Endocrine Metabolic & Immune Disorders - Drug Targets
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Author(s):  
Mojtaba Bakhtiari ◽  
Kamyar Asadipooya

Abstract: A new coronavirus pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2], has been on the rise. This virus is fatal for broad groups of populations, including elderly, men, and patients with comorbidities among which obesity is a possible risk factor. The pathophysiologic connections between obesity/metainflammation and COVID-19 may be directly related to increasing soluble ACE2 (angiotensin-converting enzyme 2] levels which potentiates the viral entrance into the host cells, or indirectly related to dysregulation of immune system, microvascular injury and hypercoagulability. The SARS-CoV-2 S-glycoprotein interacts mainly with ACE2 or possibly DDP4 receptors to enter into the host cells. The host proteases, especially TMPRSS2 (transmembrane protease serine 2], support the fusion process and virus entry. While membranous ACE2 is considered a port of entry to the cell for SARS-CoV-2, it seems that soluble ACE2 retains its virus binding capability and enhances its entry into the cells. Interestingly, ACE2 on cell membrane may have protective roles by diminishing cytokine storm-related injuries to the organs. Applying medications that can reduce soluble ACE2 levels, antagonizing TMPRSS2 or blocking DDP4 can improve the outcomes of COVID-19. Metformin and statins through immunomodulatory activities, Orlistat by reducing viral replication, and thiazolidinediones by upregulating ACE2 expression have potential beneficial effects against COVID-19. However, the combination of dipeptidyl peptidase-4 (DDP4] inhibitors and spironolactone/eplerenone seems to be more effective by reducing soluble ACE2 level, antagonizing TMPRSS2, maintaining ACE2 on cell membrane and reducing risk of viral entry into the cells.


Author(s):  
Elena Castellano ◽  
Donatella Gaviglio ◽  
Micaela Pellegrino ◽  
Laura Gianotti ◽  
Giampaolo Magro ◽  
...  

Background: The discharge from hospital of insulin-treated hyperglycemic patients is always challenging. This is even more so in patients requiring glucocorticoid treatment, such as those with COVID-19. Patients and method: A retrospective monocentric study of 23 inpatients with newly diagnosed or already known diabetes mellitus (DM) who were naïve to insulin treatment, , and who were hospitalized with COVID-19 in non-critical settings and then discharged. Patients were followed-up for one month after discharge for the management of insulin treatment by a multi-professional team through phone consultations. Results: Insulin prescriptions at discharge were 24.6 ± 14 U/day injected in 2 ± 1.5 daily shots. A mean of three phone consultations were required. One month later, the mean insulin reduction was 1.5 ± 1.3 shots and 6 ± 5 U/day. All patients reached their glycemic target without hypoglycemic events, drop-outs, or readmissions. Conclusion: This study demonstrates the feasibility, efficacy, and safety of a multi-professional approach through telemedicine for managing DM patients after discharge during COVID-19.


Author(s):  
Sreenu Thalla ◽  
Kamaraj R ◽  
Kavitha A

Abstract: Non-alcoholic fatty liver disease (NAFLD) is marked by the excessive intrusion of triglycerides into hepatocytes without any role of alcohol consumption. Various risk factors have been attributed to this disease pathogenesis which involves metabolic disorders, immune response, and even an intricate relationship between the two. The role of insulin resistance (IR) in NAFLD has long been known; however, the molecular basis of disease progression under this metabolic backdrop is still being investigated. Similarly, the periodontitis-mediated immune response is another major factor involved in NAFLD manifestation which has generated huge interest. The prevalence of pathogenic bacteria elicits a strong immune response which according to studies shows a strong correlation with NAFLD state. Such pre-existing conditions have a strong probability of explaining the disease onset. Additionally, increasing reports of inflammatory response and its links to insulin resistance have further increased the scope of understanding NAFLD. Through this review, we aim to elaborate on these factors explaining their role in the disease progression.


Author(s):  
Mohammad Javad Fattahi ◽  
Mohammad Reza Haghshenas ◽  
Abbas Ghaderi

Abstract: The initiation and progression of bladder cancer (BC), is dependent on its tumor microenvironment (TME). On the other hand, cancer cells shape and train TME to support their development, respond to treatment and migration in an organism. Immune cells exert key roles in the BC microenvironment and have complex interactions with BC cells. These complicated interplays result in metabolic competition in the TME leading to nutrient deprivation, acidosis, hypoxia and metabolite accumulation, which impair immune cell function. Recent studies have demonstrated that immune cells functions are closely correlated with their metabolism. Immunometabolism describes the functional metabolic alterations that take place within immune cells and the role of these cells in directing metabolism and immune response in tissues or diseases such as cancer. Some molecules and their metabolites in the TME including glucose, fatty acids and amino acids can regulate the phenotype, function and metabolism of immune cells. Hence, here we describe some recent advances in immunometabolism and relate them to BC progression. A profound understanding of the metabolic reprogramming of BC cells and immune cells in the TME will offer novel opportunities for targeted therapies in future.


Author(s):  
Thais Sibioni Berti Bastos ◽  
Tárcio Teodoro Braga ◽  
Mariana Rodrigues Davanso

Background: Type 1 diabetes (T1D) is a chronic autoimmune disease that affects people globally. Usually developed during childhood, T1D is characterized by the destruction of pancreatic β-cells due to immune cell attack and the establishment of an inflammatory process. Objective: The study aimed to investigate the effects of vitamin D through its nuclear receptor and the ω-3 polyunsaturated fatty acids (PUFAs) through their lipid derivatives in T1D modulation. Both components exert anti-inflammatory activity and act directly on cells of the immune system, attenuating the destruction of insulin-producing cells. Furthermore, they lead to a better glycemic level, reducing the need for insulin and a normal immune state, such as C-peptide maintenance. Method: Presently, our review highlights the significant studies that evaluated the supplementation of vitamin D and ω-3 PUFAs in humans and animal models in the modulation of T1D. Conclusion: The data collected suggests that supplementation can provide potential benefits, mainly when done early in the diagnosis, since it reduces the need for insulin and the risk of complications generated by the disease.


Author(s):  
Hong-Xia Zhang ◽  
Jie Yuan ◽  
Rong-Shan Li

Background: Previous studies have shown that endoplasmic reticulum (ER) stress is related to the apoptosis in the development of diabetic nephropathy (DN) and thalidomide (Thd) has renal-protective effects by suppressing inflammation and proliferation of MCs in DN. However, the effect of Thd on the apoptosis of MCs in DN remains largely unclear. The present research is designed to explore the effect of Thd on apoptosis in DN and the related mechanisms. Objective: The study is designed to examine the effect and mechanism of Thd on apoptosis in type 2 diabetic mice and high glucose (HG)-induced MCs. Method: We first evaluated the ER stress markers and apoptosis-related proteins with the treatment of Thd in type 2 diabetic mice and MCs in vitro under HG conditions. MTT assay was used to assess cell viability. Additionally, we evaluated the effect of Thd treatment upon MC apoptosis through flow cytometry. Real-time polymerase chain reaction (RT-PCR) and Western blot were performed to evaluate genes and protein expression related to ER stress and apoptosis. Results: The levels of blood urea BUN, CREA, Urine albumin, and UACR in diabetic mice were significantly reduced after 8 weeks of intervention with Thd. And also, there were upregulated glucose-regulated protein 78 (GRP78), Caspase-12, and downregulated B-cell lymphoma 2 (Bcl-2) in glomeruli of DN mice. In vitro, compared with the HG group, MC apoptosis reduced dramatically with Thd treatment along with upregulation of Bcl-2 and downregulation of Bax. At the same time, ER stress markers GRP78, C/EBP homologous protein (CHOP), and Caspase-12 were also mitigated following the Thd treatment. Conclusion: The present study indicates that Thd might reduce the ER stress in DN via downregulating of GRP78, CHOP, and Caspase12 expression, ultimately mitigating MCs apoptosis.


Author(s):  
Fabiana Dalla Vecchia Genvigir ◽  
Carolina Dagli Hernandez ◽  
Thiago Dominguez Crespo Hirata ◽  
Yitian Zhou ◽  
Volker M Lauschke ◽  
...  

Background: The available antihypertensive drugs are effective and well tolerated agents. However, only about half of patients with treated hypertension achieve appropriate blood pressure control. Genetic and non-genetic factors contribute to the interindividual variability of the therapeutic response Objective: This review constitutes a comprehensive update of the pharmacogenomics of antihypertensive drugs and their clinical implications in Brazil. Results: Twenty-five studies explored the influence of gene variants on drug response in patients with primary, resistant, or gestational hypertension. Variants in BDKRB2, NOS3, PRKCA, and VEGFA influenced the response to enalapril in patients with primary hypertension. AGT and MMP2 variants were associated with high risk of resistance to antihypertensive treatment, whereas NOS2 variants were related to low risk. Moreover, NAT2 slow acetylators showed an increased response to hydralazine in patients with resistant hypertension. HMOX1, NAMPT, MMP9, NOS3 and TIMP1 variants might be markers of drug responsiveness in hypertensive or preeclamptic pregnant women. Power and replication of studies, polygenic nature of response to therapy, and treatment with multiple drugs were important challenges to be overcome for identifying genetic predictors of antihypertensive response in Brazil. Conclusion: Pharmacogenomic studies in Brazilian cohorts provide some evidences of variants, mainly in pharmacodynamics genes, which influence the response to antihypertensive drugs. However, some findings are limited by cohort size or therapeutic scheme and may be influenced by interactions with other genetic and non-genetic factors. Therefore, further investigations are needed to elucidate the contribution of pharmacogenomics to the efficacy and safety of antihypertensive therapy.


Author(s):  
Gamze Akkus ◽  
Ferhat Piskin ◽  
Barış Karagun ◽  
Murat Sert ◽  
Mehtap Evran ◽  
...  

Background: Diagnostic imaging techniques including magnetic resonance imaging (MRI) should also perform on all patients with incidentalomas. However, there is a limited study whether the quantitative measurements (signal intensity index, adrenal to spleen ratio) in MRI could predict the functional status of adrenal adenomas. Material-Method: Between 2015-2020; 404 patients (265 females, 139 males) with adrenal mass who were referred to the university hospital for further investigation were included. After detailed diagnostic hormonal evaluation, all patients underwent MRI 1.5 T device (Signa, GE Medical Systems; Milwaukee, USA). The signal intensities of the adrenal lesions on T2W images were qualitatively evaluated and noted as homogenous or heterogeneous in comparison with the liver signal intensity (SI). A chemical-shift SI index and chemical shift adrenal-to-spleen SI ratio were also calculated. Results: While 331(81.9%) of the patients had nonfunctional adrenal mass, the rest of them (n=73, 18.1%) were patients with functional (autonomous cortisol secretion-ACS, cushing syndrome-CS, pheochromocytoma, primary hyperaldosteronism-PA) adrenal masses. In phase vs phase values of patients with NFAI, Pheo(n=17), ACS (n=30), CS (n=11), and PA (n=15) were 474.04±126.7 vs 226.6±132.4, 495.3±182.8 vs 282.17±189.1, 445.2±134.8 vs 203.3±76.2, 506.8±126.5 vs 212.2±73.6 and 496.2±147.5 vs 246.6±102.1, respectively. Mean signal intensity index (SII) and adrenal to spleen ratio (ASR) of all groups (NFAI, Pheo, ACS, CS, PA) were 52.0±24.8 and 0.51, 44.9±22.5 and 0.55, 49.5±24.5 and 0.53, 56.2±16.4 and 0.43, 47.6±25.1 and 0.54, respectively. Based the current accepted measurements in the case of ASR and SII, all lesions were similar and shown as fat rich adenomas (p*= 0.552, p** = 0.45). Conclusion: The quantitative assessment (SII, ASR) of intracellular lipids in an incidentally discovered adrenal tumour could only help distinguish adrenal masses in case of adenomas or non-adenomas As initial diagnostic evaluation, clinical and laboratory assessment ,to distinguish hormone secretion, should be taken in all patients with adrenal incidentalomas.


Author(s):  
Sen Zhang ◽  
Fenfang Hong ◽  
Chen Ma ◽  
Shulong Yang

: Lipid metabolism disorder plays a fundamental role in the pathogenesis of atherosclerosis. As the largest metabolic organ of the human body, liver has a key role in lipid metabolism by influencing fat production, fat decomposition, and the intake and secretion of serum lipoproteins. Numerous clinical and experimental studies have indicated that the dysfunction of hepatic lipid metabolism is closely tied to the onset of atherosclerosis. However, the identity and functional role of hepatic lipid metabolism responsible for these associations remain unknown. This review presented that cholesterol synthesis, cholesterol transport, and the metabolism of triglyceride, lipoproteins, and fatty acids are all associated with hepatic lipid metabolism and atherosclerosis. Moreover, we also discussed the roles of gut microbiota, inflammatory response, and oxidative stress in the pathological association between hepatic lipid metabolism and atherosclerosis. These significant evidences support strongly that hepatic lipid metabolism disorders may increase the risk of atherosclerosis.


Author(s):  
Vincenzo Triggiani ◽  
Giuseppe Lisco

: Chronic heart failure represents a relevant concern for public health. The endocrine system is heavily involved in the induction and progression of chronic heart failure. Among endocrine dysfunction, the most relevant alterations are related to the growth hormone-insulin like growth factor 1 axis, serum testosterone, dehydroepiandrosterone sulfate, triiodothyronine levels, insulin resistance, and type 2 diabetes mellitus. It is currently debated whether these changes might be simple adaptive mechanisms or, instead, they may deteriorate myocardial pump function over time. Medical management of patients exhibiting one or more hormonal deficiencies or metabolic disorders, including insulin resistance and diabetes mellitus, may have a therapeutic role.


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