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Nrf2 in Redox Signaling: A Double Edged Sword
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Nrf2 in Redox Signaling: A Double Edged Sword

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 (31 October 2017) | Viewed by 66188

Special Issue Editor

Prof. Dr. Andreas Von Knethen

E-Mail Website
Guest Editor
Institute of Biochemistry I, Faculty of Medicine, Goethe-University, Frankfurt am Main, Germany
Interests: sepsis; Nrf2; PPARγ; redox signaling; autophagy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In inflammatory processes, release of reactive oxygen species and synthesis of electrophilic compounds are sensed intracellularly by the cap ´n´ collar basic region leucine zipper transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 is mainly regulated posttranslationally via the proteasome. Under control conditions, Nrf2 is bound by the Kelch-like ECH-associated protein 1 (Keap1) dimer, provoking binding of the E3-ligase Cullin-3. Ubiquitination of Nrf2 targets Nrf2 for proteasomal degradation. In response to oxidative or electrophilic stress, Nrf2 is stabilized. Following its translocation to the nucleus it induces the expression of antioxidative and cytoprotective target genes. Therefore, Nrf2 activation is an important therapeutic target in diseases associated with (excessive) inflammation and injury. However, excessive or prolonged Nrf2 activation has also been shown to contribute to tumorigenesis. Taking these important functions of Nrf2 into consideration, understanding the different means of Nrf2 regulation will provide an improved background for setting up new treatment regimes.

This Special Issue, Nrf2 in Redox Signaling: A Double Edged Sword, will cover a selection of recent research topics and current review articles in the field of Nrf2-dependent research about its role in acute and chronic inflammation, and its resolution as well as tumorigenesis. Experimental papers, up-to-date review articles, and commentaries are all welcome.

Prof. Dr. Andreas von Knethen
Guest Editor

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Keywords

  • Nrf2
  • tumorigenesis
  • chronic inflammation
  • acute inflammation,
  • resolution of inflammation
  • proteasome
  • antigen presentation
  • macrophages
  • foam cells
  • redox signalling

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Published Papers (6 papers)

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Research

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2570 KiB  
Article
Nrf2-Inducers Counteract Neurodegeneration in Frataxin-Silenced Motor Neurons: Disclosing New Therapeutic Targets for Friedreich’s Ataxia
by Sara Petrillo, Emanuela Piermarini, Anna Pastore, Gessica Vasco, Tommaso Schirinzi, Rosalba Carrozzo, Enrico Bertini and Fiorella Piemonte
Int. J. Mol. Sci. 2017, 18(10), 2173; https://doi.org/10.3390/ijms18102173 - 18 Oct 2017
Cited by 58 | Viewed by 8207
Abstract
Oxidative stress is actively involved in Friedreich’s Ataxia (FA), thus pharmacological targeting of the antioxidant machinery may have therapeutic value. Here, we analyzed the relevance of the antioxidant phase II response mediated by the transcription factor Nrf2 on frataxin-deficient cultured motor neurons and [...] Read more.
Oxidative stress is actively involved in Friedreich’s Ataxia (FA), thus pharmacological targeting of the antioxidant machinery may have therapeutic value. Here, we analyzed the relevance of the antioxidant phase II response mediated by the transcription factor Nrf2 on frataxin-deficient cultured motor neurons and on fibroblasts of patients. The in vitro treatment of the potent Nrf2 activator sulforaphane increased Nrf2 protein levels and led to the upregulation of phase II antioxidant enzymes. The neuroprotective effects were accompanied by an increase in neurites’ number and extension. Sulforaphane (SFN) is a natural compound of many diets and is now being used in clinical trials for other pathologies. Our results provide morphological and biochemical evidence to endorse a neuroprotective strategy that may have therapeutic relevance for FA. The findings of this work reinforce the crucial importance of Nrf2 in FA and provide a rationale for using Nrf2-inducers as pharmacological agents. Full article
(This article belongs to the Special Issue Nrf2 in Redox Signaling: A Double Edged Sword)
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3421 KiB  
Article
Various Mechanisms Involve the Nuclear Factor (Erythroid-Derived 2)-Like (NRF2) to Achieve Cytoprotection in Long-Term Cisplatin-Treated Urothelial Carcinoma Cell Lines
by Margaretha A. Skowron, Günter Niegisch, Philipp Albrecht, Gommert Van Koeveringe, Andrea Romano, Peter Albers, Wolfgang A. Schulz and Michèle J. Hoffmann
Int. J. Mol. Sci. 2017, 18(8), 1680; https://doi.org/10.3390/ijms18081680 - 2 Aug 2017
Cited by 13 | Viewed by 5963
Abstract
Therapeutic efficacy of cisplatin-based chemotherapy for advanced-stage urothelial carcinoma (UC) is limited by drug resistance. The nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway is a major regulator of cytoprotective responses. We investigated its involvement in cisplatin resistance in long-term cisplatin treated UC cell [...] Read more.
Therapeutic efficacy of cisplatin-based chemotherapy for advanced-stage urothelial carcinoma (UC) is limited by drug resistance. The nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway is a major regulator of cytoprotective responses. We investigated its involvement in cisplatin resistance in long-term cisplatin treated UC cell lines (LTTs). Expression of NRF2 pathway components and targets was evaluated by qRT-PCR and western blotting in LTT sublines from four different parental cells. NRF2 transcriptional activity was determined by reporter assays and total glutathione (GSH) was quantified enzymatically. Effects of siRNA-mediated NRF2 knockdown on chemosensitivity were analysed by viability assays, γH2AX immunofluorescence, and flow cytometry. Increased expression of NRF2, its positive regulator p62/SQSTM1, and elevated NRF2 activity was observed in 3/4 LTTs, which correlated with KEAP1 expression. Expression of cytoprotective enzymes and GSH concentration were upregulated in some LTTs. NRF2 knockdown resulted in downregulation of cytoprotective enzymes and resensitised 3/4 LTTs towards cisplatin as demonstrated by reduced IC50 values, increased γH2AX foci formation, and elevated number of apoptotic cells. In conclusion, while LTT lines displayed diversity in NRF2 activation, NRF2 signalling contributed to cisplatin resistance in LTT lines, albeit in diverse ways. Accordingly, inhibition of NRF2 can be used to resensitise UC cells to cisplatin, but responses in patients may likewise be variable. Full article
(This article belongs to the Special Issue Nrf2 in Redox Signaling: A Double Edged Sword)
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45330 KiB  
Article
Nrf2-Knockout Protects from Intestinal Injuries in C57BL/6J Mice Following Abdominal Irradiation with γ Rays
by Wenyan Yang, Zhijuan Sun, Bing Yang and Qin Wang
Int. J. Mol. Sci. 2017, 18(8), 1656; https://doi.org/10.3390/ijms18081656 - 31 Jul 2017
Cited by 19 | Viewed by 7167
Abstract
Radiation-induced intestinal injuries (RIII) commonly occur in patients who suffer from pelvic or abdominal cancer. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a key transcriptional regulator of antioxidant, and the radioprotective role of Nrf2 is found in bone marrow, lung, and intestine, etc. [...] Read more.
Radiation-induced intestinal injuries (RIII) commonly occur in patients who suffer from pelvic or abdominal cancer. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a key transcriptional regulator of antioxidant, and the radioprotective role of Nrf2 is found in bone marrow, lung, and intestine, etc. Here, we investigated the effect of Nrf2 knockout on radiation-induced intestinal injuries using Nrf2 knockout (Nrf2−/−) mice and wild-type (Nrf2+/+) C57BL/6J mice following 13 Gy abdominal irradiation (ABI). It was found that Nrf2 knockout promoted the survival of irradiated mice, protected the crypt-villus structure of the small intestine, and elevated peripheral blood lymphocyte count and thymus coefficients. The DNA damage of peripheral blood lymphocytes and the apoptosis of intestinal epithelial cells (IECs) of irradiated Nrf2−/− mice were decreased. Furthermore, compared with that of Nrf2+/+ mice, Nrf2 knockout increased the number of Lgr5+ intestinal stem cells (ISCs) and their daughter cells including Ki67+ transient amplifying cells, Villin+ enterocytes, and lysozyme+ Paneth cells. Nuclear factor-κB (NF-κB) was accumulated in the crypt base nuclei of the small intestine, and the mRNA expression of NF-κB target genes Bcl-2, uPA, and Xiap of the small intestine from irradiated Nrf2−/− mice were increased. Collectively, Nrf2 knockout has the protective effect on small intestine damage following abdominal irradiation by prompting the proliferation and differentiation of Lgr5+ intestinal stem cells and activation of NF-κB. Full article
(This article belongs to the Special Issue Nrf2 in Redox Signaling: A Double Edged Sword)
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Review

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19 pages, 1685 KiB  
Review
The Crosstalk between Nrf2 and Inflammasomes
by Paulina Hennig, Martha Garstkiewicz, Serena Grossi, Michela Di Filippo, Lars E. French and Hans-Dietmar Beer
Int. J. Mol. Sci. 2018, 19(2), 562; https://doi.org/10.3390/ijms19020562 - 13 Feb 2018
Cited by 178 | Viewed by 10837
Abstract
The Nrf2 (nuclear factor E2-related factor or nuclear factor (erythroid-derived 2)-like 2) transcription factor is a key player in cytoprotection and activated in stress conditions caused by reactive oxygen species (ROS) or electrophiles. Inflammasomes represent central regulators of inflammation. Upon detection of various [...] Read more.
The Nrf2 (nuclear factor E2-related factor or nuclear factor (erythroid-derived 2)-like 2) transcription factor is a key player in cytoprotection and activated in stress conditions caused by reactive oxygen species (ROS) or electrophiles. Inflammasomes represent central regulators of inflammation. Upon detection of various stress factors, assembly of the inflamasome protein complex results in activation and secretion of proinflammatory cytokines. In addition, inflammasome activation causes pyroptosis, a lytic form of cell death, which supports inflammation. There is growing evidence of a crosstalk between the Nrf2 and inflammasome pathways at different levels. For example, Nrf2 activating compounds inhibit inflammasomes and consequently inflammation. This review summarizes what is known about the complex and predominantly antagonistic relationship of both stress-activated pathways. Full article
(This article belongs to the Special Issue Nrf2 in Redox Signaling: A Double Edged Sword)
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867 KiB  
Review
Effects of Glucagon-Like Peptide-1 on Oxidative Stress and Nrf2 Signaling
by Yoon Sin Oh and Hee-Sook Jun
Int. J. Mol. Sci. 2018, 19(1), 26; https://doi.org/10.3390/ijms19010026 - 22 Dec 2017
Cited by 123 | Viewed by 16157
Abstract
Oxidative cellular damage caused by free radicals is known to contribute to the pathogenesis of various diseases such as cancer, diabetes, and neurodegenerative diseases, as well as to aging. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein1 [...] Read more.
Oxidative cellular damage caused by free radicals is known to contribute to the pathogenesis of various diseases such as cancer, diabetes, and neurodegenerative diseases, as well as to aging. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein1 (Keap1) signaling pathways play an important role in preventing stresses including oxidative and inflammatory stresses. Nrf2 is a master regulator of cellular stress responses, induces the expression of antioxidant and detoxification enzymes, and protects against oxidative stress-induced cell damage. Glucagon-like peptide-1 (GLP-1) is an incretin hormone, which was originally found to increase insulin synthesis and secretion. It is now widely accepted that GLP-1 has multiple functions beyond glucose control in various tissues and organs including brain, kidney, and heart. GLP-1 and GLP-1 receptor agonists are known to be effective in many chronic diseases, including diabetes, via antioxidative mechanisms. In this review, we summarize the current knowledge regarding the role of GLP-1 in the protection against oxidative damage and the activation of the Nrf2 signaling pathway. Full article
(This article belongs to the Special Issue Nrf2 in Redox Signaling: A Double Edged Sword)
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3442 KiB  
Review
Nrf2, the Master Regulator of Anti-Oxidative Responses
by Sandra Vomund, Anne Schäfer, Michael J. Parnham, Bernhard Brüne and Andreas Von Knethen
Int. J. Mol. Sci. 2017, 18(12), 2772; https://doi.org/10.3390/ijms18122772 - 20 Dec 2017
Cited by 509 | Viewed by 16681
Abstract
Tight regulation of inflammation is very important to guarantee a balanced immune response without developing chronic inflammation. One of the major mediators of the resolution of inflammation is the transcription factor: the nuclear factor erythroid 2-like 2 (Nrf2). Stabilized following oxidative stress, Nrf2 [...] Read more.
Tight regulation of inflammation is very important to guarantee a balanced immune response without developing chronic inflammation. One of the major mediators of the resolution of inflammation is the transcription factor: the nuclear factor erythroid 2-like 2 (Nrf2). Stabilized following oxidative stress, Nrf2 induces the expression of antioxidants as well as cytoprotective genes, which provoke an anti-inflammatory expression profile, and is crucial for the initiation of healing. In view of this fundamental modulatory role, it is clear that both hyper- or hypoactivation of Nrf2 contribute to the onset of chronic diseases. Understanding the tight regulation of Nrf2 expression/activation and its interaction with signaling pathways, known to affect inflammatory processes, will facilitate development of therapeutic approaches to prevent Nrf2 dysregulation and ameliorate chronic inflammatory diseases. We discuss in this review the principle mechanisms of Nrf2 regulation with a focus on inflammation and autophagy, extending the role of dysregulated Nrf2 to chronic diseases and tumor development. Full article
(This article belongs to the Special Issue Nrf2 in Redox Signaling: A Double Edged Sword)
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