Effect and Mechanism of Cyclopamine in Reduction of Portal Venous Pressure in Rats with Liver Cirrhosis_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

WU Yu ¹ , LI Xiangnong. ²

1. Xuzhou Medical College, Xuzhou 221002, Jiangsu Province, China;;
2. Department of General Surgery, The Affiliated Hospital of Xuzhou Medical College, Xuzhou 221002, Jiangsu Province, China;

Corresponding author：

Keywords：

Liver cirrhosis; Cyclopamine; Portal venous pressure; Alpha-smooth muscle actin; TypeⅠ collagen alpha 1; SD rat

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Objective 　To explore the effect of cyclopamine （Cyc） which is the inhibitor of the Hedgehog signaling pathway on portal venous pressure of normal and liver cirrhosis rats, and it’s possible mechanisms. Moreover, to provide the experimental basis of drug efficacy and clinical treatment.
Methods 　Thirty two healthy male SD rats were randomly average divided into four groups：normal control group, normal treatment group, liver cirrhosis control group, and liver cirrhosis treatment group. The liver cirrhosis models of rat were established by using the thioacetamide （TAA） method, which made 0.03% of TAA as the initial water concentration, and then the concentration of TAA in drinking water was adjusted according to the changes of the weekly body weight of rats lasting for twelve weeks. In thirteenth week, intraperitoneal injection of corn oil （0.1 ml/100 g body weight, 1 time/d） were performed lasting for a week in rats of the normal control group and liver cirrhosis control group; intraperitoneal injection of Cyc 〔1 mg （0.1 ml）/100 g body weight, 1 time/d〕were performed lasting for a week in rats of the normal treatment group and liver cirrhosis treatment group. In fourteenth week, the liver function, portal venous pressure （PVP）, and the ration of liver or spleen weight to body weight were detected, the expressions of α-smooth muscle actin （α-SMA） and typeⅠcollagen α1 （Col1α1） of hepatic stellate cell were detected by using immunohistochemistry.
Results 　PVP were （10.7±0.9） and （12.3±1.3） cm H2O （1 cm H2O=0.098 kPa） in normal control group and normal treatment group, respectivly, the latter was higher than the former （t=-2.918，P=0.011）. PVP were （21.8±0.7） and （14.3±1.4） cm H2O in liver cirrhosis control group and liver cirrhosis treatment group, respectivly, the latter was lower than the former（t=13.602，P=0.000）. The expressions of α-SMA and Col1α1 in liver cirrhosis treatment group was lower than the liver cirrhosis control group. There were no significant difference of the liver function and ration of liver or spleen weight to body weight between the treatment group and the control group （P＞0.05）.
Conclusion 　Cyclopamine could signally reduce the PVP of liver cirrhosis rats through reducing the expressions of α-SMA and Col1α1.

Citation： WU Yu,LI Xiangnong.. Effect and Mechanism of Cyclopamine in Reduction of Portal Venous Pressure in Rats with Liver Cirrhosis. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2012, 19(7): 733-738. doi: Copy

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14.	张春清，主余华，王京，等. 银杏叶提取物对肝硬化大鼠门静脉压及肝窦病理变化的影响 [J]. 中华肝脏病杂志， 2007，15(4)：245-248.
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24.	郭传勇. 核转录因子Gli 在肝纤维化发病机制中的作用 [J].同济大学学报， 2008， 29(5)：4-6.
25.	刘平，王晓玲，刘成海，等. 虫草菌丝和丹参对肝星状细胞活化、Ⅰ型胶原及转化生长因子β1 mRNA 与蛋白表达的影响 [J]. 中华肝脏病杂志， 1999， 7(Suppl)：24-26.

1. 顾燕萍，高军，李兆申. Gli 在HH 信号通路中作用机制及在肿瘤治疗中的应用前景 [J]. 第二军医大学学报， 2007， 28(1)：98-100.
2. Basset-Seguin N， Soufir N. Patched/Sonic Hedgehog pathway and basal cell carcinoma [J]. Med Sci (Paris)， 2004， 20(10)：899-903.
3. Watkins DN， Berman DM， Burkholder SG， et al. Hedgehog signaling within airway epithelial progenitors and in small-cell lung cancer [J]. Nature， 2003， 422(6929)：313-317.
4. Katano M. Hedgehog signaling pathway as a therapeutic target in breast cancer [J]. Cancer Lett， 2005， 227(2)：99-104.
5. Sanchez P， Clement V， Ruzi Altaba A. Therapeutic targeting of the hedgehog-GLI pathway in prostate cancer [J]. Cancer Res，2005， 65(8)：2990-2992.
6. Berman DM， Karhadkar SS， Maitra A， et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours [J]. Nature， 2003， 425(6960)：846-851.
7. Sicklick JK， Li YX， Jayaraman A， et al. Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis [J]. Carcinogenesis，2006， 27(4)：748-757.
8. Choi SS， Omenetti A， Witek RP， et al. Hedgehog pathway activation and epithelial-to-mesenchymal transitions during myofibroblastic transformation of rat hepatic cells in culture and cirrhosis [J]. Am J Physiol Gastrointest Liver Physiol， 2009， 297(6)：G1093- G1106.
9. Taipale J， Beachy PA. The Hedgehog and Wnt signalling pathways in cancer [J]. Nature， 2001， 411(6835)：349-354.
10. 郭小华，刘鹰翔. Hedgehog 信号传导途径抑制剂的研究发展 [J]. 中国药物化学杂志， 2010， 20(5)：414-425.
11. Chen JK， Taipale J， Cooper MK， et al. Inhibition of Hedgehog signaling by direct binding of cyclopamine to smoothened [J].Genes Dev， 2002， 16(21)：2743-2748.
12. 李向农. 体重监测下使用硫代乙酰胺诱导大鼠肝硬化模型 [J]. 中华普通外科杂志， 2004， 19(4)：239-241.
13. Sicklick JK， Li YX， Choi SS， et al. Role for hedgehog signalingin hepatic stellate cell activation and viability [J]. Lab Invest，2005， 85(11)：1368-1380.
14. 张春清，主余华，王京，等. 银杏叶提取物对肝硬化大鼠门静脉压及肝窦病理变化的影响 [J]. 中华肝脏病杂志， 2007，15(4)：245-248.
15. 郑艳华，王建彬. 肝星状细胞的凋亡与肝纤维化的研究进展 [J]. 现代中西医结合杂志， 2011， 20(6)：772-773.
16. 刘珺，郭传勇. 肝星状细胞活化及其作用研究进展 [J]. 中国医师杂志， 2008， 10(1)：140-142.
17. Sato M， Suzuki S， Senoo H. Hepatic stellate cells：unique characteristics in cell biology and phenotype [J]. Cell Struct Funct，2003， 28(2)：105-112.
18. 方瑜洁，苌新明. 高血糖对肝纤维化大鼠肝组织α-SMA 和CTGF 表达的影响 [J]. 中国现代医药杂志， 2009， 11(7)：1-4.
19. Cheng JH， She H， Han YP， et al. Wnt antagonism inhibits hepatic tellate cell activation and liver fibrosis [J]. Am J Physiol Gastrointest Liver Physiol， 2008， 294(1)：G39- G49.
20. Safadi R， Friednman SL. Hepatic fibrosis—— role of hepatic stellate cell activation[ J]. MedGenMed， 2002， 4(3)：27.
21. Chen YW， Wu JX， Chen YW， et al. Tetrandrine inhibits activation of rat hepatic stellate cells in vitro via transforming growth factor-beta signaling [J]. World J Gastroenterol， 2005， 11(19)：2922-2926.
22. 宋明，张忠涛，王宇，等. 复方中药对肝硬化大鼠Ⅰ型胶原mRNA表达的影响 [J] . 山西医科大学学报， 2002， 33(1)：8-9.
23. Inagaki Y， Okazaki I. Emerging insights into transforming growth factor beta smad signal in hepatic fibrogenesis [J]. Gut，2007， 56(2)：284-292.
24. 郭传勇. 核转录因子Gli 在肝纤维化发病机制中的作用 [J].同济大学学报， 2008， 29(5)：4-6.
25. 刘平，王晓玲，刘成海，等. 虫草菌丝和丹参对肝星状细胞活化、Ⅰ型胶原及转化生长因子β1 mRNA 与蛋白表达的影响 [J]. 中华肝脏病杂志， 1999， 7(Suppl)：24-26.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Effect and Mechanism of Cyclopamine in Reduction of Portal Venous Pressure in Rats with Liver Cirrhosis

Abstract Full text Figures/Tables Video References Cited by

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