Endocrine, Metabolic & Immune Disorders - Drug Targets

This issue is focused on the latest developments in management of endocrine and metabolic disorders. By bringing together recent work in this area, we aim to provide an outline of the potential exploitation avenues open to endocrinologists. This issue will serve a medium for the dissemination of information on how to initiate or manage many existing and/or emerging treatments used in endocrine and metabolic conditions. Endocrine disorders involve body's over or under-production of certain hormones, while metabolic disorders affect the body's ability to process certain nutrients and vitamins. Metabolism and endocrinology trigger every aspect of our lives, from the functioning of a single cell through our ability to run a marathon. Therefore, it is not surprising that defects in endocrine or metabolic function underlie many common human diseases, including endocrinology cancer, cardiovascular disease, pediatric endocrinology (disorders of the endocrine glands), diabetes and neurodegenerative disorders. These disorders pose a serious public health challenges for both the developed and developing world as according to recent worldwide estimates, 1.7 billion people are classified as either overweight or obese, and more than 500 million have either pre-diabetes or type 2 diabetes mellitus. Many other endocrine and metabolic conditions are also very prevalent and include postmenopausal states, thyroid disorders, metabolic bone diseases, and type 1 diabetes mellitus (T1DM). This special issue focuses on all areas of endocrinology and metabolism. It lays emphasis on the use of pharmacogenomics and personalised medicine for diabetes management, discusses the use of MicroRNAs as biomarker for breast cancer, improvement: Insights and Perspectives on menopausal remediation and Quality Of Life (QoL). It brings insights into transdermal drug delivery approaches for redressal of osteoporosis and explains the significance, challenges and the ways and means in regulating endocrine disruptors. It also stresses about the role and developments of natural products for therapeutic and prophylaxis of endocrine and metabolic disorders like impact on wound healing and tissue repair properties of chitosan, natural products for obesity, molecular and immunological mechanisms of bioflavonoids e.g. rutin and bibliometrics and visualization analysis of animal model for parkinson's disease. Therapeutic advances in endocrinology and metabolism includes developments in both the existing (i.e. drug, surgery, radiotherapy, and biotherapy) and investigational treatment modalities (e.g. gene therapy, nanotechnology and regenerative medicine). One of the future goals of endocrine and metabolic clinical care is to make chronic diseases curable by having a clear understanding of the new trends in research and technology.

Frailty and cognitive impairment are common debilitating conditions associated with poor quality of life and premature mortality not only during aging but also in younger individuals with chronic disorders. Several immune alterations are found in individuals who developed a state of frailty and cognitive impairment. The knowledge of these alterations may offer the possibility to evaluate new pharmacological and nonpharmacological interventions to improve the health status leading to an improvement in patients' lives and their environment. The special issue wishes to describe recent progress in the discovery, validation, and standardization of molecular biomarkers and clinical interventions aimed to modulate the immune system in individuals with frailty and cognitive impairment. The thematic issue wished to shed new light in this exciting and insightful field of research from a multidisciplinary perspective. This issue of Endocrine, Metabolic & Immune Disorders Drug Targets, ‘‘Immune alterations in frailty syndrome and cognitive impairment” reflects the interplay between different health sciences at the leading edge of this growing research field which intensively suggests new opportunities for improving the care or to prevent adverse outcomes. In the special issue, readership will find relevant researches carried out by several health care professionals and researchers with extensive knowledge in the clinical setting and intended to address new issues of interest of specific importance to research and clinical practise. Gimeno-Mallench et al. [1] reviewed the importance and the characteristic of a balanced diet for older individuals in order to ensure proper immune and metabolic functions. Particularly, the authors focused on increasing protein intake for elderly people as long as there is no kidney damage. This increase could help fight the loss of muscle mass (sarcopenia) associated with age. Additionally, vitamin and mineral intakes are often insufficient in their diets. Therefore, diet for older individuals should be adapted not only to their age but also to the pathologies associated with aging. Through these measures, we can reduce the prevalence of comorbidity and thereby increase the health span. Therefore, both physical and nutritional interventions, including functional foods and nutraceuticals, should be taken into account. Jordá et al. [2] reviewed the role of microglia cells and astrocytes as key inflammatory cells associated with Alzheimer's disease producing several inflammatory mediators, such as cytokines and chemokines. Chemokines and their receptors are low molecular weight able to control the migration and residence of immune cells. In pathological conditions, such as Alzheimer's disease, chemokines contribute to the inflammatory response by recruiting T cells and controlling microglia/macrophages activation. Navarro- Flores and Cauli [3] review several clinical aspects relevant for the quality of life in patients with the diabetic foot, which present several immune and metabolic alterations (leading among others, to an increased susceptibility to infections and degenerative changes in several tissues and organs). Different aspects related to diabetic foot syndrome such as physical alterations, psychological complaints and even disorders, socio-economic difficulties can affect the quality of life of these patients and increased the burden of this pathology. Ageing is characterized by a peripheral subversion of the immune system with a condition of inflamm-ageing. Neuroinflammation and neurodegenerative diseases seem to be a central manifestation of a peripheral perturbation of the immune machinery. Magrone et al. [4] reviewed the role of dietary products and nutraceuticals as a useful intervention to lead to a down-regulation of the oxidative and pro-inflammatory profile in ageing and diseases-related to ageing processes. Special emphasis in their review is focused on polyunsaturated fatty acids, polyphenols, micronutrients and preprobiotics and synbiotics. Buigues et al. [5] published the results of a cardiovascular prevention and rehabilitation programme (CVPRP) are an established model of care designed to improve risk factor management in patients with coronary heart disease (CHD) in Spain. From a European multicentric study (EUROACTION). The EUROACTION nurse-led CVPRP enabled coronary patients to control lipid profile to the European targets for cardiovascular disease prevention and rehabilitation. A large proportion of patients were prescribed statin therapy as cardioprotective medication with favorable changes in medication for coronary patients. The study outlined the importance of these interdisciplinary programmes for cardiovascular prevention in CHD patients. Bodolea et al. [6] whether peripheral blood cell counts, and its subpopulations, red blood cell and platelets, morphology and different ratios (neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and red blood distribution width-toplatelet ratio) are associated with frailty syndrome in patients with cardiac diseases, and through this to improve the prediction of frailty status in patients with cardiovascular diseases. The evaluation of peripheral blood cell composition routinely measured in clinical practice can represent a valuable, but limited indicator, to diagnose frailty syndrome and eventually, the effects of interventions in frail patients with cardiovascular diseases.

Nowadays, heavy metals represent serious danger to human health. In fact, they are massively spread in the environment and, therefore, the skin, the airway and the gastro-enteric systems are the most exposed organs. In the light of the above considerations, this special issue will deal with the heavy metal-induced damage in animals and humans and also potential interventions with nutraceuticals will be discussed. Salimi and associates [1] have provided evidence on the toxic effects of nickel and raised the necessity to find out new drugs for preventing metal-associated damage. Martìnez-Martìnez and associates [2] have elucidated the role of nickel exposure in modulating dopamine release and inhibiting glutammate N-methyl-D-aspartate receptors. Tramontana and associates [3] have reviewed the issue of nickel allergy for its importance in public health with significant personal, social and economic impact. Gergovska and associates [4] have emphasized the role of nickel allergy with special reference to the skin. In fact, the morbidity due to this metal in terms of allergic contact dermatitis outcome is constantly growing worldwide. Filatova and Cherpak [5] have clarified the immunological mechanisms involved in the development of allergic contact dermatitis under nickel exposure, emphasizing the intervention of T helper 1 and T helper 2 cells as well as the reduced functions of T regulatory cells. Drenovska and associates [6] have pointed out the important role which nickel may play in the development of autoimmune disease. Son [7] has elucidated the molecular mechanisms of nickel-induced carcinogenesis with special reference to epigenetic changes, activation of hypoxia signaling pathways and reactive oxygen species generation. Das and associates [8] have clarified the mechanisms of vitamin C protection against nickel-mediated damage in the light of the notion that such a vitamin reduces ferric iron to ferrous iron in the duodenum, thus, competing with nickel intestinal absorption. Magrone and associates [9] have focused on the impact of heavy metals with host cells (e.g., Toll-like receptor-4). In addition, multiple damages provoked by nickel may be attenuated by nutritional intervention and, in particular, by polyphenol administration.

Type 2 diabetes mellitus (T2DM) is a major health burden affecting 415 million adults worldwide. The prevalence is continuously increasing at a rapid pace [1]. It is a complex metabolic disorder where both genetic and environmental factors contribute in the pathogenesis. To expand the understanding of the pathogenic mechanisms and improving the treatment strategies, identification of genetic variations predisposing to T2DM is important. Candidate gene approaches, genome-wide association studies (GWAS) and sequencing techniques have been used in the identification of common, low-frequency and rare variants of T2DM. GWAS have identified more than 100 common variants of T2DM [2-4]. Almost all of these variants regulate insulin secretion, and only a few regulate insulin sensitivity. However, all the genetic loci identified so far account for only about 10% of the overall heritability of T2DM. In addition, how the novel susceptible loci are correlated with the pathophysiology of the disease remains largely unknown. Gene-environment and gene-gene interactions are likely to contribute to the missing heritability of T2DM [5, 6]. Besides genetics, epigenetics is believed to play a role in the pathogenesis and development of T2DM. Dysregulation of the epigenome, especially, epigenetic modification of DNA methylation, histone modification and RNAassociated gene silencing are found to be associated with T2DM. In recent years, progress has been made in revealing T2DMassociated genes undergoing epigenetic alterations. Evidence suggest that environmental factors can easily influence these epigenetic markers and increase the risk of T2DM via affecting gene expressions. Additionally, it is suspected that variable drug response in patients with T2DM is due to different levels of T2DM-associated gene expressions [7, 8]. Thus, exploration in the pharmacogenetic and epigenetic aspects of T2DM is needed towards personalized treatment. In this special issue of Endocrine, Metabolic & Immune Disorders-Drug Targets (EMIDDT), Ahmed et al. [9] represented an update on the role of DNA methylation and protein misfolding in diabetes. Johar et al. [10] provided an insightful review focusing on the molecular basis of the biomolecular changes that occur in respect to glucose homeostasis and underlying links between pancreatic, renal and microvascular diseases in diabetes based on oxidative stress and the unfolded protein response. In an interesting review, Tiwari et al. [11] summarized the emerging significance of computational biology in drug designing and development, pertaining to identification and validation of lead molecules for the treatment of diabetes. Hossan et al. [12] critically updated the epigenetic modifications including DNA methylation, posttranslational histone modifications, ATP-dependent chromatin remodelling and non-coding RNAs related to the pathogenesis of T2DM. In another review, Khatami et al. [13] critically represented the most important candidate genes of T2DM such as CAPN10, TCF7L2, PPAR-γ, IRSs, KCNJ11, WFS1 and HNF homeoboxes in order to predict the efficacy of personalized medication strategies of T2DM. To sum up, we would like to complete this editorial by thanking Dr. Emilio Jirillo, the Editor-in-Chief, as well as Ms. Humaira Shabbir, Senior Manager Publications, EMIDDT, along with all the contributing authors who have enthusiastically responded to our invitations by contributing to this special issue of EMIDDT. In addition, we would like to thank all the reviewers who evaluated the submitted manuscripts for this special issue and provided their evaluation based on novelty and scientific contribution in the fields of genetics and epigenetics of diabetes.

Endocrine-Metabolic Disorders (EMDs) can arise due to hormonal imbalances in the organism that lead to important changes in glycemia, cholesterol and triglyceride levels. Metabolic disorders are a major cause of illness and death worldwide. Metabolism is the process by which the body makes energy from proteins, carbohydrates, and fats; chemically breaking these down in the digestive system towards sugars and acids which constitute the human body's fuel for immediate use, or for storage in body tissues such as the liver, muscles, and body fat. Metabolic disorders in the population are increasing and dramatically affecting human health. The main etiology of metabolic disorders is heredity; an estimated 303,000 newborns die within 4 weeks of birth every year worldwide due to congenital anomalies; and 2.68 million neonatal period deaths occurred in 2015 worldwide [1]; a major public health issue. Metabolic disorders may also develop when certain organs, such as the liver or pancreas, become diseased or do not function normally; obesity, diabetes, and hyperthyroidism are common examples [2] whose signs and symptoms include lethargy, excessive weight gain or loss, jaundice, and seizures among them [3]. Diabetes and obesity are two major diseases resulting from such hormonal imbalances. The search for new targets and effective drugs against these diseases has become the object of study for many researchers [4]. Various areas involved in therapeutic application of multi-target ligands have already been evaluated: including complex disorders, bacterial drug resistance, and drug repositioning. Although in certain cases, such disorders can be approached through combined drug therapy, multitarget ligands present clear advantages; including more predictable pharmacokinetics, better patient compliance, and reduced risk of drug interactions. Then, what are potential applications for the use of multi target ligands in metabolic disorders? Metabolic control analysis (or flux-balance analysis) uses a vast set of experimental data to evaluate all of the metabolic rates in the metabolic network, (the calculations assume that the reaction rate producing a metabolite equals the reaction rate for its consumption), and highlights key points in the metabolism where a metabolic pathology or even a parasite is present and can be targeted. Drs Singla & Dubey [5] explored the α-amylase inhibitory potential of Cocos nucifera endocarp ethanolic extract. The DNS based α-amylase assay indicated that the IC50 value for the extract was approximately 100 μg/ml. At higher doses, i.e. above 250 μg/ml, it presented greater α-amylase inhibition than the standard drug, Acarbose when tested in vitro. The ethanolic extract of C. nucifera presented no hemolytic effects when plate tested on sheep blood agar compared to the standard sodium lauryl sulphate. The extract’s phytochemical screening indicated high contents of alkaloids, tannins, flavonoids, saponins, triterpenes, glycosides, carbohydrates, terpenoids, quinones and lactones. Further, GC-MS analysis (Similarity Index was > 90%) predicted myristic acid, syringaldehyde, eugenol, vanillin, 2,4-di-tert-butylphenol, lauric acid, palmitic acid methyl ester and γ-sitosterol as the phytoconstituents most likely present in the extract. In silico docking studies were performed using VLife MDS 4.6 software and these molecules, (predicted through the GC-MS analysis), were docked co-crystallized with (Acarbose), tracking the active site and all other clefts of porcine pancreatic α-amylase (1OSE). γ-sitosterol presented the strongest affinity towards the active site which was tracked by the co-crystallized ligand along with cavities 1 and 2; significant interactions were observed at the co-crystallized active site, as well as at 1OSE cavity 4. ADMET analysis was done using StarDrop 6.4 and Derek Nexus which provided information about the structural features influencing the ADMET properties. The correlation between the ADME properties of the molecules together with their docking scores provided this design rationale for tailoring of derivatives from these molecules. Khan et al. [6] focused on preclinical studies of various glycosides with in vitro α-glucosidase inhibitory activity. The surveyed literature revealed marked (extremely potent) inhibitory profiles for various glycosides relative to the standard Acarbose. Such glycosides are strong candidates for more detailed studies that might ascertain their clinical potential to manage diabetes, where addressing multiple targets is required. Pseudomonas aeruginosa is one of the major pathogens associated with acute tissue damage in patients with Diabetic Foot Ulcer (DFU). Owing to a variety of intrinsic and acquired molecular mechanisms, antibiotic resistance in P. aeruginosa often bodes poorly for predictable and favorable clinical outcomes. In a study aimed to determine the frequency of Extended- Spectrum β-Lactamases (ESBLs) in multi-drug resistant P. aeruginosa in diabetic foot patients, Hassan et al. [7] showed that P. aeruginosa isolates present significant differences in their ESBL gene patterns. Polymxin B was found to be most effective drug against the tested P. aeruginosa isolates and SHV-1 was most the common ESBL among the strains. Panwar & Singh [8] discuss obesity, a well-known multifactor disorder facing public health authorities around the world. Increasing rates of obesity have been characterized together with liver disease, various chronic diseases, diabetes mellitus, hypertension, stroke, heart malfunction, reproductive and gastrointestinal diseases, and gallstones. Pancreatic lipase, an essential enzyme involved in digestion and absorption of lipids, has become a potential drug target for developing anti-obesity therapeutics to cure obesity. We, the Guest-Editors, would like to express our gratitude to the many authors who contributed to this special issue, reporting investigations in various aspects of Multi-Target Drugs Against Metabolic Disorders.

Neuropsychiatric disorders are common debilitating conditions associated with poor quality of life and premature mortality. Several metabolic alterations are found in these disorders and many neuropsychiatric disorders often co-occur with metabolic disturbances. The knowledge of these alterations may offer the possibility to evaluate new pharmacological and non-pharmacological interventions to modulate those alterations leading to an improvement of patients' life and their environment. The thematic issue wishes to shed new lights in this exciting and insightful field of research.

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