Canonical and non-canonical mechanisms of Nrf2 activation

Silva-Islas, Carlos Alfredo; Maldonado, Perla D.

doi:10.1016/j.phrs.2018.06.013

Cited by 283 publications

(217 citation statements)

References 104 publications

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“…Therefore, we choose the 18 h as the time point to measure the activation of Nrf2, which is essential in regulating the expression of antioxidative genes, such as HO-1. As the most important transcription factor in regulating antioxidative genes, Nrf2 was activated when it translocates into the nucleus, heterodimerizes with small Maf preteins, and then binds to the ARE sequence [26], which is known as canonical mechanisms of Nrf2 activation [27]. Our results showed that the expression of Nrf2 in nuclear was decreased after Cd exposure, which is indicative of the inhibition of Nrf2.…”

Section: Discussionmentioning

confidence: 54%

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Cadmium Induces Acute Liver Injury by Inhibiting Nrf2 and the Role of NF-κB, NLRP3, and MAPKs Signaling Pathway

Liu

Zhu

et al. 2019

IJERPH

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Acute Cadmium (Cd) exposure usually induces hepatotoxicity. It is well known that oxidative stress and inflammation causes Cd-induced liver injury. However, the effect of nuclear factor erythroid 2-related factor 2 (Nrf2) in Cd-induced liver injury is not completely understood. In this study, we observed Cd-induced liver damage and the potential contribution of Nrf2, nuclear factor-κB (NF-κB), Nod-like receptor 3 (NLRP3), and mitogen-activated protein kinases (MAPKs) signaling pathways. Changes in serum transaminases and proinflammatory cytokines expression showed that Cd could induce acute hepatotoxicity. Moreover, Nrf2 and its downstream heme oxygenase 1 (HO-1) were inhibited by Cd exposure, and Kelch-like ECH-associated protein 1 (Keap1), the inhibitory protein of Nrf2, was increased. Furthermore, NF-κB, NLRP3, and MAPKs signaling pathways were all activated by Cd intoxication. In conclusion, the inhibition of Nrf2, HO-1, and the activation of NF-κB, NLRP3, and MAPKs all contribute to Cd-induced liver injury.

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Section: Discussionmentioning

confidence: 54%

“…Our data demonstrated that the expression of Keap1 was increased by Cd treatment. The p62, which is another regulator of Nrf2, is involved in non-canonical mechanisms of Nrf2 activation [27]. The role of p62 is mainly sequestering Keap1 to autophagic degradation that ultimately results in the stabilization of Nrf2 [28,29].…”

Section: Discussionmentioning

confidence: 99%

Cadmium Induces Acute Liver Injury by Inhibiting Nrf2 and the Role of NF-κB, NLRP3, and MAPKs Signaling Pathway

Liu

Zhu

et al. 2019

IJERPH

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“…Under basal conditions, NRF2 is in its inactive form since it is associated with kelch-like ECH-associated protein 1 (Keap1), which convenes it to proteasomal degradation [56]. However, in response to cellular stimuli, NRF2 dissociates from Keap1 and translocates to the nucleus [57] where it binds to the antioxidant response elements (ARE) in the promoter region of antioxidant genes, thereby leading to their upregulation [58]. Our data clearly evidence the effectiveness of GMP to avert Fe/Asc-mediated NRF2 diminution, which explains the recovery of antioxidant enzymes.…”

Section: Discussionmentioning

confidence: 99%

Glycomacropeptide Prevents Iron/Ascorbate-Induced Oxidative Stress, Inflammation and Insulin Sensitivity with an Impact on Lipoprotein Production in Intestinal Caco-2/15 Cells

et al. 2020

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Background. Metabolic Syndrome (MetS), a major worldwide concern for the public health system, refers to a cluster of key metabolic components, and represents a risk factor for diabetes and cardiovascular diseases. As oxidative stress (OxS) and inflammation are the major triggers of insulin sensitivity (IS), a cardinal MetS feature, the principal aim of the present work is to determine whether glycomacropeptide (GMP), a milk-derived bioactive peptide, exerts beneficial effects on their expression. Methods. Fully differentiated intestinal Caco-2/15 cells are used to evaluate the preventive action of 2 mg/mL GMP against OxS and inflammation induced by the mixture iron-ascorbate (Fe/Asc) (200 μM:2 mM). The potency of GMP of decreasing the production of lipoproteins, including chylomicrons (CM), very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) is also assessed. Results. The administration of GMP significantly reduces malondialdehyde, a biomarker of lipid peroxidation, and raises superoxide dismutase 2 and glutathione peroxidase via the induction of the nuclear factor erythroid 2–related factor 2, a transcription factor, which orchestrates cellular antioxidant defenses. Similarly, GMP markedly lowers the inflammatory agents tumor necrosis factor-α and cyclooxygenase-2 via abrogation of the nuclear transcription factor-kB. Moreover, GMP-treated cells show a down-regulation of Fe/Asc-induced mitogen activated protein kinase pathway, suggesting greater IS. Finally, GMP decreases the production of CM, VLDL, and LDL. Conclusions. Our results highlight the effectiveness of GMP in attenuating OxS, inflammation and lipoprotein biogenesis, as well as improving IS, the key components of MetS. Further investigation is needed to elucidate the mechanisms mediating the preventive action of GMP.

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“…Our analysis suggested an activation of NRF2 in a subset of infected cells. Under physiological conditions, NRF2 is repressed by KEAP1, which sequesters NRF2 and facilitates its ubiquitination and degradation [44]. Upon disruption of this interaction in response to oxidative stress, NRF2 translocates into the nucleus, and induces transcription of a number of target genes, including NQO1.…”

Section: The Nrf2 Agonist Bardoxolone Methyl Restricts Hsv-1 Infectionmentioning

confidence: 99%

Single-cell RNA-sequencing of Herpes simplex virus 1-infected cells identifies NRF2 activation as an antiviral program

Wyler

Franke

Menegatti

et al. 2019

Preprint

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AbstractHerpesvirus infection initiates a range of perturbations in the host cell, which remain poorly understood at the level of individual cells. Here, we quantified the transcrips of single human primary fibroblasts during the first hours of lytic infection with HSV-1. By applying a generalizable analysis scheme, we defined a precise temporal order of early viral gene expression and found unexpected bifurcations and bottlenecks. We identified individual host cell genes and pathways relevant in early infection by combining three different computational approaches: gene and pathway overdispersion analysis, prediction of cell-state transition probabilities as well as future cell states. One transcriptional program, which was turned on in infected cells and correlated with increased resistance to infection, implicated the transcription factor NRF2. Consequently, Bardoxolone methyl, a known NRF2 agonist, impaired virus production, suggesting that NRF2 activation restricts the progression of viral infection. Our study provides novel insights into early stages of HSV-1 infection and serves as a general blueprint for the investigation of heterogenous cell states in virus infection.

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Canonical and non-canonical mechanisms of Nrf2 activation

Cited by 283 publications

References 104 publications

Cadmium Induces Acute Liver Injury by Inhibiting Nrf2 and the Role of NF-κB, NLRP3, and MAPKs Signaling Pathway

Cadmium Induces Acute Liver Injury by Inhibiting Nrf2 and the Role of NF-κB, NLRP3, and MAPKs Signaling Pathway

Glycomacropeptide Prevents Iron/Ascorbate-Induced Oxidative Stress, Inflammation and Insulin Sensitivity with an Impact on Lipoprotein Production in Intestinal Caco-2/15 Cells

Single-cell RNA-sequencing of Herpes simplex virus 1-infected cells identifies NRF2 activation as an antiviral program

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