Resveratrol inhibits the inflammatory response and oxidative stress induced by uterine ischemia reperfusion injury by activating PI3K-AKT pathway.

Abstract

Uterus transplantation is a complex surgical procedure. Uterine ischemia reperfusion (I/R) injury that occurs during this process may cause a loss of function of the uterus and the failure of transplantation. Resveratrol (RSV) is a naturally occurring polyphenol found abundantly in the skin of grapes and red wine, and it has also been used as a dietary supplement in clinical practice. RSV possesses strong anti-inflammatory and anti-oxidative effects, and exhibits a role in immune system regulation. However, the role of RSV in protecting the uterus against I/R-induced injury is yet to be fully elucidated. The aim of the present study was to investigate the effects and mechanisms underlying RSV in I/R-induced uterus injury. A total of 48 Sprague-Dawley rats were randomly divided into four groups: Control (sham operation) group, the uterus I/R group, the 20 mg/kg RSV-pre-treated I/R (I/R+RSV/20) group and the 40 mg/kg RSV-pre-treated I/R (I/R+ RSV/40) group. A regular I/R model was established to induce uterus injury in rats. RSV at 20 or 40 mg/kg was intraperitoneally administrated into rats in both I/R+ RSV groups once per day for five consecutive days prior to ischemia. The control and I/R only groups received an intraperitoneal injection of the vehicle (ethanol) for the same period prior to ischemia. Samples from blood and uterine horns were collected 3 h after reperfusion. Changes in the levels of malondialdehyde, interleukin (IL)-6, tumor necrosis factor-α, IL-10 and IL-37 were determined using ELISA, the activity levels of myeloperoxidase, catalase, and superoxidase dismutase were also determined using ELISA, the protein expression levels of PI3K, phosphorylated (p)-PI3K, AKT and p-AKT were determined using western blot analysis, and the uterine histology was investigated using H&E staining. Results of the present study demonstrated that treatment with RSV increased the capacity of antioxidants and suppressed uterine oxidative injury induced by I/R. Moreover, treatment with RSV decreased the levels of pro-inflammatory cytokines and increased the levels of anti-inflammatory cytokines. In addition, RSV promoted the phosphorylation of PI3K and AKT, thus activating the PI3K-AKT signaling pathway. Therefore, administration of RSV prior to uterine I/R effectively alleviated inflammatory response and oxidative stress via activation of the PI3K-AKT pathway, suggesting that RSV may play a protective role in I/R-induced uterus injury.