Abstract
Premature ovarian insufficiency (POI) is characterized by the loss of ovarian function before 40 years of age and affects approximately 1% of women worldwide. Caragana sinica is a traditional Miao (a Chinese ethnic minority) medicine that improves ovarian function and follicular development. In the present study, we aimed to investigate the effect of active ingredients of C. sinica on POI and determine underlying mechanisms. Herein, the chemical composition of the C. sinica compound was analyzed using ultra-high-performance liquid chromatography, which identified hyperin (HR) as one of the main ingredients in C. sinica. Then, interaction targets of HR and POI were predicted and analyzed using network pharmacology and bioinformatics. The effect of HR on triptolide (TP)-induced granulosa cell injury was evaluated, and the underlying mechanism was explored based on bioinformatic results. A total of 100 interaction targets for POI and HR were obtained. The protein-protein interaction network of identified interaction targets emphasized the topological importance of AKT1. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that HR might regulate POI by modulating the mechanistic target of rapamycin (mTOR) signaling pathway. In addition, the KEGG graph of the mTOR signaling pathway revealed that AKT phosphorylation inhibits the TSC1/2, while TSC1/2 activation inhibits the expression of mTORC1. The fundamental experiment revealed that HR increased proliferation, progesterone receptor levels, and estradiol levels decreased by TP in KGN cells. Additionally, HR alleviated TP-induced apoptosis and G1/G1 phase arrest in KGN cells. Western blotting demonstrated that HR increased the phosphorylation of AKT and mTORC1 and decreased TSC1 expression in TP-induced KGN cells. Collectively, our findings revealed that HR alleviates TP-induced granulosa cell injury by regulating AKT/TSC1/mTORC1 signaling, providing insight into the treatment of POI.
Highlights
Premature ovarian insufficiency (POI), previously known as premature menopause or premature ovarian failure, is characterized by the loss of ovarian function before the age of 40 years and is mainly manifested as menstrual cessation, decreased androgen, and elevated gonadotropin
HR Was the Main Ingredient Detected in C. sinica Compound and Regulated POI by Modulating the AKT/TSC1/ mTORC1 Signaling Pathway. e principal components of
POI refers to early menstruation to stop, and anovulation and decreased estrogen levels according to previous research have shown that its pathogenesis has strong genetic background and high heterogeneity; the genetic factors were involved in the X chromosome abnormalities, gene mutation, mitochondrial dysfunction, etc., and chromosome abnormality is one of the main causes of POI [34] and has become an important factor of the female infertility
Summary
Premature ovarian insufficiency (POI), previously known as premature menopause or premature ovarian failure, is characterized by the loss of ovarian function before the age of 40 years and is mainly manifested as menstrual cessation, decreased androgen, and elevated gonadotropin. E presently available POI treatments include stem cell treatment, assisted reproductive technology, and hormonal replacement therapy. These treatments are limited to clinical application, and improved therapeutic strategies are urgently needed [4, 5]. Caragana sinica is a traditional Miao (Chinese ethnic minority) medicine containing C. sinica, Hominis placenta, glossy privet fruit, and Eclipta, and it has many pharmacological activities, such as analgesia, antioxidation, anti-inflammatory, avoiding microthrombosis, regulating immune function, inhibiting tumor cell growth, and so on [13]. We reported that C. sinica compound promotes the ovulation rate, as well as follicle growth and Evidence-Based Complementary and Alternative Medicine development in patients with a decline in ovarian reserve [14]. The active ingredients of C. sinica and its effect on POI have not been thoroughly investigated
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