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Biomedicines
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Regulation of Keap1-Nrf2 Signaling in Health and Diseases
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Special Issue "Regulation of Keap1-Nrf2 Signaling in Health and Diseases"

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 9475

Special Issue Editors

Dr. Gobinath Shanmugam

E-Mail Website
Guest Editor
Division of Cardiovascular Diseases, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA
Interests: exercise; aging; Nrf2-antioxidant signaling; reductive stress; heart failure; redox regulation; pharmacology
Dr. Kishore Kumar S. Narasimhan
E-Mail Website
Guest Editor
Department of Pharmacology and Neurosciences, Creighton University, 2500 California Plaza, Omaha, NE, USA
Interests: Nrf2-antioxidant signaling

Special Issue Information

Dear Colleagues,

Keap1-Nrf2 signaling is a major endogenous stress response pathway involved in the regulation of not only antioxidant response genes but also other genes involved in xenobiotic metabolism, cellular growth, proliferation, differentiation and inflammatory signaling. Multiple stimuli, including electrophiles, exercise, infection and mutations either in Nrf2 or Keap1, have been reported to be involved in the activation of Nrf2 signaling in the defense against harmful reactive oxygen/nitrogen species, thereby maintaining redox homeostasis. However, recent research has illuminated the dark side of Nrf2, in which the chronic activation of Nrf2 is shown to be detrimental in multiple pathologies, including heart failure, neuronal/skeletal muscle differentiation/development, inflammation and cancer. Therefore, not only is the acute/chronic activation of Nrf2 signaling crucial but fine-tuning in the selection/stimulation the dose of Nrf2 signaling is also necessary, which determines whether Nrf2 is protective or fatal.

In this Special Issue, we invite researchers worldwide to submit original research articles, brief reports and review articles that describe the role of Nrf2 signaling in redox metabolism; cardiac function and diseases including myocardial infarction, hypertrophy, atherosclerosis, etc.; neuronal function and diseases including neurodegenerative diseases, neurodevelopmental disorders, neuroplasticity and synaptic transmission, neuropathic pain, etc.; various cancer pathologies and metabolic disorders including diabetes and obesity, inflammation, etc. In addition, we welcome articles that investigate potential natural or synthetic compounds that can activate/deactivate Nrf2-signaling, thereby preventing/leading to the progression of these diseases.

Dr. Gobinath Shanmugam
Dr. Kishore Kumar S. Narasimhan
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. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 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
  • antioxidants
  • aging
  • reactive oxygen species
  • oxidative stress
  • heart failure
  • diabetes
  • neurodegeneration
  • cancer

Published Papers (4 papers)

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Research

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NRF2 and Bip Interconnection Mediates Resistance to the Organometallic Ruthenium-Cymene Bisdemethoxycurcumin Complex Cytotoxicity in Colon Cancer Cells
by
Alessia Garufi
,
Riccardo Pettinari
,
Fabio Marchetti
,
Mara Cirone
and
Gabriella D’Orazi
Biomedicines 2023, 11(2), 593; https://doi.org/10.3390/biomedicines11020593 - 16 Feb 2023
Viewed by 855
Abstract
Organometallic ruthenium (Ru)(II)-cymene complexes display promising pharmacological properties and might represent alternative therapeutic agents in medical applications. Polyphenols, such as curcumin and curcuminoids, display beneficial properties in medicine, including chemoprevention. Here we analyzed the anticancer effect of a cationic Ruthenium (Ru)(II)-cymene Bisdemethoxycurcumin (Ru-bdcurc) [...] Read more.
Organometallic ruthenium (Ru)(II)-cymene complexes display promising pharmacological properties and might represent alternative therapeutic agents in medical applications. Polyphenols, such as curcumin and curcuminoids, display beneficial properties in medicine, including chemoprevention. Here we analyzed the anticancer effect of a cationic Ruthenium (Ru)(II)-cymene Bisdemethoxycurcumin (Ru-bdcurc) complex. The experimental data show that Ru-bdcurc induced cell death of colon cancer cells in vitro. In response to treatment, cancer cells activated the endoplasmic reticulum (ER)-resident chaperone GRP78/BiP and NRF2, the master regulators of the unfolded protein response (UPR) and the antioxidant response, respectively. Pharmacologic targeting of either NRF2 or BiP potentiated the cytotoxic effect of Ru-bdcurc. We also found that NRF2 and UPR pathways were interconnected as the inhibition of NRF2 reduced BiP protein levels. Mechanistically, the increased Ru-bdcurc-induced cell death, following NRF2 or BiP inhibition, correlated with the upregulation of the UPR apoptotic marker CHOP and with increased H2AX phosphorylation, a marker of DNA damage. The findings reveal that BiP and NRF2 interconnection was a key regulator of colon cancer cells resistance to Ru-bdcurc cytotoxic effect. Targeting that interconnection overcame the protective mechanism and enhanced the antitumor effect of the Ru-bdcurc compound. Full article
(This article belongs to the Special Issue Regulation of Keap1-Nrf2 Signaling in Health and Diseases)
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Article
The Mechanistic Perspective of Bilobetin Protective Effects against Cisplatin-Induced Testicular Toxicity: Role of Nrf-2/Keap-1 Signaling, Inflammation, and Apoptosis
by
Walaa A. Negm
,
Aya H. El-Kadem
,
Ismail A. Hussein
and
Moneerah J. Alqahtani
Biomedicines 2022, 10(5), 1134; https://doi.org/10.3390/biomedicines10051134 - 13 May 2022
Cited by 6 | Viewed by 3489
Abstract
Cisplatin (CP) is a productive anti-tumor used to treat numerous tumors. However, multiple toxicities discourage prolonged use, especially toxicity on the reproductive system. This experiment was mapped out to determine the potential therapeutic impact of Bilobetin on CP-induced testicular damage. Herein, Bilobetin was [...] Read more.
Cisplatin (CP) is a productive anti-tumor used to treat numerous tumors. However, multiple toxicities discourage prolonged use, especially toxicity on the reproductive system. This experiment was mapped out to determine the potential therapeutic impact of Bilobetin on CP-induced testicular damage. Herein, Bilobetin was isolated from Cycas thouarsii leaves R. Br ethyl acetate fractions for the first time. A single dose of CP (7 mg/kg, IP) was used to evoke testicular toxicity on the third day. Rats were classified into five groups; Normal control, Bilobetin 12 mg/kg, Untreated CP, and CP treated with Bilobetin (6 and 12 mg/kg, respectively) orally daily for ten days. Bilobetin treatment ameliorated testicular injury. In addition, it boosted serum testosterone levels considerably and restored relative testicular weight. Nevertheless, apoptosis biomarkers such as P53, Cytochrome-C, and caspase-3 decreased significantly. Additionally, it enhanced the testes’ antioxidant status via the activation of Nrf-2, inhibition of Keap-1, and significant elevation of SOD activity in addition to a reduction in lipid peroxidation. Histopathologically, Bilobetin preserved testicular architecture and improved testicular immunostaining of Ki67 substantially, showing evidence of testicular regeneration. Bilobetin’s beneficial effects on CP-induced testicular damage are associated with enhanced antioxidant effects, lowered apoptotic signals, and the restoration of testes’ regenerative capability. In addition, Bilobetin may be used in combination with CP in treatment protocols to mitigate CP-induced testicular injury. Full article
(This article belongs to the Special Issue Regulation of Keap1-Nrf2 Signaling in Health and Diseases)
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Review

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Review
Nrf2 Modulation in Breast Cancer
by
Somayyeh Ghareghomi
,
Mehran Habibi-Rezaei
,
Marzia Arese
,
Luciano Saso
and
Ali Akbar Moosavi-Movahedi
Biomedicines 2022, 10(10), 2668; https://doi.org/10.3390/biomedicines10102668 - 21 Oct 2022
Cited by 24 | Viewed by 2334
Abstract
Reactive oxygen species (ROS) are identified to control the expression and activity of various essential signaling intermediates involved in cellular proliferation, apoptosis, and differentiation. Indeed, ROS represents a double-edged sword in supporting cell survival and death. Many common pathological processes, including various cancer [...] Read more.
Reactive oxygen species (ROS) are identified to control the expression and activity of various essential signaling intermediates involved in cellular proliferation, apoptosis, and differentiation. Indeed, ROS represents a double-edged sword in supporting cell survival and death. Many common pathological processes, including various cancer types and neurodegenerative diseases, are inflammation and oxidative stress triggers, or even initiate them. Keap1-Nrf2 is a master antioxidant pathway in cytoprotective mechanisms through Nrf2 target gene expression. Activation of the Nfr2 pathway benefits cells in the early stages and reduces the level of ROS. In contrast, hyperactivation of Keap1-Nrf2 creates a context that supports the survival of both healthy and cancerous cells, defending them against oxidative stress, chemotherapeutic drugs, and radiotherapy. Considering the dual role of Nrf2 in suppressing or expanding cancer cells, determining its inhibitory/stimulatory position and targeting can represent an impressive role in cancer treatment. This review focused on Nrf2 modulators and their roles in sensitizing breast cancer cells to chemo/radiotherapy agents. Full article
(This article belongs to the Special Issue Regulation of Keap1-Nrf2 Signaling in Health and Diseases)
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Review
The Role of the NRF2 Pathway in Maintaining and Improving Cognitive Function
by
Nora E. Gray
,
Marcelo Farina
,
Paolo Tucci
and
Luciano Saso
Biomedicines 2022, 10(8), 2043; https://doi.org/10.3390/biomedicines10082043 - 21 Aug 2022
Cited by 4 | Viewed by 1628
Abstract
Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a redox-sensitive transcription factor that binds to the antioxidant response element consensus sequence, decreasing reactive oxygen species and regulating the transcription of a wide array of genes, including antioxidant and detoxifying enzymes, regulating genes involved in [...] Read more.
Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a redox-sensitive transcription factor that binds to the antioxidant response element consensus sequence, decreasing reactive oxygen species and regulating the transcription of a wide array of genes, including antioxidant and detoxifying enzymes, regulating genes involved in mitochondrial function and biogenesis. Moreover, NRF2 has been shown to directly regulate the expression of anti-inflammatory mediators reducing the expression of pro-inflammatory cytokines. In recent years, attention has turned to the role NRF2 plays in the brain in different diseases such Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and others. This review focused on the evidence, derived in vitro, in vivo and from clinical trials, supporting a role for NRF2 activation in maintaining and improving cognitive function and how its activation can be used to elicit neuroprotection and lead to cognitive enhancement. The review also brings a critical discussion concerning the possible prophylactic and/or therapeutic use of NRF2 activators in treating cognitive impairment-related conditions. Full article
(This article belongs to the Special Issue Regulation of Keap1-Nrf2 Signaling in Health and Diseases)
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