Applications of the Keap1–Nrf2 system for gene and cell therapy

Pomeshchik, Yuriy; Leinonen, Hanna; Malm, Tarja; Koistinaho, Jari; Levonen, Anna–Liisa

doi:10.1016/j.freeradbiomed.2015.06.037

Cited by 40 publications

(31 citation statements)

References 204 publications

(192 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nrf2 is an important transcription factor involved in regulating the oxidative stress response (31,32). It regulates the transcription of antioxidant and detoxification genes, such as HO-1 (33,34). In the present study, the expression levels of Nrf2 in the nucleus and HO-1 in the cytoplasm were significantly increased in the liver tissue of LPS/GalN-treated mice.…”

Section: A B Discussionsupporting

confidence: 54%

Nobiletin attenuates lipopolysaccharide/D-galactosamine-induced liver injury in mice by activating the Nrf2 antioxidant pathway and subsequently inhibiting NF-κB-mediated cytokine production

Chen

et al. 2016

Molecular Medicine Reports

View full text Add to dashboard Cite

Inflammation and oxidative stress serve an important role in the development of lipopolysaccharide/D-galactosamine (LPS/GalN)‑induced acute liver injury. Nobiletin, which is found in high quantities in the peel of citrus fruits, is able to modulate immune responses, including inflammatory response and oxidative stress. The present study aimed to evaluate the protective effects of nobiletin on LPS/GalN‑induced acute liver injury. Male C57BL/6 mice were intraperitoneally treated with nobiletin (50, 100 and 200 mg/kg) 2 h prior to LPS/GalN injection. Liver injury was observed in the LPS/GalN group, as demonstrated by increased levels of serum hepatic enzymes and hepatic inflammatory mediators, as well as by histopathological alterations. Treatment with nobiletin reduced serum alanine aminotransferase and aspartate aminotransferase levels, improved hepatic structure, and suppressed hepatic interleukin (IL)‑1β, IL‑6 and tumor necrosis factor‑α production 24 h after LPS/GalN exposure. Western blot analysis revealed that nobiletin treatment inhibited inducible nitric oxide synthase and cyclooxygenase‑2 liver expression. In addition, nobiletin suppressed LPS/GalN‑induced phosphorylation and degradation of inhibitor of nuclear factor (NF)‑κB (IκB)α, as well as NF‑κB p65 translocation into the nucleus. Nobiletin also upregulated the expression of nuclear NF‑E2‑related factor 2 (Nrf2) and cytoplasmic heme oxygenase‑1. In conclusion, these results indicate that nobiletin serves a protective role in LPS/GalN‑induced acute liver injury via activation of the Nrf2 antioxidant pathway and subsequent inhibition of NF‑κB‑mediated cytokine production. These findings support the potential for nobiletin as a therapeutic agent for the treatment of acute liver injury.

show abstract

Section: A B Discussionsupporting

confidence: 54%

Nobiletin attenuates lipopolysaccharide/D-galactosamine-induced liver injury in mice by activating the Nrf2 antioxidant pathway and subsequently inhibiting NF-κB-mediated cytokine production

Chen

et al. 2016

Molecular Medicine Reports

View full text Add to dashboard Cite

show abstract

“…We hypothesized that 1 mechanism might be the KEAP-1/nuclear factor erythroid-derived-2-related-factor (Nrf2)/antioxidant pathway, widely recognized as a prominent regulator of antioxidant enzyme gene expression (32)(33)(34)(35)(36). Several reports involving mouse models of diabetes appeared midway through our study and supported this possibility (6,(37)(38)(39).…”

Section: Introductionsupporting

confidence: 52%

Nrf2/antioxidant pathway mediates β cell self-repair after damage by high-fat diet–induced oxidative stress

Abebe¹,

Mahadevan²,

Bogachus³

et al. 2017

JCI Insight

View full text Add to dashboard Cite

“…As a redox sensitive transcription factor, Nrf2 regulates endogenous antioxidant defenses, phase II metabolism, autophagy [5] and solute transporters [6]. Nrf2 is increasingly becoming recognised as a therapeutic target for the treatment of chronic diseases associated with oxidative stress [3,4,[7][8][9]. The molecular mechanisms regulating Nrf2 signaling have predominantly been investigated in vitro using cell culture models exposed to atmospheric oxygen and identified multiple regulatory proteins which repress (Keap1, Bach1) or enhance (DJ-1, p62) Nrf2 activity [3,4,10].…”

Section: Introductionmentioning

confidence: 99%

Bach1 differentially regulates distinct Nrf2-dependent genes in human venous and coronary artery endothelial cells adapted to physiological oxygen levels

Chapple

Keeley

Mastronicola

et al. 2016

Free Radical Biology and Medicine

View full text Add to dashboard Cite

The effects of physiological oxygen tension on Nuclear Factor-E2-Related Factor 2 (Nrf2)-regulated redox signaling remain poorly understood. We report the first study of Nrf2-regulated signaling in human primary endothelial cells (EC) adapted long-term to physiological O2 (5%). Adaptation of EC to 5% O2 had minimal effects on cell ultrastructure, viability, basal redox status or HIF1-α expression. Affymetrix array profiling and subsequent qPCR/protein validation revealed that induction of select Nrf2 target genes, HO-1 and NQO1, was significantly attenuated in cells adapted to 5% O2, despite nuclear accumulation and DNA binding of Nrf2. Diminished HO-1 induction under 5% O2 was stimulus independent and reversible upon re-adaptation to air or silencing of the Nrf2 repressor Bach1, notably elevated under 5% O2. Induction of GSH-related genes xCT and GCLM were oxygen and Bach1-insensitive during long-term culture under 5% O2, providing the first evidence that genes related to GSH synthesis mediate protection afforded by Nrf2-Keap1 defense pathway in cells adapted to physiological O2 levels encountered in vivo.

show abstract

Applications of the Keap1–Nrf2 system for gene and cell therapy

Cited by 40 publications

References 204 publications

Nobiletin attenuates lipopolysaccharide/D-galactosamine-induced liver injury in mice by activating the Nrf2 antioxidant pathway and subsequently inhibiting NF-κB-mediated cytokine production

Nobiletin attenuates lipopolysaccharide/D-galactosamine-induced liver injury in mice by activating the Nrf2 antioxidant pathway and subsequently inhibiting NF-κB-mediated cytokine production

Nrf2/antioxidant pathway mediates β cell self-repair after damage by high-fat diet–induced oxidative stress

Bach1 differentially regulates distinct Nrf2-dependent genes in human venous and coronary artery endothelial cells adapted to physiological oxygen levels

Contact Info

Product

Resources

About