er was evidenced not only by testing the CDK3 Formulation antioxidant activity of Q-BZF, chromatographically

er was evidenced not only by testing the CDK3 Formulation 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 reduced than that of quercetin [57]. To the best of our knowledge, there are no reports in the literature of any flavonoid or flavonoid-derived molecule capable of acting as antioxidant inside cells at such exceptionally low concentrations. The possibility that such a difference in intracellular antioxidant potency becoming explained with regards to a 200-fold distinction in ROS-scavenging capacity is very low since; in GlyT1 Species addition to lacking the double bond present in ring C of quercetin, Q-BZF will not differ from quercetin when it comes to the quantity and position of their phenolic hydroxyl groups. Thinking about the really low concentration of Q-BZF needed to afford protection against the oxidative and lytic harm induced by hydrogen peroxide or by indomethacin to Hs68 and Caco-2 cells, Fuentes et al. [57] proposed that such effects of Q-BZF might be exerted via Nrf2 activation. With regards to the potential in the Q-BZF molecule to activate Nrf2, several chalcones have already been shown to act as potent Nrf2 activators [219,220]. The electrophilic carbonyl groups of chalcones, like these within the two,three,4-chalcan-trione intermediate of Q-BZF formation (Figure 2), may be able to oxidatively interact together 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]. Contemplating the fact that the concentration of Q-BZF needed to afford antioxidant protection is no less than 200-fold reduce than that of quercetin, and that Q-BZF may be generated for the duration of the interaction in between quercetin and ROS [135,208], a single could speculate that if such a reaction took location inside ROS-exposed cells, only one out of 200 hundred molecules of quercetin would be required to become converted into Q-BZF to account for the protection afforded by this flavonoid–though the occurrence with the latter reaction in mammalian cells remains to be established.Antioxidants 2022, 11,14 ofInterestingly, as well as quercetin, numerous other structurally connected flavonoids happen to be 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 with the 2-(benzoyl)-2-hydroxy-3(2H)benzofuranone derivatives (BZF) corresponding to every in the six previously talked about flavonoids demands that a quinone methide intermediate be formed, follows a pathway comparable to that in the Q-BZF (Figure 2), and leads to the formation of a series of BZF Antioxidants 2022, 11, x FOR PEER Review 15 of 29 exactly where only the C-ring from the parent flavonoid is changed [203,225]. From a structural requirement point of view, the formation of such BZF is limited to flavonols and appears to need, in addition to a hydroxy substituent in C3, a double bond inside the C2 3 in addition to a carbonyl group in C4 C4 (i.e., simple functions of of any flavonol), flavonol possesses at along with a carbonyl group in(i.e.,