Quercetin alleviates cyclophosphamide-induced premature ovarian insufficiency in mice by reducing mitochondrial oxidative stress and pyroptosis in granulosa cells

Abstract

Background Exposure to cyclophosphamide (CTX) induces premature ovarian insufficiency (POI). Quercetin is a natural flavonoid that exhibits anti-inflammatory and antioxidant properties, and its antioxidant activity is correlated with POI. However, the mechanism underlying its protective role in CTX-induced ovarian dysfunction is unclear. This study aimed to explore whether quercetin can protect ovarian reserves by activating mitochondrial biogenesis and inhibiting pyroptosis. Methods Thirty-six female C57BL/6 mice were randomly subdivided into six groups. Except for the control group, all groups were injected with 90 mg/kg CTX to establish a POI model and further treated with coenzyme 10 or various doses of quercetin. The mice were sacrificed 48 h after 10 IU pregnant mare serum gonadotropin was injected four weeks after treatments. We used enzyme-linked immunosorbent assays to detect serum hormone expression and light and transmission electron microscopy to assess ovarian tissue morphology and mitochondria. Additionally, we tested oxidant and antioxidant levels in ovarian tissues and mitochondrial function in granulosa cells (GCs). The expression of mitochondrial biogenesis and pyroptosis-related proteins and mRNA was analyzed using western blotting and RT-qPCR. Results Quercetin elevated serum anti-Müllerian hormone, estradiol, and progesterone levels, decreased serum follicle-stimulating hormone and luteinizing hormone levels, and alleviated ovarian pathology. It reduced the mitochondrial DNA content and mitochondrial membrane potential. Furthermore, it upregulated ATP levels and the mRNA and protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), mitochondrial transcription factor A, and superoxide dismutase 2. In addition, it suppressed NOD-like receptor pyrin domain containing 3, caspase-1, interleukin-1β, and gasdermin D levels in the GCs of POI mice. Conclusions Quercetin protected the ovarian reserve from CTX-induced ovarian damage by reversing mitochondrial dysfunction and activating mitochondrial biogenesis via the PGC1-α pathway. Moreover, quercetin may improve ovarian functions by downregulating pyroptosis in the CTX-induced POI model. Thus, quercetin can be considered a potential agent for treating POI.

Identification of the active ingredients and pharmacological effects of Kuntai capsules in the treatment of primary ovarian insufficiency: A review

“…[31] Quercetin may also protect ovarian function by decreasing oxidative activity. [32,33] Kaempferol is a natural flavonoid from plants that is involved in several bioprocesses and has antioxidant, anti-inflammatory, and anticancer activities. [34] Kaempferol can promote sheep primordial follicle activation and induces sheep-growing follicle development via the PI3K/AKT pathway.…”

α‐Ketoglutarate Improves Ovarian Reserve Function in Primary Ovarian Insufficiency by Inhibiting NLRP3‐Mediated Pyroptosis of Granulosa Cells

“…[ 67 ] Supporting this concept, studies have found that the GCs of women with POI exhibit elevated NLRP3, Caspase‐1, and IL‐1β levels. [ 19,68 ] Furthermore, the NLRP3 inflammasome is considered to be a key regulator of cellular inflammation, [ 67 ] and the expression levels of NLRP3, ASC, GSDMD, and Caspase‐1 mRNA and protein are increased, and the levels of IL‐18 and IL‐1β in serum and ovary are also raised in POI rats. [ 69 ] In line with these research findings, our study further validates the underlying connection between pyroptosis and POI.…”

“…[ 65,66 ] Specially, research has demonstrated a tight relationship between the NLRP3‐mediated pyroptosis and POI. [ 67 ] Supporting this concept, studies have found that the GCs of women with POI exhibit elevated NLRP3, Caspase‐1, and IL‐1β levels. [ 19,68 ] Furthermore, the NLRP3 inflammasome is considered to be a key regulator of cellular inflammation, [ 67 ] and the expression levels of NLRP3, ASC, GSDMD, and Caspase‐1 mRNA and protein are increased, and the levels of IL‐18 and IL‐1β in serum and ovary are also raised in POI rats.…”

“…[19] Animal experiments have also found that the expression levels of inflammasome components NLRP3, Caspase-1, IL-1𝛽, and GSDMD are significantly increased, leading to impaired ovarian function. [24] Nevertheless, when the inflammation was reduced by lowering the levels of most inflammatory markers, endocrine dysfunction and the reduced ovarian reserve were considerably restored, suggesting a potential therapeutic target for POI patients. [25] Previous studies have shown that NLRP3 inhibition attenuates ovarian aging and prolongs fertility in female mice.…”

Network pharmacology and experiment indicated that medicinal food homologous components play important roles in insomnia

“…Extracellular regulated protein kinase (ERK) (Guo et al., 2020) is the main member of the mitogen‐activated protein kinase family, which mainly regulates apoptosis, proliferation, and differentiation (Karisch et al., 2011). Phosphatase 1 (SHP‐1, also known as PTPN6) containing the Src homologous region 2 (SH2) domain is a non‐receptor protein tyrosine phosphatase (PTP) (Xu et al., 2012), a tyrosine phosphatase expressed in hematopoietic cells (Chen et al., 2022), containing two structures of SH2, the SHP‐1 gene is located in the p12–p13 region of chromosome 12, and the expressed product SHP‐1 is composed of 641 amino acid residues with a molecular weight of 70,510 Da, It plays an important role in cell signaling (Keranmu et al., 2022). Protein tyrosine phosphatase 1B (PTP1B) can bind directly to protein tyrosine kinase receptors, including IRs and epidermal growth factor receptors.…”