Cold atmospheric plasma (CAP) generates reactive species at low temperatures, and it has shown promise in oncology, wound healing, and regenerative medicine. Therapeutic mechanisms and translational potential remain unclear across a wide range of biological applications. In this article, a comprehensive assessment of mechanistic, preclinical, and emerging clinical evidence was performed, with a particular emphasis on CAP-mediated biochemical pathways and therapeutic outcomes, focusing on reproducible, mechanism-based studies. CAP modulates apoptosis, immune responses, microbial inactivation, and tissue repair through redox-driven pathways. CAP is selectively cytotoxic toward tumor cells, accelerates wound closure by enhancing angiogenesis and collagen remodeling, and reduces inflammatory signaling in dermatological disorders. CAP has also been shown to modulate cell metabolism and differentiation, enabling applications in tissue engineering and cancer treatment through controlled drug delivery. By integrating CAP with artificial intelligence-guided treatment planning, precision dosing and personalized treatment can be further enhanced. Collectively, current evidence suggests that CAP represents a promising non-invasive therapeutic approach with effects that extend beyond superficial tissue interactions, indicating its potential for applications across a wide range of medical fields. This review identifies CAP-driven biochemical and therapeutic processes and enhances understanding of targeted, multimodal interventions in oncology, wound healing and regenerative medicine.
{"title":"Mechanisms, challenges, and translational perspectives of cold atmospheric plasma in cancer and wound healing","authors":"Samaneh Hashemi , Mahboubeh Sadeghi , Amir Savardashtaki , Abolfazl Mazandarani , Abozar Ghorbani","doi":"10.1016/j.arres.2026.100159","DOIUrl":"10.1016/j.arres.2026.100159","url":null,"abstract":"<div><div>Cold atmospheric plasma (CAP) generates reactive species at low temperatures, and it has shown promise in oncology, wound healing, and regenerative medicine. Therapeutic mechanisms and translational potential remain unclear across a wide range of biological applications. In this article, a comprehensive assessment of mechanistic, preclinical, and emerging clinical evidence was performed, with a particular emphasis on CAP-mediated biochemical pathways and therapeutic outcomes, focusing on reproducible, mechanism-based studies. CAP modulates apoptosis, immune responses, microbial inactivation, and tissue repair through redox-driven pathways. CAP is selectively cytotoxic toward tumor cells, accelerates wound closure by enhancing angiogenesis and collagen remodeling, and reduces inflammatory signaling in dermatological disorders. CAP has also been shown to modulate cell metabolism and differentiation, enabling applications in tissue engineering and cancer treatment through controlled drug delivery. By integrating CAP with artificial intelligence-guided treatment planning, precision dosing and personalized treatment can be further enhanced. Collectively, current evidence suggests that CAP represents a promising non-invasive therapeutic approach with effects that extend beyond superficial tissue interactions, indicating its potential for applications across a wide range of medical fields. This review identifies CAP-driven biochemical and therapeutic processes and enhances understanding of targeted, multimodal interventions in oncology, wound healing and regenerative medicine.</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 100159"},"PeriodicalIF":2.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147395916","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 : 2026-03-01Epub Date: 2026-02-23DOI: 10.1016/j.arres.2026.100158
Danial Babaki , Nicholas E. Buglak , Bruno Musetti , Yasmin Leon-Mateo , Gang Xi , Edward M. Bahnson
Neointimal hyperplasia (NH) is a primary cause of arterial restenosis following angioplasty, driven by oxidative stress and vascular smooth muscle cell (VSMC) phenotypic modulation. This study investigated whether the class I electrophilic Nrf2 activators Bardoxolone methyl (BAR), Omaveloxolone (OMV), and Cinnamaldehyde (CA) could suppress NH through Nrf2-dependent mechanisms. Using VSCM that were Nrf2 wild-type (WT), knockout (KO), and rescued by nrf2 lentiviral transduction, we assessed the effects of these activators on PDGF-induced proliferation, migration, and phenotypic modulation. Additionally, we utilized a rat carotid artery balloon injury model with periadventitial drug delivery and light-sheet fluorescence microscopy to evaluate neointimal formation. In vitro, BAR, OMV, and CA upregulated the antioxidant enzymes HO-1 and NQO1, inhibited cell migration and proliferation, and preserved contractile markers (calponin and transgelin) in WT VSMC, but showed no effect in KO cells. Lentiviral-mediated nrf2 transduction rescued the phenotype. In vivo, treatment with CA significantly reduced neointimal volume and stenosis in WT rats, but failed to inhibit hyperplasia in Nrf2 KO rats. Aditionally, BAR also showed marked inhibition of hyperplasia in vivo. These findings demonstrate that these electrophilic activators suppress restenosis by stabilizing VSMC phenotype via strictly Nrf2-dependent signaling.
{"title":"Inhibition of smooth muscle phenotypic modulation by bardoxolone methyl, omaveloxolone, and cinnamaldehyde is Nrf-2 dependent","authors":"Danial Babaki , Nicholas E. Buglak , Bruno Musetti , Yasmin Leon-Mateo , Gang Xi , Edward M. Bahnson","doi":"10.1016/j.arres.2026.100158","DOIUrl":"10.1016/j.arres.2026.100158","url":null,"abstract":"<div><div>Neointimal hyperplasia (NH) is a primary cause of arterial restenosis following angioplasty, driven by oxidative stress and vascular smooth muscle cell (VSMC) phenotypic modulation. This study investigated whether the class I electrophilic Nrf2 activators Bardoxolone methyl (BAR), Omaveloxolone (OMV), and Cinnamaldehyde (CA) could suppress NH through Nrf2-dependent mechanisms. Using VSCM that were Nrf2 wild-type (WT), knockout (KO), and rescued by nrf2 lentiviral transduction, we assessed the effects of these activators on PDGF-induced proliferation, migration, and phenotypic modulation. Additionally, we utilized a rat carotid artery balloon injury model with periadventitial drug delivery and light-sheet fluorescence microscopy to evaluate neointimal formation. <em>In vitro</em>, BAR, OMV, and CA upregulated the antioxidant enzymes HO-1 and NQO1, inhibited cell migration and proliferation, and preserved contractile markers (calponin and transgelin) in WT VSMC, but showed no effect in KO cells. Lentiviral-mediated nrf2 transduction rescued the phenotype. <em>In vivo</em>, treatment with CA significantly reduced neointimal volume and stenosis in WT rats, but failed to inhibit hyperplasia in Nrf2 KO rats. Aditionally, BAR also showed marked inhibition of hyperplasia <em>in vivo</em>. These findings demonstrate that these electrophilic activators suppress restenosis by stabilizing VSMC phenotype via strictly Nrf2-dependent signaling.</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 100158"},"PeriodicalIF":2.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147395915","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 : 2026-03-01Epub Date: 2026-01-22DOI: 10.1016/j.arres.2026.100153
Jian Yang , Ying Gao
Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, was initially characterized as a cell-autonomous process. However, emerging evidence demonstrates that ferroptotic signals can propagate between cells, triggering synchronized death events with significant pathophysiological implications. This review examines the molecular mechanisms underlying intercellular ferroptosis propagation, including ROS-mediated trigger waves, contact-dependent lipid peroxidation transmission, paracrine signaling, and extracellular vesicle-mediated communication. We analyze the dual roles of ferroptosis propagation in the tumor microenvironment and its contribution to tissue damage in ischemia-reperfusion injury and neurodegeneration. Understanding these propagation mechanisms offers novel therapeutic opportunities for precisely modulating cellular death responses across diverse disease contexts.
{"title":"Intercellular propagation of ferroptosis","authors":"Jian Yang , Ying Gao","doi":"10.1016/j.arres.2026.100153","DOIUrl":"10.1016/j.arres.2026.100153","url":null,"abstract":"<div><div>Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, was initially characterized as a cell-autonomous process. However, emerging evidence demonstrates that ferroptotic signals can propagate between cells, triggering synchronized death events with significant pathophysiological implications. This review examines the molecular mechanisms underlying intercellular ferroptosis propagation, including ROS-mediated trigger waves, contact-dependent lipid peroxidation transmission, paracrine signaling, and extracellular vesicle-mediated communication. We analyze the dual roles of ferroptosis propagation in the tumor microenvironment and its contribution to tissue damage in ischemia-reperfusion injury and neurodegeneration. Understanding these propagation mechanisms offers novel therapeutic opportunities for precisely modulating cellular death responses across diverse disease contexts.</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 100153"},"PeriodicalIF":2.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146173244","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}
Alkaline reduced water (ARW), produced through electrolysis, has emerged as a health-promoting beverage due to its elevated pH and reduced oxidation–reduction potential (ORP). This type of water offers several notable health benefits. ARW effectively neutralizes excess body acidity, promoting a balanced internal pH, which is beneficial in counteracting the effects of an acid-heavy diet. Its smaller molecular clusters enhance cellular absorption, improving hydration and nutrient uptake, which is particularly advantageous for athletes and physically active individuals. The antioxidant properties of ARW, attributed to its negative ORP, play a crucial role in reducing oxidative stress, thereby protecting cells from damage and potentially lowering the risk of chronic diseases such as cancer, cardiovascular diseases, and neurodegenerative disorders. ARW also supports digestive health by promoting a balanced gut environment and reducing harmful bacterial load. It also enhances the solubility and bioavailability of nutrients, improving their utilization in the body. Regular consumption of ARW has been linked to a lower incidence of chronic diseases and reduced fatigue, further enhancing energy levels. Overall ARW is a valuable addition to a health-conscious lifestyle, offering comprehensive benefits by enhancing hydration and preventing diseases. However, further research is needed to fully elucidate the long-term effects of ARW.
{"title":"A concise review on health benefits of alkaline reduced water","authors":"Maninder Meenu , Mradula , Kiran Khandare , Shradha Duggal , Vasudha Bansal , Manorma Negi , Baojun Xu","doi":"10.1016/j.arres.2025.100148","DOIUrl":"10.1016/j.arres.2025.100148","url":null,"abstract":"<div><div>Alkaline reduced water (ARW), produced through electrolysis, has emerged as a health-promoting beverage due to its elevated pH and reduced oxidation–reduction potential (ORP). This type of water offers several notable health benefits. ARW effectively neutralizes excess body acidity, promoting a balanced internal pH, which is beneficial in counteracting the effects of an acid-heavy diet. Its smaller molecular clusters enhance cellular absorption, improving hydration and nutrient uptake, which is particularly advantageous for athletes and physically active individuals. The antioxidant properties of ARW, attributed to its negative ORP, play a crucial role in reducing oxidative stress, thereby protecting cells from damage and potentially lowering the risk of chronic diseases such as cancer, cardiovascular diseases, and neurodegenerative disorders. ARW also supports digestive health by promoting a balanced gut environment and reducing harmful bacterial load. It also enhances the solubility and bioavailability of nutrients, improving their utilization in the body. Regular consumption of ARW has been linked to a lower incidence of chronic diseases and reduced fatigue, further enhancing energy levels. Overall ARW is a valuable addition to a health-conscious lifestyle, offering comprehensive benefits by enhancing hydration and preventing diseases. However, further research is needed to fully elucidate the long-term effects of ARW.</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 100148"},"PeriodicalIF":2.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145926497","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 : 2026-03-01Epub 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":"2026-03-01","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 : 2025-12-01Epub 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":"2025-12-01","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 : 2025-12-01Epub 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":"2025-12-01","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 : 2025-12-01Epub Date: 2025-11-19DOI: 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 : 2025-12-01Epub Date: 2025-11-13DOI: 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}
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