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NRF2 in Chronic Diseases Underlying the Oxidative Stress as a Trigger

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 (28 October 2023) | Viewed by 11995

Special Issue Editors


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Guest Editor
Department of Pharmacy, University “G. d’Annunzio” Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy
Interests: inflammation; hyaluronic acid; biomaterials; oxidative stress; tendons
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Guest Editor
Department of Pharmacy, University “G. d'Annunzio” of Chieti-Pescara, Chieti, Italy
Interests: chemical modification of natural compounds; medicinal chemistry; food chemistry; antioxidants; antimicrobials
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

The NRF2-KEAP1 system is highly involved in the regulation of the intracellular redox balance. A dysregulation of the NRF2 pathway leads to exaggerated oxidative stress (OS), which frequently occurs in aging and in many human chronic diseases, such as metabolic disorders, diabetes, neurodegeneration and infections. The reason underlying this pathological outcome is that NRF2 influences many intracellular functions, which extend beyond the maintenance of the redox homeostasis, including metabolism, proteostasis, mitochondrial function and inflammation. Therefore, there is growing interest in understanding the molecular mechanisms underlying the NRF2 activation or inhibition for potential therapeutic purposes and better clinical outcomes. This Special Issue is aimed at providing the most recent selected contributions on NRF2 activity modulation in OS-related chronic diseases. Potential topics include, but are not limited to:

  • chronic inflammation;
  • neuroinflammation;
  • COVID-19-related cytokine storm;
  • COVID-19-related chronic inflammation;
  • aging; metabolic diseases;
  • tissue regeneration after injuries;
  • musculoskeletal.

Dr. Marialucia Gallorini
Dr. Simone Carradori
Guest Editors

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Keywords

  • Nrf2
  • Keap1
  • inflammation
  • oxidative stress
  • neuroinflammation
  • aging
  • Covid-19
  • cytokines
  • metabolic diseases
  • muscoloskeletal disorders
  • natural compounds
  • drug design of modulators

Published Papers (5 papers)

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Research

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13 pages, 3624 KiB  
Article
Natural Compounds, Optimal Combination of Brusatol and Polydatin Promote Anti-Tumor Effect in Breast Cancer by Targeting Nrf2 Signaling Pathway
by Jing Li, Jianchao Zhang, Yan Zhu, Lukman O. Afolabi, Liang Chen and Xuesong Feng
Int. J. Mol. Sci. 2023, 24(9), 8265; https://doi.org/10.3390/ijms24098265 - 5 May 2023
Cited by 3 | Viewed by 2051
Abstract
Triple-negative breast cancer (TNBC) has been clearly recognized as a heterogeneous tumor with the worst prognosis among the subtypes of breast cancer (BC). The advent and application of current small-molecule drugs for treating TNBC, as well as other novel inhibitors, among others, have [...] Read more.
Triple-negative breast cancer (TNBC) has been clearly recognized as a heterogeneous tumor with the worst prognosis among the subtypes of breast cancer (BC). The advent and application of current small-molecule drugs for treating TNBC, as well as other novel inhibitors, among others, have made treatment options for TNBC more selective. However, there are still problems, such as poor patient tolerance, large administration doses, high dosing frequency, and toxic side effects, necessitating the development of more efficient and less toxic treatment strategies. High expression of Nrf2, a vital antioxidant transcription factor, often promotes tumor progression, and it is also one of the most effective targets in BC therapy. We found that in MDA-MB-231 cells and SUM159 cells, brusatol (BRU) combined with polydatin (PD) could significantly inhibit cell proliferation in vitro, significantly downregulate the expression of Nrf2 protein as well as the expression of downstream related target genes Heme Oxygenase-1 (HO-1) and NAD(P)H dehydrogenase, quinone 1 (NQO1), and promote reactive oxygen species (ROS) levels to further strengthen the anti-tumor effect. Furthermore, we discovered in our in vivo experiments that by reducing the drug dosage three times, we could significantly reduce tumor cell growth while avoiding toxic side effects, providing a treatment method with greater clinical application value for TNBC treatment. Full article
(This article belongs to the Special Issue NRF2 in Chronic Diseases Underlying the Oxidative Stress as a Trigger)
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14 pages, 3526 KiB  
Article
Phenylsulfonimide PPARα Antagonists Enhance Nrf2 Activation and Promote Oxidative Stress-Induced Apoptosis/Pyroptosis in MCF7 Breast Cancer Cells
by Marialucia Gallorini, Valentina Di Valerio, Isabella Bruno, Simone Carradori, Rosa Amoroso, Amelia Cataldi and Alessandra Ammazzalorso
Int. J. Mol. Sci. 2023, 24(2), 1316; https://doi.org/10.3390/ijms24021316 - 10 Jan 2023
Cited by 5 | Viewed by 2249
Abstract
The NF-E2-related factor 2 transcription factor (Nrf2) orchestrates the basal and stress-inducible activation of a vast array of antioxidant genes. A high amount of reactive oxygen species (ROS) promotes carcinogenesis in cells with defective redox-sensitive signaling factors such as Nrf2. In breast cancer [...] Read more.
The NF-E2-related factor 2 transcription factor (Nrf2) orchestrates the basal and stress-inducible activation of a vast array of antioxidant genes. A high amount of reactive oxygen species (ROS) promotes carcinogenesis in cells with defective redox-sensitive signaling factors such as Nrf2. In breast cancer (BC), emerging evidence indicates that increased Nrf2 activity enhances cell metastatic potential. An interconnection between peroxisome proliferator-activated receptors (PPARs) and Nrf2 pathways in cancer has been shown. In this light, newly synthesized PPARα antagonists, namely IB42, IB44, and IB66, were tested in the BC cell line MCF7 in parallel with GW6471 as the reference compound. Our results show that the most promising compound of this phenylsulfonimide series (IB66) is able to decrease MCF7 proliferation by blocking cells at the G2/M checkpoint. The underlying mechanism has been investigated, disclosing a caspase 3/Akt-dependent apoptotic/pyroptotic pathway induced by the increased generation of oxidative stress. Moreover, the involvement of Nrf2 and COX2 in IB66-treated MCF7 cell response has been highlighted. The reported data lay the groundwork for the development of alternative targeted therapy involving the Nrf2/PPARα molecular axis, able to overcome BC cell chemoresistance and cause better clinical outcomes, promoting other forms of programmed cell death, such as pyroptosis. Full article
(This article belongs to the Special Issue NRF2 in Chronic Diseases Underlying the Oxidative Stress as a Trigger)
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Review

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23 pages, 4522 KiB  
Review
Oxidative Stress and the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Pathway in Multiple Sclerosis: Focus on Certain Exogenous and Endogenous Nrf2 Activators and Therapeutic Plasma Exchange Modulation
by Dimitar Tonev and Albena Momchilova
Int. J. Mol. Sci. 2023, 24(24), 17223; https://doi.org/10.3390/ijms242417223 - 7 Dec 2023
Viewed by 1535
Abstract
The pathogenesis of multiple sclerosis (MS) suggests that, in genetically susceptible subjects, T lymphocytes undergo activation in the peripheral compartment, pass through the BBB, and cause damage in the CNS. They produce pro-inflammatory cytokines; induce cytotoxic activities in microglia and astrocytes with the [...] Read more.
The pathogenesis of multiple sclerosis (MS) suggests that, in genetically susceptible subjects, T lymphocytes undergo activation in the peripheral compartment, pass through the BBB, and cause damage in the CNS. They produce pro-inflammatory cytokines; induce cytotoxic activities in microglia and astrocytes with the accumulation of reactive oxygen species, reactive nitrogen species, and other highly reactive radicals; activate B cells and macrophages and stimulate the complement system. Inflammation and neurodegeneration are involved from the very beginning of the disease. They can both be affected by oxidative stress (OS) with different emphases depending on the time course of MS. Thus, OS initiates and supports inflammatory processes in the active phase, while in the chronic phase it supports neurodegenerative processes. A still unresolved issue in overcoming OS-induced lesions in MS is the insufficient endogenous activation of the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) pathway, which under normal conditions plays an essential role in mitochondria protection, OS, neuroinflammation, and degeneration. Thus, the search for approaches aiming to elevate endogenous Nrf2 activation is capable of protecting the brain against oxidative damage. However, exogenous Nrf2 activators themselves are not without drawbacks, necessitating the search for new non-pharmacological therapeutic approaches to modulate OS. The purpose of the present review is to provide some relevant preclinical and clinical examples, focusing on certain exogenous and endogenous Nrf2 activators and the modulation of therapeutic plasma exchange (TPE). The increased plasma levels of nerve growth factor (NGF) in response to TPE treatment of MS patients suggest their antioxidant potential for endogenous Nrf2 enhancement via NGF/TrkA/PI3K/Akt and NGF/p75NTR/ceramide-PKCζ/CK2 signaling pathways. Full article
(This article belongs to the Special Issue NRF2 in Chronic Diseases Underlying the Oxidative Stress as a Trigger)
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22 pages, 3089 KiB  
Review
Role of the Nrf2 Signaling Pathway in Ovarian Aging: Potential Mechanism and Protective Strategies
by Xiaofan Gao, Bo Wang, Yibao Huang, Meng Wu, Yuting Li, Yinuo Li, Xiaoran Zhu and Mingfu Wu
Int. J. Mol. Sci. 2023, 24(17), 13327; https://doi.org/10.3390/ijms241713327 - 28 Aug 2023
Cited by 3 | Viewed by 1753
Abstract
The ovary holds a significant role as a reproductive endocrine organ in women, and its aging process bears implications such as menopause, decreased fertility, and long-term health risks including osteoporosis, cardiovascular disorders, and cognitive decline. The phenomenon of oxidative stress is tightly linked [...] Read more.
The ovary holds a significant role as a reproductive endocrine organ in women, and its aging process bears implications such as menopause, decreased fertility, and long-term health risks including osteoporosis, cardiovascular disorders, and cognitive decline. The phenomenon of oxidative stress is tightly linked to the aging metabolic processes. More and more studies have demonstrated that oxidative stress impacts both physiologic and pathologic ovarian aging, and the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway plays a crucial role in regulating the antioxidant response. Furthermore, various therapeutic approaches have been identified to ameliorate ovarian aging by modulating the Nrf2 pathway. This review summarizes the important role of the Nrf2/ Kelch-like ECH-associated protein 1 (Keap1) signaling pathway in regulating oxidative stress and influencing ovarian aging. Additionally, it highlights the therapeutic strategies aimed at targeting the Nrf2/Keap1 pathway. Full article
(This article belongs to the Special Issue NRF2 in Chronic Diseases Underlying the Oxidative Stress as a Trigger)
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24 pages, 3202 KiB  
Review
Nrf2 Activation: Involvement in Central Nervous System Traumatic Injuries. A Promising Therapeutic Target of Natural Compounds
by Serena Silvestro and Emanuela Mazzon
Int. J. Mol. Sci. 2023, 24(1), 199; https://doi.org/10.3390/ijms24010199 - 22 Dec 2022
Cited by 12 | Viewed by 3307
Abstract
Central nervous system (CNS) trauma, such as traumatic brain injury (TBI) and spinal cord injury (SCI), represents an increasingly important health burden in view of the preventability of most injuries and the complex and expensive medical care that they necessitate. These injuries are [...] Read more.
Central nervous system (CNS) trauma, such as traumatic brain injury (TBI) and spinal cord injury (SCI), represents an increasingly important health burden in view of the preventability of most injuries and the complex and expensive medical care that they necessitate. These injuries are characterized by different signs of neurodegeneration, such as oxidative stress, mitochondrial dysfunction, and neuronal apoptosis. Cumulative evidence suggests that the transcriptional factor nuclear factor erythroid 2-related factor 2 (Nrf2) plays a crucial defensive role in regulating the antioxidant response. It has been demonstrated that several natural compounds are able to activate Nrf2, mediating its antioxidant response. Some of these compounds have been tested in experimental models of SCI and TBI, showing different neuroprotective properties. In this review, an overview of the preclinical studies that highlight the positive effects of natural bioactive compounds in SCI and TBI experimental models through the activation of the Nrf2 pathway has been provided. Interestingly, several natural compounds can activate Nrf2 through multiple pathways, inducing a strong antioxidant response against CNS trauma. Therefore, some of these compounds could represent promising therapeutic strategies for these pathological conditions. Full article
(This article belongs to the Special Issue NRF2 in Chronic Diseases Underlying the Oxidative Stress as a Trigger)
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