Redox Biology最新文献

{"title":"Keap1-independent Nrf2 regulation: A novel therapeutic target for treating kidney disease","authors":"Jiahui Zhang ,&nbsp;Mingzhuo Zhang ,&nbsp;Marc Tatar ,&nbsp;Rujun Gong","doi":"10.1016/j.redox.2025.103593","DOIUrl":"10.1016/j.redox.2025.103593","url":null,"abstract":"<div><div>The transcription factor NF-E2-related factor 2 (Nrf2) is a master regulator of antioxidant responses in mammals, where it plays a critical role in detoxification, maintaining cellular homeostasis, combating inflammation and fibrosis, and slowing disease progression. Kelch-like ECH-associated protein 1 (Keap1), an adaptor subunit of Cullin 3-based E3 ubiquitin ligase, serves as a critical sensor of oxidative and electrophilic stress, regulating Nrf2 activity by sequestering it in the cytoplasm, leading to its proteasomal degradation and transcriptional repression. However, the clinical potential of targeting the Keap1-dependent Nrf2 regulatory pathway has been limited. This is evidenced by early postnatal lethality in Keap1 knockout mice, as well as significant adverse events after pharmacological blockade of Keap1 in human patients with Alport syndrome as well as in those with type 2 diabetes mellitus and chronic kidney disease. The exact underlying mechanisms remain elusive, but may involve non-specific and systemic activation of the Nrf2 antioxidant response in both injured and normal tissues. Beyond Keap1-dependent regulation, Nrf2 activity is modulated by Keap1-independent mechanisms, including transcriptional, epigenetic, and post-translational modifications. In particular, GSK3β has emerged as a critical convergence point for these diverse signaling pathways. Unlike Keap1-dependent regulation, GSK3β-mediated Keap1-independent Nrf2 regulation does not affect basal Nrf2 activity but modulates its response at a delayed/late phase of cellular stress. This allows fine-tuning of the inducibility, magnitude, and duration of the Nrf2 response specifically in stressed or injured tissues. As one of the most metabolically active organs, the kidney is a major source of production of reactive oxygen and nitrogen species and also a vulnerable organ to oxidative damage. Targeting the GSK3β-mediated Nrf2 regulatory pathway represents a promising new approach for the treatment of kidney disease.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"82 ","pages":"Article 103593"},"PeriodicalIF":10.7,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143643790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interleukin-35 inhibits NETs to ameliorate Th17/Treg immune imbalance during the exacerbation of cigarette smoke exposed-asthma via gp130/STAT3/ferroptosis axis","authors":"Peizhi Tao ,&nbsp;Beiting Su ,&nbsp;Xueyan Mao ,&nbsp;Yusen Lin,&nbsp;Li Zheng,&nbsp;Xiaoling Zou,&nbsp;Hailing Yang,&nbsp;Jing Liu,&nbsp;Hongtao Li","doi":"10.1016/j.redox.2025.103594","DOIUrl":"10.1016/j.redox.2025.103594","url":null,"abstract":"<div><div>Cigarette smoke (CS) exposure amplifies neutrophil accumulation. IL-35, a novel cytokine with anti-inflammatory properties, is involved in protection against asthma. However, the biological roles of neutrophils and the precise molecular mechanisms of IL-35 in CS exposed-asthma remain unclear. We showed that the exacerbation of CS exposed-asthma leads to dramatically increased neutrophil counts and an imbalance in DC-Th17/Treg immune responses. RNA sequencing revealed that NETs, part of a key biological process in neutrophils, were significantly upregulated in the context of CS exposed-asthma exacerbation and that IL-35 treatment downregulated NET-associated gene expression. Targeted degradation of NETs, rather than neutrophil depletion, alleviated the CS exposed-asthma. Mechanistically, STAT3 phosphorylation promoted ferroptosis, exacerbating NET release, which in turn enhanced dendritic cell (DC) antigen presentation, activated T cells, and specifically promoted Th17 cell differentiation while inhibiting Treg cells. IL-35 acting on the gp130 receptor alleviated STAT3-mediated ferroptosis-associated NET formation. In summary, our study revealed a novel mechanism by which IL-35 inhibited NET formation, subsequently alleviating neutrophilic inflammation and restoring the DC-Th17/Treg imbalance in CS exposed-asthma, highlighting the potential of IL-35 as a targeted therapeutic strategy.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"82 ","pages":"Article 103594"},"PeriodicalIF":10.7,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143637066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Viral inactivation of murine coronavirus via multiple gas plasma-derived reactive species","authors":"Sander Bekeschus ,&nbsp;Meike Heuser ,&nbsp;Lea Miebach ,&nbsp;Marcus Frank ,&nbsp;Thomas von Woedtke ,&nbsp;Anke Schmidt","doi":"10.1016/j.redox.2025.103591","DOIUrl":"10.1016/j.redox.2025.103591","url":null,"abstract":"<div><div>The recent pandemic has highlighted the urgent need to elucidate the pathophysiological mechanisms underlying viral effects in humans and is driving the search for innovative antiviral therapies. Several studies have investigated the ability of gas plasma, a partially ionized gas that simultaneously generates several reactive species, to be a new antiviral tool. However, several aspects of the mechanisms of antiviral action of gas plasma remained elusive. In this study, we, for the first time, used a gas plasma device approved for medical purposes and routinely applied in the clinics, especially for wound healing, to test its antiviral activity against a murine corona-virus in vitro (MHV-GFP), a research model analogous to human coronaviruses such as SARS-CoV-2. For this, we established a novel high-content imaging assay that gave quantitative and kinetic information about infection and reduced viral activity in murine fibroblasts (17Cl-1) host cells. Gas plasma treatment delayed viral infectivity and reduced overall infection and toxicity in 17Cl1 cells. Various antioxidants at different concentrations were screened to identify ROS relevant to antiviral effects. Catalase provided no virus protection, and DMSO, mannitol, histidine, Trolox, and ascorbic acid only modestly reduced gas plasma virucidal efficacy. By contrast, glutathione, tyrosine, and cysteine showed profound but not complete protection of MHV from gas plasma-derived reactive species, suggesting pivotal roles of superoxide radicals and peroxynitrite gas in plasma-driven viral inactivation. At extended gas plasma exposure times, fewer intact MHV RNA were detected, indicative of reactive species-driven RNA modifications or degradation as an additional mechanism of action. Virus particle size changes measured by electron microscopy were moderate. Collectively, we identified the potent antiviral activity of a clinically approved argon plasma jet along with potential mechanisms of action.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"82 ","pages":"Article 103591"},"PeriodicalIF":10.7,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143610793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxidative stress leads to the formation of esterified erythro- and threo-dihydroxy-fatty acids in HepG2 cells","authors":"Lilli Scholz,&nbsp;Luca M. Wende,&nbsp;Michel A. Chromik,&nbsp;Nadja Kampschulte,&nbsp;Nils Helge Schebb","doi":"10.1016/j.redox.2025.103589","DOIUrl":"10.1016/j.redox.2025.103589","url":null,"abstract":"<div><div>Oxidative stress plays a central role in pathophysiology. To assess oxidative stress, sensitive methods are required to monitor the cellular damage caused by reactive oxygen species. Phospholipid-bound isoprostanes, such as 5-iPF_2α-VI determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) are currently the best markers for oxidative stress. Here, we describe <em>erythro-</em> and <em>threo-</em>dihydroxy-polyunsaturated fatty acids (PUFA), the hydrolysis products of <em>trans</em>- and <em>cis</em>-epoxy-PUFA, as new biomarkers of oxidative stress in cells. This is demonstrated in four oxidative stress models in HepG2 cells using radical-forming <em>tert-</em>butyl hydroperoxide, glutathione peroxidase 4 inhibiting RSL-3, the redox cycling agent paraquat or rotenone blocking the electron transport chain. LC-MS/MS analysis following the liberation of esterified oxylipins by saponification unveiled in all oxidative stress models a strong formation of <em>erythro-</em> and <em>threo-</em>dihydroxy-PUFA. The levels increased concentration-dependently and correlated to isoprostane 5-iPF_2α-VI formation. Among the positional isomers derived from linoleic acid, arachidonic acid and docosahexaenoic acid, those bearing the dihydroxy-group closest to the carboxy terminus were predominantly formed. Thus, the highest concentrations were found of e<em>rythro</em>-5,6-DiHETrE and <em>erythro-</em>4,5-DiHDPE, which allowed a more sensitive detection of oxidative stress compared to 5-iPF_2α-VI levels. The (<em>erythro-</em>) dihydroxy-PUFA are a new set of markers, which enable a more comprehensive analysis of oxidative stress, particularly when combined with simultaneous LC-MS/MS quantification of <em>trans-</em>epoxy-PUFA and isoprostanes.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"82 ","pages":"Article 103589"},"PeriodicalIF":10.7,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143637065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ROS-dependent SOCS3 upregulation disrupts regulatory T cell stability during autoimmune disease development","authors":"Hiroki Satooka,&nbsp;Yuzuki Nakamura,&nbsp;Takako Hirata","doi":"10.1016/j.redox.2025.103590","DOIUrl":"10.1016/j.redox.2025.103590","url":null,"abstract":"<div><div>Autoimmune diseases including rheumatoid arthritis (RA) are often associated with high levels of reactive oxygen species (ROS); however, the ROS targets in autoimmunity are diverse and unclear. Using collagen-induced arthritis (CIA) mice as a model for RA, we report that antioxidants markedly suppress joint inflammation, antibody production, and effector T cell responses. We found that the frequency of CD4⁺ regulatory T cells (Tregs) was reduced in CIA mice, which was reversed by antioxidant treatment, and SOCS3, known to be associated with Treg instability, was upregulated in Tregs from both RA patients and CIA mice. Mechanistically, SOCS3 upregulation was induced by ROS-dependent PTEN oxidation and the resultant Akt/mTOR/STAT3 activation. We further showed that the source of ROS involved in this pathway is NADPH oxidase 2 (Nox2). Nox2 expression was upregulated in Tregs from CIA mice, and Nox2 transduction induced a decrease in Treg frequency that depended on SOCS3 upregulation. This study thus provides a mechanistic understanding of ROS-induced Treg instability and suggests that ROS-dependent disruption of Treg homeostasis underlies the development and progression of autoimmune diseases.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"82 ","pages":"Article 103590"},"PeriodicalIF":10.7,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143629423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The tryptophan metabolite 3-hydroxyanthranilic acid alleviates hyperoxia-induced bronchopulmonary dysplasia via inhibiting ferroptosis","authors":"Qiqi Ruan ,&nbsp;Yingqiu Peng ,&nbsp;Xuanyu Yi ,&nbsp;Jingli Yang ,&nbsp;Qing Ai ,&nbsp;Xiaochen Liu ,&nbsp;Yu He ,&nbsp;Yuan Shi","doi":"10.1016/j.redox.2025.103579","DOIUrl":"10.1016/j.redox.2025.103579","url":null,"abstract":"<div><div>Bronchopulmonary dysplasia (BPD) is a prevalent chronic respiratory condition in preterm infants with an increasing incidence, severely affecting their survival rate and quality of life. Exploring the underlying mechanisms of BPD helps to develop novel effective therapeutic strategies. In this study, integrated metabolomic analyses of tracheal aspirates (TAs) from BPD infants and non-BPD infants, along with lung tissues from hyperoxia-induced experimental BPD neonatal rats and control rats, demonstrated that BPD was associated with a significant reduction in 3-hydroxyanthranilic acid (3-HAA), which was confirmed to be partly caused by tryptophan-metabolizing enzyme disorders. In vivo and in vitro models were subsequently established to assess the efficacy and underlying mechanisms of 3-HAA in relation to BPD. Compared with the BPD group, 3-HAA nebulization improved lung development and suppressed inflammation in rats. Limited proteolysis-small molecule mapping (LiP-SMap) proteomic analysis revealed the involvement of the ferroptosis pathway in the underlying mechanism by which 3-HAA alleviated hyperoxia-induced BPD injury. Ferroptosis was identified by detecting Fe²⁺ levels, malondialdehyde (MDA), 4-HNE, total aldehydes, mitochondrial morphology, ferroptosis-associated protein and mRNA expression, and this dysregulation was indeed ameliorated by 3-HAA nebulization in vivo. Furthermore, a combination of LiP-SMap, molecular docking, SPR and Co-IP analyses confirmed that 3-HAA can bind directly to FTH1 and disrupt the nuclear receptor coactivator 4 (NCOA4)-FTH1 interaction. In conclusion, our study is the first to reveal that BPD is linked to the reduction of 3-HAA, and 3-HAA could inhibit the ferroptosis pathway by targeting FTH1, thereby alleviating hyperoxia-induced injury in rats and alveolar type II epithelial cells, highlighting the potential of targeting 3-HAA and ferroptosis for clinical applications in BPD.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"82 ","pages":"Article 103579"},"PeriodicalIF":10.7,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A high-resolution N-glycoproteome landscape of aging mouse ovary","authors":"Yongqi Wu,&nbsp;Zhida Zhang,&nbsp;Yongchao Xu,&nbsp;Yingjie Zhang,&nbsp;Lin Chen,&nbsp;Yiwen Zhang,&nbsp;Ke Hou,&nbsp;Muyao Yang,&nbsp;Zhehui Jin,&nbsp;Yinli Cai,&nbsp;Jiayu Zhao,&nbsp;Shisheng Sun","doi":"10.1016/j.redox.2025.103584","DOIUrl":"10.1016/j.redox.2025.103584","url":null,"abstract":"<div><div>Ovarian aging typically precedes the decline of other organ systems, yet its molecular mechanisms remain poorly understood. Glycosylation as one of the most important protein modifications has been especially unexplored in this context. Here, we present the first high-resolution glycoproteomic landscape of aging mouse ovaries, uncovering site-specific <em>N</em>-glycan signatures across subcellular components such as high proportions of complex glycans, core fucosylation, and LacdiNAc branches at the zone pellucida. We report three major glycosylation alterations in aged ovaries: the frequently changed core-fucosylation associated with cell adhesion and immune responses, the decreased LacdiNAc glycans on zona pellucida (ZP) responsible for fertility decline, and the increased sialylated glycans modified by Neu5Ac and Neu5Gc playing different roles in immune activation and responses. Integrated multi-omic analyses further highlight the unique role of glycosylation, distinct from phosphorylation, in regulating key signaling pathways, antigen processing and presentation, complement coagulation cascades, ROS biosynthetic and metabolic processes, as well as cell death. This study offers a novel glycobiological perspective on ovarian aging, broadening our understanding of its molecular mechanisms beyond traditional multi-omic approaches.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"81 ","pages":"Article 103584"},"PeriodicalIF":10.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143594086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Deciphering the ferroptosis pathways in dorsal root ganglia of Friedreich ataxia models. The role of LKB1/AMPK, KEAP1, and GSK3β in the impairment of the NRF2 response\" [Redox Biol. 76 (2024) 103339].","authors":"Arabela Sanz-Alcázar, Marta Portillo-Carrasquer, Fabien Delaspre, Maria Pazos-Gil, Jordi Tamarit, Joaquim Ros, Elisa Cabiscol","doi":"10.1016/j.redox.2025.103583","DOIUrl":"https://doi.org/10.1016/j.redox.2025.103583","url":null,"abstract":"","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":" ","pages":"103583"},"PeriodicalIF":10.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of oxidative balance score in staging and mortality risk of cardiovascular-kidney-metabolic syndrome: Insights from traditional and machine learning approaches","authors":"Yang Chen ,&nbsp;Shuang Wu ,&nbsp;Hongyu Liu ,&nbsp;Ziyi Zhong ,&nbsp;Tommaso Bucci ,&nbsp;Yimeng Wang ,&nbsp;Manlin Zhao ,&nbsp;Yang Liu ,&nbsp;Zhengkun Yang ,&nbsp;Ying Gue ,&nbsp;Garry McDowell ,&nbsp;Bi Huang ,&nbsp;Gregory Y.H. Lip","doi":"10.1016/j.redox.2025.103588","DOIUrl":"10.1016/j.redox.2025.103588","url":null,"abstract":"<div><h3>Objectives</h3><div>To evaluate the roles of oxidative balance score (OBS) in staging and mortality risk of cardiovascular-kidney-metabolic syndrome (CKM).</div></div><div><h3>Methods</h3><div>Data of this study were from the National Health and Nutrition Examination Survey 1999–2018. We performed cross-sectional analyses using multinomial logistic regression to investigate the relationship between OBS and CKM staging. Cox proportional hazards models were used to assess the impact of OBS on mortality outcomes in CKM patients. Additionally, mediation analyses were performed to explore whether OBS mediated the relationships between specific predictors (Life's Simple 7 score [LS7], systemic immune-inflammation index [SII], frailty score) and mortality outcomes. Then, machine learning models were developed to classify CKM stages 3/4 and predict all-cause mortality, with SHapley Additive exPlanations values used to interpret the contribution of OBS components.</div></div><div><h3>Results</h3><div>21,609 participants were included (20,319 CKM, median [IQR] age: 52.0 [38.0–65.0] years, 54.3% male, median [IQR] follow-up: 9.4 [5.3–14.1] years). Lower OBS quartiles were associated with advanced CKM staging. Moreover, lower OBS quartiles were related to increased mortality risk, compared to Q4 of OBS (all-cause mortality: Q1: HR 1.31, 95% CI 1.18–1.46, Q2: HR 1.27, 95% CI 1.14–1.42, Q3: HR 1.18, 95% CI 1.06–1.32; cardiovascular mortality: Q1: HR 1.44, 95% CI 1.16–1.79, Q2: HR 1.39, 95% CI 1.11–1.74, Q3: HR 1.26, 95% CI 1.01–1.57; non-cardiovascular mortality, Q1: HR 1.27, 95% CI 1.12–1.44, Q2: HR 1.23, 95% CI 1.08–1.40, Q3: HR 1.16, 95% CI 1.02–1.31), with optimal risk stratification threshold for OBS was 22. Additionally, OBS mediated (ranging 4.25%–32.85 %) effects of SII, LS7, frailty scores on mortality outcomes. Moreover, light gradient boosting machine achieved the highest performance for predicting advanced CKM staging (area under curve: 0.905) and all-cause mortality (area under curve: 0.875). Cotinine increased risk, while magnesium, vitamin B6, physical activity were protective.</div></div><div><h3>Conclusions</h3><div>This study highlights OBS as a risk stratification tool for CKM, emphasizing oxidative stress's role in CKM staging and mortality risk management.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"81 ","pages":"Article 103588"},"PeriodicalIF":10.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143594088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insulitis and aging: Immune cell dynamics in Langerhans islets","authors":"Julia Jelleschitz ,&nbsp;Sophie Heider ,&nbsp;Richard Kehm ,&nbsp;Patricia Baumgarten ,&nbsp;Christiane Ott ,&nbsp;Vanessa Schnell ,&nbsp;Tilman Grune ,&nbsp;Annika Höhn","doi":"10.1016/j.redox.2025.103587","DOIUrl":"10.1016/j.redox.2025.103587","url":null,"abstract":"<div><div>With increasing age, the risk for age-related type-2-diabetes also increases due to impaired glucose tolerance and insulin secretion. This disease process may be influenced by various factors, including immune cell triggered inflammation and fibrosis. Although immune cells are a necessary component of islets, little is known about immune cell accumulation, immune cell subtype shifts and subsequent influence on glucose metabolism in healthy aging. However, this is critical for understanding the mechanisms that influence β-cell health. Therefore, we studied young and old male C57BL/6J mice, focusing on immune cell composition, patterns of accumulation, and the presence of fibrosis within the pancreatic islets.</div><div>Our findings demonstrate that insulitis occurs in healthy aged mice without immediate development of a diabetic phenotype. Aged islets exhibited an increase in leukocytes and a shift in immune cell composition. While insulitis typically involves excessive immune cell accumulation, we observed a moderate increase in macrophages and T-cells during aging, which may support β-cell proliferation via cytokine secretion. In fact, aged mice in our study showed an increase in β-cell mass as well as a partially higher insulin secretory capacity, which compensated for the loss of β-cell functionality in insulitic islets and led to improved glucose tolerance. Furthermore, fibrosis which is normally triggered by immune cells, increased with age but appears to reach a steady state, emphasizing the importance of counter-regulatory mechanisms and immune system regulation.</div><div>Our results suggest, that immune cell subtypes change with age and that non-pathological accumulation of immune-cells may regulate glucose metabolism through secretion of cytokines.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"82 ","pages":"Article 103587"},"PeriodicalIF":10.7,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143637068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}