Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 23, Issue 1, 2023

Metabolic diseases such as type 2 diabetes mellitus are usually associated with meta-inflammation. β-cell failure is a marked feature observed in the pathogenesis of type 2 diabetes mellitus. Type 2 diabetes mellitus (T2DM) is a heterogeneous situation that is accompanied by not only defective insulin secretion but also peripheral insulin resistance. β-cells are the primary organ for insulin secretion; hence, it is crucial to maintain a significant β-cell mass in response to a variety of changes. Insulin resistance is a chief cause of T2DM, leading to increased free fatty acid (FFA) levels, which in turn elevates β-cell mass and insulin secretion as compensation for insulin insensitivity. It has recently been established that amplified numbers of innate immune cells, cytokines, and chemokines result in detrimental effects on islets in chronic conditions. Macrophage migration inhibitory factor (MIF) is the lymphokine that prevents arbitrary migration of macrophages and assembles macrophages at inflammatory loci. Inflammation is known to trigger monocytes to differentiate into macrophages. Progress of complications associated with type 2 diabetes mellitus, as indicated through recent findings, is also dependent on the buildup of macrophages in tissues vulnerable to diabetic injury. The present article scientifically evaluates the present knowledge concerning the mechanisms of monocyte and macrophage-mediated injury recruitment in complications associated with type 2 diabetes mellitus. It also describes some of the established and experimental therapies that might bring about a reduction in these inflammatory complications. Recent discoveries in the field of drug delivery have facilitated phenotype-specific targeting of macrophages. This review highlights the pathophysiology of type 2 diabetes mellitus, how macrophage induces type 2 diabetes mellitus and potential therapeutics for type 2 diabetes mellitus via macrophage-specific delivery.

Roles for adipose tissues in energy metabolism, health maintenance and disease onset have been established. Evidence indicates that white, brown and beige fats are quite different in terms of their cellular origin and biological characteristics. These differences are significant in targeting adipocytes to study the pathogenesis and prevention strategies of related diseases. The biotransformations of white, brown and beige fat cells constitute an intriguing topic worthy of further study, and the molecular mechanisms underlying the biotransformations of white, brown and beige fat cells remain to be elucidated. Hence, we herein collected evidence from studies on adipose tissue or adipocytes, and we extracted the structural features, biologic functions, and biotransformations of adipose tissue/adipocytes. The present review aimed to summarize the latest research progress and propose novel research directions with respect to adipose tissue and adipocytes. We posit that this work will provide new insights and opportunities in the effective treatment strategies for obesity, diabetes and other lipid-related diseases. It will also contribute to our knowledge of the basic biologic underpinnings of adipocyte biology.

Peptic ulcer disease (PUD) is a widespread condition that affects millions of people each year, with an incidence rate of 0.1%-1.5%, and has a significant impact on human health. A range of stimuli, such as Helicobacter pylori, non-steroidal anti-inflammatory drugs, hyperacidity, stress, alcohol, smoking, and idiopathic disease states, can produce a sore in the gastrointestinal mucosal layer. For individuals infected with H. pylori, 2%-3% remain asymptomatic throughout their life. Although PUD treatments are available, genetic variations occurring in individuals because of geographical dissimilarity and antibiotic resistance pose limitations. Specifically, inflammatory cytokine gene polymorphisms have received immense attention in recent years because they appear to affect the severity and duration of stomach inflammation, which is induced by H. pylori infection, contributing to the initiation of PUD. In such a context, in-depth knowledge of interleukins may aid in the discovery of new targets and provide precautionary approaches for the treatment of PUD. This review aims to give insights into the importance of several interleukins that cognate with PUD and contribute to ulcer progression or healing by activating or dampening the host immunity. Furthermore, the available targets with clinical evidence have been explored in this review.

Coronavirus disease 2019 (COVID-19) is caused by a severe acute respiratory syndrome, coronavirus type 2 (SARS-CoV-2), leading to acute tissue injury and an overstated immune response. In COVID-19, there are noteworthy changes in the fibrinolytic system with the development of coagulopathy. Therefore, modulation of the fibrinolytic system may affect the course of COVID-19. Tranexamic acid (TXA) is an anti-fibrinolytic drug that reduces the conversion of plasminogen to plasmin, which is necessary for SARS-CoV-2 infectivity. In addition, TXA has anti-inflammatory, anti-platelet, and anti-thrombotic effects, which may attenuate the COVID-19 severity. Thus, in this narrative review, we try to find the beneficial and harmful effects of TXA in COVID-19.

Obesity and dyslipidemia are common disorders universally. According to the acquired outcomes of recent studies, dietary supplementations which have great content of phenolic compounds exert protective effects against obesity and dyslipidemia. Grape [Vitis vinifera] seeds are considered attractive sources of phenolic compounds with anti-oxidative stress and anti-inflammatory effects. There are also various experimental studies describing hepatoprotective, neuroprotective, anti-aging, cardioprotective, and anti-carcinogenic effects of polyphenols isolated from grape seed, highlighting the therapeutic and biological aspects of proanthocyanidins. The present review article first discusses pharmacological, botanical, toxicological, and phytochemical characteristics of Vitis vinifera seeds and afterward designates the protective properties which are attributed to the intake of grape seeds in obesity and hyperlipidemia. Overall valuable and updated findings of this study display that polyphenol of grape seeds has meaningful impacts on the regulation of lipid profile levels and management of obesity.

Sleep plays an important function in neuro-immuno-endocrine homeostasis. Sleep disorders have been associated with an increased risk of metabolic and cognitive impairments. Among different factors that have an effect on sleep metabolism, a growing body of literature has investigated growth factors in the course of sleep quality and disorders. A good example of growth factors is fibroblast growth factors (FGFs), which are a large family of polypeptide growth factors. Evidence has shown that FGFs are involved in the modulation of sleep-wake behavior by their receptor subtypes and ligands, e.g., FFG1 plays an important role in the quality of sleep through somnogenic effects, while the high level of FGF23 is associated with secondary disorders in shift workers. Therefore, a controversial effect of FGFs can be seen in the course of sleep in physiologic and pathologic conditions. Further investigation on this topic would help us to understand the role of FGFs in sleep disorders as a therapeutic option and biomarker.

Background: The recently emerged novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has posed a serious threat to public health, and there is an urgent need to establish tools that can aid the clinician in the evaluation and management of highrisk patients. This meta-analysis aimed to investigate the potential of sACE2 (soluble angiotensinconverting enzyme 2) as a prognostic biomarker in COVID-19. Methods: A comprehensive search of PubMed/MEDLINE, Cochrane, and Google Scholar, was performed until May 26, 2021. Data extraction and quality assessment of the study were independently conducted by the authors. Finally, 6 studies were included in this meta-analysis. Results: ACE-2 serum or plasma levels were compared between COVID-19 patients and healthy controls. ACE-2 level was not significantly different between severe COVID-19 patients and healthy controls (SMD = 1.2; 95% CI: -1.3-1.5; P = 0.86), severe and non-severe COVID-19 patients (SMD = 0.3; 95% CI: -0.06-0.7; P = 0.1), and severe COVID-19 patients and healthy controls (SMD = 0.6; 95% CI: -1.1-2.3; P = 0.5). Conclusions:We cautiously propose that circulating levels of ACE2 cannot be used as a biomarker to assess disease severity in COVID-19 patients.

Background: Chronic liver injury leads to liver inflammation and fibrosis, activating myofibroblasts in the liver and secreting extracellular matrix proteins that make the fibrous scar. Objectives: The purpose of our study was to characterize the polyphenolic content present in Acacia jacquemontii stem and evaluate its antioxidant and hepatoprotective activity. Methods: The phenolic contents in Acacia jacquemontii polyphenolic extract (AJPPE) were characterized using high-performance liquid chromatography (HPLC). The hepatoprotective and antioxidant activity of AJPPE were determined through biochemical parameters (ALT, AST, and ALP), lipid profile (TC, TG, HDL, and LDL), antioxidant biomarkers (SOD, LPO, GSH, and CAT), anti-fibrotic activity (collagen deposition), and histopathological analysis. Results: HPLC analysis of AJPPE showed the presence of polyphenols, including chlorogenic acid, P-coumaric acid, caffeic acid, and kaempferol, in a remarkable therapeutic range. Results of the in vivo analysis showed a significant decrease in the level of lipid profile, including LDL (low-density lipoprotein), TC (total cholesterol), triglycerides, liver function markers (AST, ALT, and ALP), collagen deposition and significantly increased the level of anti-oxidative biomarkers (CAT, SOD, LPO, and GSH) by using AJPPE. Conclusion: The above-mentioned results have shown that AJPPE possesses significant antioxidative and hepatoprotective effects. Furthermore, histopathological results also supported the antioxidant and hepatoprotective potential of AJPPE.

Background: Autoimmune thyroid diseases (AITD) are the most prevalent organ-specific autoimmune disorders. Vitamin B12 plays an important role in the proper functioning of the immune system. The aim of this study was therefore to investigate the correlation between vitamin B12 deficiency and AITD. Materials and Methods: A total of 306 patients (aged 18-65 years, mean – 37.6 ± 11.3 years and comprising 87 males and 219 females) were studied retrospectively (observational study). Patients were divided into groups: with and without vitamin B12 deficiency, and with and without AITD. Differences between groups were evaluated by Fisher’s exact test for qualitative variables and by Student’s t-test for quantitative variables. Correlations for quantitative factors were determined by the Pearson correlation coefficient and for qualitative factors by Spearman correlation analysis. The sensitivity and specificity of vitamin B12 deficiency for AITD were calculated by ROC analysis. Results: The vitamin B12 level was significantly lower in patients with AITD (and 200.70 + 108.84) compared to controls (393.41+150.78 p<0.0001). Patients with vitamin B12 deficiency were characterized by significantly higher mean values of anti-TPO (236.60+455.74) compared to controls (39.51+165.57 p<0.0001). Vitamin B12 levels were inversely correlated to anti-TPO levels (r=– 0.233, p<0.001). Roc analysis of vitamin B12 as a diagnostic test for AITD gave the area under curve as 0.881 (95% CI: 0.839-0.924), a sensitivity of – 0.947, a specificity of – 0.768, and a cutoff value of – 178.9. Conclusion: The vitamin B12 level correlates significantly to AITD. The concentration of vitamin B12 should therefore be determined in patients with autoimmune thyroiditis as a diagnostic test with high sensitivity and good specificity.

Background: Diabetic patients have weakened periodontal ligaments and an increased risk of periodontitis due to uncontrolled glycemia. Betulinic acid (BA), a hypoglycemic drug, has anti-inflammatory activities. Objectives: The current study aimed to explore the protective effect of BA on the inflammation in human periodontal ligament cells (PDLCs) stimulated with lipopolysaccharide (LPS) and/or high glucose (HG) status and its mechanisms of action. Methods: Human PDLCs were exposed to LPS and/or HG, with or without BA intervention. The production of nitrite oxide (NO) and prostaglandin E2 (PGE2) were quantified by Griess reaction and enzyme-linked immunosorbent assay, respectively. Immunoblotting analyses were employed to detect the expression of inducible nitric oxide synthase (iNOS) and the cyclooxygenase-2 (COX- 2), as well as the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor kappa- B (NF-ΚB) in human PDLCs. Results: The increased production of iNOS/NO and COX-2/PGE2 and increased phosphorylated levels of IΚBα, JNK, and p38 can be detected in human PDLCs with LPS and/or HG situations, while increased phosphorylated ERK can be seen in cells under only LPS condition. Furthermore, the non-toxic concentration of BA (10 μM) prevented NF-ΚB and MAPKs activation and partly but significantly reversed the induction of COX-2/ PGE2 and iNOS/NO in human PDLCs with LPS and/or HG loaded. Conclusion: BA was proved for the first time to protect human PDLCs from the LPS-induced and/or HG-induced inflammation, which works through the mechanism involving the action of MAPKs and NF-ΚB. signaling pathways. Thus, BA could be used to alleviate diabetic complications of periodontitis.

Background: The syndrome Klinefelter syndrome (KS) is a genetic disorder due to an extra X chromosome in males. Many cases remain undiagnosed until the onset of major manifestations, which include hypergonadotropic hypogonadism and infertility. This condition is associated with many comorbidities that involve the cardiovascular, endocrine, and immune systems. Last but not the least, individuals with KS show a high risk of developing psychiatric and mood disorders in adult age. Objective: While many studies are accessible on KS in adult individuals, the neuroinflammatory condition in adolescent and prepubertal KS individuals is not fully known. Methods: Our study aims to evaluate in prepubertal and adolescent KS individuals, for the first time, the levels of the serum of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), cytokines having subtle roles in oxidative processes, and neuroinflammation with respect to the levels of TNF-α, TGF-β, MCP-1, IL-1α, IL-2, IL-6, IL-10, and IL-12 and oxidative stress by employing free oxygen radicals defense and free oxygen radicals test. Results:We found no changes in NGF and oxidative stress parameters, but BDNF decreased compared to healthy children. Quite interestingly, our data showed reduced levels of IL-2, IL-1α, IL- 12, IL-10, and IL-6 in prepubertal KS children. Conclusion: The present study discloses disrupted immune system and neurotrophin pathways in KS children.

Background: Calcium ions play a key role in the heart's functional activity. The steadystate levels of calcium are contingent on the calcium regulating hormonal system, impairment of which might result in the development of cardiac pathology. An important role in these processes is also attributed to the specific inflammatory mediator, HMGB1, one of the damage-associated molecular patterns (DAMPs) released by immune cells or cell damage. Objective: This study investigated the cardioprotective potential of the calcium-regulating hormonal system in cardiomyopathies with an emphasis on the possible role of HMGB1. Methods: Ca2+ and inorganic phosphate levels were determined in the serum using an electrolyte analyzer and spectrophotometric analyzer correspondingly. The 1-34 fragment of parathyroid hormone (PTH), calcitonin, vitamin D, and HMGB1 were detected using ELISA kits. Results: The levels of PTH, calcitonin, phosphate, and HMGB1 were found elevated in females suffering from cardiomyopathy. The same tendency was observed in men; however, statistically significant changes were registered only for PTH and phosphate. Conclusion: It can be suggested that among other reasons, the decrease of the left ventricular function in cardiomyopathy patients can be linked to the high HMGB1, whereas the activation of the calciumregulating system as manifested by the elevated PTH aims at restoration of calcium homeostasis and thus have positive, i.e. cardioprotective consequences.