目的: 应用网络药理学及分子对接方法分析蒙药嘎日迪-13治疗脑卒中的作用机制。方法: 应用TCMSP数据库中各成分口服生物利用度及类药性筛选活性成分,并根据血脑屏障通透性进一步筛选治疗中枢神经系统疾病的活性成分,通过DisGeNET数据库预测嘎日迪-13治疗脑卒中的潜在靶点;对靶点进行基因本体(gene Ontology, GO)、京都基因与基因组百科全书(kyoto Encyclopedia of Genes and Genomes,KEGG)和蛋白-蛋白相互作用(protein-protein interaction, PPI)分析,筛选关键靶点;应用分子对接验证化合物与关键靶点的结合能力。结果: 通过TCMSP数据库筛选得到嘎日迪-13的活性成分58个,获得蒙药嘎日迪-13治疗脑卒中潜在靶点114个;网络分析结果显示,嘎日迪-13通过参与核因子κB(nuclear factor kappa-B, NF-κB)信号通路、白介素17(interleukin 17, IL17) 信号通路、低氧诱导因子-1(hypoxia inducible factor-1, HIF-1) 信号通路等27条通路发挥保护作用,确定关键靶点包括:NOS3、ACE、IL6、TNF、SERPINE1、VEGFA、IL1β、MMP9、CXCL8、TP53以及MAPK1。结论: 本研究通过网络药理学及分子对接提供了蒙药嘎日迪-13治疗脑卒中的潜在分子依据,揭示了蒙药嘎日迪-13治疗脑卒中的作用机制,为后续研究及临床应用提供了理论支持。
Objective: To analyze the mechanism of the Mongolian medicine Garidi-13 in the treatment of stroke using network pharmacology and molecular docking. Methods: The active components were screened by oral bioavailability and drug-likeness in TCMSP database, and the active components in the treatment of central nervous system diseases were further screened according to the permeability of blood-brain barrier. The potential targets of Garidi-13 in the treatment of stroke were predicted with DisGeNET database. The key targets were screened by Gene Ontology (GO), Kyoto Encyclopedia of Gene and Genomes (KEGG) and Protein-Protein Interaction (PPI), and the binding ability of compounds to key targets was verified by molecular docking. Results: 58 active components of Garidi-13 were screened by TCMSP database, and 114 potential targets of Garidi-13 in treating stroke were obtained. The results of network analysis showed that Garidi-13 played a protective role by participating in 27 pathways such as nuclear factor kappa B (NF-κB) signaling pathway, interleukin 17 (IL17) signaling pathway and hypoxia inducible factor-1 (HIF-1) signaling pathway. Key targets included NOS3, ACE, IL6, TNF, SERPINE1, VEGFA, IL1 β, MMP9, CXCL8, TP53 and MAPK1 were identified. Conclusion: The potential molecular basis of Garidi-13 in the treatment of stroke through network pharmacology and molecular docking were indicated in this study, and the mechanism of Garidi-13 in treating stroke were identified, which provides theoretical support for following research and clinical application of Garidi-13.
[1] 秀布松, 特木其乐, 萨茹拉, 等. 蒙药嘎日迪-13味治疗萨病(脑梗死)恢复期疗效观察[J].中国民族医药杂志, 2020, 26(5): 7-9.
[2] 包巴根那, 乌力吉. 蒙西医结合治疗脑血管疾病45例观察[J].中国民族医药杂志, 2005, 11(4): 7.
[3] 于海波. 蒙西医结合治疗脑梗塞20例[J].中国民族医药杂志, 2009, 15(10): 36.
[4] 曹丽霞, 何静波, 郑延泽, 等. 大鼠脑缺血损伤后髓过氧化物酶的活性变化以及蒙药嘎日迪-13的干预作用[J].中国民族医药杂志, 2016, 22(12): 29-32.
[5] 曹丽霞, 郑延泽, 武海军, 等. 嘎日迪-13对大鼠脑缺血后不同时相不同脑区ICAM-1、VCAM-1表达的影响[J].中华中医药学刊, 2017, 35(12): 3009-3014, I0018, I0019.
[6] Ru JL, Li P, Wang JN, et al. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines[J].J Cheminform, 2014, 6: 13.
[7] Pang XC, Kang D, Fang JS, et al. Network pharmacology-based analysis of Chinese herbal Naodesheng formula for application to Alzheimer's disease[J].Chin J Nat Med, 2018, 16(1): 53-62.
[8] Gfeller D, Grosdidier A, Wirth M, et al. SwissTargetPrediction: a web server for target prediction of bioactive small molecules[J].Nucleic Acids Res, 2014, 42(Web Server issue): W32-W38.
[9] Piero J, Bravo à, Queralt-Rosinach N, et al. DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants[J].Nucleic Acids Res, 2017, 45(D1): D833-D839.
[10] Szklarczyk D, Morris JH, Cook H, et al. The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible[J].Nucleic Acids Res, 2017, 45(D1): D362-D368.
[11] Zhang YQ, Li YT, Mao X, et al. Thyroid hormone synthesis: a potential target of a Chinese herbal formula Haizao Yuhu Decoction acting on iodine-deficient goiter[J].Oncotarget, 2016, 7(32): 51699-51712.
[12] 付旭阳, 高丽, 吕宏, 等. 基于数据挖掘分析蒙药忠伦-5治疗类风湿关节炎的作用机制[J].中国药理学通报, 2020, 36(1): 127-134.
[13] 田彩云, 张浩楠, 何静波, 等. 嘎日迪-13对局灶性脑缺血大鼠NSE、TNF-α、IL-6表达的影响[J].中草药, 2015, 46(5): 716-720.
[14] 陶春, 林琳, 宋葆华, 等. 蒙药嘎日迪-13味丸对脑缺血大鼠海马组织白介素-1β、肿瘤坏死因子-α蛋白及神经细胞凋亡的影响[J].中国老年学杂志, 2015, 35(1): 152-154.
[15] Ma YH, Zechariah A, Qu Y, et al. Effects of vascular endothelial growth factor in ischemic stroke[J].J Neurosci Res, 2012, 90(10): 1873-1882.
[16] Van Den Steen PE, Dubois B, Nelissen I, et al. Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9)[J].Crit Rev Biochem Mol Biol, 2002, 37(6): 375-536.
[17] Rosenberg GA, Yang Y. Vasogenic edema due to tight junction disruption by matrix metalloproteinases in cerebral ischemia[J].Neurosurg Focus, 2007, 22(5): E4.
[18] Gasche Y, Fujimura M, Morita-Fujimura Y, et al. Early appearance of activated matrix metalloproteinase-9 after focal cerebral ischemia in mice: a possible role in blood-brain barrier dysfunction[J].J Cereb Blood Flow Metab, 1999, 19(9): 1020-1028.
[19] Lapchak PA, Chapman DF, Zivin JA. Metalloproteinase inhibition reduces thrombolytic (tissue plasminogen activator)-induced hemorrhage after thromboembolic stroke[J].Stroke, 2000, 31(12): 3034-3040.
[20] 刘凯雯, 刘志杰, 华甜. 趋化因子受体的结构与信号转导机制[J].自然杂志, 2021, 43(1): 18-24.
[21] Strieter RM, Kunkel SL, Showell HJ, et al. Endothelial cell gene expression of a neutrophil chemotactic factor by TNF-alpha, LPS, and IL-1 beta[J].Science, 1989, 243(4897): 1467-1469.
