Free Radical Biology and Medicine最新文献

{"title":"Endurance training enhances skeletal muscle mitochondrial respiration by promoting MOTS-c secretion.","authors":"Yiwei Feng, Zhijian Rao, Xu Tian, Yi Hu, Liantian Yue, Yifan Meng, Qiuling Zhong, Wei Chen, Wenlong Xu, Haoran Li, Yingjia Hu, Rengfei Shi","doi":"10.1016/j.freeradbiomed.2024.12.038","DOIUrl":"10.1016/j.freeradbiomed.2024.12.038","url":null,"abstract":"<p><p>The mitochondrial open reading frame of 12S rRNA-c (MOTS-c) is a biologically active mitochondria-derived peptide. However, the relationship between MOTS-c, skeletal muscle mitochondrial function, and endurance exercise adaptations is unknown. Here, we tested indices such as maximal oxygen uptake and serum MOTS-c levels in marathon runners and sedentary subjects. In addition, we tested aerobic exercise capacity, skeletal muscle mitochondrial respiration rate, and serum MOTS-c levels in mice subjected to long-term endurance training groups and sedentary groups. Our results indicated a close association between serum MOTS-c levels and aerobic exercise capacity. Circulating MOTS-c levels are expected to be an important indicator for predicting aerobic exercise capacity and assessing body fat status, endurance training load, and physical function. More importantly, we found that endurance training may enhance the mitochondrial respiratory function of skeletal muscle by promoting the secretion of MOTS-c and activating the AMPK/PGC-1α pathway.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"619-628"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871812","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":"hESC-derived extracellular vesicles enriched with MFGE-8 and the GSH redox system act as senotherapeutics for neural stem cells in ischemic stroke.","authors":"Youngseok Lee, Jihun Lee, Jeongjun Kim, Seunghyun Cho, Hye-Jin Lee, Dongho Geum, Dong-Hyuk Park, Jong-Hoon Kim","doi":"10.1016/j.freeradbiomed.2025.01.050","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.01.050","url":null,"abstract":"<p><p>Human embryonic stem cells (hESCs) and their extracellular vesicles (EVs) hold significant potential for tissue repair and regeneration. Neural stem cells (NSCs) in the adult brain often acquire senescent phenotypes after ischemic injuries, releasing neurodegenerative senescence-associated secretory phenotype factors. In this study, we investigated the senotherapeutic effects of hESC-EVs on NSCs and confirmed their neuroprotective effects in neurons via rejuvenation of NSC secretions. Proteomic profiling of hESC-EVs identified MFGE-8 as a critical bridging molecule to NSCs. We also found that the glutathione (GSH) redox system is a key contributor to the therapeutic antioxidant activity of hESC-EVs. Additionally, EVs produced by the hypoxic preconditioning of hESCs (hESC-HypoxEVs) exhibited reinforced GSH redox capacity and further enhanced the senotherapeutic effects on NSCs compared to naïve hESC-EVs. We also demonstrated that administration of hESC-HypoxEVs, precoated with MFGE-8, significantly increased the populations of NSCs and newborn neurons in the subventricular zone of the brain and improved sensorimotor functions in a rat model of ischemic stroke. Our study suggests that combining hESC-HypoxEVs with MFGE-8 may serve as an effective therapeutic modality for reversing senescence and enhancing the neurogenic potential of NSCs to treat neurodegenerative diseases.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052131","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":"α-tocopherol deficiency in follicular ovarian cyst (FOCs) follicular fluid (FF) elevates oxidative stress and impairs oocyte maturation.","authors":"Kiran Kumar P, Lava Kumar S, Silambresan Y, Mohd Athar, Ajith Kumar, Aradhana Mohanty, Anjali Kumari, Pravin Birajdar, Akshay Kumar, Sahina Sabnam, Abhilasha S, G Taru Sharma, H B D Prasada Rao","doi":"10.1016/j.freeradbiomed.2025.01.049","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.01.049","url":null,"abstract":"<p><p>Follicular ovarian cysts (FOCs) are prevalent reproductive disorders in both humans and animals, especially in livestock, where they cause economic losses by reducing fertility and productivity. FOCs are marked by a dominant follicle that fails to ovulate, disrupting the estrous cycle and reproductive efficiency. Previous studies indicate that the follicular fluid (FF) in cystic ovaries shows oxidative imbalance, affecting oocyte quality by altering glutathione peroxidase (GPX1) and selenium pathways. However, the metabolic profile of FF in cystic ovaries needs further exploration. This study examined oxidative stress and metabolic changes in FOC pathogenesis. Using untargeted metabolomics of goat FF, we found significant differences in 12,741 metabolites between cystic and control FF. Cystic FF had reduced levels of α-tocopherol and 8'-apocaroten-8'-ol, key for oxidative stress management, and increased levels of mycotoxins (e.g., Deoxynivalenol-3-glucoside) and long-chain fatty acids. Adding 200 μM α-tocopherol to FOC FF oocyte cultures doubled oocyte maturation rates and decreased reactive oxygen species (ROS). Metabolomic analysis linked low α-tocopherol to high lipid peroxyl radicals and low glutathione oxidation, emphasizing oxidative stress regulation's importance in the follicular microenvironment. Our findings suggest that α-tocopherol may serve as a biomarker and therapeutic agent to enhance oocyte maturation in FOCs.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052132","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":"Modelling the human Coenzyme Q deficiency in Drosophila melanogaster.","authors":"Daniel J M Fernández-Ayala, Sandra Jiménez-Gancedo, Ignacio Guerra, Juan D Hernández-Camacho, Marta Neto, Filippo Scialo, Verónica Astillero-López, Ana Belén Cortés-Rodríguez, Carlos Santos-Ocaña, Juan Carlos Rodríguez-Aguilera, Fernando Casares, Alberto Sanz, Guillermo López-Lluch, Plácido Navas","doi":"10.1016/j.freeradbiomed.2024.12.056","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2024.12.056","url":null,"abstract":"<p><p>The interference of the expression of each of the genes involved in the synthesis of coenzyme Q (CoQ) in Drosophila melanogaster can help to understand the pathophysiology of CoQ-dependent mitochondrial diseases in humans. We have knocked-down all genes involved in the CoQ biosynthesis pathway at different temperatures to induce depletion of CoQ at different levels throughout the body and in a tissue-specific manner. The efficiency of the knockdowns was quantified by Q-RTPCR and determination of CoQ levels by HPLC-UV+ECD. We performed mitochondria purification and quantified respiratory chain activity, both mitochondrial hydrogen peroxide and superoxide production, resistance to mechanical stress and determination of life expectancy. Finally, we evaluated the effect of CoQ10 supplementation as phenotype rescue therapy. D. melanogaster presents 3 isoforms of CoQ: CoQ8, CoQ9 and CoQ10. The level of depletion depended on the efficiency of the RNAi used and is specific for each gene. The interference of some genes interrupted fly development in embryogenesis (pdss2) or during metamorphosis (pdss1, coq3, coq5, coq8 and coq10), while in other cases viable adults can be obtained (coq2, coq6 and coq7). The knockdown of coq7 accumulated intermediates of the CoQ biosynthesis pathway at all stages of development, altered electron transfer with poor assembly of mitochondrial complexes, and deregulated mitochondrial hydrogen peroxide and superoxide production. Coq7 mutant flies showed partial lethality in metamorphosis, bang sensitivity and reduced life span of surviving animals. CoQ10 supplementation rescued the coq7-mutant phenotypes. Knock-down in the imaginal disc generated gene-specific eye deformities that can be mitigated by CoQ10 supplementation. Our results indicate that interference of the CoQ biosynthesis pathway in D. melanogaster shows a great diversity of phenotypes depending on the target gene, mirroring the heterogeneity of CoQ deficiency syndrome in humans and point to why mutations in certain genes are rarely found in patients.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045749","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":"Laminin-dystroglycan mediated ferroptosis in hemorrhagic shock and reperfusion induced-cognitive impairment through AMPK/Nrf2.","authors":"Aoxue Xu, Kai Yuan, Song Xue, Wenping Lu, Xiaoli Wu, Wei Liu, Qi Xue, Lulu Liu, Jia Hu, Liyuan Guo, Ye Zhang, Xianwen Hu, Gordon Tin Chun Wong, Lin Lu, Chunxia Huang","doi":"10.1016/j.freeradbiomed.2025.01.046","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.01.046","url":null,"abstract":"<p><p>Hemorrhagic shock and reperfusion (HSR) is the main cause of death following trauma. Cognitive impairment may persist after successful resuscitation from hemorrhagic shock, but the mechanisms remain elusive. This study demonstrated the presence of ferroptosis in an in vitro model of oxygen-glucose deprivation and reoxygenation (OGD/R) in HT22 neurons, and also in a murine model of HSR using 3-month-old C57BL/6 mice. The ferroptosis induced by OGD/R was characterized by transmission electron microscopy, the localization of FTH1 and TFR1 in HT22 cells. However, neuronal ferroptosis was prevented by suppressing AMPK through siRNA transfection or AMPK inhibitor pretreatment (compound C) in vitro. There was a consistent increase in Nrf2 with ROS accumulation, iron deposition, and lipid peroxidation in the hippocampal neurons and tissues. Nrf2 knockdown or overexpression significantly modulated OGD/R induced-ferroptosis. Activating ferroptosis by erastin (a ferroptosis inducer) or inhibiting it by ferrostatin-1 (a ferroptosis inhibitor) respectively enhanced or mitigated cognitive deficits as well as the ferroptosis-related changes induced by HSR. In addition to the improved cognition, single-nucleus transcriptome analysis of ipsilateral hippocampi from Nrf2^-/- mice demonstrated the broad decrease of ferroptosis in neuronal cell clusters. LAMA2 and DAG1 were dominantly elevated and co-localized in the hippocampal CA3 region of Nrf2^-/- mice by fluorescence in situ hybridization. The activation of astrocytes was significantly attenuated after Nrf2 knockout, associated with the increases of laminin-dystroglycan during astrocyte-neuron crosstalk. Thus, data from this study proposes a novel explanation, namely laminin-dystroglycan interactions during astrocytes-neurons crosstalk stimulating AMPK and Nrf2 induced neuronal ferroptosis, for the development of cognitive impairment after HSR.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045528","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":"Dose-response Relationship Between Dietary Nitrate Intake and Nitric Oxide Congeners in Various Blood Compartments and Skeletal Muscle: Differential Effects on Skeletal Muscle Torque and Velocity.","authors":"Chenguang Wei, Anni Vanhatalo, Matthew I Black, Raghini Rajaram, Garry Massey, Andrew M Jones","doi":"10.1016/j.freeradbiomed.2025.01.048","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.01.048","url":null,"abstract":"<p><p>Plasma nitrate (NO₃^-) and nitrite (NO₂^-) increase in a dose-dependent manner following NO₃^- ingestion. To explore if the same dose-response relationship applies to other nitric oxide (NO) congeners in different blood compartments and skeletal muscle, as well as the subsequent physiological responses, we provided 11 healthy participants with NO₃^- depleted beetroot juice (placebo), and beetroot juice (BR) containing 6.4, 12.8 and 19.2 mmol NO₃^- in a randomised, crossover design. Blood and muscle samples were collected, and resting blood pressure (BP) was assessed, before and at 2.5-3 h post-ingestion. Muscle contractile function was assessed using a 5-min all-out maximal voluntary isometric knee extension test at 3.5 h post-ingestion. We found that plasma and skeletal muscle [NO₃^-], and whole blood S-nitrosothiols ([RSNOs]) increased dose-dependently, while plasma [NO₂^-] did not increase further with doses above 6.4 mmol NO₃^-. No significant increases in skeletal muscle [NO₂^-] were found following ingestion of any of these doses. Resting BP was only reduced after ingestion of 19.2 mmol NO₃^-. Mean peak torque and mean torque impulse during the first 10 muscle contractions were significantly enhanced following ingestion of both 12.8 mmol and 19.2 mmol NO₃^- compared to placebo, while the mean absolute rate of torque development (RTD) at 0-50 ms and 0-100 ms was significantly improved following ingestion of 6.4 mmol NO₃^- compared to placebo and 19.2 mmol NO₃^-. Significant correlations were found between changes in red blood cell [RSNOs] and changes in absolute RTD at 0-50 ms (r_s=-0.70, P=0.02) and 0-100 ms (r_s=-0.84, P<0.01) following the ingestion of 6.4 mmol NO₃^-. Our findings suggest that a high dose of 12.8 mmol NO₃^- is necessary to improve muscle contractile torque, while a lower dose of 6.4 mmol NO₃^- is sufficient to enhance muscle contractile velocity, at least for the type of exercise employed in the present study.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143046188","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":"Fasting enhances the efficacy of Sorafenib in breast cancer via mitophagy mediated ROS-driven p53 pathway.","authors":"Ru Li, Yimei Ma, Anqi He, Yamin Pu, Xuanting Wan, Hongbao Sun, Ningyu Wang, Min Luo, Guan Wang, Yong Xia","doi":"10.1016/j.freeradbiomed.2025.01.047","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.01.047","url":null,"abstract":"<p><p>The multi-kinase inhibitor sorafenib has shown potential to inhibit tumor cell growth and intra-tumoral angiogenesis by targeting several kinases, including VEGFR2 and RAF. Abnormal activation of the Ras/Raf/MAPK/ERK kinase cascade and the VEGF pathway is a common feature in breast cancer. However, the efficacy of sorafenib in breast cancer treatment remains limited. Recently, fasting has emerged as a promising non-pharmacological approach to modulate cancer metabolism and enhance the effectiveness of cancer therapies. In this study, we found that fasting significantly enhances the anti-cancer effects of sorafenib monotherapy and its combination with immunotherapy in breast cancer models without causing obvious side effects. This combined treatment effectively inhibits tumor cell proliferation and intra-tumoral angiogenesis. The fasting-induced reduction in peripheral blood glucose levels strongly correlated with enhanced sensitivity to sorafenib. Mechanistically, the combined treatment induced mitophagy, characterized by mitochondrial dysfunction and activation of the PINK1-Parkin pathway. Consequently, increased mitochondrial ROS levels promoted p53 expression, amplifying cell cycle arrest and apoptosis in breast cancer cells. Furthermore, fasting reduced lactate levels within the tumor, and the consequent glucose limitation synergized with sorafenib to activate AMPK, which in turn elevated PD-L1 expression in tumor cells, potentially enhancing their sensitivity to immunotherapy. In summary, our findings demonstrate that fasting and sorafenib, as a rational combination therapy, induce mitophagy, thereby enhancing sorafenib's efficacy in treating breast cancer through the ROS-driven p53 pathway. This study underscores the potential of fasting in breast cancer therapy and provides a foundation for optimizing the clinical application of sorafenib.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045357","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":"TARGETING LUNG HEME IRON BY AEROSOL HEMOPEXIN ADMINSTRATION IN SICKLE CELL DISEASE PULMONARY HYPERTENSION.","authors":"Melissa Lucero, Christina Lisk, Francesca Cendali, Delaney Swindle, Saini Setua, Kiruphagaran Thangaraju, David I Pak, Quintin O'Boyle, Shuwei Lu, Robert Tolson, Seth Zaeske, Nishant Rana, Saqib Khan, Natalie Westover, Pavel DavizonCastillo, Gemlyn George, Kathryn Hassell, Rachelle Nuss, Nathan Brinkman, Thomas Gentinetta, Andre F Palmer, Angelo D'Alessandro, Paul W Buehler, David C Irwin","doi":"10.1016/j.freeradbiomed.2025.01.045","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.01.045","url":null,"abstract":"<p><p>Lung tissue from human patients and murine models of sickle cell disease pulmonary hypertension (SCD-PH) show perivascular regions with excessive iron accumulation. The iron accumulation arises from chronic hemolysis and extravasation of hemoglobin (Hb) into the lung adventitial spaces, where it is linked to nitric oxide depletion, oxidative stress, inflammation, and tissue hypoxia, which collectively drive SCD-PH. Here, we tested the hypothesis that intrapulmonary delivery of hemopexin (Hpx) to the deep lung is effective at scavenging heme-iron and attenuating the progression of SCD-PH. Herein, we evaluated in a murine model of hemolysis driven SCD-PH, if intrapulmonary Hpx administration bi-weekly for 10 weeks improves lung iron deposition, exercise tolerance, cardiovascular function, and multi-omic indices associated with SCD-PH. Data shows Hpx delivered with a micro-sprayer deposits Hpx in the alveolar regions. Hpx extravasates into the perivascular compartments but does not diffuse into the circulation. Histological examination shows Hpx therapy decreased lung iron deposition, 4-HNE, and HO-1 expression. This was associated with improved exercise tolerance, cardiopulmonary function, and multi-omic profile of whole lung and RV tissue. Our data provides proof of concept that treating lung heme-iron by direct administration of Hpx to the lung attenuates the progression of PH associated with SCD.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143038114","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":"Salvianolic acid B drives gluconeogenesis and peroxisomal redox remodeling in cardiac ischemia/reperfusion injury: A metabolism regulation by metabolite signal crosstalk.","authors":"Jin-Shan Li, Xiao-Ming Qi, Qing-Fang Li, Wei-Wei Wu, Yuan-Lin Zhang, Hai-Xin Liu, Jin-Hong Ren, Jun-Yan Liu, Ji-Hui Lin, Qi-Yan Wang, Yuan-Biao Qiao, Qing-Shan Li","doi":"10.1016/j.freeradbiomed.2025.01.037","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.01.037","url":null,"abstract":"<p><p>Cardiac metabolism relies on glycogen conversion by glycolysis. Glycolysis intersects fatty acid oxidation and often directs a signal crosstalk between redox metabolites. Myocardium with ischemia/reperfusion significantly diverts from normal metabolism. Prospectively, peroxisome lies central to metabolism and redox changes, but mechanisms underlying in ischemia/reperfusion remain undefined. This work aims at investigating the potential effects and mechanisms of Salvianolic acid B (Sal B) in cardioprotection through metabolic remodeling. Following experiments, we found that Sal B is absorbed in blood and rat hearts and its cardiac absorption prevents ischemia/reperfusion injury. Sal B cardioprotection relates to gluconeogenesis activation and peroxisomal redox remodeling. Gluconeogenesis compensates glycogen synthesis through upregulating pyruvate carboxylase (PC) and phosphoenolpyruvate carboxykinase. Gluconeogenic PC activity drives peroxisomal Pex2/Pex3 expressions and promotes the proliferation of peroxisome. Peroxisome quality control is enhanced with Pex5/Pex14/Pex13/Pex2 transcriptions. Nono, a non-POU domain-containing octamer-binding protein, promotes upregulation of gluconeogenic PC and peroxisomal gene transcripts through transcriptionally splicing their pre-RNAs at octamer duplex. Nono also controls the expression of SARM1/PARP1/sirtuin1 for catalyzing nicotinamide adenine dinucleotide (NAD⁺) consumption, leading to endurable redox capacities of peroxisome. Peroxisomal redox remodeling alters reactive oxygen species (ROS) and NAD⁺ contents, following which NAD⁺ affects cardiac accumulation of physiologically harmful glucocorticoid. In the tests of Sal B combinational treatments, results indicate ROS upregulation whereas NAD⁺ downregulation with glucocorticoid, ROS scavenging and glucocorticoid elimination with NAD⁺ precursor, and NAD⁺ promotion with ROS scavenger, respectively. This metabolite signal crosstalk alternatively antagonizes/agonizes Sal B cardioprotective functions on electrocardiographic output and infarction. Taken together, we reported a cardiac metabolism regulation with Sal B, capable of preventing myocardium from ischemia/reperfusion injury. The metabolite signal crosstalk was achieved by coupling reaction cascades between gluconeogenesis and peroxisomal redox remodeling.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143038110","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":"Identification of a Novel Cuproptosis Inducer That Induces ER Stress and Oxidative Stress to Trigger Immunogenic Cell Death in Tumors.","authors":"Xianling Ning, Xi Chen, Ridong Li, Yang Li, Zhiqiang Lin, Yuxin Yin","doi":"10.1016/j.freeradbiomed.2025.01.042","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.01.042","url":null,"abstract":"<p><p>Cuproptosis, a copper-dependent form of regulated cell death, has been implicated in the progression and treatment of various tumors. The copper ionophores, such as Disulfiram (DSF), an FDA-approved drug previously used to treat alcohol dependence, have been found to induce cuproptosis. However, the limited solubility and effectiveness of the combination of DSF and copper ion restrict its widespread application. In this study, through a random screening of our in-house compound library, we identified a novel cuproptosis inducer, YL21, comprising a naphthoquinone core substituted by two dithiocarbamate groups. The combination of YL21 with copper ion induces cuproptosis by disrupting mitochondrial function and promoting the oligomerization of lipoylated protein DLAT. Further, this combination induces endoplasmic reticulum (ER) stress and oxidative stress, triggering immunogenic cell death (ICD) and subsequently promoting the activation of antitumor immune responses to suppress tumor growth in the mice breast cancer model. Notably, the combination of YL21 and copper ion demonstrated improved solubility and increased antitumor activity compared to the combination of DSF and copper ion. Thus, YL21 functions as a novel cuproptosis inducer and may serve as a promising candidate for antitumor immunotherapy.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028497","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}