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Nrf2 and Heme Oxygenase: Two Players of the Same Game. Lights and Shadows

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 (31 December 2023) | Viewed by 8793

Special Issue Editor

Dr. Valeria Pittalà

E-Mail Website
Guest Editor
Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy
Interests: Nrf2; heme oxygenase; heme oxygenase-1 modulators; enzyme inhibitors; sigma receptors; serotonergic receptors; design of novel biologically active compounds
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a cytoplasmic evolutionary conserved protein responsible for cytoprotection in case of oxidative stress. Oxidative imbalance triggers Nrf2-induced transcription of several antioxidant factors, including heme oxygenase-1 (HO-1). Heme oxygenase-1 in turn by degrading heme is a source of protecting catabolites, such as carbon monoxide and bilirubin with antioxidant and cytoprotective properties. Hence, Nrf2 and HO-1 have evolved as promising drug targets for the treatment of oxidative stress-based diseases. At the same time, recent research trends highlighted their detrimental role in different types of tumours, suggesting their modulation or inhibition as a novel approach in anticancer therapy.

This Special Issue aims to collect original papers and reviews focused on the modulation of Nrf2 and HO-1 in order to shed light on their drugability in the treatment of pathologies related to an imbalanced oxidative cell status as well as cancer. Special attention will be devoted to papers helping to clarify shadows and lights of these two targets.

Dr. Antonino Nicolò Fallica ([email protected]), whose central research interest is rational design, synthesis, and biological evaluation of novel biologically active compounds, is serving as co-Guest Editor and will assist Prof. Valeria Pittalà on managing this Issue.

Prof. Dr. Valeria Pittalà
Guest Editor

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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.

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Keywords

  • keap1
  • heme oxygenase
  • inducers
  • inhibitors
  • cancer
  • oxidative stress protection
  • non-communicable diseases

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Published Papers (3 papers)

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Research

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16 pages, 9533 KiB  
Article
Paricalcitol Ameliorates Acute Kidney Injury in Mice by Suppressing Oxidative Stress and Inflammation via Nrf2/HO-1 Signaling
by Shuang Wang, Siqi Huang, Xingyao Liu, Yanjun He and Yun Liu
Int. J. Mol. Sci. 2023, 24(2), 969; https://doi.org/10.3390/ijms24020969 - 4 Jan 2023
Cited by 11 | Viewed by 1939
Abstract
Effective and targeted prevention and treatment methods for acute kidney injury (AKI), a common clinical complication, still needs to be explored. Paricalcitol is a biologically active chemical that binds to vitamin D receptors in the body to exert anti-oxidant and anti-inflammatory effects. However, [...] Read more.
Effective and targeted prevention and treatment methods for acute kidney injury (AKI), a common clinical complication, still needs to be explored. Paricalcitol is a biologically active chemical that binds to vitamin D receptors in the body to exert anti-oxidant and anti-inflammatory effects. However, the molecular mechanism of the effect of paricalcitol on AKI remains unclear. The current study uses a paricalcitol pretreatment with a mouse AKI model induced by cisplatin to detect changes in renal function, pathology and ultrastructure. Results showed that paricalcitol significantly improved renal function in mice and reduced inflammatory cell infiltration and mitochondrial damage in renal tissue. Furthermore, paricalcitol markedly suppressed reactive oxygen species and malondialdehyde levels in the kidneys of AKI mice and increased the levels of glutathione, superoxide dismutase, Catalase and total anti-oxidant capacity. In addition, we detected renal necrosis and inflammation-related proteins in AKI mice by immunofluorescence and Western blot, and found that their levels were markedly decreased after paricalcitol pretreatment. Moreover, paricalcitol promotes nuclear factor erythroid 2-related factor 2 (Nrf2) in the nucleus and activates the Nrf2/heme oxygenase-1 (HO-1) signaling pathway; while HO-1 is inhibited, the protective effect of paricalcitol on the kidney is attenuated. In conclusion, paricalcitol exerts a renoprotective effect by decreasing renal oxidative injury and inflammation through Nrf2/HO-1 signaling, providing a new insight into AKI prevention. Full article
(This article belongs to the Special Issue Nrf2 and Heme Oxygenase: Two Players of the Same Game. Lights and Shadows)
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23 pages, 3939 KiB  
Article
Different Inhibition of Nrf2 by Two Keap1 Isoforms α and β to Shape Malignant Behaviour of Human Hepatocellular Carcinoma
by Feilong Chen, Mei Xiao, Jing Feng, Reziyamu Wufur, Keli Liu, Shaofan Hu and Yiguo Zhang
Int. J. Mol. Sci. 2022, 23(18), 10342; https://doi.org/10.3390/ijms231810342 - 7 Sep 2022
Cited by 7 | Viewed by 2404
Abstract
Nrf2 (nuclear factor E2-related factor 2, encoded by Nfe2l2) acts as a master transcriptional regulator in mediating antioxidant, detoxification, and cytoprotective responses against oxidative, electrophilic, and metabolic stress, but also plays a crucial role in cancer metabolism and multiple oncogenic pathways, whereas [...] Read more.
Nrf2 (nuclear factor E2-related factor 2, encoded by Nfe2l2) acts as a master transcriptional regulator in mediating antioxidant, detoxification, and cytoprotective responses against oxidative, electrophilic, and metabolic stress, but also plays a crucial role in cancer metabolism and multiple oncogenic pathways, whereas the redox sensor Keap1 functions as a predominant inhibitor of Nrf2 and, hence, changes in its expression abundance directly affect the Nrf2 stability and transcriptional activity. However, nuanced functional isoforms of Keap1 α and β have rarely been identified to date. Herein, we have established four distinct cell models stably expressing Keap1−/−, Keap1β(Keap1Δ1–31), Keap1-Restored, and Keap1α-Restored aiming to gain a better understanding of similarities and differences of two Keap1 isoforms between their distinct regulatory profiles. Our experimental evidence revealed that although Keap1 and its isoforms are still localized in the cytoplasmic compartments, they elicited differential inhibitory effects on Nrf2 and its target HO-1. Furthermore, transcriptome sequencing unraveled that they possess similar but different functions. Such functions were further determined by multiple experiments in vivo (i.e., subcutaneous tumour formation in nude mice) and in vitro (e.g., cell cloning, infection, migration, wound healing, cell cycle, apoptosis, CAT enzymatic activity, and intracellular GSH levels). Of note, the results obtained from tumourigenesis experiments in xenograft model mice were verified based on the prominent changes in the PTEN signaling to the PI3K-AKT-mTOR pathways, in addition to substantially aberrant expression patterns of those typical genes involved in the EMT (epithelial–mesenchymal transition), cell cycle, and apoptosis. Full article
(This article belongs to the Special Issue Nrf2 and Heme Oxygenase: Two Players of the Same Game. Lights and Shadows)
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Review

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37 pages, 5071 KiB  
Review
An Overview of NRF2-Activating Compounds Bearing α,β-Unsaturated Moiety and Their Antioxidant Effects
by Melford Chuka Egbujor, Brigitta Buttari, Elisabetta Profumo, Pelin Telkoparan-Akillilar and Luciano Saso
Int. J. Mol. Sci. 2022, 23(15), 8466; https://doi.org/10.3390/ijms23158466 - 30 Jul 2022
Cited by 24 | Viewed by 3243
Abstract
The surge of scientific interest in the discovery of Nuclear Factor Erythroid 2 (NFE2)-Related Factor 2 (NRF2)-activating molecules underscores the importance of NRF2 as a therapeutic target especially for oxidative stress. The chemical reactivity and biological activities of several bioactive compounds have been [...] Read more.
The surge of scientific interest in the discovery of Nuclear Factor Erythroid 2 (NFE2)-Related Factor 2 (NRF2)-activating molecules underscores the importance of NRF2 as a therapeutic target especially for oxidative stress. The chemical reactivity and biological activities of several bioactive compounds have been linked to the presence of α,β-unsaturated structural systems. The α,β-unsaturated carbonyl, sulfonyl and sulfinyl functional groups are reportedly the major α,β-unsaturated moieties involved in the activation of the NRF2 signaling pathway. The carbonyl, sulfonyl and sulfinyl groups are generally electron-withdrawing groups, and the presence of the α,β-unsaturated structure qualifies them as suitable electrophiles for Michael addition reaction with nucleophilic thiols of cysteine residues within the proximal negative regulator of NRF2, Kelch-like ECH-associated protein 1 (KEAP1). The physicochemical property such as good lipophilicity of these moieties is also an advantage because it ensures solubility and membrane permeability required for the activation of the cytosolic NRF2/KEAP1 system. This review provides an overview of the reaction mechanism of α,β-unsaturated moiety-bearing compounds with the NRF2/KEAP1 complex, their pharmacological properties, structural activity-relationship and their effect on antioxidant and anti-inflammatory responses. As the first of its kind, this review article offers collective and comprehensive information on NRF2-activators containing α,β-unsaturated moiety with the aim of broadening their therapeutic prospects in a wide range of oxidative stress-related diseases. Full article
(This article belongs to the Special Issue Nrf2 and Heme Oxygenase: Two Players of the Same Game. Lights and Shadows)
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