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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: 15 May 2024 | Viewed by 1737

Special Issue Editor

Prof. Dr. Andreas von Knethen

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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

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. 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.

Published Papers (2 papers)

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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
Viewed by 312
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 734
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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