基于网络药理学的豨莶草治疗缺血性脑卒中作用机制研究
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摘要
豨莶草具有治疗缺血性脑卒中的作用,但其作用机制尚未完全阐明。该研究通过数据库及文献检索,结合Lipinski五原则、Veber口服生物利用度规则筛选,获得豨莶草化学成分68个。基于反向找靶获得248个潜在作用靶标,将其映射到缺血性脑卒中疾病靶标集,共获得治疗缺血性脑卒中的47个潜在作用靶标。采用分子对接技术验证了豨莶草成分与潜在靶标具有较好的结合活性。采用Clue GO对潜在靶标进行GO富集分析和通路分析。GO富集分析结果表明豨莶草主要参与神经元凋亡、胆固醇储存以及血压调节等生命过程。通路分析结果表明豨莶草通过调节VEGFA-VEGFR2信号通路中ADAMTS1,FLT1,KDR的表达,促进血管修复与新生;通过调节脑源性神经营养因子信号通路和PI3K-Akt信号通路中CAMK2AA,MDM2,MAPK1,MAPK3,CDK5,MAPK10的表达,启动细胞存活信号,抑制神经元凋亡;通过调节核受体信号通路中ESR1,NR1H3,PPARA,PPARG的表达,调节脂质稳态与炎症。此外,豨莶草还可以通过调节ITGA2B,F2,F10,ALB的表达,阻止血小板聚集,起到抗血栓作用。该文结果表明豨莶草主要通过抗血栓、促进血管新生、保护神经元、抗炎和调节血压血脂等对缺血性脑卒中发挥重要的治疗作用。
Xixiancao( Siegesbeckiae Herba) has the effect of treating ischemic stroke( IS),however,the mechanism has not been fully elucidated. In this study,combined with Lipinski's five principles and Veber oral bioavailability rules,68 chemical components of Xixiancao were obtained by database and literature search. Based on the reverse targeting,248 potential targets were obtained and mapped it to the ischemic stroke target set,47 potential targets for the treatment of ischemic stroke were obtained. Molecular docking technique was used to verify that the Xixiancao component has good binding activity to potential targets. GO enrichment analysis and pathway analysis were performed on potential targets using Clue GO. GO enrichment analysis showed that Xixiancao was mainly involved in life processes such as neuronal apoptosis,cholesterol storage and blood pressure regulation. Pathway analysis showed that Xixiancao may promote vascular repairing and regeneration by regulating the expression of ADAMTS1,FLT1 and KDR in VEGFA-VEGFR2 signaling pathway,activate cell survival signals and inhibit neuronal apoptosis by regulating the expression of CAMK2 AA,MDM2,MAPK1,MAPK3,CDK5 and MAPK10 in brain-derived neurotrophic factor signaling pathway and PI3 K-Akt signaling pathway. Lipid homeostasis and inflammation may also be regulated by Xixiancao through regulating the expression of ESR1,NR1 H3,PPARA,PPARG in the nuclear receptor signaling pathway. In addition,Xixiancao could also prevent platelet aggregation by regulating the expression of ITGA2 B,F2,F10,and ALB,and play an antithrombotic role. The results of this study indicate that Xixiancao plays an important role in the treatment of ischemic stroke mainly through anti-thrombosis,promoting angiogenesis,protecting neurons,anti-inflammatory and regulating blood pressure and lipids.
Xixiancao( Siegesbeckiae Herba) has the effect of treating ischemic stroke( IS),however,the mechanism has not been fully elucidated. In this study,combined with Lipinski's five principles and Veber oral bioavailability rules,68 chemical components of Xixiancao were obtained by database and literature search. Based on the reverse targeting,248 potential targets were obtained and mapped it to the ischemic stroke target set,47 potential targets for the treatment of ischemic stroke were obtained. Molecular docking technique was used to verify that the Xixiancao component has good binding activity to potential targets. GO enrichment analysis and pathway analysis were performed on potential targets using Clue GO. GO enrichment analysis showed that Xixiancao was mainly involved in life processes such as neuronal apoptosis,cholesterol storage and blood pressure regulation. Pathway analysis showed that Xixiancao may promote vascular repairing and regeneration by regulating the expression of ADAMTS1,FLT1 and KDR in VEGFA-VEGFR2 signaling pathway,activate cell survival signals and inhibit neuronal apoptosis by regulating the expression of CAMK2 AA,MDM2,MAPK1,MAPK3,CDK5 and MAPK10 in brain-derived neurotrophic factor signaling pathway and PI3 K-Akt signaling pathway. Lipid homeostasis and inflammation may also be regulated by Xixiancao through regulating the expression of ESR1,NR1 H3,PPARA,PPARG in the nuclear receptor signaling pathway. In addition,Xixiancao could also prevent platelet aggregation by regulating the expression of ITGA2 B,F2,F10,and ALB,and play an antithrombotic role. The results of this study indicate that Xixiancao plays an important role in the treatment of ischemic stroke mainly through anti-thrombosis,promoting angiogenesis,protecting neurons,anti-inflammatory and regulating blood pressure and lipids.
引文
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[2]何伋,鹿衡理,成义仁,等.内科诊疗学[M].济南:山东科学技术出版社,1996.
[3]周平,谢伟杰,孙桂波,等.缺血性脑卒中发病机制及药物干预研究进展[J].世界最新医学信息文摘,2018,18(34):53.
[4]孟文婷,李东翔,佟玲.缺血性脑卒中的治疗研究进展[J].中国新药杂志,2016,25(10):1114.
[5]李立,吴世政,张淑坤.缺血性脑卒中后相关免疫学研究进展[J].中华老年心脑血管病杂志,2015,17(2):219.
[6]中国药典.一部[S].2015:368.
[7]于炳伟,金范学.豨莶草的化学成分及药理作用[J].医学美学美容旬刊,2015,24(6):702.
[8]张超,吴素香,楼招欢,等.豨莶草化学成分、药理作用及临床应用研究进展[J].安徽医药,2011,15(3):274.
[9]韩蕾,周晓辉,王维伟.豨莶草对小鼠全脑缺血再灌注模型的药效学观察[J].中华中医药学刊,2012(10):2287.
[10]朱玲,夏军.豨莶通栓胶囊治疗痰瘀阻络型缺血性中风的临床观察[J].中医药导报,2015,21(9):823.
[11]王彦红,何威,李艳秋.豨莶草方加减治疗缺血性中风风痰瘀阻证的临床观察[J].中国社区医师,2018,34(3):86.
[12] Gu J,Gui Y,Chen L,et al. CVDHD:a cardiovascular disease herbal database for drug discovery and network pharmacology[J].J Cheminformatics,2013,5(1):51.
[13]滕天立,徐世芳,陈峰阳,等.中药豨莶草的化学成分及其药理作用研究进展[J].中国现代应用药学,2015,32(2):250.
[14]霍晓乾,谷宇,张燕玲.基于网络药理学的大黄利胆片的作用机制研究[J].中国中药杂志,2018,43(13):2770.
[15]陈艳昆,乔连生,霍晓乾,等.基于计算机辅助水解和蛋白互作网络的珍珠母寡肽作用机制解析[J].中国中药杂志,2017,42(17):3417.
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[17]张琼.几种抗凝血药物与人血清白蛋白的相互作用[D].兰州:西北师范大学,2011.
[18]刘江,吴延庆. ADAMTS-1与血管损伤关系的研究进展[J].南昌大学学报:医学版,2011,51(2):99.
[19]血管内皮生长因子受体2通过调节一氧化氮合酶的表达控制血压[J].中华高血压杂志,2009,17(10):959.
[20]张君.钙离子/钙调素依赖性蛋白激酶Ⅱ及其抑制剂[J].国际检验医学杂志,2002,23(4):237.
[21]王皓香.腺苷受体A1与A2A相互作用对缺血性脑损伤的影响[D].重庆:第三军医大学,2012.
[22]孙萍,于雁. Mdm2 siRNA诱导Lo Vo细胞凋亡的研究[J].哈尔滨医科大学学报,2006,40(3):204.
[23]刘芳,周小江,陈乃宏.Cdk5介导的凋亡与自噬交互作用对脑缺血的调控[J].中国药理学通报,2018,34(4):463.
[24]杨冀萍,刘怀军.丝裂原活化蛋白激酶在脑缺血损伤中的作用及其调控机制[J].中国组织工程研究,2006,10(10):138.
[25] Jér8me N Feige,Gelman L,Michalik L,et al. From molecular action to physiological outputs:peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions[J]. Prog Lipid Res,2006,45(2):120.
[26]毛彩艳,张辉,李旭生,等.FABP4在妊娠期高血压疾病胎盘滋养细胞免疫炎症反应中的作用研究[J].中国药理学通报,2017,33(8):1126.
[27]王海波,俞为荣. MMP-2/MMP-9在炎症中的研究进展[J].医学综述,2014,20(17):3120.
[28]侴桂新,金若敏,王峥涛,等.豨莶草抗血栓有效组分成分分析[J].中药材,2006(3):235.
[29]信红岭,毕娟,刘淼,等.奇任醇的抗炎免疫实验研究[J].中草药,2005,36(6):866.
[30] Liman T G,Endres M. New vessels after stroke:postischemic neovascularization and regeneration[J]. Cerebrovasc Dis,2012,33(5):492.
[31] Quittet M S,Touzani O,Sindji L,et al. Effects of mesenchymal stem cell therapy,in association with pharmacologically active microcarriers releasing VEGF,in an ischaemic stroke model in the rat[J]. Acta Biomater,2015,15:77.
[32] Zhang Z G,Zhang L,Jiang Q,et al. VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain[J]. J Clin Invest,2000,106(7):829.
[33]叶海虹.神经营养因子的功能及信号转导(英文)[C].广州:第三届海内外华人中青年学者神经科学研讨会,2004.
[34]于玲莉.窖蛋白对神经营养因子信号通路的调控研究[D].上海:华东师范大学,2013.
[35]何谐.核受体PPARγ和FXR的抗炎机制研究[D].重庆:第三军医大学,2013.
[36]马晶晶,章涛. PPARγ功能与疾病关系研究进展[J].中国药理学通报,2012,28(5):601.
[37]高敏,魏丽惠.孤儿核受体——雌激素受体相关受体研究进展[J].国外医学·计划生育分册,2005,24(3):145.
[38]彭湾,张建东,肖海.肝X受体与慢性脑缺血认知功能障碍关系的研究进展[J].中风与神经疾病杂志,2018,35(12):1132.
[39] Ma Y,Chen L,Li C,et al. Overexpression of HSPA12B protects against cerebral ischemia/reperfusion injury via a PI3K/Akt-dependent mechanism[J]. BBA-Mol Basis Dis,2013,1832(1):57.
[40]张英霞,张云.血清白蛋白的功能及应用[J].海南大学学报:自然科学版,2007,25(3):315.
[41]王雅丹,胡豫,孙春艳. Akt、ERK1/2活化在脑源性神经营养因子促血管新生中的作用[J].中国病理生理杂志,2007,23(5):833.
[42]杨洋,刘晓楠,马超,等. ERK1/2信号传导通路在大鼠局灶性急性脑缺血再灌注中的作用[J].中国动脉硬化杂志,2013,21(11):987.
[43]吉日木巴图,范娜,王蕊,等.基于分子对接技术探讨残黄片退黄作用机制[J].中国实验方剂学杂志,2019,25(10):154.
[44]陈晰,王思琪,李运曼.缺血性脑卒中后血栓素A2的作用及相关药物研究进展[J].中国心血管病研究,2015,13(2):117.
[45]常坤鹏,丁小灵.缺血性脑卒中新生血管相关因子的研究[J].脑与神经疾病杂志,2015,23(4):312.
[46] Yao R Q,Yu H L,Liu J,et al. Quercetin attenuates cell apoptosis in focal cerebral ischemia rat brain via activation of BDNFTrkB-PI3K/Akt signaling pathway[J]. Neurochem Res,2012,37(12):2777.