ABSTRACT
Excessive N-acetyl-p-benzoquinone imine(NAPQI)formation is a starting event that triggers oxidative stress and subsequent hepatocyte necrosis in acetaminophen(APAP)overdose caused acute liver failure(ALF).S-glutathionylation is a reversible redox post-translational modification and a prospective mechanism of APAP hepatotoxicity.Glutaredoxin-1(Glrx1),a glutathione-specific thioltransferase,is a primary enzyme to catalyze deglutathionylation.The objective of this study was to explored whether and how Glrx1 is associated with the development of ALF induced by APAP.The Glrx1 knockout mice(Glrx1-/-)and liver-specific overexpression of Glrx1(AAV8-Glrx1)mice were produced and underwent APAP-induced ALF.Pirfenidone(PFD),a potential inducer of Glrx1,was administrated preceding APAP to assess its protective effects.Our results revealed that the hepatic total protein S-glutathionylation(PSSG)increased and the Glrx1 level reduced in mice after APAP toxicity.Glrx1-/- mice were more sensitive to APAP overdose,with higher oxidative stress and more toxic metabolites of APAP.This was attributed to Glrx1 deficiency increasing the total hepatic PSSG and the S-glutathionylation of cytochrome p450 3a 11(Cyp3a11),which likely increased the activity of Cyp3a11.Conversely,AAV8-Glrx1 mice were defended against liver damage caused by APAP overdose by inhibiting the S-glutathionylation and activity of Cyp3a11,which reduced the toxic metabolites of APAP and oxidative stress.PFD precede administration upregulated Glrx1 expression and alleviated APAP-induced ALF by decreasing oxidative stress.We have identified the function of Glrx1 mediated PSSG in liver injury caused by APAP overdose.Increasing Glrx1 expression may be investigated for the medical treatment of APAP-caused hepatic injury.
ABSTRACT
Objective To evaluate the efficacy of liraglutide in the treatment of Nonalcoholic Fatty Liver Disease(NAFLD).Methods Randomized controlled trials(RCTs)that evaluated the efficacy of liraglutide for NAFLD treatment were searched in multiple databases,including Pubmed,EMBASE,the Cochrane library,CNKI,Wanfang database and VIP.Literature identification and data extraction were based on the inclusion and exclusion criteria.RevMan 5.3 software was used for Meta-analysis.Results A total of 7 RCTs with 500 patients of NAFLD were included.Improved liver histology,or improved the level of alanine aminotransferase[WMD=-25.32,95％CI(-37.22,-13.41),P<0.01] and aspartate aminotransferase[WMD=-24.56,95％CI(-35.10,-14.03),P<0.01] were seen in 12-48 weeks liraglutide treatment.However,liraglutide could not decreased the level of serum cholesterol[WMD=-14.38,95％CI(-48.95,-20.20),P=0.42] and triglyceride[WMD=-15.55,95％CI(-36.20,-5.10),P=0.14].Conclusion liraglutide has the therapeutic effect of NAFLD.