Protective effect of linarin against D-galactosamine and lipopolysaccharide-induced fulminant hepatic failure

Linarin was isolated from Chrysanthemum indicum L. Fulminant hepatic failure is a serious clinical syndrome that results in massive inflammation and hepatocyte death. Apoptosis is an important cellular pathological process in D-galactosamine (GalN)/lipopolysaccharide (LPS)-induced liver injury, and regulation of liver apoptosis might be an effective therapeutic method for fulminant hepatic failure. This study examined the cytoprotective mechanisms of linarin against GalN/LPS-induced hepatic failure. Mice were given an oral administration of linarin (12.5, 25 and 50 mg/kg) 1 h before receiving GalN (800 mg/kg)/LPS (40 mu g/kg). Linarin treatment reversed the lethality induced by GalN/LPS. After 6 h of GalN/LPS injection, the serum levels of alanine aminotransferase, aspartate aminotransferase, tumor necrosis factor (TNF)-alpha, interleukin-6 and interferon-gamma were significantly elevated. GalN/LPS increased roll like receptor 4 and interleukin-1 receptor associated kinase protein expression. These increases were attenuated by linarin. Linarin attenuated the increased expression of Fas-associated death domain and caspase-8 induced by GalN/LPS, reduced the cytosolic release of cytochrome c and caspase-3 cleavage induced by GalN/LPS, and reduced the pro-apoptotic Bim phosphorylation induced by GalN/LPS. However, linarin increased the level of anti-apoptotic Bcl-xL and phosphorylation of STAT3. Our results suggest that linarin alleviates GalN/LPS-induced liver injury by suppressing TNF-alpha-mediated apoptotic pathways. (C) 2014 Elsevier BY. All rights reserved.