Free Radical Biology and Medicine最新文献

{"title":"Metabolic energy expenditure in human blood long-lived neutrophils reprogrammed with inflammatory cytokines.","authors":"Yann Breton, Jules Gignac, Tân Khoa Lam, Christopher M Fortin, Helya Mortazavi, Isabelle Allaeys, Sylvain G Bourgoin, Patrice E Poubelle, Martin Pelletier","doi":"10.1016/j.freeradbiomed.2026.05.279","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2026.05.279","url":null,"abstract":"<p><p>The development of new analytical tools has revealed the heterogeneity of neutrophils in healthy and disease subjects. Knowledge of this heterogeneity has led to the identification, in healthy individuals, of a minor subset of blood neutrophils that express anti-protease genes characteristic of in vivo long-lived neutrophils, similar to those we previously described in vitro, which are expanded in autoimmune diseases. We can reprogram normal human blood neutrophils in vitro using GM-CSF, TNF, and IL-4, resulting in long-lived (LL) cells with enhanced glycolysis and oxygen consumption. We further report that these LL neutrophils express numerous genes associated with metabolism and mitochondria, including PLPP3 and SLC25A27. In addition, we confirmed that LL neutrophils express anti-peptidase genes, the most expressed being the PI3 gene, and secrete the peptidase inhibitor elafin and the secretory leukocyte protease inhibitor. Extracellular flux analysis revealed that PI3-expressing LL neutrophils exhibit enhanced glycolysis and respiration in response to pro-inflammatory cytokines, whereas non-reprogrammed neutrophils remain unresponsive. PI3-expressing LL neutrophils have a mitochondrial respiration partly driven by pyruvate oxidation, as demonstrated by the use of an inhibitor of mitochondrial pyruvate carrier. In contrast, oxygen consumption in control neutrophils was driven by fatty acid oxidation, as shown by the effect of inhibiting carnitine palmitoyltransferase 1. Thus, the reprogramming of neutrophils with GM-CSF, TNF, and IL-4 into cells capable of producing peptidase inhibitors is associated with an original metabolic phenotype characterized by active mitochondrial pathways.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835652","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":"ROS, identified as a driver for fibroblast activation, can be counteracted by glucocorticoid in LINC00605-dependent GMD machinery.","authors":"Huayu Zhu, Liang Zhu, Jiarui Zhang, Yuming Luo, Jiang Zhang, Xin Shao, Xuelian Feng, Lei Yan, Lisen Zhang, Haihong Ning, Bing Li, Hongyan Peng, Yize Li, Wendong Bai, Jun Li","doi":"10.1016/j.freeradbiomed.2026.04.162","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2026.04.162","url":null,"abstract":"<p><p>Fibroblast-to-myofibroblast transformation embodies a central facet of fibroblast activation, evidenced by elevated α-SMA levels and increased extracellular matrix synthesis. While excessive reactive oxygen species (ROS) are traditionally viewed as drivers of oxidative stress-related damage, emerging data implicate ROS in the pathological transformation of certain fibroblast subsets. However, the precise contributions of raised ROS to fibroblast activation remain to be defined. In this study, employing single-cell RNA sequencing and hypertrophic scars as a model of phenotypic transition, we demonstrate that elevated ROS promotes fibroblast transition to the myofibroblast state, marked by excessive proliferation and collagen synthesis. Conversely, ROS inhibition attenuates this phenotypic shift. Notably, glucocorticoids-classically anti-inflammatory agents-were found to suppress ROS generation in hypertrophic scar-derived fibroblasts (HSFBs). This effect is mediated by downregulation of NOXA1, a pivotal ROS-producing gene. Moreover, the glucocorticoid-mediated reduction of NOXA1 expression does not occur via the classical glucocorticoid receptor (GR) pathway but through a novel LINC00605-dependent glucocorticoid receptor-mediated mRNA degradation (GMD) mechanism. Mechanistically, GR binds NOXA1 mRNA, while glucocorticoid-induced upregulation of LINC00605 directly engages the GMD factor YBX1. The LINC00605-YBX1 complex is selectively recruited to NOXA1 mRNA via lncRNA-mRNA interactions, promoting GMD complex assembly and ultimately triggering NOXA1 mRNA decay. Collectively, these findings indicate that elevated ROS-driven fibroblast activation and intercellular phenotypic transitions can be reversed by glucocorticoids through ROS suppression, highlighting ROS-targeted strategies as promising approaches to mitigate hypertrophic scarring.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835741","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":"Corrigendum to \"Novel role of famotidine in downregulation of matrix metalloproteinase-9 during protection of ethanol-induced acute gastric ulcer\" [Free Radic. Biol. Med. 43 (2007) 289-299].","authors":"Laishram Pradeepkumar Singh, Parag Kundu, Krishnendu Ganguly, Amartya Mishra, Snehasikta Swarnakar","doi":"10.1016/j.freeradbiomed.2026.04.023","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2026.04.023","url":null,"abstract":"","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835452","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":"AKR1C3-Driven Restoration of Tetrahydrobiopterin Synthesis in Cellular Sepiapterin Reductase Deficiency.","authors":"James Woodcock, Sidhartha Tan, Jeannette Vasquez-Vivar","doi":"10.1016/j.freeradbiomed.2026.04.154","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2026.04.154","url":null,"abstract":"<p><p>Sepiapterin reductase (SPR) catalyzes several key steps in the biosynthesis of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide synthases and aromatic amino acid hydroxylases, and therefore for neurotransmitter production. Although several reductases-including carbonyl reductase 1 (CBR1), aldose reductase (AKR1B1), and AKR1C3-can substitute for SPR activity in vitro, their physiological significance remains unresolved. This study examines AKR1C3 as a component of an alternative BH4-generating pathway and evaluates its capacity to compensate for BH4 loss under diminished SPR activity. In vitro assays identified 2'-OXPH4 as the primary product of AKR1C3, redirecting pathway flux away from the canonical 1'-OXPH4 intermediate and the sepiapterin-salvage pathway. To assess the occurrence and efficiency of this route in cells, we generated SPR-knockout (SPR-KO) cell and evaluated pathway products in SPR-KO and wild-type (WT) backgrounds. In WT cells neither AKR1C3 nor SPR overexpression altered BH4 synthesis, indicating that neither enzyme is rate-limiting. In contrast, AKR1C3 increased BH4 levels in SPR-KO cells, while inhibiting sepiapterin production, revealing that AKR1C3 becomes functionally engaged only when SPR activity is decreased. Based on relative enzyme abundance, AKR1C3 and SPR exhibited comparable catalytic efficiency in this context. Importantly, AKR1C3-mediated BH4 production was sufficient to sustain tyrosine hydroxylase (TH) activity in SPR-KO cells, as demonstrated by L-DOPA formation. These findings establish AKR1C3-driven 2'-OXPH4 synthesis as a bona fide, inducible pathway capable of maintaining BH4 levels when SPR activity is limiting. This alternative path provides a compelling therapeutic target and introduces a new diagnostic consideration for patients with diminished SPR activity.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147813007","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":"Vitamin D Receptor/Sirtuin 3 Pathway Mediates the Cardioprotective Effects of Aerobic Exercise in Diabetic Mice.","authors":"Xiao-Ning Cui, Chao Li, Yi-Hua Qin, Jing-Jing Liu, Chen-Kang Jia, Xing-Yun Sun, Shi-Qi Lu, Zheng Zhu, Zhen-Bo Cao","doi":"10.1016/j.freeradbiomed.2026.04.153","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2026.04.153","url":null,"abstract":"<p><p>Aerobic exercise ameliorates diabetic cardiomyopathy (DCM) by improving myocardial mitochondrial function; however, the underlying mechanisms remain unclear. Vitamin D alleviates DCM by upregulating vitamin D receptor (VDR) expression, and aerobic exercise also increases VDR expression. Whether VDR mediates the cardioprotective effects of aerobic exercise against DCM remains unknown. This study aims to probe whether aerobic exercise alleviates DCM by upregulating VDR. A DCM mouse model was established using male C57BL/6J mice via high-fat diet feeding and streptozotocin injection, while mice fed a standard diet served as controls. Cardiac-specific VDR knockdown and overexpression were achieved via recombinant adeno-associated virus-mediated delivery in diabetic mice. Diabetic mice were further subjected to vitamin D₃ supplementation and exercise intervention. Additionally, H9C2 cardiomyocytes were exposed to high glucose and palmitate to mimic diabetic conditions in vitro. Notably, diabetic mice exhibited significant cardiac mitochondrial dysfunction, along with inflammation, fibrosis, and impaired cardiac function. However, vitamin D₃ supplementation and aerobic exercise upregulated VDR expression and enhanced mitochondrial function, thereby alleviating the pathological manifestations of DCM in diabetic mice. VDR activation also mitigated high glucose and palmitate-induced mitochondrial dysfunction in H9C2 cardiomyocytes, but this effect was abrogated by sirtuin (SIRT)-3 inhibition. These results suggest that VDR promotes SIRT3-dependent enhancement of mitochondrial function, thereby alleviating DCM. Moreover, exercise-induced cardioprotective effects on mitochondrial function were impaired by cardiac-specific VDR knockdown but mimicked by cardiac-specific VDR overexpression. Overall, this study suggests that the VDR/SIRT3 axis is an essential mechanism mediating the cardioprotective effects of aerobic exercise against DCM.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147813072","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":"Targeted delivery of nebivolol via lactoferrin-modified liposomes inhibits NEK7-mediated pyroptosis to ameliorate inflammatory bowel disease.","authors":"Hengchang Yao, Lichao Yang, Yawei Zhang, Qiang Wu, Kailing Xie, Hao Liu, Baojia Yao, Zhixian Jiang, Qi Sun, Zhuoxian Zeng, Lianwen Yuan","doi":"10.1016/j.freeradbiomed.2026.04.156","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2026.04.156","url":null,"abstract":"<p><p>Inflammatory Bowel Disease (IBD) is a chronic inflammatory disorder where pyroptosis of intestinal epithelial cells, driven by the NEK7/NLRP3 axis, is a key pathological feature. This study aimed to identify a novel inhibitor of NIMA-related kinase 7 (NEK7) and develop a targeted delivery system to enhance its therapeutic efficacy for IBD. Through a virtual screening of FDA-approved drugs, nebivolol was identified as a potent NEK7 inhibitor. Subsequent biochemical and cellular assays confirmed that nebivolol directly binds to the LYS64 site of NEK7, inhibiting its kinase activity and disrupting its interaction with NLRP3. This inhibitory action was shown to protect intestinal epithelial cells from pyroptosis in vitro and to significantly ameliorate disease symptoms, histological damage, and molecular markers of pyroptosis in a chronic DSS mouse model of colitis, with a high safety profile. To enhance therapeutic efficacy and specificity, a quantitatively characterized targeted delivery system of lactoferrin-modified liposomes loaded with nebivolol (LF-Lipo@N) was developed. This system demonstrated superior uptake by intestinal cells via lactoferrin and lactoferrin receptors (LFRs)interaction and a more potent anti-pyroptotic effect in vitro. Crucially, the quantitative biodistribution analysis showed that the targeted LF-Lipo@N system significantly accumulated in the colon in vivo, leading to a significantly enhanced therapeutic effect compared to free nebivolol while eliminating systemic side effects on heart rate. In conclusion, the targeted delivery of nebivolol via lactoferrin-modified liposomes represents a promising and effective strategy for treating IBD by specifically inhibiting NEK7-mediated intestinal pyroptosis.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147813103","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":"Corrigendum to \"Sirt1 attenuates necrotizing enterocolitis via Hif-1α deacetylation-mediated suppression of Bnip3-dependent mitophagy\" [Free Radic. Biol. Med. (2025) 150-160].","authors":"Lin Zhu, Mei Huang, Lu He, Zhihui Rong","doi":"10.1016/j.freeradbiomed.2026.04.020","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2026.04.020","url":null,"abstract":"","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147766921","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":"Reaction-yield detected magnetic resonance spectroscopy of radical pairs in cryptochrome-4a: a computational study.","authors":"Pedro H Alvarez, Luca Gerhards, Ilia A Solov'yov, P J Hore","doi":"10.1016/j.freeradbiomed.2026.04.015","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2026.04.015","url":null,"abstract":"<p><p>RYDMR (reaction-yield detected magnetic resonance) is a spectroscopic technique used to study transient radical pairs by measuring changes in the yields of their reaction products induced by a weak oscillating magnetic field in the presence of a static magnetic field. Here we report spin dynamics simulations that explore the experimental conditions required for an in vivo RYDMR study of radical pairs in the cryptochrome proteins thought to be the receptors in the magnetic compass sense of migratory songbirds. The main conclusions are as follows. (a) RYDMR signals at the Larmor resonance condition would provide strong support for a magnetoreception mechanism based on radical pair chemistry. (b) The signals should be stronger when the static and time-dependent fields are mutually perpendicular than when they are parallel. (c) Assuming one component of the pair is a flavin radical, the width of the RYDMR spectrum should depend on the direction of the static field with respect to the tricyclic flavin ring system. (d) The spectra could allow one to distinguish radical pairs in which a flavin radical is combined with either a tryptophanyl radical, a tyrosyl radical, or a radical with very weak hyperfine interactions. (e) For the clearest insights into the mechanism of magnetic sensing, the frequency of the oscillating field should exceed ∼100 MHz. (f) Harmonic signals and spin-locking effects may provide additional information on the nature of the magnetoreceptor.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147654003","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":"Corrigendum to \"Ghrelin attenuates oxidative stress and neuronal apoptosis via GHSR-1α/AMPK/Sirt1/PGC-1α/UCP2 pathway in a rat model of neonatal HIE\" [Free Radic. Biol. Med. 141 (2019) 322-337].","authors":"Juan Huang, Wei Liu, Desislava Met Doycheva, Marcin Gamdzyk, Weitian Lu, Jiping Tang, John H Zhang","doi":"10.1016/j.freeradbiomed.2026.03.070","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2026.03.070","url":null,"abstract":"","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147638453","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":"Corrigendum to \"Pituitary adenylate cyclase-activating polypeptide attenuates mitochondria-mediated oxidative stress and neuronal apoptosis after subarachnoid hemorrhage in rats\" [Free Radic. Biol. Med. 174 (2021) 236-248].","authors":"Yuanjian Fang, Hui Shi, Lei Huang, Reng Ren, Cameron Lenahan, Jie Xiao, Yu Liu, Rui Liu, Rajvee Sanghavi, Chenguang Li, Sheng Chen, Jiping Tang, Jun Yu, John H Zhang, Jianmin Zhang","doi":"10.1016/j.freeradbiomed.2026.03.072","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2026.03.072","url":null,"abstract":"","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147638400","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}