Sambhu Charan Mondal

Role of PPARg2 transcription factor in thiazolidinedione-induced insulin sensitization

Objectives  Adipose tissue is the key regulator of energy balance, playing an active role in lipid storage and metabolism and may be a dynamic buffer to control fatty acid flux. Peroxisome proliferator‐activated receptor gamma isoform‐2 (PPARg2), an isoform of the nuclear hormone receptor superfamily, has been implicated in almost all aspects of human metabolic alterations such as obesity, insulin resistance, type‐2 diabetes and dyslipidaemia. The PPARg2 isoform is highly present in adipose tissue where it functions as a thrifty phenotype, which promotes adipocyte differentiation and triglyceride storage. Thiazolidinediones, antidiabetic drugs, induce insulin sensitivity by controlling adipokines. The thiazolidinediones bind with PPARg2 in adipocytes and exert an agonist effect by enhancing adipogenesis and fatty acid uptake. Thiazolidinediones stimulate PPARg2, by which they down‐regulate tumour necrosis factor‐α, leptin, interleukin‐6 and plasminogen and also enhance insulin sensitivity. The aim of this work is to define role of PPARg2 transcription factor in thiazolidinedione‐induced insulin sensitization.

Furosemide‐induced genotoxicity and cytotoxicity in the hepatocytes, but weak genotoxicity in the bone marrow cells of mice

Furosemide (FS) is a potent loop diuretic widely used in the management of fluid retention associated with cardiac, renal, and hepatic failure as well as for the treatment of hypertension. FS is a well‐characterized and known hepatotoxin in both human and animal test systems. In this study, an attempt has been made to investigate the in vivo genotoxicity of FS at the hepatotoxic equivalent doses using the chromosomal aberration and the comet assay in the bone marrow cells of mice as the endpoints of evaluation. The animals were treated with FS at the doses of 2.5, 5, 10, 20, 40, and 80 mg/kg/body weight (bw) intraperitoneal (ip) for both single (24 h) and repeated dose (seven consecutive days) toxicity studies. FS toxicity in the hepatocytes was evaluated using the parameters, such as, alanine‐/aspartate‐aminotransferase (ALT/AST), single cell gel electrophoresis (comet), tissue histology, DNA fragmentation, and TUNEL assay as the endpoints. The results clearly demonstrate that FS produced toxic responses in the hepatocytes as evident from increased ALT/AST level, DNA damage, TUNEL positive cells and increased DNA fragmentation in mice in vivo. However, it is interesting that in bone marrow cells, FS did not induced structural chromosomal abberations, but produced mild DNA strand breaks as observed by the comet assay. So it is considered as weak genotoxic toward the bone marrow cells when compared to the hepatocytes of mice.

The target-specific transporter and current status of diuretics as antihypertensive.

The currently available diuretics increase the urinary excretion of sodium chloride by selective inhibition of specific sodium transporters in the loop of Henle and distal nephron. In recent years, the molecular cloning of the diuretic‐sensitive sodium transporters at distal convoluted tubule has improved our understanding of the cellular mechanisms of action of each class of diuretics. Diuretics are tools of considerable therapeutic importance. First, they effectively reduce blood pressure. Loop and thiazide diuretics are secreted from the proximal tubule via the organic anion transporter‐1 and exert their diuretic action by binding to the Na+‐K+‐2Cl− co‐transporter type 2 in the thick ascending limb and the Na+‐ Cl− co‐transporter in the distal convoluted tubule, respectively. Recent studies in animal models suggest that abundance of these ion transporters is affected by long‐term diuretic administration. The WHO/ISH guidelines point out that diuretics enhance the efficacy of antihypertensive drugs and will most often be a component of combination therapy.