红景天甙对乙醛刺激的大鼠肝星状细胞Wnt信号通路的影响及其意义
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摘要
目的肝纤维化是各种慢性肝病发展到肝硬化的中间可逆阶段。在肝纤维化的病程中,肝星状细胞(hepatic stellate cells HSCs)的活化是其核心环节,因此对肝星状细胞的活化进行干预是临床治疗肝纤维化的发展方向。由于肝星状细胞的活化涉及众多的细胞信号传导通路,因此了解肝星状细胞的活化中各种信号通路的作用机制十分重要。引起肝星状细胞活化的病因很多,乙醛是酒精性肝病中作用于HSCs的致病因子,将乙醛作为HSCs的激活剂在各种实验中广泛运用。乙醛刺激大鼠HSCs活化的主要特点是增殖速度增快和包括α1胶原(α1 (I) collagen)在内的细胞基质分泌增多。在前期的实验中,红景天甙已经被证实可以影响肝星状细胞活化过程中的TGFβ-Smad和Rho-ROCK信号通路从而抑制HSCs的激活和过量细胞基质的产生,但是对其抑制HSCs增殖的具体分子机制仍然不是很明确。近年对Wnt信号通路的研究发现:它通过对目的基因MYC、CyclinD1等的转录调控影响细胞的增殖和转化,并与肝星状细胞的活化密切相关。因此了解红景天甙对活化的肝星状细胞中Wnt信号通路和细胞活性的影响对研究红景天甙的药理作用和治疗肝纤维化的分子机理具重要意义。本研究项目通过观察红景天甙处理乙醛刺激的大鼠肝星状细胞生长速度的变化以及细胞中Wnt信号通路中主要下游分子及目的基因mRNA表达和蛋白水平的改变,探讨Wnt信号通路在肝星状细胞活化中的作用。
方法用红景天甙和乙醛处理体外培养的大鼠肝星状细胞,同时用正常培养细胞和单以乙醛刺激的细胞为对照[1],由MTT法绘制细胞生长曲线并对比,采用RT-PCR和Western-blot的方法分别从mRNA水平和蛋白水平观察Wnt信号通路相关指标β- catenin和细胞周期蛋白D1(cyclinD1)的表达变化,并用统计方法进行对比分析。
结果从各组细胞生长曲线的对比可以清晰发现:单用乙醛刺激可使大鼠肝星状细胞增殖速度增快,红景天甙可以明显降低大鼠肝星状细胞在乙醛刺激后的生长和增殖速度。运用RT-PCR和Western-blot的方法,在单用乙醛组的大鼠肝星状细胞中,发现I型胶原[2]、Wnt信号通路中β- catenin(β-链蛋白)和细胞周期蛋白D1(cyclinD1)的mRNA表达和蛋白合成相对于正常细胞均增强(P<0.05),在红景天甙处理组的大鼠肝星状细胞中,细胞周期蛋白D1(cyclinD1)和β- catenin(β-链蛋白)的mRNA表达和蛋白合成相较于单用乙醛组均出现不同程度的下降(P<0.05)。
结论Wnt信号通路的开放参与了乙醛刺激的肝星状细胞活化,红景天甙能有效降低大鼠肝星状细胞中Wnt信号通路的活性从而抑制乙醛刺激的大鼠肝星状细胞的活化和增殖。
AIM: Hepatic fibrosis is the middle and reversible stage from chronic liver disease to cirrhosis . The activation of hepatic stellate cell is a core of hepatic fibrosis. It is a tendency for liver fibrosis treatment that interventing the hepatic stellate cell activation. A large number of cell signaling pathways participate in the activation of hepatic stellate cells , so understanding the mechanisms of these cell signaling pathways is very important. As the etiology of alcohol liver disease, acetaldehyde have been used widely as an activator of hepatic stellate cells in experiment . Rat hepatic stellate cells activated by acetaldehyde shows mainly that cell proliferation is accelerated andα1 (I) collagen secretion is increased. The salidroside have been shown to affect the hepatic stellate cell activation through the TGFβ-Smad and Rho-ROCK signaling pathway in the early experiments. In recent years, the Wnt signaling pathway was found to relate closely with activation of hepatic stellate cells. As the Wnt pathway target genes such as cyclin-D1 have close relationship with the cell proliferation, the influence of salidroside on Wnt pathway is very important for studing the molecular mechanism of salidroside treatment for liver fibrosis. In experiment, the role of Wnt signaling pathway and the effect of salidroside on Wnt pathway in the activation of rat hepatic stellate cells was studied by detecting mRNA and protein expression levels of downstream molecules’in Wnt signaling pathway.
Methods The cryopreservating rat hepatic stellate cells was recoveryed and cultured in vitro. The acetaldehyde was used as a stimulant of hepatic stellate cell, meanwhile the rat hepatic stellate cells stimulated by acetaldehyde was treated with salidroside , using normal rat hepatic stellate cells and cells stimulated by acetaldehyde only as control. The cells growth curves were drawn using the method MTT.β-catenin、α1 (I) collagen and cyclinD1 were detected by reverse transcription PCR and West-blot.
Results From the cell growth curves drawn, we found the proliferation of rat hepatic stellate cells stimulated by acetaldehyde only can be accelerated . By comparing the salidroside treatment can inhibit growth and proliferation rate of cells stimulated by acetaldehyde. We also found that mRNA and protein synthesis ofα1 (I) collagen, cyclinD1 andβ-catenin were enhanced in rat hepatic stellate cell stimulated by acetaldehyde[1] (P<0.05),however the mRNA expression and protein synthesis of cyclinD1、β-catenin were declined in the cells treated by salidroside than these in cells stimulated by acetaldehyde only (P<0.05) .
Conclusion The opening Wnt signaling pathway may be involved in activation of hepatic stellate cells stimulated by acetaldehyde. The intervention of salidroside can reduce the proliferation of rat hepatic stellate cell through inhibiting the Wnt signaling pathway.
方法用红景天甙和乙醛处理体外培养的大鼠肝星状细胞,同时用正常培养细胞和单以乙醛刺激的细胞为对照[1],由MTT法绘制细胞生长曲线并对比,采用RT-PCR和Western-blot的方法分别从mRNA水平和蛋白水平观察Wnt信号通路相关指标β- catenin和细胞周期蛋白D1(cyclinD1)的表达变化,并用统计方法进行对比分析。
结果从各组细胞生长曲线的对比可以清晰发现:单用乙醛刺激可使大鼠肝星状细胞增殖速度增快,红景天甙可以明显降低大鼠肝星状细胞在乙醛刺激后的生长和增殖速度。运用RT-PCR和Western-blot的方法,在单用乙醛组的大鼠肝星状细胞中,发现I型胶原[2]、Wnt信号通路中β- catenin(β-链蛋白)和细胞周期蛋白D1(cyclinD1)的mRNA表达和蛋白合成相对于正常细胞均增强(P<0.05),在红景天甙处理组的大鼠肝星状细胞中,细胞周期蛋白D1(cyclinD1)和β- catenin(β-链蛋白)的mRNA表达和蛋白合成相较于单用乙醛组均出现不同程度的下降(P<0.05)。
结论Wnt信号通路的开放参与了乙醛刺激的肝星状细胞活化,红景天甙能有效降低大鼠肝星状细胞中Wnt信号通路的活性从而抑制乙醛刺激的大鼠肝星状细胞的活化和增殖。
AIM: Hepatic fibrosis is the middle and reversible stage from chronic liver disease to cirrhosis . The activation of hepatic stellate cell is a core of hepatic fibrosis. It is a tendency for liver fibrosis treatment that interventing the hepatic stellate cell activation. A large number of cell signaling pathways participate in the activation of hepatic stellate cells , so understanding the mechanisms of these cell signaling pathways is very important. As the etiology of alcohol liver disease, acetaldehyde have been used widely as an activator of hepatic stellate cells in experiment . Rat hepatic stellate cells activated by acetaldehyde shows mainly that cell proliferation is accelerated andα1 (I) collagen secretion is increased. The salidroside have been shown to affect the hepatic stellate cell activation through the TGFβ-Smad and Rho-ROCK signaling pathway in the early experiments. In recent years, the Wnt signaling pathway was found to relate closely with activation of hepatic stellate cells. As the Wnt pathway target genes such as cyclin-D1 have close relationship with the cell proliferation, the influence of salidroside on Wnt pathway is very important for studing the molecular mechanism of salidroside treatment for liver fibrosis. In experiment, the role of Wnt signaling pathway and the effect of salidroside on Wnt pathway in the activation of rat hepatic stellate cells was studied by detecting mRNA and protein expression levels of downstream molecules’in Wnt signaling pathway.
Methods The cryopreservating rat hepatic stellate cells was recoveryed and cultured in vitro. The acetaldehyde was used as a stimulant of hepatic stellate cell, meanwhile the rat hepatic stellate cells stimulated by acetaldehyde was treated with salidroside , using normal rat hepatic stellate cells and cells stimulated by acetaldehyde only as control. The cells growth curves were drawn using the method MTT.β-catenin、α1 (I) collagen and cyclinD1 were detected by reverse transcription PCR and West-blot.
Results From the cell growth curves drawn, we found the proliferation of rat hepatic stellate cells stimulated by acetaldehyde only can be accelerated . By comparing the salidroside treatment can inhibit growth and proliferation rate of cells stimulated by acetaldehyde. We also found that mRNA and protein synthesis ofα1 (I) collagen, cyclinD1 andβ-catenin were enhanced in rat hepatic stellate cell stimulated by acetaldehyde[1] (P<0.05),however the mRNA expression and protein synthesis of cyclinD1、β-catenin were declined in the cells treated by salidroside than these in cells stimulated by acetaldehyde only (P<0.05) .
Conclusion The opening Wnt signaling pathway may be involved in activation of hepatic stellate cells stimulated by acetaldehyde. The intervention of salidroside can reduce the proliferation of rat hepatic stellate cell through inhibiting the Wnt signaling pathway.
引文
1. Ha MH, Wei L, Rao HY, Liu F, Wang XY, Feng B, Fei R, Chen HS, Cong X, Effect of interferon-gamma on hepatic stellate cells stimulated by acetaldehyde ,Hepatogastroenterology. 2008 ;55(84):1059-1065
2. Pérez-Carreón JI, Martínez-Pérez L, Loredo ML, etal.. Inhibition of hepatic damage and liver fibrosis by brain natriuretic peptide, FEBS Lett. 2009 18;583:2067-2070
3. Yin MF, Lian LH, Piao DM, Nan JX, Tetrandrine stimulates the apoptosis of hepatic stellate cells and ameliorates development of fibrosis in a thioacetamide rat model,World J Gastroenterol 2007 ;13(8): 1214-1220
4. Sandra March, Mariona Graupera.Identification and Functional Characterization of the Hepatic Stellate Cell CD38 Cell Surface Molecule, Am J Pathol. 2007 ; 170(1): 176–187
5. Wang L, Wang J, Wang BE, et al.Effects of herbal compound 861 on human hepatic stellate cell proliferation and activation[J].World J Gastroenterol , 2004 ; 10 :2831-2835
6.吴哓玲,曾维政,王丕龙。红景天甙对肝纤维化大鼠TGFβ-Smad信号通路的影响[J],世界华人消化杂志, 2005; 13( 3): 341-345
7. Shimizu T, Kagawa T, Inoue T, Nonaka A, Takada S, Aburatani H, Taga T. Stabilizedbeta-catenin functions through TCF/LEF proteins and the Notch/RBP-Jkappa complex to promote proliferation and suppress differentiation of neural precursor cells. Mol Cell Biol. 2008;28(24):7427-7441. [PMID: 18852283]
8. Gordon MD, Nusse R. Wnt singaling: multiple pathways, multiple receptors,and multiple transcription factors[J].J Biol Chem,2006,281(32):22429—22433
9. Krieghof E , Behrens J , Mayr B . Nucleo-cytoplasmic distribution of beta-catenin is ergulated by retention[J].J Cell Sci,2006,119 (7):1453-1463.
10. Zeng G, Awan F, Otruba W, etal. Wnt'er in liver: expression of Wnt and frizzled genes in mouse. Hepatology, 2007,45: 195-204.
11.张影,张福奎,王宝恩,经典Wnt信号通路与肝脏关系的研究进展,世界华人消化杂志2008,3;16(0):975-981
12. Jiang F, Parsons CJ, Stefanovic B. Gene expression profile of quiescent and activated rat hepatic stellate cells implicates Wnt signaling pathway in activation. J Hepatol, 2006,45:401-404.
13. Shin HW, Park SY, Lee KB, Jang JJ , Down-regulation of Wnt signaling during apoptosis of human hepatic stellate cells. Hepatogastroenterology 2009 ;56:208-212
14. Lodygin D, Epanchintsev A, Menssen A, et al. Functional epigenomics identifies genes frequently silenced in prostate cancer. Cancer Res,2005,65( 10):4218-4227
1、Yin MF, Lian LH, Piao DM, Nan JX, Tetrandrine stimulates the apoptosis of hepatic stellate cells and ameliorates development of fibrosis in a thioacetamide rat model , World JGastroenterol 2007 ;13(8): 1214-1220,[ PMID: 17451202]
2、Sandra March, Mariona Graupera.Identification and Functional Characterization of the Hepatic Stellate Cell CD38 Cell Surface Molecule, Am J Pathol. 2007 ; 170(1): 176–187. [PMID: 17200192]
3、Feng XH, Derynck R.A.kinase subdomain of transforming growth factor-β(TGF-β) type I receptor determines the TGF-βintracellular signaling specificity . EMBO J, 1997; 16(13): 3912-3923. [PMID: 9233801]
4、郭永红罗金燕; TGF-β超家族与Smad信号转导研究进展,医学综述2005; 11( 8),685-688
5、Stopa M, Benes V, Ansorge W, Gressner AM, Dooley S. Genomic locus and promoter region of rat Smad7, an important antagonist of TGFbeta signaling. Mamm Genome, 2000; 11:169-176. [PMID: 10656934]
6、Ghosh AK,Yuan W, Mori Y, Varga J ,Smad-dependent stimulation of typeI collagen gene expression inhuman skin fibroblasts by TGF-beta involves functional cooperation with P300/Cbp transcriptional coactivators .Oneogene 2000; 19:3546一3555. [PMID: 10918613]
7、Ghosh AK,Yuan W, Mori Y, Chen Sj Varga J .Antagonistic regulation of typeI collagen gene expression by interfer ongamma and transforming growthfaetor-beta Integration at the level of P300/CBP transcriptional coactivators. J Biol Chem 2001;276:11041一11048.[ PMID: 11134049]
8、He J, Tegen SB, Krawitz AR, Martin GS, Luo K. The transforming activity of Ski and SnoN is dependent on their ability to repress the activity of Smad proteins. J Biol Chem, 2003;278(33): 30540-30547 [PMID: 12764135]
9、Kitamura Y, Ninomiya H. Smad expression of hepatic stellate cells in livercirrhosis in vivo and hepatic stellate cell line in vitro. Pathol Int, 2003; 53(1): 18-26 . [PMID: 12558865]
10、Kaimori A, Potter J, Kaimori JY, Wang C, Mezey E, Koteish A.Transforming growth factor-beta1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro .J Biol Chem., . 2007; 282( 30): 22089-22101。[PMID: 17513865]
11、Dooley S, Hamzavi J, Breitkopf K,Wiercinska E, Said HM Lorenzen J, Ten Dijke P, Gressner AM. Smad7 prevents activation of hepatic stellate cells and liver fibrosis in rats.Gastroenterology 2003 ;125(1):178-191 [PMID: 12851882]
12、Inagaki Y, Kushida M, Higashi K, Itoh J, Higashiyama R, Hong YY, Kawada N, Namikawa K, Kiyama H, Bou-Gharios G, Watanabe T, Okazaki I, Ikeda K. Cell type-specific intervention of transforming growth factor beta/smad signaling suppresses collagen gene expression and hepatic fibrosis in mice. Gastroenterology., 2005; 129(1)∶259-268.[ PMID: 16012952]
13、吴哓玲,曾维政,王丕龙。红景天甙对肝纤维化大鼠TGFβ-Smad信号通路的影响[J]。世界华人消化杂志, 2005; 13( 3): 341-345
14、Aggarwal BB, Sundaram C, Malani N, Ichikawa H .Curcumin: the Indian solid gold. Adv Exp Med Biol 2007; 595: 1–75. [PMID: 17569205]
15、Zhang XL, Liu JM, Dynamic expression of extracellular signal-regulated kinase in rat liver tissue during hepatic fibrogenesis,R World J Gastroenterol 2006 ;12(39): 6376-6381。[PMID: 17072965]
16、Seger R, Krebs EG, The MAPK signaling cascade. FASEB J , 2007; 9:: 726-735, [PMID: 7601337]
17、Jiang MD, Zheng SM, An experimental study of extracellular signal-regulated kinase and its interventional treatments in hepatic fibrosis,Hepatobiliary Pancreat Dis Int 2008;7: 51-57. [PMID: 18234639]
18、Wellbrock C, Karasarides M, Marais R. The RAF proteins take centre stage. Nat Rev Mol Cell Biol,2004; 5: 875-885,[ PMID: 15520807]
19、Chuderland D, Seger R. Protein-protein interactions in the regulation of the extracellular signal-regulated kinase.Mol Biotech-nol,2005; 29: 57-74, [PMID: 15668520]
20、Reeves HL, Friedman SL. Activation of hepatic stellate cells-a key issue in liver fibrosis. Front Biosci,2002; 7: 808-826,[ PMID: 11897564]
21、Qiang H, Lin Y, Zhang X, Zeng X, Shi J, Chen YX, Yang MF, Han ZG, Xie WF. Differential expression genesanalyzed by cDNA array in the regulation of rat hepatic fibro-genesis. Liver Int,2006; 26: 1126-1137[PMID: 17032414]
22、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: 951-958. [PMID: 10498647]
23、Saxena NK, Titus MA, Ding X, Floyd J, Srinivasan S, Sitaraman SV, Anania FA. Leptin as a novel profibrogenic cytokine in hepatic stellate cells: mitogenesis and inhibition of apoptosis mediated by extracellular regulated kinase(Erk ) and Akt phosphorylation. FASEB J,2004;18(13): 1612-1614 [PMID: 15319373]
24、Erica Novo, Stefania Cannito, Elena Zamara, Valfrèdi Bonzo L, Caligiuri A, Cravanzola C, Compagnone A, Colombatto S, Marra F, Pinzani M, Parola M. Proangiogenic Cytokines as Hypoxia-Dependent Factors Stimulating Migration of Human Hepatic Stellate Cells, Am J Pathol. 2007 ; 170(6): 1942–1953. [PMID: 17525262 ].
25、Cao Q, Mak KM, Lieber CS, DLPC decreases TGF-beta1-induced collagen mRNA by inhibiting p38 MAPK in hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2002 ; 283(5):1051-1061,[ PMID: 12381518]
26、Panzani M, Marra F,Caliqiuri A, DeFranco R, Gentilini A, Failli P, Gentilini P, Inhibition by pentoxifylline of extracellular signal-regulated kinase activation by platelet-derived growthfactor in hepatic stellate cells, Br J Pharmacol. 1996 ; 119(6): 1117-1124 [PMID: 8937713]
27、陈达凡李建英郑伟达王小众, ERK信号通路与肝纤维化,国际消化病杂志, 2007;27( 5): 370-391
28、Allen LF, Sehoh Ieopold J, Meyer MB. CI 1040 (PD-184352), a targeted signal transduction inhibitor of MEK (MAPKK ). [Review]Semin Onco1,2003;3( 1):105—116. [PMID: 14613031]
29、Davies BR, Logie A, McKay JS, Martin P, Steele S, Jenkins R, Cockerill M, Cartlidge S, Smith PD , AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models, Mol Cancer Ther. 2007 ; 6(8): 2209-2219。[PMID: 17699718]
30、Nagaoka T, Gebb SA, KaroorV, Homma N, Morris KG, McMurtry IF, Oka M. Involvement of RhoA/Rho kinase signaling in pulmonary hypertension of the fawn-hooded rat. J Appl Physio,2006; 100(3): 996-1002.. [PMID: 16322374]
31、Gosens R, Schaafsma D, BromhaarMM, Vrugt B, Zaagsma J, Meurs H, Nelemans SA. Growth factor-induced contraction ofhuman bronchial smoothmuscle isRho-kinase-dependent. Eur J Pharmaco,l 2004; 494(1): 73-76. [PMID: 15194453]
32、项蔷薇, ,罗运春。小G蛋白Rho/Rock信号转导通路与哮喘。医学综述2006; 12( 13):776-778
33、Brown JH, DelRe DP, Sussman MA. The Rac and Rho hall of fame: a decade of hypertrophic signaling hits . Circ Res,2006, 98(6): 730-742. [PMID: 16574914]
34、Murata T, Arii S, Mori A, Imamura M. Therapeutic significance of Y-27632, a Rho kinase inhibitor, on the established liver fibrosis .J Surg Res, 2003;( 114): 64-71. [PMID: 13678700]
35、王玉珍姜慧卿危彩霞陈新,法舒地尔通过Rho/ROCK信号通路抑制HSCs砧附、迁移和增殖,中华肝脏病杂志, 2006; 14.( 11): 821-823
36、Gelosa P, Cimino M, Pignieri A, Tremoli E, Guerrini U, Sironi L. The role of HMG-CoA reductase inhibition in endothelial dysfunction and inflammation, Vasc Health Risk Manag. 2007 ; 3(5): 567–577, [PMID: 18078008]
37、吴晓玲,曾维政,蒋明德,秦建平,徐辉,王钊,红景天甙对肝纤维化大鼠肝组织ROCK表达的影响,世界华人消化杂志2009;17(8):765-769
38、Ueno Y, Francis H, Glaser S, Demorrow S, Venter J, Benedetti A, Fava G, Marzioni M, Alpini G , Taurocholic Acid Feeding Prevents Tumor Necrosis Factor-–Induced Damage of Cholangiocytes by a PI3K–Mediated Pathway, Experimental Biology and Medicine ;2007;( 232): 942-949 [PMID: 17609511]
39、富翠芹,王沁,尹蓉,武令启, PI-3K信号转导通路在肝癌细胞生长和黏附中的作用。世界华人消化杂志, 2008; 16( 14): 1493-1498
40、Lechuga CG, Hernández-Nazara ZH, Hernández E, Bustamante M, Desierto G, Cotty A, Dharker N, Choe M, Rojkind M, PI3K is involved in PDGF-βreceptor upregulation post-PDGF-BB treatment in mouse HSC , Am J Physiol Gastrointest Liver Physiol:, 2006 ; (291) :1051-1061 [PMID: 16990448]
41、de Abreu LA, Fabres A, Esteves E, Masuda A, da Silva Vaz I Jr, Daffre S, Logullo C.Exogenous insulin stimulates glycogen accumulation in Rhipicephalus (Boophilus) microplus embryo cell line BME26 via PI3K/AKT pathway;comp Bilchem Physiol B Biochem Mol Biol, 2009 ;153(2):185-190 [PMID:19268713]
42、Araki N, Hamasaki M, Egami Y, Hatae T. Effect of 3-methyladenine on the fusion process of macropinosomes in EGF-stimulated A431 cells,Cell Struct Funct. 2006;31(2):145-157,[PMID: 17146146]
43、Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, Egia A, Sasaki AT, Thomas G, Kozma SC, Papa A, Nardella C, Cantley LC, Baselga J, Pandolfi PP.Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer, J Clin Invest. 2008 ; 118(9): 3065–3074, [PMID: 18725988]
44、Lane HA,Lebwohl D.Future directions in the treatment of hormone-sensitive advanced breast cancer: the RAD001 (Eveorlimus)-letrozole clinicla program, Semin Oncol, 2006; 33(7):18—25. [PMID: 16730273]
45、Hong-Hee Won, Inho Park, Eunjung Lee, Jong-Won Kim, and Doheon Lee,Comparative analysis of the JAK/STAT signaling through erythropoietin receptor and thrombopoietin receptor using a systems approach, 2009; 30( 10): 1186-1471, [PMID: 19208156]
46、Bromberg J, Darnell Jr JE. The role of STATs in transcriptional control and their impact on cellular function.Oncogene, 2000; 19(21): 2468-2473 .[PMID: 10851045].
47、Martínez-Chantar ML, Vázquez-Chantada M, Ariz U, Martínez N, Varela M, Luka Z, Capdevila A, Rodríguez J, Aransay AM, Matthiesen R, Yang H, Calvisi DF, Esteller M, Fraga M, Lu SC, Wagner C, Mato JM. Loss of the Glycine N-Methyltransferase Gene Leads to Steatosis and Hepatocellular Carcinoma in Mice , Hepatology. 2008 ; 47(4) : 1191-1199. [PMID: 18318442]
48、牛丽文,曹琦,JAK /STAT途径调节瘦素诱导的HSCsⅠ型胶原基因的表达,中国药理学通报2007; 23(10): 1280~1285
49、姚胜,姚永明,李红云,董宁,于燕,梁华平;抑制JAK/STAT通路对烫伤后金黄色葡萄球菌脓毒症大鼠肝损害的影响。中国危重病急救医学, 2002; 14( 6): 336-339。
50、Q Zhang, I Nowak, EC Vonderheid, AH Rook, ME Kadin, PC Nowell, LM Shaw, and MA Wasik, Activation of Jak/STAT proteins involved in signal transduction pathway mediated by receptor for interleukin 2 in malignant T lymphocytes derived from cutaneous anaplastic large T-celllymphoma and Sezary syndrome, Proc Natl Acad Sci U S A. 1996;93(17): 9148–9153; [PMID: 8799169]
51、Qi Cao, Ki M. Mak, Chaoling Ren, and Charles S. Lieber, Leptin Stimulates Tissue Inhibitor of Metalloproteinase-1 in Human Hepatic Stellate Cells, J Biol Chem. 2004; 279(6): 4292-4304. [PMID: 14625304]
52、于洪波,姚登福,核转录因子κB活化途径干预对肝细胞癌变的影响,中国临床药理学与治疗学,2008 ;13(2):228-233
53、Tsuka N, Motokawa M, Kaku M, Kawata T, Fujita T, Ohtani J, Koseki H, Sunagawa H, Matsuda Y, Abedini S, Hayashi H, Tanne K Biomed , Fms-Like tyrosine kinase (Flt-4) singaling participates in osteoclast differentiation in osteopetrotic (op/op) mice. Res. 2009 ;30(1):31-37, [PMID: 19265261]
54、李勇,张培建,金成,NF-κB与肝脏缺血再灌注损伤的研究进展,中国现代普通外科进展2008 ; 11( 1): 228-232
55、Olivier M, Jurg T. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell,2003, 6(114): 181~190. [PMID: 12887920]
56、赵进军,吕志平,张绪富.核转录因子在HSCs激活中的作用.中华肝脏病杂志,2002;10( 3): 227-228
57、巨立中,成军,钟彦伟.核因子κB的信号转导机制及研究策略[J].世界华人消化杂志,2004; 12(4): 948-950
58、Ethridge RT, Hashimoto K, Chung DH, Ehlers RA, Rajaraman S, Evers BM.. Selective inhibition of NF-kappaB attenuates the severity of cerulein-induced acute pancreatitis .J Am Coll Surg, 2002; 195(4): 497-505.. [PMID: 12375755]
59、甄真,宋慧娟,李武军,赵彩彦,周俊英, NF-κB和TNF-α在暴发性肝衰竭肝组织中的表达及其意义,中国组织化学与细胞化学杂志, 2008; 17( 1): 45-48
60、Jinming Yang, Yingjun Su, and Ann Richmond, Antioxidants tiron and N-acetyl-L-cysteine differentially mediate apoptosis in melanoma cells via a reactive oxygen species-independent NF-κB pathway, Free Radic Bio Med.2007; 42(9): 1369-1380, [PMID: 17395010]
61、赵宗豪,梅俏,吴军,胡咏梅,徐新华,许建明.核转录因子-kB与大鼠肝纤维化关系的实验研究.安徽医学, 2003; 24 ( 5 ): 1-3.
62、MacMaster JF, Dambach DM, Lee DB, Berry KK, Qiu Y, Zusi FC, Burke JR. An inhihitor of IKB kinase. BM S345541, Blocks endothelial cel1 adhesion molecule expression and reduces the severity of dextran sulfate sodium—induced colitis in mice.Inflamm Res,2003;(52):508-510. [PMID: 14991079]
63、Newton R, Holden NS, Catley MC, Oyelusi W, Leigh R, Proud D, Barnes PJ.Repression of Inflammatory Gene Expression in Human Pulmonary Epithelial Cells by Small-Molecule IκB Kinase Inhibitors J Pharmacol Exp Ther. 2007 ; 321(2): 734-742, [PMID: 17322026]
64、田芳,宋敏,许培荣,刘红涛,薛乐勋, siRNA阻断NF-KB信号通路联合5-FU对食管鳞癌细胞凋亡的促进作用,世界华人消化杂志2008; 16( 16): 1716-1721
65、蒋明德,甘新宇,解方为,曾维政,吴晓玲,红景天苷对乙醛刺激的大鼠HSCs增殖及胶原基因表达的影响,药学学报2002; 37(11): 841-844
66、Shimizu T, Kagawa T, Inoue T, Nonaka A, Takada S, Aburatani H, Taga T. Stabilized beta-catenin functions through TCF/LEF proteins and the Notch/RBP-Jkappa complex to promote proliferation and suppress differentiation of neural precursor cells. Mol Cell Biol. 2008; 28(24): 7427-7441. [PMID: 18852283]
67、Gordon MD, Nusse R. Wnt singaling: multiple pathways, multiple receptors, and multiple transcription factors[J].J Biol Chem,2006;281(32):22429—22433.[ PMID: 16793760]
68、Krieghof E, Behrens J, Mayr B; Nucleo—cytoplasmic distribution of beta—catenin is ergulated by retention. J Cell Sci, 2006; 119 (7): 1453—1463.[ PMID: 16554443]
69、Mi K, Dolna PJ, Johnson GV. hTe low density liopportein receptor related protein 6 interacts with glycogen synthase kinase 3 and at tenuates activity. J Biol Chem, 2006;281(8): 4787—4794.[PMID: 16365045]
70、Das Gupta R,Kaykas A, Moon RT, Perrimon N. Functional genomic analysis of the Wnt—winlgess signaling pathway.Science,2005;308(5723):826—833. [PMID: 15817814]
71、Zeng G, Awan F, Otruba W, Muller P, Apte U, Tan X, Gandhi C, Demetris AJ, Monga SP. Wnt'er in liver: expression of Wnt and frizzled genes in mouse. Hepatology, 2007 ; 45 : 195-204.[PMID: 17187422]
72、张影,张福奎,王宝恩,经典Wnt信号通路与肝脏关系的研究进展,世界华人消化杂志2008; 16(9): 975一981
73、Tsukamoto H, She H, Hazra S, Cheng J, Miyahara T. Anti-adipogenic regulation underlies hepatic stellate cell transdifferentiation. J Gastro-enterol Hepatol,2006;21:102-105.[ PMID: 16958658]
74、Veeman MT, Axelrod JD, Moon RT. A second canon: functions and mechanisms of beta-catenin-independent Wnt signa-ling. Dev Cell, 2003; 5: 367-377.[ PMID: 12967557]
75、Jiang F, Parsons CJ, Stefanovic B. Gene expression profile of quiescent and activated rat hepatic stellate cells implicates Wnt signaling pathway in activation. J Hepatol, 2006; 45:401-404. [PMID: 16780995]
76、Karner C, Wharton KA Jr , Carroll TJ . Planar cell polarity and vertebrate organogenesis. Semin Cell Dev Biol, 2006; 17(2): 194-203. [PMID: 16839790]
77、Habas R, Dawid IB, He X. Coactivation of Rac and Rho by Wnt/ Firzzled singaling is required for vertebrate gastmlation.Genes Dev,2003;17(2):295—309.[PMID: 12533515]
78、Labbe E, Letamendia A, Attisano L. Association of Smads with lymphoid enhancer binding factor1/T cell-specific factor mediates cooperative signaling by the transforming growthfactor-beta and wnt pathways. Proc Natl Acad Sci USA, 2000; 97: 8358-8360. [PMID: 10890911]
79、Habas R , He X . Activation of Rho and Rac by Wnt / frizzled singaling[J] . Methods Enzymol, 2006, 406: 500—511. [PMID: 16472682]
80、Wang J, Shou J , Chen X, Dickkopf-1, an inhibitor of the Wnt signaling pathway, is induced by p53, Oncogene ;2000; 19: 1843?1848. [PMID: 10777218]
81、Lodygin D, Epanchintsev A, Menssen A, Diebold J, Hermeking H. Functional epigenomics identifies genes frequently silenced in prostate cancer. Cancer Res,2005;65( 10):4218-4227 [PMID: 15899813]
82、Hu YA,Gu XC ,Liu JH,Yang Y,Yan Y,and Zhao CJ,Expression pattern of Wnt inhibitor factor 1(Wif1) during the development in mouse CNS。Gene Expr Patterns. 2008; (7-8):515-522. [ PMID: 18586116]
83、Koornstra JJ, Rijcken FE, Oldenhuis CN, Zwart N, van der Sluis T, Hollema H, deVries EG, Keller JJ, Offerhaus JA, Giardiello FM, Kleibeuker JH. Sulindac Inhibits ?-Catenin Expression in Normal-Appearing Colon of Hereditary Nonpolyposis Colorectal Cancer and Familial Adenomatous Polyposis Patients, Cancer Epidemiology Biomarkers & Prevention 2005; 7(14):1608-1612, [PMID: 16030090]
2. Pérez-Carreón JI, Martínez-Pérez L, Loredo ML, etal.. Inhibition of hepatic damage and liver fibrosis by brain natriuretic peptide, FEBS Lett. 2009 18;583:2067-2070
3. Yin MF, Lian LH, Piao DM, Nan JX, Tetrandrine stimulates the apoptosis of hepatic stellate cells and ameliorates development of fibrosis in a thioacetamide rat model,World J Gastroenterol 2007 ;13(8): 1214-1220
4. Sandra March, Mariona Graupera.Identification and Functional Characterization of the Hepatic Stellate Cell CD38 Cell Surface Molecule, Am J Pathol. 2007 ; 170(1): 176–187
5. Wang L, Wang J, Wang BE, et al.Effects of herbal compound 861 on human hepatic stellate cell proliferation and activation[J].World J Gastroenterol , 2004 ; 10 :2831-2835
6.吴哓玲,曾维政,王丕龙。红景天甙对肝纤维化大鼠TGFβ-Smad信号通路的影响[J],世界华人消化杂志, 2005; 13( 3): 341-345
7. Shimizu T, Kagawa T, Inoue T, Nonaka A, Takada S, Aburatani H, Taga T. Stabilizedbeta-catenin functions through TCF/LEF proteins and the Notch/RBP-Jkappa complex to promote proliferation and suppress differentiation of neural precursor cells. Mol Cell Biol. 2008;28(24):7427-7441. [PMID: 18852283]
8. Gordon MD, Nusse R. Wnt singaling: multiple pathways, multiple receptors,and multiple transcription factors[J].J Biol Chem,2006,281(32):22429—22433
9. Krieghof E , Behrens J , Mayr B . Nucleo-cytoplasmic distribution of beta-catenin is ergulated by retention[J].J Cell Sci,2006,119 (7):1453-1463.
10. Zeng G, Awan F, Otruba W, etal. Wnt'er in liver: expression of Wnt and frizzled genes in mouse. Hepatology, 2007,45: 195-204.
11.张影,张福奎,王宝恩,经典Wnt信号通路与肝脏关系的研究进展,世界华人消化杂志2008,3;16(0):975-981
12. Jiang F, Parsons CJ, Stefanovic B. Gene expression profile of quiescent and activated rat hepatic stellate cells implicates Wnt signaling pathway in activation. J Hepatol, 2006,45:401-404.
13. Shin HW, Park SY, Lee KB, Jang JJ , Down-regulation of Wnt signaling during apoptosis of human hepatic stellate cells. Hepatogastroenterology 2009 ;56:208-212
14. Lodygin D, Epanchintsev A, Menssen A, et al. Functional epigenomics identifies genes frequently silenced in prostate cancer. Cancer Res,2005,65( 10):4218-4227
1、Yin MF, Lian LH, Piao DM, Nan JX, Tetrandrine stimulates the apoptosis of hepatic stellate cells and ameliorates development of fibrosis in a thioacetamide rat model , World JGastroenterol 2007 ;13(8): 1214-1220,[ PMID: 17451202]
2、Sandra March, Mariona Graupera.Identification and Functional Characterization of the Hepatic Stellate Cell CD38 Cell Surface Molecule, Am J Pathol. 2007 ; 170(1): 176–187. [PMID: 17200192]
3、Feng XH, Derynck R.A.kinase subdomain of transforming growth factor-β(TGF-β) type I receptor determines the TGF-βintracellular signaling specificity . EMBO J, 1997; 16(13): 3912-3923. [PMID: 9233801]
4、郭永红罗金燕; TGF-β超家族与Smad信号转导研究进展,医学综述2005; 11( 8),685-688
5、Stopa M, Benes V, Ansorge W, Gressner AM, Dooley S. Genomic locus and promoter region of rat Smad7, an important antagonist of TGFbeta signaling. Mamm Genome, 2000; 11:169-176. [PMID: 10656934]
6、Ghosh AK,Yuan W, Mori Y, Varga J ,Smad-dependent stimulation of typeI collagen gene expression inhuman skin fibroblasts by TGF-beta involves functional cooperation with P300/Cbp transcriptional coactivators .Oneogene 2000; 19:3546一3555. [PMID: 10918613]
7、Ghosh AK,Yuan W, Mori Y, Chen Sj Varga J .Antagonistic regulation of typeI collagen gene expression by interfer ongamma and transforming growthfaetor-beta Integration at the level of P300/CBP transcriptional coactivators. J Biol Chem 2001;276:11041一11048.[ PMID: 11134049]
8、He J, Tegen SB, Krawitz AR, Martin GS, Luo K. The transforming activity of Ski and SnoN is dependent on their ability to repress the activity of Smad proteins. J Biol Chem, 2003;278(33): 30540-30547 [PMID: 12764135]
9、Kitamura Y, Ninomiya H. Smad expression of hepatic stellate cells in livercirrhosis in vivo and hepatic stellate cell line in vitro. Pathol Int, 2003; 53(1): 18-26 . [PMID: 12558865]
10、Kaimori A, Potter J, Kaimori JY, Wang C, Mezey E, Koteish A.Transforming growth factor-beta1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro .J Biol Chem., . 2007; 282( 30): 22089-22101。[PMID: 17513865]
11、Dooley S, Hamzavi J, Breitkopf K,Wiercinska E, Said HM Lorenzen J, Ten Dijke P, Gressner AM. Smad7 prevents activation of hepatic stellate cells and liver fibrosis in rats.Gastroenterology 2003 ;125(1):178-191 [PMID: 12851882]
12、Inagaki Y, Kushida M, Higashi K, Itoh J, Higashiyama R, Hong YY, Kawada N, Namikawa K, Kiyama H, Bou-Gharios G, Watanabe T, Okazaki I, Ikeda K. Cell type-specific intervention of transforming growth factor beta/smad signaling suppresses collagen gene expression and hepatic fibrosis in mice. Gastroenterology., 2005; 129(1)∶259-268.[ PMID: 16012952]
13、吴哓玲,曾维政,王丕龙。红景天甙对肝纤维化大鼠TGFβ-Smad信号通路的影响[J]。世界华人消化杂志, 2005; 13( 3): 341-345
14、Aggarwal BB, Sundaram C, Malani N, Ichikawa H .Curcumin: the Indian solid gold. Adv Exp Med Biol 2007; 595: 1–75. [PMID: 17569205]
15、Zhang XL, Liu JM, Dynamic expression of extracellular signal-regulated kinase in rat liver tissue during hepatic fibrogenesis,R World J Gastroenterol 2006 ;12(39): 6376-6381。[PMID: 17072965]
16、Seger R, Krebs EG, The MAPK signaling cascade. FASEB J , 2007; 9:: 726-735, [PMID: 7601337]
17、Jiang MD, Zheng SM, An experimental study of extracellular signal-regulated kinase and its interventional treatments in hepatic fibrosis,Hepatobiliary Pancreat Dis Int 2008;7: 51-57. [PMID: 18234639]
18、Wellbrock C, Karasarides M, Marais R. The RAF proteins take centre stage. Nat Rev Mol Cell Biol,2004; 5: 875-885,[ PMID: 15520807]
19、Chuderland D, Seger R. Protein-protein interactions in the regulation of the extracellular signal-regulated kinase.Mol Biotech-nol,2005; 29: 57-74, [PMID: 15668520]
20、Reeves HL, Friedman SL. Activation of hepatic stellate cells-a key issue in liver fibrosis. Front Biosci,2002; 7: 808-826,[ PMID: 11897564]
21、Qiang H, Lin Y, Zhang X, Zeng X, Shi J, Chen YX, Yang MF, Han ZG, Xie WF. Differential expression genesanalyzed by cDNA array in the regulation of rat hepatic fibro-genesis. Liver Int,2006; 26: 1126-1137[PMID: 17032414]
22、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: 951-958. [PMID: 10498647]
23、Saxena NK, Titus MA, Ding X, Floyd J, Srinivasan S, Sitaraman SV, Anania FA. Leptin as a novel profibrogenic cytokine in hepatic stellate cells: mitogenesis and inhibition of apoptosis mediated by extracellular regulated kinase(Erk ) and Akt phosphorylation. FASEB J,2004;18(13): 1612-1614 [PMID: 15319373]
24、Erica Novo, Stefania Cannito, Elena Zamara, Valfrèdi Bonzo L, Caligiuri A, Cravanzola C, Compagnone A, Colombatto S, Marra F, Pinzani M, Parola M. Proangiogenic Cytokines as Hypoxia-Dependent Factors Stimulating Migration of Human Hepatic Stellate Cells, Am J Pathol. 2007 ; 170(6): 1942–1953. [PMID: 17525262 ].
25、Cao Q, Mak KM, Lieber CS, DLPC decreases TGF-beta1-induced collagen mRNA by inhibiting p38 MAPK in hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2002 ; 283(5):1051-1061,[ PMID: 12381518]
26、Panzani M, Marra F,Caliqiuri A, DeFranco R, Gentilini A, Failli P, Gentilini P, Inhibition by pentoxifylline of extracellular signal-regulated kinase activation by platelet-derived growthfactor in hepatic stellate cells, Br J Pharmacol. 1996 ; 119(6): 1117-1124 [PMID: 8937713]
27、陈达凡李建英郑伟达王小众, ERK信号通路与肝纤维化,国际消化病杂志, 2007;27( 5): 370-391
28、Allen LF, Sehoh Ieopold J, Meyer MB. CI 1040 (PD-184352), a targeted signal transduction inhibitor of MEK (MAPKK ). [Review]Semin Onco1,2003;3( 1):105—116. [PMID: 14613031]
29、Davies BR, Logie A, McKay JS, Martin P, Steele S, Jenkins R, Cockerill M, Cartlidge S, Smith PD , AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models, Mol Cancer Ther. 2007 ; 6(8): 2209-2219。[PMID: 17699718]
30、Nagaoka T, Gebb SA, KaroorV, Homma N, Morris KG, McMurtry IF, Oka M. Involvement of RhoA/Rho kinase signaling in pulmonary hypertension of the fawn-hooded rat. J Appl Physio,2006; 100(3): 996-1002.. [PMID: 16322374]
31、Gosens R, Schaafsma D, BromhaarMM, Vrugt B, Zaagsma J, Meurs H, Nelemans SA. Growth factor-induced contraction ofhuman bronchial smoothmuscle isRho-kinase-dependent. Eur J Pharmaco,l 2004; 494(1): 73-76. [PMID: 15194453]
32、项蔷薇, ,罗运春。小G蛋白Rho/Rock信号转导通路与哮喘。医学综述2006; 12( 13):776-778
33、Brown JH, DelRe DP, Sussman MA. The Rac and Rho hall of fame: a decade of hypertrophic signaling hits . Circ Res,2006, 98(6): 730-742. [PMID: 16574914]
34、Murata T, Arii S, Mori A, Imamura M. Therapeutic significance of Y-27632, a Rho kinase inhibitor, on the established liver fibrosis .J Surg Res, 2003;( 114): 64-71. [PMID: 13678700]
35、王玉珍姜慧卿危彩霞陈新,法舒地尔通过Rho/ROCK信号通路抑制HSCs砧附、迁移和增殖,中华肝脏病杂志, 2006; 14.( 11): 821-823
36、Gelosa P, Cimino M, Pignieri A, Tremoli E, Guerrini U, Sironi L. The role of HMG-CoA reductase inhibition in endothelial dysfunction and inflammation, Vasc Health Risk Manag. 2007 ; 3(5): 567–577, [PMID: 18078008]
37、吴晓玲,曾维政,蒋明德,秦建平,徐辉,王钊,红景天甙对肝纤维化大鼠肝组织ROCK表达的影响,世界华人消化杂志2009;17(8):765-769
38、Ueno Y, Francis H, Glaser S, Demorrow S, Venter J, Benedetti A, Fava G, Marzioni M, Alpini G , Taurocholic Acid Feeding Prevents Tumor Necrosis Factor-–Induced Damage of Cholangiocytes by a PI3K–Mediated Pathway, Experimental Biology and Medicine ;2007;( 232): 942-949 [PMID: 17609511]
39、富翠芹,王沁,尹蓉,武令启, PI-3K信号转导通路在肝癌细胞生长和黏附中的作用。世界华人消化杂志, 2008; 16( 14): 1493-1498
40、Lechuga CG, Hernández-Nazara ZH, Hernández E, Bustamante M, Desierto G, Cotty A, Dharker N, Choe M, Rojkind M, PI3K is involved in PDGF-βreceptor upregulation post-PDGF-BB treatment in mouse HSC , Am J Physiol Gastrointest Liver Physiol:, 2006 ; (291) :1051-1061 [PMID: 16990448]
41、de Abreu LA, Fabres A, Esteves E, Masuda A, da Silva Vaz I Jr, Daffre S, Logullo C.Exogenous insulin stimulates glycogen accumulation in Rhipicephalus (Boophilus) microplus embryo cell line BME26 via PI3K/AKT pathway;comp Bilchem Physiol B Biochem Mol Biol, 2009 ;153(2):185-190 [PMID:19268713]
42、Araki N, Hamasaki M, Egami Y, Hatae T. Effect of 3-methyladenine on the fusion process of macropinosomes in EGF-stimulated A431 cells,Cell Struct Funct. 2006;31(2):145-157,[PMID: 17146146]
43、Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, Egia A, Sasaki AT, Thomas G, Kozma SC, Papa A, Nardella C, Cantley LC, Baselga J, Pandolfi PP.Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer, J Clin Invest. 2008 ; 118(9): 3065–3074, [PMID: 18725988]
44、Lane HA,Lebwohl D.Future directions in the treatment of hormone-sensitive advanced breast cancer: the RAD001 (Eveorlimus)-letrozole clinicla program, Semin Oncol, 2006; 33(7):18—25. [PMID: 16730273]
45、Hong-Hee Won, Inho Park, Eunjung Lee, Jong-Won Kim, and Doheon Lee,Comparative analysis of the JAK/STAT signaling through erythropoietin receptor and thrombopoietin receptor using a systems approach, 2009; 30( 10): 1186-1471, [PMID: 19208156]
46、Bromberg J, Darnell Jr JE. The role of STATs in transcriptional control and their impact on cellular function.Oncogene, 2000; 19(21): 2468-2473 .[PMID: 10851045].
47、Martínez-Chantar ML, Vázquez-Chantada M, Ariz U, Martínez N, Varela M, Luka Z, Capdevila A, Rodríguez J, Aransay AM, Matthiesen R, Yang H, Calvisi DF, Esteller M, Fraga M, Lu SC, Wagner C, Mato JM. Loss of the Glycine N-Methyltransferase Gene Leads to Steatosis and Hepatocellular Carcinoma in Mice , Hepatology. 2008 ; 47(4) : 1191-1199. [PMID: 18318442]
48、牛丽文,曹琦,JAK /STAT途径调节瘦素诱导的HSCsⅠ型胶原基因的表达,中国药理学通报2007; 23(10): 1280~1285
49、姚胜,姚永明,李红云,董宁,于燕,梁华平;抑制JAK/STAT通路对烫伤后金黄色葡萄球菌脓毒症大鼠肝损害的影响。中国危重病急救医学, 2002; 14( 6): 336-339。
50、Q Zhang, I Nowak, EC Vonderheid, AH Rook, ME Kadin, PC Nowell, LM Shaw, and MA Wasik, Activation of Jak/STAT proteins involved in signal transduction pathway mediated by receptor for interleukin 2 in malignant T lymphocytes derived from cutaneous anaplastic large T-celllymphoma and Sezary syndrome, Proc Natl Acad Sci U S A. 1996;93(17): 9148–9153; [PMID: 8799169]
51、Qi Cao, Ki M. Mak, Chaoling Ren, and Charles S. Lieber, Leptin Stimulates Tissue Inhibitor of Metalloproteinase-1 in Human Hepatic Stellate Cells, J Biol Chem. 2004; 279(6): 4292-4304. [PMID: 14625304]
52、于洪波,姚登福,核转录因子κB活化途径干预对肝细胞癌变的影响,中国临床药理学与治疗学,2008 ;13(2):228-233
53、Tsuka N, Motokawa M, Kaku M, Kawata T, Fujita T, Ohtani J, Koseki H, Sunagawa H, Matsuda Y, Abedini S, Hayashi H, Tanne K Biomed , Fms-Like tyrosine kinase (Flt-4) singaling participates in osteoclast differentiation in osteopetrotic (op/op) mice. Res. 2009 ;30(1):31-37, [PMID: 19265261]
54、李勇,张培建,金成,NF-κB与肝脏缺血再灌注损伤的研究进展,中国现代普通外科进展2008 ; 11( 1): 228-232
55、Olivier M, Jurg T. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell,2003, 6(114): 181~190. [PMID: 12887920]
56、赵进军,吕志平,张绪富.核转录因子在HSCs激活中的作用.中华肝脏病杂志,2002;10( 3): 227-228
57、巨立中,成军,钟彦伟.核因子κB的信号转导机制及研究策略[J].世界华人消化杂志,2004; 12(4): 948-950
58、Ethridge RT, Hashimoto K, Chung DH, Ehlers RA, Rajaraman S, Evers BM.. Selective inhibition of NF-kappaB attenuates the severity of cerulein-induced acute pancreatitis .J Am Coll Surg, 2002; 195(4): 497-505.. [PMID: 12375755]
59、甄真,宋慧娟,李武军,赵彩彦,周俊英, NF-κB和TNF-α在暴发性肝衰竭肝组织中的表达及其意义,中国组织化学与细胞化学杂志, 2008; 17( 1): 45-48
60、Jinming Yang, Yingjun Su, and Ann Richmond, Antioxidants tiron and N-acetyl-L-cysteine differentially mediate apoptosis in melanoma cells via a reactive oxygen species-independent NF-κB pathway, Free Radic Bio Med.2007; 42(9): 1369-1380, [PMID: 17395010]
61、赵宗豪,梅俏,吴军,胡咏梅,徐新华,许建明.核转录因子-kB与大鼠肝纤维化关系的实验研究.安徽医学, 2003; 24 ( 5 ): 1-3.
62、MacMaster JF, Dambach DM, Lee DB, Berry KK, Qiu Y, Zusi FC, Burke JR. An inhihitor of IKB kinase. BM S345541, Blocks endothelial cel1 adhesion molecule expression and reduces the severity of dextran sulfate sodium—induced colitis in mice.Inflamm Res,2003;(52):508-510. [PMID: 14991079]
63、Newton R, Holden NS, Catley MC, Oyelusi W, Leigh R, Proud D, Barnes PJ.Repression of Inflammatory Gene Expression in Human Pulmonary Epithelial Cells by Small-Molecule IκB Kinase Inhibitors J Pharmacol Exp Ther. 2007 ; 321(2): 734-742, [PMID: 17322026]
64、田芳,宋敏,许培荣,刘红涛,薛乐勋, siRNA阻断NF-KB信号通路联合5-FU对食管鳞癌细胞凋亡的促进作用,世界华人消化杂志2008; 16( 16): 1716-1721
65、蒋明德,甘新宇,解方为,曾维政,吴晓玲,红景天苷对乙醛刺激的大鼠HSCs增殖及胶原基因表达的影响,药学学报2002; 37(11): 841-844
66、Shimizu T, Kagawa T, Inoue T, Nonaka A, Takada S, Aburatani H, Taga T. Stabilized beta-catenin functions through TCF/LEF proteins and the Notch/RBP-Jkappa complex to promote proliferation and suppress differentiation of neural precursor cells. Mol Cell Biol. 2008; 28(24): 7427-7441. [PMID: 18852283]
67、Gordon MD, Nusse R. Wnt singaling: multiple pathways, multiple receptors, and multiple transcription factors[J].J Biol Chem,2006;281(32):22429—22433.[ PMID: 16793760]
68、Krieghof E, Behrens J, Mayr B; Nucleo—cytoplasmic distribution of beta—catenin is ergulated by retention. J Cell Sci, 2006; 119 (7): 1453—1463.[ PMID: 16554443]
69、Mi K, Dolna PJ, Johnson GV. hTe low density liopportein receptor related protein 6 interacts with glycogen synthase kinase 3 and at tenuates activity. J Biol Chem, 2006;281(8): 4787—4794.[PMID: 16365045]
70、Das Gupta R,Kaykas A, Moon RT, Perrimon N. Functional genomic analysis of the Wnt—winlgess signaling pathway.Science,2005;308(5723):826—833. [PMID: 15817814]
71、Zeng G, Awan F, Otruba W, Muller P, Apte U, Tan X, Gandhi C, Demetris AJ, Monga SP. Wnt'er in liver: expression of Wnt and frizzled genes in mouse. Hepatology, 2007 ; 45 : 195-204.[PMID: 17187422]
72、张影,张福奎,王宝恩,经典Wnt信号通路与肝脏关系的研究进展,世界华人消化杂志2008; 16(9): 975一981
73、Tsukamoto H, She H, Hazra S, Cheng J, Miyahara T. Anti-adipogenic regulation underlies hepatic stellate cell transdifferentiation. J Gastro-enterol Hepatol,2006;21:102-105.[ PMID: 16958658]
74、Veeman MT, Axelrod JD, Moon RT. A second canon: functions and mechanisms of beta-catenin-independent Wnt signa-ling. Dev Cell, 2003; 5: 367-377.[ PMID: 12967557]
75、Jiang F, Parsons CJ, Stefanovic B. Gene expression profile of quiescent and activated rat hepatic stellate cells implicates Wnt signaling pathway in activation. J Hepatol, 2006; 45:401-404. [PMID: 16780995]
76、Karner C, Wharton KA Jr , Carroll TJ . Planar cell polarity and vertebrate organogenesis. Semin Cell Dev Biol, 2006; 17(2): 194-203. [PMID: 16839790]
77、Habas R, Dawid IB, He X. Coactivation of Rac and Rho by Wnt/ Firzzled singaling is required for vertebrate gastmlation.Genes Dev,2003;17(2):295—309.[PMID: 12533515]
78、Labbe E, Letamendia A, Attisano L. Association of Smads with lymphoid enhancer binding factor1/T cell-specific factor mediates cooperative signaling by the transforming growthfactor-beta and wnt pathways. Proc Natl Acad Sci USA, 2000; 97: 8358-8360. [PMID: 10890911]
79、Habas R , He X . Activation of Rho and Rac by Wnt / frizzled singaling[J] . Methods Enzymol, 2006, 406: 500—511. [PMID: 16472682]
80、Wang J, Shou J , Chen X, Dickkopf-1, an inhibitor of the Wnt signaling pathway, is induced by p53, Oncogene ;2000; 19: 1843?1848. [PMID: 10777218]
81、Lodygin D, Epanchintsev A, Menssen A, Diebold J, Hermeking H. Functional epigenomics identifies genes frequently silenced in prostate cancer. Cancer Res,2005;65( 10):4218-4227 [PMID: 15899813]
82、Hu YA,Gu XC ,Liu JH,Yang Y,Yan Y,and Zhao CJ,Expression pattern of Wnt inhibitor factor 1(Wif1) during the development in mouse CNS。Gene Expr Patterns. 2008; (7-8):515-522. [ PMID: 18586116]
83、Koornstra JJ, Rijcken FE, Oldenhuis CN, Zwart N, van der Sluis T, Hollema H, deVries EG, Keller JJ, Offerhaus JA, Giardiello FM, Kleibeuker JH. Sulindac Inhibits ?-Catenin Expression in Normal-Appearing Colon of Hereditary Nonpolyposis Colorectal Cancer and Familial Adenomatous Polyposis Patients, Cancer Epidemiology Biomarkers & Prevention 2005; 7(14):1608-1612, [PMID: 16030090]