Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 19, Issue 5, 2019

Background: Probiotics can be viewed as biological agents that modify the intestinal microbiota and certain cytokine profiles, which can lead to an improvement in certain gastrointestinal diseases, including diarrhea, inflammatory bowel disease, and liver disease. Discussion: Consumption of probiotics in their various forms, including yogurt, functional foods, and dietary supplements, is frequently encountered worldwide. Often, however, the correct prescription of these agents is dampened due to a lack of knowledge of the scientific evidence and the different presentations and microbial compositions of the currently available probiotic options. Here, we provide an up-to-date review of the evidence of probiotics in the prevention and treatment of various gastrointestinal diseases. Objective: Consumption of probiotics in their various forms, including yogurt, functional foods, and dietary supplements, is frequently encountered worldwide. Often, however, the correct prescription of these agents is dampened due to a lack of knowledge of the scientific evidence and the different presentations and microbial compositions of the currently available probiotic options. Methods/Results: Here, we provide an up-to-date review of the evidence of probiotics in the prevention and treatment of various gastrointestinal diseases. Conclusion: While not efficacious in every disease process studied, probiotics have demonstrated some benefit in several specific gastrointestinal and liver diseases.

Background: In the last decades, both diabetes mellitus and Alzheimer's disease are constantly increasing. Affected individuals, therefore, represent an enormous problem for the society, governments and global organizations. These diseases are usually considered as independent conditions, but increasing evidence shows that there are links between these two disorders. Methods: In this review, we analyzed common features present in Alzheimer’s disease and diabetes mellitus, showing how these two diseases are strictly correlated to each other. Results: Some pathogenetic factors are shared by Type 2 Diabetes and Alzheimer’s Disease: chronic inflammation, oxidative stress, mitochondrial dysfunction, adiponectin deficiency, different expression of plasma cholinesterase activity and vascular damage could represent a possible explanation for the coexistence of these two conditions in many patients. Conclusion: A better understanding of this issue and an appropriate management of diabetes by means of physical activity, low fat diet, and drugs to achieve a good glycemic control, avoiding both hyperglycemia and hypoglycemia, can represent a way to prevent cognitive decline and Alzheimer’s disease.

Background: T cell tolerance both at thymic and peripheral levels is a mechanism of protection finalized to eradicate autoreactive T cell clones and/or to maintain immune homeostasis, especially, postnatally. Central tolerance occurs in the thymic medulla via a mechanism of negative selection which leads to the eradication of autoreactive T cell clones. Mechanisms of Action: Such a tolerogenic event relies on Fas-mediated apoptosis of autoreactive T cell clones operated by thymic dendritic cells (DCs), on the one hand. On the other hand, activated thymic T regulatory (Treg) cells in cooperation with medullary thymic epithelial cells and DCs suppress autoreactive T cell clones. Peripherally, different types of Treg cells exert the so-called peripheral tolerance towards autoreactive T cell clones which may have escaped from negative selection mechanisms. At the same time, peripheral Treg cells activated by tolerogenic DC have antiinflammatory activities, especially in the intestine towards food and microbial antigens. Drug Targeting: Various natural and dietary products, such as vitamins (A, C, D), lactobacilli and polyphenols will be described for their tolerogenic capacity to attenuate the inflammatory pathway, as observed in preclinical and clinical studies.

Background: Bisphenol A (BPA) is worldwide diffused as a monomer of epoxy resins and polycarbonate plastics and has recognized activity as Endocrine Disruptor (ED). It is capable to interfere or compete with endogenous hormones in many physiological activities thus having adverse outcomes on health. Diet highly affects health status and in addition to macronutrients, provides a large number of substances with recognized pro-heath activity, and thus called nutraceuticals. Objective: This mini-review aims at summarizing the possible opposite and simultaneous effects of BPA and nutraceuticals on endocrine functions. The possibility that diet may represent the first instrument to preserve health status against BPA damages has been discussed. Methods: The screening of recent literature in the field has been carried out. Results: The therapeutic and anti-oxidant properties of many nutraceuticals may reverse the adverse health effects of BPA. Conclusion: In vitro and in vivo studies provided evidence that nutraceuticals can preserve the health. Thus, the use of nutraceuticals can be considered a support for clinical treatment. In conclusion, dietary remediation may represent a successful therapeutic approach to maintain and preserve health against BPA damage.

Background and Objective: Cardiovascular disease is the most important cause of morbidity and mortality worldwide, with a significant economic burden, which is expected to increase in the next years. Alongside the management of cardiac manifestations and major risk factors for atherosclerosis, great attention has been paid to the role of comorbidities in initiating and worsening cardiac conditions. Discussion: The cardiovascular impact of a broad spectrum of endocrine disorders has been evaluated, with particular regard to their effects on cardiac function and cardiovascular prognosis in affected patients. Among the different endocrine conditions considered, the association between subclinical hypothyroidism and cardiovascular events is still uncertain. A number of observational studies have linked subclinical hypothyroidism (in particular severe elevation of TSH levels) with incident cardiovascular disease and poor prognosis, however thyroid replacement therapy is still controversial, especially in the elderly, due to the lack of evidence coming from randomized controlled trials. With regards to testosterone deficiency, even though it has been associated with metabolic abnormalities and poor prognosis in patients affected by cardiovascular diseases, the cardiac safety of replacement therapy has still to be completely clarified. Similarly, growth hormone deficiency showed detrimental effects on cardiovascular events and risk factors which seem to be reverted by replacement therapy, even if unequivocal evidence from randomized clinical trials is still lacking Another relevant chapter in cardiovascular disease management is about the cardiovascular outcomes of diabetes medical treatments. In recent years, a growing interest has been developed around the cardiovascular safety of antidiabetic medications which has led to a great number of publications addressing this issue for the different classes of antidiabetic drugs. Interestingly, the recently approved classes, i.e. incretins and SGLT-2 inhibitors, have additionally demonstrated a protective effect against major cardiovascular events, shedding new light on the management of diabetes in patients affected by cardiovascular disease. Conclusion: Important controversies still exist regarding the cardiac implications of the therapies adopted in endocrine diseases. Owing the large prevalence of these conditions, particularly in the cardiovascular population, further research is awaited in order to clarify the potential advantage and the possible cardiac risk related to treatment of the endocrine comorbidities.

Background: Type 2 Diabetes Mellitus (T2DM) is a world-wide metabolic disease with no cure from drugs and treatment. In China, The Traditional Chinese Medicine (TCM) herbal formulations have been used to treat T2DM for centuries. Methods: In this study, we proposed a formula called ShenQi Compound (SQC), which has been used in clinical therapeutics in China for several years. We evaluated the effect of SQC in a spontaneous diabetic rat model (GK rats) by detecting a series of blood indicators and performing histological observations. Meanwhile, the gene microarray and RT-qPCR experiments were used to explore the molecular mechanism of SQC treatment. In addition, western medicine, sitagliptin was employed as a comparison. Results: The results indicated that SQC and sitagliptin could effectively improve the serum lipid (blood Total Cholesterol (TC) and blood Triglycerides (TG)), hormone levels (serum insulin (INS), Glucagon (GC) and Glucagon-Like Peptide-1 (GLP-1)), alleviated the inflammatory response (hypersensitive C-Reactive Protein (hsCRP)), blood glucose fluctuation (Mean Blood Glucose (MBG), standard deviation of blood glucose (SDBG) and Largest Amplitude of plasma Glucose Excursions (LAGE)), pancreatic tissue damage and vascular injury for T2DM. Compared with sitagliptin, SQC achieved a better effect on blood glucose fluctuation (p<0.01). Meanwhile, the gene microarray and RT-qPCR experiments indicated that SQC and sitagliptin may improve the T2DM through affecting the biological functions related to apoptosis and circadian rhythm. Moreover, SQC might be able to influence the mTOR signaling pathway by regulating Pik3r1, Ddit4 expression. Conclusion: All these results indicate that SQC is an effective therapeutic drug on T2DM. Notably, SQC presents an obvious blood glucose fluctuation-preventing ability, which might be derived from the regulation of the mTOR signaling pathway.

Background: Autophagy was recently regarded as a potential mechanism in nonalcoholic fatty liver disease. Silibinin (SIL), a natural flavonoid, has been used to prevent nonalcoholic fatty liver disease, however, the underlying mechanism is unclear. The aim of the present study was to explore the effect of SIL on hepatic steatosis and the possible link with autophagy. Methods: The degree of hepatic steatosis in HepG2 cells was observed by oil-red O staining and triglyceride content. The effect of SIL on autophagy was tested by the Autophagy Detection Kit, and the expression of sterol regulatory element binding protein 1 (srebp-1), Fatty Acid Synthase (Fas), light chain 3, beclin-1, p62, AMP-activated Kinase (AMPK), and mammalian Target Of Rapamycin (mTOR) was examined by western blots. Results: The lipid accumulation of HepG2 cells increased significantly in the high-fructose group compared to the control group. After SIL intervention, lipid accumulation was decreased. Using a fluorescence microscope, SIL was found to induce autophagy. Compared to control, the expressions of srebp-1, Fas, and phosphorylated-mTOR were increased by high-fructose, while the expressions of light chain 3 and beclin-1 decreased and srebp-1, Fas, and p62 were increased by autophagy inhibition. In contrast, opposite results were found in the SIL intervention group. The protein content of phosphorylated- mTOR was decreased, while phosphorylated-AMPK was increased in the SIL group compared to the high-fructose group. Conclusion: SIL can reduce lipid accumulation in HepG2 cells exposed to high-fructose by inducing autophagy. The AMPK/mTOR signaling pathway could be one of the underlying molecular mechanisms.

Background: Monocytes are the main blood innate mononuclear phagocyte and one of the most important effector cells expressing Fcγ receptor, which is critical for the interaction with Fc domain of antibodies. Objective: To evaluate the effect of Rituximab (RTX, a chimeric human anti-CD20 monoclonal antibody) on the functional activities of Monocytes (MOs) at the onset of human Type 1 Diabetes (T1D). Methods: MOs were isolated from peripheral blood mononuclear cells (PBMCs) obtained from volunteer patients with recent-onset T1D and healthy control donors. Results: The levels of the production of Interleukin 1β (IL-1β) and IL-6 were significantly increased in MOs from patients with T1D when compared to MOs from healthy controls (respectively, p < 0.01 and p < 0.05). Similarly, Interferon γ (IFN-γ), and intracellular free Calcium Ion (ifCa2+) levels were increased in T1D MOs than in control MOs, but the difference did not reach a significant level. Conversely, the production levels of IL-4 and catalase activity, as well as of both phagocytosis and killing capacities were decreased in MOs of T1D patients compared to MOs from healthy controls, but the difference was not significant for catalase activity and killing capacity (respectively, p < 0.01, p > 0.05, p < 0.01, and p > 0.05). Additionally, treatment with RTX significantly upregulated phagocytosis (p < 0.05), markedly downregulated the release of IL-1β (p < 0.01), ifCa2+, hydrogen peroxide (H2O2), and slightly downregulated the Nitric Oxide Synthase (NOS) activity, NOS activity-to-arginase activity ratio, the levels of Lactate Dehydrogenase (LDH)-based cytotoxicity, and the production of IL-6 and IFN-γ. Moreover, RTX treatment significantly upregulated the production of IL-4 (p < 0.05), IL-10 (p < 0.01) and the catalase activity (p < 0.05). Conclusion: Our study has shown for the first time that RTX can reverse the abnormal functional activities of MOs as well as their production of proinflammatory cytokines at the onset of T1D. From a therapeutic point of view, RTX may potentially be suggested at the beginning of T1D to immunomodulate innate immunity and inflammatory conditions.

Background: Type 1 diabetes is a T cell-mediated autoimmune disease. Interferon γ plays a critical role in the pathogenesis of type 1 diabetes. Signal transducer and activator of transcription transduces type I interferon cytokines in T cells, leading to Th1 cell differentiation and production of interferon γ. Recent studies suggest that liraglutide reduces the plasma concentration of C-reative protein in patients with type 1 diabetes and protects β cell function in the non-obese diabetic mouse. Objective: The study aimed to explore the effect of glucagon-like peptide-1 analogue on interferon γ production and the underlying signaling pathway in vitro. Methods: Jurkat E6-1 cells were intervened with different concentrations of glucose and liraglutide during different time periods. Protein was extracted from Jurkat E6-1 cells. The target proteins (total and activated Janus kinase 2, signal transducers and activators of transcription 4 and interferon γ) were detected by Western blot. Results: Glucose stimulates interferon γ expression and activates Janus kinase 2/signal transducers and activators of transcription 4 signaling pathway in Jurkat E6-1 cells in a concentration and timedependent manner. Under high glucose condition, liraglutide inhibits interferon γ expression and Janus kinase 2/signal transducers and activators of transcription 4 signaling pathway in Jurkat E6-1 cells in a concentration and time-dependent manner. The Janus kinase responsible for liraglutide-inhibited signal transducers and activators of transcription 4 phosphorylation is Janus kinase 2, which is also required for the interferon γ induction. Finally, we demonstrated that under high glucose condition, liraglutide inhibits interferon γ expression via Janus kinase 2/signal transducers and activators of transcription 4 signaling pathway in Jurkat E6-1 cells. Conclusion: Liraglutide inhibits Jurkat E6-1 cells to produce interferon γ via the Janus kinase/signal transducers and activators of transcription signaling pathway under high glucose condition, which implies its potential in the immunoregulatory effect of type 1 diabetes.

Background and Objective: This study investigated whether rapamycin has a protective effect on the testis of diabetic rats by regulating autophagy, endoplasmic reticulum stress, and oxidative stress. Methods: Thirty male Sprague-Dawley rats were randomly divided into three groups: control, diabetic, and diabetic treated with rapamycin, which received gavage of rapamycin (2mg.kg-1.d-1) after induction of diabetes. Diabetic rats were induced by intraperitoneal injection of streptozotocin (STZ, 65mg.Kg-1). All rats were sacrificed at the termination after 8 weeks of rapamycin treatment. The testicular pathological changes were determined by hematoxylin and eosin staining. The protein or mRNA expression of autophagy-related proteins (Beclin1, microtubule-associated protein light chain 3 (LC3), p62), ER stress marked proteins (CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), caspase-12), oxidative stress-related proteins (p22phox, nuclear factor erythroid2-related factor 2 (Nrf2)) and apoptosis-related proteins (Bax, B cell lymphoma-2 (Bcl-2)) were assayed by western blot or real-time fluorescence quantitative PCR. Results: There were significant pathological changes in the testes of diabetic rats. The expression of Beclin1, LC3, Nrf2, Bcl-2 were significantly decreased and p62, CHOP, caspase12, p22phox, and Bax were notably increased in the testis of diabetic rats (P <0.05). However, rapamycin treatment for 8 weeks significantly reversed the above changes in the testis of diabetic rats (P <0.05). Conclusion: Rapamycin appears to produce a protective effect on the testes of diabetic rats by inducing the expression of autophagy and inhibiting the expression of ER-stress, oxidative stress, and apoptosis.

Background: Homeostasis model assessment for insulin resistance (HOMA-IR) is widely used as a marker of insulin resistance in adults and has also been validated in children and adolescents. Triglyceride (TG) and HDL-C on the other hand is a routine test and inexpensive compared to insulin. Previous studies reported conflicting findings on the usefulness of the triglyceride to HDL-C ratio (TG:HDL-C ratio) as predictor or marker of IR. The aim of this work was to investigate the usefulness of Triglyceride to HDL-C ratio (TG/HDL-C) as an Insulin Resistance (IR) marker in overweight and children with obesity. Methods: This study was a comparative cross sectional study which was conducted on ninety overweight and children with obesity attending National Nutrition Institute “Pediatric obesity clinic. They were classified into 2 groups as follows: group (1) included overweight and children with obesity with insulin resistance, group (2) included overweight and children with obesity with non-insulin resistance. All the subjects were subjected to history, clinical examination and laboratory investigations including total lipid profile, fasting glucose, insulin and TG:HDL-C ratio instead of HOMA ratio. Results: Prevalence of IR among the studied sample was 42 (46.7%). Mean value of TG/ HDL-C ratio was greater among the insulin resistance group than non insulin resistance group (p value= < 0.001)value). TG/HDL ratio ≥1.36 had 85.7% sensitivity, 66.7% specificity. There was statistically significant positive correlation between TG/HDL ratio and HOMA-IR. Conclusion: TG:HDL ratio ≥1.36 is a significant early and sensitive predictor of insulin resistance in children instead of HOMA-IR.

Background and Objective: Lipase inhibitors have gained great interest because they could help in the therapy of many diseases, however, unfortunately, only a few drugs are currently available on the market. Therefore, the aim of this work was to evaluate for the first time the lipase inhibition effect of Thapsia garganica extracts from seeds, leaves and roots. Methods: Polyphenols and flavonoids contents were determined using spectrophotometric method. Inhibitory activity of ethyl acetate extracts from seeds, leaves and roots of T. garganica against Candida rugosa lipase was determined. To uncover the active constituents responsible for this anti-lipase activity, further investigations were performed by employing theoretical docking simulations, using AutoDock Vina program to discuss the nature of interactions and the inhibition mechanism by major bioactive compounds synthesized by this plant. Results: Seeds, leaves and roots extracts of T. garganica showed appreciable contents of polyphenols and flavonoids which is most in seeds extract with 2.90±0.02mg GAE/gdw and 1.53±0.05mg QE/gdw, respectively. Hence, their inhibitory activities against Candida rugosa lipase were determined as IC50 of 1.19mg/ml, 1.96mg/ml and 1.87mg/ml, respectively. Docking simulations have shown that nortribolid and tribolid are best inhibitors for both lipases (Candida rugosa and human pancreatic lipases). Conclusion: Testing the anti-lipase activity of the ethyl acetate extracts of T. garganica revealed a potent lipase inhibition activity, which suggests the use of these molecules as anti-obesity drugs.

Background: Genetic variations of the FTO gene were associated with obesity and type 2 diabetes determinants in the European population, notably raised blood levels of insulin and glucose. Objective: The aim of this study was to test the association of FTOrs17817449 with obesity/BMI and type 2 diabetes risk among obese Egyptian population. Materials and Methods: In this case-control study, (PCR-RFLP assay) was used for genotyping FTOrs17817449polymorphism (SNP) in 120 obese children and 120 controls conducted from attendants of genetic & endocrinology Unit and outpatient clinics, Pediatric Department, Faculty of Medicine, Menoufia University Hospitals. In combination with anthropometric measurements of obesity, predisposition to T2D risk was analyzed (fasting insulin, fasting glucose, insulin resistance). Results: Consanguinity was evident in 32.5% of cases. Positive family history of both obesity and T2D was found to be significant statistically (p<0.05). FTO rs17817449G allele was positively associated with WC (Waist Circumference) (Mean ± SD 84.1 ± 9. 3), raised BMI (Body Mass Index) (32.7 ± 3.5), fasting glucose (114.1 ± 12.8mg/dl), fasting insulin (7.2 ± 1.2μU/ml) and insulin resistance (61.1% of cases) (p<0.001). The odds ratio of obesity was 1.75(95%CI 1.02-3.02) for GT and GG genotype. Fasting glucose and fasting insulin showed statistically significant risk for T2D in the obese group. Conclusion: Genetic variation in FTOrs17817449(G allele) was definitely associated with raised BMI, BMI z-score and fasting insulin, and lowered QUICKI values, that predicted the risk for type 2 diabetes among obese children harboring the mutant G allele.

Objective: The aim of the study was to examine the impact of neonatal acetaminophen (APAP; paracetamol) administrations on the thyroid-liver axis in male Wistar rats. Methods: APAP (100 or 350mg/kg) was orally administered to neonates from Postnatal Day (PND) 20 to 40. Results: Both APAP doses elicited a substantial increase in serum TSH, albumin, AST, ALT, and ALP values, and a profound decrease in serum FT4 and FT3 values at PND 40 relative to those in the control group. Additionally, the hypothyroid state in both APAP-treated groups may increase the histopathological variations in the neonatal liver, such as destructive degeneration, fibrosis, fatty degeneration, fibroblast proliferation, haemorrhage, oedema, and vacuolar degeneration, at PND 40. Moreover, in the APAP groups, a marked depression was recorded in the t-SH and GSH levels and GPx and CAT activities at PND 40 in the neonatal liver compared to those in the control group. However, the levels of hepatic LPO, H2O2, and NO were increased in both APAP-treated groups at PND 40. All previous alterations were dose- dependent. Conclusion: Neonatal APAP caused a hypothyroidism and disturbed hepatic cellular components by increasing prooxidant markers and decreasing antioxidant markers, causing hepatotoxicity. Thus, neonatal administrations of APAP may act as a neonatal thyroid-liver disruptor.

In the Original Article by Dikci et al. “The Association of Serum Vitamin D Levels with Pseudoexfoliation Glaucoma/ Syndrome” (Endocr Metab Immune Disord Drug Targets. 2019; 19(2):166-170) after publication of the article it has come to the corresponding author's attention that there were some errors in the article. In the introduction section, reference 3 should be changed as reference 2 (paragraph 1, line 4) and references 4-6 should be changed as references 3-6 (paragraph 1, lines 6,7). Reference numbers in the references section should be as follows. References 25-28 should be changed as references 7-10 respectively. References 7-24 should be changed as references 11-28 respectively.