Anluohuaxianwan Alleviates Carbon Tetrachloride-Induced Hepatic Fibrosis in Rats through Upregulation of Peroxisome Proliferator-Activated Receptor-Gamma and Downregulation of Nuclear Factor-Kappa B/IκBα Signaling Pathway
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摘要
Objective:The aim of this study was to investigate the effects of traditional Chinese medicine Anluohuaxianwan(ALHXW)on peroxisome proliferator-activated receptor-gamma(PPARγ)and nuclear factor-kappa B(NF-κB)signaling pathways using a rat model of carbon model groups were gavaged with saline for 6 weeks.Liver function was measured,and liver fibrosis and necroinflammation were assessed.Protein and messenger RNA expression levels of PPARγ,NF-κB,and Inhibitorαof NF-κB(IκBα)were analyzed by Western blot and reverse transcription–quantitative polymerase chain reaction.Results:ALHXW markedly alleviated liver injury compared with the model group,as indicated by the improvements in disease status,the morphology of liver and spleen,the liver and spleen indexes,and liver function.The extent of liver fibrosis was improved,hepatic stellate cell activation was inhibited,the expression of PPARγand IκBαwas significantly higher,and the expression of NF-κB was significantly lower in the treatment group as compared with the model group.Conclusions:ALHXW treatment can alleviate CCl4-induced liver fibrosis in rats, and the potential antifibrogenic mechanisms may occur through the upregulation of PPARγ expression and downregulation of NF-κB/IκBα signaling pathway.
Objective:The aim of this study was to investigate the effects of traditional Chinese medicine Anluohuaxianwan(ALHXW)on peroxisome proliferator-activated receptor-gamma(PPARγ)and nuclear factor-kappa B(NF-κB)signaling pathways using a rat model of carbon model groups were gavaged with saline for 6 weeks.Liver function was measured,and liver fibrosis and necroinflammation were assessed.Protein and messenger RNA expression levels of PPARγ,NF-κB,and Inhibitorαof NF-κB(IκBα)were analyzed by Western blot and reverse transcription–quantitative polymerase chain reaction.Results:ALHXW markedly alleviated liver injury compared with the model group,as indicated by the improvements in disease status,the morphology of liver and spleen,the liver and spleen indexes,and liver function.The extent of liver fibrosis was improved,hepatic stellate cell activation was inhibited,the expression of PPARγand IκBαwas significantly higher,and the expression of NF-κB was significantly lower in the treatment group as compared with the model group.Conclusions:ALHXW treatment can alleviate CCl4-induced liver fibrosis in rats, and the potential antifibrogenic mechanisms may occur through the upregulation of PPARγ expression and downregulation of NF-κB/IκBα signaling pathway.
Objective:The aim of this study was to investigate the effects of traditional Chinese medicine Anluohuaxianwan(ALHXW)on peroxisome proliferator-activated receptor-gamma(PPARγ)and nuclear factor-kappa B(NF-κB)signaling pathways using a rat model of carbon model groups were gavaged with saline for 6 weeks.Liver function was measured,and liver fibrosis and necroinflammation were assessed.Protein and messenger RNA expression levels of PPARγ,NF-κB,and Inhibitorαof NF-κB(IκBα)were analyzed by Western blot and reverse transcription–quantitative polymerase chain reaction.Results:ALHXW markedly alleviated liver injury compared with the model group,as indicated by the improvements in disease status,the morphology of liver and spleen,the liver and spleen indexes,and liver function.The extent of liver fibrosis was improved,hepatic stellate cell activation was inhibited,the expression of PPARγand IκBαwas significantly higher,and the expression of NF-κB was significantly lower in the treatment group as compared with the model group.Conclusions:ALHXW treatment can alleviate CCl4-induced liver fibrosis in rats, and the potential antifibrogenic mechanisms may occur through the upregulation of PPARγ expression and downregulation of NF-κB/IκBα signaling pathway.
引文
1.Zoubek ME,Trautwein C,Strnad P.Reversal of liver fibrosis:From fiction to reality.Best Pract Res Clin Gastroenterol 2017;31:129-41.
2.Schuppan D.Liver fibrosis:Common mechanisms and antifibrotic therapies.Clin Res Hepatol Gastroenterol 2015;39 Suppl 1:S51-9.
3.Oakley F,Meso M,Iredale JP,Green K,Marek CJ,Zhou X,et al.Inhibition of inhibitor of kappaB kinases stimulates hepatic stellate cell apoptosis and accelerated recovery from rat liver fibrosis.Gastroenterology 2005;128:108-20.
4.Zardi EM,Navarini L,Sambataro G,Piccinni P,Sambataro FM,Spina C,et al.Hepatic PPARs:Their role in liver physiology,fibrosis and treatment.Curr Med Chem 2013;20:3370-96.
5.Zhang F,Lu Y,Zheng S.Peroxisome proliferator-activated receptor-γcross-regulation of signaling events implicated in liver fibrogenesis.Cell Signal 2012;24:596-605.
6.Wang R,Yu XY,Guo ZY,Wang YJ,Wu Y,Yuan YF.Inhibitory effects of salvianolic acid B on CCl(4)-induced hepatic fibrosis through regulating NF-κB/IκBαsignaling.J Ethnopharmacol 2012;144:592-8.
7.Lin X,Zhang S,Huang Q,Wei L,Zheng L,Chen Z,et al.Protective effect of Fufang-Liu-Yue-Qing,a traditional Chinese herbal formula,on CCl4 induced liver fibrosis in rats.J Ethnopharmacol 2012;142:548-56.
8.Li XH,Lai JQ,Li XY,Yang HW,Wang CG.Therapeutic efficacy of entecavir and Anluohuaxianwan on 32 patients with hepatitis B-related cirrhosis.Infect Dis Informat 2011;24:51-4.
9.Yin H,Zhou SF,Zhang YF.Clinical Effect of Anluo Huaxian Wan in treating chronic hepatitis B and early liver cirrhosis.J Med Theor Pract2008;21:761-2.
10.Tan XH,Li CQ,Zou SR,Xie M,Zhang AM,Li WL,et al.Inhibitory effect of Anluohuaxianwan on experimental hepatic fibrosis in rats.Chinese J Hepatology 2010;18:9-12.
11.Xiang YX,Lou HY,Wang JY,Feng YM,Yu XY,Zhang XM.Treatment of Anluohuaxianwan on alcoholic fatty liver in rats.Chin J Biochem Pharm 2011;32:440-3.
12.Lu W,Gao YH,Wang ZZ,Cai YS,Yang YQ,Miao YQ,et al.Effects of Anluohuaxianwan on transforming growth factor-β1 and related signaling pathways in rats with carbon tetrachloride-induced liver fibrosis.Chinese J Hepatology 2017;25:257-62.
13.Arosio B,Santambrogio D,Gagliano N,Annoni G.Changes in expression of the albumin,fibronectin and type I procollagen genes in CCl4-induced liver fibrosis:Effect of pyridoxol L,2-pyrrolidon-5carboxylate.Pharmacol Toxicol 1993;73:301-4.
14.Lin YZ,Yao QY,Xu BL,Zhang SC,Tu CT.Effects of curcumin on liver fibrosis and hepatic expression of NADPH oxidase 4 in rats.Chin J Clin Med 2013;20:755-8.
15.Jang JH,Kang KJ,Kim YH,Kang YN,Lee IS.Reevaluation of experimental model of hepatic fibrosis induced by hepatotoxic drugs:An easy,applicable,and reproducible model.Transplant Proc2008;40:2700-3.
16.Lieber CS.Alcohol and the liver:Metabolism of alcohol and its role in hepatic and extrahepatic diseases.Mt Sinai J Med 2000;67:84-94.
17.Dong S,Chen QL,Song YN,Sun Y,Wei B,Li XY,et al.Mechanisms of CCl4-induced liver fibrosis with combined transcriptomic and proteomic analysis.J Toxicol Sci 2016;41:561-72.
18.Yu J,Wang Y,Qian H,Zhao Y,Liu B,Fu C.Polyprenols from Taxus chinensis VAr.mairei prevent the development of CCl?-induced liver fibrosis in rats.J Ethnopharmacol 2012;142:151-60.
19.Zhang F,Kong D,Lu Y,Zheng S.Peroxisome proliferator-activated receptor-γas a therapeutic target for hepatic fibrosis:From bench to bedside.Cell Mol Life Sci 2013;70:259-76.
20.She H,Xiong S,Hazra S,Tsukamoto H.Adipogenic transcriptional regulation of hepatic stellate cells.J Biol Chem 2005;280:4959-67.
21.Hazra S,Xiong S,Wang J,Rippe RA,Krishna V,Chatterjee K,et al.Peroxisome proliferator-activated receptor gamma induces a phenotypic switch from activated to quiescent hepatic stellate cells.J Biol Chem2004;279:11392-401.
22.Jin H,Lian N,Zhang F,Chen L,Chen Q,Lu C,et al.Activation of PPARγ/P53 signaling is required for curcumin to induce hepatic stellate cell senescence.Cell Death Dis 2016;7:e2189.
23.Wang HY,Cheng ML.Effects of Dan-Shao-Hua-Xian on expression of PPAR-gamma and NF-kappa B in rat liver fibrosis.Hepatobiliary Pancreat Dis Int 2008;7:179-84.
24.Huang C,Ma T,Meng X,Lv X,Zhang L,Wang J,et al.Potential protective effects of a traditional Chinese herb,Litsea coreana Levl on liver fibrosis in rats.J Pharm Pharmacol 2010;62:223-30.
25.Sun SC.The non-canonical NF-κB pathway in immunity and inflammation.Nat Rev Immunol 2017;17:545-58.
26.Mitchell S,Vargas J,Hoffmann A.Signaling via the NFκB system.Wiley Interdiscip Rev Syst Biol Med 2016;8:227-41.
27.Mann J,Mann DA.Transcriptional regulation of hepatic stellate cells.Adv Drug Deliv Rev 2009;61:497-512.
28.Fang S,Yuan J,Shi Q,Xu T,Fu Y,Wu Z,et al.Downregulation of UBC9 promotes apoptosis of activated human LX-2 hepatic stellate cells by suppressing the canonical NF-κB signaling pathway.PLoS One2017;12:e0174374.
29.Liu H,Dong F,Li G,Niu M,Zhang C,Han Y,et al.Liuweiwuling tablets attenuate BDL-induced hepatic fibrosis via modulation of TGF-β/Smad and NF-κB signaling pathways.J Ethnopharmacol 2018;210:232-41.
30.Wang RQ,Mi HM,Li H,Zhao SX,Jia YH,Nan YM.Modulation of IKKβ/NF-κB and TGF-β1/Smad via Fuzheng Huayu recipe involves in prevention of nutritional steatohepatitis and fibrosis in mice.Iran J Basic Med Sci 2015;18:404-11.
2.Schuppan D.Liver fibrosis:Common mechanisms and antifibrotic therapies.Clin Res Hepatol Gastroenterol 2015;39 Suppl 1:S51-9.
3.Oakley F,Meso M,Iredale JP,Green K,Marek CJ,Zhou X,et al.Inhibition of inhibitor of kappaB kinases stimulates hepatic stellate cell apoptosis and accelerated recovery from rat liver fibrosis.Gastroenterology 2005;128:108-20.
4.Zardi EM,Navarini L,Sambataro G,Piccinni P,Sambataro FM,Spina C,et al.Hepatic PPARs:Their role in liver physiology,fibrosis and treatment.Curr Med Chem 2013;20:3370-96.
5.Zhang F,Lu Y,Zheng S.Peroxisome proliferator-activated receptor-γcross-regulation of signaling events implicated in liver fibrogenesis.Cell Signal 2012;24:596-605.
6.Wang R,Yu XY,Guo ZY,Wang YJ,Wu Y,Yuan YF.Inhibitory effects of salvianolic acid B on CCl(4)-induced hepatic fibrosis through regulating NF-κB/IκBαsignaling.J Ethnopharmacol 2012;144:592-8.
7.Lin X,Zhang S,Huang Q,Wei L,Zheng L,Chen Z,et al.Protective effect of Fufang-Liu-Yue-Qing,a traditional Chinese herbal formula,on CCl4 induced liver fibrosis in rats.J Ethnopharmacol 2012;142:548-56.
8.Li XH,Lai JQ,Li XY,Yang HW,Wang CG.Therapeutic efficacy of entecavir and Anluohuaxianwan on 32 patients with hepatitis B-related cirrhosis.Infect Dis Informat 2011;24:51-4.
9.Yin H,Zhou SF,Zhang YF.Clinical Effect of Anluo Huaxian Wan in treating chronic hepatitis B and early liver cirrhosis.J Med Theor Pract2008;21:761-2.
10.Tan XH,Li CQ,Zou SR,Xie M,Zhang AM,Li WL,et al.Inhibitory effect of Anluohuaxianwan on experimental hepatic fibrosis in rats.Chinese J Hepatology 2010;18:9-12.
11.Xiang YX,Lou HY,Wang JY,Feng YM,Yu XY,Zhang XM.Treatment of Anluohuaxianwan on alcoholic fatty liver in rats.Chin J Biochem Pharm 2011;32:440-3.
12.Lu W,Gao YH,Wang ZZ,Cai YS,Yang YQ,Miao YQ,et al.Effects of Anluohuaxianwan on transforming growth factor-β1 and related signaling pathways in rats with carbon tetrachloride-induced liver fibrosis.Chinese J Hepatology 2017;25:257-62.
13.Arosio B,Santambrogio D,Gagliano N,Annoni G.Changes in expression of the albumin,fibronectin and type I procollagen genes in CCl4-induced liver fibrosis:Effect of pyridoxol L,2-pyrrolidon-5carboxylate.Pharmacol Toxicol 1993;73:301-4.
14.Lin YZ,Yao QY,Xu BL,Zhang SC,Tu CT.Effects of curcumin on liver fibrosis and hepatic expression of NADPH oxidase 4 in rats.Chin J Clin Med 2013;20:755-8.
15.Jang JH,Kang KJ,Kim YH,Kang YN,Lee IS.Reevaluation of experimental model of hepatic fibrosis induced by hepatotoxic drugs:An easy,applicable,and reproducible model.Transplant Proc2008;40:2700-3.
16.Lieber CS.Alcohol and the liver:Metabolism of alcohol and its role in hepatic and extrahepatic diseases.Mt Sinai J Med 2000;67:84-94.
17.Dong S,Chen QL,Song YN,Sun Y,Wei B,Li XY,et al.Mechanisms of CCl4-induced liver fibrosis with combined transcriptomic and proteomic analysis.J Toxicol Sci 2016;41:561-72.
18.Yu J,Wang Y,Qian H,Zhao Y,Liu B,Fu C.Polyprenols from Taxus chinensis VAr.mairei prevent the development of CCl?-induced liver fibrosis in rats.J Ethnopharmacol 2012;142:151-60.
19.Zhang F,Kong D,Lu Y,Zheng S.Peroxisome proliferator-activated receptor-γas a therapeutic target for hepatic fibrosis:From bench to bedside.Cell Mol Life Sci 2013;70:259-76.
20.She H,Xiong S,Hazra S,Tsukamoto H.Adipogenic transcriptional regulation of hepatic stellate cells.J Biol Chem 2005;280:4959-67.
21.Hazra S,Xiong S,Wang J,Rippe RA,Krishna V,Chatterjee K,et al.Peroxisome proliferator-activated receptor gamma induces a phenotypic switch from activated to quiescent hepatic stellate cells.J Biol Chem2004;279:11392-401.
22.Jin H,Lian N,Zhang F,Chen L,Chen Q,Lu C,et al.Activation of PPARγ/P53 signaling is required for curcumin to induce hepatic stellate cell senescence.Cell Death Dis 2016;7:e2189.
23.Wang HY,Cheng ML.Effects of Dan-Shao-Hua-Xian on expression of PPAR-gamma and NF-kappa B in rat liver fibrosis.Hepatobiliary Pancreat Dis Int 2008;7:179-84.
24.Huang C,Ma T,Meng X,Lv X,Zhang L,Wang J,et al.Potential protective effects of a traditional Chinese herb,Litsea coreana Levl on liver fibrosis in rats.J Pharm Pharmacol 2010;62:223-30.
25.Sun SC.The non-canonical NF-κB pathway in immunity and inflammation.Nat Rev Immunol 2017;17:545-58.
26.Mitchell S,Vargas J,Hoffmann A.Signaling via the NFκB system.Wiley Interdiscip Rev Syst Biol Med 2016;8:227-41.
27.Mann J,Mann DA.Transcriptional regulation of hepatic stellate cells.Adv Drug Deliv Rev 2009;61:497-512.
28.Fang S,Yuan J,Shi Q,Xu T,Fu Y,Wu Z,et al.Downregulation of UBC9 promotes apoptosis of activated human LX-2 hepatic stellate cells by suppressing the canonical NF-κB signaling pathway.PLoS One2017;12:e0174374.
29.Liu H,Dong F,Li G,Niu M,Zhang C,Han Y,et al.Liuweiwuling tablets attenuate BDL-induced hepatic fibrosis via modulation of TGF-β/Smad and NF-κB signaling pathways.J Ethnopharmacol 2018;210:232-41.
30.Wang RQ,Mi HM,Li H,Zhao SX,Jia YH,Nan YM.Modulation of IKKβ/NF-κB and TGF-β1/Smad via Fuzheng Huayu recipe involves in prevention of nutritional steatohepatitis and fibrosis in mice.Iran J Basic Med Sci 2015;18:404-11.