Transcription Factor Nrf2

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "ROS, RNS and RSS".

Deadline for manuscript submissions: closed (20 June 2022) | Viewed by 36383

Special Issue Editor

Lab Neuroprotective Strategies for Neurodegenerative Diseases, Faculty of Medicine, Autonomous University of Madrid (UAM), Madrid, Spain
Interests: NRF2; KEAP1; cell signaling; neurodegeneration; neuroinflammation; Alzheimer's disease; Parkinson's disease

Special Issue Information

Dear Colleagues,

Many non-communicable diseases (NCDs) share common pathomechanisms such as metabolic, redox, and inflammatory dysregulation, that might benefit from acting on a common molecular target: the transcription factor NRF2 (nuclear factor (erythroid-derived 2)-like 2). NRF2 regulates the expression of about 250 genes encoding a network of enzymes involved in NADPH-, glutathione-, and thioredoxin-mediated reactions, inhibition of inflammation, induction of autophagy genes, etc. Through this transcriptional network, NRF2 coordinates multifaceted responses to diverse forms of stress for maintaining a stable internal environment. This review series will present the current knowledge about the role of NRF2 in the pathophysiology of several NCDs including cancer, diabetes, autoimmune, cardiovascular, and neurodegenerative diseases, among others. Considering the impact of NRF2 on the modulation of inflammation, another aspect to be covered is the identification of NRF2 as a novel anti-inflammatory target in infectious diseases, including Covid-19. Evidence gathered for the past 10 years strongly points towards an NRF2-related strategy for drug development and repurposing in several diseases. This Special Issue will gather the current state of the art of preclinical and clinical studies on NRF2 activators and inhibitors.

We invite researchers in the field and the participants of The COST Action CA20121, Bench to Bedside Transition for Pharmacological regulation of NRF2 in non-communicable diseases (BenBedPhar) to submit their latest research findings to this Special Issue.

text

Prof. Dr. Antonio Cuadrado
Guest Editor

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Published Papers (11 papers)

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Research

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14 pages, 3239 KiB  
Article
Loss of KEAP1 Causes an Accumulation of Nondegradative Organelles
Antioxidants 2022, 11(7), 1398; https://doi.org/10.3390/antiox11071398 - 19 Jul 2022
Cited by 4 | Viewed by 1719
Abstract
KEAP1 is a cytoplasmic protein that functions as an adaptor for the Cullin-3-based ubiquitin E3 ligase system, which regulates the degradation of many proteins, including NFE2L2/NRF2 and p62/SQSTM1. Loss of KEAP1 leads to an accumulation of protein ubiquitin aggregates and defective autophagy. To [...] Read more.
KEAP1 is a cytoplasmic protein that functions as an adaptor for the Cullin-3-based ubiquitin E3 ligase system, which regulates the degradation of many proteins, including NFE2L2/NRF2 and p62/SQSTM1. Loss of KEAP1 leads to an accumulation of protein ubiquitin aggregates and defective autophagy. To better understand the role of KEAP1 in the degradation machinery, we investigated whether Keap1 deficiency affects the endosome-lysosomal pathway. We used KEAP1-deficient mouse embryonic fibroblasts (MEFs) and combined Western blot analysis and fluorescence microscopy with fluorometric and pulse chase assays to analyze the levels of lysosomal-endosomal proteins, lysosomal function, and autophagy activity. We found that the loss of keap1 downregulated the protein levels and activity of the cathepsin D enzyme. Moreover, KEAP1 deficiency caused lysosomal alterations accompanied by an accumulation of autophagosomes. Our study demonstrates that KEAP1 deficiency increases nondegradative lysosomes and identifies a new role for KEAP1 in lysosomal function that may have therapeutic implications. Full article
(This article belongs to the Special Issue Transcription Factor Nrf2)
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13 pages, 3439 KiB  
Article
Transcription Factor NRF2 Participates in Cell Cycle Progression at the Level of G1/S and Mitotic Checkpoints
Antioxidants 2022, 11(5), 946; https://doi.org/10.3390/antiox11050946 - 11 May 2022
Cited by 6 | Viewed by 1725
Abstract
Transcription factor NRF2 is a master regulator of the multiple cytoprotective responses that confer growth advantages on a cell. However, its participation in the mechanisms that govern the cell division cycle has not been explored in detail. In this study, we used several [...] Read more.
Transcription factor NRF2 is a master regulator of the multiple cytoprotective responses that confer growth advantages on a cell. However, its participation in the mechanisms that govern the cell division cycle has not been explored in detail. In this study, we used several standard methods of synchronization of proliferating cells together with flow cytometry and monitored the participation of NRF2 along the cell cycle by the knockdown of its gene expression. We found that the NRF2 levels were highest at S phase entry, and lowest at mitosis. NRF2 depletion promoted both G1 and M arrest. Targeted transcriptomics analysis of cell cycle regulators showed that NRF2 depletion leads to changes in key cell cycle regulators, such as CDK2, TFDP1, CDK6, CDKN1A (p21), CDKN1B (p27), CCNG1, and RAD51. This study gives a new dimension to NRF2 effects, showing their implication in cell cycle progression. Full article
(This article belongs to the Special Issue Transcription Factor Nrf2)
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15 pages, 2100 KiB  
Article
Pirin, an Nrf2-Regulated Protein, Is Overexpressed in Human Colorectal Tumors
Antioxidants 2022, 11(2), 262; https://doi.org/10.3390/antiox11020262 - 28 Jan 2022
Cited by 6 | Viewed by 2437
Abstract
The evolutionary conserved non-heme Fe-containing protein pirin has been implicated as an important factor in cell proliferation, migration, invasion, and tumour progression of melanoma, breast, lung, cervical, prostate, and oral cancers. Here we found that pirin is overexpressed in human colorectal cancer in [...] Read more.
The evolutionary conserved non-heme Fe-containing protein pirin has been implicated as an important factor in cell proliferation, migration, invasion, and tumour progression of melanoma, breast, lung, cervical, prostate, and oral cancers. Here we found that pirin is overexpressed in human colorectal cancer in comparison with matched normal tissue. The overexpression of pirin correlates with activation of transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) and increased expression of the classical Nrf2 target NAD(P)H:quinone oxidoreductase 1 (NQO1), but interestingly and unexpectedly, not with expression of the aldo-keto reductase (AKR) family members AKR1B10 and AKR1C1, which are considered to be the most overexpressed genes in response to Nrf2 activation in humans. Using pharmacologic and genetic approaches to either downregulate or upregulate Nrf2, we show that pirin is regulated by Nrf2 in human and mouse cells and in the mouse colon in vivo. The small molecule pirin inhibitor TPhA decreased the viability of human colorectal cancer (DLD1) cells, but this decrease was independent of the levels of pirin. Our study demonstrates the Nrf2-dependent regulation of pirin and encourages the pursuit for specific pirin inhibitors. Full article
(This article belongs to the Special Issue Transcription Factor Nrf2)
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28 pages, 2394 KiB  
Article
Novel Series of Dual NRF2 Inducers and Selective MAO-B Inhibitors for the Treatment of Parkinson’s Disease
Antioxidants 2022, 11(2), 247; https://doi.org/10.3390/antiox11020247 - 27 Jan 2022
Cited by 4 | Viewed by 2370
Abstract
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease. It is characterized by a complex network of physiopathological events where oxidative stress plays a central role among other factors such as neuroinflammation and protein homeostasis. Nuclear factor-erythroid 2 p45-related factor 2 (NRF2) [...] Read more.
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease. It is characterized by a complex network of physiopathological events where oxidative stress plays a central role among other factors such as neuroinflammation and protein homeostasis. Nuclear factor-erythroid 2 p45-related factor 2 (NRF2) has a multitarget profile itself as it controls a plethora of cellular processes involved in the progression of the disease. In this line, we designed a novel family of 2-(1H-indol-3-yl)ethan-1-amine derivatives as NRF2 inducers with complementary activities. Novel compounds are based on melatonin scaffold and include, among other properties, selective monoamine oxidase B (MAO-B) inhibition activity. Novel multitarget compounds exhibited NRF2 induction activity and MAO-B selective inhibition, combined with anti-inflammatory, antioxidant, and blood–brain barrier permeation properties. Furthermore, they exert neuroprotective properties against oxidative stress toxicity in PD-related in vitro. Hit compound 14 reduced oxidative stress markers and exerted neuroprotection in rat striatal slices exposed to 6-hydroxydopamine or rotenone. In conclusion, we developed a promising family of dual NRF2 inducers and selective MAO-B inhibitors that could serve as a novel therapeutic strategy for PD treatment. Full article
(This article belongs to the Special Issue Transcription Factor Nrf2)
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21 pages, 3569 KiB  
Article
Oxidative Stress-Induced Misfolding and Inclusion Formation of Nrf2 and Keap1
Antioxidants 2022, 11(2), 243; https://doi.org/10.3390/antiox11020243 - 27 Jan 2022
Cited by 2 | Viewed by 1910
Abstract
Cells that experience high levels of oxidative stress respond by inducing antioxidant proteins through activation of the protein transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 is negatively regulated by the E3 ubiquitin ligase Kelch-like ECH-associated protein 1 (Keap1), which binds [...] Read more.
Cells that experience high levels of oxidative stress respond by inducing antioxidant proteins through activation of the protein transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 is negatively regulated by the E3 ubiquitin ligase Kelch-like ECH-associated protein 1 (Keap1), which binds to Nrf2 to facilitate its ubiquitination and ensuing proteasomal degradation under basal conditions. Here, we studied protein folding and misfolding in Nrf2 and Keap1 in yeast, mammalian cells, and purified proteins under oxidative stress conditions. Both Nrf2 and Keap1 are susceptible to protein misfolding and inclusion formation upon oxidative stress. We propose that the intrinsically disordered regions within Nrf2 and the high cysteine content of Keap1 contribute to their oxidation and the ensuing misfolding. Our work reveals previously unexplored aspects of Nrf2 and Keap1 regulation and/or dysregulation by oxidation-induced protein misfolding. Full article
(This article belongs to the Special Issue Transcription Factor Nrf2)
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24 pages, 3775 KiB  
Article
Enantioselective Synthesis and Pharmacological Evaluation of Aza-CGP37157–Lipoic Acid Hybrids for the Treatment of Alzheimer’s Disease
Antioxidants 2022, 11(1), 112; https://doi.org/10.3390/antiox11010112 - 04 Jan 2022
Cited by 1 | Viewed by 1901
Abstract
Hybrids based on an aza-analogue of CGP37157, a mitochondrial Na+/Ca2+ exchanger antagonist, and lipoic acid were obtained in order to combine in a single molecule the antioxidant and NRF2 induction properties of lipoic acid and the neuroprotective activity of CGP37157. [...] Read more.
Hybrids based on an aza-analogue of CGP37157, a mitochondrial Na+/Ca2+ exchanger antagonist, and lipoic acid were obtained in order to combine in a single molecule the antioxidant and NRF2 induction properties of lipoic acid and the neuroprotective activity of CGP37157. The four possible enantiomers of the hybrid structure were synthesized by using as the key step a fully diastereoselective reduction induced by Ellman’s chiral auxiliary. After computational druggability studies that predicted good ADME profiles and blood–brain permeation for all compounds, the DPPH assay showed moderate oxidant scavenger capacity. Following a cytotoxicity evaluation that proved the compounds to be non-neurotoxic at the concentrations tested, they were assayed for NRF2 induction capacity and for anti-inflammatory properties and measured by their ability to inhibit nitrite production in the lipopolysaccharide-stimulated BV2 microglial cell model. Moreover, the compounds were studied for their neuroprotective effect in a model of oxidative stress achieved by treatment of SH-SY5Y neuroblastoma cells with the rotenone–oligomycin combination and also in a model of hyperphosphorylation induced by treatment with okadaic acid. The stereocenter configuration showed a critical influence in NRF2 induction properties, and also in the neuroprotection against oxidative stress experiment, leading to the identification of the compound with S and R configuration as an interesting hit with a good neuroprotective profile against oxidative stress and hyperphosphorylation, together with a relevant anti-neuroinflammatory activity. This interesting multitarget profile will be further characterized in future work. Full article
(This article belongs to the Special Issue Transcription Factor Nrf2)
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17 pages, 1654 KiB  
Article
Trimethylamine N-Oxide Promotes Autoimmunity and a Loss of Vascular Function in Toll-like Receptor 7-Driven Lupus Mice
Antioxidants 2022, 11(1), 84; https://doi.org/10.3390/antiox11010084 - 30 Dec 2021
Cited by 7 | Viewed by 2667
Abstract
Plasma levels of trimethylamine N-oxide (TMAO) are elevated in lupus patients. We analyzed the implication of TMAO in autoimmunity and vascular dysfunction of the murine model of systemic lupus erythematosus (SLE) induced by the activation of the Toll-like receptor (TLR)7 with imiquimod (IMQ). [...] Read more.
Plasma levels of trimethylamine N-oxide (TMAO) are elevated in lupus patients. We analyzed the implication of TMAO in autoimmunity and vascular dysfunction of the murine model of systemic lupus erythematosus (SLE) induced by the activation of the Toll-like receptor (TLR)7 with imiquimod (IMQ). Female BALB/c mice were randomly divided into four groups: untreated control mice, control mice treated with the trimethylamine lyase inhibitor 3,3-dimethyl-1-butanol (DMB), IMQ mice, and IMQ mice treated with DMB. The DMB-treated groups were administered the substance in their drinking water for 8 weeks. Treatment with DMB reduced plasma levels of TMAO in mice with IMQ-induced lupus. DMB prevents the development of hypertension, reduces disease progression (plasma levels of anti-dsDNA autoantibodies, splenomegaly, and proteinuria), reduces polarization of T lymphocytes towards Th17/Th1 in secondary lymph organs, and improves endothelial function in mice with IMQ-induced lupus. The deleterious vascular effects caused by TMAO appear to be associated with an increase in vascular oxidative stress generated by increased NADPH oxidase activity, derived in part from the vascular infiltration of Th17/Th1 lymphocytes, and reduced nrf2-driven antioxidant defense. In conclusion, our findings identified the bacterial-derived TMAO as a regulator of immune system, allowing for the development of autoimmunity and endothelial dysfunction in SLE mice. Full article
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19 pages, 6321 KiB  
Article
Noise-Induced Vascular Dysfunction, Oxidative Stress, and Inflammation Are Improved by Pharmacological Modulation of the NRF2/HO-1 Axis
Antioxidants 2021, 10(4), 625; https://doi.org/10.3390/antiox10040625 - 19 Apr 2021
Cited by 19 | Viewed by 3186
Abstract
Vascular oxidative stress, inflammation, and subsequent endothelial dysfunction are consequences of traditional cardiovascular risk factors, all of which contribute to cardiovascular disease. Environmental stressors, such as traffic noise and air pollution, may also facilitate the development and progression of cardiovascular and metabolic diseases. [...] Read more.
Vascular oxidative stress, inflammation, and subsequent endothelial dysfunction are consequences of traditional cardiovascular risk factors, all of which contribute to cardiovascular disease. Environmental stressors, such as traffic noise and air pollution, may also facilitate the development and progression of cardiovascular and metabolic diseases. In our previous studies, we investigated the influence of aircraft noise exposure on molecular mechanisms, identifying oxidative stress and inflammation as central players in mediating vascular function. The present study investigates the role of heme oxygenase-1 (HO-1) as an antioxidant response preventing vascular consequences following exposure to aircraft noise. C57BL/6J mice were treated with the HO-1 inducer hemin (25 mg/kg i.p.) or the NRF2 activator dimethyl fumarate (DMF, 20 mg/kg p.o.). During therapy, the animals were exposed to noise at a maximum sound pressure level of 85 dB(A) and a mean sound pressure level of 72 dB(A). Our data showed a marked protective effect of both treatments on animals exposed to noise for 4 days by normalization of arterial hypertension and vascular dysfunction in the noise-exposed groups. We observed a partial normalization of noise-triggered oxidative stress and inflammation by hemin and DMF therapy, which was associated with HO-1 induction. The present study identifies possible new targets for the mitigation of the adverse health effects caused by environmental noise exposure. Since natural dietary constituents can achieve HO-1 and NRF2 induction, these pathways represent promising targets for preventive measures. Full article
(This article belongs to the Special Issue Transcription Factor Nrf2)
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Review

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17 pages, 2554 KiB  
Review
AHR and NRF2 in Skin Homeostasis and Atopic Dermatitis
Antioxidants 2022, 11(2), 227; https://doi.org/10.3390/antiox11020227 - 25 Jan 2022
Cited by 21 | Viewed by 4433
Abstract
Skin is constantly exposed to environmental insults, including toxic chemicals and oxidative stress. These insults often provoke perturbation of epidermal homeostasis and lead to characteristic skin diseases. AHR (aryl hydrocarbon receptor) and NRF2 (nuclear factor erythroid 2-related factor 2) are transcription factors that [...] Read more.
Skin is constantly exposed to environmental insults, including toxic chemicals and oxidative stress. These insults often provoke perturbation of epidermal homeostasis and lead to characteristic skin diseases. AHR (aryl hydrocarbon receptor) and NRF2 (nuclear factor erythroid 2-related factor 2) are transcription factors that induce a battery of cytoprotective genes encoding detoxication and antioxidant enzymes in response to environmental insults. In addition to their basic functions as key regulators of xenobiotic and oxidant detoxification, recent investigations revealed that AHR and NRF2 also play critical roles in the maintenance of skin homeostasis. In fact, specific disruption of AHR function in the skin has been found to be associated with the pathogenesis of various skin diseases, most prevalently atopic dermatitis (AD). In this review, current knowledge on the roles that AHR and NRF2 play in epidermal homeostasis was summarized. Functional annotations of genetic variants, both regulatory and nonsynonymous SNPs, identified in the AHR and NRF2 loci in the human genome were also summarized. Finally, the possibility that AHR and NRF2 serve as therapeutic targets of AD was assessed. Full article
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19 pages, 2416 KiB  
Review
The KEAP1-NRF2 System in Healthy Aging and Longevity
Antioxidants 2021, 10(12), 1929; https://doi.org/10.3390/antiox10121929 - 30 Nov 2021
Cited by 42 | Viewed by 6517
Abstract
Aging is inevitable, but the inherently and genetically programmed aging process is markedly influenced by environmental factors. All organisms are constantly exposed to various stresses, either exogenous or endogenous, throughout their lives, and the quality and quantity of the stresses generate diverse impacts [...] Read more.
Aging is inevitable, but the inherently and genetically programmed aging process is markedly influenced by environmental factors. All organisms are constantly exposed to various stresses, either exogenous or endogenous, throughout their lives, and the quality and quantity of the stresses generate diverse impacts on the organismal aging process. In the current oxygenic atmosphere on earth, oxidative stress caused by reactive oxygen species is one of the most common and critical environmental factors for life. The Kelch-like ECH-associated protein 1-NFE2-related factor 2 (KEAP1-NRF2) system is a critical defense mechanism of cells and organisms in response to redox perturbations. In the presence of oxidative and electrophilic insults, the thiol moieties of cysteine in KEAP1 are modified, and consequently NRF2 activates its target genes for detoxification and cytoprotection. A number of studies have clarified the contributions of the KEAP1-NRF2 system to the prevention and attenuation of physiological aging and aging-related diseases. Accumulating knowledge to control stress-induced damage may provide a clue for extending healthspan and treating aging-related diseases. In this review, we focus on the relationships between oxidative stress and aging-related alterations in the sensory, glandular, muscular, and central nervous systems and the roles of the KEAP1-NRF2 system in aging processes. Full article
(This article belongs to the Special Issue Transcription Factor Nrf2)
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23 pages, 1795 KiB  
Review
NRF2 Activation and Downstream Effects: Focus on Parkinson’s Disease and Brain Angiotensin
Antioxidants 2021, 10(11), 1649; https://doi.org/10.3390/antiox10111649 - 20 Oct 2021
Cited by 17 | Viewed by 5959
Abstract
Reactive oxygen species (ROS) are signalling molecules used to regulate cellular metabolism and homeostasis. However, excessive ROS production causes oxidative stress, one of the main mechanisms associated with the origin and progression of neurodegenerative disorders such as Parkinson’s disease. NRF2 (Nuclear Factor-Erythroid 2 [...] Read more.
Reactive oxygen species (ROS) are signalling molecules used to regulate cellular metabolism and homeostasis. However, excessive ROS production causes oxidative stress, one of the main mechanisms associated with the origin and progression of neurodegenerative disorders such as Parkinson’s disease. NRF2 (Nuclear Factor-Erythroid 2 Like 2) is a transcription factor that orchestrates the cellular response to oxidative stress. The regulation of NRF2 signalling has been shown to be a promising strategy to modulate the progression of the neurodegeneration associated to Parkinson’s disease. The NRF2 pathway has been shown to be affected in patients with this disease, and activation of NRF2 has neuroprotective effects in preclinical models, demonstrating the therapeutic potential of this pathway. In this review, we highlight recent advances regarding the regulation of NRF2, including the effect of Angiotensin II as an endogenous signalling molecule able to regulate ROS production and oxidative stress in dopaminergic neurons. The genes regulated and the downstream effects of activation, with special focus on Kruppel Like Factor 9 (KLF9) transcription factor, provide clues about the mechanisms involved in the neurodegenerative process as well as future therapeutic approaches. Full article
(This article belongs to the Special Issue Transcription Factor Nrf2)
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