采用网络药理学研究黄芪-葶苈子药对治疗心力衰竭的作用机制
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摘要
目的:探索黄芪-葶苈子药对治疗心力衰竭的可能作用机制。方法:采用网络药理学方法。基于类药性和口服生物利用度,通过中药系统药理学数据库分析平台、GeneCards和OMIM数据库、反向分子对接服务器,筛选出黄芪-葶苈子药对治疗慢性心力衰竭的活性成分,并预测其作用靶标;采用Cytoscape 3.6.0软件绘制出黄芪-葶苈子药对的活性成分-慢性心力衰竭作用靶标网络;通过STRING数据库制作靶标相互作用网络,筛选连接度排名前5的靶标,在分子对接服务器中进行分子对接;最后在生物学信息注释数据库中进行基因本体(GO)生物过程分析、京都基因与基因组百科全书(KEGG)通路富集分析。结果:本研究共预测得到28个活性成分,其中黄芪20个、葶苈子12个,包括山柰酚、槲皮素等,有4个成分为二者共有;得到活性成分的作用靶标92个,包括热休克蛋白90α(HSP90AA1)、酪氨酸蛋白激酶SRC基因等;GO生物过程结果显示与线粒体电子传递、线粒体内膜、胞质溶胶、胞外体、线粒体基质、药物反应等相关,KEGG通路富集分析结果显示主要涉及丝裂原活化蛋白激酶(MAPK)信号通路、转化生长因子(TGF)信号通路、磷脂酰肌醇3激酶(PI3K)信号通路、环磷酸腺苷(c AMP)信号通路、蛋白激酶B信号通路、细胞外信号调节激酶1(EPK1)信号通路、核转录因子κB(NF-κB)信号通路等方面。结论:黄芪-葶苈子药对可通过上述HSP90AA1、SRC等多靶点及线粒体电子传递、MAPK信号通路等多通路来治疗慢性心力衰竭;本研究为进一步深入探讨该药对作用的物质基础以及作用机制提供了参考。
OBJECTIVE:To explore potential mechanism of"Astragalus membranaceus-Draba nemorosa"couplet medicine for heart failure. METHODS:By network pharmacology,based on drug-like and oral bioavailability,the active components of"A.membranaceus-D. nemorosa"for chronic heart failure were screened and the targets of treating chronic heart failure were predicted by using TCMSP,GeneCards database,OMIM database and DRAR-CPI. The active component-chronic heart failure target network was established by Cytoscape 3.6.0 software. The protein-protein interaction network was constructed by utilizing STRING database.Then top 5 targets in the list of connectivity were screened and performed a molecular docking in molecular docking server.Finally,GO bioprocess analysis and KEGG pathway enrichment analysis were performed in DAVID database. RESULTS:The study predicted 28 active components in total,including 20 A. membranaceus and 12 D. nemorosa,such as kaempferol and quercetin,there were four components in common. Totally 92 target gene of active components were obtained,including heat shock protein 90α(HSP90 AA1),tyrosine protein kinase SRC gene,etc. Results of GO bioprocess analysis showed an association with mitochondrial electron transport,mitochondrial intima,cytoplasmic sol,extracellular body,mitochondrial matrix and drug response. KEGG pathway enrichment analysis showed a link with MAPK signal pathway, TGF signal pathway, PI3 K signal pathway, cAMP signal pathway, protein kinase B signal pathway,EPK1 signal pathway and NF-κ B signal pathway. CONCLUSIONS:"A. membranaceus-D. nemorosa"couplet medicine exerts therapeutic effects on heart failure from multiple targets as HSP90 AA1,SRC and mitochondrial electron transport and MAPK signaling pathway. The study can provide reference for further researches on its material basis and mechanism.
OBJECTIVE:To explore potential mechanism of"Astragalus membranaceus-Draba nemorosa"couplet medicine for heart failure. METHODS:By network pharmacology,based on drug-like and oral bioavailability,the active components of"A.membranaceus-D. nemorosa"for chronic heart failure were screened and the targets of treating chronic heart failure were predicted by using TCMSP,GeneCards database,OMIM database and DRAR-CPI. The active component-chronic heart failure target network was established by Cytoscape 3.6.0 software. The protein-protein interaction network was constructed by utilizing STRING database.Then top 5 targets in the list of connectivity were screened and performed a molecular docking in molecular docking server.Finally,GO bioprocess analysis and KEGG pathway enrichment analysis were performed in DAVID database. RESULTS:The study predicted 28 active components in total,including 20 A. membranaceus and 12 D. nemorosa,such as kaempferol and quercetin,there were four components in common. Totally 92 target gene of active components were obtained,including heat shock protein 90α(HSP90 AA1),tyrosine protein kinase SRC gene,etc. Results of GO bioprocess analysis showed an association with mitochondrial electron transport,mitochondrial intima,cytoplasmic sol,extracellular body,mitochondrial matrix and drug response. KEGG pathway enrichment analysis showed a link with MAPK signal pathway, TGF signal pathway, PI3 K signal pathway, cAMP signal pathway, protein kinase B signal pathway,EPK1 signal pathway and NF-κ B signal pathway. CONCLUSIONS:"A. membranaceus-D. nemorosa"couplet medicine exerts therapeutic effects on heart failure from multiple targets as HSP90 AA1,SRC and mitochondrial electron transport and MAPK signaling pathway. The study can provide reference for further researches on its material basis and mechanism.
引文
[1]中华医学会心血管病学分会.中国心力衰竭诊断和治疗指南2014[J].中华心血管病杂志,2014,42(2):3-10.
[2]张健,张宇辉.多中心、前瞻性中国心力衰竭注册登记研究:病因、临床特点和治疗情况初步分析[J].中国循环杂志,2015,30(5):413-416.
[3]衣艳凤,袁越,宋红霞,等.心力衰竭患者症状群与生活质量的相关性研究[J].护理学报,2018,25(1):14-17.
[4]石衍梅,李洁,张庆蕊,等.基于中医传承辅助平台的治疗慢性心力衰竭方剂组方规律分析[J].中国实验方剂学杂志,2016,22(2):191-194.
[5]孙政华,邵晶,郭玫.黄芪化学成分及药理作用研究进展[J].中医临床研究,2015,7(25):22-25.
[6]张国顺,白义萍,王小兰,等.葶苈子抗心衰有效组分筛选及其作用机制分析[J].中国实验方剂学杂志,2017,23(4):118-125.
[7]许海玉,刘振明,付岩,等.中药整合药理学计算平台的开发与应用[J].中国中药杂志,2017,42(18):3633-3638.
[8]宗阳,孙明明,乐音子,等.基于网络药理学探讨白术-枳实药对治疗慢性传输型便秘的作用机制[J].中国药房,2018,29(13):1798-1802.
[9]吴俊颖,张璐,谢铱子,等.基于网络药理学研究温胆汤治疗冠心病的作用机制[J].中国药房,2018,29(23):3227-3232.
[10]徐基杰,瞿惠燕,王英杰,等.黄芪葶苈子配伍治疗慢性心力衰竭Meta分析[J].中医学报,2017,32(8):1483-1486,1546.
[11]宋杰,胡阳黔,刘坚,等.黄芪多糖对慢性心衰大鼠心肌AMPK活性和FFA代谢的影响[J].中国病理生理杂志,2015,31(1):28-32.
[12]唐斌,张金国,谭洪勇,等.黄芪甲苷对慢性心衰大鼠心肌纤维化及能量代谢的影响[J].中国病理生理杂志,2017,33(3):411-416.
[13]郭娟,陈长勋,沈云辉.葶苈子水提液对动物实验性心室重构的影响[J].中草药,2007,38(10):1519-1523.
[14]王时光,徐雁,陈晓虎.黄芪甲苷对缺氧/复氧损伤H9c2心肌细胞的影响[J].中药药理与临床,2014,30(3):45-48.
[15]潘九英,金芝贵,吴飞华.葶苈子及其复方治疗心血管系统疾病的研究进展[J].上海中医药杂志,2008,42(12):83-85.
[16]吴伟,金鸣,李金荣,等.葶苈子黄酮对血小板激活因子的拮抗作用[J].中草药,2006,37(10):1539-1541.
[17]布会敏,王妹玲,孙红,等.心肌热休克蛋白在发育大鼠慢性间歇性低压低氧中的心脏保护作用[J].中国药理学通报,2011,27(1):49-53.
[18]伍鹏龙,魏盟,朱伟.Src信号通路及在心力衰竭病理生理中的作用[J].国际心血管病杂志,2013,40(1):6-8,15.
[19]SPENCER-JONES NJ,GE D,SNIEDER H,et al.AMP-kinase 2 subunit gene PRKAA2 variants are associated with total cholesterol,low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol in normal women[J].J Med Genetics,2006,43(12):936-942.
[20]尹运堂,王燕,龚放.MAPK信号通路通过内质网应激反应调控梗死后心力衰竭小鼠心肌细胞凋亡[J].基因组学与应用生物学,2017,36(8):3438-3446.
[21]陈莉,马礼坤,胡章乐,等.心肌缺血晚期再灌注后的心肌损伤及其与核因子-κB的关系[J].临床心血管病杂志,2007,23(5):371-374.
[22]BEHNES M,HOFFMANN U,LANG S,et al.Transforming growth factor beta 1(TGF-beta 1)in atrial fibrillation and acute congestive heart failure[J].Clin Res Cardiol,2011,100(4):335-342.
[23]LIN RC,WEEKS KL,GAO XM,et al.PI3K(p110α)protects against myocardial infarction-induced heart failure identification of PI3K-regulated miRNA and mRNA[J].Arterioscler Thromb Vasc Biol,2010,30(4):724-732.
[24]ANANTHAKRISHNAN R,MOE GW,GOLDENTHALMJ,et al.Akt signaling pathway in pacing-induced heart failure[J].Mol Cell Biochem,2005,268(1/2):103-110.
[2]张健,张宇辉.多中心、前瞻性中国心力衰竭注册登记研究:病因、临床特点和治疗情况初步分析[J].中国循环杂志,2015,30(5):413-416.
[3]衣艳凤,袁越,宋红霞,等.心力衰竭患者症状群与生活质量的相关性研究[J].护理学报,2018,25(1):14-17.
[4]石衍梅,李洁,张庆蕊,等.基于中医传承辅助平台的治疗慢性心力衰竭方剂组方规律分析[J].中国实验方剂学杂志,2016,22(2):191-194.
[5]孙政华,邵晶,郭玫.黄芪化学成分及药理作用研究进展[J].中医临床研究,2015,7(25):22-25.
[6]张国顺,白义萍,王小兰,等.葶苈子抗心衰有效组分筛选及其作用机制分析[J].中国实验方剂学杂志,2017,23(4):118-125.
[7]许海玉,刘振明,付岩,等.中药整合药理学计算平台的开发与应用[J].中国中药杂志,2017,42(18):3633-3638.
[8]宗阳,孙明明,乐音子,等.基于网络药理学探讨白术-枳实药对治疗慢性传输型便秘的作用机制[J].中国药房,2018,29(13):1798-1802.
[9]吴俊颖,张璐,谢铱子,等.基于网络药理学研究温胆汤治疗冠心病的作用机制[J].中国药房,2018,29(23):3227-3232.
[10]徐基杰,瞿惠燕,王英杰,等.黄芪葶苈子配伍治疗慢性心力衰竭Meta分析[J].中医学报,2017,32(8):1483-1486,1546.
[11]宋杰,胡阳黔,刘坚,等.黄芪多糖对慢性心衰大鼠心肌AMPK活性和FFA代谢的影响[J].中国病理生理杂志,2015,31(1):28-32.
[12]唐斌,张金国,谭洪勇,等.黄芪甲苷对慢性心衰大鼠心肌纤维化及能量代谢的影响[J].中国病理生理杂志,2017,33(3):411-416.
[13]郭娟,陈长勋,沈云辉.葶苈子水提液对动物实验性心室重构的影响[J].中草药,2007,38(10):1519-1523.
[14]王时光,徐雁,陈晓虎.黄芪甲苷对缺氧/复氧损伤H9c2心肌细胞的影响[J].中药药理与临床,2014,30(3):45-48.
[15]潘九英,金芝贵,吴飞华.葶苈子及其复方治疗心血管系统疾病的研究进展[J].上海中医药杂志,2008,42(12):83-85.
[16]吴伟,金鸣,李金荣,等.葶苈子黄酮对血小板激活因子的拮抗作用[J].中草药,2006,37(10):1539-1541.
[17]布会敏,王妹玲,孙红,等.心肌热休克蛋白在发育大鼠慢性间歇性低压低氧中的心脏保护作用[J].中国药理学通报,2011,27(1):49-53.
[18]伍鹏龙,魏盟,朱伟.Src信号通路及在心力衰竭病理生理中的作用[J].国际心血管病杂志,2013,40(1):6-8,15.
[19]SPENCER-JONES NJ,GE D,SNIEDER H,et al.AMP-kinase 2 subunit gene PRKAA2 variants are associated with total cholesterol,low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol in normal women[J].J Med Genetics,2006,43(12):936-942.
[20]尹运堂,王燕,龚放.MAPK信号通路通过内质网应激反应调控梗死后心力衰竭小鼠心肌细胞凋亡[J].基因组学与应用生物学,2017,36(8):3438-3446.
[21]陈莉,马礼坤,胡章乐,等.心肌缺血晚期再灌注后的心肌损伤及其与核因子-κB的关系[J].临床心血管病杂志,2007,23(5):371-374.
[22]BEHNES M,HOFFMANN U,LANG S,et al.Transforming growth factor beta 1(TGF-beta 1)in atrial fibrillation and acute congestive heart failure[J].Clin Res Cardiol,2011,100(4):335-342.
[23]LIN RC,WEEKS KL,GAO XM,et al.PI3K(p110α)protects against myocardial infarction-induced heart failure identification of PI3K-regulated miRNA and mRNA[J].Arterioscler Thromb Vasc Biol,2010,30(4):724-732.
[24]ANANTHAKRISHNAN R,MOE GW,GOLDENTHALMJ,et al.Akt signaling pathway in pacing-induced heart failure[J].Mol Cell Biochem,2005,268(1/2):103-110.
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