Yiguanjian decoction and its ingredients inhibit angiogenesis in carbon tetrachloride-induced cirrhosis mice

BMC Complementary and Alternative Medicine

Ping Liu¹  Lie-Ming Xu³  Cheng-Hai Liu¹  Yi-Yang Hu¹  Hua Zhang³  Ming-Yu Sun³  Jia-Mei Chen³  Guang-Li Du²  Bing-Bing Ning³  Wen-Wei Fu³  Yong-Ping Mu³  Ya-Ning Zhou³ 

[1]E-institute of Shanghai Municipal Education Commission, Shanghai 201203, China

[2]Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China

[3]Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China

关键词: Yiguanjian;    Angiogenesis;    Cirrhosis;   

Others  :  1233335
DOI  :  10.1186/s12906-015-0862-6

 received in 2013-08-22, accepted in 2015-09-16,  发布年份 2015

【 摘 要 】

Background

Cirrhosis is associated with angiogenesis and disruption of hepatic vascular architecture. Yiguanjian (YGJ) decoction, a prescription from traditional Chinese medicine, is widely used for treating liver diseases. We studied whether YGJ or its ingredients (iYGJ) had an anti-angiogenic effect and explored possible mechanisms underlying this process.

Methods

Cirrhosis was induced with carbon tetrachloride (CCl ₄ ) (ip) in C57BL/6 mice for 6 weeks. From week 4 to week 6, cirrhotic mice were randomly divided into four groups: sorafenib-treated, YGJ-treated and iYGJ-treated mice and placebo. Serum biochemistries, hydroxyproline (Hyp) content and histopathological changes of hepatic tissues were measured as were α-smooth muscle actin (α-SMA), collagen I, CD31, vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR) 2 and hypoxia-inducible factor (HIF)-1α.

Results

Both YGJ and iYGJ improved serum biochemistries. Changes of histopathology showed that YGJ and iYGJ reduced hepatic tissue necroinflammatory and collagen fiber deposition in cirrhosis mice. Compared to the CCl ₄treated animals, Hyp, α-SMA, collagen I, CD31, VEGF, VEGFR, and HIF-1α expression decreased in YGJ and iYGJ groups.

Conclusions

YGJ and iYGJ inhibited liver angiogenesis in cirrhotic mice treated with CCl ₄by inhibiting the HIF-1α/VEGF signaling pathway, suggesting that anti-angiogenic effects of YGJ and iYGJ are associated with improving the hepatic hypoxic microenvironment.

【 授权许可】

   
2015 Zhou et al.

【 图 表 】

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【 参考文献 】

• [1]Bosch J, Abraldes JG, Fernández M, García-Pagán JC. Hepatic endothelial dysfunction and abnormal angiogenesis: new targets in the treatment of portal hypertension. J Hepatol. 2010; 53(3):558-567.
• [2]Fernández M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J. Angiogenesis in liver disease. J Hepatol. 2009; 50(3):604-620.
• [3]Kajdaniuk D, Marek B, Borgiel-Marek H, Kos-Kudła B. Vascular endothelial growth factor (VEGF) - part 1: in physiology and pathophysiology. Endokrynol Pol. 2011; 62(5):444-455.
• [4]Liu LX, Lu H, Luo Y, Date T, Belanger AJ, Vincent KA et al.. Stabilization of vascular endothelial growth factor mRNA by hypoxia-inducible factor 1. Biochem Biophys Res Commun. 2002; 291(4):908-914.
• [5]Lin HJ, Chen JY, Lin CF, Kao ST, Cheng JC, Chen HL et al.. Hepatoprotective effects of Yi Guan Jian, an herbal medicine, in rats with dimethylnitrosamine-induced liver fibrosis. J Ethnopharmacol. 2011; 134(3):953-960.
• [6]Wang XL, Jia DW, Liu HY, Yan XF, Ye TJ, Hu XD et al.. Effect of Yiguanjian decoction on cell differentiation and proliferation in CCl 4 -treated mice. World J Gastroenterol. 2012; 18(25):3235-3249.
• [7]Mu Y, Liu P, Du G, Du J, Wang G, Long A et al.. Action mechanism of Yi Guan Jian Decoction on CCl4 induced cirrhosis in rats. J Ethnopharmacol. 2009; 121(1):35-42.
• [8]Lin HJ, Tseng CP, Lin CF, Liao MH, Chen CM, Kao ST et al.. A Chinese herbal decoction, modified Yi Guan Jian, induces apoptosis in hepatic stellate cells through an ROS-mediated mitochondrial/caspase pathway. Evid Based Complement Alternat Med. 2011; 2011:459531.
• [9]Hu B, An HM, Shen KP, Xu L, Du Q, Deng S et al.. Modified Yi Guan Jian, a Chinese herbal formula, induces anoikis in Bel-7402 human hepatocarcinoma cells in vitro. Oncol Rep. 2011; 26(6):1465-1470.
• [10]Schnabl B, Kweon YO, Frederick JP, Wang XF, Rippe RA, Brenner DA. The role of Smad3 in mediating mouse hepatic stellate cell activation. Hepatology. 2001; 34(1):89-100.
• [11]Zhou YN, Sun MY, Mu YP, Yang T, Ning BB, Ren S et al.. Xuefuzhuyu Decoction Inhibition of Angiogenesis Attenuates Liver Fibrosis Induced by CCl 4 in Mice. J Ethnopharmacol. 2014; 153(3):659-666.
• [12]Tugues S, Fernandez-Varo G, Munoz-Luque J, Ros J, Arroyo V, Rodés J et al.. Antiangiogenic treatment with sunitinib ameliorates inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats. Hepatology. 2007; 46(6):1919-1926.
• [13]Friedman SL. Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol. 2010; 7(8):425-436.
• [14]Rosmorduc O, Housset C. Hypoxia: A Link between Fibrogenesis, Angiogenesis, and Carcinogenesis in Liver Disease. Semin Liver Dis. 2010; 30(3):258-270.
• [15]Niecknig H, Tug S, Reyes BD, Kirsch M, Fandrey J, Berchner-Pfannschmidt U. Role of reactive oxygen species in the regulation of HIF-1 by prolyl hydroxylase 2 under mild hypoxia. Free Radic Res. 2012; 46(6):705-717.
• [16]Copple BL, Bustamante JJ, Welch TP, Kim ND, Moon JO. Hypoxia-inducible factor-dependent production of profibrotic mediators by hypoxic hepatocytes. Liver Int. 2009; 29(7):1010-1021.
• [17]Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Hicklin DJ et al.. Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis. Gut. 2003; 52(9):1347-1354.
• [18]Zhao YZ, Wang B, Wang TC. Effect of vascular endothelial growth factor in experimental biliary cirrhosis. Chin J Mod Med. 2006; 16:1195-1196.
• [19]Sheng CN, Luo Y, Gao W, Chen WB. Relationship between vascular endothelial growth factor and hepatitis B. J Nanjing Mil Med Coll. 2001; 23:224-226.
• [20]Yan J, Chen W, Ma Y, Sun X. Expression of vascular endothelial growth factor in liver tissues of hepatitis B. Zhonghua Gan Zang Bing Za Zhi. 2000; 8(3):150-152.