Mechanism of Anti-depression Mechanism of Akebiae Fructus Based on Network Pharmacology
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摘要: 目的：运用网络药理学的方法揭示预知子抗抑郁的作用机制。方法：采用TCMSP、PharmMapper、Swiss TargetPrediction和GeneCards数据库挖掘预知子的活性成分及其抗抑郁的作用靶点，采用String数据库获取蛋白-蛋白相互作用关系，运用Cytoscape软件构建预知子的成分-作用靶点和PPI网络，利用DAVID数据库对关键靶点的GO和KEGG信号通路进行富集分析。最后，采用AutoDockTools-1.5.6 软件进行分子对接验证。结果：筛选得到预知子的木通苯乙醇B、豆甾醇葡萄糖苷、齐墩果酸等6个核心活性成分，EGFR、MAPK1/8、SRC、HSP90AA1、AR等8个重要抗抑郁靶点。参与调控的16条抑郁相关的信号通路包括催乳素信号通路（Prolactin signaling pathway）、ErbB信号通路（ErbB signaling pathway）、GnRH信号通路（GnRH signaling pathway）、黏着斑（Focal adhesion）等。分子对接结果显示预知子核心活性成分与靶点具有较好的结合活性。结论：预知子抗抑郁的作用机制可通过多成分-多靶点-多通路的综合作用而实现。Abstract: Objective: Revealing the anti-depression mechanism of Akebiae Fructus by network pharmacology technology. Methods: The active compounds and its corresponding depression-related targets of Akebiae Fructus were mined from the TCMSP, PharmMapper, Swiss TargetPrediction, and GeneCards databases. The protein-protein interactions were gained from the String database. The compound-target and PPI networks were built by Cytoscape software. The DAVID database was exploited for enrichment analysis of GO and KEGG signaling pathways for key targets. Finally, molecular docking was carried out for verification using AutoDockTools-1.5.6 software. Results: The 6 active compounds of Akebiae Fructus were identified, including calceolarioside B, stigmasterol glucoside, and oleanolic acid, etc. 8 major depression-related targets were predicted, such as EGFR, MAPK1/8, SRC, HSP90AA1, AR, etc. 16 depression-related signaling pathways were modulated, namely the prolactin signaling pathway, ErbB signaling pathway, GnRH signaling pathway, focal adhesion, etc. The results of molecular docking showed that the kernel components had good binding activity with the key targets. Conclusion: Akebiae Fructus exerted anti-depression effect through the comprehensive combination of multiple components, multiple targets and multiple pathways.
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Key words:
- Akebiae Fructus /
- anti-depression /
- network pharmacology /
- pathway
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图 1 成分靶点与疾病靶点交集的维恩图
Figure 1. Venn diagram after intersection of component targets and disease targets
图 5 预知子抗抑郁通路的气泡图
Figure 5. Bubble diagram of anti-depression pathway of Akebiae Fructus
表 1 预知子活性化合物基本信息
Table 1. Detailed information of active compounds of Akebiae Fructus
序号 英文名 中文名 口服生物利用度（OB，%） 类药性（DL） C1 Calceolarioside B 木通苯乙醇B 1.58 0.7 C2 oleanolic acid 齐墩果酸 29.02 0.76 C3 Daucosterol 西托糖苷 20.63 0.63 C4 / 胡萝卜苷元 36.91 0.75 C5 beta-sitosterol β 谷甾醇 36.91 0.75 C6 sitosterol 谷甾醇 36.91 0.75 C7 Ferulic acid 阿魏酸 39.56 0.06 C8 Stigmasterol 豆甾醇 43.83 0.76 C9 Friedelin 无羁萜 29.16 0.76 C10 Hederagenol 常春藤皂苷元 22.42 0.74 C11 Stigmasterol glucoside 豆甾醇葡萄糖苷 21.32 0.63 C12 Aristolochic acid D 马兜铃酸D 40.32 0.6 C13 Clionasterol γ-谷甾醇 36.91 0.75 C14 Dauricine 蝙蝠葛碱 23.65 0.37 C15 [（2R）-2,3-dihydroxypropyl] （Z）-octadec-9-enoate 2R-甘油单油酸酯 34.13 0.3 C16 Arjunolic acid 阿江榄仁酸 23.22 0.72 C17 2-Monoolein 2-十八烯酸单甘油酯 34.23 0.29 C18 1-Monoolein 1-油酸甘油单酯 34.13 0.3 C19 Sapindoside B_qt / 25.44 0.74 C20 Ariskanin A / 109.51 0.4 C21 aristolochic acid A 马兜铃酸 62.71 0.55 C22 aristolochic acid Ⅱ 马兜铃酸 Ⅱ 37.56 0.45 C23 quinatic acid / 29.98 0.77 C24 akebonoic acid 木通萜酸 15.31 0.78 C25 [（2R）-2,3-dihydroxypropyl] octadecanoate、3-Stearoyl-sn-glycerol 硬脂酸甘油酯 25.2 0.29 C26 glyceryl linolenate 甘油亚麻酸酯 38.14 0.31 
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表 2 预知子核心活性成分和核心靶点的结合能
Table 2. Binding energies of kenerl compounds and targets of Akebiae Fructus
化合物 靶点 结合能（kcal/mol） 化合物 靶点 结合能（kcal/mol） 蝙蝠葛碱 AR −6.8 西托糖苷 AR −7.8 CASP3 −6.8 CASP3 −7.2 EGFR −6.6 EGFR −6.4 ESR1 −7.5 ESR1 −7.9 HSP90AA1 −8.5 HSP90AA1 −8.1 MAPK1 −9.7 MAPK1 −9.1 MAPK8 −9.1 MAPK8 −8.5 SRC −6.2 SRC −6.5 豆甾醇葡萄糖苷 AR −7 硬脂酸甘油酯 AR −6.1 CASP3 −7.1 CASP3 −5.7 EGFR −6.5 EGFR −4.8 ESR1 −8.3 ESR1 −6.2 HSP90AA1 −8.6 HSP90AA1 −6.2 MAPK1 −9.7 MAPK1 −6.6 MAPK8 −8.1 MAPK8 −7.2 SRC −7.2 SRC −5.5 木通苯乙醇B AR −8.6 齐墩果酸 AR −8 CASP3 −7 CASP3 −7.1 EGFR −5.1 EGFR −7 ESR1 −8.7 ESR1 −7.8 HSP90AA1 −9.2 HSP90AA1 −9.0 MAPK1 −9.4 MAPK1 −8.0 MAPK8 −9.7 MAPK8 −8.3 SRC −7.5 SRC −7.6
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[1] Amato L, Vecchi S, Barbui C, et al. Systematic review to evaluate the efficacy, acceptability and safety of second-generation antipsychotics for the treatment of unipolar and bipolar depression[J]. Recenti Progressi in Medicina,2018,109(10):474−486. [2] Cui R. Editorial: A systematic review of depression[J]. Current Neuropharmacology,2015,13(4):480. doi: 10.2174/1570159X1304150831123535 [3] Sankhi S, Marasine N R, Sankhi S, et al. Adverse drug reaction due to antidepressants among patients with depression in a private psychiatric hospital of nepal[J]. BioMed Research International,2020,2020:1−5. [4] 王旭东, 乔明琦, 张樟进, 等. 中医药治疗抑郁症的研究进展[J]. 南京中医药大学学报,2016,32(1):93−96. [5] Yongli Jiang, Xuefu Zhou, Yuanrong Zheng, et al. Impact of ultrasonication/shear emulsifying/microwave-assisted enzymatic extraction on rheological, structural, and functional properties of Akebia trifoliata (Thunb.) Koidz. seed protein isolates[J]. Food Hydrocolloids,2021,112:1−10. [6] Iketani H. Native fruit tree genetic resources in Japan[J]. Breed Sci,2016,66(1):82−89. doi: 10.1270/jsbbs.66.82 [7] 唐成林, 杨斌, 陶光灿, 等. 八月瓜果实营养成分分析和评价[J]. 食品工业科技: 1−11[2021-02-05]. http://kns.cnki.net/kcms/detail/11.1759.TS.20200721.1511.006.html. [8] 国家药典委员会. 中国药典 一部[S]. 北京: 中国医药科技出版社, 2015: 297. [9] 张磊阳, 蒋健, 贺敏, 等. 抗抑郁中药的药理研究进展[J]. 中国实验方剂学杂志,2017,23(24):224−234. [10] 周丹. 预知子提取物对抑郁症大鼠海马神经可塑性相关蛋白BDNF/CREB/ Bcl-2的影响研究[J]. 药物生物技术,2019,26(02):110−113. [11] 陈启洪, 李晓飞, 段灿灿, 等. 网络药理学探讨杜仲主要活性成分及药理作用机制[J]. 中药材,2018(2):432−439. [12] 张锐, 张季林, 李冰涛, 等. 基于网络药理学研究栀子入血成分抗阿尔茨海默病的作用机制[J]. 中国中药杂志,2020,45(11):2601−2610. [13] Liu F, Zhao Q, Liu S, et al. Revealing the pharmacological mechanism of acorus tatarinowii in the treatment of ischemic stroke based on network pharmacology[J]. Evidence-Based Complementary and Alternative Medicine,2020,2020:1−16. [14] 杨柳, 张王宁, 刘月涛, 等. 基于网络药理学的黄芪治疗肾病综合征的机制研究[J]. 中草药,2019,50(8):1828−1837. doi: 10.7501/j.issn.0253-2670.2019.08.010 [15] 戴璐彬, 关婉辰, 张栋, 等. 参麦饮改善糖尿病肾病的网络药理学研究及实验验证[J]. 中药药理与临床,2020,36(4):81−87. [16] Jin H G, Kim A R, Ko H J, et al. Three new lignan glycosides with IL-6 inhibitory activity from Akebia quinata[J]. Chemical & Pharmaceutical Bulletin,2014,62(3):288−293. [17] Wang J, Xu Q L, Zheng M F, et al. Bioactive 30-noroleanane triterpenes from the pericarps of Akebia trifoliata[J]. Molecules,2014,19(4):4301−4312. doi: 10.3390/molecules19044301 [18] 刘永玲, 谢国芳, 王威, 等. 八月瓜叶、果皮和果肉中酚类、VC含量及其抗氧化能力分析[J]. 食品研究与开发,2019,40(15):66−72. doi: 10.12161/j.issn.1005-6521.2019.15.011 [19] 宗 阳, 丁美林, 贾可可, 等. 基于网络药理学和分子对接法探寻达原饮治疗新型冠状病毒肺炎(COVID-19)活性化合物的研究[J]. 中草药,2020,51(4):836−844. doi: 10.7501/j.issn.0253-2670.2020.04.002 [20] Phillips C. Brain-derived neurotrophic factor, depression, and physical activity: Making the neuroplastic connection[J]. Neural Plasticity,2017,2017:1−17. [21] Fajemiroye J O, Galdino P M, Florentino I F, et al. Plurality of anxiety and depression alteration mechanism by oleanolic acid[J]. Journal of Psychopharmacology, 28(10): 923-934. [22] Gürağaç Dereli F T, Ilhan M, Küpeli Akkol E. Identification of the main active antidepressant constituents in a traditional Turkish medicinal plant, Centaurea kurdica Reichardt[J]. Journal of Ethnopharmacology,2020,249:1−11. [23] Zhao D, Zheng L, Qi L, et al. Structural features and potent antidepressant effects of total sterols and β-sitosterol extracted from Sargassum horneri[J]. Marine Drugs,2016,14(7):123−130. doi: 10.3390/md14070123 [24] Bortolato B, Hyphantis T N, Valpione S, et al. Depression in cancer: The many biobehavioral pathways driving tumor progression[J]. Cancer Treatment Reviews,2017,52:58−70. doi: 10.1016/j.ctrv.2016.11.004 [25] Szelei A, Döme P. Cancer and depression: A concise review[J]. Orvosi Hetilap,2020,161(22):908−916. doi: 10.1556/650.2020.31759 [26] McFarland D C, Jutagir D R, Rosenfeld B, et al. Depression and inflammation among epidermal growth factor receptor (EGFR) mutant nonsmall cell lung cancer patients[J]. Psychooncology,2019,28(7):1461−1469. doi: 10.1002/pon.5097 [27] Xiang X, You X M, Li LQ. Expression of HSP90AA1/HSPA8 in hepatocellular carcinoma patients with depression[J]. OncoTargets and Therapy,2018,11:3013−3023. doi: 10.2147/OTT.S159432 [28] Iñiguez S D, Parise L F, Lobo M K, et al. Upregulation of hippocampal extracellular signal-regulated kinase (ERK)-2 induces antidepressant-like behavior in the rat forced swim test[J]. Behavioral Neuroscience,2019,133(2):225−231. doi: 10.1037/bne0000303 [29] Mohammad H, Marchisella F, Ortega-Martinez S, et al. JNK1 controls adult hippocampal neurogenesis and imposes cell-autonomous control of anxiety behaviour from the neurogenic niche[J]. Molecular Psychiatry,2018,23(2):362−374. doi: 10.1038/mp.2016.203 [30] Hung Y Y, Huang Y L, Chang C, et al. Deficiency in androgen receptor aggravates the depressive-like behaviors in chronic mild stress model of depression[J]. Cells,2019,8(9):1021−1037. doi: 10.3390/cells8091021 [31] Tan E C, Lim H W, Chua T E, et al. Investigation of variants in estrogen receptor genes and perinatal depression[J]. Neuropsychiatr Dis Treat,2018,14:919−925. doi: 10.2147/NDT.S160424 [32] Różycka A, Słopień R, Słopień A, et al. The MAOA, COMT, MTHFR and ESR1 gene polymorphisms are associated with the risk of depression in menopausal women[J]. Maturitas,2016,84:42−54. doi: 10.1016/j.maturitas.2015.10.011 [33] Duman R S, Aghajanian G K, Sanacora G, et al. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants[J]. Nature Medicine,2016,22(3):238−249. [34] Li Z, Jo J, Jia J M, et al. Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalization[J]. Cell,2010,141(5):859−871. doi: 10.1016/j.cell.2010.03.053 [35] Tian R H, Bai Y, Li J Y, et al. Reducing PRLR expression and JAK2 activity results in an increase in BDNF expression and inhibits the apoptosis of CA3 hippocampal neurons in a chronic mild stress model of depression[J]. Brain Research,2019,1725:1−12. [36] Köhler S, Cierpinsky K, Kronenberg G, et al. The serotonergic system in the neurobiology of depression: Relevance for novel antidepressants[J]. Journal of Psychopharmacology,2016,30(1):13−22. doi: 10.1177/0269881115609072 [37] Ledonne A, Mercuri N B. mGluR1-dependent long term depression in rodent midbrain dopamine neurons is regulated by neuregulin 1/ErbB signaling[J]. Frontiers in Molecular Neuroscience,2018,11:346−361. doi: 10.3389/fnmol.2018.00346 [38] Gormanns P, Mueller N S, Ditzen C, et al. Phenome-transcriptome correlation unravels anxiety and depression related pathways[J]. Journal of Psychiatric Research,2011,45(7):973−979. doi: 10.1016/j.jpsychires.2010.12.010 -
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