Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 23, Issue 4, 2023

Multiple sclerosis (MS) is one of the organ-specific autoimmune diseases in which immune cells invade the neurons in the central nervous system (CNS) due to loss of tolerance to self-antigens. Consequently, inflammation and demyelination occur in the central nervous system. The pathogenesis of MS is not completely understood. However, it seems that T cells, especially Th17 cells, have an important role in disease development. In recent years, studies on the manipulation of metabolic pathways with therapeutic targets have received increasing attention and have had promising results in some diseases, such as cancers. Glycolysis is a central metabolic pathway and plays an important role in the differentiation of T CD4+ cells to their subsets, especially Th17 cells. This suggests that manipulation of glycolysis, for example, using appropriate safe inhibitors of this pathway can represent a means to affect the differentiation of T CD4+, thus reducing inflammation and disease activity in MS patients. Hence, in this study, we aimed to discuss evidence showing that using inhibitors of 6-phosphofructo-2- kinase/fructose-2,6-biphosphatase 3(PFKFB3) as the main regulator of glycolysis may exert beneficial therapeutic effects on MS patients.

The review article reveals the role of mental as well as biological phenomena working behind immunity. In recent times, irresistible illnesses and inflammation have been thought to be hereditary or the result of the natural working mechanism of the human body in response to the pathogenic variables working inside the human system. In the past few years, the importance of psychological adjustments, mental well-being and eating habits has been studied and shown to have a marked effect on immunity. Psychoneuroimmunology considers that mental disorders are strongly interrelated with the resistant reaction. Besides, the immunological components control the wellbeing of the individual. Psychosocial mediations help reduce disease severity and enhance the functioning of the immune system. Nutrition plays a vital role in immunity and thus has an influence on our mental health.

Metabolic syndrome, an increasing problem in western society, is a cluster of conditions that affect cardiovascular health, lipid and glucose management, increasing the risk of heart diseases, stroke and diabetes. Bioactive flavonoids are a great resource of compounds with proven antiinflammatory activities. Naringin, a natural flavanone found in citrus fruits, and its aglycone have demonstrated to ameliorate obesity, dyslipidemia, and insulin resistance in animal models. The principal mechanisms by which these flavonoids exert their action involve AMPK and PPARα up-regulation and the down-regulation of genes involved in lipid metabolism. Although different studies have been carried out to define the pharmacological effects of these flavonoids, their therapeutic use is still limited.

Toll-like receptors (TLRs) are a well-characterized family of cell-bound pattern recognition receptors able to identify and respond to conserved structures of external microorganisms or Pathogen Molecular-Associated Pattern (PAMPs). They can also interact with Damage-Associated Molecular Patterns (DAMPs) involved with any infectious and sterile cell stress of tissue injury. Accumulated knowledge about TLRs has revealed that these receptors and intracellular signaling pathways triggered through TLR activation contribute to the physiopathology of different inflammatory diseases, including arthritic conditions. Mostly, the literature focuses on exploring TLRs in rheumatoid and osteoarthritis. However, TLRs also seem to be an essential mediator for monosodium urate (MSU) crystals-induced gouty arthritis, both in animal models and humans. Accordingly, naked MSU crystals have a highly negatively charged surface recognized by TLRs; intracellular adapter protein MyD88 are significant mediators of MSU crystals-induced IL1β production in mice, and gouty patients demonstrate a robust positive correlation between TLR4 mRNA level and serum IL1β. Here, we revised the literature evidence regarding the involvement of TLRs in gout arthritis pathogenesis, with particular reference to TLR2 and TLR4, by analyzing the actual literature data.

Edible vaccines are cost-effective, easy to take, storable as well as bio-friendly. If they are administered orally, they are capable of lessening the occurrence of several diseases, like HPV, Norwalk virus, as well as Polio. They are obtained by utilizing a specific portion of the plant, which results in the formulation of an attractive encoded protein. These particular encoded proteins enhance the mucosal movement along with diminishing resistance. There are different food items that are utilized in injectable antibodies, for example, wheat, rice, bananas, lettuce, potatoes, and tomatoes, which help overcome all the issues related to conventional antibodies; this demonstrates that palatable immunization is the best substitute for customary antibodies.

The SARS CoV-2 virus, the causative agent of COVID-19 uses the ACE-2 receptor of the host to penetrate and infect the cell, mainly in the pulmonary, renal, and cardiac tissues. The earlier reported Delta and the recent Omicron are the variants of concern. The mutations in the RBD region of spike protein are associated with increased RBD-ACE-2 receptor interaction. This binding affinity between spike protein and the receptor is greater in Omicron than in the Delta variant. Moreover, the Omicron variant has numerous hydrophobic amino acids in the RBD region of the spike protein, which maintain its structural integrity. Gallic acid is a phytophenol and shows high binding affinity toward the ACE-2 receptors, which may be helpful for better outcomes in the treatment of COVID-19 pathogenesis. In the present study, significant data were collected from different databases i.e., PubMed, Scopus, Science Direct, and Web of Science by using keywords like anti-oxidative, anti-inflammatory, and antimicrobial properties of gallic acid, in addition to receptor-based host cell interaction of SARS CoV-2 virus. The finding shows that gallic acid can reduce inflammation by attenuating NF-ΚB and MAPK signaling pathways to suppress the release of ICAM-1, a cell surface glycoprotein; various pro-inflammatory cytokines like TNF-α, IL 1-β, IL-6, IL-10, and chemokines like CCL-2,5, CXCL-8 along with tissue infiltration by immune cells. The purpose of this review is to highlight the therapeutic potential of gallic acid in COVID-19 pathogenesis based on its strong anti-oxidative, anti-inflammatory, and anti- microbial properties.

Under steady-state circumstances, the oral microbiota is in equilibrium with host tissues, thus contributing to local and systemic health. Any interruption of such equilibrium leads to a condition of dysbiosis with the proliferation of oral pathogens able to cause gingivitis and periodontal disease. The mechanisms of periodontitis will be described, mostly emphasizing the noxious effects exerted by oral pathogens on the periodontium either directly or indirectly via the release of an array of mediators, even including pro-inflammatory cytokines, chemokines, and enzymes. The persistence of local inflammation ultimately leads to systemic inflammation; therefore, the link between periodontitis and obesity, diabetes and cardiovascular disease will be elucidated. Some natural compounds, such as polyphenols, prebiotics, and probiotics, will be discussed for their ability to exert anti-inflammatory and anti-oxidant activities in the context of the inflamed buccal cavity and systemically, as well as for their modulation of the altered gum-gut microbiota.

Non-alcoholic fatty pancreas disease (NAFPD) is a relatively new and emerging disease that is increasingly diagnosed yearly, like non-alcoholic fatty liver disease (NAFLD). It is associated especially with metabolic syndrome and obesity. As awareness of pancreatic steatosis and its clinical implications increase, it is diagnosed more frequently. The researchers have explained the clinical importance of NAFPD and the diseases it causes, such as pancreatitis, pancreatic insufficiency, and pancreatic cancer. Although the definitive treatment is not yet established, the primary treatment approach is weight loss since NAFPD is associated with metabolic syndrome as well as obesity. Although pharmacological agents, such as oral hypoglycemic agents, have been investigated in animal experiments, studies on humans have not been conducted. Since the research on NAFPD is still insufficient, it is a subject that needs to be investigated, and further studies are needed to explore its pathophysiology, clinical impact, and its management.

Background: Uncoupling proteins (UCPs) are unpaired electron carriers that uncouple oxygen intake by the electron transport chain from ATP production in the inner membrane of the mitochondria. The physiological activities of UCPs have been hotly contested, and the involvement of UCPs in the pathogenesis and progression of diabetes mellitus is among the greatest concerns. UCPs are hypothesised to be triggered by superoxide and then reduce mitochondrial free radical production, potentially protecting diabetes mellitus patients who are experiencing oxidative stress. Objectives: The objectives of the study are to find out the newest ways to treat diabetes mellitus through protein uncoupling. Methods: Research and review papers are collected from different databases like google scholar, PubMed, Mendeley, Scopus, Science Open, Directory of open access journals, and Education Resources Information Center, using different keywords such as "uncoupling proteins in diabetes mellitus treatment", "UCP 1", "UCP 2", and "UCP 3". Results: UCP1, UCP2, and UCP 3 are potential targets as uncoupling proteins for the treatment of diabetes mellitus for new drugs. New drugs treat the disease by reducing oxidative stress through thermogenesis and energy expenditure. Conclusion: UCP1, UCP2, and UCP3 have a role in fatty acid metabolism, negative control of insulin production, and insulin sensitivity by beta-cells. Polymorphisms in the UCP 1, 2, and 3 genes significantly reduce the risk of developing diabetes mellitus. Protein uncoupling indirectly targets the GPCR and islet of Langerhans. This review summarises the advances in understanding the role of UCP1, UCP2, and UCP3 in diabetes mellitus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by damage to multiple systems and a higher risk of cardiovascular disease. In addition, several studies have found that insulin resistance (IR) is more prevalent in SLE patients than controls, increasing the risk of prediabetes, type 2 diabetes mellitus (T2DM) and morbidity. The objective of this review article was to summarize the most relevant evidence about the relationship among IR, T2DM and SLE, including the effects of proinflammatory states, acute-phase proteins, pro-inflammatory cytokines, and pharmacological SLE treatment. A better understanding of the mechanisms involved in these comorbidities will allow better treatment strategies.

Bisphenol A (BPA) is an endocrine-disrupting chemical widely present in many consumer goods that poses a significant threat to our health upon exposure. Humans are exposed to BPA, which directly or indirectly causes endocrine dysfunctions that lead to metabolic disorders like obesity, fatty liver diseases, insulin resistance, polycystic ovarian syndrome, and other endocrine- related imbalances. The duration, quantity, and period of exposure to BPA, especially during the critical stage of development, determine its impact on reproductive and non-reproductive health. Because of its endocrine-disrupting effects, the European Chemical Agency has added BPA to the candidate list of chemicals of very serious concern. Due to its estrogenic properties and structural similarities with thyroid hormones, BPA disrupts the endocrine system at different levels. It interacts with estrogen receptors at the molecular level and acts as an antagonist or agonist via an estrogen receptor-dependent signaling pathway. In particular, BPA binds to G-protein coupled receptors and estrogen receptors, activating signaling pathways that influence cellular apoptosis, proliferation, differentiation, and inflammation. BPA acts as an obesogen that promotes adipogenesis and correlates with increased lipid accumulation and elevated expression of adipogenic markers. As a metabolic and endocrine disruptor, BPA impairs cellular homeostasis by increasing oxidative mediators and decreasing antioxidant enzymes, resulting in mitochondrial dysfunction. Due to its endocrine-disrupting properties, BPA exposure induces endocrine dysfunctions, causing metabolic syndrome. This review article gives recent development and novel insights into the cellular and molecular mechanisms of BPA-induced endocrine dysfunctions and their associated metabolic disorders.

Objective: To assess the combined effect of Sodium-Glucose Transporter 2 Inhibitors (SGLT2i) and metformin treatment on inflammatory and prognostic biomarkers in patients with T2DM. Methods: Using the search terms “Sodium-Glucose Transporter 2 Inhibitors,” “Diabetes Mellitus, Type 2,” and “randomized controlled trial,” we screened the literature on PubMed, Cochrane Library, Embase, and Web of Science according to the inclusion and exclusion criteria. The studies selected were grouped to determine the combined effect of SGLT2i and metformin on inflammatory markers in patients with T2DM. Results were expressed using continuous variables, combined into weighted mean differences (WMD) and 95% confidence intervals (CI). The study was registered under the PROSPERO number CRD42022296480. Results: Meta-analysis showed that, compared with the control and metformin treatment groups, the SGLT2i coupled with metformin group was more effective in reducing C-reactive protein (CRP) (WMD, −0.185, 95% CI, −0.330 to −0.040, P < 0.05), tumor necrosis factor (TNF-α) (WMD, −0.628, 95% CI, −1.046 to −0.210, P < 0.05), uric acid (WMD, −0.653, 95% CI, −0.734 to −0.572, P < 0.05), leptin (WMD, −3.663, 95% CI, −4.812 to −2.515, P < 0.05), glycated hemoglobin (HbA1c) (WMD = −0.172, 95% CI, −0.255 to −0.089, P < 0.05), and estimated glomerular filtration rate (eGFR)(WMD = 0.978, 95% CI (0.027, 1.928), P = 0.044). In parallel, we performed a Trial Sequential Analysis (TSA) of and the results showed reliable conclusions. Conclusion: SGLT2i combined with metformin reduced inflammation levels and significantly improved glycemic control and prognosis in patients with T2DM.

Background: Interleukin-6 (IL-6) receptor blockers improve systemic inflammation, however, their inconsistent effects on lipid metabolism and drug-induced liver injuries warrant further investigation. This study aimed to determine the effects of IL-6 receptor blocker therapy on lipid metabolism and liver morphology in collagen-induced arthritis. Methods: Sixty three Sprague Dawley rats were divided into control (n = 24), inflammation (n = 24), and IL-6 blocker (n = 15) groups. Inflammation was induced in the inflammation and IL-6- blocker groups using Bovine type-II collagen and incomplete Freund’s adjuvant. At first signs of arthritis, the IL-6 blocker group received an IL-6 blocker, tocilizumab for six weeks. Serum concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and ATP-binding cassette transporter-A1 (ABCA1) were measured. Liver fibrosis was determined by histological stains and liver enzymes were measured using the colorimetric-chemistry analyzer. Results: In the inflammation group, HDL-C and ABCA1 were reduced compared to control (p < 0.0001 and p = 0.04, respectively) and IL-6 blocker (p = 0.0003 and p < 0.0001, respectively) groups. LDL-C was increased in the inflammation compared to control (p = 0.02). Markers of liver fibrosis were increased in the IL-6 blocker group compared to control and inflammation groups (picrosirius red collagen area fraction: p < 0.0001 and p = 0.0008, respectively; Masson’s trichrome collagen area fraction: p = 0.0002 and p = 0.01, respectively). Alkaline phosphatase concentrations were increased in the IL-6 blocker group compared to the control (p < 0.0001) and inflammation (p = 0.002) groups. Conclusion: IL-6 blockers ameliorated inflammation-induced lipid metabolism impairments, however they induced liver fibrosis. Although IL-6 blockers may reduce inflammation-induced metabolic impairments in chronic inflammatory disorders, routine monitoring of liver function is warranted while on treatment.

Purpose: Our primary objective in this study is to determine the relationship between serum iron (Fe³⁺) and thyroid functions in type 2 diabetes mellitus (T2DM) patients. Materials and Methods: Glucose metabolic parameters, trace elements, such as Fe³⁺, and thyroid functions for 1657 type 2 diabetic patients treated at the Shanghai Pudong Hospital's Department of Endocrinology from 2018 to 2021 were assessed. Results: Variations in free thyroid hormones (FTH) and total thyroid hormones (TTH) were insignificant; however, thyroid-stimulating hormone (TSH) levels were markedly elevated in patients with positive thyroid peroxidase antibody (TPOAb) and/or positive antithyroglobulin antibody (TgAb) (p<0.05). Additionally, gender disparities affected FTH levels (p<0.05) but not TTH and TSH levels. The female gender was significantly negatively correlated with serum Fe levels (r=-0.381, p<0.05). Serum Fe³⁺ deficiency also had an effect on FT3 in both genders, FT4 and TT4 in males (p<0.05), but not TSH (p>0.05). The multilinear regression model showed that TT3 (β=0.702), eGFR (β=0.109), Fe³⁺ (β=0.003), female gender (β=-0.061), and age (β=-0.061) were the major determinants for FT3 change. Moreover, renal function, which was represented as the estimated glomerular filtration rate (eGFR), had no effects on Fe³⁺ and TSH levels but on the levels of FTH and TTH (p<0.05). FT3/FT4 exhibited correlations with Fe³⁺ (r=0.252) and eGFR (r=0.285). Finally, changes in Fe³⁺ levels had no significant impact on fasting plasma glucose (FPG), fasting C-peptide, HbA1c, and glycated albumin levels (p>0.05). Conclusion: In addition to age, gender, and renal functions, serum Fe³⁺ levels in T2DM patients have a significant relationship with thyroid functions.