中药有效成分干预自身免疫性肝炎相关信号通路的研究进展

郝君玉; 刘光伟; 谢露; 范文艳; 陈虹秀

doi:10.3969/j.issn.1001-5256.2023.03.029

中药有效成分干预自身免疫性肝炎相关信号通路的研究进展

DOI: 10.3969/j.issn.1001-5256.2023.03.029

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:

国家自然科学基金资助项目 (81573933);

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：郝君玉负责文献检索，撰写论文；谢露、范文艳、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(ORCID: 0000-0002-6641-1625)

计量
- 文章访问数: 647
- HTML全文浏览量: 166
- PDF下载量: 109
- 被引次数: 0
出版历程
- 收稿日期: 2022-07-15
- 录用日期: 2022-08-26
- 出版日期: 2023-03-20

Research advances in effective constituents of traditional Chinese medicine in intervention of autoimmune hepatitis-related signaling pathways

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:

National Natural Science Foundation of China (81573933);

Natural Science Foundation of Henan Province (222300420490);

Traditional Chinese Medicine Discipline Construction Project of Henan Province Characteristic Backbone Discipline (STG-ZYXKY-2020017)

More Information

Corresponding author: LIU Guangwei, Liuguangwei1975@163.com(ORCID: 0000-0002-6641-1625)

摘要

摘要: 自身免疫性肝炎作为一种由免疫耐受缺失导致的慢性肝脏炎症，其发病受多种信号通路的调控，例如NF-κB/NLRP3通路、SIRT1/Nrf2/HO-1通路、Hippo-YAP/TAZ通路、JAK/STAT通路、PI3K/Akt通路和TRAF6/JNK通路等，这些通路能够通过参与细胞因子的增殖和凋亡、免疫反应以及氧化应激等过程来发挥抗免疫性肝炎的作用。针对临床应用激素和免疫制剂治疗自身免疫性肝炎出现的应答不佳、不良反应明显及复发率高等问题，本文对自身免疫性肝炎相关信号传导通路的研究文献进行了总结，并梳理了苷类、萜类、黄酮类、醌类及酚类中药有效成分通过以上信号通路干预自身免疫性肝炎疾病进程的机制，以期为科学有效地利用中药有效成分研发抗自身免疫性肝炎药物提供理论参考依据。
- 肝炎, 自身免疫性 /
- 中草药 /
- 信号传导
Abstract: As a chronic liver inflammation disease caused by the lack of immune tolerance, autoimmune hepatitis is regulated by various signaling pathways, such as the NF-κB/NLRP3 pathway, the SIRT1/Nrf2/HO-1 pathway, the Hippo-YAP/TAZ pathway, the JAK/STAT pathway, the PI3K/Akt pathway, and the TRAF6/JNK pathway. These pathways can play a role against autoimmune hepatitis by participating in the processes including the proliferation and apoptosis of cytokines, immune response, and oxidative stress. In view of the problems of suboptimal response, obvious adverse reactions, and high recurrence rate in the clinical application of hormones and immune preparations for the treatment of autoimmune hepatitis, this article summarizes the research articles on autoimmune hepatitis-related signaling pathways and the mechanism of effective constituents (glycosides, terpenoids, flavonoids, quinones, and phenols) in traditional Chinese medicine intervening against the disease process of autoimmune hepatitis through the above signaling pathways, in order to provide a theoretical basis for scientific and effective utilization of effective constituents in traditional Chinese medicine to develop anti-autoimmune hepatitis drugs.
- Hepatitis, Autoimmune /
- Drugs, Chinese Herbal /
- Signal Transduction

HTML全文

图 1 相关信号通路干预AIH的作用机制

Figure 1. Mechanisms of related signaling pathways interfering with AIH

下载: 全尺寸图片幻灯片

表 1 中药有效成分干预AIH的相关信号通路

Table 1. Effective components of traditional Chinese medicine intervene in AIH-related signaling pathways

类别	名称	来源	信号通路
苷类	金线莲苷	花叶开唇兰、恒春金线莲、金线兰等	NF-κB/NLRP3、PI3K/Akt、JAK/STAT
	人参皂苷	人参、红参、三七、西洋参等	Hippo-YAP/TAZ、JAK/STAT、NF-κB
萜类	葫芦素E	药西瓜	NF-κB/NLRP3、SIRT1/Nrf2/HO-1
	雷公藤红素	雷公藤	NF-κB/NLRP3、PI3K/Akt
黄酮类	柚皮素	桃叶、菝葜、梗树果实、樱花花蕾等	NF-κB、TRAF6/JNK
醌类	丹参酮ⅡA	丹参	NF-κB、PI3K/Akt
酚类	姜黄素	姜黄、莪术、郁金等	NF-κB、Nrf2

下载: 导出CSV

参考文献(45)

[1]	Chinese Society of Hepatology, Chinese Medical Association. Guidelines on the diagnosis and management of autoimmune hepatitis(2021)[J]. J Clin Hepatol, 2022, 38(1): 42-49. DOI: 10.3969/j.issn.1001-5256.2022.01.008. 中华医学会肝病学分会. 自身免疫性肝炎诊断和治疗指南(2021)[J]. 临床肝胆病杂志, 2022, 38(1): 42-49. DOI: 10.3969/j.issn.1001-5256.2022.01.008.
[2]	HU ML, WANG QX, MA X. Advances in the pathogenesis of autoimmune hepatitis and new targets for clinical intervention[J]. J Clin Hepatol, 2022, 38(4): 743-747. DOI: 10.3969/j.issn.1001-5256.2022.04.002. 胡明礼, 王绮夏, 马雄. 自身免疫性肝炎发病机制进展与临床干预新靶点[J]. 临床肝胆病杂志, 2022, 38(4): 743-747. DOI: 10.3969/j.issn.1001-5256.2022.04.002.
[3]	ROBINSON SM, MANN DA. Role of nuclear factor kappaB in liver health and disease[J]. Clin Sci (Lond), 2010, 118(12): 691-705. DOI: 10.1042/CS20090549.
[4]	TAN P, DONG X, MAI K, et al. Vegetable oil induced inflammatory response by altering TLR-NF-κB signalling, macrophages infiltration and polarization in adipose tissue of large yellow croaker (Larimichthys crocea)[J]. Fish Shellfish Immunol, 2016, 59: 398-405. DOI: 10.1016/j.fsi.2016.11.009.
[5]	ZAHID A, LI B, KOMBE A, et al. Pharmacological inhibitors of the NLRP3 inflammasome[J]. Front Immunol, 2019, 10: 2538. DOI: 10.3389/fimmu.2019.02538.
[6]	HE M, TAN B, VASAN K, et al. SIRT1 and AMPK pathways are essential for the proliferation and survival of primary effusion lymphoma cells[J]. J Pathol, 2017, 242(3): 309-321. DOI: 10.1002/path.4905.
[7]	VILLALBA JM, ALCAÍN FJ. Sirtuin activators and inhibitors[J]. Biofactors, 2012, 38(5): 349-359. DOI: 10.1002/biof.1032.
[8]	TANG HH, LI HL, LI YX, et al. Protective effects of a traditional Chinese herbal formula Jiang-Xian HuGan on Concanavalin A-induced mouse hepatitis via NF-κB and Nrf2 signaling pathways[J]. J Ethnopharmacol, 2018, 217: 118-125. DOI: 10.1016/j.jep.2018.02.003.
[9]	LIU HM. Study on MSCs treatment of AIH by change the polarization state of macrophages in mice[D]. Tianjing: Tianjin Medical University, 2019. 刘会敏. MSCs通过改变巨噬细胞极化状态治疗AIH小鼠的实验研究[D]. 天津: 天津医科大学, 2019.
[10]	KIM W, KHAN SK, GVOZDENOVIC-JEREMIC J, et al. Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesis[J]. J Clin Invest, 2017, 127(1): 137-152. DOI: 10.1172/JCI88486.
[11]	GUO P, WANG Z, ZHOU Z, et al. Immuno-hippo: Research progress of the hippo pathway in autoimmune disease[J]. Immunol Lett, 2021, 230: 11-20. DOI: 10.1016/j.imlet.2020.12.006.
[12]	MURAKAMI S, SHAHBAZIAN D, SURANA R, et al. Yes-associated protein mediates immune reprogramming in pancreatic ductal adenocarcinoma[J]. Oncogene, 2017, 36(9): 1232-1244. DOI: 10.1038/onc.2016.288.
[13]	ZHANG K, LI J, SHI Z, et al. Ginsenosides regulates innate immunity to affect immune microenvironment of AIH through Hippo-YAP/TAZ signaling pathway[J]. Front Immunol, 2022, 13: 851560. DOI: 10.3389/fimmu.2022.851560.
[14]	LI S, MA LJ. Role of JAK/STAT signal pathway in Con A-induced autoimmune hepatitis[J]. Progress in Biochemistry and Biophysics, 2016, 43(12): 1139-1145. DOI: 10.16476/j.pibb.2016.0204. 李莎, 马丽杰. JAK/STAT信号通路在刀豆蛋白A诱导的自身免疫性肝炎中的作用[J]. 生物化学与生物物理进展, 2016, 43(12): 1139-1145. DOI: 10.16476/j.pibb.2016.0204.
[15]	HONG F, JARUGA B, KIM WH, et al. Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS[J]. J Clin Invest, 2002, 110(10): 1503-1513. DOI: 10.1172/JCI15841.
[16]	JARUGA B, HONG F, SUN R, et al. Crucial role of IL-4/STAT6 in T cell-mediated hepatitis: up-regulating eotaxins and IL-5 and recruiting leukocytes[J]. J Immunol, 2003, 171(6): 3233-3244. DOI: 10.4049/jimmunol.171.6.3233.
[17]	ERTA M, QUINTANA A, HIDALGO J. Interleukin-6, a major cytokine in the central nervous system[J]. Int J Biol Sci, 2012, 8(9): 1254-1266. DOI: 10.7150/ijbs.4679.
[18]	HANADA M, FENG J, HEMMINGS BA. Structure, regulation and function of PKB/AKT-a major therapeutic target[J]. Biochim Biophys Acta, 2004, 1697(1-2): 3-16. DOI: 10.1016/j.bbapap.2003.11.009.
[19]	HAO JH, LI ZC, SUN WL. Network analysis and experimental verification of tanshinone ⅡA in treatment of autoimmune hepatitis[J]. J Army Med Univ, 2022, 44(10): 1033-1040. DOI: 10.16016/j.2097-0927.202111049. 郝健亨, 李振城, 孙薇丽. 丹参酮ⅡA治疗自身免疫性肝炎的网络分析及实验验证[J]. 陆军军医大学学报, 2022, 44(10): 1033-1040. DOI: 10.16016/j.2097-0927.202111049.
[20]	LIU P, CHENG H, ROBERTS TM, et al. Targeting the phosphoinositide 3-kinase pathway in cancer[J]. Nat Rev Drug Discov, 2009, 8(8): 627-644. DOI: 10.1038/nrd2926.
[21]	WANG M, ZHANG J, ZHANG J, et al. Methyl eugenol attenuates liver ischemia reperfusion injury via activating PI3K/Akt signaling[J]. Int Immunopharmacol, 2021, 99: 108023. DOI: 10.1016/j.intimp.2021.108023.
[22]	SHEN Y, SHEN X, CHENG Y, et al. Myricitrin pretreatment ameliorates mouse liver ischemia reperfusion injury[J]. Int Immunopharmacol, 2020, 89(Pt A): 107005. DOI: 10.1016/j.intimp.2020.107005.
[23]	ZHENG L, LI Z, LING W, et al. Exosomes derived from dendritic cells attenuate liver injury by modulating the balance of treg and Th17 cells after ischemia reperfusion[J]. Cell Physiol Biochem, 2018, 46(2): 740-756. DOI: 10.1159/000488733.
[24]	WANG C, KONG X, ZHU C, et al. Wu-tou decoction attenuates neuropathic pain via suppressing spinal astrocytic IL-1R1/TRAF6/JNK signaling[J]. Oncotarget, 2017, 8(54): 92864-92879. DOI: 10.18632/oncotarget.21638.
[25]	YU Q, LIU T, LI S, et al. The protective effects of levo-tetrahydropalmatine on ConA-induced liver injury are via TRAF6/JNK signaling[J]. Mediators Inflamm, 2018, 2018: 4032484. DOI: 10.1155/2018/4032484.
[26]	WANG JD, WANG HZ, ZHANG AL, et al. Recent advances in kinsenoside studies[J]. Chin Hosp Pharm J, 2015, 35(19): 1795-1798, 1802. DOI: 10.13286/j.cnki.chinhosppharmacyj.2015.19.22. 王建栋, 王红珍, 张爱莲, 等. 金线莲苷研究进展[J]. 中国医院药学杂志, 2015, 35(19): 1795-1798, 1802. DOI: 10.13286/j.cnki.chinhosppharmacyj.2015.19.22.
[27]	LIU TT. Immunosuppressive drug for autoimmune hepatitis, on dendritic cells/CD8⁺T cells communication[D]. Wuhan: Huazhong University of Science and Technology, 2017. 刘婷婷. 金线莲苷靶向树突状细胞与CD8⁺T细胞的相互作用抗自身免疫性肝炎作用机制研究[D]. 武汉: 华中科技大学, 2017.
[28]	DENG YF, XU QQ, CHEN TQ, et al. Kinsenoside alleviates inflammation and fibrosis in experimental NASH mice by suppressing the NF-κB/NLRP3 signaling pathway[J]. Phytomedicine, 2022, 104: 154241. DOI: 10.1016/j.phymed.2022.154241.
[29]	TAN WY. Effect and molecular mechanisms of kinsenoside against autoimmune hepatitis[D]. Wuhan: Huazhong University of Science and Technology, 2016. 谈婉月. 金线莲苷治疗自身免疫性肝炎的作用和分子机制研究[D]. 武汉: 华中科技大学, 2016.
[30]	LI GM, LI Y. Research status of pharmacological effects of ginsenosides[J]. Chin J Clin Pharmacol, 2020, 36(8): 1024-1027. DOI: 10.13699/j.cnki.1001-6821.2020.08.024. 李贵明, 李燕. 人参皂苷药理作用研究现状[J]. 中国临床药理学杂志, 2020, 36(8): 1024-1027. DOI: 10.13699/j.cnki.1001-6821.2020.08.024.
[31]	LING C, LI Y, ZHU X, et al. Ginsenosides may reverse the dexamethasone-induced down-regulation of glucocorticoid receptor[J]. Gen Comp Endocrinol, 2005, 140(3): 203-209. DOI: 10.1016/j.ygcen.2004.11.003.
[32]	ZHANG KH, ZHOU ME, LI Y. Prospecting the therapeutic value of ginsenosides based on the relevant knowledge of autoimmune hepatitis[J]. J Med Res, 2021, 50(4): 137-139. DOI: 10.11969/j.issn.1673-548X.2021.04.032. 张克慧, 周蒙恩, 李勇. 基于自身免疫性肝炎的相关认识展望人参皂苷的治疗价值[J]. 医学研究杂志, 2021, 50(4): 137-139. DOI: 10.11969/j.issn.1673-548X.2021.04.032.
[33]	YU Q, ZENG KW, MA XL, et al. Ginsenoside Rk1 suppresses pro-inflammatory responses in lipopolysaccharide-stimulated RAW264.7 cells by inhibiting the Jak2/Stat3 pathway[J]. Chin J Nat Med, 2017, 15(10): 751-757. DOI: 10.1016/S1875-5364(17)30106-1.
[34]	SHANG J, LIU W, YIN C, et al. Cucurbitacin E ameliorates lipopolysaccharide-evoked injury, inflammation and MUC5AC expression in bronchial epithelial cells by restraining the HMGB1-TLR4-NF-κB signaling[J]. Mol Immunol, 2019, 114: 571-577. DOI: 10.1016/j.molimm.2019.09.008.
[35]	MOHAMED GA, IBRAHIM S, EL-AGAMY DS, et al. Cucurbitacin E glucoside alleviates concanavalin A-induced hepatitis through enhancing SIRT1/Nrf2/HO-1 and inhibiting NF-κB/NLRP3 signaling pathways[J]. J Ethnopharmacol, 2022, 292: 115223. DOI: 10.1016/j.jep.2022.115223.
[36]	JIANG HX, WU QS, LIU L, et al. Research progress on triterpenoids and their pharmacological activities of Tripterygium wilfordii[J]. Chin Tradit Patent Med, 2022, 44(4): 1223-1231. DOI: 10.3969/j.issn.1001-1528.2022.04.033. 蒋红霞, 伍秋珊, 刘莉, 等. 雷公藤三萜类成分及其药理活性研究进展[J]. 中成药, 2022, 44(4): 1223-1231. DOI: 10.3969/j.issn.1001-1528.2022.04.033.
[37]	ZHANG X, ZHAO W, LIU X, et al. Celastrol ameliorates inflammatory pain and modulates HMGB1/NF-κB signaling pathway in dorsal root ganglion[J]. Neurosci Lett, 2019, 692: 83-89. DOI: 10.1016/j.neulet.2018.11.002.
[38]	ZHANG M, CHEN Y, YANG MJ, et al. Celastrol attenuates renal injury in diabetic rats via MAPK/NF-κB pathway[J]. Phytother Res, 2019, 33(4): 1191-1198. DOI: 10.1002/ptr.6314.
[39]	WANG S, HUANG Z, LEI Y, et al. Celastrol alleviates autoimmune hepatitis through the PI3K/AKT signaling pathway based on network pharmacology and experiments[J]. Front Pharmacol, 2022, 13: 816350. DOI: 10.3389/fphar.2022.816350.
[40]	PAN HH, CAO Y, HU SY, et al. Protective effect of inclusion complex of naringenin and β-cyclodextrin in acute liver injury lnduced by acetaminophen in mice[J]. J Hubei Univ Sci Technol (Med Sci), 2018, 32(1): 1-4, 6. DOI: 10.16751/j.cnki.2095-4646.2018.01.0001. 潘海华, 曹宇, 胡少洋, 等. 柚皮素-β-环糊精包合物对乙酰氨基酚致小鼠急性肝损伤的保护作用[J]. 湖北科技学院学报(医学版), 2018, 32(1): 1-4, 6. DOI: 10.16751/j.cnki.2095-4646.2018.01.0001.
[41]	ZHANG LL, YU ZJ, HE BZ. Protective effect of naringenin on a mouse model of autoimmune hepatitis by the regulation of TRAF6/JNK signaling[J]. Zhejiang J Integr Tradit Chin West Med, 2021, 31(9): 792-797, 809. DOI: 10.3969/j.issn.1005-4561.2021.09.002. 张露露, 余真君, 何宝泽. 柚皮素对自身免疫性肝炎模型小鼠保护作用及TRAF6/JNK信号通路的影响[J]. 浙江中西医结合杂志, 2021, 31(9): 792-797, 809. DOI: 10.3969/j.issn.1005-4561.2021.09.002.
[42]	LIU HY, JIANG CT, FENG J, et al. Research progress of Tanshinones[J]. Chin Pharmacol Bull, 2016, 32(12): 1643-1647. DOI: 10.3969/j.issn.1001-1978.2016.12.004. 刘慧颖, 姜长涛, 冯娟, 等. 丹参酮类化合物研究进展[J]. 中国药理学通报, 2016, 32(12): 1643-1647. DOI: 10.3969/j.issn.1001-1978.2016.12.004.
[43]	YUE S, HU B, WANG Z, et al. Salvia miltiorrhiza compounds protect the liver from acute injury by regulation of p38 and NF-κB signaling in Kupffer cells[J]. Pharm Biol, 2014, 52(10): 1278-1285. DOI: 10.3109/13880209.2014.889720.
[44]	ZHONG W, QIAN K, XIONG J, et al. Curcumin alleviates lipopolysaccharide induced sepsis and liver failure by suppression of oxidative stress-related inflammation via PI3K/AKT and NF-κB related signaling[J]. Biomed Pharmacother, 2016, 83: 302-313. DOI: 10.1016/j.biopha.2016.06.036.
[45]	DONG L, TANG HH, SHEN XY, et al. Study on the mechanism of curcumin combined with Erzhi pill inhibiting concanavalin A inducing immune hepatitis in mice[J]. Lishizhen Med Mater Med Res, 2020, 31(3): 532-536. DOI: 10.3969/j.issn.1008-0805.2020.03.007. 董玲, 唐焕焕, 沈晓燕, 等. 姜黄素联合二至丸抑制刀豆蛋白A诱导小鼠免疫性肝炎机制的研究[J]. 时珍国医国药, 2020, 31(3): 532-536. DOI: 10.3969/j.issn.1008-0805.2020.03.007.