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Mitochondrially derived ROS may also result in feedforward regulation of ROS production by induction of NADPH oxidase and XO activities. This mechanism may account for the profound protection against CIHL achieved by inhibition of NOX, an NADPH oxidase intrinsic to the cochlea. Finally, iron chelators reduce CIHL further suggesting the relevance of this condition for chronic neurodegenerative disorders. This complex interplay between ROS generation by mitochondria, NADPH oxidases, and XO as well as proinammatory signaling suggests that cisplatin triggers a series of vicious cycles that might best be controlled by simultaneously targeting multiple processes.However, combining drugs optimized for the potent inhibition of distinct cellular processes increases the risk of unacceptable side effects, especially in elderly patients who frequently take several medications.The question thus becomes: how can multiple disease mechanisms implicated in CIHL and other neurodegenerative disorders be effectively targeted in a safe manner?The primary dietary sources of these compounds are fruits, vegetables, and teas.Prospective trials have shown that habitual intake of dietary avonoids reduces the risk of dementia. These positive effects have been attributed to free radical scavenging, transition metal chelation, activation of survival genes and signaling pathways, regulation of mitochondrial function, and modulation of neuroinammation. To account for such diverse activities, it has been proposed that, when consumed in combination as part of a avonoidenriched diet, avonoids belonging to different chemical classes interact with distinct targets enabling them to exert cooperative actions. In this way, avonoid mixtures that target complementary molecular processes may promote synergistic interactions allowing use of the lowest possible amount of each compound and thereby reducing the risk of adverse side effects.Another attractive feature of this approach is that these compounds are well tolerated and may be consumed safely in high amounts.These qualities have led many investigators to propose that avonoidenriched extracts from natural sources should be given strong consideration as novel therapies for the treatment of neurodegenerative disorders.Following ingestion of Flunixin meglumin quercetin or epicatechin by humans reaches the circulation in the unaltered form, resulting in peak plasma concentrations in the low nanomolar range. This is because these avonoids are extensively transformed by phase II enzymes in the gut and liver to conjugated metabolites that reach much higher plasma concentrations. Compared with the agylcone, quercetin glycosides found in dietary sources are better absorbed, generating plasma concentrations of quercetin and its metabolites several times higher than achieved after ingestion of the aglycone. The higher bioavailability of quercetin glycosides probably resides in deglycosylation processes at the intestinal level andor carriermediated transport. Catechin and epicatechin are transported across the intestinal brush border by carriermediated Piperonyl butoxide facilitated diffusion. Flavonoids are transformed in the small intestine and liver by phase II enzymes into sulfonated, methylated, and glucuronidated metabolites. Flavonoids are also transformed by colonic microora into smaller phenolic acids, such as benzoic and hippuric acids, with various biological activities. As discussed below, one explanation for this paradox is that metabolic transformation of these avonoids generates metabolites with unique pharmacological properties.However, another explanation is that the agylcone is regenerated from glucuronidated metabolites by the action of bglucuronidase in the appropriate target tissues.

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