{"title":"Anti-Inflammatory Effects of Hydrogen Sulfide in Axes Between Gut and Other Organs.","authors":"Weizhuo Lu, Jiyue Wen","doi":"10.1089/ars.2023.0531","DOIUrl":"https://doi.org/10.1089/ars.2023.0531","url":null,"abstract":"<p><p><b><i>Significance:</i></b> Hydrogen sulfide (H<sub>2</sub>S), a ubiquitous small gaseous signaling molecule, plays a critical role in various diseases, such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA), ischemic stroke, and myocardial infarction (MI) <i>via</i> reducing inflammation, inhibiting oxidative stress, and cell apoptosis. <b><i>Recent Advances:</i></b> Uncontrolled inflammation is closely related to pathological process of ischemic stroke, RA, MI, and IBD. Solid evidence has revealed the axes between gut and other organs like joint, brain, and heart, and indicated that H<sub>2</sub>S-mediated anti-inflammatory effect against IBD, RA, MI, and ischemic stroke might be related to regulating the functions of axes between gut and other organs. <b><i>Critical Issues:</i></b> We reviewed endogenous H<sub>2</sub>S biogenesis and the H<sub>2</sub>S-releasing donors, and revealed the anti-inflammatory effects of H<sub>2</sub>S in IBD, ischemic stroke, RA, and MI. Importantly, this review outlined the potential role of H<sub>2</sub>S in the gut-joint axis, gut-brain axis, and gut-heart axis as a gasotransmitter. <b><i>Future Direction:</i></b> The rate, location, and timing of H<sub>2</sub>S release from its donors determine its potential success or failure as a useful therapeutic agent and should be focused on in the future research. Therefore, there is still a need to explore internal and external sources monitoring and controlling H<sub>2</sub>S concentration. Moreover, more efficient H<sub>2</sub>S-releasing compounds are needed; a better understanding of their chemistry and properties should be further developed. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798974","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}
Samar Farha, Kewal Asosingh, Paul M Hassoun, John Barnard, Suzy Comhair, Andrew Reichard, Nicholas Wanner, Milena Radeva, Micheala A Aldred, Gerald J Beck, Erika Berman-Rosenzweig, Barry A Borlaug, J Emanuel Finet, Robert P Frantz, Gabriele Grunig, Anna R Hemnes, Nicholas Hill, Evelyn M Horn, Christine Jellis, Jane A Leopold, Reena Mehra, Margaret M Park, Franz P Rischard, W H Wilson Tang, Serpil C Erzurum
{"title":"Alterations in Mitochondrial Function in Pulmonary Vascular Diseases.","authors":"Samar Farha, Kewal Asosingh, Paul M Hassoun, John Barnard, Suzy Comhair, Andrew Reichard, Nicholas Wanner, Milena Radeva, Micheala A Aldred, Gerald J Beck, Erika Berman-Rosenzweig, Barry A Borlaug, J Emanuel Finet, Robert P Frantz, Gabriele Grunig, Anna R Hemnes, Nicholas Hill, Evelyn M Horn, Christine Jellis, Jane A Leopold, Reena Mehra, Margaret M Park, Franz P Rischard, W H Wilson Tang, Serpil C Erzurum","doi":"10.1089/ars.2024.0557","DOIUrl":"https://doi.org/10.1089/ars.2024.0557","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Alterations of mitochondrial bioenergetics and arginine metabolism are universally present and mechanistically linked to pulmonary arterial hypertension (PAH), but there is little knowledge of arginine metabolism and mitochondrial functions across the different pulmonary hypertension (PH) groups. We hypothesize that abnormalities in mitochondrial functions are present across all PH groups and associated with clinical phenotypes. We test the hypothesis in PH patients and healthy controls from the Pulmonary Vascular Disease Phenomics Program cohort, who had comprehensive clinical phenotyping and follow-up for at least 4 years for death or transplant status. Mitochondrial transmembrane potential, superoxide production, and mass were measured by flow cytometry in fresh platelets. Metabolomics analysis was performed on plasma samples. Global arginine bioavailability was calculated as the ratio of arginine/(ornithine+citrulline). <b><i>Results:</i></b> Global arginine bioavailability is consistently lower than controls in all PH groups. Although the mitochondrial mass is similar across all PH groups and controls, superoxide production and transmembrane potential vary across groups. Mitochondrial superoxide is higher in group 1 PAH and lowest in group 3 compared with other groups, while transmembrane potential is lower in group 1 PAH than controls or group 3. The alterations in mitochondrial functions of group 1 PAH are associated with changes in fatty acid metabolism. Mitochondrial transmembrane potential in group 1 PAH is associated with transplant-free survival. <b><i>Conclusion:</i></b> While alterations in mitochondrial function are found in all PH groups, group 1 PAH has a unique mitochondrial phenotype with greater superoxide and lower transmembrane potential linked to fatty acid metabolism, and clinically to survival. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798984","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}
Kun Liu, Qi-Ming Tan, Jie Zhang, Gong-Hao Li, Yun-Feng Zhao
{"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 Ca<sup>2+</sup> 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}
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
{"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 (H<sub>2</sub>S) 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 H<sub>2</sub>S inhibition of ferroptosis. Safe, effective, and tolerable novel H<sub>2</sub>S 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 H<sub>2</sub>S is still a challenging task. <b><i>Future Directions:</i></b> Discovering more reliable and stable novel H<sub>2</sub>S donors and achieving their targeted delivery will enable further clinical trials for diseases associated with ferroptosis inhibition by H<sub>2</sub>S, 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}
Cristelle Hugo, Isaac Asante, Anastasiia Sadybekov, Vsevolod Katritch, Hussein N Yassine
{"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":"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}
Ziying Xu, Sijia He, Mst Marium Begum, Xianlin Han
{"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":"","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":"","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)<sub>1-42</sub>-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<sub>1-42</sub>-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}
Yonghong Zhu, Bowen Yang, Suyun Chen, Guanqing Chen, Xiaobian Zeng, Hui Min, Li Xu
{"title":"M6A RNA Methylation-Mediated TUG1 Stability Maintains Mitochondrial Homeostasis during Kidney Aging by Epigenetically Regulating PGC1-α Expression.","authors":"Yonghong Zhu, Bowen Yang, Suyun Chen, Guanqing Chen, Xiaobian Zeng, Hui Min, Li Xu","doi":"10.1089/ars.2024.0631","DOIUrl":"10.1089/ars.2024.0631","url":null,"abstract":"<p><p><b><i>Background:</i></b> Aging is a significant risk factor for the increased incidence of acute kidney injury and chronic kidney disease, posing significant challenges to global public health. The role of N6-methyladenosine (m6A) in the development of chronic kidney disease has been reported, but the regulatory mechanism of m6A in kidney aging remains unclear. <b><i>Results:</i></b> In this study, we identified a long noncoding RNA (lncRNA), called taurine up-regulated 1 (TUG1), which exhibited a significantly decreased level of m6A modification in human aged kidney through the m6A-lncRNA epitranscriptome microarray. Bioinformatics analysis and machine learning predicted that TUG1 had potentially strong interaction with PGC1-α. RNA immunoprecipitation and chromatin immunoprecipitation analysis showed that TUG1 promoted proliferator-activated receptor γ coactivator-1α (PGC1-α) expression by directly interacting with its TUG-1 binding element region, thereby impacting mitochondrial quality control (MQC), cellular senescence, and renal fibrosis. Silencing the RNA m6A methylase methyltransferase 14 (METTL14) or the reader protein insulin-like growth factor 2 mRNA-binding proteins (IGF2BP2) resulted in the weakened stability of lncRNA TUG1, contributing to an imbalance in MQC. <b><i>Conclusion:</i></b> Our study demonstrated that the m6A modification and stability of TUG1 were mediated by METTL14 in an IGF2BP2-dependent manner, and modulate the mitochondrial homeostasis in kidney aging by direct targeting PGC-1α. These findings provide a new perspective on potential therapeutic targets for kidney aging. <i>Antioxid. Redox Signal.</i> 41, 993-1013.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"993-1013"},"PeriodicalIF":5.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970506","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}
George Luo, Harshita Kumar, Kristin Aldridge, Stevie Rieger, EunHyang Han, Ethan Jiang, Ernest R Chan, Ahmed Soliman, Haider Mahdi, John J Letterio
{"title":"A Core NRF2 Gene Set Defined Through Comprehensive Transcriptomic Analysis Predicts Selective Drug Resistance and Poor Multicancer Prognosis.","authors":"George Luo, Harshita Kumar, Kristin Aldridge, Stevie Rieger, EunHyang Han, Ethan Jiang, Ernest R Chan, Ahmed Soliman, Haider Mahdi, John J Letterio","doi":"10.1089/ars.2023.0409","DOIUrl":"10.1089/ars.2023.0409","url":null,"abstract":"<p><p><b><i>Aims:</i></b> The nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1 (NRF2-KEAP1) pathway plays an important role in the cellular response to oxidative stress but may also contribute to metabolic changes and drug resistance in cancer. However, despite its pervasiveness and important role, most of nuclear factor erythroid 2-related factor 2 (NRF2) target genes are defined in context-specific experiments and analysis, making it difficult to translate from one situation to another. Our study investigates whether a core NRF2 gene signature can be derived and used to represent NRF2 activation in various contexts, allowing better reproducibility and understanding of NRF2. <b><i>Results:</i></b> We define a core set of 14 upregulated NRF2 target genes from 7 RNA-sequencing datasets that we generated and analyzed. This NRF2 gene signature was validated using analyses of published datasets and gene sets. An NRF2 activity score based on expression of these core target genes correlates with resistance to drugs such as PX-12 and necrosulfonamide but not to paclitaxel or bardoxolone methyl. We validated these findings in our Kelch-like ECH-associated protein 1 (<i>KEAP1</i>) knockout cancer cell lines. Finally, our NRF2 score is prognostic for cancer survival and validated in additional independent cohorts for lung adenocarcinoma and also novel cancer types not associated with NRF2-KEAP1 mutations such as clear cell renal carcinoma, hepatocellular carcinoma, and acute myeloid leukemia. <b><i>Innovation and Conclusions:</i></b> These analyses define a core NRF2 gene signature that is robust, versatile, and useful for evaluating NRF2 activity and for predicting drug resistance and cancer prognosis. Using this gene signature, we uncovered novel selective drug resistance and cancer prognosis associated with NRF2 activation. <i>Antioxid. Redox Signal.</i> 41, 1031-1050.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"1031-1050"},"PeriodicalIF":5.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141722917","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}