Association of Hypoadiponectinemia with Hypoglutathionemia in NAFLD Subjects with and without Type 2 Diabetes

Objective: The aim of this study is to measure the extent of oxidative stress and to see whether it has any correlation to changes in adiponectin levels in NAFLD subjects with and without Type 2 diabetes.Methods: Subjects recruited from the Chennai Urban Rural Epidemiology Study comprise of 1: Normal Glucose Tolerance (NGT) subjects without NAFLD; 2: NGT with NAFLD; 3: Type 2 Diabetic patients [T2DM] without NAFLD and 4: T2DM with NAFLD. Thiobarbituric acid reactive substances (TBARS), protein carbonyl (PCO), glutathione and adiponectin levels were measured by standard methods. Ultrasound of the liver was used to diagnose NAFLD.Results: T2DM subjects with NAFLD had significantly (p&lt; 0.001) higher levels of thiobarbituric acid reactive substances (TBARS) and protein carbonyls (PCO) but lower (p&lt; 0.001) GSH/GSSG ratio and adiponectin levels compared to other three groups. The association of hypoadiponectinemia withNAFLD/Type 2 diabetes was significant even after adjusting for age, gender and BMI, but lost when adjusted for parameters of oxidative stress. While palmitate significantly reduced GSH/GSSG ratio in hepatocytes, addition of exogenous recombinant adiponectin restored the GSH/GSSG ratio comparable to those of untreated cells.Conclusion: There exists an association of hypoglutathionemia and hypoadiponectinemia in subjects with NAFLD and/or T2DM. In addition to the known beneficial effects, out study also exposes the antioxidant nature of adiponectin.</jats:p

Reductive stress promotes protein aggregation and impairs neurogenesis

Redox homeostasis regulates key cellular signaling in both physiology and pathology. While perturbations result in shifting the redox homeostasis towards oxidative stress are well documented, the influence of reductive stress (RS) in neurodegenerative diseases and its mechanisms are unknown. Here, we postulate that a redox shift towards the reductive arm (through the activation of Nrf2 signaling) will damage neurons and impair neumgenesis. In proliferating and differentiating neumblastoma (Neum 2a/N2a) cells, sulforaphane-mediated Nrf2 activation resulted in increased transcription/translation of antioxidants and glutathione (GSH) production along with significantly declined ROS in a dose-dependent manner leading to a reductive-redox state (i.e. RS). Interestingly, this resulted in endoplasmic reticulum (ER) stress leading to subsequent protein aggregation/proteotoxicity in neuroblastoma cells. Under RS, we also observed elevated Tau/alpha-synuclein and their co-localization with other protein aggregates in these cells. Surprisingly, we noticed that acute RS impaired neumgenesis as evidenced from reduced neurite outgrowth/length. Furthermore, maintaining the cells in a sustained RS condition (for five consecutive generations) dramatically reduced their differentiation and prevented the formation of axons (p &lt; 0.05). This impairment in RS mediated neurogenesis occurs through the alteration of Tau dynamics i.e. RS activates the pathogenic GSK3 beta/Tau cascade thereby promoting the phosphorylation of Tau leading to proteotoxicity. Of note, intermittent withdrawal of sulforaphane from these cells suppressed the proteotoxic insult and re-activated the differentiation process. Overall, this results suggest that either acute or chronic RS could hamper neurogenesis through GSK3 beta/TAU signaling and proteotoxicity. Therefore, investigations identifying novel redox mechanisms impacting proteostasis are crucial to preserve neuronal health

Biological behavior of preneoplastic conditions of the endometrium: A retrospective 16-year study in south India

Abstract Background:The biological behavior of endometrial carcinoma differs in epidemiology, presentation, and prognosis, suggesting that there are two fundamentally different pathogenic types of disease: type I (estrogen related, endometrioid type) and type II (non-estrogen related, non-endometrioid type). Untreated hyperplasia can develop into an endometrioid type of adenocarcinoma, hence, it is important to recognize the former type. In contrast to cervical cancers, there are limited studies with respect to the biology of hyperplastic lesions documented from India. This was a 16-year retrospective study, carried out to determine the nature and outcome of proliferative lesions of the endometrium in a referral center from south India.Materials and Methods:A histopathological diagnosis of the endometrial hyperplasia, polyp, and carcinoma, on endometrial biopsy and hysterectomy specimens, over a 16 year period (1983 to 1999), were recorded in a computer and the case slides were reviewed. Using the computer software Foxpro, the patients who had come more than once for a subsequent or previous biopsy were identified. An attempt was made to look for progression, regression or a static nature of the lesion in the follow-up cases.Results:A total of 1778 cases were studied, and only 74 patients with endometrial hyperplasia and five cases of benign endometrial polyp had follow-up endometrial histopathology. Hyperplasia cases included 59 cases of simple hyperplasia, 10 cases of complex hyperplasia without atypia, and five cases with atypia. The predominant age for patients with all types of hyperplasias was 41 - 50 years. Progression to a higher grade was seen in 8.10%, regression to a lower grade was seen in 9.45%, lesions reverted to a normal pattern in 10.81% cases, and lesions persisted in 70.27% of the cases. A mixed pattern was seen in 54 cases, with predominant coexistent lesion being simple and complex hyperplasia without atypia.Conclusion:The fate of the hyperplastic lesion of the endometrium showed a varied pattern. Follow-up cases predominantly showed persistence of the lesion, possibly resulting from a fluctuating but higher level of estrogenic stimulus. Hence, it was not only the high levels of estrogen that influenced the biology, but its sustenance for a prolonged period.</jats:p

Association of hypoadiponectinemia with hypoglutathionemia in NAFLD subjects with and without type 2 diabetes

Objective: The aim of this study is to measure the extent of oxidative stress and to see whether it has any correlation to changes in adiponectin levels in NAFLD subjects with and without Type 2 diabetes. Methods: Subjects recruited from the Chennai Urban Rural Epidemiology Study comprise of 1: Normal Glucose Tolerance (NGT) subjects without NAFLD; 2: NGT with NAFLD; 3: Type 2 Diabetic patients [T2DM] without NAFLD and 4: T2DM with NAFLD. Thiobarbituric acid reactive substances (TBARS), protein carbonyl (PCO), glutathione and adiponectin levels were measured by standard methods. Ultrasound of the liver was used to diagnose NAFLD. Results: T2DM subjects with NAFLD had significantly (p&lt; 0.001) higher levels of thiobarbituric acid reactive substances (TBARS) and protein carbonyls (PCO) but lower (p&lt; 0.001) GSH/GSSG ratio and adiponectin levels compared to other three groups. The association of hypoadiponectinemia with NAFLD/Type 2 diabetes was significant even after adjusting for age, gender and BMI, but lost when adjusted for parameters of oxidative stress. While palmitate significantly reduced GSH/GSSG ratio in hepatocytes, addition of exogenous recombinant adiponectin restored the GSH/GSSG ratio comparable to those of untreated cells. Conclusion: There exists an association of hypoglutathionemia and hypoadiponectinemia in subjects with NAFLD and/or T2DM. In addition to the known beneficial effects, out study also exposes the antioxidant nature of adiponectin

CRISPR-Cas system: diversity and regulation in Enterobacteriaceae supplementarydata

Insights into the arms race between bacteria and invading mobile genetic elements have revealed the intricacies of the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas system and the counter-defenses of bacteriophages. Incredible spacer diversity but significant spacer conservation among species/subspecies dictates the specificity of the CRISPR-Cas system. Researchers have exploited this feature to type/subtype the bacterial strains, devise targeted antimicrobials and regulate gene expression. This review focuses on the nuances of the CRISPR-Cas systems in Enterobacteriaceae that predominantly harbor type I-E and I-F CRISPR systems. We discuss the systems’ regulation by the global regulators, H-NS, LeuO, LRP, cAMP receptor protein and other regulators in response to environmental stress. We further discuss the regulation of noncanonical functions like DNA repair pathways, biofilm formation, quorum sensing and virulence by the CRISPR-Cas system. The review comprehends multiple facets of the CRISPR-Cas system in Enterobacteriaceae including its diverse attributes, association with genetic features, regulation and gene regulatory mechanisms.</p

Oxidative stress is independently associated with non-alcoholic fatty liver disease (NAFLD) in subjects with and without type 2 diabetes

Objective: Our work is aimed at exploring the interrelationship of oxidative stress and insulin resistance in NAFLD subjects with and without type 2 diabetes in a population-based study. Methods: Subjects [n = 200] were recruited from the Chennai Urban Rural Epidemiology Study. 1: Normal glucose tolerance (NGT) subjects without NAFLD; 2: NGT with NAFLD; 3: type 2 diabetic subjects [T2DM] without NAFLD and 4: T2DM with NAFLD. Thiobarbituric acid reactive substances (TBARS), protein carbonyl (PCC) and glutathione levels were measured by standard methods. Ultrasound of the liver was used to diagnose NAFLD. Results TBARS and PCC levels were significantly elevated and GSH/GSSG ratio was significantly decreased in diabetic subjects with NAFLD compared to all other groups (p trend &lt; 0.001). Oxidative stress markers significantly associated with NAFLD even after adjusting for age, gender, BMI and glycemic status. Conclusions Increased oxidative stress is independently associated with NAFLD in Asian Indians without and with T2DM