the lab to the clinic. The review by Bedin et al. [5] aims at surveying the nanotechnological devices and approaches applied to the detection of circulating cancer biomarkers and to show how the integration of biotechnology, nanotechnology and microfluidic can produce quantitative, sensitive and high-throughput assays useful for new point-of-care testing (POCT) development. Specifically, the authors give an overview of nanomaterial-based approaches for the detection of nucleic acids and proteins for the diagnosis, prognosis or monitoring of cancer. Furthermore, the authors envision that the current molecular diagnostics frontiers will be pushed forward by nanobiosensors evolution in the next decade, thus allowing the introduction of new POCT in the personalized medicine. Several nanoscale carriers have been developed for diagnostic purposes or were studied by imaging techniques to design a prospective drug delivery process. Molecular imaging modalities include magnetic resonance imaging (MRI) and spectroscopy methods (fMRI), optical imaging techniques, ultrasonography and the nuclear medicinal modalities such as single photon emission computed tomography (SPECT) and positron emission tomography (PET). The review by Polyak and Ross [6] takes a short historical overview to radiocolloids, the great ancestors of (radiolabeled) nanoparticles, and then describes the general features of current types of PET and SPECT imaging associated with nanoparticle-based products and key radiolabeling methods. Finally, insights on potential prospective challenges related to radiotheranostic approaches and imaging guided therapies are described. Finally, Meneghello et al. [7] define how biosensors of different technological nature are gaining an increasing share of attention for therapeutic drug monitoring as a valid, effective alternative to conventional laboratory tests, since they can provide a revolutionary technology and tools with superior performances. Although there are still challenges that have to be addressed before such devices will enter the clinical practice, several analytical platforms have emerged in recent years, which show promising results. Primarily, the techniques employing nanobiosensors are mainly based on electrochemical, optical, and mass detection systems. In the very next future, the portability, rapid analyses, user friendly and low fabrication costs will make biosensors advantageous in view of a point of care testing.

After the development of technology, pharmaceutical analysis in medicinal chemistry has become important for the drug development, fabrication stage, formulation, stability and quality.. The development of sensitive, selective and fully validated, new analyzing methods for pharmaceutical dosage forms is important and continuous. From this point of view, I invite you to meet “Current Medicinal Chemistry” current issue under the thematic issue called as “Advances in Medicinal Chemistry from Analytical Perspectives”. The aim of the proposed special issue is to focus on the novel developments in medicinal chemistry from analytical point of view including novel developments on drug analysis, medicinal chemistry, drug targets and disease mechanism, dissolution test profiles, all analytical techniques for medicinal chemistry such as solid phase extraction, LC analysis, spectroscopic, chemometric, electrochemical techniques etc. This special issue is contributed to the field since the recent developments in medicinal chemistry researches are important and continuous. In this thematic issue you may find new innovations in medicinal chemistry, recent researches on drug targets and disease mechanism, dissolution test profiles, new analytical methods for medicinal products, novel developments on drug assay, assay methods and validation processes in drug analysis. In this thematic issue, there exist 13 review papers by several important scientists who contributed their ideas. In the latest years, a large number of adsorbent carriers of natural and synthetic origin have increasingly attracted attention due to their biocompatibility, acceptable ecological and toxicological characteristics, high capability for simple modification of physical chemical characteristics, high stability and a relatively low price. Subsequently, in this issue, the first review, by Razic, addresses the “Analytical approaches to the characterization of solid drugs delivery systems with porous adsorbent carriers”. Korecká et al., shared their ideas about “Immunosensors in Early Cancer Diagnostics: From Individual to Multiple Biomarker Assays”. In this review, recent developments in the area of electrochemical immunosensors applicable for the detection of cancer biomarkers that occur in a wide concentration range including extremely low levels, which are typical for the early stage of the disease, are discussed. Furthermore, “Tyrosinase electrochemical biosensors monitoring medicinally significant substances” topic is well discussed by the authors Milan Sýs and Karel Vytřas. In this review overview of applications of electrochemical tyrosinase biosensors in the analysis of medicinally significant substances, otherwise also known as biomarkers are shared. In the review entitled “In-vitro Drug Dissolution Studies in Medicinal Compounds”, the topic is well discussed by Bozal-Palabiyik, et al. This review paper aims to analyze in-vitro drug dissolution testing in solid dosage forms since 2010 in order to present a comprehensive outlook of recent trends. Another interesting study entitled as “Advanced methods for analysis of testosterone suggested by Livia Alexandra Gugoasa and Raluca- Ioana Stefan-van Staden. This review is dedicated to surveying recent determination methods of testosterone from different biological samples such as: serum, saliva, plasma, urine or fingernail samples. Besides, Jean-Michel Kauffmann et al., contributed to this thematic issue with a fascinating review paper entitled “Electrochemical Detectors in Liquid Chromatography: Recent Trends in Pharmaceutical and Biomedical Analysis”. The authors review the selected data in the literature devoted to pharmacologically active compounds in their dosage forms, herbal drugs in natural products, drug residues in feed and/or in biological samples. Ana-Maria Chiorcea-Paquim, Teodor Adrian Enache, and Ana Maria Oliveira-Brett, contributed a review paper entitled “Electrochemistry of Alzheimer disease amyloid beta peptides”. The recent advances on the Aβ peptides electrochemical characterization are reported in this review. In another contribution, “The role of oxidative stress modulators in breast cancer” is discussed by Gurer-Orhan et al. The authors focuses more on melatonin which we have been working on during the last decade. Since a large spectrum of electrochemical MIP-sensors has been described in the literature for the whole arsenal of drugs, e.g. the most frequently used analgesics, antibiotics and anticancer drugs, “Yarman et al., stated the recent studies on “Electrochemical MIP-Sensors for Drugs”. Meanwhile the studies of the interactions of DNA with small molecular drugs, especially anti-tumor agents, antibiotics and drugs of abuse are currently being performed to explore their mechanism of action and develop new drugs with lower side effects and high curative properties, Campuzano et al., contributed their interesting review paper “Electrochemical Nucleic Acid-Based Biosensing of Drugs of Abuse and Pharmaceuticals”. In the review by Hosu et al. “Electrochemical Immunosensors for Disease Detection and Diagnosis” topic was discussed. The authors report the research progresses of electrochemical immunosensors applied in clinical analysis that have been published in the last years. Smarzewska et al., also contributed the review paper entitled “Recent Applications of Silver Amalgam Electrodes for Analysis of Pharmaceuticals and Vitamins”. The features and applications of silver amalgam electrodes in electroanalysis of pharmaceuticals and vitamins are summarized in this review. The state-of-art in the preparation and construction of solid silver amalgam electrodes for prolonged and userfriendly use is presented. And finally, Gumustas et al., shared a short summary of the basic principles of chiral separations on an analytical and preparative scale, with the review paper entitled “Analytical and preparative scale separation of enantiomers of chiral drugs by chromatography and related methods”. In addition, some selected applications for analytical techniques, such as gas chromatography, supercritical fluid chromatography, high performance liquid chromatography, capillary electrophoresis and capillary electrochromatography for the separation of enantiomers of chiral pharmaceuticals published in last two years are also discussed. We tried to combine all different kinds of analyzing methods to maintenance the richness of analytical chemistry. Therefore, this thematic issue entitled “Advances in Medicinal Chemistry from Analytical Perspectives” will be very useful for the readers who want to have broad knowledge. I believe that you, as the valuable readers of Current Medicinal Chemistry journal, will find out new information, topic of interest and new ideas in this thematic issue and I hope that this thematic issue will encourage researchers to achieve the analysis of pharmaceutical active compounds using different kinds of methods. I would like to thank to all of the authors for their excellent contributions, and Prof. Dr. Atta-ur-Rahman , the Editor-in-Chief of “Current Medicinal Chemistry”, his kind invitation to act as a guest editor for this thematic issue.

Inflammatory response is originated by tissue injury and triggers a cascade of biochemical reactions that prime the nervous system for pain perception. Protracted inflammation supports adaptive changes that can cause altered pain signal processes. Indeed, different chronic (i.e. neuropathic) or inflammatory injuries to nervous system trigger structural and functional changes in the peripheral or central sensory circuits, resulting in behavioral dysfunctions, such as hyperalgesia and allodynia, and comorbidities. Current treatments for chronic pain are quite unsatisfying. Hence, there is a great, unmet need for research aimed at discovering novel biological targets together with the development of new pharmacological approaches for optimizing the side-effects of the classical drugs. In this mini special issue, different signaling pathways in the peripheral and central nervous systems implicated in inflammation and chronic pain and possible therapeutic approaches have been described. - The review by Magni et al. [1] focuses on the pathophysiology and therapeutic potential of purinergic signaling in pain, by reporting the available literature pre-clinical data together with the results of clinical trials. The authors accurately illustrate the complex organization of purinergic system by providing the vast variety of different (neuronal and non-neuronal) targets for resolution of chronic pain and inflammation. They also highlight the role of purines in non-conventional therapeutic approaches. - Posa and collaborators [2] show the analgesic properties of the neurohormone melatonin in several preclinical studies and patients. They systematically describe the melatonin receptor functions in the neurobiology of pain. Given the weakness of pharmacokinetic profile of melatonin per sè, they suggest the importance of developing new pharmaceutical formulations or synthetic drugs acting on melatonin receptors, giving particular emphasis to the effects mediated by MT2 receptors. Indeed, they discuss the analgesic properties of MT2 receptor partial agonists in different chronic and acute/inflammatory pain conditions. Negri et al. [3] summarize the evidence for the involvement of a new class of chemokine, the prokineticins and their receptors, in chronic pain. They appropriately describe distribution of ligands and their receptors in the periphery and at central nervous system level, by giving detailed information on their role in nociceptive, as well as, chronic pain modulation. Indeed, they indicate that a number of preclinical studies proved the effects of endogenous ligands or novel non-peptide drugs in controlling inflammation and inflammatory/ neuropathic pain. They discuss the possible molecular mechanisms responsible for prokineticins effects, by highlighting the neuron-glia and neuron-immune cells interaction in prokineticins signaling. Bedini et al. [4] remark advantages and drawbacks in the pharmacological manipulation of opioid system, by highlighting the poor effectiveness of opiates in neuropathic pain condition. In this context, they describe innovative opioid peptides (analogues of endomorphin 1 and dermorphin), showing similar analgesic properties, but reduced side effects, as compared to classic opiates (i.e. morphine), as possible lead compounds for the development of new drugs. Roohbakhsh et al. [5] describe the orexinergic system as a potential candidate for finding alternative analgesics with good efficacy and low side effects. Indeed, they clearly describe the cellular and molecular mechanisms responsible for orexins effects in pain control at both spinal and supraspinal levels. Moreover, they give information about recent preclinical findings on the manipulation of orexin signaling in pain modulation. Russo and collaborators [6] discuss the possible involvement of gut-brain axis in the regulation of inflammation and pain, that nowadays represents a hot topic research area. They report recent studies showing that the deregulation of intestinal microbioma, commonly associated with gut inflammatory disorders, is responsible for the development of several CNS pathologies. In this contest, they highlight the role of endogenous lipids, as NAEs (AEA, PEA and OEA) and the most well studied short fatty acid (butyrate) in the inflammation process, pain perception and in the CNS dysfunctions, by mainly focusing on endocannabinoids system involvement.

Since its introduction in the current clinical practice, Positron Emission Tomography (PET) provided a sensitive tool for the evaluation of several biochemical processes and for the imaging of pathological substances in-vivo. Several radiolabelled compounds for PET use were developed for the evaluation of central nervous system in the last decade. These compounds allow the evaluation of tumour metabolism, the pathological accumulation of several substances responsible for various neurodegenerative diseases and inflammation. In nuclear medicine, the creation of a radiotracer that is able to satisfy these purposes is challenging. In particular, a radiotracer for clinical use is characterized by a rapid pharmacodynamics with a significant affinity for the target thus resulting in a good signal to noise ratio. As for radiolabelled compounds designed for the evaluation of metabolic processes, a good target to background is desirable especially in brain tumours. The radiolabelled compound must ensure the detection of relapse by detecting a pathological metabolic process that is different from those of the surrounding normal brain tissue. Lastly, all these compounds should cross the blood brain barrier rapidly and, finally, levels of radiation exposure for patients should be limited. In this issue, the authors will address the pharmacological aspects and the in vivo applications of the radiotracers used for PET imaging of brain in various diseases, thus providing an in depth review of the properties and applications of these novel radiolabelled compounds. We are pleased to introduce the present Special Thematic Issue “Brain Imaging with Positron Emission Tomography: novel radiopharmaceuticals” that reviews different aspects concerning the usefulness of Positron Emission Tomography in the field of neurological sciences and cutting-edge frontiers of neuroscience. The aim of the present volume is to give an up-to-dated state of the art of those clinical and research boundaries within which this kind of methodology achieved interesting advances. In the field of clinical neuro-oncology, On hand interesting works by Treglia et al. highlighted the implementation of 18F-FET PET in differentiating brain tumours from non-neoplastic lesions as well as low-grade from highgrade gliomas, on the other hand the revised work of Quartuccio and Asselin evaluated the availability of PET radiotracers availability in measuring the high-grade gliomas related adverse hypoxia. These themes appear of relevance, considering the fundamental consequences related to treatment planning in terms of clinical efficacy, patients’ quality of life and targeting treatments. However, the present volume - overcoming these aspects also by an in depth study of PET imaging diagnostic procedures showing the involvement of Central Nervous System in systemic autoimmune diseases (Ursini et al.), focused on recent important advantages related to PET procedures in neurodegenerative disorders. In particular, Bauckneht et al. and Cistaro et al. respectively deepened the feasibility of PET procedures in evaluating Lewy bodies and Amyloid-related neurodegenerative disorders, thus representing new frontiers in diagnosis, treatment and prognosis of such health and social burden. In conclusion, this Special Issue is really trustworthy to be read considering that PET imaging may be actually considered as the present and the future in clinical research.

Cancer has become one of the fatal human diseases around the world. Every year there are millions of deaths because of cancer in the world. The golden rule for cancer is early detection/diagnosis and early treatment. If cancer can be detected or diagnosed early, particularly before its metastasis, it can prolong the lifetime and improve the quality of life. Early detection and diagnosis of cancer is still a huge challenge. The various types of functional materials, especially, a lot of functional nanomaterials can provide some opportunities for early detection and diagnosis of cancer. Based on the functional materials, it can enhance the contrast properties between the tumor area and the normal tissue, for example, contrast agents in magnetic resonance imaging (MRI) and fluorescent imaging, etc. Moreover, the diverse contrast agents are with some additional therapeutic functions, which extend the function of the contrast agents and offer the visualization capability during the therapy/treatment of cancer. In this thematic issue, we will provide new progress in some following interesting fields for cancer imaging, therapy and theranostics based on different types of functional materials: The first work was reported by Dr. Gang Wei and Prof. Zhiqiang Su and their collaborators. They reviewed “Recent advance in the cancer bioimaging with graphene quantum dots”. They present the synthesis and chemical modification of GQDs firstly, and then introduce their unique physical, chemical, and biological properties like the absorption, PL, and cytotoxicity of GQDs. Finally and most importantly, the recent applications of GQDs in cancer bioimaging are demonstrated in detail, in which they focused on the biofunctionalization of GQDs for specific cancer cell imaging and real-time molecular imaging in live cells. This work would provide valuable information on the synthesis and modification of GQDs with adjustable properties for various biomedical applications in the future. The second work was presented by Prof. Mingqian Tan and his co-workers. The title of his paper is “Multicolorful carbon dots for tumor theranostics”. This review introduces a brief history and basic photoluminescence properties of carbon dots, and then discusses synthesis strategies and applications of carbon dots in biological imaging, targeted drug delivery, photodynamic therapy, photothermal therapy as well as gene delivery for cancer theranostics. Future directions of carbon dots in cancer theranostics are also highlighted. The third work came from Prof. Renjun Pei and his group. In their review work entitled “Biocompatible Gdbased Polymeric Magnetic Resonance Imaging Agents for Tumor-Targeted Imaging”, Prof. Pei and co-workers focused on the recent progress of biocompatible Gd-based polymeric MRI agents for tumor-targeted imaging, including structures, properties and applications. Meanwhile, his review also highlights the emerging MRI mCAs with smart response and multi-function: tumor microenvironment-stimulated MRI, multi-mode imaging and MRI-based theranostics. The fourth work reported by Prof. Bingbo Zhang and his group is entitled

The pharmacological therapy of children diseases is changing very quickly in the last decades. In this respect, chronic autoimmune and inflammatory diseases are becoming a major issue for the pediatricians. In spite of the availability of new biological drugs, which has allowed to assist to a great improvement in the prognosis and quality of life of many patients, new therapeutic tools are urgently needed. This special issue will discuss innovative approaches for rational drug design and therapy personalization in the pediatric population, potentially leading to precision medicine improving efficacy and reducing adverse effects of therapy, that are particularly significant in chronic diseases. The repositioning of old drugs to treat rare pediatric immune diseases will be discussed, such as lapaquistat for Mevalonate Kinase Disease and antimalarials in interferonopathies. Also severe oncological pediatric diseases could benefit from precision drugs such as kinase inhibitors targeting specific genetic alterations; this approach will be considered. Innovative disease models are needed to lead to improved drug design and innovative therapies, and the promising application of pluripotent induced stem cells will be presented. Finally, pharmacokinetics and pharmacogenomics based on innovative molecular markers such as transcriptomics, and their application to therapy personalization and drug discovery for pediatric inflammatory bowel disease, will be also discussed.

The potassium channels family represents the most widely distributed among ion channels families. Thanks to this feature and to their ability of inducing hyperpolarization, potassium channels are involved in many physiologic processes such as tune of musculature, release of neurotransmitters, regulation of diuresis or glycemia and so on, and these properties make potassium channels suitable targets for many pharmacological approaches to different pathologies in several districts. The purpose of this issue is to offer a broad overview on the most important pharmacological tools, novel and well-known molecules, having potassium channels as therapeutic target in order to highlight promising drugs with exciting perspectives for the treatment of cardiovascular, neurological and metabolic diseases. Keywords: KATP potassium channels, BKCa potassium channels, ROMK potassium channels, Kv potassium channels, Mito-K+ potassium channels. Sub topics:  Pharmacological and chemical aspects of drugs or new molecules targeting: ATP-sensitive (KATP) potassium channels.  Large conductance Ca2+-activated (BKCa) potassium channels.  Renal Outer Medullary (ROMK) potassium channels.  Voltage-gated (Kv) potassium channels and mitochondrial potassium (Mito-K+) channels.

Pancreatic cancer (PC) is a highly aggressive cancer usually diagnosed at an advanced stage, and has the worst prognosis of any cancer malignancy, with a 5-year survival rate of <8%. Lack of early detection and effective interventions are major factors contributing to the poor prognosis and dismal survival rates of pancreatic cancer patients. Moreover, recent incidence and mortality rates suggest an increasing trend of pancreatic cancer patients. Recent developments demonstrate that pre-invasive precursors, such as PanINs, IPMNs, and cystadenomas, progress slowly over many years to develop into invasive pancreatic cancers. Thus, there is a time frame of several years for effective chemoprevention and intervention strategies. Despite many advances in the molecular genetics of human pancreatic cancers, targeted therapies have not yet translated to improved overall survival. Hence, developing chemoprevention strategies that delay/inhibit/prevent the progression of each subtype of pre-invasive lesions to pancreatic cancer is of utmost importance. Several genetically engineered mouse models (GEMs) of pancreatic cancer that recapitulate human disease progression have recently been developed. The KrasG12D and KrasG12V dependent GEM models which mimic the therapeutic response of human pancreatic cancer offer novel treatment development opportunities. The biggest challenges are to elucidate the regulatory mechanisms controlling the progression of pancreatic precursor lesions to pancreatic cancer, and to develop strategies that provide effective chemoprevention. Equally challenging is identifying high-risk cohorts with specific pancreatic precursor lesions using early detection approaches. In this special issue, different aspects of this problem are presented focusing on current challenges and opportunities aimed to address chemoprevention aspects for pancreatic cancer. Possible pancreatic cancer chemoprevention targets, mouse models and early detection, immuno-prevention of pancreatic cancer, drug candidates for pancreatic cancer chemoprevention, regulatory mechanisms controlling pancreatic cancer progression, combination chemoprevention strategies and different approaches are also considered and discussed. The first review by Mohammed et al addresses the current challenges and potential opportunities for chemoprevention of pancreatic cancer. In this review, they focused on the current situation of PC, the potential challenges, the progress in existing strategies and available opportunities, as well as suggested key areas for research within the increasingly important area of pancreatic cancer chemoprevention. They suggested that novel technologies such as next generation sequencing should be employed to identify high-risk individuals with early genetic changes in the initial lesions or even explored in blood samples to detect the presence of circulating tumor derived or related mRNA, miRNA, DNA, tumor educated platelet-mRNA as biomarkers of early detection. GEM serve as excellent models to study the early stages of PC and for early detection by molecular imaging technologies. GEM models should be extensively utilized for developing existing chemoprevention agents or screening and optimizing new agents and identifying ideal chemoprevention targets. High-risk individuals presenting IPMN/PanINs and those with hereditary PC history should be considered for chemopreventive clinical trials. Combination chemoprevention, multi-targeted agents and multi-agent low dose chemoprevention strategies might be considered to reduce toxicity and enhance efficacy. The contribution by Dhar et al. takes into consideration the mechanisms and drug targets for pancreatic cancer chemoprevention. They discussed the available drugs and their limitations, and move on to discuss the wide realm of chemopreventive efficacy that natural agents offer. While the intake of fruits and vegetables in routine diets has been linked to reduced risk of developing pancreatic cancer, a wide variety of natural agents is being evaluated as adjuvant therapies in combination with frontline chemotherapeutics in pancreatic cancer clinical trials. Completed and ongoing human studies with these natural agents have shown surprisingly successful rates for regulating pancreatic carcinogenesis. Furthermore, the underlying mechanisms of action and available information from extensive literature analysis to highlighting the novelty of these agents for their antitumor effects against pancreatic cancer, are elucidated. In the review by Hildegard, the regulatory role of G protein-coupled receptors in pancreatic cancer development and progression are described. Smoking, psychological stress, diabetes, pancreatitis and alcohol abuse are known risk factors for pancreatic cancer that cause hyperactive cyclic adenosine monophosphate (cAMP) signaling via cancer stimulating Gαs-coupled β-adrenergic and prostaglandin (PG) E2 receptors and/or by suppressing signaling via inhibitory Gαi-coupled GABAB-receptors. The activation of Gαi-coupled GABAB-receptor signaling by treatment with GABA, inhibition of β-adrenergic signaling by a beta-blocker and/or suppression of Gαs-coupled PGE2 receptor signaling by a cyclooxygenase (COX) inhibitor prevented the development and progression of PC in hamsters induced by carcinogenic nitrosamines and in transgenic mice. The re-purposing of cardiovascular therapeutics (beta-blockers, COX-2 inhibitors, Ca2+-channel blockers) that inhibit β-adrenergic and PGE2 signaling for PC intervention is problematic due to undesirable side effects under chronic treatment protocols. To avoid such side effects while effectively reducing excessive cAMP signaling, nutritional GABA supplementation or positive allosteric modulators (PAMs) of Gαi-coupled receptors (GABAB-Rs) currently in clinical trials for the treatment of addiction should be explored for pancreatic cancer intervention. Rao et al. review discusses the novel approaches of immunoprevention for PC. Vaccine-based treatments for several cancers are currently under intense investigation. Current vaccine testing for PC is usually performed in advanced stages of cancer, during which the patient's impaired immune responses improved to suppress the growing tumor. However, so far such strategies have had limited success and have not become mainstream therapies. Thus, early diagnosis is imperative for immunoprevention using vaccines. Developing vaccines towards non-self-antigens has been successful, whereas vaccines against self-antigens, without any adverse effects on normal cells, have been challenging. The development of new technologies to identify mutated antigens, post-translational alterations in proteins, and tumor-specific antigens is currently underway, with a view toward vaccine development. Combining vaccines with immune stimulators or non-toxic anticancer agents are promising for cancer prevention. Successful vaccination strategies for PC at different stages of tumor development and future challenges for immunoprevention are discussed in this review. Along this line, the paper by Subramaniam and co-authors reviewed approaches to target cancer stem cells for chemoprevention of pancreatic cancer. Emerging evidence supports the presence of a unique population of cells called cancer stem cells (CSCs) as potential cancer inducing cells and efforts are underway to develop therapeutic strategies targeting these cells. Studies have been shown that CSCs are highly resistant to standard therapy and responsible for drug resistance, cancer recurrence and metastasis. To overcome this problem, novel preventive agents that target these CSCs are needed. Natural compounds or phytochemicals have the ability to target these CSCs and their signaling pathways. Therefore, they summarized current understanding of pancreatic CSCs and their signaling pathways, and the phytochemicals that target these cells including curcumin, resveratrol, tea polyphenol EGCG (epigallocatechin-3-gallate), crocetinic acid, sulforaphane, genistein, indole-3-carbinol, vitamin E δ-tocotrienol, Plumbagin, quercetin, triptolide, Licofelene and Quinomycin. These natural/synthetic compounds or phytochemicals, which inhibit cancer stem cells, may prove to be promising agents for the prevention and treatment of pancreatic cancers. Together with the data summarized by Yu et al., the paper provides a systematic literature review and metaanalysis on the effect of metformin and statin use on survival in PC patients. Current epidemiological studies report conflicting results for the effect of statin or metformin on overall PC survival. They systematically searched for studies about the association between statin or metformin use and overall pancreatic cancer survival in electronic databases. A meta-analysis based on hazard ratios (HRs) and 95% confidence intervals (CIs) was performed using random effect models. Heterogeneity between the studies was examined using I2 statistics, and sensitivity analyses were conducted to assess the robustness of the findings. Of 116 statin-related articles identified, 6 retrospective cohort studies representing 12,057 patients were included. There was significant heterogeneity between the studies. Statin use was associated with improved survival among pancreatic cancer patients. Of 311 metformin-related articles, 8 retrospective cohort studies and 2 randomized clinical trials, representing 3,042 patients were identified. Metformin use was associated with better overall survival among pancreatic cancer patients (meta-HR = 0.79; 95% CI: 0.70, 0.92, P < 0.001), and significant heterogeneity was observed between the studies. These findings suggest that the improved survival time of pancreatic cancer patients is associated with statin or metformin use. Due to the multiple sources of heterogeneity of the original studies, these findings should be considered cautiously, and confirmed with larger prospective individual-level studies. The last review by Torres and co-authors focused on the complexity of omega-3 fatty acids modulation of signaling pathways related to PC. Recently, the role of nutrition in health and disease has attracted much attention. Several dietary ingredients are involved in metabolic, physiological, and cellular signaling affecting tumor growth and progression. Although lipids, and more specifically polyunsaturated fatty acids, have been traditionally studied due to their health effects in cardiovascular disease, it is now clear that they can affect an extensive array of cellular processes that influence a wide range of diseases such as type II diabetes, inflammatory disorders and cancer. These biological activities may be grouped as regulation of membrane structure and function, intracellular signaling pathways, transcription factor activity, gene expression, and production of bioactive lipid mediators. In this review, specifically, the current state of knowledge about the potential mechanism(s) of action and signaling pathways modulated by polyunsaturated fatty acids in pancreatic cancer are discussed.

Cardio-metabolic complications are multifactorial diseases with different facets, many of which are poorly understood, although genetics, epigenetics, humoral, habitual and environmental factors may be involved. Moreover, with the dramatic escalation of obesity, diabetes and hypertension in all segments of the population including adults, adolescence and children, the incidence of cardio-metabolic disease and related complications will further increase. Therefore, this special issue puts together a collection of review articles by leading experts in the area to give a critical appraisal of the current state of knowledge and recent accomplishments as well as challenges and future directions. The role of pigment epithelium-derived factor (PEDF) in cardiometabolic disease is a among the emerging themes of scientific interest, with the role of pigment epithelium-derived factor (PEDF) in cardiometabolic disease. PEDF is a glycoprotein that has been shown to possess anti-thrombotic and anti-fibrotic properties besides its effects against oxidative stress and inflammatory. Accordingly, in an article featuring in this special issue, Yamagishi & Matsui underscored the role of PEDF in cardiometabolic diseases and related complications, with particular focus on diseases such as diabetic retinopathy, renal dysfunction, hepatic insufficiency and disorders affecting the male and female reproductive systems. The authors discussed the potential clinical relevance of modulating PEDF for the prevention and management of these cardiometabolic disorders. In another related article, Shinlapawittayatorn et al. gave profound insights on the effects of obese insulin-resistance, a common risk factor for ischemic heart disease on ischemia-reperfusion injury of the heart. Amongst the pertinent points raised by the authors is whether improving insulin sensitivity by pharmacological interventions could ameliorate reperfusion induced myocardial injury. Dysfunctional myocardium is a common complication of diabetes. To expatiate on this problem further, Tarquini et al. wrote an article about diabetic cardiomyopathy, a pathophysiological condition in which the myocardial interstitium undergoes alterations resulting in abnormal contractile function. The authors reported that in the early stages of the disease, diastolic dysfunction is the only abnormality, but systolic dysfunction supervenes at later stages with impaired left ventricular ejection fraction. Furthermore, the authors underscored a putative correlation between diabetes and cardiomyopathy, especially in diabetic patients with co-morbid with microvascular complications, and suggested that this correlation parallels the duration and severity of hyperglycemia. Besides the heart, the kidney is an important organ for the regulation of extracellular volume and thus blood pressure. Renal dysfunction is associated with hypertension, proteinuria and kidney failure. Accordingly, novel insights on structures of the kidney, such as the glomerular filtration barrier, are important. In a related article that appears in this special issue, Ndisang wrote about the putative cross-talk amongst the major components of the glomerular filtration barrier including podocytes, endothelial cells and the basement membrane, and how the dynamic interplay and interaction between these constituents may be fundamental for effective filtration. Furthermore, the author highlighted some of the challenging issues about the interaction between: (i) glomerular endothelial cells and podocytes; (ii) glomerular endothelial cells and glomerular basement membrane; (iii) podocytes and glomerular basement membrane; (iv) the simultaneous interaction among the three components, and suggested that the elucidation of these multifaceted interactions will pave the way for greater understanding of the pathophysiology of kidney dysfunction and the formulation of novel therapies for kidney disease. In another related article, Krämer and Weidemann gave their insights on Fabry disease, pathophysiological condition associated with X-linked lysosomal storage caused by deficient activity of α-galactosidase A and intracellular accumulation of globotriaosylceramide in different physiological entities such as the vascular endothelium, nervous system, eyes, skin, heart and kidneys. A wide variety of drugs are used for the treatment and management of cardiometabolic diseases. For example, proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors are used to lower low-density lipoprotein cholesterol in patients with dyslipidemia, hypercholesterolemia or atherosclerosis. In an article, in this special issue, Schremla and Gouni-Berthold gave an in-depth insight on the use of monoclonal antibodies against PCSK9 to attenuate hypercholesterolemia, and reported that antibody-derived PCSK9 drugs such as alirocumab (Praluent®) and evolocumab (Repatha®) can reduce low-density lipoprotein cholesterol by 70%. Generally, drugs are routinely reviewed for their efficacy and safetyly. In this light, Eleftheriadou and co-workers insights on the cardiovascular safety of older and newer anti-diabetic medications. The authors reported that metformin, a first line drug for the treatment of type 2 diabetes, is also endowed with cardio- protective effects and should be considered the primary choice, while second line agents such as empagliflozin, liraglutide and semaglutide are reasonable options for patients with cardiovascular disease, whereas the class of sulfonylureas with the exception of gliclazide should be administered to diabetic patients co-morbid with other cardiometabolic diseases. In addition, the authors reported that Saxagliptin, alogliptin, sitagliptin and lixisenatide have been evaluated in cardiovascular safety trials and were shown to have neutral effects on cardiovascular outcomes, whereas pioglitazone has some cardiovascular benefits. However, Saxagliptin and alogliptin should be avoided in patients with heart failure. Consistently, in another article featuring in this special issue, Schmitz and Gouni- Berthold gave clinical evidence on the efficacy and safety of volanesorsen for the treatment of hypertriglyceridemia. Besides, drugs and other pharmaceutical formulations, dietary fibres and polyphenols are cyto-protective. Accordingly, the protective effects of dietary fibres and the antioxidant and anti- inflammatory properties of polyphenols such as curcumin, quercetin, genistein, caffeic acid phenethyl ester were examined by Pittala and co-workers. They discussed the effects of various naturally occurring polyphenols in the management of metabolic dysfunctions Collectively, the contributions of the authors of this special issue have underscored to the complexity of cardiometabolic diseases, highlighting the different facets, the accomplishments to date, the challenges that obscure the horizon and the prospects for the future, to which we can all look toward with some degree of optimism.

Nanotechnology is growing in prevalence in consumer products and medicine. Most nanomedicine are carriers that are capable of homing in, taken up easily by the target cells and eventually delivering their drug payload to the target sites and some have smart designs that release the payload according to designed stimuli. However, while there are many advantages offered through bionanotechnology, there are potential unintended consequences especially on the non-targeted cells remain a problem of toxicity of these very small particles. This special issue describes a series of the latest most exciting research in the fields of nano medicine covering cancer and anti-microbial applications and balanced with some nanotoxiological studies covering nano biology and more realistic nano materials testing platforms.

Growing evidence supports a primary role of inflammatory reactions, both acute and chronic, in the development and progression of the main human diseases. The redoxmediated pathophysiological mechanisms are crucial in the evolution of various diseases, in which inflammation is involved. In this theme issue we would like to consider the role of inflammation and redox balance in the genesis and worsening of diseases, such as atherosclerosis, metabolic syndrome, and ischemia/reperfusion injury. Reviews by scientists, with basic and clinical background, will contribute to give a comprehensive picture of the inflammation- and redox-mediated pathogenesis of the diseases and an up-to-date scenario of therapeutic approaches.

This mini theme issue will consider some classes of bioactive natural products and their role in the medicinal chemistry. Many studies have pointed out new bioactivities for well-known natural products, showing that not only” new chemical entities” obtained by natural sources but also known and “old” natural products can be a valuable source of new therapeutic agents. In the issue triterpene, sesquiterpene, coumarins, stilbenoids, and also phenolics from Cannabis will be considered focusing on both natural and synthetic (or semisynthetic) compounds, their bioactivity and their potential importance in the field of medicinal chemistry.

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