Antioxidants & redox signaling最新文献

{"title":"GPx3 Promotes Functional Recovery after Spinal Cord Injury by Inhibiting Microglial Pyroptosis Through IRAK4/ROS/NLRP3 Axis.","authors":"Zhongyuan Liu, Jiawei Shi, Kewu Tu, Hao Ma, Jiayu Chen, Xin Xiang, Peiqian Zou, Congrui Liao, Ruoting Ding, Zucheng Huang, Xinqiang Yao, Jianting Chen, Liang Wang, Zhongmin Zhang","doi":"10.1089/ars.2024.0618","DOIUrl":"10.1089/ars.2024.0618","url":null,"abstract":"<p><p><b><i>Aim:</i></b> Spinal cord injury (SCI) is a catastrophic injury characterized by oxidative stress. Glutathione peroxidase 3 (GPx3) is an antioxidant enzyme that protects against immune responses in various diseases. However, the effects of GPx3 in SCI remains unclear. This study aimed to investigate the role of GPx3 in SCI and its underlying mechanisms. <b><i>Results:</i></b> We injected adeno-associated viruses to overexpress GPx3 in mice. Primary microglia and BV2 cells were used as <i>in vitro</i> models. We knocked down or overexpressed GPx3 in BV2 cells. Additionally, BV2 cells transfected with siIRAK4 were used to perform rescue experiments. A series of histological and molecular biological analyses were used to explore the role of GPx3 in SCI. Overexpression of GPx3 inhibited oxidative stress in mice, improving functional recovery after SCI. Similarly, LPS+ATP stimulation decreased GPx3 expression in microglia. Silencing of GPx3 elevated the generation of reactive oxygen species, increased the expression of IRAK4 and pro-inflammatory factors, and promoted pyroptosis in microglia. However, overexpression of GPx3 reversed these results. Moreover, silencing of IRAK4 alleviated these phenomena, which were upregulated by GPx3 deficiency. <b><i>Innovation and Conclusion:</i></b> Our results demonstrated that GPx3 plays a critical role in SCI by inhibiting microglial pyroptosis <i>via</i> the IRAK4/ROS/NLRP3 signaling pathway. <i>Antioxid. Redox Signal.</i> 42, 711-729.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"711-729"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Potential of Targeting APE1/Ref-1 as a Therapeutic Intervention for Duchenne Muscular Dystrophy.","authors":"Hannah Lalunio, Nicole Stupka, Craig A Goodman, Alan Hayes","doi":"10.1089/ars.2024.0620","DOIUrl":"10.1089/ars.2024.0620","url":null,"abstract":"<p><p><b><i>Significance:</i></b> Inflammation and oxidative stress play crucial roles in the development and progression of skeletal muscle diseases. This review aims to examine the existing evidence regarding the involvement and inhibition of APE1/Ref-1 (apurinic/apyrimidinic endonuclease 1/redox factor 1) in diseases, then extrapolate this evidence to the context of skeletal muscle and discuss the potential beneficial effects of APE1/Ref-1 inhibition in ameliorating myopathy with a particular focus on dystrophic pathology. <b><i>Critical Issues:</i></b> Currently, therapeutic interventions targeting pathways, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and nuclear factor erythroid 2-related factor 2 (NRF2), have shown limited efficacy in both clinical and preclinical settings. Thus, there is a need for a more comprehensive treatment approach. <b><i>Recent Advances:</i></b> APE1/Ref-1 is a multifunctional protein that was initially identified as being involved in DNA repair. However, newer research has revealed its additional role as a redox-sensitive regulator of transcription factors, including NF-κB and NRF2. Numerous studies have reported increased expression of APE1/Ref-1 in various disorders and have demonstrated the beneficial effects of inhibiting its redox function using the small molecular inhibitor, APX3330. Although these pathways are similarly dysregulated in neuromuscular disorders, the specific role of APE1/Ref-1 in skeletal muscle remains unclear, with only a limited number of studies noting its presence in this tissue. <b><i>Future Directions:</i></b> Further studies investigating the role of APE1/Ref-1 in skeletal muscle and identifying whether APE1/Ref-1 is up- or downregulated in dystrophic skeletal muscle would be required to determine whether upregulating or inhibiting the redox function of APE1/Ref-1 will alleviate chronic inflammation and heightened oxidative stress. <i>Antioxid. Redox Signal.</i> 42, 641-654.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"641-654"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nrf2-Dependent Adaptation to Oxidative Stress Protects Against Progression of Diabetic Nephropathy.","authors":"Eugene Lee, Jae-Hun Ahn, Byeong-Cheol Kang, Hyun Soon Lee","doi":"10.1089/ars.2023.0431","DOIUrl":"10.1089/ars.2023.0431","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Adaptation to oxidative stress is essential for maintaining protein and redox homeostasis in mammalian cells. Palmitic acid (PA) plays a central role in oxidative stress and immunoproteasome regulation in podocytes and diabetes, and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have beneficial impact on diabetes. The role of Nrf2 in adaptation to oxidative stress and regulation of immunoproteasome by PA and EPA/DHA in podocytes and diabetic kidneys is not well defined. The present study describes the effect of PA- and EPA/DHA-induced oxidative stress in regulating Nrf2/immuoproteasome pathway in a model system relevant to diabetic nephropathy (DN). <b><i>Results:</i></b> Short PA exposure to podocytes promotes the upregulation of antioxidant proteins and immunoproteasome mediated by Nrf2, leading to acute transient oxidative stress adaptation. Both short- and long-term incubation of EPA or DHA in podocytes induced oxidative stress and activation of Nrf2, causing persistent oxidative stress adaptation. Long PA exposure to podocytes decreased the Nrf2 activity, and EPA/DHA attenuated these effects of PA. In <i>db/db</i> mice, feeding of EPA/DHA-rich fish oil increased oxidative stress in kidneys and induced renal cortical Nrf2 nuclear translocation and immunoproteasome overexpression, inhibiting the progression of DN. <b><i>Innovation and Conclusion:</i></b> We demonstrate an oxidative stress adaptation mechanism by PA and EPA/DHA regulated by Nrf2 in podocytes and kidneys of type 2 diabetes. This work provides an important insight into the pathogenetic mechanisms of DN by PA-induced oxidative stress. We conclude that activation of Nrf2-immunoproteasome signaling pathway by EPA/DHA plays a crucial role in abrogating the proteotoxic stress in DN. <i>Antioxid. Redox Signal.</i> 42, 751-766.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"751-766"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nuclear Factor Erythroid 2-Related Factor 2 Activator DDO-1039 Ameliorates Podocyte Injury in Diabetic Kidney Disease via Suppressing Oxidative Stress, Inflammation, and Ferroptosis.","authors":"Xing Liu, Xiuwen Zhai, Xiaoyu Wang, Xiaodong Zhu, Ziyue Wang, Zhengyu Jiang, Hao Bao, ZhaoHong Chen","doi":"10.1089/ars.2024.0653","DOIUrl":"10.1089/ars.2024.0653","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease, and podocyte injury is one of the major contributors to DKD. As a crucial transcriptional factor that regulates cellular response to oxidative stress, nuclear factor erythroid 2-related factor 2 (Nrf2) is an attractive therapeutic target for DKD. In this study, we evaluated the therapeutic potential of DDO-1039, a novel small-molecule Nrf2 activator developed with protein-protein interaction strategy, on podocyte injury in DKD. <b><i>Results:</i></b> DDO-1039 treatment significantly increased Nrf2 protein level and Nrf2 nuclear translocation, thereby upregulating Nrf2 target genes [heme oxygenase 1, NAD(P)H quinone dehydrogenase 1, glutamate-cysteine ligase modifier, and tyrosine-protein kinase receptor] both <i>in vitro</i> and <i>in vivo</i>. DDO-1039 attenuated glomerular sclerosis and podocyte injury in the high-fat diet/streptozotocin-induced (HFD/STZ) diabetic mice and db/db diabetic mice. It also significantly improved hyperglycemia in both diabetic mice and mitigated proteinuria in HFD/STZ mice. Meanwhile, DDO-1039 attenuated oxidative stress and inflammation as well as apoptosis <i>in vivo</i> and in podocytes stimulated with palmitic acid and high glucose. Interestingly, we identified podocyte protective factor Tyro3 as a novel Nrf2-regulated gene. In addition, podocyte ferroptosis is reduced <i>via</i> activation of glutathione peroxidase 4 by the novel Nrf2 activator. <b><i>Innovation and conclusion:</i></b> DDO-1039 activates the Nrf2-based cytoprotective system to mitigate podocyte injury in the context of diabetes, suggesting the potential of DDO-1039 in the treatment of DKD. <i>Antioxid. Redox Signal.</i> 42, 787-806.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"787-806"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sulfur Dioxide Alleviates Aortic Dissection Through Inhibiting Vascular Smooth Muscle Cell Phenotype Switch, Migration, and Proliferation <i>via</i> miR-184-3p/Cyp26b1 Axis.","authors":"Jie He, Kan Huang, Xiaoping Fan, Guangqi Chang","doi":"10.1089/ars.2023.0471","DOIUrl":"10.1089/ars.2023.0471","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Abnormal migration and proliferation of vascular smooth muscle cells (VSMCs) are considered early events in the onset of thoracic aortic dissection (TAD). Endogenous sulfur dioxide (SO₂), primarily produced by aspartate aminotransferase (AAT1) in mammals, has been reported to inhibit the migration and proliferation of VSMCs. However, the role of SO₂ in the development of TAD remains unclear. <b><i>Results:</i></b> Endogenous SO₂ production was decreased in aortic samples from patients with TAD. Supplementation with SO₂ ameliorated β-aminopropionitrile-induced vascular injury in mice. Increasing the expression of SO₂ pathway might reverse the abnormal migration, proliferation, and phenotypic switching in VSMCs. MicroRNA sequencing revealed miR-184-3p as the miRNA with the most significant increased expression level after AAT1 knockdown, and Cyp26b1 was predicted to be its potential target. A decrease in the SO₂ pathway resulted in reduced Cyp26b1 expression, impairing VSMCs function, while restoring Cyp26b1 expression with miR-184-3p inhibitors could improve the VSMCs function. <b><i>Innovation:</i></b> This research extends the application of endogenous SO₂ to the aortic diseases and elucidates the role of miRNA in endogenous SO₂ regulatory network, highlighting its potential as a target for clinical practice. <b><i>Conclusion:</i></b> Endogenous SO₂ inhibits the migration and proliferation of VSMCs in TAD progression <i>via</i> the miR-184-3p/Cyp26b1 axis. <i>Antioxid. Redox Signal.</i> 42, 672-686.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"672-686"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modes of Mitochondrial Reactive Oxygen Species Production in Inflammation.","authors":"Miguel González-Hernández, Laura Gallardo-Andalucía, Pablo Hernansanz-Agustín","doi":"10.1089/ars.2024.0737","DOIUrl":"https://doi.org/10.1089/ars.2024.0737","url":null,"abstract":"<p><p><b><i>Background:</i></b> Inflammation is one of the most important pathways in innate immunity and its relationship with redox biology is becoming increasingly clear in the last decades. However, the specific redox modes and pathways by which inflammation is produced are not yet well defined. <b><i>Significance:</i></b> In this review, we provide a general explanation of the reactive oxygen species (ROS) production and quenching modes occurring in mammalian mitochondria, as well as a summary of the most recent advances in mitochondrial redox biology and bioenergetics regarding sodium (Na⁺) homeostasis. In addition, we provide a collection of examples in which several inflammatory pathways have been associated with specific modes of either mitochondrial ROS production or quenching. <b><i>Innovation:</i></b> The role of Na⁺ in mitochondrial biology is being developed. Since its discovery as a second messenger, the research of its role in the immune system has emerged. Now, the role of Na⁺ in mitochondrial bioenergetics has recently been identified, which owns unprecedented applications. The potential implication of Na⁺ in inflammatory mechanisms grows as its role does not only cover ROS production and respiration but also the control through the management of mitochondrial membrane potential. <b><i>Future directions:</i></b> Na⁺ is becoming relevant for mitochondrial biology. Thus, processes regarding mitochondrial bioenergetics, redox state, or metabolism may probably need to include the study of Na⁺ in their road map. Some of these pathways are involved in inflammation and more are possibly to come. This review is expected to serve as a bridge between both fields. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143969532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impacts of Radiation on Metabolism and Vascular Cell Senescence.","authors":"Junichi Abe, Khanh Chau, Anahita Mojiri, Guangyu Wang, Masayoshi Oikawa, Venkata S K Samanthapudi, Abigail M Osborn, Keila C Ostos-Mendoza, Karla N Mariscal-Reyes, Tammay Mathur, Abhishek Jain, Joerg Herrmann, Syed Wamique Yusuf, Sunil Krishnan, Anita Deswal, Steven H Lin, Sivareddy Kotla, John P Cooke, Nhat-Tu Le","doi":"10.1089/ars.2024.0741","DOIUrl":"https://doi.org/10.1089/ars.2024.0741","url":null,"abstract":"<p><p><b><i>Significance:</i></b> This review investigates how radiation therapy (RT) increases the risk of delayed cardiovascular disease (CVD) in cancer survivors. Understanding the mechanisms underlying radiation-induced CVD is essential for developing targeted therapies to mitigate these effects and improve long-term outcomes for patients with cancer. <b><i>Recent Advances:</i></b> Recent studies have primarily focused on metabolic alterations induced by irradiation in various cancer cell types. However, there remains a significant knowledge gap regarding the role of chronic metabolic alterations in normal cells, particularly vascular cells, in the progression of CVD after RT. <b><i>Critical Issues:</i></b> This review centers on RT-induced metabolic alterations in vascular cells and their contribution to senescence accumulation and chronic inflammation across the vasculature post-RT. We discuss key metabolic pathways, including glycolysis, the tricarboxylic acid cycle, lipid metabolism, glutamine metabolism, and redox metabolism (nicotinamide adenine dinucleotide/Nicotinamide adenine dinucleotide (NADH) and nicotinamide adenine dinucleotide phosphate (NADP⁺)/NADPH). We further explore the roles of regulatory proteins such as p53, adenosine monophosphate-activated protein kinase, and mammalian target of rapamycin in driving these metabolic dysregulations. The review emphasizes the impact of immune-vascular crosstalk mediated by the senescence-associated secretory phenotype, which perpetuates metabolic dysfunction, enhances chronic inflammation, drives senescence accumulation, and causes vascular damage, ultimately contributing to cardiovascular pathogenesis. <b><i>Future Directions:</i></b> Future research should prioritize identifying therapeutic targets within these metabolic pathways or the immune-vascular interactions influenced by RT. Correcting metabolic dysfunction and reducing chronic inflammation through targeted therapies could significantly improve cardiovascular outcomes in cancer survivors. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144061398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Titanium Particles Activate Osteocytic Connexin 43 to Induce Oxidative Stress and Osteoclastogenesis Through the JAK-STAT Pathway.","authors":"Jiawei Ouyang, Hao Chai, Chunguang Sun, Shendong Wang, Chang She, Dechun Geng, Wei Xu","doi":"10.1089/ars.2024.0894","DOIUrl":"https://doi.org/10.1089/ars.2024.0894","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Periprosthetic osteolysis (PPO), a leading cause of aseptic loosening in joint replacement, arose from complex interactions among osteoblasts, osteoclasts, and osteocytes. Given the pivotal role of connexin 43 (Cx43) in osteocyte communication and bone remodeling, investigating its function was essential for understanding the mechanisms of osteolysis. Our previous studies showed that titanium (Ti) particles increased Cx43 expression in osteocytes. However, the role of Cx43 in osteolysis remained unclear. This study investigated the role of Cx43-mediated regulation of osteocytes on osteoclastogenesis in wear debris-induced osteolysis. <b><i>Results:</i></b> Using <i>Dmp1</i>-cre conditional <i>Cx43</i> knockout mice and the MLO-Y4 osteocyte cell line, we demonstrated that <i>Cx43</i> deficiency reduced bone resorption and osteoclastogenesis, thereby improving bone remodeling in a Ti particle-induced osteolysis model. Sequencing analysis revealed that <i>Cx43</i> gene expression changes might be linked to oxidative stress and the Janus Kinase (JAK)-STAT pathway. Elevated Cx43 expression in osteocytes stimulated by Ti particles increased STAT1 protein phosphorylation, induced oxidative stress, elevated the Receptor Activator of Nuclear Factor Kappa-Β Ligand (RANKL)/Osteoprotegerin (OPG) ratio, and promoted osteoclast activation and bone resorption. Conversely, <i>Cx43 gene</i> knockout decreased STAT1 protein phosphorylation and enhanced Nuclear Factor Erythroid 2-Related Factor 2 (NrF2) protein expression. Blocking the JAK-STAT signaling pathway activated by Cx43 increased NrF2 expression, reduced reactive oxygen species levels, and subsequently decreased the RANKL/OPG ratio. <b><i>Innovation and Conclusions:</i></b> This study identified a novel mechanism where Cx43 in osteocytes promoted osteoclastogenesis through JAK-STAT pathway activation and oxidative stress in wear debris-induced osteolysis. These findings highlighted the critical role of Cx43 in bone resorption and suggested targeting Cx43 or the JAK-STAT pathway as potential therapeutic strategies to mitigate osteolysis and improve implant longevity. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"miR-208a-3p Targets PPP6C to Regulate the Progression of Radiation-Induced Pneumonia.","authors":"Lixin Gong, Yi Liu, Jinyu Wang, Zhe Zhao, Wenfang Duan, Yu Xiao, Haibo Peng, Long Zhao, Mouna Khouchani, Takoui Abdelmajid, Nadia Aittahssaint, Tao He, Zhiqiang Jiang, Jingyi Li","doi":"10.1089/ars.2023.0459","DOIUrl":"10.1089/ars.2023.0459","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Radiation-induced pneumonia (RP) is a common complication after radiotherapy for clinical thoracic tumors, and increasing evidence suggests that miRNAs have potential value in regulating radiation-induced lung injury. However, the potential mechanism is still obscure. Here, we evaluated the miRNAs-dependent mechanism involved in the progression of RP. <b><i>Results:</i></b> Our data showed that mmu-miR-208a-3p was consistently highly expressed in the lung tissue of irradiated mice. <i>In vitro</i> studies demonstrated that the expression of miR-208a-3p in cells was significantly increased after X-ray irradiation. Further mechanism studies indicated that radiation-induced upregulation of miR-208a-3p promoted inflammatory responses by suppressing the expression of protein phosphatase 6C (PPP6C) and activating the cyclic GMP-AMP synthase/stimulator of interferon genes protein pathway. Overexpression of PPP6C can alleviate radiation-induced DNA damage and excessive accumulation of ROS. It was also observed that PPP6C inhibited ionizing RP <i>in vivo</i>. [Figure: see text] <b><i>Innovation and Conclusion:</i></b> miR-208a-3p/PPP6C represents a potential therapeutic target for RP which needs to be verified by future clinical studies. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting NADPH Oxidase with APX-115: Suppression of Platelet Activation and Thrombotic Response.","authors":"Joara Jang, Hyunseong Yu, Eun Bee Oh, Ji Won Park, Solee Kim, Taeryeong Kim, Jisue Sohn, Bo-Ram Jin, Tong-Shin Chang","doi":"10.1089/ars.2024.0695","DOIUrl":"10.1089/ars.2024.0695","url":null,"abstract":"<p><p><b><i>Aims:</i></b> NADPH oxidase (NOX)-derived reactive oxygen species (ROS) are critical for platelet activation and thrombus formation. We hypothesized that inhibiting NOX-mediated ROS production with a pan-NOX inhibitor, APX-115, could effectively suppress platelet activation and thrombus formation, potentially serving as a novel antiplatelet therapeutic. This study aimed to explore the effects of APX-115 on human platelet functional responses and ROS-mediated signaling pathways. <b><i>Results:</i></b> APX-115 inhibited intracellular and extracellular ROS production in collagen-stimulated platelets, suppressing aggregation, P-selectin exposure, and ATP release. By preserving protein tyrosine phosphatase activity, APX-115 reduced tyrosine phosphorylation-dependent pathways inhibition, including spleen tyrosine kinase, LAT, Vav1, Bruton's tyrosine kinase, and phospholipase Cγ2, leading to decreased PKC activation and calcium mobilization. APX-115 also suppressed collagen-induced integrin αIIbβ3 activation, accompanied by elevated cGMP and vasodilator-stimulated phosphoprotein phosphorylation levels. In addition, APX-115 reduced p38 MAPK and ERK5 activation, leading to diminished phospholipase A2 phosphorylation, thromboxane production, and the exposure of procoagulant phosphatidylserine. These inhibitory effects extended to thrombus development caused by platelet adherence under shear and arterial thrombosis without prolonging bleeding time in murine models. <b><i>Innovation:</i></b> This study is the first to demonstrate that APX-115 inhibits NOX-mediated ROS production, platelet activation, and thrombus formation. By uncovering its effects on collagen receptor glycoprotein VI-mediated pathways, the work highlights the promise of APX-115 as an antiplatelet and antithrombotic agent. <b><i>Conclusion:</i></b> Our findings highlight the therapeutic potential of APX-115 in treating thrombotic and cardiovascular disorders by targeting NOX-mediated ROS production to mitigate platelet hyperreactivity and thrombus formation. <i>Antioxid. Redox Signal.</i> 00, 000-000. [Figure: see text].</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}