Isorhamnetin Protects Zearalenone-induced Damage via the PI3K/Akt Signaling Pathway in Porcine Granulosa Cells

Abstract

Background: Zearalenone (ZEA) is widely derived from moldy cereal grain, which has adverse effects on animal reproduction. In particular, pigs are more sensitive to ZEA-induced toxicity than other animals. Isorhamnetin, a flavonoid has extensive of pharmacological activities. However, little is known about the effects of isorhamnetin on reproduction. Thus, it would be interesting to clarify the effect and the underlying molecular mechanism of isorhamnetin involvement in ZEA-induced cytotoxicity in porcine granulosa cells.Results: Our findings showed that isorhamnetin suppressed ZEA-induced apoptosis by regulating Bcl-2 and Bax protein changes. Changes in intracellular Ca2+ levels and CHOP, ATF6, GRP78 indicated that isorhamnetin rescued ZEA-induced endoplasmic reticulum stress (ERS). Furthermore, isorhamnetin prevented ZEA-induced reactive oxygen species (ROS) via P38 signaling pathway. Mechanistically, isorhamnetin stimulated the expression of PCNA and CyclinD, thereby raising the ratio of S phases cells in response to ZEA-induced apoptosis via PI3K/Akt signaling pathway. Isorhamnetin also recovered ZEA-induced steroidogenesis disorder by regulating steroidogenic enzyme gene and proteins (FSH-R, CYP19A1). Conclusions: Collectively, these findings show that isorhamnetin protects granulosa cells from ZEA-induced damage via the PI3K/Akt signaling pathway, which promotes proliferation, alleviates steroidogenesis disorder, ERS and oxidative stress.

Toxicity of zearalenone and its nutritional intervention by natural products

“…It is believed that isorhamnetin protects porcine granulosa cells from ZEN-induced damage through the PI3K/Akt signaling pathway and can attenuate steroidogenesis dysfunction, EnR stress, and oxidative stress, promoting cellular proliferation. 180 In addition, isorhamnetin restored the proliferation and estrogen secretion of ovarian granulosa cells disturbed by ZEN through the PI3K/Akt signaling pathway, thus reducing the damage by ZEN in porcine ovarian granulosa cells. 181 As a natural flavonoid that exhibits various biological activities, chrysin has been reported to act as a testosterone enhancer by delaying the decline in testosterone biosynthesis.…”