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华华, 刘向国, 夏庆, 吴柏合, 朱洁.基于网络药理学和动物实验探讨补气益肺方治疗慢性阻塞性肺疾病的作用机制[J].湖南中医药大学学报,2025,45(6):1169-1178[点击复制] |
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| 基于网络药理学和动物实验探讨补气益肺方治疗慢性阻塞性肺疾病的作用机制 |
| 华华,刘向国,夏庆,吴柏合,朱洁 |
| (安徽三联学院(现代康养产业学院), 安徽 合肥 230601;安徽中医药大学中西医结合学院, 安徽 合肥 230012;中卫市中医院, 宁夏 中卫 755000) |
| 摘要: |
| 目的 基于网络药理学及动物实验探讨补气益肺方治疗慢性阻塞性肺疾病（COPD）的作用机制。方法 （1）通过TCMSP和Herb数据库筛选补气益肺方的活性成分及潜在靶点，采用DrugBank、GeneCards、OMIM数据库检索COPD疾病基因；绘制韦恩图并获取药物-疾病共同靶点，借助STRING数据库和Cytoscape 3.9.1软件构建“成分-主要靶点-疾病”网络图以及蛋白质-蛋白质相互作用PPI网络图，并根据网络关系筛选核心靶点，采用DVAID数据库进行GO和KEGG富集分析，利用ADFRsuite 1.0和AutoDock Vina 1.1.2软件将度值排名前3的核心成分与核心靶点进行分子对接。（2）动物实验验证：按照随机数字表法将40只SD大鼠分为对照组、模型组、桂龙咳喘宁组、补气益肺方组，每组10只。除对照组外，其余各组采用烟熏加脂多糖气管滴入方法构建COPD动物模型，于造模第13周的第1天开始药物干预，干预结束后检测各组大鼠的肺功能指标用力肺活量（FVC）、0.3 s用力呼气容积（FEV0.3）、0.3 s用力呼气容积与用力肺活量的比值（FEV0.3/FVC）和呼气峰值流速（PEF）；HE染色观察肺组织病理变化；ELISA法检测血清肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）含量；Western blot法检测肺组织中磷脂酰肌醇3-激酶（PI3K）、磷酸化磷脂酰肌醇3-激酶（p-PI3K）、蛋白激酶B（Akt）和磷酸化蛋白激酶B（p-Akt）的蛋白表达量。结果 网络药理学研究显示，补气益肺方治疗COPD的关键活性成分为氨嗪-2-羧酸、山柰酚、槲皮素等，核心靶点有Akt1、IL-6、TNF等。GO富集分析和KEGG通路富集分析结果表明，补气益肺方治疗COPD与PI3K-Akt信号通路、AGE-RAGE信号通路、TNF信号通路等有关，其中，PI3K-Akt信号通路高度富集。分子对接结果显示，补气益肺方的关键活性成分氨嗪-2-羧酸、山柰酚、槲皮素与治疗COPD的核心靶点Akt1、IL-6均有较好的结合活性。动物实验结果显示，与模型组相比，经补气益肺方与桂龙咳喘宁治疗后，大鼠肺功能指标明显升高（P<0.01）；肺组织病理学特征显著改善；炎症指标TNF-α和IL-6水平明显降低（P<0.05）；p-PI3K/PI3K和p-Akt/Akt蛋白表达量明显降低（P<0.01）。与桂龙咳喘宁组相比，补气益肺方组肺功能指标FVC值显著上升（P<0.05），FEV0.3/FVC值明显下降（P<0.05），FEV0.3和PEF值差异无统计学意义（P>0.05）；炎症指标TNF-α和IL-6水平显著降低（P<0.05）；p-PI3K/PI3K和p-Akt/Akt蛋白表达量差异无统计学意义（P>0.05）。结论 补气益肺方治疗COPD具有多成分、多靶点、多通路的作用特点，可通过调控PI3K-Akt信号通路减轻炎症反应，增强肺功能。 |
| 关键词: 慢性阻塞性肺疾病 补气益肺方 PI3K-Akt信号通路 炎症反应 网络药理学 分子对接 |
| DOI：10.3969/j.issn.1674-070X.2025.06.028 |
| 投稿时间：2025-01-16 |
| 基金项目:安徽省高校杰出青年科研项目（2022AH0200）；安徽三联学院2024年度校级自然科学研究项目（KJZD2024003）。 |
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| Mechanism of action of Buqi Yifei Formula in treating chronic obstructive pulmonary disease based on network pharmacology and animal experiments |
| HUA Hua, LIU Xiangguo, XIA Qing, WU Baihe, ZHU Jie |
| (College of Modern Health Industry, Anhui Sanlian University, Hefei, Anhui 230601, China;College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui 230012, China;Zhongwei Traditional Chinese Medicine Hospital, Zhongwei, Ningxia 755000, China) |
| Abstract: |
| Objective To explore the mechanism of action of Buqi Yifei Formula (BQYFF) in treating chronic obstructive pulmonary disease (COPD) based on network pharmacology and animal experiments.Methods (1) The active ingredients and potential targets of BQYFF were screened through TCMSP and Herb databases, and the COPD disease genes were searched using DrugBank, Gene Cards, and OMIM databases. Then a Venn diagram was drawn and the common targets between the durg and disease were obtained. With the help of STRING database and Cytoscape 3.9.1 software, the "component-major target-disease" network diagram and PPI network diagram were constructed. Core targets were screened according to network relationships, and GO and KEGG enrichment analysis were conducted using the DVAID database. The core components with the top 3 degree values were subjected to molecular docking with the core targets using ADFRSuite 1.0 and AutoDock Vina 1.1.2 software. (2) Animal experiment verification: According to the random number table method, 40 SD rats were divided into a control group, model group, Guilong Kechuanning (GLKCN) group, and BQYFF group, with 10 rats in each group. Except for the control group, all other groups were used to construct COPD animal models by smoking and tracheal instillation of lipopolysaccharides. Drug intervention began on the first day of the 13th week of modeling, and after the intervention, the lung function indicators including forced vital capacity (FVC), forced expiratory volume in 0.3 seconds (FEV0.3), ratio of FEV0.3 to FVC (FEV0.3/FVC), and peak expiratory flow (PEF) were examined; HE staining was used to observe pathological changes in lung tissue; ELISA was used to detect the levels of serum tumor necrosis factor-alpha (TNF-α) and interleukin-6(IL-6); Western blot was used to detect the protein expression levels of phosphatidylinositol 3-kinase (PI3K), phosphorylated phosphatidylinositol 3-kinase (p-PI3K), protein kinase B (Akt), and phosphorylated protein kinase B (p-Akt) and p-Akt in lung tissue.Results Network pharmacology studies have shown that the key active ingredients of BQYFF in treating COPD were azine-2-carboxylic acid, kaempferol, quercetin, etc. The core targets included Akt1, IL-6, TNF, etc. The GO enrichment analysis and KEGG pathway enrichment analysis indicated that the treatment of COPD by BQYFF was related to the PI3K-Akt signaling pathway, AGE-RAGE signaling pathway, TNF signaling pathway, etc. Among them, the PI3K-Akt signaling pathway was highly enriched. The molecular docking Results showed that the key active ingredients of BQYFF, such as azine-2-carboxylic acid, kaempferol, and quercetin, had good binding activity with the core targets Akt1 and IL-6 for treating COPD. Animal experiments demonstrated that treatment with either BQYFF or GLKCN significantly improved pulmonary function parameters compared to the model group (P<0.01). Additionally, HE analysis revealed marked amelioration of lung tissue pathology. The levels of pro-inflammatory cytokines TNF-α and IL-6 were significantly downregulated (P<0.05), while the protein expression ratios of p-PI3K/PI3K and p-Akt/Akt were substantially reduced (P<0.01). Compared to the GLKCN group, the BQYFF group exhibited significantly enhanced FVC (P<0.05) but reduced FEV0.3/FVC ratio (P<0.05), while no statistically significant differences were observed in FEV0.3 or PEF values (P>0.05); the levels of TNF-α and IL-6 were significantly reduced (both P<0.05); the protein expression ratios of p-PI3K/PI3K and p-Akt/Akt showed no statistically significant differences (P>0.05).Conclusion BQYFF exerts its therapeutic effects on COPD through a multi-component, multi-target, and multi pathway mechanism. It can reduce inflammation and enhance lung function by regulating the PI3K-Akt signaling pathway. |
| Key words: chronic obstructive pulmonary disease Buqi Yifei Formula PI3K-Akt signaling pathway inflammatory reaction network pharmacology molecular docking |
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