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.
Keywords:
Apoptosis; Fulminant hepatic failure; Galactosamine and lipopolysaccharide; Inflammation; Linarin; Tumor necrosis factor-α.
Copyright © 2014 Elsevier B.V. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alanine Transaminase / metabolism
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Animals
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Apoptosis / drug effects
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Apoptosis Regulatory Proteins / metabolism
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Aspartate Aminotransferases / metabolism
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Bcl-2-Like Protein 11
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Caspase 3 / metabolism
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Caspase 8 / metabolism
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Cytochromes c / metabolism
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Cytoprotection / drug effects*
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Cytosol / drug effects
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Cytosol / metabolism
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Fas-Associated Death Domain Protein / metabolism
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Galactosamine / pharmacology*
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Glycosides / pharmacology*
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Interferon-gamma / blood
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Interferon-gamma / genetics
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Interleukin-1 Receptor-Associated Kinases / metabolism
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Interleukin-6 / blood
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Interleukin-6 / genetics
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Lipopolysaccharides / pharmacology*
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Liver / drug effects
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Liver / pathology
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Liver Failure, Acute / chemically induced*
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Liver Failure, Acute / metabolism
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Liver Failure, Acute / pathology
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Liver Failure, Acute / prevention & control*
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Male
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Membrane Proteins / metabolism
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Mice
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Phosphorylation / drug effects
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Proteolysis / drug effects
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Proto-Oncogene Proteins / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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STAT3 Transcription Factor / metabolism
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Signal Transduction / drug effects
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Toll-Like Receptor 4 / metabolism
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Tumor Necrosis Factor-alpha / blood
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Tumor Necrosis Factor-alpha / genetics
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bcl-X Protein / metabolism
Substances
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Apoptosis Regulatory Proteins
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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Fadd protein, mouse
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Fas-Associated Death Domain Protein
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Glycosides
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Interleukin-6
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Lipopolysaccharides
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Membrane Proteins
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Proto-Oncogene Proteins
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RNA, Messenger
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STAT3 Transcription Factor
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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Tumor Necrosis Factor-alpha
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bcl-X Protein
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Galactosamine
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Interferon-gamma
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Cytochromes c
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Aspartate Aminotransferases
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Alanine Transaminase
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Interleukin-1 Receptor-Associated Kinases
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Caspase 3
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Caspase 8
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linarin