Antioxidants & redox signaling最新文献

{"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":"Redox Control of Seed Germination is Mediated by the Crosstalk of Nitric Oxide and Reactive Oxygen Species.","authors":"Natalia V Bykova, Abir U Igamberdiev","doi":"10.1089/ars.2024.0699","DOIUrl":"https://doi.org/10.1089/ars.2024.0699","url":null,"abstract":"<p><p><b><i>Significance:</i></b> Seed germination and seedling establishment are characterized by changes in the intracellular redox state modulated by accelerated production of nitric oxide (NO) and reactive oxygen species (ROS). Redox regulation and enhanced accumulation of NO and ROS, approaching excessively high levels during seed imbibition, are critically important for breaking endodormancy and inducing germination. <b><i>Recent Advances:</i></b> Upon depletion of oxygen under the seed coat, NO is produced anaerobically in the reductive pathway associated mainly with mitochondria, and it participates in the energy metabolism of the seed until radicle protrusion. NO turnover involves nitrate reduction to nitrite in the cytosol, nitrite reduction to NO in mitochondria, and NO oxygenation in the cytosol in the reaction involving the hypoxically induced class 1 phytoglobin. In postgerminative degradation of seed tissues, NO and ROS are involved in redox signaling <i>via</i> post-translational modification of proteins and mediation of phytohormonal responses. <b><i>Critical Issues:</i></b> The crosstalk between the cellular redox potential, NO, ROS, and phytohormones integrates major physiological processes related to seed germination. Intensive accumulation of NO and ROS during imbibition is critically important for breaking seed dormancy. Upon oxygen depletion, NO and other nitrous oxides (NOx) are produced anaerobically and support energy metabolism prior to radicle protrusion. <b><i>Future Directions:</i></b> The turnover of NOx and ROS is determined by the intracellular redox balance, and it self-controls redox and energy levels upon germination. The particular details, regulation of this process, and its physiological significance remain to be established. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738146","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":"Lactate Dehydrogenase A Is a Novel Positive Regulator of Vascular Smooth Muscle Cell Ferroptosis During Aortic Dissection.","authors":"Xin Feng, Xin Yi, Bo Huo, Hanshen Luo, Jingjie Chen, Xian Guo, Ze-Min Fang, Fu-Han Gong, Xiang Wei, Ding-Sheng Jiang, Yue Chen","doi":"10.1089/ars.2024.0585","DOIUrl":"https://doi.org/10.1089/ars.2024.0585","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Vascular smooth muscle cell (VSMC) ferroptosis is a pivotal event in the process of aortic dissection (AD), and a number of agents have a protective role against AD by inhibiting VSMC ferroptosis. While glycolysis is an ancient pathway related to almost all biological processes, its precise involvement in VSMC ferroptosis and AD remains unclear. <b><i>Results:</i></b> In this study, bioinformatics analysis revealed that glycolysis-related molecules and pathways were involved in VSMC ferroptosis and AD. We focused on the key enzyme of glycolysis, lactate dehydrogenase A (LDHA), and found that LDHA overexpression promoted ferroptosis and lipid peroxidation in cystine deprivation- or imidazole ketone erastin-treated VSMCs and vice versa. Clinical specimens showed a negative correlation between elevated LDHA levels in dissected aortae and ferroptosis-related molecules glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), and ferroptosis suppressor protein 1 (FSP1). In VSMC ferroptosis, LDHA overexpression led to the suppression of GPX4, SLC7A11, and FSP1. Furthermore, the interaction between LDHA and nuclear factor (erythroid-derived 2)-like 2 (NRF2) was identified, and the overexpression or agonist of NRF2 reversed the contribution of LDHA on VSMC ferroptosis and lipid peroxidation. <b><i>Innovation and Conclusion:</i></b> These results highlight a significant association between LDHA and VSMC ferroptosis in AD development mediated through NRF2. These findings present LDHA as a potential target for AD intervention by inhibiting its expression. <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":"142738144","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}

{"title":"Roles of Glyco-Redox in Epithelial Mesenchymal Transition and Mesenchymal Epithelial Transition, Cancer, and Various Diseases.","authors":"Naoyuki Taniguchi, Yuki Ohkawa, Taiki Kuribara, Junpei Abe, Yoichiro Harada, Motoko Takahashi","doi":"10.1089/ars.2024.0774","DOIUrl":"10.1089/ars.2024.0774","url":null,"abstract":"<p><p><b><i>Significance:</i></b> Reduction-oxidation (redox) regulation is an important biological phenomenon that provides a balance between antioxidants and the generation of reactive oxygen species and reactive nitrogen species under pathophysiological conditions. Structural and functional changes in glycans are also important as post-translational modifications of proteins. The integration of glycobiology and redox biology, called glyco-redox has provided new insights into the mechanisms of epithelial-mesenchymal transition (EMT)/mesenchymal-epithelial transition (MET), cancer, and various diseases including Alzheimer's disease, chronic obstructive lung disease, type 2 diabetes, interstitial pneumonitis, and ulcerative colitis. <b><i>Recent Advances:</i></b> Glycans are biosynthesized by specific glycosyltransferases and each glycosyltransferase is either directly or indirectly regulated by oxidative stress and redox regulation. A typical example of glyco-redox is the role of N-glycan referred to as core fucose in superoxide dismutase 3. This glycan was found to be involved in the growth inhibition of cancer cell lines. <b><i>Critical Issues:</i></b> The significance of glyco-redox in EMT/MET, cancer, and various diseases was found in major N-glycan branching glycosyltransferases β1,4N-acetylglucosaminyltransferase III, β1,4N-acetylglucosaminyltransferase IV, β1,6N-acetylglucosaminyltransferase V, β1,4-acetylglucosaminyltransfearfse VI, β1,6-acetylglucosaminyltransferase IX, α-1,6 fucosyltransferase, and β-galactoside α-2,6-sialyltransferase 1. Herein, we summarize previous reports on target proteins and how this relates to oxidative stress. We also discuss the products of these processes and their significance to cancer and various diseases. <b><i>Future Direction:</i></b> A clear-cut understanding of the significance of glyco-redox in relation to prevention, diagnosis, and therapeutics is required. These studies will open a new road toward glycobiology and redox biology. <i>Antioxid. Redox Signal.</i> 41, 910-926.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"910-926"},"PeriodicalIF":5.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339727","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}