网络药理学预测麻黄治疗哮喘的抗炎作用机制
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摘要
目的探讨运用网络药理学方法预测麻黄治疗哮喘的抗炎靶点及其相关信号通路,发现哮喘的发病机制。方法在TCMSP数据库中搜索并筛选麻黄的活性成分,运用PharmMapper数据库预测活性成分的作用靶点,并进行分子对接。应用cytoscape3.6.1软件构建麻黄活性成分-预测靶点网络,并对网络拓扑结构进行分析。TTD数据库中搜索抗炎靶点,建立蛋白互作网络,并与麻黄活性成分-预测靶点网络融合,筛选活性成分作用的抗炎靶点。构建麻黄抗炎靶点对抗哮喘的体内反应网络,筛选与哮喘发病相关的抗炎靶点。使用Enrichr数据库以及cytoscape3.6.1对预测的麻黄治疗哮喘的抗炎靶点进行KEGG生物通路富集分析。结果筛选出23个化合物,对应156个靶点蛋白,其中表皮活性生长因子受体(EGFR)、E选择素(SELE)、巨噬细胞迁移抑制因子(M IF)、有丝分裂原激活蛋白激酶14(MAPK 14) 4个靶点可能是麻黄治疗哮喘的重要抗炎靶点。KEGG分析得到的与这些抗炎靶点相关的主要信号通路有上皮细胞信号通路等。结论 EGFR、SELE、MIF、MAPK14可能是麻黄在哮喘治疗中发挥抗炎作用的主要靶点,控制哮喘发生和发展,延缓病情恶化,可考虑整体控制这些抗炎靶点以及信号通路网络,而不仅仅是针对单一途径、疾病的关键靶点。
Objective To explore the pathogenesis of asthma by predicting the anti-inflammatory targets and related signaling pathway of ephedra therapy based on network pharmacology. Methods The active ingredients of ephedra were searched and screened in TCMSP database. The targets of ingredients were predicted with PharmMapper and molecular docking was performed. Then ingredients-targets network was established and analyzed with cytoscape3.6.1. The anti-inflammatory targets in TTD database were searched to build PPI network,which was merged with the ingredients-targets network to screen anti-inflammatory targets connected with ephedra. The vivo reaction network of ephedra anti-inflammatory targets against asthma was constructed to screen anti-inflammatory targets related to asthma. KEGG enrichment analysis was performed with Enrichr database and cytoscape3. 6. 1. Results Altogether 23 active ingredients were screened and 156 targets were obtained. Epidermal active growth factor receptor( EGFR),E-selectin( SELE),macrophage migration inhibitory factor( MIF),mitogen-activated protein kinase 14( MAPK14) might be the important anti-inflammatory targets of ephedra treatment of asthma. All these pathways had epithelial cell signaling pathways.Conclusion The anti-inflammatory mechanism of ephedra treatment of asthma may be related to EGFR,SELE,MIF,MAPK14 and their signaling pathways. To prevent the exacerbation of asthma,instead of a single pathway or a single target,all these targets and their signaling pathways should be controlled holistically.
Objective To explore the pathogenesis of asthma by predicting the anti-inflammatory targets and related signaling pathway of ephedra therapy based on network pharmacology. Methods The active ingredients of ephedra were searched and screened in TCMSP database. The targets of ingredients were predicted with PharmMapper and molecular docking was performed. Then ingredients-targets network was established and analyzed with cytoscape3.6.1. The anti-inflammatory targets in TTD database were searched to build PPI network,which was merged with the ingredients-targets network to screen anti-inflammatory targets connected with ephedra. The vivo reaction network of ephedra anti-inflammatory targets against asthma was constructed to screen anti-inflammatory targets related to asthma. KEGG enrichment analysis was performed with Enrichr database and cytoscape3. 6. 1. Results Altogether 23 active ingredients were screened and 156 targets were obtained. Epidermal active growth factor receptor( EGFR),E-selectin( SELE),macrophage migration inhibitory factor( MIF),mitogen-activated protein kinase 14( MAPK14) might be the important anti-inflammatory targets of ephedra treatment of asthma. All these pathways had epithelial cell signaling pathways.Conclusion The anti-inflammatory mechanism of ephedra treatment of asthma may be related to EGFR,SELE,MIF,MAPK14 and their signaling pathways. To prevent the exacerbation of asthma,instead of a single pathway or a single target,all these targets and their signaling pathways should be controlled holistically.
引文
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[19]Sokolova EA,Vodeneev VA,Deyev SM,et al. 3D in vitro models of tumors expressing EGFR family receptors:a potent tool for studying receptor biology and targeted drug development[J]. Drug Discov today,2018,pii:S1359-6446(18)30168-5. doi:10. 1016/j. drudis.2018.09.003.
[20]Vinod Prabhu V,Elangovan P,Niranjali Devaraj S,et al. Targeting apoptosis by 1,2-diazole through regulation of EGFR,Bcl-2 and CDK-2 mediated signaling pathway in human non-small cell lung carcinoma A549 cells[J].Gene,2018,679:352-359. doi:10. 1016/j. gene. 2018.09.014.
[21]晋乐飞,吴卫东,段丽菊,等.表皮生长因子受体在臭氧致小鼠肺部炎症中的作用[J].郑州大学学报(医学版),2016,51(4):450-454.JIN Yuefei,WU Weidong,DUAN Liju,et al. Role of EGF receptor in ozone-induced lung inflammation in mice[J]. Journal of Zhengzhou University(Medical Sciences),2016,51(4):450-454.
[22] Yoshikawa T,Kanazawa H. Integrated effect of EGFR and PAR-1 signaling crosstalk on airway hyperresponsiveness[J]. Int J Mol Med,2012,30(1):41-48.
[23]Habibovic A,Hristova M,Heppner DE,et al. DUOX1mediates persistent epithelial EGFR activation,mucous cell metaplasia,and airway remodeling during allergic asthma[J]. JCI Insight,2016,1(18):e88811. doi:10.1172/jci.insight.88811
[24]Wang X,Yang XQ,Li Y,et al. Lyn kinase represses mucus hypersecretion by regulating IL-13-induced endoplasmic reticulum stress in asthma[J]. EBioMedicine,2017,15:137-149. doi:10.1016/j.ebiom.2016.12.010.
[25]Tsoref O,Tyomkin D,Amit U,et al. E-selectin-targeted copolymer reduces atherosclerotic lesions,adverse cardiac remodeling,and dysfunction[J]. J Control Release,2018, 288:136-147. doi:10. 1016/j. jconrel.2018.08.029.
[26]Hamzaoui A,Ammar J,El Mekki F,et al. Elevation of serum soluble E-selectin and VCAM-1 in severe asthma[J]. Mediators Inflamm,2001,10(6):339-342.
[27] Bijanzadeh M,Ramachandra NB,Mahesh PA,et al.Soluble intercellular adhesion molecule-1 and E-selectin in patients with asthma exacerbation[J]. Lung,2009,187(5):315-320.
[28]Sabroe I,Pease JE,Williams TJ. Asthma and MIF:innately Th1and Th2[J]. Clin Exp Allergy,2000,30(9):1194-1196.
[29] Yang M,Kumar RK,Hansbro PM,et al. Emerging roles of pulmonary macrophages in driving the development of severe asthma[J]. J Leukoc Biol,2012,91(4):557-569.
[30]Wu J,Fu S,Ren X,et al. Association of MIF promoter polymorphisms with childhood asthma in a northeastern Chinese population[J]. Tissue Antigens,2009,73(4):302-306.
[2] Drake MG,Scott GD,Blum ED,et al. Eosinophils increase airway sensory nerve density in mice and in human asthma[J]. Sci Trans Med, 2018, 10(457), pii:eaar8477. doi:10.1126/scitranslmed.aar8477.
[3]杨昕宇,肖长芳,张凯熠,等.麻黄临床应用与药理作用研究进展[J].中华中医药学刊,2015,33(12):2874-2877.YANG Xiyu,XIAO Changfang,ZHANG Kaiyi,et al.Research Progress on Clinical Application and Pharmacological Functions of Ephedra[J]. Chinese archives of traditional Chinese medicine,2015,33(12):2874-2877.
[4]Hasan S,Bonde BK,Buchan NS,et al. Network analysis has diverse roles in drug discovery[J]. Drug Discov Today,2012,17(15-16):869-874.
[5]Zhai L,Ning ZW,Huang T,et al. Cyclocarya paliurus Leaves Tea Improves Dyslipidemia in Diabetic Mice:A Lipidomics-Based Network Pharmacology Study[J].Front Pharmacol,2018,9:973. doi:10. 3389/fphar.2018.00973.
[6]汝锦龙.中药系统药理学数据库和分析平台的构建和应用[D].咸阳:西北农林科技大学,2015.
[7]Xu X,Zhang WX,Huang C,et al. A novel chemometric method for the prediction of human oral bioavailability[J]. Int J Mol Sci,2012,13(6):6964-6982.
[8]Yamanishi Y,Kotera M,Kanehisa M,et al. Drug-target interaction prediction from chemical,genomic and pharmacological data in an integrated framework[J]. Bioinformatics,2010,26(12):i246-i254. doi:10.1093/bioinformatics/btq176.
[9]刘学.基于网络药理学方法研究玉屏风散治疗哮喘的作用机制[D].成都:西南交通大学,2017.
[10]Bi YH,Zhang LH,Chen SJ,et al. Antitumor Mechanisms of Curcumae Rhizoma Based on Network Pharmacology[J]. Evid Based Complement Alternat Med,2018,2018:4509892. doi:10.1155/2018/4509892.
[11] Kun-Yi H,Yukiko M,Yoshiyuki A,et al. Systemsdock:a web server of network pharmacology-based prediction and analysis[J]. Nucleic Acids Res,2016,44(W1):W507-W513. doi:10.1093/nar/gkw335.
[12] Hsin KY,Ghosh S,Kitano H. Combining machine learning systems and multiple docking simulation packages to improve docking prediction reliability for network pharmacology[J]. PLoS One,2013,8(12):e83922.doi:10.1371/journal.pone.0083922.
[13]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. doi:10.1093/nar/gkw937.
[14]雷奇林,黄雅兰,钟茜,等.基于网络药理学的黄芩抗炎作用机制研究[J].中草药,2018,49(15):3523-3530.LEI Qilin,HUANG Yalan,ZHONG Qian,et al. Antiinflammatory mechanism of Scutellarlae Radix based on network pharmacology[J]. Chinese Traditional and Herbal Drugs,2018,49(15):3523-3530.
[15] Casale TB,Pacou M,Mesana L,et al. Reslizumab Compared with Benralizumab in Patients with Eosinophilic Asthma:A Systematic Literature Reviewand Network Meta-Analysis[J]. J Allergy Clin Immunol Pract,2018. pii:S2213-2198(18)30576-2. doi:10. 1016/j.jaip.2018.08.036
[16]Hekking PP,Bel EH. Developing and emerging clinical asthma phenotypes[J]. J Allergy Clin Immunol Pract,2014,2(6):671-680.
[17] Chen SJ,Cui MC. Systematic Understanding of the Mechanism of Salvianolic Acid A via Computational Target Fishing[J]. Molecules,2017,22(4). pii:E644. doi:10.3390/molecules22040644.
[18]朱婉婷,范雪梅,位华,等.基于网络药理学探讨阿帕替尼治疗乳腺癌的作用制剂[J].中国药学杂志,2016,51(18):1569-1573.ZHU Wanting,FAN Xuemei,WEI Hua,et al. Mechanism Research of Apatinib-treated Breast Cancer Based on Network Pharmacology[J]. Chinese Pharmaceutical Journal,2016,51(18):1569-1573.
[19]Sokolova EA,Vodeneev VA,Deyev SM,et al. 3D in vitro models of tumors expressing EGFR family receptors:a potent tool for studying receptor biology and targeted drug development[J]. Drug Discov today,2018,pii:S1359-6446(18)30168-5. doi:10. 1016/j. drudis.2018.09.003.
[20]Vinod Prabhu V,Elangovan P,Niranjali Devaraj S,et al. Targeting apoptosis by 1,2-diazole through regulation of EGFR,Bcl-2 and CDK-2 mediated signaling pathway in human non-small cell lung carcinoma A549 cells[J].Gene,2018,679:352-359. doi:10. 1016/j. gene. 2018.09.014.
[21]晋乐飞,吴卫东,段丽菊,等.表皮生长因子受体在臭氧致小鼠肺部炎症中的作用[J].郑州大学学报(医学版),2016,51(4):450-454.JIN Yuefei,WU Weidong,DUAN Liju,et al. Role of EGF receptor in ozone-induced lung inflammation in mice[J]. Journal of Zhengzhou University(Medical Sciences),2016,51(4):450-454.
[22] Yoshikawa T,Kanazawa H. Integrated effect of EGFR and PAR-1 signaling crosstalk on airway hyperresponsiveness[J]. Int J Mol Med,2012,30(1):41-48.
[23]Habibovic A,Hristova M,Heppner DE,et al. DUOX1mediates persistent epithelial EGFR activation,mucous cell metaplasia,and airway remodeling during allergic asthma[J]. JCI Insight,2016,1(18):e88811. doi:10.1172/jci.insight.88811
[24]Wang X,Yang XQ,Li Y,et al. Lyn kinase represses mucus hypersecretion by regulating IL-13-induced endoplasmic reticulum stress in asthma[J]. EBioMedicine,2017,15:137-149. doi:10.1016/j.ebiom.2016.12.010.
[25]Tsoref O,Tyomkin D,Amit U,et al. E-selectin-targeted copolymer reduces atherosclerotic lesions,adverse cardiac remodeling,and dysfunction[J]. J Control Release,2018, 288:136-147. doi:10. 1016/j. jconrel.2018.08.029.
[26]Hamzaoui A,Ammar J,El Mekki F,et al. Elevation of serum soluble E-selectin and VCAM-1 in severe asthma[J]. Mediators Inflamm,2001,10(6):339-342.
[27] Bijanzadeh M,Ramachandra NB,Mahesh PA,et al.Soluble intercellular adhesion molecule-1 and E-selectin in patients with asthma exacerbation[J]. Lung,2009,187(5):315-320.
[28]Sabroe I,Pease JE,Williams TJ. Asthma and MIF:innately Th1and Th2[J]. Clin Exp Allergy,2000,30(9):1194-1196.
[29] Yang M,Kumar RK,Hansbro PM,et al. Emerging roles of pulmonary macrophages in driving the development of severe asthma[J]. J Leukoc Biol,2012,91(4):557-569.
[30]Wu J,Fu S,Ren X,et al. Association of MIF promoter polymorphisms with childhood asthma in a northeastern Chinese population[J]. Tissue Antigens,2009,73(4):302-306.