Inflammation最新文献

{"title":"\"The Ameliorative Effect of Interleukin-17A Neutralization on Doxorubicin-Induced Cardiotoxicity by Modulating the NF-κB/NLRP3/Caspase-1/IL-1β Signaling Pathway in Rats\".","authors":"Mostafa D Hassen, Nahla O Mousa, Sara M Radwan, Refaat M Gabre","doi":"10.1007/s10753-024-02187-z","DOIUrl":"https://doi.org/10.1007/s10753-024-02187-z","url":null,"abstract":"<p><p>Doxorubicin (DOX) is used as a chemotherapeutic drug for treating cancer. Nevertheless, it causes damage to the heart by activating inflammatory pathways, resulting in cardiotoxicity. Imbalance in cytokine production is a crucial component that might trigger the initiation of inflammatory processes. Inflammatory cytokines could be targeted therapies against cardiovascular diseases (CVDs). Interleukin-17A (IL-17A) is a cytokine that promotes inflammation and stimulates harmful immunological reactions. The objective of the study was to determine the efficacy of secukinumab (SEC), a completely human monoclonal IgG1/κ antibody that targets IL-17A, in ameliorating DOX-induced cardiotoxicity (DIC). We administered 2.5 mg/kg of DOX intraperitoneally to male Wistar rats three times a week for 2 weeks and simultaneously administered 0.9 mg/kg of SEC along with 2.5 mg/kg of DOX injection three times a week for a duration of two weeks. The findings indicated that DOX induced damage to the heart tissue, resulting in a significant rise in indicators of cardiotoxicity (P < 0.001), as well as oxidative stress and inflammation. DIC may have arisen from DOX's activation of the Pyrin domain containing 3 (NLRP3) inflammasome and the nuclear factor kappa beta (NF-κB) pathway. The co-administration of SEC successfully reversed all DOX-induced abnormalities by restoring cardiac functions to their baseline levels, decreasing levels of inflammatory mediators such as IL-17A and interleukin-1β (IL-1β), and improving oxidative stress by reducing levels of malondialdehyde (MDA) and increasing levels of reduced glutathione (GSH). Furthermore, it mitigated the heightened activation of the NF-κB/NLRP3 pathway caused by DOX. This study shows that IL-17A neutralization can prevent DIC by regulating the NF-κB/NLRP3/Caspase-1/IL-1β pathway to be used as potential therapeutic target for CVDs.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143597008","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}

{"title":"Substance P Augments Chemokine Production by Staphylococcus aureus Infected Murine Osteoclasts.","authors":"Sophie E Sipprell, Quinton A Krueger, Erin L Mills, Ian Marriott, M Brittany Johnson","doi":"10.1007/s10753-025-02280-x","DOIUrl":"10.1007/s10753-025-02280-x","url":null,"abstract":"<p><p>Staphylococcal osteomyelitis is a serious infection of the bone and joints characterized by progressive inflammatory tissue damage and leukocyte recruitment leading to net bone loss. Resident bone cells are capable of recognizing Staphylococcus aureus and initiating an inflammatory immune response that recruits leukocytes and alters bone homeostasis. Importantly, bone tissue is richly innervated with substance P containing nerve fibers and we have previously shown that this neuropeptide can augment the inflammatory responses of both osteoblasts and osteoclasts to S. aureus infection via neurokinin-1 receptors (NK-1R). Here, we have extended these studies by demonstrating that pharmacological inhibition of NK-1R ameliorates disease severity in a mouse model of staphylococcal osteomyelitis. This effect was associated with a significant reduction in leukocyte-attracting chemokine production following infection and reduced local levels of osteoclast and neutrophil activity. We then assessed the effect of S. aureus infection on bone-marrow derived osteoclast gene expression in the absence or presence of substance P. We determined that infection upregulates osteoclast expression of mRNAs encoding inflammatory mediators that include the neutrophil-attracting chemokines identified in vivo. Importantly, we found that, while substance P has no effect on chemokine mRNA expression in infected cells, this neuropeptide significantly increases the release of these chemokines by S. aureus challenged osteoclasts but not osteoblasts. Together, these data further support the ability of substance P to exacerbate inflammatory damage in staphylococcal osteomyelitis and indicate that this effect may be due, in part, to an augmentation of osteoclast immune responses that promote leukocyte recruitment.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582308","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}

{"title":"USP5 Deletion Inhibits KD Serum Induced-Human Coronary Artery Endothelial Cell Dysfunction by Regulating the NFATC1/TLR4-Mediated NF-κB Signaling Pathway in Kawasaki Disease.","authors":"Lidan Yao, Yupeng Lai, Heng Li, Sihan Chen, Xianjia Yu, Ni Zhou, Dandan Lang","doi":"10.1007/s10753-025-02276-7","DOIUrl":"https://doi.org/10.1007/s10753-025-02276-7","url":null,"abstract":"<p><p>Kawasaki disease (KD) is an acute febrile illness characterized by systemic vasculitis, especially in coronary arteries. Previous studies have indicated that nuclear factor of activated T cells, cytoplasmic 1 (NFATC1, also known as NFAT2) plays a crucial role in the pathogenesis of KD. However, the molecular mechanism of NFATC1 involved in KD is poorly defined. Human coronary artery endothelial cells (HCAECs) were treated with 15% serum from KD patients to mimic the inflammatory injury model in vitro. NFATC1 mRNA level was determined using real-time quantitative polymerase chain reaction (RT-qPCR). NFATC1, Bax, Bcl-2, Ubiquitin-specific peptidase 5 (USP5), Toll-like receptor 4 (TLR4), p-P65, P65, p-IκBα, and IκBα protein levels were determined by Western blot. Cell viability, proliferation, and apoptosis were assessed using the Cell Counting Kit-8 (CCK-8) assay, 5-ethynyl-2'-deoxyuridine (EdU) assay, and flow cytometry. Interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) levels were analyzed using ELISA. ROS and SOD levels were detected using special assay kits. After ubibrowser database analysis, the interaction between USP5 and NFATC1 was verified using Co-immunoprecipitation (CoIP) assay. Meanwhile, the possible interaction between NFATC1 and TLR4 was predicted by STRING databases and identified using CoIP assay. NFATC1 expression was increased in KD patients and KD serum-treated HCAECs. KD serum-mediated HCAEC viability and proliferation inhibition, apoptosis, inflammatory response, and oxidative stress promotion. Furthermore, blocking NFATC1 relieved KD serum-evoked HCAEC injury in vitro. Mechanistically, USP5 triggered the deubiquitination of NFATC1 and prevented its degradation. NFATC1 interacted with TLR4 to regulate its expression in HCAECs. Besides, KD serum activated the nuclear factor kappa-B (NF-κB) signaling pathway by regulating the USP5/NFATC1/TLR4 axis in HCAECs. USP5 deficiency mitigated KD serum-induced inflammation and injury in HCAECs through targeting NFATC1 and TLR4-mediated NF-κB signaling, providing a possible therapeutic target for KD treatment.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572827","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}

{"title":"Baicalein Reduces Pyroptosis of Acinar Cells in Hyperlipidemic Acute Pancreatitis by Inhibiting M1 Polarization of Macrophages via the HMGB1/TLR4/NLRP3 Pathway.","authors":"Xiangyang Wang, YaXiong Zhou, Yilei Liu, Tingting Mo, Zhiyuan Chen, Yu Zhang, Li Yang, Peng Liu","doi":"10.1007/s10753-025-02254-z","DOIUrl":"https://doi.org/10.1007/s10753-025-02254-z","url":null,"abstract":"<p><p>Previous studies have shown that baicalein (BAI) can reduce pyroptosis of pancreatic acinar cells (PACs) in hyperlipidemic acute pancreatitis (HAP). This study aimed to elucidate the potential molecular mechanism of PAC pyroptosis mediated by BAI in HAP. A HAP rat model was established via a high-fat diet supplemented with 5% sodium taurocholate. Macrophages were treated with palmitic acid (PA). The rats and cells were treated with BAI. Molecular docking and DARTS assay were used to analyze BAI binding to HMGB1. Co-IP revealed that HMGB1 interacted with TLR4 and NLRP3 and that TLR4 interacted with NLRP3. The interaction between PA-induced macrophages and PACs was evaluated by cell coculture. BAI treatment improved pancreatic lesions, reduced iNOS expression, and decreased the number of M1 macrophages in HAP rats. BAI decreased CD86, HMGB1, NLRP3, ASC, cleaved caspase-1, and GSDMD-N expression in pancreatic tissue and serum IL-1β and IL-18 levels in HAP rats. Molecular docking results and DARTS assays revealed that BAI combined with HMGB1. Co-IP verified that HMGB1 interacted with TLR4 and NLRP3 and that TLR4 interacted with NLRP3. BAI and the HMGB1 inhibitor EP inhibited HMGB1, TLR4, and NLRP3 levels in PA-induced macrophages, increased cell viability, reduced pyroptosis, and ROS release, and inhibited M1 polarization. BAI and EP inhibited PA-induced M1 macrophage polarization and reduced PAC pyroptosis. HMGB1 overexpression partially reversed the effects of BAI on PA-treated macrophages and PACs. Under EP treatment, BAI had no significant effect on the above functions in PA-induced macrophages and PACs. BAI inhibited PA-induced macrophage M1 polarization through the HMGB1/TLR4/NLRP3 pathway, further inhibiting PAC pyroptosis. Our findings provide a theoretical and experimental basis for the molecular mechanism underlying BAI in the treatment of HAP.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556760","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}

{"title":"VASP Knockdown Ameliorates Lipopolysaccharide-Induced Acute Lung Injury with Inhibition of M1 Macrophage Polarization Through the cGMP-PKG Signaling Pathway.","authors":"Jiajia Tang, Yiwei Ding, Wei Chen, Jun Shi, Chunyang Zhang, Xiaoyu Zhao, Jiao Li, Zhihai Han, Xuxin Chen","doi":"10.1007/s10753-025-02277-6","DOIUrl":"https://doi.org/10.1007/s10753-025-02277-6","url":null,"abstract":"<p><p>Alveolar macrophage (AM) polarization plays a pivotal role in the inflammatory response during acute lung injury (ALI). As reported previously, vasodilator-stimulated phosphoprotein (VASP) may function as an anti-inflammatory agent in hepatic tissues. However, the specific role of VASP in ALI-induced macrophage polarization remains unclear. To elucidate the role of VASP in ALI, we established a lipopolysaccharide (LPS)-induced M1 polarization model of MH-S cells. RNA sequencing was performed to identify differentially expressed genes during macrophage polarization. The results revealed significant upregulation of the VASP gene. Subsequently, VASP gene knockdown in the lungs was achieved by intratracheal delivery of VASP-AAV6, and the resulting ALI symptoms and macrophage polarization were assessed. The VASP gene was also knocked down in MH-S cells; these cells were then stimulated with LPS for 24 h, and polarization-related markers of macrophages were analyzed. Finally, to validate the involvement of the PKG-VASP signaling pathway, experiments were conducted with a PKG agonist (8-Br-cGMP) and inhibitor (KT5823), and the effects of modulating the PKG-VASP pathway on macrophage polarization were investigated. VASP knockdown notably ameliorated ALI symptoms in these mice with LPS-induced ALI. Additionally, in vitro experiments showed that the PKG-VASP signaling pathway plays a pivotal role in macrophage polarization. VASP knockdown protected mice from LPS-induced ALI by inhibiting M1 polarization, and its protective effects were partially mediated by the cGMP-PKG signaling pathway.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566991","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}

{"title":"PARP1 Exacerbates Prostatitis by Promoting M1 Macrophages Polarization through NF-κB Pathway.","authors":"Lu Jin, Jiaxing Chen, Jianhui Fu, Jingyi Lou, Yingxue Guo, Xia Liu, Xiaojuan Xu, Huiying Fu, Qiyang Shou","doi":"10.1007/s10753-025-02247-y","DOIUrl":"https://doi.org/10.1007/s10753-025-02247-y","url":null,"abstract":"<p><p>PARP1 is recognized for its role as a DNA damage sensor and its involvement in inflammatory diseases, but its impact on prostatitis remains unclear. We aimed to elucidate how PARP1 affects prostatitis progression. Our results showed that in 1% carrageenan-induced prostatitis mouse model, Parp1^-/- prostatitic mice showed less pathological damage, decreased prostate weight, and lower inflammatory indices, decreased macrophage and neutrophil infiltration, down-regulated the expression of pro-inflammatory cytokines (IL-6, IL-12p70, CCL2, TNF) and up-regulated anti-inflammatory cytokine IL-10 in prostate tissue. The expression of NF-κB, TNF, and IL-6 mRNA in the prostate tissue of Parp1^-/- prostatitic mice decreased. In vitro experiments revealed that M1(CD206^-CD86⁺⁾ macrophage in LPS-induced macrophage of Parp1^-/- mice decreased, as did iNOS, TNF, IL-6 and NF-κB mRNA expression. Mechanically, treatment with the PARP1 inhibitor (AG14361) led to a significant reduction in NF-κB mRNA and Phospho-NF-κB P65 protein expression in macrophages. Following intervention with NF-κB inhibitors (Bay 11-7082), both IL-6 protein and mRNA levels were markedly diminished, meanwhile the secretion of IL-6, IL-10, IL-12p70, CCL2, IFN-γ, and TNF exhibited a pronounced dose-dependent decrease. Collectively, these findings indicated that PARP1 exacerbates carrageenan-induced prostatitis by promoting M1 macrophages polarization via the NF-κB pathway, suggesting PARP1 could be a potential therapeutic target for macrophage-based treatments in prostatitis.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143541664","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}

{"title":"DNAJB2 Attenuates Rosacea Skin Inflammation and Angiogenesis by Inhibiting the Endoplasmic Reticulum Stress-mediated TLR2/Myd88/NF-κB pathway.","authors":"Yuxin Qing, Jiawen Wu, Bingyang Xu, Zining Xu, Shuhong Ye, Yuanqin Wang, Bin Zhao, Hong Sun, Na Wu","doi":"10.1007/s10753-025-02278-5","DOIUrl":"https://doi.org/10.1007/s10753-025-02278-5","url":null,"abstract":"<p><p>Endoplasmic reticulum stress (ERS) has recently been proposed as a core factor in the pathogenesis and aggravation of rosacea. The roles of ERS-related genes in rosacea are largely unknown and were investigated in this study. Rosacea microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed ERS-related genes in rosacea patients vs. controls were screened using the Limma package, and LASSO regression was used to screen for characteristic genes. The infiltrating fraction was evaluated using ssGSEA. Clinical rosacea samples, age-matched healthy volunteers, and LL37-induced mice models were used to investigate the expression of DNAJB2 and its function. In the GSE65914 dataset, 17 differentially expressed ERS-related genes were screened. Of these, 13 were identified as characteristic genes predicting rosacea risk. The adaptive immune response, TLR signaling pathway, and chemokine signaling pathway were activated with a high risk of rosacea. After expression validation using the GSE155141 dataset, DNAJB2 was identified as a key gene. DNAJB2 expression was significantly decreased in both datasets, clinical samples, and the LL37-induced mice model. DNAJB2 overexpression could alleviate rosacea skin injury and inhibit expression of inflammatory cytokines and chemokines as well as angiogenesis. The infiltration levels of the majority of immune cell types were elevated in rosacea samples, and DNAJB2 overexpression inhibited CD4 + T cell infiltration, as well as Th1 and Th17 polarizing genes. Moreover, DNAJB2 could inhibit ERS marker proteins and the activated TLR2/Myd88/NF-κB pathway. DNAJB2 may be a novel target for rosacea treatment.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143541355","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}

{"title":"Plasma Exosomes Derived from Patients with Primary Immune Thrombocytopenia Attenuate TBX21⁺ Regulatory T Cell-Mediated Immune Suppression via MiR-363-3p.","authors":"Yuanlan Huang, Peng Liu, Ying Xu, Cheng Qian, Tianqin Wu, Tengda Li","doi":"10.1007/s10753-025-02275-8","DOIUrl":"https://doi.org/10.1007/s10753-025-02275-8","url":null,"abstract":"<p><p>Primary Immune Thrombocytopenia (ITP) is characterized by reduced immunosuppressive function of regulatory T cells (Tregs), contributing to immune imbalance and decreased platelet counts. However, the mechanisms behind this reduced efficacy of Tregs remain unclear. Our study used a variety of methods, including Treg function assays, cytokine analysis, and single-cell sequencing, to explore these mechanisms. We found that exosomes from ITP patients inhibited TBX21 expression in Tregs, and impaired their ability to suppress Th1 cells. At the single-cell level, Tregs with high TBX21 expression were identified, and the activity of the TBX21 regulon was found to be enhanced in early-stage Treg subpopulations. We also discovered that ARID3A interacted with SPI1 and TBX21 gene regions, indicating a regulatory relationship between ARID3A, SPI1, and TBX21. Additionally, exosomes in ITP patients' plasma contained elevated levels of miR-363-3p, which negatively correlated with platelet count. These exosomes transferred miR-363-3p to Tregs, downregulating ARID3A, SPI1, and TBX21 expression, thereby weakening Tregs' ability to suppress conventional CD4 + T cells. In conclusion, exosomes from ITP patients reduced Treg function through the ARID3A/SPI1/TBX21 axis by miR-363-3p, diminishing their ability to regulate Th1 cells and contributing to the immune dysfunction observed in ITP.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143541672","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}

{"title":"NLRP3-inflammasome Related Genes as Emerging Biomarkers and Therapeutic Targets in Psoriasis.","authors":"Ao Shi, Yuan Shu, Kaibo Hu, Shivon Sudesh, Ying Tu","doi":"10.1007/s10753-025-02271-y","DOIUrl":"https://doi.org/10.1007/s10753-025-02271-y","url":null,"abstract":"<p><p>The NLRP3 inflammasome is closely associated with inflammatory diseases, including psoriasis. Objective diagnostic biomarkers and alternative therapies for psoriasis remain limited. We aimed to identify reliable biomarkers for the diagnosis of psoriasis and investigate potential therapy strategies. Machine learning methods were performed in over 1000 skin samples from public transcriptome database to identify NLRP3 inflammasome-related biomarkers. Multivariate Cox regression analysis was used to establish the biomarker-based diagnostic model. TNF-induced HaCaT cell model was used to evaluate biomarker-related inflammatory changes. Biomarker-targeting drugs was predicted with NetworkAnalyst database and validated in imiquimod (IMQ)-induced mouse model. Elevated level of four NLRP3 inflammasome-related biomarkers, including NLRP3, ASC, TXNIP and CASP-1, were identified from the public psoriasis transcriptome samples and validated in our local psoriasis skin biopsies. The biomarker-based diagnostic model was developed from training dataset and validation dataset, which both showed significant diagnostic value for psoriasis. Knocking down one of these genes in vitro showed reduced inflammatory factors, reduced cell apoptosis and improved cell viability. Furthermore, Predictive biomarker-targeting therapeutics, including resveratrol and JQ-1, demonstrated effective alleviation of psoriasis severity and reduced inflammation in IMQ-induced psoriasis mice. Combinational evaluation of NLRP3, ASC, TXNIP and CASP-1 may constitute a novel diagnostic approach for psoriasis. Targeting these proteins provide more options for psoriasis therapy.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143541459","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}

{"title":"Inhibition of Cullin3 Neddylation Alleviates Diabetic Retinopathy by Activating Nrf2 Signaling to Combat ROS-Induced Oxidative Stress and Inflammation.","authors":"Yueqin Chen, Cong Liu, Jun Tong, Chang He, Xinru Ling, Jinjin Xiang, Chunyan Xue, Genhong Yao, Lingyun Sun, Zhenggao Xie","doi":"10.1007/s10753-025-02259-8","DOIUrl":"https://doi.org/10.1007/s10753-025-02259-8","url":null,"abstract":"<p><p>Oxidative stress and inflammation induced by reactive oxygen species (ROS) play important roles in the development of diabetic retinopathy (DR). Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, which is negatively controlled by Cullin3-RING E3 ligase (CRL3) and controls ROS levels, is compromised in DR. CRL3 activity is regulated by Cullin3 neddylation. Nonetheless, the relationship between Cullin3 neddylation and DR remains uncertain. The goal of this study was to evaluate the effect of Cullin3 neddylation on DR and its underlying mechanisms by utilizing MLN4924, a neddylation inhibitor. Cullin3 neddylation was elevated in diabetic rats' retinas as well as in advanced glycation end products (AGEs)-induced endothelial cells. Inhibiting neddylation of Cullin3 with MLN4924 downregulated Nrf2 ubiquitination, promoted Nrf2 accumulation, suppressed ROS-induced oxidative stress and inflammation, and attenuated blood-retinal barrier (BRB) breakdown in both diabetic vivo and vitro models. However, the beneficial impact of MLN4924 was compromised when Nrf2 was suppressed with siRNA in vitro. This study showed that inhibition of Cullin3 neddylation with MLN4924 exerted protective effect on DR by activating Nrf2 signaling to inhibit ROS-induced retinal injury, which indicated that targeting Cullin3 neddylation could be a promising treatment option for DR.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531448","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}