Laboratory for Reproductive Immunology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
The Academy of Integrative Medicine of Fudan University, Shanghai, China.
Drug Discov Ther. 2023 Sep 15;17(4):257-269. doi: 10.5582/ddt.2023.01016. Epub 2023 Aug 20.
Although pregnancy success rates are raised with assisted reproductive technology, it still cannot meet clinical demands. Kunling Pill (KLP), a traditional Chinese medicine, is widely used in various gynecological disorders, particularly in improving fertility and pregnancy rates. However, the underlying mechanism of how KLP affects pregnancy outcomes remains unclear. This study aimed to explore the effects and mechanisms of KLP on endometrial receptivity. Firstly, a retrospective trial was conducted to validate the efficacy of KLP on repeated implantation failure (RIF) patients. The result indicated a significant increase in the proportion of live birth in KLP group (30.56%) compared to the control group (16.89%). Secondly, network pharmacology methods predicted the active components and network targets of KLP. Endometrial receptivity is closely associated with the activation of inflammatory factors, predicting the function of KLP on the immune system. The estrogen and apoptotic signaling pathways were also highlighted in the gene ontology enrichment analysis. Thirdly, a decreased endometrial receptivity model was established by controlled ovarian hyperstimulation (COH) in female C57BL/6 mice, divided into the COH and KLP groups. Normal female mice are as control group. In vivo, KLP administration could increase endometrial thickness and the number of endometrial glands and pinopodes. In the endometrium, KLP supplementation upregulated the expressions of estrogen receptor α, progesterone receptor, endothelial nitric oxide synthase, and integrin αVβ3 in the murine uterus and reduced serum levels of estrogen and progesterone. KLP regulated the uterine immune cells and inhibited cell apoptosis in the ovary via Bcl-2/Bax/caspase-3 pathway. In conclusion, KLP administration raised the live birth rate in RIF patients to optimize medication regimens, mainly because KLP ameliorated impaired endometrial receptivity.
虽然辅助生殖技术提高了妊娠成功率，但仍不能满足临床需求。坤灵丸（KLP）是一种中药，广泛用于各种妇科疾病，尤其在提高生育能力和妊娠率方面。然而，KLP 如何影响妊娠结局的潜在机制尚不清楚。本研究旨在探讨 KLP 对子宫内膜容受性的影响及其机制。首先，进行了一项回顾性试验，以验证 KLP 对反复着床失败（RIF）患者的疗效。结果表明，KLP 组活产率（30.56%）明显高于对照组（16.89%）。其次，采用网络药理学方法预测 KLP 的活性成分和网络靶点。子宫内膜容受性与炎症因子的激活密切相关，预测 KLP 对免疫系统的作用。基因本体富集分析还突出了雌激素和细胞凋亡信号通路。第三，通过对雌性 C57BL/6 小鼠进行控制性卵巢过度刺激（COH）建立子宫内膜容受性降低模型，分为 COH 组和 KLP 组。正常雌性小鼠作为对照组。体内，KLP 给药可增加子宫内膜厚度和子宫内膜腺体和微绒毛的数量。在子宫内膜中，KLP 补充上调了雌激素受体 α、孕激素受体、内皮型一氧化氮合酶和整合素αVβ3 在小鼠子宫中的表达，并降低了血清中雌激素和孕激素水平。KLP 通过 Bcl-2/Bax/caspase-3 途径调节子宫免疫细胞并抑制卵巢细胞凋亡。总之，KLP 给药可提高 RIF 患者的活产率，优化用药方案，主要是因为 KLP 改善了受损的子宫内膜容受性。
