基于网络药理学的牛膝防治阿尔茨海默病的物质基础与作用机制研究
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摘要
目的基于网络药理学及分子对接技术预测牛膝防治阿尔茨海默病(Alzheimer’s disease,AD)的主要活性成分及作用靶点,探讨其"多成分-多靶点-多通路"的作用机制。方法收集DrugBank和文献报道中AD的治疗靶点,依据中药系统药理学技术平台(TCMSP)构建牛膝的化学成分库;运用DiscoveryStudio3.5软件进行分子对接,虚拟筛选牛膝中与AD的靶点结合的化学成分集;通过KEGG数据库对虚拟筛选到的关键靶点进行通路富集分析,采用Cytoscape 3.2.1软件构建牛膝的"成分-靶点-通路"网络。结果从牛膝中筛选出58个化合物,多为小分子烷烃、酯类和羧酸类化合物,其次为黄酮类、蒽醌类等。这些有效成分可能通过调节Ca MK-IIα、Ca MK-IIβ、Ca MK-IIγ、Akt1和TNF-α等36个AD发病机制的潜在靶蛋白而发挥作用,涉及MAPK signaling pathway、Wnt signaling pathway等12条通路。结论牛膝中黄酮类、蒽醌类等活性成分可能是其治疗AD的物质基础,其作用机制涉及抗炎、抗细胞凋亡等。
Objective This study was designed to predict the main targets of Alzheimer's disease(AD) in Achyranthis Bidentatae Radix based on network pharmacology and molecular docking methods, and to explore its "multi-component, multi-target, and multi-pathway" mechanism. Methods According to the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), the library of chemical constituents of Achyranthis Bidentatae Radix was established by referring to Chinese and foreign literature reports and collecting targets for treating AD in DrugBank. The Discovery Studio 3.5 software was used to carry out molecular docking, virtual screening of the chemical composition set of Achyranthis Bidentatae Radix combined with AD target, and KEGG database was used to enrich and analyze the key target of virtual screening. The active compounds of Achyranthis Bidentatae Radix with anti-AD activities were yielded to Discovery Studio 3.5 software and molecular docking to predict the poteneial proteins and carry out related KEGG pathways notation separately. Finally, the network of "active compound-target proteins-pathway" was built and analyzed using the Cytoscape 3.2.1 software. Results The 58 active compounds were selected from Achyranthis Bidentatae Radix, of which were mostly small alkanes, esters, and carboxylic acids followed by flavonoids and terpenoids. These active ingredients may regulate 36 potential target proteins such as CaMK-IIα, Ca MK-IIβ, CaMK-IIγ, Akt1, and TNF-α to play a role in the pathogenesis of AD. The results also suggested that 12 signaling pathways were involved in the pathogenesis of AD, such as MAPK signaling pathway, Wnt signaling pathways and so on. Conclusion This research method initially revealed that the active ingredients of flavonoids and glycosides in Achyranthis Bidentatae Radix are the material basis for the treatment of AD. Its mechanism of action involved anti-inflammatory, anti-apoptosis and so on.
Objective This study was designed to predict the main targets of Alzheimer's disease(AD) in Achyranthis Bidentatae Radix based on network pharmacology and molecular docking methods, and to explore its "multi-component, multi-target, and multi-pathway" mechanism. Methods According to the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), the library of chemical constituents of Achyranthis Bidentatae Radix was established by referring to Chinese and foreign literature reports and collecting targets for treating AD in DrugBank. The Discovery Studio 3.5 software was used to carry out molecular docking, virtual screening of the chemical composition set of Achyranthis Bidentatae Radix combined with AD target, and KEGG database was used to enrich and analyze the key target of virtual screening. The active compounds of Achyranthis Bidentatae Radix with anti-AD activities were yielded to Discovery Studio 3.5 software and molecular docking to predict the poteneial proteins and carry out related KEGG pathways notation separately. Finally, the network of "active compound-target proteins-pathway" was built and analyzed using the Cytoscape 3.2.1 software. Results The 58 active compounds were selected from Achyranthis Bidentatae Radix, of which were mostly small alkanes, esters, and carboxylic acids followed by flavonoids and terpenoids. These active ingredients may regulate 36 potential target proteins such as CaMK-IIα, Ca MK-IIβ, CaMK-IIγ, Akt1, and TNF-α to play a role in the pathogenesis of AD. The results also suggested that 12 signaling pathways were involved in the pathogenesis of AD, such as MAPK signaling pathway, Wnt signaling pathways and so on. Conclusion This research method initially revealed that the active ingredients of flavonoids and glycosides in Achyranthis Bidentatae Radix are the material basis for the treatment of AD. Its mechanism of action involved anti-inflammatory, anti-apoptosis and so on.
引文
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[29]屈岭,顾蓓,张宏,等.中药筋脉通对糖尿病周围神经组织雪旺细胞自噬与凋亡的影响[A]//全国中西医结合内分泌代谢病学术大会暨中德代谢综合征高层论坛[C].北京:中国中西医结合学会,2013.
[30]Wang C,Yu J T,Miao D,et al.Targeting the m TORsignaling network for Alzheimer’s disease therapy[J].Mol Neurobiol,2014,49(1):120-135.
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[32]高平章,韩旭花,白赛赛,等.汉黄芩素抑制PI3K/AKT/mTOR信号通路影响急性白血病HL-60细胞增殖[J].泉州师范学院学报,2017,35(6):1-6.
[33]Han X,Ma Y,Liu X,et al.Changes in insulin-signaling transduction pathway underlie learning/memory deficits in an Alzheimer’s disease rat model[J].J Neural Transm,2012,119(11):1407-1416.
[2]应侠,吴振,雷严,等.阿尔茨海默病的发病机制及治疗药物研究进展[J].中国药房,2014,25(33):3152-3155.
[3]沈舒,王琼,李友宾.牛膝的化学成分和药理作用研究进展[J].海峡药学,2011,23(11):1-6.
[4]Wang Y,Xu Y,Pan Y,et al.Radix Achyranthis Bidentatae improves learning and memory capabilities in ovariectomized rats[J].Neural Regener Res,2013,8(18):1644-1654.
[5]Ru J,Li P,Wang J,et al.TCMSP:A database of systems pharmacology for drug discovery from herbal medicines[J].J Cheminformatics,2014,doi:10.1186/1758-2946-6-13.
[6]Liu J,Pei M,Zheng C,et al.A systems-pharmacology analysis of herbal medicines used in health improvement treatment:Predicting potential new drugs and targets[J].Evid-Based Compl Alter Med,2013,doi:10.1155/2013/938764.
[7]Law V,Knox C,Djoumbou Y,et al.Drug Bank 4.0:Shedding new light on drug metabolism[J].Nucl Acid Res,2014,doi:10.1093/nar/gkt1068.
[8]黄涛.蛋白质结构数据库的信息挖掘[D].上海:同济大学,2006.
[9]刘美凤,蒋利荣,刘华鼐,等.番石榴叶抗II型糖尿病活性成分的虚拟筛选[J].华南理工大学学报:自然科学版,2011,39(3):28-31.
[10]黄丽萍,燕波,侯敏,等.网络药理学探究二至丸防治阿尔茨海默病的物质基础与作用机制[J].中国中药杂志,2017,42(21):4211-4217.
[11]Zhang X,Jin H,Li Z,et al.Quercetin stabilizes apolipoprotein E and reduces brain Aβlevels in amyloid model mice[J].Neuropharmacology,2016,doi:10.1016/j.neuropharm.2016.04.032.
[12]Huang D S,Yu Y C,Wu C H,et al.Protective effects of wogonin against Alzheimer’s disease by inhibition of amyloidogenic pathway[J].Evid-Based Compl Alter Med,2017,doi:10.1155/2017/3545169.
[13]张君,程笑,杨欢,等.山柰酚对慢性脑缺血大鼠学习记忆能力的影响及机制探[J].中国药理学通报,2017,33(1):39-44.
[14]Wang W,Wang F,Yang Y J,et al.The flavonoid baicalein promotes NMDA receptor-dependent long-term potentiation and enhances memory[J].Brit J Pharmacol,2011,162(6):1364-1379.
[15]Chae U,Min J S,Leem H H,et al.Chrysophanol suppressed glutamate-induced hippocampal neuronal cell death via regulation of dynamin-related protein1-dependent mitochondrial fission[J].Pharmacology,2017,100(3/4):153-160.
[16]Kobayashi S,Tanaka T,Soeda Y,et al.Local somatodendritic translation and hyperphosphorylation of tau protein triggered by AMPA and NMDA receptor stimulation[J].Ebiomedicine,2017,doi:10.1016/j.ebiom.2017.05.012.
[17]陈雪,孙婧霞,蒋常文.Bcl-2、Caspase-3与阿尔茨海默病关系的研究进展[J].临床医学工程,2013,20(9):1177-1179.
[18]宋锦秋,陈晓春.MAPK信号通路与阿尔茨海默病中tau蛋白磷酸化的关系[J].国际神经病学神经外科学杂志,2006,33(4):339-343.
[19]李杰.大黄素和槲皮素对LRRK2突变致PD果蝇的治疗作用探讨[D].苏州:苏州大学,2016.
[20]王慧莲,孟庆良,李伟松,等.汉黄芩素通过激活活性氧簇介导的P38MAPK信号通路诱导类风湿关节炎成纤维样滑膜细胞凋亡[J].中国骨质疏松杂志,2017,23(7):890-895.
[21]陈炜平.黄芩素抗骨性关节炎的作用及其机制研究[D].杭州:浙江大学,2011.
[22]Suchal K,Malik S,Gamad N,et al.Kaempferol attenuates myocardial ischemic injuryviaInhibition of MAPK signaling pathway in experimental model of myocardial ischemia-reperfusion injury[J].Oxid Med Cell Longev,2016,doi:10.1155/2016/7580731.
[23]曹燕,王旭,梁枫.认知功能障碍相关信号通路[J].中国老年学杂志,2015,35(21):6295-6297.
[24]张跃其,王培昌.阿尔茨海默病相关信号转导通路研究进展[J].医学综述,2015,21(10):1748-1750.
[25]江华基,江小成,贺飞林,等.黄芩素通过Wnt/β-catenin信号通路促进大鼠腱骨愈合[J].分子影像学杂志,2016,39(3):297-301.
[26]He L,Lu N,Dai Q,et al.Wogonin induced G1 cell cycle arrest by regulating Wnt/β-catenin signaling pathway and inactivating CDK8 in human colorectal cancer carcinoma cells[J].Toxicology,2013,312(1):36-47.
[27]Kim H,Seo E M,Sharma A R,et al.Regulation of Wnt signaling activity for growth suppression induced by quercetin in 4T1 murine mammary cancer cells[J].Int JOncol,2013,43(4):1319-1325.
[28]焦红蕾.山柰酚通过Wnt3a/beta-catenin信号通路促进实验性脑缺血小鼠神经功能改善及神经再生[D].石家庄:河北医科大学,2016.
[29]屈岭,顾蓓,张宏,等.中药筋脉通对糖尿病周围神经组织雪旺细胞自噬与凋亡的影响[A]//全国中西医结合内分泌代谢病学术大会暨中德代谢综合征高层论坛[C].北京:中国中西医结合学会,2013.
[30]Wang C,Yu J T,Miao D,et al.Targeting the m TORsignaling network for Alzheimer’s disease therapy[J].Mol Neurobiol,2014,49(1):120-135.
[31]Granato M,Rizzello C,Montani M S,et al.Quercetin induces apoptosis and autophagy in primary effusion lymphoma cells by inhibiting PI3K/AKT/mTOR and STAT3 signaling pathways[J].J Nutr Biochem,2017,doi:10.1016/j.jnutbio.2016.12.011.
[32]高平章,韩旭花,白赛赛,等.汉黄芩素抑制PI3K/AKT/mTOR信号通路影响急性白血病HL-60细胞增殖[J].泉州师范学院学报,2017,35(6):1-6.
[33]Han X,Ma Y,Liu X,et al.Changes in insulin-signaling transduction pathway underlie learning/memory deficits in an Alzheimer’s disease rat model[J].J Neural Transm,2012,119(11):1407-1416.