The role of serum inflammatory cytokines and berberine in the insulin signaling pathway among women with polycystic ovary syndrome.

OBJECTIVE: To study the role of selected serum inflammatory cytokines and berberine in the insulin signaling pathway among women with polycystic ovary syndrome (PCOS). METHODS: Selected serum inflammatory cytokines were analyzed in the particle cells, which were interfered by berberine, from 78 infertile women who were to be treated with In Vitro Fertilization (IVF) /Intracytoplasmic Sperm Injection-Embryo Transfer (icsi-et). Among them, 49 patients had PCOS infertility, and 29 were non-PCOS patients whose infertility resulted from fallopian tube and male factors. The elisa method was used to detect the changes in the expression levels of inflammatory factors in the cells. The correlations between the serum inflammatory cytokine expression levels and the corresponding clinical hormones were analyzed. The changes in the expression (mRNA and protein) levels of the serum inflammatory cytokines were studied by real-time quantitative PCR and protein printing. Fluorescence microscope and flow cytometry were used to detect the glucose uptake capacity of ovarian granulosa cells in PCOS patients under the action of insulin after berberine. RESULTS: In the PCOS group, IL-17a (P = 0.001), IL-1Ra (P<0.0001), and IL-6 (P = 0.035) were significantly higher than those in the non-PCOS group. In the non-PCOS group, AMH level was negatively correlated with inflammatory cytokines IL-17a (r = -0.819;P = 0.004), IL-1a (r = -0.716;P = 0.0.02), IL-1b (r = -0.678;P = 0.031), IL-2 (r = -0.765;P = 0.01), and IL-8 (r = -0.705;P = 0.023). However, in the PCOS group, AMH levels were not significantly correlated with the levels of the examined inflammatory cytokines. Berberine significantly reduced the expression level of mTOR mRNA (P = 0.001), and increased the expression level of IRS-1 mRNA (P = 0.009) in the PCOS granule cells. CONCLUSION: In this study, we find that the elevated levels of serum inflammatory factors IL-17a, IL-1Ra, and IL-6 cause women to be in a subclinical inflammatory state for a long time. Abnormal changes in inflammatory factors alter their original negative correlations with AMH levels, thereby weakening the metabolism of glycolipids, promoting insulin resistance, destroying the normal ovulation and fertilization system of women, leading to polycystic ovary syndrome characterized by menstrual thinning and abnormal ovulation. Berberine can improve the sensitivity of insulin by regulating the signal pathway of insulin receptor substrate-1 (IRS-1) and mammalian target of rapamycin (mTOR) in PCOS patients and achieve a therapeutic effect of treating PCOS.

Berberine increases glucose uptake and intracellular ROS levels by promoting Sirtuin 3 ubiquitination.

OBJECTIVE: Berberine improves insulin sensitivity and ovulation function in PCOS patients. However, the mechanism by which berberine initiates glucose metabolism-related signaling pathways in ovarian cells remains unknown. This study unveiled a new mechanism by which berberine promotes ovarian cell glucose uptake, and demonstrated that SIRT3 ubiquitination is involved in the insulin sensitizing effect of berberine. METHODS: Berberine was used at different concentrations to treat cultured KGN cells. Then, cell viability, cell apoptosis, intracellular ROS levels, mitochondrial depolarization and activation of related signaling pathways were evaluated. RESULTS: Berberine administration led to mitochondrial depolarization and AMP accumulation by promoting SIRT3 ubiquitination. We confirmed that AMP accumulation activated AMPK signaling and further promoted glucose uptake. Meanwhile, berberine reduced the activity of mitochondrial complex I in a dose-depended manner, but not that of mitochondrial complex II. Furthermore, intracellular ROS levels and the expression of mitochondrial apoptosis pathway related factors increased with berberine concentration. Berberine caused significant SIRT3 ubiquitination and degradation by activating the AMPK pathway and increasing intracellular ROS levels. Interestingly, berberine induced ubiquitination paralleled the increased FOXO3a phosphorylation and FOXO3a/Parkin pathway activation. CONCLUSIONS: Berberine promotes glucose uptake and inhibits mitochondrial function by promoting SIRT3 ubiquitination, and is likely to regulate autophagy related function in ovarian cells by activating the AMPK pathway. These findings may provide novel insights into the development of drugs for the treatment of abnormal reproductive functions of the ovary.