基于网络药理学与分子对接研究四逆散治疗肝癌的作用机制

李菁; 莫嘉浩; 许洪彬; 朱俊霞; 史佩玉; 邢万里; 钟崇; 林丽珠

doi:10.3969/j.issn.1001-5256.2020.09.018

基于网络药理学与分子对接研究四逆散治疗肝癌的作用机制

DOI: 10.3969/j.issn.1001-5256.2020.09.018

1. 广州中医药大学第一临床医学院
2. 湖南中医药大学第一附属医院肿瘤科
3. 广州中医药大学第二临床医学院
4. 广州中医药大学第一附属医院

基金项目:

国家自然科学基金(81873303)；湖南省自然基金青年项目(2016JJ6113)；湖南中医药大学中医学一流学科开放基金项目(2018ZYX51)；湖南省卫健委科研计划项目(20200949)；广东省中医药管理局名中医传承工作室建设项目(粤中医办函2018[5]号)；

详细信息

中图分类号: R285
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出版历程
- 收稿日期: 2020-02-24
- 出版日期: 2020-09-20

Mechanism of action of Sini powder in treatment of liver cancer based on network pharmacology and molecular docking

The First Clinical Medical College,Guangzhou University of Chinese Medicine
Department of Oncology,The First Affiliated Hospital of Hunan University of Chinese Medicine
The Second Clinical Medical School,Guangzhou University of Chinese Medicine
The First Affiliated Hospital of Guangzhou University of Chinese Medicine

Research funding:

摘要

摘要: 目的联合网络药理学-分子对接研究四逆散治疗肝癌的作用机制。方法运用中药系统药理学数据库和分析平台（TCMSP）获取四逆散的化合物及靶标,通过Uniprot获取对应的基因Symbol;从人类基因数据库获取肝癌的疾病基因,并筛选出与四逆散靶标基因的交集基因;运用Cytoscape3.7.1软件绘制"中药-化合物-治疗靶标"网络图;运用STRING构建蛋白质相互作用（PPI）网络、R studio软件对治疗靶标进行GO和KEGG富集分析,并对结果进行可视化;选择靶点数目最多的活性成分作为配体,PPI网络中度值（Degree）最大的靶点作为受体,预测受体-配体复合物结构与相互结合的氨基酸残基。结果研究筛选得到四逆散治疗肝癌核心靶标91个,相关活性成分141种,其中槲皮素、山柰酚等为四逆散治疗肝癌的主要活性成分; TP53、HSP90AA1等是治疗主要作用靶标; GO富集分析后共获得符合筛选标准的条目1007条,主要涉及抗氧化反应、蛋白丝氨酸-苏氨酸激酶活性调控、细胞应激反应等多个生物过程,KEGG富集分析共获得102条,主要调控乙型肝炎通路、PI3K-Akt信号通路以防治肝癌,分子对接结果验证...
- 四逆散 /
- 肝肿瘤 /
- 分子对接模拟 /
- 网络药理学
Abstract: Objective To investigate the mechanism of action of Sini powder in the treatment of liver cancer based on network pharmacology and molecular docking. Methods Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform was used to obtain the compound and target of Sini powder,and the corresponding gene Symbol was obtained through Uniprot. The disease genes of liver cancer were obtained from Human Genome Database,and the genes with intersection with the target genes of Sini powder were screened out. Cytoscape3. 7. 1 software was used to draw the map of“traditional Chinese medicine( TCM)-compound-target”network. STRING was used to construct a protein-protein interaction( PPI) network,R studio software was used to conduct gene ontology( GO) and Kyoto Encyclopedia of Genes and Genomes( KEGG) enrichment analyses on therapeutic targets,and then the results were visualized. The active component with the highest number of targets was selected as the ligand,and the target with the highest degree in the PPI network was selected as the receptor,so as to predict the structure of receptor-ligand complex and the amino acid residues that bind to each other. Results In this study,91 core targets and 141 relevant active components of Sini powder were screened out,among which quercetin and kaempferol were the main active components in the treatment of liver cancer. TP53 and HSP90 AA1 were the main therapeutic targets. The GO enrichment analysis obtained 1007 items which met the screening criteria,which were mainly involved in the biological processes of antioxidation reaction,activity regulation of protein serine and threonine kinase,and cellular stress response. The KEGG enrichment analysis obtained 102 pathways,which mainly regulated the hepatitis B pathway and the PI3 K-Akt signaling pathway in the prevention and treatment of liver cancer. The results of molecular docking showed a synergistic antitumor effect between the crystal structure domains VAL147,CYS220,GLU221,and PRO222 of quercetin-TP53. Conclusion This study reveals the mechanism of action of Sini powder in the treatment of liver cancer by acting on multiple targets and signaling pathways,which provides a theoretical basis for biological experiments.
- Sini powders /
- liver neoplasms /
- molecular docking simulation /
- network pharmacology

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参考文献(33)

[1] GE JB,XU YJ. Internal medicine[M]. 9th Ed. Beijing:People’s medical publishing house,2018.(in Chinese)葛均波，徐永健．内科学[M]．第9版．北京:人民卫生出版社，2018.

[2] FERLAY J,SOERJOMATARAM I,DIKSHIT R,et al. Cancer incidence and mortality worldwide:Sources, methods and major patterns in GLOBOCAN 2012[J]. Int J Cancer,2015,136(5):e359-e386.

[3] ZHU XS,LIU WC. The progress in epidemiology and risk factors of primary liver cancer worldwide[J]. Mod Oncol,2008,26(14):2297-2301.(in Chinese)朱笑生，刘文超．原发性肝癌全球流行情况和危险因素的新进展[J]．现代肿瘤医学，2018,26(14):2297-2301.

[4] ZHAO HT,ZHAI XF. The clinical progress on the treatment of primary liver cancer by chinese medicine compound preparations[J]. Chin J Tradit Chin Med,2017,23(17):107-110.(in Chinese)赵河通，翟笑枫．中药复方治疗原发性肝癌的临床研究进展[J]．中医药导报，2017,23(17):107-110.

[5] LING CQ,YUE XQ,LING C. Three advantages of using traditional Chinese medicine to prevent and treat tumor[J]. J Integr Med,2014,12(4):331-335.

[6] ZHAO CQ,ZHOU Y,PING J,et al. Traditional Chinese medicine for treatment of liver diseases:Progress,challenges and opportunities[J]. J Integr Med,2014,12(5):401-408.

[7] FANG XF,ZHAO L,LYU YK. Experience of treating hepatocellular carcinoma with sini SAN[J]. Zhejiang J Integr Tradit Chin West Med,2010,20(7):414.(in Chinese)方晓芬，赵磊，吕宇克．周维顺应用四逆散加减治疗肝癌经验[J]．浙江中西医结合杂志，2010,20(7):414.

[8] WANG W,YI LY,GAO JM. Effects of Sini Powder on transplanted hepatocarcinoma in nude mice Sirt1 and p53 expression[J]. Pharmocol Clin Chin Mater Med,2014,30(3):16-18.(in Chinese)王玮，伊莉雅，高健美．四逆散对HepG2移植性肝癌裸鼠Sirt1和p53表达的影响[J]．中药药理与临床，2014,30(3):16-18.

[9] MORRIS GM,LIM-WILBY M. Molecular docking[J]. Methods Mol Biol,2008,443:365-382.

[10] LI KN,ZHENG HT,ZHANG Y,et al. Simulation and prediction of material foundation of Puerariae Radix for ischemic stroke based on molecular docking technology[J]. Chin Tradit Herb Drug,2008,49(8):1847-1853.(in Chinese)李克宁，郑惠婷，张雨，等．基于分子对接技术虚拟筛选葛根治疗缺血性脑卒中的物质基础研究[J]．中草药，2018,49(8):1847-1853.

[11] XIAO Y,REN MD,LU GF,et al. The effects of saikosaponind on the expression of human hepatocellular carcinoma cell BECN1 and autophagic function[J]. J Xi’an Jiaotong Univ(Med Sci),2017,38(1):127-130.(in Chinese)肖祎，任牡丹，卢桂芳，等．柴胡皂甙d对人肝癌细胞BECN1表达及自噬功能的影响[J]．西安交通大学学报(医学版)，2017,38(1):127-130.

[12] WANG YL,SONG T,HU YN,et al. Effects of saikosaponins-d on Ang-2 and VEGF expressions in experimental hepatocarcinoma in rats[J]. J Xi’an Jiaotong Univ(Med Sci),2013,34(5):664-668.(in Chinese)王艳丽，宋涛，胡雅楠，等．柴胡皂甙d对实验性大鼠肝癌Ang-2及VEGF表达的影响[J]．西安交通大学学报(医学版)，2013,34(5):664-668.

[13] ZHANG FH,HUANG XS. Effect of radix bupleurae saponin D on in vitro differentiation of hepatocellular carcinoma cells[J].Guangdong Med,2009,30(12):1775-1777.(in Chinese)张丰华，黄秀深．柴胡皂甙D对肝癌细胞体外分化的影响[J]．广东医学，2009,30(12):1775-1777.

[14] ZHANG J,JIANG TY,WANG SL. Application of prodrug design in improving anticancer drug properties[J]. World Clin Med,2007,28(1):47-51.(in Chinese)张婧，姜同英，王思玲．前药设计在改善抗癌药物特性中的应用[J]．世界临床药物，2007,28(1):47-51.

[15] WANG BW. Structural based drug design for smal molecular stabilizers of p53 mutant Y220C[J/CD]. J Clin Med Literature(Electronic Edition),2007,4(103):20367-20369.(in Chinese)汪博闻．基于结构的p53突变体Y220C小分子稳定剂的药物设计[J/CD]．临床医药文献电子杂志，2017,4(103):20367-20369.

[16] BAUER MR,JONES RN,TAREQUE RK,et al. A structureguided molecular chaperone approach for restoring the transcriptional activity of the p53 cancer mutant Y220C[J]. Future Med Chem,2019,11(19):2491-2504.

[17] XU Q,SUN Y,CHEN T,et al. A case study of sini SAN on the role of Chinese medicine in compound compounds[J]. Pharmocol Clin Chin Mater Med,2007,23(5):45.(in Chinese)徐强，孙洋，陈婷，等．以四逆散为例谈中药成分在复方中的作用地位[J]．中药药理与临床，2007,23(5):45.

[18] HUANG DB,GUAN J. The improvement of TCM syndrome and prognosis of primary liver cancer treated with jiawei sinisan[J]. Nei Mongol J Tradit Chin Med,2008,37(6):1-2.(in Chinese)黄东彬，管静．四逆散加味治疗原发性肝癌的中医证候改善及预后分析[J]．内蒙古中医药，2018,37(6):1-2.

[19] ZHAO LM. Effect observation of jiawei sini SAN in the treatment of primary liver cancer[J/CD]. J Cardiov Dis Integr Tradit Western Med,2016,4(29):149-151.(in Chinese)赵利孟．加味四逆散治疗原发性肝癌的效果观察[J/CD]．中西医结合心血管病电子杂志，2016,4(29):149-151.

[20] LI ZQ. 25 cases of primary liver cancer pain treated by jiawei sini SAN[J/CD]. J Clin Chin Med,2014,26(8):788-789.(in Chinese)李自强．加味四逆散治疗原发性肝癌疼痛25例[J]．中医药临床杂志，2014,26(8):788-789.

[21] ZHU G,LIU X,LI H,et al. Kaempferol inhibits proliferation,migration,and invasion of liver cancer HepG2 cells by downregulation of microRNA-21[J]. Int J Immunopathol Pharmacol,2018,32:2058738418814341.

[22] YOUNESS RA,ASSAL RA,EZZAT SM,et al. A methoxylated quercetin glycoside harnesses HCC tumor progression in a TP53/miR-15/miR-16 dependent manner[J]. Nat Prod Res,2018.[Online ahead of print]

[23] ZHANG XY. Relationship between changes in TP53,CTNNB1and CDKN2A genes and HBV infection associated hepatocellular carcinoma in fujian province[D]. Fuzhou:Fujian Medical University,2017.(in Chinese)张馨月．TP53、CTNNB1、CDKN2A基因改变与福建省HBV感染相关肝细胞癌的关系[D]．福州:福建医科大学，2017.

[24] WEI YL,XIANG X,ZHAO LY,et al. Expression of HSP90AA1/HSPA8 in hepatocellular carcinoma patients with depression and its clinical significance[J]. China Cancer,2019,28(5):387-394.(in Chinese)韦珏伶，向骁，赵凌云，等．HSP90AA1/HSPA8在合并抑郁情绪的肝癌患者中的表达及临床意义[J]．中国肿瘤，2019,28(5):387-394.

[25] XU QN,LU YF,TANG BZ,et al. Correlation between mRNA expression of heat shock protein in tumor tissue and tumor stage in patients with HBV-related hepatocellular carcinoma[J]. J Clin Hepatol,2017,33(5):869-874.(in Chinese)徐庆年，陆云飞，汤伯宗，等．HBV相关肝细胞癌肿瘤组织中热休克蛋白mRNA表达水平与肿瘤分期的相关性分析[J]．临床肝胆病杂志，2017,33(5):869-874.

[26] HAN D,LI W,WANG Q. Expression and diagnostic value of serine/threonine kinase,Wnt2 pathway related proteins and c-myc gene in hepatocellular carcinoma[J]. Chin J Integr Tradit West Med Liver Dis,2016,26(3):173-175.(in Chinese)韩丹，李炜，王倩．丝氨酸/苏氨酸激酶、Wnt2通路相关蛋白及C-myc基因在肝癌中的表达及诊断价值[J]．中西医结合肝病杂志，2016,26(3):173-175.

[27] CHEN WQ,CUI FQ,FAN CS,et al. Strategies of primary prevention of liver cancer in China:Expert Consensus(2018)[J]. China Oncol,2008,27(9):660-669.(in Chinese)陈万青，崔富强，樊春笋，等．中国肝癌一级预防专家共识(2018)[J]．中国肿瘤，2018,27(9):660-669.

[28] FENG LN,JIN QL. Tenofovir can reduce the risk of hepatocellular carcinoma in patients with chronic HBV infection[J]. J Clin Hepatol,2020,36(2):463.(in Chinese)冯丽娜，金清龙．替诺福韦可降低慢性HBV感染者发生肝细胞癌的风险[J]．临床肝胆病杂志，2020,36(2):463.

[29] LI WJ,TANG XP,JIANG FQ,et al. The clinicopathological significance of cyclin D1,Bcl-2,P53 and survivin in hepatitis C virus related hepatocellular carcinoma[J]. Prog Mod Biomed,2016,16(8):1439-1446.(in Chinese)李文娟，唐晓鹏，蒋芳清，等．CyclinD1,Bcl-2,P53和Survivin在丙型肝炎病毒相关肝细胞肝癌中临床病理意义[J]．现代生物医学进展，2016,16(8):1439-1446.

[30] JIANG J,ZHANG Y,GUO Y,et al. MicroRNA-3127 promotes cell proliferation and tumorigenicity in hepatocellular carcinoma by disrupting of PI3K/AKT negative regulation[J].Oncotarget,2015,6(8):6359-6372.

[31] LIU PY. Regulation of quercetin on mitochondrial homeostasis and autophagy in hepatic steatosis and the mediating mechanism of Frataxin[D]. Wuhan:Huazhong University of Science and Technology,2018.(in Chinese)刘佩意．槲皮素对肝脂肪变性中线粒体稳态与自噬的调控及Frataxin的介导机制[D]．武汉:华中科技大学，2018.

[32] WANG ZX,ZHOU J,TANG Y,et al. Quercetin induces P53-independent G2/M arrest and apoptosis in cancer cells[J]. Chin J Pharmacol Toxicol,2008,32(10):790-796.(in Chinese)王梓萱，周静，唐玥，等．槲皮素诱导肿瘤细胞P53非依赖的G2/M周期阻滞和凋亡[J]．中国药理学与毒理学杂志，2018,32(10):790-796.

[33] ZHANG C,YANG LJ,LI J,et al. Radix paeoniae alba and radix bupleuri therapeutic mechanism for hepatocellular carcinoma based on network pharmacology[J]. Chin Arch Tradit Chin Med,2020,38(2):175-179,286.(in Chinese)张弛，杨良俊，李菁，等．基于网络药理学的白芍-柴胡药对治疗肝细胞癌的作用机制探析[J]．中华中医药学刊，2020,38(2):175-179,286.

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