Free Radical Biology and Medicine最新文献

{"title":"Baicalin restores dopamine homeostasis in the ADHD model by regulating DAT-VMAT2 transport imbalance through activation of the Nrf2/Keap-1/HO-1 pathway","authors":"Xueying Ding ,&nbsp;Bingxiang Ma ,&nbsp;Rongyi Zhou ,&nbsp;Yongting Zhang ,&nbsp;Yuyan Zhang ,&nbsp;Xinyue Xie ,&nbsp;Mengfei Wang ,&nbsp;Chenlei Wu ,&nbsp;Jia Jia","doi":"10.1016/j.freeradbiomed.2025.02.032","DOIUrl":"10.1016/j.freeradbiomed.2025.02.032","url":null,"abstract":"<div><div>The 'dopamine (DA) deficit' theory is pivotal in understanding the pathogenesis of attention deficit hyperactivity disorder (ADHD). However, the relationship betweeen an imbalance in the dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) the DA deficit remains poorly understood. Using the internationally recognized spontaneously hypertensive rats (SHRs) models, we investigated how a high oxidative stress (OS) state in vivo disrupts DAT-VMAT2 transport balance, a key factor influencing DA homeostasis. Our findings revealed abnormal levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG), catalase (CAT), total antioxidant capacity (T-AOC), glutathione (GSH), and tumor necrosis factor-α (TNF-α) in SHRs. Furthermore, the antioxidative stress-related nuclear factor erythroid 2-related factor (Nrf2)/kelch-like ECH-associated protein 1 (Keap-1)/heme oxygenase-1 (HO-1) pathway was inhibited, leading to excessive DAT activation and functional antagonism of VMAT2. Notably, Baicalin (BA) ameliorated these imbalances. Treatment with the VMAT2 inhibitor tetrabenazine (TBZ) exacerbated VMAT2 inhibition in SHRs brains, further activating DAT and restricting Nrf2 nuclear translocation. These results confirmed the strong link between the Nrf2/Keap-1/HO-1 pathway the DAT-VMAT2 imbalance. Moreover, under high OS conditions, the phosphorylation of nuclear factor-κB P65 (NF-κB P65) was triggered, leading to the upregulation of heat shock cognate protein 70 (HSC70). We aslo identified a potential negative feedback mechanism between HSC70 and VMAT2. In summary, our study uncovered a novel mechanism in ADHD pathogenesis, demonstrating that the DA deficits resulted from an imbalance between DAT and VMAT2. Remarkably, BA significantly reduced high levels of OS and inflammation by activating the Nrf2/Keap-1/HO-1 pathway, thereby restoring DAT-VMAT2 transport balance and enhancing DA homeostasis. This discovery provides a solid foundation for further exploration of ADHD pathogenesis and offers new molecular insights for ADHD treatment.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"232 ","pages":"Pages 107-127"},"PeriodicalIF":7.1,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537055","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":"Cyclophilin D (CypD) ablation prevents neurodegeneration and cognitive damage induced by caspase-3 cleaved tau","authors":"Margrethe A. Olesen ,&nbsp;Francisca Villavicencio-Tejo ,&nbsp;Gail V.W. Johnson ,&nbsp;George A. Porter ,&nbsp;Rodrigo A. Quintanilla","doi":"10.1016/j.freeradbiomed.2025.02.035","DOIUrl":"10.1016/j.freeradbiomed.2025.02.035","url":null,"abstract":"<div><div>Abnormal tau modifications are one of the main contributors to neurodegenerative processes present during Alzheimer's disease (AD). In this context, truncated tau by caspase-3, a pathological tau form, affects mitochondrial function and antioxidant regulation, contributing to synaptic and cognitive impairment in AD mouse models. We previously showed that the presence of caspase-3 cleaved tau promotes mitochondrial impairment in neuronal cells, where Cyclophilin-D (CypD) protein could be a crucial element. CypD is considered the master regulator of mitochondrial permeability transition pore (mPTP) opening, and its ablation prevents neurodegenerative and cognitive damage induced by β−amyloid in mouse models of AD. However, the possible role of CypD in the neurodegenerative processes mediated by caspase-3-cleaved tau has not been explored. Here, we use tau (−/−) and CypD (−/−) knock-out mice that were subjected to right-side hippocampal stereotaxic injection to induce GFP (AAV-Syn-GFP), full-length (AAV-Syn-GFP-T4) or caspase-3-cleaved (AAV-Syn-GFP-T4C3) tau expression. Then, cognitive performance, synaptic architecture, and hippocampal mitochondrial function were evaluated two months later. We observed that caspase-3 cleaved tau expression inducing cognitive decline, vesicle and synaptic protein deregulation, and mitochondrial impairment generated by the mPTP opening. More interestingly, when caspase-3 cleaved tau was expressed in the hippocampus of CypD (−/−) mice, cognitive decline, synaptic impairment, and mitochondrial damage mediated by mPTP were prevented, demonstrating a novel role of CypD in neurodegenerative changes induced by truncated tau in AD.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"232 ","pages":"Pages 128-141"},"PeriodicalIF":7.1,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537056","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-derived mesenchymal stem cells attenuate liver fibrosis by inhibiting hepatocyte ferroptosis through mitochondrial transfer","authors":"Zhiyu Xiong ,&nbsp;Ping Chen ,&nbsp;Zheng Wang ,&nbsp;Lichao Yao ,&nbsp;Mengqin Yuan ,&nbsp;Pingji Liu ,&nbsp;Muhua Sun ,&nbsp;Kan Shu ,&nbsp;Yingan Jiang","doi":"10.1016/j.freeradbiomed.2025.02.045","DOIUrl":"10.1016/j.freeradbiomed.2025.02.045","url":null,"abstract":"<div><div>Liver fibrosis is a reversible dynamic pathological process induced by chronic liver injury. Without intervention, liver fibrosis can progress to become cirrhosis, liver failure, or hepatocellular carcinoma, thus posing a high global health burden. Therefore, effective therapies for liver fibrosis are urgently required. Although transplantation of mesenchymal stem cells (MSCs) has significant value as a treatment strategy for liver damage, the underlying mechanisms remain unclear. Chronic liver injury progression is significantly influenced by hepatocyte ferroptosis, and targeting ferroptosis is emerging as a potential treatment strategy for liver fibrosis. Here, we showed that the infusion of human umbilical cord-derived MSCs (hUC-MSCs) alleviated TAA-induced liver fibrosis, improved liver functionality, and decreased ferroptosis in mice. hUC-MSCs inhibit ferroptosis-related mitochondrial damage and lipid peroxidation in AML12 cells <em>in vitro</em>. Mechanistically, under oxidative stress, hUC-MSCs transfer healthy mitochondria to damaged hepatocytes through tunneling nanotubes (TNTs). Cytochalasin D (CytoD), an inhibitor of TNT formation, abrogated the protective effects of hUC-MSCs against ferroptosis. This research emphasizes the ability of hUC-MSCs to serve as a promising treatment for liver fibrosis via mitochondrial transfer through TNTs.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"231 ","pages":"Pages 163-177"},"PeriodicalIF":7.1,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143527414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adipose stem cells ameliorate erectile dysfunction in diabetes mellitus rats by attenuating ferroptosis through NRP1 with SLC7A11 interaction","authors":"Jun-qi Luo ,&nbsp;Li Wang ,&nbsp;Zi-qi Liao ,&nbsp;Bing-xin Lu ,&nbsp;Cai-yu Luo ,&nbsp;Hai-yang He ,&nbsp;Zhi-han Ou yang ,&nbsp;Song-bo Duan ,&nbsp;Shu-hua He ,&nbsp;An-yang Wei ,&nbsp;Hai-bo Zhang","doi":"10.1016/j.freeradbiomed.2025.02.041","DOIUrl":"10.1016/j.freeradbiomed.2025.02.041","url":null,"abstract":"<div><h3>Background</h3><div>Adipose stem cells (ADSCs) have garneVred increasing attention for their potential to treat diabetes mellitus erectile dysfunction (DMED), but the underlying molecular mechanisms remain unclear. The aim of this study was to identify and investigate the key cytokines and mechanisms by which ADSCs improve erectile function in DMED rats.</div></div><div><h3>Methods</h3><div>We performed in vivo and in vitro assays, including rat erectile function assessment, cell co-culture, cytokine microarray screening and co-immunoprecipitation to investigate the role of ADSCs in improving erectile function in DMED rats.</div></div><div><h3>Results</h3><div>Our analyses confirmed the occurrence of ferroptosis in the corpus cavernosum of DMED rats, while ADSCs treatment significantly restored erectile function and improved relevant indicators of ferroptosis. In vitro assays further indicated that corpus cavernosum smooth muscle cells (CCSMCs) co-cultured with ADSCs exhibited enhanced resistance to ferroptosis, with notably lower levels of cytoplasmic and lipid reactive oxygen species compared to the ferroptosis inducer Erastin-treated group. Mechanistic studies revealed that Neuropilin 1 (NRP1) may be a key molecule in ADSCs to improve erectile function in DMED rats. Furthermore, NRP1 in CCSMCs can interact with solute carrier family 7 member 11 (SLC7A11) to enhance the function of the glutamate-cysteine countertransport (Xc-) system and ferroptosis resistance in CCSMCs.</div></div><div><h3>Conclusion</h3><div>In conclusion, our findings indicate that NRP1 is a key molecule for ADSCs treatment to alleviate ferroptosis and improve erectile function in DMED rats, providing a promising target for DMED treatment and prognosis.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"232 ","pages":"Pages 40-55"},"PeriodicalIF":7.1,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531256","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":"Edaravone mitigates TDP-43 mislocalization in human amyotrophic lateral sclerosis neurons with potential implication of the SIRT1-XBP1 pathway","authors":"Satsuki Mikuriya,&nbsp;Tomo Takegawa-Araki,&nbsp;Makoto Tamura","doi":"10.1016/j.freeradbiomed.2025.01.012","DOIUrl":"10.1016/j.freeradbiomed.2025.01.012","url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss along with pathological mislocalization of TAR DNA-binding protein 43 (TDP-43), a protein implicated in RNA metabolism. Although edaravone, a free-radical scavenger, has been approved for ALS treatment, its precise mechanism of action is not fully understood, particularly in relation to TDP-43 pathology. Here, we investigated the effects of edaravone on induced pluripotent stem cell (iPSC)-derived motor neurons in a patient with ALS harboring a TDP-43 mutation. Our results demonstrated that edaravone significantly attenuated neurodegeneration, as evidenced by neurite preservation, neuronal cell death reduction, and correction of aberrant cytoplasmic localization of TDP-43. These neuroprotective effects were not observed with vitamin C, indicating a unique mechanism of action for edaravone, distinct from its antioxidative properties. RNA sequencing revealed that edaravone rapidly modulated gene expression, including protein quality control pathway, such as the ubiquitin-proteasome system. Further analysis identified X-box binding protein (XBP1), a key regulator of the endoplasmic reticulum stress response, as a critical factor in the therapeutic effects of edaravone. This study suggests that edaravone may offer a multifaceted therapeutic approach for ALS by targeting oxidative stress and TDP-43 mislocalization through distinct molecular pathways.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"230 ","pages":"Pages 283-293"},"PeriodicalIF":7.1,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143487633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxidation products of proteins in plasma of newborns reflect damage inflicted by O2 supplementation and correlate with gestational age","authors":"Juan David Figueroa ,&nbsp;Jorge Gómez-Cayupan ,&nbsp;Fresia Solís-Egaña ,&nbsp;Carlos Jara-Gutiérrez ,&nbsp;Viviana Valero ,&nbsp;Miriam Faunes ,&nbsp;Stephanie Campbell ,&nbsp;Paulina Toso ,&nbsp;Michael J. Davies ,&nbsp;Paola Casanello ,&nbsp;Camilo López-Alarcón","doi":"10.1016/j.freeradbiomed.2025.02.037","DOIUrl":"10.1016/j.freeradbiomed.2025.02.037","url":null,"abstract":"<div><div>Treatment of neonates, and especially preterm newborns, with supplementary O₂, can result in oxidative stress and both short- and long-term health complications. Oxidation products formed on proteins, which are the principal targets of reactive species in plasma, can be used to assess damage arising from O₂ therapy. We hypothesized that this may be particularly relevant for preterm neonates. Oxidation products formed on proteins in the plasma of term and preterm newborns were quantified to assess their possible use as biomarkers. Plasma samples from 114 term and preterm neonates with and without O₂ supplementation (fraction of inspired oxygen, FiO₂ &gt; 21 % and 21 %, respectively) were analyzed. Total protein content and protein carbonyls were determined spectrophotometrically, whilst specific oxidation products from Tyr, Trp and Met were quantified using liquid chromatography coupled to mass detection (LC-MS). Kynurenine (Kyn), <em>N</em>-formylkynurenine (NFKyn), dihydroxydiphenylalanine (DOPA), 3-nitrotyrosine (3-NTyr), methionine sulfoxide (MetSO) and di-tyrosine (di-Tyr) were assessed in their protein-bound form. Alcohols, hydroperoxides and dimers of Trp were also investigated. Carbonyl groups, as well as 3-NTyr and MetSO, showed statistical differences between term and preterm neonates. However, only MetSO was sensitive to O₂ supplementation in both term and preterm subjects. The plasma levels of these products showed an inverse association with gestational age. The advantages and limitations of these products as biomarkers of protein oxidation, and the experimental procedures needed to quantify these accurately, should be considered when designing future clinical investigations.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"232 ","pages":"Pages 185-193"},"PeriodicalIF":7.1,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531288","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 alleviates acute ischemic stroke induced ferroptosis via regulating xCT/GPX4 pathway","authors":"Yujun Ye ,&nbsp;Xuexin Xie ,&nbsp;Yiming Bi ,&nbsp;Qing Liu ,&nbsp;Lingling Qiu ,&nbsp;He Zhao ,&nbsp;Chengyin Wang ,&nbsp;Weifeng Zhu ,&nbsp;Ting Zeng","doi":"10.1016/j.freeradbiomed.2025.02.040","DOIUrl":"10.1016/j.freeradbiomed.2025.02.040","url":null,"abstract":"<div><div>Ferroptosis is a form of regulating cell death, and iron accumulation in the brain after acute ischemic stroke (AIS) is associated with the triggering of iron metabolism. Nuclear factor erythroid 2-related factor 2 (<em>Nrf2</em>), one of the most critical antioxidant transcription factors in cells, is closely associated with ferroptosis and oxidative stress.In the present study, we explore the intrinsic mechanisms by which <em>Nrf2</em> exerts neuroprotective effects against AIS-induced ferroptosis.<em>In vivo</em> experiments, we explored the protective effects of AIS induced by middle cerebral artery occlusion (MCAO) and its mechanisms by using intraperitoneal injections of ferrostatin-1 (Fer-1, an inhibitor of ferroptosis), Oltipraz (an agonist of <em>Nrf2</em>) and ML385 (an inhibitor of <em>Nrf2</em>) in wild-type (WT) mice, as well as using <em>Nrf2</em>^{<em>−/−</em>} mice. <em>In vitro</em> experiments, we investigated the mechanism of action of <em>Nrf2</em> on the establishment of a ferroptosis cell model induced by Erastin by overexpressing or silencing <em>Nrf2</em> expression using shRNA in SH-SY5Y cells.Ferroptosis played an important role in AIS, and Fer-1 inhibited iron accumulation and alleviated neuronal damage caused by AIS.Oltipraz attenuated AIS-induced neuronal damage and cerebral infarction by increasing cortical blood flow (CBF). Additionally, Oltipraz protected against AIS-induced ferroptosis by reducing oxidative stress and iron overload. Meanwhile, in Oltipraz-treated AIS mice, <em>Nrf2</em>, solute carrier family 7 member 11 (SLC7A11/xCT), and glutathione peroxidase 4 (GPX4) were upregulated. Conversely, ML385 decreased CBF and exacerbated IS-induced neuronal damage. Furthermore, both ML385 treatment and <em>Nrf2</em> knockout mice exacerbated oxidative stress injury and iron overload and downregulated the expression of both xCT and GPX4. Consistent with the in vivo results, <em>Nrf2</em> conferred ferroptosis resistance <em>in vitro</em> upon exposure to compounds that induce ferroptosis, by modulating the xCT/GPX4 pathway.The present study confirmed that <em>Nrf2</em> could attenuate AIS-induced neuronal ferroptosis and oxidative stress by regulating xCT/GPX4.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"231 ","pages":"Pages 153-162"},"PeriodicalIF":7.1,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143527416","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":"MSC exosomes and MSC exosomes loaded with LncRNA H19 as nanotherapeutics regulate the neurogenetic potential of Müller Glial Cells in dry age-related macular degeneration","authors":"Yue Tang,&nbsp;Caiyi Cheng,&nbsp;Rui Ding,&nbsp;Jingyuan Qian,&nbsp;Min Liu,&nbsp;Yuzun Guo,&nbsp;Qian Li","doi":"10.1016/j.freeradbiomed.2025.02.039","DOIUrl":"10.1016/j.freeradbiomed.2025.02.039","url":null,"abstract":"<div><div>In retinal degeneration diseases such as dry age-related macular degeneration (AMD), Müller Glial Cells (MGCs) in mammals undergo a process of reactive gliosis leading to the progression of dry AMD. Here, It is demonstrated that exosomes derived from mesenchymal stem cells (MSC exosomes) and MSC exosomes loaded with LncRNA H19, acting as nanotherapeutics, can be regulated by MGCs in dry AMD. In the <em>in vivo</em> study, MSC exosomes were administered via intravitreal injection. MSC exosomes effectively redirected MGCs from gliosis to dedifferentiation and alleviated MGCs-to-epithelial transition by inhibiting oxidative stress in mice with dry AMD induced by NaIO₃. In the in vitro study, MSC exosomes promoted MGCs dedifferentiation by activating Wnt/β-catenin signaling pathway and prevented oxidative stress-induced MGCs gliosis and MGCs-to-epithelial transition by inhibiting TGFβ1 signaling pathway. MSC exosomes loaded with LncRNA H19 enhanced the activation of Wnt/β-catenin signaling pathway and the inhibition of the TGFβ1 signaling pathway compared with MSC exosomes. These results suggest that MSC exosomes regulate the neurogenetic potential of MGCs by redirecting MGCs from gliosis to dedifferentiation and alleviating the transformation of MGCs to epithelial cells through regulating oxidative stress. Regulating LncRNA H19 in MGCs to promote mammalian retinal regeneration in dry AMD was suggested for the first time.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"231 ","pages":"Pages 178-192"},"PeriodicalIF":7.1,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523048","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":"HnRNPA2B1 promotes cardiac ferroptosis via m6A-dependent stabilization of PFN2 mRNA in myocardial ischemia-reperfusion injury","authors":"Shuotao Shi ,&nbsp;Qi Chen ,&nbsp;Ying Yang ,&nbsp;Zipei Li ,&nbsp;Ruiyan Zheng ,&nbsp;Rong Zhang ,&nbsp;Zhongqiu Liu ,&nbsp;Yuanyuan Cheng","doi":"10.1016/j.freeradbiomed.2025.02.038","DOIUrl":"10.1016/j.freeradbiomed.2025.02.038","url":null,"abstract":"<div><div>Myocardial ischemia-reperfusion damage (MIRI) is a clinical problem and lacks proven treatment approaches. As a m6A reader, hnRNPA2B1 controls RNA destiny in the pathophysiology of neurodegenerative and cancerous disorders. Recently, we found that the level of hnRNPA2B1 was elevated in patients with myocardial infarction after percutaneous coronary intervention (PCI), which was positively correlated with cTnI. However, the role of hnRNPA2B1 in MIRI is still unknown. In the present study, we investigated the mechanism underlying MIRI-induced ferroptosis by focusing on a novel function of hnRNPA2B1. Our results showed that HnRNPA2B1 was also significantly increased in cardiomyocytes of MIRI models <em>in vitro</em> and <em>in vivo</em>. Genetically deleting hnRNPA2B1 effectively mitigated myocardial injury and cardiac function during MIRI. Silencing hnRNPA2B1 in cardiomyocytes boosted cell survival and decreased ferroptosis by lowering lipid ROS, MDA, Fe2+, and raising GSH, FTH1 levels, while overexpressing hnRNPA2B1 had the opposite impact. Mechanistic investigations revealed that hnRNPA2B1 recognized and interacted with the m6A site of PFN2 mRNA at “AGACU” to enhance the stability of PFN2 mRNA transcripts. Furthermore, PFN2 knockdown resulted in decreased MDA and Fe²⁺ levels and an increase in FTH1 expression. Importantly, silencing PFN2 attenuated ferroptosis in cardiomyocytes overexpressing hnRNPA2B1 during OGD/R injury. Collectively, hnRNPA2B1 potentially acts as a therapeutic target of MIRI through regulating caridac ferroptosis mediated by m6A-PFN2/FTH1 pathway.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"232 ","pages":"Pages 231-243"},"PeriodicalIF":7.1,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515108","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":"Maternal lactoferrin supplementation prevents mitochondrial and redox homeostasis dysfunction, and improves antioxidant defenses through Nrf2 and UCP2 signaling after neonatal hypoxia-ischemia","authors":"Andrey Vinicios S. Carvalho ,&nbsp;Eduardo F. Sanches ,&nbsp;Rafael T. Ribeiro ,&nbsp;Luz Elena Durán-Carabali ,&nbsp;Osmar Ramires Júnior ,&nbsp;Bruna Dutra Muniz ,&nbsp;Moacir Wajner ,&nbsp;Angela T. Wyse ,&nbsp;Carlos Alexandre Netto ,&nbsp;Stéphane V. Sizonenko","doi":"10.1016/j.freeradbiomed.2025.02.036","DOIUrl":"10.1016/j.freeradbiomed.2025.02.036","url":null,"abstract":"<div><div>Neonatal hypoxia-ischemia (HI) is a major cause of mortality and neurological impairments in infants. Main HI-induced pathological mechanisms include mitochondrial dysfunction and oxidative stress due to insufficient oxygen and energetic substrates to the nervous cells. Bovine lactoferrin (Lf) has demonstrated neuroprotective effects in several experimental models of neonatal brain injury in rodents, however its mechanisms remain unclear. This study aimed to evaluate the early impact of maternal dietary supplementation with Lf on redox and hippocampal mitochondrial function following neonatal HI. From postnatal day 6 (PND6), pregnant Wistar rats were fed with a diet supplemented with Lf (1 g/kg) or with an isocaloric control diet until offspring euthanasia. At PND7, pups of both sexes were subjected to experimental HI through the occlusion of the right common carotid artery followed by 60 min of hypoxia (8 % oxygen). Lf prevented HI-induced increased levels of DCFH and lipoperoxidation in hippocampus. Furthermore, Lf enhanced antioxidant defenses including SOD, GPx, and GSH, counteracting HI-induced oxidative stress. HI injury altered the activities of enzymes in the mitochondrial respiratory chain and increased the mitochondrial membrane potential. Both effects were counteracted by Lf supplementation. Lactoferrin prevented oxidative stress and to restored mitochondrial function by upregulating Nrf2 and UCP2 expression following experimental HI. Our results show that even a shorter period of Lf delivery to rat pups is able to improve hippocampal response to neonatal hypoxia-ischemia, reversing initial mechanisms of damage in the cascade of HI injury.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"231 ","pages":"Pages 68-79"},"PeriodicalIF":7.1,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143509733","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}