[关键词]
[摘要]
目的 基于成分分析、网络药理学和分子对接技术探讨郁金治疗胃癌的作用机制。方法 通过HPLC-Q-TOF-MS/MS技术及PubChem、SwissTargetPrediction和中药系统药理学数据库与分析平台(TCMSP)数据库收集郁金的活性成分和相关靶点;利用Disgenet、GeneCards数据库检索胃癌疾病靶点,利用韦恩图绘制平台获取共有的关键作用靶点,并将信息导入Cytoscope 3.9.1软件和STRING在线分析平台,进行网络拓扑学分析,构建郁金有效成分–核心作用靶点网络;基于核心作用靶点通过DAVID数据库进行基因本体(GO)和京都基因与基因组百科全书(KEGG)富集分析;然后通过Autodock Tools 1.5.6软件对有效成分-核心作用靶点进行分子对接验证,得到郁金治疗胃癌疾病的关键有效成分。结果 结合质谱分析与数据库筛选得到郁金化学成分65个,其中活性成分62个,活性成分的对应作用靶点599个,胃癌疾病靶点1 813个,两者的共同交集靶点262个,对应的关键活性成分49个;经蛋白质相互作用(PPI)及网络拓扑分析后,获取核心作用靶点7个,有效成分16个,核心作用靶点分别是表皮生长因子受体(EGFR)、信号转导和转录激活因子3(STAT3)、丝氨酸/苏氨酸蛋白激酶1(Akt1)、非受体酪氨酸激酶(SRC)、白细胞介素-6(IL-6)、热休克蛋白HSP 90α家族A类成员1(HSP90AA1)、缺氧诱导因子-1α(HIF-1A);GO富集到基因功能122个,KEGG富集到基因通路71条,分析结果表明,郁金治疗胃癌的作用机制是通过调节癌症通路、缺氧诱导因子1(HIF-1)信号通路、人类巨细胞病毒感染、肿瘤中程序性死亡配体1(PD-L1)的表达和程序死亡蛋白1(PD-1)关卡通路、Th17 细胞分化、叉头框蛋白O(FoxO)信号通路、雌激素信号通路、酪氨酸激酶-信号转导和转录激活因子(JAK/STAT)信号通路、磷脂酰肌醇3激酶(PI3K)-蛋白激酶B(Akt)信号通路等来发挥治疗胃癌的作用。通过分子对接验证,筛选得到郁金治疗胃癌疾病的10个关键有效成分,包括原莪术二醇、莪术内酯B、雪松烯、β-榄香烯、β-芹子烯、γ-榄香烯、β-cuparenone、新莪术二酮、石竹烯氧化物、姜黄内酯C。结论 揭示了郁金治疗胃癌的有效成分和作用机制,为郁金治疗胃癌的临床实践及后续研究提供参考。
[Key word]
[Abstract]
Objective Based on component analysis, network pharmacology and molecular docking technology, to explore the effective components and mechanism of Curcumae Radix in treatment of gastric cancer. Methods The active components and related targets of Curcumae Radix were collected by HPLC-Q-TOF-MS/MS technology, PubChem, SwissTargetPrediction, and TCMSP. The targets of gastric cancer diseases were retrieved by using Disgenet and GeneCards databases, and the common key targets were obtained by using Venn mapping platform, and the information was imported into Cytoscope 3.9.1 software and STRING online analysis platform, and the network topology analysis was carried out to construct the effective component-core target network of Curcumae Radix. GO and KEGG were enriched and analyzed by DAVID database based on the core target. Then, the key effective components of Curcumae Radix in treatment of gastric cancer were obtained by molecular docking verification of the effective components-core target through Autodock Tools 1.5.6 software. Results 65 Chemical constituents of Curcumae Radix were obtained by combining mass spectrometry analysis and database screening, including 62 active constituents, 599 corresponding targets of active constituents, 1 813 targets of gastric cancer diseases, 262 common targets and 49 corresponding key active constituents. After protein interaction analysis (PPI) and network topology analysis, 7 core targets and 16 effective components were obtained. The core targets were EGFR, STAT3, Akt1, SRC, IL-6, and HSP90AA1. GO enriched 122 gene functions and KEGG enriched 71 gene pathways. The analysis results showed that, The mechanism of Curcumae Radix in treating gastric cancer is through regulating cancer pathway, HIF-1 signaling pathway, human cytomegalovirus infection, the expression of programmed death ligand 1(PD-L1) and programmed death protein 1 (PD-1) checkpoint pathway, Th17 cell differentiation, foxo signaling pathway, estrogen signaling pathway, tyrosine kinase-signal transduction and transcription. Through molecular docking verification, 10 key effective components of Curcumae Radix for treating gastric cancer were screened out, including protocurcumdiol, curcumolide B, cedrene, β-elemene, β-selinene, γ-elemene, β-cuparenone, new curdione, caryophyllene oxide, and curcumolide C. Conclusion The effective components and mechanism of Curcumae Radix in treatment of gastric cancer were preliminarily revealed, which provided reference for clinical practice and follow-up research of Curcumae Radix in treatment of gastric cancer and the development of anti-gastric cancer drugs.
[中图分类号]
R285
[基金项目]
国家中医药管理局科技司-浙江省中医药管理局共建科技计划项目(GZY-ZJ-KJ-24040);杭州市农业与社会发展科研重点项目(202204A06);浙江中医药大学中药饮片有限公司科技创新项目(2022ZZKY001);浙江中医药大学中药饮片有限公司科技创新项目(2024ZZKY002)