Antioxidants

Research

19 pages, 2521 KiB

Open AccessArticle

Dimethyl Fumarate Prevents the Development of Chronic Social Stress-Induced Hypertension in Borderline Hypertensive Rats

by Michal Kluknavsky, Peter Balis, Silvia Liskova, Andrea Micurova, Martin Skratek, Jan Manka and Iveta Bernatova

Antioxidants 2024, 13(8), 947; https://doi.org/10.3390/antiox13080947 - 3 Aug 2024

Viewed by 979

Abstract

This study investigated the effects of chronic crowding-induced social stress and dimethyl fumarate (DMF) on borderline hypertensive rats, focusing on the transcription nuclear factor (erythroid-derived 2)-like 2 (NRF2) gene Nfe2l2, on the expression of selected NFR2-mediated gene expressions in the heart, and [...] Read more.

This study investigated the effects of chronic crowding-induced social stress and dimethyl fumarate (DMF) on borderline hypertensive rats, focusing on the transcription nuclear factor (erythroid-derived 2)-like 2 (NRF2) gene Nfe2l2, on the expression of selected NFR2-mediated gene expressions in the heart, and on vascular function. Rats were exposed to chronic crowding, DMF treatment (30 mg/kg/day, p.o.), or a combination of both for six weeks. Blood pressure (BP) was measured non-invasively, gene expressions were analysed using RT-qPCR, and vascular function was assessed by measuring noradrenaline (NA)-induced vasoconstriction and endothelium-dependent and -independent relaxations in the femoral arteries using a wire myograph. Chronic stress increased BP, Nfe2l2 expression, and NA-induced vasoconstriction, though it did not affect relaxation responses nor the left heart ventricle-to-body weight (LHV/BW) ratio. DMF elevated Nfe2l2 expression (as the main effect) in the heart but did not alter BP and vascular functions vs. control when administered alone. Interestingly, DMF increased the LHV/BW ratio, supposedly due to reductive stress induced by continuous NRF2 activation. When combined with stress, DMF treatment prevented stress-induced hypertension and mitigated NA-induced vasoconstriction without altering relaxation functions. In addition, the combination of stress and DMF increased Tnf and Nos2 expression and the expressions of several genes involved in iron metabolism. In conclusion, these findings suggest that DMF can prevent chronic stress-induced hypertension by reducing vascular contractility. Moreover, DMF itself may produce reductive stress in the heart and induce inflammation when combined with stress. This indicates a need for the careful consideration of long-term DMF treatment considering its impact on the heart. Full article

(This article belongs to the Special Issue Oxidative Stress and NRF2 in Health and Disease)

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19 pages, 2104 KiB

Open AccessArticle

Sesamin Exerts an Antioxidative Effect by Activating the Nrf2 Transcription Factor in the Glial Cells of the Central Nervous System in Drosophila Larvae

by Akihiro Tsuji, Eiji Kotani and Yoshihiro H. Inoue

Antioxidants 2024, 13(7), 787; https://doi.org/10.3390/antiox13070787 - 28 Jun 2024

Cited by 1 | Viewed by 875

Abstract

Sesame seeds are abundant in sesamin, which exerts health-promoting effects such as extending the lifespan of adult Drosophila and suppressing oxidative stress by activating the Nrf2 transcription factor. Here, we investigated whether sesamin activated Nrf2 in larval tissues and induced the expression of [...] Read more.

Sesame seeds are abundant in sesamin, which exerts health-promoting effects such as extending the lifespan of adult Drosophila and suppressing oxidative stress by activating the Nrf2 transcription factor. Here, we investigated whether sesamin activated Nrf2 in larval tissues and induced the expression of Nrf2 target genes. In the sesamin-fed larvae, Nrf2 was activated in the central nervous system (CNS), gut, and salivary glands. The ectopic expression of Keap1 in glial cells inhibited sesamin-induced Nrf2 activation in the whole CNS more than in the neurons, indicating that sesamin activates Nrf2 in glia efficiently. We labeled the astrocytes as well as cortex and surface glia with fluorescence to identify the glial cell types in which Nrf2 was activated; we observed their activation in both cell types. These data suggest that sesamin may stimulate the expression of antioxidative genes in glial cells. Among the 17 candidate Nrf2 targets, the mRNA levels of Cyp6a2 and Cyp6g1 in cytochrome P450 were elevated in the CNS, gut, and salivary glands of the sesamin-fed larvae. However, this elevation did not lead to resistance against imidacloprid, which is detoxified by these enzymes. Our results suggest that sesamin may exert similar health-promoting effects on the human CNS and digestive tissues. Full article

(This article belongs to the Special Issue Oxidative Stress and NRF2 in Health and Disease)

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11 pages, 3619 KiB

Open AccessCommunication

Myeloid Nrf2 Protects against Neonatal Oxidant-Stress-Induced Lung Inflammation and Alveolar Simplification in Mice

by Chandra Mohan Tamatam, Lalith Kumar Venkareddy, Aparna Ankireddy, Narsa Machireddy and Sekhar P. Reddy

Antioxidants 2024, 13(6), 698; https://doi.org/10.3390/antiox13060698 - 7 Jun 2024

Viewed by 920

Abstract

Bronchopulmonary dysplasia (BPD) is a chronic condition affecting preterm infants, characterized by lung alveolar simplification/hypoalveolarization and vascular remodeling. The nuclear factor erythroid 2 like 2 (Nfe2l2, or Nrf2) plays a critical role in the cytoprotective response to neonatal hyperoxia, and its global deficiency [...] Read more.

Bronchopulmonary dysplasia (BPD) is a chronic condition affecting preterm infants, characterized by lung alveolar simplification/hypoalveolarization and vascular remodeling. The nuclear factor erythroid 2 like 2 (Nfe2l2, or Nrf2) plays a critical role in the cytoprotective response to neonatal hyperoxia, and its global deficiency exacerbates hypoalveolarization in mice. The abnormal recruitment and activation of myeloid cells are associated with the pathogenesis of BPD. Therefore, we employed a genetic approach to investigate the role of myeloid Nrf2 in regulating hyperoxia-induced hypoalveolarization. Pups, both wild-type (Nrf2^f/f) and those with a myeloid Nrf2 deletion (abbreviated as Nrf2^∆/∆mye), were exposed to hyperoxia for 72 h at postnatal day 1 (Pnd1), and then sacrificed at either Pnd4 or Pnd18 following a two-week recovery period. We analyzed the hypoalveolarization, inflammation, and gene expression related to cytoprotective and inflammatory responses in the lungs of these pups. The hypoalveolarization induced by hyperoxia was significantly greater in Nrf2^∆/∆mye pups compared to their Nrf2^f/f counterparts (35.88% vs. 21.01%, respectively) and was accompanied by increased levels of inflammatory cells and IL-1β activation in the lungs. Antioxidant gene expression in response to neonatal hyperoxia was lower in Nrf2^∆/∆mye pups compared to their Nrf2^f/f counterparts. Furthermore, Nrf2-deficient macrophages exposed to hyperoxia exhibited markedly decreased cytoprotective gene expression and increased IL-1β levels compared to Nrf2-sufficient cells. Our findings demonstrate the crucial role of myeloid Nrf2 in mitigating hyperoxia-induced lung hypoalveolarization and inflammatory responses in neonatal mice. Full article

(This article belongs to the Special Issue Oxidative Stress and NRF2 in Health and Disease)

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16 pages, 3111 KiB

Open AccessArticle

AQP3 and AQP5 Modulation in Response to Prolonged Oxidative Stress in Breast Cancer Cell Lines

by Monika Mlinarić, Ivan Lučić, Marko Tomljanović, Ivana Tartaro Bujak, Lidija Milković and Ana Čipak Gašparović

Antioxidants 2024, 13(6), 626; https://doi.org/10.3390/antiox13060626 - 21 May 2024

Viewed by 1239

Abstract

Aquaporins are membrane pores regulating the transport of water, glycerol, and other small molecules across membranes. Among 13 human aquaporins, six have been shown to transport H₂O₂ and are therefore called peroxiporins. Peroxiporins are implicated in cancer development and progression, [...] Read more.

Aquaporins are membrane pores regulating the transport of water, glycerol, and other small molecules across membranes. Among 13 human aquaporins, six have been shown to transport H₂O₂ and are therefore called peroxiporins. Peroxiporins are implicated in cancer development and progression, partly due to their involvement in H₂O₂ transport. Oxidative stress is linked to breast cancer development but is also a mechanism of action for conventional chemotherapy. The aim of this study is to investigate the effects of prolonged oxidative stress on Aquaporin 3 (AQP3), Aquaporin 5 (AQP5), and signaling pathways in breast cancer cell lines of different malignancies alongside a non-tumorigenic breast cell line. The prolonged oxidative stress caused responses in viability only in the cancer cell lines, while it affected cell migration in the MCF7 cell line. Changes in the localization of NRF2, a transcription factor involved in oxidative stress response, were observed only in the cancer cell lines, and no effects were recorded on its downstream target proteins. Moreover, the prolonged oxidative stress caused changes in AQP3 and AQP5 expression only in the cancer cell lines, in contrast to their non-malignant counterparts. These results suggest peroxiporins are potential therapeutic targets in cancer treatment. However, further research is needed to elucidate their role in the modulation of therapy response, highlighting the importance of research on this topic. Full article

(This article belongs to the Special Issue Oxidative Stress and NRF2 in Health and Disease)

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25 pages, 3912 KiB

Open AccessArticle

The Triterpenoid CDDO-Methyl Ester Reduces Tumor Burden, Reprograms the Immune Microenvironment, and Protects from Chemotherapy-Induced Toxicity in a Preclinical Mouse Model of Established Lung Cancer

by Jessica A. Moerland and Karen T. Liby

Antioxidants 2024, 13(6), 621; https://doi.org/10.3390/antiox13060621 - 21 May 2024

Viewed by 1459

Abstract

NRF2 activation protects epithelial cells from malignancy, but cancer cells can upregulate the pathway to promote survival. NRF2 activators including CDDO-Methyl ester (CDDO-Me) inhibit cancer in preclinical models, suggesting NRF2 activation in other cell types may promote anti-tumor activity. However, the immunomodulatory effects [...] Read more.

NRF2 activation protects epithelial cells from malignancy, but cancer cells can upregulate the pathway to promote survival. NRF2 activators including CDDO-Methyl ester (CDDO-Me) inhibit cancer in preclinical models, suggesting NRF2 activation in other cell types may promote anti-tumor activity. However, the immunomodulatory effects of NRF2 activation remain poorly understood in the context of cancer. To test CDDO-Me in a murine model of established lung cancer, tumor-bearing wildtype (WT) and Nrf2 knockout (KO) mice were treated with 50–100 mg CDDO-Me/kg diet, alone or combined with carboplatin/paclitaxel (C/P) for 8–12 weeks. CDDO-Me decreased tumor burden in an Nrf2-dependent manner. The combination of CDDO-Me plus C/P was significantly (p < 0.05) more effective than either drug alone, reducing tumor burden by 84% in WT mice. CDDO-Me reduced the histopathological grade of WT tumors, with a significantly (p < 0.05) higher proportion of low-grade tumors and a lower proportion of high-grade tumors. These changes were augmented by combination with C/P. CDDO-Me also protected WT mice from C/P-induced toxicity and improved macrophage and T cell phenotypes in WT mice, reducing the expression of CD206 and PD-L1 on macrophages, decreasing immunosuppressive FoxP3+ CD4+ T cells, and increasing activation of CD8+ T cells in a Nrf2-dependent manner. Full article

(This article belongs to the Special Issue Oxidative Stress and NRF2 in Health and Disease)

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22 pages, 3371 KiB

Open AccessArticle

Cellular Pre-Adaptation to the High O₂ Concentration Used in Standard Cell Culture Confers Resistance to Subsequent H₂O₂-Induced Cell Death

by Jack B. Jordan, Miranda J. Smallwood, Gary R. Smerdon and Paul G. Winyard

Antioxidants 2024, 13(3), 269; https://doi.org/10.3390/antiox13030269 - 22 Feb 2024

Cited by 2 | Viewed by 2109

Abstract

The addition of hydrogen peroxide (H₂O₂) to cultured cells is widely used as a method to modulate redox-regulated cellular pathways, including the induction of programmed cell death in cell culture experiments and the testing of pro- and antioxidant compounds. [...] Read more.

The addition of hydrogen peroxide (H₂O₂) to cultured cells is widely used as a method to modulate redox-regulated cellular pathways, including the induction of programmed cell death in cell culture experiments and the testing of pro- and antioxidant compounds. Here, we assessed the effect on the cellular response to H₂O₂ of pre-adapting squamous cell carcinoma cells (A431) to the standard cell culture oxygenation of 18.6% O₂, compared to cells pre-adapted to a physiological skin O₂ concentration (3.0% O₂). We showed that cells pre-adapted to 18.6% O₂ resisted H₂O₂-induced cell death compared to cells pre-adapted to 3.0% O₂ for 96 h prior to treatment with H₂O₂. Moreover, the enzymatic activities of catalase and glutathione reductase, as well as the protein expression levels of catalase, were higher in cells pre-adapted to 18.6% O₂ compared to cells pre-adapted to 3.0% O_2. H₂O₂-resistant cells, pre-adapted to 18.6% O₂, exhibited increased nuclear Nrf-2 levels. It is concluded that A431 cells pre-adapted to standard cell culture oxygenation conditions resist H₂O₂-induced cell death. This effect may be related to their heightened activation of Nrf-2. Full article

(This article belongs to the Special Issue Oxidative Stress and NRF2 in Health and Disease)

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14 pages, 1980 KiB

Open AccessArticle

Oxidative Stress Induces Skin Pigmentation in Melasma by Inhibiting Hedgehog Signaling

by Nan-Hyung Kim and Ai-Young Lee

Antioxidants 2023, 12(11), 1969; https://doi.org/10.3390/antiox12111969 - 6 Nov 2023

Cited by 3 | Viewed by 2522

Abstract

There is growing evidence that oxidative stress plays a role in melasma and disrupts primary cilia formation. Additionally, primary cilia have been suggested to have an inhibitory role in melanogenesis. This study examined the potential link between oxidative stress, skin hyperpigmentation, and primary [...] Read more.

There is growing evidence that oxidative stress plays a role in melasma and disrupts primary cilia formation. Additionally, primary cilia have been suggested to have an inhibitory role in melanogenesis. This study examined the potential link between oxidative stress, skin hyperpigmentation, and primary cilia. We compared the expression levels of the nuclear factor E2-related factor 2 (NRF2), intraflagellar transport 88 (IFT88), and glioma-associated oncogene homologs (GLIs) in skin samples from patients with melasma, both in affected and unaffected areas. We also explored the roles of NRF2, IFT88, and GLIs in ciliogenesis and pigmentation using cultured adult human keratinocytes, with or without melanocytes. Our findings revealed decreased levels of NRF2, heme oxygenase-1, IFT88, and GLIs in lesional skin from melasma patients. The knockdown of NRF2 resulted in reduced expressions of IFT88 and GLI1, along with fewer ciliated cells. Furthermore, NRF2, IFT88, or GLI1 knockdown led to increased expressions in protease-activated receptor-2 (PAR2), K10, involucrin, tyrosinase, and/or melanin. These effects were reversed by the smoothened agonist 1.1. Calcium also upregulated these proteins, but not NRF2. The upregulation of involucrin and PAR2 after NRF2 knockdown was mitigated with a calcium chelator. In summary, our study suggests that oxidative stress in NRF2-downregulated melasma keratinocytes impedes ciliogenesis and related molecular processes. This inhibition stimulates keratinocyte differentiation, resulting in melanin synthesis and melanosome transfer, ultimately leading to skin hyperpigmentation. Full article

(This article belongs to the Special Issue Oxidative Stress and NRF2 in Health and Disease)

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14 pages, 2022 KiB

Open AccessArticle

AMPK-Mediated Phosphorylation of Nrf2 at S374/S408/S433 Favors Its βTrCP2-Mediated Degradation in KEAP1-Deficient Cells

by Eleni Petsouki, Sylvia Ender, Shara Natalia Sosa Cabrera and Elke H. Heiss

Antioxidants 2023, 12(8), 1586; https://doi.org/10.3390/antiox12081586 - 9 Aug 2023

Cited by 2 | Viewed by 4433

Abstract

Nrf2 is a transcription factor facilitating cells’ resilience against redox and various other forms of stress. In the absence of stressors, KEAP1 and/or βTrCP mediate the ubiquitination of Nrf2 and prevent Nrf2-dependent gene expression and detoxification. AMPK regulates cellular energy homeostasis and redox [...] Read more.

Nrf2 is a transcription factor facilitating cells’ resilience against redox and various other forms of stress. In the absence of stressors, KEAP1 and/or βTrCP mediate the ubiquitination of Nrf2 and prevent Nrf2-dependent gene expression and detoxification. AMPK regulates cellular energy homeostasis and redox balance. Previous studies indicated a potential Nrf2-AMPK cooperativity. In line with this, our lab had previously identified three AMPK-dependent phosphorylation sites (S374/408/433) in Nrf2. Given their localization in or near the Neh6 domain, known to regulate βTrCP-mediated degradation, we examined whether they may influence the βTrCP-driven degradation of Nrf2. By employing expression plasmids for WT and triple mutant (TM)-Nrf2 (Nrf2^{S374/408/433→A}), (co)immunoprecipitation, proximity ligation, protein half-life, knockdown, ubiquitination experiments, and qPCR in Keap1-null mouse embryonic fibroblasts, we show that TM-Nrf2^{S→A374/408/433} had enhanced stability due to impeded interaction with βTrCP2 and reduced ubiquitination in comparison to WT-Nrf2. In addition, TM-Nrf2 elicited higher expression of the Nrf2 target gene Gclc, potentiated in the presence of a pharmacological AMPK activator. Overall, we propose that AMPK-dependent phospho-sites of Nrf2 can favor its βTrCP2-mediated degradation and dampen the extent of Nrf2 target gene expression. Therefore, targeting AMPK might be able to diminish Nrf2-mediated responses in cells with overactive Nrf2 due to KEAP1 deficiency. Full article

(This article belongs to the Special Issue Oxidative Stress and NRF2 in Health and Disease)

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24 pages, 6300 KiB

Open AccessArticle

Nrf2 as a Therapeutic Target in the Resistance to Targeted Therapies in Melanoma

by Marie Angèle Cucci, Margherita Grattarola, Chiara Monge, Antonella Roetto, Giuseppina Barrera, Emilia Caputo, Chiara Dianzani and Stefania Pizzimenti

Antioxidants 2023, 12(6), 1313; https://doi.org/10.3390/antiox12061313 - 20 Jun 2023

Cited by 3 | Viewed by 3674

Abstract

The use of specific inhibitors towards mutant BRAF (BRAFi) and MEK (MEKi) in BRAF-mutated patients has significantly improved progression-free and overall survival of metastatic melanoma patients. Nevertheless, half of the patients still develop resistance within the first year of therapy. Therefore, understanding the [...] Read more.

The use of specific inhibitors towards mutant BRAF (BRAFi) and MEK (MEKi) in BRAF-mutated patients has significantly improved progression-free and overall survival of metastatic melanoma patients. Nevertheless, half of the patients still develop resistance within the first year of therapy. Therefore, understanding the mechanisms of BRAFi/MEKi-acquired resistance has become a priority for researchers. Among others, oxidative stress-related mechanisms have emerged as a major force. The aim of this study was to evaluate the contribution of Nrf2, the master regulator of the cytoprotective and antioxidant response, in the BRAFi/MEKi acquired resistance of melanoma. Moreover, we investigated the mechanisms of its activity regulation and the possible cooperation with the oncogene YAP, which is also involved in chemoresistance. Taking advantage of established in vitro melanoma models resistant to BRAFi, MEKi, or dual resistance to BRAFi/MEKi, we demonstrated that Nrf2 was upregulated in melanoma cells resistant to targeted therapy at the post-translational level and that the deubiquitinase DUB3 participated in the control of the Nrf2 protein stability. Furthermore, we found that Nrf2 controlled the expression of YAP. Importantly, the inhibition of Nrf2, directly or through inhibition of DUB3, reverted the resistance to targeted therapies. Full article

(This article belongs to the Special Issue Oxidative Stress and NRF2 in Health and Disease)

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20 pages, 9994 KiB

Open AccessArticle

CD38-Induced Metabolic Dysfunction Primes Multiple Myeloma Cells for NAD⁺-Lowering Agents

by Pamela Becherini, Debora Soncini, Silvia Ravera, Elisa Gelli, Claudia Martinuzzi, Giulia Giorgetti, Antonia Cagnetta, Fabio Guolo, Federico Ivaldi, Maurizio Miglino, Sara Aquino, Katia Todoerti, Antonino Neri, Andrea Benzi, Mario Passalacqua, Alessio Nencioni, Ida Perrotta, Maria Eugenia Gallo Cantafio, Nicola Amodio, Antonio De Flora, Santina Bruzzone, Roberto M. Lemoli and Michele Cea Show full author list Hide full author list

Antioxidants 2023, 12(2), 494; https://doi.org/10.3390/antiox12020494 - 15 Feb 2023

Cited by 2 | Viewed by 3073

Abstract

Cancer cells fuel growth and energy demands by increasing their NAD⁺ biosynthesis dependency, which therefore represents an exploitable vulnerability for anti-cancer strategies. CD38 is a NAD⁺-degrading enzyme that has become crucial for anti-MM therapies since anti-CD38 monoclonal antibodies represent the [...] Read more.

Cancer cells fuel growth and energy demands by increasing their NAD⁺ biosynthesis dependency, which therefore represents an exploitable vulnerability for anti-cancer strategies. CD38 is a NAD⁺-degrading enzyme that has become crucial for anti-MM therapies since anti-CD38 monoclonal antibodies represent the backbone for treatment of newly diagnosed and relapsed multiple myeloma patients. Nevertheless, further steps are needed to enable a full exploitation of these strategies, including deeper insights of the mechanisms by which CD38 promotes tumorigenesis and its metabolic additions that could be selectively targeted by therapeutic strategies. Here, we present evidence that CD38 upregulation produces a pervasive intracellular-NAD⁺ depletion, which impairs mitochondrial fitness and enhances oxidative stress; as result, genetic or pharmacologic approaches that aim to modify CD38 surface-level prime MM cells to NAD⁺-lowering agents. The molecular mechanism underlying this event is an alteration in mitochondrial dynamics, which decreases mitochondria efficiency and triggers energetic remodeling. Overall, we found that CD38 handling represents an innovative strategy to improve the outcomes of NAD⁺-lowering agents and provides the rationale for testing these very promising agents in clinical studies involving MM patients. Full article

(This article belongs to the Special Issue Oxidative Stress and NRF2 in Health and Disease)

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Review

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27 pages, 2696 KiB

Open AccessReview

The Multifaceted Roles of NRF2 in Cancer: Friend or Foe?

by Christophe Glorieux, Cinthya Enríquez, Constanza González, Gabriela Aguirre-Martínez and Pedro Buc Calderon

Antioxidants 2024, 13(1), 70; https://doi.org/10.3390/antiox13010070 - 2 Jan 2024

Cited by 13 | Viewed by 5799

Abstract

Physiological concentrations of reactive oxygen species (ROS) play vital roles in various normal cellular processes, whereas excessive ROS generation is central to disease pathogenesis. The nuclear factor erythroid 2-related factor 2 (NRF2) is a critical transcription factor that regulates the cellular antioxidant systems [...] Read more.

Physiological concentrations of reactive oxygen species (ROS) play vital roles in various normal cellular processes, whereas excessive ROS generation is central to disease pathogenesis. The nuclear factor erythroid 2-related factor 2 (NRF2) is a critical transcription factor that regulates the cellular antioxidant systems in response to oxidative stress by governing the expression of genes encoding antioxidant enzymes that shield cells from diverse oxidative alterations. NRF2 and its negative regulator Kelch-like ECH-associated protein 1 (KEAP1) have been the focus of numerous investigations in elucidating whether NRF2 suppresses tumor promotion or conversely exerts pro-oncogenic effects. NRF2 has been found to participate in various pathological processes, including dysregulated cell proliferation, metabolic remodeling, and resistance to apoptosis. Herein, this review article will examine the intriguing role of phase separation in activating the NRF2 transcriptional activity and explore the NRF2 dual impacts on tumor immunology, cancer stem cells, metastasis, and long non-coding RNAs (LncRNAs). Taken together, this review aims to discuss the NRF2 multifaceted roles in both cancer prevention and promotion while also addressing the advantages, disadvantages, and limitations associated with modulating NRF2 therapeutically in cancer treatment. Full article

(This article belongs to the Special Issue Oxidative Stress and NRF2 in Health and Disease)

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20 pages, 1513 KiB

Open AccessReview

Targeting Nrf2 Signaling Pathway in Cancer Prevention and Treatment: The Role of Cannabis Compounds

by Anna Rybarczyk, Aleksandra Majchrzak-Celińska and Violetta Krajka-Kuźniak

Antioxidants 2023, 12(12), 2052; https://doi.org/10.3390/antiox12122052 - 28 Nov 2023

Cited by 5 | Viewed by 3051

Abstract

The development and progression of cancer are associated with the dysregulation of multiple pathways involved in cell proliferation and survival, as well as dysfunction in redox balance, immune response, and inflammation. The master antioxidant pathway, known as the nuclear factor erythroid 2-related factor [...] Read more.

The development and progression of cancer are associated with the dysregulation of multiple pathways involved in cell proliferation and survival, as well as dysfunction in redox balance, immune response, and inflammation. The master antioxidant pathway, known as the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, regulates the cellular defense against oxidative stress and inflammation, making it a promising cancer prevention and treatment target. Cannabinoids have demonstrated anti-tumor and anti-inflammatory properties, affecting signaling pathways, including Nrf2. Increased oxidative stress following exposure to anti-cancer therapy prompts cancer cells to activate antioxidant mechanisms. This indicates the dual effect of Nrf2 in cancer cells—influencing proliferation and apoptotic processes and protecting against the toxicity of anti-cancer therapy. Therefore, understanding the complex role of cannabinoids in modulating Nrf2 might shed light on its potential implementation as an anti-cancer support. In this review, we aim to highlight the impact of cannabinoids on Nrf2-related factors, with a focus on cancer prevention and treatment. Additionally, we have presented the results of several research studies that combined cannabidiol (CBD) with other compounds targeting Nrf2. Further studies should be directed toward exploring the anti-inflammatory effects of cannabinoids in the context of cancer prevention and therapy. Full article

(This article belongs to the Special Issue Oxidative Stress and NRF2 in Health and Disease)

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32 pages, 2108 KiB

Open AccessReview

Roles of Oxidative Stress and Nrf2 Signaling in Pathogenic and Non-Pathogenic Cells: A Possible General Mechanism of Resistance to Therapy

by Mira Hammad, Mohammad Raftari, Rute Cesário, Rima Salma, Paulo Godoy, S. Noushin Emami and Siamak Haghdoost

Antioxidants 2023, 12(7), 1371; https://doi.org/10.3390/antiox12071371 - 30 Jun 2023

Cited by 52 | Viewed by 9853

Abstract

The coordinating role of nuclear factor erythroid-2-related factor 2 (Nrf2) in cellular function is undeniable. Evidence indicates that this transcription factor exerts massive regulatory functions in multiple signaling pathways concerning redox homeostasis and xenobiotics, macromolecules, and iron metabolism. Being the master regulator of [...] Read more.

The coordinating role of nuclear factor erythroid-2-related factor 2 (Nrf2) in cellular function is undeniable. Evidence indicates that this transcription factor exerts massive regulatory functions in multiple signaling pathways concerning redox homeostasis and xenobiotics, macromolecules, and iron metabolism. Being the master regulator of antioxidant system, Nrf2 controls cellular fate, influencing cell proliferation, differentiation, apoptosis, resistance to therapy, and senescence processes, as well as infection disease success. Because Nrf2 is the key coordinator of cell defence mechanisms, dysregulation of its signaling has been associated with carcinogenic phenomena and infectious and age-related diseases. Deregulation of this cytoprotective system may also interfere with immune response. Oxidative burst, one of the main microbicidal mechanisms, could be impaired during the initial phagocytosis of pathogens, which could lead to the successful establishment of infection and promote susceptibility to infectious diseases. There is still a knowledge gap to fill regarding the molecular mechanisms by which Nrf2 orchestrates such complex networks involving multiple pathways. This review describes the role of Nrf2 in non-pathogenic and pathogenic cells. Full article

(This article belongs to the Special Issue Oxidative Stress and NRF2 in Health and Disease)

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18 pages, 2146 KiB

Open AccessSystematic Review

Ozone Exposure Controls Oxidative Stress and the Inflammatory Process of Hepatocytes in Murine Models

by Silvania Mol Pelinsari, Mariáurea Matias Sarandy, Emerson Ferreira Vilela, Rômulo Dias Novaes, Jade Schlamb and Reggiani Vilela Gonçalves

Antioxidants 2024, 13(2), 212; https://doi.org/10.3390/antiox13020212 - 8 Feb 2024

Cited by 3 | Viewed by 2241

Abstract

(1) Background: Ozone exposure is a promising tool for treating liver damage since it is known to control the release of free radicals and increase the expression of antioxidant enzymes. The objective is to investigate the main intracellular pathways activated after exposure to [...] Read more.

(1) Background: Ozone exposure is a promising tool for treating liver damage since it is known to control the release of free radicals and increase the expression of antioxidant enzymes. The objective is to investigate the main intracellular pathways activated after exposure to ozone, considering the dosage of antioxidant enzymes and markers of oxidative stress. (2) Methods: This systematic review was performed based on the PRISMA guidelines and using a structured search in MEDLINE (PubMed), Scopus, and Web of Science. Bias analysis and methodological quality assessments were examined using the SYRCLE Risk of Bias tool. (3) Results: Nineteen studies were selected. The results showed that the exposure to ozone has a protective effect on liver tissue, promoting a decrease in inflammatory markers and a reduction in oxidative stress in liver tissue. In addition, ozone exposure also promoted an increase in antioxidant enzymes. The morphological consequences of controlling these intracellular pathways were reducing the tissue inflammatory process and reducing areas of degeneration and necrosis. (4) Conclusions: Ozone exposure has a beneficial effect on models of liver injury through the decrease in oxidative stress in tissue and inflammatory markers. In addition, it regulates the Nrf2/ARE antioxidant pathway and blocks the NF-κB inflammatory pathway. Full article

(This article belongs to the Special Issue Oxidative Stress and NRF2 in Health and Disease)

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23 pages, 1327 KiB

Open AccessSystematic Review

Docosahexaenoic Acid as Master Regulator of Cellular Antioxidant Defenses: A Systematic Review

by Sara Margherita Borgonovi, Stefania Iametti and Mattia Di Nunzio

Antioxidants 2023, 12(6), 1283; https://doi.org/10.3390/antiox12061283 - 15 Jun 2023

Cited by 3 | Viewed by 2397

Abstract

Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid that benefits the prevention of chronic diseases. Due to its high unsaturation, DHA is vulnerable to free radical oxidation, resulting in several unfavorable effects, including producing hazardous metabolites. However, in vitro and in vivo investigations [...] Read more.

Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid that benefits the prevention of chronic diseases. Due to its high unsaturation, DHA is vulnerable to free radical oxidation, resulting in several unfavorable effects, including producing hazardous metabolites. However, in vitro and in vivo investigations suggest that the relationship between the chemical structure of DHA and its susceptibility to oxidation may not be as clear-cut as previously thought. Organisms have developed a balanced system of antioxidants to counteract the overproduction of oxidants, and the nuclear factor erythroid 2-related factor 2 (Nrf2) is the key transcription factor identified for transmitting the inducer signal to the antioxidant response element. Thus, DHA might preserve the cellular redox status promoting the transcriptional regulation of cellular antioxidants through Nrf2 activation. Here, we systematically summarize the research on the possible role of DHA in controlling cellular antioxidant enzymes. After the screening process, 43 records were selected and included in this review. Specifically, 29 studies related to the effects of DHA in cell cultures and 15 studies concerned the effects of consumption or treatment with DHA in animal. Despite DHA’s promising and encouraging effects at modulating the cellular antioxidant response in vitro/in vivo, some differences observed among the reviewed studies may be accounted for by the different experimental conditions adopted, including the time of supplementation/treatment, DHA concentration, and cell culture/tissue model. Moreover, this review offers potential molecular explanations for how DHA controls cellular antioxidant defenses, including involvement of transcription factors and the redox signaling pathway. Full article

(This article belongs to the Special Issue Oxidative Stress and NRF2 in Health and Disease)

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Oxidative Stress and NRF2 in Health and Disease

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