Curcumin protects ANIT-induced cholestasis through signaling pathway of FXR-regulated bile acid and inflammation
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- 英文论文题名：Curcumin protects ANIT-induced cholestasis through signaling pathway of FXR-regulated bile acid and inflammation
- 论文作者：Fan Yang ; Xiaowen Tang ; Lili Ding ; Yue zhou ; Qiaoling Yang ; Junting Gong ; Guangyun Wang ; Zhengtao Wang ; Li Yang
- 英文论文作者：Fan Yang ; Xiaowen Tang ; Lili Ding ; Yue zhou ; Qiaoling Yang ; Junting Gong ; Guangyun Wang ; Zhengtao Wang ; Li Yang ; The MOE Key Laboratory for Standardization of Chinese Medicines and the SHTCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines ; Institute of Chinese Materia Medica ; Shanghai University of Traditional Chinese Medicine ; Center for Chinese Medical Therapy and Systems Biology ; Shanghai University of Traditional Chinese Medicine
- 年：2016
- 作者机构：The MOE Key Laboratory for Standardization of Chinese Medicines and the SHTCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines,Institute of Chinese Materia Medica,Shanghai University of Traditional Chinese Medicine;Center for Chinese Medical Therapy and Systems Biology,Shanghai University of Traditional Chinese Medicine;
- 会议召开时间：2016-09-27
- 会议录名称：中国药学会第十三届青年药学科研成果交流会论文集
- 语种：英文
- 分类号：R575
- 学会代码：YYWS
- 会议名称：中国药学会第十三届青年药学科研成果交流会
- 会议地点：中国江西南昌
- 主办单位：中国药学会
- 学会名称：中国药学会
- 页数：11
- 文件大小：2252k
- 原文格式：O
- 会议级别：全国
摘要
Cholestasis is a clinically significant symptom and widely associated with liver diseases,however,there are very few effective therapies for cholestasis.Danning tablet(DNT,a Chinese patent medicine preparation) has been clinically used to treat human liver and gallbladder diseases for more than 20 years in China.However,which ingredients of DNT contributed to this beneficial effect and their mechanistic underpinnings have been largely unknown.In the present study,we discovered that DNT not only demonstrated greater benefits for cholecystitis patients after cholecystectomy surgery in clinic but also showed protective effect against alpha-naphthylisothiocyanate(ANIT)-induced cholestasis model in rodent.Curcumin,one major compound derived from DNT,exerted the protective effect against cholestasis through farnesoid X receptor(FXR),which has been focused as potential therapeutic targets for treating cholestasis.The underlying mechanism of curcumin against cholestasis was restoring bile acid homeostasis and antagonizing inflammatory responses in a FXR-dependent manner and in turn contributed to overall cholestasis attenuation.Collectively,curcumin can be served as a potential treatment option for liver injury with cholestasis.
Cholestasis is a clinically significant symptom and widely associated with liver diseases,however,there are very few effective therapies for cholestasis.Danning tablet(DNT,a Chinese patent medicine preparation) has been clinically used to treat human liver and gallbladder diseases for more than 20 years in China.However,which ingredients of DNT contributed to this beneficial effect and their mechanistic underpinnings have been largely unknown.In the present study,we discovered that DNT not only demonstrated greater benefits for cholecystitis patients after cholecystectomy surgery in clinic but also showed protective effect against alpha-naphthylisothiocyanate(ANIT)-induced cholestasis model in rodent.Curcumin,one major compound derived from DNT,exerted the protective effect against cholestasis through farnesoid X receptor(FXR),which has been focused as potential therapeutic targets for treating cholestasis.The underlying mechanism of curcumin against cholestasis was restoring bile acid homeostasis and antagonizing inflammatory responses in a FXR-dependent manner and in turn contributed to overall cholestasis attenuation.Collectively,curcumin can be served as a potential treatment option for liver injury with cholestasis.
Cholestasis is a clinically significant symptom and widely associated with liver diseases,however,there are very few effective therapies for cholestasis.Danning tablet(DNT,a Chinese patent medicine preparation) has been clinically used to treat human liver and gallbladder diseases for more than 20 years in China.However,which ingredients of DNT contributed to this beneficial effect and their mechanistic underpinnings have been largely unknown.In the present study,we discovered that DNT not only demonstrated greater benefits for cholecystitis patients after cholecystectomy surgery in clinic but also showed protective effect against alpha-naphthylisothiocyanate(ANIT)-induced cholestasis model in rodent.Curcumin,one major compound derived from DNT,exerted the protective effect against cholestasis through farnesoid X receptor(FXR),which has been focused as potential therapeutic targets for treating cholestasis.The underlying mechanism of curcumin against cholestasis was restoring bile acid homeostasis and antagonizing inflammatory responses in a FXR-dependent manner and in turn contributed to overall cholestasis attenuation.Collectively,curcumin can be served as a potential treatment option for liver injury with cholestasis.
引文
1.Yoshidome,H.et al.Obstructive jaundice impairs hepatic sinusoidal endothelial cell function and renders liver susceptible to hepatic ischemia/reperfusion.J.Hepatol.33,59-67(2000).
2.Mieli-Vergani,G.&Vergani,D.Biliary atresia.Semin Immunopathol.31,371-381(2009).
3.Moghadamrad,S.,Montani,M.,Weimann,R.&De Gottardi,A.Cholestasis in a patient with gallstones and a normal gamma-glutamyl transferase.Hepatology.57,2539-2541(2013).
4.Tekin,R.et al.Evaluation of adults with acute viral hepatitis a and review of the literature.Clin Ter.164,537-541(2013).
5.Flora,K.D.&Benner,K.G.Liver disease in cystic fibrosis.Clin Liver Dis.2,51-61(1998).
6.Eaton,J.E.,Talwalkar,J.A.,Lazaridis,K.N.,Gores,G.J.&Lindor,K.D.Pathogenesis of primary sclerosing cholangitis and advances in diagnosis and management.Gastroenterology.145,521-536(2013).
7.Hirschfield,G.M.et al.The genetics of complex cholestatic disorders.Gastroenterology.144,1357-1374(2013).
8.Fickert,P.et al.Differential effects of norUDCA and UDCA in obstructive cholestasis in mice.J.Hepatol.58,1201-1208(2013).
9.Liu,Y et al.Hepatoprotection by the famesoid X receptor agonist GW4064 in rat models of intra-and extiahepatic cholestasis.J.Clin Invest.112,1678-1687(2003).
10.Ding,L.,Zhang,B.,Zhan,C,Yang,L.&Wang,Z.Danning tablets attenuates alpha-naphthylisothiocyanate-induced cholestasis by modulating the expression of transporters and metabolic enzymes.BMC.Complement Altern Med.14,249(2014).
11.Ding,L.L.et al.Protective effect of Danning tablet on acute livery injury with cholestasis induced by alpha-naphthylisothiocyanate in rats.J.Ethnopharmacol.140,222-229(2012).
12.Woolbright,B.L.&Jaeschke,H.Novel insight into mechanisms of cholestatic liver injury.World J.Gastroenterol.18,4985-4993(2012).
13.Herr,K.J.et al.Loss of alpha-catenin elicits a cholestatic response and impairs liver regeneration.Sci.Rep.4,6835(2014).
14.Shaik,F.B.,Prasad,D.V.&Narala,V.R.Role of famesoid X receptor in inflammation and resolution.Inflamm Res.64,9-20(2015).
15.Wang,YD.,Chen,W.D.,Moore,D.D.&Huang,W.FXR:a metabolic regulator and cell protector.Cell Res.18,1087-1095(2008).
16.Knab,L.M.,Boiler,A.M.&Mahvi,D.M.Cholecystitis.Surg Clin North Am.94,455-470(2014).
17.Jonkera,J.W.,Liddle C,Downes M.FXR and PXR:Potential therapeutic targets in cholestasis.J.SteroidBiochem Mol Biol.130,147-158(2011).
18.Verbeke,L.et al.The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats.Am J.Pathol.185,409-419(2015).
19.Wang,T.et al.Resveratrol effectively attenuates alpha-naphthyl-isothiocyanate-induced acute cholestasis and liver injury through choleretic and anti-inflammatory mechanisms.Acta Pharmacol Sin.35,1527-1536(2014).
20.Chen,M.L.et al.Resveratrol Attenuates Trimethylamine-N-Oxide(TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota.MBio.7,e02210-15(2016).
21.Lu,C.et al.Curcumin attenuates ethanol-induced hepatic steatosis through modulating Nrf2/FXR signaling in hepatocytes.IUBMB Life.67,645-658(2015).
22.Liu,Z.J.et al.Curcumin protects neurons against oxygen-glucose deprivation/reoxygenation-induced injury through activation of peroxisome proliferator-activated receptor-gamma function.J.Neurosci Res.92,1549-1559(2014).
23.Meng,Z.,Yu,X.H.,Chen,J.,Li,L.&Li,S.Curcumin attenuates cardiac fibrosis in spontaneously hypertensive rats through PPAR-gamma activation.Acta Pharmacol Sin.35,1247-1256(2014).
24.Baghdasaryan,A.et al.Curcumin improves sclerosing cholangitis in Mdr2-/-mice by inhibition of cholangiocyte inflammatory response and portal myofibroblast proliferation.Gut.59,521-530(2010).
25.Narala,V.R.et al.Curcumin is not a ligand for peroxisome proliferator-activated receptor-gamma.Gene Ther Mol Biol.13,20-25(2009).
26.Hirschfield,G.M.,Heathcote,E.J.&Gershwin,M.E.Pathogenesis of cholestatic liver disease and therapeutic approaches.Gastroenterology.139,1481-1496(2010).
27.Hofmann,A.F.The continuing importance of bile acids in liver and intestinal disease.Arch Intern Med.159,2647-2658(1999).
28.Matsuda,H.,Ninomiya,K.,Morikawa,T.&Yoshikawa,M.Inhibitory effect and action mechanism of sesquiterpenes from Zedoariae Rhizoma on D-galactosamine/lipopolysaccharide-induced liver injury.Bioorg Med Chem Lett.8,339-344(1998).
29.Morikawa,T.,Matsuda,H.,Ninomiya,K.&Yoshikawa,M.Medicinal foodstuffs.XXDC.Potent protective effects of sesquiterpenes and curcumin from Zedoariae Rhizoma on liver injury induced by D-galactosamine/lipopolysaccharide or tumor necrosis factor-alpha.Biol Pharm Bull.25,627-631(2002).
30.Kaur,G.et al.Inhibition of oxidative stress and cytokine activity by curcumin in amelioration of endotoxin-induced experimental hepatoxicity in rodents.Clin Exp Immunol.145,313-321(2006).
31.Yun,S.S.,Kim,S.P.,Kang,M.Y.&Nam,S.H.Inhibitory effect of curcumin on liver injury in a murine model of endotoxemic shock.Biotechnol Lett.32,209-214(2010).
32.Xu,Z.et al.FXR ligands protect against hepatocellular inflammation via SOCS3 induction.Cell Signal.24,1658-1664(2012).
33.Vavassori,P.,Mencarelli,A.,Renga,B.,Distrutti,E.&Fiorucci,S.The bile acid receptor FXR is a modulator of intestinal innate immunity.J Immunol.183,6251-6261(2009).
34.Woolbright,B.L.et al.Bile acid-induced necrosis in primary human hepatocytes and in patients with obstructive cholestasis.Toxicol Appl Pharmacol.283,168-177(2015).
35.Woolbright,B.L.,McGill,M.R.,Yan,H.&Jaeschke,H.Bile Acid-Induced Toxicity in HepaRG Cells Recapitulates the Response in Primary Human Hepatocytes.Basic Clin Pharmacol Toxicol.118,160-167(2016).
36.Allen,K.,Jaeschke,H.&Copple,B.L.Bile acids induce inflammatory genes in hepatocytes:a novel mechanism of inflammation during obstructive cholestasis.Am J Pathol.178,175-186(2011).
37.Martinez-Diez,M.C.,Serrano,M.A.,Monte,M.J.&Marin,J.J.Comparison of the effects of bile acids on cell viability and DNA synthesis by rat hepatocytes in primary culture.Biochim BiophysActa.1500,153-160(2000).
38.Zhang,Y.et al.Effect of bile duct ligation on bile acid composition in mouse serum and liver.Liver Int.32,58-69(2012).
39.Rolo,A.P.,Palmeira,CM.&Wallace,K.B.Interactions of combined bile acids on hepatocyte viability:cytoprotection or synergism.Toxicol Lett.126,197-203(2002).
40.Perreault,M.et al.Role of glucuronidation for hepatic detoxification and urinary elimination of toxic bile acids during biliary obstruction.PLoS One.8,e80994(2013).
41.Hartupee,J.&Mann,D.L.Role of inflammatory cells in fibroblast activation.J.Mol Cell Cardiol.In Press(2015).
42.Park,K.C.et al.A new histone deacetylase inhibitor improves liver fibrosis in BDL rats through suppression of hepatic stellate cells.Br.J Pharmacol.171,4820-4830(2014).
43.Mukhopadhyay,P.et al.Poly(ADP-ribose)polymerase-1 is a key mediator of liver inflammation and fibrosis.Hepatology.59,1998-2009(2014).
44.Deters,M.,Klabunde,T.,Meyer,H.,Resch,K.&Kaever,V.Effects of curcumin on cyclosporine-induced cholestasis and hypercholesterolemia and on cyclosporine metabolism in the rat.Planta Med.69,337-343(2003).
45.Reyes-Gordillo,K.et al.Curcumin prevents and reverses cirrhosis induced by bile duct obstruction or CC14 in rats:role of TGF-beta modulation and oxidative stress.Fundam Clin Pharmacol.22,417-427(2008).
46.Fiorucci,S.et al.Protective effects of 6-ethyl chenodeoxycholic acid,a farnesoid X receptor ligand,in estrogen-induced cholestasis.J.Pharmacol Exp Ther.313,604-612(2005).
2.Mieli-Vergani,G.&Vergani,D.Biliary atresia.Semin Immunopathol.31,371-381(2009).
3.Moghadamrad,S.,Montani,M.,Weimann,R.&De Gottardi,A.Cholestasis in a patient with gallstones and a normal gamma-glutamyl transferase.Hepatology.57,2539-2541(2013).
4.Tekin,R.et al.Evaluation of adults with acute viral hepatitis a and review of the literature.Clin Ter.164,537-541(2013).
5.Flora,K.D.&Benner,K.G.Liver disease in cystic fibrosis.Clin Liver Dis.2,51-61(1998).
6.Eaton,J.E.,Talwalkar,J.A.,Lazaridis,K.N.,Gores,G.J.&Lindor,K.D.Pathogenesis of primary sclerosing cholangitis and advances in diagnosis and management.Gastroenterology.145,521-536(2013).
7.Hirschfield,G.M.et al.The genetics of complex cholestatic disorders.Gastroenterology.144,1357-1374(2013).
8.Fickert,P.et al.Differential effects of norUDCA and UDCA in obstructive cholestasis in mice.J.Hepatol.58,1201-1208(2013).
9.Liu,Y et al.Hepatoprotection by the famesoid X receptor agonist GW4064 in rat models of intra-and extiahepatic cholestasis.J.Clin Invest.112,1678-1687(2003).
10.Ding,L.,Zhang,B.,Zhan,C,Yang,L.&Wang,Z.Danning tablets attenuates alpha-naphthylisothiocyanate-induced cholestasis by modulating the expression of transporters and metabolic enzymes.BMC.Complement Altern Med.14,249(2014).
11.Ding,L.L.et al.Protective effect of Danning tablet on acute livery injury with cholestasis induced by alpha-naphthylisothiocyanate in rats.J.Ethnopharmacol.140,222-229(2012).
12.Woolbright,B.L.&Jaeschke,H.Novel insight into mechanisms of cholestatic liver injury.World J.Gastroenterol.18,4985-4993(2012).
13.Herr,K.J.et al.Loss of alpha-catenin elicits a cholestatic response and impairs liver regeneration.Sci.Rep.4,6835(2014).
14.Shaik,F.B.,Prasad,D.V.&Narala,V.R.Role of famesoid X receptor in inflammation and resolution.Inflamm Res.64,9-20(2015).
15.Wang,YD.,Chen,W.D.,Moore,D.D.&Huang,W.FXR:a metabolic regulator and cell protector.Cell Res.18,1087-1095(2008).
16.Knab,L.M.,Boiler,A.M.&Mahvi,D.M.Cholecystitis.Surg Clin North Am.94,455-470(2014).
17.Jonkera,J.W.,Liddle C,Downes M.FXR and PXR:Potential therapeutic targets in cholestasis.J.SteroidBiochem Mol Biol.130,147-158(2011).
18.Verbeke,L.et al.The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats.Am J.Pathol.185,409-419(2015).
19.Wang,T.et al.Resveratrol effectively attenuates alpha-naphthyl-isothiocyanate-induced acute cholestasis and liver injury through choleretic and anti-inflammatory mechanisms.Acta Pharmacol Sin.35,1527-1536(2014).
20.Chen,M.L.et al.Resveratrol Attenuates Trimethylamine-N-Oxide(TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota.MBio.7,e02210-15(2016).
21.Lu,C.et al.Curcumin attenuates ethanol-induced hepatic steatosis through modulating Nrf2/FXR signaling in hepatocytes.IUBMB Life.67,645-658(2015).
22.Liu,Z.J.et al.Curcumin protects neurons against oxygen-glucose deprivation/reoxygenation-induced injury through activation of peroxisome proliferator-activated receptor-gamma function.J.Neurosci Res.92,1549-1559(2014).
23.Meng,Z.,Yu,X.H.,Chen,J.,Li,L.&Li,S.Curcumin attenuates cardiac fibrosis in spontaneously hypertensive rats through PPAR-gamma activation.Acta Pharmacol Sin.35,1247-1256(2014).
24.Baghdasaryan,A.et al.Curcumin improves sclerosing cholangitis in Mdr2-/-mice by inhibition of cholangiocyte inflammatory response and portal myofibroblast proliferation.Gut.59,521-530(2010).
25.Narala,V.R.et al.Curcumin is not a ligand for peroxisome proliferator-activated receptor-gamma.Gene Ther Mol Biol.13,20-25(2009).
26.Hirschfield,G.M.,Heathcote,E.J.&Gershwin,M.E.Pathogenesis of cholestatic liver disease and therapeutic approaches.Gastroenterology.139,1481-1496(2010).
27.Hofmann,A.F.The continuing importance of bile acids in liver and intestinal disease.Arch Intern Med.159,2647-2658(1999).
28.Matsuda,H.,Ninomiya,K.,Morikawa,T.&Yoshikawa,M.Inhibitory effect and action mechanism of sesquiterpenes from Zedoariae Rhizoma on D-galactosamine/lipopolysaccharide-induced liver injury.Bioorg Med Chem Lett.8,339-344(1998).
29.Morikawa,T.,Matsuda,H.,Ninomiya,K.&Yoshikawa,M.Medicinal foodstuffs.XXDC.Potent protective effects of sesquiterpenes and curcumin from Zedoariae Rhizoma on liver injury induced by D-galactosamine/lipopolysaccharide or tumor necrosis factor-alpha.Biol Pharm Bull.25,627-631(2002).
30.Kaur,G.et al.Inhibition of oxidative stress and cytokine activity by curcumin in amelioration of endotoxin-induced experimental hepatoxicity in rodents.Clin Exp Immunol.145,313-321(2006).
31.Yun,S.S.,Kim,S.P.,Kang,M.Y.&Nam,S.H.Inhibitory effect of curcumin on liver injury in a murine model of endotoxemic shock.Biotechnol Lett.32,209-214(2010).
32.Xu,Z.et al.FXR ligands protect against hepatocellular inflammation via SOCS3 induction.Cell Signal.24,1658-1664(2012).
33.Vavassori,P.,Mencarelli,A.,Renga,B.,Distrutti,E.&Fiorucci,S.The bile acid receptor FXR is a modulator of intestinal innate immunity.J Immunol.183,6251-6261(2009).
34.Woolbright,B.L.et al.Bile acid-induced necrosis in primary human hepatocytes and in patients with obstructive cholestasis.Toxicol Appl Pharmacol.283,168-177(2015).
35.Woolbright,B.L.,McGill,M.R.,Yan,H.&Jaeschke,H.Bile Acid-Induced Toxicity in HepaRG Cells Recapitulates the Response in Primary Human Hepatocytes.Basic Clin Pharmacol Toxicol.118,160-167(2016).
36.Allen,K.,Jaeschke,H.&Copple,B.L.Bile acids induce inflammatory genes in hepatocytes:a novel mechanism of inflammation during obstructive cholestasis.Am J Pathol.178,175-186(2011).
37.Martinez-Diez,M.C.,Serrano,M.A.,Monte,M.J.&Marin,J.J.Comparison of the effects of bile acids on cell viability and DNA synthesis by rat hepatocytes in primary culture.Biochim BiophysActa.1500,153-160(2000).
38.Zhang,Y.et al.Effect of bile duct ligation on bile acid composition in mouse serum and liver.Liver Int.32,58-69(2012).
39.Rolo,A.P.,Palmeira,CM.&Wallace,K.B.Interactions of combined bile acids on hepatocyte viability:cytoprotection or synergism.Toxicol Lett.126,197-203(2002).
40.Perreault,M.et al.Role of glucuronidation for hepatic detoxification and urinary elimination of toxic bile acids during biliary obstruction.PLoS One.8,e80994(2013).
41.Hartupee,J.&Mann,D.L.Role of inflammatory cells in fibroblast activation.J.Mol Cell Cardiol.In Press(2015).
42.Park,K.C.et al.A new histone deacetylase inhibitor improves liver fibrosis in BDL rats through suppression of hepatic stellate cells.Br.J Pharmacol.171,4820-4830(2014).
43.Mukhopadhyay,P.et al.Poly(ADP-ribose)polymerase-1 is a key mediator of liver inflammation and fibrosis.Hepatology.59,1998-2009(2014).
44.Deters,M.,Klabunde,T.,Meyer,H.,Resch,K.&Kaever,V.Effects of curcumin on cyclosporine-induced cholestasis and hypercholesterolemia and on cyclosporine metabolism in the rat.Planta Med.69,337-343(2003).
45.Reyes-Gordillo,K.et al.Curcumin prevents and reverses cirrhosis induced by bile duct obstruction or CC14 in rats:role of TGF-beta modulation and oxidative stress.Fundam Clin Pharmacol.22,417-427(2008).
46.Fiorucci,S.et al.Protective effects of 6-ethyl chenodeoxycholic acid,a farnesoid X receptor ligand,in estrogen-induced cholestasis.J.Pharmacol Exp Ther.313,604-612(2005).