Abstract
Oxidative damage can lead to severe ovarian dysfunctions and even premature ovarian failure. Nrf2, a significant transcription factor that regulates the oxidative stress response of cells, declines with age. Daphnetin, as a kind of natural Chinese herbal medicine, can activate Nrf2 and further promote the antioxidant defense of cells. However, whether Daphnetin treatment can protect ovary from premature ovarian failure and the specific mechanism involved are not understood. This study aimed to investigate the protective function of Daphnetin against the ovarian aging induced by D-galactose in wild-type and Nrf2−/− mice. Female C57BL/6 mice with Wild-type and Nrf2−/− were divided into five groups separately and the premature ovarian failure model were established by D-galactose and then Daphnetin and VE were given for treatment. After 42 days, ovaries tissue and serum were collected for biochemical determination, H&E staining, Immunohistochemical staining and western blot analysis. In the WT-POF group, ovarian function was broke, and the expression of the ovarian senescence-associated protein P16 and the level of oxidative stress were significantly increased, while the expression of the anti-senescence protein klotho was significantly decreased. In addition, the expression of Nrf2 and the antioxidases GCLC, HO-1 and NQO1 were decreased, but TXNIP and NLRP3 were significantly increased. Furthermore, the characteristics of premature ovarian failure were more significant in Nrf2 knockout mice than in wild-type mice, especially the expression of NLRP3 and TXNIP. Moreover, daphnetin, an Nrf2 activator, rescued d-gal-induced POF in a dose-dependent manner, while the protective effect was weakened or even lost in Nrf2 knockout mice. Our results suggested that daphnetin is likely to be a candidate drug for premature ovarian failure treatment and it is mostly possible referred to the molecular mechanism of increasing Nrf2 expression and inhibiting NLRP3 activation in the ovarian aging process.
Highlights
Premature ovarian failure (POF), the current term for ovarian dysfunction called premature ovarian insufficiency (POI), occurs in women under 40 years of age whose follicle-stimulating hormone (FSH) level is > 40 IU/ml and is accompanied by secondary amenorrhea, infertility and low estrogen symptoms (Perry et al, 2013; Hewlett and Mahalingaiah, 2015)
The results showed that the control group exhibited regular oestrous cycles about 4 days, and the using of D-gal could lengthen the cycle from 4 to 5 days; this phenomenon was more significant in Nuclear factor erythroid-2 related factor 2 (Nrf2)−/− mice with an obviously increased length of the dioestrus period (Figure 2B)
Our results demonstrated that D-gal-induced NLR family pyrin domain containing 3 (NLRP3) and senescence-associated protein P16 were much higher in Nrf2−/− mice, while the anti-senescence protein klotho was much lower (Figures 2G–J), suggesting that Nrf2 could be of great value in protection against D-galinduced POF by inhibiting NLRP3
Summary
Premature ovarian failure (POF), the current term for ovarian dysfunction called premature ovarian insufficiency (POI), occurs in women under 40 years of age whose follicle-stimulating hormone (FSH) level is > 40 IU/ml and is accompanied by secondary amenorrhea, infertility and low estrogen symptoms (Perry et al, 2013; Hewlett and Mahalingaiah, 2015). Epidemiological surveys have shown that the prevalence of POF in the population is approximately 1–3%, and in amenorrheic patients, it is approximately 2–10% (Rafique et al, 2012). The incidence of POF has been increasing year by year because of factors such as the environment and the increase in women’s work intensity. POF is a highly heterogeneous female disease with extremely complex etiology, and risk factors include genetics, autoimmune, metabolic disorders and iatrogenic diseases, which contribute to the difficulty of treatment (Qin et al, 2015; Kirshenbaum and Orvieto, 2019; Christianson et al, 2020). Hormone replacement therapy (HRT) is being abandoned for some female patients because of the potential risk of endometrial, breast cancer and thrombotic diseases (Deady, 2004). The ovarian stem cell treatment method is still under investigation (Wang et al, 2013)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
