药学学报, 2014, 49(11): 1483-1490
孙永, 彭明利. 姜黄素及其衍生物在肝脏相关疾病中防治作用的研究进展[J]. 药学学报, 2014, 49(11): 1483-1490.
SUN Yong, PENG Ming-li. Recent advances in curcumin and its derivatives for treatment of liver diseases[J]. Acta Pharmaceutica Sinica, 2014, 49(11): 1483-1490.

孙永, 彭明利
重庆医科大学感染性疾病分子生物学教育部重点实验室, 重庆 400016
姜黄素是植物姜黄主要的多酚类活性成分, 在亚洲传统医学中用于治疗关节炎、溃疡、黄疸等疾病由来已久。近年多项研究发现, 姜黄素在治疗肝脏疾病方面显示出良好的应用前景, 姜黄素通过抑制炎症因子释放、抗氧化应激、改善胰岛素抵抗和调节脂质代谢而对抗肝损伤及非酒精性脂肪肝病理进程; 姜黄素通过调控过氧化物酶体增殖物激活受体γ(PPARγ)、抑制核转录因子κB(NF-κB)和转化生长因子β(TGF-β)等信号通路, 抑制肝星状细胞的活化, 减少细胞外基质的沉积, 从而发挥抗纤维化作用; 姜黄素通过作用于细胞周期引起肝癌细胞G2/M阻滞及凋亡, 发挥抗癌作用。但姜黄素生物利用度低大大限制了其临床应用, 以姜黄素为母体的新剂型和结构修饰是目前研究的热点。本文综述了姜黄素及衍生物作用于肝脏相关疾病的最新研究进展。
关键词:    姜黄素      炎症      脂肪肝      纤维化      肝癌      衍生物     
Recent advances in curcumin and its derivatives for treatment of liver diseases
SUN Yong, PENG Ming-li
Key Laboratory of Molecular Biology of Infectious Disease, Chongqing University of Medical Science, Chongqing 400016, China
Curcumin is a principal polyphenolic curcuminoid extracted from turmeric rhizome, which has been used for treating inflammation of joints, ulcers, jaundice and other disorders in Asian traditional medicine. In recent years, many studies have indicated that curcumin plays important roles in treatment of liver diseases. Curcumin attenuates liver injury and non-alcoholic fatty liver disease by lowering the release of inflammation cytokines, minimizing oxidative stress, enhancing the sensitivity of insulin and altering lipid metabolism. Curcumin shows potent anti-fibrosis activity, contributing to inhibit the activation of hepatic stellate cells and reduce the deposition of extracellular matrix by its regulation of PPAR-γ, NF-κB and TGF-β signaling pathways. Moreover, curcumin exhibits anti-cancer effect by inducing G2/M phase cell cycle arrest and apoptosis in several hepatoma cell lines. However, poor water solubility and low bioavailability of curcumin limit its clinical applications. To overcome its limited systemic bioavailability, many new approaches have been explored to deliver curcumin effectively. This article focuses on advances in the effects of curcumin and its derivatives for treatment of liver injury, non-alcoholic fatty liver disease, liver fibrosis and hepatocarcinoma.
Key words:    curcumin    inflammation    fatty liver    fibrosis    hepatoma    derivative   
收稿日期: 2014-03-08
通讯作者: 彭明利
Email: sallypeng2002@gmail.com
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孙永  在本刊中的所有文章
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[1] Jurenka JS. Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research [J]. Altern Med Rev, 2009, 14: 141-153.
[2] Vera-Ramirez L, Perez-Lopez P, Varela-Lopez A, et al. Curcumin and liver disease [J]. BioFactors, 2013, 39: 88-100.
[3] Ghosh N, Ghosh R, Mandal V, et al. Recent advances in herbal medicine for treatment of liver diseases [J]. Pharm Biol, 2011, 49: 970-988.
[4] Shapiro H, Bruck R. Therapeutic potential of curcumin in non-alcoholic steatohepatitis [J]. Nutr Res Rev, 2005, 18: 212-221.
[5] Tu CT, Han B, Liu HC, et al. Curcumin protects mice against concanavalin A-induced hepatitis by inhibiting intrahepatic intercellular adhesion molecule-1(ICAM-1)and CXCL10 expression [J]. Moll Cell Biochem, 2011, 358: 53-60.
[6] Tu CT, Han B, Yao QY, et al. Curcumin attenuates concanavalin A-induced liver injury in mice by inhibition of Toll-like receptor(TLR)2, TLR4 and TLR9 expression [J]. Int Immunopharmacol, 2012, 12: 151-157.
[7] Wang C, Nie H, Li K, et al. Curcumin inhibits HMGB1 releasing and attenuates concanavalin A-induced hepatitis in mice [J]. Eur J Pharmacol, 2012, 697: 152-157.
[8] Charoensuk L, Pinlaor P, Prakobwong S, et al. Curcumin induces a nuclear factor-erythroid 2-related factor 2-driven response against oxidative and nitrative stress after praziquantel treatment in liver fluke-infected hamsters [J]. Int J Parasitol, 2011, 41: 615-626.
[9] Li G, Chen JB, Wang C, et al. Curcumin protects against acetaminophen-induced apoptosis in hepatic injury [J]. World J Gastroenterol, 2013, 19: 7440-7446.
[10] Palma HE, Wolkmer P, Gallio M, et al. Oxidative stress parameters in blood, liver, and kidney of diabetic rats treated with curcumin and/or insulin [J]. Mol Cell Biochem, 2014, 386: 199-210.
[11] Cerny D, Lekic N, Vanova K, et al. Hepatoprotective effect of curcumin in lipopolysaccharide/-galactosamine model of liver injury in rats: relationship to HO-1/CO antioxidant system [J]. Fitoterapia, 2011, 82: 786-791.
[12] García-Niño WR, Tapia E, Zazueta C, et al. Curcumin pretreatment prevents potassium dichromate-induced hepato­toxicity, oxidative stress, decreased respiratory complex I activity, and membrane permeability transition pore opening [J]. Evid Based Complement Alternat Med, 2013, doi: 10.1155/2013/424692.
[13] Waseem M, Parvez S. Mitochondrial dysfunction mediated cisplatin induced toxicity: modulatory role of curcumin [J]. Food Chem Toxicol, 2013, 53: 334-342.
[14] Rao DS, Sekhara NC, Satyanarayana MN, et al. Effect of curcumin on serum and liver cholesterol levels in the rat [J]. J Nutr, 1970, 100: 1307-1315.
[15] Hu GX, Lin H, Lian QQ, et al. Curcumin as a potent and selective inhibitor of 11β-hydroxysteroid dehydrogenase 1: improving lipid profiles in high-fat-diet-treated rats [J]. PLoS One, 2013, 8: e49976. doi: 10.1371/journal.pone.0049976.
[16] Um MY, Hwang KH, Ahn J, et al. Curcumin attenuates diet-induced hepatic steatosis by activating AMP-activated protein kinase [J]. Basic Clin Pharmacol Toxicol, 2013, 113: 152-157.
[17] Kang OH, Kim SB, Seo YS, et al. Curcumin decreases oleic acid-induced lipid accumulation via AMPK phosphorylation in hepatocarcinoma cells [J]. Eur Rev Med Pharmacol Sci, 2013, 17: 2578-2586.
[18] Oner-Lyidog Y, Kocak H, Seyidhanoglu M, et al. Curcumin prevents liver fat accumulation and serum fetuin-a increase in rats fed a high-fat diet [J]. J Physiol Biochem, 2013, 69: 677-686.
[19] Wang Y, Li J, Zhuge L, et al. Comparison between the efficacies of curcumin and puerarin in c57bl/6 mice with steatohepatitis induced by a methionine and choline deficient diet [J]. Exp Ther Med, 2014, 7: 663-668.
[20] Mouzaoui S, Rahim I, Djerdjouri B. Aminoguanidine and curcumin attenuated tumor necrosis factor(TNF)-alpha- induced oxidative stress, colitis and hepatotoxicity in mice [J]. Int Immunopharmacol, 2012, 12: 302-311.
[21] Weisberg SP, Leibel R, Tortoriello DV. Dietary curcumin significantly improves obesity-associated inflammation and diabetes in mouse models of diabesity [J]. Endocrinology, 2008, 149: 3549-3558.
[22] Kuo JJ, Chang HH, Tsai TH, et al. Positive effect of curcumin on inflammation and mitochondrial dysfunction in obese mice with liver steatosis [J]. Int J Mol Med, 2012, 30: 673-679.
[23] Shao W, Yu Z, Chiang Y, et al. Curcumin prevents high fat diet induced insulin resistance and obesity via attenuating lipogenesis in liver and inflammatory pathway in adipocytes [J]. PLoS One, 2012, 7: e28784. doi: 10.1371/journal.pone. 0028784.
[24] Kuo JJ, Chang HH, Tsai TH, et al. Curcumin ameliorates mitochondrial dysfunction associated with inhibition of gluconeogenesis in free fatty acid-mediated hepatic lipoapoptosis [J]. Int J Mol Med, 2012, 30: 643-649.
[25] Messner DJ, Rhieu BH, Kowdley KV. Iron overload causes oxidative stress and impaired insulin signaling in AML-12 hepatocytes [J]. Dig Dis Sci, 2013, 58: 1899-1908.
[26] Lin J, Zheng S, Chen A. Curcumin attenuates the effects of insulin on stimulating hepatic stellate cell activation by interrupting insulin signaling and attenuating oxidative stress [J]. Lab Invest, 2009, 89: 1397-1409.
[27] Lin J, Chen A. Curcumin diminishes the impacts of hyperglycemia on the activation of hepatic stellate cells by suppressing membrane translocation and gene expression of glucose transporter-2 [J]. Mol Cell Endocrinol, 2011, 333: 160-171.
[28] Tang Y, Chen A. Curcumin prevents leptin raising glucose levels in hepatic stellate cells by blocking translocation of glucose transporter-4 and increasing glucokinase [J]. Br J Pharmacol, 2010, 161: 1137-1149.
[29] Lee U, Friedman SL. Mechanisms of hepatic fibrogenesis [J]. Best Pract Res Clin Gastroenterol, 2011, 25: 195-206.
[30] Rechtman MM, Har-Noy O, Bar-Yishay I, et al. Curcumin inhibits hepatitis B virus via down-regulation of the metabolic coactivator PGC-1a [J]. FEBS Lett, 2010, 584: 2485-2490.
[31] Chen MH, Lee MY, Chuang JJ, et al. Curcumin inhibits HCV replication by induction of heme oxygenase-1 and suppression of AKT [J]. Int J Mol Med, 2012, 30: 1021-1028.
[32] Anggakusuma, Colpitts CC, Schang LM, et al. Turmeric curcumin inhibits entry of all hepatitis C virus genotypes into human liver cells [J]. Gut, 2014, 63: 1137-1149.
[33] Lin YL, Lin CY, Chi CW, et al. Study on antifibrotic effects of curcumin in rat hepatic stellate cells [J]. Phytother Res, 2009, 23: 927-932.
[34] Qiu J, Zhou Q, Zhai X, et al. Curcumin regulates delta-like homolog1 expression in activated hepatic stellate cell [J]. Eur J Pharmacol, 2014, 728: 9-15.
[35] Zheng S, Chen A. Activation of PPAR-γ is required for curcumin to induce apoptosis and to inhibit the expression of extracellular matrix genes in hepatic stellate cells in vitro [J]. Biochem J, 2004, 384: 149-157.
[36] Chen A, Zheng S. Curcumin inhibits connective tissue growth factor gene expression in activated hepatic stellate cells in vitro by blocking NF-κB and ERK signaling [J]. Br J Pharmacol, 2008, 153: 557-567.
[37] Lin J, Tang Y, Kang Q, et al. Curcumin eliminates the inhibitory effect of advanced glycation end-products(AGEs)on gene expression of AGE receptor-1 in hepatic stellate cells in vitro [J]. Lab Invest, 2012, 92: 827-841.
[38] Tang Y, Chen A. Curcumin eliminates the effect of advanced glycation end-products(AGEs)on the divergent regulation of gene expression of receptors of AGEs by interrupting leptin signaling [J]. Lab Invest, 2014, 94: 503-516.
[39] Reyes-Gordillo K, Segovia J, Shibayama M, et al. Curcumin protects against acute liver damage in the rat by inhibiting NF-κB, proinflammatory cytokines production and oxidative stress [J]. Biochim Biophys Acta, 2007, 1770: 989-996.
[40] Reyes-Gordillo K, Segovia J, Shibayama M, et al. Curcumin prevents and reverses cirrhosis induced by bile duct obstruct­tion or CCl4 in rats: role of TGF-β modulation and oxidative stress [J]. Fundam Clin Pharmacol, 2008, 22: 417-427.
[41] Zhang Z, Guo Y, Zhang S, et al. Curcumin modulates cannabinoid receptors in liver fibrosis in vivo and inhibits extracellular matrix expression in hepatic stellate cells by suppressing cannabinoid receptortype-1 in vitro [J]. Eur J Pharmacol, 2013, 721: 133-140.
[42] Tu CT, Yao QY, Xu BL, et al. Protective effects of curcumin against hepatic fibrosis induced by carbon tetrachloride: modulation of high-mobility group box 1, Toll-like receptor 4 and 2 expression [J]. Food Chem Toxicol, 2012, 50: 3343- 3351.
[43] Yao Q, Lin Y, Li X, et al. Curcumin ameliorates intrahepatic angiogenesis and capillarization of the sinusoids in carbon tetrachloride-induced rat liver fibrosis [J]. Toxicol Lett, 2013, 222: 72-82.
[44] Zhang F, Zhang Z, Chen L, et al. Curcumin attenuates angiogenesis in liver fibrosis and inhibits angiogenic properties of hepatic stellate cells [J]. J Cell Mol Med, 2014, 18: 1392- 1406.
[45] Hassan ZK, Al-Olayan EM. Curcumin reorganizes miRNA expression in a mouse model of liver fibrosis [J]. Asian Pac J Cancer Prev, 2012, 13: 5405-5408.
[46] Zheng J, Wu C, Lin Z, et al. Curcumin up-regulates phosphatase and tensin homologue deleted on chromosome 10 through microRNA-mediated control of DNA methylation - a novel mechanism suppressing liver fibrosis [J]. FEBS J, 2014, 281: 88-103.
[47] Darvesh AS, Aggarwal BB, Bishayee A. Curcumin and liver cancer: a review [J]. Curr Pharm Biotechnol, 2012, 13: 218-228.
[48] Chiablaem K, Lirdprapamongkol K, Keeratichamroen S, et al. Curcumin suppresses vasculogenic mimicry capacity of hepatocellular carcinoma cells through STAT3 and PI3K/AKT inhibition [J]. Anticancer Res, 2014, 34: 1857-1864.
[49] Sehgai A, Kumar M, Jain M, et al. Modulatory effects of curcumin in conjunction with piperine on benzo(a)pyrene- mediated DNA adducts and biotransformation enzymes [J]. Nutr Cancer, 2013, 65: 885-890.
[50] Huang CZ, Huang WZ, Zhang G, et al. In vivo study on the effects of curcumin on the expression profiles of anti-tumour genes(VEGF, CyclinD1 and CDK4)in liver of rats injected with DEN [J]. Mol Biol Rep, 2013, 40: 5825-5831.
[51] Kim HJ, Park SY, Park OJ, et al. Curcumin suppresses migration and proliferation of Hep3B hepatocarcinoma cells through inhibition of the Wnt signaling pathway [J]. Mol Med Rep, 2013, 8: 282-286.
[52] Yoysungnoen P, Wirachwong P, Bhattarakosol P, et al. Effects of curcumin on tumor angiogenesis and biomarkers, COX-2 and VEGF, in hepatocellular carcinoma cell-implanted nude mice [J]. Clin Hemorheol Microcirc, 2006, 34: 109-115.
[53] Bae MK, Kim SH, Jeong JW, et al. Curcumin inhibits hypoxia-induced angiogenesis via down-regulation of HIF-1 [J]. Oncol Rep, 2006, 15: 1557-1562.
[54] Cao J, Liu Y, Jia L, et al. Curcumin induces apoptosis through mitochondrial hyperpolarization and mtDNA damage in human hepatoma G2 cells [J]. Free Radic Biol Med, 2007, 43: 968-975.
[55] Fan H, Tian W, Ma X. Curcumin induces apoptosis of HepG2 cells via inhibiting fatty acid synthase [J]. Target Oncol, 2013, doi: 10.1007/s11523-013-0286-5.
[56] Wang WZ, Cheng J, Luo J, et al. Abrogation of G2/M arrest sensitizes curcumin-resistant hepatoma cells to apoptosis [J]. FEBS Lett, 2008, 582: 2689-2695.
[57] Cheng CY, Lin YH, Su CC. Curcumin inhibits the proliferation of human hepatocellular carcinoma J5 cells by inducing endoplasmic reticulum stress and mitochondrial dysfunction [J]. Int J Mol Med, 2010, 26: 673-678.
[58] Jiang J, Jin H, Liu L, et al. Curcumin disturbed cell-cycle distribution of HepG2 cells via cytoskeletal arrangement [J]. Scanning, 2013, 35: 253-260.
[59] Wang WZ, Li L, Liu MY, et al. Curcumin induces FasL-related apoptosis through p38 activation in human hepatocellular carcinoma Huh7 cells [J]. Life Sci, 2013, 92: 352-358.
[60] Yu J, Zhou X, He X, et al. Curcumin induces apoptosis involving bax/bcl-2 in human hepatoma SMMC-7721 cells [J]. Asian Pac J Cancer Prev, 2011, 12: 1925-1929.
[61] Cheng AL, Hsu CH, Lin JK, et al. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high- risk or pre-malignant lesions [J]. Anticancer Res, 2001, 21: 2895-2900.
[62] Bisht S, Khan MA, Bekhit M, et al. A polymeric nanoparticle formulation of curcumin(NanoCurcTM)ameliorates CCl4- induced hepatic injury and fibrosis through reduction of pro- inflammatory cytokines and stellate cell activation [J]. Lab Invest, 2011, 91: 1383-1395.
[63] Ucisik MH, Küpcü S, Schuster B, et al. Characterization of curcuEmulsomes: nanoformulation for enhanced solubility and delivery of curcumin [J]. J Nanobiotechnology, 2013, doi: 10.1186/1477-3155-11-37.
[64] Ghosh D, Choudhury ST, Ghosh S, et al. Nanocapsulated curcumin: oral chemopreventive formulation against diethylni­trosamine induced hepatocellular carcinoma in rat [J]. Chem Biol Interact, 2012, 195: 206-214.
[65] Tang H, Murphy CJ, Zhang B, et al. Amphiphilic curcumin conjugate-forming nanoparticles as anticancer prodrug and drug carriers: in vitro and in vivo effects [J]. Nanomedicine, 2010, 5: 855-865.
[66] Zeng CH, Zeng P, Deng YH, et al. The effects of curcumin derivative on experimental Steatohepatitis [J]. Chin J Hepatol(中华肝脏病杂志), 2011, 19: 454-459.
[67] Shen N, Deng YH, Ling N, et al. Effects and its mechanisms of Curc-OEG on experimental hepatic fibrosis in rats [J]. Chin J Clin Pharmacol(中国临床药理学杂志), 2012, 28: 358- 360.
[68] Deng YH, Shen N, Ling N, et al. Efficacy of the Curc-OEG on rat liver fibrosis induced carbon tetrachloride [J]. Chin J Clin pharmacol Ther(中国临床药理学与治疗学), 2012, 17: 147-153.
[69] Adams BK, Ferstl EM, Davis MC, et al. Synthesis and biological evaluation of novel curcumin analogs as anti-cancer and anti-angiogenesis agents [J]. Bioorg Med Chem, 2004, 12: 3871-3883.
[70] Liu H, Liang Y, Wang L, et al. In vivo and in vitro suppres­sion of hepatocellular carcinoma by EF24, acurcumin analog [J]. PLoS One, 2012, 7: e48075. doi: 10.1371/journal.pone. 0048075.
[71] Liang Y, Zheng T, Song R, et al. Hypoxia-mediated sorafenib resistance can be overcome by EF24 through Von Hippel-Lindau tumor suppressor-dependent HIF-1α inhibition in hepatocellular carcinoma [J]. Hepatology, 2013, 57: 1847-1857.
[72] Sehgai A, Kumar M, Jain M, et al. Combined effects of curcumin and piperine in ameliorating benzo(a)pyrene induced DNA damage [J]. Food Chem Toxicol, 2011, 49: 3002-3006.
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