基于系统药理学的白芍-甘草药对作用机制分析
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摘要
目的基于系统药理学方法,借助中药系统药理学分析平台(TCMSP),整合中医药大数据,探讨白芍-甘草药对的功效物质基础并分析其作用机制。方法在TCMSP检索"白芍"和"甘草"2味中药获得其化学成分,采用双侧曼-惠特尼U检验法对所有化学成分的分子描述符进行比较,以口服生物利用度(OB)和类药性(DL)为指标筛选药对的活性成分、靶点和相关疾病,进而构建成分-靶点-疾病网络模型和蛋白互作(PPI)网络模型,对靶蛋白进行基因本体(GO)生物过程和KEGG代谢通路富集分析,探讨药对物质基础和作用机制。结果通过OB、DL参数筛选得到49个药物活性成分、100个作用靶点和230种相关疾病。其中度(degree)值较高的药物活性成分有芒柄花黄素(formononetin)、柚皮素(naringenin)和维斯体素(vestitol);度值较高的靶点有前列腺素g/H合酶2(PTGS2)、雌激素受体(ESR1)和钙调蛋白(CALM);度值较高的相关疾病是非特异性癌症(cancer,unspecific)、炎症(inflammation)、非特异性心血管疾病(cardiovasculardisease,unspecific)、阿尔茨海默病(Alzheimer’s disease)和帕金森病(Parkinson’s disease),主要涉及肿瘤、神经系统疾病、内分泌、营养和代谢疾病及某些传染病和寄生虫病等16类疾病。靶蛋白参与信号传导、药物反应、细胞增殖、RNA聚合酶II启动子调控、细胞外信号调节激酶1(ERK1)和ERK2级联的正调节等生物过程,调控磷脂酰肌醇-3-激酶(PI3K)-蛋白激酶B(Akt)、5-羟色胺能突触等代谢通路。结论初步探索了白芍-甘草药对的基本药理作用及其机制,为该药对及其中药方剂的研究提供新的思路。
Objective To study the functional material basis of herb pair Paeoniae Radix Alba-Glycyrrhizae Radix et Rhizoma and analyze their mechanism of action by the systematic pharmacological method based on the platform of traditional Chinese medicine systematic pharmacological analysis(TCMSP) and the big data of traditional Chinese medicine. Methods TCMSP was used to search for the chemical constituents of the two Chinese herbal medicines, "Baishao" and "Gancao". The molecular descriptors of the components were compared by the two tailed Mann-Whitney U test method, and the oral bioavailability(OB) and drug-likeness(DL) were used as indicators to screen the active components, targets and related diseases of the herb pair. The"component-target-disease" and PPI network models were constructed, and bioprocess and metabolic pathway were analyzed to explore the drug-based material basis and mechanism of action. Results Through the OB and DL parameters screening, 49 active pharmaceutical ingredients, 100 targets and 230 related diseases were obtained. The active ingredients with higher degree were formononetin, naringenin, and vestitol; The higher degree of targets were prostaglandin g/H synthase 2(PTGS2), estrogen receptor(ESR1), and calmodulin(CALM); The higher-grade related diseases were unspecific cancer, inflammation, cardiovascular disease,unspecified, Alzheimer's disease, and Parkinson's disease, mainly involving 16 categories of diseases such as cancer, nervous system diseases, endocrine, nutritional and metabolic diseases and certain infectious diseases and parasitic diseases. Target proteins are involved in bioprocess including signal transduction, drug response, cell proliferation, RNA polymerase II promoter regulation, positive regulation of ERK1 and ERK2 cascades, regulating metabolic pathways such as PI3 K-Akt and 5-hydroxytryptamine synapses. Conclusion This study preliminarily verified the basic pharmacological effects and mechanisms of the Paeoniae Radix Alba-Glycyrrhizae Radix et Rhizoma herb pair, and explored new ideas for the study of the herb pair and related traditional Chinese medicine prescriptions.
Objective To study the functional material basis of herb pair Paeoniae Radix Alba-Glycyrrhizae Radix et Rhizoma and analyze their mechanism of action by the systematic pharmacological method based on the platform of traditional Chinese medicine systematic pharmacological analysis(TCMSP) and the big data of traditional Chinese medicine. Methods TCMSP was used to search for the chemical constituents of the two Chinese herbal medicines, "Baishao" and "Gancao". The molecular descriptors of the components were compared by the two tailed Mann-Whitney U test method, and the oral bioavailability(OB) and drug-likeness(DL) were used as indicators to screen the active components, targets and related diseases of the herb pair. The"component-target-disease" and PPI network models were constructed, and bioprocess and metabolic pathway were analyzed to explore the drug-based material basis and mechanism of action. Results Through the OB and DL parameters screening, 49 active pharmaceutical ingredients, 100 targets and 230 related diseases were obtained. The active ingredients with higher degree were formononetin, naringenin, and vestitol; The higher degree of targets were prostaglandin g/H synthase 2(PTGS2), estrogen receptor(ESR1), and calmodulin(CALM); The higher-grade related diseases were unspecific cancer, inflammation, cardiovascular disease,unspecified, Alzheimer's disease, and Parkinson's disease, mainly involving 16 categories of diseases such as cancer, nervous system diseases, endocrine, nutritional and metabolic diseases and certain infectious diseases and parasitic diseases. Target proteins are involved in bioprocess including signal transduction, drug response, cell proliferation, RNA polymerase II promoter regulation, positive regulation of ERK1 and ERK2 cascades, regulating metabolic pathways such as PI3 K-Akt and 5-hydroxytryptamine synapses. Conclusion This study preliminarily verified the basic pharmacological effects and mechanisms of the Paeoniae Radix Alba-Glycyrrhizae Radix et Rhizoma herb pair, and explored new ideas for the study of the herb pair and related traditional Chinese medicine prescriptions.
引文
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[11]李伯英.芍药甘草汤加减联合针刺疗法治疗原发性三叉神经痛的效果观察[J].承德医学院学报,2018,35(2):129-131.
[12]李龙婷,张艳丽.手法配合加味芍药甘草汤治疗乳房痉挛初探[J].亚太传统医药,2018,14(9):129-130.
[13]赵志敏,李朝军.芍药甘草汤加减治疗干眼症36例[J].中医药学,2006,18(3):220-222.
[14]张庭基.跟师曹田梅教授学习芍药甘草汤治疗便秘的运用心得[J].内蒙古中医药,2018,37(3):41.
[15]高歌,潘晓华,等.基于系统药理学的续断治疗骨质疏松作用机制研究[J].中草药,2018,49(19):4581-4585.
[16]聂娟,唐标.基于系统药理学分析三七总皂苷干预脑血管疾病的作用机制[J].湖南中医药大学学报,2018,38(9):1032-1037.
[17]张力军,陈曦,冯世秀,等.基于系统药理学探索裸花紫珠有效成分的作用机制[J].药物评价研究,2018,41(10):1759-1769.
[18]Ru J L,Li P,Wang Y H,et al.TCMSP:A database of systems pharmacology for drug discovery from herbal medicines[J].J Cheminform,2014,doi:10.1186/1758-2946-6-13.
[19]Xu H Y,Liu Z M,Fu Y,et al.Exploiture and application of an internet-based computation platform for integrative pharmacology of traditional Chinese chronic obstructive pulmonary disease[J].Sci Rep,2015,5(8):15290-15296.
[20]Shen X,Zhao Z,Wang H,et al.Elucidation of the anti-inflammatory mechanisms of Bupleuri and Scutellariae Radix using system pharmacological analyses[J].Mediat Inflamm,2017,doi:10.1155/2017/3709874.
[21]李明玥,倪健,尹兴斌.改善中药口服生物利用度的制剂技术研究进展[J].中华中医药学刊,2016,34(2):307-311.
[22]吴嘉瑞,金燕萍,段笑娇,等.基于网络药理学的“桔梗-甘草”药对作用机制分析[J].中国实验方剂学杂志,2017,23(5):184-188.
[23]Zaru R,Magrane M,O’Donovan C.Uni Prot consortium from the research laboratory to the database:The caenorhabditis elegans kinome in UniProtKB biochem[J].Biochem J,2017,474(4):493-515.
[24]Smoot M E,Ono K,Ruscheinski J,et al.Cytoscape 2.8:New features for data integration and network visualization[J].Bioinformatics,2011,27(3):431-432.
[25]Szklarczyk D,Gable A L,Lyon D,et al.Protein-protein association networks with increased coverage,supporting functional discovery in genome-wide experimental datasets[J].Nucl Acid Res,2019,doi:10.1093/nar/gky1131.
[26]Jiao X,Sherman B T,Stephens R,et al.DAVID-WS:Astateful web service to facilitate gene/protein list analysis[J].Bioinformatics,2012,28(13):1805-1806.
[27]Li J Z,Tang X N,Li T T,et al.Paeoniflorin inhibits doxorubicin-induced cardiomyocyte apoptosis by downregulating micro RNA-1 expression[J].Exp Ther Med,2016,11(6):2407-2412.
[28]Yang N M,Cui H,Han F,et al.Paeoniflorin inhibits human pancreatic cancer cell apoptosis via suppression of MMP-9 and ERK signaling[J].Oncol Lett,2016,12(2):1471-1476.
[29]Zhang Y,Wang L L,Wu Y,et al.Paeoniflorin attenuates hippocampal damage in a rat model of vascular dementia[J].Exp Ther Med,2016,12(6):3729-3734.
[30]Zhang L G,Wang L J,Shen Q Q.Paeoniflorin improves regional cerebral blood flow and suppresses inflammatory factor in the hippocampus of rats withvascular dementia[J].Chin J Integr Med,2015,doi:10.1007/s11655-015-2124-3.
[31]马伟,马卫东,苗珍花,等.芍药苷神经保护作用的实验研究[J].宁夏医科大学学报,2011,33(2):132-134.
[32]许可,吴碧华,江承平,等.甘草总黄酮对脑缺血后神经元特异性烯醇化酶和一氧化氮的影响[J].川北医学院学报,2006,21(3):220-223.
[33]张幸,梁梅花,黄文君,等.芒柄花黄素诱导膀胱癌细胞凋亡作用[J].中国公共卫生,2015,31(3):314-317.
[34]郭琳,李珏宏,李昌平,等.STAT3、PPAR-γ在小鼠溃疡性结肠炎的作用及姜黄素的影响[J].世界华人消化杂志,2016,14(1):28-36.
[35]吴晨方.PPAR-α/γ激动剂对代谢综合征心室重构的保护机制研究[D].长沙:中南大学,2014.
[36]张雪松.红景天苷对糖尿病大鼠肾脏Nrf2、γ-GCS、PPAR-γ表达的影响[D].石家庄:河北医科大学,2014.
[37]北京协和医院世界卫生组织疾病分类合作中心.疾病和有关健康问题的国际统计分类(ICD-10)(第1卷)[M].北京:人民卫生出版社,2006.
[38]Coban N,Kaya A,Erkan A F,et al.The role of CYP19A1,ESR1 and MIF genes polymorphims on the angiographic severity and the extent of atherosclerotic coronary artery disease[J].Atherosclerosis,2017,doi:10.1016/j.atherosclerosis.2017.06.385.
[39]Mansour D F,Saleh D O,Mostafa R E.Genistein ameliorates cyclophosphamide-induced hepatotoxicity by modulation of oxidative stress and inflammatory mediators[J].Open Access Maced J Med Sci,2017,5(7):836-843.
[40]宁云红,郭承伟.以21篇临床文献综述芍药甘草汤应用概况[J].中医药导报,2017,23(3):83-84.
[41]赵征昊.芍药甘草汤临床应用概况[J].中国民族民间医药,2018,27(1):66-68.
[42]Albina S,Benatti C,Capone G.Time-dependent effects of escitalopram on brain derived neurotrophic factor(BDNF)and neuroplasticityrelated targets in the central nervous system of rats[J].Eur J Pharmacol,2010,643(2/3):180-187.
[43]Kohler S,Cierpinsky K,Kronenberg G,et al.The serotonergic system in the neurobiology of depression:Relevance for novel antidepressants[J].JPsychopharmacol,2016,30(1):13-22.
[2]张正慧.芍药甘草汤加味治疗慢性踝关节损伤的疗效观察[J].当代医药论丛,2018,16(16):15-16.
[3]杜国福.芍药甘草汤加减治疗急性胃溃疡的效果探析[J].当代医药论丛,2018,16(19):138-140.
[4]曾纪权,郑智,朱伟,等.芍药甘草汤保留灌肠预防放射性直肠炎临床观察[J].江西中医药大学学报,2019,31(1):52-53.
[5]王妮娜.地黄饮子合芍药甘草汤治疗帕金森病疗效观察[J].山西中医,2018,34(2):11-12.
[6]杨庆堂,宋颖民.芍药甘草汤合甘麦大枣汤加减治疗帕金森病临床观察[J].中医临床研究,2012,4(11):1-2.
[7]胡茸.芍药甘草汤加减治疗帕金森病继发肌张力障碍24例[J].四川中医,2011,29(1):138-140.
[8]戈盾.止颤汤合芍药甘草汤治疗帕金森病疼痛的临床疗效观察[J].内蒙古中医药,2017(14):44-45.
[9]徐骁,戴琴.芍药甘草汤加味治疗帕金森病临床研究[J].河南中医,2018,38(6):874-876.
[10]韩冰.加味芍药甘草汤结合康复训练治疗老年脑卒中偏瘫的疗效及对患者运动功能、生活质量的影响[J].中国老年学杂志,2018,38(5):1046-1048.
[11]李伯英.芍药甘草汤加减联合针刺疗法治疗原发性三叉神经痛的效果观察[J].承德医学院学报,2018,35(2):129-131.
[12]李龙婷,张艳丽.手法配合加味芍药甘草汤治疗乳房痉挛初探[J].亚太传统医药,2018,14(9):129-130.
[13]赵志敏,李朝军.芍药甘草汤加减治疗干眼症36例[J].中医药学,2006,18(3):220-222.
[14]张庭基.跟师曹田梅教授学习芍药甘草汤治疗便秘的运用心得[J].内蒙古中医药,2018,37(3):41.
[15]高歌,潘晓华,等.基于系统药理学的续断治疗骨质疏松作用机制研究[J].中草药,2018,49(19):4581-4585.
[16]聂娟,唐标.基于系统药理学分析三七总皂苷干预脑血管疾病的作用机制[J].湖南中医药大学学报,2018,38(9):1032-1037.
[17]张力军,陈曦,冯世秀,等.基于系统药理学探索裸花紫珠有效成分的作用机制[J].药物评价研究,2018,41(10):1759-1769.
[18]Ru J L,Li P,Wang Y H,et al.TCMSP:A database of systems pharmacology for drug discovery from herbal medicines[J].J Cheminform,2014,doi:10.1186/1758-2946-6-13.
[19]Xu H Y,Liu Z M,Fu Y,et al.Exploiture and application of an internet-based computation platform for integrative pharmacology of traditional Chinese chronic obstructive pulmonary disease[J].Sci Rep,2015,5(8):15290-15296.
[20]Shen X,Zhao Z,Wang H,et al.Elucidation of the anti-inflammatory mechanisms of Bupleuri and Scutellariae Radix using system pharmacological analyses[J].Mediat Inflamm,2017,doi:10.1155/2017/3709874.
[21]李明玥,倪健,尹兴斌.改善中药口服生物利用度的制剂技术研究进展[J].中华中医药学刊,2016,34(2):307-311.
[22]吴嘉瑞,金燕萍,段笑娇,等.基于网络药理学的“桔梗-甘草”药对作用机制分析[J].中国实验方剂学杂志,2017,23(5):184-188.
[23]Zaru R,Magrane M,O’Donovan C.Uni Prot consortium from the research laboratory to the database:The caenorhabditis elegans kinome in UniProtKB biochem[J].Biochem J,2017,474(4):493-515.
[24]Smoot M E,Ono K,Ruscheinski J,et al.Cytoscape 2.8:New features for data integration and network visualization[J].Bioinformatics,2011,27(3):431-432.
[25]Szklarczyk D,Gable A L,Lyon D,et al.Protein-protein association networks with increased coverage,supporting functional discovery in genome-wide experimental datasets[J].Nucl Acid Res,2019,doi:10.1093/nar/gky1131.
[26]Jiao X,Sherman B T,Stephens R,et al.DAVID-WS:Astateful web service to facilitate gene/protein list analysis[J].Bioinformatics,2012,28(13):1805-1806.
[27]Li J Z,Tang X N,Li T T,et al.Paeoniflorin inhibits doxorubicin-induced cardiomyocyte apoptosis by downregulating micro RNA-1 expression[J].Exp Ther Med,2016,11(6):2407-2412.
[28]Yang N M,Cui H,Han F,et al.Paeoniflorin inhibits human pancreatic cancer cell apoptosis via suppression of MMP-9 and ERK signaling[J].Oncol Lett,2016,12(2):1471-1476.
[29]Zhang Y,Wang L L,Wu Y,et al.Paeoniflorin attenuates hippocampal damage in a rat model of vascular dementia[J].Exp Ther Med,2016,12(6):3729-3734.
[30]Zhang L G,Wang L J,Shen Q Q.Paeoniflorin improves regional cerebral blood flow and suppresses inflammatory factor in the hippocampus of rats withvascular dementia[J].Chin J Integr Med,2015,doi:10.1007/s11655-015-2124-3.
[31]马伟,马卫东,苗珍花,等.芍药苷神经保护作用的实验研究[J].宁夏医科大学学报,2011,33(2):132-134.
[32]许可,吴碧华,江承平,等.甘草总黄酮对脑缺血后神经元特异性烯醇化酶和一氧化氮的影响[J].川北医学院学报,2006,21(3):220-223.
[33]张幸,梁梅花,黄文君,等.芒柄花黄素诱导膀胱癌细胞凋亡作用[J].中国公共卫生,2015,31(3):314-317.
[34]郭琳,李珏宏,李昌平,等.STAT3、PPAR-γ在小鼠溃疡性结肠炎的作用及姜黄素的影响[J].世界华人消化杂志,2016,14(1):28-36.
[35]吴晨方.PPAR-α/γ激动剂对代谢综合征心室重构的保护机制研究[D].长沙:中南大学,2014.
[36]张雪松.红景天苷对糖尿病大鼠肾脏Nrf2、γ-GCS、PPAR-γ表达的影响[D].石家庄:河北医科大学,2014.
[37]北京协和医院世界卫生组织疾病分类合作中心.疾病和有关健康问题的国际统计分类(ICD-10)(第1卷)[M].北京:人民卫生出版社,2006.
[38]Coban N,Kaya A,Erkan A F,et al.The role of CYP19A1,ESR1 and MIF genes polymorphims on the angiographic severity and the extent of atherosclerotic coronary artery disease[J].Atherosclerosis,2017,doi:10.1016/j.atherosclerosis.2017.06.385.
[39]Mansour D F,Saleh D O,Mostafa R E.Genistein ameliorates cyclophosphamide-induced hepatotoxicity by modulation of oxidative stress and inflammatory mediators[J].Open Access Maced J Med Sci,2017,5(7):836-843.
[40]宁云红,郭承伟.以21篇临床文献综述芍药甘草汤应用概况[J].中医药导报,2017,23(3):83-84.
[41]赵征昊.芍药甘草汤临床应用概况[J].中国民族民间医药,2018,27(1):66-68.
[42]Albina S,Benatti C,Capone G.Time-dependent effects of escitalopram on brain derived neurotrophic factor(BDNF)and neuroplasticityrelated targets in the central nervous system of rats[J].Eur J Pharmacol,2010,643(2/3):180-187.
[43]Kohler S,Cierpinsky K,Kronenberg G,et al.The serotonergic system in the neurobiology of depression:Relevance for novel antidepressants[J].JPsychopharmacol,2016,30(1):13-22.