title: Salvianolic acid A preconditioning confers protection against concanavalin A-induced liver injury through SIRT1-mediated repression of p66shc in mice.
abstract: 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-γ) and tumor necrosis factor-alpha (TNF-α). Moreover, the SalA pretreatment ameliorated the increases in NF-κB 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.
authors.affiliation: Department of Pharmacology, Dalian Medical University, Dalian 116044, China.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Xu
authors.forename: Yan
authors.initials: Y
authors.lastname: Hu
authors.forename: Xiaohan
authors.initials: X
authors.lastname: Zhai
authors.forename: Musen
authors.initials: M
authors.lastname: Lin
authors.forename: Zhao
authors.initials: Z
authors.lastname: Chen
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Tian
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Dongyan
authors.initials: D
authors.lastname: Gao
authors.forename: Xiaochi
authors.initials: X
authors.lastname: Ma
authors.forename: Li
authors.initials: L
authors.lastname: Lv
authors.forename: Jihong
authors.initials: J
authors.lastname: Yao
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D002109:Caffeic Acids / Q000494:pharmacology*; D053148:Caspase 3 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000473:pathology; D003208:Concanavalin A / Q000633:toxicity*; D015536:Down-Regulation; D063185:Epigenetic Repression; D056945:Hep G2 Cells; D006505:Hepatitis / Q000473:pathology; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D007773:Lactates / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000097:blood / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D002109:Caffeic Acids; D007773:Lactates; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D003208:Concanavalin A; C066201:salvianolic acid A; D007371:Interferon-gamma; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: AIH; ALT; AST; B-cell lymphoma-extra large; Bcl-xL; ConA; Concanavalin A; Hepatitis; IFN-γ; NF-κB; SIRT1; SalA; Salvianolic acid A; TNF-α; alanine aminotransferase; aspartate aminotransferase; autoimmune hepatitis; concanavalin A; interferon gamma; nuclear factor κB; p66shc; salvianolic acid A; sirtuin1; the 66kDa isoform of the growth factor adapter Shc; tumor necrosis factor-α