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The Role of NRF2 in Health and Disease

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

Deadline for manuscript submissions: closed (20 December 2024) | Viewed by 10171

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Dr. Daniela Impellizzeri

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Department of Chemical biological, pharmaceutical and environmental sciences, Università degli Studi di Messina, 98166 Messina, Italy
Interests: inflammation; oxidative stress; biochemistry; pharmacology; molecular biology
Special Issues, Collections and Topics in MDPI journals

Dr. Ramona D'Amico

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Department of Chemical Biological, Pharmaceutical and Environmental Sciences, Università degli Studi di Messina, 98166 Messina, Italy
Interests: biomarkers; molecular pathways; oxidative stress; inflammation; natural compound; clinical and pre-clinical studies
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Dr. Rosalba Siracusa

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Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy
Interests: clinical biochemistry; inflammation; oxidative stress; neurodegeneration; natural compounds
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Special Issue Information

Dear Colleagues,

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a major transcription factor involved in redox homeostasis and in the response induced by oxidative injury. It plays a major role in the dynamic regulation of a network of antioxidant and cytoprotective genes through binding to and activating the expression of promoters containing the antioxidant response element (ARE). Nrf2 activity is regulated by many mechanisms, suggesting that tight control is necessary for normal cell function, and both the hypoactivation and hyperactivation of Nrf-2 could play a role in various aspects of inflammatory diseases. Multiple classes of chemical inducers are known to elevate endogenous antioxidants by activating Nrf2. This Special Issue will focus on the role of NRF-2 in health or disease conditions and on the targeted activation of the Nrf-2 pathway, which could be a useful avenue in developing new therapeutics.

The Special Issue will feature original articles on in vivo and in vitro studies and reviews.

Dr. Daniela Impellizzeri
Dr. Ramona D'Amico
Dr. Rosalba Siracusa
Guest Editors

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Keywords

Nrf2
disease
inflammation
oxidative stress
therapeutics
animal models studies
in vitro studies

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Published Papers (6 papers)

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Research

15 pages, 2263 KiB

Open AccessArticle

Nrf2 Regulates Basal Glutathione Production in Astrocytes

by Jiali He and Sandra J. Hewett

Int. J. Mol. Sci. 2025, 26(2), 687; https://doi.org/10.3390/ijms26020687 - 15 Jan 2025

Viewed by 372

Abstract

Astrocytes produce and export glutathione (GSH), an important thiol antioxidant essential for protecting neural cells from oxidative stress and maintaining optimal brain health. While it has been established that oxidative stress increases GSH production in astrocytes, with Nrf2 acting as a critical transcription factor regulating key components of the GSH synthetic pathway, the role of Nrf2 in controlling constitutive GSH synthetic and release mechanisms remains incompletely investigated. Our data show that naïve primary mouse astrocytes cultured from the cerebral cortices of Nrf2 knockout (Nrf2^−/−) pups have significantly less intracellular and extracellular GSH levels when compared to astrocytes cultured from Nrf2 wild-type (Nrf2^+/+) pups. Key components of the GSH synthetic pathway, including xCT (the substrate-specific light chain of the substrate-importing transporter, system x_c⁻), glutamate-cysteine ligase [catalytic (GCLc) and modifying (GCLm) subunits], were affected. To wit: qRT-PCR analysis demonstrates that naïve Nrf2^−/− astrocytes have significantly lower basal mRNA levels of xCT and both GCL subunits compared to naïve Nrf2^+/+ astrocytes. No change in mRNA levels of glutathione synthetase (GS) or the GSH exporting transporter, Mrp1, was found. Western blot analysis reveals reduced protein levels of both subunits of GCL, while (seleno)cystine uptake into Nrf2^−/− astrocytes was reduced compared to Nrf2^+/+ astrocytes, confirming decreased system x_c⁻ activity. These findings suggest that Nrf2 regulates the basal production of GSH in astrocytes through constitutive transcriptional regulation of GCL and xCT. Full article

(This article belongs to the Special Issue The Role of NRF2 in Health and Disease)

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13 pages, 3129 KiB

Open AccessArticle

Chemical Inhibition of NRF2 Transcriptional Activity Influences Colon Function and Oestrogen Receptor Expression in Mice at Different Ages

by Aleksandra Piechota-Polanczyk, Zanya Mariwani, Jakub Fichna, Andrzej Polanczyk and Alicja Jozkowicz

Int. J. Mol. Sci. 2024, 25(24), 13647; https://doi.org/10.3390/ijms252413647 - 20 Dec 2024

Viewed by 524

Abstract

We aim to investigate whether chemical inhibition of NRF2 transcriptional activity (TA) influences distal colon contractions, particularly in an age-dependent manner in females, and whether it impacts oestrogen receptor signalling in female mice. This study was performed on 3 and 6-month-old female mice treated with ML385 (30 mg/kg) or a vehicle for 7 days (i.p.). The colon functionality was verified with a colon bead expulsion test; serum samples were collected for oestradiol levels, and colon samples were stored for various histological analyses. The results show that the seven-day treatment of ML385 significantly downregulated TA (p < 0.05) and impacted its contractility. Additionally, young females treated with ML385 exhibited an increase in goblet cell number and significantly increased ERα, but not ERβ, especially in older mice. It is worth noting that the basal level of the membrane oestrogen receptor GPR30 was higher in older mice within the epithelial layer, and ML385 treatment led to a downregulation of GPR30 in 6-month-old mice. In summary, ML385 decreases NRF2 TA in the colon and impacts its contractility and goblet cell numbers. Additionally, NRF2 TA influences the expression of oestrogen receptors in the colons of female mice. Full article

(This article belongs to the Special Issue The Role of NRF2 in Health and Disease)

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19 pages, 5330 KiB

Open AccessArticle

Dual Deletion of Keap1 and Rbpjκ Genes in Liver Leads to Hepatomegaly and Hypercholesterolemia

by Nobunao Wakabayashi, Yoko Yagishita, Tanvi Joshi and Thomas W. Kensler

Int. J. Mol. Sci. 2024, 25(9), 4712; https://doi.org/10.3390/ijms25094712 - 26 Apr 2024

Viewed by 1265

Abstract

The hepatic deletion of Rbpjκ (Rbpj^F/F::AlbCre) in the mouse leads to exhibition of the Alagille syndrome phenotype during early postnatal liver development with hyperlipidemia and cholestasis due to attenuated disruption of NOTCH signaling. Given the roles of NRF2 signaling in the regulation of lipid metabolism and bile ductal formation, it was anticipated that these symptoms could be alleviated by enhancing NRF2 signaling in the Rbpj^F/F::AlbCre mouse by hepatic deletion of Keap1 in compound Keap1^F/F::Rbpj^F/F::AlbCre mice. Unexpectedly, these mice developed higher hepatic and plasma cholesterol levels with more severe cholestatic liver damage during the pre-weaning period than in the Rbpj^F/F::AlbCre mice. In addition, hypercholesterolemia and hepatic damage were sustained throughout the growth period unlike in the Rbpj^F/F::AlbCre mouse. These enhanced abnormalities in lipid metabolism appear to be due to NRF2-dependent changes in gene expression related to cholesterol synthetic and subsequent bile acid production pathways. Notably, the hepatic expression of Cyp1A7 and Abcb11 genes involved in bile acid homeostasis was significantly reduced in Keap1^F/F::Rbpj^F/F::AlbCre compared to Rbpj^F/F::AlbCre mice. The accumulation of liver cholesterol and the weakened capacity for bile excretion during the 3 pre-weaning weeks in the Keap1^F/F::Rbpj^F/F::AlbCre mice may aggravate hepatocellular damage level caused by both excessive cholesterol and residual bile acid toxicity in hepatocytes. These results indicate that a tuned balance of NOTCH and NRF2 signaling is of biological importance for early liver development after birth. Full article

(This article belongs to the Special Issue The Role of NRF2 in Health and Disease)

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25 pages, 21251 KiB

Open AccessArticle

KEAP1-Mutant Lung Cancers Weaken Anti-Tumor Immunity and Promote an M2-like Macrophage Phenotype

by Christopher J. Occhiuto and Karen T. Liby

Int. J. Mol. Sci. 2024, 25(6), 3510; https://doi.org/10.3390/ijms25063510 - 20 Mar 2024

Viewed by 2226

Abstract

Considerable advances have been made in lung cancer therapies, but there is still an unmet clinical need to improve survival for lung cancer patients. Immunotherapies have improved survival, although only 20–30% of patients respond to these treatments. Interestingly, cancers with mutations in Kelch-like ECH-associated protein 1 (KEAP1), the negative regulator of the nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor, are resistant to immune checkpoint inhibition and correlate with decreased lymphoid cell infiltration. NRF2 is known for promoting an anti-inflammatory phenotype when activated in immune cells, but the study of NRF2 activation in cancer cells has not been adequately assessed. The objective of this study was to determine how lung cancer cells with constitutive NRF2 activity interact with the immune microenvironment to promote cancer progression. To assess, we generated CRISPR-edited mouse lung cancer cell lines by knocking out the KEAP1 or NFE2L2 genes and utilized a publicly available single-cell dataset through the Gene Expression Omnibus to investigate tumor/immune cell interactions. We show here that KEAP1-mutant cancers promote immunosuppression of the tumor microenvironment. Our data suggest KEAP1 deletion is sufficient to alter the secretion of cytokines, increase expression of immune checkpoint markers on cancer cells, and alter recruitment and differential polarization of immunosuppressive macrophages that ultimately lead to T-cell suppression. Full article

(This article belongs to the Special Issue The Role of NRF2 in Health and Disease)

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20 pages, 4351 KiB

Open AccessArticle

Antioxidant Activity of a Sicilian Almond Skin Extract Using In Vitro and In Vivo Models

by Alessia Arangia, Agnese Ragno, Marika Cordaro, Ramona D’Amico, Rosalba Siracusa, Roberta Fusco, Francesca Marino Merlo, Antonella Smeriglio, Daniela Impellizzeri, Salvatore Cuzzocrea, Giuseppina Mandalari and Rosanna Di Paola

Int. J. Mol. Sci. 2023, 24(15), 12115; https://doi.org/10.3390/ijms241512115 - 28 Jul 2023

Cited by 2 | Viewed by 2336

Abstract

Almond skins are known for their antioxidative and anti-inflammatory properties, which are mainly due to the presence of polyphenols. The aim of the present study was to evaluate the antioxidant and anti-inflammatory effects of almond skin extract (ASE) obtained from the Sicilian cultivar “Fascionello” and to evaluate the possible mechanisms of action using an in vitro model of human monocytic U937 cells as well as an in vivo model of carrageenan (CAR)-induced paw edema. The in vitro studies demonstrated that pretreatment with ASE inhibited the formation of ROS and apoptosis. The in vivo studies showed that ASE restored the CAR-induced tissue changes; restored the activity of endogenous antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione; and decreased neutrophil infiltration, lipid peroxidation, and the release of proinflammatory mediators. The anti-inflammatory and antioxidant effects of ASE could be associated with the inhibition of the pro-inflammatory nuclear NF-κB and the activation of the nuclear factor-erythroid 2-related factor 2 (Nrf2) antioxidant pathways. In conclusion, almond skin could reduce the levels of inflammation and oxidative stress and could be beneficial in the treatment of several disorders. Full article

(This article belongs to the Special Issue The Role of NRF2 in Health and Disease)

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27 pages, 6762 KiB

Open AccessArticle

The Effect of Cerebrolysin in an Animal Model of Forebrain Ischemic-Reperfusion Injury: New Insights into the Activation of the Keap1/Nrf2/Antioxidant Signaling Pathway

by Basma H. Marghani, Shaymaa Rezk, Ahmed I. Ateya, Badriyah S. Alotaibi, Basma H. Othman, Samy M. Sayed, Mohammed Ali Alshehri, Mustafa Shukry and Mohamed M. Mansour

Int. J. Mol. Sci. 2023, 24(15), 12080; https://doi.org/10.3390/ijms241512080 - 28 Jul 2023

Cited by 5 | Viewed by 2323

Abstract

Forebrain ischemia-reperfusion (IR) injury causes neurological impairments due to decreased cerebral autoregulation, hypoperfusion, and edema in the hours to days following the restoration of spontaneous circulation. This study aimed to examine the protective and/or therapeutic effects of cerebrolysin (CBL) in managing forebrain IR injury and any probable underlying mechanisms. To study the contribution of reperfusion to forebrain injury, we developed a transient dual carotid artery ligation (tDCAL/IR) mouse model. Five equal groups of six BLC57 mice were created: Group 1: control group (no surgery was performed); Group 2: sham surgery (surgery was performed without IR); Group 3: tDCAL/IR (surgery with IR via permanently ligating the left CA and temporarily closing the right CA for 30 min, followed by reperfusion for 72 h); Group 4: CBL + tDCAL/IR (CBL was given intravenously at a 60 mg/kg BW dose 30 min before IR); and Group 5: tDCAL/IR + CBL (CBL was administered i.v. at 60 mg/kg BW three hours after IR). At 72 h following IR, the mice were euthanized. CBL administration 3 h after IR improved neurological functional recovery, enhanced anti-inflammatory and antioxidant activities, alleviated apoptotic neuronal death, and inhibited reactive microglial and astrocyte activation, resulting in neuroprotection after IR injury in the tDCAL/IR + CBL mice group as compared to the other groups. Furthermore, CBL reduced the TLRs/NF-kB/cytokines while activating the Keap1/Nrf2/antioxidant signaling pathway. These results indicate that CBL may improve neurologic function in mice following IR. Full article

(This article belongs to the Special Issue The Role of NRF2 in Health and Disease)

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