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Antioxidants
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Keap1/Nrf2 Signaling Pathway
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Keap1/Nrf2 Signaling Pathway

A special issue of Antioxidants (ISSN 2076-3921).

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 93597

Special Issue Editor

Dr. Gerasimos P. Sykiotis

E-Mail Website
Guest Editor
Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
Interests: Nrf2; Keap1; oxidative stress; inflammation; antioxidant; cytoprotection; physiology; sulforaphane; triterpenoid; chemoprevention; cancer; thyroid; hormone; endocrine

Special Issue Information

Dear Colleagues,

The pathway centered on the nuclear factor, erythroid 2-like transcription factor 2 (Nrf2), and its cytoplasmic inhibitor, kelch-like ECH-associated protein 1 (Keap1), orchestrates the expression of the antioxidant and cytoprotective genes so as to maintain homeostasis. The Keap1/Nrf2 pathway is activated by various triggers, including exposure to oxidative or electrophilic stresses; proteasome inhibitors; and so-called indirect antioxidants, including sulforaphane, curcumin, resveratrol, and various other natural compounds or synthetic substances. Currently in its third decade, research on Nrf2 has expanded so as to encompass not only basic, but also clinical studies. While the molecular biology, biochemistry, and related aspects of the Keap1/Nrf2 pathway are still very actively being investigated, Nrf2-related research has begun to spread to more clinical areas like cardiology, nephrology, endocrinology, and metabolism. Clinical trials have indeed tested the Nrf2 pathway modulators in the form of purified drugs or as dietary supplements for diverse indications like cancer chemoprevention, detoxification of environmental pollutants, metabolic disease, diabetic nephropathy, relapsing forms of multiple sclerosis, and others. Nrf2 is thus the subject of a globally active research field that keeps growing exponentially, and extends from bench to bedside. The present Special Issue will celebrate this flourishing field by publishing original research studies or reviews focused on the basic or clinical aspects of the Keap1/Nrf2 pathway.

PD Dr. Gerasimos P. Sykiotis
Guest Editor

Manuscript Submission Information

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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
  • oxidative stress
  • inflammation
  • antioxidant
  • cytoprotection
  • physiology
  • sulforaphane
  • triterpenoid
  • chemoprevention
  • cancer

Published Papers (19 papers)

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Editorial

Jump to: Research, Review

7 pages, 198 KiB  
Editorial
Keap1/Nrf2 Signaling Pathway
by Gerasimos P. Sykiotis
Antioxidants 2021, 10(6), 828; https://doi.org/10.3390/antiox10060828 - 22 May 2021
Cited by 17 | Viewed by 2581
Abstract
Nuclear factor, erythroid 2-like transcription factor 2 (Nrf2) and its cytoplasmic inhibitor, kelch-like ECH-associated protein 1 (Keap1), comprise a redox-responsive endogenous antioxidant defense module that orchestrates the expression of cytoprotective genes to maintain homeostasis [...] Full article
(This article belongs to the Special Issue Keap1/Nrf2 Signaling Pathway)

Research

Jump to: Editorial, Review

15 pages, 2784 KiB  
Article
Defining the Functional Targets of Cap‘n’collar Transcription Factors NRF1, NRF2, and NRF3
by Lara Ibrahim, Jaleh Mesgarzadeh, Ian Xu, Evan T. Powers, R. Luke Wiseman and Michael J. Bollong
Antioxidants 2020, 9(10), 1025; https://doi.org/10.3390/antiox9101025 - 21 Oct 2020
Cited by 26 | Viewed by 4831
Abstract
The NRF transcription factors NRF1, NRF2, and NRF3, are a subset of Cap‘n’collar transcriptional regulators which modulate the expression of genes harboring antioxidant-response element (ARE) sequences within their genomic loci. Despite the emerging physiological importance of NRF family members, the repertoire of their [...] Read more.
The NRF transcription factors NRF1, NRF2, and NRF3, are a subset of Cap‘n’collar transcriptional regulators which modulate the expression of genes harboring antioxidant-response element (ARE) sequences within their genomic loci. Despite the emerging physiological importance of NRF family members, the repertoire of their genetic targets remains incompletely defined. Here we use RNA-sequencing-based transcriptional profiling and quantitative proteomics to delineate the overlapping and differential genetic programs effected by the three NRF transcription factors. We then create consensus target gene sets regulated by NRF1, NRF2, and NRF3 and define the integrity of these gene sets for probing NRF activity in mammalian cell culture and human tissues. Together, our data provide a quantitative assessment of how NRF family members sculpt proteomes and transcriptomes, providing a framework to understand the critical physiological importance of NRF transcription factors and to establish pharmacologic approaches for therapeutically activating these transcriptional programs in disease. Full article
(This article belongs to the Special Issue Keap1/Nrf2 Signaling Pathway)
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Graphical abstract

15 pages, 2903 KiB  
Article
Ozone Activates the Nrf2 Pathway and Improves Preservation of Explanted Adipose Tissue In Vitro
by Barbara Cisterna, Manuela Costanzo, Alice Nodari, Mirco Galiè, Serena Zanzoni, Paolo Bernardi, Viviana Covi, Gabriele Tabaracci and Manuela Malatesta
Antioxidants 2020, 9(10), 989; https://doi.org/10.3390/antiox9100989 - 14 Oct 2020
Cited by 11 | Viewed by 3296
Abstract
In clinical practice, administration of low ozone (O3) dosages is a complementary therapy for many diseases, due to the capability of O3 to elicit an antioxidant response through the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)-dependent pathway. Nrf2 is also [...] Read more.
In clinical practice, administration of low ozone (O3) dosages is a complementary therapy for many diseases, due to the capability of O3 to elicit an antioxidant response through the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)-dependent pathway. Nrf2 is also involved in the adipogenic differentiation of mesenchymal stem cells, and low O3 concentrations have been shown to stimulate lipid accumulation in human adipose-derived adult stem cells in vitro. Thus, O3 treatment is a promising procedure to improve the survival of explanted adipose tissue, whose reabsorption after fat grafting is a major problem in regenerative medicine. In this context, we carried out a pilot study to explore the potential of mild O3 treatment in preserving explanted murine adipose tissue in vitro. Scanning and transmission electron microscopy, Western blot, real-time polymerase chain reaction and nuclear magnetic resonance spectroscopy were used. Exposure to low O3 concentrations down in the degradation of the explanted adipose tissue and induced a concomitant increase in the protein abundance of Nrf2 and in the expression of its target gene Hmox1. These findings provide a promising background for further studies aimed at the clinical application of O3 as an adjuvant treatment to improve fat engraftment. Full article
(This article belongs to the Special Issue Keap1/Nrf2 Signaling Pathway)
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Graphical abstract

16 pages, 3402 KiB  
Article
Protective Effect of Geraniol on Oxidative, Inflammatory and Apoptotic Alterations in Isoproterenol-Induced Cardiotoxicity: Role of the Keap1/Nrf2/HO-1 and PI3K/Akt/mTOR Pathways
by Nancy S. Younis, Mohamed S. Abduldaium and Maged E. Mohamed
Antioxidants 2020, 9(10), 977; https://doi.org/10.3390/antiox9100977 - 12 Oct 2020
Cited by 52 | Viewed by 5450
Abstract
Background: Myocardial infarction (MI) is still a major contributor to mortality worldwide, and therefore, searching for new drugs is an urgent priority. Natural products are a renewable source for medicinally and pharmacologically active molecules. The objective of this study was to explore the [...] Read more.
Background: Myocardial infarction (MI) is still a major contributor to mortality worldwide, and therefore, searching for new drugs is an urgent priority. Natural products are a renewable source for medicinally and pharmacologically active molecules. The objective of this study was to explore the potential of geraniol, a monoterpene alcohol, to protect against MI. Methods: Five groups of Wister rats were used: a control group; a group treated only with geraniol; a group treated only with isoproterenol, to induce MI; and two groups pretreated with geraniol (100 or 200 mg/kg, respectively) for 14 days and challenged with isoproterenol on the 13th and 14th days. Several parameters were measured including electrocardiogram (ECG), cardiac markers, the expression of Kelch-like ECH-associated protein 1 (Keap1), nuclear factor erythroid 2-related factor 2 (Nrf2), and other downstream antioxidant enzymes, as well as the expression of phosphoinositide 3-kinases (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and other downstream apoptotic and inflammatory mediators. Results: Geraniol treatment reduced the size of the infarct region, attenuated the levels of cardiac indicators, and diminished myocardial necrosis and immune cell infiltration. Geraniol treatment also activated the Keap1/Nrf2/heme oxygenase-1 (HO-1) pathway, increased antioxidant enzyme activities, modulated the PI3K/Akt/mTOR pathway, and ameliorated myocardial autophagy, inflammation, and apoptosis. Conclusion: Geraniol may possess a protective effect against MI through moderating MI-induced myocardial oxidative stress (glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione S-transferase (GST), and Keap1/Nrf2 pathway), inflammation (IL-1β, IL-6, TNF-α, and Nuclear factor-κB (NF-κB)), apoptosis (caspase-3, caspase-9, Bcl2, and Bax), and autophagy (PI3K/Akt/mTOR pathway). Full article
(This article belongs to the Special Issue Keap1/Nrf2 Signaling Pathway)
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Graphical abstract

19 pages, 4805 KiB  
Article
Epigenetic Scanning of KEAP1 CpG Sites Uncovers New Molecular-Driven Patterns in Lung Adeno and Squamous Cell Carcinomas
by Federico Pio Fabrizio, Tommaso Mazza, Stefano Castellana, Angelo Sparaneo and Lucia Anna Muscarella
Antioxidants 2020, 9(9), 904; https://doi.org/10.3390/antiox9090904 - 22 Sep 2020
Cited by 8 | Viewed by 2607
Abstract
Background: The KEAP1/NRF2 (Kelch-like ECH-associated protein 1/nuclear factor erythroid 2–related factor 2) pathway modulates detoxification processes and participates in the resistance of solid tumors to therapy. Scientific evidence about the presence of genetic and epigenetic abnormalities of the KEAP1 gene was firstly reported [...] Read more.
Background: The KEAP1/NRF2 (Kelch-like ECH-associated protein 1/nuclear factor erythroid 2–related factor 2) pathway modulates detoxification processes and participates in the resistance of solid tumors to therapy. Scientific evidence about the presence of genetic and epigenetic abnormalities of the KEAP1 gene was firstly reported in non-small-cell lung cancer (NSCLC) and then described in other tumors. At present, the prognostic role of aberrant methylation at cytosine-guanine dinucleotide (CpG) sites of the KEAP1 gene promoter is debated in NSCLC, and its correlation with transcriptional changes and protein levels remains to be defined in large sample cohorts. Methods: We evaluated and compared multiple KEAP1 omics data (methylation, transcript, and protein expression levels) from The Cancer Genome Atlas (TCGA) to explore the role of CpGs located in different portions of KEAP1 and the correlation between methylation, transcription, and protein levels. Data from two subsets of lung adenocarcinoma (LUAD, n = 617) and lung squamous cell carcinoma (LUSC, n = 571) cohorts of NSCLC patients with different disease stages were evaluated. Results: We found that the methylation levels of many KEAP1 CpGs at various promoter and intragenic locations showed a significant inverse correlation with the transcript levels. Interestingly, these results were limited to the KRAS wild-type LUSC and LUAD cohorts, whereas in LUAD the effect of the epigenetic silencing of KEAP1 on its transcription was also observed in the EGFR mutated subpopulation. Conclusions: These results support the idea that the prognostic role of KEAP1 CpG sites warrants more in-depth investigation and that the impact of their changes in methylation levels may differ among specific NSCLC histologies and molecular backgrounds. Moreover, the observed impact of epigenetic silencing on KEAP1 expression in specific KRAS and EGFR settings may suggest a potential role of KEAP1 methylation as a predictive marker for NSCLC patients for whom anti-EGFR treatments are considered. Full article
(This article belongs to the Special Issue Keap1/Nrf2 Signaling Pathway)
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Graphical abstract

21 pages, 6118 KiB  
Article
The Transcriptomic Response of the Murine Thyroid Gland to Iodide Overload and the Role of the Nrf2 Antioxidant System
by Dionysios V. Chartoumpekis, Panos G. Ziros, Ilias Georgakopoulos-Soares, Adam A. T. Smith, Ana Claudia Marques, Mark Ibberson, Peter A. Kopp, Ioannis Habeos, Ioannis P. Trougakos, Nicholas K. H. Khoo and Gerasimos P. Sykiotis
Antioxidants 2020, 9(9), 884; https://doi.org/10.3390/antiox9090884 - 18 Sep 2020
Cited by 8 | Viewed by 4179
Abstract
Background: Thyroid follicular cells have physiologically high levels of reactive oxygen species because oxidation of iodide is essential for the iodination of thyroglobulin (Tg) during thyroid hormone synthesis. Thyroid follicles (the functional units of the thyroid) also utilize incompletely understood autoregulatory mechanisms to [...] Read more.
Background: Thyroid follicular cells have physiologically high levels of reactive oxygen species because oxidation of iodide is essential for the iodination of thyroglobulin (Tg) during thyroid hormone synthesis. Thyroid follicles (the functional units of the thyroid) also utilize incompletely understood autoregulatory mechanisms to defend against exposure to excess iodide. To date, no transcriptomic studies have investigated these phenomena in vivo. Nuclear erythroid factor 2 like 2 (Nrf2 or Nfe2l2) is a transcription factor that regulates the expression of numerous antioxidant and other cytoprotective genes. We showed previously that the Nrf2 pathway regulates the antioxidant defense of follicular cells, as well as Tg transcription and Tg iodination. We, thus, hypothesized that Nrf2 might be involved in the transcriptional response to iodide overload. Methods: C57BL6/J wild-type (WT) or Nrf2 knockout (KO) male mice were administered regular water or water supplemented with 0.05% sodium iodide for seven days. RNA from their thyroids was prepared for next-generation RNA sequencing (RNA-Seq). Gene expression changes were assessed and pathway analyses were performed on the sets of differentially expressed genes. Results: Analysis of differentially expressed messenger RNAs (mRNAs) indicated that iodide overload upregulates inflammatory-, immune-, fibrosis- and oxidative stress-related pathways, including the Nrf2 pathway. Nrf2 KO mice showed a more pronounced inflammatory–autoimmune transcriptional response to iodide than WT mice. Compared to previously published datasets, the response patterns observed in WT mice had strong similarities with the patterns typical of Graves’ disease and papillary thyroid carcinoma (PTC). Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) also responded to iodide overload, with the latter targeting mRNAs that participate mainly in inflammation pathways. Conclusions: Iodide overload induces the Nrf2 cytoprotective response and upregulates inflammatory, immune, and fibrosis pathways similar to autoimmune hyperthyroidism (Graves’ disease) and PTC. Full article
(This article belongs to the Special Issue Keap1/Nrf2 Signaling Pathway)
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20 pages, 3887 KiB  
Article
Restraint Stress Alters Expression of Glucocorticoid Bioavailability Mediators, Suppresses Nrf2, and Promotes Oxidative Stress in Liver Tissue
by Hsiao-Jou Cortina Chen, Tsz Yip, Johnny K. Lee, Juliani Juliani, Conrad Sernia, Andrew F. Hill, Nickolas A. Lavidis and Jereme G. Spiers
Antioxidants 2020, 9(9), 853; https://doi.org/10.3390/antiox9090853 - 11 Sep 2020
Cited by 9 | Viewed by 3485
Abstract
Hepatic glutathione synthesis and antioxidant protection are critically important for efficient detoxification processes in response to metabolic challenges. However, this biosynthetic pathway, regulated by nuclear factor (erythroid-derived 2)-like 2 (Nrf2), previously demonstrated paradoxical repression following exposure to glucocorticoid stress hormones in cultured hepatic [...] Read more.
Hepatic glutathione synthesis and antioxidant protection are critically important for efficient detoxification processes in response to metabolic challenges. However, this biosynthetic pathway, regulated by nuclear factor (erythroid-derived 2)-like 2 (Nrf2), previously demonstrated paradoxical repression following exposure to glucocorticoid stress hormones in cultured hepatic cells. Therefore, the present study used an in vivo model of sub-acute psychological stress to investigate the relationship between hepatic corticosteroid regulation and antioxidant systems. Male Wistar rats were kept under control conditions or subjected to six hours of restraint stress applied for 1 or 3 days (n = 8 per group) after which the liver was isolated for assays of oxidative/nitrosative status and expression of corticosteroid regulatory and Nrf2-antioxidant response element pathway members. A single stress exposure produced a significant increase in the expression of corticosterone reactivator, 11-beta-hydroxysteroid dehydrogenase 1 (11β-Hsd1), while the 11β-Hsd2 isozyme and corticosteroid-binding globulin were down-regulated following stress, indicative of an elevated availability of active corticosterone. Exposure to restraint significantly decreased hepatic concentrations of total cysteine thiols and the antioxidant reduced glutathione on Day 1 and increased 3-nitrotyrosinated and carbonylated proteins on Day 3, suggestive of oxidative/nitrosative stress in the liver following stress exposure. Conversely, there was a sustained down-regulation of Nrf2 mRNA and protein in addition to significant reductions in downstream glutamate-cysteine ligase catalytic subunit (Gclc), the rate-limiting enzyme in glutathione synthesis, on Day 1 and 3 of stress treatment. Interestingly, other antioxidant genes including superoxide dismutase 1 and 2, and glutathione peroxidase 4 were significantly up-regulated following an episode of restraint stress. In conclusion, the results of the present study indicate that increased expression of 11β-Hsd1, indicative of elevated tissue glucocorticoid concentrations, may impair the Nrf2-dependent antioxidant response. Full article
(This article belongs to the Special Issue Keap1/Nrf2 Signaling Pathway)
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Graphical abstract

16 pages, 5142 KiB  
Article
Protective Effect of Low Molecular Weight Peptides from Solenocera crassicornis Head against Cyclophosphamide-Induced Nephrotoxicity in Mice via the Keap1/Nrf2 Pathway
by Shuoqi Jiang, Zhuangwei Zhang, FangFang Huang, Zuisu Yang, Fangmiao Yu, Yunping Tang and Guofang Ding
Antioxidants 2020, 9(8), 745; https://doi.org/10.3390/antiox9080745 - 13 Aug 2020
Cited by 18 | Viewed by 3294
Abstract
The major component of the Solenocera crassicornis head protein hydrolysates-fraction 1 (SCHPs-F1) are low molecular weight peptides (MW < 1 kDa). In this study, we investigated the potential renoprotective effects of SCHPs-F1 in a cyclophosphamide (CTX) toxicity mouse model. In brief, 40 male [...] Read more.
The major component of the Solenocera crassicornis head protein hydrolysates-fraction 1 (SCHPs-F1) are low molecular weight peptides (MW < 1 kDa). In this study, we investigated the potential renoprotective effects of SCHPs-F1 in a cyclophosphamide (CTX) toxicity mouse model. In brief, 40 male mice were randomly divided into 5 groups and received either saline or 80 mg/kg body weight (BW) CTX by intraperitoneal injection for 5 days, followed by either saline or SCHPs-F1 (100, 200, and 400 mg/kg BW) by intragastric administration for 15 days. SCHPs-F1 treatment significantly reversed the CTX-induced decreases in the levels of blood urea nitrogen (BUN), creatinine (CRE), and cytochrome P450 (CYP450), as well as the renal histological lesions. Furthermore, the results indicated that SCHPs-F1 potentially alleviated CTX-induced nephrotoxicity through mitigating inflammatory responses, oxidative stress, and apoptosis status of the kidneys, as evidenced by decreased levels of malondialdehyde (MDA), interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ and increased levels of total antioxidant capacity (T-AOC), catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Moreover, overexpression of pro-apoptotic proteins pair B-cell lymphoma-2 (Bcl-2)-associated X (Bax)/Bcl-2, cysteinyl aspartate specific proteinase (caspase)-3 and caspase-9 in renal tissues were suppressed by treatment with SCHPs-F1. In addition, the protein levels of the antioxidant factor nuclear factor erythroid-2 related factor 2 (Nrf2) and the expression levels of its downstream target genes heme-oxygenase (HO-1), glutamate-cysteine ligase modifier subunit (GCLM) and NAD(P)H dehydrogenase (quinone) 1 (NQO-1) were stimulated by treatment with SCHPs-F1 in the CTX-induced renal injury model. Taken together, our data suggested that SCHPs-F1 could provide a novel potential strategy in mitigating the nephrotoxicity caused by CTX. Full article
(This article belongs to the Special Issue Keap1/Nrf2 Signaling Pathway)
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9 pages, 2088 KiB  
Article
Dimethyl Fumarate Alleviates Dextran Sulfate Sodium-Induced Colitis, through the Activation of Nrf2-Mediated Antioxidant and Anti-inflammatory Pathways
by Shiri Li, Chie Takasu, Hien Lau, Lourdes Robles, Kelly Vo, Ted Farzaneh, Nosratola D. Vaziri, Michael J. Stamos and Hirohito Ichii
Antioxidants 2020, 9(4), 354; https://doi.org/10.3390/antiox9040354 - 24 Apr 2020
Cited by 23 | Viewed by 4174
Abstract
Oxidative stress and chronic inflammation play critical roles in the pathogenesis of ulcerative colitis (UC) and inflammatory bowel diseases (IBD). A previous study has demonstrated that dimethyl fumarate (DMF) protects mice from dextran sulfate sodium (DSS)-induced colitis via its potential antioxidant capacity, and [...] Read more.
Oxidative stress and chronic inflammation play critical roles in the pathogenesis of ulcerative colitis (UC) and inflammatory bowel diseases (IBD). A previous study has demonstrated that dimethyl fumarate (DMF) protects mice from dextran sulfate sodium (DSS)-induced colitis via its potential antioxidant capacity, and by inhibiting the activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. This study aims to clarify the nuclear factor erythroid 2-related factor 2/antioxidant responsive element (Nrf2/ARE) pathway pharmacological activation and anti-inflammatory effect by DMF, through focusing on other crucial antioxidant enzymes and inflammatory mediator, including glutamate-cysteine ligase catalytic subunit (GCLC), glutathione peroxidase (GPX) and cyclooxygenase-2 (COX-2), in a DSS-induced colitis mouse model. The oral administration of DMF attenuated the shortening of colons and alleviated colonic inflammation. Furthermore, the expression of key antioxidant enzymes, including GCLC and GPX, in the colonic tissue were significantly increased by DMF administration. In addition, protein expression of the inflammatory mediator, COX-2, was reduced by DMF administration. Our results suggest that DMF alleviates DSS-induced colonic inflammatory damage, likely via up-regulating GCLC and GPX and down-regulating COX-2 protein expression in colonic tissue. Full article
(This article belongs to the Special Issue Keap1/Nrf2 Signaling Pathway)
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Review

Jump to: Editorial, Research

31 pages, 2403 KiB  
Review
Protective Role of Nrf2 in Renal Disease
by Melania Guerrero-Hue, Sandra Rayego-Mateos, Cristina Vázquez-Carballo, Alejandra Palomino-Antolín, Cristina García-Caballero, Lucas Opazo-Rios, José Luis Morgado-Pascual, Carmen Herencia, Sebastián Mas, Alberto Ortiz, Alfonso Rubio-Navarro, Javier Egea, José Manuel Villalba, Jesús Egido and Juan Antonio Moreno
Antioxidants 2021, 10(1), 39; https://doi.org/10.3390/antiox10010039 - 31 Dec 2020
Cited by 50 | Viewed by 5200
Abstract
Chronic kidney disease (CKD) is one of the fastest-growing causes of death and is predicted to become by 2040 the fifth global cause of death. CKD is characterized by increased oxidative stress and chronic inflammation. However, therapies to slow or prevent CKD progression [...] Read more.
Chronic kidney disease (CKD) is one of the fastest-growing causes of death and is predicted to become by 2040 the fifth global cause of death. CKD is characterized by increased oxidative stress and chronic inflammation. However, therapies to slow or prevent CKD progression remain an unmet need. Nrf2 (nuclear factor erythroid 2-related factor 2) is a transcription factor that plays a key role in protection against oxidative stress and regulation of the inflammatory response. Consequently, the use of compounds targeting Nrf2 has generated growing interest for nephrologists. Pre-clinical and clinical studies have demonstrated that Nrf2-inducing strategies prevent CKD progression and protect from acute kidney injury (AKI). In this article, we review current knowledge on the protective mechanisms mediated by Nrf2 against kidney injury, novel therapeutic strategies to induce Nrf2 activation, and the status of ongoing clinical trials targeting Nrf2 in renal diseases. Full article
(This article belongs to the Special Issue Keap1/Nrf2 Signaling Pathway)
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14 pages, 2338 KiB  
Review
Patent Review (2017–2020) of the Keap1/Nrf2 Pathway Using PatSeer Pro: Focus on Autoimmune Diseases
by Dionysios V. Chartoumpekis, Chun-Yan Fu, Panos G. Ziros and Gerasimos P. Sykiotis
Antioxidants 2020, 9(11), 1138; https://doi.org/10.3390/antiox9111138 - 17 Nov 2020
Cited by 12 | Viewed by 2947
Abstract
Research on the antioxidant pathway comprising the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and its cytoplasmic inhibitor Kelch-like ECH-associated protein 1 (Keap1) is ever increasing. As modulators of this pathway have started to be used in clinical trials and clinical [...] Read more.
Research on the antioxidant pathway comprising the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and its cytoplasmic inhibitor Kelch-like ECH-associated protein 1 (Keap1) is ever increasing. As modulators of this pathway have started to be used in clinical trials and clinical practice, Nrf2 has become the subject of several patents. To assess the patent landscape of the last three years on Nrf2 and evaluate the main fields they refer to, we used the web-based tool PatSeer Pro to identify patents mentioning the Nrf2 pathway between January 2017 and May 2020. This search resulted in 509 unique patents that focus on topics such as autoimmune, neurodegenerative, liver, kidney, and lung diseases and refer to modulators (mainly activators) of the Nrf2 pathway as potential treatments. Autoimmunity emerged as the main theme among the topics of Nrf2 patents, including a broad range of diseases, such as systemic sclerosis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel diseases, Hashimoto’s thyroiditis, etc.; however, there was a dearth of experimental support for the respective patents’ claims. Given that chronic inflammation is the main element of the pathophysiology of most autoimmune diseases, the majority of patents referring to activation of Nrf2 as a method to treat autoimmune diseases base their claims on the well-established anti-inflammatory role of Nrf2. In conclusion, there is strong interest in securing intellectual property rights relating to the potential use of Nrf2 pathway activators in a variety of diseases, and this trend parallels the rise in related research publications. However, in the case of autoimmunity, more research is warranted to support the potential beneficial effects of Nrf2 modulation in each disease. Full article
(This article belongs to the Special Issue Keap1/Nrf2 Signaling Pathway)
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14 pages, 971 KiB  
Review
The Keap1/Nrf2 Signaling Pathway in the Thyroid—2020 Update
by Christina Thanas, Panos G. Ziros, Dionysios V. Chartoumpekis, Cédric O. Renaud and Gerasimos P. Sykiotis
Antioxidants 2020, 9(11), 1082; https://doi.org/10.3390/antiox9111082 - 04 Nov 2020
Cited by 21 | Viewed by 6961
Abstract
The thyroid gland has a special relationship with oxidative stress. On the one hand, like all other tissues, it must defend itself against reactive oxygen species (ROS). On the other hand, unlike most other tissues, it must also produce reactive oxygen species in [...] Read more.
The thyroid gland has a special relationship with oxidative stress. On the one hand, like all other tissues, it must defend itself against reactive oxygen species (ROS). On the other hand, unlike most other tissues, it must also produce reactive oxygen species in order to synthesize its hormones that contribute to the homeostasis of other tissues. The thyroid must therefore also rely on antioxidant defense systems to maintain its own homeostasis in the face of continuous self-exposure to ROS. One of the main endogenous antioxidant systems is the pathway centered on the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) and its cytoplasmic inhibitor Kelch-like ECH-associated protein 1 (Keap1). Over the last few years, multiple links have emerged between the Keap1/Nrf2 pathway and thyroid physiology, as well as various thyroid pathologies, including autoimmunity, goiter, hypothyroidism, hyperthyroidism, and cancer. In the present mini-review, we summarize recent studies shedding new light into the roles of Keap1/Nrf2 signaling in the thyroid. Full article
(This article belongs to the Special Issue Keap1/Nrf2 Signaling Pathway)
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23 pages, 1725 KiB  
Review
Roles of Nrf2 in Liver Diseases: Molecular, Pharmacological, and Epigenetic Aspects
by Marina Galicia-Moreno, Silvia Lucano-Landeros, Hugo Christian Monroy-Ramirez, Jorge Silva-Gomez, Jorge Gutierrez-Cuevas, Arturo Santos and Juan Armendariz-Borunda
Antioxidants 2020, 9(10), 980; https://doi.org/10.3390/antiox9100980 - 13 Oct 2020
Cited by 64 | Viewed by 5175
Abstract
Liver diseases represent a critical health problem with 2 million deaths worldwide per year, mainly due to cirrhosis and its complications. Oxidative stress plays an important role in the development of liver diseases. In order to maintain an adequate homeostasis, there must be [...] Read more.
Liver diseases represent a critical health problem with 2 million deaths worldwide per year, mainly due to cirrhosis and its complications. Oxidative stress plays an important role in the development of liver diseases. In order to maintain an adequate homeostasis, there must be a balance between free radicals and antioxidant mediators. Nuclear factor erythroid 2-related factor (Nrf2) and its negative regulator Kelch-like ECH-associated protein 1 (Keap1) comprise a defense mechanism against oxidative stress damage, and growing evidence considers this signaling pathway as a key pharmacological target for the treatment of liver diseases. In this review, we provide detailed and updated evidence regarding Nrf2 and its involvement in the development of the main liver diseases such as alcoholic liver damage, viral hepatitis, steatosis, steatohepatitis, cholestatic damage, and liver cancer. The molecular and cellular mechanisms of Nrf2 cellular signaling are elaborated, along with key and relevant antioxidant drugs, and mechanisms on how Keap1/Nrf2 modulation can positively affect the therapeutic response are described. Finally, exciting recent findings about epigenetic modifications and their link with regulation of Keap1/Nrf2 signaling are outlined. Full article
(This article belongs to the Special Issue Keap1/Nrf2 Signaling Pathway)
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23 pages, 1985 KiB  
Review
Epigenetic Regulation of NRF2/KEAP1 by Phytochemicals
by Shamee Bhattacharjee and Roderick H. Dashwood
Antioxidants 2020, 9(9), 865; https://doi.org/10.3390/antiox9090865 - 14 Sep 2020
Cited by 59 | Viewed by 7069
Abstract
Epigenetics has provided a new dimension to our understanding of nuclear factor erythroid 2–related factor 2/Kelch-like ECH-associated protein 1 (human NRF2/KEAP1 and murine Nrf2/Keap1) signaling. Unlike the genetic changes affecting DNA sequence, the reversible nature of epigenetic alterations provides an attractive avenue for [...] Read more.
Epigenetics has provided a new dimension to our understanding of nuclear factor erythroid 2–related factor 2/Kelch-like ECH-associated protein 1 (human NRF2/KEAP1 and murine Nrf2/Keap1) signaling. Unlike the genetic changes affecting DNA sequence, the reversible nature of epigenetic alterations provides an attractive avenue for cancer interception. Thus, targeting epigenetic mechanisms in the corresponding signaling networks represents an enticing strategy for therapeutic intervention with dietary phytochemicals acting at transcriptional, post-transcriptional, and post-translational levels. This regulation involves the interplay of histone modifications and DNA methylation states in the human NFE2L2/KEAP1 and murine Nfe2l2/Keap1 genes, acetylation of lysine residues in NRF2 and Nrf2, interaction with bromodomain and extraterminal domain (BET) acetyl “reader” proteins, and non-coding RNAs such as microRNA (miRNA) and long non-coding RNA (lncRNA). Phytochemicals documented to modulate NRF2 signaling act by reversing hypermethylated states in the CpG islands of NFE2L2 or Nfe2l2, via the inhibition of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), through the induction of ten-eleven translocation (TET) enzymes, or by inducing miRNA to target the 3′-UTR of the corresponding mRNA transcripts. To date, fewer than twenty phytochemicals have been reported as NRF2 epigenetic modifiers, including curcumin, sulforaphane, resveratrol, reserpine, and ursolic acid. This opens avenues for exploring additional dietary phytochemicals that regulate the human epigenome, and the potential for novel strategies to target NRF2 signaling with a view to beneficial interception of cancer and other chronic diseases. Full article
(This article belongs to the Special Issue Keap1/Nrf2 Signaling Pathway)
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24 pages, 3059 KiB  
Review
The KEAP1/NRF2 Signaling Pathway in Keratinization
by Yosuke Ishitsuka, Tatsuya Ogawa and Dennis Roop
Antioxidants 2020, 9(8), 751; https://doi.org/10.3390/antiox9080751 - 14 Aug 2020
Cited by 18 | Viewed by 8888
Abstract
Keratinization is a tissue adaptation, but aberrant keratinization is associated with skin disorders such as ichthyoses, atopic dermatitis, psoriasis, and acne. The disease phenotype stems from the interaction between genes and the environment; therefore, an understanding of the adaptation machinery may lead to [...] Read more.
Keratinization is a tissue adaptation, but aberrant keratinization is associated with skin disorders such as ichthyoses, atopic dermatitis, psoriasis, and acne. The disease phenotype stems from the interaction between genes and the environment; therefore, an understanding of the adaptation machinery may lead to a new appreciation of pathomechanisms. The KEAP1/NRF2 signaling pathway mediates the environmental responses of squamous epithelial tissue. The unpredicted outcome of the Keap1-null mutation in mice allowed us to revisit the basic principle of the biological process of keratinization: sulfur metabolism establishes unparalleled cytoprotection in the body wall of terrestrial mammals. We summarize the recent understanding of the KEAP1/NRF2 signaling pathway, which is a thiol-based sensor-effector apparatus, with particular focuses on epidermal differentiation in the context of the gene-environment interaction, the structure/function principles involved in KEAP1/NRF2 signaling, lessons from mouse models, and their pathological implications. This synthesis may provide insights into keratinization, which provides physical insulation and constitutes an essential innate integumentary defense system. Full article
(This article belongs to the Special Issue Keap1/Nrf2 Signaling Pathway)
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36 pages, 2426 KiB  
Review
Current Landscape of NRF2 Biomarkers in Clinical Trials
by Yoko Yagishita, Tonibelle N. Gatbonton-Schwager, Melissa L. McCallum and Thomas W. Kensler
Antioxidants 2020, 9(8), 716; https://doi.org/10.3390/antiox9080716 - 07 Aug 2020
Cited by 49 | Viewed by 6992
Abstract
The transcription factor NF-E2 p45-related factor 2 (NRF2; encoded by NFE2L2) plays a critical role in the maintenance of cellular redox and metabolic homeostasis, as well as the regulation of inflammation and cellular detoxication pathways. The contribution of the NRF2 pathway to [...] Read more.
The transcription factor NF-E2 p45-related factor 2 (NRF2; encoded by NFE2L2) plays a critical role in the maintenance of cellular redox and metabolic homeostasis, as well as the regulation of inflammation and cellular detoxication pathways. The contribution of the NRF2 pathway to organismal homeostasis is seen in many studies using cell lines and animal models, raising intense attention towards targeting its clinical promise. Over the last three decades, an expanding number of clinical studies have examined NRF2 inducers targeting an ever-widening range of diseases. Full understanding of the pharmacokinetic and pharmacodynamic properties of drug candidates rely partly on the identification, validation, and use of biomarkers to optimize clinical applications. This review focuses on results from clinical trials with four agents known to target NRF2 signaling in preclinical studies (dimethyl fumarate, bardoxolone methyl, oltipraz, and sulforaphane), and evaluates the successes and limitations of biomarkers focused on expression of NRF2 target genes and others, inflammation and oxidative stress biomarkers, carcinogen metabolism and adduct biomarkers in unavoidably exposed populations, and targeted and untargeted metabolomics. While no biomarkers excel at defining pharmacodynamic actions in this setting, it is clear that these four lead clinical compounds do touch the NRF2 pathway in humans. Full article
(This article belongs to the Special Issue Keap1/Nrf2 Signaling Pathway)
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20 pages, 1952 KiB  
Review
Nuclear Factor-Erythroid 2-Related Factor 2 (Nrf2) and Mitochondrial Dynamics/Mitophagy in Neurological Diseases
by Tae-Cheon Kang
Antioxidants 2020, 9(7), 617; https://doi.org/10.3390/antiox9070617 - 15 Jul 2020
Cited by 60 | Viewed by 5861
Abstract
Mitochondria play an essential role in bioenergetics and respiratory functions for cell viability through numerous biochemical processes. To maintain mitochondria quality control and homeostasis, mitochondrial morphologies change rapidly in response to external insults and changes in metabolic status through fusion and fission (so [...] Read more.
Mitochondria play an essential role in bioenergetics and respiratory functions for cell viability through numerous biochemical processes. To maintain mitochondria quality control and homeostasis, mitochondrial morphologies change rapidly in response to external insults and changes in metabolic status through fusion and fission (so called mitochondrial dynamics). Furthermore, damaged mitochondria are removed via a selective autophagosomal process, referred to as mitophagy. Although mitochondria are one of the sources of reactive oxygen species (ROS), they are themselves vulnerable to oxidative stress. Thus, endogenous antioxidant defense systems play an important role in cell survival under physiological and pathological conditions. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that maintains redox homeostasis by regulating antioxidant-response element (ARE)-dependent transcription and the expression of antioxidant defense enzymes. Although the Nrf2 system is positively associated with mitochondrial biogenesis and mitochondrial quality control, the relationship between Nrf2 signaling and mitochondrial dynamics/mitophagy has not been sufficiently addressed in the literature. This review article describes recent clinical and experimental observations on the relationship between Nrf2 and mitochondrial dynamics/mitophagy in various neurological diseases. Full article
(This article belongs to the Special Issue Keap1/Nrf2 Signaling Pathway)
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21 pages, 1636 KiB  
Review
NRF2 and Primary Cilia: An Emerging Partnership
by Ana Martin-Hurtado, Isabel Lastres-Becker, Antonio Cuadrado and Francesc R. Garcia-Gonzalo
Antioxidants 2020, 9(6), 475; https://doi.org/10.3390/antiox9060475 - 02 Jun 2020
Cited by 6 | Viewed by 4035
Abstract
When not dividing, many cell types target their centrosome to the plasma membrane, where it nucleates assembly of a primary cilium, an antenna-like signaling structure consisting of nine concentric microtubule pairs surrounded by membrane. Primary cilia play important pathophysiological roles in many tissues, [...] Read more.
When not dividing, many cell types target their centrosome to the plasma membrane, where it nucleates assembly of a primary cilium, an antenna-like signaling structure consisting of nine concentric microtubule pairs surrounded by membrane. Primary cilia play important pathophysiological roles in many tissues, their dysfunction being associated with cancer and ciliopathies, a diverse group of congenital human diseases. Several recent studies have unveiled functional connections between primary cilia and NRF2 (nuclear factor erythroid 2-related factor 2), the master transcription factor orchestrating cytoprotective responses to oxidative and other cellular stresses. These NRF2-cilia relationships are reciprocal: primary cilia, by promoting autophagy, downregulate NRF2 activity. In turn, NRF2 transcriptionally regulates genes involved in ciliogenesis and Hedgehog (Hh) signaling, a cilia-dependent pathway with major roles in embryogenesis, stem cell function and tumorigenesis. Nevertheless, while we found that NRF2 stimulates ciliogenesis and Hh signaling, a more recent study reported that NRF2 negatively affects these processes. Herein, we review the available evidence linking NRF2 to primary cilia, suggest possible explanations to reconcile seemingly contradictory data, and discuss what the emerging interplay between primary cilia and NRF2 may mean for human health and disease. Full article
(This article belongs to the Special Issue Keap1/Nrf2 Signaling Pathway)
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12 pages, 1196 KiB  
Review
Potential Benefits of Nrf2/Keap1 Targeting in Pancreatic Islet Cell Transplantation
by Alberto Jarrin Lopez, Hien Lau, Shiri Li and Hirohito Ichii
Antioxidants 2020, 9(4), 321; https://doi.org/10.3390/antiox9040321 - 16 Apr 2020
Cited by 14 | Viewed by 4528
Abstract
Permanent pancreatic islet cell destruction occurs in type 1 diabetes mellitus (T1DM) through the infiltration of inflammatory cells and cytokines. Loss of β-cell integrity secondary to oxidation leads to an inability to appropriately synthesize and secrete insulin. Allogenic islet cell transplantation (ICT) has [...] Read more.
Permanent pancreatic islet cell destruction occurs in type 1 diabetes mellitus (T1DM) through the infiltration of inflammatory cells and cytokines. Loss of β-cell integrity secondary to oxidation leads to an inability to appropriately synthesize and secrete insulin. Allogenic islet cell transplantation (ICT) has risen as a therapeutic option to mitigate problematic hypoglycemia. Nevertheless, during the process of transplantation, islet cells are exposed to oxidatively caustic conditions that severely decrease the islet cell yield. Islet cells are at a baseline disadvantage to sustain themselves during times of metabolic stress as they lack a robust anti-oxidant defense system, glycogen stores, and vascularity. The Nrf2/Keap1 system is a master regulator of antioxidant genes that has garnered attention as pharmacologic activators have shown a protective response and a low side effect profile. Herein, we present the most recently studied Nrf2/Keap1 activators in pancreas for application in ICT: Dh404, dimethyl fumarate (DMF), and epigallocatechin gallate (EGCG). Furthermore, we discuss that Nrf2/Keap1 is a potential target to ameliorate oxidative stress at every step of the Edmonton Protocol. Full article
(This article belongs to the Special Issue Keap1/Nrf2 Signaling Pathway)
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