世界中医药

目的：基于异病同治理论，采用网络药理学及动物实验分析坤泰胶囊治疗卵巢早衰和绝经综合征的作用机制。方法：在中药系统药理学数据库与分析平台（TCMSP）、中药分子机制生物信息学分析工具（BATMAN-TCM）获取坤泰胶囊活性成分和作用靶点，通过GeneCards、OMIM等数据库获得疾病靶点，取坤泰胶囊治疗卵巢早衰和绝经综合征的共同靶点。构建“药物-疾病-共同靶点”及蛋白质-蛋白质相互作用（PPI）网络，DAVID数据库分别进行基因本体（GO）富集分析和京都基因和基因组百科全书（KEGG）富集分析。动物实验：制备卵巢早衰及围绝经期大鼠模型，随机分为空白组（假手术组）、模型组、补佳乐组（模型组+补佳乐干预）、坤泰胶囊组（模型组+坤泰胶囊干预），每组8只。采用酶联免疫吸附测定（ELISA）方法检测各组大鼠卵泡生成素（FSH）、雌二醇（E2）及黄体生成素（LH）水平，同时比较各组大鼠血清中白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）水平。结果：1）获得坤泰胶囊治疗卵巢早衰及绝经综合征共有靶点128个，包括甘油醛-3-磷酸脱氢酶（GAPDH）、原癌基因酪氨酸受体激酶（SRC）、IL-6、TNF、雌激素受体1（ESR1）等。核心靶点主要富集在癌症、HIF-1、PI3K-AKT、TNF等信号通路。2）实验结果显示：卵巢早衰及绝经综合征模型组较空白组（假手术）大鼠血清FSH、LH均明显增高，而E2显著降低。药物干预后，坤泰胶囊组较模型组大鼠血清FSH、LH水平均有所降低，E2水平升高；与空白组（假手术组）比较，模型组大鼠血清IL-6、TNF-α水平均明显上升(均P<0.05)。药物干预后，坤泰胶囊组大鼠血清IL-6、TNF-α水平较模型组明显下降(均P<0.05)。结论：坤泰胶囊治疗卵巢早衰和绝经综合征可能通过调控GAPDH、SRC、IL-6、TNF等核心靶点参与HIF-1信号通路、PI3K-AKT信号通路、TNF信号通路等发挥治疗作用。

English Summary:

To explore the mechanism of Kuntai Capsules in treating premature ovarian failure and menopausal syndrome based on the theory of simultaneous treatment of different diseases by network pharmacology and animal experiments.Methods:The active components and targets of Kuntai Capsules were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCSMP) and a Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine(BATMAN-TCM)，and the disease targets were obtained from GeneCards，Online Mendelian Inheritance in Man(OMIM) and other databases.The common targets shared by Kuntai Capsules，premature ovarian failure，and menopausal syndrome were identified.The “drug-disease-common target” network and the protein-protein interaction(PPI) network were built.DAVID was used for gene ontology(GO) annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis.Furthermore，the rat model of premature ovarian failure and menopausal syndrome was established，and the modeled rats were randomized into blank control(sham operation)，model，progynova(model+progynova)，and Kuntai Capsules(model+Kuntai Capsules) groups(n=8).Enzyme-linked immunosorbent assay was employed to measure the levels of sex hormones including follicle-stimulating hormone(FSH)，estradiol(E2) and luteinizing hormone(LH) in each group.The serum levels of interleukin-6(IL-6) and tumor necrosis factor-alpha(TNF-α) were compared among different groups.Results:1) A total of 128 targets of Kuntai Capsules in the treatment of premature ovarian failure and menopausal syndrome were obtained，including glyceraldehyde-3-phosphate dehydrogenase(GAPDH)，proto-oncogene tyrosine-protein kinase SRC，IL-6，TNF，and estrogen receptor 1(ESR1).The core targets were mainly enriched in cancer，hypoxia-inducible factor-1(HIF-1)，phosphatidylinositol 3-kinase(PI3K)-protein kinase B(AKT)，and TNF signaling pathways.2) The results of animal experiments showed that the model group had higher FSH and LH levels and lower E2 level than the sham operation group.The Kuntai Capsules group had lower FSH and LH levels and higher E2 level than the sham operation group.Compared with the sham operation group，the model group showed elevated IL-6 and TNF-α levels(P<0.05).After intervention with Kuntai Capsules，the IL-6 and TNF-α levels declined(P<0.05).Conclusion:Kuntai Capsules may treat premature ovarian failure and menopausal syndrome by regulating the HIF-1，PI3K，and TNF signaling pathways via the core targets such as GAPDH，SRC，IL-6，and TNF.

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