Redox Biology最新文献

{"title":"IDO1 improves postischemic neovascularization in aged mice by boosting endothelial NAD+ de novo synthesis and curbing endothelial senescence","authors":"Minghong Chen ,&nbsp;Junyu Chen ,&nbsp;Yu Liu ,&nbsp;Jing Chen ,&nbsp;Meilian Yao ,&nbsp;Xuerui Wang ,&nbsp;Jian Zhang ,&nbsp;Miao Pan ,&nbsp;Jipeng Zhou ,&nbsp;Yongping Bai","doi":"10.1016/j.redox.2025.103695","DOIUrl":"10.1016/j.redox.2025.103695","url":null,"abstract":"<div><h3>Introduction</h3><div>Peripheral arterial disease (PAD) is prevalent among the elderly, and therapeutic neovascularization is a research hotspot in PAD treatment. Supplementing nicotinamide adenine dinucleotide (NAD⁺) precursors is an important approach for promoting neovascularization, but clinical trials in the elderly PAD patients have shown limited success. This study aims to find effective ways to boost NAD⁺ levels in elderly PAD patients to enhance neovascularization.</div></div><div><h3>Methods</h3><div>Transcriptome and NAD⁺-targeted metabolomics analyses were conducted on ischemic hindlimb muscle endothelial cells (ECs). The role of indoleamine 2,3-dioxygenase 1 (IDO1) in postischemic neovascularization was studied using global knockout mice. Mechanisms regulating IDO1 expression were investigated through transcriptomics and functional experiments. The effects of IDO1 protein on postischemic neovascularization were evaluated <em>in vivo</em> and <em>in vitro</em>. Plasma IDO1 levels were measured in young and elderly PAD patients and correlated with clinical indicators of PAD.</div></div><div><h3>Results</h3><div>In aged mice, ECs exhibited decreased NAD⁺ de novo synthesis and IDO1 transcription. IDO1 deficiency induced the decline of ECs NAD⁺ de novo synthesis and ECs senescence, impaired neovascularization in young mice. Elevated IL-17A/F inhibited IDO1 transactivation via CREB, impairing neovascularization. IDO1 administration alleviated the decline of ECs NAD⁺ de novo synthesis and ECs senescence, and enhanced neovascularization in aged mice. Plasma IDO1 levels were lower in elderly PAD patients, correlating positively with disease severity, onset risk, and cardiovascular outcomes.</div></div><div><h3>Conclusion</h3><div>ECs NAD⁺ metabolism imbalance is driven by decreased de novo synthesis of NAD⁺ and targeting IDO1 to elevate NAD⁺ levels could be a potential therapeutic direction for elderly PAD patients.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"84 ","pages":"Article 103695"},"PeriodicalIF":10.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144154616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacologic ascorbate resistant pancreatic cancer demonstrates enhanced metastatic potential","authors":"Amanda Pope ,&nbsp;Brianne O'Leary ,&nbsp;Juan Du ,&nbsp;Garry R. Buettner ,&nbsp;Michael Henry ,&nbsp;Joseph J. Cullen","doi":"10.1016/j.redox.2025.103694","DOIUrl":"10.1016/j.redox.2025.103694","url":null,"abstract":"<div><div>Pharmacological ascorbate (P-AscH, high-dose, intravenous, vitamin C), is a pro-drug that generates hydrogen peroxide (H₂O₂) and is being investigated as a neoadjuvant treatment for pancreatic adenocarcinoma (PDAC). In a randomized, phase II clinical trial, P-AscH demonstrated encouraging results in terms of efficacy and safety. However, some patients do not respond to P-AscH suggesting that resistance occurs in a subset of patients. The aims of this study were two-fold: first to characterize PDAC cells resistant to P-AscH, and second, determine if these alterations enhance metastatic potential. Resistance to P-AscH increased the ability to detoxify H₂O₂, altered redox metabolism and cell cycle regulation, however mechanisms to P-AscH resistance were different in the cell lines studied. Transcriptomic analysis demonstrated a significant enrichment of the epithelial-to-mesenchymal gene expression pattern in the cell lines studied, suggesting that upregulation of metastatic phenotypes occur during acquisition of resistance to P-AscH. Cells resistant to P-AscH demonstrated increased invasive potential, more aggressive tumor colonization, and higher abundance of circulating tumor cells <em>in vivo</em>. Our data support that resistance to oxidative stress enhances metastatic disease and indicates a potential route for PDAC to tolerate high levels of P-AscH and may explain why some patients do not respond to this treatment regimen.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"84 ","pages":"Article 103694"},"PeriodicalIF":10.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144154613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cannabinol (CBN) alleviates age-related cognitive decline by improving synaptic and mitochondrial health","authors":"Nawab John Dar ,&nbsp;Antonio Currais ,&nbsp;Taketo Taguchi ,&nbsp;Nick Andrews ,&nbsp;Pamela Maher","doi":"10.1016/j.redox.2025.103692","DOIUrl":"10.1016/j.redox.2025.103692","url":null,"abstract":"<div><div>Age-related cognitive decline and neurodegenerative diseases, such as Alzheimer's disease, represent major global health challenges, particularly with an aging population. Mitochondrial dysfunction appears to play a central role in the pathophysiology of these conditions by driving redox dysregulation and impairing cellular energy metabolism. Despite extensive research, effective therapeutic options remain limited. Cannabinol (CBN), a cannabinoid previously identified as a potent inhibitor of oxytosis/ferroptosis through mitochondrial modulation, has demonstrated promising neuroprotective effects. In cell culture, CBN targets mitochondria, preserving mitochondrial membrane potential, enhancing antioxidant defenses and regulating bioenergetic processes. However, the <em>in vivo</em> therapeutic potential of CBN, particularly in aging models, has not been thoroughly explored. To address this gap, this study investigated the effects of CBN on age-associated cognitive decline and metabolic dysfunction using the SAMP8 mouse model of accelerated aging. Our results show that CBN significantly improves spatial learning and memory, with more pronounced cognitive benefits observed in female mice. These cognitive improvements are accompanied by sex-specific changes in metabolic parameters, such as enhanced oxygen consumption and energy expenditure. Mechanistically, CBN modulates key regulators of mitochondrial dynamics, including mitofusin 2 (MFN2) and dynamin-related protein 1 (DRP1), while upregulating markers of mitochondrial biogenesis including mitochondrial transcription factor A (TFAM) and translocase of outer mitochondrial membrane 20 (TOM20). Additionally, CBN upregulates key synaptic proteins involved in vesicle trafficking and postsynaptic signaling suggesting that it enhances synaptic function and neurotransmission, further reinforcing its neuroprotective effects. This study provides <em>in vivo</em> evidence supporting CBN's potential to mitigate age-related cognitive and metabolic dysfunction, with notable sex-specific effects, highlighting its promise for neurodegenerative diseases and cognitive decline.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"84 ","pages":"Article 103692"},"PeriodicalIF":10.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144116184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting oxidative stress-mediated regulated cell death as a vulnerability in cancer","authors":"Danyao Chen ,&nbsp;Ziyu Guo ,&nbsp;Lei Yao ,&nbsp;Yuming Sun ,&nbsp;Yating Dian ,&nbsp;Deze Zhao ,&nbsp;Yizhe Ke ,&nbsp;Furong Zeng ,&nbsp;Chunfang Zhang ,&nbsp;Guangtong Deng ,&nbsp;Linfeng Li","doi":"10.1016/j.redox.2025.103686","DOIUrl":"10.1016/j.redox.2025.103686","url":null,"abstract":"<div><div>Reactive oxygen species (ROS), regulators of cellular behaviors ranging from signaling to cell death, have complex production and control mechanisms to maintain a dynamic redox balance under physiological conditions. Redox imbalance is frequently observed in tumor cells, where ROS within tolerable limits promote oncogenic transformation, while excessive ROS induce a range of regulated cell death (RCD). As such, targeting ROS-mediated regulated cell death as a vulnerability in cancer. However, the precise regulatory networks governing ROS-mediated cancer cell death and their therapeutic applications remain inadequately characterized. In this Review, we first provide a comprehensive overview of the mechanisms underlying ROS production and control within cells, highlighting their dynamic balance. Next, we discuss the paradoxical nature of the redox system in tumor cells, where ROS can promote tumor growth or suppress it, depending on the context. We also systematically explored the role of ROS in tumor signaling pathways and revealed the complex ROS-mediated cross-linking networks in cancer cells. Following this, we focus on the intricate regulation of ROS in RCD and its current applications in cancer therapy. We further summarize the potential of ROS-induced RCD-based therapies, particularly those mediated by drugs targeting specific redox balance mechanisms. Finally, we address the measurement of ROS and oxidative damage in research, discussing existing challenges and future prospects of targeting ROS-mediated RCD in cancer therapy. We hope this review will offer promise for the clinical application of targeting oxidative stress-mediated regulated cell death in cancer therapy.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"84 ","pages":"Article 103686"},"PeriodicalIF":10.7,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144137798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitigating microplastic-induced organ Damage: Mechanistic insights from the microplastic-macrophage axes","authors":"Yinxing Cui ,&nbsp;Yuqi Wu ,&nbsp;Pan Shi ,&nbsp;Yan Ni ,&nbsp;Huaying Zeng ,&nbsp;Zhao Zhang ,&nbsp;Chunling Zhao ,&nbsp;Weichao Sun ,&nbsp;Qian Yi","doi":"10.1016/j.redox.2025.103688","DOIUrl":"10.1016/j.redox.2025.103688","url":null,"abstract":"<div><div>We live in a world increasingly dominated by plastic, leading to the generation of microplastic particles that pose significant global health concerns. Microplastics can enter the body via ingestion, inhalation, and direct contact, accumulating in various tissues and potentially causing harm. Despite this, the specific cellular mechanisms and signaling pathways involved remain poorly understood. Macrophages are essential in absorbing, distributing, and eliminating microplastics, playing a key role in the body's defense mechanisms. Recent evidence highlights oxidative stress signaling as a key pathway in microplastic-induced macrophage dysfunction. The accumulation of microplastics generates reactive oxygen species (ROS), disrupting normal macrophage functions and exacerbating inflammation and organ damage. This review serves as the first comprehensive examination of the interplay between microplastics, macrophages, and oxidative stress. It discusses how oxidative stress mediates macrophage responses to microplastics and explores the interactions with gut microbiota. Additionally, it reviews the organ damage resulting from alterations in macrophage function mediated by microplastics and offers a novel perspective on the defense, assessment, and treatment of microplastic-induced harm from the viewpoint of macrophages.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"84 ","pages":"Article 103688"},"PeriodicalIF":10.7,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144116181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The crosstalk between glutathione metabolism and non-coding RNAs in cancer progression and treatment resistance","authors":"Lu Chang ,&nbsp;Chao Qin ,&nbsp;Jianbo Wu,&nbsp;Haoqin Jiang,&nbsp;Qianqian Xu,&nbsp;Jian Chen,&nbsp;Xiao Xu,&nbsp;Xinju Zhang,&nbsp;Ming Guan,&nbsp;Xuan Deng","doi":"10.1016/j.redox.2025.103689","DOIUrl":"10.1016/j.redox.2025.103689","url":null,"abstract":"<div><div>Excessive reactive oxygen species (ROS) are closely associated with the initiation and progression of cancers. As the most abundant intracellular antioxidant, glutathione (GSH) plays a critical role in regulating cellular ROS levels, modulating physiological processes, and is intricately linked to tumor progression and drug resistance. However, the underlying mechanisms remain not fully elucidated. Non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), are key regulators of GSH levels. Different ncRNAs modulate various pathways involved in GSH metabolism, and these regulatory targets have the potential to serve as therapeutic targets for enhancing cancer treatment. In this review, we summarize the functions of GSH metabolism and highlight the significance of ncRNA-mediated regulation of GSH in cancer progression, drug resistance, and clinical applications.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"84 ","pages":"Article 103689"},"PeriodicalIF":10.7,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144107808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypobaric hypoxia-driven energy metabolism disturbance facilitates vascular endothelial dysfunction","authors":"Yuyu Zhang ,&nbsp;Jinghuan Wang ,&nbsp;Mengting He ,&nbsp;Jiayao Liu,&nbsp;Jialin Zhao,&nbsp;JinTao He,&nbsp;Caiyun Wang,&nbsp;Yuhui Li,&nbsp;Chenxi Xiao,&nbsp;Chunxiang Fan,&nbsp;Jun Chang,&nbsp;Xinhua Liu","doi":"10.1016/j.redox.2025.103675","DOIUrl":"10.1016/j.redox.2025.103675","url":null,"abstract":"<div><div>Hypobaric hypoxia in plateau environments inevitably disrupts metabolic homeostasis and contributes to high-altitude diseases. Vascular endothelial cells play a crucial role in maintaining vascular homeostasis. However, it remains unclear whether hypoxia-mediated changes in energy metabolism compromise vascular system stability and function. Through integrated transcriptomic and targeted metabolomic analyses, we identified that hypoxia induces vascular endothelial dysfunction via energy metabolism dysregulation. Specifically, hypoxia drives a metabolic shift toward glycolysis over oxidative phosphorylation in vascular endothelial cells, resulting in excessive lactate production. This lactate overload triggers PKM2 lactylation, which stabilizes PKM2 by inhibiting ubiquitination, forming a feedforward loop that exacerbates mitochondrial collapse and vascular endothelial dysfunction. Importantly, blocking the pyruvate-lactate axis helps maintain the balance between glycolysis and oxidative phosphorylation, thereby protecting vascular endothelial function under hypoxic conditions. Our findings not only elucidate a novel mechanism underlying hypoxia-induced vascular damage but also highlight the pyruvate-lactate axis as a potential therapeutic target for preventing vascular diseases in both altitude-related and pathological hypoxia.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"84 ","pages":"Article 103675"},"PeriodicalIF":10.7,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144090238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vivo protein half-life analysis identifies the SREBF1-SLC27a5 axis governs antioxidant response in preclinical alcoholic rat model","authors":"Nupur Sharma ,&nbsp;Sadam H. Bhat ,&nbsp;Shweta Chaudhary ,&nbsp;Babu Mathew ,&nbsp;Sushmita Pandey ,&nbsp;Sanju Yadav ,&nbsp;Manisha Yadav ,&nbsp;Vasundhra Bindal ,&nbsp;Gaurav Tripathi ,&nbsp;Neha Sharma ,&nbsp;Vipul Sharma ,&nbsp;Abhishak Gupta ,&nbsp;Ranjan Nanda ,&nbsp;Anupama Kumari ,&nbsp;Shvetank Sharma ,&nbsp;Jaswinder Singh Maras","doi":"10.1016/j.redox.2025.103674","DOIUrl":"10.1016/j.redox.2025.103674","url":null,"abstract":"<div><h3>Background</h3><div>ALD causes liver dysfunction with inflammation, steatosis, and fibrosis. While abstinence reverses damage, its effect on protein half-lives remains unclear. This study examines site-specific protein half-life changes, transcription regulation, and recovery mechanisms.</div></div><div><h3>Method</h3><div>Long-Evans rats were fed ethanol or control diets for 24 weeks to induce ALD, with some switched to a control diet for 7 days to model abstinence. Protein half-lives, pathways, and transcription factors were analyzed using deuterium labeling and were validated in ALD rats, abstinent rats, and human biopsies.</div></div><div><h3>Results</h3><div>Liver histology showed increased steatosis (28 %) and fibrosis (15 %) in ALD rats, both reduced with abstinence (&lt;20 %, &lt;12 %, p &lt; 0.05). Liver function and lipid profiles improved, while alcohol-metabolizing and inflammatory markers were decreased (&gt;1.5-fold, p &lt; 0.05) following abstinence. ALD induced change in protein half-life specific to liver (82↑, 54↓), intestine (26↑, 30↓), and plasma (11↑, 17↓). Abstinence modulated; liver (64↑, 62↓), intestine (13↑, 25↓), and plasma (10↑, 12↓; FC &gt; 1.5, p &lt; 0.05). Specifically, abstinence reversed protein half-lives linked to lipid metabolism in the liver, neurodegeneration in the intestine, and NET formation in plasma (p &lt; 0.05).</div><div>Abstinence restored protein half-lives of Cyp2d10, Ugt1a1, Slc27a5, and Hsp90b1, regulated by Srebf1. Proteomic validation confirmed increased Acat1, Ugt1a1, and Slc27a5 in ALD, linked to steatosis and inflammation, which decreased with abstinence. Severe alcoholic hepatitis patients also documented that abstinence work on modulating protein turnover under the Srebf1-Slc27a5 axis and thereby ameliorate liver damage.</div></div><div><h3>Conclusion</h3><div>Alcohol abstinence modulates protein half-lives through Srebf1-Slc27a5 axis, reducing inflammation, steatosis, and oxidative stress, potentially aiding in alcohol-induced liver damage treatment.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103674"},"PeriodicalIF":10.7,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144271780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Broad-spectrum antioxidant and neuroprotective Prussian blue nanocatalyst for therapeutic intervention in autism spectrum disorder","authors":"Yan Gong ,&nbsp;Lele Yu ,&nbsp;Lili Xia ,&nbsp;Jilu Jin ,&nbsp;Yue Lang ,&nbsp;Shini Feng ,&nbsp;Wei Feng ,&nbsp;Fuxue Chen ,&nbsp;Yu Chen","doi":"10.1016/j.redox.2025.103671","DOIUrl":"10.1016/j.redox.2025.103671","url":null,"abstract":"<div><div>Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by diverse clinical presentations, often associated with dysregulated oxidative stress mechanisms leading to heightened production of reactive oxygen species (ROS) in the brain. Due to its multifactorial etiology, effective therapeutic approaches for ASD remain challenging to ascertain. This work engineers Prussian blue nanoparticles (PB NPs) designed to mimic the enzymatic functions of key antioxidants such as superoxide dismutase, glutathione peroxidase, catalase, and peroxidase. PB NPs effectively scavenge ROS and restore cellular redox homeostasis. These nanoparticles attenuate neuronal apoptosis by reducing activation of apoptotic markers like cleaved caspase-3 and B-cell lymphoma-2 associated X protein, while enhancing the expression of anti-apoptotic protein B-cell lymphoma-2. Furthermore, PB NPs mitigate neuroinflammation by downregulating pro-inflammatory cytokines and upregulating anti-inflammatory cytokines, thereby alleviating glial cell hyperactivity. In preclinical ASD models, PB NPs significantly improve social interaction deficits, diminish anxiety-like behaviors, and enhance cognitive functions. The therapeutic application of PB NPs represents a notable advancement in ASD treatment, offering a novel approach for clinical intervention aimed at enhancing the quality of life for individuals affected by ASD.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"84 ","pages":"Article 103671"},"PeriodicalIF":10.7,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144116183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Formation of singlet oxygen in addition to hydroxyl radical via the Fenton reaction","authors":"Rino Shimizu,&nbsp;Haruki Watanabe,&nbsp;Sayaka Iida,&nbsp;Yorihiro Yamamoto,&nbsp;Akio Fujisawa","doi":"10.1016/j.redox.2025.103687","DOIUrl":"10.1016/j.redox.2025.103687","url":null,"abstract":"<div><div>We established an LC-MS/MS method for detecting uric acid oxidation metabolites to evaluate reactive oxygen and nitrogen species, as uric acid gives specific products. Parabanic acid was identified during attempts to detect hydroxyl radical–specific products in the Fenton reaction. As parabanic acid is a singlet oxygen–specific product of uric acid, this indicates the Fenton system, which is known for the generation of hydroxyl radicals, also forms singlet oxygen products. This notion was confirmed by replacing uric acid with tryptophan, which resulted in the formation of singlet oxygen–specific oxidation products (<em>cis</em>- and <em>trans</em>-WOOH) and their reductants, <em>cis</em>- and <em>trans</em>-WOH. Product amounts were reduced in a dose-dependent manner by the addition of the singlet oxygen quenchers sodium azide or 1,4-diazabicyclo[2.2.2]octane. Surprisingly, the estimated amount of singlet oxygen produced was 50- to 70-fold greater than that of hydroxyl radical, considering the quantum yield of the reaction between uric acid and singlet oxygen. The formation of singlet oxygen under anaerobic conditions suggested it was derived from hydrogen peroxide. The production of non-labeled parabanic acid, even in an ¹⁸O₂ atmosphere or the presence of H₂¹⁸O, supported this hypothesis. These results confirmed that singlet oxygen was derived from hydrogen peroxide. The proposed mechanism of singlet oxygen formation is as follows. Two hydrogen peroxyl radicals formed by the reaction of hydrogen peroxide and ferric ion or hydroxyl radical are coupled to form a hydrogen tetraoxide, which subsequently decomposes to form singlet oxygen and hydrogen peroxide via a Russell-like mechanism. Finally, it was observed that significantly more singlet oxygen was generated in whole human blood compared with red blood cell–depleted blood during pseudo-inflammation initiated by lipopolysaccharide addition, suggesting that singlet oxygen formation was due to the Fenton reaction. Thus, the Fenton reaction may be a novel pathway for singlet oxygen production.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"84 ","pages":"Article 103687"},"PeriodicalIF":10.7,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}