trans-Resveratrol in Gnetum gnemon Protects against Oxidative-Stress-Induced Endothelial Senescence

Gnetum gnemon is an arboreal dioecious plant that is cultivated in Indonesia. The seeds of this species mainly contain dimeric stilbenoid compounds [gnetin C (1), gnemonoside A (2), and gnemonoside D (3)] along with trans-resveratrol (4). trans-Resveratrol has been reported to have antiaging, anticancer, and antidiabetic effects, as well as being a calorie restriction mimetic. SIRT1 exerts a protective effect against vascular senescence. In this study, the effects of these four main stilbenoid derivatives of a G. gnemon seed endosperm ethanolic extract on endothelial senescence were investigated. In streptozotocin-induced diabetic mice, administration of the G. gnemon ethanolic extract increased SIRT1 and decreased endothelial senescence. The concentration of 1 in blood plasma was 6-fold higher than 4 in these mice. Next, the in vitro effects of the four main stilbenoid derivatives of G. gnemon seeds were investigated. Senescent human umbilical vein endothelial cells were induced by hydrogen peroxide. Endothelial senescence was inhibited by 4, which increased the expression of endothelial nitric oxide synthase and SIRT1, whereas 1-3 had no effect. These results indicated that the ethanolic extract of G. gnemon seeds inhibits endothelial senescence, suggesting that 4 plays a critical role in the prevention of endothelial senescence.