ex-527 and Chemical-and-Drug-Induced-Liver-Injury

The study examined the protective effect of exogenous administration of dehydroepiandrosterone (DHEA) against acetaminophen (APAP) -induced liver damage in rats and tested the underlying mechanism(s). Male rats were divided into 5 groups as control, control + DHEA, APAP, APAP + DHEA, and APAP + DHEA + EX-527 (SIRT1 inhibitor). Treatments were conducted for 10 days and then followed by intragastric administration of a single dose of APAP. DHEA not only reduced serum alanine transaminase (ALT) and aspartate aminotransferase (AST) but also preserved the liver structures. Besides, DHEA reduced hepatic levels of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), Bax, cleaved caspase-3. In the livers of both the control and APAP-treated rats, DHEA suppressed the generation of reactive oxygen species (ROS) and malondialdehyde (MDA), increased levels of glutathione (GSH), MnSOD (SOD2), and Bcl-2 levels, lowered Bax/Bcl-2 ratio, enhanced the activity of nuclear factor erythroid-derived 2-like 2 (Nrf2), and inhibited nuclear factor kappaB (NF-κB) p65. All these effects coincided with a significant increase in the levels and activity of SIRT1 and a reduction in the acetylation of Nrf2, p53, forkhead box class O transcription factor 1 (FOXO1), and NF-κB p65. Except for Bcl-2, treating the rats with EX-527 abolished the beneficial effects of DHEA on all these markers. In conclusion, DHEA prevents APAP-induced liver damage by concomitant upregulation of Bcl-2 and SIRT1-dependent effect.

Topics: Acetaminophen; Animals; Carbazoles; Chemical and Drug Induced Liver Injury; Dehydroepiandrosterone; Male; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Wistar; Reactive Oxygen Species; Signal Transduction; Sirtuin 1; Up-Regulation

D-Galactosamine/Lipopolysaccharide (D-GalN/LPS) is a well known model of hepatotoxicity that closely resembles acute liver failure (ALF) seen clinically. The role of sirtuin 1 in this model has not yet been documented. However, there have been a number of studies about the cytoprotective effects of resveratrol, a SIRT1 activator, in the liver. This study was aimed at elucidating the roles of SIRT1 protein expression or catalytic activity in D-GalN/LPS model of hepatotoxicity. ALF was induced in male Wistar rats by intraperitoneal injection of D-GalN and LPS. Some groups of animals were pretreated with resveratrol and/or EX-527 (SIRT1 inhibitor). The effects of these treatments were evaluated by biochemical and Western blot studies. D-GalN/LPS treatment was able to induce hepatotoxicity and significantly increase all markers of liver damage and lipid peroxidation. A dramatic decrease of SIRT1 levels in response to D-GalN/LPS treatment was also documented. Resveratrol pretreatment attenuated D-GalN/LPS-induced hepatotoxicity. EX-527 blocked the cytoprotective effects of resveratrol. However, both resveratrol and EX-527 pretreatments did not exhibit any significant effect on SIRT1 protein expression. Collectively, these results suggest that downregulation of SIRT1 expression is involved in the cytotoxic effects of D-GalN/LPS model and SIRT1 activity contributes to the cytoprotective effects of resveratrol in the liver.

Topics: Animals; Antioxidants; Carbazoles; Chemical and Drug Induced Liver Injury; Cytoprotection; Disease Models, Animal; Down-Regulation; Enzyme Inhibitors; Galactosamine; Lipid Peroxidation; Lipopolysaccharides; Liver; Male; Rats, Wistar; Resveratrol; Sirtuin 1; Stilbenes