Antioxidants & redox signaling最新文献

{"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}

{"title":"Remote Organ Damage Induced by Stroke: Molecular Mechanisms and Comprehensive Interventions.","authors":"Jie Wang, Sen Gao, Yue Cui, Xun-Zhi Liu, Xiang-Xin Chen, Chun-Hua Hang, Wei Li","doi":"10.1089/ars.2024.0720","DOIUrl":"https://doi.org/10.1089/ars.2024.0720","url":null,"abstract":"<p><p><b><i>Significance:</i></b> Damage after stroke is not only limited to the brain but also often occurs in remote organs, including the heart, lung, liver, kidney, digestive tract, and spleen, which are frequently affected by complex pathophysiological changes. The organs in the human body are closely connected, and signals transmitted through various molecular substances could regulate the pathophysiological changes of remote organs. <b><i>Recent Advances:</i></b> The latest studies have shown that inflammatory response plays an important role in remote organ damage after stroke, and can aggravate remote organ damage by activating oxidative stress, sympathetic axis, and hypothalamic axis, and disturbing immunological homeostasis. Remote organ damage can also cause damage to the brain, aggravating inflammatory response and oxidative damage. <b><i>Critical Issues:</i></b> Therefore, an in-depth exploration of inflammatory and oxidative mechanisms and adopting corresponding comprehensive intervention strategies have become necessary to reduce damage to remote organs and promote brain protection. <b><i>Future Directions:</i></b> The comprehensive intervention strategy involves multifaceted treatment methods such as inflammation regulation, antioxidants, and neural stem cell differentiation. It provides a promising treatment alternative for the comprehensive recovery of stroke patients and an inspiration for future research and treatment. The various organs of the human body are interconnected at the molecular level. Only through comprehensive intervention at the molecular and organ levels can we save remote organ damage and protect the brain after stroke to the greatest extent. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762522","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":"TRPC6 Channel Regulates Airway Remodeling in Chronic Obstructive Pulmonary Disease Causing Right Heart Failure.","authors":"Kun Liu, Qi-Ming Tan, Jie Zhang, Gong-Hao Li, Yun-Feng Zhao","doi":"10.1089/ars.2024.0571","DOIUrl":"10.1089/ars.2024.0571","url":null,"abstract":"<p><p>The role of the canonical transient receptor potential 6 (TRPC6) channel in chronic obstructive pulmonary disease (COPD) remains poorly understood at the mechanistic level. <b><i>Objects:</i></b> This study aims to investigate the involvement of TRPC6 in COPD and its signaling mechanisms in human airway smooth muscle cells (HASMCs). <i><b>Methods and Results:</b></i> The study found that mRNA and protein expression of TRPC6 increased in cultured HASMCs that were incubated with nicotine, as measured by reverse transcription quantitative polymerase chain reaction and Western blot analysis. Nicotine treatment significantly enhanced TRPC6 transcriptional activity in HASMCs through nuclear factor (NF)-κB, as demonstrated by co-immunoprecipitation and electrophoretic mobility shift assays. Furthermore, miR-135a/b-5p was shown to downregulate TRPC6 expression in HASMCs at the mRNA and protein levels, as confirmed by luciferase reporter assays. Immunohistochemistry assays in a mouse model of cigarette-induced airway remodeling revealed a significant increase in smooth muscle (SM) cell proliferation and SM layer mass. <i><b>Conclusion:</b></i> These findings suggest that nicotine exposure increases HASMC proliferation and migration through NF-κB signaling, and that cigarette smoke inhalation causes airway SM layer remodeling <i>via</i> altered TRPC6-induced Ca²⁺ influx, which is abolished by miR-135a/b-5p both <i>in vitro</i> and <i>in vivo</i>. <i>Antioxid. Redox Signal.</i> 42, 480-493.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"480-493"},"PeriodicalIF":5.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142778929","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 Oxidoreductase Retinol Saturase in Thyroid Gland Is Regulated by Hypothyroidism and Iodide Overload and Its Deletion Impairs Metabolic Homeostasis in Mice.","authors":"Na Yang, Lisa Wessoly, Yueming Meng, Marie F Kiefer, Yingfu Chen, Madita Vahrenbrink, Sascha Wulff, Chen Li, Jonah W Schreier, Julia S Steinhoff, Moritz Oster, Manuela Sommerfeld, Sylvia J Wowro, Konstantin M Petricek, Roberto E Flores, Panos G Ziros, Gerasimos P Sykiotis, Eva K Wirth, Michael Schupp","doi":"10.1089/ars.2023.0458","DOIUrl":"10.1089/ars.2023.0458","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Thyroid hormones (TH) are major regulators of cell differentiation, growth, and metabolic rate. TH synthesis in the thyroid gland requires high amounts of H₂O₂ to oxidize iodide for the iodination of thyroglobulin (TG). Retinol Saturase (RetSat) is an oxidoreductase implicated in dihydroretinol formation and cellular sensitivity toward peroxides and ferroptosis. RetSat is highly expressed in metabolically active organs where it regulates lipid metabolism and the production of reactive oxygen species. Due to the high expression of RetSat in the thyroid gland and its role in peroxide sensitivity, we investigated the regulation and function of RetSat in the thyroid gland in appropriate mouse models. <b><i>Results:</i></b> RetSat is strongly expressed in thyrocytes, induced by hypothyroidism, and decreased by iodide overload in mice. Thyrocyte-specific deletion of <i>RetSat</i> increased circulating thyroid-stimulating hormone levels, altered thyroid morphology, and disturbed metabolic homeostasis in a diet- and sex-dependent manner without major effects on the concentrations of circulating TH. Moreover, deletion of <i>RetSat</i> increased TG protein levels but lowered TG iodination upon iodide overload. In cultured thyrocytes, acute RetSat depletion altered the expression of genes involved in TH biosynthesis and the response to endoplasmic reticulum stress. <b><i>Innovation:</i></b> This is the first report that specifically dissects the regulation and function of the oxidoreductase RetSat in the thyroid gland. <b><i>Conclusion:</i></b> Deletion of <i>RetSat</i> in thyrocytes induces compensatory feedback mechanisms to maintain TH homeostasis in mice. We conclude that RetSat in the thyroid gland is required for TH biosynthesis and secretion and metabolic homeostasis in mice. <i>Antioxid. Redox Signal.</i> 42, 463-479.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"463-479"},"PeriodicalIF":5.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930480","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":"Viral Infections and the Glutathione Peroxidase Family: Mechanisms of Disease Development.","authors":"Qingqing Lu, Yuan Ding, Wen Liu, Shuzhen Liu","doi":"10.1089/ars.2024.0645","DOIUrl":"10.1089/ars.2024.0645","url":null,"abstract":"<p><p><b><i>Significance:</i></b> The glutathione peroxidase (GPx) family is recognized for its essential function in maintaining cellular redox balance and countering the overproduction of reactive oxygen species (ROS), a process intricately linked to the progression of various diseases including those spurred by viral infections. The modulation of GPx activity by viruses presents a critical juncture in disease pathogenesis, influencing cellular responses and the trajectory of infection-induced diseases. <b><i>Recent Advances:</i></b> Cutting-edge research has unveiled the GPx family's dynamic role in modulating viral pathogenesis. Notably, GPX4's pivotal function in regulating ferroptosis presents a novel avenue for the antiviral therapy. The discovery that selenium, an essential micronutrient for GPx activity, possesses antiviral properties has propelled us toward rethinking traditional treatment modalities. <b><i>Critical Issues:</i></b> Deciphering the intricate relationship between viral infections and GPx family members is paramount. Viral invasion can precipitate significant alterations in GPx function, influencing disease outcomes. The multifaceted nature of GPx activity during viral infections suggests that a deeper understanding of these interactions could yield novel insights into disease mechanisms, diagnostics, prognostics, and even chemotherapeutic resistance. <b><i>Future Directions:</i></b> This review aims to synthesize current knowledge on the impact of viral infections on GPx activity and expression and identify key advances. By elucidating the mechanisms through which GPx family members intersect with viral pathogenesis, we propose to uncover innovative therapeutic strategies that leverage the antioxidant properties of GPx to combat viral infections. The exploration of GPx as a therapeutic target and biomarker holds promise for the development of next-generation antiviral therapies. <i>Antioxid. Redox Signal.</i> 42, 623-639.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"623-639"},"PeriodicalIF":5.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493408","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":"Liposomes-Loaded miR-9-5p Alleviated Hypoxia-Ischemia-Induced Mitochondrial Oxidative Stress by Targeting ZBTB20 to Inhibiting Nrf2/Keap1 Interaction in Neonatal Mice.","authors":"Yijing Zhao, Chengcheng Gai, Shuwen Yu, Yan Song, Bing Gu, Qian Luo, Xixi Wang, Quan Hu, Weiyang Liu, Dexiang Liu, Zhen Wang","doi":"10.1089/ars.2024.0640","DOIUrl":"10.1089/ars.2024.0640","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Hypoxia ischemia (HI) is a leading cause of cerebral palsy and long-term neurological sequelae in infants. Given that mitochondrial dysfunction in neurons contributes to HI brain damage, this study aimed to investigate the regulatory role of miR-9-5p in mitochondrial function following HI injury. <b><i>Results:</i></b> Overexpression of miR-9-5p in HI mice or H₂O₂-exposed PC12 cells suppressed neuronal injury, associated with increased mitochondrial copy number, normalizing mitochondrial membrane potential, improved nuclear factor-erythroid factor 2-related factor 2 (Nrf2) activation, and downregulation of Keap1. This was mediated, in part, through the ability of this miR-9-5p to bind and regulate the transcriptional activity of zinc finger and BTB domain-containing protein 20 (ZBTB20). Further study suggested that the knockdown of ZBTB20 exerts neuroprotection by inhibiting Nrf2/Keap1 interaction to promote the translocation of Nrf2 from the cytoplasm to the nucleus and the consequent expression of antioxidant proteins. Notably, the protective effects of miR-9-5p overexpression against HI-induced mitochondrial damage were reversed by the Nrf2 inhibitor ML385. Finally, the utilization of liposomes for the delivery of miR-9-5p (miR-9-5p@Lip) presents a promising therapeutic strategy for the treatment of HI injury. <b><i>Innovation:</i></b> miR-9-5p is a potential therapeutic agent for ischemic stroke through its modulation of the ZBTB20/Nrf2/Keap1 signaling pathway, influencing mitochondrial function and antioxidant response. Furthermore, the use of liposomal delivery for miR-9-5p offers a promising therapeutic strategy for HI injury. <b><i>Conclusion:</i></b> Overexpression of miR-9-5p protects against cerebral HI injury by modulating mitochondrial function through the ZBTB20/Nrf2/Keap1 signaling pathway. <i>Antioxid. Redox Signal.</i> 42, 512-528. [Figure: see text].</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"512-528"},"PeriodicalIF":5.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045393","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":"Adeno-Associated Virus-Mediated <i>Dickkopf-1</i> Gene Transduction Reduces Silica-Induced Oxidative Stress and Silicosis in Mouse Lung.","authors":"Jia Ma, Jiaqi Wang, Ruiting Sun, Zheqing Hu, Zhaojun Wang, Jing Xue, Shuang Wu, Wenfeng Hu, Jing Wang, Liyuan Yang, Qian Cai, Jiali Yang, Juan Chen, Xiaoming Liu","doi":"10.1089/ars.2024.0646","DOIUrl":"10.1089/ars.2024.0646","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Silicosis is a lung disease caused by inhalation of silica particles. Both silica-induced oxidative stress and aberrant activation of the Wnt/β-catenin signaling pathway are potential targets in the treatment of pulmonary fibrosis. Dickkopf-1 (Dkk1), an inhibitor of the Wnt/β-catenin signaling pathway, plays regulatory roles in cell fate determination and immune responses. Our previous study demonstrated that adenoviral vector-mediated <i>Dkk1</i> gene transfer alleviated the silica-induced mouse silicosis. However, the mechanism of therapeutic action of Dkk1 in silicosis is yet completely understood; together with the drawbacks of adenoviral vectors in gene therapy, we investigated the therapeutic effect and mechanisms of Dkk1 by employing an adeno-associated virus (AAV) vector in a silicosis mouse model. <b><i>Results:</i></b> The AAV vector could efficiently transduce the <i>Dkk1</i> gene in silicotic lung during both the early and the late phases of disease, resulting in an alleviation of silicotic lesions, improvement of pulmonary compliance, and radiological findings. Mechanistic studies further demonstrated that the transduction of <i>Dkk1</i> inhibited the silica-activated Wnt/β-catenin signaling and reduced the silica-induced reactive oxygen species-producing enzyme NADPH oxidase 4, oxidative stress regulator nuclear factor erythroid 2-related factor 2, and signaling molecules binding immunoglobulin protein and C/EBP homologous protein. In addition, shRNA-mediated downregulation of <i>Dkk1</i> exacerbated the progression of silicosis in mice, whereas the treatment of ROS scavenger n-acetylcysteine showed a comparable mitigation of silicosis that was seen in the AAV-Dkk1 treatment. <b><i>Innovation and Conclusion:</i></b> This study provides an insight into the mechanism by which Dkk1 inhibits the silica-induced Wnt signaling and oxidative stress to mitigate the pathogenesis of lung silicosis and evidence of the potential of AAV-mediated Dkk1 gene transfer as an alternative approach in silicosis treatment. <i>Antioxid. Redox Signal.</i> 42, 529-546.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"529-546"},"PeriodicalIF":5.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613514","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":"Physiological Fatty Acid-Stimulated Insulin Secretion and Redox Signaling <i>Versus</i> Lipotoxicity.","authors":"Petr Ježek","doi":"10.1089/ars.2024.0799","DOIUrl":"10.1089/ars.2024.0799","url":null,"abstract":"<p><p><b><i>Significance:</i></b> Type 2 diabetes as a world-wide epidemic is characterized by the insulin resistance concomitant to a gradual impairment of β-cell mass and function (prominently declining insulin secretion) with dysregulated fatty acids (FAs) and lipids, all involved in multiple pathological development. <b><i>Recent Advances:</i></b> Recently, redox signaling was recognized to be essential for insulin secretion stimulated with glucose (GSIS), branched-chain keto-acids, and FAs. FA-stimulated insulin secretion (FASIS) is a normal physiological event upon postprandial incoming chylomicrons. This contrasts with the frequent lipotoxicity observed in rodents. <b><i>Critical Issues</i></b>: Overfeeding causes FASIS to overlap with GSIS providing repeating hyperinsulinemia, initiates prediabetic states by lipotoxic effects and low-grade inflammation. In contrast the protective effects of lipid droplets in human β-cells counteract excessive lipids. Insulin by FASIS allows FATP1 recruitment into adipocyte plasma membranes when postprandial chylomicrons come late at already low glycemia. <b><i>Future Directions:</i></b> Impaired states of pancreatic β-cells and peripheral organs at prediabetes and type 2 diabetes should be revealed, including the inter-organ crosstalk by extracellular vesicles. Details of FA/lipid molecular physiology are yet to be uncovered, such as complex phenomena of FA uptake into cells, postabsorptive inactivity of G-protein-coupled receptor 40, carnitine carrier substrate specificity, the role of carnitine-O-acetyltransferase in β-cells, and lipid droplet interactions with mitochondria. <i>Antioxid. Redox Signal.</i> 42, 566-622.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"566-622"},"PeriodicalIF":5.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998919","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":"Regulation of Mitochondrial Quality Control of Intestinal Stem Cells in Homeostasis and Diseases.","authors":"Xudan Lei, Zhenni Xu, Yujun Huang, Lingxiao Huang, Jinyi Lang, Mingyue Qu, Dengqun Liu","doi":"10.1089/ars.2023.0489","DOIUrl":"10.1089/ars.2023.0489","url":null,"abstract":"<p><p><b><i>Significance:</i></b> Intestinal stem cells (ISCs) are crucial for the continuous renewal and regeneration of the small intestinal epithelium. ISC fate decisions are strictly controlled by metabolism. Mitochondria act as the central hubs of energetic metabolism and dynamically remodel their morphology to perform required metabolic functions. Mitochondrial dysfunction is closely associated with a variety of gastrointestinal diseases. <b><i>Recent Advances:</i></b> In recent years, several studies have reported that mitochondria are potential therapeutic targets for regulating ISC function to alleviate intestinal diseases. However, how mitochondrial quality control mediates ISCs under physiological conditions and protects against intestinal injury remains to be comprehensively reviewed. <b><i>Critical Issues:</i></b> In this review, we summarize the available studies about how mitochondrial metabolism, redox state, dynamics, autophagy, and proteostasis impact ISC proliferation, differentiation, and regeneration, respectively. <b><i>Future Directions:</i></b> We propose that remodeling the function of mitochondria in ISCs may be a promising potential future direction for the treatment of intestinal diseases. This review may provide new strategies for therapeutically targeting the mitochondria of ISCs in intestinal diseases. <i>Antioxid. Redox Signal.</i> 42, 494-511.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"494-511"},"PeriodicalIF":5.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118835","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":"4-Octyl Itaconate Attenuates Cell Proliferation by Cellular Senescence <i>via</i> Glutathione Metabolism Disorders and Mitochondrial Dysfunction in Melanoma.","authors":"Yoshikazu Hayashi, Ayaka Saeki, Shohei Yoshimoto, Ena Yano, Atsushi Yasukochi, Soi Kimura, Tomoe Utsunomiya, Kento Minami, Yuji Aso, Yuji Hatakeyama, Yi-Chen Lo, Masato Hirata, Eijiro Jimi, Tomoyo Kawakubo-Yasukochi","doi":"10.1089/ars.2024.0629","DOIUrl":"10.1089/ars.2024.0629","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Itaconate (IA) is synthesized in the citric acid cycle <i>via</i> cis-aconitate decarboxylase (ACOD1); however, its biological significance in cancer remains incompletely understood. In previous studies, 4-octyl itaconate (OI) was used as a membrane-permeable form of IA, but little detailed verification of the difference in biological activities between IA and OI exists. Here, we investigated the direct effects of IA and OI on melanoma. <b><i>Results:</i></b> The proliferation of melanoma cells treated with OI was significantly suppressed <i>in vitro</i>, and our transcriptomic analysis revealed drastic changes in the expression of glutathione metabolism-related genes in OI-treated cells. Indeed, OI treatment decreased intracellular glutathione levels, followed by increased production of reactive oxygen species and expression of γH2AX, a marker of DNA damage, and β-galactosidase, a marker of cellular senescence. We further showed that the mitochondrial respiratory capacity in B16 cells was significantly decreased by OI treatment. OI administration also suppressed the growth of B16 tumor transplants <i>in vivo</i>, and the expression of γH2AX was increased in tumor tissues of OI-treated mice. In addition, minimal effects of OI treatment were observed in melanocytes and normal tissues. We also proved that not only exogenous IA, which enters intracellularly, but also endogenous IA has little effect on melanoma proliferation activity, <i>via</i> an investigation using <i>Acod1</i>-overexpressing transfectants and <i>Acod1</i>-deficient mice. <b><i>Conclusion:</i></b> This work revealed that OI disrupts the antioxidant system <i>via</i> the collapse of glutathione metabolism and inhibits cancer cell proliferation. <i>Antioxid. Redox Signal.</i> 42, 547-565.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"547-565"},"PeriodicalIF":5.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390001","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}