er was evidenced not just by testing the antioxidant activity of Q-BZF, chromatographically isolated from Qox, but also, soon after comparing the activity of Qox with that of a Qox preparation from which Q-BZF was experimentally removed by chemical subtraction. Remarkably, the antioxidant protection afforded by the isolated Q-BZF was observed at a 50 nM concentration, namely at a concentration 200-fold lower than that of quercetin [57]. To the very best of our information, there are actually no reports inside the literature of any flavonoid or flavonoid-derived molecule capable of acting as antioxidant CYP26 Gene ID within cells at such incredibly low concentrations. The possibility that such a difference in intracellular antioxidant potency being explained when it comes to a 200-fold distinction in ROS-scavenging capacity is really low since; in addition to lacking the double bond present in ring C of quercetin, Q-BZF does not differ from quercetin in terms of the number and position of their phenolic hydroxyl groups. Thinking of the exceptionally low concentration of Q-BZF needed to afford protection against the oxidative and lytic damage induced by hydrogen peroxide or by indomethacin to Hs68 and Caco-2 cells, Fuentes et al. [57] proposed that such effects of Q-BZF may very well be exerted by means of Nrf2 activation. Regarding the potential of the Q-BZF molecule to activate Nrf2, quite a few chalcones have already been shown to act as HD2 supplier potent Nrf2 activators [219,220]. The electrophilic carbonyl groups of chalcones, like these within the 2,three,4-chalcan-trione intermediate of Q-BZF formation (Figure 2), could be capable to oxidatively interact with the cysteinyl residues present in Keap1, the regulatory sensor of Nrf2. Interestingly, an upregulation of this pathway has already been established for quercetin [14345]. Considering the fact that the concentration of Q-BZF necessary to afford antioxidant protection is no less than 200-fold reduce than that of quercetin, and that Q-BZF might be generated for the duration of the interaction in between quercetin and ROS [135,208], a single may speculate that if such a reaction took spot within ROS-exposed cells, only 1 out of 200 hundred molecules of quercetin would be needed to become converted into Q-BZF to account for the protection afforded by this flavonoid–though the occurrence from the latter reaction in mammalian cells remains to be established.Antioxidants 2022, 11,14 ofInterestingly, as well as quercetin, numerous other structurally associated flavonoids have already been reported to undergo chemical and/or electrochemical oxidation that results in the formation of metabolites with structures comparable to that of Q-BZF. Examples of your latter flavonoids are kaempferol [203,221], morin and myricetin [221], fisetin [22124], rhamnazin [225] and rhamnetin [226] (Figure 3). The formation from the 2-(benzoyl)-2-hydroxy-3(2H)benzofuranone derivatives (BZF) corresponding to each and every on the six previously described flavonoids demands that a quinone methide intermediate be formed, follows a pathway comparable to that of your Q-BZF (Figure 2), and results in the formation of a series of BZF Antioxidants 2022, 11, x FOR PEER Evaluation 15 of 29 exactly where only the C-ring of your parent flavonoid is changed [203,225]. From a structural requirement perspective, the formation of such BZF is restricted to flavonols and appears to need, along with a hydroxy substituent in C3, a double bond in the C2 3 and a carbonyl group in C4 C4 (i.e., basic features of of any flavonol), flavonol possesses at and also a carbonyl group in(i.e.,
