Keap1/Nrf2/ARE redox-sensitive signaling system as a pharmacological target

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

doi:10.1134/s0006297913010033

Cited by 67 publications

(48 citation statements)

References 155 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, these plant extracts have a very wide range of biological effects, making it difficult to distinguish the true contribution of Nrf2 induction. Currently, more specific and effective synthetic chemicals are being developed [11]. In this study we report that lansoprazole is a strong and effective inducer of Nrf2 transcription in hepatocytes, in addition to acting as a proton pump inhibitor.…”

Section: Introductionmentioning

confidence: 76%

“…Nrf2 is a master transcription factor that regulates antioxidant response element (ARE)-mediated transcription of genes involved in the regulation of the synthesis and conjugation of glutathione (glutamate-cysteine ligase catalytic subunit), antioxidant proteins specializing in the detoxification of certain reactive species (HO-1), drug-metabolizing enzymes (UDP-glucuronosyl-transferase 1A1), xenobiotic transporters (multidrug resistance protein 1), and molecular chaperones [9]–[11]. Nrf2 is sequestered in the cytoplasm by Kelch-like ECH-associated protein (Keap1) under un-stimulated conditions, while Nrf2 is translocated into the nucleus and activates the electrophilic response element/antioxidant response element (EpRE/ARE) upon exposure to oxidative insults [9]–[11]. It was shown that significant amounts of the Nrf2-Keap1 complex remained in the bound form after exposure to electrophiles [12], [13].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Nrf2-Inducing Anti-Oxidation Stress Response in the Rat Liver - New Beneficial Effect of Lansoprazole

et al. 2014

View full text Add to dashboard Cite

Lansoprazole is a potent anti-gastric ulcer drug that inhibits gastric proton pump activity. We identified a novel function for lansoprazole, as an inducer of anti-oxidative stress responses in the liver. Gastric administration of lansoprazole (10–100 mg/kg) to male Wistar rats produced a dose-dependent increase in hepatic mRNA levels of nuclear factor, erythroid-derived 2, -like 2 (Nrf2), a redox-sensitive transcription factor, at 3 h and Nrf2 immunoreactivity (IR) in whole hepatic lysates at 6 h. Conversely, the levels of Kelch-like ECH-associated protein (Keap1), which sequesters Nrf2 in the cytoplasm under un-stimulated conditions, were unchanged. Translocation of Nrf2 into the nuclei of hepatocytes was observed using western blotting and immunohistochemistry. Expression of mRNAs for Nrf2-dependent antioxidant and phase II enzymes, such as heme oxygenase 1 (HO-1), NAD (P) H dehydrogenase, quinone 1 (Nqo1), glutathione S-transferase A2 (Gsta2), UDP glucuronosyltransferase 1 family polypeptide A6 (Ugt1a6), were dose-dependently up-regulated at 3 h. Furthermore, the levels of HO-1 IR were dose-dependently increased in hepatocytes at 6 h. Subcutaneous administration of lansoprazole (30 mg/kg/day) for 7 successive days resulted in up-regulation and nuclear translocation of Nrf2 IR in hepatocytes and up-regulation of HO-1 IR in the liver. Pretreatment with lansoprazole attenuated thioacetamide (500 mg/kg)-induced acute hepatic damage via both HO-1-dependent and -independent pathways. Up-stream networks related to Nrf2 expression were investigated using microarray analysis, followed by data mining with Ingenuity Pathway Analysis. Up-regulation of the aryl hydrocarbon receptor (AhR)-cytochrome P450, family 1, subfamily a, polypeptide 1 (Cyp1a1) pathway was associated with up-regulation of Nrf2 mRNA. In conclusion, lansoprazole might have an alternative indication in the prevention and treatment of oxidative hepatic damage through the induction of both phase I and phase II drug-metabolizing systems, i.e. the AhR/Cyp1a1/Nrf2 pathway in hepatocytes.

show abstract

Section: Introductionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Nrf2-Inducing Anti-Oxidation Stress Response in the Rat Liver - New Beneficial Effect of Lansoprazole

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Upon inflammation response, cells maintain redox homeostasis by regulating oxidative stress by induction of phase II antioxidant enzymes such as heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase-1 (NQO-1), and c-glutamylcysteine synthase (c-GCLC) is regulated by the nuclear factor erythroid 2-related factor-2 (Nrf2) signaling [25][26][27]. The activation of Nrf2 signaling induces the translocation of Nrf2 into the nucleus and mediates the its transcriptional activity, resulting in the increased expression of antioxidant enzymes that play important roles in scavenging free radicals, such as superoxide dismutase (SOD) and catalase (CAT) [28]. Therefore, Nrf2 signaling and its related activities are critically involved in the NF-jB-dependent inflammation response.…”

Section: Introductionmentioning

confidence: 99%

Melatonin Protects Methamphetamine-Induced Neuroinflammation Through NF-κB and Nrf2 Pathways in Glioma Cell Line

et al. 2015

View full text Add to dashboard Cite

Methamphetamine (METH) is known as a toxin for neuronal and glial cells. Previous studies have found that METH-induced glial cell death and inflammation is mediated by oxidative stress. However, the exact mechanisms of the inflammatory response remain unclear. Therefore, we hypothesized that the activation of nuclear factor-κB (NF-κB) signaling, a key mediator of inflammation, and the inhibition of nuclear factor erythroid 2-related factor-2 (Nrf2) signaling, a regulator of the antioxidant response, would be significant events occurring in response to METH-induced inflammation in a rat glioma cell line (C6 cells). Our results show that METH increased the production of nitric oxide (NO) and up-regulated the expression of its main regulatory protein, inducible nitric oxide synthase (iNOS). METH also induced NF-κB activation by increasing inhibitory κBα (IκBα) degradation and translocation of the NF-κB (p65) subunit into the nucleus. Additionally, METH inhibited the activation of the Nrf2 pathway by decreasing the translocation of Nrf2 into the nucleus and also by suppressing the expression of heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase-1 (NQO-1), and glutamate-cysteine ligase catalytic subunit (γ-GCLC), resulting in the suppression of superoxide dismutase (SOD) activity. Pretreatment with melatonin effectively promoted Nrf2 activation and reversed the METH-induced NF-κB response. Melatonin increased the expression of HO-1, NQO-1, and γ-GCLC, resulting in increased SOD activity. In addition, melatonin also decreased IκBα degradation, translocation of the p65 subunit, and expression of iNOS, resulting in decreased NO production. Taken together, our results indicate that melatonin diminishes the proinflammatory mediator in METH-stimulated C6 cells by inhibiting NF-κB activation and inducing Nrf2-mediated HO-1, NQO-1, and γ-GCLC expression.

show abstract

“…Inactive NRF2 is retained in the cytoplasm by association with the kelch-like ECH-associated protein 1 (KEAP1), but during inflammation or oxidative stress, the phosphorylation of some intracellular kinases, such as phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT), elicits the translocation of NRF2 to the nucleus. Then, NRF2 binds to the antioxidant response elements (ARE) within the promoter of antioxidant enzymes, activating their transcription [10]. The most relevant of these enzymes are heme oxygenase-1 (HO1), nicotinamide adenine dinucleotide phosphate dehydrogenase quinone 1 (NQO1), superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) [11].…”

Section: Introductionmentioning

confidence: 99%

The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress

et al. 2016

View full text Add to dashboard Cite

Alterations in the innate inflammatory response may underlie the pathophysiology of psychiatric diseases. Current antipsychotics modulate pro-/anti-inflammatory pathways, but their specific actions on these pathways remain only partly explored. This study was conducted to elucidate the regulatory role of paliperidone (1 mg/kg i.p.) on acute (6 h) and chronic (6 h/day for 21 consecutive days) restraint stressinduced alterations in 2 emerging endogenous anti-inflammatory/antioxidant mechanisms: nuclear factor erythroid-related factor 2 (NRF2)/antioxidant enzymes pathway, and the cytokine milieu regulating M1/M2 polarization in microglia, analyzed at the mRNA and protein levels in prefrontal cortex samples. In acute stress conditions, paliperidone enhanced NRF2 levels, possibly related to phosphoinositide 3-kinase upregulation and reduced kelch-Like ECH-associated protein 1 expression. In chronic conditions, paliperidone tended to normalize NRF2 levels through a phosphoinositide 3-kinase related-mechanism, with no effects on kelch-Like ECH-associated protein 1. Antioxidant response element-dependent antioxidant enzymes were upregulated by paliperidone in acute stress, while in chronic stress, paliperidone tended to prevent stress-induced downregulation of the endogenous antioxidant machinery. However, paliperidone increased transforming growth factor-β and interleukin-10 in favor of an M2 microglia profile in acute stress conditions, which was also corroborated by paliperidone-induced increased levels of the M2 cellular markers arginase I and folate receptor 2. This latter effect was also produced in chronic conditions. Immunofluorescence studies suggested an increase in the number of microglial cells expressing arginase I and folate receptor 2 in the stressed animals pretreated with paliperidone. In conclusion, the enhancement of endogenous antioxidant/anti-inflammatory pathways by current and new antipsychotics could represent an interesting therapeutic strategy for the future.

show abstract

Keap1/Nrf2/ARE redox-sensitive signaling system as a pharmacological target

Cited by 67 publications

References 155 publications

Nrf2-Inducing Anti-Oxidation Stress Response in the Rat Liver - New Beneficial Effect of Lansoprazole

Nrf2-Inducing Anti-Oxidation Stress Response in the Rat Liver - New Beneficial Effect of Lansoprazole

Melatonin Protects Methamphetamine-Induced Neuroinflammation Through NF-κB and Nrf2 Pathways in Glioma Cell Line

The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress

Contact Info

Product

Resources

About