Resveratrol Plays a Protective Role against Premature Ovarian Failure and Prompts Female Germline Stem Cell Survival

Abstract

This study was designed to investigate the protective effect of resveratrol (RES) on premature ovarian failure (POF) and the proliferation of female germline stem cells (FGSCs) at the tissue and cell levels. POF mice were lavaged with RES, and POF ovaries were co-cultured with RES and/or GANT61 in vitro. FGSCs were pretreated with Busulfan and RES and/or GANT61 and co-cultured with M1 macrophages, which were pretreated with RES. The weights of mice and their ovaries, as well as their follicle number, were measured. Ovarian function, antioxidative stress, inflammation, and FGSCs survival were evaluated. RES significantly increased the weights of POF mice and their ovaries as well as the number of follicles, while it decreased the atresia rate of follicles. Higher levels of Mvh, Oct4, SOD2, GPx, and CAT were detected after treatment with RES in vivo and in vitro. RES treatment resulted in significantly lower TNF-α and IL-6 concentrations and an obviously higher IL-10 concentration in the ovaries. In FGSCs, higher Mvh, Oct4, and SOD2 concentrations and lower TNF-α, IL-6, and MDA concentrations were measured in the RES group. Blockage of the Hh signaling pathway reversed the protective effect of RES on FGSCs. In conclusion, RES effectively improved the ovarian function of the POF model and the productive capacity of FGSCs via relieving oxidative stress and inflammation and a mechanism involving the Hh signaling pathway, suggesting that RES is a potential agent against POF and can aid in the survival of FGSCs.

Crosstalk between the muscular estrogen receptor α and BDNF/TrkB signaling alleviates metabolic syndrome via 7,8-dihydroxyflavone in female mice

“…Follicles were counted and classified as primordial follicles as shown in (E) and indicated with green arrows; primary follicles as shown in (F) and marked by cyan circles; secondary follicles as shown in (G) and indicated with blue circles; healthy antral follicles as shown in (H) and indicated with purple circles; and atretic follicles as shown in (I) and indicated with red arrows. The classification method for different stage follicles was performed mainly according to previous reports [ 56 , 57 ]. (J)–(L) Serum concentrations of IL-6, TNF-α, and LPS (n = 10–12; ∗ p < 0.05, ∗∗ p < 0.01, ∗∗∗ p < 0.001, LFD control vs LFD+DHF 10 , Student's t test; ## p < 0.01, ### p < 0.001, HFD control vs LFD control, Student's t test; &&& p < 0.001, HFD control vs HFD+DHF 5 , HF+DHF 10 , and HFD+DHF 20 , one-way ANOVA).…”

“…Increased inflammation is closely associated with aging-related diseases, including visceral obesity, insulin resistance, and ovarian failure [ [54] , [55] , [56] , [57] ]. To examine the suppressive effect on inflammation of 7,8-DHF, we investigated representative pro-inflammatory factors, including IL-6 and TNF-α.…”

The Role of Oxidative Stress and Natural Antioxidants in Ovarian Aging

“…Furthermore, studies have demonstrated that TNFα, IL-1β, and IFN-γ induce ROS production in multiple types of human cells ( Yang et al, 2007 ; Agharazii et al, 2014 ). Similarly, increased levels of pro-inflammatory factors and oxidative products have been observed in animal POI models induced by chemotherapy drugs or radiotherapy, and antioxidats can simultaneously reduce pro-inflammatory factors (TNF α, IL-6, and IL-10) and oxidative product (malondialdehyde (MDA), H 2 O 2 , and ROS) levels by activating PI3K/AKT/mTOR or inhibiting NF-κB signaling pathways, thereby improving ovarian function ( He et al, 2017 ; Liu C et al, 2018 ; Li and Liu, 2018 ; Jiang et al, 2019 ). In summary, oxidative stress can promote inflammation in the ovaries and cause ovarian aging ( Figure 3 ).…”

Exploring the mechanism of (-)-Epicatechin on premature ovarian insufficiency based on network pharmacology and experimental evaluation

“…Antioxidants such as resveratrol and curcumin can up-regulate the expression of AKT and reduce OS level in ovarian tissue in animal models of POI, thereby regulating apoptosis in granulosa cells and improving ovarian function [ 28 , 29 ]. IL-6 is a typical immune response regulatory factor and its expression is closely related to levels of OS damage in cells or tissues, regardless of premature ovarian failure (POF) [ 30 ], polycystic ovarian syndrome (PCOS) [ 31 ], or ovarian damage caused by environmental pollutants [ 32 ]. CASP3 represents a terminal executioner caspase and can be activated by various signals including OS, which can cause DNA breakage and granulosa cell apoptosis, ultimately leading follicular atresia and damage to ovarian function [ 33 ].…”