Manuela Leo , Caterina Mancini , Giulia Lori , Pietro Delre , Irene Ferraris , Filippo Lucchini , Annamaria Molinario , Manuela Leri , Andrea Castellaneta , Ilario Losito , Tommaso Cataldi , Marzia Rossato , Vittorio Colantuoni , Maria Letizia Taddei , Antonio Lavecchia , Lina Sabatino
{"title":"Secoiridoid-enriched extra virgin olive oil extracts enhance mitochondrial activity and antioxidant response in colorectal cancer cells: The role of Oleacein and Oleocanthal in PPARγ interaction","authors":"Manuela Leo , Caterina Mancini , Giulia Lori , Pietro Delre , Irene Ferraris , Filippo Lucchini , Annamaria Molinario , Manuela Leri , Andrea Castellaneta , Ilario Losito , Tommaso Cataldi , Marzia Rossato , Vittorio Colantuoni , Maria Letizia Taddei , Antonio Lavecchia , Lina Sabatino","doi":"10.1016/j.freeradbiomed.2025.04.031","DOIUrl":"10.1016/j.freeradbiomed.2025.04.031","url":null,"abstract":"<div><div>The secoiridoid-enriched fraction of extra virgin olive oil (EVOO) provides significant health benefits, but its underlying mechanisms have not been fully elucidated. To investigate this, we analyzed the transcriptome of HCT116 colorectal cancer cells treated with secoiridoid-enriched EVOO extracts using bioinformatic tools and identified differentially expressed genes enriched in mitochondrial pathways. In vitro validation showed increased mitochondrial mass and DNA driven by enhanced biogenesis and fusion events, accompanied by higher mitochondrial respiration and ATP production. The resulting increase in reactive oxygen species (ROS) triggered a cellular response involving AMPK, NRF2, and antioxidant genes, along with PGC-1α, a master regulator of mitochondrial metabolism. To correlate the biological effects with the components of the secoiridoid-enriched EVOO extracts, we focused on Oleacein (OL) and Oleocanthal (OC). Molecular docking and dynamics simulations predicted both compounds bind to peroxisome proliferator-activated receptor gamma (PPARγ) as partial agonists, with OL exhibiting stronger affinity. Treatments with isolated OL and OC mostly replicated the results of the whole extracts. Mechanistically, we provided evidence of the crucial role played by PPARγ as the effects on the pathways analyzed were reduced by either blocking the receptor with an irreversible inhibitor and silencing the <em>PPARG</em> gene with specific siRNAs.</div><div>This study reveals the AMPK-PGC-1α-PPARγ axis as a key regulator of OL and OC's effects on mitochondrial function and antioxidant response, supporting their potential as nutraceuticals for health promotion and opening avenues for developing novel PPARγ modulators to complement existing therapeutic strategies.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"235 ","pages":"Pages 56-72"},"PeriodicalIF":7.1,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876894","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":"Oxidative stress-induced release of mitochondrial DNA (mtDNA) promotes the progression of vitiligo by activating the cGAS-STING signaling pathway in monocytes","authors":"Tong Wu , Xiaoqi Chen , Jinrong Fan , Peina Ye, Jia Zhang, Zeqian Wang, Yuqi Zhou, Bo Wang, Xiaodong Jin, Shishi Xiong, Shanshan Gao, Yuqian Chang, Chunying Li, Zhe Jian","doi":"10.1016/j.freeradbiomed.2025.04.033","DOIUrl":"10.1016/j.freeradbiomed.2025.04.033","url":null,"abstract":"<div><div>Vitiligo, driven by cytotoxic CD8<sup>+</sup> T cells destroying melanocytes, has recently been linked to mitochondrial DNA (mtDNA), a DAMP known to trigger innate immunity. However, the precise role of mtDNA in vitiligo pathogenesis remains poorly understood. In this study, we observed significantly elevated mtDNA levels in both the serum and depigmented lesions of vitiligo patients. Importantly, we found that oxidative stress induces mtDNA production in keratinocytes and vascular endothelial cells, providing a plausible source for its systemic and localized accumulation. Using the mouse odel, we demonstrated that exogenous mtDNA administration markedly accelerated progression of vitiligo, as evidenced by pronounced tail depigmentation. Mechanistically, mtDNA can activate the cGAS-STING-IFN-α/β pathway in monocytes, leading to an increased production of IFN-γ by CD8<sup>+</sup> T cells while simultaneously reducing the frequency and functionality of regulatory CD4<sup>+</sup> T cells (Tregs). Consistent with these findings, mtDNA treatment in vitiligo mice led to heightened infiltration of IFN-γ<sup>+</sup> CD8<sup>+</sup> T cells into affected tissues, accompanied by a significant decrease in Treg numbers and activity, thereby exacerbating the autoimmune response. Collectively, these findings underscore the pivotal role of mtDNA-STING signaling in vitiligo progression and highlight this pathway as a promising target for therapeutic intervention. Our findings suggest that mtDNA may serve as a crucial mediator in the pathogenesis of vitiligo and other autoimmune diseases, providing new insights into potential therapeutic targets.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"235 ","pages":"Pages 43-55"},"PeriodicalIF":7.1,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143873899","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}
Reyna Rodríguez-Mortera , Pascual Torres , Anna Fernàndez-Bernal , Rebeca Berdún , Omar Ramírez-Núñez , Meritxell Martín-Garí , José CE. Serrano , John C. He , Joan Prat , Reinald Pamplona , Jaime Uribarri , Manuel Portero-Otin
{"title":"Non-enzymatic modification of aminophospholipids induces angiogenesis, inflammation, and insulin signaling dysregulation in human renal glomerular endothelial cells in vitro","authors":"Reyna Rodríguez-Mortera , Pascual Torres , Anna Fernàndez-Bernal , Rebeca Berdún , Omar Ramírez-Núñez , Meritxell Martín-Garí , José CE. Serrano , John C. He , Joan Prat , Reinald Pamplona , Jaime Uribarri , Manuel Portero-Otin","doi":"10.1016/j.freeradbiomed.2025.04.030","DOIUrl":"10.1016/j.freeradbiomed.2025.04.030","url":null,"abstract":"<div><h3>Aims/hypothesis</h3><div>Advanced glycation end-products (AGEs) formation in proteins are involved in healthy aging and a variety of diseases including Alzheimer's disease, atherosclerosis, and diabetic complications. However, the biological effects of the non-enzymatic modification of aminophospholipids (lipid-AGEs) at cellular level are poorly understood. This study aimed to investigate the effects of lipid-AGEs on angiogenesis, inflammation, insulin signaling, and mitochondrial function in human renal glomerular endothelial cells (HRGEC), exploring their potential role in the pathophysiology of diabetic nephropathy (DN).</div></div><div><h3>Methods</h3><div>HRGEC cells were exposed to non-enzymatically modified phosphatidylethanolamine (PE) by AGEs (lipid-AGEs), non-modified PE (nmPE) (aminophospholipid without modification), employed as a negative control, and lipopolysaccharides (LPS) as a positive control. Angiogenesis was assessed through vascular network formation metrics, including capillary area, junction density, and endpoints, under different extracellular matrices. Gene expression of inflammatory and angiogenic markers was quantified by RT-qPCR. Insulin signaling components, including IRS1 and AKT phosphorylation, were evaluated by immunoblotting. Mitochondrial function was assessed using high-resolution respirometry to determine ATP production rates from glycolysis and oxidative phosphorylation.</div></div><div><h3>Results</h3><div>Lipid-AGEs induced dose-, time-, and matrix-dependent angiogenesis, with effects comparable to LPS, particularly in Engelbreth-Holm-Swarm extracellular matrix (ECM) (capillary area increase: 25 %, p < 0.05). Lipid-AGEs significantly upregulated the expression of inflammatory genes <em>IL8</em> and <em>NFKB</em> (p < 0.05), and the angiogenesis-related markers <em>TGFB1</em> and <em>ANGPT2</em> (p < 0.05). Insulin signaling was disrupted, as lipid-AGEs enhanced inhibitory phosphorylation of IRS1 (Ser-1101, 1.8-fold increase, p < 0.01) and modulated AKT (Ser-473) and p42/p44 ERK activation. At lower doses, lipid-AGEs reduced eNOS phosphorylation (p < 0.05) impairing insulin responsiveness. High-resolution respirometry revealed that lipid-AGEs reduced basal oxygen consumption rates (OCR) by 20 % (p < 0.05), with no significant changes in glycolytic ATP production.</div></div><div><h3>Conclusion</h3><div>Lipid-AGEs induce angiogenesis, inflammation, and insulin signaling disruption in HRGEC, contributing to endothelial dysfunction. These findings underscore the potential role of lipid-AGEs in age-related decline of renal function, as well as the pathogenic potential in DN highlighting their relevance as therapeutic targets for mitigating vascular and metabolic complications in diabetes.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"235 ","pages":"Pages 15-24"},"PeriodicalIF":7.1,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863347","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}
Rujin Liu , Lina Dai , Sihui Jia , Shijia Geng , Yan Niu , Jie Chen , Chongyang Dong , Chenlei Li , Yuanjia Shi , Xiaomeng Wang , Jing Zhang , Ningxia Zhao , Zhanfeng Gao , Xi Yang , Shang Gao
{"title":"Fut8 regulated Unc5b hyperfucosylation reduces macrophage emigration and accelerates atherosclerosis development via the ferroptosis pathway","authors":"Rujin Liu , Lina Dai , Sihui Jia , Shijia Geng , Yan Niu , Jie Chen , Chongyang Dong , Chenlei Li , Yuanjia Shi , Xiaomeng Wang , Jing Zhang , Ningxia Zhao , Zhanfeng Gao , Xi Yang , Shang Gao","doi":"10.1016/j.freeradbiomed.2025.04.025","DOIUrl":"10.1016/j.freeradbiomed.2025.04.025","url":null,"abstract":"<div><div>The accumulation of foam cells in the arterial walls is a defining characteristic of atherosclerosis. Enhancing their migration from plaques may represent a key strategy for slowing disease progression. Recent studies suggest that fucosyltransferase 8 (Fut8) impairs macrophage migration from the intima by modifying the Unc5b membrane receptor, thereby influencing the development of atherosclerosis. This study investigated the roles of Fut8 and Unc5b in foam cell migration using ApoE<sup>−/−</sup> mouse and foam cell models, employing techniques such as western blotting, mitochondrial function assays, wound healing experiments, and immunofluorescence staining. The findings indicate that Fut8 upregulation increases P53 expression and reduces SLC7A11 and GPX4 levels, leading to altered intracellular concentrations of GSH and Fe<sup>2+</sup>, impaired mitochondrial function, and reduced migration capacity, all of which promote atherosclerosis. These mechanisms are closely associated with ferroptosis. Intervention with N-acetylcysteine (NAC) and buthionine sulfoximine (BSO) demonstrated that NAC mitigates oxidative stress and migration inhibition, induced by oxidized low-density lipoprotein (ox-LDL). Additionally, inhibiting ferroptosis slowed the progression of atherosclerosis in ApoE<sup>−/−</sup> mice. Together, these results highlight that Fut8 exacerbates atherosclerosis through a P53/SLC7A11-mediated enhancement of ferroptosis in foam cells, offering a novel perspective on the pathophysiology of atherosclerosis.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"235 ","pages":"Pages 1-14"},"PeriodicalIF":7.1,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863442","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}
Hongtu Hu , Juan Wang , Zhuan Peng, Yanqin Fan, Qian Yang, Jijia Hu
{"title":"Dapagliflozin attenuates diabetes-induced podocyte lipotoxicity via ERRα-Mediated lipid metabolism","authors":"Hongtu Hu , Juan Wang , Zhuan Peng, Yanqin Fan, Qian Yang, Jijia Hu","doi":"10.1016/j.freeradbiomed.2025.04.028","DOIUrl":"10.1016/j.freeradbiomed.2025.04.028","url":null,"abstract":"<div><div>Diabetic kidney disease (DKD) is a major complication of diabetes mellitus, characterized by podocyte injury and lipid accumulation, which contribute to high morbidity and mortality. Current treatments primarily alleviate symptoms, underscoring the need for targeted therapies to address the underlying mechanisms of DKD progression. This study explores the protective effects of dapagliflozin (DAPA), a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, on podocyte lipotoxicity and its regulatory role in the estrogen-related receptor alpha (ERRα)-acyl-CoA oxidase 1 (ACOX1) axis. Using db/db mice and streptozotocin-induced DKD models, we demonstrate that DAPA significantly reduces the urinary albumin-to-creatinine ratio (ACR) and improves renal pathology by alleviating glomerular hypertrophy, mesangial matrix expansion, and podocyte foot process effacement. DAPA also decreases triglyceride and free fatty acid accumulation in glomeruli, as evidenced by Oil Red O and BODIPY staining. Mechanistically, DAPA upregulates ERRα and ACOX1 expression in podocytes, enhancing fatty acid oxidation (FAO) and mitigating lipidtoxicity. Loss of ERRα exacerbates lipid-induced podocyte injury, while ERRα overexpression confers protective effects. These findings highlight DAPA’s renoprotective effects via modulation of the ERRα-ACOX1 axis, suggesting that targeting ERRα could be a promising therapeutic strategy for DKD.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"234 ","pages":"Pages 178-191"},"PeriodicalIF":7.1,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143860600","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}
Yan Zhang , Yuanyuan Ren , Zhen Wang , Xi Zhang , Xiaofang Li , Yi Yu , Lu Qian , Yuyan Xiong
{"title":"Exosomal SLC1A5 from senescent endothelial cells promotes gastric cancer progression by dampening ferroptosis via the EGFR/SRC/YAP1/GPX4 signaling","authors":"Yan Zhang , Yuanyuan Ren , Zhen Wang , Xi Zhang , Xiaofang Li , Yi Yu , Lu Qian , Yuyan Xiong","doi":"10.1016/j.freeradbiomed.2025.04.029","DOIUrl":"10.1016/j.freeradbiomed.2025.04.029","url":null,"abstract":"<div><div>A high-fat diet and obesity significantly increase the risk of gastric cancer (GC), with persistent obesity contributing to a notable rise in GC incidence. However, the underlying molecular mechanisms remain largely unclear. In this study, we identified exosomal SLC1A5 (Exo-SLC1A5) as a novel senescence-associated secretory phenotype (SASP) factor that promotes GC malignancy. Exosomal SLC1A5 drives GC progression by suppressing ferroptosis in a GPX4-dependent manner. Mechanistically, in the context of obesity, senescent endothelial cells release exosomal SLC1A5, which engages EGFR on GC cells, triggering SRC phosphorylation at Tyr416 and subsequent YAP1 activation at Tyr357. This leads to YAP1 interaction with MYO1B to enhance the nuclear translocation of YAP1, and subsequent upregulation of GPX4, resulting in ferroptosis suppression and accelerated GC progression. In vivo, depletion of exosomal SLC1A5 from PA-induced senescent ECs attenuated GC tumor growth and metastasis in a xenograft mouse model. These findings reveal a novel mechanism by which exosomal SLC1A5 promotes GC progression through the EGFR/SRC/YAP1/GPX4 signaling axis. Targeting the Exo-SLC1A5/EGFR/SRC/YAP1/GPX4 axis may provide a therapeutic strategy for GC.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"235 ","pages":"Pages 25-42"},"PeriodicalIF":7.1,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143868948","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}
Ziqian Zhang , Min Xiang , Huihua Yang , Wenting Guo , Tao Bai , Rongchuan Huang , Xiaomin Zhang , Liangle Yang
{"title":"Exposure to phenols mixture, oxidative stress, and fasting blood glucose: Association and potential mediation analyses","authors":"Ziqian Zhang , Min Xiang , Huihua Yang , Wenting Guo , Tao Bai , Rongchuan Huang , Xiaomin Zhang , Liangle Yang","doi":"10.1016/j.freeradbiomed.2025.04.024","DOIUrl":"10.1016/j.freeradbiomed.2025.04.024","url":null,"abstract":"<div><div>Phenols exposure may affect glucose metabolism and increase the risk of type 2 diabetes (T2D). However, the underlying biological mechanisms were poorly understood. In this longitudinal panel study of 122 Chinese adults with three repeated measurements, we aimed to evaluate the associations of multiple phenols exposure with fasting blood glucose (FBG), odds of impaired fasting glucose (IFG) and T2D, and further assess the mediating role of oxidative stress in the above associations. FBG and urinary concentrations of 6 phenols and 3 oxidative stress biomarkers were repeatedly measured for each participant. Linear mixed-effect (LME) models, generalized estimating equations (GEEs), quantile g-computation models, and structural equation models (SEM) were employed to estimate the associations. We observed that urinary methyl paraben (MeP), ethyl paraben (EtP), and propyl paraben (PrP) at multiple lag days were independently associated with increased FBG (all <em>P</em>-FDR <0.05). Exposure to phenols mixture at lag 0 day was positively correlated with FBG, and urinary PrP was the predominant contributor. Meanwhile, exposure to phenols mixture at lag 1 day or at lag 3 day was marginally linked to increased FBG. No significant relationships of phenols exposure at different lag days with risk of IFG and T2D were observed. In addition, we found that 8-hydroxy-deoxyguanosine (8-OHdG) mediated 35.7 % of the association of urinary phenols mixture at lag 1 day with FBG. Our study revealed that phenols exposure, either separately or as a mixture, was related to increased FBG, and oxidative stress is a potential mediating mechanism.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"234 ","pages":"Pages 169-177"},"PeriodicalIF":7.1,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143860599","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}
Jiahan Wang , Yongzheng Peng , Yarui Liu , Zhuoshi Lian , Zheng Cai , Ye Chen , Haoqing He , Meilin Yang , Jie Zhao
{"title":"Indole lactic acid derived from Akkermansia muciniphila activates the aryl hydrocarbon receptor to inhibit ferroptosis in ischemic stroke","authors":"Jiahan Wang , Yongzheng Peng , Yarui Liu , Zhuoshi Lian , Zheng Cai , Ye Chen , Haoqing He , Meilin Yang , Jie Zhao","doi":"10.1016/j.freeradbiomed.2025.04.020","DOIUrl":"10.1016/j.freeradbiomed.2025.04.020","url":null,"abstract":"<div><div>Ischemic stroke concurrent with gut microbiome dysbiosis induces intestinal damage, which exacerbates cerebral infarction. Probiotic or prebiotic interventions that reverse gut microbiome dysbiosis can promote recovery after ischemic stroke. <em>Akkermansia muciniphila</em> (AKK) safeguards intestinal health and is a promising probiotic; however, its role in ischemic stroke remains unclear. In this study, we found that live AKK, but not pasteurized AKK, mitigated ischemic-stroke-induced neurological injury, reduced cerebral infarction, and enhanced both blood-brain and intestinal barrier integrity. Moreover, the AKK supernatant reduced intestinal and cerebral injury, demonstrating efficacy comparable to that of live AKK. Metabolomic analysis revealed that the AKK supernatant was significantly enriched in indole lactic acid (ILA), a tryptophan metabolite. ILA levels were elevated in the serum and brains of pseudo-germ-free stroke rats administered AKK. Exogenous gavage with ILA mitigated ischemic-stroke-induced brain and intestinal damage. Mechanistically, ILA activated the aryl hydrocarbon receptor (AhR) and the nuclear transcription factor Nrf2, leading to the upregulation of SLC7A11 and GPX4 protein expression. This attenuated lipid peroxidation and intracellular iron accumulation triggered by ischemic stroke. Notably, intervention with the AhR inhibitor CH223191 abrogated the protective effects of ILA in ischemic stroke rats. These findings suggest that the therapeutic efficacy of AKK in ischemic stroke is at least partially attributable to ILA-mediated ferroptosis inhibition via AhR activation. AKK was selectively enriched by <em>Puerariae lobatae</em> Radix-resistant starch (PRS), promoting ILA generation more effectively than inulin and β-glucan. AKK and PRS synergistically alleviated ischemic-stroke-induced impairments, outperforming monomicrobial or prebiotic treatment alone. These findings reveal the unique mechanisms of AKK in ischemic stroke and provide a viable strategy for the clinical treatment of ischemic stroke through a novel synbiotic combination.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"234 ","pages":"Pages 113-130"},"PeriodicalIF":7.1,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855630","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":"Cuproptosis, a potential target for the therapy of diabetic critical limb ischemia","authors":"Tao Bai, Luhao Wang, Zhentao Qiao, Zhiwei Wang","doi":"10.1016/j.freeradbiomed.2025.04.022","DOIUrl":"10.1016/j.freeradbiomed.2025.04.022","url":null,"abstract":"<div><div>Diabetic patients are considered as the high risk population to develop critical limb ischemia (CLI), a peripheral vascular disease (PVD) resulted from atherosclerosis. Cuproptosis is a novel copper-dependent cell death that has shown the regulatory role in diabetes, while its effect on diabetic CLI has not been explored yet. In this study, Diabetic CLI mice was induced by femoral artery ligation (FAL) on diabetic mice. Endothelial injury in diabetic CLI was mimicked in human microvascular endothelial cells (HMEC-1) via the induction with high glucose (HG) and nutrient deprivation (ND). Besides, copper chelator Ammonium Tetrathiomolybdate (TM), which has shown the anti-cuproptosis property, was administrated to explore its potential effects on diabetic CLI mice and HG/ND-induced HMEC-1 cells. Strikingly, obvious cuproptosis was found in the gastrocnemius muscles of diabetic CLI mice and HG/ND-induced HMEC-1 cells, as evidenced by the copper overload and dysregulated cuproptosis-related proteins (such as Fe-S cluster proteins, copper exporter ATP7A, and copper importer SLC31A1). More importantly, TM protected against the hindlimb ischemic damages in diabetic CLI mice and alleviated cuproptosis-associated cell deaths in HG/ND-induced HMEC-1 cells. In summary, this study indicates the involvements of cuproptosis in diabetic CLI, and provides novel insights into copper chelator TM on diabetic CLI therapy.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"234 ","pages":"Pages 131-140"},"PeriodicalIF":7.1,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855631","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}
Ning Zhao , Wenqiang Tao , XiuFang Ouyang , Xinyi Yang , Zhijian Sun , Fen Liu , Kejian Qian
{"title":"Nicotinamide mononucleotide mitigates hyperoxia-aggravated septic lung injury via the GPx4-mediated anti-ferroptosis signaling pathway in alveolar epithelial cells","authors":"Ning Zhao , Wenqiang Tao , XiuFang Ouyang , Xinyi Yang , Zhijian Sun , Fen Liu , Kejian Qian","doi":"10.1016/j.freeradbiomed.2025.04.021","DOIUrl":"10.1016/j.freeradbiomed.2025.04.021","url":null,"abstract":"<div><h3>Background</h3><div>The molecular mechanisms and optimal treatment strategies underlying hyperoxia-aggravated septic lung injury remain elusive. We explored the effects and mechanisms of nicotinamide mononucleotide (NMN) on hyperoxia-aggravated septic lung injury.</div></div><div><h3>Methods</h3><div>The rat and cellular models of sepsis-induced lung injury were established and subjected to hyperoxygenation treatment, followed by treatment with NMN, ferroptosis promoter, or inhibitor separately. The extent of lung injury was assessed based on histological examination, lung histological injury scores, wet/dry weight ratio of lung tissues, oxygenation indexes, TNF-ɑ and IL-6 levels, and cell viability. Meanwhile, ferroptosis was assessed through various methods. The levels of glutathione peroxidase 4 (GPx4) and 4-hydroxynonenal (4-HNE) in lung tissues were determined by immunohistochemistry, while iron deposition was evaluated using Prussian blue staining. Fe<sup>2+</sup>, MDA, and GSH levels were also detected with the respective kits. The reactive oxygen species (ROS) level was measured by flow cytometry and immunofluorescence techniques. The protein and mRNA levels of GPx4 and ACSL4 were also detected. The relationship between sirtuin 6 (SIRT6) and GPx4 was clarified by using SIRT6 inhibitor and activator, as well as in combination with sh-GPx4.</div></div><div><h3>Results</h3><div>Hyperoxia exacerbated lung injury in rats subjected to cecal ligation and puncture (CLP). Hyperoxia also intensified damage to alveolar epithelial cells (AECs) in a lipopolysaccharide (LPS) model. However, NMN ameliorated these detrimental effects. Furthermore, LPS + Hyperoxia treatment significantly upregulated Fe<sup>2+</sup>, MDA, ROS, and ACSL4 levels, exacerbating oxidative damage. Also, LPS + Hyperoxia treatment downregulated GSH and GPx4 levels, thereby reducing antioxidant capacity. Additionally, Erastin, a ferroptosis promoter, further intensified oxidative stress damage and inflammatory response. However, ferroptosis inhibitor Fer-1 alleviated this damage. Similarly, NMN inhibited ferroptosis in hyperoxia-aggravated septic lung injury. Co-treatment with NMN and sh-GPx4 reversed the protective effect of NMN against LPS-stimulated injury exacerbated by hyperoxia in AECs. NMN supplementation increased SIRT6 expression in AECs. SIRT6 inhibition decreased GPx4 expression and raised ferroptosis markers, while SIRT6 activation had opposite effects. Co-treatment with SIRT6 activator and sh-GPx4 reversed the inhibitory effect on ferroptosis.</div></div><div><h3>Conclusion</h3><div>Hyperoxia aggravates septic lung injury by inducing ferroptosis of AECs. NMN can mitigate hyperoxia-aggravated septic lung injury by up-regulating GPx4 through increasing SIRT6 and inhibiting ferroptosis of AECs.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"234 ","pages":"Pages 86-99"},"PeriodicalIF":7.1,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834730","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}