FOXO3a Activation by oxyresveratrol of Morus bombycis koidzumi extract mediates antioxidant activity

Although Morus bombycis koidzumi (MB) extract has been reported to have antioxidant activity, the mechanism underlying its antioxidant activity has not been elucidated. In this report, we showed that FOXO3a was activated by MB extract. FOXO3a is a transcription factor that is involved in various biological functions such as cell cycle control, apoptosis, DNA repair, and reactive oxygen species (ROS) detoxification. Protein levels of FOXO3a and MnSOD, target gene of FOXO3a were increased by the MB extract. The ROS level was decreased by the MB extract in human embryonic fibroblast (HEF) cells. Among components of the MB extract, oxyresveratrol (2,4,3,5-tetrahydroxystilbene) was identified and turned out to activate FOXO3a. The protein level of FOXO3a was increased by oxyresveratrol. Promoter activities of target genes of FOXO3a such as MnSOD, p27, and GADD45 were activated by oxyresveratrol. The ROS level was decreased by oxyresveratrol in HEF cells in a dose-dependent manner. However, the ROS level was elevated in HEF cells when FOXO3a was knocked down by si-FOXO3a, while overexpression of wt-FOXO3a decreased the cellular ROS level, indicating that antioxidant activity by oxyresveratrol is FOXO3a-dependent. These results indicate that oxyresveratrol of MB extract mediates an antioxidant activity through upregulation of MnSOD by FOXO3a activation.