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Special Issue "The Nrf2 Pathway: Regulation, Functions, and Potential Applications"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 31 December 2019.

Special Issue Editors

Prof. Makoto Kobayashi
E-Mail Website
Guest Editor
Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
Tel. +81-29-853-8457
Interests: gene regulation; natural products; Nrf2; organelle stress; redox homeostasis; zebrafish
Prof. Dr. Ken Itoh
E-Mail
Guest Editor
Department of Stress Response Science, Center for Advanced Medical Sciences, Hirosaki University Graduate School of Medicine, 5 Zaifucho, Hirosaki 036-8562, Japan
Interests: Nrf2; ATF4; mito-nuclear communication; mitochondrial antioxidant; Keap1; anti-aging
Special Issues and Collections in MDPI journals
Prof. Dr. Andreas Von Knethen
E-Mail
Guest Editor
Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt/Main, Germany
Interests: sepsis; Nrf2; PPARγ; redox signaling; autophagy
Special Issues and Collections in MDPI journals
Prof. Mi-Kyoung Kwak
E-Mail Website
Guest Editor
College of Pharmacy, The Catholic University of Korea, Youngdeungpo, South Korea
Interests: stress resistance of cancers; cancer stem cells; oxidative stress and human diseases

Special Issue Information

Dear colleagues,

The Nrf2 pathway, a master regulator of redox homeostasis discovered in the mid 1990s, is an integrated cellular response for electrophiles and thiol reactive compounds (e.g., ROS, RNS, heavy metals). In addition to its activation by environmental electrophiles such as quinones, diverse mechanisms of Nrf2 activation have been reported, namely, endogenous electrophiles, glucose metabolism, phosphorylation, and miRNAs. The Nrf2 pathway has a wide variety of functions, such as defense against oxidative stress and electrophilic toxicity, carcinogenesis protection, tumorigenesis, anti-inflammation, stem cells regulation, anti-aging, reducing mechanical stress and organelle stress (autophagy, endoplasmic reticulum, mitochondria), protection against brain and skin injuries, and so forth. At present, drug discovery targeting the Nrf2 pathway has been explored extensively, since dysregulation of the Nrf2 pathway leads to a number of human diseases and disorders, including cancer, diabetes, atherosclerosis, and neurodegeneration.

In this Special Issue, we widely recruit original articles that describe new discoveries in the Nrf2 pathway in any relevant topics, such as physiological functions, gene regulation, activation mechanism, drug discovery, evolution, human diseases, protein structure, and genome. We also welcome review articles and commentaries.

Prof. Makoto Kobayashi
Prof. Ken Itoh
Prof. Dr. Andreas von Knethen
Prof. Mi-Kyoung Kwak
Guest Editors

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 papers will be 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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • anti-aging
  • anti-inflammation
  • autophagy
  • cancer
  • chemoprevention
  • drug discovery
  • energy metabolism
  • evolution
  • gene regulation
  • human disease
  • miRNA
  • natural products
  • organelle stress
  • oxidative stress
  • redox homeostasis
  • stem cells
  • toxicology

Published Papers (10 papers)

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Research

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Open AccessArticle
Polymorphism in the Promoter Region of NFE2L2 Gene Is a Genetic Marker of Susceptibility to Cirrhosis Associated with Alcohol Abuse
Int. J. Mol. Sci. 2019, 20(14), 3589; https://doi.org/10.3390/ijms20143589 - 23 Jul 2019
Abstract
Alcoholic liver disease (ALD) is a highly prevalent spectrum of pathologies caused by alcohol overconsumption. Morbidity and mortality related to ALD are increasing worldwide, thereby demanding strategies for early diagnosis and detection of ALD predisposition. A potential candidate as a marker for ALD [...] Read more.
Alcoholic liver disease (ALD) is a highly prevalent spectrum of pathologies caused by alcohol overconsumption. Morbidity and mortality related to ALD are increasing worldwide, thereby demanding strategies for early diagnosis and detection of ALD predisposition. A potential candidate as a marker for ALD susceptibility is the transcription factor nuclear factor erythroid-related factor 2 (Nrf2), codified by the nuclear factor erythroid 2-related factor 2 gene (NFE2L2). Nrf2 regulates expression of proteins that protect against oxidative stress and inflammation caused by alcohol overconsumption. Here, we assessed genetic variants of NFE2L2 for association with ALD. Specimens from patients diagnosed with cirrhosis caused by ALD were genotyped for three NFE2L2 single nucleotide polymorphisms (SNP) (SNPs: rs35652124, rs4893819, and rs6721961). Hematoxylin & eosin and immunohistochemistry were performed to determine the inflammatory score and Nrf2 expression, respectively. SNPs rs4893819 and rs6721961 were not specifically associated with ALD, but analysis of SNP rs35652124 suggested that this polymorphism predisposes to ALD. Furthermore, SNP rs35652124 was associated with a lower level of Nrf2 expression. Moreover, liver samples from ALD patients with this polymorphism displayed more severe inflammatory activity. Together, these findings provide evidence that the SNP rs35652124 variation in the Nrf2-encoding gene NFE2L2 is a potential genetic marker for susceptibility to ALD. Full article
(This article belongs to the Special Issue The Nrf2 Pathway: Regulation, Functions, and Potential Applications)
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Open AccessArticle
β-Catenin/TCF4 Complex-Mediated Induction of the NRF3 (NFE2L3) Gene in Cancer Cells
Int. J. Mol. Sci. 2019, 20(13), 3344; https://doi.org/10.3390/ijms20133344 - 08 Jul 2019
Abstract
Remarkable upregulation of the NRF2 (NFE2L2)-related transcription factor NRF3 (NFE2L3) in several cancer tissues and its correlation with poor prognosis strongly suggest the physiological function of NRF3 in tumors. Indeed, we had recently uncovered the function of NRF3, which promotes cancer cell proliferation [...] Read more.
Remarkable upregulation of the NRF2 (NFE2L2)-related transcription factor NRF3 (NFE2L3) in several cancer tissues and its correlation with poor prognosis strongly suggest the physiological function of NRF3 in tumors. Indeed, we had recently uncovered the function of NRF3, which promotes cancer cell proliferation by p53 degradation via the 20S proteasome. Nevertheless, the molecular mechanism underlying the induction of NRF3 gene expression in cancer cells is highly elusive. We herein describe that NRF3 upregulation is induced by the β-catenin/TCF4 complex in colon cancer cells. We first confirmed high NRF3 mRNA expression in human colon cancer specimens. The genome database indicated that the human NRF3 gene possesses a species-conserved WRE sequence (TCF/LEF consensus element), implying that the β-catenin/TCF complex activates NRF3 expression in colon cancer. Consistently, we observed that the β-catenin/TCF4 complex mediates NRF3 expression by binding directly to the WRE site. Furthermore, inducing NRF3 activates cell proliferation and the expression of the glucose transporter GLUT1. The existence of the β-catenin/TCF4-NRF3 axis was also validated in the intestine and organoids of Apc-deficient mice. Finally, the positive correlation between NRF3 and β-catenin target gene expression strongly supports our conclusion. Our findings clearly demonstrate that NRF3 induction in cancer cells is controlled by the Wnt/β-catenin pathway. Full article
(This article belongs to the Special Issue The Nrf2 Pathway: Regulation, Functions, and Potential Applications)
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Open AccessArticle
Effects of KEAP1 Silencing on the Regulation of NRF2 Activity in Neuroendocrine Lung Tumors
Int. J. Mol. Sci. 2019, 20(10), 2531; https://doi.org/10.3390/ijms20102531 - 23 May 2019
Abstract
Background. The KEAP1/NRF2 pathway has been widely investigated in tumors since it was implicated in cancer cells survival and therapies resistance. In lung tumors the deregulation of this pathway is mainly related to point mutations of KEAP1 and NFE2L2 genes and KEAP1 promoter [...] Read more.
Background. The KEAP1/NRF2 pathway has been widely investigated in tumors since it was implicated in cancer cells survival and therapies resistance. In lung tumors the deregulation of this pathway is mainly related to point mutations of KEAP1 and NFE2L2 genes and KEAP1 promoter hypermethylation, but these two genes have been rarely investigated in low/intermediate grade neuroendocrine tumors of the lung. Methods. The effects of KEAP1 silencing on NRF2 activity was investigated in H720 and H727 carcinoid cell lines and results were compared with those obtained by molecular profiling of KEAP1 and NFE2L2 in a collection of 47 lung carcinoids. The correlation between methylation and transcript levels was assessed by 5-aza-dC treatment. Results. We demonstrated that in carcinoid cell lines, the KEAP1 silencing induces an upregulation of NRF2 and some of its targets and that there is a direct correlation between KEAP1 methylation and its mRNA levels. A KEAP1 hypermethylation and Loss of Heterozygosity at KEAP1 gene locus was also observed in nearly half of lung carcinoids. Conclusions. This is the first study that has described the effects of KEAP1 silencing on the regulation of NRF2 activity in lung carcinoids cells. The epigenetic deregulation of the KEAP1/NRF2 by a KEAP1 promoter hypermethylation system appears to be a frequent event in lung carcinoids. Full article
(This article belongs to the Special Issue The Nrf2 Pathway: Regulation, Functions, and Potential Applications)
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Open AccessArticle
Concomitant Nrf2- and ATF4-Activation by Carnosic Acid Cooperatively Induces Expression of Cytoprotective Genes
Int. J. Mol. Sci. 2019, 20(7), 1706; https://doi.org/10.3390/ijms20071706 - 05 Apr 2019
Cited by 2
Abstract
Carnosic acid (CA) is a phytochemical found in some dietary herbs, such as Rosmarinus officinalis L., and possesses antioxidative and anti-microbial properties. We previously demonstrated that CA functions as an activator of nuclear factor, erythroid 2 (NF-E2)-related factor 2 (Nrf2), an oxidative stress-responsive [...] Read more.
Carnosic acid (CA) is a phytochemical found in some dietary herbs, such as Rosmarinus officinalis L., and possesses antioxidative and anti-microbial properties. We previously demonstrated that CA functions as an activator of nuclear factor, erythroid 2 (NF-E2)-related factor 2 (Nrf2), an oxidative stress-responsive transcription factor in human and rodent cells. CA enhances the expression of nerve growth factor (NGF) and antioxidant genes, such as HO-1 in an Nrf2-dependent manner in U373MG human astrocytoma cells. However, CA also induces NGF gene expression in an Nrf2-independent manner, since 50 μM of CA administration showed striking NGF gene induction compared with the classical Nrf2 inducer tert-butylhydroquinone (tBHQ) in U373MG cells. By comparative transcriptome analysis, we found that CA activates activating transcription factor 4 (ATF4) in addition to Nrf2 at high doses. CA activated ATF4 in phospho-eIF2α- and heme-regulated inhibitor kinase (HRI)-dependent manners, indicating that CA activates ATF4 through the integrated stress response (ISR) pathway. Furthermore, CA activated Nrf2 and ATF4 cooperatively enhanced the expression of NGF and many antioxidant genes while acting independently to certain client genes. Taken together, these results represent a novel mechanism of CA-mediated gene regulation evoked by Nrf2 and ATF4 cooperation. Full article
(This article belongs to the Special Issue The Nrf2 Pathway: Regulation, Functions, and Potential Applications)
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Open AccessArticle
Endogenous and Exogenous Modulation of Nrf2 Mediated Oxidative Stress Response in Bovine Granulosa Cells: Potential Implication for Ovarian Function
Int. J. Mol. Sci. 2019, 20(7), 1635; https://doi.org/10.3390/ijms20071635 - 02 Apr 2019
Cited by 3
Abstract
Nrf2 is a redox sensitive transcription factor regulating the expression of antioxidant genes as defense mechanism against various stressors. The aim of this study is to investigate the potential role of noncoding miRNAs as endogenous and quercetin as exogenous regulators of Nrf2 pathway [...] Read more.
Nrf2 is a redox sensitive transcription factor regulating the expression of antioxidant genes as defense mechanism against various stressors. The aim of this study is to investigate the potential role of noncoding miRNAs as endogenous and quercetin as exogenous regulators of Nrf2 pathway in bovine granulosa cells. For this cultured granulosa cells were used for modulation of miRNAs (miR-28, 153 and miR-708) targeting the bovine Nrf2 and supplementation of quercentin to investigate the regulatory mechanisms of the Nrf2 antioxidant system. Moreover, cultured cells were treated with hydrogen peroxide to induce oxidative stress in those cells. Our results showed that, oxidative stress activated the expression of Nrf2 as a defense mechanism, while suppressing the expression of those miRNAs. Overexpression of those miRNAs resulted in downregulation of Nrf2 expression resulted in higher ROS accumulation, reduced mitochondrial activity and cellular proliferation. Quercetin supplementation showed its protective role against oxidative stress induced by H2O2 by inducing the expression of antioxidant enzymes. In conclusion, this study highlighted the involvement of miR-153, miR-28 and miR-708 in regulatory network of Nrf2 mediated antioxidant system in bovine granulosa cells function. Furthermore, quercetin at a low dose played a protective role in bovine granulosa cells against oxidative stress damage. Full article
(This article belongs to the Special Issue The Nrf2 Pathway: Regulation, Functions, and Potential Applications)
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Review

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Open AccessReview
Effect of Hepatitis Viruses on the Nrf2/Keap1-Signaling Pathway and Its Impact on Viral Replication and Pathogenesis
Int. J. Mol. Sci. 2019, 20(18), 4659; https://doi.org/10.3390/ijms20184659 - 19 Sep 2019
Abstract
With respect to their genome and their structure, the human hepatitis B virus (HBV) and hepatitis C virus (HCV) are complete different viruses. However, both viruses can cause an acute and chronic infection of the liver that is associated with liver inflammation (hepatitis). [...] Read more.
With respect to their genome and their structure, the human hepatitis B virus (HBV) and hepatitis C virus (HCV) are complete different viruses. However, both viruses can cause an acute and chronic infection of the liver that is associated with liver inflammation (hepatitis). For both viruses chronic infection can lead to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Reactive oxygen species (ROS) play a central role in a variety of chronic inflammatory diseases. In light of this, this review summarizes the impact of both viruses on ROS-generating and ROS-inactivating mechanisms. The focus is on the effect of both viruses on the transcription factor Nrf2 (nuclear factor erythroid 2 (NF-E2)-related factor 2). By binding to its target sequence, the antioxidant response element (ARE), Nrf2 triggers the expression of a variety of cytoprotective genes including ROS-detoxifying enzymes. The review summarizes the literature about the pathways for the modulation of Nrf2 that are deregulated by HBV and HCV and describes the impact of Nrf2 deregulation on the viral life cycle of the respective viruses and the virus-associated pathogenesis. Full article
(This article belongs to the Special Issue The Nrf2 Pathway: Regulation, Functions, and Potential Applications)
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Open AccessReview
Can Nrf2 Modulate the Development of Intestinal Fibrosis and Cancer in Inflammatory Bowel Disease?
Int. J. Mol. Sci. 2019, 20(16), 4061; https://doi.org/10.3390/ijms20164061 - 20 Aug 2019
Abstract
One of the main mechanisms carried out by the cells to counteract several forms of stress is the activation of the nuclear factor erythroid 2-related factor (Nrf2) signaling. Nrf2 signaling controls the expression of many genes through the binding of a specific cis [...] Read more.
One of the main mechanisms carried out by the cells to counteract several forms of stress is the activation of the nuclear factor erythroid 2-related factor (Nrf2) signaling. Nrf2 signaling controls the expression of many genes through the binding of a specific cis-acting element known as the antioxidant response element (ARE). Activation of Nrf2/ARE signaling can mitigate several pathologic mechanisms associated with an autoimmune response, digestive and metabolic disorders, as well as respiratory, cardiovascular, and neurodegenerative diseases. Indeed, several studies have demonstrated that Nrf2 pathway plays a key role in inflammation and in cancer development in many organs, including the intestine. Nrf2 appears to be involved in inflammatory bowel disease (IBD), an immune-mediated chronic and disabling disease, with a high risk of developing intestinal fibrotic strictures and cancer. Currently, drugs able to increase cytoprotective Nrf2 function are in clinical trials or already being used in clinical practice to reduce the progression of some degenerative conditions. The role of Nrf2 in cancer development and progression is controversial, and drugs able to inhibit abnormal levels of Nrf2 are also under investigation. The goal of this review is to analyze and discuss Nrf2-dependent signals in the initiation and progression of intestinal fibrosis and cancers occurring in IBD. Full article
(This article belongs to the Special Issue The Nrf2 Pathway: Regulation, Functions, and Potential Applications)
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Open AccessReview
The Role of Nrf2 in the Antioxidant Cellular Response to Medical Ozone Exposure
Int. J. Mol. Sci. 2019, 20(16), 4009; https://doi.org/10.3390/ijms20164009 - 17 Aug 2019
Cited by 1
Abstract
Ozone (O3) is a natural, highly unstable atmospheric gas that rapidly decomposes to oxygen. Although not being a radical molecule, O3 is a very strong oxidant and therefore it is potentially toxic for living organisms. However, scientific evidence proved that [...] Read more.
Ozone (O3) is a natural, highly unstable atmospheric gas that rapidly decomposes to oxygen. Although not being a radical molecule, O3 is a very strong oxidant and therefore it is potentially toxic for living organisms. However, scientific evidence proved that the effects of O3 exposure are dose-dependent: high dosages stimulate severe oxidative stress resulting in inflammatory response and tissue injury, whereas low O3 concentrations induce a moderate oxidative eustress activating antioxidant pathways. These properties make O3 a powerful medical tool, which can be used as either a disinfectant or an adjuvant agent in the therapy of numerous diseases. In this paper, the cellular mechanisms involved in the antioxidant response to O3 exposure will be reviewed with special reference to the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its role in the efficacy of ozone therapy. Full article
(This article belongs to the Special Issue The Nrf2 Pathway: Regulation, Functions, and Potential Applications)
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Open AccessReview
Regulation of Wound Healing by the NRF2 Transcription Factor—More Than Cytoprotection
Int. J. Mol. Sci. 2019, 20(16), 3856; https://doi.org/10.3390/ijms20163856 - 08 Aug 2019
Cited by 1
Abstract
The nuclear factor-erythroid 2-related factor 2 (NRF2) transcription factor plays a central role in mediating the cellular stress response. Due to their antioxidant properties, compounds activating NRF2 have received much attention as potential medications for disease prevention, or even for therapy. Accumulating evidence [...] Read more.
The nuclear factor-erythroid 2-related factor 2 (NRF2) transcription factor plays a central role in mediating the cellular stress response. Due to their antioxidant properties, compounds activating NRF2 have received much attention as potential medications for disease prevention, or even for therapy. Accumulating evidence suggests that activation of the NRF2 pathway also has a major impact on wound healing and may be beneficial in the treatment of chronic wounds, which remain a considerable health and economic burden. While NRF2 activation indeed shows promise, important considerations need to be made in light of corresponding evidence that also points towards pro-tumorigenic effects of NRF2. In this review, we discuss the evidence to date, highlighting recent advances using gain- and loss-of-function animal models and how these data fit with observations in humans. Full article
(This article belongs to the Special Issue The Nrf2 Pathway: Regulation, Functions, and Potential Applications)
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Open AccessReview
Cerebrovascular and Neurological Disorders: Protective Role of NRF2
Int. J. Mol. Sci. 2019, 20(14), 3433; https://doi.org/10.3390/ijms20143433 - 12 Jul 2019
Cited by 2
Abstract
Cellular defense mechanisms, intracellular signaling, and physiological functions are regulated by electrophiles and reactive oxygen species (ROS). Recent works strongly considered imbalanced ROS and electrophile overabundance as the leading cause of cellular and tissue damage, whereas oxidative stress (OS) plays a crucial role [...] Read more.
Cellular defense mechanisms, intracellular signaling, and physiological functions are regulated by electrophiles and reactive oxygen species (ROS). Recent works strongly considered imbalanced ROS and electrophile overabundance as the leading cause of cellular and tissue damage, whereas oxidative stress (OS) plays a crucial role for the onset and progression of major cerebrovascular and neurodegenerative pathologies. These include Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), stroke, and aging. Nuclear factor erythroid 2-related factor (NRF2) is the major modulator of the xenobiotic-activated receptor (XAR) and is accountable for activating the antioxidative response elements (ARE)-pathway modulating the detoxification and antioxidative responses of the cells. NRF2 activity, however, is also implicated in carcinogenesis protection, stem cells regulation, anti-inflammation, anti-aging, and so forth. Herein, we briefly describe the NRF2–ARE pathway and provide a review analysis of its functioning and system integration as well as its role in major CNS disorders. We also discuss NRF2-based therapeutic approaches for the treatment of neurodegenerative and cerebrovascular disorders. Full article
(This article belongs to the Special Issue The Nrf2 Pathway: Regulation, Functions, and Potential Applications)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

A Review related to the toxicological aspects of the Nrf2 pathway

Authors: Yoshito Kumagai (University of Tsukuba, Japan), et al.

 

A review related to protective activity of the Nrf2 pathway against kidney disease

Authors: Norio Suzuki (Tohoku University, Japan), et al.


A review of role of Nrf2 in chronic obstructive pulmonary disease

Authors: Chin Kook Rhee, et al.

 

A review on Detection of Nrf2  activity in vivo

Authors:  Andreas von Knethen, et al.

 

A review of role of Nrf2 in chronic obstructive pulmonary disease

Authors:  
Chin Kook Rhee, et al.

 

A Review on the role of Nrf2 in infections by intracellular pathogens

Authors:  Ulisses Lopes, et al.

 

 

Optimal regulation of NRF2 by TAZ is essential for protection against lung injury

Authors:
Eun Sook Hwang, et al.

 

The role of hyaluronic acid synthase inhibitor in CD44-mediated NRF2 activation in cancer stem-like cells

Authors: Mi-Kyoung Kwak, et al.

 

Endeogenous and exogenous modulation of NRF2 mediated oxidative stress response in bovine granulosa cells

Authors: Dawit Tesfaye, et al.

 

Effect of hepatitis viruses on the Nrf2 pathway and its impact on viral replication and pathogenesis

Authors: Eberhard Hildt, et al.

 

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