期刊论文详细信息
BMC Complementary and Alternative Medicine
Inhibition by curcumin of multiple sites of the transforming growth factor-beta1 signalling pathway ameliorates the progression of liver fibrosis induced by carbon tetrachloride in rats
Chuan-tao Tu1  Shun-cai Zhang1  Hong-chun Liu1  Ji-yao Wang1  Bei-li Xu1  Qun-yan Yao1 
[1] Department of Gastroenterology and Hepatology, Zhongshan hospital, Fudan University, 180# Fenglin Road, Shanghai, 200032, People’s Republic of China
关键词: Connective tissue growth factor;    Smads;    Transforming growth factor-beta;    Liver fibrosis;    Hepatic stellate cells;    Curcumin;   
Others  :  1232012
DOI  :  10.1186/1472-6882-12-156
 received in 2012-05-21, accepted in 2012-09-08,  发布年份 2012
【 摘 要 】

Background

At present there is no effective and accepted therapy for hepatic fibrosis. Transforming growth factor (TGF)-β1 signaling pathway contributes greatly to hepatic fibrosis. Reducing TGF-β synthesis or inhibiting components of its complex signaling pathway represent important therapeutic targets. The aim of the study was to investigate the effect of curcumin on liver fibrosis and whether curcumin attenuates the TGF-β1 signaling pathway.

Methods

Sprague–Dawley rat was induced liver fibrosis by carbon tetrachloride (CCl4) for six weeks together with or without curcumin, and hepatic histopathology and collagen content were employed to quantify liver necro-inflammation and fibrosis. Moreover, the mRNA and protein expression levels of TGF-β1, Smad2, phosphorylated Smad2, Smad3, Smad7 and connective tissue growth factor (CTGF) were determined by quantitative real time-PCR, Western blot, or immunohistochemistry.

Results

Rats treated with curcumin improved liver necro-inflammation, and reduced liver fibrosis in association with decreased α-smooth muscle actin expression, and decreased collagen deposition. Furthermore, curcumin significantly attenuated expressions of TGFβ1, Smad2, phosphorylated Smad2, Smad3, and CTGF and induced expression of the Smad7.

Conclusions

Curcumin significantly attenuated the severity of CCl4-induced liver inflammation and fibrosis through inhibition of TGF-β1/Smad signalling pathway and CTGF expression. These data suggest that curcumin might be an effective antifibrotic drug in the prevention of liver disease progression.

【 授权许可】

   
2012 Yao et al.; licensee BioMed Central Ltd.

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【 参考文献 】
  • [1]Iredale JP: Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J Clin Invest 2007, 117:539-548.
  • [2]Friedman SL: Mechanisms of hepatic fibrogenesis. Gastroenterology 2008, 134:1655-1669.
  • [3]Leask A, Abraham DJ: TGF-beta signaling and the fibrotic response. FASEB J 2004, 18:816-827.
  • [4]Lee UE, Friedman SL: Mechanisms of hepatic fibrogenesis. Best Pract Res Clin Gastroenterol 2011, 25:195-206.
  • [5]Bataller R, Brenner DA: Liver fibrosis. Clin Invest 2005, 115:209-218.
  • [6]Gressner AM, Weiskirchen R: Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets. J Cell Mol Med 2006, 10:76-99.
  • [7]Shi Y, Massague J: Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 2003, 113:685-700.
  • [8]Roberts AB, Russo A, Felici A, Flanders KC: Smad3: a key player in pathogenetic mechanisms dependent on TGF-beta. Ann N Y Acad Sci 2003, 995:1-10.
  • [9]Kisseleva T, Brenner DA: Anti-fibrogenic strategies and the regression of fibrosis. Best Pract Res Clin Gastroenterol 2011, 25:305-317.
  • [10]Bradham DM, Igarashi A, Potter RL, Grotendorst GR: Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10. J Cell Biol 1991, 114:1285-1294.
  • [11]Holmes A, Abraham DJ, Sa S, Shiwen X, Black CM, Leask A: CTGF and SMADs, maintenance of scleroderma phenotype is independent of SMAD signaling. J Biol Chem 2001, 276:10594-10601.
  • [12]Jun JI, Lau LF: Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets. Nat Rev Drug Discov 2011, 10:945-963.
  • [13]Mori T, Kawara S, Shinozaki M, Hayashi N, Kakinuma T, Igarashi A, Takigawa M, Nakanishi T, Takehara K: Role and interaction of connective tissue growth factor with transforming growth factor-beta in persistent fibrosis: A mouse fibrosis model. J Cell Physiol 1999, 181:153-159.
  • [14]Grotendorst GR: Connective tissue growth factor: a mediator of TGF-beta action on fibroblasts. Cytokine Growth Factor Rev 1997, 8:171-179.
  • [15]Gressner OA, Gressner AM: Connective tissue growth factor: a fibrogenic master switch in fibrotic liver diseases. Liver Int 2008, 28:1065-1079.
  • [16]Weng HL, Ciuclan L, Liu Y, Hamzavi J, Godoy P, Gaitantzi H, Kanzler S, Heuchel R, Ueberham U, Gebhardt R, Breitkopf K, Dooley S: Profibrogenic transforming growth factor-beta/activin receptor-like kinase 5 signaling via connective tissue growth factor expression in hepatocytes. Hepatology 2007, 46:1257-1270.
  • [17]Gressner OA, Lahme B, Demirci I, Gressner AM, Weiskirchen R: Differential effects of TGF-beta on connective tissue growth factor (CTGF/CCN2) expression in hepatic stellate cells and hepatocytes. J Hepatol 2007, 47:699-710.
  • [18]Li G, Xie Q, Shi Y, Li D, Zhang M, Jiang S, Zhou H, Lu H, Jin Y: Inhibition of connective tissue growth factor by siRNA prevents liver fibrosis in rats. J Gene Med 2006, 8:889-900.
  • [19]Rivera-Espinoza Y, Muriel P: Pharmacological actions of curcumin in liver diseases or damage. Liver Int 2009, 29:1457-1466.
  • [20]Tu CT, Han B, Liu HC, Zhang SC: Curcumin protects mice against concanavalin A-induced hepatitis by inhibiting intrahepatic intercellular adhesion molecule-1(ICAM-1) and CXCL10 expression. Mol Cell Biochem 2011, 358:53-60.
  • [21]Corson TW, Crews CM: Molecular understanding and modern application of traditional medicines: triumphs and trials. Cell 2007, 130:769-774.
  • [22]Aggarwal BB, Harikumar KB: Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biol 2009, 41:40-59.
  • [23]Fu Y, Zheng S, Lin J, Ryerse J, Chen A: Curcumin protects the rat liver from CCl4-caused injury and fibrogenesis by attenuating oxidative stress and suppressing inflammation. Mol Pharmacol 2008, 73:399-409.
  • [24]Bruck R, Ashkenazi M, Weiss S, Goldiner I, Shapiro H, Aeed H, Genina O, Helpern Z, Pines M: Prevention of liver cirrhosis in rats by curcumin. Liver Int 2007, 27:373-383.
  • [25]Bisht S, Khan MA, Bekhit M, Bai H, Cornish T, Mizuma M, Rudek MA, Zhao M, Maitra A, Ray B, Lahiri D, Maitra A, Anders RA: A polymeric nanoparticle formulation of curcumin (NanoCurc™) ameliorates CCl4-induced hepatic injury and fibrosis through reduction of pro-inflammatory cytokines and stellate cell activation. Lab Invest 2011, 91:1383-1395.
  • [26]Bedossa P, Poynard T: An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology 1996, 24:289-293.
  • [27]Tu CT, Guo JS, Wang M, Wang JY: Antifibrotic activity of rofecoxib in vivo is associated with reduced portal hypertension in rats with carbon tetrachloride-induced liver injury. J Gastroenterol Hepatol 2007, 22:877-884.
  • [28]Kodama T, Takehara T, Hikita H, Shimizu S, Shigekawa M, Tsunematsu H, Li W, Miyagi T, Hosui A, Tatsumi T, et al.: Increases in p53 expression induce CTGF synthesis by mouse and human hepatocytes and result in liver fibrosis in mice. J Clin Invest 2011, 121:3343-3356.
  • [29]Friedman SL: Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol 2010, 7:425-436.
  • [30]Goel A, Jhurani S, Aggarwal BB: Multi-targeted therapy by curcumin: how spicy is it? Mol Nutr Food Res 2008, 52:1010-1030.
  • [31]Padhye S, Chavan D, Pandey S, Deshpande J, Swamy KV, Sarkar FH: Perspectives on chemopreventive and therapeutic potential of curcumin analogs in medicinal chemistry. Mini Rev Med Chem 2010, 10:372-387.
  • [32]Reyes-Gordillo K, Segovia J, Shibayama M, Tsutsumi V, Vergara P, Moreno MG, Muriel P: Curcumin prevents and reverses cirrhosis induced by bile duct obstruction or CCl4 in rats: role of TGF-beta modulation and oxidative stress. Fundam Clin Pharmacol 2008, 22:417-427.
  • [33]Gaedeke J, Noble NA, Border WA: Curcumin blocks multiple sites of the TGF-beta signaling cascade in renal cells. Kidney Int 2004, 66:112-120.
  • [34]Bissell DM, Roulot D, George J: Transforming growth factor beta and the liver. Hepatology 2001, 34:859-867.
  • [35]Dooley S, Ten Dijke P: TGF-β in progression of liver disease. Cell Tissue Res 2012, 347:245-256.
  • [36]Schnabl B, Kweon YO, Frederick JP, Wang XF, Rippe RA, Brenner DA: The role of Smad3 in mediating mouse hepatic stellate cell activation. Hepatology 2001, 34:89-100.
  • [37]Latella G, Vetuschi A, Sferra R, Catitti V, D’Angelo A, Zanninelli G, Flanders KC, Gaudio E: Targeted disruption of Smad3 confers resistance to the development of dimethylnitrosamine-induced hepatic fibrosis in mice. Liver Int 2009, 29:997-1009.
  • [38]Hu Y, Liang H, Du Y, Zhu Y, Wang X: Curcumin inhibits transforming growth factor-beta activity via inhibition of Smad signaling in HK-2 cells. Am J Nephrol 2010, 31:332-341.
  • [39]George J, Tsutsumi M: siRNA-mediated knockdown of connective tissue growth factor prevents N-nitrosodimethylamine-induced hepatic fibrosis in rats. Gene Ther 2007, 14:790-803.
  • [40]Chen A, Zheng S: Curcumin inhibits connective tissue growth factor gene expression in activated hepatic stellate cells in vitro by blocking NF-kappaB and ERK signalling. Br J Pharmacol 2008, 153:557-567.
  • [41]Li HL, Liu C, de Couto G, Ouzounian M, Sun M, Wang AB, Huang Y, He CW, Shi Y, Chen X, et al.: Curcumin prevents and reverses murine cardiac hypertrophy. J Clin Invest 2008, 118:879-893.
  • [42]Liu Y, Meyer C, Müller A, Herweck F, Li Q, Müllenbach R, Mertens PR, Dooley S, Weng HL: IL-13 induces connective tissue growth factor in rat hepatic stellate cells via TGF-β- independent Smad signaling. J Immunol 2011, 187:2814-2823.
  • [43]Tache D, Bogdan F, Pisoschi C, Baniţă M, Stănciulescu C, Fusaru AM, Comănescu V: Evidence for the involvement of TGF-β1-CTGF axis in liver fibrogenesis secondary to hepatic viral infection. Rom J Morphol Embryol 2011, 52:s409-s412.
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