International immunopharmacology最新文献

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Luteolin attenuates cadmium neurotoxicity by suppressing glial inflammation and supporting neuronal survival
IF 4.8 2区 医学
International immunopharmacology Pub Date : 2025-03-10 DOI: 10.1016/j.intimp.2025.114406
Hui-Yong Ma , Jing Wang , Jun Wang , Zhe Guo , Xiao-Yan Qin , Rongfeng Lan , Yang Hu
{"title":"Luteolin attenuates cadmium neurotoxicity by suppressing glial inflammation and supporting neuronal survival","authors":"Hui-Yong Ma ,&nbsp;Jing Wang ,&nbsp;Jun Wang ,&nbsp;Zhe Guo ,&nbsp;Xiao-Yan Qin ,&nbsp;Rongfeng Lan ,&nbsp;Yang Hu","doi":"10.1016/j.intimp.2025.114406","DOIUrl":"10.1016/j.intimp.2025.114406","url":null,"abstract":"<div><div>Cadmium (Cd), a neurotoxic metal, is associated with the development of neurological disorders. This study investigated the neuroprotective effects of Luteolin against Cd-induced toxicity in cultured cells and mouse models. Our findings demonstrate that Luteolin protects hippocampal neurons from Cd toxicity and mitigates Cd-triggered inflammatory responses in microglial BV2 cells. In Cd-exposed mice, symptoms such as weight loss, motor retardation, multi-organ damage, and cognitive deficits were observed. Remarkably, Luteolin treatment reversed these effects, repaired organ damage, and restored learning and memory abilities. Mechanistically, Cd toxicity induced significant upregulation of pro-inflammatory factors and neuroinflammation in the hippocampus and prefrontal cortex, including elevated glial cell markers (IBA1, GFAP, and CD68) and reduced neuronal marker MAP2. Luteolin counteracted these adverse effects by inhibiting the Notch1/Hes1 inflammatory signaling axis and restoring the BDNF-TrkB/AKT1 signaling axis, thereby promoting neuronal survival. These results highlight the potential of Luteolin as a natural neuroprotective agent against Cd-induced neurotoxicity, offering a promising therapeutic strategy for mitigating Cd-related neurological damage.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"152 ","pages":"Article 114406"},"PeriodicalIF":4.8,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143577206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Corrigendum to "Icariin inhibition of NLRP3 mediated Leydig cell pyroptosis and insulin resistance ameliorates spermatogenesis disorders in obese mice" [Int. Immunopharmacol. 151 (2025) 114280].
IF 4.8 2区 医学
International immunopharmacology Pub Date : 2025-03-10 DOI: 10.1016/j.intimp.2025.114402
Yanhong Wei, Jian Tu, Lin Ji, Rutong Wang, Runtang Zhou, Xiaocan Lei, Linlin Hu, Hua Huang
{"title":"Corrigendum to \"Icariin inhibition of NLRP3 mediated Leydig cell pyroptosis and insulin resistance ameliorates spermatogenesis disorders in obese mice\" [Int. Immunopharmacol. 151 (2025) 114280].","authors":"Yanhong Wei, Jian Tu, Lin Ji, Rutong Wang, Runtang Zhou, Xiaocan Lei, Linlin Hu, Hua Huang","doi":"10.1016/j.intimp.2025.114402","DOIUrl":"https://doi.org/10.1016/j.intimp.2025.114402","url":null,"abstract":"","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":" ","pages":"114402"},"PeriodicalIF":4.8,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The transcription factor XBP1 regulates mitochondrial remodel and autophagy in spontaneous abortion
IF 4.8 2区 医学
International immunopharmacology Pub Date : 2025-03-10 DOI: 10.1016/j.intimp.2025.114398
Weihua He , Yating Zhao , Lijun Yin , Qiangxing Du , Wenfen Ren , Liwei Mao , Aixia Liu , Dimin Wang , Jianhua Qian
{"title":"The transcription factor XBP1 regulates mitochondrial remodel and autophagy in spontaneous abortion","authors":"Weihua He ,&nbsp;Yating Zhao ,&nbsp;Lijun Yin ,&nbsp;Qiangxing Du ,&nbsp;Wenfen Ren ,&nbsp;Liwei Mao ,&nbsp;Aixia Liu ,&nbsp;Dimin Wang ,&nbsp;Jianhua Qian","doi":"10.1016/j.intimp.2025.114398","DOIUrl":"10.1016/j.intimp.2025.114398","url":null,"abstract":"<div><h3>Purpose</h3><div>Spontaneous abortion (SA) remains a clinical challenge in early pregnancy. It has been reported that endoplasmic reticulum stress (ERS) is implicated in pregnancy-related complications. However, the precise mechanistic role of ERS in SA pathogenesis remains elusive. This study aims to explore the therapeutic potential of targeting ERS-related decidual dysfunction in SA.</div></div><div><h3>Methods</h3><div>An ERS model was established in both decidualized stromal cells (DSCs) and pregnant mice through tunicamycin (Tu) administration. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were performed to determine the interaction between XBP1s and the transcription factor binding site (TFBS) of tumor necrosis factor receptor-associated factor 6 (TRAF6). Mitochondrial membrane potential (MMP) and mitochondrial function were assessed using JC-1 and TMRM staining following ERS induction in DSCs. The effects of XBP1s inhibitors on mitochondrial metabolism and autophagy were evaluated through RT-qPCR, Western blotting, RNA-Seq, TUNEL assays, ROS and MitoSOX detection, and histological analyses in Tu-treated DSCs and SA patients. STF-083010 (STF) or shXBP1 was utilized to assess the inhibitory effects of X-box binding protein 1 (XBP1s) on DSC function both <em>in vitro</em> and <em>in vivo</em>.</div></div><div><h3>Results</h3><div>We observed significant upregulation of XBP1s in decidual tissues from SA patients and Tu-exposed DSCs. Tu exposure significantly increased the proportion of TUNEL-positive cells and upregulated pro-inflammatory cytokines (IL-1β, TNF-α, IL-6, IL-18) in DSCs. XBP1s inhibition <em>via</em> shXBP1 or pharmacological inhibitor STF attenuated Tu-induced apoptosis and inflammatory cytokine expression. Notably, STF or shXBP1 treatment enhanced MMP and upregulated LC3-II expression in Tu-treated DSCs, indicating autophagy activation.Intriguingly, chloroquine (CQ)-mediated autophagy suppression exacerbated apoptosis in STF/Tu-co-treated DSCs, suggesting that XBP1s inhibition confers cytoprotection through autophagy induction. Mechanistically, XBP1s directly bound to the TFBS of TRAF6, a ubiquitin E3 ligase. TRAF6 overexpression exacerbated mitochondrial dysfunction and apoptosis while suppressing autophagy <em>via</em> inhibition of mTORC2/Akt pathway in Tu-treated DSCs.</div></div><div><h3>Conclusion</h3><div>XBP1s inhibition restored mitochondrial homeostasis and promoted autophagy by modulating the TRAF6/mTORC2 axis under ERS conditions, providing novel mechanistic insights into SA pathogenesis and potential therapeutic targets.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"152 ","pages":"Article 114398"},"PeriodicalIF":4.8,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143592546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Met-Exo attenuates pyroptosis in miniature pig liver IRI by improving mitochondrial quality control
IF 4.8 2区 医学
International immunopharmacology Pub Date : 2025-03-10 DOI: 10.1016/j.intimp.2025.114437
Lei Cao , Pujun Li , Tao Liu , Yajun Ma , Xiangyu Lu , Hongbin Wang
{"title":"Met-Exo attenuates pyroptosis in miniature pig liver IRI by improving mitochondrial quality control","authors":"Lei Cao ,&nbsp;Pujun Li ,&nbsp;Tao Liu ,&nbsp;Yajun Ma ,&nbsp;Xiangyu Lu ,&nbsp;Hongbin Wang","doi":"10.1016/j.intimp.2025.114437","DOIUrl":"10.1016/j.intimp.2025.114437","url":null,"abstract":"<div><div>Metformin(Met) and adipose-derived stem cell exosomes(ADSCs-Exo) both demonstrate therapeutic effects on mitochondrial dysfunction and pyroptosis. There is also a phenomenon of mutual promotion between these two pathological states. The synergistic effect of metformin-loaded exosomes (Met-Exo) via electroporation in a miniature pig liver ischemia-reperfusion injury (IRI) model remains unexplored. This study established a liver IRI model in miniature pigs to compare the effects of ADSCs-Exo and Met-Exo. We found that Met-Exo intervention better activated the Adenosine 5′-monophosphate activated protein kinase (AMPK)/NAD-dependent deacetylase sirtuin-1(SIRT1) axis, improved mitochondrial dynamics, promoted mitochondrial biogenesis, and inhibited the sustained excessive autophagy of mitochondria after liver IRI. It was then demonstrated that by improving mitochondrial dysfunction, ATP production in liver tissue could be ensured, and ROS generation could be suppressed. This also further inhibited the occurrence of pyroptosis and ensured that mitochondria were protected from gasdermin D-N(GSDMD-N) attack. Met-Exo inhibited the occurrence of pyroptosis through the above pathways, reducing the release of inflammatory factors such as IL-1β and IL-18, and alleviating inflammation. This provides a new therapeutic approach for clinical treatment of liver IRI and improving the success rate of liver transplantation.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"152 ","pages":"Article 114437"},"PeriodicalIF":4.8,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143592557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Unraveling the role of the IL-20 cytokine family in neurodegenerative diseases: Mechanisms and therapeutic insights
IF 4.8 2区 医学
International immunopharmacology Pub Date : 2025-03-10 DOI: 10.1016/j.intimp.2025.114399
Pouya Goleij , Alireza Amini , Mohammad Amin Khazeei Tabari , Mahboube Hadipour , Aryan Rezaee , Maria Daglia , Michael Aschner , Pantea Majma Sanaye , Alan Prem Kumar , Haroon Khan
{"title":"Unraveling the role of the IL-20 cytokine family in neurodegenerative diseases: Mechanisms and therapeutic insights","authors":"Pouya Goleij ,&nbsp;Alireza Amini ,&nbsp;Mohammad Amin Khazeei Tabari ,&nbsp;Mahboube Hadipour ,&nbsp;Aryan Rezaee ,&nbsp;Maria Daglia ,&nbsp;Michael Aschner ,&nbsp;Pantea Majma Sanaye ,&nbsp;Alan Prem Kumar ,&nbsp;Haroon Khan","doi":"10.1016/j.intimp.2025.114399","DOIUrl":"10.1016/j.intimp.2025.114399","url":null,"abstract":"<div><div>The IL-20 cytokine family, comprising IL-19, IL-20, IL-22, IL-24, and IL-26, has emerged as a critical player in the pathogenesis of neurodegenerative diseases due to its multiple roles in inflammation, tissue repair, and immune modulation. These cytokines signal through IL-20 receptor complexes (IL-20RA/IL-20RB and IL-22RA1/IL-20RB), triggering diverse immune processes. Recent evidence highlights their significant contributions to neuroinflammation and neurodegeneration in central nervous system disorders. IL-20 family cytokines impact microglial activation, which, when dysregulated, exacerbates neuronal damage. Specifically, IL-20 and IL-24 are linked to elevated pro-inflammatory markers in glial cells, promoting neurodegeneration. In contrast, IL-22 exhibits dual functionality, exerting protective and pathological roles depending on the inflammatory milieu. Key mechanisms involve the regulation of blood-brain barrier integrity, oxidative stress, and autophagy. IL-22 and IL-24 also protect neurons by enhancing antioxidant defenses and maintaining epithelial barrier function, while their dysregulation contributes to blood-brain barrier disruption and protein aggregate accumulation, hallmark features of Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Elevated IL-22 levels in Alzheimer's disease and IL-19's regulatory role in multiple sclerosis suggest they may serve as potential biomarkers and therapeutic targets. IL-26's role in amplifying inflammatory cascades further underscores the complexity of this cytokine family in neurodegenerative pathology. Therapeutically, strategies targeting IL-20 cytokines include monoclonal antibodies, receptor modulation, and recombinant cytokine administration. These approaches aim to mitigate neuroinflammation, restore immune balance, and protect neuronal integrity. This review underscores the IL-20 family's emerging relevance in neurodegenerative diseases, highlighting its potential for novel diagnostic and therapeutic strategies.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"152 ","pages":"Article 114399"},"PeriodicalIF":4.8,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143577190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Research progress of DNA methylation in the diagnosis and treatment of thyroid carcinoma
IF 4.8 2区 医学
International immunopharmacology Pub Date : 2025-03-09 DOI: 10.1016/j.intimp.2025.114426
Xin Zhang , Bing Luo , Minjie Sun , Deyu Gao , Sufang Xu
{"title":"Research progress of DNA methylation in the diagnosis and treatment of thyroid carcinoma","authors":"Xin Zhang ,&nbsp;Bing Luo ,&nbsp;Minjie Sun ,&nbsp;Deyu Gao ,&nbsp;Sufang Xu","doi":"10.1016/j.intimp.2025.114426","DOIUrl":"10.1016/j.intimp.2025.114426","url":null,"abstract":"<div><div>Thyroid cancer is the most prevalent endocrine malignancy, and its timely and accurate diagnostic and prognostic assessments are crucial for enhancing patient survival rates. As an important epigenetic modification, DNA methylation plays a key role in the regulation of gene expression and tumorigenesis. Recent studies increasingly indicate that abnormal DNA methylation patterns are closely associated with the onset and progression of thyroid cancer. This review discusses the role of DNA methylation in diagnosing thyroid adenocarcinoma, its impact on prognosis, and its potential utility in cancer immunotherapy. Additionally, it explores the prospect of using DNA methylation as a biomarker and highlights its significant potential in the personalized treatment of thyroid cancer. This article aims to serve as a resource for future research and clinical applications to advance the diagnosis and treatment of thyroid cancer.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"152 ","pages":"Article 114426"},"PeriodicalIF":4.8,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143577098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Long-term benefit of afatinib combined with bevacizumab in a lung adenocarcinoma patient with a novel rare EGFR Q787L mutation
IF 4.8 2区 医学
International immunopharmacology Pub Date : 2025-03-09 DOI: 10.1016/j.intimp.2025.114368
Yingying Huang, Shouming Qin, Haijuan Tang, Jing Jiang, Qiuli Liang
{"title":"Long-term benefit of afatinib combined with bevacizumab in a lung adenocarcinoma patient with a novel rare EGFR Q787L mutation","authors":"Yingying Huang,&nbsp;Shouming Qin,&nbsp;Haijuan Tang,&nbsp;Jing Jiang,&nbsp;Qiuli Liang","doi":"10.1016/j.intimp.2025.114368","DOIUrl":"10.1016/j.intimp.2025.114368","url":null,"abstract":"<div><h3>Background</h3><div>The epidermal growth factor receptor (EGFR) is among the most frequently mutated genes in lung adenocarcinomas (LUAC). The combination of afatinib and bevacizumab has primarily been reported in LUAC cases exhibiting resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI), particularly in classical variants such as EGFR exon 19 deletions and the L858R mutation in exon 21. However, the clinical efficacy of afatinib combined with bevacizumab in treating rare EGFR mutations remains underexplored.</div></div><div><h3>Case presentation</h3><div>We present a case of T4N0M0 stage IIIA LUAC in which disease progression occurred following tumor resection and subsequent chemotherapy combined with bevacizumab. Next-generation sequencing of peripheral blood identified a novel and rare EGFR exon 20 Q787L mutation. Maintenance therapy with icotinib, a first-generation EGFR-TKI, combined with bevacizumab was initiated, but the patient developed resistance to icotinib after 8 months. No drug availability variants or acquired resistance-related mutations were detected. Subsequently, maintenance therapy with oral afatinib plus bevacizumab was initiated, resulting in partial remission after 3 months. As of the most recent CT scan in November 2023, the patient has achieved a progression-free survival (PFS) of 56 months on afatinib plus bevacizumab maintenance therapy, representing the longest reported duration to date, with no severe side effects observed.</div></div><div><h3>Conclusion</h3><div>Our findings suggest that the combination of afatinib and bevacizumab may offer long-term clinical benefits for LUAC patients harboring the novel and rare EGFR Q787L mutation. This case highlights a potential therapeutic strategy warranting further investigation in clinical studies.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"152 ","pages":"Article 114368"},"PeriodicalIF":4.8,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143577096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Nanoparticle delivery of CD68 siRNA inhibits neuroimmune responses by inhibiting activation of M1 macrophages
IF 4.8 2区 医学
International immunopharmacology Pub Date : 2025-03-09 DOI: 10.1016/j.intimp.2025.114380
Yue Guo , Mao Shen , Hongkai Yang , Sen Lin , Dahao Wang
{"title":"Nanoparticle delivery of CD68 siRNA inhibits neuroimmune responses by inhibiting activation of M1 macrophages","authors":"Yue Guo ,&nbsp;Mao Shen ,&nbsp;Hongkai Yang ,&nbsp;Sen Lin ,&nbsp;Dahao Wang","doi":"10.1016/j.intimp.2025.114380","DOIUrl":"10.1016/j.intimp.2025.114380","url":null,"abstract":"<div><div>CD68 is a vital costimulatory molecule expressed on macrophages/microglia (M/Ms) and plays a critical role in their activation. By targeting this molecule, therapeutic interventions can potentially prevent the homing of M/Ms. to the lesion site. In this study, we developed a biomimetic nanoparticle-based system (siCD68/NPs) to deliver CD68 small interfering RNA (siCD68) more efficiently into M/Ms.Administration of siCD68/NPs was found to not only polarize M1 macrophages toward M2 phenotype, but also reduce the reactive oxygen species (ROS) levels in lipopolysaccharide (LPS) plus interferon-γ (IFN-γ) induced macrophages/microglia (M/Ms). Moreover, treatment with siCD68/NPs significantly extended the survival time in a mouse spinal cord injury (SCI) model.In summary, siCD68/NPs were found to activate an anti-neuroinflammatory immune response and reprogram the polarization of M/Ms., leading to a significant improvement in the recovery of spinal cord injury. This study contributes to the field of biomimetic nanoparticle-based therapies and offers novel insights into potential treatments for neuroinflammation-induced SCI.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"152 ","pages":"Article 114380"},"PeriodicalIF":4.8,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143577021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Unraveling the crucial role of SDF-1 in osteoarthritis progression: IL6/HIF-1α positive feedback and chondrocyte ferroptosis
IF 4.8 2区 医学
International immunopharmacology Pub Date : 2025-03-09 DOI: 10.1016/j.intimp.2025.114400
Tengyun Yang, Xianguang Yang, Guoliang Wang, Di Jia, Yanlin Li
{"title":"Unraveling the crucial role of SDF-1 in osteoarthritis progression: IL6/HIF-1α positive feedback and chondrocyte ferroptosis","authors":"Tengyun Yang,&nbsp;Xianguang Yang,&nbsp;Guoliang Wang,&nbsp;Di Jia,&nbsp;Yanlin Li","doi":"10.1016/j.intimp.2025.114400","DOIUrl":"10.1016/j.intimp.2025.114400","url":null,"abstract":"<div><h3>Background</h3><div>Osteoarthritis (OA) is a common joint disease with an incompletely understood pathogenesis. SDF-1, a key factor in cartilage matrix degradation, is involved in OA cartilage degeneration, yet its mechanism, especially regarding ferroptosis, remains unclear. This study focuses on elucidating the role of SDF-1-induced chondrocyte ferroptosis and the IL6/HIF-1α signalling axis in OA.</div></div><div><h3>Methods</h3><div>A rabbit OA model was created via SDF-1 induction. Knee cartilage tissues were sequenced and analyzed bioinformatically to identify key genes, and explore critical pathways. Clinical tissue samples were utilized to validate their clinical relevance. Furthermore, cell and rabbit models were constructed through gene interference and pathway blocking. The expression of related genes and proteins was detected by QPCR, ELISA, Western blot, and immunofluorescence. Additionally, OA and ferroptosis indicators such as cell viability, immunohistochemistry, ROS, lipid ROS, Fe<sup>2+</sup>, MDA, and mitochondrial morphology were evaluated to uncover the molecular mechanism by which SDF-1 regulates the IL6/HIF-1α signalling axis to mediate chondrocyte ferroptosis.</div></div><div><h3>Results</h3><div>Bioinformatics revealed that ferroptosis was significantly activated in SDF-1-induced OA, with IL6 and HIF-1 pathways implicated. In vitro and in vivo, SDF-1 increased the expression and secretion of MMP13 but decreased COL2A1 and ACAN in chondrocytes, leading to OA-like changes. It also suppressed the expression levels of SLC7A11 and GPX4, upregulated the gene and protein levels of ACSL4, promoted the accumulation of MDA, Fe<sup>2+</sup>, and ROS, and caused mitochondrial morphological changes. These ferroptosis manifestations could be alleviated by the ferroptosis inhibitor Fer-1. IL6 was an important mediator of SDF-1-induced ferroptosis, and knocking down IL6 also inhibited chondrocyte ferroptosis changes. Overexpressing IL6 (oeIL6) and using PX478 to inhibit the HIF-1 signalling pathway showed that PX478 could significantly relieve the cytotoxicity produced by the culture of oeIL6 and SDF-1, enhance chondrocyte viability, reverse the decreased expression of SLC7A11 and GPX4 caused by oeIL6, increase the expression of ACSL4, reverse the accumulation of MDA, Fe<sup>2+</sup>, and ROS. Moreover, PX478 could also significantly reduce the expression and secretion of IL6.</div></div><div><h3>Conclusion</h3><div>SDF-1 mediates chondrocyte ferroptosis via the IL6/HIF-1α positive feedback, promoting OA.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"152 ","pages":"Article 114400"},"PeriodicalIF":4.8,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143577099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Epithelial FETUB-mediated the inhibition of NEP activity aggravates asthma
IF 4.8 2区 医学
International immunopharmacology Pub Date : 2025-03-09 DOI: 10.1016/j.intimp.2025.114397
Peng Sun , Qi Hua , Heng Fu , Lei Yao , Xijing Yuan , Qian Li , Yuebei Li , Man Jia , Rong Xia , Xin Yao
{"title":"Epithelial FETUB-mediated the inhibition of NEP activity aggravates asthma","authors":"Peng Sun ,&nbsp;Qi Hua ,&nbsp;Heng Fu ,&nbsp;Lei Yao ,&nbsp;Xijing Yuan ,&nbsp;Qian Li ,&nbsp;Yuebei Li ,&nbsp;Man Jia ,&nbsp;Rong Xia ,&nbsp;Xin Yao","doi":"10.1016/j.intimp.2025.114397","DOIUrl":"10.1016/j.intimp.2025.114397","url":null,"abstract":"<div><h3>Background</h3><div>Neuropeptide accumulation exacerbates asthma, with reduced neprilysin (NEP) activity implicated. However, this regulatory mechanism remains unexplored.</div></div><div><h3>Objective</h3><div>To identify and characterize epithelial-derived modulators of NEP activity and their role in asthma pathogenesis.</div></div><div><h3>Methods</h3><div>Bioinformatics and molecular docking identified fetuin B (FETUB) as a NEP inhibitor. FETUB expression in human lung tissue was assessed by immunohistochemistry, and its levels in exhaled breath condensate (EBC) and serum were quantified by ELISA. Functional assays and a lung-specific FETUB knockdown mouse model using Adeno-associated virus (AAV) vector confirmed its role in NEP inhibition and asthma pathogenesis.</div></div><div><h3>Results</h3><div>Bioinformatic analysis, protein binding assays, and fluorescence substrate degradation experiments confirmed that FETUB is an inhibitor of NEP. Serum FETUB levels were elevated in asthmatics and positively correlated with serum IgE, eosinophil counts. Similarly, in asthmatic EBC, FETUB levels were significantly higher than in healthy controls and negatively correlated with asthma control test, FEV<sub>1</sub> and FEV<sub>1</sub>%pred. The expression of FETUB was elevated in asthma lung tissue and primarily localized to airway epithelial cells. Combined bioinformatics and experimental data indicated that IL-13 as a key inducer of epithelial FETUB expression. Lung-specific FETUB knockdown restored NEP activity, reduced neuropeptides CGRP and SP, and improved airway inflammation and hyperresponsiveness in asthma.</div></div><div><h3>Conclusion</h3><div>The findings suggest that epithelial-derived FETUB exacerbates airway inflammation and hyperresponsiveness in asthma through the inhibition of NEP activity and the resultant accumulation of CGRP and SP.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"152 ","pages":"Article 114397"},"PeriodicalIF":4.8,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143577022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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