ly reported mediator of these indirect antioxidant actions is the redox-sensitive transcription protein, nuclear issue (erythroid-derived 2)-like 2 (Nrf2), that regulates the expression of a big number of genes that include an enhancer sequence in their promoter MCT4 Purity & Documentation regulatory regions termed antioxidant response components (AREs), or possibly extra accurately named, electrophile-response components (EpRE) [67,136,137]. The regulation from the Nrf2 pathway is primarily mediated by the interaction amongst Nrf2 and its cytoplasmic repressor Kelch-like ECH-associated protein 1 (Keap1), an E3 ubiquitin ligase substrateAntioxidants 2022, 11,9 ofadaptor that beneath physiological or unstressed conditions targets Nrf2 for speedy ubiquitination and proteasomal degradation, resulting inside a restricted cytoplasmatic concentration of Nrf2 [138,139]. Keap1 contains, even so, quite a few hugely reactive cysteine residues that, upon undergoing conformational modification, facilitate the swift translocation of Nrf2 in to the nucleus (i.e., Nrf2-Keap1 activation). Even though a few of the crucial cysteines in Keap1 could be directly oxidized or covalently modified, the Nrf2 eap1 pathway can also be modulated by the transcriptional modification of Nrf2, particularly via 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 compact musculoaponeurotic fibrosarcoma oncogene homologue (sMAF) proteins. The heterodimers therefore formed induce the de novo synthesis of many different proteins which can be encoded in the ARE/EpRE-containing genes. The activation with 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 CB1 review enzymes (e.g., glutathione S-transferases, UDP-glucuronosyltransferases) [149]. Even though under typical conditions the Nrf2 eap1 pathway plays an important function in keeping the intracellular redox homeostasis, substantial evidence indicates that its activation by particular ROS and/or by a large variety of electrophiles is pivotal to safeguard cells in the detrimental effects linked using the intracellular accumulation of these species [15052]. An early Nrf2 activation by low concentrations of particular ROS and/or electrophiles would protect cells not only by stopping them undergoing the otherwise redox-imbalance (oxidative stress) expected to arise from a sustained accumulation of ROS, but also by stopping the covalent binding of electrophiles to DNA and particular proteins whose normal functioning is essential to cells. When compared with the antioxidant effects that arise in the ROS-scavenging/reducing actions of flavonoids, these resulting in the activation of Nrf2 require a lag time for you to manifest but are comparatively longer lasting considering the fact that their duration is primarily defined by the half-lives of de novo synthesized antioxidant enzymes. On top of that, as a result of 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 with the direct acting flavonoids whose antioxidant effects are restricted by their stoichiometric oxidative consumption. Cumu
