| 李慧,杨华娣,毛佩瑜,张婷,陆申奕,叶恬恬.基于网络药理学与实验验证探讨裘氏内异方治疗子宫内膜异位症的作用机制[J].浙江中西医结合杂志,2024,34(2): |
| 基于网络药理学与实验验证探讨裘氏内异方治疗子宫内膜异位症的作用机制 |
| To explore the mechanism of the treatment of endometriosis with Qiu's Neiyi Decoction based on network pharmacology and experimental verification |
| 投稿时间：2023-05-22 修订日期：2024-01-04 |
| DOI： |
| 中文关键词: 子宫内膜异位症 网络药理学 实验验证 裘氏内异方 |
| 英文关键词:Endometriosis network pharmacology Animal experiments Qiu"s Neiyi Decoction |
| 基金项目:国家自然科学青年(No. 82104909)；浙江省中医药科技计划项目(No. 2023ZL036)作者单位：1. 浙江中医药大学附属第一医院(杭州 310006)；2. 浙江中医药大学第一临床学院(杭州 310053)通讯作者：杨华娣,Tel：18868706975,E-mail：88mummy@163.com 杨华娣1 毛佩瑜1 张婷1 陆申奕1 叶恬恬2 |
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| 中文摘要: |
| 目的 运用网络药理学结合动物实验验证,探究裘氏内异方治疗子宫内膜异位症(EMs)的作用机制。方法 利用超高效液相色谱-飞行时间质谱(UPLC-Q/TOF-MS)联用技术结合文献检索筛选出裘氏内异方有效活性成分；于TCMSP数据库获取活性成分的基因靶标；于DisGeNET、DRUGBANK、GeneCards、OMIM 数据库筛选疾病相关靶点,利用 Venny 2.0 数据库获取药物作用靶点与EMs疾病靶点的交集靶点；通过 STRING11.0数据库平台,构建蛋白互作(PPI)网络,筛选核心作用靶点；利用Cytosacpe软件构建活性成分-靶标网络；利用 DAVID数据库平台分析 KEGG 通路。通过子宫异位内膜大鼠模型进行相关验证,随机分为 6 组,分别为正常组(假手术组)、模型组(空白对照组)、孕三烯酮组(阳性对照组)、裘氏内异方高剂量组(QNY-H组)、裘氏内异方中剂量组(QNY-M组)、裘氏内异方低剂量组(QNY-L组),每组 10只。不同药物处理 4周,测定各组子宫内膜异位病灶面积及病变的粘连评分,并进行病理形态学观察。同时测定各组经网络药理学筛选出的最有可能的核心靶标和通路的靶蛋白和靶基因表达水平,以验证裘氏内异方治疗EMs的机制。结果 共筛选出裘氏内异方有效活性成分19种,对应裘氏内异方的240个靶标。3816个基因与EMs密切相关,其中132个与裘氏内异方的靶点重叠,被认为与治疗相关。通过网络药理学分析,预测裘氏内异主要活性成分木犀草苷、槲皮素、延胡索甲素、淫羊藿苷、山柰酚等,可能通过 AKT1、IL-6、VEGFA、EGFR、JUN等靶点,作用于 PI3K-AKT、雌激素等信号通路从而治疗EMs。动物实验方面,与正常组相比,模型组大鼠子宫异位内膜面积、Di Paola R评分、子宫HE评分、PI3K、Akt、VEGFA蛋白表达水平均显著上升(P<0.01),p-PI3K/PI3K、p-Akt/Akt蛋白表达水平显著性降低(P<0.01)；与模型组相比,孕三烯酮组和裘氏内异方高、中、低剂量组大鼠子宫异位内膜面积、Di Paola R评分、子宫HE评分、PI3K、Akt、VEGFA蛋白表达水平显著性降低均显著下降(P<0.05或P<0.01),p-PI3K/PI3K、p-Akt/Akt蛋白表达水平显著性升高(P<0.05或P<0.01)。结论 裘氏内异方是通过多组分、多靶点和多途径协同治疗EMs,干预PI3K-AKT 信号通路可能是其主要作用机制之一。 |
| 英文摘要: |
| ABSTRACT Objective To explore the mechanism of Qiu's Neiyi Decoction for endometriosis (EMs) based on network pharmacology and animal experiments. Methods To screen out the active ingredients in Qiu's Neiyi Decoction by ultra-high performance liquid chromatography-time-of-flight mass spectrometry (UPLC-Q/TOF-MS) combined with literature search. To Obtain gene targets of active ingredients from TCMSP database. To Screen of disease-related targets in the DisGeNET, DRUGBANK, GeneCards and OMIM databases, and obtain the intersection of drug targets and EMs disease targets by the Venny 2.0 database. To establish the protein interaction (PPI) network and screen the core targets by the STRING11.0 database, construct the active ingredient-target network by Cytosacpe software, and analyze the KEGG pathway by the DAVID database. The rat model of endometriosis was verified and randomly divided into 6 groups, which were normal group (sham operation group), model group (blank control group), pregntrienone group (positive control group), high dose group (QNY-H group), medium dose group (QNY-M group) and low dose group (QNY-L group). Each group consisted of 10 rats. After 4 weeks of treatment with different drugs, to measure the area and the adhesion score of endometriosis lesions, and observe the pathological morphology. At the same time, the expression levels of target proteins and target genes of the most likely core targets and pathways screened by network pharmacology in each group were determined, so as to verify the mechanism of the treatment of EMs with Qiu's Neiyi Decoction. Results A total of 19 kinds of active ingredients of Qiu's Neiyi Decoction were screened, which correspond to 240 targets of the Decoction. 3816 genes are closely related to EMs, of which 132 overlap with targets within Qiu's Neiyi Decoction and are thought to be relevant for treatment. Through the network pharmacological analysis, it is predicted that the main active components of Luteoloside, Quercetin, Corydaline, Icarrin and kaempferol, etc. may act on PI3K-AKT, estrogen and other signaling pathways through AKT1, IL-6, VEGFA, EGFR, JUN and other targets to treat EMs. In animal experiments, compared to the normal group, the expression of ectopic endometrial volume, Di Paola R score, uterine HE score, PI3K, Akt and VEGFA protein in the model group increased significantly (P<0.01), and the expression of p-PI3K/PI3K and p-Akt/Akt proteins decreased significantly (P <0.01). Compared to the model group, the expression of uterine ectopic endometria, Di Paola R score, uterine HE score, PI3K, Akt and VEGFA proteins decreased significantly (P<0.05 or P<0.01), and the expression of p-PI3K/PI3K and p-Akt/Akt proteins increased significantly (P<0.05 or P<0.01) in the gestrinone group and Qiu's Neiyi Decoction groups. Conclusion Qiu's Neiyi Decoction is a multi-component, multi-target, and multi-pathway synergistic treatment of EMs, and intervention in PI3K-AKT signaling pathway may be one of its main mechanisms. |
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