Differential effect of covalent protein modification and glutathione depletion on the transcriptional response of Nrf2 and NF-κB

Chia, Alvin J. L.; Goldring, Christopher E.; Kitteringham, Neil R.; Wong, Shi Quan; Morgan, Paul; Park, B. Kevin

doi:10.1016/j.bcp.2010.04.004

Cited by 30 publications

(25 citation statements)

References 40 publications

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“…In response to oxidative stress, modification of reactive cysteine residues within Keap1 induces a conformational change leading to Nrf2-Keap1 dissociation allowing Nrf2 nuclear translocation and binding to AREresponsive target genes [68]. Interestingly, some authors have described that depletion of GSH disrupts Nrf2 interaction with Keap1 [69][70][71]. Our data showed that the combination of PA plus LA induced an early nuclear accumulation of Nrf2 at 4 h and this resulted in a strong protection against PA-induced apoptosis.…”

Section: Discussionmentioning

confidence: 50%

Essential role of Nrf2 in the protective effect of lipoic acid against lipoapoptosis in hepatocytes

Valdecantos

Prieto-Hontoria

Pardo

et al. 2015

Free Radical Biology and Medicine

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Section: Discussionmentioning

confidence: 50%

Essential role of Nrf2 in the protective effect of lipoic acid against lipoapoptosis in hepatocytes

Valdecantos

Prieto-Hontoria

Pardo

et al. 2015

Free Radical Biology and Medicine

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“…Our observations support the role of the SAMe and SB combination in hepatoprotection in vitro and may be useful in promoting and managing liver disorders. Considering that the NF‐κB and Nrf2 pathways coordinate separate, but partially overlapping biochemical responses to oxidative stress and pro‐inflammatory stimuli, it has recently been suggested that the balance between both transcription factors might serve as a key cytoprotective mechanism to sense and respond to cellular stress in hepatocytes (Chia et al., 2010). The present study demonstrates that the combination of SAMe and SB acts on two principal pathways involved in the defence of hepatocytes, specifically against oxidative stress and inflammation.…”

Section: Discussionmentioning

confidence: 99%

Hepatoprotective effects of S‐adenosylmethionine and silybin on canine hepatocytes in vitro

Hasenwinkel

Frondoza

2012

Animal Physiology Nutrition

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Inflammation and oxidative stress are associated with liver injury and development of liver disease. The transcription factors nuclear factor-kappa beta (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2) play critical roles in modulating liver injury and damage. Activation of NF-κB induces production of pro-inflammatory molecules including prostaglandin E2 (PGE2 ), interleukin-8 (IL-8) and macrophage chemotactic protein-1 (MCP-1). Nrf2 regulates genes controlling antioxidants. Our laboratory previously showed that hepatocytes, the primary functional cell type comprising liver tissue, respond to the cytokine interleukin-1 beta (IL-1β) by increased production of PGE2 , IL-8 and MCP-1. This increase is associated with nuclear translocation of NF-κB. In this study, we evaluated whether primary canine hepatocytes pre-treated with the combination of S-adenosylmethionine (SAMe; 30 and 2000 ng/ml) and silybin (SB; 298 ng/ml), agents with known anti-inflammatory and antioxidant properties, could attenuate IL-1β-induced inflammation and oxidative stress. The SAMe and SB combination reduced cytokine-induced PGE2 , IL-8 and MCP-1 production while also inhibiting NF-κB nuclear translocation. These changes were accompanied by increased antioxidant enzyme-reduced glutathione (GSH) comparable to control levels. The study shows for the first time that the SAMe and SB combination inhibits both inflammation and oxidative stress through two separate signalling pathways.

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“…Nrf2 induces a negative feedback loop, thereby decreasing the expression of GCLC and the formation of endogenous GSH (Kaspar & Jaiswal, ). Second, GSH depletion itself (when ROS is absent) also induces Nrf2 activation (Chia et al, ). Finally, the formed protein GCL has a catalytic subunit that only functions when GSH levels are low, meaning that GSH synthesis by GCL is only increased when low levels of GSH are present (Huang, Chang, Anderson, & Meister, ; Rahman, Bel, Mulier, Donaldson, & MacNee, ; Rahman & MacNee, ; Sthijns et al, ; Tian, Shi, & Forman, ).…”

Section: Molecular Targets For Tissue Engineersmentioning

confidence: 99%

Redox regulation in regenerative medicine and tissue engineering: The paradox of oxygen

Sthijns

Blitterswijk

LaPointe

2018

J Tissue Eng Regen Med

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One of the biggest challenges in tissue engineering and regenerative medicine is to incorporate a functioning vasculature to overcome the consequences of a lack of oxygen and nutrients in the tissue construct. Otherwise, decreased oxygen tension leads to incomplete metabolism and the formation of the so‐called reactive oxygen species (ROS). Cells have many endogenous antioxidant systems to ensure a balance between ROS and antioxidants, but if this balance is disrupted by factors such as high levels of ROS due to long‐term hypoxia, there will be tissue damage and dysfunction. Current attempts to solve the oxygen problem in the field rarely take into account the importance of the redox balance and are instead centred on releasing or generating oxygen. The first problem with this approach is that although oxygen is necessary for life, it is paradoxically also a highly toxic molecule. Furthermore, although some oxygen‐generating biomaterials produce oxygen, they also generate hydrogen peroxide, a ROS, as an intermediate product. In this review, we discuss why it would be a superior strategy to supplement oxygen delivery with molecules to safeguard the important redox balance. Redox sensor proteins that can stimulate the anaerobic metabolism, angiogenesis, and enhancement of endogenous antioxidant systems are discussed as promising targets. We propose that redox regulating biomaterials have the potential to tackle some of the challenges related to angiogenesis and that the knowledge in this review will help scientists in tissue engineering and regenerative medicine realize this aim.

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Differential effect of covalent protein modification and glutathione depletion on the transcriptional response of Nrf2 and NF-κB

Abstract: Graphical abstractCRMs activate Nrf2, but inhibit NF-κB, and GSH depletion without covalent modification activates both Nrf2 and NF-κB. This leads to cellular protection against the potentially harmful effects of redox perturbation.

Cited by 30 publications

References 40 publications

Essential role of Nrf2 in the protective effect of lipoic acid against lipoapoptosis in hepatocytes

Essential role of Nrf2 in the protective effect of lipoic acid against lipoapoptosis in hepatocytes

Hepatoprotective effects of S‐adenosylmethionine and silybin on canine hepatocytes in vitro

Redox regulation in regenerative medicine and tissue engineering: The paradox of oxygen

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