ly reported mediator of those indirect antioxidant actions is the redox-sensitive transcription protein, nuclear issue (erythroid-derived two)-like two (Nrf2), that regulates the expression of a large number of genes that contain an enhancer sequence in their promoter regulatory regions termed antioxidant response components (AREs), or almost certainly a lot more accurately named, electrophile-response elements (EpRE) [67,136,137]. The regulation on the Nrf2 pathway is mostly 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 circumstances targets Nrf2 for fast ubiquitination and proteasomal degradation, resulting within a restricted cytoplasmatic concentration of Nrf2 [138,139]. Keap1 contains, even so, quite a few extremely reactive cysteine residues that, upon undergoing conformational modification, facilitate the swift translocation of Nrf2 in to the nucleus (i.e., Nrf2-Keap1 activation). Though a few of the important cysteines in Keap1 can be directly oxidized or covalently modified, the Nrf2 eap1 pathway can also be modulated by the transcriptional modification of Nrf2, particularly by means of phosphorylation by a series of redox-sensitive protein kinases for instance 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 tiny musculoaponeurotic fibrosarcoma oncogene homologue (sMAF) proteins. The heterodimers hence formed induce the de novo synthesis of a range of proteins that are encoded in the ARE/EpRE-containing genes. The activation of the Nrf2-dependent ARE/EpRE signaling pathway CDK14 Species 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 selection of electrophiles by means of phase II biotransformation enzymes (e.g., glutathione S-transferases, UDP-glucuronosyltransferases) [149]. Despite the fact that under standard conditions the Nrf2 eap1 pathway plays an crucial part in maintaining the intracellular redox homeostasis, substantial evidence indicates that its activation by particular ROS and/or by a big number of electrophiles is ALK7 manufacturer pivotal to guard cells in the detrimental effects associated with all the intracellular accumulation of those species [15052]. An early Nrf2 activation by low concentrations of certain ROS and/or electrophiles would defend cells not only by stopping them undergoing the otherwise redox-imbalance (oxidative strain) expected to arise from a sustained accumulation of ROS, but in addition by preventing the covalent binding of electrophiles to DNA and certain proteins whose regular functioning is important to cells. When compared with the antioxidant effects that arise from 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 considering the fact that their duration is essentially defined by the half-lives of de novo synthesized antioxidant enzymes. Also, as a result of the catalytic character of any enzyme, the antioxidant effects of flavonoids exerted through this indirect mechanism are amplified and manifested beyond the time-restricted action of the direct acting flavonoids whose antioxidant effects are restricted by their stoichiometric oxidative consumption. Cumu
