Pub Date : 2025-12-02DOI: 10.1016/j.arres.2025.100146
Ji ZeZhao
Methylglyoxal (MG), a core byproduct of glycolysis, exerts a dual role in cancer via a "dose-dependent hormesis effect". At low concentrations, it promotes tumor proliferation and metastasis by regulating polyamine metabolism, epigenetic modifications, and the immune microenvironment. In contrast, high concentrations of MG trigger tumor cell apoptosis through inducing DNA damage and protein glycation. Unlike traditional reviews that focus solely on "MG toxicity" or "GLO1 as a single target", this review takes "metabolic network-signal crosstalk-cross-disease association" as the core context. It systematically dissects the bidirectional regulatory mechanisms of MG in cancer, highlights emerging pathways such as non-coding RNA-mediated GLO1 regulation, MG-polyamine metabolism crosstalk, and immunometabolic reprogramming, and integrates the MG regulatory network in cross-disease scenarios including diabetes, HIV infection, and occupational exposure. Finally, a "stratified targeting + synergistic intervention" precision therapeutic strategy is proposed, providing a novel perspective for basic research and clinical translation of MG-related cancers.
{"title":"Methylglyoxal in cancer: Bidirectional regulatory networks and precision intervention—From metabolic reprogramming to cross-disease synergistic targeting","authors":"Ji ZeZhao","doi":"10.1016/j.arres.2025.100146","DOIUrl":"10.1016/j.arres.2025.100146","url":null,"abstract":"<div><div>Methylglyoxal (MG), a core byproduct of glycolysis, exerts a dual role in cancer via a \"dose-dependent hormesis effect\". At low concentrations, it promotes tumor proliferation and metastasis by regulating polyamine metabolism, epigenetic modifications, and the immune microenvironment. In contrast, high concentrations of MG trigger tumor cell apoptosis through inducing DNA damage and protein glycation. Unlike traditional reviews that focus solely on \"MG toxicity\" or \"GLO1 as a single target\", this review takes \"metabolic network-signal crosstalk-cross-disease association\" as the core context. It systematically dissects the bidirectional regulatory mechanisms of MG in cancer, highlights emerging pathways such as non-coding RNA-mediated GLO1 regulation, MG-polyamine metabolism crosstalk, and immunometabolic reprogramming, and integrates the MG regulatory network in cross-disease scenarios including diabetes, HIV infection, and occupational exposure. Finally, a \"stratified targeting + synergistic intervention\" precision therapeutic strategy is proposed, providing a novel perspective for basic research and clinical translation of MG-related cancers.</div></div>","PeriodicalId":72106,"journal":{"name":"Advances in redox research : an official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe","volume":"18 ","pages":"Article 100146"},"PeriodicalIF":2.7,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145791803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chronic inflammatory diseases (CIDs) are defined by prolonged inflammation and oxidative stress (OS), both of which are associated with disease progression and consequences. Ozone (O3) therapy is recognized as a promising complementary therapy for regulating OS indicators. The purpose of this systematic review and meta-analysis is to investigate the effect of O3 therapy on OS parameters in patients with CID.
Methods
A comprehensive literature search was conducted across multiple databases, including PubMed, Cochrane Library, Google Scholar, and Scopus, for randomized controlled trials (RCTs) published up to October 2024. Studies were selected if they investigated the effect of ozone therapy on OS parameters, including malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), total hydroperoxides (TH), advanced oxidation protein products (AOPP), and protein peroxidation (PP) in CID patients. Fixed- or Random-effects models were used in the meta-analysis to determine weighted mean differences (WMD) and 95 % confidence intervals (CIs).
Results
12 RCTs with 846 participants included in the current study. Our findings showed that O3 therapy had no significant difference in OS parameters when compared to control groups. According to subgroup analysis, O3 therapy significantly increased SOD activity in patients with T2D (WMD = 7.59, 95 % CI [2.98 to 12.19], I² = 97.75 %, p = <0.001) and arthritis (WMD = 9.21, 95 % CI [6.02 to 12.40], I² = 66.96 %, p = 0.08). In addition, the rectal method showed a statistically significant effect on GPx activity (WMD = 20.00, 95 % CI [0.55 to 39.45], I² = 92.42 %, p = <0.001). O3 therapy also significantly reduced AOPP levels at doses of ≥20 µg/ml and treatment durations of both <30 days (WMD = −5.15, 95 % CI [−7.90 to −2.40], I² = 96.03 %, p = <0.001).
Conclusion
Ozone therapy could improve OS markers in individuals with CIDs, mostly by lowering AOPP and strengthening antioxidant defense systems. More large-scale RCTs are required to validate these outcomes and better comprehend the fundamental mechanisms of action.
{"title":"Effect of ozone therapy on oxidative stress indices in chronic inflammatory diseases: A systematic review and meta-analysis of randomized clinical trials","authors":"Mina Alimohammadi , Seyedeh Mahdieh Khoshnazar , Hamid Khajehpour , Morteza Izadi , Behzad Einollahi , Kiavash Hushmandi","doi":"10.1016/j.arres.2025.100143","DOIUrl":"10.1016/j.arres.2025.100143","url":null,"abstract":"<div><h3>Background</h3><div>Chronic inflammatory diseases (CIDs) are defined by prolonged inflammation and oxidative stress (OS), both of which are associated with disease progression and consequences. Ozone (O<sub>3</sub>) therapy is recognized as a promising complementary therapy for regulating OS indicators. The purpose of this systematic review and meta-analysis is to investigate the effect of O<sub>3</sub> therapy on OS parameters in patients with CID.</div></div><div><h3>Methods</h3><div>A comprehensive literature search was conducted across multiple databases, including PubMed, Cochrane Library, Google Scholar, and Scopus, for randomized controlled trials (RCTs) published up to October 2024. Studies were selected if they investigated the effect of ozone therapy on OS parameters, including malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), total hydroperoxides (TH), advanced oxidation protein products (AOPP), and protein peroxidation (PP) in CID patients. Fixed- or Random-effects models were used in the meta-analysis to determine weighted mean differences (WMD) and 95 % confidence intervals (CIs).</div></div><div><h3>Results</h3><div>12 RCTs with 846 participants included in the current study. Our findings showed that O<sub>3</sub> therapy had no significant difference in OS parameters when compared to control groups. According to subgroup analysis, O<sub>3</sub> therapy significantly increased SOD activity in patients with T2D (WMD = 7.59, 95 % CI [2.98 to 12.19], I² = 97.75 %, <em>p</em> = <0.001) and arthritis (WMD = 9.21, 95 % CI [6.02 to 12.40], I² = 66.96 %, <em>p</em> = 0.08). In addition, the rectal method showed a statistically significant effect on GPx activity (WMD = 20.00, 95 % CI [0.55 to 39.45], I² = 92.42 %, <em>p</em> = <0.001). O<sub>3</sub> therapy also significantly reduced AOPP levels at doses of ≥20 µg/ml and treatment durations of both <30 days (WMD = −5.15, 95 % CI [−7.90 to −2.40], I² = 96.03 %, <em>p</em> = <0.001).</div></div><div><h3>Conclusion</h3><div>Ozone therapy could improve OS markers in individuals with CIDs, mostly by lowering AOPP and strengthening antioxidant defense systems. More large-scale RCTs are required to validate these outcomes and better comprehend the fundamental mechanisms of action.</div></div>","PeriodicalId":72106,"journal":{"name":"Advances in redox research : an official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe","volume":"17 ","pages":"Article 100143"},"PeriodicalIF":2.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145693687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.arres.2025.100144
Zachery R. Jarrell, Ho Young Lee, Choon-Myung Lee, Michael L. Orr, Dean P. Jones, Young-Mi Go
Biological systems have evolved highly regulated systems to ensure homeostatic levels of trace minerals, such as selenium (Se), which are important to metabolic function and signaling. Much of the understanding of these systems is limited to endogenous proteins and small molecules used for trafficking of minerals. Phytochelatins, a class of plant-derived metal chelating peptides with the general structure, (γ-Glu-Cys)n-Gly, are ubiquitous in the diet and were recently found associated with Se and other metals in human urine. These findings suggest that diet-derived phytochelatins could influence metal homeostasis alongside known endogenous metal-binding compounds. In the present study, we investigated the impact of long-term, oral phytochelatin supplementation on metal homeostasis in a murine model. Phytochelatin supplementation increased Se, zinc and cobalt in the liver and increased urinary Se. Integrative analysis of liver metal profiles with untargeted, high-resolution liver metabolomics revealed dynamic metallome interaction with lipid and carbohydrate metabolism. These results highlight an active role of dietary phytochelatins in modulating mammalian metal homeostasis and associated metabolism. Such dietary components could play a pivotal role in regulating trace metal homeostasis and metal-driven pathophysiology.
{"title":"Dietary metal chelator, phytochelatin 2, increases selenium and alters metal homeostasis and associated lipid metabolism in the liver","authors":"Zachery R. Jarrell, Ho Young Lee, Choon-Myung Lee, Michael L. Orr, Dean P. Jones, Young-Mi Go","doi":"10.1016/j.arres.2025.100144","DOIUrl":"10.1016/j.arres.2025.100144","url":null,"abstract":"<div><div>Biological systems have evolved highly regulated systems to ensure homeostatic levels of trace minerals, such as selenium (Se), which are important to metabolic function and signaling. Much of the understanding of these systems is limited to endogenous proteins and small molecules used for trafficking of minerals. Phytochelatins, a class of plant-derived metal chelating peptides with the general structure, (γ-Glu-Cys)<sub>n</sub>-Gly, are ubiquitous in the diet and were recently found associated with Se and other metals in human urine. These findings suggest that diet-derived phytochelatins could influence metal homeostasis alongside known endogenous metal-binding compounds. In the present study, we investigated the impact of long-term, oral phytochelatin supplementation on metal homeostasis in a murine model. Phytochelatin supplementation increased Se, zinc and cobalt in the liver and increased urinary Se. Integrative analysis of liver metal profiles with untargeted, high-resolution liver metabolomics revealed dynamic metallome interaction with lipid and carbohydrate metabolism. These results highlight an active role of dietary phytochelatins in modulating mammalian metal homeostasis and associated metabolism. Such dietary components could play a pivotal role in regulating trace metal homeostasis and metal-driven pathophysiology.</div></div>","PeriodicalId":72106,"journal":{"name":"Advances in redox research : an official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe","volume":"17 ","pages":"Article 100144"},"PeriodicalIF":2.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145624034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.arres.2025.100142
Nazmun Nahar , Md. Shihab Uddin Sohag
Mitochondria, a crucial subcellular organelle, serve as the primary generator of reactive oxygen species (producing around 90 % of total ROS), utilizing over 98 % of cellular oxygen for ATP synthesis while converting 1–2 % into ROS. Excess reactive oxygen species disrupt redox homeostasis, inducing oxidative stress, resulting in mitochondrial dysfunction and damage. Furthermore, defective or impaired mitochondria might intensify ROS production. This "necessary evil" serves dual functions: regulating signaling, apoptosis, proliferation, differentiation, autophagy, and immunological responses while simultaneously inflicting oxidative damage on lipids, proteins, and DNA, hence contributing to numerous diseases. Thus, the targeted suppression of mitochondrial ROS-induced oxidative damage and dysfunction by mitochondria-targeted antioxidants (MTAs) represents a precise therapeutic strategy that has attracted growing interest and offers substantial opportunities for clinical application by directly alleviating oxidative stress at its origin within affected cells. Lipophilic cation-linked MTAs, amino acid- and peptide-based MTAs, metallo-complex-based MTAs, and nanoparticle-based MTAs (Nano-MTAs) can selectively localize to mitochondria and diminish excessive mitochondrial ROS. Incorporating these MTAs into precision medicine facilitates tailored therapies based on individual mitochondrial dysfunction characteristics and disease-specific redox imbalances. This review classifies current mitochondria-targeted antioxidants according to the characteristics of their targeting moieties and examines their composition and antioxidant efficacy. We also evaluate nanoparticle-based MTAs, including liposomes, DQAsomes, solid lipid nanoparticles, MITO-Porters, micelles, dendrimers, nanoemulsions, metal nanoparticles, quantum dots, and nanopolyplexes. Furthermore, we summarize recent experimental findings regarding MTAs across diverse disease models including cancer, neurological disorders (e.g., Alzheimer’s, Huntington’s, Parkinson’s, ataxia, TBI, and epilepsy); cardiovascular diseases; asthma; COPD; auditory impairments; diabetic complications; ocular, renal, hepatic, and inflammatory disorders; sepsis; infertility; aging-longevity; and their potential as antibiotics to clarify the evidence supporting their therapeutic efficacy.
{"title":"Advancements in mitochondrial-targeted antioxidants: Organelle-specific drug delivery for disease management","authors":"Nazmun Nahar , Md. Shihab Uddin Sohag","doi":"10.1016/j.arres.2025.100142","DOIUrl":"10.1016/j.arres.2025.100142","url":null,"abstract":"<div><div>Mitochondria, a crucial subcellular organelle, serve as the primary generator of reactive oxygen species (producing around 90 % of total ROS), utilizing over 98 % of cellular oxygen for ATP synthesis while converting 1–2 % into ROS. Excess reactive oxygen species disrupt redox homeostasis, inducing oxidative stress, resulting in mitochondrial dysfunction and damage. Furthermore, defective or impaired mitochondria might intensify ROS production. This \"necessary evil\" serves dual functions: regulating signaling, apoptosis, proliferation, differentiation, autophagy, and immunological responses while simultaneously inflicting oxidative damage on lipids, proteins, and DNA, hence contributing to numerous diseases. Thus, the targeted suppression of mitochondrial ROS-induced oxidative damage and dysfunction by mitochondria-targeted antioxidants (MTAs) represents a precise therapeutic strategy that has attracted growing interest and offers substantial opportunities for clinical application by directly alleviating oxidative stress at its origin within affected cells. Lipophilic cation-linked MTAs, amino acid- and peptide-based MTAs, metallo-complex-based MTAs, and nanoparticle-based MTAs (Nano-MTAs) can selectively localize to mitochondria and diminish excessive mitochondrial ROS. Incorporating these MTAs into precision medicine facilitates tailored therapies based on individual mitochondrial dysfunction characteristics and disease-specific redox imbalances. This review classifies current mitochondria-targeted antioxidants according to the characteristics of their targeting moieties and examines their composition and antioxidant efficacy. We also evaluate nanoparticle-based MTAs, including liposomes, DQAsomes, solid lipid nanoparticles, MITO-Porters, micelles, dendrimers, nanoemulsions, metal nanoparticles, quantum dots, and nanopolyplexes. Furthermore, we summarize recent experimental findings regarding MTAs across diverse disease models including cancer, neurological disorders (e.g., Alzheimer’s, Huntington’s, Parkinson’s, ataxia, TBI, and epilepsy); cardiovascular diseases; asthma; COPD; auditory impairments; diabetic complications; ocular, renal, hepatic, and inflammatory disorders; sepsis; infertility; aging-longevity; and their potential as antibiotics to clarify the evidence supporting their therapeutic efficacy.</div></div>","PeriodicalId":72106,"journal":{"name":"Advances in redox research : an official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe","volume":"17 ","pages":"Article 100142"},"PeriodicalIF":2.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145624035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-26DOI: 10.1016/j.arres.2025.100145
Ahmed Abdulrazzaq Bapir , Burhan Ahmed Salih , Goran Othman
Background
Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder characterized by chronic hyperglycemia, oxidative stress, and low-grade inflammation. The CYP8B1 gene, a key regulator of bile acid synthesis and hepatic metabolism, may be influenced by oxidative status and has emerged as a potential contributor to T2DM pathogenesis. This study examined the association between CYP8B1 rs3732860 polymorphism, gene expression levels, and various biochemical and oxidative stress markers in individuals with T2DM.
Methods
A total of 198 subjects (132 T2DM patients and 66 healthy controls) were genotyped for the CYP8B1 rs3732860 variant. Biochemical parameters including HbA1c, glutathione peroxidase (GPX), catalase, malondialdehyde (MDA), superoxide dismutase (SOD), interleukin-10 (IL-10), interferon-gamma (IFN-γ), and nitric oxide (NO) were measured. CYP8B1 expression was assessed using qPCR (ΔCt values). Statistical analyses included logistic regression, chi-square, ANOVA, and ROC curve analysis.
Results
The TC genotype was significantly associated with increased T2DM risk (OR = 4.51, 95 % CI: 1.85–11.01, p = 0.001), while the CC genotype showed a non-significant trend (OR = 2.25, p = 0.078). CYP8B1 expression differed significantly among genotypes (p < 0.001), with highest expression in CC carriers. MDA levels also varied by genotype (p = 0.001), suggesting a link between oxidative stress and gene regulation. ROC analysis identified catalase (AUC = 0.909) and SOD (AUC = 0.764) as strong predictors of T2DM.
Conclusion
The CYP8B1 rs3732860 polymorphism is associated with altered gene expression and oxidative stress in T2DM, highlighting its potential role as a metabolic regulator and biomarker of disease susceptibility.
{"title":"Association of CYP8B1 rs3732860 polymorphism and gene expression with oxidative stress and biochemical markers in Type 2 diabetes mellitus","authors":"Ahmed Abdulrazzaq Bapir , Burhan Ahmed Salih , Goran Othman","doi":"10.1016/j.arres.2025.100145","DOIUrl":"10.1016/j.arres.2025.100145","url":null,"abstract":"<div><h3>Background</h3><div>Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder characterized by chronic hyperglycemia, oxidative stress, and low-grade inflammation. The CYP8B1 gene, a key regulator of bile acid synthesis and hepatic metabolism, may be influenced by oxidative status and has emerged as a potential contributor to T2DM pathogenesis. This study examined the association between CYP8B1 rs3732860 polymorphism, gene expression levels, and various biochemical and oxidative stress markers in individuals with T2DM.</div></div><div><h3>Methods</h3><div>A total of 198 subjects (132 T2DM patients and 66 healthy controls) were genotyped for the CYP8B1 rs3732860 variant. Biochemical parameters including HbA1c, glutathione peroxidase (GPX), catalase, malondialdehyde (MDA), superoxide dismutase (SOD), interleukin-10 (IL-10), interferon-gamma (IFN-γ), and nitric oxide (NO) were measured. CYP8B1 expression was assessed using qPCR (ΔCt values). Statistical analyses included logistic regression, chi-square, ANOVA, and ROC curve analysis.</div></div><div><h3>Results</h3><div>The TC genotype was significantly associated with increased T2DM risk (OR = 4.51, 95 % CI: 1.85–11.01, <em>p</em> = 0.001), while the CC genotype showed a non-significant trend (OR = 2.25, <em>p</em> = 0.078). CYP8B1 expression differed significantly among genotypes (<em>p</em> < 0.001), with highest expression in CC carriers. MDA levels also varied by genotype (<em>p</em> = 0.001), suggesting a link between oxidative stress and gene regulation. ROC analysis identified catalase (AUC = 0.909) and SOD (AUC = 0.764) as strong predictors of T2DM.</div></div><div><h3>Conclusion</h3><div>The CYP8B1 rs3732860 polymorphism is associated with altered gene expression and oxidative stress in T2DM, highlighting its potential role as a metabolic regulator and biomarker of disease susceptibility.</div></div>","PeriodicalId":72106,"journal":{"name":"Advances in redox research : an official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe","volume":"18 ","pages":"Article 100145"},"PeriodicalIF":2.7,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145694906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 10.1016/j.arres.2025.100141
Amal Taher Elhaw , Priscilla W. Tang , Shriya Kamlapurkar , Sarah Al-Saad , Sneha Srinivasan , Danyang Li , George C. Tseng , Adam C. Straub , Nadine Hempel
During metastatic spread, tumor cells adapt to evade anchorage-independent cell death by upregulating mitochondrial antioxidant systems. We previously showed that ovarian cancer cells upregulate mitochondrial manganese superoxide dismutase (SOD2) following detachment and multicellular aggregate (MCA) formation. SOD2 scavenges mitochondrial superoxide and manipulates cellular hydrogen peroxide levels, both functions necessary for metastasis. Here, we investigated SOD2′s metastatic function by assessing its transcriptomic effects in OVCA433 ovarian cancer cells cultured in low-attachment conditions that induce MCAs, mimicking anchorage-independent states in malignant ascites. SOD2 siRNA-mediated knockdown effects in MCAs were compared to adherent culture conditions. RNA sequencing and pathway analysis revealed that SOD2 lies upstream of pro-metastatic pathways, including PI3K/AKT signaling. Notably, in MCAs, cytokine and immune cell signaling pathways were more significantly enriched following SOD2 knockdown. We previously identified SIRT3 as an important SOD2 activity regulator in MCAs. While SIRT3 knockdown resulted in minor transcriptional changes, we identified that FOXO3 and ELF4 transcription factors, important for stress response and immune regulation, are downregulated by both SIRT3 and SOD2 knockdown. Comparing SOD2 knockdown transcriptional changes to the Cancer Genome Atlas, we found SOD2 expression strongly associates with pro-tumorigenic immune signaling in serous ovarian cancer specimens, including genes identified downstream of SOD2 from our siRNA screen. Moreover, SOD2 expression correlated with signatures related to pro-tumorigenic neutrophil and T-regulatory cell populations. Our data suggest SOD2 positively regulates pro-metastatic pathways, and those identified in MCAs more closely reflect gene expression profiles associated with SOD2 expression in patient tumors.
{"title":"Mapping transcriptomic signatures downstream of mitochondrial superoxide dismutase SOD2 in OVCA433 multicellular aggregates","authors":"Amal Taher Elhaw , Priscilla W. Tang , Shriya Kamlapurkar , Sarah Al-Saad , Sneha Srinivasan , Danyang Li , George C. Tseng , Adam C. Straub , Nadine Hempel","doi":"10.1016/j.arres.2025.100141","DOIUrl":"10.1016/j.arres.2025.100141","url":null,"abstract":"<div><div>During metastatic spread, tumor cells adapt to evade anchorage-independent cell death by upregulating mitochondrial antioxidant systems. We previously showed that ovarian cancer cells upregulate mitochondrial manganese superoxide dismutase (SOD2) following detachment and multicellular aggregate (MCA) formation. SOD2 scavenges mitochondrial superoxide and manipulates cellular hydrogen peroxide levels, both functions necessary for metastasis. Here, we investigated SOD2′s metastatic function by assessing its transcriptomic effects in OVCA433 ovarian cancer cells cultured in low-attachment conditions that induce MCAs, mimicking anchorage-independent states in malignant ascites. SOD2 siRNA-mediated knockdown effects in MCAs were compared to adherent culture conditions. RNA sequencing and pathway analysis revealed that SOD2 lies upstream of pro-metastatic pathways, including PI3K/AKT signaling. Notably, in MCAs, cytokine and immune cell signaling pathways were more significantly enriched following SOD2 knockdown. We previously identified SIRT3 as an important SOD2 activity regulator in MCAs. While SIRT3 knockdown resulted in minor transcriptional changes, we identified that FOXO3 and ELF4 transcription factors, important for stress response and immune regulation, are downregulated by both SIRT3 and SOD2 knockdown. Comparing SOD2 knockdown transcriptional changes to the Cancer Genome Atlas, we found SOD2 expression strongly associates with pro-tumorigenic immune signaling in serous ovarian cancer specimens, including genes identified downstream of SOD2 from our siRNA screen. Moreover, SOD2 expression correlated with signatures related to pro-tumorigenic neutrophil and T-regulatory cell populations. Our data suggest SOD2 positively regulates pro-metastatic pathways, and those identified in MCAs more closely reflect gene expression profiles associated with SOD2 expression in patient tumors.</div></div>","PeriodicalId":72106,"journal":{"name":"Advances in redox research : an official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe","volume":"17 ","pages":"Article 100141"},"PeriodicalIF":2.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145528713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-27DOI: 10.1016/j.arres.2025.100140
Thiago S. Freire, Milena S. Martins, Nadja C. de Souza-Pinto
Ebselen is a small organic molecule developed as a mimetic of the antioxidant enzyme GPx. Ebselen has been extensively studied in cellular models, animals and is now in clinical trials to treat several pathological conditions in which oxidative stress is the predominant factor. Many of the positive results of ebselen treatment have been attributed to its role as a direct antioxidant. However, there is evidence of cytotoxic activity of ebselen, mostly explored in cancer cells, bacteria and fungi. Based on previous results and ongoing research, our mechanistic proposal is that at low doses ebselen behaves as a hormetic compound via its GPx mimetic activity, initially depleting reduced GSH levels, creating a redox stress that leads to an adaptive response orchestrated by NRF-2. The net result would be a more robust antioxidant profile, hence the protective effect. On the other hand, at high doses, the redox stress exceeds the cellular adaptive capacity and leads to apoptosis, probably via the mitochondrial pathway. Thus, our mechanistic proposal has the potential to reconcile several results present in the literature that often seem contradictory. Since ebselen is currently being tested in several phase 1, phase 2 and phase 3 clinical trials, in addition to having already shown positive clinical results, our mechanistic proposal has the potential to provide support for the development of treatment protocols that are more effective in the pathological conditions that can benefit from the effects promoted ebselen’s hormetic effect.
{"title":"Hormetic mechanism of ebselen: A general mechanistic hypothesis","authors":"Thiago S. Freire, Milena S. Martins, Nadja C. de Souza-Pinto","doi":"10.1016/j.arres.2025.100140","DOIUrl":"10.1016/j.arres.2025.100140","url":null,"abstract":"<div><div>Ebselen is a small organic molecule developed as a mimetic of the antioxidant enzyme GPx. Ebselen has been extensively studied in cellular models, animals and is now in clinical trials to treat several pathological conditions in which oxidative stress is the predominant factor. Many of the positive results of ebselen treatment have been attributed to its role as a direct antioxidant. However, there is evidence of cytotoxic activity of ebselen, mostly explored in cancer cells, bacteria and fungi. Based on previous results and ongoing research, our mechanistic proposal is that at low doses ebselen behaves as a hormetic compound via its GPx mimetic activity, initially depleting reduced GSH levels, creating a redox stress that leads to an adaptive response orchestrated by NRF-2. The net result would be a more robust antioxidant profile, hence the protective effect. On the other hand, at high doses, the redox stress exceeds the cellular adaptive capacity and leads to apoptosis, probably via the mitochondrial pathway. Thus, our mechanistic proposal has the potential to reconcile several results present in the literature that often seem contradictory. Since ebselen is currently being tested in several phase 1, phase 2 and phase 3 clinical trials, in addition to having already shown positive clinical results, our mechanistic proposal has the potential to provide support for the development of treatment protocols that are more effective in the pathological conditions that can benefit from the effects promoted ebselen’s hormetic effect.</div></div>","PeriodicalId":72106,"journal":{"name":"Advances in redox research : an official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe","volume":"17 ","pages":"Article 100140"},"PeriodicalIF":2.7,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145474360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-26DOI: 10.1016/j.arres.2025.100139
Ryan Sasse
Tumors characterized by a prominent desmoplastic stroma – including pancreatic ductal adenocarcinoma, the desmoplastic melanoma subtype, and a subset of triple-negative breast cancer feature a dense, collagen-rich stroma that impairs drug penetration, skews myeloid cellular function, and either excludes, permits, or exhausts effective lymphocyte function. Nitric oxide sits at the center of this microenvironmental interchange. To delineate nitric oxide’s dual functions, this study surveyed mechanistic and translational studies on NO signaling in fibrotic tumor microenvironments indexed in PubMed and Web of Science through 2025. In pancreatic ductal adenocarcinoma, chronic inducible nitric oxide synthase activity within cancer-associated fibroblasts, tumor cells, and myeloid-derived suppressor cells stabilizes HIF-1α, drives PD-L1 expression, and reinforces a self-perpetuating loop of T-cell dysfunction. In desmoplastic melanoma, sustained nitric oxide flux may converge on JNK and PI3K/Akt dependent PD-L1 upregulation, fostering adaptive resistance. In triple negative breast cancer, Roughly 34 % develop a fibrotic stroma where inducible nitric oxide synthase overexpression predicts poor survival. This poor survival is reflected in the highly fibrotic, immune-excluded milieu of TNBC with high TGF-β and HIF-1α activity. Like PDAC, sustained nitric oxide flux further stabilizes HIF-1α, amplifying hypoxia responsive gene programs and reinforcing stromal fibrosis. Collectively, these findings reveal a concentration, isoform, and context-specific spectrum of nitric oxide activity: pathologic high output inducible nitric oxide synthase-derived flux promotes immunosuppression and metastasis, whereas basal or controlled nitric oxide levels supports vascular integrity and, in some contexts, antitumor immunity. Therapeutically, a multifaceted approach combining inducible nitric oxide inhibition, calibrated nitric oxide donors, myeloid-derived suppressor cell inhibition, and tumor associated macrophage repolarization with immune checkpoint inhibitors offers a precision framework to dismantle fibrotic stromal barriers and convert immune-cold desmoplastic cancers into responsive disease.
以显著的间质增生为特征的肿瘤，包括胰腺导管腺癌、间质增生黑色素瘤亚型和三阴性乳腺癌的一个亚群，其特征是致密、富含胶原的间质损害药物渗透，扭曲髓细胞功能，排除、允许或耗尽有效淋巴细胞功能。一氧化氮位于这个微环境交换的中心。为了描述一氧化氮的双重功能，本研究调查了截至2025年PubMed和Web of Science收录的纤维化肿瘤微环境中NO信号传导的机制和转化研究。在胰腺导管腺癌中，癌症相关成纤维细胞、肿瘤细胞和髓源性抑制细胞中的慢性诱导型一氧化氮合酶活性稳定HIF-1α，驱动PD-L1表达，并加强t细胞功能障碍的自我延续循环。在粘连性黑色素瘤中，持续的一氧化氮通量可能会聚在JNK和PI3K/Akt依赖的PD-L1上调上，从而促进适应性抵抗。在三阴性乳腺癌中，大约34%的患者发展为纤维化基质，诱导型一氧化氮合酶过表达预示着较差的生存率。这种低生存率反映在TNBC高度纤维化，免疫排斥的环境中，具有高TGF-β和HIF-1α活性。与PDAC一样，持续的一氧化氮通量进一步稳定了HIF-1α，放大了缺氧反应基因程序并加强了间质纤维化。总的来说，这些发现揭示了一氧化氮活性的浓度、异构体和环境特异性谱：病理性高输出诱导型一氧化氮合酶衍生的通量促进免疫抑制和转移，而基础或控制的一氧化氮水平支持血管完整性，并在某些情况下支持抗肿瘤免疫。在治疗上，结合诱导型一氧化氮抑制、校准型一氧化氮供体、髓源性抑制细胞抑制和肿瘤相关巨噬细胞复极化与免疫检查点抑制剂的多方面方法，提供了一个精确的框架来拆除纤维化间质屏障，并将免疫冷性结缔组织增生癌转化为反应性疾病。
{"title":"The immunologic and stromal functions of nitric oxide in fibrotic tumor microenvironments: A mini-review","authors":"Ryan Sasse","doi":"10.1016/j.arres.2025.100139","DOIUrl":"10.1016/j.arres.2025.100139","url":null,"abstract":"<div><div>Tumors characterized by a prominent desmoplastic stroma – including pancreatic ductal adenocarcinoma, the desmoplastic melanoma subtype, and a subset of triple-negative breast cancer feature a dense, collagen-rich stroma that impairs drug penetration, skews myeloid cellular function, and either excludes, permits, or exhausts effective lymphocyte function. Nitric oxide sits at the center of this microenvironmental interchange. To delineate nitric oxide’s dual functions, this study surveyed mechanistic and translational studies on NO signaling in fibrotic tumor microenvironments indexed in PubMed and Web of Science through 2025. In pancreatic ductal adenocarcinoma, chronic inducible nitric oxide synthase activity within cancer-associated fibroblasts, tumor cells, and myeloid-derived suppressor cells stabilizes HIF-1α, drives PD-L1 expression, and reinforces a self-perpetuating loop of T-cell dysfunction. In desmoplastic melanoma, sustained nitric oxide flux may converge on JNK and PI3K/Akt dependent PD-L1 upregulation, fostering adaptive resistance. In triple negative breast cancer, Roughly 34 % develop a fibrotic stroma where inducible nitric oxide synthase overexpression predicts poor survival. This poor survival is reflected in the highly fibrotic, immune-excluded milieu of TNBC with high TGF-β and HIF-1α activity. Like PDAC, sustained nitric oxide flux further stabilizes HIF-1α, amplifying hypoxia responsive gene programs and reinforcing stromal fibrosis. Collectively, these findings reveal a concentration, isoform, and context-specific spectrum of nitric oxide activity: pathologic high output inducible nitric oxide synthase-derived flux promotes immunosuppression and metastasis, whereas basal or controlled nitric oxide levels supports vascular integrity and, in some contexts, antitumor immunity. Therapeutically, a multifaceted approach combining inducible nitric oxide inhibition, calibrated nitric oxide donors, myeloid-derived suppressor cell inhibition, and tumor associated macrophage repolarization with immune checkpoint inhibitors offers a precision framework to dismantle fibrotic stromal barriers and convert immune-cold desmoplastic cancers into responsive disease.</div></div>","PeriodicalId":72106,"journal":{"name":"Advances in redox research : an official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe","volume":"17 ","pages":"Article 100139"},"PeriodicalIF":2.7,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-29DOI: 10.1016/j.arres.2025.100138
Muhammad Khan , Maida Mushtaq , Muhammad Usman , Muhammad Aziz Ur Rahman , Guobo Quan
Oxidative stress, resulting from an imbalance between reactive oxygen species (ROS) and antioxidant defenses, impairs animal health, immunity, reproduction, and productivity. This review summarizes the roles of key dietary antioxidants vitamin A, melatonin, essential trace minerals (copper, zinc, magnesium), flavonoids, polyphenols, and L-carnitine, in mitigating oxidative stress in farm animals. Vitamin A supports epithelial integrity, scavenges ROS, and upregulates antioxidant enzymes via redox-sensitive transcription factors. Melatonin functions as a potent free radical scavenger and activates the Nrf2 pathway to enhance antioxidant enzyme expression. Copper, zinc, and magnesium act as cofactors for enzymatic antioxidants such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), helping maintain redox homeostasis. Flavonoids and polyphenols, including quercetin, curcumin, and EGCG, exert antioxidant effects by scavenging ROS, chelating metal ions, and enhancing endogenous defense pathways. L-carnitine improves mitochondrial function, reduces ROS generation, and enhances glutathione activity, especially during stress conditions such as heat, transport, or weaning. Supplementation with these compounds across species has been shown to increase antioxidant enzyme activity, reduce oxidative biomarkers like malondialdehyde (MDA), and improve immunity, metabolic efficiency, and performance. These natural or synthetic antioxidants offer promising nutritional strategies to improve oxidative stability, health, and productivity in farm animals. Their integration into feed programs provides a sustainable and cost-effective approach to improving animal welfare and resilience under intensive production systems.
{"title":"Oxidative stress-induced cytotoxicity and the role of dietary antioxidants in farm animals: A review","authors":"Muhammad Khan , Maida Mushtaq , Muhammad Usman , Muhammad Aziz Ur Rahman , Guobo Quan","doi":"10.1016/j.arres.2025.100138","DOIUrl":"10.1016/j.arres.2025.100138","url":null,"abstract":"<div><div>Oxidative stress, resulting from an imbalance between reactive oxygen species (ROS) and antioxidant defenses, impairs animal health, immunity, reproduction, and productivity. This review summarizes the roles of key dietary antioxidants vitamin A, melatonin, essential trace minerals (copper, zinc, magnesium), flavonoids, polyphenols, and L-carnitine, in mitigating oxidative stress in farm animals. Vitamin A supports epithelial integrity, scavenges ROS, and upregulates antioxidant enzymes via redox-sensitive transcription factors. Melatonin functions as a potent free radical scavenger and activates the Nrf2 pathway to enhance antioxidant enzyme expression. Copper, zinc, and magnesium act as cofactors for enzymatic antioxidants such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), helping maintain redox homeostasis. Flavonoids and polyphenols, including quercetin, curcumin, and EGCG, exert antioxidant effects by scavenging ROS, chelating metal ions, and enhancing endogenous defense pathways. L-carnitine improves mitochondrial function, reduces ROS generation, and enhances glutathione activity, especially during stress conditions such as heat, transport, or weaning. Supplementation with these compounds across species has been shown to increase antioxidant enzyme activity, reduce oxidative biomarkers like malondialdehyde (MDA), and improve immunity, metabolic efficiency, and performance. These natural or synthetic antioxidants offer promising nutritional strategies to improve oxidative stability, health, and productivity in farm animals. Their integration into feed programs provides a sustainable and cost-effective approach to improving animal welfare and resilience under intensive production systems.</div></div>","PeriodicalId":72106,"journal":{"name":"Advances in redox research : an official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe","volume":"16 ","pages":"Article 100138"},"PeriodicalIF":2.7,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144748957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Endovascular treatment (EVT) is an effective therapeutic option for patients with peripheral artery disease (PAD). However, EVT is associated with inflammatory adverse effects, and the systemic oxidative status after EVT remains unclear. In this pilot study, we compared the activity of leukocytes derived from circulating blood before and immediately after (within 1 h of) EVT in 30 cases with PAD. The ankle-brachial index (ABI) improved immediately after EVT (p < 0.001), suggesting successful revascularization. The levels of leukocyte-produced superoxide radicals (O2•−) increased (p < 0.05), those of hypochlorite ions (OCl−) remained unchanged, and the OCl−/O2•− levels reduced (p < 0.001) immediately after EVT. We observed two subtypes of alterations in leukocyte activity immediately after EVT: type A exhibiting increased levels of both O2•− and OCl−, and type B showing increased O2•− levels, while relatively small changes in OCl− levels. In addition, the interleukin-6 levels increased (p < 0.05) immediately after EVT. Moreover, EVT increased the leukocyte count (p < 0.001) and dynamically changed the balance of leukocyte components, with a notable increase in the neutrophil percentage. These findings and results of our correlation analyses imply that inflammatory response and/or ischemia–reperfusion potentially alters O2•−production by leukocytes. This study contributes to the understanding of the pathophysiology of EVT-associated systemic oxidative events, which includes vascular inflammation and ischemia–reperfusion injury. The findings can support further development of diagnostic and therapeutic strategies for the health conditions after EVT.
{"title":"Altered activity of leukocytes derived from circulating blood immediately after revascularization in peripheral artery disease","authors":"Kozo Takeuchi , Kimiko Kazumura , Akihiro Yoshida , Tappei Furuta , Kazunori Hayashi , Masashi Nagai , Yukiko Hatano , Michitaka Naito , Etsushi Matsushita","doi":"10.1016/j.arres.2025.100137","DOIUrl":"10.1016/j.arres.2025.100137","url":null,"abstract":"<div><div>Endovascular treatment (EVT) is an effective therapeutic option for patients with peripheral artery disease (PAD). However, EVT is associated with inflammatory adverse effects, and the systemic oxidative status after EVT remains unclear. In this pilot study, we compared the activity of leukocytes derived from circulating blood before and immediately after (within 1 h of) EVT in 30 cases with PAD. The ankle-brachial index (ABI) improved immediately after EVT (<em>p</em> < 0.001), suggesting successful revascularization. The levels of leukocyte-produced superoxide radicals (O<sub>2</sub><sup>•−</sup>) increased (<em>p</em> < 0.05), those of hypochlorite ions (OCl<sup>−</sup>) remained unchanged, and the OCl<sup>−</sup>/O<sub>2</sub><sup>•−</sup> levels reduced (<em>p</em> < 0.001) immediately after EVT. We observed two subtypes of alterations in leukocyte activity immediately after EVT: type A exhibiting increased levels of both O<sub>2</sub><sup>•−</sup> and OCl<sup>−</sup>, and type B showing increased O<sub>2</sub><sup>•−</sup> levels, while relatively small changes in OCl<sup>−</sup> levels. In addition, the interleukin-6 levels increased (<em>p</em> < 0.05) immediately after EVT. Moreover, EVT increased the leukocyte count (<em>p</em> < 0.001) and dynamically changed the balance of leukocyte components, with a notable increase in the neutrophil percentage. These findings and results of our correlation analyses imply that inflammatory response and/or ischemia–reperfusion potentially alters O<sub>2</sub><sup>•−</sup>production by leukocytes. This study contributes to the understanding of the pathophysiology of EVT-associated systemic oxidative events, which includes vascular inflammation and ischemia–reperfusion injury. The findings can support further development of diagnostic and therapeutic strategies for the health conditions after EVT.</div></div>","PeriodicalId":72106,"journal":{"name":"Advances in redox research : an official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe","volume":"16 ","pages":"Article 100137"},"PeriodicalIF":0.0,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144534320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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