Isorhamnetin protects porcine oocytes from zearalenone-induced reproductive toxicity through the PI3K/Akt signaling pathway

Abstract

Background Zearalenone (ZEA) widely exists in moldy grains, which seriously destroys the fertility of females. Isorhamnetin, a natural flavonoid, has extensive of pharmacological activities. However, the beneficial effect and the underlying molecular mechanism of isorhamnetin involvement in ZEA-induced porcine oocyte damage have not been investigated. Methods Oocytes were treated with different concentrations of ZEA (3, 5, 8 and 10 μmol/L) and isorhamnetin (5, 10, 20 and 30 μmol/L) for 44 h at 39 ℃. ZEA (5 μmol/L) and isorhamnetin (10 μmol/L) were selected for subsequent studies. Polar body exclusion rate, apoptosis rate and apoptosis related proteins, ROS levels and SOD2 protein, mitochondrial membrane potential and distribution, endoplasmic reticulum distribution and proteins expression, and PI3K, Akt and p-Akt proteins expression of oocytes were detected. In addition, the effect of PI3K antagonist (LY294002) on oocyte nuclear maturation and apoptosis were used to determine the involvement of PI3K/Akt signaling pathway. Results Our findings showed that ZEA exposure damaged oocytes and isorhamnetin therapy restored the developmental capability of porcine oocytes. Isorhamnetin promoted polar body extrusion rate to rescue ZEA-induced meiotic arrest in porcine oocytes. Isorhamnetin alleviated ZEA-induced oxidative stress by stimulating SOD2 protein expression and inhibiting ROS production. Moreover, isorhamnetin enhanced normal mitochondrial distribution and mitochondrial membrane potential to prevent mitochondrial dysfunction induced by ZEA. Changing the expression of endoplasmic reticulum stress-related marker proteins (CHOP, GRP78) and the distribution rate of normal endoplasmic reticulum showed that isorhamnetin relieved ZEA-caused endoplasmic reticulum stress. Mechanistically, isorhamnetin decreased Bax/Bcl-2 protein expression and inhibited ZEA-induced apoptosis through PI3K/Akt signaling pathway. Conclusions Collectively, these results suggest that isorhamnetin protects oocytes from ZEA-caused damage through PI3K/Akt signaling pathway, which enhances meiotic maturation and mitochondrial function, and inhibits early apoptosis, oxidative stress and endoplasmic reticulum stress in porcine oocytes. Our study provides a new strategy for solving the reproductive toxicity induced by ZEA and treating woman infertility. Graphical Abstract A possible mechanism by which isorhamnetin protected porcine oocytes from ZEA-induced damage. Isorhamnetin inhibited meiosis arrest and apoptosis of porcine oocytes induced by ZEA through the PI3K/Akt signaling pathway. Moreover, isorhamnetin repaired ZEA-induced oocyte damage by alleviating oxidative stress, mitochondrial dysfunction and ER stress.

Endoplasmic reticulum stress in pancreatic β-cell dysfunction: The potential therapeutic role of dietary flavonoids

“… ↓β-cell apoptosis. Li et al (2020) ( Zhang and Qiu, 2020 ) ( Zhong et al, 2018 ) 13 Isorhamnetin ↑Nrf2 ↑HO-1 ↓ CHOP ↓ GRP78 ↑PKCε ↓XBP-1, ↓ATF6, ↓CHOP ↓ Oxidative stress ↓ ER stress ↑ Islet cell survival ↑ Insulin secretion in pancreatic islets Yang et al (2014) ( Li et al, 2023 ; Zheng et al, 2019 ) Kvezereli et al (2008) Rodríguez-Rodríguez et al (2015) 14 Kaempferol ↑ AMPK, ↓ mTOR ↑ AMPK, ↓ mTOR ↓ CHOP ↓ GRP78, ↑ Nrf2 ↑ Autophagy to sustain pancreatic β-cell mass and function. ↑ Autophagy to improve ER stress and lipid mobilization in pancreatic β-cells.…”

“…Despite having similar structures, isorhamnetin exhibits different physiological properties from its aglycone parent, quercetin, in terms of scavenging radicals, enzymatic activity, and vasodilation ( Jiang et al, 2019 ). Isorhamnetin has known antioxidant effects of activating Nrf2/heme oxygenase-1 (HO-1) and PI3K/Akt pathways ( Li et al, 2023 ; Yang et al, 2014 ), leading to the aversion of ER stress and apoptosis in pancreatic β-cells. By activating Protein kinase C epsilon (PKCε), it is argued that isorhamnetin could suppress the expression of GRP78, leading to cytoprotection of islet β-cells by relieving them of ER stress-induced intracellular Ca 2+ overload, ROS production, and apoptosis ( Kvezereli et al, 2008 ).…”

CO2-Breathing Prior to Simulated Diving Increases Decompression Sickness Risk in a Mouse Model: The Microbiota Trail Is Not Forgotten

“…Recent work suggests that the microbiota plays an increasingly important role in thermoregulation through its metabolic derivatives [38] or through its serotonergic effects via modulation of the gut-brain axis [32,33]. For instance, the inhibition of serotonin reuptake with fluoxetine has been shown to reduce DCS [27,28] and it would be interesting to explore this question further through the influence of the microbiota.…”

Screening and Mechanism Study of Three Antagonistic Drugs, Oxysophoridine, Rutin, and Phellodendrine, against Zearalenone-Induced Reproductive Toxicity in Ovine Oocytes

“…Additionally, resveratrol has been shown to correct mitochondrial depolarization, oxidative stress, and apoptosis through the PINK1/Parkin pathway, thereby reducing the damage caused by ZEN to porcine oocytes [ 14 ]. Finally, isorhamnetin has been shown to stimulate SOD2 protein expression and inhibit cell apoptosis through the PI3K/Akt signaling pathway, thereby reducing the damage caused by ZEN to porcine oocytes [ 22 ]. Agricultural breeding livestock are sensitive to ZEN; however, there is a lack of investigation into screening potential drugs that could reduce the reproductive toxicity of ZEN in ovines.…”