title: Protective effect of linarin against D-galactosamine and lipopolysaccharide-induced fulminant hepatic failure.
abstract: 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.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Seok-Joo
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Hong-Ik
authors.initials: HI
authors.lastname: Cho
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: So-Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Jin-Hyun
authors.initials: JH
authors.lastname: Park
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Joon-Sung
authors.initials: JS
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Sang Kook
authors.initials: SK
authors.lastname: Lee
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Jong-Hwan
authors.initials: JH
authors.lastname: Kwak
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea. Electronic address: sunmee@skku.edu.
authors.forename: Sun-Mee
authors.initials: SM
authors.lastname: Lee
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001219:Aspartate Aminotransferases / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D005688:Galactosamine / Q000494:pharmacology*; D006027:Glycosides / Q000494:pharmacology*; D007371:Interferon-gamma / Q000097:blood / Q000235:genetics; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D006027:Glycosides; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D005688:Galactosamine; D007371:Interferon-gamma; D045304:Cytochromes c; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D053592:Interleukin-1 Receptor-Associated Kinases; D053148:Caspase 3; D053181:Caspase 8; C008282:linarin
keywords: Apoptosis; Fulminant hepatic failure; Galactosamine and lipopolysaccharide; Inflammation; Linarin; Tumor necrosis factor-α