Mechanism of action of Xiayuxue decoction in inhibiting liver fibrosis by regulating glial cell line-derived neurotrophic factor

Wei ZHANG; Guangyue YANG; Dongxiao SHEN; Wenting MA; Le TAO; Liu WU; Ping YAN; Cheng LIU

doi:10.3969/j.issn.1001-5256.2021.03.015

Volume 37 Issue 3

Mar. 2021

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Article Navigation > Journal of Clinical Hepatology > 2021 > 37(3): 575-581

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Mechanism of action of Xiayuxue decoction in inhibiting liver fibrosis by regulating glial cell line-derived neurotrophic factor

DOI: 10.3969/j.issn.1001-5256.2021.03.015

a.
Laboratory of Liver Diseases of Experimental Center, Putuo Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
b.
Department of Infectious Diseases, Putuo Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China

Received Date: 2020-09-11
Accepted Date: 2020-11-05
Published Date: 2021-03-20

Abstract

Abstract

Objective To investigate whether Xiayuxue decoction exerts an anti-liver fibrosis effect by inhibiting glial cell line-derived neurotrophic factor (GDNF). Methods A total of 24 C57BL/6 mice were randomly divided into control group, model group, and Xiayuxue decoction group. The mice in the model group and the Xiayuxue decoction group were given intraperitoneal injection of 10% CCl₄, and those in the Xiayuxue decoction group were given 0.4678 g/kg Xiayuxue decoction by gavage since week 4. The liver function parameters alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured, and liver histopathology was observed. Immunohistochemistry was used to measure the protein expression of alpha-smooth muscle actin (α-SMA) and GDNF. GFP-Col-HSC and human primary hepatic stellate cells (HSCs) were treated with GDNF (10 ng/ml), and HSC activation was measured. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t-test was used for further comparison between two groups. Results Compared with the control group, the model group had significant increases in the levels of ALT and AST, and compared with the model group, the Xiayuxue decoction group had significant reductions in the levels of ALT and AST (all P < 0.01). Liver histopathology showed that the model group had marked inflammatory cell infiltration and formation of fibrous septa by proliferated collagen fibers, and the Xiayuxue decoction group had loose fibrous septa and alleviated inflammatory cell infiltration. Immunohistochemistry showed that compared with the control group, the model group had significant increases in the expression of α-SMA and GDNF (both P < 0.01), which were observed in fibrous septa, and compared with the model group, the Xiayuxue decoction group had significant reductions in the expression of α-SMA and GDNF (both P < 0.05). Western blotting showed that the control group had relatively low expression of GDNF in liver tissue, the formation of liver fibrosis at week 6 of CCl₄ modeling, and an around 10-fold increase in the expression of GDNF, and the Xiayuxue decoction group had significantly inhibited protein expression of GDNF (P < 0.01); there were significant increases in the expression of α-SMA and collagen type I α1 (Col1) in mice with liver fibrosis, with significant reductions in α-SMA and Col1 after treatment with Xiayuxue decoction (all P < 0.01). The in vitro experiment showed that GDNF induced the significant increases in the protein expression of α-SMA and Col1 in HSCs, which was significantly inhibited by Xiayuxue decoction (all P < 0.01). Conclusion The expression of GDNF is significantly upregulated in the formation of liver fibrosis. GDNF can induce HSC activation, and Xiayuxue decoction can exert an anti-liver fibrosis effect by inhibiting GDNF.
- Liver Cirrhosis,
- Xia-Yu-Xue Decoction,
- Glial Cell Line-Derived Neurotrophic Factor

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[1]	SCHUMACHER JD, KONG B, WU J, et al. Direct and indirect effects of Fibroblast Growth Factor (FGF)15 and FGF19 on liver fibrosis development[J]. Hepatology, 2020, 71(2): 670-685. DOI: 10.1002/hep.30810
[2]	SHI N, CHEN XL, WU H, et al. Role of hepatic lymphangiogenesis in the progression of liver fibrosis[J]. J Clin Hepatol, 2020, 36(9): 2079-2082. (in Chinese. DOI: 10.3969/j.issn.1001-5256.2020.09.038 石纳, 陈修利, 吴昊, 等. 肝脏淋巴管新生在肝纤维化进展中的作用[J]. 临床肝胆病杂志, 2020, 36(9): 2079-2082. DOI: 10.3969/j.issn.1001-5256.2020.09.038
[3]	XIANG J, ZHANG N, SUN H, et al. Disruption of SIRT7 increases the efficacy of checkpoint inhibitor via MEF2D regulation of programmed cell death 1 ligand 1 in hepatocellular carcinoma cells[J]. Gastroenterology, 2020, 158(3): 664-678. e24. DOI: 10.1053/j.gastro.2019.10.025
[4]	DONNELLY CR, SHAH AA, MISTRETTA CM, et al. Biphasic functions for the GDNF-Ret signaling pathway in chemosensory neuron development and diversification[J]. Proc Natl Acad Sci U S A, 2018, 115(3): e516-e525. DOI: 10.1073/pnas.1708838115
[5]	TAO L, MA W, WU L, et al. Glial cell line-derived neurotrophic factor (GDNF) mediates hepatic stellate cell activation via ALK5/Smad signalling[J]. Gut, 2019, 68(12): 2214-2227. DOI: 10.1136/gutjnl-2018-317872
[6]	TAO L, ZHANG J, YAN P, et al. Clinical observation of the effects of supplemented discharging blood stasis decoction on chronic viral hepatitis B[J]. Henan Tradit Chin Med, 2017, 37(11): 1946-1949. (in Chinese. https://www.cnki.com.cn/Article/CJFDTOTAL-HNZY201711026.htm 陶乐, 张洁, 严萍, 等. 加味下瘀血汤治疗慢性乙型病毒性肝炎临床观察[J]. 河南中医, 2017, 37(11): 1946-1949. https://www.cnki.com.cn/Article/CJFDTOTAL-HNZY201711026.htm
[7]	LIU C, YUAN X, TAO L, et al. Xia-yu-xue decoction (XYXD) reduces carbon tetrachloride (CCl₄)-induced liver fibrosis through inhibition hepatic stellate cell activation by targeting NF-κB and TGF-β1 signaling pathways[J]. BMC Complement Altern Med, 2015, 15: 201. DOI: 10.1186/s12906-015-0733-1
[8]	MA W, TAO L, ZHANG W, et al. Xia-Yu-Xue decoction inhibits intestinal epithelial cell apoptosis in CCl₄-induced liver fibrosis[J]. Cell Physiol Biochem, 2017, 44(1): 333-344. DOI: 10.1159/000484904
[9]	LI Y, TANG L, GUO L, et al. CXCL13-mediated recruitment of intrahepatic CXCR5+CD8+ T cells favors viral control in chronic HBV infection[J]. J Hepatol, 2020, 72(3): 420-430. DOI: 10.1016/j.jhep.2019.09.031
[10]	GONG H, LI LP. Research advances of portal vein thrombosis in nonalcoholic fatty liver disease[J]. J Clin Hepatol, 2020, 36(9): 2107-2110. (in Chinese. DOI: 10.3969/j.issn.1001-5256.2020.09.045 龚航, 李良平. 非酒精性脂肪性肝病并发门静脉血栓的研究进展[J]. 临床肝胆病杂志, 2020, 36(9): 2107-2110. DOI: 10.3969/j.issn.1001-5256.2020.09.045
[11]	CHU H, DUAN Y, LANG S, et al. The Candida albicans exotoxin candidalysin promotes alcohol-associated liver disease[J]. J Hepatol, 2020, 72(3): 391-400. DOI: 10.1016/j.jhep.2019.09.029
[12]	SHE S, WU X, ZHENG D, et al. PSMP/MSMP promotes hepatic fibrosis through CCR2 and represents a novel therapeutic target[J]. J Hepatol, 2020, 72(3): 506-518. DOI: 10.1016/j.jhep.2019.09.033
[13]	DAI KM. Jiang Chunhua's experience in using Xiayuxue decoction[J]. Shanxi J Tradit Chin Med, 2012, 28(1): 4-6. (in Chinese. https://www.cnki.com.cn/Article/CJFDTOTAL-SHIX201201003.htm 戴克敏. 姜春华运用下瘀血汤的经验[J]. 山西中医, 2012, 28(1): 4-6. https://www.cnki.com.cn/Article/CJFDTOTAL-SHIX201201003.htm
[14]	LIU C, CAI J, CHENG Z, et al. Xiayuxue decoction reduces renal injury by promoting macrophage apoptosis in hepatic cirrhotic rats[J]. Genet Mol Res, 2015, 14(3): 10760-10773. DOI: 10.4238/2015.September.9.15
[15]	WU L, ZHANG J, MA WT, et al. Xiayuxue decoction inhibits methionine-choline-deficient-induced nonalcoholic steatohepatitis in mice[J/CD]. Chin J Liver Dis (Electronic Version), 2018, 10(3): 48-55. (in Chinese. 吴柳, 张洁, 马文婷, 等. 下瘀血汤对MCD诱导小鼠非酒精性脂肪性肝炎干预作用研究[J/CD]. 中国肝脏病杂志(电子版), 2018, 10(3): 48-55.
[16]	SHEN DX, MA WT, WU L, et al. Mechanism of Xiayuxue decoction on improving liver fibrosis by inhibiting pancreatic macrophage infiltration[J]. Acta Univ Tradit Med Sin Pharmacol Shanghai, 2019, 33(2): 73-80. (in Chinese. https://www.cnki.com.cn/Article/CJFDTOTAL-SHZD201902015.htm 沈东晓, 马文婷, 吴柳, 等. 下瘀血汤抑制胰腺巨噬细胞浸润改善肝纤维化的机制研究[J]. 上海中医药大学学报, 2019, 33(2): 73-80. https://www.cnki.com.cn/Article/CJFDTOTAL-SHZD201902015.htm
[17]	NAHARI E, RAZI M. Silymarin amplifies apoptosis in ectopic endometrial tissue in rats with endometriosis; implication on growth factor GDNF, ERK1/2 and Bcl-6b expression[J]. Acta Histochem, 2018, 120(8): 757-767. DOI: 10.1016/j.acthis.2018.08.003
[18]	KAWAMOTO K, YAGI M, STÖVER T, et al. Hearing and hair cells are protected by adenoviral gene therapy with TGF-beta1 and GDNF[J]. Mol Ther, 2003, 7(4): 484-492. DOI: 10.1016/S1525-0016(03)00058-3
[19]	NENCINI S, RINGUET M, KIM DH, et al. GDNF, Neurturin, and Artemin activate and sensitize bone afferent neurons and contribute to inflammatory bone pain[J]. J Neurosci, 2018, 38(21): 4899-4911. DOI: 10.1523/JNEUROSCI.0421-18.2018

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Mechanism of action of Xiayuxue decoction in inhibiting liver fibrosis by regulating glial cell line-derived neurotrophic factor

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Mechanism of action of Xiayuxue decoction in inhibiting liver fibrosis by regulating glial cell line-derived neurotrophic factor

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