The therapeutic potential of polyphenols for targeting methylglyoxal and the associated glycation pathways: A review

• Methylglyoxal, major dicarbonyl implicated in glycation and associated diseases. • Natural response: detoxification via the glyoxalase pathway • Polyphenols as alternative or supplements (functional foods) for antiglycation through methylglyoxal trapping or scavenging • Mechanisms and efficacy of different polyphenols in methylglyoxal scavenging and/or trapping Methylglyoxal (MGO) is a highly reactive α-dicarbonyl compound and a major reactive carbonyl species (RCS), implicated in glycation and associated diseases. MGO readily reacts with protein nucleophilic sites, leading to the formation of advanced glycation end products (AGEs), that activate pro-inflammatory signalling pathways, induce oxidative stress, causing cellular dysfunction leading to cell death. Although endogenous detoxification systems, such as the glyoxalase pathway and aldehyde dehydrogenase, play a key role in neutralising MGO, under pathological conditions, these mechanisms are often not sufficient. The synthetic AGE inhibitor, aminoguanidine, effectively reduces MGO and AGE accumulation but due to safety concerns further clinical studies were terminated. Consequently, polyphenols have emerged as promising alternatives due to their safety profile and ability to trap MGO; up- and down-regulate associated antioxidant and inflammatory respectively. This review provides evidence-based insights on the trapping potential of polyphenols, effectively reduce the effects of MGO, and includes the mechanisms of interaction and the associated pathways. The MGO-trapping and pathway regulation by polyphenols is a novel and possibly an effective approach to prevent or reduce RCS-induced adverse effects thereby promoting metabolic health.