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Pharmaceuticals
Special Issues
Potential Applications of NRF2 Modulators in Therapy
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Potential Applications of NRF2 Modulators in Therapy

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 18118

Special Issue Editor

Dr. Cara Timpani

E-Mail Website
Guest Editor
1. Institute for Health and Sport, Victoria University, Melbourne, VIC 8001, Australia
2. Institute for Musculoskeletal Science (AIMSS), Inherited and Acquired Myopathy Program, Victoria University, St Albans, VIC 3021, Australia
3. Department of Medicine-Western Health, Melbourne Medical School, The University of Melbourne, Melbourne, VIC 3021, Australia
Interests: skeletal muscle; muscle wasting; metabolism; mitochondria; therapy; pre-clinical testing

Special Issue Information

Dear Colleagues,

Nuclear factor erythroid 2-related factor 2 (Nrf2) is considered the master regulator of the cytoprotective response in cells. Activated by reactive oxygen species and other toxic stimuli, Nrf2 elicits a plethora of beneficial effects that reduce inflammation and oxidative stress, promote mitochondrial function and enhance autophagy, amongst others. Given the positive broad-spectrum effect of Nrf2 activation, stimulating the Nrf2 pathway in disease is of growing interest. For example, the potent Nrf2 activator, dimethyl fumarate, is currently utilised in the treatment of relapsing-remitting Multiple Sclerosis, a neurological disease characterised by chronic inflammation and dysregulated immune system responses.

This Special Issue will explore the potential application of Nrf2 pharmacological modulators in novel disease states and provide updates on the role of Nrf2 in health and disease to further our understanding of Nrf2 therapeutics and their clinical application. All submission types (including original research, reviews and perspectives) are invited and research ranging from basic to pre-clinical to clinical is welcome.

Dr. Cara Timpani
Guest Editor

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. Pharmaceuticals 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 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

  • Nuclear factor erythroid 2-related factor 2 (Nrf2)
  • Therapeutics
  • Disease
  • Novel Applications
  • Oxidative Stress
  • Inflammation
  • Basic Science
  • Pre-Clinical
  • Clinical

Published Papers (7 papers)

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Research

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15 pages, 2417 KiB  
Article
Dihydromyricetin Modulates Nrf2 and NF-κB Crosstalk to Alleviate Methotrexate-Induced Lung Toxicity
by Asmaa I. Matouk, Eman M. Awad, Nashwa F. G. El-Tahawy, Azza A. K. El-Sheikh and Aliaa Anter
Pharmaceuticals 2023, 16(4), 481; https://doi.org/10.3390/ph16040481 - 23 Mar 2023
Cited by 3 | Viewed by 1872
Abstract
Background: Methotrexate (MTX) is an effective anticancer, anti-inflammatory, and immunomodulatory agent. However, it induces a serious pneumonitis that leads to irreversible fibrotic lung damage. This study addresses the protective role of the natural flavonoid dihydromyricetin (DHM) against MTX-induced pneumonitis via modulation of Nrf2/NF-κB [...] Read more.
Background: Methotrexate (MTX) is an effective anticancer, anti-inflammatory, and immunomodulatory agent. However, it induces a serious pneumonitis that leads to irreversible fibrotic lung damage. This study addresses the protective role of the natural flavonoid dihydromyricetin (DHM) against MTX-induced pneumonitis via modulation of Nrf2/NF-κB signaling crosstalk. Methods: Male Wistar rats were divided into 4 groups: control, which received the vehicle; MTX, which received a single MTX (40 mg/kg, i.p) at day 9 of the experiment; (MTX + DHM), which received oral DHM (300 mg/kg) for 14 days and methotrexate (40 mg/kg, i.p) on the 9th day; and DHM, which received DHM (300 mg/kg, p.o) for 14 days. Results: Lung histopathological examination and scoring showed a decline in MTX-induced alveolar epithelial damage and decreased inflammatory cell infiltration by DHM treatment. Further, DHM significantly alleviated the oxidative stress by decreasing MDA while increasing GSH and SOD antioxidant levels. Additionally, DHM suppressed the pulmonary inflammation and fibrosis through decreasing levels of NF-κB, IL-1β, and TGF-β1 while promoting the expression of Nrf2, a positive regulator of antioxidant genes, and its downstream modulator, HO-1. Conclusion: This study identified DHM as a promising therapeutic target against MTX-induced pneumonitis via activation of Nrf2 antioxidant signaling while suppressing the NF-κB mediated inflammatory pathways. Full article
(This article belongs to the Special Issue Potential Applications of NRF2 Modulators in Therapy)
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14 pages, 5124 KiB  
Article
Possible Implication of Nrf2, PPAR-γ and MAPKs Signaling in the Protective Role of Mangiferin against Renal Ischemia/Reperfusion in Rats
by Abdallah M. Gendy, Amira A. El-Gazar, Ghada M. Ragab, Asmaa K. Al-Mokaddem, Alaadin E. El-Haddad, Heba Mohammed Refat M. Selim, Einas Mohamed Yousef, Najat O. Hamed and Sherihan Salaheldin Abdelhamid Ibrahim
Pharmaceuticals 2023, 16(1), 6; https://doi.org/10.3390/ph16010006 - 21 Dec 2022
Cited by 11 | Viewed by 2191
Abstract
Mangiferin (Mang) is a known glucosylxanthone that has proven its shielding effect against ischemia/reperfusion (Is/R). However, its full underlying mechanistic perspective against renal Is/R induced lesions is not fully revealed. Consequently, the purpose of this study is to track further non-investigated modulatory signals [...] Read more.
Mangiferin (Mang) is a known glucosylxanthone that has proven its shielding effect against ischemia/reperfusion (Is/R). However, its full underlying mechanistic perspective against renal Is/R induced lesions is not fully revealed. Consequently, the purpose of this study is to track further non-investigated modulatory signals of Mang against the renal Is/R model involving nuclear factor erythroid 2-related factor (Nrf)2/heme oxygenase (HO)-1, peroxisome proliferator-activated receptor (PPAR)-γ/nuclear factor (NF)-κB, p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK) signaling. To ratify our aim, Mang was administrated (20 mg/kg, i.p for seven days) before the induction of bilateral Is/R. Mechanistic maneuver revealed that Mang balanced oxidative state via increasing the expression of the antioxidant Nrf2/HO-1 cue with subsequent enhancement of GSH besides MDA lessening. Additionally, Mang enhanced PPAR-γ mRNA expression and declined p-p38 MAPK and p-JNK expression with concomitant NF-κB downsizing leading to iNOS/NOx and TNF-α rebating. Furthermore, the Mang anti-apoptotic trait was affirmed by enriching Bcl-2 expression as well as decreasing Bax and caspase-3 expression. All these potentials were in the line with the molecular docking results and the improved histopathological findings and renal function biomarkers. Consequently, Mang provided plausible protective mechanisms against renal Is/R-related events, possibly by amending oxidative status, inflammatory mediators, and apoptotic cell death through the involvement of Nrf2, PPAR-γ, MAPK, JNK, and NF-κB signaling. Full article
(This article belongs to the Special Issue Potential Applications of NRF2 Modulators in Therapy)
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14 pages, 4486 KiB  
Article
Taxifolin Prevents Cisplatin Nephrotoxicity by Modulating Nrf2/HO-1 Pathway and Mitigating Oxidative Stress and Inflammation in Mice
by Abdulkareem A. Alanezi, Afaf F. Almuqati, Manal A. Alfwuaires, Fawaz Alasmari, Nader I. Namazi, Osama Y. Althunibat and Ayman M. Mahmoud
Pharmaceuticals 2022, 15(11), 1310; https://doi.org/10.3390/ph15111310 - 24 Oct 2022
Cited by 11 | Viewed by 2091
Abstract
Cisplatin (CIS) is an effective chemotherapeutic agent used in the treatment of several malignancies. The clinical use of CIS is associated with adverse effects, including acute kidney injury (AKI). Oxidative stress and inflammation are key events in the development of CIS-induced AKI. This [...] Read more.
Cisplatin (CIS) is an effective chemotherapeutic agent used in the treatment of several malignancies. The clinical use of CIS is associated with adverse effects, including acute kidney injury (AKI). Oxidative stress and inflammation are key events in the development of CIS-induced AKI. This study investigated the protective effect of taxifolin (TAX), a bioactive flavonoid with promising health-promoting properties, on CIS-induced nephrotoxicity in mice. TAX was orally given to mice for 10 days and a single dose of CIS was injected at day 7. Serum blood urea nitrogen (BUN) and creatinine were elevated, and multiple histopathological alterations were observed in the kidney of CIS-administered mice. CIS increased renal malondialdehyde (MDA), nitric oxide (NO), nuclear factor-kappaB (NF-κB) p65, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β, and decreased cellular antioxidants in mice. TAX remarkably prevented kidney injury, ameliorated serum BUN and creatinine, and renal MDA, NO, NF-κB p65, and pro-inflammatory cytokines, and boosted antioxidant defenses in CIS-administered mice. TAX downregulated Bax and caspase-3, and upregulated Bcl-2. These effects were associated with upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) expression and heme oxygenase (HO)-1 activity in CIS-administered mice. In conclusion, TAX prevented CIS-induced AKI by mitigating tissue injury, oxidative stress, inflammation, and cell death. The protective efficacy of TAX was associated with the upregulation of Nrf2/HO-1 signaling. Full article
(This article belongs to the Special Issue Potential Applications of NRF2 Modulators in Therapy)
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20 pages, 1907 KiB  
Article
Brain Protection by Methylene Blue and Its Derivative, Azur B, via Activation of the Nrf2/ARE Pathway in Cisplatin-Induced Cognitive Impairment
by Ekaterina P. Krutskikh, Daria V. Potanina, Natalia A. Samoylova, Mariya V. Gryaznova, Irina S. Sadovnikova, Artem P. Gureev and Vasily N. Popov
Pharmaceuticals 2022, 15(7), 815; https://doi.org/10.3390/ph15070815 - 30 Jun 2022
Cited by 6 | Viewed by 2641
Abstract
Cisplatin is a cytotoxic chemotherapeutic drug that leads to DNA damage and is used in the treatment of various types of tumors. However, cisplatin has several serious adverse effects, such as deterioration in cognitive ability. The aim of our work was to study [...] Read more.
Cisplatin is a cytotoxic chemotherapeutic drug that leads to DNA damage and is used in the treatment of various types of tumors. However, cisplatin has several serious adverse effects, such as deterioration in cognitive ability. The aim of our work was to study neuroprotectors capable of preventing cisplatin-induced neurotoxicity. Methylene blue (MB) and AzurB (AzB) are able to neutralize the neurotoxicity caused by cisplatin by protecting nerve cells as a result of the activation of the Ntf2 signaling pathway. We have shown that cisplatin impairs learning in the Morris water maze. This is due to an increase in the amount of mtDNA damage, a decrease in the expression of most antioxidant genes, the main determinant of the induction of which is the Nrf2/ARE signaling pathway, and genes involved in mitophagy regulation in the cortex. The expression of genes involved in long-term potentiation was suppressed in the hippocampus of cisplatin-injected mice. MB in most cases prevented cisplatin-induced impairment of learning and decrease of gene expression in the cortex. AzB prevented the cisplatin-induced decrease of genes in the hippocampus. Also, cisplatin induced disbalance in the gut microbiome, decreased levels of Actinotalea and Prevotella, and increased levels of Streptococcus and Veillonella. MB and AzB also prevented cisplatin-induced changes in the bacterial composition of the gut microbiome. Full article
(This article belongs to the Special Issue Potential Applications of NRF2 Modulators in Therapy)
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13 pages, 2539 KiB  
Article
Activation of Nrf2/HO-1 Antioxidant Pathway by Heme Attenuates Calcification of Human Lens Epithelial Cells
by Arpan Chowdhury, Enikő Balogh, Haneen Ababneh, Andrea Tóth and Viktória Jeney
Pharmaceuticals 2022, 15(5), 493; https://doi.org/10.3390/ph15050493 - 19 Apr 2022
Cited by 6 | Viewed by 2437
Abstract
Cataract, an opacification in the crystalline lens, is a leading cause of blindness. Deposition of hydroxyapatite occurs in a cataractous lens that could be the consequence of osteogenic differentiation of lens epithelial cells (LECs). Nuclear factor erythroid 2-related factor 2 (Nrf2) controls the [...] Read more.
Cataract, an opacification in the crystalline lens, is a leading cause of blindness. Deposition of hydroxyapatite occurs in a cataractous lens that could be the consequence of osteogenic differentiation of lens epithelial cells (LECs). Nuclear factor erythroid 2-related factor 2 (Nrf2) controls the transcription of a wide range of cytoprotective genes. Nrf2 upregulation attenuates cataract formation. Here we aimed to investigate the effect of Nrf2 system upregulation in LECs calcification. We induced osteogenic differentiation of human LECs (HuLECs) with increased phosphate and calcium-containing osteogenic medium (OM). OM-induced calcium and osteocalcin deposition in HuLECs. We used heme to activate Nrf2, which strongly upregulated the expression of Nrf2 and heme oxygenase-1 (HO-1). Heme-mediated Nrf2 activation was dependent on the production of reactive oxygens species. Heme inhibited Ca deposition, and the OM-induced increase of osteogenic markers, RUNX2, alkaline phosphatase, and OCN. Anti-calcification effect of heme was lost when the transcriptional activity of Nrf2 or the enzyme activity of HO-1 was blocked with pharmacological inhibitors. Among products of HO-1 catalyzed heme degradation iron mimicked the anti-calcification effect of heme. We concluded that heme-induced upregulation of the Nrf2/HO-1 system inhibits HuLECs calcification through the liberation of heme iron. Full article
(This article belongs to the Special Issue Potential Applications of NRF2 Modulators in Therapy)
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Review

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26 pages, 4176 KiB  
Review
A Pivotal Role of Nrf2 in Neurodegenerative Disorders: A New Way for Therapeutic Strategies
by Sibel Suzen, Paolo Tucci, Elisabetta Profumo, Brigitta Buttari and Luciano Saso
Pharmaceuticals 2022, 15(6), 692; https://doi.org/10.3390/ph15060692 - 31 May 2022
Cited by 15 | Viewed by 2963
Abstract
Clinical and preclinical research indicates that neurodegenerative diseases are characterized by excess levels of oxidative stress (OS) biomarkers and by lower levels of antioxidant protection in the brain and peripheral tissues. Dysregulations in the oxidant/antioxidant balance are known to be a major factor [...] Read more.
Clinical and preclinical research indicates that neurodegenerative diseases are characterized by excess levels of oxidative stress (OS) biomarkers and by lower levels of antioxidant protection in the brain and peripheral tissues. Dysregulations in the oxidant/antioxidant balance are known to be a major factor in the pathogenesis of neurodegenerative diseases and involve mitochondrial dysfunction, protein misfolding, and neuroinflammation, all events that lead to the proteostatic collapse of neuronal cells and their loss. Nuclear factor-E2-related factor 2 (Nrf2) is a short-lived protein that works as a transcription factor and is related to the expression of many cytoprotective genes involved in xenobiotic metabolism and antioxidant responses. A major emerging function of Nrf2 from studies over the past decade is its role in resistance to OS. Nrf2 is a key regulator of OS defense and research supports a protective and defending role of Nrf2 against neurodegenerative conditions. This review describes the influence of Nrf2 on OS and in what way Nrf2 regulates antioxidant defense for neurodegenerative conditions. Furthermore, we evaluate recent research and evidence for a beneficial and potential role of specific Nrf2 activator compounds as therapeutic agents. Full article
(This article belongs to the Special Issue Potential Applications of NRF2 Modulators in Therapy)
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Other

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20 pages, 1747 KiB  
Perspective
Adenylosuccinic Acid: An Orphan Drug with Untapped Potential
by Emma Rybalka, Stephanie Kourakis, Charles A. Bonsett, Behzad Moghadaszadeh, Alan H. Beggs and Cara A. Timpani
Pharmaceuticals 2023, 16(6), 822; https://doi.org/10.3390/ph16060822 - 31 May 2023
Cited by 2 | Viewed by 2963
Abstract
Adenylosuccinic acid (ASA) is an orphan drug that was once investigated for clinical application in Duchenne muscular dystrophy (DMD). Endogenous ASA participates in purine recycling and energy homeostasis but might also be crucial for averting inflammation and other forms of cellular stress during [...] Read more.
Adenylosuccinic acid (ASA) is an orphan drug that was once investigated for clinical application in Duchenne muscular dystrophy (DMD). Endogenous ASA participates in purine recycling and energy homeostasis but might also be crucial for averting inflammation and other forms of cellular stress during intense energy demand and maintaining tissue biomass and glucose disposal. This article documents the known biological functions of ASA and explores its potential application for the treatment of neuromuscular and other chronic diseases. Full article
(This article belongs to the Special Issue Potential Applications of NRF2 Modulators in Therapy)
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