The genus Gnetum: Traditional use, phytochemistry, nutritional value, biosynthesis, synthesis, pharmacology, toxicology, synthetic advance, and pharmacokinetics.

Background: Gnetum is the sole genus within the family Gnetaceae. Numerous species are edible, their seeds can be roasted, and the leaves can be consumed as vegetables. Gnetum plants have been highly esteemed in traditional folk medicine worldwide for many years. An extensive review highlighting the significant value of this genus is currently unavailable.

Objective: This study aims to systematically present the state of the art in phytochemistry, food chemistry, biosynthesis, synthesis, pharmacology, toxicology, synthetic advance, and pharmacokinetics.

Method: The relevant references were collected from various electronic sources, including Google Scholar, Web of Science, and reputable journals. "Gnetum" was the primary keyword used to search for publications. Data collection was conducted from 1978 to now, and more than 150 articles have been reviewed.

Results: Among the 261 identified phytochemicals, 180 compounds were elucidated as stilbenoids. Gnetum metabolites also contained other classes, such as lignans, flavonoids, monophenols, alkaloids, and fatty acids. The major compound, isorhapontigenin, is considered the most important agent in the genus Gnetum. It is also noted that Gnetum plants are rich in nutritional content, including fibers, carbohydrates, vitamins, essential amino acids, and minerals. Gnetum plant extracts are safe, with low toxicity levels. In general, oxidative reactions among radicals are responsible for the biosynthesis of Gnetum stilbenoids, whereas glucuronidation of hydroxyl groups is the main pharmacokinetic action. Pharmacological activities of Gnetum constituents have been reported to include anticancer, antioxidative, anti-inflammatory, antimicrobial, antidiabetic, antihyperuricemic, anti-obesity, antimalarial, antiviral, antiplatelet, estrogenic, and protective actions for various organs. Various in vitro and in vivo pharmacological assays have successfully explained these activities through molecular mechanisms, such as the MAPK (mitogen-activated protein kinase) or NF-κB (nuclear factor-kappa B) signaling pathways.

Conclusion: Further pharmacological assessments are warranted, particularly focusing on minor and newly discovered compounds. Enhancements in bioavailability and the development of novel synthetic agents derived from Gnetum are anticipated.