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

• Published in: European journal of pharmacology Vol. 738; pp. 66 - 73
• Main Authors: Kim, Seok-Joo, Cho, Hong-Ik, Kim, So-Jin, Park, Jin-Hyun, Kim, Joon-Sung, Kim, Young Ho, Lee, Sang Kook, Kwak, Jong-Hwan, Lee, Sun-Mee
• Format: Journal Article
• Language: English
• Published: Netherlands 05.09.2014
• Subjects: Alanine Transaminase - metabolism; Animals; Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; Aspartate Aminotransferases - metabolism; Bcl-2-Like Protein 11; bcl-X Protein - metabolism; Caspase 3 - metabolism; Caspase 8 - metabolism; Chrysanthemum; Cytochromes c - secretion; Cytoprotection - drug effects; Cytosol - drug effects; Cytosol - secretion; Fas-Associated Death Domain Protein - metabolism; Galactosamine - pharmacology; Glycosides - pharmacology; Interferon-gamma - blood; Interferon-gamma - genetics; Interleukin-1 Receptor-Associated Kinases - metabolism; Interleukin-6 - blood; Interleukin-6 - genetics; Lipopolysaccharides - pharmacology; Liver - drug effects; Liver - pathology; Liver Failure, Acute - chemically induced; Liver Failure, Acute - metabolism; Liver Failure, Acute - pathology; Liver Failure, Acute - prevention & control; Male; Membrane Proteins - metabolism; Mice; Phosphorylation - drug effects; Proteolysis - drug effects; Proto-Oncogene Proteins - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - drug effects; STAT3 Transcription Factor - metabolism; Toll-Like Receptor 4 - metabolism; Tumor Necrosis Factor-alpha - blood; Tumor Necrosis Factor-alpha - genetics; Inflammation; Tumor necrosis factor-α; Galactosamine and lipopolysaccharide; Linarin; Fulminant hepatic failure; Apoptosis
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2014.05.024

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 50mg/kg) 1h before receiving GalN (800 mg/kg)/LPS (40 μg/kg). Linarin treatment reversed the lethality induced by GalN/LPS. After 6h of GalN/LPS injection, the serum levels of alanine aminotransferase, aspartate aminotransferase, tumor necrosis factor (TNF)-α, interleukin-6 and interferon-γ were significantly elevated. GalN/LPS increased toll-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-α-mediated apoptotic pathways.