Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 19, Issue 4, 2019

Background: The α-glucosidase (EC 3.2.1.20), a calcium-containing intestinal enzyme which is positioned in the cells which cover the intestinal microvilli brush border. The carbohydrates require metabolism by α-glucosidase before being absorbed into the small intestine, and as a result, this enzyme represents a significant drug target for the effective management of diabetes. There are few α- glucosidase inhibitors in the clinical practice that is challenged by several limitations. Thus, new effective and safe therapeutic agents in this class are required. In this regard, plant secondary metabolites are a very promising source to be investigated. Herein in this review, we have focused on the preclinical studies on various glycosides with in vitro α-glucosidase inhibitory activity. Methods: The literature available on various websites such as GoogleScholar, PubMed, Scopus. All the peer-reviewed articles were included without considering the impact factor. Results: The surveyed literature revealed marked inhibitory profile of various glycosides derived from plants, and some of them were extremely potent relatively to the standard, acarbose in preclinical trials and exhibited multiple targeted effects. Conclusion: Keeping in view the results, these glycosides are strong candidates for further, more detailed studies to ascertain their clinical potential and for effective contribution in effective management of diabetes, where multiple targets are required to address.

Background: 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 to store in body tissues, such as the liver, muscles, and body fat. Objective: The efficiency of treatments for multifactor diseases has not been proved. It is accepted that to manage multifactor diseases, simultaneous modulation of multiple targets is required leading to the development of new strategies for discovery and development of drugs against metabolic disorders. Methods: In silico studies are increasingly being applied by researchers due to reductions in time and costs for new prototype synthesis; obtaining substances that present better therapeutic profiles. Discussion: In the present work, in addition to discussing multi-target drug discovery and the contributions of in silico studies to rational bioactive planning against metabolic disorders such as diabetes and obesity, we review various in silico study contributions to the fight against human metabolic pathologies. Conclusion: In this review, we have presented various studies involved in the treatment of metabolic disorders; attempting to obtain hybrid molecules with pharmacological activity against various targets and expanding biological activity by using different mechanisms of action to treat a single pathology.

Background: Drugs with post-prandial action constitute one of the main courses of treatments for diabetes. Objective: In the present investigation, we have explored the α-amylase inhibitory potential of ethanolic extract of Cocos nucifera endocarp. Methods: DNS based assay was done to assess the α-amylase inhibition potential of ethanolic extract. Phytochemical screening and GC-MS analysis were done in order to assess the chemical profiling of extract. In silico docking studies were done using VLife MDS 4.6 software and the probable molecules, predicted after GC-MS analysis, were docked with the co-crystallized (acarbose) tracked active site and rest all cavities of porcine pancreatic α-amylase (1OSE). ADMET analysis was done using StarDrop 6.4, Derek Nexus and P450 Modules from Optibrium Ltd. and LHASA Ltd. Results: DNS based α-amylase assay indicated that the IC50 value of extract lies in the range of 63- 126 μg/ml and at higher doses, i.e. above 250 μg/ml, it has better α-amylase inhibition than the standard drug, acarbose. Phytochemical screening indicated that ethanolic extract is rich in alkaloids, tannins, flavonoids, saponins, triterpenes, glycosides, carbohydrates, terpenoids, quinones and lactones. Further, GC-MS analysis (where Similarity Index was > 90) predicted that the probable phytoconstituents present in the ethanolic extract are myristic acid, syringaldehyde, eugenol, vanillin, 2,4-di-tert-butylphenol, lauric acid, palmitic acid methyl ester and γ-sitosterol. γ-Sitosterol showed the strong affinity towards the active site which was tracked by a co-crystallized ligand along with cavity 1 and 2 while significant interactions were observed in case of co-crystallized tracked active site as well as cavity 4 of 1OSE. Ethanolic extract of C. nucifera has no hemolytic effect. Conclusion: Its ability to effectively inhibit α-amylase may be attributed to the presence of the above probable molecules, which will be explored further.

Introduction: Pseudomonas aeruginosa is one of the major pathogens associated with the acute tissue damage in patients having Diabetic Foot Ulcer (DFU). The treatment of such infections can be an uphill battle due to the serious resistance to all the mainstay antibiotics, owing to overzealous production of Extended-Spectrum Beta-Lactamases (ESBLs). Pakistan also has a high prevalence of diabetes and complications related to it, however genetic disposition of the pathogens remains underinvestigated. Aim: The main objective of the study was to determine the frequency of ESBLs in Multi-drug resistant P. aeruginosa from diabetic foot patients. Methods: The duration of the present study was one year and 100 patients having DFU were enrolled. All the pus samples were subjected to the bacterial culture, gram staining, catalase test, oxidase test and antimicrobial susceptibility pattern to various antibiotics for the confirmation of P. aeruginosa. Of 23 positive isolates of P. aeruginosa, 10 were ESBLs positive as detected by double disk diffusion test. The positive ESBL strain shows an increase of ≥5mm in the zone of inhibition of the combination discs in comparison to the alone ceftazidime disc. Results: The ESBLs positive strains were also tested for TEM-1, SHV-1, PER-1, and VEB-1, where: (07/10) strains carried SHV-1, (05/10) strains were positive for TEM-1, while none of the isolates were PCR-positive for PER-1 and VEB-1. Conclusion: The findings of the current study show a difference in the pattern of ESBL genes compared to that of other such endeavors. The present study also warrants the PCR-based detection of the type of ESBL as a potential factor to consider in deciding the therapeutic strategy at any point during the treatment.

Background: Obesity is well known multifactorial disorder towards the public health concern in front of the world. Increasing rates of obesity are characterized by liver diseases, chronic diseases, diabetes mellitus, hypertension and stroke, improper function of the heart, reproductive and gastrointestinal diseases, and gallstones. An essential enzyme pancreatic lipase recognized for the digestion and absorption of lipids can be a promising drug target towards the future development of antiobesity therapeutics in the cure of obesity disorders. Objective: The purpose of present study is to identify an effective potential therapeutic agent for the inhibition of pancreatic lipase. Methods: A trio of in-silico procedure of HTVS, SP and XP in Glide module, Schrodinger with default parameters, was applied on Specs databases to identify the best potential compound based on receptor grid. Finally, based on binding interaction, docking score and glide energy, selected compounds were taken forward to the platform of IFD, ADME, MMGBSA, DFT, and MDS for analyzing the ligands behavior into the protein binding site. Results: Using in silico protocol of structure-based virtual screening on pancreatic lipase top two compounds AN-465/43369242 & AN-465/43384139 from Specs database were reported. The result suggested that both the compounds are competitive inhibitors with higher docking score and greatest binding affinity than the reported inhibitor. Conclusion: We anticipate that results could be future therapeutic agents and may present an idea toward the experimental studies against the inhibition of pancreatic lipase.

Objective: In healthy individuals, leptin is produced from adipose tissue and is secreted into the circulation to communicate energy balance status to the brain and control fat metabolism. Corticotropin- Releasing Hormone (CRH) is synthesized in the hypothalamus and regulates stress responses. Among the many adipokines and hormones that control fat metabolism, leptin and CRH both curb appetite and inhibit food intake. Despite numerous reports on leptin and CRH properties and function, little has been actually shown about their association in the adipose tissue environment. Methods: In this article, we summarized the salient information on leptin and CRH in relation to metabolism. We also investigated the direct effect of recombinant CRH on leptin secretion by primary cultures of human adipocytes isolated from subcutaneous abdominal adipose tissue of 7 healthy children and adolescents, and measured CRH and leptin levels in plasma collected from peripheral blood of 24 healthy children and adolescents to assess whether a correlation exists between CRH and leptin levels in the periphery. Results and Conclusion: The available data indicate that CRH exerts a role in the regulation of leptin in human adipocytes. We show that CRH downregulates leptin production by mature adipocytes and that a strong negative correlation exists between CRH and leptin levels in the periphery, and suggest the possible mechanisms of CRH control of leptin. Delineation of CRH control of leptin production by adipocytes may explain unknown pathogenic mechanisms linking stress and metabolism.

Background: Sulphonylureas (SU) are known to cause weight gain. Some investigators have reported increased insulin sensitivity with some sulphonylurea agents. Objective: To review available evidence of SU agents having PPARγ agonist activity. Methods: We searched online databases of PubMed®, Embase®, Google Scholar® and Web of Science® as per current guidance, published in English, between 1st January 1970 and 31st December 2017. The search found 6 articles. Results: None of the 1st generation SU drugs have any demonstrable PPARγ agonist activity. Most of the 2nd generation SU agents had a positive correlation between their concentration and PPARγ agonist activity except Gliclazide. The demonstrated PPARγ agonist activity was maximum in experiments with Glimepiride and Gliquidone and was seen in these in-vitro experiments at concentrations which were pharmacologically achievable in-vivo. The PPARγ agonist activity may be responsible for some sideeffect of the SU agents as weight gain. On the contrary, the clinical efficacy of the thiazolidinediones could theoretically be reduced when used in combination with the SUs with significant PPARγ agonist activity. Conclusion: The PPARγ agonist activity demonstrated in vitro experiments may have clinical connotations.

Objective: The aim of this narrative review was to analyze the role played by brain areas, neurohormones and neurotransmitters in the regulation of emotional and sexual behavior in the male. Methods: We analyzed the currently available literature dealing with brain structures, neurotransmitters and neurohormones involved in the regulation of emotional and sexual behavior in the male. Results: A common brain pathway is involved in these two aspects. The Hippocampus seems to control the signals coming from the external environment, while the amygdala and the hypothalamus control the response to social stimuli. Stimulation of amygdala in the animal models increases sexual performance, while it triggers violent emotional responses. Stimulation of the hypothalamus causes reactions of violent anger and increases sexual activity. Catecholaminergic stimulation of the amygdala and hypothalamus increases emotional and sexual behavior, while serotonin plays an inhibitory role. Cholinergic inhibition leads to a suppression of copulatory activity, while the animal becomes hyperemotive. Opioids, such as β-endorphin and met-enkephalin, reduce copulatory activity and induce impotence. Gonadal steroid hormones, such as estrogen in female and testosterone in male, which play a major role in the control of sexual behavior and gender difference have been highlighted in this review. Vasopressin, oxytocin and their receptors are expressed in high density in the “social behavior neural network” and play a role as signal system controlling social behavior. Finally, the neuropeptide kisspeptin and its receptors, located in the limbic structures, mediate olfactory control of the gonadotropic axis. Conclusion: Further studies are needed to evaluate possible implications in the treatment of psychosexual and reproductive disorders.

Background: Metabolic syndrome is a cluster of medical conditions that synergistically increase the risk of heart diseases and diabetes. The current treatment strategy for metabolic syndrome focuses on treating its individual components. A highly effective agent for metabolic syndrome has yet to be developed. To develop a target for metabolic syndrome, the mechanism encompassing different organs - nervous system, pancreas, skeletal muscle, liver and adipose tissue - needs to be understood. Many animal models have been developed to understand the pathophysiology of metabolic syndrome. Promising molecular targets have emerged while characterizing these animals. Modulating these targets is expected to treat some components of metabolic syndrome. Objective: To discuss the emerging molecular targets in an animal model of metabolic syndrome. Methods: A literature search was performed for the retrieval of relevant articles. Conclusion: Multiple genes/pathways that play important role in the development of Metabolic Syndrome are discussed.

Background: Sepsis is a clinical condition due to an infectious event which leads to an early hyper-inflammatory phase followed by a status of tolerance or immune paralysis. Hyper-inflammation derives from a massive activation of immune (neutrophils, monocytes/macrophages, dendritic cells and lymphocytes) and non-immune cells (platelets and endothelial cells) in response to Gram-negative and Gram-positive bacteria and fungi. Discussion: A storm of pro-inflammatory cytokines and reactive oxygen species accounts for the systemic inflammatory response syndrome. In this phase, bacterial clearance may be associated with a severe organ failure development. Tolerance or compensatory anti-inflammatory response syndrome (CARS) depends on the production of anti-inflammatory mediators, such as interleukin-10, secreted by T regulatory cells. However, once triggered, CARS, if prolonged, may also be detrimental to the host, thus reducing bacterial clearance. Conclusion: In this review, the description of pathogenic mechanisms of sepsis is propaedeutic to the illustration of novel therapeutic attempts for the prevention or attenuation of experimental sepsis as well as of clinical trials. In this direction, inhibitors of NF-ΚB pathway, cell therapy and use of dietary products in sepsis will be described in detail.

Aims: Arganimide A (4,4-dihydroxy-3,3-imino-di-benzoic acid) is a compound belonging to a family of aminophenolics found in fruit of Argania spinosa. The purpose of this study was to investigate the glucose and lipid lowering activity of Arganimide A (ARG A). Methods: The effect of a single dose and daily oral administration of Arganimide A (ARG A) on blood glucose levels and plasma lipid profile was tested in normal and streptozotocin (STZ) diabetic rats at a dose of 2 mg/kg body weight. Results: Single oral administration of ARG A reduced blood glucose levels from 26.50±0.61 mmol/L to 14.27±0.73 mmol/L (p<0.0001) six hours after administration in STZ diabetic rats. Furthermore, blood glucose levels were decreased from 5.35±0.30 mmol/L to 3.57±0.17 mmol/L (p<0.0001) and from 26.50±0.61 mmol/L to 3.67±0.29 mmol/L (p<0.0001) in normal and STZ diabetic rats, respectively, after seven days of treatment. Moreover, no significant changes in body weight in normal and STZ rats were shown. According to the lipid profile, the plasma triglycerides levels were decreased significantly in diabetic rats after seven days of ARG treatment (p<0.05). Moreover, seven days of ARG A treatment decreased significantly the plasma cholesterol concentrations (p<0.001). Conclusion: ARG A possesses glucose and lipid-lowering activity in diabetic rats and this natural compound may be beneficial in the treatment of diabetes.

Background: Hyperprolactinemia can lead to weight gain, insulin resistance, abnormal glucose homeostasis and dyslipidemia. Reversibility of these changes after normalization of prolactin with dopamine agonists is still controversial and needs more clarification. Objective: We aimed to: 1) evaluate and compare metabolic and anthropometric profile in female with newly diagnosed prolactin-secreting adenoma versus female idiopathic hyperprolactinemic patients; 2) compare the effects of one year cabergoline therapy on the metabolic profile and anthropometric parameters (by using visceral adiposity index as index for evaluation of adipose tissue dysfunction) in females with prolactinoma to female idiopathic hyperprolactinemic patients. Patients and Methods: We enrolled 40 female patients with newly diagnosed prolactinoma and 40 female patients with idiopathic hyperprolactinemia, who were matched according to: age; weight; BMI; waist; and prolactin levels. We enrolled the participants in this study at the time of diagnosis before therapy and they were followed up for 12 months. Results: Cabergoline therapy had significant favorable effects on metabolic and anthropometric parameters, visceral adiposity index and in all patients (apart from HDLc in prolactinoma patients). Cabergoline therapy was significantly more effective in patient with idiopathic hyperprolactinemia than prolactinoma patients with regard to BMI, waist circumference, HDLc and visceral adiposity index despite normalization of prolactin levels in both groups. Conclusion: 12 months of Cabergoline treatment improved most of the anthropometric and metabolic parameters, and visceral adiposity index as a marker for adipose tissue dysfunction in both idiopathic hyperprolactinemia and prolactinoma patients. However, Cabergoline treatment was more effective in idiopathic hyperprolactinemic than prolactinoma patients.

Background: In Egypt, it seems that adolescent girls are a candidate for Vitamin D Deficiency (VDD), mostly due to inadequate sun exposure as a result of the culture and social dress codes and dietary factors. Currently, there is growing evidence that VDD is associated with Iron Deficiency Anemia (IDA). Aim: To investigate the frequency of VDD in adolescent females with IDA in comparison to healthy control and demonstrate whether VD level was correlated with serum iron indices. Subjects and Methods: Forty adolescent females with known cases of IDA (group 1) and 30 healthy females matched for age as a control (group 2) were selected. We compared the differences between the two groups to determine the degree of VD level; where VDD was defined as 25-hydroxyvitamin D [25(OH)D] ≤20 ng/mL, vitamin D insufficiency (VDI) as 25(OH) D of 20-30 ng/mL, and vitamin D sufficiency (VDS) as 25(OH)D >30 ng/mL. Body mass index (BMI), complete blood count (CBC), serum iron, total iron binding capacity (TIBC), serum ferritin, serum creatinine, ionized calcium and 25(OH)D were measured for all participants. Results: We found that subnormal vitamin D (VDD and VDI) was more frequent in the IDA group (75%) than control (40%), (p = 0.025); where 19 adolescent female patients (47.5%) were VDD, 11 (27.5%) were VDI and 10 (25%) were VDS, while in the control group, VDD was present in 4 (20%), VDI in 4 (20%) and VDS in 12 (60%) respectively. There was not any significant correlation between serum VD and serum iron indices (r =0.168, p < 0.05) and Hb (r = 0.360, p < 0.001). There was no significant difference in serum hemoglobin level between IDA patients with subnormal VD and those with VDS. The mean level of serum 25(OH) D was significantly lower in winter months than summer in both groups; (16.87 vs. 31.57 mg/dL, p < 0.001) and (31.9 vs. 35.04 mg/dL, p < 0.001) respectively. BMI, Iron, TIBC and seasonal variation were not predictors of 25(OH) D levels in adolescent girls with IDA. Conclusion: VDD has a higher frequency in Egyptian adolescent females with IDA than healthy control. However, vitamin D levels were not significantly correlated with iron indices. Our result might direct the attention for measuring vitamin D level in patients with IDA with the possibility of VD supplementation with iron.

Background and Objective: Hepatopancreas is an accessory organ associated with the liver in some fish, even including sea bass (Dicentrharcus labrax L.). Hepatopancreas contains an exocrine portion but until now its function has poorly been investigated. Methods: Here, European farmed sea bass have been treated with a feed enriched in polyphenols extracted from seeds of red grape (Nero di Troia cultivar) at two different doses (100 and 200 mg/kg, respectively) from day 273 to day 323. In fish samples, hepatopancreas area sizes have been measured to evaluate the effects of this dietary regimen on its morphology. Results: Quite interestingly, in treated fish area sizes of hepatopancreas were higher than those detected in untreated fish. Two hundred mg dose of polyphenols was more effective than that of 100 mg/kg polyphenols. Finally, hepatic polyphenol concentration was diminished in fish receiving 100 mg dose polyphenols and normalized with 200 mg dose in comparison to untreated fish. This evidence suggests the utilization of polyphenols for liver function, even including hepatopancreas development. Conclusion: Our data suggest an expansion of hepatopancreas induced by polyphenol administration that is also associated with less mortality in farmed fish.

Background: US National Osteoporosis Foundation has specified age cut-offs for osteoporosis screening in older women and men. Objective: In this study, we investigated whether Turkish seniors undergo their first ever osteoporosis screening early, on time or late. Methods: We determined the age of older women and men at their first-time Bone Mass Densitometry (BMD) testing using the medical records of a geriatric outpatient unit. The timing of the BMD test was considered ‘’late’’ when performed after the age of 65 and 70 in women and men, respectively. An “early” screening was defined as having a BMD measurement before these age cut-offs. Results: We included 481 individuals in the study (mean age: 74.5±6.5 years, women: 62%). On admission, around 18% of the sample could give no definite information and another 35% had never been assessed for osteoporosis. Among those with a past screening, 64.8% reported comorbid osteoporosis and 33% reported no osteoporosis. Mean age of the first-time BMD measurement was 67.4±7.7 years. The first-time BMD measurement was on time in 9.7%, early in 37.4% and late in 52.9% of the subjects. Half of the individuals with a self-reported osteoporosis diagnosis were non-osteoporotic on a new BMD ordered following the geriatric assessment. Multimorbidity (≥3), parental hip fracture, and smoking were the independent predictors of being early screened. Conclusion: We found two-thirds of women and men unscreened for osteoporosis despite being indicated by age. Early and late screening were both prevalent. Self-reported osteoporosis diagnosis was mostly inconsistent with BMD testing in our sample.

Background: Thiopurine S-methyltransferase (TPMT) is a cytoplasmic enzyme that catalyzes thiopurine drugs such as 6-mercaptopurine, 6-thioguanine, and azathioprine. There is a correlation between thiopurine drug metabolism, response, and toxicity and genetic polymorphism of TPMT. The aim of this study is to assess TPMT genetic polymorphisms activity and metabolic products of AZA in patients with IBD. Methods: Blood samples were obtained from 50 IBD unrelated patients from a private laboratory. We used polymerase chain reaction-restriction length polymorphism (PCR-RFLP) and allele-specific PCRbased assays to determine the TPMT gene for the different variants. A high-performance liquid chromatography system (HPLC) was carried out to determine the whole blood 6-TGN concentration. Determination of serum TMPT activity was done by ELISA kit. Results: In IBD patients, 46/50 (92%) subjects were homozygous for the wild-type allele (TPMT*1/*1). Mutant TPMT*1/*2 and TPMT*1/*3C alleles were found in 4/46 (8%) and 3/47 (6%) of IBD patients, respectively. TPMT*1/*3B variant was not detected in any of the IBD patients. TPMT enzyme activity was higher in wild-type than that mutant variants TPMT*1/*2 and TPMT*1/*3C, suggesting that there are statistically significant differences between 6-TG levels and polymorphisms of TMPT enzyme. 6-TG levels significantly increased in IBD patients mutant variants TPMT*1/*2 and TPMT*1/*3C. Conclusions: Our results showed that TPMT polymorphisms are associated with 6-TGN levels in patients using AZA. This study suggests that AZA dosage may be determined according to the high or low prevalence of a TPMT genotype. Moreover, the results present the determination of metabolite for assessing possible safe effective dosage of the drug.