基于网络药理学的注射用益气复脉(冻干)作用机制研究
|
摘要
目的基于网络药理学平台研究注射用益气复脉(冻干,YQFM)治疗心血管疾病的作用机制。方法在前期研究基础上结合文献选出YQFM主要化合物结构母核,通过DRAR-CPI服务器对结构母核进行模拟分子-靶蛋白对接,筛选靶点;对获取的靶点信息通过KEGG数据库进行注释,结合文献对所得通路进行分析;利用Cytoscape 3.6.0软件,构建上述靶点的"化合物-靶点-通路-网络"整合模型;阐述YQFM治疗心血管疾病的作用机制。结果本研究共筛选了7个化合物母核:20(S)-原人参三醇、齐墩果酸、2'-羟基异麦冬黄酮A、麦冬黄酮B、麦冬皂苷元、五味子甲素、五味子乙素;主要对应GASP、AKT、INS、AKT、GSK3β、JNK、GSK3β、ERK1、ERK2等127个作用靶点,以及丝裂原活化蛋白激酶(MAPK)、腺苷酸活化蛋白激酶(AMPK)心血管功能及糖脂代谢相关、肿瘤坏死因子(TNF)、雷帕霉素靶蛋白(m TOR)炎症相关等信号通路。结论 YQFM主要通过心血管保护、炎症与免疫调节、以及糖脂代谢干预等多条途径实现气阴两虚证的心血管疾病治疗作用。网络药理学方法可以简便、系统地预测YQFM的主要药效成分的网络机制,为中医药治疗心血管疾病提供研究方向。
Objective To study the mechanism of Yiqi Fumai Lyophilized Injection(YQFM) in the treatment of cardiovascular diseases based on the network pharmacology platform. Methods Based on the preliminary studies and related literature, the structural core of YQFM main compound was selected, and the molecular target protein docking was simulated by DRAR-CPI server to screen target. The obtained information of target was annotated by the KEGG database, and the access path was analyzed in combination with references. Cytoscape 3.6.0 software were used to construct the "compound – target – channe – network"integration model of the target, and the mechanism of YQFM in the treatment of cardiovascular disease was also be elaborated.Results A total of seven compounds were screened: 20(s)-protopanaxatriol, oleanolic acid, 2'-hydroxyl isoophio pogonone A,ophiopogon B, Ophiogenin, schisandrin A, and schisandrin B, mainly corresponding to 127 target points, such as GASP, AKT, INS,AKT, GSK3 beta, JNK, GSK3 beta, ERK1, ERK2, etc, as well as MAPK, AMPK related cardiovascular function and glycolipid metabolic pathway, TNF, m TOR related inflammatory signaling pathway, etc. Conclusion YQFM achieves the regulation of Qi Yin Liang Xu symptom and other cardiovascular disease treatment mainly through the cardiovascular protection, inflammation and immune regulation, glucose-lipid metabolism intervention and other pathways. The network pharmacological method can be used to predict the network mechanism of the main active ingredients of YQFM conveniently and systematically, and provide a research direction for the treatment of cardiovascular diseases by traditional Chinese medicine.
Objective To study the mechanism of Yiqi Fumai Lyophilized Injection(YQFM) in the treatment of cardiovascular diseases based on the network pharmacology platform. Methods Based on the preliminary studies and related literature, the structural core of YQFM main compound was selected, and the molecular target protein docking was simulated by DRAR-CPI server to screen target. The obtained information of target was annotated by the KEGG database, and the access path was analyzed in combination with references. Cytoscape 3.6.0 software were used to construct the "compound – target – channe – network"integration model of the target, and the mechanism of YQFM in the treatment of cardiovascular disease was also be elaborated.Results A total of seven compounds were screened: 20(s)-protopanaxatriol, oleanolic acid, 2'-hydroxyl isoophio pogonone A,ophiopogon B, Ophiogenin, schisandrin A, and schisandrin B, mainly corresponding to 127 target points, such as GASP, AKT, INS,AKT, GSK3 beta, JNK, GSK3 beta, ERK1, ERK2, etc, as well as MAPK, AMPK related cardiovascular function and glycolipid metabolic pathway, TNF, m TOR related inflammatory signaling pathway, etc. Conclusion YQFM achieves the regulation of Qi Yin Liang Xu symptom and other cardiovascular disease treatment mainly through the cardiovascular protection, inflammation and immune regulation, glucose-lipid metabolism intervention and other pathways. The network pharmacological method can be used to predict the network mechanism of the main active ingredients of YQFM conveniently and systematically, and provide a research direction for the treatment of cardiovascular diseases by traditional Chinese medicine.
引文
[1]罗国安,梁琼麟,王义明,等.中医药系统生物学发展及展望[J].中国天然药物,2009,7(4):242-248.
[2]Liu C X,Liu R,Fan H R,et al.Network pharmacology bridges traditional application and modern development of traditional Chinese medicine[J].Chin Herb Med,2015,7(1):3-17
[3]窦新宇,冯晓敬.注射用益气复脉(冻干)治疗房颤气阴两虚证的临床观察[J].中西医结合心脑血管病志,2017,15(5):582-584.
[4]李泮霖,苏薇薇.网络药理学在中药研究中的最新应用进展[J].中草药,2016,47(16):2938-2942.
[5]褚延斌,苏小琴,李德坤,等.基于一测多评法对注射用益气复脉(冻干)中9种成分的质量控制研究[J].中草药,2017,48(17):3537-3544.
[6]陈宁红.生脉饮红参方治疗气阴两虚型心律失常的临床观察[J].光明中医,2017,32(16):2297-2299.
[7]刘鑫馗,吴嘉瑞,张丹,等.基于网络药理学的生脉散作用机制分析[J].中国实验方剂学杂志,2017,23(16):219-225.
[8]揭红波.浅谈心血管疾病的发病机理与预防[J].中外医疗,2011,30(12):184.
[9]王蒙,陈绍良.P38 MAPK信号通路与心血管疾病关系的研究进展[J].现代生物医学进展,2012,12(30):5968-5970.
[10]Li F,Zhang Y,Zeng D L,et al.The combination of three components derived from Sheng Mai San protects myocardial ischemic diseases and inhibits oxidative stress via modulating MAPKs and JAK2-STAT3 signaling pathways based on bioinformatics approach[J].Front Pharmacol,2017,8:21.Doi:10.3389/fphar.2017.00021.
[11]Yang Y,Tian Y S,Hu S Y,et al.Extract of Sheng-Mai-San ameliorates myocardial ischemiainduced heart failure by modulating Ca2+-calcineurinmediated Drp1 signaling pathways[J].Int J Mol Sci,2017,18(9):1825.Doi:10.3390/ijms18091825.
[12]李昊娲,武乾,石晓璐,等.益气复脉合剂抗心律失常作用机制研究[J].中西医结合心脑血管病杂志,2015,13(2):132-134.
[13]Takahiko H,Hiroki M,Harashima S,et al.Transmembrane TNF-α:structure,function and interaction with anti-TNF agents[J].Rheumatology(Oxford),2010,49(7):1215-1228.
[14]George D K,Lionel B I.TNF biology,pathogenic mechanisms and emerging therapeutic strategies[J].Nat Rev Rheumatol,2016,12(1):49-62.
[15]Yuan Q,Wang J,Fang Q H,et al.Attenuating effect of pretreatment with Yiqifumai on lipopolysaccharideinduced intestine injury and survival rate in rat[J].J Inflamm(Lond),2011,8:10.doi:10.1186/1476-9255-8-10.
[16]Martin L P.The NO/ONOO-Cycle as the central cause ofheart failure[J].Int J Mol Sci,2013,14(11):22274-22330.
[17]Tan Y,Li F,Lv Y,et al.Study on the multi-targets mechanism of Yiqifumai powder injection on cardiocerebral ischemic diseases based on network pharmacology[J].J Proteomics Comput Biol,2014,1(1):1-9.
[18]Kim N,Vishva M D.Signaling in Innate Immunity and Inflammation.[J].Cold Spring Harb Perspect Biol,2012,4(3):829-841.
[19]何志明,陈冬清,吕小强,等.自拟益气复脉通络方对冠心病介入治疗后心绞痛疗效及对VEGF、s ICAM-1、MMPs-9、炎症因子表达的影响[J].中国中医急症,2017,26(7):1306-1308.
[20]陈柳,李悌聪,胡静波,等.橘红麦冬药对的免疫增强实验研究[J].中华中医药学刊,2014,32(6):1481-1483.
[21]吴红,韩薇.m TOR信号通路在心血管系统中作用研究的进展[J].心血管康复医学杂志,2016,25(2):225-228.
[22]张英驰,程涛,袁卫平.PI3K/AKT/m TOR信号通路在造血干细胞中作用的研究进展[J].中国实验血液学杂志,2013,21(1):245-249.
[23]Guo Z S,Cao G S,Yang H P,et al.A combination of four active compounds alleviates cerebral ischemiareperfusion injury in correlation with inhibition of autophagy and modulation of AMPK/m TOR and JNK pathways[J].J Neurosci Res,2014,92(10):1295-1306.
[24]李晓阳,杨志欣.注射用益气复脉(冻干)研究概况[J].黑龙江科技信息,2016(6):79.
[25]刘北.葛根素通过AMPK/m TOR信号通路调控自噬发挥对心肌肥厚的保护作用[D].南方医科大学,2016.
[26]王钰钢,范启明,汤亭亭.AMPK信号通路对骨代谢的调节作用[J].中国骨质疏松杂志,2014,20(3):322-326.
[27]Morrison A,Li J.PPAR-γand AMPK-advantageous targets for myocardial ischemia/reperfusion therapy[J].Biochem Pharmacol,2011,82:195-200.
[28]Li F,Fan X,Zhang Y.,et al.Cardioprotection by combination of three compounds from Sheng Mai preparations in mice with myocardial ischemia/reperfusion injury through AMPK activation-mediated mitochondrial fission[J].Sci.Rep,2016,6:37114.
[29]苗艳艳,苗明三,马霄,等.五味子醇提部位对反复脑缺血再灌注模型小鼠脑能量代谢的影响[J].中华中医药杂志,2009,24(9):1207-1209.
[30]Cao G,Ye X,Xu Y,et al.Yi Qi Fu Mai powder injection ameliorates blood-brain barrier dysfunction and brain edema after focal cerebral ischemia-reperfusion injury in mice[J].Drug.Des.Dev.Ther,2016,10:315-325.
[31]Cao G,Zhou H,Jiang N,et al.Yi Qi Fu Mai powder injection ameliorates cerebral ischemia by inhibiting endoplasmic reticulum stress-mediated neuronal apoptosis[J].Oxid Med Cell Longev,2016,2016:5493279-5493293.
[32]Li F,Fan X,Zhang Y,et al.Cardioprotection by combination of three compounds from Sheng Mai preparations in mice with myocardial ischemia/reperfusion injury through AMPK activation-mediated mitochondrial fission[J].Sci.Rep,2016,6:37114.
[33]Li F,Lv Y N,Tan Y S,et al.An integrated pathway interaction network for the combination of four effective compounds from Sheng Mai preparations in the treatment of cardio-cerebral ischemic diseases[J].Acta Pharmacol Sin,2015,36:1337-1348.
[34]任俊芳,秦旭平.AMPK与心血管重构[J].国际病理科学与临床杂志,2008(1):33-36.
[2]Liu C X,Liu R,Fan H R,et al.Network pharmacology bridges traditional application and modern development of traditional Chinese medicine[J].Chin Herb Med,2015,7(1):3-17
[3]窦新宇,冯晓敬.注射用益气复脉(冻干)治疗房颤气阴两虚证的临床观察[J].中西医结合心脑血管病志,2017,15(5):582-584.
[4]李泮霖,苏薇薇.网络药理学在中药研究中的最新应用进展[J].中草药,2016,47(16):2938-2942.
[5]褚延斌,苏小琴,李德坤,等.基于一测多评法对注射用益气复脉(冻干)中9种成分的质量控制研究[J].中草药,2017,48(17):3537-3544.
[6]陈宁红.生脉饮红参方治疗气阴两虚型心律失常的临床观察[J].光明中医,2017,32(16):2297-2299.
[7]刘鑫馗,吴嘉瑞,张丹,等.基于网络药理学的生脉散作用机制分析[J].中国实验方剂学杂志,2017,23(16):219-225.
[8]揭红波.浅谈心血管疾病的发病机理与预防[J].中外医疗,2011,30(12):184.
[9]王蒙,陈绍良.P38 MAPK信号通路与心血管疾病关系的研究进展[J].现代生物医学进展,2012,12(30):5968-5970.
[10]Li F,Zhang Y,Zeng D L,et al.The combination of three components derived from Sheng Mai San protects myocardial ischemic diseases and inhibits oxidative stress via modulating MAPKs and JAK2-STAT3 signaling pathways based on bioinformatics approach[J].Front Pharmacol,2017,8:21.Doi:10.3389/fphar.2017.00021.
[11]Yang Y,Tian Y S,Hu S Y,et al.Extract of Sheng-Mai-San ameliorates myocardial ischemiainduced heart failure by modulating Ca2+-calcineurinmediated Drp1 signaling pathways[J].Int J Mol Sci,2017,18(9):1825.Doi:10.3390/ijms18091825.
[12]李昊娲,武乾,石晓璐,等.益气复脉合剂抗心律失常作用机制研究[J].中西医结合心脑血管病杂志,2015,13(2):132-134.
[13]Takahiko H,Hiroki M,Harashima S,et al.Transmembrane TNF-α:structure,function and interaction with anti-TNF agents[J].Rheumatology(Oxford),2010,49(7):1215-1228.
[14]George D K,Lionel B I.TNF biology,pathogenic mechanisms and emerging therapeutic strategies[J].Nat Rev Rheumatol,2016,12(1):49-62.
[15]Yuan Q,Wang J,Fang Q H,et al.Attenuating effect of pretreatment with Yiqifumai on lipopolysaccharideinduced intestine injury and survival rate in rat[J].J Inflamm(Lond),2011,8:10.doi:10.1186/1476-9255-8-10.
[16]Martin L P.The NO/ONOO-Cycle as the central cause ofheart failure[J].Int J Mol Sci,2013,14(11):22274-22330.
[17]Tan Y,Li F,Lv Y,et al.Study on the multi-targets mechanism of Yiqifumai powder injection on cardiocerebral ischemic diseases based on network pharmacology[J].J Proteomics Comput Biol,2014,1(1):1-9.
[18]Kim N,Vishva M D.Signaling in Innate Immunity and Inflammation.[J].Cold Spring Harb Perspect Biol,2012,4(3):829-841.
[19]何志明,陈冬清,吕小强,等.自拟益气复脉通络方对冠心病介入治疗后心绞痛疗效及对VEGF、s ICAM-1、MMPs-9、炎症因子表达的影响[J].中国中医急症,2017,26(7):1306-1308.
[20]陈柳,李悌聪,胡静波,等.橘红麦冬药对的免疫增强实验研究[J].中华中医药学刊,2014,32(6):1481-1483.
[21]吴红,韩薇.m TOR信号通路在心血管系统中作用研究的进展[J].心血管康复医学杂志,2016,25(2):225-228.
[22]张英驰,程涛,袁卫平.PI3K/AKT/m TOR信号通路在造血干细胞中作用的研究进展[J].中国实验血液学杂志,2013,21(1):245-249.
[23]Guo Z S,Cao G S,Yang H P,et al.A combination of four active compounds alleviates cerebral ischemiareperfusion injury in correlation with inhibition of autophagy and modulation of AMPK/m TOR and JNK pathways[J].J Neurosci Res,2014,92(10):1295-1306.
[24]李晓阳,杨志欣.注射用益气复脉(冻干)研究概况[J].黑龙江科技信息,2016(6):79.
[25]刘北.葛根素通过AMPK/m TOR信号通路调控自噬发挥对心肌肥厚的保护作用[D].南方医科大学,2016.
[26]王钰钢,范启明,汤亭亭.AMPK信号通路对骨代谢的调节作用[J].中国骨质疏松杂志,2014,20(3):322-326.
[27]Morrison A,Li J.PPAR-γand AMPK-advantageous targets for myocardial ischemia/reperfusion therapy[J].Biochem Pharmacol,2011,82:195-200.
[28]Li F,Fan X,Zhang Y.,et al.Cardioprotection by combination of three compounds from Sheng Mai preparations in mice with myocardial ischemia/reperfusion injury through AMPK activation-mediated mitochondrial fission[J].Sci.Rep,2016,6:37114.
[29]苗艳艳,苗明三,马霄,等.五味子醇提部位对反复脑缺血再灌注模型小鼠脑能量代谢的影响[J].中华中医药杂志,2009,24(9):1207-1209.
[30]Cao G,Ye X,Xu Y,et al.Yi Qi Fu Mai powder injection ameliorates blood-brain barrier dysfunction and brain edema after focal cerebral ischemia-reperfusion injury in mice[J].Drug.Des.Dev.Ther,2016,10:315-325.
[31]Cao G,Zhou H,Jiang N,et al.Yi Qi Fu Mai powder injection ameliorates cerebral ischemia by inhibiting endoplasmic reticulum stress-mediated neuronal apoptosis[J].Oxid Med Cell Longev,2016,2016:5493279-5493293.
[32]Li F,Fan X,Zhang Y,et al.Cardioprotection by combination of three compounds from Sheng Mai preparations in mice with myocardial ischemia/reperfusion injury through AMPK activation-mediated mitochondrial fission[J].Sci.Rep,2016,6:37114.
[33]Li F,Lv Y N,Tan Y S,et al.An integrated pathway interaction network for the combination of four effective compounds from Sheng Mai preparations in the treatment of cardio-cerebral ischemic diseases[J].Acta Pharmacol Sin,2015,36:1337-1348.
[34]任俊芳,秦旭平.AMPK与心血管重构[J].国际病理科学与临床杂志,2008(1):33-36.