姜黄素预防性治疗肝纤维化的机制
摘要
肝纤维化(hepatic fibrosis)是指各种致病因素引起肝脏损害和炎症,在修复过程中导致肝脏细胞外基质(extracellular matrix,ECM)异常增多和过度沉积的病理过程。肝纤维化是可以逆转的,对其逆转因素的研究可为了解肝纤维化进程及其发生机制提供重要线索。目前对肝纤维化的治疗尚无行之有效的方案,因此,肝纤维化防治仍是肝病治疗的重点难点。姜黄素(Curcumin)是从姜科姜黄属植物姜黄中提取的一种黄色酸性酚类物质,是姜黄发挥药理作用的主要活性成分。目前认为,姜黄素在防治肝纤维化过程中有非常广阔的应用前景,但对其姜黄素的作用机制及临床制剂方面的研究还有待进一步深入。
本研究通过CCl4致肝损伤并导致肝纤维化的动物模型,并结合体外HSC培养,系统探讨姜黄素对大鼠实验性肝纤维化的防治作用,并对其机制作深入探讨,为姜黄素的应用提供理论依据。本研究主要得到以下结论:⑴姜黄素对CCl4所致大鼠肝损伤有保护作用,有利于维持肝脏正常形态,保护肝脏功能;⑵姜黄素体内、体外均显示出抑制肝脏过度表达ECM,从而实现其保护肝脏功能,维系肝脏正常结构的作用;⑶姜黄素可抑制重要的致纤维化因子TGF-β和CTGF mRNA的表达,提示TGF-β和CTGF是姜黄素防治肝纤维化的治疗靶点之一;⑷姜黄素可抑制实验性肝纤维化大鼠肝脏及体外培养HSC EGF的表达,从而抑制HSC增殖并促进其调亡;⑸MAPK途径是参与肝纤维化的重要信号转导途径之一,姜黄素可干扰其中多种信号蛋白的表达,从而抑制MAPK信号系统的功能,抑制或延缓肝纤维化的进程。
总之,本研究结果显示,姜黄素对保护肝脏功能、延缓肝纤维化进程有重要作用,但该作用不是通过单一途径进行的,而是通过包括抑制MAPK信号通路在内的多个靶点实现的。
Background
Hepatic fibrosis represents the consequences of injury-recovery response to various chronic liver diseases, which leads to the over-produced extracellular matrix (ECM) accumulate in the liver. It is accepted the procedure is reversible though the origin and mechanisms of each liver fibrogenesis are difference without effective therapy, Hepatic fibrosis can progress into cirrhosis even liver cancer. Because the mechanisms of LF are too complicated, the knowledge of Hepatic fibrosis is poor by now which limit the progress of its therapy. Accroding to the achievement of research of liver diseases, two theraputic strategies are developed. One is to remove the etiological factors and another is to treat fibrosis. The later refers to vious anti-fibrosis medicine currently. How to avoid hepatic fibrosis is rather important since no effective anti-fibrosis treatment is established.
Curcumin is the product obtained by solvent extraction of turmeric i.e., the ground rhizomes of Curcuma longa L. (Curcuma domestica Valeton) and purification of the extract by crystallization. Multiple studies indicated that curcumin is a potential tool to protect liver from fibrosis. The mechanisms of this effect need further investigation. Furthermore, how to make curcumin clinical available is another task since it is difficult to solve in water and relatively unstable.
Methods
Rat liver fibrostic model induced with CCl4 was used in this study. Meantime,culturative HSC was also utilized in the study together to explore the preventive effect of curcumin and the possible mechanism on liver fibrosis, trying to elucidate the theraputic value of curcumin. Various volume of curcumin was administrated to SD rat. Liver functions and immunohistochemistry images were analyzed before and after administration. The level of liver fibrosis was evaluated and compared within different groups. Furthermore, the proliferation and apoptosis of CFSC-2G cell were determined before and after co-incubated with various concentration of curcumin. Meanwhile, the mRNA expression of several cytokines, including TGF-βand CTGF, was detected at the indicated time.
Result
(1)in vivo study: A Comparing with control group, the hepatic index was significantly higher in curcumin treated(P<0.05) groups; B Compare with normal SD rat, AST and ALT of liver fibrostic rat is much higher (P<0.01)but decreased dramatically after treatment with curcumin (P<0.05); C In CCl4 induced liver fibrosis rat, as shown in the result, accompanied with the injection of ccl4, hepatocyes necrosis, inflammatory infiltration as well as fiber septa formation occurred, implying the progression of liver fibrosis; in contrast with model group, liver tissue kept relatively normal structure in curcumin treated groups though mild fibrosis was identified; D Masson stain also confirmed that liver fibrosis is milder in curcumin treated group than in model group. Moreover, quantitative determination of Masson stain showed that fiber synthesis is much more than normal group(P<0.01)but less than that of model group(P<0.05); E As shown in the figures, type I collagen synthesis was identified in model group(P<0.01) but this effect was diminished in curcumin treated groups( P<0.05); Meantime, synthesis of type III collagen also showed the same pattern with that of type I collagen and curcumin inhibited both types of collagen; F 1.6 mRNA expression of TGF-β1 and CTGF elevated in model group than normal group(P<0.01) but curcumin inhibited the expression of TGF-β1 mRNA significantly (P<0.01); however, though CTGF mRNA was inhibited by curcumin, it is not statistically dramatic; G Expression of Erk, JNK, p38 and Akt are higher than normal group(P<0.01); But after treatment of low concentration of curcumin, the expression of Erk was dramatically decreased than that of model rat group(P<0.01); However, in the groups of medium or high concentration of curcuma ; Erk expression increased significantly than normal rat group(P<0.01); no significant difference with model rat group; H Meanwhile, JNK expression was decreased in all three curcumin groups(P<0.05 in low con. group, P<0.01 in medium and high con. group)than in model rat group; I As for the p38 expression, only high con. group show decreased p38 expression dramatically(P<0.05) than model rat group, medium con. group also showed such tendency but not statistic significantly; J Akt expression was decreased in all three curcumin treated group dramatically(P<0.01)than model rat group; K As shown in the result, EGF expression of model rat was higher than normal rat(P<0.01), but curcumin treatment suppressed the expression of EGF significantly(P<0.01)than that of model group. (2) In vitro study: A MTT assay showed that HSC proliferation was suppressed 12h after being co-incuated with various con. of curcumin(5,10,15,20,40μmol/L)and 48h after con-incubation, this effect was greater than negative control group(colchicines); the suppression effect showed concentration dependent pattern; B After 24h treated with curcumin, type III and type I collagen was decreased in supernatant than control group (P < 0.05); C After 48 h of co-incubation with 20μmol/Lcurcumin, apoptosis was dramatically increased(P < 0.01) than control group but lower than colchicines treated group(P < 0.05); D the synthesis of type I Collagen and type III Col lagen was suppressed in curcumin treated group(P < 0.01); E the expression of TGF-β1、CTGF and EGF was increased together with the HSC culture but declined significantly after the treatment of curcumin; F Compare with normal control group, Akt, ERK and JNK expression were decreased in curcumin and colchicines treated groups (P<0.01), p38 expression was decreased significantly in colchicines group, though the similar pattern was also seen in curcumin, the decrease was not statistic significantly.
Conclusion
The result of this study indicated that:⑴Curcumin protects rat from liver damage and facilitates keeping the normal tissue structure and normal liver function;⑵in vivo as well as in vitro study showed that curcumin inhibits the synthesis of ECM in liver thus maintain the liver function and normal tissue structure;⑶curcumin inhibit the mRNA expression of TGF-βand CTGF, which are considered the important pro-fibrosis factor, implying TGF-βand CTGF are two potential targets for anti-fibrosis therapy;⑷curcumin inhibits expression of EGF in HSC of rats with liver fibrosis thus inhibits the proliferation and enhances appoptosis of HSC;⑸MAPK signaling pathway was involved in liver fibrogenesis. Curcumin inhibited liver fibrogenesis through suppressing the expression of multiple cytokines which participate in MAPK signaling. In a word, curcumin aids to protect liver from damages and slow down the progress of liver fibrosis through mataining the liver function, and this effect is achieved via regulating multiple targets including MAPK signaling.
本研究通过CCl4致肝损伤并导致肝纤维化的动物模型,并结合体外HSC培养,系统探讨姜黄素对大鼠实验性肝纤维化的防治作用,并对其机制作深入探讨,为姜黄素的应用提供理论依据。本研究主要得到以下结论:⑴姜黄素对CCl4所致大鼠肝损伤有保护作用,有利于维持肝脏正常形态,保护肝脏功能;⑵姜黄素体内、体外均显示出抑制肝脏过度表达ECM,从而实现其保护肝脏功能,维系肝脏正常结构的作用;⑶姜黄素可抑制重要的致纤维化因子TGF-β和CTGF mRNA的表达,提示TGF-β和CTGF是姜黄素防治肝纤维化的治疗靶点之一;⑷姜黄素可抑制实验性肝纤维化大鼠肝脏及体外培养HSC EGF的表达,从而抑制HSC增殖并促进其调亡;⑸MAPK途径是参与肝纤维化的重要信号转导途径之一,姜黄素可干扰其中多种信号蛋白的表达,从而抑制MAPK信号系统的功能,抑制或延缓肝纤维化的进程。
总之,本研究结果显示,姜黄素对保护肝脏功能、延缓肝纤维化进程有重要作用,但该作用不是通过单一途径进行的,而是通过包括抑制MAPK信号通路在内的多个靶点实现的。
Background
Hepatic fibrosis represents the consequences of injury-recovery response to various chronic liver diseases, which leads to the over-produced extracellular matrix (ECM) accumulate in the liver. It is accepted the procedure is reversible though the origin and mechanisms of each liver fibrogenesis are difference without effective therapy, Hepatic fibrosis can progress into cirrhosis even liver cancer. Because the mechanisms of LF are too complicated, the knowledge of Hepatic fibrosis is poor by now which limit the progress of its therapy. Accroding to the achievement of research of liver diseases, two theraputic strategies are developed. One is to remove the etiological factors and another is to treat fibrosis. The later refers to vious anti-fibrosis medicine currently. How to avoid hepatic fibrosis is rather important since no effective anti-fibrosis treatment is established.
Curcumin is the product obtained by solvent extraction of turmeric i.e., the ground rhizomes of Curcuma longa L. (Curcuma domestica Valeton) and purification of the extract by crystallization. Multiple studies indicated that curcumin is a potential tool to protect liver from fibrosis. The mechanisms of this effect need further investigation. Furthermore, how to make curcumin clinical available is another task since it is difficult to solve in water and relatively unstable.
Methods
Rat liver fibrostic model induced with CCl4 was used in this study. Meantime,culturative HSC was also utilized in the study together to explore the preventive effect of curcumin and the possible mechanism on liver fibrosis, trying to elucidate the theraputic value of curcumin. Various volume of curcumin was administrated to SD rat. Liver functions and immunohistochemistry images were analyzed before and after administration. The level of liver fibrosis was evaluated and compared within different groups. Furthermore, the proliferation and apoptosis of CFSC-2G cell were determined before and after co-incubated with various concentration of curcumin. Meanwhile, the mRNA expression of several cytokines, including TGF-βand CTGF, was detected at the indicated time.
Result
(1)in vivo study: A Comparing with control group, the hepatic index was significantly higher in curcumin treated(P<0.05) groups; B Compare with normal SD rat, AST and ALT of liver fibrostic rat is much higher (P<0.01)but decreased dramatically after treatment with curcumin (P<0.05); C In CCl4 induced liver fibrosis rat, as shown in the result, accompanied with the injection of ccl4, hepatocyes necrosis, inflammatory infiltration as well as fiber septa formation occurred, implying the progression of liver fibrosis; in contrast with model group, liver tissue kept relatively normal structure in curcumin treated groups though mild fibrosis was identified; D Masson stain also confirmed that liver fibrosis is milder in curcumin treated group than in model group. Moreover, quantitative determination of Masson stain showed that fiber synthesis is much more than normal group(P<0.01)but less than that of model group(P<0.05); E As shown in the figures, type I collagen synthesis was identified in model group(P<0.01) but this effect was diminished in curcumin treated groups( P<0.05); Meantime, synthesis of type III collagen also showed the same pattern with that of type I collagen and curcumin inhibited both types of collagen; F 1.6 mRNA expression of TGF-β1 and CTGF elevated in model group than normal group(P<0.01) but curcumin inhibited the expression of TGF-β1 mRNA significantly (P<0.01); however, though CTGF mRNA was inhibited by curcumin, it is not statistically dramatic; G Expression of Erk, JNK, p38 and Akt are higher than normal group(P<0.01); But after treatment of low concentration of curcumin, the expression of Erk was dramatically decreased than that of model rat group(P<0.01); However, in the groups of medium or high concentration of curcuma ; Erk expression increased significantly than normal rat group(P<0.01); no significant difference with model rat group; H Meanwhile, JNK expression was decreased in all three curcumin groups(P<0.05 in low con. group, P<0.01 in medium and high con. group)than in model rat group; I As for the p38 expression, only high con. group show decreased p38 expression dramatically(P<0.05) than model rat group, medium con. group also showed such tendency but not statistic significantly; J Akt expression was decreased in all three curcumin treated group dramatically(P<0.01)than model rat group; K As shown in the result, EGF expression of model rat was higher than normal rat(P<0.01), but curcumin treatment suppressed the expression of EGF significantly(P<0.01)than that of model group. (2) In vitro study: A MTT assay showed that HSC proliferation was suppressed 12h after being co-incuated with various con. of curcumin(5,10,15,20,40μmol/L)and 48h after con-incubation, this effect was greater than negative control group(colchicines); the suppression effect showed concentration dependent pattern; B After 24h treated with curcumin, type III and type I collagen was decreased in supernatant than control group (P < 0.05); C After 48 h of co-incubation with 20μmol/Lcurcumin, apoptosis was dramatically increased(P < 0.01) than control group but lower than colchicines treated group(P < 0.05); D the synthesis of type I Collagen and type III Col lagen was suppressed in curcumin treated group(P < 0.01); E the expression of TGF-β1、CTGF and EGF was increased together with the HSC culture but declined significantly after the treatment of curcumin; F Compare with normal control group, Akt, ERK and JNK expression were decreased in curcumin and colchicines treated groups (P<0.01), p38 expression was decreased significantly in colchicines group, though the similar pattern was also seen in curcumin, the decrease was not statistic significantly.
Conclusion
The result of this study indicated that:⑴Curcumin protects rat from liver damage and facilitates keeping the normal tissue structure and normal liver function;⑵in vivo as well as in vitro study showed that curcumin inhibits the synthesis of ECM in liver thus maintain the liver function and normal tissue structure;⑶curcumin inhibit the mRNA expression of TGF-βand CTGF, which are considered the important pro-fibrosis factor, implying TGF-βand CTGF are two potential targets for anti-fibrosis therapy;⑷curcumin inhibits expression of EGF in HSC of rats with liver fibrosis thus inhibits the proliferation and enhances appoptosis of HSC;⑸MAPK signaling pathway was involved in liver fibrogenesis. Curcumin inhibited liver fibrogenesis through suppressing the expression of multiple cytokines which participate in MAPK signaling. In a word, curcumin aids to protect liver from damages and slow down the progress of liver fibrosis through mataining the liver function, and this effect is achieved via regulating multiple targets including MAPK signaling.
引文
[1] Friedman SL. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury_J]. J Biol Chem, 2000, 275: 2247-2250.
[2] Friedman SL, Maher JJ, Bissell DM. Mechanisms and therapy of hepatic fibrosis: report of the AASI D Single Topic Basic Research Conference. Hepatology, 2000, 2(6): 1403-1408.
[3] Britton RS, Bacon BR. Intracellular signaling pathways in stellate cell activation. Alcohol Clin Exp Res, I999, 23: 922-925.
[4] Dudas J, Kovalszky I, Gallai M. Expression of decorin, transforming growth factor-beta 1, tissue inhibitor metalloproteinase 1 and 2, and type IV collagenases in chronic hepatitiws. Cell Biochem, 2003, 89: 311-320.
[5] Jia J, Bauer M, Boigk G. Expression of collagen XVIII mRNA in rat liver fibrosis.中华肝脏病杂志, 2000, 8(5): 274-275.
[6] Knittel T, Mehde M, Grundmann A, et a1. Expression of matrix metalIoproteinases and their inhibitors during hepatic tissue repair in the rat. Histochem Cell Biol, 2000, 113 (6): 443-453.
[7] Issa R, Zhou X, Constandinou CM, et a1. Spontaneous recovery from micronodular cirrhosis:evidence for incomplete resolution associated with matrix CROSS-linking. Gastroenterology, 2004, I26: 1795-1808.
[8] Arthur MJ, Mann DA, Iredale JP. Tissue inhibitors of metalloproteinases, hepatic stellate cells and liver fibrosis. J Gastroenterol Hepatol, 1998, 13(Supp1): S33-38.
[9] Weng ZH, Lei YC, Peng C, et al. Effect of blocking Wnt/beta-catenin signaling pathway on apoptosis of activated hepatic stellate cells.中华肝脏病杂志, 2007, 15(6): 471-472.
[10] Han YP. Matrix metalloproteinase, the [ros and cons, in liver fibrosis.J Gastroenterol Hepadtol, 2006(Suppl 3): S88-91
[11] Lindert S, Wickert L, Sawitza I, et al. Transdifferentiation-dependent expression of alpha-SMA in hepatic stellate cells does not involve TGF-beta pathways leading to coinduction of collagen type I and thrombospondin-2. Matrix Biol, 2005; 24(3): 198-207.
[12] 12.Friedman SL, Roll FJ, Boyles J, et al. Maintenance of differentiated phenotype of cultured rat hepatic lipocytes by basement membrane matrix. J Biol Chem, 1989, 264(18): 10756-10762.
[13] Jarnagin WR, Rockey DC, Koteliansky VE, et al. Expression of variant fibronectins in wound healing: cellular source and biological activity of the EⅢA segment in rat hepaticfibrogenesis. J Cell Biol, 1994; 127(6pt2): 2037-2048
[14] Parkes JG, Templeton DM. Effects of retinol and hepatocyte-conditioned medium on cultured rat hepatic stellate cells. Ann Clin Lab Sci, 2003; 33(3): 295-305.
[15] Senoo H, Imai K, Matano Y, et al. Molecular mechanisms in the reversible regulation of morphology, proliferation and structure of the extracellular matrix. J Gastroeuterol Hepatol, 1998; 13(suppl): 19-32.
[16] Sanz S,Pucilowska JB,Liu S,et al. Expression of insulin 2 like growth factor 1 by activated hepatic stellate cells reduces fibrogenesis and enhances regeneration after liver injury. Gut, 2005; 54(1): 134-141.
[17] Marra F, Gentilini A, Pinzani M, et al. Phosphatidylinositol 3-kinase is required for platelet-derived growth factor’s actions on hepatic stellate cells. Gastroenterology, 1997, 112(4): 1297-1306.
[18] Proell V,Carmona-Cuencal,Murillo MM,et al. TGF-beta dependent regulation of oxygen radicals during trans differentiation of activated hepatic stellate cells to myofibroblastoid cells. Comp Hepatol, 2007; 6(1): 1.
[19] Dooley S. Smad7 Prevents activation of hepatic stellate cells and 1iver fibrosis in rat. Gastroenterology, 2003; 125(1): 178-191.
[20] Furukawa F, Matsuzaki K, Mori S, et al. P38 MAPK mediated fibrogenic signal through Smad3 phosphorylation in rat myofibroblasts. Hepatology, 2003; 38(4): 879-889.
[21] Shek FW, Benyon RC. How can transforming growth factor beta be targeted usefully to combat liver fibrosis? Eur J Gastroenterol Hepatol, 2004; 16(2): 123-126.
[22] Chen M, Wang GJ, Diao Y, et al. Adeno-assoeiated virus meidiated interferon-gamma inhibits the progression of hepatic fibrosis in vitro and in vivo. World J Gastroenterol, 2005; 11(26): 4045-4051.
[23] Weng H, Mertens PR, Gressner AM, et al. IFN-gamma abrogates profibrogenic TGF-beta signaling in liver by targeting expression of inhibitory and receptor Smads. J Hepatol. 2007; 46(2): 295-303.
[24] Han YP, Zhou L, Wang J, et al. Essential role of matrix metalloproteinases in interleukin-1-induced myofibroblastic activation of hepatic stellate cell in collagen. J Biol Chem, 2004; 279(6): 4820-4828.
[25] Mauviel A, Lapière JC, Halcin C, et al. Differential cytokine regulation of type I and type VII collagen gene expression in cultured human dermal fibroblasts.J Biol Chem, 1994; 269(1): 25-28.
[26] Zhang LJ, Yu JP, Li D, et al. Effects of cytokines on carbon tetrachloride-induced hepatic fibrogenesis in rats. World J Gastroenterol, 2004; 10(1): 77-81.
[27] Zheng WD, Zhang LJ, Shi MN, et al. Expression of matrix metalloproteinase-2 in hepatic Stellate cells during rat hepatic fibrosis and its intervention by IL-10. World Gastroenterol, 2005; 11(12): 1753-1758.
[28] Wang XZ, Zhang SJ, Chen YX, et al. Effects of Platelet-derived growth factor and interleukin-10 on Fas/Fas-ligand and Bcl-2/Bax mRNA expression in rat hepatic stellate cells in vitro. World J Gastroenterol, 2004; 10(18): 2706-2710.
[29] Liu XY, Zhou HF, Pan YL, et al. Electro-acupuncture stimulation protects dopaminergic neurons from inflammation-mediated damage in medial forebrain bundle-transected rats. Exp Neurol, 2004; 189(1): 189-196.
[30] Tomita K, Tamiya G, Ando S, et al. Tumour necrosis factor alpha signaling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohePatitis in mice. Gut, 2006; 55(3): 415-424.
[31] Paradis V, Dargere D, Vidaud M, et al. Expression of connective tissue growth factor in experimental rat and human liver fibrosis. Hepatology, 1999; 30(4): 968-976
[32] George J, Tsutsumi M. siRNA-mediated knockdown of connective tissue growth factor prevents N-nitrosodimethylamine-indueed hepatic fibrosis in rats. Gene Ther, 2007; 14(10):790-803.
[33] Li G, Xie Q, Shi Y, et al. Inhibition of connective tissue growth factor by siRNA Prevents liver fibrosis in rats. J Gene Med, 2006; 8(7): 889-900.
[34]周爱玲,罗琳,茅家慧,等.苦参素对实验性肝纤维化的防治作用及对MMP-2表达的影响.中国临床药理学与治疗学, 2004, 9(10): 1096-1100.
[35]施光峰,李谦,翁心华,等.苦参素对大鼠纤维化肝脏金属蛋白酶-1和平滑肌肌动蛋白表达的影响.中华肝脏病杂志, 2004, 12(1): 56.
[36]余小虎,朱金水,朱祖明,等.氧化苦参碱抗肝纤维化作用的病理学研究.胃肠病学和肝病学杂志, 2004, 13(5): 485-487.
[37]余小虎,朱金水,俞华芳,等.氧化苦参碱抗大鼠肝纤维化及其免疫调控作用.中国临床医学, 2004; 11(2): 163-166.
[38]真岩波,刘效华,赵平.苦参碱对乙型肝炎肝纤维化患者血清IL-6、IL-8含量的影响.临床肝胆病杂志, 2004; 20(2): 87-88.
[39]卢清,张清波,张继明,等.氧化苦参碱对大鼠肝星状细胞旁分泌活化途径的抑制作用.肝脏, 2004; 9(1): 31-33.
[40]林明华,闫海明,李凯霞,等.氧化苦参碱对成纤维细胞增殖及Ⅰ型胶原合成的影响.黑龙江医药科学, 2004; 27(1): 13-14.
[41]方翠艳,杨金枝,富新伟,等.苦参素葡萄糖注射液治疗慢性乙型肝炎的疗效观察.实用肝脏病杂志, 2004; 7(4): 238-239.
[42]王英,林小玲,张福华.苦参素对慢性乙型肝炎患者血清肝纤维化指标的影响.实用肝脏病杂志, 2004; 7(4): 239-240.
[43]彭安邦,姚育红,谢黎明,等.苦参素治疗乙肝所致肝纤维化的临床观察.临床肝胆病杂志, 2004; 20(5): 279-280.
[44]孙永年,徐斌,黄祝青,等.苦参素治疗对慢乙肝患者TGF-β1、TNF-α、HA、PcⅢ水平的影响.中国现代医学杂志, 2004; 14(3): 41-44.
[45] Liu P, Liu CH, Wang HN, et al. Effect of salvianolic acid B on collagen production and mitogen-activated protein kinase activity in rat hepatic stellate cells. Acta Pharmacol Sin, 2002; 23(8): 733-738.
[46]刘成,赵俊芳,刘成海,等.丹酚酸B对转化生长因子β1促肝星状细胞分泌胶原的影响.肝脏, 2003; 8(3): 20-22.
[47]薛冬英,洪嘉禾,徐列明.丹参酚酸B对大鼠肝星状细胞中丝裂原激活的蛋白激酶通路的抑制作用.中华肝病杂志, 2004; 12(8): 471-474.
[48]王晓玲,崔云华,胡旭东,等.丹酚酸B对大鼠肝星状细胞增殖周期的抑制作用.中华消化杂志, 2004; 24(1): 59.
[49]崔云华,王晓玲,严振国,等.丹参酸乙对大鼠肝星状细胞内氧化水平及增殖细胞核抗原的影响.中西医结合肝病杂志, 2003; 13(4): 210-212.
[50] Liu P, Hu YY, Liu C, et al. Clinical observation of salvianolic acid B in treatment of liver fibrosis in chronic hepatitis B. World J Gastroenterol, 2002; 8(4): 679-685.
[51] Iinuma Y, Kubota M, Yagi M, et al. Effects of the herbal medicine Inchinko-to on liver function in postoperative patients with biliary atresia-a pilot study. J Pediatr Surg, 2003; 38(11): 1607-1611.
[52] Lanzini A D, Tavonatti MG, Panarotto B, et al. Intestinal absorption of the bile acid analogue 75Se-homocholic acid-taurine is increased in primary biliary cirrhosis, and reverts to normal during ursodeoxycholic acid administration. Gut, 2003; 52(9): 1371-1375.
[53] Overman GP, Teter GJ, Guthrie SK. Acamprosate for the adjunctive treatment of alcohol dependence. Ann Pharmacother, 2003; 37(7-8): 1090-1099.
[54]韦新,梁健,毛德文,等.牛磺酸对大鼠肝纤维化形成的影响.中国中西医结合消化杂志, 2004; 12(1): 6-7.
[55] Muriel P, Moreno MG. Effects of silymarin and vitamins E and C on liver damage induced by prolonged biliary obstruction in the rat. Basic Clin Pharmacol Toxicol, 2004; 94(2): 99-104.
[56] Jia JD, Bauer M, Cho JJ, et al. Antifibrotic effect of silymarin in rat secondary biliary fibrosis is mediated by downregulation of procollagen alphal(Ⅰ)and TIMP-1. J Hepatol, 2001; 35(3): 392-398.
[57] Lieber CS, Leo MA, Cao Q, et al. Silymarin retards the progression of alcohol-induced hepatic fibrosis in baboons ilymarin retards the progression of alcohol-induced hepatic fibrosis in baboons. J Clin Gastroenterol, 2003; 37(4): 336-339.
[58] Lee SJ, Kim YG, Kang KW, et al. Effects of colchicine on liver functions of cirrhotic rats: beneficial effects result from stellate cell inactivation and inhibition of TGF beta1 expression. Chem Biol Interact, 2004; 147(1): 9-21.
[59]石小枫,刘杞,刘林,等.三七总苷抗实验性肝纤维化的研究.中药药理与临床, 2004; 20(1): 12-14.
[60]武凡,张树三,康格非.三七皂甙对肝纤维化大鼠分泌型磷脂酶A2和肿瘤坏死因子表达的影响.中华肝脏病杂志, 2003; 11(1): 51-52.
[61]齐莉莉,王进波.单体姜黄素稳定性的研究.食品工业科技, 2007; 28(1): 181-182.
[62]韩刚,霍文,李秋影,等.姜黄素的稳定性研究.中成药, 2007; 29(2): 291-293.
[63]崔晶,翟光喜,娄红祥.姜黄素的研究进展.中南药学, 2005; 3(2): 108-111.
[64] Alaikov T, Konstantinov SM, Tzanova T, et al. Antineo-plastic and anti clastogenic properties of curcumin. Signal transduction pathways, part c: cell signaling in health and disease. Ann NY Acad Sci, 2007, 1095(1): 355-370.
[65] Li M, Zhang Z, Donald L, et al. Curcumin, a dietary component, has anticancer, chemosensitization, and radiosensitization effects by downregulating the MDM2 oncogene through the PI3K/mTOR/ETS2 pathway. Cancer Res, 2007; 67(5): 1988-1996.
[66] Bruck R, Ashkenazi M, Weiss S, et al. Prevention of liver cirrhosis in rats by curcumin. Liver Int, 2007; 27(3): 373-383.
[67]麦国丰,简燕婷,杨玉捷,等.姜黄素对肠炎大鼠肠黏膜基质金属蛋白酶-9的调控.第四军医大学学报, 2005; 26(14): 1257-1260.
[68] Shakibaei M, John T, Schulze-Tanzil G, et al. Suppression of NF kappa B activation by curcumin leads to inhibition of expression of cyclo oxygenase 2 and matrix metalloproteinase 9 in human articular chondrocytes: implications for the treatment of osteoarthritis. Biochem Pharmacol, 2007; 73(9): 1434-1445.
[69] Wu A, Ying Z, Gomez-Pinilla F. Dietary curcumin counteracts the outcome of traumatic brain injury on oxidative stress, synaptic plasticity, and cognition. Exp Neurol, 2006; 197(2): 309-317.
[70] Shen SQ, Zhang Y, Xiang JJ, et al. Protective effect of curcumin against liver warm ischemia/reperfusion injury in rat model is associated with regulation of heat shock protein and antioxidant enzymes. World J Gastroenterol, 2007; 13(13): 1953-1961.
[71]赵心宇,孟秀香,贾莉,等.姜黄素抗肿瘤机制.实用药物与临床, 2006; 9(l): 51-52.
[72]许东晖,王胜,金晶,等.姜黄素的药理作用研究进展.中草药, 2005, 36(11): 1737-1740.
[73] Bush JA, Cheung KJJr, Li G. Curcumin induces apoptosis in human melanoma cells through a Fas receptor/caspase-8 pathway independent of P53. EXP Cell Res, 2001; 271(2): 305-314.
[74]舒建昌,王红利,叶国荣,等.姜黄素治疗肝纤维化及相关细胞因子变化的研究. 2007; 30(11): 1422-1425.
[75]舒建昌,叶国荣,何雅军,等.姜黄素预防大鼠肝纤维化效果的观察.中药材, 2006; 29(12): 1347-1349.
[76] Brenner DA, Waterboer T, Choi SK, et al. New aspects of hepatic fibrosis. J Hepatol, 2000; 32(SuPPl): 32-38.
[77] Gabele E, Brenner DA, Rippe RA. Liver fibrosis: signals leading to the amplification of the fibrogenic hepatic stellate cell. Front Biosei, 2003; 8(1): d69-77.
[78] Phan TT, See P, Lee ST, et al. Protective effects of curcumin against oxidative damage on skin cells invitro: its implication for wound healing. J Trauma, 2001; 51(5): 927-931.
[79] Choudhuri T, Pal S, Agwarwal ML, et al. Curcumin induces apoptosis in human breast cancer cells through P53-dependent Bax induction. FEBS Lett, 2002; 512(1-3): 334-340.
[80] Phan TT, See P, Lee ST, et al. Protective effects of curcumin against oxidative damage on skin cells invitro: its implication for wound healing. J Trauma, 2001; 51(5): 927-931.
[81] Choudhuri T, Pal S, Agwarwal ML, et al. Curcumin induces apoptosis in human breast cancer cells through P53-dependent Bax induction. FEBS Lett, 2002; 512(1-3): 334-340.
[82] Nnji AA, Jokelainen K, Tipoe GL, et al. Curcumin prevents alcohol-induced liver disease in rats by inhibiting the expression of NF-kappa B dependent genes. Am J Physiol Gastrointest Liver Physiol, 2003; 284(2): 321-327.
[83] Park EJ, Jeon CH, Ko G, et al. Protective effect of curcumin in rat liver injury induced by carbon tetrachloride. J Pham Pharmacol, 2000; 52(4): 437-440.
[84] Bruck R, Ashkenazi M, Weiss S, et al. Prevention of liver cirrhosis in rats by curcumin. Liver Int, 2007, 27(3): 373-383.
[85] Bruck R, Weiss S, Aeed H, et al. Additive inhibitory effect of experimentally induced hepatic cirrhosis by agonists of peroxisome proliferator activator receptor gamma and retinoic acid receptor. Dig Dis Sci, 2009, 54(2):292-299.
[86] Galli A, Pinaire J, Fischer M, et al. The transcriptional and DNA binding activity of peroxisome proliferator-activated receptor alpha is inhibited by ethanol metabolism. A novel mechanism for the development of ethanol-induced fatty liver. J Biol Chem, 2001, 276(1):68-75.
[87] Galli A, Ceni E, Crabb DW, et al. Antidiabetic thiazolidinediones inhibit invasiveness of pancreatic cancer cells via PPARgamma independent mechanisms. Gut, 2004, 53(11):1688-1697.
[88] Xu J, Fu Y, Chen A. Activation of peroxisome proliferator-activated receptor-gamma contributes to the inhibitory effects of curcumin on rat hepatic stellate cell growth. Am J Physiol Gastrointest Liver Physiol, 2003, 285(1):G20-30.
[89]平键,成扬,徐列明.姜黄素通过激活过氧化物酶体增殖子活化受体γ诱导肝星状细胞凋亡.中国药理学通报, 2007, 23(10):1295-1299.
[90]平键,成扬,徐列明,等.姜黄素激活PPARγ下调肝星状细胞α-SMA和I型胶原的基因表达.中国中西医结合消化杂志, 2006, 14(4): 215-218.
[91] Zheng S, Chen A. Disruption of transforming growth factor-beta signaling by curcumin induces gene expression of peroxisome proliferator-activated receptor-gamma in rat hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol, 2007, 292(1): G113-23.
[92] Zheng S, Chen A. Curcumin suppresses the expression of extracellular matrix genes in activated hepatic stellate cells by inhibiting gene expression of connective tissue growth factor. Am J Physiol Gastrointest Liver Physiol, 2006, 290(5): G883-G893.
[93] Zheng S, Chen A. Activation of PPARgamma is required for curcumin to induce apoptosis and to inhibit the expression of extracellular matrix genes in hepatic stellate cells in vitro. Biochem J, 2004, 384(Pt 1): 149-157.
[94] Zhang M, Deng C, Zheng J, et al. Curcumin inhibits trinitrobenzene sulphonic acid-induced colitis in rats by activation of peroxisome proliferator-activated receptor gamma. Int Immunopharmacol, 2006, 6(8):1233-1242.
[95] Chon KH, Zhong Y, Moore LC, et al. Analysis of nonstationarity in renal autoregulation mechanisms using time-varying transfer and coherence functions. Am J Physiol Regul Integr Comp Physiol, 2008, 295(3): R821-R828.
[96] Cheng Y, Ping J, Liu C, et al. Study on effects of extracts from Salvia Miltiorrhiza and Curcuma Longa in inhibiting phosphorylated extracellular signal regulated kinase expression in rat's hepatic stellate cells. Chin J Integr Med, 2006, 12(3):207-211.
[97] Park SD, Jung JH, Lee HW, et al. Zedoariae rhizoma and curcumin inhibits platelet-derived growth factor-induced proliferation of human hepatic myofibroblasts. Int Immunopharmacol, 2005, 5(3):555-569.
[98] Sun K, Wang Q, Huang XH. PPAR gamma inhibits growth of rat hepatic stellate cells and TGF beta-induced connective tissue growth factor expression. Acta Pharmacol Sin, 2006, 27(6):715-723.
[99]谢明,廖晓宏,杨元胜,等.姜黄素对肝星状细胞株CTGF表达的影响.实用医学杂志, 22(15):1724-1726.
[100]刘永刚,刘永忠,王晓东.姜黄素抗大鼠肝星状细胞氧应激脂质过氧化作用的研究.中成药, 2004; 26(10): 829-832.
[101] Chen CS, Mrksich M, Huang S, et al. Geometric control of cell life and death. Science. 1997 May 30; 276(5317):1425-8.
[102] Senoo H, Hata R. Extracellular matrix regulates cell morphology, proliferation, and tissue formation. Kaibogaku Zasshi. 1994 Dec; 69(6):719-33.
[103] Imai K, Senoo H. Morphology of sites of adhesion between hepatic stellate cells (vitamin A-storing cells) and a three-dimensional extracellular matrix. Anat Rec. 1998 Apr; 250(4):430-7.
[104] Marra F, Arrighi MC, Fazi M, Caligiuri A, Pinzani M, Romanelli RG, Efsen E, Laffi G, Gentilini P. Extracellular signal-regulated kinase activation differentially regulates platelet-derived growth factor's actions in hepatic stellate cells, and is induced by in vivo liver injury in the rat. Hepatology. 1999 Oct; 30(4):951-8.
[105] Wang DR, Sato M, Sato T, Kojima N, Higashi N, Senoo H. Regulation of matrix metallo-proteinase expression by extracellular matrix components in cultured hepatic stellate cells. Comp Hepatol. 2004 Jan 14; 3 Suppl 1:S20.
[106] Safadi R, Friedman SL. Hepatic fibrosis--role of hepatic stellate cell activation. MedGenMed. 2002 Jul 15; 4(3):27.
[107] Li D, Friedman SL. Liver fibrogenesis and the role of hepatic stellate cells: new insights and prospects for therapy. J Gastroenterol Hepatol. 1999 Jul; 14(7):618-633.
[108] Senoo H, Sato M, Imai K. Hepatic stellate cells--from the viewpoint of retinoid handling and function of the extracellular matrix. Kaibogaku Zasshi. 1997 Apr; 72(2):79-94.
[109] Sato M, Sato T, Kojima N, et al. 3-D structure of extracellular matrix regulates gene expression in cultured hepatic stellate cells to induce process elongation. Comp Hepatol. 2004 Jan 14; 3 Suppl 1:S4.
[110] Pinzani M, Marra F. Cytokine receptors and signaling in hepatic stellate cells. Semin Liver Dis. 2001 Aug; 21(3):397-416.
[111] Wu J, Zern MA. Hepatic stellate cells: a target for the treatment of liver fibrosis. J Gastroenterol. 2000; 35(9):665-672.
[112] Marra F, Arrighi MC, Fazi M, Caligiuri A, Pinzani M, Romanelli RG, Efsen E, Laffi G, Gentilini P. Extracellular signal-regulated kinase activation differentially regulates platelet-derived growth factor's actions in hepatic stellate cells, and is induced by in vivo liver injury in the rat. Hepatology. 1999, 30(4):951-958.
[113] Nnji AA, Jokelainen K, Tipoe GL, et al. Curcumin prevents alcohol-induced liver disease in rats by inhibiting the expression of NF-kappa B dependent genes. Am J Physiol Gastrointest Liver Physiol, 2003; 284(2): 321-327.
[114] Liu SQ, Yu JP, Chen HL, et al. Therapeutic effects and molecular mechanisms of Ginkgo biloba extract on liver fibrosis in rats. Am J Chin Med, 2006; 34(1): 99-114.
[115] Mas M, Convert B, Oncu K, Vural SA, et al. The effect of taurine treatment on oxidative stress in experimental liver fibrosis. Hepato Res, 2004; 28(4): 207-215.
[116] Benyon RC, Arthur MJP. Mechanisms of hepatic fibrosis. J Pediatr Gastroenterol Nutr, 1998; 27(1): 75-85.
[117] Bogatkevich GS, Ludwicka-Bradley A, Singleton CB, et al. Proteomic analysis of CTGF-activated lung fibroblasts: identification of IQGAP1 as a key player in lung fibroblast migration. Am J Physiol Lung Cell Mol Physiol, 2008; 295(4): L603-611.
[118]小菁,吴文超,陈槐卿. CTGF基因沉默对肺成纤维细胞增殖及表型转化的影响.生物医学工程学杂志, 2008; 25(2): 407-412.
[119] .Healy E, Brady HR. Role of tubule epithelial cells in pathogenesis of tubulointerstitial fibrosis induced by glomerular disease. Curr Opin Nephrol Hypertens, 1998; 7(5):525-530.
[120] Tong ZY, Brigstock DR. Intrinsic biological activity of the thrombospondin structural homology repeat in connective tissue growth factor. J Endocrinol, 2006; 188(3): R1-R8.
[121] Tamatai T, Kobayashi H, Tezuka K, et al. Establishmentof the enzymelinked immunosorbent assay for connective tissue growth factor (CTGF) and its detection in the sera of biliary atresia. Biochem Biophys Res Commum, 1998; 251(3): 748-752.
[122] Patricia De Winter, Patricia Leoni , David Abraham . Connective tissue growth factor: Structure-function relationships of a mosaic, multifunctional protein . Growth Factors, April 2008,26(2), 80– 91.
[123] Napoli J, Prentice D, Niinami C, et al. Sequential increases in the intrahepatic expression of epidermal growth factor, basic fibroblast growth factor, and transforming growth factor beta in a bile duct ligated rat model of cirrhosis. Hepatology. 1997; 26(3): 624-633.
[124] Komuves LG, Feren A, Jones AL, Fodor E. Expression of epidermal growth factor and its receptor in cirrhotic lever disease. J Histochem Cytochem, 2000; 48(6): 821-830.
[125] Maria J. Perugorria, M. Ujue Latasa , Alexandra Nicou . The epidermal growth factor receptor ligand amphiregulin participates in the development of mouse liver fibrosis Hepatology, 48(4 ):1251–1261.
[126] Ikegami T, Zhang Y, Matsuzaki Y. Liver Fibrosis: Possibe Involvement of EMT. Cells Tissues Organs 2007;185:213–221
[127] Docherty NG, O'Sullivan OE, Healy DA, et al. TGF-beta1-induced EMT can occur independently of its proapoptotic effects and is aided by. Am J Physiol Renal Physiol (2006) 290: F1202-F1212.
[128] Shi MN, Zheng WD, Zhang LJ, et al. Effect of IL-10 on the expression of HSC growth factors in hepatic fibrosis rat. World J Gastroenterol, 2005; 11(31): 4788-4793.
[129] Friedman SL. Molecular regulation of hepatic fibrosis,an integrated cellular response to tissue injury. J Biol Chem, 2000; 275(4): 2247-2250.
[130] Eng FJ, Friedman SL. Fibrogenesis I.New insights into hepatic stellate cell activation: the simple becomes complex. Am J Physiol Gastrointest Liver Physiol, 2000; 279(1):G7-G11.
[131] Goddard CJ, Smith A, Hoyland JA, et al. Localisation and semiquantitative assessment of hepatic procollagen mRNA in primary biliary cirrhosis. Gut, 1998; 43(3): 433-440.
[132] Kinnman N, Francoz C, Barbu V, et al. The myofibroblastic conversion of peribiliary fibrogenic cells distinct from hepatic stellate cells is stimulated by platelet-derived growth factor during liver fibrogenesis. Lab Invest, 2003; 83(2):163-173.
[133] Gong W, Roth S, Michel K, et al. Isoforms and splice variant of transforming growthfactor beta-binding protein in rat hepatic stellate cells. Gastroenterology, 1998; 114(2): 352-363.
[134] Dedhar S. Cell-substrate interactions and signaling through ILK. Curr Opin Cell Biol. 2000 Apr; 12(2):250-256.
[135] Zhang Y,Ikegami T, Honda A, et al. Involvement of integrin-linked kinase in carbon tetrachloride-induced hepatic fibrosis in rats. Hepatology. 2006 Sep;44(3):612-622.
[136] Feng DY, Zheng H, Tan Y, et al. Effect of phosphorylation of MAPK and Stat3 and expression of c-fos and c-jun proteins on hepatocarcinogenesis and their clinical significance. World J Gastroenterol, 2001; 7(1):33-36.
[137] Ono K, Han J. The p38 signal transduction pathway: activation and function.Cell Signal, 2000; 12(1): 1-13.
[138] Raingeaud J, Gupta S, Rogers JS, et al. Pro-inflammatory cytokines and environ- mental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem, 1995; 270(13): 7420-7426.
[139] Raingeaud J, Whitmarsh AJ, Barrett T, et al. MKK3-and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Mol Cell Biol, 1996; 16(3):1247-1255.
[140] Dérijard B, Raingeaud J, Barrett T, et al. Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science, 1995; 267(5198): 682-685.
[141] Janknecht R, Hunter T. Convergence of MAP kinase pathways on the ternary complex factor Sap-1a. EMBO J, 1997; 16(7): 1620-1627.
[142] Matsuoka H, Arai T, Mori M, et al. A p38 MAPK inhibitor, FR-167653, ameliorates murine bleomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol, 2002; 283(1): L103-L112
[143] Chin BY, Mohsenin A, Li SX, et al. Stimulation of pro-alpha(1) (I)collagen by TGF-beta(1) in mesangial cells:role of the p38 MAPK pathway. Am J Physiol Renal Physiol, 2001; 280(3): F495-F504.
[144] Tsukada S, Westwick JK, Ikejima K, et al. SMAD and p38 MAPK signaling pathways independently regulate alpha1(I) collagen gene expression in unstimulated and transforming growth factor-beta stimulated hepatic stellate cells. J Biol Chem, 2005; 280(11): 10055-10064.
[145] Marra F, Delogu W, Petrai I, et al. Differential requirement of members of the MAPK family for CCL2 expression by hepatic stellate cells. Am J Physiol Gastrointest LiverPhysiol, 2004; 287(1): G18-G26.
[146] Dent P, Reardon DB, Park JS, et al. Radiation-induced release of transforming growth factor alpha activates the epidermal growth factor receptor and mitogen-activated protein kinase pathway in carcinoma cells, leading to increased proliferation and protection from radiation-induced cell death. Mol Biol Cell, 1999; 10(8): 2493-2506.
[147] Smart DE, Green K, Oakley F, et al. JunD is a profibrogenic transcription factor regulated by Jun N-terminal kinase-independent phosphorylation. Hepatology, 2006; 44(6): 1432-1440.
[148] Datta, S. R., Dudek, H., Tao, X., et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997 Oct 17; 91(2):231-241.
[149] DelPeso, L., Gonzales-Garcia, M., Page, C., et al. Interleukin-3-Induced Phosphorylation of BAD Through the Protein Kinase Akt. Science, 1997, 278(5338), 687-689.
[150] Kops, G. J., Ruiter, N. D., DeVries-Smits, A. M., et al. Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature. 1999 Apr 15; 398(6728):630-634.
[151] Cardone, M. H., Roy, N., Stennicke, H. R., et al. Regulation of Cell Death Protease Caspase-9 by Phosphorylation. Science, 1998, 282(5392): 1318-1321.
[152] Brunet A, Bonni A, Zigmond MJ, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999 Mar 19; 96(6):857-868.
[153] Sizemore N, Leung S, Stark GR. Activation of phosphatidylinositol 3-kinase in response to interleukin-1 leads to phosphorylation and activation of the NF-kappaB p65/RelA subunit. Mol Cell Biol. 1999 Jul; 19(7):4798-4805.
[154] Romashkova JA, Makarov SS. NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature. 1999 Sep 2; 401(6748):86-90.
[155] Kane LP, Shapiro VS, Stokoe D, Weiss A. Induction of NF-kappaB by the Akt/PKB kinase. Curr Biol. 1999 Jun 3; 9(11):601-604.
[2] Friedman SL, Maher JJ, Bissell DM. Mechanisms and therapy of hepatic fibrosis: report of the AASI D Single Topic Basic Research Conference. Hepatology, 2000, 2(6): 1403-1408.
[3] Britton RS, Bacon BR. Intracellular signaling pathways in stellate cell activation. Alcohol Clin Exp Res, I999, 23: 922-925.
[4] Dudas J, Kovalszky I, Gallai M. Expression of decorin, transforming growth factor-beta 1, tissue inhibitor metalloproteinase 1 and 2, and type IV collagenases in chronic hepatitiws. Cell Biochem, 2003, 89: 311-320.
[5] Jia J, Bauer M, Boigk G. Expression of collagen XVIII mRNA in rat liver fibrosis.中华肝脏病杂志, 2000, 8(5): 274-275.
[6] Knittel T, Mehde M, Grundmann A, et a1. Expression of matrix metalIoproteinases and their inhibitors during hepatic tissue repair in the rat. Histochem Cell Biol, 2000, 113 (6): 443-453.
[7] Issa R, Zhou X, Constandinou CM, et a1. Spontaneous recovery from micronodular cirrhosis:evidence for incomplete resolution associated with matrix CROSS-linking. Gastroenterology, 2004, I26: 1795-1808.
[8] Arthur MJ, Mann DA, Iredale JP. Tissue inhibitors of metalloproteinases, hepatic stellate cells and liver fibrosis. J Gastroenterol Hepatol, 1998, 13(Supp1): S33-38.
[9] Weng ZH, Lei YC, Peng C, et al. Effect of blocking Wnt/beta-catenin signaling pathway on apoptosis of activated hepatic stellate cells.中华肝脏病杂志, 2007, 15(6): 471-472.
[10] Han YP. Matrix metalloproteinase, the [ros and cons, in liver fibrosis.J Gastroenterol Hepadtol, 2006(Suppl 3): S88-91
[11] Lindert S, Wickert L, Sawitza I, et al. Transdifferentiation-dependent expression of alpha-SMA in hepatic stellate cells does not involve TGF-beta pathways leading to coinduction of collagen type I and thrombospondin-2. Matrix Biol, 2005; 24(3): 198-207.
[12] 12.Friedman SL, Roll FJ, Boyles J, et al. Maintenance of differentiated phenotype of cultured rat hepatic lipocytes by basement membrane matrix. J Biol Chem, 1989, 264(18): 10756-10762.
[13] Jarnagin WR, Rockey DC, Koteliansky VE, et al. Expression of variant fibronectins in wound healing: cellular source and biological activity of the EⅢA segment in rat hepaticfibrogenesis. J Cell Biol, 1994; 127(6pt2): 2037-2048
[14] Parkes JG, Templeton DM. Effects of retinol and hepatocyte-conditioned medium on cultured rat hepatic stellate cells. Ann Clin Lab Sci, 2003; 33(3): 295-305.
[15] Senoo H, Imai K, Matano Y, et al. Molecular mechanisms in the reversible regulation of morphology, proliferation and structure of the extracellular matrix. J Gastroeuterol Hepatol, 1998; 13(suppl): 19-32.
[16] Sanz S,Pucilowska JB,Liu S,et al. Expression of insulin 2 like growth factor 1 by activated hepatic stellate cells reduces fibrogenesis and enhances regeneration after liver injury. Gut, 2005; 54(1): 134-141.
[17] Marra F, Gentilini A, Pinzani M, et al. Phosphatidylinositol 3-kinase is required for platelet-derived growth factor’s actions on hepatic stellate cells. Gastroenterology, 1997, 112(4): 1297-1306.
[18] Proell V,Carmona-Cuencal,Murillo MM,et al. TGF-beta dependent regulation of oxygen radicals during trans differentiation of activated hepatic stellate cells to myofibroblastoid cells. Comp Hepatol, 2007; 6(1): 1.
[19] Dooley S. Smad7 Prevents activation of hepatic stellate cells and 1iver fibrosis in rat. Gastroenterology, 2003; 125(1): 178-191.
[20] Furukawa F, Matsuzaki K, Mori S, et al. P38 MAPK mediated fibrogenic signal through Smad3 phosphorylation in rat myofibroblasts. Hepatology, 2003; 38(4): 879-889.
[21] Shek FW, Benyon RC. How can transforming growth factor beta be targeted usefully to combat liver fibrosis? Eur J Gastroenterol Hepatol, 2004; 16(2): 123-126.
[22] Chen M, Wang GJ, Diao Y, et al. Adeno-assoeiated virus meidiated interferon-gamma inhibits the progression of hepatic fibrosis in vitro and in vivo. World J Gastroenterol, 2005; 11(26): 4045-4051.
[23] Weng H, Mertens PR, Gressner AM, et al. IFN-gamma abrogates profibrogenic TGF-beta signaling in liver by targeting expression of inhibitory and receptor Smads. J Hepatol. 2007; 46(2): 295-303.
[24] Han YP, Zhou L, Wang J, et al. Essential role of matrix metalloproteinases in interleukin-1-induced myofibroblastic activation of hepatic stellate cell in collagen. J Biol Chem, 2004; 279(6): 4820-4828.
[25] Mauviel A, Lapière JC, Halcin C, et al. Differential cytokine regulation of type I and type VII collagen gene expression in cultured human dermal fibroblasts.J Biol Chem, 1994; 269(1): 25-28.
[26] Zhang LJ, Yu JP, Li D, et al. Effects of cytokines on carbon tetrachloride-induced hepatic fibrogenesis in rats. World J Gastroenterol, 2004; 10(1): 77-81.
[27] Zheng WD, Zhang LJ, Shi MN, et al. Expression of matrix metalloproteinase-2 in hepatic Stellate cells during rat hepatic fibrosis and its intervention by IL-10. World Gastroenterol, 2005; 11(12): 1753-1758.
[28] Wang XZ, Zhang SJ, Chen YX, et al. Effects of Platelet-derived growth factor and interleukin-10 on Fas/Fas-ligand and Bcl-2/Bax mRNA expression in rat hepatic stellate cells in vitro. World J Gastroenterol, 2004; 10(18): 2706-2710.
[29] Liu XY, Zhou HF, Pan YL, et al. Electro-acupuncture stimulation protects dopaminergic neurons from inflammation-mediated damage in medial forebrain bundle-transected rats. Exp Neurol, 2004; 189(1): 189-196.
[30] Tomita K, Tamiya G, Ando S, et al. Tumour necrosis factor alpha signaling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohePatitis in mice. Gut, 2006; 55(3): 415-424.
[31] Paradis V, Dargere D, Vidaud M, et al. Expression of connective tissue growth factor in experimental rat and human liver fibrosis. Hepatology, 1999; 30(4): 968-976
[32] George J, Tsutsumi M. siRNA-mediated knockdown of connective tissue growth factor prevents N-nitrosodimethylamine-indueed hepatic fibrosis in rats. Gene Ther, 2007; 14(10):790-803.
[33] Li G, Xie Q, Shi Y, et al. Inhibition of connective tissue growth factor by siRNA Prevents liver fibrosis in rats. J Gene Med, 2006; 8(7): 889-900.
[34]周爱玲,罗琳,茅家慧,等.苦参素对实验性肝纤维化的防治作用及对MMP-2表达的影响.中国临床药理学与治疗学, 2004, 9(10): 1096-1100.
[35]施光峰,李谦,翁心华,等.苦参素对大鼠纤维化肝脏金属蛋白酶-1和平滑肌肌动蛋白表达的影响.中华肝脏病杂志, 2004, 12(1): 56.
[36]余小虎,朱金水,朱祖明,等.氧化苦参碱抗肝纤维化作用的病理学研究.胃肠病学和肝病学杂志, 2004, 13(5): 485-487.
[37]余小虎,朱金水,俞华芳,等.氧化苦参碱抗大鼠肝纤维化及其免疫调控作用.中国临床医学, 2004; 11(2): 163-166.
[38]真岩波,刘效华,赵平.苦参碱对乙型肝炎肝纤维化患者血清IL-6、IL-8含量的影响.临床肝胆病杂志, 2004; 20(2): 87-88.
[39]卢清,张清波,张继明,等.氧化苦参碱对大鼠肝星状细胞旁分泌活化途径的抑制作用.肝脏, 2004; 9(1): 31-33.
[40]林明华,闫海明,李凯霞,等.氧化苦参碱对成纤维细胞增殖及Ⅰ型胶原合成的影响.黑龙江医药科学, 2004; 27(1): 13-14.
[41]方翠艳,杨金枝,富新伟,等.苦参素葡萄糖注射液治疗慢性乙型肝炎的疗效观察.实用肝脏病杂志, 2004; 7(4): 238-239.
[42]王英,林小玲,张福华.苦参素对慢性乙型肝炎患者血清肝纤维化指标的影响.实用肝脏病杂志, 2004; 7(4): 239-240.
[43]彭安邦,姚育红,谢黎明,等.苦参素治疗乙肝所致肝纤维化的临床观察.临床肝胆病杂志, 2004; 20(5): 279-280.
[44]孙永年,徐斌,黄祝青,等.苦参素治疗对慢乙肝患者TGF-β1、TNF-α、HA、PcⅢ水平的影响.中国现代医学杂志, 2004; 14(3): 41-44.
[45] Liu P, Liu CH, Wang HN, et al. Effect of salvianolic acid B on collagen production and mitogen-activated protein kinase activity in rat hepatic stellate cells. Acta Pharmacol Sin, 2002; 23(8): 733-738.
[46]刘成,赵俊芳,刘成海,等.丹酚酸B对转化生长因子β1促肝星状细胞分泌胶原的影响.肝脏, 2003; 8(3): 20-22.
[47]薛冬英,洪嘉禾,徐列明.丹参酚酸B对大鼠肝星状细胞中丝裂原激活的蛋白激酶通路的抑制作用.中华肝病杂志, 2004; 12(8): 471-474.
[48]王晓玲,崔云华,胡旭东,等.丹酚酸B对大鼠肝星状细胞增殖周期的抑制作用.中华消化杂志, 2004; 24(1): 59.
[49]崔云华,王晓玲,严振国,等.丹参酸乙对大鼠肝星状细胞内氧化水平及增殖细胞核抗原的影响.中西医结合肝病杂志, 2003; 13(4): 210-212.
[50] Liu P, Hu YY, Liu C, et al. Clinical observation of salvianolic acid B in treatment of liver fibrosis in chronic hepatitis B. World J Gastroenterol, 2002; 8(4): 679-685.
[51] Iinuma Y, Kubota M, Yagi M, et al. Effects of the herbal medicine Inchinko-to on liver function in postoperative patients with biliary atresia-a pilot study. J Pediatr Surg, 2003; 38(11): 1607-1611.
[52] Lanzini A D, Tavonatti MG, Panarotto B, et al. Intestinal absorption of the bile acid analogue 75Se-homocholic acid-taurine is increased in primary biliary cirrhosis, and reverts to normal during ursodeoxycholic acid administration. Gut, 2003; 52(9): 1371-1375.
[53] Overman GP, Teter GJ, Guthrie SK. Acamprosate for the adjunctive treatment of alcohol dependence. Ann Pharmacother, 2003; 37(7-8): 1090-1099.
[54]韦新,梁健,毛德文,等.牛磺酸对大鼠肝纤维化形成的影响.中国中西医结合消化杂志, 2004; 12(1): 6-7.
[55] Muriel P, Moreno MG. Effects of silymarin and vitamins E and C on liver damage induced by prolonged biliary obstruction in the rat. Basic Clin Pharmacol Toxicol, 2004; 94(2): 99-104.
[56] Jia JD, Bauer M, Cho JJ, et al. Antifibrotic effect of silymarin in rat secondary biliary fibrosis is mediated by downregulation of procollagen alphal(Ⅰ)and TIMP-1. J Hepatol, 2001; 35(3): 392-398.
[57] Lieber CS, Leo MA, Cao Q, et al. Silymarin retards the progression of alcohol-induced hepatic fibrosis in baboons ilymarin retards the progression of alcohol-induced hepatic fibrosis in baboons. J Clin Gastroenterol, 2003; 37(4): 336-339.
[58] Lee SJ, Kim YG, Kang KW, et al. Effects of colchicine on liver functions of cirrhotic rats: beneficial effects result from stellate cell inactivation and inhibition of TGF beta1 expression. Chem Biol Interact, 2004; 147(1): 9-21.
[59]石小枫,刘杞,刘林,等.三七总苷抗实验性肝纤维化的研究.中药药理与临床, 2004; 20(1): 12-14.
[60]武凡,张树三,康格非.三七皂甙对肝纤维化大鼠分泌型磷脂酶A2和肿瘤坏死因子表达的影响.中华肝脏病杂志, 2003; 11(1): 51-52.
[61]齐莉莉,王进波.单体姜黄素稳定性的研究.食品工业科技, 2007; 28(1): 181-182.
[62]韩刚,霍文,李秋影,等.姜黄素的稳定性研究.中成药, 2007; 29(2): 291-293.
[63]崔晶,翟光喜,娄红祥.姜黄素的研究进展.中南药学, 2005; 3(2): 108-111.
[64] Alaikov T, Konstantinov SM, Tzanova T, et al. Antineo-plastic and anti clastogenic properties of curcumin. Signal transduction pathways, part c: cell signaling in health and disease. Ann NY Acad Sci, 2007, 1095(1): 355-370.
[65] Li M, Zhang Z, Donald L, et al. Curcumin, a dietary component, has anticancer, chemosensitization, and radiosensitization effects by downregulating the MDM2 oncogene through the PI3K/mTOR/ETS2 pathway. Cancer Res, 2007; 67(5): 1988-1996.
[66] Bruck R, Ashkenazi M, Weiss S, et al. Prevention of liver cirrhosis in rats by curcumin. Liver Int, 2007; 27(3): 373-383.
[67]麦国丰,简燕婷,杨玉捷,等.姜黄素对肠炎大鼠肠黏膜基质金属蛋白酶-9的调控.第四军医大学学报, 2005; 26(14): 1257-1260.
[68] Shakibaei M, John T, Schulze-Tanzil G, et al. Suppression of NF kappa B activation by curcumin leads to inhibition of expression of cyclo oxygenase 2 and matrix metalloproteinase 9 in human articular chondrocytes: implications for the treatment of osteoarthritis. Biochem Pharmacol, 2007; 73(9): 1434-1445.
[69] Wu A, Ying Z, Gomez-Pinilla F. Dietary curcumin counteracts the outcome of traumatic brain injury on oxidative stress, synaptic plasticity, and cognition. Exp Neurol, 2006; 197(2): 309-317.
[70] Shen SQ, Zhang Y, Xiang JJ, et al. Protective effect of curcumin against liver warm ischemia/reperfusion injury in rat model is associated with regulation of heat shock protein and antioxidant enzymes. World J Gastroenterol, 2007; 13(13): 1953-1961.
[71]赵心宇,孟秀香,贾莉,等.姜黄素抗肿瘤机制.实用药物与临床, 2006; 9(l): 51-52.
[72]许东晖,王胜,金晶,等.姜黄素的药理作用研究进展.中草药, 2005, 36(11): 1737-1740.
[73] Bush JA, Cheung KJJr, Li G. Curcumin induces apoptosis in human melanoma cells through a Fas receptor/caspase-8 pathway independent of P53. EXP Cell Res, 2001; 271(2): 305-314.
[74]舒建昌,王红利,叶国荣,等.姜黄素治疗肝纤维化及相关细胞因子变化的研究. 2007; 30(11): 1422-1425.
[75]舒建昌,叶国荣,何雅军,等.姜黄素预防大鼠肝纤维化效果的观察.中药材, 2006; 29(12): 1347-1349.
[76] Brenner DA, Waterboer T, Choi SK, et al. New aspects of hepatic fibrosis. J Hepatol, 2000; 32(SuPPl): 32-38.
[77] Gabele E, Brenner DA, Rippe RA. Liver fibrosis: signals leading to the amplification of the fibrogenic hepatic stellate cell. Front Biosei, 2003; 8(1): d69-77.
[78] Phan TT, See P, Lee ST, et al. Protective effects of curcumin against oxidative damage on skin cells invitro: its implication for wound healing. J Trauma, 2001; 51(5): 927-931.
[79] Choudhuri T, Pal S, Agwarwal ML, et al. Curcumin induces apoptosis in human breast cancer cells through P53-dependent Bax induction. FEBS Lett, 2002; 512(1-3): 334-340.
[80] Phan TT, See P, Lee ST, et al. Protective effects of curcumin against oxidative damage on skin cells invitro: its implication for wound healing. J Trauma, 2001; 51(5): 927-931.
[81] Choudhuri T, Pal S, Agwarwal ML, et al. Curcumin induces apoptosis in human breast cancer cells through P53-dependent Bax induction. FEBS Lett, 2002; 512(1-3): 334-340.
[82] Nnji AA, Jokelainen K, Tipoe GL, et al. Curcumin prevents alcohol-induced liver disease in rats by inhibiting the expression of NF-kappa B dependent genes. Am J Physiol Gastrointest Liver Physiol, 2003; 284(2): 321-327.
[83] Park EJ, Jeon CH, Ko G, et al. Protective effect of curcumin in rat liver injury induced by carbon tetrachloride. J Pham Pharmacol, 2000; 52(4): 437-440.
[84] Bruck R, Ashkenazi M, Weiss S, et al. Prevention of liver cirrhosis in rats by curcumin. Liver Int, 2007, 27(3): 373-383.
[85] Bruck R, Weiss S, Aeed H, et al. Additive inhibitory effect of experimentally induced hepatic cirrhosis by agonists of peroxisome proliferator activator receptor gamma and retinoic acid receptor. Dig Dis Sci, 2009, 54(2):292-299.
[86] Galli A, Pinaire J, Fischer M, et al. The transcriptional and DNA binding activity of peroxisome proliferator-activated receptor alpha is inhibited by ethanol metabolism. A novel mechanism for the development of ethanol-induced fatty liver. J Biol Chem, 2001, 276(1):68-75.
[87] Galli A, Ceni E, Crabb DW, et al. Antidiabetic thiazolidinediones inhibit invasiveness of pancreatic cancer cells via PPARgamma independent mechanisms. Gut, 2004, 53(11):1688-1697.
[88] Xu J, Fu Y, Chen A. Activation of peroxisome proliferator-activated receptor-gamma contributes to the inhibitory effects of curcumin on rat hepatic stellate cell growth. Am J Physiol Gastrointest Liver Physiol, 2003, 285(1):G20-30.
[89]平键,成扬,徐列明.姜黄素通过激活过氧化物酶体增殖子活化受体γ诱导肝星状细胞凋亡.中国药理学通报, 2007, 23(10):1295-1299.
[90]平键,成扬,徐列明,等.姜黄素激活PPARγ下调肝星状细胞α-SMA和I型胶原的基因表达.中国中西医结合消化杂志, 2006, 14(4): 215-218.
[91] Zheng S, Chen A. Disruption of transforming growth factor-beta signaling by curcumin induces gene expression of peroxisome proliferator-activated receptor-gamma in rat hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol, 2007, 292(1): G113-23.
[92] Zheng S, Chen A. Curcumin suppresses the expression of extracellular matrix genes in activated hepatic stellate cells by inhibiting gene expression of connective tissue growth factor. Am J Physiol Gastrointest Liver Physiol, 2006, 290(5): G883-G893.
[93] Zheng S, Chen A. Activation of PPARgamma is required for curcumin to induce apoptosis and to inhibit the expression of extracellular matrix genes in hepatic stellate cells in vitro. Biochem J, 2004, 384(Pt 1): 149-157.
[94] Zhang M, Deng C, Zheng J, et al. Curcumin inhibits trinitrobenzene sulphonic acid-induced colitis in rats by activation of peroxisome proliferator-activated receptor gamma. Int Immunopharmacol, 2006, 6(8):1233-1242.
[95] Chon KH, Zhong Y, Moore LC, et al. Analysis of nonstationarity in renal autoregulation mechanisms using time-varying transfer and coherence functions. Am J Physiol Regul Integr Comp Physiol, 2008, 295(3): R821-R828.
[96] Cheng Y, Ping J, Liu C, et al. Study on effects of extracts from Salvia Miltiorrhiza and Curcuma Longa in inhibiting phosphorylated extracellular signal regulated kinase expression in rat's hepatic stellate cells. Chin J Integr Med, 2006, 12(3):207-211.
[97] Park SD, Jung JH, Lee HW, et al. Zedoariae rhizoma and curcumin inhibits platelet-derived growth factor-induced proliferation of human hepatic myofibroblasts. Int Immunopharmacol, 2005, 5(3):555-569.
[98] Sun K, Wang Q, Huang XH. PPAR gamma inhibits growth of rat hepatic stellate cells and TGF beta-induced connective tissue growth factor expression. Acta Pharmacol Sin, 2006, 27(6):715-723.
[99]谢明,廖晓宏,杨元胜,等.姜黄素对肝星状细胞株CTGF表达的影响.实用医学杂志, 22(15):1724-1726.
[100]刘永刚,刘永忠,王晓东.姜黄素抗大鼠肝星状细胞氧应激脂质过氧化作用的研究.中成药, 2004; 26(10): 829-832.
[101] Chen CS, Mrksich M, Huang S, et al. Geometric control of cell life and death. Science. 1997 May 30; 276(5317):1425-8.
[102] Senoo H, Hata R. Extracellular matrix regulates cell morphology, proliferation, and tissue formation. Kaibogaku Zasshi. 1994 Dec; 69(6):719-33.
[103] Imai K, Senoo H. Morphology of sites of adhesion between hepatic stellate cells (vitamin A-storing cells) and a three-dimensional extracellular matrix. Anat Rec. 1998 Apr; 250(4):430-7.
[104] Marra F, Arrighi MC, Fazi M, Caligiuri A, Pinzani M, Romanelli RG, Efsen E, Laffi G, Gentilini P. Extracellular signal-regulated kinase activation differentially regulates platelet-derived growth factor's actions in hepatic stellate cells, and is induced by in vivo liver injury in the rat. Hepatology. 1999 Oct; 30(4):951-8.
[105] Wang DR, Sato M, Sato T, Kojima N, Higashi N, Senoo H. Regulation of matrix metallo-proteinase expression by extracellular matrix components in cultured hepatic stellate cells. Comp Hepatol. 2004 Jan 14; 3 Suppl 1:S20.
[106] Safadi R, Friedman SL. Hepatic fibrosis--role of hepatic stellate cell activation. MedGenMed. 2002 Jul 15; 4(3):27.
[107] Li D, Friedman SL. Liver fibrogenesis and the role of hepatic stellate cells: new insights and prospects for therapy. J Gastroenterol Hepatol. 1999 Jul; 14(7):618-633.
[108] Senoo H, Sato M, Imai K. Hepatic stellate cells--from the viewpoint of retinoid handling and function of the extracellular matrix. Kaibogaku Zasshi. 1997 Apr; 72(2):79-94.
[109] Sato M, Sato T, Kojima N, et al. 3-D structure of extracellular matrix regulates gene expression in cultured hepatic stellate cells to induce process elongation. Comp Hepatol. 2004 Jan 14; 3 Suppl 1:S4.
[110] Pinzani M, Marra F. Cytokine receptors and signaling in hepatic stellate cells. Semin Liver Dis. 2001 Aug; 21(3):397-416.
[111] Wu J, Zern MA. Hepatic stellate cells: a target for the treatment of liver fibrosis. J Gastroenterol. 2000; 35(9):665-672.
[112] Marra F, Arrighi MC, Fazi M, Caligiuri A, Pinzani M, Romanelli RG, Efsen E, Laffi G, Gentilini P. Extracellular signal-regulated kinase activation differentially regulates platelet-derived growth factor's actions in hepatic stellate cells, and is induced by in vivo liver injury in the rat. Hepatology. 1999, 30(4):951-958.
[113] Nnji AA, Jokelainen K, Tipoe GL, et al. Curcumin prevents alcohol-induced liver disease in rats by inhibiting the expression of NF-kappa B dependent genes. Am J Physiol Gastrointest Liver Physiol, 2003; 284(2): 321-327.
[114] Liu SQ, Yu JP, Chen HL, et al. Therapeutic effects and molecular mechanisms of Ginkgo biloba extract on liver fibrosis in rats. Am J Chin Med, 2006; 34(1): 99-114.
[115] Mas M, Convert B, Oncu K, Vural SA, et al. The effect of taurine treatment on oxidative stress in experimental liver fibrosis. Hepato Res, 2004; 28(4): 207-215.
[116] Benyon RC, Arthur MJP. Mechanisms of hepatic fibrosis. J Pediatr Gastroenterol Nutr, 1998; 27(1): 75-85.
[117] Bogatkevich GS, Ludwicka-Bradley A, Singleton CB, et al. Proteomic analysis of CTGF-activated lung fibroblasts: identification of IQGAP1 as a key player in lung fibroblast migration. Am J Physiol Lung Cell Mol Physiol, 2008; 295(4): L603-611.
[118]小菁,吴文超,陈槐卿. CTGF基因沉默对肺成纤维细胞增殖及表型转化的影响.生物医学工程学杂志, 2008; 25(2): 407-412.
[119] .Healy E, Brady HR. Role of tubule epithelial cells in pathogenesis of tubulointerstitial fibrosis induced by glomerular disease. Curr Opin Nephrol Hypertens, 1998; 7(5):525-530.
[120] Tong ZY, Brigstock DR. Intrinsic biological activity of the thrombospondin structural homology repeat in connective tissue growth factor. J Endocrinol, 2006; 188(3): R1-R8.
[121] Tamatai T, Kobayashi H, Tezuka K, et al. Establishmentof the enzymelinked immunosorbent assay for connective tissue growth factor (CTGF) and its detection in the sera of biliary atresia. Biochem Biophys Res Commum, 1998; 251(3): 748-752.
[122] Patricia De Winter, Patricia Leoni , David Abraham . Connective tissue growth factor: Structure-function relationships of a mosaic, multifunctional protein . Growth Factors, April 2008,26(2), 80– 91.
[123] Napoli J, Prentice D, Niinami C, et al. Sequential increases in the intrahepatic expression of epidermal growth factor, basic fibroblast growth factor, and transforming growth factor beta in a bile duct ligated rat model of cirrhosis. Hepatology. 1997; 26(3): 624-633.
[124] Komuves LG, Feren A, Jones AL, Fodor E. Expression of epidermal growth factor and its receptor in cirrhotic lever disease. J Histochem Cytochem, 2000; 48(6): 821-830.
[125] Maria J. Perugorria, M. Ujue Latasa , Alexandra Nicou . The epidermal growth factor receptor ligand amphiregulin participates in the development of mouse liver fibrosis Hepatology, 48(4 ):1251–1261.
[126] Ikegami T, Zhang Y, Matsuzaki Y. Liver Fibrosis: Possibe Involvement of EMT. Cells Tissues Organs 2007;185:213–221
[127] Docherty NG, O'Sullivan OE, Healy DA, et al. TGF-beta1-induced EMT can occur independently of its proapoptotic effects and is aided by. Am J Physiol Renal Physiol (2006) 290: F1202-F1212.
[128] Shi MN, Zheng WD, Zhang LJ, et al. Effect of IL-10 on the expression of HSC growth factors in hepatic fibrosis rat. World J Gastroenterol, 2005; 11(31): 4788-4793.
[129] Friedman SL. Molecular regulation of hepatic fibrosis,an integrated cellular response to tissue injury. J Biol Chem, 2000; 275(4): 2247-2250.
[130] Eng FJ, Friedman SL. Fibrogenesis I.New insights into hepatic stellate cell activation: the simple becomes complex. Am J Physiol Gastrointest Liver Physiol, 2000; 279(1):G7-G11.
[131] Goddard CJ, Smith A, Hoyland JA, et al. Localisation and semiquantitative assessment of hepatic procollagen mRNA in primary biliary cirrhosis. Gut, 1998; 43(3): 433-440.
[132] Kinnman N, Francoz C, Barbu V, et al. The myofibroblastic conversion of peribiliary fibrogenic cells distinct from hepatic stellate cells is stimulated by platelet-derived growth factor during liver fibrogenesis. Lab Invest, 2003; 83(2):163-173.
[133] Gong W, Roth S, Michel K, et al. Isoforms and splice variant of transforming growthfactor beta-binding protein in rat hepatic stellate cells. Gastroenterology, 1998; 114(2): 352-363.
[134] Dedhar S. Cell-substrate interactions and signaling through ILK. Curr Opin Cell Biol. 2000 Apr; 12(2):250-256.
[135] Zhang Y,Ikegami T, Honda A, et al. Involvement of integrin-linked kinase in carbon tetrachloride-induced hepatic fibrosis in rats. Hepatology. 2006 Sep;44(3):612-622.
[136] Feng DY, Zheng H, Tan Y, et al. Effect of phosphorylation of MAPK and Stat3 and expression of c-fos and c-jun proteins on hepatocarcinogenesis and their clinical significance. World J Gastroenterol, 2001; 7(1):33-36.
[137] Ono K, Han J. The p38 signal transduction pathway: activation and function.Cell Signal, 2000; 12(1): 1-13.
[138] Raingeaud J, Gupta S, Rogers JS, et al. Pro-inflammatory cytokines and environ- mental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem, 1995; 270(13): 7420-7426.
[139] Raingeaud J, Whitmarsh AJ, Barrett T, et al. MKK3-and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Mol Cell Biol, 1996; 16(3):1247-1255.
[140] Dérijard B, Raingeaud J, Barrett T, et al. Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science, 1995; 267(5198): 682-685.
[141] Janknecht R, Hunter T. Convergence of MAP kinase pathways on the ternary complex factor Sap-1a. EMBO J, 1997; 16(7): 1620-1627.
[142] Matsuoka H, Arai T, Mori M, et al. A p38 MAPK inhibitor, FR-167653, ameliorates murine bleomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol, 2002; 283(1): L103-L112
[143] Chin BY, Mohsenin A, Li SX, et al. Stimulation of pro-alpha(1) (I)collagen by TGF-beta(1) in mesangial cells:role of the p38 MAPK pathway. Am J Physiol Renal Physiol, 2001; 280(3): F495-F504.
[144] Tsukada S, Westwick JK, Ikejima K, et al. SMAD and p38 MAPK signaling pathways independently regulate alpha1(I) collagen gene expression in unstimulated and transforming growth factor-beta stimulated hepatic stellate cells. J Biol Chem, 2005; 280(11): 10055-10064.
[145] Marra F, Delogu W, Petrai I, et al. Differential requirement of members of the MAPK family for CCL2 expression by hepatic stellate cells. Am J Physiol Gastrointest LiverPhysiol, 2004; 287(1): G18-G26.
[146] Dent P, Reardon DB, Park JS, et al. Radiation-induced release of transforming growth factor alpha activates the epidermal growth factor receptor and mitogen-activated protein kinase pathway in carcinoma cells, leading to increased proliferation and protection from radiation-induced cell death. Mol Biol Cell, 1999; 10(8): 2493-2506.
[147] Smart DE, Green K, Oakley F, et al. JunD is a profibrogenic transcription factor regulated by Jun N-terminal kinase-independent phosphorylation. Hepatology, 2006; 44(6): 1432-1440.
[148] Datta, S. R., Dudek, H., Tao, X., et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997 Oct 17; 91(2):231-241.
[149] DelPeso, L., Gonzales-Garcia, M., Page, C., et al. Interleukin-3-Induced Phosphorylation of BAD Through the Protein Kinase Akt. Science, 1997, 278(5338), 687-689.
[150] Kops, G. J., Ruiter, N. D., DeVries-Smits, A. M., et al. Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature. 1999 Apr 15; 398(6728):630-634.
[151] Cardone, M. H., Roy, N., Stennicke, H. R., et al. Regulation of Cell Death Protease Caspase-9 by Phosphorylation. Science, 1998, 282(5392): 1318-1321.
[152] Brunet A, Bonni A, Zigmond MJ, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999 Mar 19; 96(6):857-868.
[153] Sizemore N, Leung S, Stark GR. Activation of phosphatidylinositol 3-kinase in response to interleukin-1 leads to phosphorylation and activation of the NF-kappaB p65/RelA subunit. Mol Cell Biol. 1999 Jul; 19(7):4798-4805.
[154] Romashkova JA, Makarov SS. NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature. 1999 Sep 2; 401(6748):86-90.
[155] Kane LP, Shapiro VS, Stokoe D, Weiss A. Induction of NF-kappaB by the Akt/PKB kinase. Curr Biol. 1999 Jun 3; 9(11):601-604.