論文

査読有り
2007年3月

An inhibitor of c-Jun NH2-terminal kinase, SP600125, protects mice from D-galactosamine/lipopolysaccharide-induced hepatic failure by modulating BH3-only proteins

LIFE SCIENCES
  • Masaaki Takamura
  • ,
  • Yasunobu Matsuda
  • ,
  • Satoshi Yamagiwa
  • ,
  • Yasushi Tamura
  • ,
  • Yutaka Honda
  • ,
  • Kenji Suzuki
  • ,
  • Takafumi Ichida
  • ,
  • Yutaka Aoyagi

80
14
開始ページ
1335
終了ページ
1344
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1016/j.lfs.2006.12.034
出版者・発行元
PERGAMON-ELSEVIER SCIENCE LTD

Fulminant hepatic failure (FHF) is a dramatic clinical syndrome characterized by massive hepatocyte apoptosis and very high mortality. The c-Jun-N-terminal kinase (JNK) pathway is an important stress-responsive kinase activated by several forms of liver injury. The aim of this study is to assess the role of JNK during D-galactosamine (GalN)/lipopolysaccharide (LPS)-induced liver injury, an experimental model of FHF, using SP600125. a small molecule JNK-specific inhibitor. Mice were given an intraperitoneal dose of GalN (800 mu g/g body weight)/LPS (100 ng/g body weight) with and without subcutaneous SP600125 (50 mg/kg body weight) treatment (at 6 and 2 h before and 2 h after GalN/LPS administration). GalN/LPS treatment induced sustained INK activation. Administration of SP600125 diminished INK activity, suppressed lethality and the elevation of both serum alanine aminotransferase and aspartate aminotransferase, but had no effect on serum tumor necrosis factor-alpha. and reduced hepatocyte apoptosis after GalN/LPS administration. In support of the role of JNK in promoting the mitochondria-mediated apoptosis pathway, SP600125 prevented cytochrome c release, caspase-9 and caspase-3 activity. Moreover, SP600125 downregulated the mRNA and protein expression of Bad in the early periods following GalN/LPS injection and prevented Bid cleavage in the late periods. These results confirm the role of JNK as a critical apoptotic mediator in GalN/LPS-induced FHF. SP600125 has the potential to protect FTF by downregulating Bad and inhibiting Bid cleavage. (c) 2007 Elsevier Inc. All rights reserved.

リンク情報
DOI
https://doi.org/10.1016/j.lfs.2006.12.034
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/17300814
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000245230200012&DestApp=WOS_CPL
ID情報
  • DOI : 10.1016/j.lfs.2006.12.034
  • ISSN : 0024-3205
  • PubMed ID : 17300814
  • Web of Science ID : WOS:000245230200012

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