Diosmetin ameliorates inflammation and apoptosis in the pathomechanism of PCOS through the NRF2/AKT/PPARγ signalling pathway.

Abstract

Ethnopharmacological relevance: Diosmetin (DIO) is a flavonoid extracted from the traditional Chinese medicine Schizonepeta tenuifolia Briq. The anti-inflammatory and neuroprotective properties of DIO have shown promise. However, the underlying mechanisms need further elucidation.

Study aim: This research aimed to explore how DIO reduces oxidative stress and inflammation in the ovaries and slows the pathological development of polycystic ovary syndrome by influencing the AKT/PPARγ signalling pathway.

Materials and methods: DIO targets were screened via network pharmacology tools. The protective effect of DIO on polycystic ovary syndrome was assessed via haematoxylin‒eosin (H&E) staining. Immunohistochemical staining, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence were used to determine the effects of DIO on ovarian granulosa cell inflammation. In addition, we performed Western blotting to determine the expression of TNF-α, IL-6 and AKT/PPARγ pathway proteins.

Results: This research demonstrated an increase in TNF-α and IL-6 expression in a rat model of polycystic ovary syndrome (PCOS) induced by letrozole. Histological analysis indicated that the ovaries of rats in the PCOS group showed significant follicular loss and vacuolation changes compared with those in the normal control (NC) group. Treatment with DIO improved the cystic changes in the ovaries. Metabolic assessments revealed that the PCOS group presented significantly altered levels of FSH (4.2 ± 0.3 IU/L), TG (0.65 ± 0.2 mmol/L), E2 (106 ± 14 pg/L), TC (3.9 ± 0.7 mmol/L), LH (7.8 ± 0.2 IU/L), and TEST (11 ± 3 ng/mL) compared with those in the NC group (FSH: 6.3 ± 1.7 IU/L; TG: 1.2 ± 0.2 mmol/L; E2: 147 ± 21 pg/mL; TC: 2.2 ± 0.4 mmol/L; LH: 5.8 ± 1.2 IU/L; and TEST: 5.5 ± 2 ng/mL), indicating hyperandrogenaemia. Additionally, at the conclusion of the study, the PCOS group (310 ± 7 g) presented a significant increase in body weight compared with the NC group (310 ± 7 g), whereas treatment with 50 mg/kg DIO (351 ± 6 g) or 100 mg/kg DIO (342 ± 8 g) mitigated this weight gain. Immunohistochemistry, Western blot, and immunofluorescence results revealed that DIO reduced inflammation and alleviated the pathological changes associated with PCOS. Furthermore, DIO improved the inflammatory condition of the ovaries in the PCOS group by inhibiting the AKT/PPARγ signalling pathway. The suppression of AKT and PPARγ diminished the anti-inflammatory effects of DIO. Additionally, DIO countered inflammation and apoptosis in testosterone-induced ovarian granulosa cells by enhancing the expression of AKT/PPARγ signalling.

Conclusion: The present study confirms that DIO has important therapeutic potential for treating polycystic ovary syndrome by inhibiting ovarian inflammation and oxidative stress through the modulation of AKT/PPARγ signalling.