Oxidative stress response and Nrf2 signaling in aging

Zhang, Hongqiao; Davies, Kelvin J.A.; Forman, Henry Jay

doi:10.1016/j.freeradbiomed.2015.05.036

Cited by 679 publications

(556 citation statements)

References 405 publications

(447 reference statements)

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“…By analyzing the nuclear proteins, we showed that OI-stabilized Nrf2 translocated to cell nuclei (Fig. 1C), which is a key step for Nrf2 activation [10,33]. Indeed, we showed that mRNA (Fig.…”

Section: Oi Activated Nrf2 Signaling In Thp-1 Cells and Sle Patient-dmentioning

confidence: 89%

4-Octyl Itaconate Activates Nrf2 Signaling to Inhibit Pro-Inflammatory Cytokine Production in Peripheral Blood Mononuclear Cells of Systemic Lupus Erythematosus Patients

Tang¹,

Wang²,

Xie³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Increased production of multiple pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, plays an essential pathogenic role in the progression of systemic lupus erythematosus (SLE). Recent studies have characterized itaconate as a novel and potent nuclear-factor-E2-related factor 2 (Nrf2) activator that activates Nrf2 signaling by alkylating cysteine residues on Keap1 (Kelch-like ECH-associated protein 1). Methods: THP-1 human macrophages and peripheral blood mononuclear cells (PBMCs) of SLE patients were treated with 4-octyl itaconate (OI). Nrf2 signaling activation was tested by qPCR assay and western blotting. mRNA expression and the production of multiple pro-inflammatory cytokines were tested by qPCR and enzyme-linked immunosorbent assays, respectively. Nuclear factor (NF)-κB activation was tested by the p65 DNA-binding assay. Results: We demonstrated that OI, the cell-permeable derivative of itaconate, induced Keap1-Nrf2 dissociation, Nrf2 protein accumulation, and nuclear translocation, which enabled the transcription and expression of multiple Nrf2-dependentantioxidant enzymes (heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1, and glutamate-cysteine ligase modifier subunit) in THP-1 human macrophages. OI also induced significant Nrf2 activation in SLE patient-derived PBMCs. OI pretreatment inhibited mRNA expression and the production of multiple pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in SLE patient-derived PBMCs and lipopolysaccharide (LPS)-activated THP-1 cells. OI potently inhibited NF-κB activation in SLE patient-derived PBMCs and LPS-activated THP-1 cells. Importantly, Nrf2 silencing (by targeted short hairpin RNA) or knockout (by CRISPR/Cas9 gene-editing method) almost abolished OI-induced anti-oxidant and anti-inflammatory actions in SLE patient-derived PBMCs and LPS-activated THP-1 cells. Conclusion: OI activates Nrf2 signaling to inhibit the production of pro-inflammatory cytokines in human macrophages and SLE patient-derived PBMCs. OI and itaconate could have important therapeutic value for the treatment of SLE.

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Section: Oi Activated Nrf2 Signaling In Thp-1 Cells and Sle Patient-dmentioning

confidence: 89%

4-Octyl Itaconate Activates Nrf2 Signaling to Inhibit Pro-Inflammatory Cytokine Production in Peripheral Blood Mononuclear Cells of Systemic Lupus Erythematosus Patients

Tang¹,

Wang²,

Xie³

et al. 2018

Cell Physiol Biochem

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“…miRs could contribute to the modulation of the stress response mediated by Nrf2 at various levels in different physiopathological contexts including neurological disorders [9,40,107]. Firstly, several miRs are directly implicated in Nrf2 post-transcriptional regulation by targeting its mRNA, thus reducing Nrf2 protein levels and, consequentially, stress defenses (Table 1).…”

Section: Oxidative Stress and Micrornasmentioning

confidence: 99%

“…Several works indicate that an optimal activity of Nrf2 is essential to protect cells against different stressors, and that its dysfunction is correlated with decreased tolerance to oxidative/chemical insults [8]. Therefore, alterations of the Nrf2 activity has been linked to the natural aging process [9,10] and to the pathogenesis of many human chronic diseases, including neurodegenerative [reviewed in [11][12][13] and cardiovascular diseases [14], fibrosis [15], inflammatory states [16], as well as with abnormalities in the susceptibility of tumor cells to chemo-and radio-therapy [reviewed in 17,18]. For these reasons, pharmacological/natural strategies that potentiate Nrf2 activity could be beneficial for preventing diseases in which oxidative stress exerts a pivotal role [7,[19][20][21].…”

mentioning

confidence: 99%

Nrf2 Pathway in Age-Related Neurological Disorders: Insights into MicroRNAs

Paladino

Conte

Caggiano

et al. 2018

Cell Physiol Biochem

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A general hallmark of neurological diseases is the loss of redox homeostasis that triggers oxidative damages to biomolecules compromising neuronal function. Under physiological conditions the steady-state concentrations of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are finely regulated for proper cellular functions. Reduced surveillance of endogenous antioxidant defenses and/or increased ROS/RNS production leads to oxidative stress with consequent alteration of physiological processes. Neuronal cells are particularly susceptible to ROS/RNS due to their biochemical composition. Overwhelming evidences indicate that nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-linked pathways are involved in protective mechanisms against oxidative stress by regulating antioxidant and phase II detoxifying genes. As such, Nrf2 deregulation has been linked to both aging and pathogenesis of many human chronic diseases, including neurodegenerative ones such as Parkinson’s disease, Alzheimer’s disease and amyotrophic lateral sclerosis. Nrf2 activity is tightly regulated by a fine balance between positive and negative modulators. A better understanding of the regulatory mechanisms underlying Nrf2 activity could help to develop novel therapeutic interventions to prevent, slow down or possibly reverse various pathological states. To this end, microRNAs (miRs) are attractive candidates because they are linked to intracellular redox status being regulated and, post-transcriptionally, regulating key components of ROS/RNS pathways, including Nrf2.

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“…While observations of redox signaling at the ER are relatively scarce at this stage, it is clear that H 2 O 2 is widely utilized as a signaling molecule in vivo [28] and it is quite predictable that further mechanisms specific to the ER will be uncovered in the future [18]. Other examples, which are connected to H 2 O 2 transit across the ER membrane, are granulocyte colonystimulating factor receptor signaling [29], oxidative DNA damage in response to cellular stresses [30][31][32], activation of survival pathways upon H 2 O 2 generation in the ER [33,34], and the regulatory roles of ER-luminal peroxidases in various settings of cytosolic signal transduction [29,[35][36][37][38].…”

Section: H 2 O 2 Can Readily Permeate Through the Endoplasmic Reticulmentioning

confidence: 99%