肝纤维化相关信号通路及中药活性成分靶向调节作用机制

范文艳; 郝君玉; 陈虹秀; 刘光伟

doi:10.3969/j.issn.1001-5256.2022.11.033

肝纤维化相关信号通路及中药活性成分靶向调节作用机制

DOI: 10.3969/j.issn.1001-5256.2022.11.033

1.
河南中医药大学第一临床医学院，郑州 450000
2.
河南中医药大学第一附属医院脾胃肝胆科，郑州 450000

基金项目:

河南省自然科学基金 (222300420490);

河南省特色骨干学科中医学学科建设项目 (STG-ZYXKY-2020017)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：范文艳负责文献检索，撰写论文；郝君玉、陈虹秀负责资料分析；刘光伟负责指导撰写文章并最终定稿。

详细信息

通信作者:
刘光伟，liuguangwei1975@163.com

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出版历程
- 收稿日期: 2022-03-05
- 录用日期: 2022-04-14
- 出版日期: 2022-11-20

Research progress on signal pathways in hepatic fibrosis and targeted regulation mechanisms of active ingredients from traditional Chinese medicine

1.
The First Clinical Medical College of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, China
2.
Department of Hepatology and Spleen-Stomach, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, China

Research funding:

Natural Science Foundation of Henan Province (222300420490);

The Traditional Chinese Medicine Subject of Characteristic Discipline Construction in Henan Province (STG-ZYXKY-2020017)

More Information

Corresponding author: LIU Guangwei, liuguangwei1975@163.com(ORCID: 0000-0002-6641-1625)

摘要

摘要: 肝纤维化是许多慢性肝病的共同病理阶段，肝星状细胞的激活被认为是肝纤维化过程的关键环节。肝纤维化的发病受多种细胞因子及信号通路的调控，主要涉及NF-κB信号通路、TGFβ/Smad信号通路、Wnt/β-catenin信号通路、Hedgehog信号通路等。随着现代药理学及生物科技的发展，中药活性成分抗肝纤维化的作用机制被进一步阐明，本文对肝纤维化相关信号通路及中药活性成分抗肝纤维化的研究成果作一总结，以期为医治肝纤维化提供潜在候选药物，开拓肝纤维化治疗的新领域。
- 肝硬化 /
- 肝星状细胞 /
- 信号传导 /
- 中草药
Abstract: Hepatic fibrosis is a common pathological stage of many chronic liver diseases. Activation of hepatic stellate cells is considered as a key event in the progression of hepatic fibrosis. The pathogenesis of liver fibrosis is modulated by various cytokines involved in several signal pathways, including NF-κB, TGF-β/Smad, Wnt/β-catenin, Hedgehog etc. With the rapid development of modern pharmacology and biotechnology, the underlying molecular mechanism of anti-liver fibrosis of active components from traditional Chinese medicine has been further elucidated. This article summarizes scientific outcomes of signal pathways involved in liver fibrosis and how active components of Chinese herbal medicines exhibit anti-liver fibrosis effects, aiming to provide a potential drug candidate as a treatment for liver fibrosis and to open up a new research field of therapeutics for liver fibrosis.
- Liver Cirrhosis /
- Hepatic Stellate Cells /
- Signal Transduction /
- Drugs, Chinese Herbal

HTML全文

表 1 中药活性成分靶向信号通路抗肝纤维化的机制总结

Table 1. Mechanism of anti-hepatic fibrosis by targeted signal pathway of active ingredients of Chinese medicine

类别	名称	来源	信号通路	抗肝纤维化作用	文献
酚类	Cur	姜黄、莪术、郁金等	TGFβ/Smad	HSC增殖↓、促纤维化分子↓	[22-23]
	RSV	虎杖、藜芦、决明等	NF-κB、Hh	HSC凋亡↑、上皮细胞间质转化↓	[25-26]
	SalA、B	丹参	Wnt/β-catenin、NF-κB、TGFβ/Smad	α-SMA↓、TIMP-1↓、胶原合成↓	[27-28]
萜类	ART	青蒿素	Wnt/β-catenin、NF-κB、MAPK	HSC凋亡↑、胶原合成↓	[32-33]
	UA	枇杷、女贞、夏枯草等	TGFβ/Smad、PI3K/Akt、MAPK	MMP-1↑、TIMP-1↓、PPARγ↑、HSC增殖↓	[34-35]
生物碱类	TMPZ	川芎、郁金等	TGFβ/Smad、JAK/STAT	IL-6↓、IL-1β↓、IL-10↑、HSC凋亡↑	[36-38]
	OMT	苦参	Wnt/β-catenin	HSC活化↓	[40-41]
皂苷类	DIO	黄山药、菝葜等	PI3K/Akt、MAPK	α-SMA↓、胶原合成↓	[42-43]
	PNS	三七	TGFβ/Smad	Bcl-2↑、Bax↓、肝细胞凋亡↓	[44-45]
黄酮类	QUE	紫花地丁、仙鹤草、车前子、三七等	Wnt/β-catenin、NF-κB、MAPK	胶原沉积↓、羟脯氨酸↓	[46-47]
	TFL	荔枝核	TGFβ/Smad、NF-κB	PPARγ↑、HSC活化↓	[48-49]
多糖类	DP	石斛	NF-κB	HSC活化↓、胶原沉积↓、肠屏障通透性↓	[50-51]
	LBP	枸杞	NF-κB	IGF-2↓、HSC活化↓	[52-53]
	DCP	狗肝菜	MAPK、NF-κB	胶原沉积↓	[54-55]
注：↑代表上升；↓代表下降。

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参考文献(55)

[1]	YIN C, EVASON KJ, ASAHINA K, et al. Hepatic stellate cells in liver development, regeneration, and cancer[J]. J Clin Invest, 2013, 123(5): 1902-1910. DOI: 10.1172/JCI66369.
[2]	VAN ROSSEN E, LIU Z, BLIJWEERT D, et al. Syncoilin is an intermediate filament protein in activated hepatic stellate cells[J]. Histochem Cell Biol, 2014, 141(1): 85-99. DOI: 10.1007/s00418-013-1142-5.
[3]	HUANG P, YAN R, ZHANG X, et al. Activating Wnt/β-catenin signaling pathway for disease therapy: Challenges and opportunities[J]. Pharmacol Ther, 2019, 196: 79-90. DOI: 10.1016/j.pharmthera.2018.11.008.
[4]	LAI SL, CHIEN AJ, MOON RT. Wnt/Fz signaling and the cytoskeleton: potential roles in tumorigenesis[J]. Cell Res, 2009, 19(5): 532-545. DOI: 10.1038/cr.2009.41.
[5]	JIANG F, PARSONS CJ, STEFANOVIC B. Gene expression profile of quiescent and activated rat hepatic stellate cells implicates Wnt signaling pathway in activation[J]. J Hepatol, 2006, 45(3): 401-409. DOI: 10.1016/j.jhep.2006.03.016.
[6]	LI WT, CHEN XL, LI Y, et al. Effect of Dickkopf-1 on the activation of hepatic stellate cells[J]. Chin Hepatol, 2010, 15(5): 338-341. DOI: 10.3969/j.issn.1008-1704.2010.05.010. 李文庭, 陈西柳, 李宜, 等. Wnt抑制因子-1对肝星状细胞活化的影响[J]. 肝脏, 2010, 15(5): 338-341. DOI: 10.3969/j.issn.1008-1704.2010.05.010.
[7]	WRANA JL, ATTISANO L, WIESER R, et al. Mechanism of activation of the TGF-beta receptor[J]. Nature, 1994, 370(6488): 341-347. DOI: 10.1038/370341a0.
[8]	FINNSON KW, MCLEAN S, di GUGLIELMO GM, et al. Dynamics of transforming growth factor beta signaling in wound healing and scarring[J]. Adv Wound Care (New Rochelle), 2013, 2(5): 195-214. DOI: 10.1089/wound.2013.0429.
[9]	FU R, WU J, DING J, et al. Targeting transforming growth factor βRⅡ expression inhibits the activation of hepatic stellate cells and reduces collagen synthesis[J]. Exp Biol Med (Maywood), 2011, 236(3): 291-297. DOI: 10.1258/ebm.2010.010231.
[10]	MURIEL P. NF-kappaB in liver diseases: a target for drug therapy[J]. J Appl Toxicol, 2009, 29(2): 91-100. DOI: 10.1002/jat.1393.
[11]	de GREGORIO E, COLELL A, MORALES A, et al. Relevance of SIRT1-NF-κB axis as therapeutic target to ameliorate inflammation in liver disease[J]. Int J Mol Sci, 2020, 21(11): 3858. DOI: 10.3390/ijms21113858.
[12]	LIU T, ZHANG L, JOO D, et al. NF-κB signaling in inflammation[J]. Signal Transduct Target Ther, 2017, 2: 17023. DOI: 10.1038/sigtrans.2017.23.
[13]	OAKLEY F, MESO M, IREDALE JP, et al. Inhibition of inhibitor of kappaB kinases stimulates hepatic stellate cell apoptosis and accelerated recovery from rat liver fibrosis[J]. Gastroenterology, 2005, 128(1): 108-120. DOI: 10.1053/j.gastro.2004.10.003.
[14]	GUY CD, SUZUKI A, ZDANOWICZ M, et al. Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease[J]. Hepatology, 2012, 55(6): 1711-1721. DOI: 10.1002/hep.25559.
[15]	LU AM, YU TG. Role of Hedgehog pathway in the development and progression of metabolicdysfunction associated fatty liver disease[J]. Chem Life, 2021, 41(5): 983-988. DOI: 10.13488/j.smhx.20210036. 逯爱梅, 于天贵. Hedgehog信号通路在代谢相关脂肪性肝病发生与发展中的作用[J]. 生命的化学, 2021, 41(5): 983-988. DOI: 10.13488/j.smhx.20210036.
[16]	SYN WK, JUNG Y, OMENETTI A, et al. Hedgehog-mediated epithelial-to-mesenchymal transition and fibrogenic repair in nonalcoholic fatty liver disease[J]. Gastroenterology, 2009, 137(4): 1478-1488. e8. DOI: 10.1053/j.gastro.2009.06.051.
[17]	JENG KS, LU SJ, WANG CH, et al. Liver fibrosis and inflammation under the control of ERK2[J]. Int J Mol Sci, 2020, 21(11): 3796. DOI: 10.3390/ijms21113796.
[18]	WANG Q, ZHAN JH. Research progress of leptin regulation of hepatic stellate cell activation in liver fibrosis[J]. Tianjin Med J, 2022, 50(1): 25-29. DOI: 10.11958/20211117. 王琼, 詹江华. 瘦素对肝星状细胞活化的调控及其在肝纤维化进展中的作用[J]. 天津医药, 2022, 50(1): 25-29. DOI: 10.11958/20211117.
[19]	CHAKRABORTY D, ŠUMOVÁ B, MALLANO T, et al. Activation of STAT3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis[J]. Nat Commun, 2017, 8(1): 1130. DOI: 10.1038/s41467-017-01236-6.
[20]	SON G, HINES IN, LINDQUIST J, et al. Inhibition of phosphatidylinositol 3-kinase signaling in hepatic stellate cells blocks the progression of hepatic fibrosis[J]. Hepatology, 2009, 50(5): 1512-1523. DOI: 10.1002/hep.23186.
[21]	ZHOU YB, HUA J, QI LL, et al. Protective effect of curcumin pre-treatment on liver of acute ischemia-reperfusion model rats[J]. J Jilin Univ: Med Edit, 2020, 46(2): 297-301, front insert 2. https://www.cnki.com.cn/Article/CJFDTOTAL-BQEB202002015.htm 周亚宾, 华进, 戚伶俐, 等. 姜黄素预处理对急性缺血再灌注模型大鼠肝脏的保护作用[J]. 吉林大学学报(医学版), 2020, 46(2): 297-301, 前插2. https://www.cnki.com.cn/Article/CJFDTOTAL-BQEB202002015.htm
[22]	BRUCK R, ASHKENAZI M, WEISS S, et al. Prevention of liver cirrhosis in rats by curcumin[J]. Liver Int, 2007, 27(3): 373-383. DOI: 10.1111/j.1478-3231.2007.01453.x.
[23]	WANG GT, LI JT, WEI HL, et al. Curcumin inhibits fibrosis of human hepatic stellate cells by inhibiting TGF-β/smad2 signaling pathway[J]. Chin J Immunol, 2020, 36(4): 422-427. DOI: 10.3969/j.issn.1000-484X.2020.04.008. 王国泰, 李京涛, 魏海梁, 等. 姜黄素通过抑制TGF-β/smad2信号通路抑制人肝星状细胞纤维化作用研究[J]. 中国免疫学杂志, 2020, 36(4): 422-427. DOI: 10.3969/j.issn.1000-484X.2020.04.008.
[24]	NIU PQ, GUO CY. Research progress on pharmacological effects of resveratrol[J]. Herald Med, 2006, 25(6): 524-525. DOI: 10.3870/j.issn.1004-0781.2006.06.015. 牛培勤, 郭传勇. 白藜芦醇药理作用的研究进展[J]. 医药导报, 2006, 25(6): 524-525. DOI: 10.3870/j.issn.1004-0781.2006.06.015.
[25]	YU B, QIN SY, HU BL, et al. Resveratrol improves CCl₄-induced liver fibrosis in mouse by upregulating endogenous IL-10 to reprogramme macrophages phenotype from M(LPS) to M(IL-4)[J]. Biomed Pharmacother, 2019, 117: 109110. DOI: 10.1016/j.biopha.2019.109110.
[26]	ZHOU Y, QUE RY, LI Y, et al. Rresveratrol suppresses activation of HSC cells through regulateng and controlling Hedgehog signaling pathway[J]. J Guangzhou Univ Tradit Chin Med, 2020, 37(3): 516-522. DOI: 10.13359/j.cnki.gzxbtcm.2020.03.025. 周薏, 阙任烨, 李勇, 等. 白藜芦醇调控Hedgehog信号通路抑制肝星状细胞活化的研究[J]. 广州中医药大学学报, 2020, 37(3): 516-522. DOI: 10.13359/j.cnki.gzxbtcm.2020.03.025.
[27]	WU XJ, ZHU HY, HUANG WF. The effect of salvianolic acid A on Wnt/β-catenin signal pathway in hepatic fibrosis rats[J]. J Gannan Med Univ, 2018, 38(11): 1079-1082. DOI: 10.3969/j.issn.1001-5779.2018.11.003. 吴雄健, 朱海燕, 黄文峰. 丹酚酸A对肝纤维化大鼠Wnt/β-catenin信号通路的影响[J]. 赣南医学院学报, 2018, 38(11): 1079-1082. DOI: 10.3969/j.issn.1001-5779.2018.11.003.
[28]	SONG FY, WANG R, LI SN, et al. Anti-fibrotic effect of salvianolic acid A on hepatic fibrosis in rats by targeting NF-κB/IκBα signaling pathway[J]. Cent South Pharm, 2018, 16(3): 330-335. DOI: 10.7539/j.issn.1672-2981.2018.03.008. 宋复兴, 王蓉, 李胜男, 等. 丹酚酸A通过调节NF-κB/IκBα信号通路抑制肝纤维化[J]. 中南药学, 2018, 16(3): 330-335. DOI: 10.7539/j.issn.1672-2981.2018.03.008.
[29]	MA Y, FANG M, WU C, et al. Salvianolic acid B exerts antihepatic fibrosiscarcinoma effect via mediation of pSmad3C/pSmad3L[J]. Chin Pharmacol Bull, 2018, 34(1): 44-50. DOI: 10.3969/j.issn.1001-1978.2018.01.011. 马滢, 方萌, 伍超, 等. 丹酚酸B调控pSmad3C/pSmad3L发挥抗肝纤维化-肝细胞癌作用[J]. 中国药理学通报, 2018, 34(1): 44-50. DOI: 10.3969/j.issn.1001-1978.2018.01.011.
[30]	QIAN P. Research progress of anti-hepatic fibrosis mechanism of artesunate[J]. Chongqing Med, 2017, 46(2): 269-271. DOI: 10.3969/j.issn.1671-8348.2017.02.043. 钱鹏. 青蒿琥酯抗肝纤维化作用机制的研究进展[J]. 重庆医学, 2017, 46(2): 269-271. DOI: 10.3969/j.issn.1671-8348.2017.02.043.
[31]	LIU BF, ZHOU DS, LIANG ZQ, et al. Effects of artesunate on NF-κB and TNF-α in liver tissue of mice with nonalcoholic fatty liver disease[J]. Pharmocol Clin Chin Mater Med, 2014, 30(5): 23-26. DOI: 10.13412/j.cnki.zyyl.2014.05.008. 刘博峰, 周冬生, 梁志清, 等. 青蒿琥酯对非酒精性脂肪肝小鼠肝组织NF-κB、TNF-α的影响[J]. 中药药理与临床, 2014, 30(5): 23-26. DOI: 10.13412/j.cnki.zyyl.2014.05.008.
[32]	ZHANG Y, ZHANG H, PENG R, et al. Mechanism research on Artesunate in the treatment of liver fibrosis by inhibiting miR-154/β-catenin in hepatic stellate cell[J]. China Med Her, 2016, 13(1): 35-38. https://www.cnki.com.cn/Article/CJFDTOTAL-YYCY201601010.htm 张英, 张洪, 彭锐, 等. 青蒿琥酯抑制肝星状细胞microRNA-154/β-catenin治疗肝纤维化的机制研究[J]. 中国医药导报, 2016, 13(1): 35-38. https://www.cnki.com.cn/Article/CJFDTOTAL-YYCY201601010.htm
[33]	KONG QM, DAI FW, DING HJ, et al. Effects of artesunate on schistosomal liver fibrosis in mice[J]. Chin Pharmacol Bull, 2019, 35(6): 854-858. DOI: 10.3969/j.issn.1001-1978.2019.06.023. 孔庆明, 戴方伟, 丁豪杰, 等. 青蒿琥酯抗小鼠血吸虫性肝纤维化的作用[J]. 中国药理学通报, 2019, 35(6): 854-858. DOI: 10.3969/j.issn.1001-1978.2019.06.023.
[34]	SHI F, HE WH, ZHU X, et al. Effects of ursolic acid(UA) on NADPH oxidase(NOX) subunit and its regulation on downstream signaling pathways in rat activated hepatic stellate cells(HSC)[J]. J Fudan Univ Med Sci, 2014, 41(3): 328-334, 339. DOI: 10.3969/j.issn.1672-8467.2014.03.008. 施凤, 何文华, 朱萱, 等. 熊果酸(UA)对大鼠活化型肝星状细胞(HSC) 的NADPH氧化酶(NOX)亚基及PI3K/Akt、P38MAPK信号通路活化的影响[J]. 复旦学报(医学版), 2014, 41(3): 328-334, 339. DOI: 10.3969/j.issn.1672-8467.2014.03.008.
[35]	ZHANG YW, LUO WS, CHEN S, et al. Effects of ursolic acid from loquat leaves on proliferation inhibition andexpression of PPAR-γ, TGF-β1 in rat hepatic stellate cells[J]. Chin Pharmacol Bull, 2017, 33(4): 517-521. DOI: 10.3969/j.issn.1001-1978.2017.04.014. 张扬武, 罗伟生, 陈姗, 等. 枇杷叶熊果酸对大鼠肝星状细胞增殖抑制作用及对PPAR-γ、TGF-β1表达的影响[J]. 中国药理学通报, 2017, 33(4): 517-521. DOI: 10.3969/j.issn.1001-1978.2017.04.014.
[36]	CHEN QX, FU JB, YAO Z, et al. Effects of tetramethylpyrazine on proliferation and apoptosis of hepatic stellate cells[J]. Pharmacol Clin Chin Mater Med, 2018, 34(1): 48-53. DOI: 10.13412/j.cnki.zyyl.2018.01.012. 陈巧霞, 付金柏, 姚真, 等. 川芎嗪对肝星状细胞的增殖及凋亡的影响[J]. 中药药理与临床, 2018, 34(1): 48-53. DOI: 10.13412/j.cnki.zyyl.2018.01.012.
[37]	YAN DL, SHAO WB, GE C, et al. Effects of ligustrazine on JAK2/STAT3 signaling pathway in concanavalin A-induced liver fibrosis in mice[J]. Chin Hepatol, 2018, 23(3): 255-259. DOI: 10.3969/j.issn.1008-1704.2018.03.022. 严栋梁, 邵伟斌, 葛创, 等. 川芎嗪对刀豆蛋白A诱导的小鼠肝纤维化JAK2/STAT3信号通路的影响[J]. 肝脏, 2018, 23(3): 255-259. DOI: 10.3969/j.issn.1008-1704.2018.03.022.
[38]	CHEN K, QIU JL. Tetramethylpyrazine regulates hepatic fibrosis and Smad3 signaling pathway in biliary atresia animal model through miR-145[J]. Chin Pharmacol Bull, 2021, 37(4): 590-591. DOI: 10.3969/j.issn.1001-1978.2021.04.025. 陈昆, 邱建利. TMP通过miR-145调控胆道闭锁动物模型肝纤维化及Smad3信号通路的研究[J]. 中国药理学通报, 2021, 37(4): 590-591. DOI: 10.3969/j.issn.1001-1978.2021.04.025.
[39]	YAO G, CHEN F, YIN YT. Research progress on pharmacological activity of matrine[J]. Jiangxi J Trad Chin Med, 2021, 52(12): 78-80. https://www.cnki.com.cn/Article/CJFDTOTAL-JXZY202112035.htm 姚刚, 陈芳, 殷玉婷. 苦参素药理活性研究进展[J]. 江西中医药, 2021, 52(12): 78-80. https://www.cnki.com.cn/Article/CJFDTOTAL-JXZY202112035.htm
[40]	MA ZH, ZHANG JY, YANG L, et al. Oxymatrine inhibits hepatic stellate cell(HSC) autophagy during HSC activation induced by arsenic[J]. Chin J Pathophysiol, 2019, 35(9): 1662-1667. DOI: 10.3969/j.issn.1000-4718.2019.09.020. 马子华, 张景允, 杨柳, 等. 氧化苦参碱干预砷致肝星状细胞活化中细胞自噬的研究[J]. 中国病理生理杂志, 2019, 35(9): 1662-1667. DOI: 10.3969/j.issn.1000-4718.2019.09.020.
[41]	BAO L, ZHAO ZH, LI WT. Matrine inhibits hepatic stellate cell activation by regulating Wnt/Jnk pathway mediated glucose metabolism[J]. Chin Hepatol, 2017, 22(10): 937-941. DOI: 10.3969/j.issn.1008-1704.2017.10.023. 鲍磊, 赵宗豪, 李文庭. 苦参素调节Wnt/Jnk通路介导的糖代谢抑制肝星状细胞活化[J]. 肝脏, 2017, 22(10): 937-941. DOI: 10.3969/j.issn.1008-1704.2017.10.023.
[42]	GU L, TAO X, XU Y, et al. Dioscin alleviates BDL-and DMN-induced hepatic fibrosis via Sirt1/Nrf2-mediated inhibition of p38 MAPK pathway[J]. Toxicol Appl Pharmacol, 2016, 292: 19-29. DOI: 10.1016/j.taap.2015.12.024.
[43]	LU SY, LIN Y, LIN ZH, et al. Effect of dioscin on hepatic tissue damage and PI3 K/Akt signaling pathway in mouse liver fibrosis model[J]. Chin J Clin Pharmacol, 2021, 37(20): 2834-2837. DOI: 10.13699/j.cnki.1001-6821.2021.20.029. 卢世云, 林云, 林志辉, 等. 薯蓣皂苷对小鼠肝纤维化模型肝组织损伤和PI3K/Akt信号通路的影响[J]. 中国临床药理学杂志, 2021, 37(20): 2834-2837. DOI: 10.13699/j.cnki.1001-6821.2021.20.029.
[44]	JIANG H, GAO JR, ZHANG JF, et al. Protective effect of panax notoginseng saponins on experimental liver fibrosis in rats and to explore its possible mechanisms[J]. Pharmacol Clin Chin Mater Med, 2013, 29(3): 71-74. DOI: 10.13412/j.cnki.zyyl.2013.03.030. 姜辉, 高家荣, 张家富, 等. 三七总皂苷对肝纤维化大鼠的保护作用及机制[J]. 中药药理与临床, 2013, 29(3): 71-74. DOI: 10.13412/j.cnki.zyyl.2013.03.030.
[45]	WANG JK, WANG YC, WANG ZY. Research of panax notoginseng saponins on the expression of transforming growth factor-β1 and recombinant human mothers against decapentaplegic homolog3 in the mice with liver fibrosis[J]. Chin J Clin Pharmacol, 2021, 37(10): 1163-1166. DOI: 10.13699/j.cnki.1001-6821.2021.10.008. 王京凯, 王艳春, 王振宇. 三七总皂苷对肝纤维化小鼠转化生长因子β-1及重组人SMAD家族成员3的调控作用研究[J]. 中国临床药理学杂志, 2021, 37(10): 1163-1166. DOI: 10.13699/j.cnki.1001-6821.2021.10.008.
[46]	WANG R, ZHANG H, WANG Y, et al. Inhibitory effects of quercetin on the progression of liver fibrosis through the regulation of NF-кB/IкBα, p38 MAPK, and Bcl-2/Bax signaling[J]. Int Immunopharmacol, 2017, 47: 126-133. DOI: 10.1016/j.intimp.2017.03.029.
[47]	CHEN WL, DAI FZ, SHAO ZY, et al. Inhibitory and protective effects of quercetin on hepatic fibrosis induced by carbon tetrachloride in rats[J]. Chin J Immunol, 2021, 37(1): 46-50. DOI: 10.3969/j.issn.1000-484X.2021.01.008. 陈文龙, 戴富臻, 邵正勇, 等. 槲皮素对四氯化碳诱导的大鼠肝纤维化抑制作用和肝保护作用[J]. 中国免疫学杂志, 2021, 37(1): 46-50. DOI: 10.3969/j.issn.1000-484X.2021.01.008.
[48]	CHENG QC, QIN W, ZHUO L, et al. Comparison of total flavone of litchi chinensis soon in two kinds of hepatic fibrosis model of rats[J]. Her Med, 2020, 39(9): 1179-1184. DOI: 10.3870/j.issn.1004-0781.2020.09.001. 成秋宸, 覃雯, 卓朗, 等. 荔枝核总黄酮对两种肝纤维化大鼠模型的作用比较[J]. 医药导报, 2020, 39(9): 1179-1184. DOI: 10.3870/j.issn.1004-0781.2020.09.001.
[49]	CHEN S, LUO WS, ZHANG YW, et al. Inhibition of total flavonoids from litchi nucleus on proliferation of rat hepatic stellate cells and its effect on expression of PPARγ and C-ski[J]. Acta Chin Med, 2019, 34(8): 1670-1674. DOI: 10.16368/j.issn.1674-8999.2019.08.395. 陈姗, 罗伟生, 张扬武, 等. 荔枝核总黄酮对大鼠肝星状细胞增殖抑制作用及对PPARγ、C-ski表达的影响[J]. 中医学报, 2019, 34(8): 1670-1674. DOI: 10.16368/j.issn.1674-8999.2019.08.395.
[50]	AN ZX, HE YL, HUANG D, et al. Effect of dendrobium nobile polysaccharides on the expression of TGF-β1, α-SMA, type I, Ⅲ collagen in rats with hepatic fibrosis[J]. Chin J Gerontol, 2022, 42(2): 381-385. DOI: 10.3969/j.issn.1005-9202.2022.02.033. 安祯祥, 何远利, 黄丹, 等. 金钗石斛多糖对肝纤维化大鼠TGF-β1、α-SMA、Ⅰ型胶原、Ⅲ型胶原表达的影响[J]. 中国老年学杂志, 2022, 42(2): 381-385. DOI: 10.3969/j.issn.1005-9202.2022.02.033.
[51]	WANG K, YANG X, WU Z, et al. Dendrobium officinale polysaccharide protected CCl4-induced liver fibrosis through intestinal homeostasis and the LPS-TLR4-NF-κB signaling pathway[J]. Front Pharmacol, 2020, 11: 240. DOI: 10.3389/fphar.2020.00240.
[52]	GAO S, HUO LM, HAN YZ, et al. Effects of Lycium barbarum polysaccharide on the expression of IGF-2 and IGFBP-2 in blood and liver tissue of hepatic fibrosis rats[J]. Mod J Integr Tradit Chin West Med, 2022, 31(3): 325-328. DOI: 10.3969/j.issn.1008-8849.2022.03.006. 高深, 霍丽民, 韩艳珍, 等. 枸杞多糖对肝纤维化大鼠血液及肝组织中IGF-2和IGFBP-2表达的影响[J]. 现代中西医结合杂志, 2022, 31(3): 325-328. DOI: 10.3969/j.issn.1008-8849.2022.03.006.
[53]	GAN F, LIU Q, LIU Y, et al. Lycium barbarum polysaccharides improve CCl4-induced liver fibrosis, inflammatory response and TLRs/NF-kB signaling pathway expression in wistar rats[J]. Life Sci, 2018, 192: 205-212. DOI: 10.1016/j.lfs.2017.11.047.
[54]	XU J, ZHONG ML, WANG YF, et al. Study on intervention of DCP on MAPK signaling to inhibit infla-mmatory response and alleviate progression of liver fibrosis in rats[J]. Chin Pharmacol Bull, 2022, 38(4): 531-537. DOI: 10.12360/CPB202106059. 徐杰, 钟明利, 王跃峰, 等. 狗肝菜多糖干预MAPK信号通路抑制炎症反应缓解大鼠肝纤维化进程[J]. 中国药理学通报, 2022, 38(4): 531-537. DOI: 10.12360/CPB202106059.
[55]	ZHENG DX, ZHANG KF, JIN L, et al. Study on the mechanism of polysaccharides from Dicliptera chinensis in alleviating liver fibrosis based on LIN28 A/NF-κB signaling pathway[J]. Nat Prod Res Dev, 2021, 33(3): 386-393. DOI: 10.16333/j.1001-6880.2021.3.005. 郑董璇, 张可锋, 晋玲, 等. 基于LIN28A/NF-κB信号通路研究狗肝菜多糖缓解肝纤维化的作用机制[J]. 天然产物研究与开发, 2021, 33(3): 386-393. DOI: 10.16333/j.1001-6880.2021.3.005.