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IF 6.4 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Translational Research

Pub Date : 2025-03-10 DOI: 10.1016/S1931-5244(25)00031-3

引用次数: 0

Information for Readers 读者资讯

IF 6.4 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Translational Research

Pub Date : 2025-03-10 DOI: 10.1016/S1931-5244(25)00032-5

引用次数: 0

Editorial Advisory Board 编辑顾问委员会

IF 6.4 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Translational Research

Pub Date : 2025-03-10 DOI: 10.1016/S1931-5244(25)00030-1

引用次数: 0

Caspase-12 exhibits non-redundant functions in response to endoplasmic reticulum stress to promote GSDMD-mediated NETosis, leading to thoracic aortic dissection Caspase-12在内质网应激反应中表现出非冗余功能，促进gsdmd介导的NETosis，导致胸主动脉夹层。

IF 6.4 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Translational Research

Pub Date : 2025-02-25 DOI: 10.1016/j.trsl.2025.02.005

Hanchuan Chen , Kun Yang , Shumin Zhang , Gulinazi Yesitayi , Yunzhi Ling , Rifeng Gao , Yang Lyu , Wei Wei , Jiaran Shi , Yulin Li , Xiang Ma , Pingjin Gao , Junbo Ge , Aijun Sun

Background

Thoracic aortic dissection (TAD) is a highly lethal condition that is characterized by inflammatory cell infiltration. Recent evidence has indicated that Gasdermin D (GSDMD) plays an important role in vascular inflammation and degeneration. However, its effects on neutrophil extracellular trap formation and release (NETosis) during TAD remain unknown.

Methods

A TAD mouse model was generated using four-week-old male neutrophil-specific GSDMD-knockout mice (GSDMD^F/F; Elane^Cre) and dimethyl fumarate (DMF)-treated C57BL/6J mice by administering β-aminopropionitrile monofumarate (BAPN; 1 g/kg/day) in their drinking water for 4 weeks. Immunoprecipitation and immunofluorescence assays were performed to examine the role of the endoplasmic reticulum (ER) and its associated protein, caspase-12, in GSDMD-induced NETosis.

Results

GSDMD was elevated and co-localized primarily in neutrophils in the aortic tissues of patients with TAD and mice with BAPN-induced TAD. This was accompanied by increased NETosis. Neutrophil-specific GSDMD knockout and the NETosis inhibitor, GSK484, mitigated TAD development in mice. However, GSK484 did not provide additional therapeutic effects against TAD in the neutrophil-specific, GSDMD knockout mice. Mechanistically, ER stress promoted GSDMD cleavage by caspase-4/11, thereby inducing NETosis. Furthermore, caspase-12 exhibited non-redundant functions in the cleavage of GSDMD by caspase-4/11. The GSDMD inhibitor, DMF, partially prevented TAD development.

Conclusions

The ER stress/GSDMD/NETosis signaling pathway provides a potential therapeutic target for the prevention and treatment of TAD.

背景：胸主动脉夹层（TAD）是一种以炎症细胞浸润为特征的高致死率疾病。最近的证据表明，GSDMD在血管炎症和变性中起重要作用。然而，其对TAD期间中性粒细胞胞外陷阱形成和释放（NETosis）的影响尚不清楚。方法：采用4周龄雄性中性粒细胞特异性gsdmd敲除小鼠(GSDMDF/F；ElaneCre)和富马酸二甲酯（DMF）治疗C57BL/6J小鼠的方法是给药β-氨基丙腈单马酸酯(BAPN；1 g/kg/天)，持续4周。采用免疫沉淀法和免疫荧光法检测内质网（ER）及其相关蛋白caspase-12在gsdmd诱导的NETosis中的作用。结果：GSDMD在TAD患者和bapn诱导的TAD小鼠主动脉组织的中性粒细胞中升高并共定位。这伴随着NETosis的增加。中性粒细胞特异性GSDMD敲除和NETosis抑制剂GSK484可减轻小鼠TAD的发展。然而，GSK484对中性粒细胞特异性GSDMD敲除小鼠的TAD没有提供额外的治疗作用。机制上，内质网应激通过caspase-4/11促进GSDMD裂解，从而诱导NETosis。此外，caspase-12在caspase-4/11对GSDMD的切割中表现出非冗余功能。GSDMD抑制剂DMF部分阻止了TAD的发展。结论：内质网应激/GSDMD/NETosis信号通路为TAD的预防和治疗提供了潜在的治疗靶点。

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引用次数: 0

Effects of senotherapeutics on gut microbiome dysbiosis and intestinal inflammation in Crohn's disease: A pilot study 老年治疗药物对克罗恩病肠道菌群失调和肠道炎症的影响：一项初步研究

IF 6.4 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Translational Research

Pub Date : 2025-02-20 DOI: 10.1016/j.trsl.2025.02.004

Nannapat Sangfuang , Laura E. McCoubrey , Atheer Awad , Massimo Marzorati , Jonas Ghyselinck , Lynn Verstrepen , Julie De Munck , Jelle De Medts , Simon Gaisford , Abdul W. Basit

Inflammatory Bowel Disease (IBD) is characterized by chronic inflammation in the gastrointestinal tract, and is usually accompanied by dysbiosis in the gut microbiome, a factor that contributes to disease progression. Excessive production of reactive oxygen species (ROS) because of gut microbiome dysbiosis—one of the hallmark features of IBD—promotes chronic inflammation and facilitates the transformation of normal cells into senescent cells. Cellular senescence is associated with the development of various chronic and age-related diseases. We hypothesise that senolytic agents, specifically dasatinib (D) and quercetin (Q), could have a beneficial effect on both the gut microbiome and intestinal cells in IBD. The modulatory effects of a combination of D + Q was assessed in the M-SHIME model with faecal microbiota sourced from Crohn's disease patients. D + Q significantly modulated butyrate and lactate levels in the samples from specific patients. In addition, metabolomic analysis showed that D + Q positively impacted the abundance of anti-inflammatory bacteria while also significantly reducing the several species of pathogenic bacteria. Findings from a Caco-2 cell/THP1 co-culture model of IBD demonstrated that D + Q exerted strong immunomodulatory effects on the gut epithelium, evidenced by reduced NF-kB activity, and lower levels of the pro-inflammatory markers TNF-α, CXCL-10, and MCP-1. Furthermore, D + Q induced the secretion of anti-inflammatory cytokines, including IL-6 and IL-10. However, it should be noted that D + Q also led to the secretion of the pro-inflammatory cytokines IL-8. These findings suggest that D + Q could offer a novel therapeutic approach for advanced IBD management by modulating both the gut microbiome and inflammatory pathways. The results support the potential repurposing of senotherapeutic agents as a strategy for addressing the chronic inflammation central to IBD pathogenesis

炎症性肠病（IBD）以胃肠道慢性炎症为特征，通常伴有肠道微生物群的生态失调，这是导致疾病进展的一个因素。肠道微生物群失调导致活性氧（ROS）的过量产生——ibd的标志性特征之一——会促进慢性炎症，并促进正常细胞向衰老细胞的转化。细胞衰老与各种慢性和年龄相关疾病的发展有关。我们假设，抗衰老药物，特别是达沙替尼(D)和槲皮素(Q)，可能对IBD的肠道微生物群和肠道细胞都有有益的影响。在M-SHIME模型中评估D + Q组合的调节作用，该模型使用来自克罗恩病患者的粪便微生物群。D + Q可显著调节特定患者样品中的丁酸盐和乳酸水平。此外，代谢组学分析显示，D + Q正影响抗炎细菌的丰度，同时也显著减少了几种致病菌。来自IBD Caco-2细胞/THP1共培养模型的研究结果表明，D + Q对肠道上皮具有很强的免疫调节作用，其证据是NF-kB活性降低，促炎标志物TNF-α、CXCL-10和MCP-1水平降低。此外，D + Q诱导抗炎细胞因子IL-6和IL-10的分泌。但需要注意的是，D + Q也导致促炎细胞因子IL-8的分泌。这些发现表明，D + Q可以通过调节肠道微生物群和炎症途径，为晚期IBD治疗提供一种新的治疗方法。这些结果支持将老年治疗药物作为解决IBD发病机制中心慢性炎症的一种策略

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引用次数: 0

Tailored CD4+ lymphocytes expressing human CHAT protein as a novel vasodilator in attenuating RV pressure in PAH animal model 表达人CHAT蛋白的定制CD4+淋巴细胞作为一种新型血管扩张剂在PAH动物模型中减弱RV压力。

IF 6.4 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Translational Research

Pub Date : 2025-02-15 DOI: 10.1016/j.trsl.2025.02.001

Akash Gupta , Nahla Zaghloul , Senthil Kumar Thulasingam , Ian Richard Robbins , Geetanjali Gupta , Jad Bader , Joe GN Garcia , Mohamed Ahmed

ChAT-expressing T cells represent ∼0.01 % of total circulating T lymphocytes in adult wild-type mice. However, we previously reported that systemic infusion of ChAT+ve Jurkat T cells into adult mice elicits vasodilation and instantaneous decline in the mean systolic blood pressure, suggesting potential as a biologic therapeutic to attenuate pathologic increases in pulmonary arterial pressures. We now report that ChAT gene-expressing Jurkat cells dose-dependently decrease right ventricular systolic pressures (RVSP) in hypoxic mice and that transgenic mice with ChAT KO restricted to endothelial cells (KO END/ChAT-/-) exhibit significantly elevated pulmonary arterial pressure and peripheral systemic resistance (compared to WT mice). To rigorously characterize the role of CD4 ChAT+ T cells in regulating pulmonary arterial hypertension (PAH) hemodynamics and molecular signatures, we infused CD4+ ChAT+ve cells (0.5 to 2.0 million cells/animal) into adult PAH mice and noted significant reductions in RVSP within 2-3 min post injection (∼ 50 % reduction). The tailored tail vein injection effect was sustained until the animal was euthanized (30-40 min). Mice KO END/ChAT-/-showed a significant and severe hypoxia-induced PAH phenotype compared to WT adult mice. Tail vein injection of biologically active CD4 ChAT+ve cells into either KO END/ChAT-/-mice with hypoxia-induced PAH or into adult rats with hypoxia/Sugen-induced PAH resulted in significant attenuation of RVP elevations. RNA seq data analysis of human pulmonary endothelial cells (HPAECs) incubated with CD4 ChAT+ve T cells showed significant differential regulation of pathways involved in systemic and pulmonary pressure regulation, NO synthesis/regulation, antioxidant expression, and vasodilation. In conclusion, CD4 ChAT+ve T cells have a unique, vasodilating innate immunity mechanism to augment nitric oxide release and potentially mitigate molecular and genetic pathways involved in PAH pathogenesis.

在成年野生型小鼠中，表达chat的T细胞占循环T淋巴细胞总量的0.01%。然而，我们之前报道过，将ChAT+ve Jurkat T细胞全身输注成年小鼠可引起血管舒张和平均收缩压的瞬时下降，这表明它有可能作为一种生物疗法来减轻病理性肺动脉压升高。我们现在报道，表达ChAT基因的Jurkat细胞剂量依赖性地降低了缺氧小鼠的右心室收缩压（RVSP），并且与WT小鼠相比，限制内皮细胞（KO END/ChAT-/-）的ChAT- KO转基因小鼠表现出显著升高的肺动脉压和外周全身抵抗。为了严格表征CD4 ChAT+ T细胞在调节肺动脉高压（PAH）血流动力学和分子特征中的作用，我们将CD4+ ChAT+ T细胞（50万至200万个细胞/只动物）注入成年PAH小鼠，并在注射后2-3分钟内发现RVSP显著降低（约50%）。量身定制的尾静脉注射效果持续到动物安乐死（30-40分钟）。与WT成年小鼠相比，小鼠KO END/ChAT-/-表现出明显且严重的缺氧诱导的PAH表型。将具有生物活性的CD4 ChAT+ve细胞尾静脉注射到缺氧诱导PAH的KO END/ChAT-/-小鼠或缺氧/糖诱导PAH的成年大鼠中，RVP升高显著降低。对人肺内皮细胞（HPAECs）与CD4 ChAT+ve T细胞孵育的RNA seq数据分析显示，参与全身和肺压力调节、NO合成/调节、抗氧化表达和血管舒张的途径存在显著差异。总之，CD4 ChAT+ve T细胞具有独特的血管舒张先天免疫机制，可以增加一氧化氮的释放，并可能减轻参与PAH发病的分子和遗传途径。

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引用次数: 0

Macrophage-driven inflammation in acute kidney injury: Therapeutic opportunities and challenges 急性肾损伤中巨噬细胞驱动的炎症：治疗的机遇和挑战

IF 6.4 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Translational Research

Pub Date : 2025-02-13 DOI: 10.1016/j.trsl.2025.02.003

Ya-Fan Mu , Zi-Hui Mao , Shao-Kang Pan , Dong-Wei Liu , Zhang-Suo Liu , Peng Wu , Zhong-Xiuzi Gao

Acute kidney injury (AKI) is increasingly being recognized as a systemic disorder associated with significant morbidity and mortality. AKI manifests with extensive cellular damage, necrosis, and an intense inflammatory response, often leading to late-stage interstitial fibrosis. Although the mechanisms underlying renal injury and repair remain poorly understood, macrophages (pivotal inflammatory cells) play central roles in AKI. They undergo polarization into pro-inflammatory and anti-inflammatory phenotypes, contributing dynamically to both the injury and repair processes while maintaining homeostasis. Macrophages modulate microenvironmental inflammation by releasing extracellular vesicles (EVs) containing pro- or anti-inflammatory signaling molecules, thereby influencing the regulation of tissue injury. The injured tissue cells release EVs and activate local macrophages to initiate these responses. Our bibliometric analysis indicated that a shift has occurred in AKI macrophage research towards therapeutic strategies and clinical translation, focusing on macrophage-targeted therapies, including exosomes and nanoparticles. This review highlights the roles and mechanisms of macrophage activation, phenotypic polarization, and trans-differentiation in AKI and discusses macrophage-based approaches for AKI prevention and treatment. Understanding the involvement of macrophages in AKI contributes to the comprehension of related immune mechanisms and lays the groundwork for novel diagnostic and therapeutic avenues.

急性肾损伤（AKI）越来越被认为是一种与显著发病率和死亡率相关的全身性疾病。AKI表现为广泛的细胞损伤、坏死和强烈的炎症反应，常导致晚期间质纤维化。尽管肾损伤和修复的机制尚不清楚，但巨噬细胞（关键炎症细胞）在AKI中起着核心作用。它们经历促炎和抗炎表型的极化，在维持体内平衡的同时动态地促进损伤和修复过程。巨噬细胞通过释放含有促炎或抗炎信号分子的细胞外囊泡（EVs）调节微环境炎症，从而影响组织损伤的调节。受伤的组织细胞释放ev并激活局部巨噬细胞来启动这些反应。我们的文献计量分析表明，AKI巨噬细胞研究已经转向治疗策略和临床翻译，重点是巨噬细胞靶向治疗，包括外泌体和纳米颗粒。本文综述了巨噬细胞激活、表型极化和反式分化在AKI中的作用和机制，并讨论了基于巨噬细胞的AKI预防和治疗方法。了解巨噬细胞在AKI中的作用有助于理解相关的免疫机制，并为新的诊断和治疗途径奠定基础。

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引用次数: 0

Multi-Omics Analysis Links Mitochondrial-Related Genes to Idiopathic Pulmonary Fibrosis and In Vivo Transcriptome Validation 多组学分析将线粒体相关基因与特发性肺纤维化和体内转录组验证联系起来。

IF 6.4 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Translational Research

Pub Date : 2025-02-12 DOI: 10.1016/j.trsl.2025.02.002

Xiaoxia Li , Qiaojing Lin , Bingyue Guan , Minghuan Yang , Xingxin Huang , Lianhuang Li , Chun Chen , Jinsheng Hong , Mingwei Zhang

Mitochondrial dysfunction is closely associated with idiopathic pulmonary fibrosis (IPF). However, the causal association between mitochondria-related genes and IPF remains to be determined. We obtained gene expression, protein abundance, and methylation quantitative trait locus data for mitochondria-related genes from previous studies. Genome-wide association study data for patients with IPF were obtained from the FinnGen study. A two-sample Mendelian randomisation analysis was conducted to assess the association between mitochondria-related genes and IPF. Furthermore, we conducted validation of expression differences utilizing transcriptome data derived from the BLM-induced pulmonary fibrosis mouse model (n=15). Concurrently, multiphoton imaging was utilized to quantify collagen contents and structural assessment. The direction of causality was verified using the Steiger test, and colocalisation analysis was used to better validate causality. Single-cell data were used to explore the localisation and expression of positive genes across different cell types. The study identified significant associations between mitochondria-related genes and IPF, with POLG and NDUFB10 classified as Grade 1; LYRM4, NBR1, and ACSF3 as Grade 2; MCL1, GFER, MFN2, IVD, and SLC25A35 as Grade 3; and METAP1D and MTX1 as Grade 4. Single-cell analysis showed elevated expression of NBR1, MCL1, and MTX1 in pulmonary myofibroblasts of IPF. This study elucidated the causal effects of mitochondria-related genes on IPF, underscoring their significance in pathogenesis. These findings contribute to an improved understanding of the mechanisms underlying IPF, offering new potential therapeutic targets for interventions.

线粒体功能障碍与特发性肺纤维化（IPF）密切相关。然而，线粒体相关基因与IPF之间的因果关系仍有待确定。我们从之前的研究中获得了线粒体相关基因的基因表达、蛋白丰度和甲基化数量性状位点数据。IPF患者全基因组关联研究数据来自FinnGen研究。采用双样本孟德尔随机化分析来评估线粒体相关基因与IPF之间的关系。此外，我们利用来自blm诱导肺纤维化小鼠模型的转录组数据验证了表达差异（n=15）。同时，多光子成像用于定量胶原含量和结构评估。使用Steiger检验验证因果关系的方向，并使用共定位分析来更好地验证因果关系。单细胞数据用于探索不同细胞类型中阳性基因的定位和表达。该研究发现线粒体相关基因与IPF之间存在显著关联，POLG和NDUFB10被列为1级；LYRM4、NBR1、ACSF3为二级；MCL1、GFER、MFN2、IVD、SLC25A35为3级；METAP1D和MTX1为4级。单细胞分析显示，IPF肺肌成纤维细胞中NBR1、MCL1和MTX1的表达升高。本研究阐明了线粒体相关基因对IPF的因果作用，强调了它们在发病机制中的重要意义。这些发现有助于提高对IPF机制的理解，为干预提供了新的潜在治疗靶点。

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IF 6.4 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Translational Research

Pub Date : 2025-02-11 DOI: 10.1016/S1931-5244(25)00017-9

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IF 6.4 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Translational Research

Pub Date : 2025-02-11 DOI: 10.1016/S1931-5244(25)00018-0

引用次数: 0

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