Free Radical Biology and Medicine最新文献

{"title":"Low-dose valproic acid ameliorates osteoporosis by restoring redox homeostasis and suppressing ferritinophagy-dependent ferroptosis via EZH2/H3K27me3 signaling","authors":"Yifan Gu ,&nbsp;Ziru Wang ,&nbsp;Kun Wang ,&nbsp;Yicong Wang ,&nbsp;Yiheng Li ,&nbsp;Shuai Jiang ,&nbsp;Yu Zheng ,&nbsp;Run Feng ,&nbsp;Min Yang","doi":"10.1016/j.freeradbiomed.2025.09.023","DOIUrl":"10.1016/j.freeradbiomed.2025.09.023","url":null,"abstract":"<div><h3>Background</h3><div>Valproic acid (VPA), a histone deacetylase inhibitor, exhibits dose-dependent effects on bone homeostasis. This study investigates whether low-dose VPA protects against ovariectomy (OVX)-induced osteoporosis by targeting oxidative stress and ferroptosis.</div></div><div><h3>Methods</h3><div>OVX rats received low- (100 mg/kg/d) or high-dose (300 mg/kg/d) VPA for 12 weeks. Bone microstructure was analyzed by micro-CT. Systemic redox status was evaluated by measuring MDA, SOD, GSH, and Fe²⁺. Ferroptosis markers (GPX4, ACSL4, FTH1, NCOA4) were examined. In MC3T3-E1 cells pretreated with VPA (0.5–3 mM), erastin was used to induce ferroptosis. The EZH2/H3K27me3 pathway and osteoclastogenesis were further assessed.</div></div><div><h3>Results</h3><div>OVX induced bone loss, oxidative stress (elevated MDA/Fe²⁺, decreased SOD/GSH), and ferroptosis activation (increased ACSL4/NCOA4, decreased GPX4/FTH1). Low-dose VPA reversed these changes, improved bone density and microarchitecture, and reduced bone resorption. High-dose VPA showed no protective effects. In vitro, 1 mM VPA attenuated erastin-induced lipid peroxidation, mitochondrial damage, and ferroptosis. Mechanistically, VPA activated EZH2/H3K27me3 signaling, enhancing H3K27me3 enrichment at the NCOA4 promoter to suppress ferritinophagy and ferroptosis. VPA also inhibited RANKL-induced osteoclast differentiation.</div></div><div><h3>Conclusion</h3><div>Low-dose VPA ameliorates osteoporosis by restoring redox homeostasis, epigenetically inhibiting NCOA4-mediated ferritinophagy via EZH2/H3K27me3 activation, and suppressing osteoclastogenesis. These findings identify low-dose VPA as a multifaceted anti-osteoporotic agent and highlight the EZH2/H3K27me3/NCOA4 axis as a pivotal regulatory pathway in bone redox biology.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 76-89"},"PeriodicalIF":8.2,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063295","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":"“Susceptibility of hiPSC-derived NSCs and neurons to paraquat treatment: insights into differential neurotoxicity mechanisms related to mitochondria.”","authors":"A. Czerniczyniec ,&nbsp;S. Mucci ,&nbsp;M.A. Lopez ,&nbsp;M. Apecetche ,&nbsp;D. García-Chialva ,&nbsp;W. Quilumbaquin ,&nbsp;M. Marazita ,&nbsp;G.E. Sevlever ,&nbsp;M.E. Scassa ,&nbsp;V. Vanasco ,&nbsp;L. Romorini","doi":"10.1016/j.freeradbiomed.2025.09.024","DOIUrl":"10.1016/j.freeradbiomed.2025.09.024","url":null,"abstract":"<div><div>Environmental exposure to paraquat (PQ), a widely used herbicide, has been associated with an increased risk of neurodegenerative diseases such as Parkinson's disease. However, species-specific limitations of traditional animal models hinder mechanistic insights into human neurotoxicity. We used a human-relevant cellular platform based on neural stem cells (NSCs) and neurons derived from human induced pluripotent stem cells (hiPSCs) to investigate the differential mitochondrial response and cell fate following PQ exposure. Our results reveal that hiPSC-derived neurons exhibit markedly higher susceptibility to PQ-induced toxicity than their corresponding neural progenitor cells. The neuronal vulnerability is characterized by profound mitochondrial membrane depolarization, reduced mitochondrial mass, elevated reactive oxygen species, increased nitric oxide levels, decreased ATP production, and activation of mitochondrial-dependent apoptosis pathways, including caspase-9 and caspase-3 cleavage, concomitant with an increased BAX/BCL-X_L ratio. In contrast, hiPSC-derived NSCs maintain viability by upregulating glycolytic activity, evidenced by increased GLUT-1 expression and hexokinase activity, suggesting a metabolic adaptation that supports resistance to mitochondrial impairment. Notably, the antioxidant N-acetyl-L-cysteine partially restored mitochondrial membrane potential and metabolism in hiPSC-derived NSCs, but failed to protect neurons, highlighting cell-type-specific sensitivity. Alterations in mitochondrial dynamics, particularly decreased OPA-1 and MFN-2 protein expression in neurons, further support a disruption in mitochondrial structure and homeostasis. Our research highlights the translational potential of hiPSC-derived neural models as a powerful platform for unravelling the mechanisms of neurotoxicity induced by PQ and other chemicals associated with Parkinson's disease risk, as well as for uncovering unique cellular responses to oxidative mitochondrial stress. These findings offer critical insights into neuronal vulnerability during early development and provide a foundation for targeted interventions to preserve mitochondrial integrity in neurodegenerative contexts.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 90-103"},"PeriodicalIF":8.2,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069484","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":"Aloe-emodin mitigates cisplatin-induced acute kidney injury by Nrf2-mediated ferroptosis regulation","authors":"Qiangfang Dai ,&nbsp;Yang Xiang ,&nbsp;Rongrong Qiang ,&nbsp;Gen Li ,&nbsp;Yuxuan Song ,&nbsp;Yanxin Yu ,&nbsp;Jing Liu ,&nbsp;Mengdi Lv ,&nbsp;Wenqi Liu ,&nbsp;Jumei Zhao ,&nbsp;Xiaoli Wei ,&nbsp;Xiaolong Liu","doi":"10.1016/j.freeradbiomed.2025.09.016","DOIUrl":"10.1016/j.freeradbiomed.2025.09.016","url":null,"abstract":"<div><div>Acute kidney injury (AKI) is a common clinical critical illness, with currently limited treatment options available. Cisplatin (CDDP), a first-line drug for cancer chemotherapy, a significant contributor to nephrotoxicity, which severely restricts its clinical application. Therefore, there is an urgent need for pharmacological interventions to alleviate cisplatin (CDDP)-induced acute kidney injury (CI-AKI). Aloe-emodin (AE), as a novel ferroptosis inhibitor, shows great potential in mitigating cisplatin-induced acute kidney injury. This study aims to explore the effect and mechanism of aloe-emodin on cisplatin-induced acute kidney injury. By establishing in vitro and in vivo models, we evaluated indicators related to renal function, oxidative stress, ferroptosis, and the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway using techniques such as biochemical analysis, immunofluorescence, and Western blotting. The results indicated that AE significantly improves renal function indices, reduces levels of oxidative stress products, inhibits alterations in ferroptosis marker molecules, and alleviates renal pathological damage. Mechanistically, AE activates the Nrf2 pathway and upregulates the expression of its downstream antioxidant and anti-ferroptosis genes. Inhibition of the Nrf2 pathway significantly diminishes the protective effects of AE. This study suggests that AE mitigates CI-AKI by activating the Nrf2 pathway and inhibiting ferroptosis, thus providing new insights for clinical prevention and treatment.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 104-116"},"PeriodicalIF":8.2,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063313","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":"Licochalcone B alleviates exercise-induced muscle fatigue through its antioxidant activity in experimental mice","authors":"Aeyung Kim ,&nbsp;Yu Ri Kim ,&nbsp;Jayasinghage Nirmani Chathurangika Jayasinghe ,&nbsp;Musun Park ,&nbsp;Seongwon Cha ,&nbsp;Sang-Min Park ,&nbsp;No Soo Kim","doi":"10.1016/j.freeradbiomed.2025.09.022","DOIUrl":"10.1016/j.freeradbiomed.2025.09.022","url":null,"abstract":"<div><div>Muscle fatigue is a major constraint on physical performance and is driven by multiple factors such as excessive oxidative stress and ATP depletion. This study investigated the protective effects of licochalcone B (LicoB), a phenolic chalcone compound isolated from <em>Glycyrrhiza glabra</em> Linné, on oxidative stress-induced damage in C2C12 cells. Additionally, its anti-fatigue potential was evaluated in mice subjected to exhaustive swimming. In C2C12 myotubes, LicoB significantly reduced H₂O₂-induced oxidative damage and preserved myotube integrity by scavenging free radicals. Transcriptomic analysis of C2C12 cells showed that LicoB reversed stress-induced dysregulation of antioxidant and myogenic genes, indicating protective transcriptional reprogramming. An <em>in vivo</em> mouse model employing weight-loaded forced swimming further supported the beneficial effects of LicoB. Four weeks of oral administration of LicoB improved physical endurance, increased liver glycogen content, antioxidant enzyme activity in muscle, and blood free fatty acid level, while reducing circulating blood corticosterone and lactate levels, as well as lipid peroxidation in muscle tissues. Upregulation of TP53-induced regulator of glycolysis and apoptosis, sirtuin 1, and peroxisome proliferator-activated receptor-γ coactivator 1α in skeletal muscles suggested enhanced mitochondrial function and reduced oxidative damage. Additionally, transcriptomic analysis of skeletal muscle indicated that LicoB induced gene programs involved in myogenesis, neuromuscular junctions, and glucose metabolism. Collectively, these findings suggest that LicoB plays multi-targeted protective roles against excessive exercise-induced muscle fatigue by attenuating oxidative stress and modulating energy metabolism. Therefore, LicoB is a promising nutraceutical candidate for improving muscle endurance and recovery after strenuous physical activity.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 204-219"},"PeriodicalIF":8.2,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063284","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":"Sirt1 attenuates necrotizing enterocolitis via Hif-1α deacetylation-mediated suppression of Bnip3-Dependent mitophagy","authors":"Lin Zhu,&nbsp;Mei Huang,&nbsp;Lu He,&nbsp;Zhihui Rong","doi":"10.1016/j.freeradbiomed.2025.09.020","DOIUrl":"10.1016/j.freeradbiomed.2025.09.020","url":null,"abstract":"<div><div>Necrotizing enterocolitis (NEC), a life-threatening neonatal disease, involves mitochondrial dysfunction whose regulation remains unclear. This study identifies a novel Sir1/Hif-1α regulatory axis in NEC pathogenesis. We demonstrate that Sirt1 downregulation in NEC leads to Hif-1α hyperacetylation, resulting in Bnip3-mediated mitophagy activation and intestinal epithelial injury. Using clinical samples and experimental models, we show that Sirt1 downregulation correlates with mitochondrial dysfunction and intestinal barrier disruption. Pharmacological Sirt1 activation by SRT1720 effectively attenuated NEC progression through Hif-1α deacetylation and subsequent mitophagy inhibition. Importantly, we provide the first evidence that Sirt1 directly regulates Hif-1α acetylation status in intestinal epithelial cells, establishing a new molecular mechanism linking protein acetylation to mitochondrial quality control in NEC. These findings reveal Sirt1 as a master regulator of intestinal homeostasis and highlight Sirt1 activation as a promising therapeutic approach for NEC treatment.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 150-160"},"PeriodicalIF":8.2,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063276","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":"Fat mass and obesity-associated protein inhibits macrophage-mediated inflammation via the m6A demethylation of c-Jun in COPD","authors":"Hai-Guang Xu ,&nbsp;Jia-Yuan Liang ,&nbsp;Chen-Yang Luo,&nbsp;Shuang Zhang,&nbsp;Qiao-Li He,&nbsp;Zhi-Yi He","doi":"10.1016/j.freeradbiomed.2025.09.021","DOIUrl":"10.1016/j.freeradbiomed.2025.09.021","url":null,"abstract":"<div><div>Fat mass and obesity-associated protein (FTO), which is a key regulator of N6-methyladenosine (m6A) RNA modification, is associated with inflammatory processes. Chronic obstructive pulmonary disease (COPD) is a prevalent inflammatory disease that affects airways. However, the precise mechanism underlying the FTO-mediated regulation of inflammation in COPD remains unclear. This study aimed to investigate the molecular mechanisms through which FTO-mediated m6A RNA demethylation regulates macrophage-driven inflammation in COPD. Bioinformatics analysis of a GEO dataset (GSE148004) and validation in lung tissues revealed significant downregulation of FTO expression in patients with COPD (n = 10). Consistent with these findings, decreased FTO protein levels and a significant increase in global m6A methylation were observed in CSE-stimulated U937-derived macrophages (n = 3) and alveolar macrophages from mice with COPD (n = 6). Additionally, FTO overexpression attenuated CSE-induced IL-6 and TNF-α production by U937-derived macrophages (n = 3), and this overexpression alleviated emphysematous changes and airway inflammation in mice with COPD (n = 6). Moreover, RNA sequencing analysis revealed c-Jun as a downstream target of FTO. Mechanistically, FTO suppressed the m6A modification of c-Jun mRNA, leading to increased c-Jun mRNA degradation, thereby attenuating macrophage-mediated inflammatory responses (n = 3). Thus, FTO negatively regulates macrophage-driven inflammation in COPD by promoting the m6A demethylation and destabilization of c-Jun mRNA. These findings indicate that FTO may represent a promising therapeutic target for mitigating inflammation in patients with COPD.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 14-23"},"PeriodicalIF":8.2,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145047814","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":"VDAC1 oligomerization-mediated mtDNA release under sublethal oxidative stress: A novel inflammatory mechanism in vitiligo","authors":"Rongyin Gao ,&nbsp;Duo Meng ,&nbsp;Zhilin Zhao ,&nbsp;Hui Xue ,&nbsp;Nan Hu ,&nbsp;Peiwen Jiang ,&nbsp;Wenhao Yu ,&nbsp;Wenhui Xu ,&nbsp;Chuanwei Yin ,&nbsp;Huansha Zhang ,&nbsp;Jinpeng Lv","doi":"10.1016/j.freeradbiomed.2025.09.018","DOIUrl":"10.1016/j.freeradbiomed.2025.09.018","url":null,"abstract":"<div><div>Oxidative stress is a critical initiating factor in vitiligo, yet the early molecular events linking redox imbalance to melanocyte immune activation remain unclear. Here, we demonstrate that sub-lethal hydrogen peroxide (H₂O₂, 0.1 mM) exposure in human epidermal melanocytes induces a robust pro-inflammatory response independent of apoptosis or pyroptosis. This response is driven by the selective cytosolic release of mitochondrial DNA (mtDNA), which activates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. Mechanistically, voltage-dependent anion channel 1 (VDAC1) oligomerization cooperates with mitochondrial permeability transition pore (mPTP) opening to mediate mtDNA release. Both genetic VDAC1 knockdown and pharmacological inhibition blocked mtDNA leakage and downstream cytokine production. In H₂O₂-induced vitiligo mice, intradermal administration of the VDAC1 oligomerization inhibitor VBIT-4 restored melanin pigmentation, reduced CD8⁺ T cell infiltration, and alleviated cutaneous inflammation. These findings identify VDAC1-dependent mtDNA release as a key driver of innate immune activation in melanocytes and highlight VDAC1 as a potentially druggable therapeutic target for early intervention in vitiligo.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 1-13"},"PeriodicalIF":8.2,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145047779","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":"NAD+ rescues Phosphatidylinositol-induced granulosa cell Pyroptosis to restore follicular development in PCOS","authors":"Xiuli Yang ,&nbsp;Kongwei Huang ,&nbsp;Jinfang Qin ,&nbsp;Xueying Cui ,&nbsp;Zhihan Zhang ,&nbsp;Qiumei Huang ,&nbsp;Yafei Wu ,&nbsp;Xiaocan Lei ,&nbsp;Shun Zhang","doi":"10.1016/j.freeradbiomed.2025.09.019","DOIUrl":"10.1016/j.freeradbiomed.2025.09.019","url":null,"abstract":"<div><div>Polycystic ovary syndrome (PCOS) is a systemic endocrine metabolic disorder that seriously affects women's reproductive health. This study aimed to investigate the mechanism by which NAD⁺ precursors inhibits granulosa cell (GCs) pyroptosis induced by increased phosphatidylinositol (PI) levels in PCOS. Metabolomic profiling of PCOS patients demonstrated significant lipid metabolic disturbances, with differentially metabolites significantly enriched in phosphatidylinositol signaling, pyroptosis and inflammatory pathways (<em>p</em> &lt; 0.05). Furthermore, PI levels were higher in the follicular fluid of PCOS patients compared to controls. In the letrozole/high-fat diet-induced PCOS rat model, intervention with NAD⁺ precursors significantly reduced androgen levels and alleviated abnormal accumulation of PI and improved ovarian dysplasia. Notably, co-analysis metabolomics and transcriptomics showed that PI levels were positively correlated with pyroptosis factors such as NLRP3, IL-1β, IL-18. Subsequently, <em>In vitro</em> excess PI promotes KGN cell pyroptosis, as evidenced by increased membrane permeability and membrane rupture (by TEM), increased LDH release and increased secretion of IL-1β and IL-18. Importantly, supplementation with NAD⁺ inhibits the aberrant accumulation of PI, thereby ameliorating GCs pyroptosis. In this study, we found that PI levels accumulate abnormally in PCOS ovary and that NAD⁺ ameliorates GCs pyroptosis induced by increased PI. Collectively, PI represents a candidate PCOS biomarker, and NAD⁺ may thereby offer a targeted therapeutic approach.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 287-298"},"PeriodicalIF":8.2,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058416","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 \"The PGC1α/NRF1-MPC1 axis suppresses tumor progression and enhances the sensitivity to sorafenib/doxorubicin treatment in hepatocellular carcinoma\" [Free Radic. Biol. Med. 163 (2021) 141-152].","authors":"Chaoqun Wang, Liqian Dong, Xiaozhuang Li, Yao Li, Bao Zhang, Huibo Wu, Benqiang Shen, Panfei Ma, Zuoyu Li, Yang Xu, Bangliang Chen, Shangha Pan, Yao Fu, Zhongqi Huo, Hongchi Jiang, Yaohua Wu, Yong Ma","doi":"10.1016/j.freeradbiomed.2025.09.003","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.09.003","url":null,"abstract":"","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145052727","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":"The contributions of increased reactive oxygen species and inflammatory macrophages to the development of aortic valve calcification","authors":"Fatemeh Salemizadehparizi ,&nbsp;Peter Huang ,&nbsp;Mei-Hsiu Chen ,&nbsp;Gretchen J. Mahler","doi":"10.1016/j.freeradbiomed.2025.09.017","DOIUrl":"10.1016/j.freeradbiomed.2025.09.017","url":null,"abstract":"<div><div>Calcific aortic valve disease (CAVD), an active cardiovascular disease, is the most common cause of aortic valve stenosis. The risk of developing CAVD increases with age. In this study, a three-dimensional (3D) model of the aortic valve fibrosa layer was created to evaluate the role of monocytes/macrophages in the development of CAVD in the presence of reactive oxygen species (ROS). The 3D model includes porcine aortic valve interstitial cells (PAVIC), porcine aortic valve endothelial cells (PAVECs), and THP-1 monocytes that have differentiated into M1-like macrophages. Hydrogen peroxide (H₂O₂) was used to induce ROS at a concentration of 100 μM to mimic pathophysiological ROS conditions and promote calcification while maintaining cell viability. Prolonged exposure to H₂O₂ (up to 14 days) caused calcification in the in vitro 3D model. The introduction of THP-1 monocytes or M1-like macrophages after pretreatment with H₂O₂ accelerated the calcification process. The M1-tri-culture model formed nodules with increased calcium and phosphate when compared with controls and co-culture models. Except in the M1-tri-culture model, H₂O₂ treatment inhibited hydrogel contraction, indicating a connection between ROS and cellular contraction. These findings provide information on the pathogenesis of CAVD, demonstrating the crucial role of monocytes/macrophages and ROS in the calcification of the aortic valve fibrosa layer. This 3D model offers a robust platform for additional study on CAVD-specific therapeutic strategies.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 64-75"},"PeriodicalIF":8.2,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058542","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}