Current Pharmaceutical Design

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.