br Flavonoid function Antioxidants are compounds when

Flavonoid function Antioxidants are compounds - when present at a lower concentration compared oxidizable substrate - that delay or prevent oxidation of the substrate [14], [106]. Antioxidants act as nucleophiles to reduce an oxidative molecule to prevent its interaction with another molecule [14], [107]. Endogenous antioxidants produced by the body function in prevention and neutralization of ROS and free radicals, repair of damaged macromolecules, and redox signaling [14]. Exogenous antioxidants consumed through food and drink also play an important role in cellular defense and survival, and have shown to aid the body in combating oxidative stress and inflammation [108], [109] Flavonoids are secondary plant metabolites commonly found in fruits and vegetables [25]. Flavonoids are a family of polyphenol antioxidants that are effective in combating high levels of OS [10], [14]. Flavonoids are distinguished by the presence of multiple phenol rings, C to C double bonds, and hydroxyl groups [26]. These structural characteristics confer the antioxidant function of flavonoids, and the number and location of hydroxyl groups influence the biological activity of the flavonoids [110], [106]. The lipophilicity is also influenced by structure, which allows some flavonoids to favorably pass through the blood DTP3 australia barrier [111], [112], [113], [114] The hydroxyl groups are critical for antioxidant activity, and scavenge free radicals and ROS by donation of a proton [114]. This class of antioxidant molecules possesses several distinct mechanisms of protection from oxidative stress. Flavonoids can directly scavenge and neutralize ROS and free radicals, increase intracellular GSH, prevent glutamate mediated Ca+2 influx, and modulation of signaling pathways involved in cellular survival [4], [25], [26] Directly neutralizing ROS prevents the oxidation of proteins, amino acids, lipids, metal ions, and other macromolecules. Oxidative modification irreversibly changes structure and prevents normal function of macromolecules. The presences of flavonoids are able to protect these molecules from MG mediated modification into AGEs. Glutathione is a major constituent of the glyoxalase pathway, and one of the most important endogenous antioxidants for neutralization of dicarbonyl compounds and maintaining redox balance in cells [26]. Flavonoid treatment was found to increase GSH concentration, and increased mRNA transcript levels of both GSH constituent subunits [4], [26]. GSH is also an essential substrate of astrocytic detoxification in the brain [47]. GSH is also critical for prevention of glutamate mediated apoptosis [115]. Elevated levels of glutamate are cytotoxic, and lead to apoptosis via influx of Ca+2. Excess glutamate depletes GSH, leading to a decrease in activity of glo 1 [25]. Flavonoids have shown to reduce intracellular Ca+2 influx in the presence of toxic levels of glutamate [25]. Flavonoid molecules can regulate signaling pathways to modulate cellular, immune, and metabolic processes [4]. Flavonoids are able to modulate a variety of pathways including NF-κB, MAPK, ERK, and Nrf2 [116], [117] Flavonoid molecules can modulate and reduce expression of proapoptotic and proinflammatory products of genes [118], [119]. ROS are used as signaling molecules during immune responses, and the presence of antioxidants can prevent ROS mediated phosphorylation of molecules and pathway targets, preventing their activation and transcription [109]. Flavonoids can also inhibit activation of kinases and phosphatases that would contribute to apoptotic cell death [120], [121]4]. After a flavonoid is oxidized by a free radical, the resulting quinones are involved in signaling pathways involved in cellular antioxidant and repair activities (Fig. 3). Flavonoids can have a direct impact [122] and influence on the function of the gyloxalase pathway. Flavonoids can bind and scavenge free radicals, and also increase the intracellular levels of GSH, while flavonoids are able to scavenge free radicals, in physiological concentrations they are not effectively able to scavenge free radicals [25]. The most effective form of neuroprotection by flavonoids is preventing formation of free radicals by modulation of cell signaling pathways [109], [123], [124]. Flavonoid antioxidant treatment can lower the intracellular levels of free radicals and ROS, and also enhance the performance of the glyoxalase system by modulating signaling pathways involved in cellular proliferation and survival, glutathione synthesis and expression of antioxidative proteins [4], [10], [14], [25], [121]