Nrf2-Keap1 signaling in oxidative and reductive stress

Abstract

Nrf2 and its endogenous inhibitor, Keap1, function as a ubiquitous, evolutionarily conserved intracellular defense mechanism to counteract oxidative stress. Sequestered by cytoplasmic Keap1 and targeted to proteasomal degradation in basal conditions, in case of oxidative stress Nrf2 detaches from Keap1 and translocates to the nucleus, where it heterodimerizes with one of the small Maf proteins. The heterodimers recognize the AREs, that are enhancer sequences present in the regulatory regions of Nrf2 target genes, essential for the recruitment of key factors for transcription. In the present review we briefly introduce the Nrf2-Keap1 system and describe Nrf2 functions, illustrate the Nrf2-NF-κB cross-talk, and highlight the effects of the Nrf2-Keap1 system in the physiology and pathophysiology of striated muscle tissue taking into account its role(s) in oxidative stress and reductive stress.

Itaconate: an emerging determinant of inflammation in activated macrophages

“…Under quiescent conditions, Nrf2 is sequestered by Kelch‐like ECH‐associated protein 1 (Keap1) in the cytoplasm for proteasomal degradation. Upon exposure to endogenous or environmental stimuli, Nrf2 is dissociated from Keap1 and then translocated to the nucleus to trigger an anti‐inflammatory program . The alkylation is an important form of protein modification.…”

Nrf2 promotes breast cancer cell migration via up‐regulation of G6PD/HIF‐1α/Notch1 axis

“…7 The stabilized Nrf2 accumulates in nuclei, heterodimerizes with small Maf proteins and activates target genes for cytoprotection through the antioxidant response element (ARE)/electrophile response element (EpRE). 7 The stabilized Nrf2 accumulates in nuclei, heterodimerizes with small Maf proteins and activates target genes for cytoprotection through the antioxidant response element (ARE)/electrophile response element (EpRE).…”

Cellular and molecular mechanisms of sarcopenia: the S100B perspective

“…A minority of proliferating myoblasts return to a state of quiescence to replenish the SC reserve pool. 42 Defective activity or abundance of Nrf2, an antioxidant factor playing a fundamental role in the maintenance of intracellular redox homeostasis, characterizes the aging muscle tissue (reviewed by Bellezza et al 43 ), an event counteracted by a regular exercise that attenuates the age-related changes in Nrf2-mediated pathways and potentially restores the redox homeostasis 28,[44][45][46] (Figure 2). Pericytes and IL-4-activated FAPs also participate in the regeneration process.…”

“…Yet the finding that downregulation of S100B partly restored their proliferation and differentiation capability 135 suggests that at elevated levels, S100B contributes to myoblast senescence. Given the reported NF-κB/ Nrf2 interplay whereby excess NF-κB activity leads to reduced Nrf2 activity, 43 it is possible that up-regulated S100B in myoblasts from sarcopenic subjects reduces Nrf2 levels and/or activity through its stimulatory effect on NF-κB, thereby fostering oxidative stress. Given the reported NF-κB/ Nrf2 interplay whereby excess NF-κB activity leads to reduced Nrf2 activity, 43 it is possible that up-regulated S100B in myoblasts from sarcopenic subjects reduces Nrf2 levels and/or activity through its stimulatory effect on NF-κB, thereby fostering oxidative stress.…”