Role of Nrf2 in Disease: Novel Molecular Mechanisms and Therapeutic Approaches II

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Cellular Biochemistry".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 25609

Special Issue Editor


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Guest Editor
1. Instituto de Investigaciones Biomédicas “Sols-Moreale” UAM-CSIC, c/Arturo Duperier 4, 28029 Madrid, Spain
2. Department of Biochemistry, School of Medicine, Universidad Autónoma de Madrid, 28040 Madrid, Spain
3. Institute Teófilo Hernando for Drug Discovery, Universidad Autónoma de Madrid, 28029 Madrid, Spain
4. Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28031 Madrid, Spain
Interests: neurodegenerative diseases; NRF2; oxidative stress; neuroinflammation; RNA-binding proteins; mitochondria
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Special Issue Information

Dear Colleagues,

Following a very successful first run, we are pleased to announce the launch of a second edition of a Special Issue on the Role of Nrf2 in Disease.

Since it was cloned and characterized, the transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2) has been implicated in processes associated with redox balance; inflammation; proteostasis; and metabolism of lipids, purines, and pentoses, becoming recognized as a pleiotropic transcription factor. For this reason, Nrf2 has received interest as a polyvalent target against various pathologies, where the signaling system of Nrf2 is altered. Under normal conditions, basal Nrf2 levels are low due to its interaction with Kelch-like ECH-associated protein 1 (KEAP1), which binds to and negatively regulates Nrf2. Electrophiles or oxidative stress induce the inactivation of KEAP1 by direct modification of reactive cysteine residues, leading to the release and stabilization of Nrf2, which translocates to the nucleus to bind to the antioxidant response element (ARE) sequence in the promoter regions of Nrf2-dependent genes. This system makes it a good pharmacological target to modulate the activation of Nrf2 and, therefore, its application in various pathologies.

This Special Issue on Nrf2 should, on one hand, emphasize the importance of this transcription factor, and, on the other hand, it should also highlight existing pharmacological components that can modify the Nrf2 signaling pathway. In this regard, we would like to invite review articles that address the above-mentioned issues from different perspectives. Alternatively, any original research papers contributing significantly to Nrf2 signaling progress or advancing our understanding of biological implications are highly welcome.

We also invite researchers in the field and the participants of The COST Action CA20121, Bench to Bedside Transition for Pharmacological regulation of NRF2 in non-communicable diseases (BenBedPhar) to submit their latest research findings to this Special Issue. We look forward to reading your contributions.

Prof. Isabel Lastres-Becker
Guest Editor

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Keywords

  • inflammation
  • autophagy
  • proteasome
  • proteostasis
  • oxidative stress
  • neurodegeneration
  • metabolism
  • KEAP1
  • redox balance

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Published Papers (9 papers)

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Editorial

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2 pages, 178 KiB  
Editorial
Special Issue “Role of NRF2 in Disease: Novel Molecular Mechanisms and Therapeutic Approaches II”
by Isabel Lastres-Becker
Biomolecules 2023, 13(5), 813; https://doi.org/10.3390/biom13050813 - 10 May 2023
Viewed by 830
Abstract
This Special Issue (https://www [...] Full article

Research

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16 pages, 5453 KiB  
Article
Spatial Analysis of NQO1 in Non-Small Cell Lung Cancer Shows Its Expression Is Independent of NRF1 and NRF2 in the Tumor Microenvironment
by Boback Kaghazchi, In Hwa Um, Mustafa Elshani, Oliver J. Read and David J. Harrison
Biomolecules 2022, 12(11), 1652; https://doi.org/10.3390/biom12111652 - 08 Nov 2022
Cited by 4 | Viewed by 2072
Abstract
Nuclear factor erythroid 2-related factor 1 (NFE2L1, NRF1) and nuclear factor erythroid 2-related factor 2 (NFE2L2, NRF2) are distinct oxidative stress response transcription factors, both of which have been shown to perform cytoprotective functions, modulating cell stress response and homeostasis. NAD(P)H:quinone oxidoreductase (NQO1) [...] Read more.
Nuclear factor erythroid 2-related factor 1 (NFE2L1, NRF1) and nuclear factor erythroid 2-related factor 2 (NFE2L2, NRF2) are distinct oxidative stress response transcription factors, both of which have been shown to perform cytoprotective functions, modulating cell stress response and homeostasis. NAD(P)H:quinone oxidoreductase (NQO1) is a mutual downstream antioxidant gene target that catalyzes the two-electron reduction of an array of substrates, protecting against reactive oxygen species (ROS) generation. NQO1 is upregulated in non-small cell lung cancer (NSCLC) and is proposed as a predictive biomarker and therapeutic target. Antioxidant protein expression of immune cells within the NSCLC tumor microenvironment (TME) remains undetermined and may affect immune cell effector functions and survival outcomes. Multiplex immunofluorescence was performed to examine the co-localization of NQO1, NRF1 and NRF2 within the tumor and TME of 162 chemotherapy-naïve, early-stage NSCLC patients treated by primary surgical resection. This study demonstrates that NQO1 protein expression is high in normal, tumor-adjacent tissue and that NQO1 expression varies depending on the cell type. Inter and intra-patient heterogenous NQO1 expression was observed in lung cancer. Co-expression analysis showed NQO1 is independent of NRF1 and NRF2 in tumors. Density-based co-expression analysis demonstrated NRF1 and NRF2 double-positive expression in cancer cells is associated with improved overall survival. Full article
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17 pages, 2232 KiB  
Article
New Statement about NRF2 in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
by Isabel Lastres-Becker, Eva de Lago, Ana Martínez and Javier Fernández-Ruiz
Biomolecules 2022, 12(9), 1200; https://doi.org/10.3390/biom12091200 - 29 Aug 2022
Cited by 7 | Viewed by 2045
Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative disorders displaying substantial overlay, although there are substantial differences at the molecular level. Currently, there is no effective treatment for these diseases. The transcription factor NRF2 has been postulated as a promising [...] Read more.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative disorders displaying substantial overlay, although there are substantial differences at the molecular level. Currently, there is no effective treatment for these diseases. The transcription factor NRF2 has been postulated as a promising therapeutic target as it is capable of modulating key pathogenic events affecting cellular homeostasis. However, there is little experimental evidence on the status of this pathway in both ALS and FTD. Therefore, in this work, we wanted to carry out an exhaustive analysis of this signaling pathway in both transgenic mouse models (ALS and FTD) and human samples from patients with sporadic ALS (sALS) versus controls. In samples from patients with sALS and in the transgenic model with overexpression of TDP-43A315T, we observed a significant increase in the NRF2/ARE pathway in the motor cortex and the spinal cord, indicating that NRF2 antioxidant signaling was being induced, but it was not enough to reach cellular homeostasis. On the other hand, in the transgenic FTD model with overexpression of the TDP-43WT protein in forebrain neurons, a significantly decreased expression of NQO1 in the prefrontal cortex was seen, which cannot be attributed to alterations in the NRF2 pathway. Our results show that NRF2 signature is differently affected for ALS and FTD. Full article
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12 pages, 1717 KiB  
Communication
p62/SQSTM1/Keap1/NRF2 Axis Reduces Cancer Cells Death-Sensitivity in Response to Zn(II)–Curcumin Complex
by Alessia Garufi, Eugenia Giorno, Maria Saveria Gilardini Montani, Giuseppa Pistritto, Alessandra Crispini, Mara Cirone and Gabriella D’Orazi
Biomolecules 2021, 11(3), 348; https://doi.org/10.3390/biom11030348 - 25 Feb 2021
Cited by 18 | Viewed by 2677
Abstract
The hyperactivation of nuclear factor erythroid 2 p45-related factor 2 (NRF2), frequently found in many tumor types, can be responsible for cancer resistance to therapies and poor patient prognosis. Curcumin has been shown to activate NRF2 that has cytotprotective or protumorigenic roles according [...] Read more.
The hyperactivation of nuclear factor erythroid 2 p45-related factor 2 (NRF2), frequently found in many tumor types, can be responsible for cancer resistance to therapies and poor patient prognosis. Curcumin has been shown to activate NRF2 that has cytotprotective or protumorigenic roles according to tumor stage. The present study aimed at investigating whether the zinc–curcumin Zn(II)–curc compound, which we previously showed to display anticancer effects through multiple mechanisms, could induce NRF2 activation and to explore the underlying molecular mechanisms. Biochemical studies showed that Zn(II)–curc treatment increased the NRF2 protein levels along with its targets, heme oxygenase-1 (HO-1) and p62/SQSTM1, while markedly reduced the levels of Keap1 (Kelch-like ECH-associated protein 1), the NRF2 inhibitor, in the cancer cell lines analyzed. The silencing of either NRF2 or p62/SQSTM1 with specific siRNA demonstrated the crosstalk between the two molecules and that the knockdown of either molecule increased the cancer cell sensitivity to Zn(II)–curc-induced cell death. This suggests that the crosstalk between p62/SQSTM1 and NRF2 could be therapeutically exploited to increase cancer patient response to therapies. Full article
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Review

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14 pages, 828 KiB  
Review
The Role of the Transcription Factor Nrf2 in Alzheimer’s Disease: Therapeutic Opportunities
by Laura Maria De Plano, Giovanna Calabrese, Maria Giovanna Rizzo, Salvatore Oddo and Antonella Caccamo
Biomolecules 2023, 13(3), 549; https://doi.org/10.3390/biom13030549 - 17 Mar 2023
Cited by 8 | Viewed by 2506
Abstract
Alzheimer’s disease (AD) is a common neurodegenerative disorder that affects the elderly. One of the key features of AD is the accumulation of reactive oxygen species (ROS), which leads to an overall increase in oxidative damage. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) [...] Read more.
Alzheimer’s disease (AD) is a common neurodegenerative disorder that affects the elderly. One of the key features of AD is the accumulation of reactive oxygen species (ROS), which leads to an overall increase in oxidative damage. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a master regulator of the antioxidant response in cells. Under low ROS levels, Nrf2 is kept in the cytoplasm. However, an increase in ROS production leads to a translocation of Nrf2 into the nucleus, where it activates the transcription of several genes involved in the cells’ antioxidant response. Additionally, Nrf2 activation increases autophagy function. However, in AD, the accumulation of Aβ and tau reduces Nrf2 levels, decreasing the antioxidant response. The reduced Nrf2 levels contribute to the further accumulation of Aβ and tau by impairing their autophagy-mediated turnover. In this review, we discuss the overwhelming evidence indicating that genetic or pharmacological activation of Nrf2 is as a potential approach to mitigate AD pathology. Full article
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17 pages, 1119 KiB  
Review
NRF2 in the Epidermal Pigmentary System
by Tatsuya Ogawa and Yosuke Ishitsuka
Biomolecules 2023, 13(1), 20; https://doi.org/10.3390/biom13010020 - 22 Dec 2022
Cited by 2 | Viewed by 2315
Abstract
Melanogenesis is a major part of the environmental responses and tissue development of the integumentary system. The balance between reduction and oxidation (redox) governs pigmentary responses, for which coordination among epidermal resident cells is indispensable. Here, we review the current understanding of melanocyte [...] Read more.
Melanogenesis is a major part of the environmental responses and tissue development of the integumentary system. The balance between reduction and oxidation (redox) governs pigmentary responses, for which coordination among epidermal resident cells is indispensable. Here, we review the current understanding of melanocyte biology with a particular focus on the “master regulator” of oxidative stress responses (i.e., the Kelch-like erythroid cell-derived protein with cap‘n’collar homology-associated protein 1-nuclear factor erythroid-2-related factor 2 system) and the autoimmune pigment disorder vitiligo. Our investigation revealed that the former is essential in pigmentogenesis, whereas the latter results from unbalanced redox homeostasis and/or defective intercellular communication in the interfollicular epidermis (IFE). Finally, we propose a model in which keratinocytes provide a “niche” for differentiated melanocytes and may “imprint” IFE pigmentation. Full article
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21 pages, 7165 KiB  
Review
Activation of Nrf2 to Optimise Immune Responses to Intracerebral Haemorrhage
by James J. M. Loan, Rustam Al-Shahi Salman, Barry W. McColl and Giles E. Hardingham
Biomolecules 2022, 12(10), 1438; https://doi.org/10.3390/biom12101438 - 07 Oct 2022
Cited by 5 | Viewed by 3143
Abstract
Haemorrhage into the brain parenchyma can be devastating. This manifests as spontaneous intracerebral haemorrhage (ICH) after head trauma, and in the context of vascular dementia. Randomised controlled trials have not reliably shown that haemostatic treatments aimed at limiting ICH haematoma expansion and surgical [...] Read more.
Haemorrhage into the brain parenchyma can be devastating. This manifests as spontaneous intracerebral haemorrhage (ICH) after head trauma, and in the context of vascular dementia. Randomised controlled trials have not reliably shown that haemostatic treatments aimed at limiting ICH haematoma expansion and surgical approaches to reducing haematoma volume are effective. Consequently, treatments to modulate the pathophysiological responses to ICH, which may cause secondary brain injury, are appealing. Following ICH, microglia and monocyte derived cells are recruited to the peri-haematomal environment where they phagocytose haematoma breakdown products and secrete inflammatory cytokines, which may trigger both protective and harmful responses. The transcription factor Nrf2, is activated by oxidative stress, is highly expressed by central nervous system microglia and macroglia. When active, Nrf2 induces a transcriptional programme characterised by increased expression of antioxidant, haem and heavy metal detoxification and proteostasis genes, as well as suppression of proinflammatory factors. Therefore, Nrf2 activation may facilitate adaptive-protective immune cell responses to ICH by boosting resistance to oxidative stress and heavy metal toxicity, whilst limiting harmful inflammatory signalling, which can contribute to further blood brain barrier dysfunction and cerebral oedema. In this review, we consider the responses of immune cells to ICH and how these might be modulated by Nrf2 activation. Finally, we propose potential therapeutic strategies to harness Nrf2 to improve the outcomes of patients with ICH. Full article
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14 pages, 1586 KiB  
Review
Targeting Nrf2 with Probiotics and Postbiotics in the Treatment of Periodontitis
by Basar Karaca, Mustafa Yilmaz and Ulvi Kahraman Gursoy
Biomolecules 2022, 12(5), 729; https://doi.org/10.3390/biom12050729 - 22 May 2022
Cited by 11 | Viewed by 4107
Abstract
Periodontitis is a destructive disease of the tooth-surrounding tissues. Infection is the etiological cause of the disease, but its extent and severity depend on the immune–inflammatory response of the host. Immune cells use reactive oxygen species to suppress infections, and there is homeostasis [...] Read more.
Periodontitis is a destructive disease of the tooth-surrounding tissues. Infection is the etiological cause of the disease, but its extent and severity depend on the immune–inflammatory response of the host. Immune cells use reactive oxygen species to suppress infections, and there is homeostasis between oxidative and antioxidant mechanisms during periodontal health. During periodontitis, however, increased oxidative stress triggers tissue damage, either directly by activating apoptosis and DNA damage or indirectly by activating proteolytic cascades. Periodontal treatment aims to maintain an infection and inflammation-free zone and, in some cases, regenerate lost tissues. Although mechanical disruption of the oral biofilm is an indispensable part of periodontal treatment, adjunctive measures, such as antibiotics or anti-inflammatory medications, are also frequently used, especially in patients with suppressed immune responses. Recent studies have shown that probiotics activate antioxidant mechanisms and can suppress extensive oxidative stress via their ability to activate nuclear factor erythroid 2-related factor 2 (Nrf2). The aim of this narrative review is to describe the essential role of Nrf2 in the maintenance of periodontal health and to propose possible mechanisms to restore the impaired Nrf2 response in periodontitis, with the aid of probiotic and postbiotics. Full article
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20 pages, 1290 KiB  
Review
Loricrin at the Boundary between Inside and Outside
by Yosuke Ishitsuka and Dennis R. Roop
Biomolecules 2022, 12(5), 673; https://doi.org/10.3390/biom12050673 - 06 May 2022
Cited by 3 | Viewed by 3641
Abstract
Cornification is a specialized mode of the cell-death program exclusively allowed for terrestrial amniotes. Recent investigations suggest that loricrin (LOR) is an important cornification effector. As the connotation of its name (“lorica” meaning an armor in Latin) suggests, the keratin-associated protein LOR promotes [...] Read more.
Cornification is a specialized mode of the cell-death program exclusively allowed for terrestrial amniotes. Recent investigations suggest that loricrin (LOR) is an important cornification effector. As the connotation of its name (“lorica” meaning an armor in Latin) suggests, the keratin-associated protein LOR promotes the maturation of the epidermal structure through organizing covalent cross-linkages, endowing the epidermis with the protection against oxidative injuries. By reviewing cornification mechanisms, we seek to classify ichthyosiform dermatoses based on their function, rather than clinical manifestations. We also reviewed recent mechanistic insights into the Kelch-like erythroid cell-derived protein with the cap “n” collar homology-associated protein 1/nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway in skin health and diseases, as LOR and NRF2 coordinate the epidermis-intrinsic xenobiotic metabolism. Finally, we refine the theoretical framework of cross-talking between keratinocytes and epidermal resident leukocytes, dissecting an LOR immunomodulatory function. Full article
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