Melinjo (Gnetum gnemon L.) seed extract (MSE) containing trans-resveratrol (3,5,4′-trihydroxy-trans-stilbene) and other derivatives exerts various beneficial effects. However, its mechanism of action in humans remains unknown. In this study, we aimed to investigate beneficial effects of MSE in healthy adult males. In this double-blind, randomized controlled study, 30 males aged 35–70 years with ≤10% flow-mediated dilatation received placebo or 750？mg MSE powder for 8 weeks, and twenty-nine males ( years old) completed the trial. There was a significant difference in the melinjo and placebo groups. Compared with the placebo control, MSE significantly reduced serum uric acid at 4 weeks and 8 weeks ( and 15, resp.). HDL cholesterol was significantly increased in the melinjo group. To clarify the mechanism of MSE for reducing uric acid, we investigated xanthine oxidase inhibitory activity, angiotensin II type 1 (AT1) receptor binding inhibition rate, and agonistic activities for PPARα and PPARγ. MSE, trans-resveratrol, and a resveratrol dimer, gnetin C (GC), significantly inhibit AT1 receptor binding and exhibit mild agonistic activities for PPARα and PPARγ. In conclusion, MSE may decrease serum uric acid regardless of insulin resistance and may improve lipid metabolism by increasing HDL cholesterol. 1. Introduction Melinjo (Gnetum gnemon L.) belongs to the family Gnetaceae, native to Indonesia. The tree is small to medium in size, 15–20？m tall, with evergreen leaves. The fruit-like strobilus consists of little skin and a large nut-like seed that is 2–4？cm long inside, with both the fruits and leaves being very popular in Indonesian cuisines. Kato et al. found that melinjo seed extract (MSE) contains various stilbenoids including trans-resveratrol (3,5,4′-trihydroxy-trans-stilbene), gnetin C (GC; resveratrol dimer), gnetin L (GC derivative), gnemonoside A (GC-diglucoside), gnemonoside C (GC-monoglucoside), and gnemonoside D (GC-monoglucoside) . These derivatives are collectively referred to as “Melinjo resveratrol.” Recently, trans-resveratrol has attracted considerable attention because it extended the lifespan of mice that were fed a high-calorie diet . Moreover, human studies indicated that trans-resveratrol is beneficial in the management of diabetes  and cardiovascular diseases . However, several in vitro studies on the resveratrol derivatives in MSE revealed its nutraceutical effects such as the inhibition of lipase and amylase, antibacterial properties , inhibition of angiogenesis , and immunostimulatory effects . In mice, MSE
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