ly reported mediator of those indirect antioxidant actions could be the redox-sensitive transcription protein, nuclear factor (erythroid-derived two)-like two (Nrf2), that regulates the expression of a big number of genes that include an enhancer sequence in their promoter regulatory regions termed antioxidant response components (AREs), or possibly a lot more accurately named, electrophile-response components (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 mAChR2 list targets Nrf2 for fast ubiquitination and proteasomal degradation, resulting inside a limited cytoplasmatic concentration of Nrf2 [138,139]. Keap1 consists of, on the other hand, various highly 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 number of the crucial cysteines in Keap1 can be directly oxidized or covalently modified, the Nrf2 eap1 pathway can also be modulated by the transcriptional modification of Nrf2, especially by means of phosphorylation by a series of redox-sensitive protein kinases including the extracellular signal-regulated protein ERĪ² Formulation kinase (ERK1/2), protein kinase C (PKC) and c-Jun N-terminal kinase (JNK) [140,141]. Following its translocation into the nucleus, Nrf2 undergoes dimerization with little musculoaponeurotic fibrosarcoma oncogene homologue (sMAF) proteins. The heterodimers hence formed induce the de novo synthesis of various proteins which are encoded in the ARE/EpRE-containing genes. The activation of your Nrf2-dependent ARE/EpRE signaling pathway translates into growing 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 through phase II biotransformation enzymes (e.g., glutathione S-transferases, UDP-glucuronosyltransferases) [149]. Even though beneath normal conditions the Nrf2 eap1 pathway plays an essential role in preserving the intracellular redox homeostasis, substantial proof indicates that its activation by specific ROS and/or by a sizable variety of electrophiles is pivotal to defend cells from the detrimental effects associated with the intracellular accumulation of those species [15052]. An early Nrf2 activation by low concentrations of particular ROS and/or electrophiles would defend cells not merely by preventing them undergoing the otherwise redox-imbalance (oxidative strain) anticipated to arise from a sustained accumulation of ROS, but additionally by stopping 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 require a lag time to manifest but are comparatively longer lasting considering that their duration is essentially defined by the half-lives of de novo synthesized antioxidant enzymes. Furthermore, due to 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 your direct acting flavonoids whose antioxidant effects are limited by their stoichiometric oxidative consumption. Cumu
