虎杖治疗动脉粥样硬化物质基础与作用机制的网络药理学研究
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摘要
目的探讨活血解毒中药虎杖治疗动脉粥样硬化(AS)的物质基础与潜在分子机制。方法基于网络药理学研究思路和方法,利用BATMAN-TCM平台筛选虎杖活性成分及潜在靶点基因,利用PALM-IST平台对PubMed数据库进行文本挖掘,获取AS相关靶点基因,采用Cytoscape 3.2.1软件构建虎杖治疗AS的"活性成分—作用靶点"网络并进行拓扑结构分析,采用FunRich 3.1.3软件进行基因富集分析。结果获得虎杖治疗AS的活性成分21个,其中白藜芦醇、反式白藜芦醇、大黄蒽醌类和有机酸类是其主要药效成分;靶点基因160个,其中PTGS2、PTGS1、PGR、ESR1、ALOX5、VDR、SOX9和MED1为重要靶点;虎杖能通过参与信号转导、细胞通讯、能量通路和代谢等4个生物学过程,调控18条生物信号通路发挥抗AS作用,其中调控Toll样受体、维甲酸受体及其介导的下游信号转导系统是其主要潜在作用机制。结论从网络药理学角度初步阐释了虎杖多成分、多靶点、多途径治疗AS的作用特点,为进一步开展实验研究揭示其药效物质基础及作用机制提供了依据。
Objective To explore the material basis and underlying molecular mechanism of Japanese Fleeceflower,a Chinese herb for acti-vating blood circulation and detoxicating,in treating atherosclerosis(AS).Methods Based on network pharmacology,Bioinformatics A-nalysis Tool for Molecular mechanism of Traditional Chinese Medicine(BATMAN-TCM)was used to filtrate active components and po-tential target genes of Japanese Fleeceflower.PALM-IST was used to perform literature mining from PubMed database to gain targetgenes of AS and Cytoscape 3.2.1 software was used to build the"component-target"network of Japanese Fleeceflower in treating AS andto analyze its topological structure.Gene enrichment analysis was carried out using FunRich 3.1.3 software.Results Twenty-one activecomponents of Japanese Fleeceflower were acquired,mainly consisted of resveratrol,trans-resveratrol,Rheum anthraquinones and organicacids.One hundred and sixty target genes were found and the important target genes were PTGS2,PTGS1,PGR,ESR1,ALOX5,VDR,SOX9 and MED1.Japanese Fleeceflower found to be involved in 4 biological processes including signal transduction,cell communication,energy pathway and metabolism,and 18 signaling pathways.Regulating on Toll-like receptors(TLRs),RARs and downstream signaltransduction systems was the main potential mechanisms of Japanese Fleeceflower in anti-atherosclerosis treatment.Conclusion The re-sults preliminarily demonstrate the multi-component,multi-target and multi-pathway effects of Japanese Fleeceflower in anti-atherosclero-sis,and provide the basis for further pharmacological research.
Objective To explore the material basis and underlying molecular mechanism of Japanese Fleeceflower,a Chinese herb for acti-vating blood circulation and detoxicating,in treating atherosclerosis(AS).Methods Based on network pharmacology,Bioinformatics A-nalysis Tool for Molecular mechanism of Traditional Chinese Medicine(BATMAN-TCM)was used to filtrate active components and po-tential target genes of Japanese Fleeceflower.PALM-IST was used to perform literature mining from PubMed database to gain targetgenes of AS and Cytoscape 3.2.1 software was used to build the"component-target"network of Japanese Fleeceflower in treating AS andto analyze its topological structure.Gene enrichment analysis was carried out using FunRich 3.1.3 software.Results Twenty-one activecomponents of Japanese Fleeceflower were acquired,mainly consisted of resveratrol,trans-resveratrol,Rheum anthraquinones and organicacids.One hundred and sixty target genes were found and the important target genes were PTGS2,PTGS1,PGR,ESR1,ALOX5,VDR,SOX9 and MED1.Japanese Fleeceflower found to be involved in 4 biological processes including signal transduction,cell communication,energy pathway and metabolism,and 18 signaling pathways.Regulating on Toll-like receptors(TLRs),RARs and downstream signaltransduction systems was the main potential mechanisms of Japanese Fleeceflower in anti-atherosclerosis treatment.Conclusion The re-sults preliminarily demonstrate the multi-component,multi-target and multi-pathway effects of Japanese Fleeceflower in anti-atherosclero-sis,and provide the basis for further pharmacological research.
引文
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[19]范玲,严冬,李爽,等.一测多评法测定虎杖中虎杖苷、白藜芦醇、大黄素及大黄素甲醚的含量[J].中国实验方剂学杂志,2013,19(7):103-107.
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[22]张翔,江兴林,周利玲,等.大黄素对氧化应激所致动脉粥样硬化模型大鼠的干预研究[J].中医药导报,2016,22(21):27-29.
[23]汤喜兰,刘建勋,李磊.中药有机酸类成分的药理作用及在心血管疾病的应用[J].中国实验方剂学杂志,2012,18(5):243-246.
[24]王海坤,韩代书.Toll样受体(TLRs)的信号转导与免疫调节[J].生物化学与生物物理进展,2006,33(9):820-827.
[25]TAKEDA K,AKIRA S.Toll-like receptors in innate immunity[J].International Immunology,2005,17(1):1-14.
[26]胡国晶,路娇扬,王双.Toll样受体与动脉粥样硬化易损斑块的关系[J].中国动脉硬化杂志,2012,20(5):477-480.
[27]ALTUCCI L,LEIBOWITZ M D,OGILVIE K M,et al.RAR and RXR modulation in cancer and metabolic disease[J].Nature Reviews Drug Discovery,2007,6(10):793-810.
[28]王育盛,杨剑,曾春雨.全反式维甲酸对血管粥样硬化病变作用的研究进展[J].心血管病学进展,2012,33(3):375-378.
[2]LIBBY P,RIDKER P M.Progress and challenges in translating the biology of atherosclerosis[J].Nature,2011,473(7347):317-325.
[3]徐浩,史大卓,殷惠军,等.“瘀毒致变”与急性心血管事件:假说的提出与临床意义[J].中国中西医结合杂志,2008,28(10):934-938.
[4]徐浩.活血解毒中药抗炎及稳定易损斑块的探索与思考[J].中国中西医结合杂志,2008,28(5):393-394.
[5]樊慧婷,丁世兰,林洪生.中药虎杖的药理研究进展[J].中国中药杂志,2013,38(15):2545-2548.
[6]周明学,徐浩,陈可冀,等.活血解毒中药有效部位对ApoE基因敲除小鼠血脂和动脉粥样硬化斑块炎症反应的影响[J].中国中西医结合杂志,2008,28(2):126-130.
[7]HOPKINS A L.Network pharmacology:the next paradigm in drug discovery[J].Nature Chemical Biology,2008,4(11):682-690.
[8]许海玉,黄璐琦,卢鹏,等.基于体内ADME过程和网络药理学的中药现代研究思路[J].中国中药杂志,2012,37(2):142-145.
[9]LIU Z,GUO F,WANG Y,et al.BATMAN-TCM:a bioinformatics analysis tool for molecular mechanism of traditional chinese medicine[J].Scientific Reports,2016,6:21146.
[10]PATHAN M,KEERTHIKUMAR S,ANG C S,et al.FunRich:an open access standalone functional enrichment and interaction network analysis tool[J].Proteomics,2015,15(15):2597-2601.
[11]时圣明,潘明佳,王文倩,等.虎杖的化学成分及药理作用研究进展[J].药物评价研究,2016,39(2):317-321.
[12]RAUF A,IMRAN M,SULERIA H,et al.A comprehensive review of the health perspectives of resveratrol[J].Food&Function,2017,8(12):4284-4305.
[13]宋蕊,李婉秋,窦健霖,等.白藜芦醇可通过抑制核因子κB和丝裂原活化蛋白激酶信号通路抗兔动脉粥样硬化[J].中华心血管病杂志,2013,41(10):866-869.
[14]CHANG G R,CHEN P L,HOU P H.Resveratrol protects against diet-induced atherosclerosis by reducing low-density lipoprotein cholesterol and inhibiting inflammation in apolipoprotein E-deficient mice[J].Iranian Journal of Basic Medical Sciences,2015,8(11):1063-1071.
[15]刘海梅,闫福曼,徐进文,等.白藜芦醇调节TRPC1/STIM1介导的SOCC抗动脉粥样硬化机制[J].中国实验方剂学杂志,2018,24(4):96-102.
[16]段宇,王婷婷,张明明,等.白藜芦醇通过调节自噬延缓ApoE~(-/-)小鼠动脉粥样硬化进展[J].心脏杂志,2017,29(3):259-263.
[17]NORATA G D,MARCHESI P,PASSAMONTI S,et al.Anti-inflammatory and anti-atherogenic effects of cathechin,caffeic acid and trans-resveratrol in apolipoprotein E deficient mice[J].Atherosclerosis,2007,191(2):265-271.
[18]王亦君,冯舒涵,程锦堂,等.大黄蒽醌类化学成分和药理作用研究进展[J].中国实验方剂学杂志,2018,24(10):126-133.
[19]范玲,严冬,李爽,等.一测多评法测定虎杖中虎杖苷、白藜芦醇、大黄素及大黄素甲醚的含量[J].中国实验方剂学杂志,2013,19(7):103-107.
[20]ZHOU M,XU H,PAN L,et al.Emodin promotes atherosclerotic plaque stability in fat-fed apolipoprotein E-deficient mice[J].The Tohoku Journal of Experimental Medicine,2008,215(1):61-69.
[21]PANG X,LIU J,LI Y,et al.Emodin inhibits homocysteine-induced C-reactive protein generation in vascular smooth muscle cells by regulating PPARγexpression and ROS-ERK1/2/p38 signal pathway[J].PLoS One,2015,10(7):e0131295.
[22]张翔,江兴林,周利玲,等.大黄素对氧化应激所致动脉粥样硬化模型大鼠的干预研究[J].中医药导报,2016,22(21):27-29.
[23]汤喜兰,刘建勋,李磊.中药有机酸类成分的药理作用及在心血管疾病的应用[J].中国实验方剂学杂志,2012,18(5):243-246.
[24]王海坤,韩代书.Toll样受体(TLRs)的信号转导与免疫调节[J].生物化学与生物物理进展,2006,33(9):820-827.
[25]TAKEDA K,AKIRA S.Toll-like receptors in innate immunity[J].International Immunology,2005,17(1):1-14.
[26]胡国晶,路娇扬,王双.Toll样受体与动脉粥样硬化易损斑块的关系[J].中国动脉硬化杂志,2012,20(5):477-480.
[27]ALTUCCI L,LEIBOWITZ M D,OGILVIE K M,et al.RAR and RXR modulation in cancer and metabolic disease[J].Nature Reviews Drug Discovery,2007,6(10):793-810.
[28]王育盛,杨剑,曾春雨.全反式维甲酸对血管粥样硬化病变作用的研究进展[J].心血管病学进展,2012,33(3):375-378.