基于网络药理学的五苓散多成分-多靶点-多通路作用机制研究

doi:10.3976/j.issn.1002-4026.2020.01.008

摘要/Abstract

摘要： 通过中药系统药理学数据库与分析平台（traditional Chinese medicine system pharmacology datebase and analysis platform,TCMSP)筛选五苓散组分白术、茯苓、猪苓、泽泻、桂枝的潜在活性成分，PharmMapper服务器预测潜在靶点，构建化合物-靶点网络、蛋白互作( protein-protein interaction，PPI) 网络，进行基因本体( gene ontology，GO) 富集分析、基于KEGG( Kyoto encyclopedia of genes and enomes) 的生物通路富集分析。结果表明，筛选得到五苓散中50种活性成分，构建化合物靶点网络共459个节点，关键靶点包括CSDE1、PRPS1、HSD17B4、CLPP、ACBD7、AZGP1等。构建五苓散靶点的PPI互作网络包含155个节点和527条相互作用关系，关键节点包括CSDE1、CITED2、RANBP2、HSD17B4、TAF13、SOD2等。GO富集分析途径相关条目主要涉及细胞溶质、细胞对有机物质和化学刺激的反应，含氮物质代谢，有机物循环代谢进程，蛋白、小分子和离子结合及转运活性等。KEGG代谢通路分析包括膀胱癌、前列腺癌、内分泌抵抗、癌症中的蛋白聚糖、流体剪切应力和动脉粥样硬化等途径。研究结果初步验证了五苓散药理作用的分子机制，为进一步深入揭示其分子作用机制奠定了基础，预测五苓散的潜在作用靶点如PRPS1、HSD17B4等，可为五苓散的深入研究提供新思路。

关键词: 五苓散, 网络药理学, PPI, GO , KEGG

Abstract: The potential active components of Wulingsan were obtained using the TCMSP database, and the potential targets were predicated using PharmMapper servers. The compoundtarget and protein-protein interaction (PPI) networks were constructed to perform enrichment analyses of gene ontology (GO) and biological pathway based on the Kyoto Encyclopedia of Genes and Genomes (KEGG). Results show that a compound-target network comprising 50 major active components and 459 targets was obtained; the key targets included CSDE1, PRPS1, HSD17B4, CLPP, ACBD7, and AZGP1. A PPI network responsible for constructing Wulingsan targets consisted of 155 nodes and 527 interactions; key targets included CSDE1, CITED2, RANBP2, HSD17B4, TAF13, and SOD2. The items associated with the GO enrichment analysis pathway primarily involved cytosol, protein, and small molecules as well as cells’ reaction to organic substances and chemical stimulations, nitrogen metabolism, organic matter metabolism, and ion binding and transport activity. A KEGG metabolic pathway enrichment analysis included proteoglycans in cancer as well as bladder cancer, prostate cancer, endocrine resistance, fluid shear stress, and atherosclerosis. Results initially verified molecular mechanism for the pharmacological action of the main active components of Wulingsan, thereby providing evidence for further elucidation of its molecular mechanism, predicting its potential targets (such as PRPS1 and HSD17B4), and delivering a new method for studies on Wulingsan development and application.

Key words: Wulingsan, network pharmacology, proteinprotein interaction (PPI), gene ontology (GO), kyoto encyclopedia of genes and genomes (KEGG)

中图分类号:

R285.5

曹铭晨, 于振英, 辛兆洋, 徐龙, 杨智威, 任炜, 邢晓敏, 荆凡波. 基于网络药理学的五苓散多成分-多靶点-多通路作用机制研究[J]. 山东科学, 2020, 33(1): 51-60.

CAO Ming-chen, YU Zhen-ying, XIN Zhao-yang, XU Long, YANG Zhi-wei, REN Wei, XING Xiao-min, JING Fan-bo. Multicomponent-multitarget-multichannel mechanism of Wulingsan based on network pharmacology[J]. Shandong Science, 2020, 33(1): 51-60.

参考文献 33

1	时悦, 姚璎珈, 蔺莹, 等. 基于网络药理学的开心散治疗阿尔茨海默病的作用机制分析[J]. 药学学报, 2018, 53(9): 1458-1466. doi: 10.16438/j.0513-4870.2018-0474
2	杨欣, 李亚辉, 钱海兵, 等. 基于网络药理学及分子对接分析熊果酸抗类风湿性关节炎的分子机制[J]. 中国实验方剂学杂志, 2018, 24(18): 207-214. doi: 10.13422/j.cnki.syfjx.20181828
3	梁学振, 许波, 李刚, 等. 基于网络药理学和生物信息学研究补肾活血胶囊治疗骨性关节炎分子机制[J]. 中华中医药杂志, 2018, 33(5): 2084-2088.
4	倪诚. 王琦教授从化气布津论五苓散制方思想及其运用心法[J]. 北京中医药大学学报, 2011, 34(10): 699-701.
5	储生康. 五苓散临床应用体会[J]. 中医药临床杂志, 2015, 27(4): 561-562. doi: 10.16448/j.cjtcm.2015.0214
6	夏黎明. 五苓散临床应用及现代研究[J]. 现代生物医学进展, 2006, 6(6): 75. doi: 10.13241/j.cnki.pmb.2006.06.034
7	RU J L, LI P, WANG J N, et al. TCMSP: A database of systems pharmacology for drug discovery from herbal medicines[J]. Journal of Cheminformatics, 2014, 6: 13. doi: 10.1186/1758-2946-6-1
8	WISHART D S, FEUNANG Y D, GUO A C,et al. DrugBank 5.0: A major update to the DrugBank database for 2018［J］. Nucleic Acids Research. 2018,46(1):1074-1082. doi: 10.1093/nar/gkx1037
9	WANG X, SHEN Y H, WANG S W, et al. PharmMapper 2017 update: A web server for potential drug target identification with a comprehensive target pharmacophore database[J]. Nucleic Acids Research, 2017, 45(1): 356-360. doi: 10.1093/nar/gkx374
10	APWILER R,BAIROCH A,WUCH,et al.UniProt: the universal protein knowledgebase[J]. Nucleic Acids Research, 2017, 45(1):158-169. doi: 10.1093/nar/gky092
11	US National Library of Medicine.PubChem[DB/OL].[2018-9-23] . https://pubchem.ncbi.nlm.nih.gov.
12	SHANNON P. Cytoscape: A software environment for integrated models of biomolecular interaction networks[J]. Genome Research, 2003, 13(11): 2498-2504. doi: 10.1101/gr.1239303
13	HUANG D W, SHERMAN B T, LEMPICKI R A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources[J]. Nature Protocols, 2009, 4(1): 44-57. doi: 10.1038/nprot.2008.211
14	Kanehisa Laboratories.KEGG:Kyoto Encyclopedia of Genes and Genomes[DB/OL].[2018-9-23]. https://www.kegg.jp/kegg.
15	SZKLARCZYK D, GABLE A L, LYON D, et al. STRING v11:protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets[J]. Nucleic Acids Research, 2019, 47(1): 607-613. doi: 10.1093/nar/gky1131
16	The R Foundation.R:The R Project for Statistical Computing [EB/OL].[2018-10-13]. https://www.r-project.org.
17	赵鸣芳. 五苓散的应用思路及机理分析[J]. 江苏中医药, 2005, 26(7): 36-38. doi: 10.3969/j.issn.1672-397X.2005.07.022
18	马盼盼. Vitamin K2抑制HSD17B4促肝癌细胞增殖的机制研究[D]. 石家庄: 河北医科大学, 2016.<br />
19	路欣. HSD17B4促进肝癌细胞增殖及其机制的研究[D]. 石家庄: 河北医科大学, 2015.<br />
20	邱红星. 五苓散加味治疗痛风性关节炎70例临床观察[J]. 中国药物经济学, 2014, 9(3): 59-60.<br />
21	ZAKATAEVA N P, ROMANENKOV D V, SKRIPNIKOVA V S, et al. Wild-type and feedback-resistant phosphoribosyl pyrophosphate synthetases from Bacillus amyloliquefaciens:Purification, characterization, and application to increase purine nucleoside production[J]. Applied Microbiology and Biotechnology, 2012, 93(5): 2023-2033. doi: 10.1007/s00253-011-3687-3
22	BIN G, BO Z, JING W, et al. Fluid shear stress suppresses TNF-α-induced apoptosis in MC3T3-E1 cells: Involvement of ERK5-AKT-FoxO3a-Bim/FasL signaling pathways[J]. Experimental Cell Research, 2016, 343(2): 208-217. doi: 10.1016/j.yexcr.2016.03.014
23	LIM K T, KIM J, SEONWOO H, et al. Enhanced osteogenesis of human alveolar bone-derived mesenchymal stem cells for tooth tissue engineering using fluid shear stress in a rocking culture method[J]. Tissue Engineering Part C: Methods, 2013, 19(2): 128-145. doi: 10.1089/ten.tec.2012.0017
24	JIANG J, ZHAO L G, TENG Y J, et al. ERK5 signalling pathway is essential for fluid shear stress-induced COX-2 gene in MC3T3-E1 osteoblast[J]. Molecular and Cellular Biochemistry, 2015, 406(1/2): 237-243. doi: 10.1007/s11010-015-2441-z
25	黄红维. Ezrin/Radixin/Moesin蛋白在类风湿关节炎滑膜中的表达及其对成纤维样滑膜细胞增殖的影响[D]. 广州: 中山大学, 2010.
26	ALEXY T，JAMES A M，SEARIES C D．Shear sensitive microRNAs and atherosclerosis［J］． Biorheology，2014，51(2/3):47-158． doi: 10.3233/BIR-140657
27	LIVAK K J, SCHMITTGEN T D. Analysis of relative gene data using real-time quantitative PCR and the 2-ΔΔC T method[J]. Methods, 2001, 25(4): 402-408. doi: 10.1006/meth.2001.1262
28	KOHLSTEDT K, TROUVAIN C, BOETTGER T, et al. AMP-activated protein kinase regulates endothelial cell angiotensin-converting enzyme via p53 and the post-transcriptional regulation of microRNA-143/145[J]. Circulation Research, 2013, 112(8): 1150-1158. doi: 10.1161/circresaha.113.301282
29	CHEN K, FAN W D, WANG X, et al. MicroRNA-101 mediates the suppressive effect of laminar shear stress on mTOR in vascular endothelial cells[J]. Biochemical and Biophysical Research Communications, 2012, 427(1): 138-142. doi: 10.1016/j.bbrc.2012.09.026
30	侯丽娜. 慢性心力衰竭尿液蛋白标记物的筛选、鉴定及应用研究[D]. 广州: 南方医科大学, 2013.
31	KOBAYASHI H, KAWAUCHI D, HASHIMOTO Y, et al. The control of precerebellar neuron migration by RNA-binding protein Csde1[J]. Neuroscience, 2013, 253: 292-303. DOI:. doi: 10.1016/j.neuroscience.2013.08.055
32	LANFRAY D, RICHARD D. Emerging signaling pathway in arcuate feeding-related neurons: role of the Acbd7[J]. Frontiers in Neuroscience, 2017, 11: 328. DOI:. doi: 10.3389/fnins.2017.00328
33	刘瑛. 锌-α2-糖蛋白在癫痫形成分子机制中作用的研究[D]. 重庆: 重庆医科大学, 2018.

[1]	刘可春, 王勇澄, 臧晓涵, 夏青, 张云, 张姗姗, 孙晨. 网络药理学和斑马鱼模型在中药药效物质及作用机制研究中的应用进展[J]. 山东科学, 2024, 37(2): 29-35.
[2]	付朝举, 成果, 林登梅, 李军, 张楠楠. 阔叶十大功劳抗炎作用机制的实验研究及网络药理学分析[J]. 山东科学, 2024, 37(1): 24-31.
[3]	陈春, 祁大庆, 潘靖文. 基质细胞评分的胃癌临床意义及胃复春胶囊干预机制[J]. 山东科学, 2023, 36(6): 38-47.
[4]	慕娜娜, 廖彬彬, 李镇, 李吉品, 李伊花, 王莹, 陈旭冰. 基于网络药理学和分子对接技术探究地胆草治疗溃疡性结肠炎的作用机制[J]. 山东科学, 2023, 36(6): 48-55.
[5]	王一帆, 张喆, 田财军. 基于网络药理学和分子对接探讨三黄泻心汤治疗阿尔茨海默病的机制[J]. 山东科学, 2023, 36(5): 19-26.
[6]	付梦雅, 敖慧豪, 卜超, 朋汤义, 吴德玲, 韩燕全, 洪燕. 基于指纹图谱和网络药理学的干姜质量标志物预测分析[J]. 山东科学, 2023, 36(4): 35-41.
[7]	尹志鹏, 高云云, 刘文文, 郭蓬勃, 赵英会. 基于网络药理学和分子对接探讨香砂六君子汤治疗幽门螺杆菌相关性胃炎的作用机制[J]. 山东科学, 2023, 36(4): 52-60.
[8]	孙铁锋, 董丽敏, 焦子麒, 王平. 基于数据挖掘及网络药理学探讨中医药抗呼吸道合胞病毒的用药规律及作用机制[J]. 山东科学, 2023, 36(3): 1-9.
[9]	朱洁, 王征, 梁艳妮. 基于网络药理学探究小青龙汤治疗新型冠状病毒肺炎的作用机制[J]. 山东科学, 2023, 36(3): 10-17.
[10]	董朋峻, 蔡彬. 基于网络药理学与代谢组学探讨枳实-厚朴药对治疗慢传输型便秘的作用机制[J]. 山东科学, 2023, 36(3): 18-26.
[11]	赵鑫, 黄碧云, 吴丹, 张梅. 基于网络药理学和分子对接探讨桂芍镇痫片治疗颞叶癫痫的作用机制[J]. 山东科学, 2023, 36(3): 27-37.
[12]	王一帆, 张艳艳, 田财军. 基于网络药理学探讨尪痹方治疗类风湿性关节炎的机制[J]. 山东科学, 2023, 36(3): 38-45.
[13]	刘文文, 高云云, 尹志鹏, 吕刚, 王玉, 赵英会. 基于网络药理学和分子对接探讨黄连温胆汤治疗幽门螺杆菌相关性胃炎的作用机制[J]. 山东科学, 2023, 36(2): 23-32.
[14]	刘纹纹, 李长庚, 孔娜, 刘双, 董红敬. 基于网络药理学和分子对接研究十味益脾颗粒的作用机制[J]. 山东科学, 2023, 36(2): 33-40.
[15]	申凤霞, 范建伟, 李倩, 马云, 冯群, 关永霞. 基于网络药理学及分子对接探究茵栀黄颗粒治疗肝纤维化的作用机制[J]. 山东科学, 2023, 36(1): 23-33.