Antioxidants & redox signaling最新文献

{"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}

{"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}

{"title":"Cholesterol Metabolism in Neurodegenerative Diseases.","authors":"Keqiang He, Zhiwei Zhao, Juan Zhang, Dingfeng Li, Sheng Wang, Qiang Liu","doi":"10.1089/ars.2024.0674","DOIUrl":"10.1089/ars.2024.0674","url":null,"abstract":"<p><p><b><i>Significance:</i></b> Cholesterol plays a crucial role in the brain, where it is highly concentrated and tightly regulated to support normal brain functions. It serves as a vital component of cell membranes, ensuring their integrity, and acts as a key regulator of various brain processes. Dysregulation of cholesterol metabolism in the brain has been linked to impaired brain function and the onset of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease, and Huntington's disease. <b><i>Recent Advances:</i></b> A significant advancement has been the identification of astrocyte-derived apoliprotein E as a key regulator of <i>de novo</i> cholesterol biosynthesis in neurons, providing insights into how extracellular signals influence neuronal cholesterol levels. In addition, the development of antibody-based therapies, particularly for AD, presents promising opportunities for therapeutic interventions. <b><i>Critical Issues:</i></b> Despite significant research, the association between cholesterol and neurodegenerative diseases remains inconclusive. It is crucial to distinguish between plasma cholesterol and brain cholesterol, as these pools are relatively independent. This differentiation should be considered when evaluating statin-based treatment approaches. Furthermore, assessing not only the total cholesterol content in the brain but also its distribution among different types of brain cells is essential. <b><i>Future Direction:</i></b> Establishing a causal link between changes in brain/plasma cholesterol levels and the onset of brain dysfunction/neurodegenerative diseases remains a key objective. In addition, conducting cell-specific analyses of cholesterol homeostasis in various types of brain cells under pathological conditions will enhance our understanding of cholesterol metabolism in neurodegenerative diseases. Manipulating cholesterol levels to restore homeostasis may represent a novel approach for alleviating neurological symptoms. <i>Antioxid. Redox Signal.</i> 41, 1051-1072.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"1051-1072"},"PeriodicalIF":5.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141260691","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":"Sirt3-Mediated Opa1 Deacetylation Protects Against Sepsis-Induced Acute Lung Injury by Inhibiting Alveolar Macrophage Pro-Inflammatory Polarization.","authors":"Maomao Sun, Yuying Li, Gege Xu, Junrui Zhu, Ruimin Lu, Sheng An, Zhenhua Zeng, Zhiya Deng, Ran Cheng, Qin Zhang, Yi Yao, Junjie Wu, Yuan Zhang, Hongbin Hu, Zhongqing Chen, Qiaobing Huang, Jie Wu","doi":"10.1089/ars.2023.0322","DOIUrl":"10.1089/ars.2023.0322","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Mitochondrial dynamics in alveolar macrophages (AMs) are associated with sepsis-induced acute lung injury (ALI). In this study, we aimed to investigate whether changes in mitochondrial dynamics could alter the polarization of AMs in sepsis-induced ALI and to explore the regulatory mechanism of mitochondrial dynamics by focusing on sirtuin (SIRT)3-induced optic atrophy protein 1 (OPA1) deacetylation. <b><i>Results:</i></b> The AMs of sepsis-induced ALI showed imbalanced mitochondrial dynamics and polarization to the M1 macrophage phenotype. In sepsis, SIRT3 overexpression promotes mitochondrial dynamic equilibrium in AMs. However, 3-(1H-1, 2, 3-triazol-4-yl) pyridine (3TYP)-specific inhibition of SIRT3 increased the mitochondrial dynamic imbalance and pro-inflammatory polarization of AMs and further aggravated sepsis-induced ALI. OPA1 is directly bound to and deacetylated by SIRT3 in AMs. In AMs of sepsis-induced ALI, SIRT3 protein expression was decreased and OPA1 acetylation was increased. OPA1 acetylation at the lysine 792 amino acid residue (OPA1-K792) promotes self-cleavage and is associated with an imbalance in mitochondrial dynamics. However, decreased acetylation of OPA1-K792 reversed the pro-inflammatory polarization of AMs and protected the barrier function of alveolar epithelial cells in sepsis-induced ALI. <b><i>Innovation:</i></b> Our study revealed, for the first time, the regulation of mitochondrial dynamics and AM polarization by SIRT3-mediated deacetylation of OPA1 in sepsis-induced ALI, which may serve as an intervention target for precision therapy of the disease. <b><i>Conclusions:</i></b> Our data suggest that imbalanced mitochondrial dynamics promote pro-inflammatory polarization of AMs in sepsis-induced ALI and that deacetylation of OPA1 mediated by SIRT3 improves mitochondrial dynamic equilibrium, thereby ameliorating lung injury. <i>Antioxid. Redox Signal.</i> 41, 1014-1030.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"1014-1030"},"PeriodicalIF":5.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141316603","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":"Human Umbilical Cord Mesenchymal Stem Cells Alleviate Diabetic Nephropathy by Inhibiting Ferroptosis via the JNK/KEAP1/NRF2 Signaling Pathway.","authors":"Yuexin Zhu, Changqing Dong, Zhiheng Xu, Yan Lou, Na Tian, Yucan Guan, Ping Nie, Manyu Luo, Ping Luo","doi":"10.1089/ars.2024.0575","DOIUrl":"https://doi.org/10.1089/ars.2024.0575","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Diabetic nephropathy (DN) is a major cause of end-stage renal disease, with no therapeutic interventions available to control its progression. Ferroptosis, an iron-dependent regulated cell death characterized by lipid peroxidation, plays a pivotal role in the pathogenesis of DN. Human umbilical cord mesenchymal stem cells (hUCMSCs) are an effective treatment modality for DN; however, the underlying mechanism of action remains unclear. The aim of the present study was to investigate whether hUCMSCs alleviate DN via inhibiting ferroptosis and its molecular mechanisms in type 2 diabetic mice and high-glucose and palmitate-stimulated human renal tubular epithelial cell (HK-11) models. <b><i>Results:</i></b> Our findings revealed that hUCMSCs improved the renal structure and function and tubular injuries. HUCMSC treatment can inhibit ferroptosis by decreasing iron content, reducing reactive oxygen species, malondialdehyde and 4-hydroxynonenal generation, decreasing the expression of positive ferroptosis mediator transferrin receptor 1 and long-chain acyl-CoA synthetase 4, and enhancing the expression of negative ferroptosis mediators (<i>i.e.,</i> ferritin heavy chain, glutathione peroxidase 4, and system Xc-cystine/glutamate reverse transporter). Mechanistically, hUCMSC treatment inhibited c-Jun N-terminal kinase (JNK) and Kelch-like ECH-associated protein 1 (KEAP1) activation while increasing the expression of nuclear factor erythroid 2-related factor 2 (NRF2). Furthermore, pretreatment of HK-11 cells with NRF2 siRNA, the JNK inhibitor SP600125, or the JNK agonist anisomycin demonstrated the regulation of the JNK/KEAP1/NRF2 signaling pathway by hUCMSCs. <b><i>Innovation and Conclusion:</i></b> HUCMSCs inhibit ferroptosis in DN via the JNK/KEAP1/NRF2 signaling pathway, providing a new perspective and scientific evidence for treating DN. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738142","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":"https://doi.org/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> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-11-12","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":"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":"https://doi.org/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> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-11-12","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":"New Emerging Therapeutic Strategies Based on Manipulation of the Redox Regulation Against Therapy Resistance in Cancer.","authors":"Ahmad Nazari, Parisa Osati, Siavash Seifollahy Fakhr, Ferdos Faghihkhorasani, Masoud Ghanaatian, Fereshteh Faghihkhorasani, Fatemeh Rezaei-Tazangi, Nazanin Pazhouhesh Far, Amir Shourideh, Nasim Ebrahimi, Amir Reza Aref","doi":"10.1089/ars.2023.0491","DOIUrl":"10.1089/ars.2023.0491","url":null,"abstract":"<p><p><i><b>Background:</b></i> Resistance to standard therapeutic methods, including chemotherapy, immunotherapy, and targeted therapy, remains a critical challenge in effective cancer treatment. Redox homeostasis modification has emerged as a promising approach to address medication resistance. <i><b>Objective:</b></i> This review aims to explore the mechanisms of redox alterations and signaling pathways contributing to treatment resistance in cancer. <i><b>Methods:</b></i> In this study, a comprehensive review of the molecular mechanisms underlying drug resistance governed by redox signaling was conducted. Emphasis was placed on understanding how tumor cells manage increased reactive oxygen species (ROS) levels through upregulated antioxidant systems, enabling resistance across multiple therapeutic pathways. <i><b>Results:</b></i> Key mechanisms identified include alterations in drug efflux, target modifications, metabolic changes, enhanced DNA damage repair, stemness preservation, and tumor microenvironment remodeling. These pathways collectively facilitate tumor cells' adaptive response and resistance to various cancer treatments. <i><b>Conclusion:</b></i> Developing a detailed understanding of the interrelationships between these redox-regulated mechanisms and therapeutic resistance holds potential to improve treatment effectiveness, offering valuable insights for both fundamental and clinical cancer research. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590116","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":"Androgen Receptor Mediates Dopamine Agonist Resistance by Regulating Intracellular Reactive Oxygen Species in Prolactin-Secreting Pituitary Adenoma.","authors":"Linpeng Xu, Zhuowei Lei, Quanji Wang, Qian Jiang, Biao Xing, Xingbo Li, Xiang Guo, Zihan Wang, Sihan Li, Yimin Huang, Ting Lei","doi":"10.1089/ars.2024.0611","DOIUrl":"10.1089/ars.2024.0611","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Dopamine agonists (DAs) are the first-line treatment for patients with prolactin-secreting pituitary adenoma (PRL adenoma). However, a subset of individuals exhibits poor responses, known as DA resistance. Previous studies have reported that DA resistance is more prevalent in male patients. This study aims to investigate the relationship between androgen receptor (AR) expression and DA resistance, as well as to explore underlying mechanisms of AR-mediated DA resistance. <b><i>Results:</i></b> Our results demonstrated that patients with higher AR expression exhibit greater resistance to DA in our cohort of DA-resistant PRL adenoma. Furthermore, AR was found to be involved in cell proliferation, PRL secretion, and resistance to bromocriptine (BRC) both <i>in vitro</i> and <i>in vivo</i>. Mechanistically, we demonstrated that intracellular reactive oxygen species (ROS) function as upstream mediators of apoptosis and ferroptosis following BRC treatment. As a ligand-dependent transcription factor, AR could translocate to the nucleus and transcriptionally promote NFE2-like bZIP transcription factor 2 (NRF2) expression, which regulates intracellular ROS levels, thereby enhancing cell viability and conferring DA resistance to pituitary adenoma (PA) cells. Finally, AR targeting agents were used to inhibit AR signaling, downregulate NRF2 transcription, and sensitize PA cells to BRC treatment. <b><i>Conclusion and Innovation:</i></b> We demonstrated that AR plays a crucial role in mediating DA resistance in PRL adenoma. Mechanistically, AR promotes cell proliferation and PRL secretion and confers drug resistance by transcriptionally regulating NRF2 expression to maintain redox homeostasis in PA cells. Finally, combining AR targeting agents with BRC shows promise as a therapeutic strategy for treating PRL adenomas. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364066","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":"Angiotensin-Converting Enzyme-Dependent Intrarenal Angiotensin II Contributes to CTP: Phosphoethanolamine Cytidylyltransferase Downregulation, Mitochondrial Membranous Disruption, and Reactive Oxygen Species Overgeneration in Diabetic Tubulopathy.","authors":"Xia-Qing Li, Zhang-Zhang Xiao, Ke Ma, Xia-Yun Liu, Huan-Huan Liu, Bo Hu, Qian Zhao, Hong-Yue Li, Rui-Chang Chen, Yu Meng, Liang-Hong Yin","doi":"10.1089/ars.2024.0637","DOIUrl":"https://doi.org/10.1089/ars.2024.0637","url":null,"abstract":"<p><p><b><i>Aims:</i></b> The limited therapeutic options for diabetic tubulopathy (DT) in early diabetic kidney disease (DKD) reflect the difficulty of targeting renal tubular compartment. While renin-angiotensin-aldosterone system (RAS) inhibitors are commonly utilized in the management of DKD, how intrarenal RAS contributes to diabetic tubular injury is not fully understood. Mitochondrial disruption and reactive oxygen species (ROS) overgeneration have been involved in diabetic tubular injury. Herein, we aim to test the hypothesis that angiotensin-converting enzyme (ACE)-dependent intrarenal angiotensin II (AngII) disrupts tubular mitochondrial membranous homeostasis and causes excessive ROS generation in DT. <b><i>Results:</i></b> Mice suffered from renal tubular mitochondrial disruption and ROS overgeneration following high-fat diet/streptozocin-type 2 diabetic induction. Intrarenal AngII generation is ACE-dependent in DT. Local AngII accumulation in renal tissues was achieved by intrarenal artery injection. ACE-dependent intrarenal AngII-treated mice exhibit markedly elevated levels of makers of tubular injury. CTP: Phosphoethanolamine cytidylyltransferase (PCYT2), the primary regulatory enzyme for the biosynthesis of phosphatidylethanolamine, was enriched in renal tubules according to single-cell RNA sequencing. ACE-dependent intrarenal AngII-induced tubular membranous disruption, ROS overgeneration, and PCYT2 downregulation. The diabetic ambiance deteriorated the detrimental effect of ACE-dependent intrarenal AngII on renal tubules. Captopril, the ACE inhibitor (ACEI), showed efficiency in partially ameliorating ACE-dependent intrarenal AngII-induced tubular deterioration pre- and post-diabetic induction. <b><i>Innovation and Conclusion:</i></b> This study uncovers a critical role of ACE-dependent intrarenal AngII in mitochondrial membranous disruption, ROS overgeneration, and PCYT2 deficiency in diabetic renal tubules, providing novel insight into DT pathogenesis and ACEI-combined therapeutic targets. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574798","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}