南方医科大学学报

南方医科大学学报 ›› 2021, Vol. 41 ›› Issue (3): 319-328.doi: 10.12122/j.issn.1673-4254.2021.03.02

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滋阴方治疗排卵障碍性不孕症的机制及价值：基于网络药理学方法

罗倩倩，谈 勇，胡荣魁，夏 云，夏桂成   

  • 出版日期:2021-03-20 发布日期:2021-04-06

Mechanism of Ziyin recipe for treatment of ovulatory infertility: a network pharmacology-based study and clinical observations

  • Online:2021-03-20 Published:2021-04-06

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摘要： 目的 基于网络药理学分析滋阴方治疗排卵障碍性不孕症的作用机制并设计临床对照试验观察滋阴方对该病的治疗疗效。方法 利用TCMSP、PubChem、Genecards、STRING、Swiss Target Prediction、UniProt等数据库，获得滋阴方所有作用靶点和排卵障碍性不孕症相关的靶点。构建靶点蛋白质相互作用网络，进行GO生物学过程与KEGG通路富集分析，使用Cytoscape3.6.0构建滋阴方治疗排卵障碍性不孕症的“中药-有效成分-靶点-通路”网络。同时设计临床对照试验，试验组及对照组均以克罗米芬联合人绝经期促性腺激素进行促排卵治疗，试验组在此基础上添加滋阴方，通过观察两组HMG用量、卵泡发育天数、扳机日单个优势卵泡雌二醇水平（E2）水平、周期排卵率、未破裂卵泡黄素化综合征发生率、周期妊娠率等指标，验证滋阴方的临床有效性。结果 滋阴方共有22个活性成分，354个作用靶点，排卵障碍性不孕症靶点791个，取交集获得滋阴方治疗排卵障碍性不孕症作用靶点 96 个。根据 Degree 找出关键靶点为 SRC、MAPK1、HSP90AA1、MAPK3、PTPN11、ESR1、AKT1、EGFR、NR3C1、KNG1。GO生物学过程富集分析显示，滋阴方治疗排卵障碍性不孕症主要集中在类固醇激素介导的信号通路、氧化、还原、凋亡等过程。KEGG通路富集分析表明富集最显著的信号通路PI3K-Akt信号通路、Rap1信号通路、HIF-1信号通路、雌激素信号通路、卵巢类固醇生成、类固醇激素生物合成。临床试验显示滋阴方能减少人绝经期促性腺激素用量，缩短卵泡发育天数，提高扳机日单个优势卵泡E2水平、周期排卵率及妊娠率。结论 滋阴方中多种有效活性成分可以通过不同的途径发挥其促进卵泡发育的作用，从而提高排卵障碍不孕症患者排卵率及临床妊娠率，具有良好的临床应用前景。

关键词:

Abstract: Objective To explore the mechanisms of Ziyin recipe for treatment of ovulatory infertility based on network pharmacology analysis and evaluate the clinical efficacy of this recipe. Methods TCMSP, PubChem, Genecards, String, Swiss Target Prediction, and Uniprot databases were searched to identify all the action targets of Ziyin recipe and ovulatory infertility to construct the PPI network. Gene ontology (GO) and KEGG pathway enrichment analyses were performed and the "TCM-active ingredient-target-pathway" network was constructed using Cytoscape 3.6.0. We also designed a controlled clinical trial to verify the clinical effectiveness of Ziyin recipe. The patients were randomized into 2 groups to receive treatment with Western medicine including CC and HMG (control group) and additional treatment with Ziyin recipe, and the dosage of GN, follicular development days, E2 level of a single dominant follicle on trigger day, ovulation rate, the rate of LUFS, and clinical pregnancy rate were compared between the two groups. Results We identified 22 active ingredients and 354 targets of action in Ziyin recipe, 791 targets of ovulatory infertility, and 96 common targets of action shared by Ziyin recipe and ovulatory infertility. According to Degree, the key targets included SRC, MAPK1, HSP90aa1, MAPK3, PTPN11, ESR1, Akt1, EGFR, NR3C1 and KNG1. Enrichment analysis of GO biological process showed that Ziyin recipe mainly focused on steroid hormonemediated signaling pathway, oxidation, reduction, and apoptosis. The most significantly enriched signaling pathways included PI3K-Akt signaling pathway, RAP1 signaling pathway, HIF-1 signaling pathway, estrogen signaling pathway, ovarian steroid production, and steroid hormone biosynthesis. The results of the clinical trial showed that Ziyin recipe significantly reduced the dose of GN, accelerated follicle development, increased E2 level of single dominant follicle on the trigger day, and increased the cycle ovulation rate and pregnancy rate. Conclusion The therapeutic effects of Ziyin recipe are probably mediated through different pathways to promote follicle development, thus improving ovulation rate and clinical pregnancy rate of infertile patients with ovulatory disorders.

Key words: network pharmacology; ovulation disorder; infertility; Ziyin recipe; clinical observation