Escin ameliorates letrozole-induced polycystic ovarian syndrome by modulating inflammatory, oxidative stress, and steroidogenic pathways in Wistar rats: integration of network pharmacology and molecular docking.

Polycystic ovary syndrome (PCOS) is a multifarious and chronic hormonal disease of women that is marked by hyperandrogenism, insulin resistance, and continued anovulation. This study aimed to evaluate the therapeutic effect of escin in PCOS. For this purpose, a network pharmacology and molecular docking study was performed to find potential targets and to explore the interaction of escin with major proteins associated with PCOS pathogenesis, including CYP19A1, the estrogen receptor, TNF-α, and SHBG. In this study, letrozole (1 mg/kg) was administered orally for 28 days to induce PCOS in all Wistar rats except for normal control. After PCOS induction, normal and PCOS + Veh group received 1 ml of 0.5% CMC, PCOS + Met treated with metformin (300 mg/kg), whereas treatment groups received PCOS + Escin 5, 10, and 15 mg/kg daily via oral route for 28 days. At the end of the experiment, body weight, oral glucose, hormonal level (sex hormone-binding globulin (SHBG), estrogen, progesterone, luteinizing hormone, follicle-stimulating hormone (FSH), testosterone), lipid profile, and liver tests were performed. Activity of CAT and SOD, and level of MDA and reduced GSH were measured in the ovary homogeneity. mRNA expression of TNF-α, IL-6, Nrf2/Keap-1, PGR, FSHR, and CYP19A1 were quantified in ovarian tissue by real-time PCR. The docking analysis demonstrated favorable binding affinities and stable ligand-protein interactions to CYP19A1, estrogen receptor, TNF-α, and SHBG, suggesting that escin might be regulated for steroidogenesis, inflammatory signaling, and hormonal imbalance through multi-target mechanisms in PCOS. Escin treatment groups significantly (p < 0.05) reduced body weight and normalized glucose, hormonal levels, lipid profile, and liver function in treated rats in contrast to PCOS + Veh group. PCOS + Escin treatment groups (5-15 mg/kg) notably reduced the oxidative stress as compared to the PCOS + Veh group. PCOS + Escin 15 significantly downregulated expression of TNF-α, IL-6, Keap-1, NF-KB, and PGR whereas upregulated FSHR, Nrf2, and CYP19A1 in treated rats as compared to the PCOS + Veh group. PCOS + Escin dose dependently reduced the level of TNF-α and IL-6 in the serum of treated rats in contrast to PCOS + Veh. It can be inferred from findings that escin dose dependently restored inflammatory, oxidative stress, and steroidogenic pathways in letrozole-induced PCOS in treated rats as in silico study confirmed the binding affinity of escin with CYP19A1, estrogen receptor, and TNF-α, and SHBG.