Free Radical Biology and Medicine最新文献

{"title":"Oxidative stress in trauma patients receiving a restrictive or liberal oxygen strategy - A sub-study of the TRAUMOX2 trial.","authors":"Tobias Arleth, Josefine Baekgaard, Felicia Dinesen, Andreas Creutzburg, Helene Dalsten, Carl Johan Queitsch, Sarah Sofie Wadland, Oscar Rosenkrantz, Volkert Siersma, Claus Moser, Peter Østrup Jensen, Lars S Rasmussen, Jacob Steinmetz","doi":"10.1016/j.freeradbiomed.2025.02.016","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.02.016","url":null,"abstract":"<p><strong>Introduction: </strong>A liberal supplemental oxygen approach is recommended for all severely injured trauma patients despite limited evidence. Liberal oxygen administration may cause oxidative stress. The aim of this study was to investigate the effect of an early restrictive oxygen strategy versus a liberal oxygen strategy in adult trauma patients on biomarkers of oxidative stress within 48 hours of hospital admission.</p><p><strong>Materials and methods: </strong>This was a single-centre, sub-study of an international, randomised controlled trial TRAUMOX2. In TRAUMOX2, patients were randomised shortly after trauma to a restrictive oxygen strategy (arterial oxygen saturation target of 94%) or a liberal oxygen strategy (12-15 litres of oxygen per minute or fraction of inspired oxygen of 0.6-1.0) for eight hours. Blood samplings were performed at four time points within 48 hours after randomisation: upon arrival at the trauma centre, and at eight, 24, and 48 hours post-randomisation. The primary outcome was the plasma level of malondialdehyde (MDA) 24 hours post-randomisation. Secondary outcomes were numerous, and included the level of MDA at other time points, superoxide dismutase (SOD) at all time points, 30-day mortality, and major respiratory complications.</p><p><strong>Results: </strong>The sub-study included 90 adult trauma patients. The median MDA levels at 24 hours post-randomisation was 60.9 μM (95% CI 49.5 to 73.4) in the restrictive oxygen group and 56.7 μM (95% CI 46.9 to 68.2) in the liberal oxygen group, corresponding to a difference of -4.2 μM (95% CI -19.8 to 10.5; P = 0.35). No significant differences were found in MDA or SOD at the other time points either. Neither did we find a significant difference in 30-day mortality or major respiratory complications.</p><p><strong>Conclusions: </strong>In this sub-study of the TRAUMOX2 trial, no significant differences were found in biomarkers of oxidative stress between a restrictive oxygen strategy and liberal oxygen strategy in adult trauma patients.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432647","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":"Biallelic FDXR mutations induce ferroptosis in a rare mitochondrial disease with ataxia","authors":"Juan Wang ,&nbsp;Rongjuan Zhao ,&nbsp;Jing Ma ,&nbsp;Jiangbo Qin ,&nbsp;Huiqiu Zhang ,&nbsp;Junhong Guo ,&nbsp;Xueli Chang ,&nbsp;Wei Zhang","doi":"10.1016/j.freeradbiomed.2025.02.012","DOIUrl":"10.1016/j.freeradbiomed.2025.02.012","url":null,"abstract":"<div><div>Biallelic mutations in the <em>FDXR</em> are known to cause rare mitochondrial diseases. However, the underlying pathogenic mechanisms remain elusive. This study investigated a patient affected by optic atrophy, ataxia, and peripheral neuropathy resulting from compound heterozygous mutations in <em>FDXR</em>. Structural abnormalities in mitochondria were observed in muscle and nerve tissues. Lymphoblastic cell lines (LCLs) and muscle samples from the patient exhibited signs of mitochondrial dysfunction, iron overload, oxidative stress, and lipid peroxidation. Dysregulation of the glutathione peroxidase-4 was noted in the LCLs. Furthermore, treatment with deferoxamine, N-acetyl-cysteine, and ferrostatin-1 effectively alleviated oxidative stress and cell death. Cortical neurons demonstrate that FDXR deficiency impacts the morphogenesis of neurites. Collectively, these findings suggest that ferroptosis plays a significant role in the pathogenesis of FDXR-associated diseases. Additionally, idebenone appeared to have protective effects against various cellular injuries induced by <em>FDXR</em> mutations, providing novel insights and therapeutic approaches for the treatment of FDXR-associated diseases.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"230 ","pages":"Pages 248-262"},"PeriodicalIF":7.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425130","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":"Regular exercise alleviates metabolic dysfunction-associated steatohepatitis through rescuing mitochondrial oxidative stress and dysfunction in liver","authors":"Baoxuan Lin ,&nbsp;Tong Wu ,&nbsp;Mohammad Nasb ,&nbsp;Zeyun Li ,&nbsp;Ning Chen","doi":"10.1016/j.freeradbiomed.2025.02.017","DOIUrl":"10.1016/j.freeradbiomed.2025.02.017","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by severe mitochondrial dysfunction, associated with the production of mitochondrial reactive oxygen species (mROS). The substantial generation of mROS in the MASH liver, resulting from lipid surplus and electron transport chain (ETC) overload, impairs mitochondrial structure and functionality, thereby contributing to the development of severe hepatic steatosis and inflammation. Regular exercise represents an effective strategy for the treatment of MASH. Understanding the effects of exercise on oxidative stress and mitochondrial function is essential for effective treatment of MASH. This article reviews the pathological alterations in mitochondrial β-oxidation, ETC efficiency and mROS production within MASH liver. Additionally, it discusses how exercise influences the redox state and mitochondrial quality control mechanisms—such as biogenesis, mitophagy, fusion, and fission—within the MASH liver. The article emphasizes the importance of in-depth studies on exercise-induced MASH mitigation through the enhancement of mitochondrial redox balance, quality control, and function. Exploring the relationship between exercise and hepatic mitochondria could provide valuable insights into identifying potential therapeutic targets for MASH.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"230 ","pages":"Pages 163-176"},"PeriodicalIF":7.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419612","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":"Resveratrol and grape pomace extract incorporated in modified phospholipid vesicles: A potential strategy to mitigate cigarette smoke-induced oxidative stress","authors":"Rita Abi Rached ,&nbsp;Ashok K. Shakya ,&nbsp;Federica Fulgheri ,&nbsp;Matteo Aroffu ,&nbsp;Ines Castangia ,&nbsp;Fátima García-Villén ,&nbsp;Maria Ferraro ,&nbsp;Xavier Fernàndez-Busquets ,&nbsp;Jose Luis Pedraz ,&nbsp;Nicolas Louka ,&nbsp;Richard G. Maroun ,&nbsp;Maria Manconi ,&nbsp;Maria Letizia Manca","doi":"10.1016/j.freeradbiomed.2025.02.009","DOIUrl":"10.1016/j.freeradbiomed.2025.02.009","url":null,"abstract":"<div><div>In this study, the extraction process of grape pomace from the Lebanese autochthonous cultivar <em>Asswad Karech</em> was enhanced through the selection of specific parameters, yielding an antioxidant extract (20 mg/mL) that was co-loaded with resveratrol (5 mg/mL) into phospholipid vesicles containing penetration enhancers (PEVs). Propylene glycol (PG) was incorporated as a penetration enhancer at concentrations of 10, 20, and 30 % to obtain 10 PG-PEVs, 20 PG-PEVs, and 30 PG-PEVs. Vesicle preparation was achieved through direct sonication, yielding unilamellar and bilamellar vesicles with an average size of ∼205; 234 nm, a monodisperse distribution (polydispersity index &lt;0.3), and a negative surface charge (∼-54;-56 mV). The formulations containing 30 % propylene glycol exhibited long-term stability, maintaining a consistent mean diameter over 12 months at room temperature (25 °C). Upon nebulization using the Next Generation Impactor, the vesicular dispersions successfully reached the deepest stages of the impactor, mimicking deposition in the lower respiratory airways. Biocompatibility studies on A549 and CuFi-1 cell lines demonstrated that the vesicles co-loaded with grape extract and resveratrol effectively counteracted apoptosis induced by hydrogen peroxide. Furthermore, when 16HBE bronchial epithelial cells were exposed to cigarette smoke extract, vesicles containing 30 % propylene glycol inhibited reactive oxygen species (ROS) generation. These findings highlight the potential of phospholipid vesicles co-loaded with grape pomace extract and resveratrol, particularly those formulated with 30 % propylene glycol, for pulmonary administration to mitigate oxidative damage associated with cigarette smoke exposure and related respiratory diseases.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"230 ","pages":"Pages 151-162"},"PeriodicalIF":7.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419614","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":"S100A8 induces cyclophosphamide-induced alopecia via NCF2/NOX2-mediated ferroptosis","authors":"Wen Xu ,&nbsp;Yujie Li ,&nbsp;Sheng Wan ,&nbsp;Beilei Zhang ,&nbsp;Dongfan Wei ,&nbsp;Hongyan Zhang ,&nbsp;Xiaofan Jin ,&nbsp;Bo Xie ,&nbsp;Cuiping Guan ,&nbsp;Xiuzu Song","doi":"10.1016/j.freeradbiomed.2025.02.014","DOIUrl":"10.1016/j.freeradbiomed.2025.02.014","url":null,"abstract":"<div><div>Chemotherapy-induced alopecia (CIA), commonly associated with agents such as cyclophosphamide (CYP), is a prevalent and distressing side effect of numerous chemotherapeutic treatments, significantly impacting patients’ quality of life. S100A8, a calcium-binding protein involved in inflammatory responses and oxidative stress regulation, plays a pivotal role in cellular homeostasis. In this study, we investigated the involvement of S100A8 in ferroptosis within a CYP-induced CIA mouse model. We found that CYP treatment upregulated S100A8, NCF2, and NOX2 while reducing GPX4 levels in hair follicles, indicating elevated oxidative stress and ferroptosis. Administration of the S100A8 inhibitor paquinimod (PAQ) alleviated alopecia and decreased markers of oxidative stress and ferroptosis. <em>In vitro</em> experiments using human outer root sheath keratinocytes (ORSKs) confirmed that S100A8 promotes ferroptosis via the NCF2/NOX2 pathway, as inhibition of NCF2 or NOX2 reversed these effects. These findings suggest that targeting the S100A8–NCF2/NOX2 axis may provide a novel therapeutic strategy for mitigating CIA induced by various chemotherapeutic agents.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"230 ","pages":"Pages 112-126"},"PeriodicalIF":7.1,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413203","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 ameliorates defective autophagic processes and thereby inhibits ferroptosis in acute pancreatitis by suppressing Beclin1-Slc7a11 complex formation","authors":"Jie Li ,&nbsp;Yu-chen Jia ,&nbsp;Haoyu Zhang ,&nbsp;Zheng Wang ,&nbsp;Yixuan Ding ,&nbsp;Feng Cao ,&nbsp;Gang Wang ,&nbsp;Fei Li","doi":"10.1016/j.freeradbiomed.2025.02.011","DOIUrl":"10.1016/j.freeradbiomed.2025.02.011","url":null,"abstract":"<div><div>Ferroptosis is a mode of programmed cell death that plays an important role in an increasing number of diseases. Recently, ferroptosis was found to be involved in the pathology of acute pancreatitis (AP). We determined that nuclear factor erythroid 2-related factor 2 (Nrf2) plays a pivotal role in the ferroptosis process in AP. By inhibiting Nrf2 expression, the death of acinar cells in AP can be increased. Therefore, to help treat AP to a certain extent, we analyzed the effects of astaxanthin and found that it can activate Nrf2 and reduce the pathological process of AP. The activation of Nrf2 improves defective autophagy in AP and inhibits ferroptosis in acinar cells. Specifically, Nrf2 can promote the expression of Gpx4 and ferritin, and can inhibit the formation of Beclin-Slc7a11 complex by improving autophagy, thereby increasing the membrane expression of Slc7a11. Slc7a11/Gpx4 is an important anti-ferroptosis pathway; Slc7a11 can promote the synthesis of glutathione, while Gpx4 can utilize glutathione to exert antioxidative effects. Thus, we demonstrated that Nrf2 activation not only ameliorated defective autophagy at the time of AP but also promoted membrane expression of Slc7a11 to inhibit ferroptosis in acinar cells, thereby alleviating AP.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"230 ","pages":"Pages 294-308"},"PeriodicalIF":7.1,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413039","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":"Hypoxia induced mitophagy generates reversible metabolic and redox heterogeneity with transient cell death switch driving tumorigenesis","authors":"Shivanshu Kumar Tiwari ,&nbsp;Aneesh Chandrasekharan ,&nbsp;Santhik Subhasingh Lupitha ,&nbsp;Krupa Ann Mathew ,&nbsp;Shine Varghese Jancy ,&nbsp;Aman Munirpasha Halikar ,&nbsp;Vishnu S. Sanjeev ,&nbsp;K.C. Sivakumar ,&nbsp;Tilak Prasad ,&nbsp;K.G. Anurup ,&nbsp;Aijaz Ahmad Rather ,&nbsp;Jain Tiffee P J ,&nbsp;Aparna Geetha Jayaprasad ,&nbsp;Aswathy Sivasailam ,&nbsp;T.R. Santhoshkumar","doi":"10.1016/j.freeradbiomed.2025.02.007","DOIUrl":"10.1016/j.freeradbiomed.2025.02.007","url":null,"abstract":"<div><div>Tumor hypoxia determines tumor growth, metastasis, drug resistance, and tumor heterogeneity through multiple mechanisms, largely dependent on the extent of hypoxia, further modulated by re-oxygenation events. In order to track the cell fates under hypoxia and re-oxygenation, we have developed a sensor cell for real-time tracking of apoptotic, necrotic, and surviving mitophagy cells under hypoxia and re-oxygenation. The study using this sensor revealed a cell death switch from apoptosis to necrosis by hypoxia-exposed cells under re-oxygenation, where mitophagy plays a key role in acquiring temporally evolving functional phenotypes, including metabolic heterogeneity and mitochondrial redox heterogeneity. RNA transcriptomics also revealed a temporally evolving genomic landscape supporting the complex transcriptional plasticity of cells as a non-genetic adaptive event. Interestingly, cells regained from these distinct stages retained their metastatic potential despite slow growth in animal models. Overall, the study demonstrated that cells acquire distinct functions by tumor hypoxia and re-oxygenation, secondarily acquiring transient functional traits and metabolic heterogeneity governed by cell inherent mitochondrial dynamics. Such cell autonomous temporal alterations in cell states governed by organelle integrity with distinct cell proliferation and apoptosis-necrosis switch may be advantageous for the growing tumor to evolve under complex microenvironmental stress, further contributing to tumorigenesis.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"230 ","pages":"Pages 190-208"},"PeriodicalIF":7.1,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412932","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 alleviates doxorubicin-induced endoplasmic reticulum stress and myocardial injury by interacting with SERCA2a","authors":"Shuwei Ning ,&nbsp;Jianhui Li ,&nbsp;Mei He ,&nbsp;Yuexin Yu ,&nbsp;Zhikun Guo","doi":"10.1016/j.freeradbiomed.2025.02.010","DOIUrl":"10.1016/j.freeradbiomed.2025.02.010","url":null,"abstract":"<div><div>The clinical use of the anticancer drug doxorubicin (DOX) is limited due to its time- and dose-dependent cardiotoxicity. Therefore, there is an urgent need to explore the molecular mechanism and coping strategies for alleviating DOX-induced cardiotoxicity (DIC) and solve the difficulties in clinical application. The role and mechanism of androgen receptor (AR), which is the target of androgen, in DIC remain unclear. Here, we elucidated the molecular mechanisms of AR in DOX-induced cardiotoxicity. Inhibition of AR aggravated the DOX-induced cardiac function impairment, while the activation of AR showed obvious therapeutic effect and rescued cardiac function of rats. AR can physically interact with SERCA2a. Activation of AR participates in the regulation of DOX-induced myocardial injury by modulating SERCA2a, attenuating DOX-induced endoplasmic reticulum stress, improving calcium (Ca²⁺) cycling homeostasis, and inhibiting ROS levels and apoptosis, thereby participating in the regulation of DOX induced myocardial injury. Altogether, these findings reveal for the first time the relationship and role between AR and SERCA2a in regulating the progression of DIC, suggesting that AR may play a therapeutic role as a new target against DIC.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"230 ","pages":"Pages 127-137"},"PeriodicalIF":7.1,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412750","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":"Rpl13a snoRNAs-regulated NADPH oxidase 1-dependent ROS generation: A novel RBC pathway mediating complement C3a deposition and triggering thrombosis in aging and venous blood clotting disorders","authors":"Waseem Chauhan,&nbsp;Shirin Ferdowsi,&nbsp;S.J. Sudharshan,&nbsp;Rahima Zennadi","doi":"10.1016/j.freeradbiomed.2025.02.008","DOIUrl":"10.1016/j.freeradbiomed.2025.02.008","url":null,"abstract":"<div><div>Adults older than 45 years old are at higher risk of developing venous blood clotting known as venous thrombosis/thromboembolism than a cohort &lt;45 years old. Complement activation, which can be mediated by oxidative stress, plays a central role in venous thrombosis. Yet, whether RBCs contribute to complement activation triggering thrombosis in aging and in patients with venous thrombosis/thromboembolism remains an open question. RBCs from healthy Mid-life stage (55–68 years old) adults and patients with venous thrombosis/thromboembolism showed higher deposition of the complement C3 and the anaphylatoxin C3a, and NADPH oxidase (Nox)1 expression than a younger cohort (21–30 years old). Increased C3/C3a deposition on RBCs from mid-life stage adults and patients with venous thrombosis/thromboembolism triggered prothrombin activation via Nox1-dependent reactive oxygen species (ROS) generation, and G protein-coupled receptor kinase 2 (GRK2) activation. Interaction of C3/C3a positive RBCs from mid-life stage adults with endothelial cells led to increased endothelial ROS production. TGF-β1-stimulated GRK2 and Nox1 activation in RBCs from the younger and older adults exacerbated RBC C3/C3a deposition and C3/C3a-mediated prothrombotic activation, which appears to result from ROS-mediated increased RBC phosphatidylserine exposure. Using human RBCs, and <em>Rpl13a</em> snoRNA knockout aged mice, we show that <em>Rpl13a</em> snoRNAs, the master regulators of ROS levels and oxidative stress response, regulate human and murine RBC C3a deposition and prothrombic activation in aging by modulating <em>Nox1</em> mRNA expression. <em>In vivo Rpl13a</em> snoRNA knockout in aged mice decreased thrombi size by blunting RBC C3a deposition, and RBCs-triggering prothrombin activation. These findings point out to a novel role of RBC <em>Rpl13a</em> snoRNAs in dysregulating RBC ROS-induced C3a deposition promoting venous thrombosis in aging.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"230 ","pages":"Pages 138-150"},"PeriodicalIF":7.1,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143406878","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":"Penile endothelial dysfunction, impaired redox metabolism and blunted mitochondrial bioenergetics in diet-induced obesity: Compensatory role of H2O2","authors":"Alfonso Gómez del Val ,&nbsp;Ana Sánchez ,&nbsp;Óscar Freire-Agulleiro ,&nbsp;María Pilar Martínez ,&nbsp;Mercedes Muñoz ,&nbsp;Lucia Olmos ,&nbsp;Javier Sáenz Medina ,&nbsp;Simon Gabriel Comerma-Steffensen ,&nbsp;Ulf Simonsen ,&nbsp;Luis Rivera ,&nbsp;Miguel López ,&nbsp;Cristina Contreras ,&nbsp;Dolores Prieto","doi":"10.1016/j.freeradbiomed.2025.02.004","DOIUrl":"10.1016/j.freeradbiomed.2025.02.004","url":null,"abstract":"<div><h3>Objective</h3><div>Erectile dysfunction (ED) is considered an early manifestation of cardiovascular disease (CVD), endothelial dysfunction being the link between CVD and vasculogenic ED. Mitochondrial reactive oxygen species (mtROS) have been involved in the vascular complications of metabolic disorders. The aim of this study was to assess the impact of obesity on endothelial function, redox metabolism and mitochondrial bioenergetics of penile erectile tissue.</div></div><div><h3>Methods</h3><div>Wistar rats were fed a high-fat diet (HFD) or standard diet (STD), and penile vascular function was assessed in microvascular myographs. mtROS levels were measured by mitoSOX (O₂^.-) and Amplex Red (H₂O₂) fluorimetry, and the effect of the mitochondrial antioxidant mitoTempo on endothelium-dependent relaxations was tested. Mitochondrial respiration of intact microarteries was assessed with an Agilent Seahorse XF Pro analyzer, and the expression of mitochondria redox regulators was analysed by Western blot.</div></div><div><h3>Results</h3><div>Endothelium-dependent relaxations to acetylcholine (ACh) and to the mitoK_ATP channel activator BMS191095 were reduced in penile arteries from HFD. mtROS levels were significantly increased and associated with upregulation of the endothelial NADPH oxidase 4 (Nox4) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in HFD erectile tissue. MitoTempo inhibited endothelial relaxations in control and HFD penile arteries. The bioenergetic profile was significantly reduced in HFD penile arteries compared to STD rats.</div></div><div><h3>Conclusions</h3><div>Mitochondrial dysfunction with impaired bioenergetics and reduced mitoK_ATP channel-mediated relaxation underlie endothelial and vascular dysfunction of erectile tissue in obesity, despite a compensatory mechanism that enhances Nox4-derived endothelial vasodilator mtROS. Therapeutic strategies aimed to stabilize mitochondria could restore redox balance and improve mitochondrial bioenergetics thus preventing oxidative stress and vascular dysfunction underlying metabolic disease associated ED.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"230 ","pages":"Pages 222-233"},"PeriodicalIF":7.1,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390525","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}