Mechanism of the Nrf2/Keap1/ARE signaling system

Tkachev, Victor; Menshchikova, E. B.; Зенков, Н. К.

doi:10.1134/s0006297911040031

Cited by 182 publications

(146 citation statements)

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“…In the second step, four signaling pathways (ARE, GR, Wnt, and NFAT) were identified as the potential mediator for the initial action of ebselen by analyzing gene promoters of the four key regulators of GSIS. Indeed, these pathways are highly responsive to redox regulation (31,32,62,70) and involved in transcriptional regulation of the key regulators of GSIS (8,24,59,65). In the third step, the candidate pathways (ARE and GR) and mediators (PGC-1a and C/EBPb) were chosen based on their gene expression responsiveness to ebselen.…”

Section: Figmentioning

confidence: 99%

“…The first is the peroxisome proliferatoractivated receptor gamma coactivator 1 alpha (PGC-1a)-mediated antioxidant response element (ARE) signaling pathway. While PGC-1a is involved in responses of various genes to redox regulation (62) and regulates GSIS in human islets (40), two of its gene variants are associated with increased risks of type 2 diabetes in the Indian population (6,73). The second is the glucocorticoid receptor (GR) pathway that is negatively regulated by ROS or H 2 O 2 in inflammation and immune responses (31).…”

Section: Introductionmentioning

confidence: 99%

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Glutathione Peroxidase Mimic Ebselen Improves Glucose-Stimulated Insulin Secretion in Murine Islets

Wang

Yun²,

Lei³

2014

Antioxidants & Redox Signaling

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Aims: Glutathione peroxidase (GPX) mimic ebselen and superoxide dismutase (SOD) mimic copper diisopropylsalicylate (CuDIPs) were used to rescue impaired glucose-stimulated insulin secretion (GSIS) in islets of GPX1 and(or) SOD1-knockout mice. Results: Ebselen improved GSIS in islets of all four tested genotypes. The rescue in the GPX1 knockout resulted from a coordinated transcriptional regulation of four key GSIS regulators and was mediated by the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1a)-mediated signaling pathways. In contrast, CuDIPs improved GSIS only in the SOD1 knockout and suppressed gene expression of the PGC-1a pathway. Innovation: Islets from the GPX1 and(or) SOD1 knockout mice provided metabolically controlled intracellular hydrogen peroxide (H 2 O 2 ) and superoxide conditions for the present study to avoid confounding effects. Bioinformatics analyses of gene promoters and expression profiles guided the search for upstream signaling pathways to link the ebselen-initiated H 2 O 2 scavenging to downstream key events of GSIS. The RNA interference was applied to prove PGC-1a as the main mediator for that link. Conclusion: Our study revealed a novel metabolic use and clinical potential of ebselen in rescuing GSIS in the GPX1-deficient islets and mice, along with distinct differences between the GPX and SOD mimics in this regard. These findings highlight the necessities and opportunities of discretional applications of various antioxidant enzyme mimics in treating insulin secretion disorders. Redox Signal. 20,[191][192][193][194][195][196][197][198][199][200][201][202][203]

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Section: Figmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Glutathione Peroxidase Mimic Ebselen Improves Glucose-Stimulated Insulin Secretion in Murine Islets

Wang

Yun²,

Lei³

2014

Antioxidants & Redox Signaling

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“…The pharmacological Nrf2 activators include: i) phenolic compounds, such as butylated hydroxyanisole, butylated hydroxytoluene, and tert-butyl hydroquinone; ii) 1,2-mercapto-3-sulfur ketone derivatives, such as oltipraz; iii) isopropyl sulfur cyanogen compounds, such as SF and its synthetic analogs; iv) natural compounds from plants, such as curcumin, resveratrol, tanshinone, plumbagin, puerarin, luteolin, oleanolic acid, mangiferin, and quercetin, etc. ; v) hydrogen peroxide compounds, such as hydrogen peroxide, isopropyl benzene hydrogen peroxide, and 4-butyl hydroperoxide; and vi) compounds that are rich in arsenic, selenium, trace elements, and heavy metal ions, such as As 2 O 3 , ebselen, and Co 2C (Tkachev et al 2011). To date, large amounts of evidence have established that a growing list of antioxidants exert their vasoprotective functions via Nrf2-ARE-related pathways.…”

Section: Activators Of Nrf2/keap1-are Pathways As Clinical Therapeutimentioning

confidence: 99%

The role of Nrf2 in oxidative stress-induced endothelial injuries

Chen¹,

Lu²,

Chen³

et al. 2015

Journal of Endocrinology

318

244

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Endothelial dysfunction is an important risk factor for cardiovascular disease, and it represents the initial step in the pathogenesis of atherosclerosis. Failure to protect against oxidative stress-induced cellular damage accounts for endothelial dysfunction in the majority of pathophysiological conditions. Numerous antioxidant pathways are involved in cellular redox homeostasis, among which the nuclear factor-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)-antioxidant response element (ARE) signaling pathway is perhaps the most prominent. Nrf2, a transcription factor with a high sensitivity to oxidative stress, binds to AREs in the nucleus and promotes the transcription of a wide variety of antioxidant genes. Nrf2 is located in the cytoskeleton, adjacent to Keap1. Keap1 acts as an adapter for cullin 3/ring-box 1-mediated ubiquitination and degradation of Nrf2, which decreases the activity of Nrf2 under physiological conditions. Oxidative stress causes Nrf2 to dissociate from Keap1 and to subsequently translocate into the nucleus, which results in its binding to ARE and the transcription of downstream target genes. Experimental evidence has established that Nrf2-driven free radical detoxification pathways are important endogenous homeostatic mechanisms that are associated with vasoprotection in the setting of aging, atherosclerosis, hypertension, ischemia, and cardiovascular diseases. The aim of the present review is to briefly summarize the mechanisms that regulate the Nrf2/Keap1-ARE signaling pathway and the latest advances in understanding how Nrf2 protects against oxidative stress-induced endothelial injuries. Further studies regarding the precise mechanisms by which Nrf2-regulated endothelial protection occurs are necessary for determining whether Nrf2 can serve as a therapeutic target in the treatment of cardiovascular diseases.

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“…50 They include endogenous activators (e.g., ROS, lipid aldehydes) and exogenous agents (e.g., heavy metals, electropholic xenobiotics). 51 Some nutraceutical compounds are also activators of Nrf2 (e.g., sulforaphane, curcumin, resveratrol, caffeic acid phenyl ester, tocopherol). 49,50 Sulforaphane, an isothiocyanate compound present in high concentrations in broccoli sprouts and other crucifers, was found to be a potent inducer of the Nrf2-regulated cytoprotective adaptive response.…”

Section: Interventional Therapiesmentioning

confidence: 99%

Update on the pathogenesis of complex regional pain syndrome: Role of oxidative stress

Taha

Blaise

2012

Can J Anesth/J Can Anesth

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Purpose Complex regional pain syndrome (CRPS) is a chronic inflammatory pain syndrome that affects one or more extremities of the body. It is characterized by burning pain and abnormalities in the sensory, motor, and autonomic nervous systems. This review illustrates how oxidative stress and nuclear factor erythroid 2-related factor (Nrf2) activation might contribute to understanding the etiopathogenesis of CRPS.Principal findings The precise cause of CRPS remains unclear, and current treatments are not effective in many patients. The mechanism underlying CRPS may differ across patients and even within a single patient over time. Inflammatory and neuronal mechanisms have been suggested as key contributors to CRPS. Recent evidence demonstrates that oxidative stress is associated with clinical symptoms in patients with CRPS-I. Oxidative stress plays a key role in CRPS pathogenesis. The Nrf2 factor is a master regulator of the transcription of multiple antioxidants, which protects against oxidative stress and inflammation by inducing antioxidant and detoxifying genes through binding with an antioxidant response element. It has antinociceptive effects against inflammatory pain in an animal model. Conclusion This review summarises the effect of oxidative stress and mitochondrial dysfunction in the pathogenesis of CRPS. It also addresses the question of whether there is a potential role for Nrf2 (activated by pharmacological or nutritional activators) in alleviating the clinical features of CRPS or preventing its progression. RésuméObjectif Le syndrome douloureux re´gional complexe (SDRC) est un syndrome de douleur inflammatoire chronique affectant un ou plusieurs membres; il est caracte´rise´par des douleurs de type bruˆlures et par des anomalies des syste`mes nerveux sensitif, moteur et autonome. La cause pre´cise du SDRC est encore inconnue et les traitements actuels sont inefficaces chez de nombreux patients. Le me´canisme sous-jacent du SDRC peut varier selon les patients et meˆme chez un meˆme patient au fil du temps. Des me´canismes inflammatoires et neuronaux ont e´te´propose´s comme jouant un rôle cle´dans la gene`se du SDRC. Les constatations tire´es des e´tudes re´centes montrent que le stress oxydatif est associe´aux symptômes cliniques du SDRC-1. L'objectif de cet article de synthe`se est d'illustrer comment le stress oxydatif et l'activation d'un facteur apparente´au facteur nucle´aire e´rythroı¨de-2 (Nrf2) pourraient contribuer a`la compre´hension de l'e´tiopathogene`se du SDRC. Constatations principales Le stress oxydatif joue un rôle essentiel dans la pathogene`se du SDRC. Le facteur apparente´au facteur nucle´aire e´rythroı¨de-2 est le maıˆtre re´gulateur de la transcription de multiples antioxydants prote´geant contre le stress oxydatif et l'inflammation par Author contributions Rame Taha and Gilbert Blaise have made substantial contributions to design and drafting the reviewand both of them have approved the final version to be published.

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Mechanism of the Nrf2/Keap1/ARE signaling system

Cited by 182 publications

References 142 publications

Glutathione Peroxidase Mimic Ebselen Improves Glucose-Stimulated Insulin Secretion in Murine Islets

Glutathione Peroxidase Mimic Ebselen Improves Glucose-Stimulated Insulin Secretion in Murine Islets

The role of Nrf2 in oxidative stress-induced endothelial injuries

Update on the pathogenesis of complex regional pain syndrome: Role of oxidative stress

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