ly reported mediator of those indirect antioxidant actions is definitely the redox-sensitive transcription protein, nuclear issue (erythroid-derived 2)-like 2 (Nrf2), that regulates the expression of a large quantity of genes that contain an enhancer sequence in their promoter regulatory regions termed antioxidant response elements (AREs), or almost certainly additional accurately named, electrophile-response elements (EpRE) [67,136,137]. The regulation from the Nrf2 pathway is mainly mediated by the interaction involving Nrf2 and its cytoplasmic repressor Kelch-like ECH-associated protein 1 (Keap1), an E3 ubiquitin ligase substrateAntioxidants 2022, 11,9 ofadaptor that below physiological or unstressed situations targets Nrf2 for speedy ubiquitination and proteasomal degradation, resulting in a restricted cytoplasmatic concentration of Nrf2 [138,139]. Keap1 contains, however, several very reactive cysteine residues that, upon undergoing conformational modification, facilitate the swift translocation of Nrf2 into the nucleus (i.e., Nrf2-Keap1 activation). Even though some of the vital cysteines in Keap1 could be straight oxidized or covalently modified, the Nrf2 eap1 pathway may also be modulated by the transcriptional modification of Nrf2, specifically through phosphorylation by a series of redox-sensitive protein kinases for example the extracellular signal-regulated protein kinase (ERK1/2), protein kinase C (PKC) and c-Jun N-terminal kinase (JNK) [140,141]. Following its translocation in to the nucleus, Nrf2 undergoes dimerization with small musculoaponeurotic fibrosarcoma oncogene homologue (sMAF) proteins. The heterodimers therefore formed induce the de novo synthesis of a range of proteins which can be encoded inside the ARE/EpRE-containing genes. The activation from the Nrf2-dependent ARE/EpRE signaling pathway translates into increasing the cells’ enzymatic (e.g., SOD, CAT, GSHpx, NQO1, HO-1) and non-enzymatic (e.g., GSH) antioxidant capacity [14248] and/or its capacity to conjugate a broad array of electrophiles through phase II biotransformation enzymes (e.g., glutathione S-transferases, UDP-glucuronosyltransferases) [149]. Even though beneath standard conditions the Nrf2 eap1 pathway plays an necessary function in preserving the intracellular redox homeostasis, Caspase 11 Accession substantial proof indicates that its activation by particular ROS and/or by a sizable number of electrophiles is pivotal to shield cells from the detrimental effects linked with the intracellular accumulation of these species [15052]. An early Nrf2 activation by low concentrations of particular ROS and/or electrophiles would safeguard cells not merely by preventing them undergoing the D5 Receptor Source otherwise redox-imbalance (oxidative strain) expected to arise from a sustained accumulation of ROS, but also by stopping the covalent binding of electrophiles to DNA and particular proteins whose regular functioning is very important to cells. In comparison to the antioxidant effects that arise in the ROS-scavenging/reducing actions of flavonoids, these resulting in the activation of Nrf2 need a lag time for you to manifest but are comparatively longer lasting since their duration is essentially defined by the half-lives of de novo synthesized antioxidant enzymes. Moreover, resulting from the catalytic character of any enzyme, the antioxidant effects of flavonoids exerted via this indirect mechanism are amplified and manifested beyond the time-restricted action on the direct acting flavonoids whose antioxidant effects are restricted by their stoichiometric oxidative consumption. Cumu
