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Molecular Targets of Oxidative Stress: Focus on the Nrf2 Signaling...
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Molecular Targets of Oxidative Stress: Focus on the Nrf2 Signaling Pathway in Health and Disease

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

Deadline for manuscript submissions: closed (20 August 2023) | Viewed by 41902

Special Issue Editor

Prof. Dr. Marcel Bonay

E-Mail Website
Guest Editor
1. Department of Physiology and Functional Explorations, Ambroise Paré Hospital - Assistance Publique Hôpitaux de Paris, 92104 Boulogne, France
2. Inserm U1179 and ISPC-preclinical laboratory, University of Paris Saclay (UVSQ), 78000 Versailles, France
Interests: immune regulation; immunology of infectious diseases; innate immunity; oxidative stress; Nrf2; respiratory diseases; macrophage; exercise
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Oxidative stress, known to increase the risk of multiple metabolic and chronic disorders or cancer development, is defined by an imbalance between the production of reactive oxygen species (ROS) and the capacity of antioxidants to counteract the deleterious effects of oxidants. To regulate the oxidation/reduction (redox) balance, numerous antioxidant enzymes and nonenzymatic antioxidants exist. Free radicals activate transcription factors to promote antioxidants production and mitochondrial biogenesis. One of these transcription factors, nuclear factor erythroid 2-related factor 2 (Nrf2), is a master regulator of the antioxidant and anti-inflammatory responses. Indeed, Nrf2 contributes to redox balance by initiating the transcription of hundreds of genes involved in the antioxidant and cytoprotective responses. A better understanding of the molecular targets of oxidative stress and their interaction with the Nrf2 signaling pathway would strengthen the relevance of their preventive or therapeutic use in health and diseases.

We invite researchers to submit original articles or review articles on different aspects of the modulation of oxidative stress in animal models or in humans. The topic includes the biological and physiological effects of the Nrf2 signaling pathway in chronic diseases or their prevention.

Prof. Dr. Marcel Bonay
Guest Editor

Manuscript Submission Information

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

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

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

Published Papers (19 papers)

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Editorial

Jump to: Research, Review, Other

5 pages, 177 KiB  
Editorial
Molecular Targets of Oxidative Stress: Focus on the Nrf2 Signaling Pathway in Health and Disease
by Marcel Bonay
Antioxidants 2024, 13(3), 262; https://doi.org/10.3390/antiox13030262 - 21 Feb 2024
Viewed by 823
Abstract
Oxidative stress, known to increase the risk of multiple metabolic and chronic disorders or cancer development, is defined as an imbalance between the production of reactive oxygen species (ROS) and the capacity of antioxidants to counteract the deleterious effects of oxidants [...] Full article
(This article belongs to the Special Issue Molecular Targets of Oxidative Stress: Focus on the Nrf2 Signaling Pathway in Health and Disease)

Research

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18 pages, 4099 KiB  
Article
Inhibitory Effects of Ehretia tinifolia Extract on the Excessive Oxidative and Inflammatory Responses in Lipopolysaccharide-Stimulated Mouse Kupffer Cells
by Jae Sung Lim, Sung Ho Lee, Hyosuk Yun, Da Young Lee, Namki Cho, Guijae Yoo, Jeong Uk Choi, Kwang Youl Lee, Tran The Bach, Su-Jin Park and Young-Chang Cho
Antioxidants 2023, 12(10), 1792; https://doi.org/10.3390/antiox12101792 - 22 Sep 2023
Viewed by 1044
Abstract
Ehretia tinifolia (E. tinifolia) L., an evergreen tree with substantial biological activity, including antioxidant and anti-inflammatory effects, has been used in many herbal and traditional medicines. To elucidate its antioxidant and anti-inflammatory activity and the underlying mechanisms, we applied a methanol [...] Read more.
Ehretia tinifolia (E. tinifolia) L., an evergreen tree with substantial biological activity, including antioxidant and anti-inflammatory effects, has been used in many herbal and traditional medicines. To elucidate its antioxidant and anti-inflammatory activity and the underlying mechanisms, we applied a methanol extract of E. tinifolia (ETME) to lipopolysaccharide (LPS)-stimulated mouse immortalized Kupffer cells. ETME suppressed the LPS-induced increase in nitric oxide, a mediator for oxidative stress and inflammation, and restored LPS-mediated depletion of total glutathione level by stabilizing antioxidative nuclear factor erythroid 2-related factor 2 (Nrf2) and the subsequent increase in heme oxygenase-1 levels. Furthermore, ETME inhibited the LPS-induced production of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1β, and IL-6. The inhibitory effects of ETME on pro-inflammatory responses were regulated by ETME-mediated dephosphorylation of mitogen-activated protein kinases (MAPKs: p38, p44/p42, and stress-associated protein kinase/c-Jun N-terminal kinase) and inhibition of nuclear localization of nuclear factor kappa B (NF-κB). These results suggest that ETME is a possible candidate for protecting Kupffer cells from LPS-mediated oxidative stress and excessive inflammatory responses by activating antioxidant Nrf2/HO-1 and inhibiting pro-inflammatory NF-κB and MAPKs, respectively. Full article
(This article belongs to the Special Issue Molecular Targets of Oxidative Stress: Focus on the Nrf2 Signaling Pathway in Health and Disease)
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18 pages, 4776 KiB  
Article
High-Frequency Repetitive Magnetic Stimulation Activates Bactericidal Activity of Macrophages via Modulation of p62/Keap1/Nrf2 and p38 MAPK Pathways
by Therese B. Deramaudt, Ahmad Chehaitly, Théo Charrière, Julie Arnaud and Marcel Bonay
Antioxidants 2023, 12(9), 1695; https://doi.org/10.3390/antiox12091695 - 30 Aug 2023
Viewed by 1495
Abstract
The effects of repetitive magnetic stimulation (rMS) have predominantly been studied in excitable cells, with limited research in non-excitable cells. This study aimed to investigate the impact of rMS on macrophages, which are crucial cells in the innate immune defense. THP-1-derived macrophages subjected [...] Read more.
The effects of repetitive magnetic stimulation (rMS) have predominantly been studied in excitable cells, with limited research in non-excitable cells. This study aimed to investigate the impact of rMS on macrophages, which are crucial cells in the innate immune defense. THP-1-derived macrophages subjected to a 5 min session of 10 Hz rMS exhibited increased Nrf2 activation and decreased Keap1 expression. We found that activation of the Nrf2 signaling pathway relied on rMS-induced phosphorylation of p62. Notably, rMS reduced the intracellular survival of Staphylococcus aureus in macrophages. Silencing Nrf2 using siRNA in THP-1-derived macrophages or utilizing Nrf2 knockout in alveolar macrophages abolished this effect. Additionally, rMS attenuated the expression of IL-1β and TNF-α inflammatory genes by S. aureus and inhibited p38 MAPK activation. These findings highlight the capacity of rMS to activate the non-canonical Nrf2 pathway, modulate macrophage function, and enhance the host’s defense against bacterial infection. Full article
(This article belongs to the Special Issue Molecular Targets of Oxidative Stress: Focus on the Nrf2 Signaling Pathway in Health and Disease)
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16 pages, 2397 KiB  
Article
Rutin Protects Fibroblasts from UVA Radiation through Stimulation of Nrf2 Pathway
by Elisabetta Tabolacci, Giuseppe Tringali, Veronica Nobile, Sara Duca, Michela Pizzoferrato, Patrizia Bottoni and Maria Elisabetta Clementi
Antioxidants 2023, 12(4), 820; https://doi.org/10.3390/antiox12040820 - 28 Mar 2023
Cited by 6 | Viewed by 1380
Abstract
This study explores the photoprotective effects of rutin, a bioflavonoid found in some vegetables and fruits, against UVA-induced damage in human skin fibroblasts. Our results show that rutin increases cell viability and reduces the high levels of ROS generated by photo-oxidative stress (1 [...] Read more.
This study explores the photoprotective effects of rutin, a bioflavonoid found in some vegetables and fruits, against UVA-induced damage in human skin fibroblasts. Our results show that rutin increases cell viability and reduces the high levels of ROS generated by photo-oxidative stress (1 and 2 h of UVA exposure). These effects are related to rutin’s ability to modulate the Nrf2 transcriptional pathway. Interestingly, activation of the Nrf2 signaling pathway results in an increase in reduced glutathione and Bcl2/Bax ratio, and the subsequent protection of mitochondrial respiratory capacity. These results demonstrate how rutin may play a potentially cytoprotective role against UVA-induced skin damage through a purely antiapoptotic mechanism. Full article
(This article belongs to the Special Issue Molecular Targets of Oxidative Stress: Focus on the Nrf2 Signaling Pathway in Health and Disease)
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12 pages, 1851 KiB  
Article
Profiling the miRNA from Exosomes of Non-Pigmented Ciliary Epithelium-Derived Identifies Key Gene Targets Relevant to Primary Open-Angle Glaucoma
by Padmanabhan Paranji Pattabiraman, Valeria Feinstein and Elie Beit-Yannai
Antioxidants 2023, 12(2), 405; https://doi.org/10.3390/antiox12020405 - 07 Feb 2023
Cited by 1 | Viewed by 1609
Abstract
Oxidative stress (OS) on tissues is a major pathological insult leading to elevated intraocular pressure (IOP) and primary open-angle glaucoma (POAG). Aqueous humor (AH) produced by the non-pigmentary ciliary epithelium (NPCE) drains out via the trabecular meshwork (TM) outflow pathway in the anterior [...] Read more.
Oxidative stress (OS) on tissues is a major pathological insult leading to elevated intraocular pressure (IOP) and primary open-angle glaucoma (POAG). Aqueous humor (AH) produced by the non-pigmentary ciliary epithelium (NPCE) drains out via the trabecular meshwork (TM) outflow pathway in the anterior chamber. The exosomes are major constituents of AH, and exosomes can modulate the signaling events, as well as the responses of their target TM tissue. Despite the presence of molecular mechanisms to negate OS, oxidative damage directly, as well as indirectly, influences TM health, AH drainage, and IOP. We proposed that the expression of microRNA (miRNAs) carried by exosomes in the AH can be affected by OS, and this can modulate the pathways in target cells. To assess this, we subjected NPCE to acute and chronic OS (A-OS and C-OS), enriched miRNAs, performed miRNA microarray chip analyses, and miRNA-based gene targeting pathway prediction analysis. We found that various miRNA families, including miR27, miR199, miR23, miR130b, and miR200, changed significantly. Based on pathway prediction analysis, we found that these miRNAs can regulate the genes including Nrf2, Keap1, GSK3B, and serine/threonine-protein phosphatase2A (PP2A). We propose that OS on the NPCE exosomal miRNA cargo can modulate the functionality of the TM tissue. Full article
(This article belongs to the Special Issue Molecular Targets of Oxidative Stress: Focus on the Nrf2 Signaling Pathway in Health and Disease)
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28 pages, 4219 KiB  
Article
Transcriptomic Profiling and Pathway Analysis of Mesenchymal Stem Cells Following Low Dose-Rate Radiation Exposure
by John E. Slaven, Matthew Wilkerson, Anthony R. Soltis, W. Bradley Rittase, Dmitry T. Bradfield, Michelle Bylicky, Lynnette Cary, Alena Tsioplaya, Roxane Bouten, Clifton Dalgard and Regina M. Day
Antioxidants 2023, 12(2), 241; https://doi.org/10.3390/antiox12020241 - 21 Jan 2023
Cited by 3 | Viewed by 2035
Abstract
Low dose-rate radiation exposure can occur in medical imaging, as background from environmental or industrial radiation, and is a hazard of space travel. In contrast with high dose-rate radiation exposure that can induce acute life-threatening syndromes, chronic low-dose radiation is associated with Chronic [...] Read more.
Low dose-rate radiation exposure can occur in medical imaging, as background from environmental or industrial radiation, and is a hazard of space travel. In contrast with high dose-rate radiation exposure that can induce acute life-threatening syndromes, chronic low-dose radiation is associated with Chronic Radiation Syndrome (CRS), which can alter environmental sensitivity. Secondary effects of chronic low dose-rate radiation exposure include circulatory, digestive, cardiovascular, and neurological diseases, as well as cancer. Here, we investigated 1–2 Gy, 0.66 cGy/h, 60Co radiation effects on primary human mesenchymal stem cells (hMSC). There was no significant induction of apoptosis or DNA damage, and cells continued to proliferate. Gene ontology (GO) analysis of transcriptome changes revealed alterations in pathways related to cellular metabolism (cholesterol, fatty acid, and glucose metabolism), extracellular matrix modification and cell adhesion/migration, and regulation of vasoconstriction and inflammation. Interestingly, there was increased hypoxia signaling and increased activation of pathways regulated by iron deficiency, but Nrf2 and related genes were reduced. The data were validated in hMSC and human lung microvascular endothelial cells using targeted qPCR and Western blotting. Notably absent in the GO analysis were alteration pathways for DNA damage response, cell cycle inhibition, senescence, and pro-inflammatory response that we previously observed for high dose-rate radiation exposure. Our findings suggest that cellular gene transcription response to low dose-rate ionizing radiation is fundamentally different compared to high-dose-rate exposure. We hypothesize that cellular response to hypoxia and iron deficiency are driving processes, upstream of the other pathway regulation. Full article
(This article belongs to the Special Issue Molecular Targets of Oxidative Stress: Focus on the Nrf2 Signaling Pathway in Health and Disease)
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16 pages, 6193 KiB  
Article
Quantitative Proteomics Identifies Novel Nrf2-Mediated Adaptative Signaling Pathways in Skeletal Muscle Following Exercise Training
by Anjali Bhat, Rafay Abu, Sankarasubramanian Jagadesan, Neetha Nanoth Vellichirammal, Ved Vasishtha Pendyala, Li Yu, Tara L. Rudebush, Chittibabu Guda, Irving H. Zucker, Vikas Kumar and Lie Gao
Antioxidants 2023, 12(1), 151; https://doi.org/10.3390/antiox12010151 - 09 Jan 2023
Cited by 4 | Viewed by 2479
Abstract
Exercise training (ExT) improves skeletal muscle health via multiple adaptative pathways. Nrf2 is a principal antioxidant transcription factor responsible for maintaining intracellular redox homeostasis. In this study, we hypothesized that Nrf2 is essential for adaptative responses to ExT and thus beneficial for muscle. [...] Read more.
Exercise training (ExT) improves skeletal muscle health via multiple adaptative pathways. Nrf2 is a principal antioxidant transcription factor responsible for maintaining intracellular redox homeostasis. In this study, we hypothesized that Nrf2 is essential for adaptative responses to ExT and thus beneficial for muscle. Experiments were carried out on male wild type (WT) and iMS-Nrf2flox/flox inducible muscle-specific Nrf2 (KO) mice, which were randomly assigned to serve as sedentary controls (Sed) or underwent 3 weeks of treadmill ExT thus generating four groups: WT-Sed, WT-ExT, KO-Sed, and KO-ExT groups. Mice were examined for exercise performance and in situ tibialis anterior (TA) contractility, followed by mass spectrometry-based proteomics and bioinformatics to identify differentially expressed proteins and signaling pathways. We found that maximal running distance was significantly longer in the WT-ExT group compared to the WT-Sed group, whereas this capacity was impaired in KO-ExT mice. Force generation and fatigue tolerance of the TA were enhanced in WT-ExT, but reduced in KO-ExT, compared to Sed controls. Proteomic analysis further revealed that ExT upregulated 576 proteins in WT but downregulated 207 proteins in KO mice. These proteins represent pathways in redox homeostasis, mitochondrial respiration, and proteomic adaptation of muscle to ExT. In summary, our data suggest a critical role of Nrf2 in the beneficial effects of SkM and adaptation to ExT. Full article
(This article belongs to the Special Issue Molecular Targets of Oxidative Stress: Focus on the Nrf2 Signaling Pathway in Health and Disease)
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12 pages, 6527 KiB  
Article
Broccoli-Derived Glucoraphanin Activates AMPK/PGC1α/NRF2 Pathway and Ameliorates Dextran-Sulphate-Sodium-Induced Colitis in Mice
by Qiyu Tian, Zhixin Xu, Qi Sun, Alejandro Bravo Iniguez, Min Du and Mei-Jun Zhu
Antioxidants 2022, 11(12), 2404; https://doi.org/10.3390/antiox11122404 - 04 Dec 2022
Cited by 3 | Viewed by 2046
Abstract
As the prevalence of inflammatory bowel diseases (IBD) rises, the etiology of IBD draws increasing attention. Glucoraphanin (GRP), enriched in cruciferous vegetables, is a precursor of sulforaphane, known to have anti-inflammatory and antioxidative effects. We hypothesized that dietary GRP supplementation can prevent mitochondrial [...] Read more.
As the prevalence of inflammatory bowel diseases (IBD) rises, the etiology of IBD draws increasing attention. Glucoraphanin (GRP), enriched in cruciferous vegetables, is a precursor of sulforaphane, known to have anti-inflammatory and antioxidative effects. We hypothesized that dietary GRP supplementation can prevent mitochondrial dysfunction and oxidative stress in an acute colitis mouse model induced by dextran sulfate sodium (DSS). Eight-week-old mice were fed a regular rodent diet either supplemented with or without GRP. After 4 weeks of dietary treatments, half of the mice within each dietary group were subjected to 2.5% DSS treatment to induce colitis. Dietary GRP decreased DSS-induced body weight loss, disease activity index, and colon shortening. Glucoraphanin supplementation protected the colonic histological structure, suppressed inflammatory cytokines, interleukin (IL)-1β, IL-18, and tumor necrosis factor-α (TNF-α), and reduced macrophage infiltration in colonic tissues. Consistently, dietary GRP activated AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α, and nuclear factor erythroid 2-related factor 2 (NRF2) pathways in the colonic tissues of DSS-treated mice, which was associated with increased mitochondrial DNA and decreased content of the oxidative product 8-hydroxydeoxyguanosine (8-OHDG), a nucleotide oxidative product of DNA. In conclusion, dietary GRP attenuated mitochondrial dysfunction, inflammatory response, and oxidative stress induced by DSS, suggesting that dietary GRP provides a dietary strategy to alleviate IBD symptoms. Full article
(This article belongs to the Special Issue Molecular Targets of Oxidative Stress: Focus on the Nrf2 Signaling Pathway in Health and Disease)
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19 pages, 3628 KiB  
Article
Dipeptide Repeat Pathology in C9orf72-ALS Is Associated with Redox, Mitochondrial and NRF2 Pathway Imbalance
by José Jiménez-Villegas, Janine Kirby, Ana Mata, Susana Cadenas, Martin R. Turner, Andrea Malaspina, Pamela J. Shaw, Antonio Cuadrado and Ana I. Rojo
Antioxidants 2022, 11(10), 1897; https://doi.org/10.3390/antiox11101897 - 25 Sep 2022
Cited by 8 | Viewed by 2271
Abstract
The hexanucleotide expansion of the C9orf72 gene is found in 40% of familial amyotrophic lateral sclerosis (ALS) patients. This genetic alteration has been connected with impaired management of reactive oxygen species. In this study, we conducted targeted transcriptional profiling in leukocytes from C9orf72 [...] Read more.
The hexanucleotide expansion of the C9orf72 gene is found in 40% of familial amyotrophic lateral sclerosis (ALS) patients. This genetic alteration has been connected with impaired management of reactive oxygen species. In this study, we conducted targeted transcriptional profiling in leukocytes from C9orf72 patients and control subjects by examining the mRNA levels of 84 redox-related genes. The expression of ten redox genes was altered in samples from C9orf72 ALS patients compared to healthy controls. Considering that Nuclear factor erythroid 2-Related Factor 2 (NRF2) modulates the expression of a wide range of redox genes, we further investigated its status on an in vitro model of dipeptide repeat (DPR) toxicity. This model mimics the gain of function, toxic mechanisms attributed to C9orf72 pathology. We found that exposure to DPRs increased superoxide levels and reduced mitochondrial potential as well as cell survival. Importantly, cells overexpressing DPRs exhibited reduced protein levels of NRF2 and its target genes upon inhibition of the proteasome or its canonical repressor, the E3 ligase adapter KEAP1. However, NRF2 activation was sufficient to recover cell viability and redox homeostasis. This study identifies NRF2 as a putative target in precision medicine for the therapy of ALS patients harboring C9orf72 expansion repeats. Full article
(This article belongs to the Special Issue Molecular Targets of Oxidative Stress: Focus on the Nrf2 Signaling Pathway in Health and Disease)
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17 pages, 3650 KiB  
Article
AMPK-Nrf2 Signaling Pathway in Phrenic Motoneurons following Cervical Spinal Cord Injury
by Pauline Michel-Flutot, Laurie Efthimiadi, Lynda Djerbal, Therese B. Deramaudt, Marcel Bonay and Stéphane Vinit
Antioxidants 2022, 11(9), 1665; https://doi.org/10.3390/antiox11091665 - 26 Aug 2022
Viewed by 1865
Abstract
High spinal cord injuries (SCI) induce the deafferentation of phrenic motoneurons, leading to permanent diaphragm paralysis. This involves secondary injury associated with pathologic and inflammatory processes at the site of injury, and at the level of phrenic motoneurons. In the present study, we [...] Read more.
High spinal cord injuries (SCI) induce the deafferentation of phrenic motoneurons, leading to permanent diaphragm paralysis. This involves secondary injury associated with pathologic and inflammatory processes at the site of injury, and at the level of phrenic motoneurons. In the present study, we evaluated the antioxidant response in phrenic motoneurons involving the AMPK-Nrf2 signaling pathway following C2 spinal cord lateral hemi-section in rats. We showed that there is an abrupt reduction in the expression of phosphorylated AMPK and Nrf2 at one hour post-injury in phrenic motoneurons. A rebound is then observed at one day post-injury, reflecting a return to homeostasis condition. In the total spinal cord around phrenic motoneurons, the increase in phosphorylated AMPK and Nrf2 occurred at three days post-injury, showing the differential antioxidant response between phrenic motoneurons and other cell types. Taken together, our results display the implication of the AMPK-Nrf2 signaling pathway in phrenic motoneurons’ response to oxidative stress following high SCI. Harnessing this AMPK-Nrf2 signaling pathway could improve the antioxidant response and help in spinal rewiring to these deafferented phrenic motoneurons to improve diaphragm activity in patients suffering high SCI. Full article
(This article belongs to the Special Issue Molecular Targets of Oxidative Stress: Focus on the Nrf2 Signaling Pathway in Health and Disease)
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16 pages, 4997 KiB  
Article
Antioxidant Genetic Profile Modifies Probability of Developing Neurological Sequelae in Long-COVID
by Marko Ercegovac, Milika Asanin, Ana Savic-Radojevic, Jovan Ranin, Marija Matic, Tatjana Djukic, Vesna Coric, Djurdja Jerotic, Nevena Todorovic, Ivana Milosevic, Goran Stevanovic, Tatjana Simic, Zoran Bukumiric and Marija Pljesa-Ercegovac
Antioxidants 2022, 11(5), 954; https://doi.org/10.3390/antiox11050954 - 12 May 2022
Cited by 10 | Viewed by 4769
Abstract
Understanding the sequelae of COVID-19 is of utmost importance. Neuroinflammation and disturbed redox homeostasis are suggested as prevailing underlying mechanisms in neurological sequelae propagation in long-COVID. We aimed to investigate whether variations in antioxidant genetic profile might be associated with neurological sequelae in [...] Read more.
Understanding the sequelae of COVID-19 is of utmost importance. Neuroinflammation and disturbed redox homeostasis are suggested as prevailing underlying mechanisms in neurological sequelae propagation in long-COVID. We aimed to investigate whether variations in antioxidant genetic profile might be associated with neurological sequelae in long-COVID. Neurological examination and antioxidant genetic profile (SOD2, GPXs and GSTs) determination, as well as, genotype analysis of Nrf2 and ACE2, were conducted on 167 COVID-19 patients. Polymorphisms were determined by the appropriate PCR methods. Only polymorphisms in GSTP1AB and GSTO1 were independently associated with long-COVID manifestations. Indeed, individuals carrying GSTP1 Val or GSTO1 Asp allele exhibited lower odds of long-COVID myalgia development, both independently and in combination. Furthermore, the combined presence of GSTP1 Ile and GSTO1 Ala alleles exhibited cumulative risk regarding long-COVID myalgia in carriers of the combined GPX1 LeuLeu/GPX3 CC genotype. Moreover, individuals carrying combined GSTM1-null/GPX1LeuLeu genotype were more prone to developing long-COVID “brain fog”, while this probability further enlarged if the Nrf2 A allele was also present. The fact that certain genetic variants of antioxidant enzymes, independently or in combination, affect the probability of long-COVID manifestations, further emphasizes the involvement of genetic susceptibility when SARS-CoV-2 infection is initiated in the host cells, and also months after. Full article
(This article belongs to the Special Issue Molecular Targets of Oxidative Stress: Focus on the Nrf2 Signaling Pathway in Health and Disease)
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20 pages, 5367 KiB  
Article
P2X7 Receptor Augments LPS-Induced Nitrosative Stress by Regulating Nrf2 and GSH Levels in the Mouse Hippocampus
by Duk-Shin Lee and Ji-Eun Kim
Antioxidants 2022, 11(4), 778; https://doi.org/10.3390/antiox11040778 - 13 Apr 2022
Cited by 2 | Viewed by 2097
Abstract
P2X7 receptor (P2X7R) regulates inducible nitric oxide synthase (iNOS) expression/activity in response to various harmful insults. Since P2X7R deletion paradoxically decreases the basal glutathione (GSH) level in the mouse hippocampus, it is likely that P2X7R may increase the demand for GSH for the [...] Read more.
P2X7 receptor (P2X7R) regulates inducible nitric oxide synthase (iNOS) expression/activity in response to various harmful insults. Since P2X7R deletion paradoxically decreases the basal glutathione (GSH) level in the mouse hippocampus, it is likely that P2X7R may increase the demand for GSH for the maintenance of the intracellular redox state or affect other antioxidant defense systems. Therefore, the present study was designed to elucidate whether P2X7R affects nuclear factor-erythroid 2-related factor 2 (Nrf2) activity/expression and GSH synthesis under nitrosative stress in response to lipopolysaccharide (LPS)-induced neuroinflammation. In the present study, P2X7R deletion attenuated iNOS upregulation and Nrf2 degradation induced by LPS. Compatible with iNOS induction, P2X7R deletion decreased S-nitrosylated (SNO)-cysteine production under physiological and post-LPS treated conditions. P2X7R deletion also ameliorated the decreases in GSH, glutathione synthetase, GS and ASCT2 levels concomitant with the reduced S-nitrosylations of GS and ASCT2 following LPS treatment. Furthermore, LPS upregulated cystine:glutamate transporter (xCT) and glutaminase in P2X7R+/+ mice, which were abrogated by P2X7R deletion. LPS did not affect GCLC level in both P2X7R+/+ and P2X7R−/− mice. Therefore, our findings indicate that P2X7R may augment LPS-induced neuroinflammation by leading to Nrf2 degradation, aberrant glutamate-glutamine cycle and impaired cystine/cysteine uptake, which would inhibit GSH biosynthesis. Therefore, we suggest that the targeting of P2X7R, which would exert nitrosative stress with iNOS in a positive feedback manner, may be one of the important therapeutic strategies of nitrosative stress under pathophysiological conditions. Full article
(This article belongs to the Special Issue Molecular Targets of Oxidative Stress: Focus on the Nrf2 Signaling Pathway in Health and Disease)
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Review

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25 pages, 1687 KiB  
Review
NRF2, a Superstar of Ferroptosis
by Ruihan Yan, Bingyi Lin, Wenwei Jin, Ling Tang, Shuming Hu and Rong Cai
Antioxidants 2023, 12(9), 1739; https://doi.org/10.3390/antiox12091739 - 08 Sep 2023
Cited by 6 | Viewed by 2677
Abstract
Ferroptosis is an iron-dependent and lipid peroxidation-driven cell death cascade, occurring when there is an imbalance of redox homeostasis in the cell. Nuclear factor erythroid 2-related factor 2 (NFE2L2, also known as NRF2) is key for cellular antioxidant responses, which promotes downstream genes [...] Read more.
Ferroptosis is an iron-dependent and lipid peroxidation-driven cell death cascade, occurring when there is an imbalance of redox homeostasis in the cell. Nuclear factor erythroid 2-related factor 2 (NFE2L2, also known as NRF2) is key for cellular antioxidant responses, which promotes downstream genes transcription by binding to their antioxidant response elements (AREs). Numerous studies suggest that NRF2 assumes an extremely important role in the regulation of ferroptosis, for its various functions in iron, lipid, and amino acid metabolism, and so on. Many pathological states are relevant to ferroptosis. Abnormal suppression of ferroptosis is found in many cases of cancer, promoting their progression and metastasis. While during tissue damages, ferroptosis is recurrently promoted, resulting in a large number of cell deaths and even dysfunctions of the corresponding organs. Therefore, targeting NRF2-related signaling pathways, to induce or inhibit ferroptosis, has become a great potential therapy for combating cancers, as well as preventing neurodegenerative and ischemic diseases. In this review, a brief overview of the research process of ferroptosis over the past decade will be presented. In particular, the mechanisms of ferroptosis and a focus on the regulation of ferroptosis by NRF2 will be discussed. Finally, the review will briefly list some clinical applications of targeting the NRF2 signaling pathway in the treatment of diseases. Full article
(This article belongs to the Special Issue Molecular Targets of Oxidative Stress: Focus on the Nrf2 Signaling Pathway in Health and Disease)
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14 pages, 1587 KiB  
Review
Nrf2-Mediated Antioxidant Defense and Thyroid Hormone Signaling: A Focus on Cardioprotective Effects
by Laura Sabatino
Antioxidants 2023, 12(6), 1177; https://doi.org/10.3390/antiox12061177 - 30 May 2023
Cited by 3 | Viewed by 1640
Abstract
Thyroid hormones (TH) perform a plethora of actions in numerous tissues and induce an overall increase in metabolism, with an augmentation in energy demand and oxygen expenditure. Oxidants are required for normal thyroid-cell proliferation, as well as for the synthesis of the main [...] Read more.
Thyroid hormones (TH) perform a plethora of actions in numerous tissues and induce an overall increase in metabolism, with an augmentation in energy demand and oxygen expenditure. Oxidants are required for normal thyroid-cell proliferation, as well as for the synthesis of the main hormones secreted by the thyroid gland, triiodothyronine (T3) and thyroxine (T4). However, an uncontrolled excess of oxidants can cause oxidative stress, a major trigger in the pathogenesis of a broad spectrum of diseases, including inflammation and cancer. In particular, oxidative stress is implicated in both hypo- and hyper-thyroid diseases. Furthermore, it is important for the TH system to rely on efficient antioxidant defense, to maintain balance, despite sustained tissue exposure to oxidants. One of the main endogenous antioxidant responses is the pathway centered on the nuclear factor erythroid 2-related factor (Nrf2). The aim of the present review is to explore the multiple links between Nrf2-related pathways and various TH-associated conditions. The main aspect of TH signaling is described and the role of Nrf2 in oxidant–antioxidant homeostasis in the TH system is evaluated. Next, the antioxidant function of Nrf2 associated with oxidative stress induced by TH pathological excess is discussed and, subsequently, particular attention is given to the cardioprotective role of TH, which also acts through the mediation of Nrf2. In conclusion, the interaction between Nrf2 and most common natural antioxidant agents in altered states of TH is briefly evaluated. Full article
(This article belongs to the Special Issue Molecular Targets of Oxidative Stress: Focus on the Nrf2 Signaling Pathway in Health and Disease)
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20 pages, 4558 KiB  
Review
Activators of Nrf2 to Counteract Neurodegenerative Diseases
by Rosa Amoroso, Cristina Maccallini and Ilaria Bellezza
Antioxidants 2023, 12(3), 778; https://doi.org/10.3390/antiox12030778 - 22 Mar 2023
Cited by 9 | Viewed by 2190
Abstract
Neurodegenerative diseases are incurable and debilitating conditions that result in progressive degeneration and loss of nerve cells. Oxidative stress has been proposed as one factor that plays a potential role in the pathogenesis of neurodegenerative disorders since neuron cells are particularly vulnerable to [...] Read more.
Neurodegenerative diseases are incurable and debilitating conditions that result in progressive degeneration and loss of nerve cells. Oxidative stress has been proposed as one factor that plays a potential role in the pathogenesis of neurodegenerative disorders since neuron cells are particularly vulnerable to oxidative damage. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is strictly related to anti-inflammatory and antioxidative cell response; therefore, its activation and the consequent enhancement of the related cellular pathways have been proposed as a potential therapeutic approach. Several Nrf2 activators with different mechanisms and diverse structures have been reported, but those applied for neurodisorders are still limited. However, in the very last few years, interesting progress has been made, particularly in enhancing the blood–brain barrier penetration, to make Nrf2 activators effective drugs, and in designing Nrf2-based multitarget-directed ligands to affect multiple pathways involved in the pathology of neurodegenerative diseases. The present review gives an overview of the most representative findings in this research area. Full article
(This article belongs to the Special Issue Molecular Targets of Oxidative Stress: Focus on the Nrf2 Signaling Pathway in Health and Disease)
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15 pages, 3941 KiB  
Review
Phenotypic Modulation of Cancer-Associated Antioxidant NQO1 Activity by Post-Translational Modifications and the Natural Diversity of the Human Genome
by Angel L. Pey
Antioxidants 2023, 12(2), 379; https://doi.org/10.3390/antiox12020379 - 04 Feb 2023
Cited by 2 | Viewed by 1510
Abstract
Human NAD(P)H:quinone oxidoreductase 1 (hNQO1) is a multifunctional and antioxidant stress protein whose expression is controlled by the Nrf2 signaling pathway. hNQO1 dysregulation is associated with cancer and neurological disorders. Recent works have shown that its activity is also modulated by different post-translational [...] Read more.
Human NAD(P)H:quinone oxidoreductase 1 (hNQO1) is a multifunctional and antioxidant stress protein whose expression is controlled by the Nrf2 signaling pathway. hNQO1 dysregulation is associated with cancer and neurological disorders. Recent works have shown that its activity is also modulated by different post-translational modifications (PTMs), such as phosphorylation, acetylation and ubiquitination, and these may synergize with naturally-occurring and inactivating polymorphisms and mutations. Herein, I describe recent advances in the study of the effect of PTMs and genetic variations on the structure and function of hNQO1 and their relationship with disease development in different genetic backgrounds, as well as the physiological roles of these modifications. I pay particular attention to the long-range allosteric effects exerted by PTMs and natural variation on the multiple functions of hNQO1. Full article
(This article belongs to the Special Issue Molecular Targets of Oxidative Stress: Focus on the Nrf2 Signaling Pathway in Health and Disease)
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17 pages, 958 KiB  
Review
Stress Activated MAP Kinases and Cyclin-Dependent Kinase 5 Mediate Nuclear Translocation of Nrf2 via Hsp90α-Pin1-Dynein Motor Transport Machinery
by Tetsuro Ishii, Eiji Warabi and Giovanni E. Mann
Antioxidants 2023, 12(2), 274; https://doi.org/10.3390/antiox12020274 - 26 Jan 2023
Cited by 3 | Viewed by 2482
Abstract
Non-lethal low levels of oxidative stress leads to rapid activation of the transcription factor nuclear factor-E2-related factor 2 (Nrf2), which upregulates the expression of genes important for detoxification, glutathione synthesis, and defense against oxidative damage. Stress-activated MAP kinases p38, ERK, and JNK cooperate [...] Read more.
Non-lethal low levels of oxidative stress leads to rapid activation of the transcription factor nuclear factor-E2-related factor 2 (Nrf2), which upregulates the expression of genes important for detoxification, glutathione synthesis, and defense against oxidative damage. Stress-activated MAP kinases p38, ERK, and JNK cooperate in the efficient nuclear accumulation of Nrf2 in a cell-type-dependent manner. Activation of p38 induces membrane trafficking of a glutathione sensor neutral sphingomyelinase 2, which generates ceramide upon depletion of cellular glutathione. We previously proposed that caveolin-1 in lipid rafts provides a signaling hub for the phosphorylation of Nrf2 by ceramide-activated PKCζ and casein kinase 2 to stabilize Nrf2 and mask a nuclear export signal. We further propose a mechanism of facilitated Nrf2 nuclear translocation by ERK and JNK. ERK and JNK phosphorylation of Nrf2 induces the association of prolyl cis/trans isomerase Pin1, which specifically recognizes phosphorylated serine or threonine immediately preceding a proline residue. Pin1-induced structural changes allow importin-α5 to associate with Nrf2. Pin1 is a co-chaperone of Hsp90α and mediates the association of the Nrf2-Pin1-Hsp90α complex with the dynein motor complex, which is involved in transporting the signaling complex to the nucleus along microtubules. In addition to ERK and JNK, cyclin-dependent kinase 5 could phosphorylate Nrf2 and mediate the transport of Nrf2 to the nucleus via the Pin1-Hsp90α system. Some other ERK target proteins, such as pyruvate kinase M2 and hypoxia-inducible transcription factor-1, are also transported to the nucleus via the Pin1-Hsp90α system to modulate gene expression and energy metabolism. Notably, as malignant tumors often express enhanced Pin1-Hsp90α signaling pathways, this provides a potential therapeutic target for tumors. Full article
(This article belongs to the Special Issue Molecular Targets of Oxidative Stress: Focus on the Nrf2 Signaling Pathway in Health and Disease)
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Graphical abstract

15 pages, 1137 KiB  
Review
The Nrf2 in Obesity: A Friend or Foe?
by Yudong Xia, Xiaoying Zhai, Yanning Qiu, Xuemei Lu and Yi Jiao
Antioxidants 2022, 11(10), 2067; https://doi.org/10.3390/antiox11102067 - 20 Oct 2022
Cited by 8 | Viewed by 2953
Abstract
Obesity and its complications have become serious global health concerns recently and increasing work has been carried out to explicate the underlying mechanism of the disease development. The recognized correlations suggest oxidative stress and inflammation in expanding adipose tissue with excessive fat accumulation [...] Read more.
Obesity and its complications have become serious global health concerns recently and increasing work has been carried out to explicate the underlying mechanism of the disease development. The recognized correlations suggest oxidative stress and inflammation in expanding adipose tissue with excessive fat accumulation play important roles in the pathogenesis of obesity, as well as its associated metabolic syndromes. In adipose tissue, obesity-mediated insulin resistance strongly correlates with increased oxidative stress and inflammation. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been described as a key modulator of antioxidant signaling, which regulates the transcription of various genes coding antioxidant enzymes and cytoprotective proteins. Furthermore, an increasing number of studies have demonstrated that Nrf2 is a pivotal target of obesity and its related metabolic disorders. However, its effects are controversial and even contradictory. This review aims to clarify the complicated interplay among Nrf2, oxidative stress, lipid metabolism, insulin signaling and chronic inflammation in obesity. Elucidating the implications of Nrf2 modulation on obesity would provide novel insights for potential therapeutic approaches in obesity and its comorbidities. Full article
(This article belongs to the Special Issue Molecular Targets of Oxidative Stress: Focus on the Nrf2 Signaling Pathway in Health and Disease)
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49 pages, 1489 KiB  
Systematic Review
The Nrf2 Pathway in Depressive Disorders: A Systematic Review of Animal and Human Studies
by Gabriele Sani, Stella Margoni, Andrea Brugnami, Ottavia Marianna Ferrara, Evelina Bernardi, Alessio Simonetti, Laura Monti, Marianna Mazza, Delfina Janiri, Lorenzo Moccia, Georgios D. Kotzalidis, Daniela Pia Rosaria Chieffo and Luigi Janiri
Antioxidants 2023, 12(4), 817; https://doi.org/10.3390/antiox12040817 - 27 Mar 2023
Cited by 7 | Viewed by 2442
Abstract
There is increasing interest in the involvement of antioxidative systems in protecting from depression. Among these, Nrf2 occupies a central place. We aimed to review the role of Nrf2 in depression. For this reason, we conducted a PubMed search using as search strategy [...] Read more.
There is increasing interest in the involvement of antioxidative systems in protecting from depression. Among these, Nrf2 occupies a central place. We aimed to review the role of Nrf2 in depression. For this reason, we conducted a PubMed search using as search strategy (psychiatr*[ti] OR schizo*[ti] OR psychot*[ti] OR psychos*[ti] OR depress*[ti] OR MDD[ti] OR BD[ti] OR bipolar[ti] OR Anxiety[ti] OR antidepress*[ti] OR panic[ti] OR obsess*[ti] OR compulsio*[ti] OR “mood disord*”[ti] OR phobi*[ti] OR agoraphob*[ti] OR anorex*[ti] OR anorect*[ti] OR bulimi*[ti] OR “eating disorder*”[ti] OR neurodevelopm*[ti] OR retardation[ti] OR autism[ti] OR autistic[ti] OR ASM[ti] OR adhd[ti] OR “attention-deficit”[ti]) AND nrf2, which on the 9th of March produced 208 results of which 89 were eligible for our purposes. Eligible articles were studies reporting data of Nrf2 manipulations or content by any treatment in human patients or animals with any animal model of depression. Most studies were on mice only (N = 58), 20 on rats only, and three on both rats and mice. There were two studies on cell lines (in vitro) and one each on nematodes and fish. Only four studies were conducted in humans, one of which was post mortem. Most studies were conducted on male animals; however, human studies were carried out on both men and women. The results indicate that Nrf2 is lower in depression and that antidepressant methods (drugs or other methods) increase it. Antioxidant systems and plasticity-promoting molecules, such as those in the Nrf2–HO-1, BDNF–TrkB, and cyclic AMP–CREB pathways, could protect from depression, while glycogen synthase kinase-3β and nuclear factor κB oppose these actions, thus increasing depressive-like behaviours. Since Nrf2 is also endowed with tumorigenic and atherogenic potential, the balance between benefits and harms must be taken into account in designing novel drugs aiming at increasing the intracellular content of Nrf2. Full article
(This article belongs to the Special Issue Molecular Targets of Oxidative Stress: Focus on the Nrf2 Signaling Pathway in Health and Disease)
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