Free Radical Biology and Medicine最新文献

{"title":"Mitochondrial and microtubule defects in Exfoliation Glaucoma","authors":"Arunkumar Venkatesan ,&nbsp;Marc Ridilla ,&nbsp;Nileyma Castro ,&nbsp;J Mario Wolosin ,&nbsp;Jessica L. Henty-Ridilla ,&nbsp;Barry E. Knox ,&nbsp;Preethi S. Ganapathy ,&nbsp;Jamin S. Brown ,&nbsp;Anthony F. DeVincentis III ,&nbsp;Sandra Sieminski ,&nbsp;Audrey M. Bernstein","doi":"10.1016/j.freeradbiomed.2025.03.046","DOIUrl":"10.1016/j.freeradbiomed.2025.03.046","url":null,"abstract":"<div><div>Exfoliation Syndrome is an age-related systemic condition characterized by large aggregated fibrillar material deposition in the anterior eye tissues. This aggregate formation and deposition on the aqueous humor outflow pathway are significant risk factors for developing Exfoliation Glaucoma (XFG). XFG is a multifactorial late-onset disease that shares common features of neurodegenerative diseases, such as increased protein aggregation, impaired protein degradation, and oxidative and cellular stress. XFG patients display decreased mitochondrial membrane potential and mitochondrial DNA deletions. Here, using Tenon Capsule Fibroblasts (TFs) from patients without glaucoma (No Glaucoma, NG) and XFG patients, we found that XFG TFs have impaired mitochondrial bioenergetics and increased reactive oxygen species accumulation. These defects are associated with mitochondrial abnormalities as XFG TFs exhibit smaller mitochondria that contain dysmorphic cristae, with increased mitochondrial localization to lysosomes and slowed mitophagic flux. Mitochondrial dysfunction in the XFG TFs was associated with hyperdynamic microtubules, decreased acetylated tubulin, and increased HDAC6 activity. Treatment of XFG TFs with a mitophagy inducer, Urolithin A (UA), and a mitochondrial biogenesis inducer, Nicotinamide Ribose (NR), improved mitochondrial bioenergetics and reduced ROS accumulation. Our results demonstrate that XFG TFs have abnormal mitochondria and suggest that mitophagy inducers may represent a potential class of therapeutics for reversing mitochondrial dysfunction in XFG patients.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 226-239"},"PeriodicalIF":7.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting LKB1-AMPK-SIRT1-induced autophagy and mitophagy pathways improves cerebrovascular homeostasis in APP/PS1 mice.","authors":"Yawen Li, Tongxing Wang, Hongrong Li, Yuning Jiang, Xiaogang Shen, Ning Kang, Zhifang Guo, Runtao Zhang, Xuan Lu, Tianyu Kang, Mengnan Li, Yunlong Hou, Yiling Wu","doi":"10.1016/j.freeradbiomed.2025.03.045","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.03.045","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is the most common and severe degenerative disorder of the central nervous system in the elderly, profoundly impacting patients' quality of life. However, effective therapeutic agents for AD are still lacking. Bazi Bushen (BZBS) is a traditional Chinese herbal compound with potential neuroprotective effects, yet its underlying mechanisms remain poorly understood.</p><p><strong>Methods: </strong>In this study, we utilized APP/PS1 transgenic mice to assess the therapeutic efficacy of BZBS. Initially, we evaluated the spatial learning and memory of the mice using the Barnes maze. The brain microcirculation was assessed through a small-animal ultrasound system, two-photon in vivo imaging, and micro-computed tomography angiography. Molecular, biochemical, and pathological analyses were conducted on brain tissues. Through network pharmacology, we identified potential intervention pathways and targets for BZBS in the treatment of AD, which we subsequently validated both in vivo and in vitro. Additionally, we employed molecular virtual docking screening and bio-layer interferometry to elucidate the direct interactions of ginsenoside Rg5 and ginsenoside Ro in BZBS with AMPK and LKB1 proteins.</p><p><strong>Results: </strong>The BZBS intervention significantly enhanced spatial learning and memory in APP/PS1 mice while decreasing Aβ deposition. Furthermore, BZBS protected cerebrovascular homeostasis and mitigated neuroinflammation, as evidenced by decreased blood-brain barrier permeability, increased expression of tight-junction proteins, and restored cerebral blood flow. Mechanistically, ginsenosides Rg5 and Ro in BZBS directly bind to AMPK and LKB1 proteins, activating the LKB1-AMPK-SIRT1 signaling pathway, promoting autophagy and mitochondrial autophagy, and alleviating oxidative stress damage in endothelial cells.</p><p><strong>Conclusions: </strong>BZBS enhances autophagy-related activity, decreases Aβ deposition, and improves endothelial cell homeostasis through the activation of the LKB1-AMPK-SIRT1 signaling pathway, ultimately leading to improved cognitive function in mice with AD. This study highlights the importance of enhancing autophagic activity and maintaining cerebrovascular homeostasis in mitigating cognitive decline in AD, providing evidence and new insights into the application of compound medicines for treating age-related neurological disorders.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779278","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":"Formin INF2 supplementation alleviates cytoskeleton-based mitochondria defects for oocyte quality under obesity","authors":"Hao-Lin Zhang ,&nbsp;Zhen-Nan Pan ,&nbsp;Jia-Qian Ju ,&nbsp;Yi-Ming Ji ,&nbsp;Yue Wang ,&nbsp;Shao-Chen Sun","doi":"10.1016/j.freeradbiomed.2025.04.003","DOIUrl":"10.1016/j.freeradbiomed.2025.04.003","url":null,"abstract":"<div><div>Obesity is one main cause of reproductive disorders in female, and oocytes show meiotic maturation defects under obesity, which leads to infertility. However, the molecular characterization for the obese oocytes remains largely unclear. Inverted-formin 2 (INF2) is a formin family member which is involved in actin-based multiple cellular events including vesicle transport and oxidative stress-induced apoptosis. In present study, we reported that INF2 deficiency linked with declined oocyte quality of obesity. Our results showed that INF2 expression decreased in the oocytes of obese mice. INF2 deficiency caused the failure of polar body extrusion and induced large polar bodies. We showed that INF2 depletion disturbed mitochondrial distribution and function, which might be due to the association with mitochondria fission factor DRP1. INF2 co-localized with cytoplasmic actin and its depletion reduced actin polymerization, which further caused the failure of spindle migration in both mouse and porcine oocytes. In addition, we also found that INF2 interacted with HDAC6 and further affected tubulin acetylation for microtubule stability, which disturbed mitochondrial transport. Exogenous INF2 mRNA supplement rescued the meiotic maturation defects of oocytes from obese mice. Thus, our study demonstrated that INF2 is responsible for both mouse and porcine oocyte maturation through its regulation on actin polymerization and tubulin acetylation for mitochondrial function, and its deficiency might be one cause for obesity-induced oocyte defects.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 250-263"},"PeriodicalIF":7.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778932","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":"Nitric oxide mediates negative feedback on the TXNIP/NLRP3 inflammasome pathway to prevent retinal neurovascular unit dysfunction in early diabetic retinopathy","authors":"Li Yang ,&nbsp;Yao Yao ,&nbsp;Weidong Zheng ,&nbsp;Xuedong Zheng ,&nbsp;Maosong Xie ,&nbsp;Libin Huang","doi":"10.1016/j.freeradbiomed.2025.03.050","DOIUrl":"10.1016/j.freeradbiomed.2025.03.050","url":null,"abstract":"<div><div>Diabetic retinopathy (DR) is a leading cause of vision impairment in working-age adults, and is driven by complex neurovascular dysfunction. This study aimed to elucidate whether nitric oxide (NO) can modulate the TXNIP/NLRP3 inflammasome pathway and mitigate retinal neurovascular unit (NVU) damage during early DR. In an <em>in vitro</em> co-culture system, silencing TXNIP or NLRP3 in retinal microglia (RMG) significantly upregulated glial cell-derived neurotrophic factor (GDNF) and downregulated inducible nitric oxide synthase (iNOS) expression in retinal ganglion cells (RGC). Moreover, it resulted in decreased iNOS and vascular endothelial growth factor A (VEGFA) levels and enhanced the expression of tight junction proteins (Occludin and ZO-1) in retinal microvascular endothelial cells (RMEC), while also reducing NO release and inhibiting RMEC tube formation. Treatment with S-nitroso-N-acetyl penicillamine (SNAP), an NO donor, significantly downregulated TXNIP/NLRP3 inflammasome signaling in RMG, decreased RGC apoptosis, and inhibited tube formation in RMEC. It also upregulated GDNF, suppressed iNOS in RGC, decreased VEGFA, and improved tight junction proteins in RMEC. Treatment with 1400W, an iNOS inhibitor, resulted in decreased NO concentration and increased IL-1β levels in the co-culture supernatant, without significantly affecting iNOS expression in RGC or RMEC. In an early DR rat model, Electroretinogram (ERG), Optical Coherence Tomography (OCT), Fluorescein Angiography (FFA), Evans blue assays, Immunofluorescence staining, and TUNEL staining confirmed that sodium nitroprusside (SNP), NO donor administration mitigated retinal neural and vascular dysfunction, and preserved retinal NVU integrity. Concurrently, SNP treatment reduced IL-1β expression and increased GDNF and Occludin levels in the early DR retina. Genetic Association Database (GAD) enrichment analysis and protein-protein interaction (PPI) network validation indicated that NO functions as a downstream mediator of the TXNIP/NLRP3 inflammasome pathway and exhibits a strong association with DR. These findings suggest that NO mediates negative feedback in the TXNIP/NLRP3 inflammasome pathway to exert protective effects against retinal NVU dysfunction in early DR, thereby offering potential therapeutic strategies for early intervention in DR.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 279-291"},"PeriodicalIF":7.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779054","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":"Adipocyte-secreted ANGPTL2 promotes hyperuricemia through inhibiting AKT/ABCG2 signaling","authors":"Longyan Yang ,&nbsp;Ruili Yin ,&nbsp;Ziyu Shan,&nbsp;Anqi Feng,&nbsp;Kun Li,&nbsp;Yan Wang,&nbsp;Ke Yu,&nbsp;Yongsong Xu,&nbsp;Lin Mao,&nbsp;Jianan Lang,&nbsp;Baoyu Zhang,&nbsp;Dong Zhao","doi":"10.1016/j.freeradbiomed.2025.03.048","DOIUrl":"10.1016/j.freeradbiomed.2025.03.048","url":null,"abstract":"<div><h3>Aims</h3><div>Overweight and obesity are closely associated with hyperuricemia (HUA). However, the effect of obesity-induced adipokine on the level of serum uric acid (UA) has not been fully elucidated. This study aimed to determine the role of adipokine in the pathogenesis of HUA.</div></div><div><h3>Methods</h3><div>Omental adipose tissues from HUA patients with obesity were collected for data-independent acquisition (DIA) proteomics analysis, and the secreted protein angiopoietin-like protein (ANGPTL2) was identified and further validated via Western blot and ELISA. Angptl2 knockout (ko) and adipocyte-specific ANGPTL2 overexpression mice were generated to establish HUA models. HK2 cells and primary renal tubule epithelial cells (RTECs) were applied to induce HUA cell model and treated with recombinant human ANGPTL2 or supernatants derived from C3H10 cells differentiated into adipocytes.</div></div><div><h3>Result</h3><div>ANGPTL2 levels were significantly elevated in the omental adipose tissue from HUA with obesity patients compared to control participants. Circulating ANGPTL2 levels were also increased, and positively correlated with serum UA levels, especially in male participants. Plasma UA levels were significantly decreased in Angptl2 ko mice, coinciding with up-regulated expression of ATP binding cassette subfamily G member 2 (ABCG2) and down-regulated glucose transporter 9 (GLUT9) in renal tissue. However, plasma UA levels were significantly increased, accompanied by decreased ABCG2 expression and enhanced GLUT9 expression after adipocyte-specific ANGPTL2 overexpression. Furthermore, adipocyte-derived ANGPTL2 increased UA level in cell supernatants through the inhibition of protein kinase B (AKT)/ABCG2 signaling in RTECs and HK2 cells.</div></div><div><h3>Conclusion</h3><div>Adipokine ANGPTL2 levels were significantly elevated in HUA patients with obesity. Circulating ANGPTL2 concentrations were independently associated with serum UA levels, particularly in obese males. Adipocyte-secreted ANGPTL2 promoted the level of UA through AKT/ABCG2 signaling in renal tubular cells. These findings establish ANGPTL2 as a critical adipokine linking obesity to hyperuricemia and suggest its potential as a novel therapeutic target for HUA.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 209-225"},"PeriodicalIF":7.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776887","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":"Selenium supplementation protects cancer cells from the oxidative stress and cytotoxicity induced by the combination of ascorbate and menadione sodium bisulfite","authors":"Radosveta Gencheva ,&nbsp;Lucia Coppo ,&nbsp;Elias S.J. Arnér ,&nbsp;Xiaoyuan Ren","doi":"10.1016/j.freeradbiomed.2025.03.049","DOIUrl":"10.1016/j.freeradbiomed.2025.03.049","url":null,"abstract":"<div><div>The combination of ascorbate (vitamin C) and menadione sodium bisulfite (MSB, vitamin K3), here called VC/VK3 (also named Apatone®, or M/A), has shown selective cytotoxicity in cancer cells and is under clinical investigation as a cancer therapy. However, the mechanisms of VC/VK3-induced cell death are not fully understood. In this <em>in vitro</em> study using human glioblastoma and non-transformed glial cell lines, we found that VC/VK3 caused higher toxicity in cancer cells in an H₂O₂- and iron-dependent manner, suggesting that ferroptosis may play a role in the cell death process. Furthermore, selenium supplementation significantly protected cancer cells from VC/VK3 treatment concomitantly with enhanced expression levels and enzymatic activity of antioxidant selenoproteins, including thioredoxin reductases (TXNRDs) and glutathione reductases (GPXs). We also found that VC/VK3 competes for electrons with thioredoxin (TXN), impairing peroxiredoxin 1 (PRDX1) in cells. Finally, chemically inhibiting TXNRDs or the glutathione-dependent antioxidant systems exaggerated the toxicity of VC/VK3. Overall, this study elucidated parts of the cell death mechanisms of VC/VK3 and identified combination strategies to overcome selenium-mediated resistance, advancing the translational potential of this prooxidant treatment.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 317-329"},"PeriodicalIF":7.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779277","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":"Non-genetic and genetic determinants of serum selenium and selenium species in the Aragon Workers Health Study.","authors":"Zulema Rodriguez-Hernandez, Anabel Paredes-Douton, Marta Galvez-Fernandez, Maria Grau-Perez, Mercedes Sotos-Prieto, Pilar Rentero-Garrido, Montserrat Gonzalez-Estecha, Maria Teresa Llorente-Ballesteros, Jose L Gomez-Ariza, Belen Callejon-Leblic, Pablo Fernandez-Navarro, Martin Laclaustra, Ana Cenarro, Fernando Civeira, Ronald A Glabonjat, Daniel Monleon, Roberto Pastor-Barriuso, Belen Moreno-Franco, Tamara Garcia-Barrera, Maria Tellez-Plaza","doi":"10.1016/j.freeradbiomed.2025.03.044","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.03.044","url":null,"abstract":"<p><p>Understanding potential determinants of selenium biomarkers can help to unravel selenium health effects. We evaluated the contribution of non-genetic (sociodemographic and lifestyle) and genetic factors to serum selenium biomarkers and selenium species (quantified as selenium) including selenium in glutathione peroxidase (GPx), selenoprotein P (SeP), selenoalbumin (SeAlb) and total selenometabolites (Se-metabolites) in the Aragon Workers Health Study (AWHS), a predominantly male cohort of car assembly factory workers in Spain. Total serum selenium and selenium species were measured by HPLC/ICP-QQQ-MS in 1,624 AWHS participants. Blood and urine selenium, measured by ICP-MS, were available in a subset. A Healthy Lifestyle Score (HLS) included Mediterranean diet, physical activity, smoking, BMI and alcohol intake. Candidate gene and genome-wide discovery analyses (CGA and GDA, respectively) were based on TOPMed imputed SNPs. In sex and age-adjusted models, overall HLS, physical activity, and specific foods intake showed positive associations with serum total selenium, SeAlb and Se-metabolites concentrations. The associations between smoking status and BMI with total serum selenium; age, smoking status, BMI and meat intake with SeAlb; and smoking status with Se-metabolites, were inverse. In the GDA, we identified 20, 24, 21, 26, 16, 20 and 68 independent genetic loci for serum total selenium, GPx, SeP, SeAlb, Se-metabolites, and total blood and urine selenium, respectively, with some overlapping genes also relevant in the CGA. Enrichment analysis pointed to biological pathways including circadian rhythm regulation, immune system processes, signaling and receptor- and transporter-related pathways. The explained variability of selenium markers ranged from 15 % for SeP to 21 % for SeAlb and from 0.2 % for SeP to 3.5% for SeAlb in environmental determinants-adjusted models with and without the specific selenium biomarker polygenic score, respectively. While the genetic contribution is substantial, selenium status might be influenced by reinforced healthy lifestyle interventions. Follow-up genetic studies to evaluate selenium health consequences are granted.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751959","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":"Investigation of malondialdehyde as a trait marker associated with familial risk in patients with newly diagnosed bipolar disorder and their unaffected first-degree relatives – A longitudinal cohort study","authors":"Klara Coello ,&nbsp;Sharleny Stanislaus ,&nbsp;Julie Lyng Forman ,&nbsp;Hanne Lie Kjærstad ,&nbsp;Kimie Stefanie Ormstrup Sletved ,&nbsp;Kamilla Woznica Miskowiak ,&nbsp;Maria Faurholt-Jepsen ,&nbsp;Klaus Munkholm ,&nbsp;Henrik Enghusen Poulsen ,&nbsp;Maj Vinberg ,&nbsp;Jens Lykkesfeldt ,&nbsp;Lars V. Kessing","doi":"10.1016/j.freeradbiomed.2025.03.041","DOIUrl":"10.1016/j.freeradbiomed.2025.03.041","url":null,"abstract":"<div><h3>Aims</h3><div>Increased oxidative stress-generated tissue damage seems to play a pivotal role in the pathophysiology and progression of bipolar disorder (BD). Malondialdehyde (MDA), a product of lipid oxidation, may represent a trait marker in BD associated with familial risk. However, MDA is scarcely studied in patients with <em>newly diagnosed</em> bipolar disorder (BD) and their unaffected relatives (UR).</div></div><div><h3>Methods</h3><div>In this prospective \"the Bipolar Illness Onset study\", we investigated repeated measurements of MDA in a cohort of 371 patients with newly diagnosed/first-episode BD (1016 visits), 139 of their unaffected first-degree relatives (307 visits) and 199 healthy control individuals (HC) with no personal or first-degree family history of affective disorder (537 visits) with a median follow-up time of 2.0. [0.1; 3.8] years for patients with BD, 1.4 [0; 2.4] years for UR, and 2.5 [1.1; 3.9] years for HC. Amongst patients with BD, we further investigated associations of MDA with affective phases and medicine- and illness variables over a period of 7 years.</div></div><div><h3>Results</h3><div>Unaffected relatives had 42.3 % higher levels of MDA at baseline compared with HC in analyses adjusted for sex and age corrected for multiple comparisons (<em>B</em> = = 1.423, 95 % CI = 1.139, 1.777, p = &lt;0.044). However, this difference did not persist over time. No statistically significant differences in MDA levels were observed over time between BD patients and either HC or UR. Additionally, MDA levels were not associated with psychotropic use, illness variables, or affective phase alterations.</div></div><div><h3>Conclusions</h3><div>Against expectations, our findings did not support increased lipid oxidation being a trait phenomenon in BD.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 186-195"},"PeriodicalIF":7.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751958","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":"Paeoniflorin alleviated experimental Sjögren's syndrome by inhibiting NLRP3 inflammasome activation of submandibular gland cells via activating Nrf2/HO-1 pathway.","authors":"Tingting Jiang, Xuanqi Liu, Shumin Wang, Yu Chen, Yong Wang, Xiaojing Li, Genhong Yao","doi":"10.1016/j.freeradbiomed.2025.03.043","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.03.043","url":null,"abstract":"<p><strong>Background: </strong>Total glucosides of white paeony (TGP) has been used for treatment of Sjögren's syndrome (SS) patients. Paeoniflorin (PF) is the main active ingredient of TGP and has antioxidant and anti-inflammatory effects, but its underlying mechanism on SS remains to be explored. Aberrant activation of NLRP3 inflammasome can cause injury of submandibular gland (SG) in SS. However, whether PF regulates NLRP3 inflammasome activation in SS is unknown.</p><p><strong>Objective: </strong>This study aims to investigate whether PF alleviated SS through suppressing NLRP3 inflammation activation. To explore the mechanism of PF in improving Sjögren-like symptoms in non-obese diabetic (NOD) mice.</p><p><strong>Methods: </strong>The gene expression profiles of the labial gland (LG) between SS patients and non-SS patients were analyzed by bioinformatics. Non-obese diabetic (NOD) mice were selected as SS model. Mice were divided into normal saline group and two different doses of PF-treatment groups (50 and 100 mg/kg). The SS-like symptoms and pathological changes of submandibular gland (SG) were analyzed after 4 weeks of administration. SG cells were treated with or without PF and with or without ML385 (a specific inhibitor of Nrf2) in vitro, and then lipopolysaccharide(LPS) and adenosine triphosphate (ATP) were used to induce NLRP3 inflammasome activation in SG cells. Results NLRP3 was up-regulated in LG of SS patients and SG of SS mice. PF alleviated SS-like symptoms in SS mice Compared with control group, NLRP3 and caspase-1 in the SG, and serum IL-1β and IL-18 of NOD mice were decreased in PF group. Furthermore, we found that PF inhibited NLRP3 activation via activating the Nrf2/HO-1 pathway in SG cells. In addition, we observed the activation of Nrf2/HO-1 in the SG of mice after PF administration.</p><p><strong>Conclusions: </strong>Our findings suggested that PF inhibited NLRP3 inflammasome activation through regulating the Nrf2/HO-1 axis in SG of SS mice, which might be the underlying mechanism for the therapeutic effects of PF on SS.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751960","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":"STING immune activation of microglia aggravating neurovascular unit damage in diabetic retinopathy","authors":"Hong-Ying Li ,&nbsp;Jingfan Wang ,&nbsp;Tianhao Xiao ,&nbsp;Qinyuan Gu ,&nbsp;Yuanyuan Fan ,&nbsp;Pengfei Ge ,&nbsp;Jingyi Xu ,&nbsp;Cheng Wang ,&nbsp;Ping Xie ,&nbsp;Zizhong Hu","doi":"10.1016/j.freeradbiomed.2025.03.042","DOIUrl":"10.1016/j.freeradbiomed.2025.03.042","url":null,"abstract":"<div><div>Diabetic retinopathy (DR) is the leading cause of blindness and is pathologically characterized by neuroinflammation and neovascularization. Retinal homeostasis is critically maintained by the retinal neurovascular unit (NVU), which can be disrupted by abnormal activation of microglia in DR. However, the underlying mechanism remains unclear. Here, we provide the first evidence of upregulated stimulator of interferon genes (STING) in microglia within fibrovascular membranes (FVMs) and retinas from oxygen-induced retinopathy (OIR) and streptozotocin (STZ)-induced diabetic mice. Furthermore, we identified STING upregulation in BV2 cells stimulated with high glucose (HG) or hypoxia, accompanied by mitochondrial dysfunction and cytoplasmic leakage of damaged mitochondrial DNA (mtDNA). Pharmacologic or genetic inhibition of STING in microglia prevented their activation and polarization. Next, we demonstrated that STING-deficient BV2 cells reversed the proangiogenic behavior of endothelial cells and protected retinal ganglion cells (RGCs) from oxidative stress. Finally, intravitreal injection of AAV-STING alleviated retinal neurovascular pathologies in both OIR and STZ mice. This study demonstrated that the release of mtDNA mediates STING immune activation of microglia, which further exacerbates NVU damage in DR. In contrast, immunosuppressing STING in microglia could serve as a potential therapeutic strategy.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 86-101"},"PeriodicalIF":7.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143725675","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}