Nrf2 – Latest Studies

Nrf2 is a field of medical study that is becoming very popular in recent years. Research regarding the topic of Nrf2 now is the topic of mainstream medical conferences such as the Biochemical Conference held at Cambridge University.

The purpose of the meeting was to share progress in the fields of:

The transcription factor Nrf2 is a key mediator of the antioxidant response and is important in inflammation, cancer, multi-drug resistance, autophagy, aging, neurodegeneration, lipogenesis and many other physiological and pathological processes. This meeting will provide an opportunity for researchers interested in Nrf2 to discuss recent developments in this area.

Topics:

  • Structure, function and regulation of Nrf2
  • Repression of Nrf2 by Keap1
  • Role of Nrf2 target genes
  • Importance of Nrf2 in homeostasis and tissue repair
  • Role in chronic diseases, including cancer and cardiovascular disease
  • Keap1-independent mechanisms of Nrf2 repression
  • Nrf2 as a therapeutic target

While conferences only come around every now and again, here are the latest Nrf2 studies on Pubmed.gov

Docosahexaenoic acid enhances methylmercury-induced endoplasmic reticulum stress and cell death and eicosapentaenoic acid potentially attenuates these effects in mouse embryonic fibroblasts
Takanezawa Y, Nakamura R, Hamaguchi M, Yamamoto K, Sone Y, Uraguchi S and Kiyono M
Fish consumption has both the risk of methylmercury (MeHg) poisoning and the benefit of obtaining n-3 polyunsaturated fatty acids (n-3 PUFAs), particularly docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). However, the cellular interaction between MeHg and PUFAs remains unknown. Therefore, the aim of this study was to investigate the effects of MeHg and n-3 PUFA exposure on mouse embryonic fibroblasts (MEFs). The results showed that EPA had a negligible effect on MeHg-induced cell death, whereas DHA promoted it. Thiobarbituric acid reactive substance (TBARS) concentrations in cells exposed to DHA and MeHg were higher than in those exposed to EPA and MeHg. Treatment with DHA and MeHg markedly induced the expression of endoplasmic reticulum (ER) stress (CHOP and DNAJB9) and Nrf2 target gene (p62 and HMOX-1) mRNA levels. Unexpectedly, EPA supplementation in addition to DHA and MeHg attenuated DHA- and MeHg-induced cell death and suppressed ER stress and expression of Nrf2 target genes. Our results revealed a differential impact of DHA and EPA on MeHg-induced cell death, and combined treatment with DHA and EPA along with MeHg attenuated MeHg-induced toxicity.
Aloin reduces inflammatory gene iNOS via inhibition activity and p-STAT-1 and NF-κB
Lee W, Yang S, Lee C, Park EK, Kim KM, Ku SK and Bae JS
Aloin is the major anthraquinone glycoside obtained from the Aloe species and exhibits anti-inflammatory and anti-oxidative activities. Here, we aimed to determine the effects of aloin on heme oxygenase-1 (HO-1) induction and on the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX) 2 in lipopolysaccharide (LPS)-activated human umbilical vein endothelial cells (HUVECs). To the end, aloin was tested whether aloin reduces iNOS protein expression and inflammatory markers (interleukin (IL)-1β and tumor necrosis factor (TNF)-α) in LPS-treated mice lung tissue. The results indicated that aloin affected HO-1 induction and reduced LPS-activated NF-κB-luciferase activity showed to preferential inhibition of iNOS/NO and COX-2/PGE2 that was partly related to inhibition of STAT-1 phosphorylation. In particular, aloin induced translocation of Nrf2 from cytosol into the nucleus by an increased Nrf2-ARE binding activity, and reduced IL-1β production in LPS-activated HUVECs. The reduced expression of iNOS/NO by aloin was reversed by siHO-1RNA-transfection. In LPS-treated mice, aloin significantly reduced iNOS protein in lung tissues, and TNF-α levels in the BALF. We concluded that aloin may be beneficial for treatment of lung injury.
CX3CR1-deficient microglia shows impaired signalling of the transcription factor NRF2: Implications in tauopathies
Castro-Sánchez S, García-Yagüe ÁJ, Kügler S and Lastres-Becker I
TAU protein aggregation is the main characteristic of neurodegenerative diseases known as tauopathies. Low-grade chronic inflammation is also another hallmark that indicates crosstalk between damaged neurons and glial cells. Previously, we have demonstrated that neurons overexpressing TAU release CX3CL1, which activates the transcription factor NRF2 signalling to limit over-activation in microglial cells in vitro and in vivo. However, the connection between CX3CL1/CX3CR1 and NRF2 system and its functional implications in microglia are poorly described. We evaluated CX3CR1/NRF2 axis in the context of tauopathies and its implication in neuroinflammation. Regarding the molecular mechanisms that connect CX3CL1/CX3CR1 and NRF2 systems, we observed that in primary microglia from Cx3cr1 mice the mRNA levels of Nrf2 and its related genes were significantly decreased, establishing a direct linking between both systems. To determine functional relevance of CX3CR1, migration and phagocytosis assays were evaluated. CX3CR1-deficient microglia showed impaired cell migration and deficiency of phagocytosis, as previously described for NRF2-deficient microglia, reinforcing the idea of the relevance of the CX3CL1/CX3CR1 axis in these events. The importance of these findings was evident in a tauopathy mouse model where the effects of sulforaphane (SFN), an NRF2 inducer, were examined on neuroinflammation in Cx3cr1 and Cx3cr1 mice. Interestingly, the treatment with SFN was able to modulate astrogliosis but failed to reduce microgliosis in Cx3cr1 mice. These findings suggest an essential role of the CX3CR1/NRF2 axis in microglial function and in tauopathies. Therefore, polymorphisms with loss of function in CX3CR1 or NRF2 have to be taken into account for the development of therapeutic strategies.
Edaravone reduces Aβ-induced oxidative damage in SH-SY5Y cells by activating the Nrf2/ARE signaling pathway
Zhang L, Guo Y, Wang H, Zhao L, Ma Z, Li T, Liu J, Sun M, Jian Y, Yao L, Du Y and Zhang G
Edaravone potentially alleviates cognitive deficits in a mouse model of Alzheimer's disease (AD). However, the mechanism of edaravone in suppressing AD progression remains unclear. We aim to investigate the mechanism of edaravone in suppressing oxidative stress-mediated AD progression in vitro.
Activation of anti-oxidant of curcumin pyrazole derivatives through preservation of mitochondria function and Nrf2 signaling pathway
Liao L, Shi J, Jiang C, Zhang L, Feng L, Liu J and Zhang J
Oxidative stress is an important cause of neurodegenerative diseases. Antioxidant is an potential important method to treat such diseases. The aim of this study is to discover new and effective antioxidants and their mechanism. The neuroprotective effect of six curcumin pyrozole compounds were first evaluated on sodium nitroprusside (SNP) - induced PC12 cell injury by testing cell viability and LDH release. The results showed that four compounds (C1-C4) have more significant protective effects compared to curcumin and edaravone. Furthermore, compounds C1-C4 can attenuate the intracellular ROS, and compound C3 is the most effective one which can preservate the mitochondria function by inhibiting the mitochondrial membrane potential loss and enhance nuclear translocation of Nrf2 in PC12 cell. These results indicated that C3 may be a potential candidate drug for treating neurodegenerative diseases.
Curcumin prevents high glucose damage in retinal pigment epithelial cells through ERK1/2-mediated activation of the Nrf2/HO-1 pathway
Bucolo C, Drago F, Maisto R, Romano GL, D'Agata V, Maugeri G and Giunta S
To study the effects of curcumin on human retinal pigment epithelial (RPE) cells exposed to high glucose (HG) insult, we performed in vitro studies on RPE cells cultured both in normal and HG conditions to assess the effects of curcumin on the cell viability, nuclear factor erythroid 2-related factor 2 (Nrf2) expression, HO-1 activity, and ERK1/2 expression. RPE cells exposed to HG insult were treated with curcumin. The cell viability, apoptosis, HO-1 activity, ERK, and Nrf2 expression were evaluated. The data indicated that treatment with curcumin caused a significant decrease in terms of apoptosis. Further, curcumin was able to induce HO-1 expression via Nrf2 activation and counteracts the damage elicited by HG. The present study demonstrated that curcumin provides protection against HG-induced damage in RPE cells through the activation of Nrf2/HO-1 signaling that involves the ERK pathway, suggesting that curcumin may have therapeutic value in the treatment of diabetic retinopathy.
Melatonin alleviates aluminium chloride-induced immunotoxicity by inhibiting oxidative stress and apoptosis associated with the activation of Nrf2 signaling pathway
Yu H, Zhang J, Ji Q, Yu K, Wang P, Song M, Cao Z, Zhang X and Li Y
The present study aimed to investigate whether melatonin (MT) treatment can attenuate immunotoxicity induced by aluminum chloride (AlCl) in rat spleen. Forty-eight healthy male Wistar rats were randomly allocated and treated with AlCl and/or MT. Rats were orally administered with AlCl for 90 days, from 61st days, rats were injected intraperitoneally with MT for 30 days. Firstly, we found that MT relieved the AlCl-induced immunosuppression by improving spleen structural damage, CD3 and CD4 T lymphocyte subsets, IL-2 and TNF-α mRNA expressions and decreasing CD8 T lymphocyte subsets. Secondly, MT attenuated the AlCl-induced oxidative stress in rat spleen by decreasing the levels of ROS and MDA, while increasing the activities of SOD and CAT. Thirdly, MT relieved the AlCl-induced apoptosis in rat spleen by increasing the MMP and Bcl-2 mRNA and protein expressions, while decreasing apoptosis rates, activity of Caspase-3 and pro-apoptotic gene expression. Finally, MT increased Nrf2 nuclear translocation, and Nrf2 target genes (HO-1, NQO1, SOD1 and CAT) mRNA expressions in the spleen of AlCl-exposed rat. These results suggest that MT may alleviate AlCl-induced immunotoxicity by inhibiting oxidative stress and apoptosis associated with the activation of Nrf2 signaling pathway, which could lay the foundation for the treatment of AlCl immunotoxicity.
UVB drives different stages of epigenome alterations during progression of skin cancer
Yang Y, Wu R, Sargsyan D, Yin R, Kuo HC, Yang I, Wang L, Cheng D, Wang C, Li S, Hudlikar R, Lu Y and Kong AN
Exposure to ultraviolet B (UVB) irradiation results in multitude of cellular responses including generation of reactive oxygen species and DNA damage and is responsible for non-melanoma skin cancers (NMSCs). Although genetic mutation is well documented, the epi-mutation, the alteration in epigenetics, remains elusive. In this study, we utilized CpG Methyl-seq to identify a genome-wide DNA CpG methylation, to profile the DNA methylation in UVB-irradiated SKH-1 mouse skin epidermis and non-melanoma skin papillomas at various stages. Methyl-seq and RNA-seq were performed to examine the methylation and corresponding transcriptome alterations. The methylation profiles in mouse epidermis were altered by UVB-irradiation as time progresses. Ingenuity Pathways Analysis (IPA) identified many cancer related pathways including PTEN, p53, Nrf2 and inflammatory signaling in UVB-irradiation induced carcinogenesis. Additionally, some novel genes involved in skin carcinogenesis that were not previously reported were differentially methylated, including Enf2, Mgst2, Vegfa, and Cdk4. Taken together, the current study provides novel profiles and insights of methylation and transcriptomic changes at different stages of carcinogenesis in UVB-irradiation induced NMSC and offers potential targets for prevention and treatment of NMSC at different stages of human skin cancer.
An isopentenyl-substituted flavonoid norartocarpin activates Nrf2 signaling pathway and prevents oxidative insults in human lung epithelial cells
Yang WJ, He JX, Zhou MX, Huang M, Wang SQ, Wang XN, Lou HX, Ren DM and Shen T
The nuclear factor erythroid 2-related factor 2 (Nrf2) plays a crucial role in regulating the intracellular oxidative stress, and thus activation of Nrf2 by nature-derived molecules effectively alleviates the pathological process of oxidative stress-induced chronic diseases. The isopentenyl-substituted flavonoid norartocarpin (NOR) induced the activity of NAD(P)H: quinone reductase (QR), implying that it might be a potential Nrf2 activator. Further studies indicated that NOR upregulated the protein levels of Nrf2 and its downstream genes, NAD(P)H quinone oxidoreductase 1 (NQO1), and γ-glutamyl cysteine synthetase (GCLM) through facilitating the nuclear translocation of Nrf2 and enhancing Nrf2 protein stability. NOR-induced activation of Nrf2 pathway was associated with multiple upstream kinases, including mitogen-activated protein kinase (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), protein kinase C (PKC), and protein kinase R-like endoplasmic reticulum kinase (PERK). Moreover, NOR protected human lung epithelial Beas-2B cells against sodium arsenite [As(III)]-induced cytotoxicity in an Nrf2-dependent manner. Collectively, NOR was firstly identified to be an Nrf2 activator, which demonstrated the capability of preventing oxidative insults in human lung epithelial cells.
The angiotensin-(1-7)/Mas receptor axis protects from endothelial cell senescence via klotho and Nrf2 activation
Romero A, San Hipólito-Luengo Á, Villalobos LA, Vallejo S, Valencia I, Michalska P, Pajuelo-Lozano N, Sánchez-Pérez I, León R, Bartha JL, Sanz MJ, Erusalimsky JD, Sánchez-Ferrer CF, Romacho T and Peiró C
Endothelial cell senescence is a hallmark of vascular aging that predisposes to vascular disease. We aimed to explore the capacity of the renin-angiotensin system (RAS) heptapeptide angiotensin (Ang)-(1-7) to counteract human endothelial cell senescence and to identify intracellular pathways mediating its potential protective action. In human umbilical vein endothelial cell (HUVEC) cultures, Ang II promoted cell senescence, as revealed by the enhancement in senescence-associated galactosidase (SA-β-gal+) positive staining, total and telomeric DNA damage, adhesion molecule expression, and human mononuclear adhesion to HUVEC monolayers. By activating the G protein-coupled receptor Mas, Ang-(1-7) inhibited the pro-senescence action of Ang II, but also of a non-RAS stressor such as the cytokine IL-1β. Moreover, Ang-(1-7) enhanced endothelial klotho levels, while klotho silencing resulted in the loss of the anti-senescence action of the heptapeptide. Indeed, both Ang-(1-7) and recombinant klotho activated the cytoprotective Nrf2/heme oxygenase-1 (HO-1) pathway. The HO-1 inhibitor tin protoporphyrin IX prevented the anti-senescence action evoked by Ang-(1-7) or recombinant klotho. Overall, the present study identifies Ang-(1-7) as an anti-senescence peptide displaying its protective action beyond the RAS by consecutively activating klotho and Nrf2/HO-1. Ang-(1-7) mimetic drugs may thus prove useful to prevent endothelial cell senescence and its related vascular complications.
Epidermal growth factor protects against myocardial ischemia reperfusion injury through activating Nrf2 signaling pathway
Ma J and Jin G
Alleviating the oxidant stress associated with myocardial ischemia reperfusion has been demonstrated as a potential therapeutic approach to limit ischemia reperfusion (I/R)-induced cardiac damage. It's reported that EGFR/erbB2 signaling is an important cardiac survival pathway in cardiac function and activation of EGFR has a cardiovascular effect in global ischemia. Epidermal growth factor (EGF), a typical EGFR ligand, was considered to have a significant role in activating EGFR. However, no evidence has been published whether exogenous EGF has protective effects on myocardial ischemia reperfusion. This study aims to investigate the effects of EGF in I/R-induced heart injury and to demonstrate its mechanisms. H9c2 cells challenged with HO were used for in vitro biological activity and mechanistic studies. The malondialdehyde (MDA) and Superoxide Dismutase (SOD) levels in H9c2 cells were determined, and the cell viability was assessed by MTT assay. Myocardial I/R mouse administrated with or without EGF were used for in vivo studies. Pretreatment of H9c2 cells with EGF activated Nrf2 signaling pathway, attenuated HO-increased MDA and HO-reduced SOD level, followed by the inhibition of HO-induced cell death. In in vivo animal models of myocardial I/R, administration of EGF reduced infarct size and myocardial apoptosis. These data support that EGF decreases oxidative stress and attenuates myocardial ischemia reperfusion injury via activating Nrf2.
PMA-triggered PKCε activity enhances Nrf2-mediated antiviral response on fish rhabdovirus infection
Dang YF, Qiu TX, Song DW and Liu L
Viral infection is often accompanied with alteration of intracellular redox state, especially an imbalance between reactive oxygen species (ROS) production and antioxidant cellular defenses. The previous studies showed that an antioxidant cellular defense system, the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), played an important role against spring viraemia of carp virus (SVCV) infection in fish. To further reveal the mediated mechanism that Nrf2 active state was affected by protein kinase C (PKC), here we evaluated SVCV replication in host cells by treated with a strong activator of PKC phorbol-12-myristate-13-acetate (PMA) and an inhibitor staurosporine. Our results showed that PMA significantly repressed SVCV replication and viral-induced apoptosis in Epithelioma papulosum cyprini (EPC) cell, suggesting that PKC may exhibit an anti-SVCV effect. Likewise, PMA resulted in a higher phosphorylation levels of PKCε rather than PKCα/β to participate in the activation of Nrf2, mainly involved in the activation of Nrf2 phosphorylation of Ser40 to favor Nrf2 translocation to nucleus. Furthermore, the data revealed that PMA up-regulated an antiviral response heme oxygenase-1 (HO1) gene expression that was confirmed as the key player against SVCV infection by HO1 specific siRNA. Overall, this study provided a new therapeutic target for the treatment of SVCV infection, and modulating PKC activity could be used for the prevention and treatment of SVCV.
Ambient PM2.5 caused depressive-like responses through Nrf2/NLRP3 signaling pathway modulating inflammation
Chu C, Zhang H, Cui S, Han B, Zhou L, Zhang N, Su X, Niu Y, Chen W, Chen R, Zhang R and Zheng Y
PM2.5 pollution has been associated with numerous adverse effects including cardiovascular, respiratory and metabolic diseases as well as emotional disorders. However, the potential mechanism has not known clearly. Twenty-four rats were divided into 3 groups and exposed to various airs: filtered air (FA), unfiltered air (UA) and concentrated PM2.5 air (CA), respectively. Thirty wild type (WT) and 30 Nrf2 knockout (KO) mice were divided into 2 groups and exposed to FA and UA, respectively. The changes of neurobehavioral function, neurotransmitter secretion, toxic elements deposition, oxidative stress and the inflammation in prefrontal cortex were investigated during 9-12 weeks with/without PM2.5 exposure. Results showed that CA rats and KO-UA mice emerged obviously depressive-like responses. Li, Be, Al, Cr, Co, Ni, Se, Cd, Ba, Ti and Pb could deposit in the prefrontal cortex of rats after PM2.5 exposure. The neurotransmitters were significantly disorder in prefrontal cortex of CA rats. The NLRP3 signaling pathway was more activated in Nrf2 than WT mice after PM2.5 exposure for 9 weeks. Nrf2/ NLRP3 signaling pathway modulating the inflammation might play an important role in the depression induced by ambient PM2.5.
Correction: The Nrf2 inhibitor brusatol is a potent antitumour agent in an orthotopic mouse model of colorectal cancer
Evans JP, Winiarski BK, Sutton PA, Jones RP, Ressel L, Duckworth CA, Pritchard DM, Lin ZX, Fretwell VL, Tweedle EM, Costello E, Goldring CE, Copple IM, Park BK, Palmer DH and Kitteringham NR
[This corrects the article DOI: 10.18632/oncotarget.25497.].
p-Hydroxybenzyl Alcohol Prevents Memory Deficits by Increasing Neurotrophic Factors and Decreasing Inflammatory Factors in a Mice Model of Alzheimer's Disease
Ding Y, Bao X, Lao L, Ling Y, Wang Q and Xu S
p-hydroxybenzyl alcohol (HBA) is one of the major components of Gastrodia elata Blume (GEB) phenolic compound. HBA has been reported to have a protective effect on amyloid-β (Aβ) induced cell death. However, the systemic effects and the detail molecular mechanism of HBA in Alzheimer's disease (AD) animal models is not clear. In this study, we revealed the protective effects and the potential mechanisms of HBA on the impairments of cognitive function induced by soluble Aβ oligomers. Our results showed that HBA prevented neuronal cells death in a dose-dependent manner. The working memory and the spatial memory were significantly lower in AD model mice. HBA treatment prevented the memory deficits of the AD mice. HBA treatment significantly prevented the decreased spine density and decreased expression levels of synaptic proteins induced by Aβ42. In addition, both mRNA levels and protein levels of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) in the Aβ42-treated mice were decreased, the decreases were prevented by HBA treatment. The expression levels of TNF-α and IL-1β were increased by Aβ42 treatment and the increase can be prevented by the HBA treatment. Moreover, HBA prevents the decreases in the level of nuclear erythroid 2 p45-related factor 2 (Nrf2) induced by Aβ42 in hippocampal. Thus, we predict that HBA might prevent Aβ42 oligomer-induced synapse and cognitive impairments through multiple targets including increasing Nrf2, increasing neurotrophic factors and decreasing inflammatory factors. Our study provided novel insights into the cellular mechanisms for the protective effects of HBA on AD.

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