Fisetin Protects C2C12 Mouse Myoblasts from Oxidative Stress-Induced Cytotoxicity through Regulation of the Nrf2/HO-1 Signaling

Abstract

IntroductionReactive oxygen species (ROS) are generally maintained at appropriate levels in the cells and act as regulators of signaling pathways involved in maintaining cellular homeostasis. However, excessive accumulation of ROS, defined as oxidative stress, causes irreversible oxidative damage to proteins, lipids, DNA and organelles, ultimately leading to apoptosis [1,2]. Therefore, it is necessary to strictly control the level of ROS through antioxidants or intracellular antioxidant systems to maintain normal cell function [3,4]. Recently, polyphenols, which are abundant in the plant kingdom, have been found to have various pharmacological effects, including inhibition of oxidative stress-dependent pathological conditions. Their antioxidant activity mainly involves ROS scavenging and activation of intracellular antioxidant signaling pathways, and can terminate oxidative damage-mediated responses before cells are severely affected for survival [5,6].Among polyphenols, fisetin, a flavonol molecule, has shown health-improving potential in numerous previous studies [7,8]. This phytochemical is found as a coloring component in fruits and vegetables such as apples, cucumbers, onions, and persimmons. According to accumulated studies, fisetin is known to have multiple pharmacological effects, including neuroprotective, antidiabetics, antiallergic, antithrombotic, senotherapeutic, Fisetin is a bioactive flavonol molecule and has been shown to have antioxidant potential, but its efficacy has not been fully validated. The aim of the present study was to investigate the protective efficacy of fisetin on C2C12 murine myoblastjdusts under hydrogen peroxide (H 2 O 2 )-induced oxidative damage. The results revealed that fisetin significantly weakened H 2 O 2 -induced cell viability inhibition and DNA damage while blocking reactive oxygen species (ROS) generation. Fisetin also significantly alleviated cell cycle arrest by H 2 O 2 treatment through by reversing the upregulation of p21WAF1/CIP1 expression and the downregulation of cyclin A and B levels. In addition, fisetin significantly blocked apoptosis induced by H 2 O 2 through increasing the Bcl-2/Bax ratio and attenuating mitochondrial damage, which was accompanied by inactivation of caspase-3 and suppression of poly(ADP-ribose) polymerase cleavage. Furthermore, fisetin-induced nuclear translocation and phosphorylation of Nrf2 were related to the increased expression and activation of heme oxygenase-1 (HO-1) in H 2 O 2stimulated C2C12 myoblasts. However, the protective efficacy of fisetin on H 2 O 2 -mediated cytotoxicity, including cell cycle arrest, apoptosis and mitochondrial dysfunction, were greatly offset when HO-1 activity was artificially inhibited. Therefore, our results indicate that fisetin as an Nrf2 activator effectively abrogated oxidative stress-mediated damage in C2C12 myoblasts.

Effects of Fisetin Treatment on Cellular Senescence of Various Tissues and Organs of Old Sheep

“…Fisetin enhanced phosphorylation and nuclear translocation of Nrf2, which subsequently activated antioxidant enzyme heme oxygenase-1 (HO-1) in retinal pigment epithelium (RPE) cells, contributing to the amelioration of oxidative stress-induced ocular disorders [15]. A similar effect was observed in C2C12 myoblasts cells [16].…”