Subrata Kumar Biswas

Homeostatic nuclear RAGE-ATM interaction is essential for efficient DNA repair

Abstract The integrity of genome is a prerequisite for healthy life. Indeed, defects in DNA repair have been associated with several human diseases, including tissue-fibrosis, neurodegeneration and cancer. Despite decades of extensive research, the spatio-mechanical processes of double-strand break (DSB)-repair, especially the auxiliary factor(s) that can stimulate accurate and timely repair, have remained elusive. Here, we report an ATM-kinase dependent, unforeseen function of the nuclear isoform of the Receptor for Advanced Glycation End-products (nRAGE) in DSB-repair. RAGE is phosphorylated at Serine376 and Serine389 by the ATM kinase and is recruited to the site of DNA-DSBs via an early DNA damage response. nRAGE preferentially co-localized with the MRE11 nuclease subunit of the MRN complex and orchestrates its nucleolytic activity to the ATR kinase signaling. This promotes efficient RPA2S4-S8 and CHK1S345 phosphorylation and thereby prevents cellular senescence, IPF and carcinoma formation. Accordingly, loss of RAGE causatively linked to perpetual DSBs signaling, cellular senescence and fibrosis. Importantly, in a mouse model of idiopathic pulmonary fibrosis (RAGE−/−), reconstitution of RAGE efficiently restored DSB-repair and reversed pathological anomalies. Collectively, this study identifies nRAGE as a master regulator of DSB-repair, the absence of which orchestrates persistent DSB signaling to senescence, tissue-fibrosis and oncogenesis.

Effect of aqueous extract of Aegle marmelos fruit and leaf on glycemic, insulinemic and lipidemic status of type 2 diabetic model rats

Abstract Background Aegle marmelos is a popular fruit plant in the Indian subcontinent, various parts of which are traditionally used against various illnesses including diabetes mellitus (DM). However, the underlying mechanisms of the antidiabetic effects of the plant are not clear, especially in type 2 DM. The present study was undertaken to investigate the effect of aqueous extracts of A. marmelos fruits (AMFE) and leaves (AMLE) on glycemic, lipidemic, insulinemic, insulin resistance and β-cell functional status of type 2 diabetic model rats. Methods An interventional study was designed using 20 type 2 diabetic rats. Type 2 DM was induced in Long Evans rats by a single intra-peritoneal injection of streptozotocin (90 mg/kg body weight) to 48 h old pups. Three months after induction of diabetes, the rats were divided into three independent groups: water-treated control group (n=6), AMLE-treated group (n=7) and AMFE-treated group (n=7). The rats were fed with extracts or water for 21 consecutive days and blood samples were collected at days 0 and 21 after an overnight fast. Data were expressed as mean±SD and analyzed by paired t-test or ANOVA as appropriate. Results There were significantly lower blood glucose values in AMLE and AMFE groups at Endpoint compared to Baseline (mmol/l, mean±SD, Baseline vs. Endpoint, 7.04±1.0 vs. 6.06±0.92; p=0.032 and 7.04±0.97 vs. 5.87±0.93; p=0.047). There were also significantly lower serum insulin levels in AMLE and AMFE groups at Endpoint compared to Baseline (µIU/mL, mean±SD, Baseline vs. Endpoint, 14.02±5.48 vs. 7.57±2.90; p=0.026 and 11.54±4.83 vs. 6.58±4.36; p=0.008). Insulin resistance (HOMA-IR) was significantly improved both in AMLE and AMFE groups at Endpoint compared to Baseline (mean±SD, Baseline vs. Endpoint, 4.22±1.68 vs. 2.05±0.90; p=0.021 and 3.69±1.79 vs. 1.69±1.61; p=0.013). However, β-cell function or lipid profile did not show any significant alteration at Endpoint compared to Baseline in AMLE and AMFE groups. Conclusions Aqueous extracts of A. marmelos leaf and fruit have hypoglycemic property which seem to be mediated by lowering of insulin resistance. These findings highlight the therapeutic potential of the extracts of A. marmelos in human type 2 DM and provides strong impetus for further studies.

Biomarkers of cardiovascular and metabolic diseases in otherwise healthy overweight subjects in Bangladesh

Biomarkers of cardiovascular and metabolic diseases were assessed in Bangladeshi overweight subjects categorized by Asian BMI criteria. After screening 300 people, 90 apparently healthy subjects were enrolled and grouped into normal weight, overweight and obese. Compared to normal weight, the overweight and obese groups showed significant elevation of serum triglyceride, insulin, homocysteine, insulin resistance/sensitivity, and atherogenic index of plasma. Cardiometabolic biomarkers did not differ between overweight and obese groups. Some biomarkers showed correlation with BMI in overweight but not in obese group. It was concluded that cardiometabolic biomarkers are elevated in Bangladeshi overweight subjects categorized by Asian BMI criteria.

NecroX-7 may appear as a new molecule to stabilize atherosclerotic plaques

Atherosclerosis is a slowly progressive inflammatory disease characterized by the accumulation of lipids and fibrous tissue in the intimal layer of arteries. The process of atherosclerosis begins with endothelial cell dysfunction followed by expression of adhesion molecules that allow adhesion of endothelial cells with circulating monocytes [1,2]. Adherent monocytes migrate to the subendothelial space and acquire the characteristics of tissue macrophage. The subendothelial macrophages engulf lipoproteins (mainly modified/oxidized LDL) and become foam cells, the hallmark of the early fatty streak lesion. The foam cells secrete proinflammatory cytokines and reactive oxygen species (ROS) that further amplify local inflammatory response and consequently, smooth muscle cells (SMC) migrate into the intima and proliferate, producing the fibrous cap of the atherosclerotic plaque [1,2]. Different types of cells in advanced human atherosclerotic plaques undergo both necrotic and apoptotic cell death [3,4]. High levels of oxidative stress, depletion of ATP, impaired clearance of apoptotic cells and increased intracellular calcium level can induce necrotic cell death in atherosclerotic plaques. Necrotic cell death contributes to progression of atherosclerosis and plaque instability through induction of inflammation and enlargement of necrotic core [3]. In advanced atherosclerotic plaques, macrophages

Neutrophil elastase and myeloperoxidase mRNA expression in overweight and obese subjects

Neutrophil elastase and myeloperoxidase enzymes have been implicated in high-fat diet-induced obesity, insulin resistance (IR) and atherosclerosis in animal models. The aim of the present study was to explore neutrophil elastase and myeloperoxidase mRNA expressions in the peripheral blood leukocytes (PBL) in overweight and obese subjects, and to correlate those mRNA expressions with BMI, IR and cardiovascular biomarkers. In this cross-sectional study, 74 apparently healthy subjects including 22 lean, 27 overweight and 25 obese subjects were recruited. Cardiovascular and metabolic biomarkers were evaluated from fasting blood samples. The mRNA levels of neutrophil elastase and myeloperoxidase genes in the PBL were quantified by real-time PCR. Compared to lean group, the overweight and obese groups showed significant upregulation of both neutrophil elastase (p < 0.001) and myeloperoxidase (p < 0.03) mRNA expressions in the PBL. But no difference was found between overweight and obese groups. The neutrophil elastase and myeloperoxidase mRNA levels showed significant positive correlation with BMI, serum triglyceride, atherogenic index of plasma and 10-year risk of developing cardiovascular disease. But no correlation was found with glucose, insulin or IR. It was concluded that the neutrophil elastase and myeloperoxidase genes are up-regulated in both overweight and obese subjects and are associated with BMI and markers of cardiovascular disease.

Optimised rapeseed oil optimises oxidative stress and lipid profile

Despite extensive research throughout the 20th century, cardioascular disease (CVD) is still the leading cause of deathworldwide. therosclerosis is the most important contributor to and underying mechanism for CVD. Atherosclerosis is a slowly progressive isease characterized by the accumulation of lipids and fibrous issue in the intimal layer of arteries. The involvement of blood ipids, particularly hypercholesterolemia, in the pathogenesis of therosclerosis has been confirmed in animal studies and clinical rials with lipid lowering agents. In fact, it has been demonstrated hat each 40mg per deciliter reduction in LDL cholesterol correponds to a 24% reduction of major cardiovascular events [1], and ach 1mg per deciliter increase in HDL-cholesterol is associated ith a 2–3% reduction in the risk of future coronary heart disease 2]. Recent research, however, indicates the direct involvement of nflammationandoxidative stress for the initiationandprogression f atherosclerosis [3,4]. The process of atherosclerosis involves complex interactions mong the genetic and environmental factors. Many of the isk factors for atherosclerosis and CVD including dyslipidemia, ypertension, obesity, diabetes mellitus, smoking, hyperhomoysteinemia and sedentary life style can induce endothelial cell ysfunction, oneof theearly events in atherosclerosis.Normally the ndothelium resists prolonged contact with circulating leukocytes. owever, following endothelial cell dysfunction or inflammatory