Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 20, Issue 4, 2020

Background: Glyphosate (G) is the most common weed-killer in the world. Every year tons and tons of G are applied on crop fields. G was first introduced in the mid 1970s and since then its usage has gradually increased to reach a peak since 2005. Now G usage is approximately 100 -fold what it was in 1970. Its impact on human health was considered benign at the beginning. But over the years, evidence of a pervasive negative effect of this pesticide on humans has been mounting. Nonetheless, G usage is allowed by government health control agencies (both in the United States and Europe), that rely upon the evidence produced by the G producer. However, the IARC (International Agency for Research on Cancer) in 2015 has stated that G is probable carcinogenic (class 2A), the second highest class in terms of risk. Objective: In this review, we explore the effect of G on human health, focusing in particular on more recent knowledge. Results: We have attempted to untangle the controversy about the dangers of the product for human beings in view of a very recent development, when the so -called Monsanto Papers, consisting of Emails and memos from Monsanto came to light, revealing a coordinated strategy to manipulate the debate about the safety of glyphosate to the company’s advantage. Conclusion: The story of G is a recurrent one (see the tobacco story), that seriously jeopardizes the credibility of the scientific study in the modern era.

Background & Objective: Significant health and social burdens have been created by the growth of metabolic disorders like type 2 diabetes mellitus (T2DM), atherosclerosis, and non-alcoholic steatohepatitis, worldwide. The number of the affected population is as yet rising, and it is assessed that until 2030, 4−5 million individuals will acquire diabetes. A blend of environmental, genetic, epigenetic, and other factors, such as diet, are accountable for the initiation and progression of metabolic disorders. Several researches have shown strong relevance of adiponectin gene and metabolic disorders. In this review, the potential influence of epigenetic mechanisms of adiponectin gene “ADIPOQ” on increasing the risk of developing metabolic disorders and their potential in treating this major disorder are discussed. Results & Conclusion: Various studies have postulated that a series of factors such as maternal High fat diet (HFD), oxidative stress, pro-inflammatory mediators, sleep fragmentation throughout lifetime, from gestation to old age, could accumulate epigenetic marks, including histone remodeling, DNA methylation, and microRNAs (miRNAs) that, in turn, alter the expression of ADIPOQ gene and result in hypoadiponectinemia which precipitates insulin resistance (IR) that in turn might induce or accelerate the onset and development of metabolic disorder. A better understanding of global patterns of epigenetic modifications and further their alterations in metabolic disorders will bestow better treatment strategies design.

Background: Gender dysphoria is a clinical condition in which a state of inner suffering, stress and anxiety is detected when biological sex and a person's gender identity do not coincide. People who identify themselves as transgender people are more vulnerable and may have higher rates of dissatisfaction with their bodies which are often associated with a disorderly diet in an attempt to change the bodily characteristics of the genus of birth and, conversely, to accentuate the characteristics of the desired sexual identity. Aim: The purpose of this work is to examine the association between dissatisfaction with one's own body and eating and weight disorders in people with gender dysphoria. Results: Gender dysphoria and eating disorders are characterized by a serious discomfort to the body and the body suffers in both conditions. The results of our study suggest that rates of pathological eating behaviors and symptoms related to a disordered diet are high in patients with gender dysphoria and that standard screening for these symptoms must be considered in both populations at the time of evaluation and during the course of the treatment. Conclusion: In light of this evidence, clinicians should always investigate issues related to sexuality and gender identity in patients with eating disorders, to develop more effective prevention measures and better strategies for therapeutic intervention.

Background and Objective: Atherosclerosis, a chronic and progressive inflammatory disease, is triggered by the activation of endothelial cells followed by infiltration of innate and adaptive immune cells including monocytes and T cells in arterial walls. Major populations of T cells found in human atherosclerotic lesions are antigen-specific activated CD4+ effectors and/or memory T cells from Th1, Th17, Th2 and Treg subsets. In this review, we will discuss the significance of T cell orchestrated immune inflammation in the development and progression of atherosclerosis. Discussion: Pathogen/oxidative stress/lipid induced primary endothelial wound cannot develop to a full-blown atherosclerotic lesion in the absence of chronically induced inflammation. While the primary inflammatory response might be viewed as a lone innate response, the persistence of such a profound response over time must be (and is) associated with diverse local and systemic T cell responses. The interplay between T cells and innate cells contributes to a phenomenon called immuneinflammation and has an impact on the progression and outcome of the lesion. In recent years immuneinflammation, an old term, has had a comeback in connecting the puzzle pieces of chronic inflammatory diseases. Conclusion: Taking one-step back and looking from afar at the players of immune-inflammation may help us provide a broader perspective of these complicated interactions. This may lead to the identification of new drug targets and the development of new therapies as well as preventative measures.

Background: According to the views of psychoneuroendocrinoimmunology, many interactions exist between nervous, endocrine and immune system the purpose of which is to achieve adaptive measures restoring an internal equilibrium (homeostasis) following stress conditions. The center where these interactions converge is the hypothalamus. This is a center of the autonomic nervous system that controls the visceral systems, including the immune system, through both the nervous and neuroendocrine mechanisms. The nervous mechanisms are based on nervous circuits that bidirectionally connect hypothalamic neurons and neurons of the sympathetic and parasympathetic system; the neuroendocrine mechanisms are based on the release by neurosecretory hypothalamic neurons of hormones that target the endocrine cells and on the feedback effects of the hormones secreted by these endocrine cells on the same hypothalamic neurons. Moreover, the hypothalamus is an important subcortical center of the limbic system that controls through nervous and neuroendocrine mechanisms the areas of the cerebral cortex where the psychic functions controlling mood, emotions, anxiety and instinctive behaviors take place. Accordingly, various studies conducted in the last decades have indicated that hypothalamic diseases may be associated with immune and/or psychic disorders. Objective: Various researches have reported that the hypothalamus is controlled by the cerebellum through a feedback nervous circuit, namely the hypothalamocerebellar circuit, which bi-directionally connects regions of the hypothalamus, including the immunoregulatory ones, and related regions of the cerebellum. An objective of the present review was to analyze the anatomical bases of the nervous and neuroendocrine mechanisms for the control of the immune system and, in particular, of the interaction between hypothalamus and cerebellum to achieve the immunoregulatory function. Conclusion: Since the hypothalamus represents the link through which the immune functions may influence the psychic functions and vice versa, the cerebellum, controlling several regions of the hypothalamus, could be considered as a primary player in the regulation of the multiple functional interactions postulated by psychoneuroendocrinoimmunology.

Background: Acute lung injury is one of the common conditions caused due to bleomycin therapy which leads to pulmonary fibrosis, which is one of the severe interstitial lung diseases most commonly affecting the elderly individuals. EGFR and Ki67 can be marked as beneficial markers for detecting pulmonary fibrosis based on which clinicians can guide the therapy. Objective: The aim of the study was to evaluate the effect of curcumin as an intervention on two prognostic markers EGFR and Ki67 in bleomycin-induced basal alveolar epithelial cells and C57BL/6 mice. Protein expressions and pathological expressions of EGFR and Ki67 were evaluated to analyze the effect of curcumin via both in vitro and in vivo approaches. Methods: The effect of curcumin was investigated both on cell lines (A549) and animal model (both normal and bleomycin-induced mice, n=6) via techniques like western blotting for protein expression. Techniques like immunofluorescence and immunohistochemistry were carried out and examined under confocal microscopy and phase contrast microscopy to analyze the expressions of the said biomarkers. Bleomycin was used as a causative agent to induce inflammation. Results: The natural polyphenol curcumin could downregulate the expressions levels of Ki67 and EGFR both in vitro and in vivo. Immunofluorescence analysis of proliferative marker Ki67 showed a reduced expression on curcumin treatment in vitro. The pathological sections from treated lungs showed a significant decrease in EGFR and Ki67 levels when exposed to curcumin. Conclusion: We conclude that curcumin, a well-known natural bioactive compound holds strong antiproliferative effects on Ki67 and EGFR expressions.We observed that a clinical outcome in the diagnosis of pulmonary fibrosis remains to be unconvincing so far. Curcumin can be considered as a potential therapeutic.

Background: The concept of metabolic syndrome (MetS) as a cluster of risk factors of type 2 diabetes and cardiovascular diseases has undergone some evolutionary transformations over the past years. Integrating the autonomic dysfunction into the pathogenesis of MetS creates the possibility of including a range of nosologies affecting treatment and clinical manifestations of pathologies belonging to MetS into the MetS cluster. The purpose of this work is to determine the involvement of autonomic dysfunction in the pathogenesis of associated pathological conditions in patients and MetS. Methods: A cross-sectional study was conducted. The sample consisted of 158 patients with metabolic syndrome. The patients underwent a physical examination, including BMI; a blood chemistry test with the determination of the hormonal status (insulin, testosterone, dihydrotestosterone); a 24-hour monitoring of blood pressure (BP); an assessment of heart rate variability; studies showing the presence of gastric reflux (#128;Ц#157;-measurement) or its damaging impact (endoscopy); men were tested with the IPSSQOL questionnaire and underwent transrectal ultrasound of the prostate and ultrasound of the bladder. Results: It is revealed that because of MetS, the occurrence of cardiac autonomic neuropathy reaches 37.5%. Some features of gastroesophageal reflux disease in patients with MetS are shown. Regurgitation prevails in the structure of complaints. In case of fibrogastroduodenoscopy, an endoscopynegative form of the disease occurs in 38%. According to the data of daily pH-measurement, when DeMeester score is high, in the supine position, 25% of the time accounts for alkaline reflux (#128;Ц#157; > 7). It is found out that young men experience the enlargement of prostate volume and size; according to the IPSS questionnaire, the scores correspond to the initial manifestations of hyperplastic diseases of the prostate gland due to insulin resistance and normal level of androgens. Conclusion: The paper demonstrates that the autonomic dysfunction of the nervous system (on a par with insulin resistance) is the main link in the development of MetS. This provides the basis for including the mentioned states – cardiac autonomic neuropathy, lower urinary tract symptoms, and gastroesophageal reflux disease – into the MetS cluster.

Background: Metabolic syndrome is a complex pattern of disorders that occur jointly and is associated with an increased risk of cardiovascular and cerebrovascular disease. Therefore the need for more-efficient options of treatment has become imperative. Objective: This study examined the effect of dietary-melatonin in the management of behavioural, metabolic, antioxidant, and organ changes due to high-fat/high-sugar (HFHS) diet-induced metabolic syndrome in mice. Methods: Mice were randomly assigned into five groups of ten animals each. Groups were normal control [fed standard diet (SD)], HFHS control, and 3 groups of melatonin incorporated into HFHS at 2.5, 5, and 10 mg/kg of feed. Mice were fed for seven weeks, and body weight was assessed weekly. Open-field behaviours, radial-arm, and Y-maze spatial memory were scored at the end of the experimental period. Twenty-four hours after the last behavioural test, blood was taken for estimation of blood glucose levels after an overnight fast. Animals were then euthanised, and blood was taken for estimation of plasma insulin, leptin, and adiponectin levels, and serum lipid profile. The liver, kidneys, and brain were excised and processed for general histology, while homogenates of the liver and whole brain were used to assess oxidative stress parameters. Results: Results showed that dietary melatonin (compared to HFHS diet) was associated with a decrease in body weight, food intake, and novelty-induced behaviours; and an increase in spatial-working memory scores. A decrease in glucose, insulin, leptin, and malondialdehyde levels; and an increase in adiponectin levels and superoxide dismutase activity were also observed. Histomorphological/ histomorphometric examination revealed evidence of organ injury with HFHS diet, and varying degrees of amelioration with melatonin-supplemented diet. Conclusion: In conclusion, dietary melatonin supplementation may have beneficial effects in the management of the metabolic syndrome.

Background: Diabetes Mellitus (DM) is a progressive metabolic disorder. Objective: The aim of this study was to investigate the relationship between antioxidant and oxidative stress markers in the saliva of patients with type 2 DM and a healthy control group. Methods: In this study, 20 patients with diabetes and 20 healthy individuals were evaluated. Salivary antioxidants markers consisted of total antioxidant capacity (TAC), uric acid (UA), peroxidase and catalase. Oxidative stress markers included total oxidant status (TOS), malondealdehyde (MDA) and total thiol (SH). Sialochemical analysis was performed with spectrophotometric assay. All the statistical analyses were conducted using STATA software. Results: TAC decreased significantly in patients with diabetes. Although salivary UA and peroxidase were lower in patients with diabetes compared to the control group, the difference was not significant. Salivary catalase in patients with diabetes was significantly lower than that in the control group. MDA and TOS exhibited significantly higher levels in type 2 DM. SH levels were slightly higher in DM. Conclusion: According to the results of the present study, there were some changes in the salivary levels of some antioxidants and oxidative stress markers in patients with type 2 DM and could be measured as an indicator of serum changes.

Objective: This study aims to discover a potential cytokine biomarker for early diagnosis of thyroid cancer. Methods: We employed data mining of The Cancer Genome Atlas (TCGA) and experimentally elucidated its mechanistic contributions. The differential expression genes (DEGs) between thyroid cancer and health population were analyzed with TCGA online bioinformatic tools. The relative expression of Bone Morphogenetic Protein 8A (BMP8A) was determined by real-time PCR in ultrasonic diagnosed thyroid cancer both in vivo and in vitro. The serous BMP8A content was quantified with an ELISA kit. Protein levels of BMP8A, OCLN, ZEB1, EZH2 and β-Actin were analyzed by Western blot. Cell viability was measured by the MTT assay, and anchorage-independent growth was measured by the soft agar colony formation assay. Cell migrative and invasive capacities were interrogated with transwell chamber assays. Results: We identified aberrantly high expression of BMP8A in thyroid cancer, which was associated with unfavorable prognosis and tumor progression. The serous BMP8A was also significantly up-regulated in thyroid cancer patients. Ectopic over-expression of BMP8A remarkably stimulated cell viability and anchorage-independent growth. Meanwhile, the migrative and invasive capacities were greatly increased in response to BMP8A over-expression. Mechanistically, we characterized the positive correlation between BMP8A and TCF7L1, and forced expression of TCF7L1 induced BMP8A expression in TPC-1 cells. Conclusion: In summary, we have identified a novel biomarker for early diagnosis in addition to Ultrasound for thyroid cancer, which is subjected to TCF7L1 regulation.

Background: Due to the increased prevalence of diabetes-associated complications of the eye like diabetic retinopathy and cataract, the need for a novel therapeutic agent is urgent. Due to the advantages that the polyphenolic compounds enjoy in diabetes and associated complications, we postulated that Taxifolin (TXF), a poly-phenolic flavanol, could show anti-retinopathic and anti-cataract effect in diabetes-induced rats. Methods: TXF at a dose of 10, 25, and 50 mg/kg was given by oral route to STZ mediated diabetic rats for a time period of 10 weeks. The opacity of lens was studied after every 7 days of treatment till 10 weeks; evaluation of the severity of cataract and changes in the histology of lens as well as retina was done. Tissue homogenates of lens isolated after the end of the study were evaluated for markers of oxidative stress, levels of aldose reductase, p38MAPK, VEGF, and ERK1/2. Results: Outcomes suggested that TXF improved retinopathy and cataract in diabetes-induced rats. The treatment of TXF also improved the status of oxidative stress and inhibited the levels of p38MAPK, VEGF, and ERK1/2. The treatment also improved the lens opacity in diabetic rats. The results suggest that the protective effect of TXF against cataract and retinopathy may be due to the anti-oxidative potential of TXF and its inhibiting effect on VEGF, ERK1/2, p38MAPK, and aldose reductase. Conclusion: The study confirms that TXF is a potential candidate showing a protective effect against diabetic induced retinopathy and cataract.

Background: Hashimoto’s thyroiditis (HT) is characterized by lymphocytic infiltration of the thyroid parenchyma, which ultimately leads to tissue destruction and loss of function. Caveolin-1 (Cav-1) is an essential structural constituent of lipid rafts in the plasma membrane of cells and is reported to be significantly reduced in thyrocytes from HT patients. However, the mechanism of Cav-1 involvement in HT pathogenesis is still largely unclear. Methods: Cav-1 expression in thyroid tissues from HT patients and euthyroid nodular goiter tissues was detected by immunohistochemistry staining. Cav-1 knockdown and overexpression were constructed by lentiviral transfection in the human thyroid follicular epithelial cell (TFC) line of Nthy-ori 3-1. The mRNA expression levels of chemokines in TFCs were determined by quantitative real-time PCR (qPCR). Cav-1 and peroxisome proliferator-activated receptor gamma (PPARγ) levels were analysed by qPCR and Western blot analysis. The migration ability of peripheral blood mononuclear cells (PBMCs) was detected by the Transwell assay. Results: In this study, Cav-1 and PPARγ expression was reduced in the thyroid tissues from HT patients. In vitro experiments showed that the expressions of chemokine (C-C motif) ligand 5 (CCL5) and migration of PBMCs were markedly increased, while the level of PPARγ was significantly decreased after the lentivirus-mediated knockdown of Cav-1 in Nthy-ori 3-1 cells. Interestingly, pioglitazone, a PPARγ agonist, not only upregulated PPARγ and Cav-1 proteins significantly, but also effectively reversed the Cav-1-knockdown-induced upregulation of CCL5 in Nthy-ori 3-1 cells and reduced the infiltration of lymphocytes. Conclusion: The inhibition of Cav-1 upregulated the CCL5 expression and downregulated the PPARγ expression in TFC while pioglitazone, a PPARγ agonist, reversed the detrimental consequence. This outcome might be a potential target for the treatment of lymphocyte infiltration into the thyroid gland and HT development.

Background: Previous studies have shown that cytomegalovirus (CMV) induced innate immune response via activation of Toll-like receptor 2 (TLR2). The association between CMV among specific single-nucleotide polymorphisms (SNPs) in the TLR2 gene was also investigated. Objective: This study investigated the relationship between specific SNPs in the TLR2 gene (G>A), TLR2-Arg753Gln (rs5743708), and CMV replication after bone marrow transplantation. Methods: The TLR2-Arg753Gln SNP was genotyped in 181 patients after bone marrow transplantation: 83 and 98 patients with and without CMV infection, respectively. CMV load was determined in serially collected blood samples using real-time PCR. Genotyping was performed using specific sequence primer PCR (SSP-PCR), and the results were confirmed by restriction fragment length polymorphism (RFLP) analysis of the PCR-amplified fragments for GG (wild type), GA and AA identification. Results: Roughly, 85% of the patients screened for the presence of the TLR2-Arg753Gln were GG homozygous, and 15% were GA heterozygous; no patients were homozygous for the mutant allele (A). The GA heterozygous allele was more frequent in the CMV-infected group after bone marrow transplantation. Conclusion: To our knowledge, this is a novel observation that supports the notion that the functional missense mutation (TLR2-Arg753Gln polymorphism) is possibly associated with CMV replication after bone marrow transplantation. This suggests a role for TLR2 in the innate immune response of human CMV infection in Egyptian bone marrow recipients.

Background: The importance of diet in health is widely accepted and recognized. Diet lipid profile is important to prevent chronic diseases and improve the quality of an individual’s life. Objective: The objective of this report is to analyze the effect of different sources of dietary lipids with standard and high concentration on growing rats. Methods: Experimental diets contained 15 or 42% kcal of fat, provided by butter (B), olive oil (O), high oleic sunflower oil (HO), and sunflower oil (S). Control diet (C) was normocaloric with 15% kcal of fat provided by soy oil. All diets were complete in the other nutrients according to AIN 1993 and were administered for 40 days. Results: Daily intake was similar in all groups. The administration of these diets provoked changes in serum fatty acid profile in response to the different sources of dietary lipids used; no changes were observed in the brain´s fatty acids. Conclusion: These results would suggest that the organism tries first to supply the brain´s fatty acid needs at the expense of its modification in serum.