Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
8.8
7.0
Journals
Antioxidants
Special Issues
Role of NRF2 in Diseases: Novel Molecular Mechanism and Therapeutic...
share announcement

Role of NRF2 in Diseases: Novel Molecular Mechanism and Therapeutic Approaches

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 15876

Special Issue Editor

Dr. Young-Sam Keum

E-Mail
Guest Editor
College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea
Interests: NRF2; KEAP1; E3 ubiquitin ligase; pro-inflammatory diseases; cancer; antioxidants; post-translational modifications

Special Issue Information

Dear Colleagues,

Oganisms are constantly exposed to a variety of oxidative stresses, resulting in the impairment of proteins, lipids, and nucleic acids. Therefore, the organisms possess diverse antioxidants and enzymatic defense systems to relieve oxidative damages. NF-E2-related factor 2 (NRF2) is such a transcription factor that regulates redox homeostasis and provides protection against oxidants and electrophiles by inducing the expression of a wide array of phase II cytoprotective genes in cells, and the stability of NRF2 is primarily regulated via poly-ubiquitination by Kelch-like ECH-associated protein 1 (KEAP1), an adaptor protein for Cullin 3 (CUL3)-based E3 ubiquitin ligase. By far, many NRF2 activators have been developed for chemoprevention and treatment of chronic diseases. The development of NRF2 inhibitors has gained significant interest in the field of oncology because NRF2 confers chemoresistance and radioresistance in cancer due to mutations in the KEAP1/ NRF2 pathway.

This Special Issue aims to publish original research papers and reviews regarding to the elucidation of novel regulatory mechanisms of CUL3/KEAP1/NRF2 as well as the identification of novel NRF2 activators and inhibitors. We call upon scientists in this field to contribute their valuable manuscripts to this Special Issue.

Dr. Young-Sam Keum
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antioxidants is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • NRF2
  • KEAP1
  • NRF2 regulators

Published Papers (6 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Research

21 pages, 2928 KiB  
Article
The Transcription Factor NRF2 Has Epigenetic Regulatory Functions Modulating HDACs, DNMTs, and miRNA Biogenesis
by Ignacio Silva-Llanes, Chang Hoon Shin, José Jiménez-Villegas, Myriam Gorospe and Isabel Lastres-Becker
Antioxidants 2023, 12(3), 641; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox12030641 - 04 Mar 2023
Cited by 5 | Viewed by 2152
Abstract
The epigenetic regulation of gene expression is a complex and tightly regulated process that defines cellular identity and is associated with health and disease processes. Oxidative stress is capable of inducing epigenetic modifications. The transcription factor NRF2 (nuclear factor erythroid-derived 2-like 2) is [...] Read more.
The epigenetic regulation of gene expression is a complex and tightly regulated process that defines cellular identity and is associated with health and disease processes. Oxidative stress is capable of inducing epigenetic modifications. The transcription factor NRF2 (nuclear factor erythroid-derived 2-like 2) is a master regulator of cellular homeostasis, regulating genes bearing antioxidant response elements (AREs) in their promoters. Here, we report the identification of ARE sequences in the promoter regions of genes encoding several epigenetic regulatory factors, such as histone deacetylases (HDACs), DNA methyltransferases (DNMTs), and proteins involved in microRNA biogenesis. In this research, we study this possibility by integrating bioinformatic, genetic, pharmacological, and molecular approaches. We found ARE sequences in the promoter regions of genes encoding several HDACs, DNMTs, and proteins involved in miRNA biogenesis. We confirmed that NRF2 regulates the production of these genes by studying NRF2-deficient cells and cells treated with dimethyl fumarate (DMF), an inducer of the NRF2 signaling pathway. In addition, we found that NRF2 could be involved in the target RNA-dependent microRNA degradation (TDMD) of miR-155-5p through its interaction with Nfe2l2 mRNA. Our data indicate that NRF2 has an epigenetic regulatory function, complementing its traditional function and expanding the regulatory dimensions that should be considered when developing NRF2-centered therapeutic strategies. Full article
(This article belongs to the Special Issue Role of NRF2 in Diseases: Novel Molecular Mechanism and Therapeutic Approaches)
►▼ Show Figures

Graphical abstract

35 pages, 3344 KiB  
Article
Hydralazine Revives Cellular and Ocular Lens Health-Span by Ameliorating the Aging and Oxidative-Dependent Loss of the Nrf2-Activated Cellular Stress Response
by Bhavana Chhunchha, Eri Kubo, Ronald R. Krueger and Dhirendra P. Singh
Antioxidants 2023, 12(1), 140; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox12010140 - 06 Jan 2023
Cited by 3 | Viewed by 2324
Abstract
A major hallmark of aging-associated diseases is the inability to evoke cellular defense responses. Transcriptional protein Nrf2 (nuclear factor erythroid-derived 2-related factor) plays a pivotal role in the oxidative stress response, cellular homeostasis, and health span. Nrf2’s activation has been identified as a [...] Read more.
A major hallmark of aging-associated diseases is the inability to evoke cellular defense responses. Transcriptional protein Nrf2 (nuclear factor erythroid-derived 2-related factor) plays a pivotal role in the oxidative stress response, cellular homeostasis, and health span. Nrf2’s activation has been identified as a therapeutic target to restore antioxidant defense in aging. Here, we demonstrated that FDA-approved drug, hydralazine (Hyd), was a reactivator of the Nrf2/ARE (antioxidant response element) pathway in various ages and types of mouse (m) or human (h) lens epithelial cells (LECs) and mice lenses in-vitro/in-vivo. This led to Hyd-driven abatement of carbonyls, reduced reactive oxygen species (ROS), and reduced 4-HNE/MDA-adducts with cytoprotection, and extended lens healthspan by delaying/preventing lens opacity against aging/oxidative stress. We elucidated that Hyd activated the protective signaling by inducing Nrf2 to traverse from the cytoplasm to the nucleus and potentiated the ARE response by direct interaction of Nrf2 and ARE sequences of the promoter. Loss-of-function study and cotreatment of Hyd and antioxidant, N-acetyl cysteine (NAC) or Peroxiredoxin (Prdx)6, specified that Nrf2/ARE-driven increase in the promoter activity was Hyd-dependent. Our study provides proof-of concept evidence and, thereby, paves the way to repurposing Hyd as a therapeutic agent to delay/prevent aging and oxidative-related disorders. Full article
(This article belongs to the Special Issue Role of NRF2 in Diseases: Novel Molecular Mechanism and Therapeutic Approaches)
►▼ Show Figures

Graphical abstract

19 pages, 2510 KiB  
Article
The Triterpenoid CDDO-Methyl Ester Redirects Macrophage Polarization and Reduces Lung Tumor Burden in a Nrf2-Dependent Manner
by Jessica A. Moerland, Ana S. Leal, Beth Lockwood, Elena Y. Demireva, Huirong Xie, Teresa Krieger-Burke and Karen T. Liby
Antioxidants 2023, 12(1), 116; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox12010116 - 03 Jan 2023
Cited by 3 | Viewed by 1850
Abstract
The NRF2/KEAP1 pathway protects healthy cells from malignant transformation and maintains cellular homeostasis. Up to 30% of human lung tumors gain constitutive NRF2 activity which contributes to cancer cell survival and chemoresistance, but the effects of NRF2 activation in immune cells within the [...] Read more.
The NRF2/KEAP1 pathway protects healthy cells from malignant transformation and maintains cellular homeostasis. Up to 30% of human lung tumors gain constitutive NRF2 activity which contributes to cancer cell survival and chemoresistance, but the effects of NRF2 activation in immune cells within the tumor microenvironment are underexplored. Macrophages can promote cancer progression or regression depending on context, and NRF2 activation affects macrophage activity. The NRF2 activator CDDO-Methyl ester (CDDO-Me or bardoxolone methyl) reprogrammed Nrf2 wild-type (WT) tumor-educated bone marrow-derived macrophages (TE-BMDMs) from a tumor-promoting to a tumor-inhibiting phenotype, marked by an increase in M1 markers TNFα, IL-6, and MHC-II and a decrease in the tumor-promoting factors VEGF, CCL2, and CD206. No changes were observed in Nrf2 knockout (KO) TE-BMDMs. CDDO-Me decreased tumor burden (p < 0.001) and improved pathological grade (p < 0.05) in WT but not Nrf2 KO A/J mice. Tumor burden in Nrf2 KO mice was 4.6-fold higher (p < 0.001) than in WT mice, irrespective of treatment. CDDO-Me increased the number of lung-infiltrating macrophages in WT mice but lowered CD206 expression in these cells (p < 0.0001). In summary, Nrf2 KO exacerbates lung tumorigenesis in A/J mice, and CDDO-Me promotes an Nrf2-dependent, anti-cancer macrophage phenotype. Full article
(This article belongs to the Special Issue Role of NRF2 in Diseases: Novel Molecular Mechanism and Therapeutic Approaches)
►▼ Show Figures

Figure 1

17 pages, 2538 KiB  
Article
NRF2 Activation in Autophagy Defects Suppresses a Pharmacological Transactivation of the Nuclear Receptor FXR
by Eun Young Kim and Jae Man Lee
Antioxidants 2022, 11(2), 370; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11020370 - 12 Feb 2022
Cited by 1 | Viewed by 2258
Abstract
NF-E2-related factor 2 (NRF2), an antioxidant transcription factor, is activated in autophagy-deficient mice due to the accumulations of p62/SQSTM1 and its subsequent interaction with Kelch-like-ECH-associated protein 1 (KEAP1), an adaptor component for Cullin3-based E3 ubiquitin ligase complex. Farnesoid x receptor (FXR/NR1H4) is a [...] Read more.
NF-E2-related factor 2 (NRF2), an antioxidant transcription factor, is activated in autophagy-deficient mice due to the accumulations of p62/SQSTM1 and its subsequent interaction with Kelch-like-ECH-associated protein 1 (KEAP1), an adaptor component for Cullin3-based E3 ubiquitin ligase complex. Farnesoid x receptor (FXR/NR1H4) is a ligand-dependent transcription factor that belongs to the nuclear receptor superfamily. FXR plays an essential role in bile acid synthesis and enterohepatic circulation, affecting glucose and lipid metabolism. Obeticholic acid as a potent FXR agonist has been approved to treat primary biliary cholangitis and clinical trials for its use in the treatment of other liver diseases are underway. Here we show that NRF2 activation in autophagy defects impedes a transactivation of FXR. Liver-specific Atg7 knockout mice or a treatment of autophagy inhibitor showed decreased inductions of FXR target genes upon its synthetic agonists. Moreover, enforced NRF2 activations with small molecules potently decreased the pharmacological activation of FXR in cultured cells. Finally, we demonstrate that NRF2 activation by the treatment with the food antioxidant butylated hydroxyanisole is necessary and sufficient to inhibit the pharmacological activation of FXR in vivo. These results reveal a novel function of the basal autophagy-NRF2 axis for the regulation of FXR transactivation, and shed light on a potential therapeutic strategy in metabolic disease. Full article
(This article belongs to the Special Issue Role of NRF2 in Diseases: Novel Molecular Mechanism and Therapeutic Approaches)
►▼ Show Figures

Figure 1

17 pages, 3177 KiB  
Article
BAP1 Downregulates NRF2 Target Genes and Exerts Anti-Tumorigenic Effects by Deubiquitinating KEAP1 in Lung Adenocarcinoma
by Jong-Su Kang, Le Ba Nam, Ok-Kyung Yoo, Kyeong Lee, Young-Ah Suh, Dalyong Kim, Woo Kyung Kim, Chi-Yeon Lim, Haeseung Lee and Young-Sam Keum
Antioxidants 2022, 11(1), 114; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11010114 - 05 Jan 2022
Cited by 4 | Viewed by 2285
Abstract
KELCH-ECH-associated protein 1 (KEAP1) is an adaptor protein of Cullin 3 (CUL3) E3 ubiquitin ligase that targets a redox sensitive transcription factor, NF-E2-related factor 2 (NRF2). BRCA1-associated protein 1 (BAP1) is a tumor suppressor and deubiquitinase whose mutations increase the risk of several [...] Read more.
KELCH-ECH-associated protein 1 (KEAP1) is an adaptor protein of Cullin 3 (CUL3) E3 ubiquitin ligase that targets a redox sensitive transcription factor, NF-E2-related factor 2 (NRF2). BRCA1-associated protein 1 (BAP1) is a tumor suppressor and deubiquitinase whose mutations increase the risk of several types of familial cancers. In the present study, we have identified that BAP1 deubiquitinates KEAP1 by binding to the BTB domain. Lentiviral transduction of BAP1 decreased the expression of NRF2 target genes, suppressed the migration and invasion, and sensitized cisplatin-induced apoptosis in human lung adenocarcinoma (LUAD) A549 cells. Examination of the lung tissues in KrasG12D/+ mice demonstrated that the level of Bap1 and Keap1 mRNAs progressively decreases during lung tumor progression, and it is correlated with NRF2 activation and the inhibition of oxidative stress. Supporting this observation, lentiviral transduction of BAP1 decreased the growth of A549 xenografts in athymic nude mice. Transcriptome analysis of human lung tissues showed that the levels of Bap1 mRNA are significantly higher in normal samples than LUAD samples. Moreover, the expression of Bap1 mRNA is associated with a better survival of LUAD patients. Together, our study demonstrates that KEAP1 deubiquitination by BAP1 is novel tumor suppressive mechanism of LUAD. Full article
(This article belongs to the Special Issue Role of NRF2 in Diseases: Novel Molecular Mechanism and Therapeutic Approaches)
►▼ Show Figures

Figure 1

25 pages, 4345 KiB  
Article
Differential Yet Integral Contributions of Nrf1 and Nrf2 in the Human HepG2 Cells on Antioxidant Cytoprotective Response against Tert-Butylhydroquinone as a Pro-Oxidative Stressor
by Reziyamu Wufuer, Zhuo Fan, Keli Liu and Yiguo Zhang
Antioxidants 2021, 10(10), 1610; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10101610 - 13 Oct 2021
Cited by 14 | Viewed by 3775
Abstract
In the past 25 years, Nrf2 (nuclear factor erythroid 2-related factor 2, also called NFE2L2) had been preferentially parsed as a master hub of regulating antioxidant, detoxification, and cytoprotective genes; albeit as a matter of fact that Nrf1 (nuclear factor erythroid 2-related factor [...] Read more.
In the past 25 years, Nrf2 (nuclear factor erythroid 2-related factor 2, also called NFE2L2) had been preferentially parsed as a master hub of regulating antioxidant, detoxification, and cytoprotective genes; albeit as a matter of fact that Nrf1 (nuclear factor erythroid 2-related factor 1, also called NFE2L1)—rather than Nrf2—is indispensable for cell homeostasis and organ integrity during normal growth and development. Herein, distinct genotypic cell lines (i.e., Nrf1α−/−, Nrf2−/−ΔTA, and caNrf2ΔN) are employed to determine differential yet integral roles of Nrf1 and Nrf2 in mediating antioxidant responsive genes to tert-butylhydroquinone (tBHQ) serving as a pro-oxidative stressor. In Nrf1α−/− cells, Nrf2 was highly accumulated but also could not fully compensate specific loss of Nrf1α’s function in its basal cytoprotective response against endogenous oxidative stress, though it exerted partially inducible antioxidant response, as the hormetic effect of tBHQ, against apoptotic damages. By contrast, Nrf2−/−ΔTA cells gave rise to a substantial reduction of Nrf1 in both basal and tBHQ-stimulated expression levels and hence resulted in obvious oxidative stress, but it can still be allowed to mediate a potent antioxidant response, as accompanied by a significantly decreased ratio of GSSG (oxidized glutathione) to GSH (reduced glutathione). Conversely, a remarkable increase of Nrf1 expression resulted from the constitutive active caNrf2ΔN cells, which were not manifested with oxidative stress, whether or not it was intervened with tBHQ. Such inter-regulatory effects of Nrf1 and Nrf2 on the antioxidant and detoxification genes (encoding HO-1, NQO1, GCLC, GCLM, GSR, GPX1, TALDO, MT1E, and MT2), as well on the ROS (reactive oxygen species)-scavenging activities of SOD (superoxide dismutase) and CAT (catalase), were further investigated. The collective results unraveled that Nrf1 and Nrf2 make distinctive yet cooperative contributions to finely tuning basal constitutive and/or tBHQ-inducible expression levels of antioxidant cytoprotective genes in the inter-regulatory networks. Overall, Nrf1 acts as a brake control for Nrf2’s functionality to be confined within a certain extent, whilst its transcription is regulated by Nrf2. Full article
(This article belongs to the Special Issue Role of NRF2 in Diseases: Novel Molecular Mechanism and Therapeutic Approaches)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-6
Back to TopTop