Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

The Nrf2 Pathway: Regulation, Functions, and Potential Applications 2.0

Special Issue Editors
Special Issue Information
Keywords
Benefits of Publishing in a Special Issue
Published Papers

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 (30 June 2022) | Viewed by 26816

Share This Special Issue

Special Issue Editors

Prof. Makoto Kobayashi

E-Mail Website
Guest Editor

Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
Interests: gene regulation; natural products; Nrf2; organelle stress; redox homeostasis; zebrafish
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Ken Itoh

E-Mail Website
Guest Editor

Department of Stress Response Science, Center for Advanced Medical Sciences, Hirosaki University Graduate School of Medicine, 5 Zaifucho, Hirosaki 036-8562, Japan
Interests: Nrf2; ATF4; mito-nuclear communication; mitochondrial antioxidant; Keap1; anti-aging
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

The Nrf2 pathway, a master regulator of redox homeostasis discovered in the mid-1990s, is an integrated cellular response for electrophiles and thiol reactive compounds (e.g., ROS, RNS, heavy metals). In addition to its activation by environmental electrophiles such as quinones, diverse mechanisms of Nrf2 activation have been reported, namely, endogenous electrophiles, glucose metabolism, phosphorylation, and miRNAs. The Nrf2 pathway has a wide variety of functions, such as defense against oxidative stress and electrophilic toxicity, carcinogenesis protection, tumorigenesis, anti-inflammation, stem cells regulation, anti-aging, reducing mechanical stress and organelle stress (autophagy, endoplasmic reticulum, mitochondria), protection against brain and skin injuries, and so forth. At present, drug discovery targeting the Nrf2 pathway has been explored extensively, since dysregulation of the Nrf2 pathway leads to a number of human diseases and disorders, including cancer, diabetes, atherosclerosis, and neurodegeneration.

In this Special Issue, we widely recruit original articles that describe new discoveries in the Nrf2 pathway in any relevant topics, such as physiological functions, gene regulation, activation mechanism, drug discovery, evolution, human diseases, protein structure, and genome. We also welcome review articles and commentaries.

Prof. Makoto Kobayashi
Prof. Dr. Ken Itoh
Guest Editors

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

anti-aging
anti-inflammation
autophagy
cancer
chemoprevention
drug discovery
energy metabolism
evolution
food antioxidants
gene regulation
lifestyle-related diseases
natural products
neurodegenerative diseases
Nrf, Maf, Bach and Keap1 family proteins
organelle stress
oxidative stress
protein structure
redox homeostasis
stem cells
toxicology

Benefits of Publishing in a Special Issue

Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

Further information on MDPI's Special Issue polices can be found here.

Published Papers (8 papers)

Download All Papers

Order results

Result details

Show export options Show export options

Select all

Export citation of selected articles as:

Research

18 pages, 1980 KiB

Open AccessArticle

Sulforaphane Increase Mitochondrial Biogenesis-Related Gene Expression in the Hippocampus and Suppresses Age-Related Cognitive Decline in Mice

by Sunao Shimizu, Shuya Kasai, Hiromi Yamazaki, Yota Tatara, Junsei Mimura, Máté János Engler, Kunikazu Tanji, Yoshikazu Nikaido, Takuro Inoue, Hiroyuki Suganuma, Koichi Wakabayashi and Ken Itoh

Int. J. Mol. Sci. 2022, 23(15), 8433; https://doi.org/10.3390/ijms23158433 - 29 Jul 2022

Cited by 7 | Viewed by 2993

Abstract

Sulforaphane (SFN) is a potent activator of the transcriptional factor, Nuclear Factor Erythroid 2 (NF-E2)-Related factor 2 (NRF2). SFN and its precursor, glucoraphanin (sulforaphane glucosinolate, SGS), have been shown to ameliorate cognitive function in clinical trials and in vivo studies. However, the effects of SGS on age-related cognitive decline in Senescence-Accelerated Mouse Prone 8 (SAMP8) is unknown. In this study, we determined the preventive potential of SGS on age-related cognitive decline. One-month old SAMP8 mice or control SAM resistance 1 (SAMR1) mice were fed an ad libitum diet with or without SGS-containing broccoli sprout powder (0.3% w/w SGS in diet) until 13 months of age. SGS significantly improved long-term memory in SAMP8 at 12 months of age. Interestingly, SGS increased hippocampal mRNA and protein levels of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1α) and mitochondrial transcription factor A (TFAM), which are master regulators of mitochondrial biogenesis, both in SAMR1 and SAMP8 at 13 months of age. Furthermore, mRNAs for nuclear respiratory factor-1 (NRF-1) and mitochondrial DNA-encoded respiratory complex enzymes, but not mitochondrial DNA itself, were increased by SGS in SAMP8 mice. These results suggest that SGS prevents age-related cognitive decline by maintaining mitochondrial function in senescence-accelerated mice. Full article

(This article belongs to the Special Issue The Nrf2 Pathway: Regulation, Functions, and Potential Applications 2.0)

► Show Figures

Figure 1

14 pages, 5985 KiB

Open AccessArticle

Nrf2 Transcriptional Activity Governs Intestine Development

by Aleksandra Kopacz, Damian Kloska, Dominika Klimczyk, Magdalena Kopec, Alicja Jozkowicz and Aleksandra Piechota-Polanczyk

Int. J. Mol. Sci. 2022, 23(11), 6175; https://doi.org/10.3390/ijms23116175 - 31 May 2022

Cited by 10 | Viewed by 2514

Abstract

Our recent findings indicate that Nrf2 transcriptional activity is essential in maintaining the proper large intestinal structure in adult mice. Here, we aimed to verify whether Nrf2-related intestine abnormalities stemmed from the early weaning or gestational periods. Therefore, we analyzed 4-day-old pups and embryos devoid of Nrf2 transcriptional activity (tKO) and their wild-type counterparts. We found significant changes in the intestinal structure of 4-day-old Nrf2 tKO pups including a longer colon, altered crypt distribution, and enlargement of the goblet cells with a markedly higher level of mucin 2. Tracing back the origin of these alterations, we observed that they appeared as early as day 14.5 of embryonic development, independently of sex. Importantly, in this period, we observed a significant increase in the Nrf2 level and a distinctive, untimely pattern of expression of the proliferation factor Ki67. At the latest stage of embryonic development, we detected a premature drop in the differentiation factor Notch1. We suspect that intestine abnormalities in mice lacking Nrf2 transcriptional activity stem from sex-independent disturbed intestinal cell proliferation and could be further exacerbated by altered differentiation. Summing up, we identified Nrf2 transcriptional activity as an important regulator of intestinal formation. It influences the hindgut cell proliferation and differentiation at different stages of embryonic development. Full article

(This article belongs to the Special Issue The Nrf2 Pathway: Regulation, Functions, and Potential Applications 2.0)

► Show Figures

Figure 1

10 pages, 2647 KiB

Open AccessArticle

Soy-Derived Equol Induces Antioxidant Activity in Zebrafish in an Nrf2-Independent Manner

by Asami Watanabe, Kyoji Muraki, Junya Tamaoki and Makoto Kobayashi

Int. J. Mol. Sci. 2022, 23(9), 5243; https://doi.org/10.3390/ijms23095243 - 8 May 2022

Cited by 5 | Viewed by 2783

Abstract

Antioxidant effects of soy-derived isoflavones are predicted to be mediated by the Keap1-Nrf2 pathway. Recently, we constructed an assay system to evaluate the antioxidant effects of dietary phytochemicals in zebrafish and revealed a relationship between these effects and the Keap1-Nrf2 pathway. In this study, we used this system to examine the antioxidant effects of seven isoflavones. Among those seven, equol showed strong antioxidant effects when arsenite was used as an oxidative stressor. The antioxidant effect of equol was also shown in Nrf2-mutant zebrafish nfe2l2a^fh318, suggesting that this effect was not mediated by the Keap1-Nrf2 pathway. To elucidate this unidentified mechanism, the gene expression profiles of equol-treated larvae were analyzed using RNA-seq and qRT-PCR, while no noticeable changes were detected in the expression of genes related to antioxidant effects, except weak induction of Nrf2 target genes. Because nfe2l2a^fh318 is an amino acid-substitution mutant (Arg485Lue), we considered that the antioxidant effect of equol in this mutant might be due to residual Nrf2 activity. To examine this possibility, we generated an Nrf2-knockout zebrafish nfe2l2a^it321 using CRISPR-Cas9 and analyzed the antioxidant effect of equol. As a result, equol showed strong antioxidant effects even in Nrf2-knockout larvae, suggesting that equol indeed upregulates antioxidant activity in zebrafish in an Nrf2-independent manner. Full article

(This article belongs to the Special Issue The Nrf2 Pathway: Regulation, Functions, and Potential Applications 2.0)

► Show Figures

Figure 1

18 pages, 3762 KiB

Open AccessArticle

The Expression of TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR) Can Be Controlled by the Antioxidant Orchestrator NRF2 in Human Carcinoma Cells

by Helga Simon-Molas, Cristina Sánchez-de-Diego, Àurea Navarro-Sabaté, Esther Castaño, Francesc Ventura, Ramon Bartrons and Anna Manzano

Int. J. Mol. Sci. 2022, 23(3), 1905; https://doi.org/10.3390/ijms23031905 - 8 Feb 2022

Cited by 8 | Viewed by 2755

Abstract

Hyperactivation of the KEAP1-NRF2 axis is a common molecular trait in carcinomas from different origin. The transcriptional program induced by NRF2 involves antioxidant and metabolic genes that render cancer cells more capable of dealing with oxidative stress. The TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR) is an important regulator of glycolysis and the pentose phosphate pathway that was described as a p53 response gene, yet TIGAR expression is detected in p53-null tumors. In this study we investigated the role of NRF2 in the regulation of TIGAR in human carcinoma cell lines. Exposure of carcinoma cells to electrophilic molecules or overexpression of NRF2 significantly increased expression of TIGAR, in parallel to the known NRF2 target genes NQO1 and G6PD. The same was observed in TP53KO cells, indicating that NRF2-mediated regulation of TIGAR is p53-independent. Accordingly, downregulation of NRF2 decreased the expression of TIGAR in carcinoma cell lines from different origin. As NRF2 is essential in the bone, we used mouse primary osteoblasts to corroborate our findings. The antioxidant response elements for NRF2 binding to the promoter of human and mouse TIGAR were described. This study provides the first evidence that NRF2 controls the expression of TIGAR at the transcriptional level. Full article

(This article belongs to the Special Issue The Nrf2 Pathway: Regulation, Functions, and Potential Applications 2.0)

► Show Figures

Figure 1

13 pages, 3416 KiB

Open AccessArticle

Triptolide Suppresses NF-κB-Mediated Inflammatory Responses and Activates Expression of Nrf2-Mediated Antioxidant Genes to Alleviate Caerulein-Induced Acute Pancreatitis

by Jing Yang, Xujiao Tang, Xue Ke, Yutong Dai and Jinsong Shi

Int. J. Mol. Sci. 2022, 23(3), 1252; https://doi.org/10.3390/ijms23031252 - 23 Jan 2022

Cited by 27 | Viewed by 2819

Abstract

Triptolide (TP), the main active ingredient of Tripterygium wilfordii Hook.f., displays potent anti-inflammatory, antioxidant, and antiproliferative activities. In the present study, the effect of TP on acute pancreatitis and the underlying mechanisms of the disease were investigated using a caerulein-induced animal model of acute pancreatitis (AP) and an in vitro cell model. In vivo, pretreatment with TP notably ameliorated pancreatic damage, shown as the improvement in serum amylase and lipase levels and pancreatic morphology. Meanwhile, TP modulated the infiltration of neutrophils and macrophages (Ly6G staining and CD68 staining) and decreased the levels of proinflammatory factors (TNF-α and IL-6) through inhibiting the transactivation of nuclear factor-κB (NF-κB) in caerulein-treated mice. Furthermore, TP reverted changes in oxidative stress markers, including pancreatic glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA), in acute pancreatitis mice. Additionally, TP pretreatment inhibited intracellular reactive oxygen species (ROS) levels via upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and Nrf2-regulated redox genes expression (HO-1, SOD1, GPx1 and NQO1) in vitro. Taken together, our data suggest that TP exert protection against pancreatic inflammation and tissue damage by inhibiting NF-κB transactivation, modulating immune cell responses and activating the Nrf2-mediated antioxidative system, thereby alleviating acute pancreatitis. Full article

(This article belongs to the Special Issue The Nrf2 Pathway: Regulation, Functions, and Potential Applications 2.0)

► Show Figures

Figure 1

13 pages, 7352 KiB

Open AccessArticle

PM_2.5 Exacerbates Oxidative Stress and Inflammatory Response through the Nrf2/NF-κB Signaling Pathway in OVA-Induced Allergic Rhinitis Mouse Model

by Chun Hua Piao, Yanjing Fan, Thi Van Nguyen, Hee Soon Shin, Hyoung Tae Kim, Chang Ho Song and Ok Hee Chai

Int. J. Mol. Sci. 2021, 22(15), 8173; https://doi.org/10.3390/ijms22158173 - 29 Jul 2021

Cited by 47 | Viewed by 3943

Abstract

Air pollution-related particulate matter (PM) exposure reportedly enhances allergic airway inflammation. Some studies have shown an association between PM exposure and a risk for allergic rhinitis (AR). However, the effect of PM for AR is not fully understood. An AR mouse model was developed by intranasal administration of 100 μg/mouse PM with a less than or equal to 2.5 μm in aerodynamic diameter (PM_2.5) solution, and then by intraperitoneal injection of ovalbumin (OVA) with alum and intranasal challenging with 10 mg/mL OVA. The effects of PM_2.5 on oxidative stress and inflammatory response via the Nrf2/NF-κB signaling pathway in mice with or without AR indicating by histological, serum, and protein analyses were examined. PM_2.5 administration enhanced allergic inflammatory cell expression in the nasal mucosa through increasing the expression of inflammatory cytokine and reducing the release of Treg cytokine in OVA-induced AR mice, although PM_2.5 exposure itself induced neither allergic responses nor damage to nasal and lung tissues. Notably, repeated OVA-immunization markedly impaired the nasal mucosa in the septum region. Moreover, AR with PM_2.5 exposure reinforced this impairment in OVA-induced AR mice. Long-term PM_2.5 exposure strengthened allergic reactions by inducing the oxidative through malondialdehyde production. The present study also provided evidence, for the first time, that activity of the Nrf2 signaling pathway is inhibited in PM_2.5 exposed AR mice. Furthermore, PM_2.5 exposure increased the histopathological changes of nasal and lung tissues and related the inflammatory cytokine, and clearly enhanced PM_2.5 phagocytosis by alveolar macrophages via activating the NF-κB signaling pathway. These obtained results suggest that AR patients may experience exacerbation of allergic responses in areas with prolonged PM_2.5 exposure. Full article

(This article belongs to the Special Issue The Nrf2 Pathway: Regulation, Functions, and Potential Applications 2.0)

► Show Figures

Figure 1

13 pages, 2470 KiB

Open AccessArticle

Docosahexaenoic Acid Esters of Hydroxy Fatty Acid Is a Novel Activator of NRF2

by Siddabasave Gowda B. Gowda, Takayuki Tsukui, Hirotoshi Fuda, Yusuke Minami, Divyavani Gowda, Hitoshi Chiba and Shu-Ping Hui

Int. J. Mol. Sci. 2021, 22(14), 7598; https://doi.org/10.3390/ijms22147598 - 15 Jul 2021

Cited by 17 | Viewed by 3895

Abstract

Fatty acid esters of hydroxy fatty acids (FAHFAs) are a new class of endogenous lipids with interesting physiological functions in mammals. Despite their structural diversity and links with nuclear factor erythroid 2-related factor 2 (NRF2) biosynthesis, FAHFAs are less explored as NRF2 activators. Herein, we examined for the first time the synthetic docosahexaenoic acid esters of 12-hydroxy stearic acid (12-DHAHSA) or oleic acid (12-DHAHOA) against NRF2 activation in cultured human hepatoma-derived cells (C3A). The effect of DHA-derived FAHFAs on lipid metabolism was explored by the nontargeted lipidomic analysis using liquid chromatography-mass spectrometry. Furthermore, their action on lipid droplet (LD) oxidation was investigated by the fluorescence imaging technique. The DHA-derived FAHFAs showed less cytotoxicity compared to their native fatty acids and activated the NRF2 in a dose-dependent pattern. Treatment of 12-DHAHOA with C3A cells upregulated the cellular triacylglycerol levels by 17-fold compared to the untreated group. Fluorescence imaging analysis also revealed the suppression of the degree of LDs oxidation upon treatment with 12-DHAHSA. Overall, these results suggest that DHA-derived FAHFAs as novel and potent activators of NRF2 with plausible antioxidant function. Full article

(This article belongs to the Special Issue The Nrf2 Pathway: Regulation, Functions, and Potential Applications 2.0)

► Show Figures

Graphical abstract

10 pages, 1135 KiB

Open AccessArticle

Nrf2 Activation Sensitizes K-Ras Mutant Pancreatic Cancer Cells to Glutaminase Inhibition

by Shin Hamada, Ryotaro Matsumoto, Yu Tanaka, Keiko Taguchi, Masayuki Yamamoto and Atsushi Masamune

Int. J. Mol. Sci. 2021, 22(4), 1870; https://doi.org/10.3390/ijms22041870 - 14 Feb 2021

Cited by 22 | Viewed by 3572

Abstract

Pancreatic cancer remains intractable owing to the lack of effective therapy for unresectable cases. Activating mutations of K-ras are frequently found in pancreatic cancers, but these have not yet been targeted by cancer therapies. The Keap1-Nrf2 system plays a crucial role in mediating the oxidative stress response, which also contributes to cancer progression. Nrf2 activation reprograms the metabolic profile to promote the proliferation of cancer cells. A recent report suggested that K-ras- and Nrf2-active lung cancer cells are sensitive to glutamine depletion. This finding led to the recognition of glutaminase inhibitors as novel anticancer agents. In the current study, we used murine pancreatic cancer tissues driven by mutant K-ras and p53 to establish cell lines expressing constitutively activated Nrf2. Genetic or pharmacological Nrf2 activation in cells via Keap1 deletion or Nrf2 activation sensitized cells to glutaminase inhibition. This phenomenon was confirmed to be dependent on K-ras activation in human pancreatic cancer cell lines harboring mutant K-ras, i.e., Panc-1 and MiaPaCa-2 in response to DEM pretreatment. This phenomenon was not observed in BxPC3 cells harboring wildtype K-ras. These results indicate the possibility of employing Nrf2 activation and glutaminase inhibition as novel therapeutic interventions for K-ras mutant pancreatic cancers. Full article

(This article belongs to the Special Issue The Nrf2 Pathway: Regulation, Functions, and Potential Applications 2.0)

► Show Figures

Journal Menu

Journal Browser

The Nrf2 Pathway: Regulation, Functions, and Potential Applications 2.0

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (8 papers)

Research

Further Information

Guidelines

MDPI Initiatives

Follow MDPI