Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
School of Pharmacy, Second Military Medical University, Shanghai, 200433, China.
J Ethnopharmacol. 2022 Sep 15;295:115442. doi: 10.1016/j.jep.2022.115442. Epub 2022 Jun 8.
Dingkun Pill (DKP), a traditional Chinese medicine prescription, was modified from Bujing decoction and Xusijiangsheng pill by the imperial physician in the Qing dynasty (1700' s). It was believed to treat various gynecological diseases by nourishing qi and blood. Accumulating evidence indicates that it is effective in treating polycystic ovary syndrome (PCOS). However, the therapeutic efficacy and mechanism of action DKP against PCOS need to be further elucidated.
To investigate the therapeutic effect and action mechanism of DKP against PCOS using an integrated approach of metabolomics and network pharmacology.
The rat model of PCOS was established by dehydroepiandrosterone. An integrated metabolomics and network pharmacology strategy was applied to systemically clarify the mechanism of DKP against PCOS. Theca cells were prepared to evaluate the effect of DKP and its ingredients on testosterone synthesis in vitro.
The pharmacological experiments demonstrated that DKP could effectively convert the disordered estrous cyclicity, decrease the level of testosterone and the luteinizing hormone/follicle stimulating hormone ratio, and inhibit abnormal follicle formation in PCOS rats. By metabolomics analysis, 164 serum endogenous differential metabolites and 172 urine endogenous differential metabolites were tentatively identified. Steroid hormone biosynthesis and ovarian steroidogenesis were the most significantly impacted pathways. Based on network pharmacology and metabolomics studies, the ingredient-target-pathway network of DKP in the treatment of PCOS was constructed. Among the 10 key targets, CYP17A1, CYP19A1, STS, AR, ESR1, and MYC were closely involved in ovarian androgen synthesis. In theca cell-based assay of testosterone synthesis, DKP and its two active compounds (ligustilide and picrocrocin) showed inhibitory effects.
DKP effectively improved symptoms in rats with dehydroepiandrosterone-induced PCOS. The mechanism of DKP in the treatment of PCOS is related to the CYP17A1 enzyme required for androgen synthesis.
定坤丹（DKP）是一种中药方剂，由清朝（18 世纪）的宫廷医生从补中益气汤和四物加香附丸修改而来。它被认为可以通过补气养血来治疗各种妇科疾病。越来越多的证据表明，它在治疗多囊卵巢综合征（PCOS）方面是有效的。然而，DKP 治疗 PCOS 的疗效和作用机制仍需进一步阐明。
采用代谢组学和网络药理学相结合的方法研究 DKP 治疗 PCOS 的疗效和作用机制。
采用脱氢表雄酮（DHEA）建立 PCOS 大鼠模型。采用代谢组学和网络药理学相结合的方法，系统阐明 DKP 治疗 PCOS 的作用机制。体外分离大鼠卵巢颗粒细胞，观察 DKP 及其成分对睾酮合成的影响。
药效学实验表明，DKP 能有效改善 PCOS 大鼠的异常动情周期，降低血清睾酮和促黄体生成素/卵泡刺激素比值，抑制异常卵泡形成。通过代谢组学分析，初步鉴定出 164 种血清内源性差异代谢物和 172 种尿液内源性差异代谢物。类固醇激素生物合成和卵巢类固醇生成是受影响最显著的途径。基于网络药理学和代谢组学研究，构建了 DKP 治疗 PCOS 的成分-靶点-通路网络。在 10 个关键靶点中，CYP17A1、CYP19A1、STS、AR、ESR1 和 MYC 与卵巢雄激素合成密切相关。在睾酮合成的卵巢颗粒细胞实验中，DKP 及其两种活性化合物（藁本内酯和藏红花酸）均显示出抑制作用。
DKP 能有效改善 DHEA 诱导的 PCOS 大鼠的症状。DKP 治疗 PCOS 的作用机制与雄激素合成所需的 CYP17A1 酶有关。
