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Deferoxamine attenuates sepsis-induced liver injury by suppressing ferroptosis 去铁胺通过抑制铁下垂减轻败血症引起的肝损伤。
IF 2.3 4区 医学 Q3 IMMUNOLOGY Pub Date : 2025-10-03 DOI: 10.1016/j.imbio.2025.153125
Haidan Zhang, Hongyao Li, Shixian Liu, Jiahui Zheng, Peiwu Li

Background

The liver is among the organs most frequently damaged during sepsis, and sepsis-induced liver injury is an independent risk factor for early patient mortality. Ferroptosis has been implicated in sepsis-related organ dysfunction; however, its role in sepsis-induced liver injury remains unclear. This study aimed to investigate the role and underlying mechanisms of ferroptosis in sepsis-associated liver injury.

Methods

A rat sepsis model was established in vivo using cecal ligation and puncture (CLP). In vitro, BRL-3A hepatocytes were exposed to lipopolysaccharide (LPS). Deferoxamine (DFO) was administered prior to model induction. Inflammatory cytokine concentrations and the extent of liver injury were assessed. Ferroptosis-related biomarkers, including ferrous ions (Fe2+), prostaglandin-endoperoxide synthase 2 (PTGS2), acyl-CoA synthetase long-chain family member 4(ACSL4), malondialdehyde (MDA), glutathione (GSH) and peroxidase 4 (GPX4) were quantified. Lipid peroxidation was measured using the BODIPY 581/591 C11 fluorescent probe. Mitochondrial function was evaluated using electron microscopy and JC-1 fluorescent probe assays.

Results

(1) In vivo, DFO treatment was found to alleviate systemic inflammation in septic rats and provided protective effects on the liver. It increased the 7-day survival rate, reduced serum levels of interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α), decreased alanine aminotransferase and aspartate aminotransferase levels, and mitigated histopathological damage in liver tissue. In vitro, DFO treatment enhanced the viability of LPS-stimulated BRL-3A hepatocytes. (2) Ferroptosis was observed to be activated in septic rats as well as in LPS-stimulated BRL-3A hepatocytes. DFO reduced the intracellular concentration of ferrous ions and reduced lipid peroxidation as indicated by decreased PTGS2, ACSL4 and MDA. Furthermore, DFO alleviated mitochondrial damage (manifested as reduced mitochondrial volume, decreased membrane density, reduced cristae and outer membrane rupture, etc.), and mitochondrial function was improved. Finally, DFO elevated the levels of GSH and GPX4, which enhanced the antioxidant capacity of hepatocytes.

Conclusion

Ferroptosis plays a critical role in the pathogenesis of sepsis-induced liver injury. Targeting the activation of ferroptosis in hepatocytes during sepsis through intervention with DFO may represent a promising therapeutic strategy for the management of this condition.
背景:肝脏是败血症中最常受损的器官之一,败血症引起的肝损伤是早期患者死亡的独立危险因素。铁质下垂与败血症相关的器官功能障碍有关;然而,其在脓毒症引起的肝损伤中的作用尚不清楚。本研究旨在探讨铁下垂在脓毒症相关肝损伤中的作用和潜在机制。方法:采用盲肠结扎穿刺法(CLP)建立大鼠脓毒症模型。在体外,BRL-3A肝细胞暴露于脂多糖(LPS)。模型诱导前给予去铁胺(DFO)。评估炎症细胞因子浓度和肝损伤程度。测定了铁中毒相关的生物标志物,包括铁离子(Fe2+)、前列腺素内过氧化物合成酶2 (PTGS2)、酰基辅酶a合成酶长链家族成员4(ACSL4)、丙二醛(MDA)、谷胱甘肽(GSH)和过氧化物酶4(GPX4)。脂质过氧化用BODIPY 581/591 C11荧光探针检测。用电镜和JC-1荧光探针检测线粒体功能。结果:(1)在体内,DFO治疗可减轻脓毒症大鼠的全身炎症,并对肝脏有保护作用。提高大鼠7天生存率,降低血清白细胞介素-6 (IL-6)和肿瘤坏死因子-α (TNF-α)水平,降低丙氨酸转氨酶和天冬氨酸转氨酶水平,减轻肝组织病理损伤。在体外,DFO处理增强了lps刺激的BRL-3A肝细胞的活力。(2)在脓毒症大鼠和lps刺激的BRL-3A肝细胞中,观察到铁凋亡被激活。从PTGS2、ACSL4和MDA的降低可以看出,DFO降低了细胞内亚铁离子浓度,减少了脂质过氧化。DFO减轻了线粒体损伤(表现为线粒体体积减小、膜密度降低、嵴减少、外膜破裂等),改善了线粒体功能。最后,DFO提高了GSH和GPX4的水平,从而增强了肝细胞的抗氧化能力。结论:铁下垂在脓毒症肝损伤的发病机制中起重要作用。针对脓毒症期间肝细胞铁下垂的激活,通过DFO干预可能是一种很有前途的治疗策略。
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引用次数: 0
Specific human antibodies against SARS-CoV-2 and monkeypox virus generated via a rapid construction and screening system 通过快速构建和筛选系统生成针对SARS-CoV-2和猴痘病毒的特异性人抗体
IF 2.3 4区 医学 Q3 IMMUNOLOGY Pub Date : 2025-10-02 DOI: 10.1016/j.imbio.2025.153124
Guanglei Gu , Jinhai Wang , Xiaoyun Hu , Xiuling Gu , Shirui Li , Hanle Li , Min Fang
Monoclonal antibodies are playing an increasingly important role in modern medicine. Human monoclonal antibodies have become a key focus in the development of monoclonal antibody therapeutics due to their safety. We developed an integrated platform that rapidly constructs and screens human antibodies by combining recombinant antigen production, fluorescent antigen tetramers, memory B-cell sorting, single-cell gene amplification, and single-chain antibody expression for rapid screening of antibody specificity. Using peripheral blood mononuclear cells from healthy donors, we successfully generated human monoclonal antibodies targeting the N and S1 proteins of SARS-CoV-2. Furthermore, we applied the platform to produce protective human antibodies against the M1R protein of the monkeypox virus (MPXV). These results demonstrate that our system enables the rapid and efficient discovery of specific monoclonal antibodies, offering broad applicability for combating emerging infectious diseases and advancing cancer immunotherapies.
单克隆抗体在现代医学中发挥着越来越重要的作用。人单克隆抗体由于其安全性已成为单克隆抗体治疗发展的一个重点。我们开发了一个综合平台,通过重组抗原生产、荧光抗原四聚体、记忆b细胞分选、单细胞基因扩增和单链抗体表达,快速构建和筛选人抗体,快速筛选抗体特异性。利用健康供者外周血单个核细胞,成功制备了针对SARS-CoV-2 N和S1蛋白的人单克隆抗体。此外,我们利用该平台制备了猴痘病毒(MPXV) M1R蛋白的保护性人抗体。这些结果表明,我们的系统能够快速有效地发现特异性单克隆抗体,为对抗新出现的传染病和推进癌症免疫治疗提供广泛的适用性。
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引用次数: 0
A novel approach to poliovirus vaccine neurovirulence testing: development of an enhanced 4-level scoring system 脊髓灰质炎疫苗神经毒力检测的新方法:增强型4级评分系统的发展。
IF 2.3 4区 医学 Q3 IMMUNOLOGY Pub Date : 2025-09-29 DOI: 10.1016/j.imbio.2025.153121
Xi Wang , Yunguang Hu , Anguo Yin , Changxu Chen , Hong Xiang , Li Wang , Bochuan Liu , Yuan Tian , Yu Gao , Mingrun Zhang , Yan Li , Yina Cun , Jian Zhou
The ongoing promotion and administration of vaccines play a critical role in the global effort to eradicate poliovirus. The Monkey Neurovirulence Test (MNVT) is an essential method for evaluating the neurovirulence of viruses in both the Oral Attenuated Live Poliovirus Vaccine (OPV) and the Sabin Inactivated Poliovirus Vaccine (sIPV) to ensure they meet required safety standards. The “4-level scoring method” recommended by the World Health Organization (WHO) has served as a key pathological evaluation criterion in this test. However, its lack of scoring granularity often leads to subjective interpretation discrepancies among evaluators, which compromises the consistency and reliability of the MNVT results. To address these limitations, we have mapped the primary neuronal nuclei in monkey tissue sections and analyzed viral-induced damage distribution. As a result, we developed an Enhanced 4-Level Scoring System (integrating precise anatomical mapping and quantitative lesion analysis), which minimizes evaluator bias and significantly improves scoring stability and consistency.
正在进行的疫苗推广和接种工作在全球根除脊髓灰质炎病毒的努力中发挥着关键作用。猴神经毒力试验(MNVT)是评估口服脊髓灰质炎减毒活疫苗(OPV)和沙宾灭活脊髓灰质炎疫苗(sIPV)中病毒神经毒力的重要方法,以确保它们符合规定的安全标准。世界卫生组织(WHO)推荐的“4级评分法”作为本试验的主要病理评价标准。然而,它缺乏评分粒度,常常导致评估者之间的主观解释差异,从而损害了MNVT结果的一致性和可靠性。为了解决这些局限性,我们绘制了猴组织切片的初级神经元核,并分析了病毒诱导的损伤分布。因此,我们开发了一个增强的4级评分系统(整合精确的解剖制图和定量的病变分析),它最大限度地减少了评估者的偏见,并显著提高了评分的稳定性和一致性。
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引用次数: 0
sgp130Fc alleviates cartilage degeneration and knee osteoarthritis by inhibiting IL-6 trans-signaling pathway sgp130Fc通过抑制IL-6反式信号通路缓解软骨退变和膝关节骨关节炎。
IF 2.3 4区 医学 Q3 IMMUNOLOGY Pub Date : 2025-09-22 DOI: 10.1016/j.imbio.2025.153122
Chunrong He , Lingjie Tan , Chi Liang , Jiewen Luo , Ke Xiao , Song Wu , Jinshen He

Background

Interleukin-6 (IL-6) trans-signaling plays a pivotal role in the pathogenesis and progression of osteoarthritis (OA), contributing to chronic intra-articular inflammation and cartilage degradation. Soluble gp130-Fc (sgp130Fc) is a selective inhibitor of IL-6 trans-signaling that spares classical signaling. This study aimed to elucidate the role of IL-6 trans-signaling in knee OA and evaluate the therapeutic potential of sgp130Fc.

Methods

Synovial fluid from OA patients at different disease stages was analyzed for IL-6, soluble IL-6 receptor (sIL-6R), and sgp130 levels by ELISA. Primary rat chondrocytes were treated with Hyper-IL-6 to activate IL-6 trans-signaling and co-treated with sgp130Fc to assess cell viability, gene expression, and lipid metabolism alterations. A rat OA model was established via the Hulth method, followed by intra-articular administration of sgp130Fc. Histological, immunohistochemical, and lipidomic analyses were performed to evaluate cartilage integrity and inflammatory responses.

Results

Levels of IL-6, sIL-6R, and sgp130 in synovial fluid increased with OA progression. Hyper-IL-6 impaired chondrocyte viability, activated JAK1-STAT3 signaling, promoted inflammatory and catabolic gene expression, and disrupted lipid metabolism, all of which were reversed by sgp130Fc treatment. In vivo, sgp130Fc injections alleviated cartilage degradation, reduced synovitis, suppressed inflammatory mediators, and restored lipid homeostasis.

Conclusions

Targeted inhibition of IL-6 trans-signaling with sgp130Fc effectively mitigates cartilage degeneration and inflammation in OA, highlighting its potential as a novel disease-modifying therapeutic strategy for knee osteoarthritis.
背景:白细胞介素-6 (IL-6)反式信号在骨关节炎(OA)的发病和进展中起关键作用,导致慢性关节内炎症和软骨降解。可溶性gp130-Fc (sgp130Fc)是IL-6反式信号传导的选择性抑制剂,可避免经典信号传导。本研究旨在阐明IL-6反式信号在膝关节OA中的作用,并评估sgp130Fc的治疗潜力。方法:采用酶联免疫吸附法(ELISA)分析不同病程OA患者滑液中IL-6、可溶性IL-6受体(sIL-6R)和sgp130水平。用Hyper-IL-6处理原代大鼠软骨细胞以激活IL-6反式信号,并与sgp130Fc共处理以评估细胞活力、基因表达和脂质代谢改变。采用Hulth法建立大鼠骨性关节炎模型,然后关节内给药sgp130Fc。进行组织学、免疫组织化学和脂质组学分析以评估软骨完整性和炎症反应。结果:滑液中IL-6、sIL-6R和sgp130的水平随着OA的进展而升高。Hyper-IL-6损伤软骨细胞活力,激活JAK1-STAT3信号,促进炎症和分解代谢基因表达,破坏脂质代谢,所有这些都被sgp130Fc治疗逆转。在体内,注射sgp130Fc可缓解软骨退化,减轻滑膜炎,抑制炎症介质,恢复脂质稳态。结论:sgp130Fc靶向抑制IL-6反式信号传导可有效减轻OA患者的软骨退变和炎症,突显其作为膝关节骨关节炎一种新的疾病改善治疗策略的潜力。
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引用次数: 0
Changpu Yujin Tang mitigates tourette syndrome by enhancing mitophagy and suppressing NLRP3 inflammasome-mediated pyroptosis 长骨育金汤通过增强线粒体自噬和抑制NLRP3炎症小体介导的焦亡来减轻图雷特综合征
IF 2.3 4区 医学 Q3 IMMUNOLOGY Pub Date : 2025-09-22 DOI: 10.1016/j.imbio.2025.153118
Shuang Huang , Liwei Huang , Mengxue Li , Mingyang Sun , Kexin Sun , Xing Wei , Bing Jiang , Yuezhen He , Fuchun Xue , Lv Gao , Manqi Lu , Jing Shang , Zhenggang Shi

Background

Changpu Yujin Tang (CPYJT) is an effective Chinese herbal compound for treating Tourette syndrome (TS). However, its precise molecular mechanisms remain to be fully elucidated.

Methods

105 SD rats were randomly divided into the Control (n = 15) and the TS (n = 90) groups. The TS group was induced by intraperitoneal injection of 3,3′-iminodipropionitrile. After successful modeling, the TS group was further divided into 6 subgroups (n = 15 in each group): the Model group, the Tiapride group, the CPYJT group, the Rapamycin (RAPA) group, the 3-methyladenine (3-MA) group, and the CPYJT +3-MA group, and were treated with the corresponding drugs for 4 weeks.

Results

Compared with the Control group, rats in the Model group showed increased stereotyped and motor behaviors, damage to striatal neuronal cells and mitochondrial ultrastructure, decreased PINK1/Parkin-mediated mitophagy, and activation of NLRP3 inflammasome. CPYJT reduced stereotyped and motor behaviors, attenuated neuronal cell damage, and repaired mitochondrial pathology in the TS rats. Furthermore, both CPYJT and RAPA enhanced PINK1/Parkin-mediated mitophagy, eliminated ROS accumulation, and inhibited NLRP3 inflammasome activation. Notably, CPYJT counteracted 3-MA's inhibitory effect on PINK1/Parkin-mediated mitophagy, thereby suppressing NLRP3 inflammasome activation and pyroptosis.

Conclusion

CPYJT inhibits NLRP3 inflammasome activation and reduces pyroptosis by enhancing PINK1/Parkin-mediated mitophagy and attenuating ROS accumulation, which in turn ameliorates TS.
长朴育金汤是治疗抽动秽语综合征(TS)的有效中药复方。然而,其精确的分子机制仍有待充分阐明。方法105只SD大鼠随机分为对照组(n = 15)和TS组(n = 90)。TS组采用3,3′-亚氨基二丙腈腹腔注射诱导。造模成功后,将TS组进一步分为模型组、噻必利组、CPYJT组、雷帕霉素(RAPA)组、3-甲基腺嘌呤(3-MA)组、CPYJT +3-MA组6个亚组(每组n = 15),分别给予相应药物治疗4周。结果与对照组相比,模型组大鼠的刻板行为和运动行为增加,纹状体神经元细胞和线粒体超微结构受损,PINK1/ parkin介导的线粒体自噬减少,NLRP3炎症小体活化。CPYJT减少了TS大鼠的刻板和运动行为,减轻了神经元细胞损伤,并修复了线粒体病理。此外,CPYJT和RAPA均能增强PINK1/ parkinson介导的有丝分裂,消除ROS积累,抑制NLRP3炎性体活化。值得注意的是,CPYJT抵消了3-MA对PINK1/ parkin介导的有丝分裂的抑制作用,从而抑制NLRP3炎性体的激活和热凋亡。结论cpyjt通过增强PINK1/ parkin介导的线粒体自噬和减少ROS积累,抑制NLRP3炎性小体活化,减少焦亡,从而改善TS。
{"title":"Changpu Yujin Tang mitigates tourette syndrome by enhancing mitophagy and suppressing NLRP3 inflammasome-mediated pyroptosis","authors":"Shuang Huang ,&nbsp;Liwei Huang ,&nbsp;Mengxue Li ,&nbsp;Mingyang Sun ,&nbsp;Kexin Sun ,&nbsp;Xing Wei ,&nbsp;Bing Jiang ,&nbsp;Yuezhen He ,&nbsp;Fuchun Xue ,&nbsp;Lv Gao ,&nbsp;Manqi Lu ,&nbsp;Jing Shang ,&nbsp;Zhenggang Shi","doi":"10.1016/j.imbio.2025.153118","DOIUrl":"10.1016/j.imbio.2025.153118","url":null,"abstract":"<div><h3>Background</h3><div>Changpu Yujin Tang (CPYJT) is an effective Chinese herbal compound for treating Tourette syndrome (TS). However, its precise molecular mechanisms remain to be fully elucidated.</div></div><div><h3>Methods</h3><div>105 SD rats were randomly divided into the Control (<em>n</em> = 15) and the TS (<em>n</em> = 90) groups. The TS group was induced by intraperitoneal injection of 3,3′-iminodipropionitrile. After successful modeling, the TS group was further divided into 6 subgroups (<em>n</em> = 15 in each group): the Model group, the Tiapride group, the CPYJT group, the Rapamycin (RAPA) group, the 3-methyladenine (3-MA) group, and the CPYJT +3-MA group, and were treated with the corresponding drugs for 4 weeks.</div></div><div><h3>Results</h3><div>Compared with the Control group, rats in the Model group showed increased stereotyped and motor behaviors, damage to striatal neuronal cells and mitochondrial ultrastructure, decreased PINK1/Parkin-mediated mitophagy, and activation of NLRP3 inflammasome. CPYJT reduced stereotyped and motor behaviors, attenuated neuronal cell damage, and repaired mitochondrial pathology in the TS rats. Furthermore, both CPYJT and RAPA enhanced PINK1/Parkin-mediated mitophagy, eliminated ROS accumulation, and inhibited NLRP3 inflammasome activation. Notably, CPYJT counteracted 3-MA's inhibitory effect on PINK1/Parkin-mediated mitophagy, thereby suppressing NLRP3 inflammasome activation and pyroptosis.</div></div><div><h3>Conclusion</h3><div>CPYJT inhibits NLRP3 inflammasome activation and reduces pyroptosis by enhancing PINK1/Parkin-mediated mitophagy and attenuating ROS accumulation, which in turn ameliorates TS.</div></div>","PeriodicalId":13270,"journal":{"name":"Immunobiology","volume":"230 6","pages":"Article 153118"},"PeriodicalIF":2.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145155629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Serum exosome smallRNA array analysis identifies 5’tiRNA-PheGAA and tRF-1-IleAAT as potential biomarkers for diagnosis of rheumatoid arthritis 血清外泌体smallRNA阵列分析发现5'tiRNA-PheGAA和tRF-1-IleAAT是诊断类风湿关节炎的潜在生物标志物
IF 2.3 4区 医学 Q3 IMMUNOLOGY Pub Date : 2025-09-20 DOI: 10.1016/j.imbio.2025.153123
Yuanyuan Li , Meiling Xu , Nan Zhao , Chong Qi , Tingshuang Xu
tRNA-derived small RNAs (tsRNAs) are a recently identified class of non-coding RNAs (ncRNAs) that exhibit aberrant expression in various diseases and are involved in multiple pathological processes. In this study, we isolated exosomes from the serum of patients with rheumatoid arthritis (RA) and healthy individuals, and extracted total RNA for analysis using small RNA microarrays and tsRNA sequencing. We identified 866 tsRNAs that were differentially expressed between RA patients and healthy controls, with 146 upregulated and 720 downregulated. Among the upregulated tsRNAs, the five with the most significant increases were selected for further validation. qRT-PCR analysis confirmed that 5’tiRNA-PheGAA and tRF-1-IleAAT were significantly upregulated in RA patients. Pathway enrichment analysis suggested that these two tsRNAs are involved in tryptophan metabolism, autophagy, chemokine signaling, Rap1 signaling, and focal adhesion pathways. ROC curve analysis indicated that both tsRNAs exhibit strong diagnostic potential for RA. Collectively, our findings demonstrate that serum exosomal tsRNAs may serve as promising biomarkers for the effective diagnosis and prognosis of rheumatoid arthritis.
trna衍生的小rna (tsrna)是最近发现的一类非编码rna (ncRNAs),它们在多种疾病中表现出异常表达,并参与多种病理过程。在这项研究中,我们从类风湿关节炎(RA)患者和健康个体的血清中分离出外泌体,并提取总RNA用于小RNA微阵列和tsRNA测序分析。我们确定了866个tsRNAs在RA患者和健康对照组之间差异表达,其中146个上调,720个下调。在上调的tsRNAs中,选择5个增加最显著的tsRNAs进行进一步验证。qRT-PCR分析证实,5'tiRNA-PheGAA和tRF-1-IleAAT在RA患者中显著上调。途径富集分析表明,这两种tsrna参与了色氨酸代谢、自噬、趋化因子信号、Rap1信号和局灶黏附途径。ROC曲线分析显示,这两种tsrna对RA具有很强的诊断潜力。总之,我们的研究结果表明,血清外泌体tsRNAs可能作为类风湿性关节炎有效诊断和预后的有希望的生物标志物。
{"title":"Serum exosome smallRNA array analysis identifies 5’tiRNA-PheGAA and tRF-1-IleAAT as potential biomarkers for diagnosis of rheumatoid arthritis","authors":"Yuanyuan Li ,&nbsp;Meiling Xu ,&nbsp;Nan Zhao ,&nbsp;Chong Qi ,&nbsp;Tingshuang Xu","doi":"10.1016/j.imbio.2025.153123","DOIUrl":"10.1016/j.imbio.2025.153123","url":null,"abstract":"<div><div>tRNA-derived small RNAs (tsRNAs) are a recently identified class of non-coding RNAs (ncRNAs) that exhibit aberrant expression in various diseases and are involved in multiple pathological processes. In this study, we isolated exosomes from the serum of patients with rheumatoid arthritis (RA) and healthy individuals, and extracted total RNA for analysis using small RNA microarrays and tsRNA sequencing. We identified 866 tsRNAs that were differentially expressed between RA patients and healthy controls, with 146 upregulated and 720 downregulated. Among the upregulated tsRNAs, the five with the most significant increases were selected for further validation. qRT-PCR analysis confirmed that 5’tiRNA-PheGAA and tRF-1-IleAAT were significantly upregulated in RA patients. Pathway enrichment analysis suggested that these two tsRNAs are involved in tryptophan metabolism, autophagy, chemokine signaling, Rap1 signaling, and focal adhesion pathways. ROC curve analysis indicated that both tsRNAs exhibit strong diagnostic potential for RA. Collectively, our findings demonstrate that serum exosomal tsRNAs may serve as promising biomarkers for the effective diagnosis and prognosis of rheumatoid arthritis.</div></div>","PeriodicalId":13270,"journal":{"name":"Immunobiology","volume":"230 6","pages":"Article 153123"},"PeriodicalIF":2.3,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145155630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
ATP–NLRP3 inflammasome axis enhances the immunosuppressive effect of myeloid-derived suppressor cells ATP-NLRP3炎性小体轴增强髓源性抑制细胞的免疫抑制作用
IF 2.3 4区 医学 Q3 IMMUNOLOGY Pub Date : 2025-09-17 DOI: 10.1016/j.imbio.2025.153119
Tatsuya Ando , Kouhei Sakurai , Masato Hoshi , Hiroyuki Tezuka , Yasuhiro Sakai , Taku Kato , Hiroyasu Ito
The effectiveness of immune checkpoint inhibitors is diminished by the presence of myeloid-derived suppressor cells (MDSCs). Recent studies indicate that the NLR family pyrin domain-containing 3 (NLRP3) inflammasome regulates MDSC function, thereby reducing the efficacy of immune checkpoint inhibitors. However, the specific mechanism by which NLRP3 expression induces the immunosuppressive effects in MDSCs remains unclear. Here, we demonstrate that the adenosine triphosphate (ATP)–NLRP3 inflammasome axis enhances the immunosuppressive effects of MDSCs. We found that ATP increases the mRNA levels of immunosuppressive molecules in MDSCs, leading to the suppression of T cell proliferation. Additionally, we showed the efficacy of a novel immune checkpoint therapy that combines an ATP receptor inhibitor (P2X7 receptor inhibitor), an NLRP3 inhibitor, and an anti-PD-L1 antibody (Ab). This combination treatment significantly inhibited tumor growth compared to treatment with only the NLRP3 inhibitor and anti-PD-L1 Ab. These results suggest that the ATP–NLRP3 axis enhances the immunosuppressive effect of MDSCs. In conclusion, this study elucidates the mechanism through which MDSCs acquire immunosuppressive functions, potentially informing the development of novel cancer immunotherapies.
免疫检查点抑制剂的有效性因髓源性抑制细胞(MDSCs)的存在而降低。最近的研究表明,NLR家族pyrin domain-containing 3 (NLRP3)炎性小体调节MDSC功能,从而降低免疫检查点抑制剂的疗效。然而,NLRP3表达在MDSCs中诱导免疫抑制作用的具体机制尚不清楚。在这里,我们证明了三磷酸腺苷(ATP) -NLRP3炎症小体轴增强了MDSCs的免疫抑制作用。我们发现ATP增加了MDSCs中免疫抑制分子的mRNA水平,导致T细胞增殖受到抑制。此外,我们还展示了一种新型免疫检查点疗法的疗效,该疗法结合了ATP受体抑制剂(P2X7受体抑制剂)、NLRP3抑制剂和抗pd - l1抗体(Ab)。与仅使用NLRP3抑制剂和抗pd - l1抗体相比,这种联合治疗明显抑制肿瘤生长。这些结果表明,ATP-NLRP3轴增强了MDSCs的免疫抑制作用。总之,本研究阐明了MDSCs获得免疫抑制功能的机制,可能为开发新的癌症免疫疗法提供信息。
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引用次数: 0
Role and mechanism of METTL3 in fibrosis-associated signaling in CVB3-infected H9c2 cardiomyocytes through the lncRNA MEG3/c-MYC/SMAD2 axis METTL3通过lncRNA MEG3/c-MYC/SMAD2轴在cvb3感染的H9c2心肌细胞纤维化相关信号传导中的作用和机制
IF 2.3 4区 医学 Q3 IMMUNOLOGY Pub Date : 2025-09-15 DOI: 10.1016/j.imbio.2025.153117
Lu Huang , Li Wang , Jiaojiao Guo, Shiqian Lu, Qian Zhang, Taiming Liu
Viral myocarditis (VMC) is an inflammatory disease of the heart muscle caused by viral infection and may lead to myocardial fibrosis. This study aims to investigate the role of METTL3 in myocardial fibrosis in VMC. METTL3 expression was intervened with in VMC cell models, followed by measurement of LDH, CK-MB, and TGF-β1. The expression of METTL3, lncRNA MEG3, c-MYC, SMAD2, Collagen I, Collagen III, and α-SMA was detected by RT-qPCR and Western blot. α-SMA expression was observed by immunofluorescence. MeRIP-qPCR was used to detect m6A levels of MEG3. RNA stability experiments were conducted to determine the residual level of MEG3. The bindings of lncRNA MEG3 to c-MYC and c-MYC to the SMAD2 promoter were analyzed. Results showed that METTL3, c-MYC, and SMAD2 were highly expressed in VMC cell models. METTL3 inhibition increased cell viability and reduced LDH, CK-MB, TGF-β1, Collagen I, Collagen III, and α-SMA. METTL3-mediated m6A modification promoted MEG3 expression, and MEG3 bound to c-MYC and enhanced SMAD2 expression. Overexpression of MEG3 or SMAD2 partially reversed the inhibitory effect of METTL3 on fibrotic-like changes of myocardial cells. In conclusion, METTL3 promotes fibrotic-like changes of myocardial cells in VMC cell models through the lncRNA MEG3/c-MYC/SMAD2 axis via m6A modification.
病毒性心肌炎(VMC)是一种由病毒感染引起的心肌炎症性疾病,可导致心肌纤维化。本研究旨在探讨METTL3在VMC心肌纤维化中的作用。在VMC细胞模型中干预METTL3的表达,随后测量LDH、CK-MB和TGF-β1。RT-qPCR和Western blot检测METTL3、lncRNA、MEG3、c-MYC、SMAD2、Collagen I、Collagen III、α-SMA的表达。免疫荧光法观察α-SMA的表达。采用MeRIP-qPCR检测MEG3的m6A水平。通过RNA稳定性实验确定MEG3的残留水平。分析了lncRNA MEG3与c-MYC和c-MYC与SMAD2启动子的结合。结果显示,METTL3、c-MYC和SMAD2在VMC细胞模型中高表达。METTL3抑制提高了细胞活力,降低了LDH、CK-MB、TGF-β1、胶原I、胶原III和α-SMA。mettl3介导的m6A修饰促进了MEG3的表达,并且MEG3与c-MYC结合并增强了SMAD2的表达。MEG3或SMAD2的过表达部分逆转了METTL3对心肌细胞纤维化样变化的抑制作用。综上所述,METTL3通过m6A修饰lncRNA MEG3/c-MYC/SMAD2轴,促进VMC细胞模型心肌细胞的纤维化样变化。
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引用次数: 0
TRIM59 alleviates acute respiratory distress syndrome by regulating inflammatory cytokines through RING domain TRIM59通过RING结构域调节炎症因子,缓解急性呼吸窘迫综合征
IF 2.3 4区 医学 Q3 IMMUNOLOGY Pub Date : 2025-09-13 DOI: 10.1016/j.imbio.2025.153116
Zheng Jin , Xiaopeng Jing , Ji Zeng , Zhenhua Zhu
Acute respiratory distress syndrome (ARDS) is characterized by significant morbidity and mortality. Particularly since the outbreak of COVID-19, the incidence and complexity of ARDS have been further highlighted. The etiology and pathogenesis of ARDS are multifactorial, involving complex interactions among genetic, environmental, and host factors. Further exploration of these factors is essential to enhance our understanding of ARDS and to develop more effective therapeutic strategies. Alveolar macrophages (AMs) are the first line of defense of innate immunity and are key to regulate the immune system, and are closely related to cytokine storm in ARDS. Therefore, macrophages are an important part to alleviate ARDS. TRIM59 is a molecule expressed on macrophages. Our previous studies have shown that TRIM59 was capable of modulating macrophage function. However, the role of TRIM59 in the pathogenesis and progression of ARDS remains to be elucidated. In this study, we established an animal model of ARDS using mice in which TRIM59 was specifically knocked out in bone marrow-derived macrophages (BMDMs). Our results confirmed that TRIM59 exerted a protective effect against ARDS in vivo via its regulation on macrophages. Mechanistic investigations revealed that TRIM59 inhibited the activation of the nuclear factor-κB (NF-κB) signaling pathway through its RING domain. In summary, the present findings indicate that TRIM59 may serve as a crucial regulatory molecule in the ARDS, potentially offering a novel therapeutic target for its alleviation.
急性呼吸窘迫综合征(ARDS)具有显著的发病率和死亡率。特别是自2019冠状病毒病暴发以来,ARDS的发病率和复杂性进一步凸显。ARDS的病因和发病机制是多因素的,涉及遗传、环境和宿主因素之间复杂的相互作用。进一步探索这些因素对于提高我们对ARDS的认识和制定更有效的治疗策略至关重要。肺泡巨噬细胞(Alveolar macrophages, AMs)是先天免疫的第一道防线,是调节免疫系统的关键,与ARDS的细胞因子风暴密切相关。因此,巨噬细胞是缓解ARDS的重要组成部分。TRIM59是巨噬细胞上表达的一种分子。我们之前的研究表明TRIM59能够调节巨噬细胞的功能。然而,TRIM59在ARDS发病和进展中的作用仍有待阐明。在本研究中,我们利用骨髓源性巨噬细胞(bmdm)特异性敲除TRIM59的小鼠建立了ARDS动物模型。我们的研究结果证实TRIM59通过调节巨噬细胞在体内对ARDS具有保护作用。机制研究表明,TRIM59通过其RING结构域抑制核因子-κB (NF-κB)信号通路的激活。综上所述,目前的研究结果表明TRIM59可能是ARDS的关键调控分子,可能为缓解其提供新的治疗靶点。
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引用次数: 0
Pan-cancer analysis of GINS1 identifies its prognostic and immunotherapy predictive value with in vitro experimental validation in nasopharyngeal carcinoma 泛癌分析证实GINS1在鼻咽癌中的预后和免疫治疗预测价值,并进行了体外实验验证
IF 2.3 4区 医学 Q3 IMMUNOLOGY Pub Date : 2025-09-11 DOI: 10.1016/j.imbio.2025.153114
Yang Xu , Qingqing Zhang , Wanting Qin , Zhiyu Yan , Shuhan Ma , Yuanyuan Chang , Kaihua Chen , Ling Li , Xiaodong Zhu

Background

GINS complex subunit 1 (GINS1) is part of the tetrameric GINS complex involved in DNA replication, playing a vital role in controlling the start and continuation of DNA replication. Its role in cancer, however, is not well understood. Still, its relevance to cancer is uncertain. This study focused on exploring the role of GINS1 in different forms of cancer.

Methods

Using a range of publicly available databases, we conducted a comprehensive study on the oncogenic function of GINS1 in pan-cancer through analyses of differential expression, survival, enrichment, gene mutations and tumor immune cell infiltration. Additionally, the expression and effects of GINS1 in nasopharyngeal carcinoma (NPC) were analyzed through a series of in vitro experiments.

Results

GINS1 was found to be overexpressed in nearly all tumors, demonstrating notable diagnostic and prognostic potential. Moreover, the relationship between GINS1 and specific immune characteristics (such as immune cell infiltration, immune checkpoint genes, tumor mutational burden, and microsatellite instability) suggests its potential role in guiding immunotherapy approaches. In vitro studies show that GINS1 notably enhances proliferation, migration, and invasion of NPC cells, with elevated expression levels correlating with a poorer prognosis.

Conclusions

GINS1 might serve as a prognostic and immunotherapy marker for different types of cancers, such as nasopharyngeal carcinoma.
GINS1复合物亚基1 (GINS1)是参与DNA复制的四聚体GINS复合物的一部分,在控制DNA复制的开始和继续方面起着至关重要的作用。然而,它在癌症中的作用尚不清楚。然而,它与癌症的关系尚不确定。本研究的重点是探索GINS1在不同形式癌症中的作用。方法利用一系列公开的数据库,通过分析GINS1在泛癌中的差异表达、存活、富集、基因突变和肿瘤免疫细胞浸润等方面,全面研究GINS1在泛癌中的致癌功能。此外,通过一系列体外实验分析GINS1在鼻咽癌(NPC)中的表达及其作用。结果gins1在几乎所有肿瘤中均过表达,显示出显著的诊断和预后潜力。此外,GINS1与特异性免疫特性(如免疫细胞浸润、免疫检查点基因、肿瘤突变负担和微卫星不稳定性)之间的关系提示其在指导免疫治疗方法方面的潜在作用。体外研究表明,GINS1显著增强鼻咽癌细胞的增殖、迁移和侵袭,表达水平升高与预后较差相关。结论sgins1可作为鼻咽癌等不同类型肿瘤的预后和免疫治疗标志物。
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Immunobiology
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