龙血竭及龙血素B单体对肝星状细胞促血管新生和肝纤维化的影响
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摘要
第一部分：龙血竭对药物诱导大鼠肝纤维化的干预作用及可能机制
目的：观察龙血竭对药物诱导的肝纤维化大鼠的治疗作用并初步探讨其作用机制。
方法：健康清洁级SD雄性大鼠36只,体重(200±20)g,随机分为3组：正常对照组、模型组、药物干预组,每组12只,以硫代乙酰胺诱导大鼠肝纤维化。模型组、药物干预组均给予10%硫代乙酰胺-生理盐水溶液腹腔注射(首次250mg/kg,此后200mg/kg),空白组给予生理盐水0.5m1腹腔注射,2次/周。2周后,模型组、空白组每天加用生理盐水2ml灌胃。药物干预组：每只每天加用龙血竭0.6克溶于3ml生理盐水灌胃,共8周。第8周末处死大鼠,测定各组肝纤维化大鼠血清中谷丙转氨酶、谷草转氨酶及透明质酸酶、层粘连蛋白、IV型胶原的含量。取肝组织作病理切片,进行HE染色观察肝脏的病理变化,masson染色观察肝组织中胶原的增生程度。
结果：硫代乙酰胺8周后成功诱导大鼠肝纤维化模型。模型组大鼠血清中透明质酸酶、层粘连蛋白和IV型胶原水平较正常组均升高(P<0.05),有统计学意义；给药六周后,大鼠血清透明质酸酶、层粘连蛋白和IV型胶原水平与模型组相比明显降低(P<0.01)；模型组大鼠血清中谷丙转氨酶和谷草转氨酶水平较正常组均显著升高(P<0.05),药物干预组大鼠血清谷丙转氨酶和谷草转氨酶水平与模型组相比明显降低(P<0.01)；纤维化程度：正常对照组大鼠无肝纤维化；模型组与正常对照组大鼠相比肝脏组织纤维化程度更高,药物肝脏纤维化程度均优于模型组；masson染色后观察,模型组胶原纤维沉积较为明显,药物干预组胶原纤维沉积较模型组有明显改善。
结论：硫代乙酰胺可成功诱导大鼠肝纤维化。龙血竭能够降低肝纤维化大鼠血清中透明质酸酶、层粘连蛋白和IV型胶原及谷丙转氨酶和谷草转氨酶水平,并能改善纤维化大鼠程肝脏的病理损伤程度,减少肝纤维化大鼠肝组织中胶原纤维的增生,上述作用可能与其主要成分龙血素B单体抑制肝星状细胞的增殖,促进活化的肝星状细胞凋亡,从而抑制参与肝纤维化及血管新生启动与进展的重要因子有关。
第二部分：龙血素B对肝星状细胞增殖及促血管新生的影响
目的：观察龙血素B对肝星状细胞增殖及透明质酸酶、层粘连蛋白、IV型胶原含量的影响。检测肝星状细胞药物处理前后血管内皮生长因子、低氧诱导因子、神经纤毛蛋白1mRNA表达的影响。
方法：用MTT法观察龙血素B对肝星状细胞增殖的影响。计算IC50,以IC50,IC50/2, IC50/10三个浓度处理细胞,并检测细胞上清中透明质酸酶、层粘连蛋白、Ⅳ型胶原的含量；采用荧光实时定量PCR(RT-PCR)(?),检测肝星状细胞药物处理前后血管内皮生长因子、低氧诱导因子、神经纤毛蛋白1mRNA表达的影响。
结果：龙血素B的IC50为0.3ug.ul-1;与正常对照组相比药物干预组细胞上清中透明质酸酶、层粘连蛋白和Ⅳ型胶原水平均减低(P<0.05)；与正常对照组相比药物干预组细胞内VEGF和HIF-1及NRP-1的基因表达明显下调。
结论：龙血素B可抑制肝星状细胞的增殖,并降低细胞上清中透明质酸酶、层粘连蛋白和Ⅳ型胶原的含量,还可下调细胞内血管内皮生长因子,神经纤毛蛋白1和低氧诱导因子mRNA的表达。
Part I:
Loureirin B on experimental hepatic fibrosis and its possible mechanism
Objective:To investigate Loureirin B on experimental hepatic fibrosis, and present possible mechanisms。
Method:36clean male SD (Sprague-Dawley) rats were randomly divided into4groups:Control group, model group, drug treatment group; With thioacetamide (TAA) inducing liver fibrosis model, to bserve serum transaminase (ALT, AST), fibrosis markers (HA, LN, IV-C), liver histopathology changes.
Results:To compare with model group,(1)liver pathology grade, Control group were more serious than the model group; drug treatment group were better than the model group;(2) The level of drug treatment group ALT, AST decreases significantly (P<0.01),(3) The level of drug treatment group HA, LN, IV-C is significantly decreased (P<0.01)。
Conclusion:Rat liver fibrosis model induced by TAA is established Successfully; dragon's blood can protect TAA-induced liver fibrosis in liver function, and improve the quality of life in rats with liver fibrosis; dragon's blood treatment on liver fibrosis may be positively correlated with the dosage.
Part Ⅱ:
Effect of Loureirin B on Proliferation and Extracellular Matrix Secretion of Rat Hepatic Stellate Cells in Vitro
Objective:To investigate the effects of loureirin B on proliferation and extracellular matrix secretion of rat hepatic stellate cells in vitro.
Methods:HSC-T6was cultured in96-well plates for24hours.Then they were incubated with different concentration of loureirin B for48hours.MTT colorimetry was used for assaying proliferation of hepatic stellate cells.lnhibition rate was calculated. Hyaluronic acid Laminin and Collagen type IV were measured by radioimmunoassay.The expression of vascular endothelial growth factor hypoxia-inducible factor and neuropilin-1mRNA.
Results:Addition of loureirin B into culture medium could significantly inhibit HSC proliferation,and the higher concentration of the loureirin B the stronger inhibition rate of the hepatic stellate cells. It also inhibit Hyaluronic acid、Laminin and Collagen type IV secretion in different degree. The expression of vascular endothelial growth factor hypoxia-inducible factor and neuropilin-1mRNA.
Conclusion:Loureirin B can significantly inhibite hepatic stellate cells proliferation and extracellular matrix secretion. And inhibite the expression of vascular endothelial growth factor hypoxia-inducible factor and neuropilin-1.
目的：观察龙血竭对药物诱导的肝纤维化大鼠的治疗作用并初步探讨其作用机制。
方法：健康清洁级SD雄性大鼠36只,体重(200±20)g,随机分为3组：正常对照组、模型组、药物干预组,每组12只,以硫代乙酰胺诱导大鼠肝纤维化。模型组、药物干预组均给予10%硫代乙酰胺-生理盐水溶液腹腔注射(首次250mg/kg,此后200mg/kg),空白组给予生理盐水0.5m1腹腔注射,2次/周。2周后,模型组、空白组每天加用生理盐水2ml灌胃。药物干预组：每只每天加用龙血竭0.6克溶于3ml生理盐水灌胃,共8周。第8周末处死大鼠,测定各组肝纤维化大鼠血清中谷丙转氨酶、谷草转氨酶及透明质酸酶、层粘连蛋白、IV型胶原的含量。取肝组织作病理切片,进行HE染色观察肝脏的病理变化,masson染色观察肝组织中胶原的增生程度。
结果：硫代乙酰胺8周后成功诱导大鼠肝纤维化模型。模型组大鼠血清中透明质酸酶、层粘连蛋白和IV型胶原水平较正常组均升高(P<0.05),有统计学意义；给药六周后,大鼠血清透明质酸酶、层粘连蛋白和IV型胶原水平与模型组相比明显降低(P<0.01)；模型组大鼠血清中谷丙转氨酶和谷草转氨酶水平较正常组均显著升高(P<0.05),药物干预组大鼠血清谷丙转氨酶和谷草转氨酶水平与模型组相比明显降低(P<0.01)；纤维化程度：正常对照组大鼠无肝纤维化；模型组与正常对照组大鼠相比肝脏组织纤维化程度更高,药物肝脏纤维化程度均优于模型组；masson染色后观察,模型组胶原纤维沉积较为明显,药物干预组胶原纤维沉积较模型组有明显改善。
结论：硫代乙酰胺可成功诱导大鼠肝纤维化。龙血竭能够降低肝纤维化大鼠血清中透明质酸酶、层粘连蛋白和IV型胶原及谷丙转氨酶和谷草转氨酶水平,并能改善纤维化大鼠程肝脏的病理损伤程度,减少肝纤维化大鼠肝组织中胶原纤维的增生,上述作用可能与其主要成分龙血素B单体抑制肝星状细胞的增殖,促进活化的肝星状细胞凋亡,从而抑制参与肝纤维化及血管新生启动与进展的重要因子有关。
第二部分：龙血素B对肝星状细胞增殖及促血管新生的影响
目的：观察龙血素B对肝星状细胞增殖及透明质酸酶、层粘连蛋白、IV型胶原含量的影响。检测肝星状细胞药物处理前后血管内皮生长因子、低氧诱导因子、神经纤毛蛋白1mRNA表达的影响。
方法：用MTT法观察龙血素B对肝星状细胞增殖的影响。计算IC50,以IC50,IC50/2, IC50/10三个浓度处理细胞,并检测细胞上清中透明质酸酶、层粘连蛋白、Ⅳ型胶原的含量；采用荧光实时定量PCR(RT-PCR)(?),检测肝星状细胞药物处理前后血管内皮生长因子、低氧诱导因子、神经纤毛蛋白1mRNA表达的影响。
结果：龙血素B的IC50为0.3ug.ul-1;与正常对照组相比药物干预组细胞上清中透明质酸酶、层粘连蛋白和Ⅳ型胶原水平均减低(P<0.05)；与正常对照组相比药物干预组细胞内VEGF和HIF-1及NRP-1的基因表达明显下调。
结论：龙血素B可抑制肝星状细胞的增殖,并降低细胞上清中透明质酸酶、层粘连蛋白和Ⅳ型胶原的含量,还可下调细胞内血管内皮生长因子,神经纤毛蛋白1和低氧诱导因子mRNA的表达。
Part I:
Loureirin B on experimental hepatic fibrosis and its possible mechanism
Objective:To investigate Loureirin B on experimental hepatic fibrosis, and present possible mechanisms。
Method:36clean male SD (Sprague-Dawley) rats were randomly divided into4groups:Control group, model group, drug treatment group; With thioacetamide (TAA) inducing liver fibrosis model, to bserve serum transaminase (ALT, AST), fibrosis markers (HA, LN, IV-C), liver histopathology changes.
Results:To compare with model group,(1)liver pathology grade, Control group were more serious than the model group; drug treatment group were better than the model group;(2) The level of drug treatment group ALT, AST decreases significantly (P<0.01),(3) The level of drug treatment group HA, LN, IV-C is significantly decreased (P<0.01)。
Conclusion:Rat liver fibrosis model induced by TAA is established Successfully; dragon's blood can protect TAA-induced liver fibrosis in liver function, and improve the quality of life in rats with liver fibrosis; dragon's blood treatment on liver fibrosis may be positively correlated with the dosage.
Part Ⅱ:
Effect of Loureirin B on Proliferation and Extracellular Matrix Secretion of Rat Hepatic Stellate Cells in Vitro
Objective:To investigate the effects of loureirin B on proliferation and extracellular matrix secretion of rat hepatic stellate cells in vitro.
Methods:HSC-T6was cultured in96-well plates for24hours.Then they were incubated with different concentration of loureirin B for48hours.MTT colorimetry was used for assaying proliferation of hepatic stellate cells.lnhibition rate was calculated. Hyaluronic acid Laminin and Collagen type IV were measured by radioimmunoassay.The expression of vascular endothelial growth factor hypoxia-inducible factor and neuropilin-1mRNA.
Results:Addition of loureirin B into culture medium could significantly inhibit HSC proliferation,and the higher concentration of the loureirin B the stronger inhibition rate of the hepatic stellate cells. It also inhibit Hyaluronic acid、Laminin and Collagen type IV secretion in different degree. The expression of vascular endothelial growth factor hypoxia-inducible factor and neuropilin-1mRNA.
Conclusion:Loureirin B can significantly inhibite hepatic stellate cells proliferation and extracellular matrix secretion. And inhibite the expression of vascular endothelial growth factor hypoxia-inducible factor and neuropilin-1.
引文
[1]Friedman S. L. Liver fibrosis-from bench to bedside. Journal of Hepatology,2003,38:S38-S53.
[2]Bataller R.Brenner D A. Liver fibrosis. The Journal of Clinical Investigation.2005,115: 208-218.
[3]Medina J,Arroyo AG,Sanchez-Madrid F,et al. Angiogenesis in Chronic Inflammatory Liver Disease. Hepatology,2004,39:1185-1195.
[4]Vanheule E,Geerts AM,Van Huysse J,et al. An intravital microscopic study of the hepatic microcirculation in cirrhotic mice models:relationship between fibrosis and angiogenesis. Int J Exp Pathol,2008,89(6):419-432.
[5]Fernandez M,Semela D,Bruix J,et al. Angiogenesis in liver disease. J Hepatol.2009,50(3): 604-620.
[6]Medina J, Caveda L, Sanz-Cameno P,et al. Hepatocyte growth factor activates endothelial proangiogenic mechanisms relevant in chronic hepatitis C-associated neoangiogenesis. Journal of Hepatology,2003,38:660-667.
[7]Liu Y, Lui EL, Friedman SL,et al. PTK787/ZK22258 attenuates stellate cell activation and hepatic fibrosis in vivo by inhibiting VEGF signaling. Lab Invest,2009,89(2):209-221.
[8]Jaroszewicz J, Januszkiewicz M, Flisiak R.et al. Circulating vascular endothelial growth factor and its soluble receptors in patients with liver cirrhosis:possible association with hepatic function impairment. Cytokine.2008,44(1):14-17.
[9]Yoshiji H, Kuriyama S, Yoshii J.et al. Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis. GUT,2003,52:1347-1352.
[10]Medinal J, Sanz-Camenol P, Garci'a-Bueyl L,et al. Evidence of angiogenesis in primary biliary cirrhosis:an immunohistochemical descriptive study. Journal of Hepatology,2005, 42:124-131.
[11]Tugues S, Fernandez-Varo G, Luque J M,et al. Antiangiogenic Treatment with Sunitinib Ameliorates Inflammatory Infiltrate, Fibrosis,and Portal Pressure in Cirrhotic Rats. Hepatology, 2007,46:1919-1926
[12]Mejias M, Garcia-Pras E, Tiani C.et al. Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats. Hepatology.2008,25. [Epub ahead of print
[13]Watanabe N.Takashimizu S,Nishizaki Y et al.An endothelin A receptor antagonist induces dilatation of sinusoidal endothelial fenestrae.implications for endothelin-1 in hepatic microcirculation.J Gastroenter01.2007.42:775.782.
[14]Semenza GL.Life with oxygen[J].Science.2007.318:62-64.
[15]伺书平,血竭的药理研究中国药房,2008，19(24)1912-1913.
[16]聂莉,郑碧霞,程德云等.龙血竭对肺纤维化大鼠肺组织TGF-β/Smads信号通路分了mRNA表达的影响四川大学学报(医学版)，2007，38(5)：802-805.
[17]张培华,罗少军,汤少明等.血竭素对瘢痕成纤维细胞胶原合成的影响中国美容医学.2006，15(6)624-626.
[18]张培华,罗少军,肖佐环等.血竭素高氯酸盐促进瘢痕成纤维细胞凋亡的作用中国皮肤性病学杂志,2006,20(6)338-340.
[1]邓家刚,黄海滨,农毅清.龙血素B的药效学实验研究[J].广西中医药,2004,2；27(1)：44-46
[2]方伟蓉,李运曼,邓嘉元.龙血竭总黄酮对动物心肌缺血的保护作用[J].中国临床药理学与治疗学，20059；10(9)：1020-1023
[3]Azuma Watanabe, Muhammad Adnan Sohail, Dawidson Assis Gomes.et al.Inflammasome mediated regulation of hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol,2009,296: G1248-G1257
[4]Hitoshi Yoshiji, Ryuichi Noguchi, Shigeki Kuriyama.etal. lmatinib mesylate (STI-571) attenuates liver fibrosis development in rats. Am J Physiol Gastrointest Liver Physiol,2005,288:G907-G913.
[5]S. Wallace, T. Blanchard, L. Rabin.et al. Ductal Plate Malformation in a Nonhuman Primate. Veterinary Pathology,2009; 46:84-87.
[6]Bachir Taouli, Anuj J. Tolia, Mariela Losada,et al.Diffusion-Weighted MR1 for Quantification of Liver Fibrosis:reliminary Experience. Am. J. Roentgenol.,2007,189:799-806.
[7]Claudia von Montfort, Juliane I. Beier, J. Phillip Kaiser.et al. PAI-1 plays a protective role in CCl4-induced hepatic fibrosis in mice:role of hepatocyte division. Am J Physiol Gastrointest Liver Physiol,2010,298:G657-G666.
[8]Zhongsheng Peng.Patricia Fernandez,Tuere Wilder.et al.Ecto-5'-nucleotidase (CD73)-mediated extracellular adenosine production plays a critical role in hepatic fibrosis. FASEB J.2008,22:2263-2272.
[9]周馨,李宣海,李定国.库普弗细胞与肝纤维化.世界华人消化杂志.2002,10(1)：65-68.
[10]Hitoshi Ikeda, Naoko Watanabe, Isao Ishii.et al. Sphingosine 1-phosphate regulates regeneration and fibrosis after liver injury via sphingosine 1-phosphate receptor 2. J. Lipid Res..2009.50:556-564.
[11]钱燕,范建高,郑晓英.己酮可可碱对高脂饮食大鼠脂肪性肝炎并肝纤维化的干预作用.肝脏.2005，10(2)：136-137
[12]Juan A. Pineda.Juan Macias. Progression of liver fibrosis in patients coinfected with hepatitis C virus and human immunodeficiency virus undergoing antiretroviral therapy. J. Antimicrob. Chemother..,2005,55:417-419.
[13]Lauren N. Bell, Lydia Lee, Romil Saxena,et al. Serum proteomic analysis of diet-induced steatohepatitis and metabolic syndrome in the Ossabaw miniature swine. Am J Physiol Gastrointest Liver Physiol,2010,298:G746-G754.
[14]郑伟达,王小众.基质金属蛋白酶及其抑制物与实验性肝纤维化.世界华人消化杂志2004,12(2)：428-431.
[15]Takeshi Nara, Kyoichi Iizumi, Hiroshi Ohmae,et al.Candidate for schistosomiasis, and their correlations with resistance and fibrosis in patients infected with schistosoma japonicum in leyte, the philippines. Am J Trop Med Hyg,2007,76:384-391.
[16]J Macias, J A Giron-Gonzalez, M Gonzalez-Serrano,et al. Prediction of liver fibrosis in human immunodeficiency virus/hepatitis C virus coinfected patients by simple non-invasive indexes. Gut, 2006,55:409-414.
[17]Miguel Marcos, Isabel Pastor, Rogelio GonzAlez-Sarmiento,et al. Interleukin-10 Gene Polymorphism is Associated with Alcoholism but not With Alcoholic Liver Disease. Alcohol Alcohol., Sep 2008,43:523-528.
[18]G Svegliati-Baroni, E Bugianesi, T Bouserhal,et al. Post-load insulin resistance is an independent predictor of hepatic fibrosis in virus C chronic hepatitis and in non-alcoholic fatty liver disease. Gut,2007,56:1296-1301.
[19]Michelle S. Hsiang, Elizabeth J. Carlton, Yi Zhang.et al. Use of Ultrasonography to Evaluate Schistosoma japonicum-Related Morbidity in Children, Sichuan Province, China,2000-2007.Am J Trop Med Hyg,2010,82:103-111.
[20]Nobuyuki Tamaki, Etsuro Hatano, Kojiro Taura.et al. CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury. Am J Physiol Gastrointest Liver Physiol,2008,294:G498-G505.
[21]Chun-Nan Yeh,Anirban Maitra, Kam-Fai Lee,et al. Thioacetamide-induced intestinal-typecholangiocarcinoma in rat:an animal model recapitulating the multi-stage progression of human cholangiocarcinoma. Carcinogenesis, Apr 2004,25:631-636.
[22]Yucel Ustundag, Banu Bilezikci, Sedat Boyacioglu.et al. The utility of AST/ALT ratio as a non-invasive demonstration of the degree of liver fibrosis in chronic HCV patients on long-term haemodialysis. Nephrol. Dial. Transplant.,2000,15:1716-1717.
[23]C Beyeler, J Reichen. SR Thomann.et al. Quantitative liver function in patients with rheumatoid arthritis treated with low-dose methotrexat:a longitudinal study.Rheumatology,1997,36:338-344.
[24]Eric R. Lemmer, Pauline de la Motte Hall, Nobuhiko Omori,et al. Histopathology and gene expression changes in rat liver during feeding of fumonisin Bl, a carcinogenic mycotoxin produced by Fusarium moniliforme.Carcinogenesis,1999,20:817-824.
[25]Yasushi Ohmachi, Wataru Toriumi, Kohki Takashima,et al. Systemic Histopathology of Rats Treated with 6-Sulfanilamidoindazole, a Novel Arthritogenic Sulfonamide. Toxicol Pathol. Mar 1998,26:262-270.
[26]刘晓强,周海中,吴靖珍.肝病患者血清HA、PC-Ⅲ、C-Ⅳ、LN测定的临床意义[J].实用临床医药杂志,2009,13(6)：40-42.
[1]Friedman SL. Seminars in medicine of the Beth Israel Hosp ital.Boston. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies.N Engl J Med,1993,328 (25):1828 1835.
[2]Guo J, Friedman SL. Hepatic fibrogenesis. Semin LiverDis,2007,27 (4):413-426.
[3]Suskind DL,MuenchMO. Searching for common stem cells of the hepatic and hematopoietic systems in the human fetal live:CD34+cytokeratin7/8+cells exp ressmarkers for stellate cells. J Hepatol,2004,40 (2):261-268.
[4]Asahina K, Tsai SY,Li P, et al. Mesenchymal origin of hepatic stellate cells, submesothelial cells, and perivascularmesenchymal cells duringmouse liver development. Hepatology,2009,49 (3):98-1011.
[5]Baba S, Fujii H, Hirose T, et al. Commitment of bone marrow cells to hepatic stellate cells in mouse. J Hepatol,2004,40 (2):255-260.
[6]陈在忠，王红.川芎嗪抗肝纤维化作用的实验研究.中西医结合肝病杂志，1997,7：156.
[7]刘增全.川芎嗪刘大鼠肝细胞凋亡的影响.中西医结合肝病杂志,2004,14(5)：281-283.
[8]刘梁英,李孝生,万晓强.川芎嗪和大黄酸对肝细胞增殖和凋亡的影响.中华肝病杂志,2006,14(3)：219-221
[9]Lin Y L, Wu C H,Luo M H, et al. In vitro protective effects of salvianolic acid B on primary hepatocytes and hepatic stellate cells.Journal of Ethnopharmacology,2006.105(1-2):215-22.
[10]Park E J, Zhao Y Z, Kim Y C, et al. PF2401-SF, standardized fraction of Sal via miltiorrhiza and its constituents, tanshinone I.tanshinone IIA, and cryptotans-hine, protect primary cultured rat hepatocytes from bile acid induced apoptosis by inhibiting JNK phosphorylation. Food Chem Toxicol,2007,45(10):1891-1898
[11]Oh SH, Nan J X. Salvia miltiorrhiza inhibits biliary obstruction-induced hepatocyte apoptosis by cytoplasmic sequestration of p53.Toxicology and applied pharmacology,2002,182(1):27-33
[12]国家药典委员会.中华人民共和国药典(一部)[S].北京：化学工业出版社，2000：110.
[13]Zheng QA.Li HZ,Zhang YJ.et al. Dracaenogenins A and B.new spirostanols from the red resin of Dracaena cochinchinensis[J].Steroids.2006,71 (2):160.
[14]孙晓博,金描真,李雪,等.龙血竭中龙血素A与龙血素B在大鼠体内的组织分布研究[J].广东 药学院学报,2008,6；24(3)：214-216
[15]闫波,陈飞虎,吴繁荣.鬼针草总黄酮对肝纤维化大鼠治疗作用及机制探讨[J]中国药理学通报,2008,12；24(12)：1640—1645
[16]聂莉,程德云,朱刚艳.龙血竭对肺纤维化大鼠肺组织转化生长因子β1 mRNA及I型胶原蛋白表达的影响[J].河北中医,,2010,7132(7)：1071-1072.
[17]彭伟,范红,宋正己.龙血素B对实验性肝纤维化的干预作用及机制[J].中华消化杂志,2010,230(2)：129-130.
[18]刘晓强,周海中,吴靖珍.肝病患者血清HA、PC-Ⅲ、C-Ⅳ、LN测定的临床意义[J].实用临床医药杂志,2009,13(6)：40-42.
[19]陈永生.脂肪肝患者色素上皮衍生因子(PEDF)、血管内皮生长因子(VEGF)及结缔组织生长因子(CTGF)表达的相关性研究.[J]现代检验医学杂志2010：25(1)58-62,
[20]倪效,燕敏.VEGF受体功能研究进展[J].生命科学,2006,20：26-28.
[21]Y[oshiji H;Kuriyama S;Yoshii J;Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis.[J]Gut.2003:52(9):1347-1354.
[22]Klagsbrun M,Takashima S,Mamluk R.The role of neuropilin in vascular and tumor biology[J].Adv Exp Med Biol,2002,515:33-48.
[23]张佳,张速勤,董频.喉鳞癌组织中NRP-1、VEGF的表达变化及意义[J]山东医药.2010：50(8)94-95.
[24]郭水英,伍钢,李贵玲,裸鼠肺癌移植瘤中NRP-1的表达及其意义[J].临床肿瘤学杂志.2006：11(8)567-569.
[25]Whitaker GB, Limberg BJ, Rosenbaum JS. Vascular endothelial growth receptor-2 and neuropilin-1 form a receptor complex that is responsible for the differential signaling potency of VEGF 165 and VEGF121. J Biol Chem 200;276:25520-31.
[26]Fong GH. Mechanisms of adaptive angiogenesis to tissue hypoxia Angiogenesis.2008,11: 121-140.
[27]吕靖,陆雄,陶艳艳，等.肝纤维化小鼠肝组织血管新生特点及其形成机制.[J]肝脏,2011,16(1)：35-40
[28]Corpechot C,Barbu V,Wendum D.et al. Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis. Hepatoiogy.2002; 35: 1010-1021.
[29]Semenza GL. Life with oxygen[J]. Science,2007,318:62-64.
[1]Medina J, Arroyo AG, Sanchez-Madrid F,et al. Angiogenesis in Chronic Inflammatory Liver Disease. Hepatology,2004,39:1185-1195.
[2]Vanheule E, Geerts AM, Van Huysse J,et al. An intravital microscopic study of the hepatic microcirculation in cirrhotic mice models relationship between fibrosis and angiogenesis. Int J Exp Pathol,2008,89(6):419-432.
[3]Fernandez M, Semela D, Bruix J,et al. Angiogenesis in liver disease. J Hepatol.2009,50(3): 604-620.
[4]Bataller R, Brenner D A. Liver fibrosis. The Journal of Clinical Investigation.2005,115: 208-218.
[5]Semenza GL. Life with oxygen[J]. Science,2007,318:62-64.
[6]Liu Y, Lui EL, Friedman SL, et al. PTK787/ZK22258 attenuates stellate cell activation and hepatic fibrosis in vivo by inhibiting VEGF signaling. Lab Invest,2009,89(2):209-221.
[7]Jaroszewicz J, Januszkiewicz M, Flisiak R,et al. Circulating vascular endothelial growth factor and its soluble receptors in patients with liver cirrhosis:possible association with hepatic function impairment. Cytokine,2008,44(1):14-17.
[8]Yoshiji H, Kuriyama S, Yoshii J,et al. Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis. GUT,2003,52:1347-1352.
[9]Medinal J, Sanz-Camenol P, Garci'a-Bueyl L.et al. Evidence of angiogenesis in primary biliary cirrhosis:an immunohistochemical descriptive study. Journal of Hepatology,2005,42:124-131.
[10]Tugues S, Fernandez-Varo G, Luque J M,et al. Antiangiogenic Treatment with Sunitinib Ameliorates Inflammatory Infiltrate, Fibrosis, and Portal Pressure in Cirrhotic Rats. Hepatology, 2007,46:1919-1926
[11]Mejias M, Garcia-Pras E, Tiani C,et al. Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats. Hepatology. 2008,25.
[12]陈永生脂肪肝患者色素上皮衍生因子(PEDF)、血管内皮生长因子(VEGF)及结缔组织生长因子(CTGF)表达的相关性研究.[J]现代检验医学杂志2010；(25)1 58-62.
[13]Yao Y.Pan Y,Chen J.et al. Endoglin (CD 105) expression in angiogenesis of primary hepatocellular carcinomas:analysis using tissue microarrays and comparisons with CD34 and VEGF [J]Ann Clin Lab Sci 2007;37:39-48.
[14]Ho JW, Poon RT, Sun CK,et al. Clinicopathological and prognostic implications of endoglin (CD105) expression in hepatocellular carcinoma and its adjacent non-tumorous liver[J] Word J Gastroenterol 2005; 11:176-181
[15]黄世杰血管新生的生物学：最重要的分子机制[J].国际药学研究杂志.2008；2(35)1：65-67
[16]Benetti A:Berenzi A; Gambarotti M Transforming growth factor-betal and CD 105 promote the migration of hepatocellular carcinoma-derived endothelium. [J] Cancer Res 2008;68:(20) 8626-8634
[17]Cross MJ.Lu L,Magnusson P,et al.The Shb adaptor protein binds to tyrosine 766 in the FGFR-1 and regulates the Ras/MEK/MAPK pathway via FRS2 phosphorylation in endothelial cells [J].Mol Biol Cell,2002,13(8):2881-2893.
[18]K Sugimachi, S Tanaka.K Taguchi et al. Angiopoietin switching regulates angiogenesis and Progression of human hepatocellular carcinoma [J]Clin Pathol 2003:56:854-860.
[19]董玲,孙剑勇,杜施霖.等.基因芯片研究甘草酸对大鼠肝星状细胞转化生长因子-β信号通路的影响[J].中华消化杂志，,2006，26(3)：594-597.
[20]张蔷.林勇.CTGF在低氧性肺血管重建中的作用[J].东南大学学报.2005,246：395-398.
[2]Bataller R.Brenner D A. Liver fibrosis. The Journal of Clinical Investigation.2005,115: 208-218.
[3]Medina J,Arroyo AG,Sanchez-Madrid F,et al. Angiogenesis in Chronic Inflammatory Liver Disease. Hepatology,2004,39:1185-1195.
[4]Vanheule E,Geerts AM,Van Huysse J,et al. An intravital microscopic study of the hepatic microcirculation in cirrhotic mice models:relationship between fibrosis and angiogenesis. Int J Exp Pathol,2008,89(6):419-432.
[5]Fernandez M,Semela D,Bruix J,et al. Angiogenesis in liver disease. J Hepatol.2009,50(3): 604-620.
[6]Medina J, Caveda L, Sanz-Cameno P,et al. Hepatocyte growth factor activates endothelial proangiogenic mechanisms relevant in chronic hepatitis C-associated neoangiogenesis. Journal of Hepatology,2003,38:660-667.
[7]Liu Y, Lui EL, Friedman SL,et al. PTK787/ZK22258 attenuates stellate cell activation and hepatic fibrosis in vivo by inhibiting VEGF signaling. Lab Invest,2009,89(2):209-221.
[8]Jaroszewicz J, Januszkiewicz M, Flisiak R.et al. Circulating vascular endothelial growth factor and its soluble receptors in patients with liver cirrhosis:possible association with hepatic function impairment. Cytokine.2008,44(1):14-17.
[9]Yoshiji H, Kuriyama S, Yoshii J.et al. Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis. GUT,2003,52:1347-1352.
[10]Medinal J, Sanz-Camenol P, Garci'a-Bueyl L,et al. Evidence of angiogenesis in primary biliary cirrhosis:an immunohistochemical descriptive study. Journal of Hepatology,2005, 42:124-131.
[11]Tugues S, Fernandez-Varo G, Luque J M,et al. Antiangiogenic Treatment with Sunitinib Ameliorates Inflammatory Infiltrate, Fibrosis,and Portal Pressure in Cirrhotic Rats. Hepatology, 2007,46:1919-1926
[12]Mejias M, Garcia-Pras E, Tiani C.et al. Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats. Hepatology.2008,25. [Epub ahead of print
[13]Watanabe N.Takashimizu S,Nishizaki Y et al.An endothelin A receptor antagonist induces dilatation of sinusoidal endothelial fenestrae.implications for endothelin-1 in hepatic microcirculation.J Gastroenter01.2007.42:775.782.
[14]Semenza GL.Life with oxygen[J].Science.2007.318:62-64.
[15]伺书平,血竭的药理研究中国药房,2008，19(24)1912-1913.
[16]聂莉,郑碧霞,程德云等.龙血竭对肺纤维化大鼠肺组织TGF-β/Smads信号通路分了mRNA表达的影响四川大学学报(医学版)，2007，38(5)：802-805.
[17]张培华,罗少军,汤少明等.血竭素对瘢痕成纤维细胞胶原合成的影响中国美容医学.2006，15(6)624-626.
[18]张培华,罗少军,肖佐环等.血竭素高氯酸盐促进瘢痕成纤维细胞凋亡的作用中国皮肤性病学杂志,2006,20(6)338-340.
[1]邓家刚,黄海滨,农毅清.龙血素B的药效学实验研究[J].广西中医药,2004,2；27(1)：44-46
[2]方伟蓉,李运曼,邓嘉元.龙血竭总黄酮对动物心肌缺血的保护作用[J].中国临床药理学与治疗学，20059；10(9)：1020-1023
[3]Azuma Watanabe, Muhammad Adnan Sohail, Dawidson Assis Gomes.et al.Inflammasome mediated regulation of hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol,2009,296: G1248-G1257
[4]Hitoshi Yoshiji, Ryuichi Noguchi, Shigeki Kuriyama.etal. lmatinib mesylate (STI-571) attenuates liver fibrosis development in rats. Am J Physiol Gastrointest Liver Physiol,2005,288:G907-G913.
[5]S. Wallace, T. Blanchard, L. Rabin.et al. Ductal Plate Malformation in a Nonhuman Primate. Veterinary Pathology,2009; 46:84-87.
[6]Bachir Taouli, Anuj J. Tolia, Mariela Losada,et al.Diffusion-Weighted MR1 for Quantification of Liver Fibrosis:reliminary Experience. Am. J. Roentgenol.,2007,189:799-806.
[7]Claudia von Montfort, Juliane I. Beier, J. Phillip Kaiser.et al. PAI-1 plays a protective role in CCl4-induced hepatic fibrosis in mice:role of hepatocyte division. Am J Physiol Gastrointest Liver Physiol,2010,298:G657-G666.
[8]Zhongsheng Peng.Patricia Fernandez,Tuere Wilder.et al.Ecto-5'-nucleotidase (CD73)-mediated extracellular adenosine production plays a critical role in hepatic fibrosis. FASEB J.2008,22:2263-2272.
[9]周馨,李宣海,李定国.库普弗细胞与肝纤维化.世界华人消化杂志.2002,10(1)：65-68.
[10]Hitoshi Ikeda, Naoko Watanabe, Isao Ishii.et al. Sphingosine 1-phosphate regulates regeneration and fibrosis after liver injury via sphingosine 1-phosphate receptor 2. J. Lipid Res..2009.50:556-564.
[11]钱燕,范建高,郑晓英.己酮可可碱对高脂饮食大鼠脂肪性肝炎并肝纤维化的干预作用.肝脏.2005，10(2)：136-137
[12]Juan A. Pineda.Juan Macias. Progression of liver fibrosis in patients coinfected with hepatitis C virus and human immunodeficiency virus undergoing antiretroviral therapy. J. Antimicrob. Chemother..,2005,55:417-419.
[13]Lauren N. Bell, Lydia Lee, Romil Saxena,et al. Serum proteomic analysis of diet-induced steatohepatitis and metabolic syndrome in the Ossabaw miniature swine. Am J Physiol Gastrointest Liver Physiol,2010,298:G746-G754.
[14]郑伟达,王小众.基质金属蛋白酶及其抑制物与实验性肝纤维化.世界华人消化杂志2004,12(2)：428-431.
[15]Takeshi Nara, Kyoichi Iizumi, Hiroshi Ohmae,et al.Candidate for schistosomiasis, and their correlations with resistance and fibrosis in patients infected with schistosoma japonicum in leyte, the philippines. Am J Trop Med Hyg,2007,76:384-391.
[16]J Macias, J A Giron-Gonzalez, M Gonzalez-Serrano,et al. Prediction of liver fibrosis in human immunodeficiency virus/hepatitis C virus coinfected patients by simple non-invasive indexes. Gut, 2006,55:409-414.
[17]Miguel Marcos, Isabel Pastor, Rogelio GonzAlez-Sarmiento,et al. Interleukin-10 Gene Polymorphism is Associated with Alcoholism but not With Alcoholic Liver Disease. Alcohol Alcohol., Sep 2008,43:523-528.
[18]G Svegliati-Baroni, E Bugianesi, T Bouserhal,et al. Post-load insulin resistance is an independent predictor of hepatic fibrosis in virus C chronic hepatitis and in non-alcoholic fatty liver disease. Gut,2007,56:1296-1301.
[19]Michelle S. Hsiang, Elizabeth J. Carlton, Yi Zhang.et al. Use of Ultrasonography to Evaluate Schistosoma japonicum-Related Morbidity in Children, Sichuan Province, China,2000-2007.Am J Trop Med Hyg,2010,82:103-111.
[20]Nobuyuki Tamaki, Etsuro Hatano, Kojiro Taura.et al. CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury. Am J Physiol Gastrointest Liver Physiol,2008,294:G498-G505.
[21]Chun-Nan Yeh,Anirban Maitra, Kam-Fai Lee,et al. Thioacetamide-induced intestinal-typecholangiocarcinoma in rat:an animal model recapitulating the multi-stage progression of human cholangiocarcinoma. Carcinogenesis, Apr 2004,25:631-636.
[22]Yucel Ustundag, Banu Bilezikci, Sedat Boyacioglu.et al. The utility of AST/ALT ratio as a non-invasive demonstration of the degree of liver fibrosis in chronic HCV patients on long-term haemodialysis. Nephrol. Dial. Transplant.,2000,15:1716-1717.
[23]C Beyeler, J Reichen. SR Thomann.et al. Quantitative liver function in patients with rheumatoid arthritis treated with low-dose methotrexat:a longitudinal study.Rheumatology,1997,36:338-344.
[24]Eric R. Lemmer, Pauline de la Motte Hall, Nobuhiko Omori,et al. Histopathology and gene expression changes in rat liver during feeding of fumonisin Bl, a carcinogenic mycotoxin produced by Fusarium moniliforme.Carcinogenesis,1999,20:817-824.
[25]Yasushi Ohmachi, Wataru Toriumi, Kohki Takashima,et al. Systemic Histopathology of Rats Treated with 6-Sulfanilamidoindazole, a Novel Arthritogenic Sulfonamide. Toxicol Pathol. Mar 1998,26:262-270.
[26]刘晓强,周海中,吴靖珍.肝病患者血清HA、PC-Ⅲ、C-Ⅳ、LN测定的临床意义[J].实用临床医药杂志,2009,13(6)：40-42.
[1]Friedman SL. Seminars in medicine of the Beth Israel Hosp ital.Boston. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies.N Engl J Med,1993,328 (25):1828 1835.
[2]Guo J, Friedman SL. Hepatic fibrogenesis. Semin LiverDis,2007,27 (4):413-426.
[3]Suskind DL,MuenchMO. Searching for common stem cells of the hepatic and hematopoietic systems in the human fetal live:CD34+cytokeratin7/8+cells exp ressmarkers for stellate cells. J Hepatol,2004,40 (2):261-268.
[4]Asahina K, Tsai SY,Li P, et al. Mesenchymal origin of hepatic stellate cells, submesothelial cells, and perivascularmesenchymal cells duringmouse liver development. Hepatology,2009,49 (3):98-1011.
[5]Baba S, Fujii H, Hirose T, et al. Commitment of bone marrow cells to hepatic stellate cells in mouse. J Hepatol,2004,40 (2):255-260.
[6]陈在忠，王红.川芎嗪抗肝纤维化作用的实验研究.中西医结合肝病杂志，1997,7：156.
[7]刘增全.川芎嗪刘大鼠肝细胞凋亡的影响.中西医结合肝病杂志,2004,14(5)：281-283.
[8]刘梁英,李孝生,万晓强.川芎嗪和大黄酸对肝细胞增殖和凋亡的影响.中华肝病杂志,2006,14(3)：219-221
[9]Lin Y L, Wu C H,Luo M H, et al. In vitro protective effects of salvianolic acid B on primary hepatocytes and hepatic stellate cells.Journal of Ethnopharmacology,2006.105(1-2):215-22.
[10]Park E J, Zhao Y Z, Kim Y C, et al. PF2401-SF, standardized fraction of Sal via miltiorrhiza and its constituents, tanshinone I.tanshinone IIA, and cryptotans-hine, protect primary cultured rat hepatocytes from bile acid induced apoptosis by inhibiting JNK phosphorylation. Food Chem Toxicol,2007,45(10):1891-1898
[11]Oh SH, Nan J X. Salvia miltiorrhiza inhibits biliary obstruction-induced hepatocyte apoptosis by cytoplasmic sequestration of p53.Toxicology and applied pharmacology,2002,182(1):27-33
[12]国家药典委员会.中华人民共和国药典(一部)[S].北京：化学工业出版社，2000：110.
[13]Zheng QA.Li HZ,Zhang YJ.et al. Dracaenogenins A and B.new spirostanols from the red resin of Dracaena cochinchinensis[J].Steroids.2006,71 (2):160.
[14]孙晓博,金描真,李雪,等.龙血竭中龙血素A与龙血素B在大鼠体内的组织分布研究[J].广东 药学院学报,2008,6；24(3)：214-216
[15]闫波,陈飞虎,吴繁荣.鬼针草总黄酮对肝纤维化大鼠治疗作用及机制探讨[J]中国药理学通报,2008,12；24(12)：1640—1645
[16]聂莉,程德云,朱刚艳.龙血竭对肺纤维化大鼠肺组织转化生长因子β1 mRNA及I型胶原蛋白表达的影响[J].河北中医,,2010,7132(7)：1071-1072.
[17]彭伟,范红,宋正己.龙血素B对实验性肝纤维化的干预作用及机制[J].中华消化杂志,2010,230(2)：129-130.
[18]刘晓强,周海中,吴靖珍.肝病患者血清HA、PC-Ⅲ、C-Ⅳ、LN测定的临床意义[J].实用临床医药杂志,2009,13(6)：40-42.
[19]陈永生.脂肪肝患者色素上皮衍生因子(PEDF)、血管内皮生长因子(VEGF)及结缔组织生长因子(CTGF)表达的相关性研究.[J]现代检验医学杂志2010：25(1)58-62,
[20]倪效,燕敏.VEGF受体功能研究进展[J].生命科学,2006,20：26-28.
[21]Y[oshiji H;Kuriyama S;Yoshii J;Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis.[J]Gut.2003:52(9):1347-1354.
[22]Klagsbrun M,Takashima S,Mamluk R.The role of neuropilin in vascular and tumor biology[J].Adv Exp Med Biol,2002,515:33-48.
[23]张佳,张速勤,董频.喉鳞癌组织中NRP-1、VEGF的表达变化及意义[J]山东医药.2010：50(8)94-95.
[24]郭水英,伍钢,李贵玲,裸鼠肺癌移植瘤中NRP-1的表达及其意义[J].临床肿瘤学杂志.2006：11(8)567-569.
[25]Whitaker GB, Limberg BJ, Rosenbaum JS. Vascular endothelial growth receptor-2 and neuropilin-1 form a receptor complex that is responsible for the differential signaling potency of VEGF 165 and VEGF121. J Biol Chem 200;276:25520-31.
[26]Fong GH. Mechanisms of adaptive angiogenesis to tissue hypoxia Angiogenesis.2008,11: 121-140.
[27]吕靖,陆雄,陶艳艳，等.肝纤维化小鼠肝组织血管新生特点及其形成机制.[J]肝脏,2011,16(1)：35-40
[28]Corpechot C,Barbu V,Wendum D.et al. Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis. Hepatoiogy.2002; 35: 1010-1021.
[29]Semenza GL. Life with oxygen[J]. Science,2007,318:62-64.
[1]Medina J, Arroyo AG, Sanchez-Madrid F,et al. Angiogenesis in Chronic Inflammatory Liver Disease. Hepatology,2004,39:1185-1195.
[2]Vanheule E, Geerts AM, Van Huysse J,et al. An intravital microscopic study of the hepatic microcirculation in cirrhotic mice models relationship between fibrosis and angiogenesis. Int J Exp Pathol,2008,89(6):419-432.
[3]Fernandez M, Semela D, Bruix J,et al. Angiogenesis in liver disease. J Hepatol.2009,50(3): 604-620.
[4]Bataller R, Brenner D A. Liver fibrosis. The Journal of Clinical Investigation.2005,115: 208-218.
[5]Semenza GL. Life with oxygen[J]. Science,2007,318:62-64.
[6]Liu Y, Lui EL, Friedman SL, et al. PTK787/ZK22258 attenuates stellate cell activation and hepatic fibrosis in vivo by inhibiting VEGF signaling. Lab Invest,2009,89(2):209-221.
[7]Jaroszewicz J, Januszkiewicz M, Flisiak R,et al. Circulating vascular endothelial growth factor and its soluble receptors in patients with liver cirrhosis:possible association with hepatic function impairment. Cytokine,2008,44(1):14-17.
[8]Yoshiji H, Kuriyama S, Yoshii J,et al. Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis. GUT,2003,52:1347-1352.
[9]Medinal J, Sanz-Camenol P, Garci'a-Bueyl L.et al. Evidence of angiogenesis in primary biliary cirrhosis:an immunohistochemical descriptive study. Journal of Hepatology,2005,42:124-131.
[10]Tugues S, Fernandez-Varo G, Luque J M,et al. Antiangiogenic Treatment with Sunitinib Ameliorates Inflammatory Infiltrate, Fibrosis, and Portal Pressure in Cirrhotic Rats. Hepatology, 2007,46:1919-1926
[11]Mejias M, Garcia-Pras E, Tiani C,et al. Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats. Hepatology. 2008,25.
[12]陈永生脂肪肝患者色素上皮衍生因子(PEDF)、血管内皮生长因子(VEGF)及结缔组织生长因子(CTGF)表达的相关性研究.[J]现代检验医学杂志2010；(25)1 58-62.
[13]Yao Y.Pan Y,Chen J.et al. Endoglin (CD 105) expression in angiogenesis of primary hepatocellular carcinomas:analysis using tissue microarrays and comparisons with CD34 and VEGF [J]Ann Clin Lab Sci 2007;37:39-48.
[14]Ho JW, Poon RT, Sun CK,et al. Clinicopathological and prognostic implications of endoglin (CD105) expression in hepatocellular carcinoma and its adjacent non-tumorous liver[J] Word J Gastroenterol 2005; 11:176-181
[15]黄世杰血管新生的生物学：最重要的分子机制[J].国际药学研究杂志.2008；2(35)1：65-67
[16]Benetti A:Berenzi A; Gambarotti M Transforming growth factor-betal and CD 105 promote the migration of hepatocellular carcinoma-derived endothelium. [J] Cancer Res 2008;68:(20) 8626-8634
[17]Cross MJ.Lu L,Magnusson P,et al.The Shb adaptor protein binds to tyrosine 766 in the FGFR-1 and regulates the Ras/MEK/MAPK pathway via FRS2 phosphorylation in endothelial cells [J].Mol Biol Cell,2002,13(8):2881-2893.
[18]K Sugimachi, S Tanaka.K Taguchi et al. Angiopoietin switching regulates angiogenesis and Progression of human hepatocellular carcinoma [J]Clin Pathol 2003:56:854-860.
[19]董玲,孙剑勇,杜施霖.等.基因芯片研究甘草酸对大鼠肝星状细胞转化生长因子-β信号通路的影响[J].中华消化杂志，,2006，26(3)：594-597.
[20]张蔷.林勇.CTGF在低氧性肺血管重建中的作用[J].东南大学学报.2005,246：395-398.