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Nrf2 Signaling Pathway: Biological Function, Clinical Implications and Therapeutic Agents

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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 February 2023) | Viewed by 19617

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Special Issue Editor

Prof. Dr. Zhengyu Jiang

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Guest Editor

Department of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
Interests: therapetiuc agents targeting Keap1-Nrf2-ARE signaling; redox system-related prodrugs and probes; innovative molecules acting on protein complex; E3 ligase complex
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Nrf2 is a multifunctional transcription factor which plays an important role in cytoprotective system. Enhancing Nrf2 activity has long been regarded as a promising way for the treatment of a set of diseases that appear to be mechanistically linked with oxidative stress. In addition, more and more evidence indicates that overactivation of Nrf2 plays an important role in tumour occurrence and malignant transformation. During the last decade, a growing body of research has focused on blocking NRF2 activity in cancer cells, attempting to disturb the redox balance, antagonize the oncogenic metabolism, and reverse the resistance to treatment. Thus, properly timed and fine-tuned manipulation of the Nrf2 signalling is critical for the development of clinical drugs.

This Special Issue aims to collect research articles and review papers dealing with all aspects of Nrf2. Papers describing the new findings about the biological function of Nrf2, the fresh clinical implications of Nrf2 targeting agents and the development of Nrf2-tageting therapeutic agents will be especially welcome. Profound review papers about the relevant fields are also favored.

Prof. Dr. Zhengyu Jiang
Guest Editor

Manuscript Submission Information

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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.

Keywords

Nrf2
Keap1
oxidative stress
ROS
inflammation
cancer

Published Papers (7 papers)

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Research

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18 pages, 5571 KiB

Open AccessArticle

Novel Hydrogen Sulfide Hybrid Derivatives of Keap1-Nrf2 Protein–Protein Interaction Inhibitor Alleviate Inflammation and Oxidative Stress in Acute Experimental Colitis

by Xian Zhang, Keni Cui, Xiaolu Wang, Yuanyuan Tong, Chihong Liu, Yuechao Zhu, Qidong You, Zhengyu Jiang and Xiaoke Guo

Antioxidants 2023, 12(5), 1062; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox12051062 - 08 May 2023

Viewed by 1656

Abstract

Ulcerative colitis (UC) is an idiopathic inflammatory disease of unknown etiology possibly associated with intestinal inflammation and oxidative stress. Molecular hybridization by combining two drug fragments to achieve a common pharmacological goal represents a novel strategy. The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway provides an effective defense mechanism for UC therapy, and hydrogen sulfide (H₂S) shows similar and relevant biological functions as well. In this work, a series of hybrid derivatives were synthesized by connecting an inhibitor of Keap1-Nrf2 protein–protein interaction with two well-established H₂S-donor moieties, respectively, via an ester linker, to find a drug candidate more effective for the UC treatment. Subsequently, the cytoprotective effects of hybrids derivatives were investigated, and DDO-1901 was identified as a candidate showing the best efficacy and used for further investigation on therapeutic effect on dextran sulfate sodium (DSS)-induced colitis in vitro and in vivo. Experimental results indicated that DDO-1901 could effectively alleviate DSS-induced colitis by improving the defense against oxidative stress and reducing inflammation, more potent than parent drugs. Compared with either drug alone, such molecular hybridization may offer an attractive strategy for the treatment of multifactorial inflammatory disease. Full article

(This article belongs to the Special Issue Nrf2 Signaling Pathway: Biological Function, Clinical Implications and Therapeutic Agents)

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15 pages, 2088 KiB

Open AccessArticle

Maternal Calorie Restriction Induces a Transcriptional Cytoprotective Response in Embryonic Liver Partially Dependent on Nrf2

by George I. Habeos, Fotini Filippopoulou, Evagelia E. Habeos, Electra Kalaitzopoulou, Marianna Skipitari, Polyxeni Papadea, George Lagoumintzis, Athanasios Niarchos, Christos D. Georgiou and Dionysios V. Chartoumpekis

Antioxidants 2022, 11(11), 2274; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11112274 - 17 Nov 2022

Cited by 2 | Viewed by 1727

Abstract

Background: Calorie restriction is known to enhance Nrf2 signaling and longevity in adult mice, partially by reducing reactive oxygen species, but calorie restriction during pregnancy leads to intrauterine growth retardation. The latter is associated with fetal reprogramming leading to increased incidence of obesity, metabolic syndrome and diabetes in adult life. Transcription factor Nrf2 is a central regulator of the antioxidant response and its crosstalk with metabolic pathways is emerging. We hypothesized that the Nrf2 pathway is induced in embryos during calorie restriction in pregnant mothers. Methods: From gestational day 10 up to day 16, 50% of the necessary mouse diet was provided to Nrf2 heterozygous pregnant females with fathers being of the same genotype. Embryos were harvested at the end of gestational day 16 and fetal liver was used for qRT-PCR and assessment of oxidative stress (OS). Results: Intrauterine calorie restriction led to upregulation of mRNA expression of antioxidant genes (Nqo1, Gsta1, Gsta4) and of genes related to integrated stress response (Chac1, Ddit3) in WT embryos. The expression of a key gluconeogenic (G6pase) and two lipogenic genes (Acacb, Fasn) was repressed in calorie-restricted embryos. In Nrf2 knockout embryos, the induction of Nqo1 and Gsta1 genes was abrogated while that of Gsta4 was preserved, indicating an at least partially Nrf2-dependent induction of antioxidant genes after in utero calorie restriction. Measures of OS showed no difference (superoxide radical and malondialdehyde) or a small decrease (thiobarbituric reactive substances) in calorie-restricted WT embryos. Conclusions: Calorie restriction during pregnancy elicits the transcriptional induction of cytoprotective/antioxidant genes in the fetal liver, which is at least partially Nrf2-dependent, with a physiological significance that warrants further investigation. Full article

(This article belongs to the Special Issue Nrf2 Signaling Pathway: Biological Function, Clinical Implications and Therapeutic Agents)

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Review

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21 pages, 1868 KiB

Open AccessReview

Is Nuclear Factor Erythroid 2-Related Factor 2 a Target for the Intervention of Cytokine Storms?

by Zihang Liu, Panpan Deng, Shengnan Liu, Yiying Bian, Yuanyuan Xu, Qiang Zhang, Huihui Wang and Jingbo Pi

Antioxidants 2023, 12(1), 172; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox12010172 - 11 Jan 2023

Cited by 7 | Viewed by 2645

Abstract

The term “cytokine storm” describes an acute pathophysiologic state of the immune system characterized by a burst of cytokine release, systemic inflammatory response, and multiple organ failure, which are crucial determinants of many disease outcomes. In light of the complexity of cytokine storms, specific strategies are needed to prevent and alleviate their occurrence and deterioration. Nuclear factor erythroid 2-related factor 2 (NRF2) is a CNC-basic region-leucine zipper protein that serves as a master transcription factor in maintaining cellular redox homeostasis by orchestrating the expression of many antioxidant and phase II detoxification enzymes. Given that inflammatory response is intertwined with oxidative stress, it is reasonable to assume that NRF2 activation limits inflammation and thus cytokine storms. As NRF2 can mitigate inflammation at many levels, it has emerged as a potential target to prevent and treat cytokine storms. In this review, we summarized the cytokine storms caused by different etiologies and the rationale of interventions, focusing mainly on NRF2 as a potential therapeutic target. Full article

(This article belongs to the Special Issue Nrf2 Signaling Pathway: Biological Function, Clinical Implications and Therapeutic Agents)

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22 pages, 1436 KiB

Open AccessReview

Nrf2 Pathway and Autophagy Crosstalk: New Insights into Therapeutic Strategies for Ischemic Cerebral Vascular Diseases

by Yue Hu, Yumin Luo and Yangmin Zheng

Antioxidants 2022, 11(9), 1747; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11091747 - 02 Sep 2022

Cited by 8 | Viewed by 2338

Abstract

Cerebrovascular disease is highly prevalent and has a complex etiology and variable pathophysiological activities. It thus poses a serious threat to human life and health. Currently, pathophysiological research on cerebrovascular diseases is gradually improving, and oxidative stress and autophagy have been identified as important pathophysiological activities that are gradually attracting increasing attention. Many studies have found some effects of oxidative stress and autophagy on cerebrovascular diseases, and studies on the crosstalk between the two in cerebrovascular diseases have made modest progress. However, further, more detailed studies are needed to determine the specific mechanisms. This review discusses nuclear factor erythroid 2-related factor 2 (Nrf2) molecules, which are closely associated with oxidative stress and autophagy, and the crosstalk between them, with the aim of providing clues for studying the two important pathophysiological changes and their crosstalk in cerebrovascular diseases as well as exploring new target treatments. Full article

(This article belongs to the Special Issue Nrf2 Signaling Pathway: Biological Function, Clinical Implications and Therapeutic Agents)

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22 pages, 7450 KiB

Open AccessReview

The Role of Nrf2 in Pulmonary Fibrosis: Molecular Mechanisms and Treatment Approaches

by Yu Wang, Juan Wei, Huimin Deng, Li Zheng, Hao Yang and Xin Lv

Antioxidants 2022, 11(9), 1685; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11091685 - 29 Aug 2022

Cited by 13 | Viewed by 3416

Abstract

Pulmonary fibrosis is a chronic, progressive, incurable interstitial lung disease with high mortality after diagnosis and remains a global public health problem. Despite advances and breakthroughs in understanding the pathogenesis of pulmonary fibrosis, there are still no effective methods for the prevention and treatment of pulmonary fibrosis. The existing treatment options are imperfect, expensive, and have considerable limitations in effectiveness and safety. Hence, there is an urgent need to find novel therapeutic targets. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a central regulator of cellular antioxidative responses, inflammation, and restoration of redox balance. Accumulating reports reveal that Nrf2 activators exhibit potent antifibrosis effects and significantly attenuate pulmonary fibrosis in vivo and in vitro. This review summarizes the current Nrf2-related knowledge about the regulatory mechanism and potential therapies in the process of pulmonary fibrosis. Nrf2 orchestrates the activation of multiple protective genes that target inflammation, oxidative stress, fibroblast–myofibroblast differentiation (FMD), and epithelial–mesenchymal transition (EMT), and the mechanisms involve Nrf2 and its downstream antioxidant, Nrf2/HO−1/NQO1, Nrf2/NOX4, and Nrf2/GSH signaling pathway. We hope to indicate potential for Nrf2 system as a therapeutic target for pulmonary fibrosis. Full article

(This article belongs to the Special Issue Nrf2 Signaling Pathway: Biological Function, Clinical Implications and Therapeutic Agents)

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40 pages, 2226 KiB

Open AccessReview

Clinical Research Progress of Small Molecule Compounds Targeting Nrf2 for Treating Inflammation-Related Diseases

by Zhenzhen Zhai, Yanxin Huang, Yawei Zhang, Lili Zhao and Wen Li

Antioxidants 2022, 11(8), 1564; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11081564 - 12 Aug 2022

Cited by 9 | Viewed by 2904

Abstract

Studies have found that inflammation is a symptom of various diseases, such as coronavirus disease 2019 (COVID-19) and rheumatoid arthritis (RA); it is also the source of other diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), lupus erythematosus (LE), and liver damage. Nrf2 (nuclear factor erythroid 2-related factor 2) is an important multifunctional transcription factor in cells and plays a central regulatory role in cellular defense mechanisms. In recent years, several studies have found a strong association between the activation of Nrf2 and the fight against inflammation-related diseases. A number of small molecule compounds targeting Nrf2 have entered clinical research. This article reviews the research status of small molecule compounds that are in clinical trials for the treatment of COVID-19, rheumatoid arthritis, Alzheimer’s disease, Parkinson’s disease, lupus erythematosus, and liver injury. Full article

(This article belongs to the Special Issue Nrf2 Signaling Pathway: Biological Function, Clinical Implications and Therapeutic Agents)

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28 pages, 4957 KiB

Open AccessReview

Methods for the Discovery and Identification of Small Molecules Targeting Oxidative Stress-Related Protein–Protein Interactions: An Update

by Xuexuan Wu, Qiuyue Zhang, Yuqi Guo, Hengheng Zhang, Xiaoke Guo, Qidong You and Lei Wang

Antioxidants 2022, 11(4), 619; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11040619 - 23 Mar 2022

Cited by 7 | Viewed by 3656

Abstract

The oxidative stress response pathway is one of the hotspots of current pharmaceutical research. Many proteins involved in these pathways work through protein–protein interactions (PPIs). Hence, targeting PPI to develop drugs for an oxidative stress response is a promising strategy. In recent years, small molecules targeting protein–protein interactions (PPIs), which provide efficient methods for drug discovery, are being investigated by an increasing number of studies. However, unlike the enzyme–ligand binding mode, PPIs usually exhibit large and dynamic binding interfaces, which raise additional challenges for the discovery and optimization of small molecules and for the biochemical techniques used to screen compounds and study structure–activity relationships (SARs). Currently, multiple types of PPIs have been clustered into different classes, which make it difficult to design stationary methods for small molecules. Deficient experimental methods are plaguing medicinal chemists and are becoming a major challenge in the discovery of PPI inhibitors. In this review, we present current methods that are specifically used in the discovery and identification of small molecules that target oxidative stress-related PPIs, including proximity-based, affinity-based, competition-based, structure-guided, and function-based methods. Our aim is to introduce feasible methods and their characteristics that are implemented in the discovery of small molecules for different types of PPIs. For each of these methods, we highlight successful examples of PPI inhibitors associated with oxidative stress to illustrate the strategies and provide insights for further design. Full article

(This article belongs to the Special Issue Nrf2 Signaling Pathway: Biological Function, Clinical Implications and Therapeutic Agents)

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