RESUMO
The mechanisms through which the androgen-dependent activation of the androgen receptor (AR) regulates gravid uterine ferroptosis remain unknown. We show that while co-exposure of pregnant rats to the androgen 5α-dihydrotestosterone (DHT) and insulin (INS) triggered uterine ferroptotic signaling cascades, additional treatment with the anti-androgen flutamide increased expression of the key ferroptosis-inhibitory proteins SLC7A11, GSH, and GPX4; reduced iron content; normalized levels of ferroptosis-associated Tfrc, Fpn1, and Ho1 mRNAs; reduced levels of proteins modified by 4-HNE (a marker of ferroptosis); and restored protein levels of NRF2, a key transcription factor regulating antioxidant defense signaling, in the gravid uterus. Furthermore, exposure to DHT alone increased uterine ferroptosis, and NRF2 abundance was negatively correlated with AR status. Co-immunoprecipitation and Western blot assays revealed that the AR physically interacted with endogenous NRF2, and this interaction was increased by DHT exposure in vivo. Our results suggest that AR overactivation and NRF2 suppression cooperate in the regulation of NRF2-targets in uterine ferroptosis.
Assuntos
Ferroptose , Androgênios , Animais , Di-Hidrotestosterona/metabolismo , Di-Hidrotestosterona/farmacologia , Feminino , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Gravidez , Ratos , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Transdução de Sinais , Útero/metabolismoRESUMO
It has been confirmed by growing evidence that common hormone replacement therapy is associated with an increasing risk of causing cardiovascular disease and cancer, while complementary and alternative medicine (CAM) is gaining popularity and application in more and more patients with premature ovarian failure (POF). Although there is little data concerning the clinical safety and efficacy of CAM, the literature includes application studies on the phytoestrogen-rich herbal, acupuncture treatment and intervention therapy. This article reviews recent literature on CAM therapy for POF, aiming to provide theoretical support for clinical application.