Salvianolic acid A preconditioning confers protection against concanavalin A-induced liver injury through SIRT1-mediated repression of p66shc in mice

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• 作者：Xiaomei Xu ; Yan Hu ; Xiaohan Zhai ; Musen Lin ; Zhao Chen ; Xiaofeng Tian ; Feng Zhang ; Dongyan Gao ; Xiaochi Ma ; Li Lv ; Jihong Yao
• 关键词：SalA ; salvianolic acid A ; ConA ; concanavalin A ; ALT ; alanine aminotransferase ; AST ; aspartate aminotransferase ; TNF-伪 ; tumor necrosis factor-伪 ; IFN-纬 ; interferon gamma ; SIRT1 ; sirtuin1 ; Bcl-xL ; B-cell lymphoma-extra large ; NF-魏B ; nuclear factor 魏B ; AIH ; autoimmune hepatitis ; p66shc ; the 66  ; kDa isoform of the growth factor adapter Shc
• 刊名：Toxicology and Applied Pharmacology
• 出版年：15 November, 2013
• 年：2013
• 卷：273
• 期：1
• 页码：68-76
• 全文大小：1290 K

文摘

Salvianolic acid A (SalA) is a phenolic carboxylic acid derivative extracted from Salvia miltiorrhiza. It has many biological and pharmaceutical activities. The purpose of this study was to investigate the effect of SalA on concanavalin A (ConA)-induced acute hepatic injury in Kunming mice and to explore the role of SIRT1 in such an effect. The results showed that in vivo pretreatment with SalA significantly reduced ConA-induced elevation in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and decreased levels of the hepatotoxic cytokines such as interferon-gamma (IFN-纬) and tumor necrosis factor-alpha (TNF-伪). Moreover, the SalA pretreatment ameliorated the increases in NF-魏B and in cleaved caspase-3 caused by ConA exposure. Whereas, the pretreatment completely reversed expression of the B-cell lymphoma-extra large (Bcl-xL). More importantly, the SalA pretreatment significantly increased the expression of SIRT1, a NAD⁺-dependent deacetylase, which was known to attenuate acute hypoxia damage and metabolic liver diseases. In our study, the increase in SIRT1 was closely associated with down-regulation of the p66 isoform (p66shc) of growth factor adapter Shc at both protein and mRNA levels. In HepG2 cell culture, SalA pretreatment increased SIRT1 expression in a time and dose-dependent manner and such an increase was abrogated by siRNA knockdown of SIRT1. Additionally, inhibition of SIRT1 significantly reversed the decreased expression of p66shc, and attenuated SalA-induced p66shc down-regulation. Collectively, the present study indicated that SalA may be a potent activator of SIRT and that SalA can alleviate ConA-induced hepatitis through SIRT1-mediated repression of the p66shc pathway.