Redox Biology最新文献

{"title":"CD40-TRAF6 inhibition suppresses cardiovascular inflammation, oxidative stress and functional complications in a mouse model of arterial hypertension","authors":"Lea Strohm ,&nbsp;Henning Ubbens ,&nbsp;Dominika Mihalikova ,&nbsp;Alexander Czarnowski ,&nbsp;Paul Stamm ,&nbsp;Michael Molitor ,&nbsp;Stefanie Finger ,&nbsp;Matthias Oelze ,&nbsp;Dorothee Atzler ,&nbsp;Philip Wenzel ,&nbsp;Philipp Lurz ,&nbsp;Thomas Münzel ,&nbsp;Christian Weber ,&nbsp;Esther Lutgens ,&nbsp;Andreas Daiber ,&nbsp;Steffen Daub","doi":"10.1016/j.redox.2025.103520","DOIUrl":"10.1016/j.redox.2025.103520","url":null,"abstract":"<div><div>Cardiovascular disease is the leading cause of disease burden and death worldwide and is fueled by vascular inflammation. CD40L–CD40–TRAF signaling is involved in the progression of atherosclerosis and drives the development of coronary heart disease (CHD). The present study investigates whether the CD40L-CD40-TRAF6 signaling pathway with focus on immune cells and adipocytes could be a therapeutic target in arterial hypertension.</div><div>Arterial hypertension was induced in WT (C57BL6/J) and cell-specific CD40(L) knockout mice (AdipoqCre x CD40 fl/fl, CD4Cre x CD40 fl/fl, CD19Cre x CD40 fl/fl, and GP1baCre x CD40L fl/fl) via angiotensin (AT-II) infusion (1 mg/kg/d) for seven days. Hypertensive WT mice were also treated with a CD40-TRAF6 inhibitor (2.5 mg/kg/d, for 7d). The TRAF6 inhibitor treatment normalized endothelial dysfunction and reduced blood pressure in hypertensive wild type animals. Reactive oxygen species production was decreased by TRAF6 inhibition in blood, aorta, heart, kidney, and perivascular fat tissue. Additionally, FACS analysis revealed that TRAF6 inhibition prevents immune cell migration into the aortic vessel wall observed by reduced CD45⁺ leukocyte, Ly6G⁺/Ly6C⁺ neutrophil, and Ly6C^high inflammatory monocyte content. The hypertensive cell type-specific CD40(L) knockout animals showed only a minor effect on endothelial function, blood pressure, and oxidative stress. Therefore, we conclude that targeting CD40 directly on adipocytes, B-cells, T-cells, or CD40L on platelets is not a promising target to prevent hypertension complications.</div><div>In summary, TRAF6 inhibition but not adipocyte, B-cell, or T-cell-specific CD40 or platelet-specific CD40L deficiency reduces pathophysiological vascular inflammation in hypertensive mice, suggesting TRAF6 inhibition as a potential therapeutic target in hypertensive patients.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"80 ","pages":"Article 103520"},"PeriodicalIF":10.7,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143071579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protective role of vitamin D receptor against mitochondrial calcium overload from PM2.5-Induced injury in renal tubular cells","authors":"Mengqiu Lu ,&nbsp;Zishun Zhan ,&nbsp;Dan Li ,&nbsp;Hengbing Chen ,&nbsp;Aimei Li ,&nbsp;Jing Hu ,&nbsp;Zhijun Huang ,&nbsp;Bin Yi","doi":"10.1016/j.redox.2025.103518","DOIUrl":"10.1016/j.redox.2025.103518","url":null,"abstract":"<div><h3>Purpose</h3><div>This research explores the consequences of being exposed to PM_2.5 contribute to renal injury while also evaluating the protective role of Vitamin D-VDR signaling in alleviating mitochondrial calcium imbalance and oxidative stress in renal tubular cells.</div></div><div><h3>Methods</h3><div>Animal models of chronic PM_2.5 exposure were used to simulate environmental conditions in wild type and VDR-overexpressing mice specific to renal tubules. In parallel, HK-2 cell lines were treated with PM_2.5 in vitro. Mitochondrial function, calcium concentration, and oxidative stress markers were assessed. VDR activation, achieved through genetic overexpression and paricalcitol, was induced to examine its effect on mitochondrial calcium uniporter (MCU) expression and mitochondrial calcium regulation.</div></div><div><h3>Results</h3><div>PM_2.5 exposure caused significant mitochondrial damage in renal tubular cells, including mitochondrial calcium overload, increased oxidative stress, reduced membrane potential, and diminished ATP production. Elevated MCU expressions were a key contributor to these disruptions. VDR activation effectively reversed these effects by downregulating MCU, restoring mitochondrial calcium balance, reducing oxidative stress, and improving renal function.</div></div><div><h3>Conclusion</h3><div>This study shows that activating Vitamin D-VDR signaling shields the kidneys from PM_2.5-induced damage by reestablishing mitochondrial calcium balance and lowering oxidative stress via inhibition of the MCU. These results unveil a new protective role of VDR in defending against environmental pollutants and suggest that targeting the MCU could offer a potential therapeutic strategy for treating chronic kidney disease linked to pollution exposure.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"80 ","pages":"Article 103518"},"PeriodicalIF":10.7,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143071342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Applications and enhancement strategies of ROS-based non-invasive therapies in cancer treatment","authors":"Qiuyan Guo ,&nbsp;Yingnan Tang ,&nbsp;Shengmei Wang ,&nbsp;Xinhua Xia","doi":"10.1016/j.redox.2025.103515","DOIUrl":"10.1016/j.redox.2025.103515","url":null,"abstract":"<div><div>Reactive oxygen species (ROS) play a crucial role in the pathogenesis of cancer. Non-invasive therapies that promote intracellular ROS generation, including photodynamic therapy (PDT), sonodynamic therapy (SDT), and chemodynamic therapy (CDT), have emerged as novel approaches for cancer treatment. These therapies directly kill tumor cells by generating ROS, and although they show great promise in tumor treatment, many challenges remain to be addressed in practical applications. Firstly, the inherent complexity of the tumor microenvironment (TME), such as hypoxia and elevated glutathione (GSH) levels, hinders ROS generation, thereby significantly diminishing the efficacy of ROS-based therapies. In addition, these therapies are influenced by their intrinsic mechanisms. To overcome these limitations, various nanoparticle (NP) systems have been developed to improve the therapeutic efficacy of non-invasive therapies against tumors. This review first summarizes the mechanisms of ROS generation for each non-invasive therapy and their current limitations, with a particular focus on the enhancement strategies for each therapy based on NP systems. Additionally, various strategies to modulate the TME are highlighted. These strategies aim to amplify ROS generation in non-invasive therapies and enhance their anti-tumor efficiency. Finally, the current challenges and possible solutions for the clinical translation of ROS-based non-invasive therapies are also discussed.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"80 ","pages":"Article 103515"},"PeriodicalIF":10.7,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143145346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Norharmane prevents muscle aging via activation of SKN-1/NRF2 stress response pathways","authors":"Farida S. Nirmala ,&nbsp;Hyunjung Lee ,&nbsp;Yejin Cho ,&nbsp;Min Young Um ,&nbsp;Hyo Deok Seo ,&nbsp;Chang Hwa Jung ,&nbsp;Jeong-Hoon Hahm ,&nbsp;Jiyun Ahn","doi":"10.1016/j.redox.2025.103512","DOIUrl":"10.1016/j.redox.2025.103512","url":null,"abstract":"<div><div>Sarcopenia, the age-related decline in muscle mass and function, is a significant contributor to increased frailty and mortality in the elderly. Currently, no FDA-approved treatment exists for sarcopenia. Here, we identified norharmane (NR), a β-carboline alkaloid, as a potential therapeutic agent for mitigating muscle aging. We aimed to determine the ability of NR to delay muscle aging in <em>Caenorhabditis elegans</em> (<em>C. elegans</em>), mouse, and muscle cells in mice and humans. NR treatment improved swimming ability and increased the maximum velocity in aged <em>C. elegans</em>. Transcriptomic analysis revealed that NR upregulated detoxification genes in <em>C. elegans</em>, including cytochrome P450, UGT, and GST enzymes. NR-induced benefits were dependent on the SKN-1/Nrf2 stress response pathway. In mammalian models, NR delayed cellular senescence in human skeletal muscle myoblasts and enhanced myogenesis in C2C12 cells and primary aged myoblasts. NR supplementation in aged mice prevented muscle loss, improved muscle function, and reduced markers of cellular senescence. We found that the p38 MAPK pathway mediated NR activation of Nrf2 by disrupting the Nrf2-Keap1 interaction. NR also improved oxygen consumption rates and promoted mitochondrial biogenesis. These findings suggest that NR is a promising candidate for preventing sarcopenia and improving muscle health.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"80 ","pages":"Article 103512"},"PeriodicalIF":10.7,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methamphetamine-mediated astrocytic pyroptosis and neuroinflammation involves miR-152–NLRP6 inflammasome signaling axis","authors":"Abiola Oladapo,&nbsp;Muthukumar Kannan,&nbsp;Uma Maheswari Deshetty,&nbsp;Seema Singh,&nbsp;Shilpa Buch,&nbsp;Palsamy Periyasamy","doi":"10.1016/j.redox.2025.103517","DOIUrl":"10.1016/j.redox.2025.103517","url":null,"abstract":"<div><div>Methamphetamine is a widely abused drug associated with significant neuroinflammation and neurodegeneration, mainly through the activation of glial cells and neurons in the central nervous system. This study investigates the role of the astrocyte-specific NOD-like receptor family pyrin domain-containing protein 6 (NLRP6) inflammasome in methamphetamine-induced astrocytic pyroptosis and neuroinflammation. Our findings demonstrate that methamphetamine exposure induces NLRP6-dependent pyroptosis, astrocyte activation, and the release of proinflammatory cytokines in mouse primary astrocytes. Gene silencing of NLRP6 reduces methamphetamine-induced pyroptosis and proinflammatory cytokines release. We also identified miR-152 as a critical upstream regulator of NLRP6, which is downregulated in methamphetamine-exposed astrocytes. Overexpression of miR-152 decreases NLRP6 expression, mitigating methamphetamine-induced pyroptosis and inflammation. <em>In vivo</em> and <em>ex vivo</em> studies in methamphetamine-exposed mice confirmed these results and showed that methamphetamine induces anxiety-like, cognitive impairment, and depression-like behavior, further linking astrocyte-specific NLRP6 signaling to methamphetamine-induced neuroinflammation. This study highlights the potential of targeting the NLRP6 inflammasome in astrocytes as a therapeutic approach to alleviate methamphetamine-induced central nervous system pathology. Further research is warranted to explore clinical applications and identify therapeutic targets for methamphetamine-related neurological disorders.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"80 ","pages":"Article 103517"},"PeriodicalIF":10.7,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Redox regulation of focal adhesions","authors":"Gianmarco Matrullo ,&nbsp;Giuseppe Filomeni ,&nbsp;Salvatore Rizza","doi":"10.1016/j.redox.2025.103514","DOIUrl":"10.1016/j.redox.2025.103514","url":null,"abstract":"<div><div>Focal adhesions (FAs), multi-protein complexes that link the extracellular matrix to the intracellular cytoskeleton, are key mediators of cell adhesion, migration, and proliferation. These dynamic structures act as mechanical sensors, transmitting stimuli from the extracellular to intracellular environment activating in this way signaling pathways and enabling cells to adapt to environmental changes. As such, FAs are critical for tissue organization and serve as hubs governing cell spatial arrangement within the organism.</div><div>The assembly, reactivity, and functional regulation of FAs are tightly controlled by post-translational modifications, including redox modulation by reactive oxygen and nitrogen species. Increasing evidence suggests that redox signaling plays a pivotal role in both the physiological and pathological functions of FAs and their downstream processes. Redox regulation affects various components of the FA complex, including integrins, focal adhesion kinase 1 (FAK1), SRC, adapter proteins, and cytoskeletal elements.</div><div>In this review, we provide an updated overview of the complex interplay between redox signaling and post-translational modifications in FAs. We explore how redox reactions influence the structure, dynamics, and function of FAs, shedding light on their broader implications in health and disease.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"80 ","pages":"Article 103514"},"PeriodicalIF":10.7,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143067636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nitrite reverses nitroglycerin tolerance via repletion of a nitrodilator-activated nitric oxide store in vascular smooth muscle cells","authors":"Taiming Liu ,&nbsp;Meijuan Zhang ,&nbsp;Qian Li ,&nbsp;Hobe Schroeder ,&nbsp;Gordon G. Power ,&nbsp;Arlin B. Blood","doi":"10.1016/j.redox.2025.103513","DOIUrl":"10.1016/j.redox.2025.103513","url":null,"abstract":"<div><div>Repeated use of nitroglycerin results in a loss of its vasodilatory efficacy which limits its clinical use for the treatment of angina pectoris. This tolerance phenomenon is a defining characteristic of all compounds classified as nitrodilators, which includes NTG as well as S-nitrosothiols and dinitrosyl iron complexes. These compounds vasodilate via activation of soluble guanylate cyclase, although they do not release requisite amounts of free nitric oxide (NO) and some do not even cross the plasma membrane. Here we demonstrate that nitrodilators cause vasodilation via mobilization of NO moiety from a nitrodilator-activated NO store (NANOS) pre-formed in the vascular smooth muscle cell, similar to the mechanism by which UV light is also known to cause vasodilation and tolerance. Intraperitoneal nitrite prevented NTG tolerance in coronary arteries of rats that received NTG transdermal patches for 4 days, and potentiated NTG- and GSNO- mediated mesenteric vasodilation in intact rats. Consistent with the incorporation of nitrite into the depletable NANOS, incubation of arteries with ¹⁵N-nitrite resulted in the accumulation of high molecular weight ¹⁵N–NO-containing compounds in arteries, and subsequent exposure to NTG, GSNO, or UV light resulted in efflux of ¹⁵N–NO species. In addition, H₂O₂ and metal/metalloproteins synergistically facilitated NO release from nitrite, while the oxidative stress associated with inflammation and nitrite synergistically potentiated the nitrodilator-mediated vasodilation. In conclusion, NTG mediates vasodilation via activation of a depletable intracellular store of NO that can be replenished by nitrite, thereby preventing tolerance.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"80 ","pages":"Article 103513"},"PeriodicalIF":10.7,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143067626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The UCP2/PINK1/LC3b-mediated mitophagy is involved in the protection of NRG1 against myocardial ischemia/reperfusion injury","authors":"Xin-Tao Li ,&nbsp;Xin-Yue Li ,&nbsp;Tian Tian ,&nbsp;Wen-He Yang ,&nbsp;Shuai-Guo Lyv ,&nbsp;Yi Cheng ,&nbsp;Kai Su ,&nbsp;Xi-Hua Lu ,&nbsp;Mu Jin ,&nbsp;Fu-Shan Xue","doi":"10.1016/j.redox.2025.103511","DOIUrl":"10.1016/j.redox.2025.103511","url":null,"abstract":"<div><div>Available evidence indicates that neuregulin-1 (NRG-1) can provide a protection against myocardial ischemia/reperfusion (I/R) injury and is involved in various cardioprotective interventions by potential regulation of mitophagy. However, the molecular mechanisms linking NRG-1 and mitophagy remain to be clarified. In this study, both an <em>in vivo</em> myocardial I/R injury model of rats and an <em>in vitro</em> hypoxia/reoxygenation (H/R) model of H9C2 cardiomyocytes were applied to determine whether NRG-1 postconditioning attenuated myocardial I/R injury through the regulation of mitophagy and to explore the underlying mechanisms. In the <em>in vivo</em> experiment, cardioprotective effects of NRG-1 were determined by infarct size, cardiac enzyme and histopathologic examinations. The potential downstream signaling pathways and molecular targets of NRG-1 were screened by the RNA sequencing and the Protein-Protein Interaction Networks. The expression levels of mitochondrial uncoupling protein 2 (UCP2) and mitophagy-related proteins in both the I/R myocardium and H/R cardiomyocytes were measured by immunofluorescence staining and Western blots. The activation of mitophagy was observed with transmission electron microscopy and JC-1 staining. The KEGG and GSEA analyses showed that the mitophagy-related signaling pathways were enriched in the I/R myocardium treated with NRG-1, and UCP2 exhibited a significant correlation between mitophagy and interaction with PINK1. Meanwhile, the treatment with mitophagy inhibitor Mdivi-1 significant eliminated the cardioprotective effects of NRG-1 postconditioning <em>in vivo</em>, and the challenge with UCP2 inhibitor genipin could also attenuate the activating effect of NRG-1 postconditioning on mitophagy. Consistently, the <em>in vitro</em> experiment using H9C2 cardiomyocytes showd that NRG-1 treatment significantly up-regulated the expression levels of UCP2 and mitophagy-related proteins, and activated the mitophagy, whereas the challenge with small interfering RNA-mediated UCP2 knockdown abolished the effects of NRG-1. Thus, it is conclused that NRG-1 postconditioning can produce a protection against the myocardial I/R injury by activating mitophagy through the UCP2/PINK1/LC3B signaling pathway.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"80 ","pages":"Article 103511"},"PeriodicalIF":10.7,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological ascorbate combined with rucosopasem selectively radio-chemo-sensitizes NSCLC via generation of H2O2","authors":"C.F. Pulliam ,&nbsp;M.A. Fath ,&nbsp;S. Sho ,&nbsp;S.T. Johnson ,&nbsp;B.A. Wagner ,&nbsp;M. Singhania ,&nbsp;A.L. Kalen ,&nbsp;K. Bayanbold ,&nbsp;S.R. Solst ,&nbsp;B.G. Allen ,&nbsp;B.N. George ,&nbsp;J.M. Caster ,&nbsp;G.R. Buettner ,&nbsp;D.P. Riley ,&nbsp;J.L. Keene ,&nbsp;R.A. Beardsley ,&nbsp;D.R. Spitz","doi":"10.1016/j.redox.2025.103505","DOIUrl":"10.1016/j.redox.2025.103505","url":null,"abstract":"<div><div>Differences in cancer and normal cell oxidative metabolism provide a unique therapeutic opportunity for developing combined modality approaches with redox-active small molecules as radio-chemosensitizers that are well-tolerated by normal tissues. Pentaazamacrocyclic Mn (II)-containing (MnPAM) superoxide dismutase (SOD) mimetics and pharmacological ascorbate given IV to achieve [mM] plasma levels (pharmacological ascorbate: P-AscH‾) have been shown to act individually as cancer cell radio- and chemosensitizers via the generation of H₂O₂ <em>in vivo</em>. The current study shows that the combination of newly developed MnPAM dismutase mimetic, rucosopasem manganese (RUC) with P-AscH‾ radio-sensitizes non-small cell lung cancer cells (NSCLC) and increases steady state levels of intracellular H₂O₂ with no additional toxicity to normal human bronchial epithelial cells (HBECs). Conditional over expression of catalase (CAT) in H1299T CATc15 cells demonstrates that the combination of RUC and P-AscH‾ causes radio-sensitization through an H₂O₂-dependent mechanism. Interestingly, RUC combined with P-AscH‾ demonstrates more than additive cytotoxicity in both H1299T and A549 NSCLC cells, but conditional over-expression of ferritin heavy chain (FtH) protected only the H1299T, and not the A549, from this toxicity. Most importantly, the combination of RUC + P-AscH‾ was found to sensitize both H1299T and A549 cell types to radio-chemotherapy with cisplatin (CIS) + etoposide (ETOP). Finally, in H1299T NSCLC xenografts the combination of RUC + P-AscH‾ with CIS + ETOP and 12 × 2 Gy radiation significantly inhibits tumor growth and increased median overall over survival. These results support the hypothesis that selective MnPAM dismutase mimetic + P-AscH‾ enhances the efficacy of radio-chemotherapy in NSCLC through a mechanism governed by redox active metals and H₂O₂ production.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"80 ","pages":"Article 103505"},"PeriodicalIF":10.7,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143067599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Noncanonical inhibition of topoisomerase II alpha by oxidative stress metabolites","authors":"Amy C. Flor,&nbsp;Donald J. Wolfgeher,&nbsp;Stephen J. Kron","doi":"10.1016/j.redox.2025.103504","DOIUrl":"10.1016/j.redox.2025.103504","url":null,"abstract":"<div><div>During its catalytic cycle, the homodimeric ATPase topoisomerase II alpha (TOP2A) cleaves double stranded DNA and remains covalently bound to 5′ ends via tyrosine phosphodiester bonds. After passing a second, intact duplex through, TOP2A rejoins the break and releases from the DNA. Thereby, TOP2A can relieve strain accumulated during transcription, replication and chromatin remodeling and disentangle sister chromatids for mitosis. Chemotherapy agents such as etoposide are poisons that trap TOP2A mid-cycle, covalently bound to cleaved DNA, leaving behind DNA double strand breaks and activating DNA damage response. While etoposide has been proposed to stabilize the TOP2A-DNA cleavage complex (TOP2Acc) via interfacial inhibition, we have elucidated a complementary mechanism mediated by the ability of etoposide and other TOP2A poisons to induce oxidative stress. Consequently, lipid peroxidation and accumulation of lipid-derived electrophiles such as 4-hydroxynonenal (HNE) results in covalent modification of TOP2A, both blocking ATPase activity and trapping TOP2Acc. HNE modifies multiple sites on human TOP2A <em>in vitro</em>, including alkylating Cys216 in the ATPase domain in a DNA-dependent fashion. Taken together, our data suggest an underappreciated role for TOP2A as a redox sensor in tumor cells, connecting oxidative stress to DNA damage signaling and thereby creating a target for redox-active drugs.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"80 ","pages":"Article 103504"},"PeriodicalIF":10.7,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143067630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}