基于网络药理学分析玉竹治疗2 型糖尿病的活性物质及作用机制

Analysis of the Active Components and Mechanism of Action of Polygonati Odorati Rhizoma in the Treatment of Type 2 Diabetes Mellitus Based on Network Pharmacology

摘要:

目的：基于网络药理学分析玉竹治疗2型糖尿病（T2DM） 的药效物质基础及作用机制。方法：借助中药系统药理学数据库与分析平台（TCMSP） 对玉竹的有效活性成分及其对应靶点进行筛选；随后，通过SwissTargetPrediction平台进一步预测和补充玉竹活性成分的潜在作用靶点。利用GeneCards数据库获取T2DM相关靶点；运用Venny2.1.0在线软件获取药物和疾病交集靶点；分别利用Cytoscape v3.9.0软件和STRING数据库绘制与分析“药物-成分-靶点-疾病”关系网络及蛋白互作（PPI） 网络；借助Metascape数据库，对交集靶点开展基因本体（GO） 功能注释和京都基因与基因组百科全书（KEGG） 通路富集分析；最终对核心成分与关键靶点进行分子对接验证。结果：从玉竹中筛选获得6个活性成分为4'，5，7-三羟基-6，8-二甲基-同异丙烷酮、4'-甲氧基-5，7-二羟基-6，8-二甲基-同类氟烷酮、（Z） -3-（4-羟基-3-甲氧基-苯基） -N-［2-（4-羟基苯基） 乙基］丙烯酰胺、4'，5，7-三羟基-6-甲基-8-甲氧基-同异氟烷酮、正恩-花糖酸糖酪胺、多苷类E_qt，对应202 个作用靶点。与T2DM 有关的作用靶点856 个，交集靶点59 个。获得核心靶点为周期蛋白依赖性激酶2 （CDK2）、丝氨酸蛋白酶抑制剂1 （SERPINE1）、基质金属蛋白酶2 （MMP2）、激酶插入区受体（KDR）、丝氨酸/苏氨酸蛋白激酶（mTOR）、基质金属蛋白酶9 （MMP9）、丝裂原活化蛋白激酶1（MAPK1）、过氧化物酶体增殖物激活受体γ（PPARG）、前列腺素内过氧化物合酶2（PTGS2）、雌激素受体1（ESR1）、类固醇受体辅助激活因子（SRC）、靶向表皮生长因子受体（EGFR）、肿瘤坏死因子（TNF）。GO分析主要涉及蛋白质磷酸化的正调控、丝氨酸磷酸化、腺体发育等方面。KEGG分析显著富集于癌症、前列腺癌、低氧诱导因子-1（HIF-1）、白细胞介素-17（IL-17）、胰岛素抵抗等信号通路。分子对接结果显示，主要活性成分与核心靶点的分子对接结合能均低于-5.0 kcal/mol，结合亲和力高，可稳定作用于靶点。结论：网络药理学分析表明玉竹干预T2DM 的作用机制为4'，5，7-三羟基-6，8-二甲基-同异丙烷酮、4'-甲氧基-5，7-二羟基-6，8-二甲基-同类氟烷酮、（Z） -3-（4-羟基-3-甲氧基-苯基） -N-［2-（4-羟基苯基） 乙基］丙烯酰胺等成分，作用于TNF、EGFR、SRC、ESR1、PTGS2、PPARG等靶点，调控细胞增殖/代谢、胰岛素抵抗等通路，发挥改善胰岛素抵抗、抗炎、保护胰岛功能等作用。

Abstract:

Abstract： Objective： To analyze the pharmacodynamic material basis and mechanism of action of Polygonati Odorati Rhizoma in the treatment of type 2 diabetes mellitus （T2DM） based on network pharmacology. Methods：The active components of Polygonati Odorati Rhizoma and their corresponding targets were screened using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP）. Subsequently，the potential targets of the active components were further predicted and supplemented through the SwissTargetPrediction. T2DM-related targets were obtained from GeneCards. Intersection targets between drugs and disease were obtained using Venny 2.1.0. The "drug-component-target-disease" interaction network and protein-protein interaction （PPI） network were constructed and analyzed using Cytoscape v3.9.0 and STRING，respectively. Gene Ontology（ GO） functional annotation and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analyses of the intersection targets were performed using Metascape. Finally， molecular docking was conducted to validate the core components and key targets. Results：Six active components were screened from Polygonati Odorati Rhizoma，namely 4'，5，7-trihydroxy- 6，8-dimethyl-homoisoflavanone，4'-methoxy-5，7-dihydroxy-6，8-dimethyl-homoflavanone，（Z）-3-（4-hydroxy- 3-methoxy-phenyl） -N- [2-（4-hydroxyphenyl） ethyl] acrylamide， 4'，5，7-trihydroxy-6-methyl-8-methoxyhomoisoflavanone， N-coumaroyltryptamine， and polygoside E_qt， corresponding to 202 action targets. There were 856 targets related to T2DM， with 59 intersection targets. The core targets were identified as cyclin-dependent kinase 2 （CDK2）， serpin family E member 1 （SERPINE1）， matrix metalloproteinase 2 （MMP2）， kinase insert domain receptor （KDR），mechanistic target of rapamycin （mTOR），matrix metalloproteinase 9 （MMP9），mitogenactivated protein kinase 1 （MAPK1）， peroxisome proliferator-activated receptor gamma （PPARG）， prostaglandinendoperoxide synthase 2 （PTGS2）， estrogen receptor 1 （ESR1）， steroid receptor coactivator （SRC）， epidermal growth factor receptor （EGFR），and tumor necrosis factor （TNF）. GO analysis mainly involved positive regulation of protein phosphorylation， serine phosphorylation， and gland development. KEGG analysis showed significant enrichment in signaling pathways such as cancer，prostate cancer，hypoxia-inducible factor-1（ HIF-1），interleukin- 17（ IL-17），and insulin resistance. Molecular docking results demonstrated that the binding energies between the main active components and the core targets were all lower than -5.0 kcal/mol， indicating high binding affinity and stable interaction with the targets. Conclusion： Network pharmacology analysis indicates that the mechanism of action of Polygonati Odorati Rhizoma in intervening T2DM involves components such as 4'，5，7-trihydroxy-6，8-dimethylhomoisoflavanone， 4'-methoxy-5，7-dihydroxy-6，8-dimethyl-homoflavanone，and （Z）-3-（4-hydroxy-3-methoxyphenyl）- N- [2-（4-hydroxyphenyl）ethyl] acrylamide， acting on targets including TNF， EGFR， SRC， ESR1， PTGS2，and PPARG，and regulating pathways related to cell proliferation/metabolism and insulin resistance，thereby exerting effects such as improving insulin resistance，anti-inflammatory，and protecting islet function.