Antioxidants & redox signaling最新文献

{"title":"Superoxide is an Intrinsic Signaling Molecule Triggering Muscle Hypertrophy.","authors":"Siyu Lu, Yiming Zhou, Mincong Liu, Lijun Gong, Li Liu, Zhigui Duan, Keke Chen, Frank J Gonzalez, Fang Wei, Rong Xiang, Guolin Li","doi":"10.1089/ars.2024.0595","DOIUrl":"10.1089/ars.2024.0595","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Redox signaling plays a key role in skeletal muscle remodeling induced by exercise and prolonged inactivity, but it is unclear which oxidant triggers myofiber hypertrophy due to the lack of strategies to precisely regulate individual oxidants <i>in vivo</i>. In this study, we used tetrathiomolybdate (TM) to dissociate the link between superoxide (O₂^•-) and hydrogen peroxide and thereby to specifically explore the role of O₂^•- in muscle hypertrophy in C2C12 cells and mice. <b><i>Results:</i></b> TM can linearly regulate intracellular O₂^•- levels by inhibition of superoxide dismutase 1 (SOD1). A 70% increase in O₂^•- levels in C2C12 myoblast cells and mice is necessary and sufficient for triggering hypertrophy of differentiated myotubes and can enhance exercise performance by more than 50% in mice. SOD1 knockout blocks TM-induced O₂^•- increments and thereby prevents hypertrophy, whereas SOD1 restoration rescues all these effects. Scavenging O₂^•- with antioxidants abolishes TM-induced hypertrophy and the enhancement of exercise performance, whereas the restoration of O₂^•- levels with a O₂^•- generator promotes muscle hypertrophy independent of SOD1 activity. <b><i>Innovation and Conclusion:</i></b> These findings suggest that O₂^•- is an endogenous initiator of myofiber hypertrophy and that TM may be used to treat muscle wasting diseases. Our work not only suggests a novel druggable mechanism to increase muscle mass but also provides a tool for precisely regulating O₂^•- levels <i>in vivo</i>. <i>Antioxid. Redox Signal.</i> 42, 1-15.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"1-15"},"PeriodicalIF":5.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11807898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141320367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 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":"https://doi.org/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> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-12-27","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":"Adverse Effects of Nrf2 in Different Organs and the Related Diseases.","authors":"Xuemei Jin, Long Chen, Yuelan Yang, Rongshao Tan, Chunjie Jiang","doi":"10.1089/ars.2024.0586","DOIUrl":"https://doi.org/10.1089/ars.2024.0586","url":null,"abstract":"<p><p><b><i>Significance:</i></b> Under normal physiological conditions, Nrf2 undergoes ubiquitination and subsequent proteasome degradation to maintain its basal activity. Oxidative stress can trigger Nrf2 activation, prompting its translocation to the nucleus where it functions as a transcription factor, activating various antioxidant pathways, and conferring antioxidant properties. <b><i>Recent Advances:</i></b> While extensive research has shown Nrf2's protective role in various diseases, emerging evidence suggests that Nrf2 activation can also produce harmful effects. <b><i>Critical Issues:</i></b> This review examines the pathological contexts in which Nrf2 assumes different roles, emphasizing the mechanisms and conditions that result in adverse outcomes. <b><i>Future Directions:</i></b> Persistent Nrf2 activation may have deleterious consequences, necessitating further investigation into the specific conditions and mechanisms through which Nrf2 exerts its harmful effects. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891543","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":"https://doi.org/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> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-12-24","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":"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":"https://doi.org/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> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-12-04","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":"Development of Calcium-Dependent Phospholipase A2 Inhibitors to Target Cellular Senescence and Oxidative Stress in Neurodegenerative Diseases.","authors":"Cristelle Hugo, Isaac Asante, Anastasiia Sadybekov, Vsevolod Katritch, Hussein N Yassine","doi":"10.1089/ars.2024.0794","DOIUrl":"10.1089/ars.2024.0794","url":null,"abstract":"<p><p><b><i>Significance:</i></b> Cellular senescence is a critical process underlying aging and is associated with age-related diseases such as Alzheimer's disease. Lipids are implicated in cellular senescence. Fatty acids, particularly eicosanoids, have been associated with various forms of senescence and inflammation, and the associated reactive oxygen species production has been proposed as a therapeutic target for mitigating senescence. When overactivated, calcium-dependent phospholipase A2 (cPLA2) catalyzes the conversion of arachidonic acid into eicosanoids such as leukotrienes and prostaglandins. <b><i>Recent Advances:</i></b> With a growing understanding of the importance of lipids as mediators and modulators of senescence, cPLA2 has emerged as a compelling drug target. cPLA2 overactivation plays a significant role in several pathways associated with senescence, including neuroinflammation and oxidative stress. <b><i>Critical Issues:</i></b> Previous cPLA2 inhibitors have shown potential in ameliorating inflammation and oxidative stress, but the dominant hurdles in the central nervous system-targeting drug discovery are specificity and blood-brain barrier penetrance. <b><i>Future Directions:</i></b> With the need for more effective drugs against neurological diseases, we emphasize the significance of discovering new brain-penetrant, potent, and specific cPLA2 inhibitors. We discuss how the recently developed Virtual Synthon Hierarchical Enumeration Screening, an iterative synthon-based approach for fast structure-based virtual screening of billions of compounds, provides an efficient exploration of large chemical spaces for the discovery of brain-penetrant cPLA2 small-molecule inhibitors. <i>Antioxid. Redox Signal.</i> 41, 1100-1116.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"1100-1116"},"PeriodicalIF":5.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685862","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 Emerging Roles of Hydrogen Sulfide in Ferroptosis.","authors":"Yi-Wen Zhu, Zi-Tao Liu, Ao-Qi Tang, Xiao-Yi Liang, Yan Wang, Ya-Fang Liu, Yu-Qing Jin, Wei Gao, Hang Yuan, Da-Yong Wang, Xin-Ying Ji, Dong-Dong Wu","doi":"10.1089/ars.2023.0535","DOIUrl":"10.1089/ars.2023.0535","url":null,"abstract":"<p><p><b><i>Significance:</i></b> Ferroptosis, a form of regulated cell death characterized by a large amount of lipid peroxidation-mediated membrane damage, joins the evolution of multisystem diseases, for instance, neurodegenerative diseases, chronic obstructive pulmonary disease, acute respiratory distress syndrome, osteoporosis, osteoarthritis, and so forth. Since being identified as the third gasotransmitter in living organisms, the intricate role of hydrogen sulfide (H₂S) in ferroptosis has emerged at the forefront of research. <b><i>Recent Advances:</i></b> Novel targets in the relevant metabolic pathways have been found, including transferrin receptor 1, cystine/glutamate antiporter, and others, coupled with the exploration of new signaling pathways, particularly the p53 signaling pathway, the nitric oxide/nuclear factor erythroid 2-related factor 2 signaling pathway, and so on. Many diseases such as emphysema and airway inflammation, myocardial diseases, endothelial dysfunction in aging arteries, and traumatic brain injury have recently been found to be alleviated directly by H₂S inhibition of ferroptosis. Safe, effective, and tolerable novel H₂S donors have been developed and have shown promising results in phase I clinical trials. <b><i>Critical Issues:</i></b> Complicated cross talk between the ferroptosis signaling pathway and oncogenic factors results in the risk of cancer when inhibiting ferroptosis. Notably, targeted delivery of H₂S is still a challenging task. <b><i>Future Directions:</i></b> Discovering more reliable and stable novel H₂S donors and achieving their targeted delivery will enable further clinical trials for diseases associated with ferroptosis inhibition by H₂S, determining their safety, efficacy, and tolerance. <i>Antioxid. Redox Signal.</i> 41, 1150-1172.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"1150-1172"},"PeriodicalIF":5.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141747283","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":"High Uric Acid Orchestrates Ferroptosis to Promote Cardiomyopathy Via ROS-GPX4 Signaling.","authors":"Chenxi Xu, Mengni Wu, Wei Yu, De Xie, Qiang Wang, Binyang Chen, Yuemei Xi, Linqian Yu, Yunbo Yan, Tetsuya Yamamoto, Hidenori Koyama, Hong Zhao, Jidong Cheng","doi":"10.1089/ars.2023.0473","DOIUrl":"10.1089/ars.2023.0473","url":null,"abstract":"<p><p><b><i>Aims:</i></b> High uric acid (HUA), as a pro-oxidant, plays a significant role in the pathophysiology of cardiovascular disease. Studies have indicated that elevated uric acid levels can adversely affect cardiovascular health. Nevertheless, the impact of hyperuricemia on cardiomyopathy remains uncertain. Further research is needed to elucidate the relationship between HUA and cardiomyopathy, shedding light on its potential implications for heart health. <b><i>Results:</i></b> We demonstrated that uricase knockout (Uox-KO) mice accelerated the development of cardiomyopathy, causing significantly impaired cardiac function and myocardial fibrosis. Meanwhile, the mitochondrial morphology was destroyed, the lipid peroxidation products increased in number and the antioxidant function was weakened. In addition, we evaluated the effects of ferrostatin-1 (Fer-1), the ferroptosis inhibitor. Myocardial damage can be reversed by the Fer-1 treatment caused by HUA combined with doxorubicin (DOX) treatment. Benzbromarone, a uric acid-lowering drug, decreases myocardial fibrosis, and ferroptosis by alleviating hyperuricemia in Uox-KO mice by DOX administration. In vitro, we observed that the activity of cardiomyocytes treated with HUA combined with DOX decreased significantly, and lipid reactive oxygen species (ROS) increased significantly. Afterward, we demonstrated that HUA can promote oxidative stress in DOX, characterized by increased mitochondrial ROS, and downregulate protein levels of glutathione peroxidase 4 (GPX4). <i>N</i>-acetyl-l-cysteine, an antioxidant, inhibits the process by which HUA promotes DOX-induced ferroptosis by increasing the GPX4 expression. <b><i>Innovation:</i></b> We verified that HUA can exacerbate myocardial damage. This has clinical implications for the treatment of cardiac damage in patients with hyperuricemia. <b><i>Conclusions:</i></b> Our data suggested that HUA promotes the cardiomyopathy. HUA promotes DOX-induced ferroptosis by increasing oxidative stress and downregulating GPX4. <i>Antioxid. Redox Signal.</i> 41, 1134-1149.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"1134-1149"},"PeriodicalIF":5.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141900784","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":"Myelin Lipid Alterations in Neurodegenerative Diseases: Landscape and Pathogenic Implications.","authors":"Ziying Xu, Sijia He, Mst Marium Begum, Xianlin Han","doi":"10.1089/ars.2024.0676","DOIUrl":"10.1089/ars.2024.0676","url":null,"abstract":"<p><p><b><i>Significance:</i></b> Lipids, which constitute the highest portion (over 50%) of brain dry mass, are crucial for brain integrity, energy homeostasis, and signaling regulation. Emerging evidence revealed that lipid profile alterations and abnormal lipid metabolism occur during normal aging and in different forms of neurodegenerative diseases. Moreover, increasing genome-wide association studies have validated new targets on lipid-associated pathways involved in disease development. Myelin, the protective sheath surrounding axons, is crucial for efficient neural signaling transduction. As the primary site enriched with lipids, impairments of myelin are increasingly recognized as playing significant and complex roles in various neurodegenerative diseases, beyond simply being secondary effects of neuronal loss. <b><i>Recent Advances:</i></b> With advances in the lipidomics field, myelin lipid alterations and their roles in contributing to or reflecting the progression of diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and others, have recently caught great attention. <b><i>Critical Issues:</i></b> This review summarizes recent findings of myelin lipid alterations in the five most common neurodegenerative diseases and discusses their implications in disease pathogenesis. <b><i>Future Directions:</i></b> By highlighting myelin lipid abnormalities in neurodegenerative diseases, this review aims to encourage further research focused on lipids and the development of new lipid-oriented therapeutic approaches in this area. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"1073-1099"},"PeriodicalIF":5.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11971557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adenosine A2A Receptor Antagonist Sch58261 Improves the Cognitive Function in Alzheimer's Disease Model Mice Through Activation of Nrf2 via an Autophagy-Dependent Pathway.","authors":"Yi Sun, Chao Liu, Ling He","doi":"10.1089/ars.2023.0455","DOIUrl":"10.1089/ars.2023.0455","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Adenosine, an important endogenous neuromodulator, contributes to a broad set of several neurodegenerative diseases. The adenosine A2A receptor (A2AR) is the most involved in neuropathological effects and plays an important role in the pathogenesis of Alzheimer's disease (AD). However, the effect of A2AR antagonist and the underlying mechanism in AD model mice remains unclear. <b><i>Results:</i></b> The amyloid beta (Aβ)_1-42-induced mice AD models were used in this study. Several behavioral experiments were performed to evaluate the improvement of AD mice treated with A2AR antagonist. For mechanism analysis, autophagy-related proteins, Kelch-like ECH-associated protein1 (Keap1)-nuclear factor erythroid-derived factor 2-related factor (Nrf2) pathway activation, and synaptic function were studied using Western blot, immunofluorescence, immunohistochemistry, transmission electron microscope, real-time quantitative PCR, and patch clamp. Pharmacological blockade of adenosine A2AR by SCH58261 (SCH) ameliorated cognitive deficits and decreased expression levels of several AD biomarkers, including Aβ and hyperphosphorylation of Tau. Moreover, SCH activated the Nrf2 pathway through autophagy mediated Keap1 degradation, resulting in the improvement of neuron autophagy dysfunction, synaptic plasticity, and synaptic transmission. <b><i>Innovation:</i></b> Our data clarified that the SCH (an antagonist of A2AR) could increase the level of autophagy, promote the ability of antioxidative stress by the activation of Keap1-Nrf2 pathway, and improve the synaptic function in Aβ_1-42-induced AD mice or cell model, which provided a potential therapeutic strategy for AD. <b><i>Conclusion:</i></b> A2AR antagonism represents a promising strategy for the anti-AD agent development through autophagy-dependent pathway. <i>Antioxid. Redox Signal.</i> 41, 1117-1133.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"1117-1133"},"PeriodicalIF":5.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140890819","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}