Wang Wenshuang, Yang Wen, Wang Fangwenting, Gao He, Liu Kaixin, Zhang Jinling, Li Yunjuan, Zhang Man, Zhou Guirong, Hou Yuanyuan, Bai Gang
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.
State Key Laboratory of Chinese Medicine Modernization, Tasly Pharmaceutical Group Co., Ltd., Tianjin, China.
Front Pharmacol. 2025 Mar 26;16:1554479. doi: 10.3389/fphar.2025.1554479. eCollection 2025.
Ovarian function decline results in reduced estrogen levels, leading to endocrine disorders, oxidative stress damage, and excessive activation of inflammatory factors, all of which contribute to the development of premenstrual syndrome (PMS). Kunxinning Granules (KXN) has been clinically approved for PMS treatment, but its bioactive ingredients and mechanism of action remain unclear. This study aimed to investigate the active metabolites and molecular mechanism of KXN in treating PMS rats, laying a foundation for the clinical development of PMS treatment.
An ovariectomized (OVX) rat model was established to evaluate the efficacy of KXN in treating PMS. Molecular network (MN) analysis, combined with UPLC/Q-TOF-MS, identified prototype compounds in the samples and constructed a chemical classification map based on their structures. A network analysis and proteomics were conducted to predict potential pathways through which KXN regulates PMS. Quantitative metabolomics assays were used to confirm these potential pathways. Additionally, target prediction and binding enzyme activity detection elucidated the key active metabolites and mechanisms of action in KXN.
KXN exhibited significant effectiveness in supplementing estrogen deficiency and uterine atrophy in the OVX model. We identified 16 absorbed metabolites as the potential pharmacological ingredients of KXN . The steroid hormone biosynthesis pathway, a crucial pathway of KXN in PMS, played a key role in KXN's effectiveness. KXN improved hormonal metabolic disorders by regulating this pathway. The main metabolites in KXN, including astragaloside IV, icariin and baohuoside I increased estradiol levels by enhancing the activity of CYP19A1, the representative enzyme in hormone biosynthesis pathway.
This study shows that KXN could relieve anxiety, depression, and osteoporosis in PMS. This pharmacological effect is exerted through steroid hormone synthesis to address estrogen deficiency. The findings provide valuable insights into the underlying mechanisms and support its clinical application.
卵巢功能衰退导致雌激素水平降低，引发内分泌紊乱、氧化应激损伤以及炎症因子过度激活，所有这些都促使经前综合征（PMS）的发生。坤宁心颗粒（KXN）已获临床批准用于治疗PMS，但其生物活性成分及作用机制尚不清楚。本研究旨在探究KXN治疗PMS大鼠的活性代谢产物及分子机制，为PMS治疗的临床开发奠定基础。
建立去卵巢（OVX）大鼠模型以评估KXN治疗PMS的疗效。分子网络（MN）分析结合超高效液相色谱/四极杆飞行时间质谱（UPLC/Q-TOF-MS）鉴定样品中的原型化合物，并根据其结构构建化学分类图谱。进行网络分析和蛋白质组学以预测KXN调节PMS的潜在途径。采用定量代谢组学分析来确认这些潜在途径。此外，靶点预测和结合酶活性检测阐明了KXN中的关键活性代谢产物及作用机制。
KXN在OVX模型中对补充雌激素缺乏和子宫萎缩具有显著效果。我们鉴定出16种吸收代谢产物作为KXN的潜在药理成分。类固醇激素生物合成途径是KXN治疗PMS的关键途径，在KXN的疗效中起关键作用。KXN通过调节该途径改善激素代谢紊乱。KXN中的主要代谢产物，包括黄芪甲苷IV、淫羊藿苷和宝藿苷I，通过增强激素生物合成途径中的代表性酶CYP19A1的活性来提高雌二醇水平。
本研究表明KXN可缓解PMS中的焦虑、抑郁和骨质疏松。这种药理作用是通过类固醇激素合成来解决雌激素缺乏问题。这些发现为潜在机制提供了有价值的见解，并支持其临床应用。
