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陈思睿,吴天鸿,刘洁,张文青,姚敬心,何迎春,史红健,王贤文,范婧莹.基于网络药理学、分子对接、实验研究探讨白屈菜治疗鼻咽癌的物质基础及潜在机制[J].湖南中医药大学学报英文版,2024,44(2):278-287.[Click to copy
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| 基于网络药理学、分子对接、实验研究探讨白屈菜治疗鼻咽癌的物质基础及潜在机制 |
| 陈思睿,吴天鸿,刘洁,张文青,姚敬心,何迎春,史红健,王贤文,范婧莹 |
| (湖南中医药大学, 湖南 长沙 410208;湖南中医药大学, 湖南 长沙 410208;中医药防治眼耳鼻咽喉疾病湖南省重点实验室, 湖南 长沙 410208;中医药防治眼耳鼻咽喉疾病湖南省重点实验室, 湖南 长沙 410208;湖南中医药大学第一附属医院, 湖南 长沙 410007) |
| 摘要: |
| 目的 运用网络药理学和分子对接技术预测白屈菜抗鼻咽癌（nasopharyngeal carcinoma，NPC）的作用靶点和机制，并通过实验验证主要活性成分对NPC细胞增殖和凋亡的影响。方法 借助在线数据平台TCMSP、ETCM和BATMAN-TCM检索白屈菜的化学成分和作用靶点。通过GEO数据库检索NPC相关靶点，生信在线工具分析白屈菜与NPC的交集靶点。使用STRING构建共同靶点的PPI网络，运用Cytoscape 3.7.1获得核心靶点。通过R软件编程进行GO功能富集分析和KEGG通路富集分析。分子对接分析核心靶点与主要活性成分之间的结合情况。实验验证：（1）将5-8F细胞分为溶剂对照组、血根碱（2.5μmol·L-1、5μmol·L-1）组、白屈菜红碱（2.5μmol·L-1、5μmol·L-1）组、顺铂4μg·mL-1组。MTT检测白屈菜主要活性成分对NPC细胞增殖的影响。（2）将5-8F细胞分为溶剂对照组、血根碱5μmol·L-1组、白屈菜红碱5μmol·L-1组、顺铂4μg·mL-1组；Annexin-V FITC/PI双荧光染色法检测细胞凋亡；Western blot检测白屈菜主要活性成分对NPC细胞增殖、凋亡、丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）和磷脂酰肌醇三激酶（phosphatidylinositol 3-kinase，PI3K）/蛋白激酶B（protein kinase B，AKT）信号通路关键蛋白的影响。结果 检索得到白屈菜37个主要活性成分和1 419个作用靶点。检索GEO数据库共收集到7 852个NPC疾病基因，白屈菜与NPC共有327个交集靶点，其中核心靶基因共10个，分别是EGFR、TP53、VEGFA、TNF、FN1、MMP9、JUN、FGF2、LYN、F2。GO分析主要涉及泛素蛋白连接酶结合、硫化物结合、整合素结合、肝素结合和糖胺聚糖结合，KEGG分析主要涉及MAPK、PI3K/AKT信号通路等，分子对接结果显示核心靶点与对应的活性成分具有良好的结合能力。实验验证显示，与溶剂对照组相比，血根碱和白屈菜红碱均明显降低NPC细胞相对增殖率（P<0.01），并提高细胞凋亡率（P<0.01），且血根碱和白屈菜红碱降低5-8F细胞中XIAP、PCNA、ERK1/2、AKT的蛋白表达水平（P<0.05或P<0.01）。结论 白屈菜可通过多成分、多靶点和多通路发挥抗NPC的作用，且经实验验证，血根碱和白屈菜红碱均可抑制NPC细胞增殖并诱导凋亡，其机制可能与MAPK信号通路、PI3K/AKT信号通路有关。 |
| 关键词: 鼻咽癌 网络药理学 分子对接 白屈菜 MAPK信号通路 PI3K/AKT信号通路 |
| DOI：10.3969/j.issn.1674-070X.2024.02.015 |
| Received:July 09, 2023 |
| 基金项目:国家自然科学基金资助项目（81973914）；湖南省中医药管理局项目（D2022105，B2023014）；湖南省教育厅科研项目（21C0241，21B0358，22C0176）；湖南中医药大学校级科研基金项目（2021XJJJ014）；湖南中医药大学大学生创新课题（2022-165）；湖南中医药大学中医学一流学科开放基金项目（2021ZYX34）；长沙市自然科学基金项目（kzd22008）。 |
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| Material basis and potential mechanism of Baiqucai（Chelidonii Herba） in treating nasopharyngeal carcinoma based on network pharmacology, molecular docking, and experimental research |
| CHEN Sirui,WU Tianhong,LIU Jie,ZHANG Wenqing,YAO Jingxin,HE Yingchun,SHI Hongjian,WANG Xianwen,FAN Jingying |
| (Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;Hunan Key Laboratory for Prevention & Treatment of Ophthalmology and Otolaryngology Diseases with Chinese Medicine, Changsha, Hunan 410208, China;Hunan Key Laboratory for Prevention & Treatment of Ophthalmology and Otolaryngology Diseases with Chinese Medicine, Changsha, Hunan 410208, China;The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China) |
| Abstract: |
| Objective To predict the action targets and mechanism of Baiqucai(Chelidonii Herba) against nasopharyngeal carcinoma(NPC) by network pharmacology and molecular docking techniques, and to verify the effects of its main active ingredients on the proliferation and apoptosis of NPC cells through experiments.Methods Through the online platforms of TCMSP, ETCM, and BATMAN-TCM, the chemical constituents and action targets of Baiqucai(Chelidonii Herba) were searched. The relevant targets of NPC were retrieved through the GEO database, and the intersection targets of Baiqucai(Chelidonii Herba) and NPC were analyzed by Shengxin online tool. STRING was used to build a protein-protein interaction(PPI) network of the common targets, and Cytoscape3.7.1 was used to obtain core targets. GO function and KEGG pathway enrichment analyses were performed by R software programming.The condition of binding between the core targets and the main active ingredients was analyzed by molecular docking. Experimental verification:(1) 5-8F cells were divided into solvent control, sanguinarine(2.5 μmol·L-1, 5 μmol·L-1), chelerythrine(2.5 μmol·L-1,5 μmol·L-1), and cisplatin 4 μg·mL-1groups; MTT was used to test the effects of the main active ingredients of Baiqucai(Chelidonii Herba) on the proliferation of NPC cells.(2) 5-8F cells were divided into solvent control, sanguinarine 5 μmol·L-1, chelerythrine5 μmol·L-1, and cisplatin 4 μg·mL-1groups; apoptosis was determined by Annexin-V FITC/PI double fluorescence staining; Western blot was used to measure the effects of the main active ingredients on the proliferation, apoptosis, as well as the key proteins of mitogen-activated protein kinase(MAPK) and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT) signaling pathways of NPC cells.Results A total of 37 main active ingredients and 1 419 action targets of Baiqucai(Chelidonii Herba) were obtained. A total of7 852 NPC disease genes were collected by searching the GEO database. There were 327 intersection targets between Baiqucai(Chelidonii Herba) and NPC, among which ten core target genes were EGFR, TP53, VEGFA, TNF, FN1, MMP9, JUN, FGF2, LYN,and F2. GO analysis mainly involved ubiquitin protein ligase binding, ubiquitin-like protein ligase binding, sulfur compound binding, integrin binding, heparin binding, and glycosaminoglycan binding. KEGG analysis mainly involved MAPK and PI3K/AKT signaling pathways. Molecular docking showed that the core targets had good binding ability with corresponding active ingredients.The experimental verification showed that compared with the solvent control group, sanguinarine and chelerythrine significantly reduced the relative proliferation rate of NPC cells(P <0.01), increased the apoptosis rate(P <0.01), and decreased the protein expression levels of XIAP, PCNA, ERK1/2, and AKT in 5-8F cells(P<0.05 or P<0.01).Conclusion Baiqucai(Chelidonii Herba) can play an anti-NPC role through multi-component, multi-target, and multi-pathway, and it has been verified by experiments that sanguinarine and chelerythrine can both inhibit the proliferation of NPC cells and induce apoptosis, the mechanism of which may be related to MAPK and PI3K/AKT signaling pathways. |
| Key words: nasopharyngeal carcinoma network pharmacology molecular docking Baiqucai(Chelidonii Herba) MAPK signaling pathway PI3K/AKT signaling pathway |
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