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The Nrf2 Pathway: Regulation, Functions, and Potential Applications 3.0
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The Nrf2 Pathway: Regulation, Functions, and Potential Applications 3.0

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: closed (15 May 2024) | Viewed by 5815

Special Issue Editor

Prof. Dr. Andreas von Knethen

E-Mail Website
Guest Editor
Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy–Experimental Unit, University Hospital Frankfurt, Theodor-Stern-Kai 7, Building 9B, 3rd Floor, 60590 Frankfurt, Germany
Interests: sepsis; ARDS; macrophages; T cells; Nrf2; PPARgamma; mouse sepsis models
Special Issues, Collections and Topics in MDPI journals

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 cell 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 discoveries targeting the Nrf2 pathway have 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 are widely recruiting original articles that describe new discoveries in the Nrf2 pathway regarding any relevant topic, such as physiological functions, gene regulation, activation mechanism, drug discovery, evolution, human diseases, protein structure, animal models, and genomes. We also welcome review articles and commentaries.

Prof. Dr. Andreas von Knethen
Guest Editor

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Published Papers (4 papers)

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Research

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16 pages, 3157 KiB  
Article
Transcriptional Up-Regulation of FBXW7 by KCa1.1 K+ Channel Inhibition through the Nrf2 Signaling Pathway in Human Prostate Cancer LNCaP Cell Spheroid Model
by Susumu Ohya, Hiroaki Kito, Junko Kajikuri, Yohei Yamaguchi and Miki Matsui
Int. J. Mol. Sci. 2024, 25(11), 6019; https://doi.org/10.3390/ijms25116019 - 30 May 2024
Viewed by 1010
Abstract
The tumor suppressor gene F-box and WD repeat domain-containing (FBXW) 7 reduces cancer stemness properties by promoting the protein degradation of pluripotent stem cell markers. We recently demonstrated the transcriptional repression of FBXW7 by the three-dimensional (3D) spheroid formation of several cancer cells. [...] Read more.
The tumor suppressor gene F-box and WD repeat domain-containing (FBXW) 7 reduces cancer stemness properties by promoting the protein degradation of pluripotent stem cell markers. We recently demonstrated the transcriptional repression of FBXW7 by the three-dimensional (3D) spheroid formation of several cancer cells. In the present study, we found that the transcriptional activity of FBXW7 was promoted by the inhibition of the Ca2+-activated K+ channel, KCa1.1, in a 3D spheroid model of human prostate cancer LNCaP cells through the Akt-Nrf2 signaling pathway. The transcriptional activity of FBXW7 was reduced by the siRNA-mediated inhibition of the CCAAT-enhancer-binding protein C/EBP δ (CEBPD) after the transfection of miR223 mimics in the LNCaP spheroid model, suggesting the transcriptional regulation of FBXW7 through the Akt-Nrf2-CEBPD-miR223 transcriptional axis in the LNCaP spheroid model. Furthermore, the KCa1.1 inhibition-induced activation of FBXW7 reduced (1) KCa1.1 activity and protein levels in the plasma membrane and (2) the protein level of the cancer stem cell (CSC) markers, c-Myc, which is a molecule degraded by FBXW7, in the LNCaP spheroid model, indicating that KCa1.1 inhibition-induced FBXW7 activation suppressed CSC conversion in KCa1.1-positive cancer cells. Full article
(This article belongs to the Special Issue The Nrf2 Pathway: Regulation, Functions, and Potential Applications 3.0)
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15 pages, 3333 KiB  
Article
The Experimental and In Silico-Based Evaluation of NRF2 Modulators, Sulforaphane and Brusatol, on the Transcriptome of Immortalized Bovine Mammary Alveolar Cells
by Hunter R. Ford and Massimo Bionaz
Int. J. Mol. Sci. 2024, 25(8), 4264; https://doi.org/10.3390/ijms25084264 - 12 Apr 2024
Cited by 1 | Viewed by 1049
Abstract
Changes during the production cycle of dairy cattle can leave these animals susceptible to oxidative stress and reduced antioxidant health. In particular, the periparturient period, when dairy cows must rapidly adapt to the sudden metabolic demands of lactation, is a period when the [...] Read more.
Changes during the production cycle of dairy cattle can leave these animals susceptible to oxidative stress and reduced antioxidant health. In particular, the periparturient period, when dairy cows must rapidly adapt to the sudden metabolic demands of lactation, is a period when the production of damaging free radicals can overwhelm the natural antioxidant systems, potentially leading to tissue damage and reduced milk production. Central to the protection against free radical damage and antioxidant defense is the transcription factor NRF2, which activates an array of genes associated with antioxidant functions and cell survival. The objective of this study was to evaluate the effect that two natural NRF2 modulators, the NRF2 agonist sulforaphane (SFN) and the antagonist brusatol (BRU), have on the transcriptome of immortalized bovine mammary alveolar cells (MACT) using both the RT-qPCR of putative NRF2 target genes, as well as RNA sequencing approaches. The treatment of cells with SFN resulted in the activation of many putative NRF2 target genes and the upregulation of genes associated with pathways involved in cell survival, metabolism, and antioxidant function while suppressing the expression of genes related to cellular senescence and DNA repair. In contrast, the treatment of cells with BRU resulted in the upregulation of genes associated with inflammation, cellular stress, and apoptosis while suppressing the transcription of genes involved in various metabolic processes. The analysis also revealed several novel putative NRF2 target genes in bovine. In conclusion, these data indicate that the treatment of cells with SFN and BRU may be effective at modulating the NRF2 transcriptional network, but additional effects associated with cellular stress and metabolism may complicate the effectiveness of these compounds to improve antioxidant health in dairy cattle via nutrigenomic approaches. Full article
(This article belongs to the Special Issue The Nrf2 Pathway: Regulation, Functions, and Potential Applications 3.0)
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13 pages, 5301 KiB  
Article
The Functional Significance of McMafF_G_K in Molluscs: Implications for Nrf2-Mediated Oxidative Stress Response
by Ronghui Yao, Longmei Qiu, Li Zhu, Xinglu Chen, Jiaying Zhai, Weifeng Wang, Pengzhi Qi, Zhi Liao, Isabella Buttino, Xiaojun Yan and Baoying Guo
Int. J. Mol. Sci. 2023, 24(23), 16800; https://doi.org/10.3390/ijms242316800 - 27 Nov 2023
Viewed by 1173
Abstract
The nuclear factor erythroid 2-related factor 2 (Nrf2) is a pivotal regulator of antioxidant gene expression in mammals, forming heterodimer complexes with small Maf proteins through its BZip domain. However, the underlying mechanism of Nrf2 action in molluscs remains poorly understood. The thick [...] Read more.
The nuclear factor erythroid 2-related factor 2 (Nrf2) is a pivotal regulator of antioxidant gene expression in mammals, forming heterodimer complexes with small Maf proteins through its BZip domain. However, the underlying mechanism of Nrf2 action in molluscs remains poorly understood. The thick shell mussel, Mytilus coruscus, represents a model organism for the marine environment and molluscs interaction research. In this study, we used in silico cloning to obtain a small Maf homologue called McMafF_G_K from M. coruscus. McMafF_G_K possesses a typical BZip domain, suggesting its affiliation with the traditional small Maf family and its potential involvement in the Nrf2 signaling pathway. Transcriptional analysis revealed that McMafF_G_K exhibited a robust response to benzo[a]pyrene (Bap) in the digestive glands. However, this response was down-regulated upon interference with McMafF_G_K-siRNA. Interestingly, the expression levels of Nrf2, NAD(P)H: quinone oxidoreductase (NQO-1), and Glutathione Peroxidase (GPx), which are key players in oxidative stress response, showed a positive correlation with McMafF_G_K in digested adenocytes of M. coruscus. Furthermore, in vitro analysis of antioxidant capacity in digestive gland cells demonstrated that Bap exposure led to an increase in reactive oxygen species (ROS) levels, accompanied by an elevation in total antioxidant capacity (T-AOC), potentially counterbalancing the excessive ROS. Strikingly, transfection of McMafF_G_K siRNA resulted in a significant rise in ROS level and a down-regulation of T-AOC level. To validate the functional relevance of McMafF_G_K, a glutathione S-transferase (GST) pull-down assay confirmed its interaction with McNrf2, providing compelling evidence of their protein interaction. This study significantly contributes to our understanding of the functional role of McMafF_G_K in the Nrf2 signaling pathway and sheds light on its potential as a target for further research in oxidative stress response. Full article
(This article belongs to the Special Issue The Nrf2 Pathway: Regulation, Functions, and Potential Applications 3.0)
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Review

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26 pages, 3918 KiB  
Review
The Role of the Nrf2 Pathway in Airway Tissue Damage Due to Viral Respiratory Infections
by Arnaud John Kombe Kombe, Leila Fotoohabadi, Ravikanth Nanduri, Yulia Gerasimova, Maria Daskou, Chandrima Gain, Eashan Sharma, Michael Wong and Theodoros Kelesidis
Int. J. Mol. Sci. 2024, 25(13), 7042; https://doi.org/10.3390/ijms25137042 - 27 Jun 2024
Viewed by 1545
Abstract
Respiratory viruses constitute a significant cause of illness and death worldwide. Respiratory virus-associated injuries include oxidative stress, ferroptosis, inflammation, pyroptosis, apoptosis, fibrosis, autoimmunity, and vascular injury. Several studies have demonstrated the involvement of the nuclear factor erythroid 2-related factor 2 (Nrf2) in the [...] Read more.
Respiratory viruses constitute a significant cause of illness and death worldwide. Respiratory virus-associated injuries include oxidative stress, ferroptosis, inflammation, pyroptosis, apoptosis, fibrosis, autoimmunity, and vascular injury. Several studies have demonstrated the involvement of the nuclear factor erythroid 2-related factor 2 (Nrf2) in the pathophysiology of viral infection and associated complications. It has thus emerged as a pivotal player in cellular defense mechanisms against such damage. Here, we discuss the impact of Nrf2 activation on airway injuries induced by respiratory viruses, including viruses, coronaviruses, rhinoviruses, and respiratory syncytial viruses. The inhibition or deregulation of Nrf2 pathway activation induces airway tissue damage in the presence of viral respiratory infections. In contrast, Nrf2 pathway activation demonstrates protection against tissue and organ injuries. Clinical trials involving Nrf2 agonists are needed to define the effect of Nrf2 therapeutics on airway tissues and organs damaged by viral respiratory infections. Full article
(This article belongs to the Special Issue The Nrf2 Pathway: Regulation, Functions, and Potential Applications 3.0)
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