Polyphenol-based modulation of the Glo1–Nrf2–RAGE axis in diabetes and neurodegeneration: mechanistic evidence, translational constraints, and critical appraisal

Abstract

The key pathological mechanisms in diabetes and neurodegeneration generally involve a progressive accumulation of reactive carbonyl species (RCS), accompanied by increased oxidative stress and the accumulation of inflammatory mediators. Thus, a clear understanding of the Glo1–Nrf2–RAGE axis is crucial as it plays a key role in redox imbalance, regulation of cell responses to methylglyoxal (MG)-induced glycation, and chronic inflammation. Even though glyoxalase I (Glo1) detoxifies MG to mitigate advanced glycation end product (AGE) formation, the transcription of antioxidant enzymes by nuclear factor erythroid 2–related factor 2 (Nrf2) is reactivated. Conversely, persistent activation of the receptor for AGE (RAGE) further amplifies inflammatory cascades and tissue damage. A continuous dysregulation of “this axis” can contribute to the pathogenesis of several complications, including diabetes and neurodegeneration. Nevertheless, polyphenols have emerged as nutraceutical candidates that may modulate the Glo1–Nrf2–RAGE axis due to their specialized structural features. Key polyphenols, such as quercetin, resveratrol, curcumin, epigallocatechin gallate, luteolin, and apigenin, enhance Glo1 expression and activity, promote Nrf2 nuclear translocation via Keap1 modification, and lower RAGE expression and ligand binding. However, numerous challenges, such as limited bioavailability, metabolic instability, and “interindividual variability,” hinder their clinical translation. We have tried to fill the research gap by combining recent evidence from preclinical, clinical, and molecular studies, with the aim of highlighting the pleiotropic effects of these metabolites. In addition, the molecular effects of polyphenolics with reference to modulation of mitochondrial function, regulation of epigenetic mechanisms, and interactions with the gut–brain axis are detailed.