title: (Z)2-(5-(4-methoxybenzylidene)-2, 4-dioxothiazolidin-3-yl) acetic acid protects rats from CCl(4) -induced liver injury.
abstract: OBJECTIVE
  (Z)2-(5-(4-methoxybenzylidene)-2, 4-dioxothiazolidin-3-yl) acetic acid (MDA) is an aldose reductase (AR) inhibitor. Recent studies suggest that AR contributes to the pathogenesis of inflammation by affecting the nuclear factor κB (NF-κB)-dependent expression of cytokines and chemokines and therefore could be a novel therapeutic target for inflammatory pathology. The current study evaluated the in vivo role of MDA in protecting the liver against injury and fibrogenesis caused by CCl(4) in rats, and the underlying mechanisms.
  
  
  METHODS
  A single injection of CCl(4) induced acute hepatitis, and repeated injections were used to induce hepatic fibrosis in rats. Therapeutic efficacy was assessed by comparison of the severity of hepatic injury and fibrosis in MDA-treated rats versus untreated controls.
  
  
  RESULTS
  MDA significantly protected the liver from injury by reducing the activity of serum alanine aminotransferase, and improving the histological architecture of the liver. MDA modulated NF-κB-dependent activation of inflammatory cytokines by reducing hepatic mRNA levels of tumor necrosis factor-α, interleukin-1β, inducible nitric oxide (NO) synthase and transforming growth factor-β. In addition, MDA attenuated oxidative stress by increasing the content of hepatic glutathione. These favorable changes were associated with suppressed hepatic NF-κB activation by MDA. MDA treatment improved liver fibrosis in rats that received repeated CCl(4) injections. In vitro, MDA attenuated phosphorylation of IκB and activation of NF-κB, and thus prevented biosynthesis of NO in lipopolysaccharide-activated RAW264.7 cells.
  
  
  CONCLUSIONS
  The present study suggests that AR is a novel therapeutic anti-inflammatory target for the treatment of hepatitis and liver fibrosis.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Zhen-ling
authors.initials: ZL
authors.lastname: Wang
authors.forename: Chong-yang
authors.initials: CY
authors.lastname: Deng
authors.forename: Hao
authors.initials: H
authors.lastname: Zheng
authors.forename: Cai-feng
authors.initials: CF
authors.lastname: Xie
authors.forename: Xian-huo
authors.initials: XH
authors.lastname: Wang
authors.forename: You-fu
authors.initials: YF
authors.lastname: Luo
authors.forename: Zhi-zhi
authors.initials: ZZ
authors.lastname: Chen
authors.forename: Ping
authors.initials: P
authors.lastname: Cheng
authors.forename: Li-juan
authors.initials: LJ
authors.lastname: Chen
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D002251:Carbon Tetrachloride; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005978:Glutathione / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C575035:(Z)2-(5-(4-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl)acetic acid; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D053583:Interleukin-1beta; D016328:NF-kappa B; D012333:RNA, Messenger; D045162:Thiazolidinediones; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D002251:Carbon Tetrachloride; D000449:Aldehyde Reductase; D052247:Nitric Oxide Synthase Type II; D000410:Alanine Transaminase; D005978:Glutathione