Translational Research最新文献

{"title":"Soluble ST2 is an early marker and treatment target for hypertensive nephrosclerosis signatured in glomerular mesangial cells","authors":"Jeong Min Cho ,&nbsp;Seong Joon Park ,&nbsp;Young Joo Kim ,&nbsp;Saram Lee ,&nbsp;Sunhwa Lee ,&nbsp;Dha Woon Im ,&nbsp;Semin Cho ,&nbsp;Ran-hui Cha ,&nbsp;Jae Wook Lee ,&nbsp;Dong Ki Kim ,&nbsp;Kook-Hwan Oh ,&nbsp;Kwon Wook Joo ,&nbsp;Yon Su Kim ,&nbsp;Yong Chul Kim ,&nbsp;Seung Hee Yang","doi":"10.1016/j.trsl.2025.03.001","DOIUrl":"10.1016/j.trsl.2025.03.001","url":null,"abstract":"<div><div>The absence of a biologic marker for hypertensive nephrosclerosis (HN) remains a challenge. This study aimed at exploring the relationship between sST2 and early HN and examining their interaction in glomerular mesangial cells. The serum sST2 levels of healthy controls (HC; n=9), patients with HN (n=15), and patients with lupus nephritis (LN; n=27) were measured using ELISA. The association between the serum sST2 levels and clinicopathologic characteristics, including kidney function and mesangial proliferation, were assessed. The expression of ST2 and fibrotic markers in glomerular mesangial cells in hypertensive conditions was evaluated using a 5/6 nephrectomy rat model. To mimic intraglomerular hypertension, human primary glomerular mesangial cells (hPGMCs) were subjected to a 3-mmHg pressure using a newly developed mechanical pressurizing device. The cells were then treated with anti-ST2 antibody (0.5 and 1 μg/mL) to examine inflammation, apoptosis, and necrosis. The serum sST2 levels were significantly higher in the HN and LN groups than in the HC group. Increased expression of ST2 and fibrotic markers in glomerular mesangial cells was observed in the hypertension-induced animal model. In the <em>in vitro</em> study, pressure-stimulated hPGMCs exhibited increased population of early and late apoptosis, which were markedly reduced after treatment with anti-ST2 antibody (1.0 μg/mL). ST2 indicates the early pathologic changes of hypertensive kidney damage and may serve as a mesangial cell-specific marker for HN in terms of determining kidney function and pathologic findings. Thus, ST2 blockade could be a novel therapeutic approach for HN.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"279 ","pages":"Pages 16-26"},"PeriodicalIF":6.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653032","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":"Author Guidelines","authors":"","doi":"10.1016/S1931-5244(25)00044-1","DOIUrl":"10.1016/S1931-5244(25)00044-1","url":null,"abstract":"","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"279 ","pages":"Pages iii-iv"},"PeriodicalIF":6.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143886499","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":"Kv1.3 expression on CD4 (+) T cells promotes interleukin-17A-associated airway inflammation and airway remodeling in asthma","authors":"Bingqing Sun ,&nbsp;Jiangtao Lin","doi":"10.1016/j.trsl.2025.04.001","DOIUrl":"10.1016/j.trsl.2025.04.001","url":null,"abstract":"<div><h3>Background</h3><div>Different types of T helper cells play an important role in disease severity and treatment response in patients with asthma. The potassium channel Kv1.3 is a type of potentially therapeutic target in T-cell-mediated inflammatory diseases.</div></div><div><h3>Objective</h3><div>This study aimed to explore the potential of Kv1.3 as a therapeutic target for asthma and to assess the efficacy of the Kv1.3 inhibitor PAP-1 in the treatment of asthma.</div></div><div><h3>Methods</h3><div>Kv1.3 expression on CD4⁺T cells was determined using data from public databases. CD4⁺T cells were isolated from peripheral blood samples obtained from healthy individuals and patients with asthma. The mouse models of OVA-induced asthma and Kv1.3 knockout were established. The underlying mechanism was investigated using mouse splenic CD4⁺T cells and BEAS-2B cells. OVA-induced asthmatic mice were treated with the Kv1.3 selective blocker PAP-1.</div></div><div><h3>Results</h3><div>Based on public data, we determined the distribution of Kv1.3 on CD4⁺T cells, its up-regulation in asthma, and its correlation with Th17/Treg balance. Upregulation of Kv1.3 in CD4⁺T cells was associated with enhanced activation of these cells and airway inflammation in patients and mice with asthma, accompanied by increased IL-17A levels in alveolar lavage fluid. Conversely, Kv1.3 deficiency significantly attenuated airway inflammation, lowered IL-17A levels in bronchoalveolar lavage fluid, and inhibited airway epithelial-mesenchymal transition in asthmatic mice. Furthermore, treatment with the Kv1.3 selective blocker PAP-1 attenuated inflammation in lung tissues and prevented airway remodeling in OVA-induced asthmatic mice.</div></div><div><h3>Conclusions</h3><div>Kv1.3 expression on CD4⁺ T cells was correlated with IL-17A-associated airway inflammation and remodeling in asthma, which may be regarded as a potential diagnostic marker and therapeutic target for asthma.</div></div><div><h3>Translational significance</h3><div>Based on our study, Kv1.3 expression on CD4⁺T cells was correlated with IL-17A-associated airway inflammation and remodeling in asthma, which may be regarded as a potential diagnostic marker and therapeutic target for asthma. The treatment with the Kv1.3 selective blocker PAP-1 attenuated inflammation in lung tissues and prevented airway remodeling in OVA-induced asthmatic mice. Our discoveries offer novel perspectives for a better understanding of IL-17A-associated airway remodeling in asthma. The development of drugs targeting Kv1.3 holds application value for IL-17A-associated asthma.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"279 ","pages":"Pages 40-54"},"PeriodicalIF":6.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143860264","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":"Tailored CD4+ lymphocytes expressing human CHAT protein as a novel vasodilator in attenuating RV pressure in PAH animal model","authors":"Akash Gupta ,&nbsp;Nahla Zaghloul ,&nbsp;Senthil Kumar Thulasingam ,&nbsp;Ian Richard Robbins ,&nbsp;Geetanjali Gupta ,&nbsp;Jad Bader ,&nbsp;Joe GN Garcia ,&nbsp;Mohamed Ahmed","doi":"10.1016/j.trsl.2025.02.001","DOIUrl":"10.1016/j.trsl.2025.02.001","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"278 ","pages":"Pages 22-35"},"PeriodicalIF":6.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443109","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":"Caspase-12 exhibits non-redundant functions in response to endoplasmic reticulum stress to promote GSDMD-mediated NETosis, leading to thoracic aortic dissection","authors":"Hanchuan Chen ,&nbsp;Kun Yang ,&nbsp;Shumin Zhang ,&nbsp;Gulinazi Yesitayi ,&nbsp;Yunzhi Ling ,&nbsp;Rifeng Gao ,&nbsp;Yang Lyu ,&nbsp;Wei Wei ,&nbsp;Jiaran Shi ,&nbsp;Yulin Li ,&nbsp;Xiang Ma ,&nbsp;Pingjin Gao ,&nbsp;Junbo Ge ,&nbsp;Aijun Sun","doi":"10.1016/j.trsl.2025.02.005","DOIUrl":"10.1016/j.trsl.2025.02.005","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>A TAD mouse model was generated using four-week-old male neutrophil-specific <em>GSDMD</em>-knockout mice (<em>GSDMD</em>^F/F; <em>Elane</em>^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.</div></div><div><h3>Results</h3><div>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 <em>GSDMD</em> 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, <em>GSDMD</em> 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.</div></div><div><h3>Conclusions</h3><div>The ER stress/GSDMD/NETosis signaling pathway provides a potential therapeutic target for the prevention and treatment of TAD.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"278 ","pages":"Pages 48-60"},"PeriodicalIF":6.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143525472","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}

{"title":"Effects of senotherapeutics on gut microbiome dysbiosis and intestinal inflammation in Crohn's disease: A pilot study","authors":"Nannapat Sangfuang ,&nbsp;Laura E. McCoubrey ,&nbsp;Atheer Awad ,&nbsp;Massimo Marzorati ,&nbsp;Jonas Ghyselinck ,&nbsp;Lynn Verstrepen ,&nbsp;Julie De Munck ,&nbsp;Jelle De Medts ,&nbsp;Simon Gaisford ,&nbsp;Abdul W. Basit","doi":"10.1016/j.trsl.2025.02.004","DOIUrl":"10.1016/j.trsl.2025.02.004","url":null,"abstract":"<div><div>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 <em>D</em> + <em>Q</em> was assessed in the M-SHIME model with faecal microbiota sourced from Crohn's disease patients. <em>D</em> + <em>Q</em> significantly modulated butyrate and lactate levels in the samples from specific patients. In addition, metabolomic analysis showed that <em>D</em> + <em>Q</em> 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 <em>D</em> + <em>Q</em> 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, <em>D</em> + <em>Q</em> induced the secretion of anti-inflammatory cytokines, including IL-6 and IL-10. However, it should be noted that <em>D</em> + <em>Q</em> also led to the secretion of the pro-inflammatory cytokines IL-8. These findings suggest that <em>D</em> + <em>Q</em> 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</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"278 ","pages":"Pages 36-47"},"PeriodicalIF":6.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143474855","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}

{"title":"Author Guidelines","authors":"","doi":"10.1016/S1931-5244(25)00031-3","DOIUrl":"10.1016/S1931-5244(25)00031-3","url":null,"abstract":"","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"278 ","pages":"Pages iii-iv"},"PeriodicalIF":6.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143580081","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":"Multi-Omics Analysis Links Mitochondrial-Related Genes to Idiopathic Pulmonary Fibrosis and In Vivo Transcriptome Validation","authors":"Xiaoxia Li ,&nbsp;Qiaojing Lin ,&nbsp;Bingyue Guan ,&nbsp;Minghuan Yang ,&nbsp;Xingxin Huang ,&nbsp;Lianhuang Li ,&nbsp;Chun Chen ,&nbsp;Jinsheng Hong ,&nbsp;Mingwei Zhang","doi":"10.1016/j.trsl.2025.02.002","DOIUrl":"10.1016/j.trsl.2025.02.002","url":null,"abstract":"<div><div>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 <em>POLG</em> and <em>NDUFB10</em> classified as Grade 1; <em>LYRM4, NBR1</em>, and <em>ACSF3</em> as Grade 2; <em>MCL1, GFER, MFN2, IVD</em>, and <em>SLC25A35</em> as Grade 3; and <em>METAP1D</em> and <em>MTX1</em> as Grade 4. Single-cell analysis showed elevated expression of <em>NBR1, MCL1</em>, and <em>MTX1</em> 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.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"278 ","pages":"Pages 10-21"},"PeriodicalIF":6.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426815","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":"Information for Readers","authors":"","doi":"10.1016/S1931-5244(25)00032-5","DOIUrl":"10.1016/S1931-5244(25)00032-5","url":null,"abstract":"","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"278 ","pages":"Page IBC"},"PeriodicalIF":6.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143580082","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":"Editorial Advisory Board","authors":"","doi":"10.1016/S1931-5244(25)00030-1","DOIUrl":"10.1016/S1931-5244(25)00030-1","url":null,"abstract":"","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"278 ","pages":"Page ii"},"PeriodicalIF":6.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143580080","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}