Clinical and Translational Medicine最新文献

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Integrating spatial transcriptomics and single-cell RNA-seq dissects immune microenvironment in fatty liver regeneration 整合空间转录组学和单细胞RNA-seq分析脂肪肝再生中的免疫微环境
IF 7.9 1区 医学
Clinical and Translational Medicine Pub Date : 2025-06-13 DOI: 10.1002/ctm2.70365
Chenhao Xu, Renyi Su, Yisu Song, Wenzhi Shu, Mengfan Yang, Zhe Yang, Xiao Xu, Xuyong Wei
{"title":"Integrating spatial transcriptomics and single-cell RNA-seq dissects immune microenvironment in fatty liver regeneration","authors":"Chenhao Xu, Renyi Su, Yisu Song, Wenzhi Shu, Mengfan Yang, Zhe Yang, Xiao Xu, Xuyong Wei","doi":"10.1002/ctm2.70365","DOIUrl":"https://doi.org/10.1002/ctm2.70365","url":null,"abstract":"<p>Dear Editor,</p><p>Liver zonal regeneration in healthy states involves a dynamic interplay between parenchymal and nonparenchymal cells, whereas fatty liver chronicity disrupts immune-niche coordination, altering intercellular crosstalk.<span><sup>1, 2</sup></span> While single-cell technologies resolve cellular heterogeneity, they often overlook spatial regulation of cellular functions. We performed PHx (partial hepatectomy) on healthy mice and mice on a high-fat diet, and sampling was performed on postoperative days 0, 2, 4, and 6. Our study integrates spatial transcriptomics with single-cell profiling, bulk RNA-seq, and smFISH to construct a spatiotemporal atlas of liver regeneration post-PHx.</p><p>We constructed single-cell maps (105 442 cells after quality control) and spatial maps (25 995 points) depicting the dynamics of liver regeneration after hepatectomy in normal and fatty livers (Figure 1A,B). Batch-effect-free integration (Figure S1A–C) confirmed impaired ecological niche coordination in the fatty microenvironment. Clustering identified 14 major cell types (annotated by literature calibration markers; Figure 1C; Table S1), in which Kupffer/endothelial cells—key regenerative mediators—were reduced in the fatty liver state and parenchymal cells (hepatocytes/BECs) were diminished (Figure 1D; Figure S1B).<span><sup>3, 4</sup></span> Spatial validation confirmed lipid-laden in the fatty model (Figure 1E). The temporal analysis highlighted a different immune response: fatty livers exhibited an early neutrophil/monocyte surge at day 2 (Figure S1D), in contrast to the 48 h regeneration peak in normal livers.<span><sup>5</sup></span> These data establish a spatiotemporal map that identifies fatty liver-specific defects in parenchymal-immune crosstalk and delayed regenerative activation.</p><p>Meanwhile, spatial mapping validated the classical 1, 2, and 3 zonation markers (Sds/Igfbp2/Oat; Figure 1E–G) and identified 7 molecular niches after PHx (Figure S1E–H).<span><sup>6-8</sup></span> To further characterize the features of each molecular niche, we performed differential analysis to identify the representative markers (Table S2). Niche 2 and niche 1/6 expressed Cyp2f2/Sds and Cyp2e1/Oat, respectively, whereas midlobular niche 3/4 was enriched in Igfbp2.<span><sup>6</sup></span> The molecular niches might be representative of the spatial structure (Figure 2A,C). Spatial projection confirmed niche-structure alignment: the zonal structure remains clear and significant in different disease states and at different points in time (Figure 2B). Pathway analysis showed attenuated Wnt activation (Figure 2E,F) and similarly attenuated TGF-β inhibition (Figure S2A,B) in fatty liver compared with normal liver.<span><sup>9, 10</sup></span> Single-cell profiling showed that regeneration of hepatocytes in the fatty liver was delayed—Wnt signalling and proliferative activity peaked on day 4, whereas in the normal group, it peaked on day 2 (Figure 2D,G; F","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 6","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70365","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144281363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Neutrophil extracellular traps in cancer: From mechanisms to treatments 癌症中的中性粒细胞胞外陷阱:从机制到治疗
IF 7.9 1区 医学
Clinical and Translational Medicine Pub Date : 2025-06-13 DOI: 10.1002/ctm2.70368
Yifan Wang, Kangjie Yang, Juan Li, Chuanxin Wang, Peilong Li, Lutao Du
{"title":"Neutrophil extracellular traps in cancer: From mechanisms to treatments","authors":"Yifan Wang,&nbsp;Kangjie Yang,&nbsp;Juan Li,&nbsp;Chuanxin Wang,&nbsp;Peilong Li,&nbsp;Lutao Du","doi":"10.1002/ctm2.70368","DOIUrl":"https://doi.org/10.1002/ctm2.70368","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Neutrophil extracellular traps (NETs) are reticular ultrastructures released by activated neutrophils. As the reaction products of neutrophils, NETs have been identified as crucial effectors in pathogen defence and autoimmune diseases. Recently, increasing evidence suggest that this process also occurs in cancer. The formation and clearance of NETs are dynamically influenced by the tumour microenvironment, while NETs reciprocally play a dual role in either promoting or inhibiting tumour progression through their DNA scaffold, proteases and other granule-derived proteins. Given the interplay between NETs and tumours, active exploration is currently underway to harness their potential as tumour biomarkers and therapeutic targets. Here, we delve into the biochemical and immunological mechanisms underlying NETs formation within the tumour microenvironment, along with recent advances elucidating their multifaceted roles in tumourigenesis, metastasis and tumour-associated co-morbidities. Furthermore, we present emerging strategies for NETs-based tumour diagnostic approaches and therapeutics, with a special focus on the challenging questions that need to be answered within this field.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>The formation and clearance of NETs are dynamically influenced by the tumor microenvironment.</li>\u0000 \u0000 <li>NETs are engaged in tumorigenesis, formation, metastatic spread, and cancer-associated co-morbidities.</li>\u0000 \u0000 <li>NETs-based tumor biomarkers and therapeutic strategies warrant significant attention.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 6","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70368","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144273338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
CLINICAL AND TRANSLATIONAL MEDICINE 临床和转化医学
IF 7.9 1区 医学
Clinical and Translational Medicine Pub Date : 2025-06-09 DOI: 10.1002/ctm2.70372
{"title":"CLINICAL AND TRANSLATIONAL MEDICINE","authors":"","doi":"10.1002/ctm2.70372","DOIUrl":"https://doi.org/10.1002/ctm2.70372","url":null,"abstract":"","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 6","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70372","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144244594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
MLKL‒OPTN axis regulates herpesvirus-induced neurological sequelae MLKL-OPTN轴调控疱疹病毒诱导的神经系统后遗症
IF 7.9 1区 医学
Clinical and Translational Medicine Pub Date : 2025-06-09 DOI: 10.1002/ctm2.70353
Ilina Bhattacharya, Rashmi Kadam, Tejabhiram Yadavalli, Chandrashekhar D. Patil, Hemant Borase, Ipsita Volety, Sergey Kalinin, Douglas L. Feinstein, Henry C. Tseng, Deepak Shukla
{"title":"MLKL‒OPTN axis regulates herpesvirus-induced neurological sequelae","authors":"Ilina Bhattacharya,&nbsp;Rashmi Kadam,&nbsp;Tejabhiram Yadavalli,&nbsp;Chandrashekhar D. Patil,&nbsp;Hemant Borase,&nbsp;Ipsita Volety,&nbsp;Sergey Kalinin,&nbsp;Douglas L. Feinstein,&nbsp;Henry C. Tseng,&nbsp;Deepak Shukla","doi":"10.1002/ctm2.70353","DOIUrl":"https://doi.org/10.1002/ctm2.70353","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Herpes simplex virus-1 (HSV-1) infections are lifelong and linked to neurological diseases such as multiple sclerosis (MS), yet the underlying mechanisms in the host remain poorly understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods and Results</h3>\u0000 \u0000 <p>This study investigates new molecular dynamics following HSV-1 infection, uncovering the pivotal role of the mixed lineage kinase domain-like (MLKL) protein. Beyond its known function in necroptosis, MLKL was found to control HSV-1 transport into the nucleus, tightly regulated by Optineurin (OPTN). We evidenced an essential regulatory interaction between MLKL and OPTN, governing MLKL's activity in both necroptosis-dependent and independent pathways. In vivo, studies using Optn knockout mice demonstrated how this MLKL-OPTN axis contributes to demyelination and neurological symptoms mimicking MS. This axis critically prevents oligodendrocyte death and the associated demyelination during HSV-1 infection. Furthermore, pharmacological interventions with Necrosulfonamide (NSA), an MLKL inhibitor, showed therapeutic potential in preserving myelin integrity and reducing neurological deficits in HSV-1-infected models, suggesting a viable strategy for managing virus-induced neurodegeneration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings highlight the significant role of MLKL in HSV-1 pathogenesis and suggest that MLKL dysregulation is a key mechanism behind severe neurological damage.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>MLKL plays a significant role in regulating endosomal transport of HSV-1 to nucleus during early stages of infection.</li>\u0000 \u0000 <li>Formation of p-MLKL bodies during HSV-1 infection leads to death of oligodendrocyte and subsequent demyelination.</li>\u0000 \u0000 <li>OPTN can negatively modulate MLKL levels to restrict infection and consequential oligodendrocyte death during HSV-1 infection.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 6","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70353","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144244389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
LncRNA MIR503HG regulates NETs-mediated NLRP3 inflammasome activation and NSCLC metastasis by enhancing the ubiquitination of C/EBPβ LncRNA MIR503HG通过增强C/EBPβ泛素化调节nets介导的NLRP3炎性体激活和NSCLC转移
IF 7.9 1区 医学
Clinical and Translational Medicine Pub Date : 2025-06-09 DOI: 10.1002/ctm2.70342
Xin Ye, Chen Fang, Weiwei Hong, Xiaoying Qian, Biao Yu, Bingbiao Zhou, Xinyuan Yao, Dengying Chen, Chengsi Shu, Chuanhong Luo, Yong Wang, Yong Li
{"title":"LncRNA MIR503HG regulates NETs-mediated NLRP3 inflammasome activation and NSCLC metastasis by enhancing the ubiquitination of C/EBPβ","authors":"Xin Ye,&nbsp;Chen Fang,&nbsp;Weiwei Hong,&nbsp;Xiaoying Qian,&nbsp;Biao Yu,&nbsp;Bingbiao Zhou,&nbsp;Xinyuan Yao,&nbsp;Dengying Chen,&nbsp;Chengsi Shu,&nbsp;Chuanhong Luo,&nbsp;Yong Wang,&nbsp;Yong Li","doi":"10.1002/ctm2.70342","DOIUrl":"https://doi.org/10.1002/ctm2.70342","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Neutrophil extracellular traps (NETs) are pivotal in the metastasis of non-small cell lung cancer (NSCLC). Our previous research demonstrated that NETs facilitate NSCLC metastasis by triggering the stimulation of the NOD-like receptor protein 3 (NLRP3) inflammasome, which is mediated through the suppression of the long non-coding RNA MIR503HG. However, the precise molecular mechanisms linking MIR503HG to NLRP3 are still not fully understood.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;By employing protein mass spectrometry and the Human TFDB database, key molecules involved in NLRP3 regulation were identified. The involvement of CCAAT enhancer binding protein beta (C/EBPβ) in NSCLC metastasis was examined in both cellular and animal models. Dual-luciferase and CUT&amp;RUN assays confirmed the mechanism by which C/EBPβ controls NLRP3. The regulatory relationship between MIR503HG and C/EBPβ was explored through RNA pulldown, RNA immunoprecipitation and coimmunoprecipitation assays. Additionally, methylation-specific PCR and other studies revealed that NETs suppress MIR503HG via DNA methylation.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We found that C/EBPβ mediates the regulation of NLRP3 by MIR503HG. Further investigation confirmed that C/EBPβ promotes the migration and invasion of NSCLC both in vivo and in vitro and is highly expressed in NSCLC tissue. Mechanistically, C/EBPβ binds to the NLRP3 promoter to promote NLRP3 expression. Conversely, MIR503HG suppressed C/EBPβ expression by facilitating C/EBPβ interaction with the E3 ubiquitin ligase RNF43, which in turn reduced NLRP3 expression and NSCLC metastasis. Meanwhile, we investigated the mechanism by which NETs inhibit MIR503HG expression and found that DNA methylation is involved in the suppression of MIR503HG by NETs. Additionally, reversing this methylation partially restored MIR503HG and NLRP3 expression and mitigated the metastatic effects of NETs in NSCLC.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This study emphasises the critical roles of C/EBPβ and DNA methylation in NETs-mediated NSCLC metastasis. These findings unveil C/EBPβ and DNA methylation as potential novel targets for NSCLC with high NETs expression.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;NETs suppress the expression of MIR503HG by inducing promoter DNA methylation.&lt;/li&gt;\u0000 \u0000","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 6","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70342","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144244502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Targeting enabled homolog with daunorubicin inhibits ERK1/2/c-Fos pathway and suppresses hepatocellular carcinoma progression 靶向激活与柔红霉素同源抑制ERK1/2/c-Fos通路并抑制肝细胞癌进展
IF 7.9 1区 医学
Clinical and Translational Medicine Pub Date : 2025-06-09 DOI: 10.1002/ctm2.70366
Zhi-Mei Li, Guan Liu, Qing-Qing Liu, Wei-Ming You, Ming-Gao Zhao
{"title":"Targeting enabled homolog with daunorubicin inhibits ERK1/2/c-Fos pathway and suppresses hepatocellular carcinoma progression","authors":"Zhi-Mei Li,&nbsp;Guan Liu,&nbsp;Qing-Qing Liu,&nbsp;Wei-Ming You,&nbsp;Ming-Gao Zhao","doi":"10.1002/ctm2.70366","DOIUrl":"https://doi.org/10.1002/ctm2.70366","url":null,"abstract":"&lt;p&gt;Dear Editor&lt;/p&gt;&lt;p&gt;The enabled/vasodilator stimulated phosphoprotein family (Ena/VASP) of actin regulatory proteins are critical players in maintenance of cell shape, motility, regulation of molecular interactions, and contribute to hepatocellular carcinoma (HCC) development,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; rendering them ideal candidate targets for therapy, whereas understanding their regulatory mechanisms remains an unmet challenge and no sufficiently potent compounds to interfere with Ena/VASP in HCC have been reported.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; In this context, we identified enabled homolog (ENAH), a member of Ena/VASP, as a promising target for pharmaceutical intervention derived from multi-omics analysis. Using biochemical and molecular biology assays, for the first time we report daunorubicin, a known drug used to treat acute myeloid leukaemia, as an ENAH inhibitor. This study aims to uncover the underlying mechanism and investigate the therapeutic potential of daunorubicin in preclinical HCC models.&lt;/p&gt;&lt;p&gt;We collected resected primary tumour samples and normal paired adjacent tissues (NATs) from 20 early-stage HCC patients without radiotherapy or prior chemotherapy (Table S1). Four pairs of qualified samples were selected for proteomic and transcriptomic analyses. Using isobaric standard mass tag labelling, 371 differentially expressed proteins (DEPs) were identified in tumours compared to NATs (Figure S1A and C and Table S2). mRNA sequencing (mRNA-seq) profiled 24 381 genes, among which 1888 and 1924 protein-coding genes were significantly down- and upregulated, respectively, in HCCs (Figure S1B and D and Table S3). DEPs featured biological activities of metabolic processes, focal adhesion, and actin binding function. Compared with proteomic data, mRNA-seq profile additionally exhibited functional enrichment with GTPase activity, MAPK cascade, ERK1/ERK2, and other signalling pathways in HCC (Figure S1E–H and Table S4).&lt;/p&gt;&lt;p&gt;Among 3812 dysregulated protein-coding genes, 56 showed concordances between mRNA and protein abundance (Figure 1A). Signatures specific to the amino acid metabolic process and ERK1/2 regulation were significantly enriched in the tumours (Figure S2A). In particular, novel molecules such as ENAH, HOGA1, and FGFR2, were related to focal adhesion, cytoskeleton organisation, and actin filament process, which are implicated in tumourigenesis and metastasis. Using correlation analysis, 32 proteins were identified as representative signatures associated with HCC (Figure S2B), of which 20 were significantly dysregulated in TCGA dataset (Figure S2C). Among them (highlighted in Figure 1B), seven molecules, especially TPX2, CDCA3, and ENAH, displayed very high risk scores for the mortality prognosis of HCC. Here, we focused on ENAH, which exhibited upregulated mRNA levels associated with higher stage/pathological grade/poor clinical prognosis of patients and has been reported to be a critical effector mediating cellular cytoskelet","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 6","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70366","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144244595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Antisenescence therapies for age-related bone loss: Target factors, medicines, biomedical materials 年龄相关性骨质流失的抗衰老疗法:靶因子,药物,生物医学材料
IF 7.9 1区 医学
Clinical and Translational Medicine Pub Date : 2025-06-09 DOI: 10.1002/ctm2.70350
Qiyue Zhu, Menglong Hu, Likun Wu, Erfan Wei, Xingtong Pan, Hao Liu, Yunsong Liu
{"title":"Antisenescence therapies for age-related bone loss: Target factors, medicines, biomedical materials","authors":"Qiyue Zhu,&nbsp;Menglong Hu,&nbsp;Likun Wu,&nbsp;Erfan Wei,&nbsp;Xingtong Pan,&nbsp;Hao Liu,&nbsp;Yunsong Liu","doi":"10.1002/ctm2.70350","DOIUrl":"https://doi.org/10.1002/ctm2.70350","url":null,"abstract":"<p>Progress in living conditions and medical technology have extended the human life span such that population aging, and thus the development of multi-system degenerative diseases, has become a major problem in many countries. Bone is a metabolically dynamic tissue and bone aging is closely related to a shift in the balance between bone resorption and bone formation. The resulting loss of bone mass and bone mechanical properties in older adults place them at risk of injury and premature death. Cellular senescence occurs in response to endogenous and exogenous stresses that lead to permanent cell cycle arrest and, thus, to tissue degeneration and dysfunction. Senescence in the bone microenvironment, as occurs during aging, induces a decline in bone formation. Research into the treatment of bone aging has therefore focused on the senescence process. This review begins with a summary of the key events in cellular senescence and bone aging and then examines recent progress in the targeting of cellular senescence, both to treat aging-related bone diseases. Novel therapeutic agents, natural products, and innovative biomedical materials are considered. Our discussion concludes by considering areas of future research.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 6","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70350","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144244600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Imbalanced NK cell subpopulations and TIGIT expression limit cetuximab efficacy in colorectal cancer: A promising target for treatment enhancement 失衡的NK细胞亚群和TIGIT表达限制了西妥昔单抗在结直肠癌中的疗效:一个有希望的治疗靶点
IF 7.9 1区 医学
Clinical and Translational Medicine Pub Date : 2025-06-09 DOI: 10.1002/ctm2.70351
Carmen Navarrete-Sirvent, Ana Mantrana, Aurora Rivas-Crespo, Alejandra Díaz-Chacón, Nerea M. Herrera-Casanova, María Teresa Sánchez-Montero, Marta Toledano-Fonseca, María Victoria García-Ortiz, María José Ortiz-Morales, Gema Pulido, Mª Teresa Cano, Auxiliadora Gómez-España, Rafael González-Fernández, Lionel Le Bourhis, Silvia Guil-Luna, Antonio Rodríguez-Ariza, Enrique Aranda
{"title":"Imbalanced NK cell subpopulations and TIGIT expression limit cetuximab efficacy in colorectal cancer: A promising target for treatment enhancement","authors":"Carmen Navarrete-Sirvent,&nbsp;Ana Mantrana,&nbsp;Aurora Rivas-Crespo,&nbsp;Alejandra Díaz-Chacón,&nbsp;Nerea M. Herrera-Casanova,&nbsp;María Teresa Sánchez-Montero,&nbsp;Marta Toledano-Fonseca,&nbsp;María Victoria García-Ortiz,&nbsp;María José Ortiz-Morales,&nbsp;Gema Pulido,&nbsp;Mª Teresa Cano,&nbsp;Auxiliadora Gómez-España,&nbsp;Rafael González-Fernández,&nbsp;Lionel Le Bourhis,&nbsp;Silvia Guil-Luna,&nbsp;Antonio Rodríguez-Ariza,&nbsp;Enrique Aranda","doi":"10.1002/ctm2.70351","DOIUrl":"https://doi.org/10.1002/ctm2.70351","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Antibody-dependent cell-mediated cytotoxicity (ADCC) induced by natural killer (NK) cells is one important mechanism by which the anti-EGFR cetuximab exerts its anti-tumoral effect,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; but no studies have examined NK cell profiles as a predictor of response to cetuximab in metastatic colorectal cancer (mCRC). Our findings suggest that imbalanced NK cell subpopulations and the expression of inhibitory receptors on NKs are key mechanisms that may limit the effectiveness of cetuximab, highlighting TIGIT as a promising target for enhancing treatment outcomes.&lt;/p&gt;&lt;p&gt;We collected blood samples from 31 mCRC patients prior to cetuximab treatment to purify NK cells for immune profiling and proteomic analyses. Patients were categorized as non-responders (NR, &lt;i&gt;n&lt;/i&gt; = 14) if they progressed before 9 months, and responders (R, &lt;i&gt;n&lt;/i&gt; = 17) if progression occurred after (Appendix 1). Results of clinical-pathological data and survival analyses are shown in Appendix 2 (Tables S1, S2). The only significant clinical parameter distinguishing NR and R patients was the number of cetuximab cycles (Appendix 2, Table S1). In terms of survival (Appendix 3, Figure S1), NR patients showed shorter overall survival (OS) and time to progression (TTP) compared with R patients. Besides, in our cohort the median OS and TTP were 21 and 9 months, respectively, which are comparable to results from clinical trials such as COIN (OS: 17 months, TTP: 8.6 months) or TAILOR (OS: 20 months and TTP: 9 months).&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; These findings validate the clinical relevance of our cohort and underscore the need for biomarkers to aid in the selection of patients who would benefit from cetuximab treatment.&lt;/p&gt;&lt;p&gt;To compare the molecular phenotype of NK cells between R and NR patients before cetuximab treatment, we analyzed their proteomic profiles using a data-independent acquisition (DIA) approach. Of the 4914 proteins identified, 932 were differentially expressed, with 585 downregulated and 347 upregulated in NR compared with R patients (Figure 1A; Appendix 2: Tables S3, S4). PCA analysis (Figure 1B) and unsupervised clustering (Figure 1C) revealed distinct protein expression patterns that clearly distinguished between the two groups. Moreover, the GSEA analysis of proteomic data (Figure 1D,E) revealed alterations in several biological processes in NKs from NR, including TGFβ, p53, TNFα, and KRAS signalling pathways, suggesting NK dysfunction.&lt;span&gt;&lt;sup&gt;3, 4&lt;/sup&gt;&lt;/span&gt; Hence, metabolic alteration in NK cells has been linked to the overexpression of peroxisome proliferator-activated receptors (PPARs), which suppresses mTOR-mediated glycolysis and interferes with the maturation process from less cytotoxic to potent cytotoxic NK phenotypes.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Therefore, the overactivation of these pathways may contribute to impaired NK function through a variety of immune evasion mechanisms which correlates with the reduced respo","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 6","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70351","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144244387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
The new era of siRNA therapy: Advances in cancer treatment siRNA治疗的新时代:癌症治疗的进展
IF 7.9 1区 医学
Clinical and Translational Medicine Pub Date : 2025-06-09 DOI: 10.1002/ctm2.70363
Zhuan Zhang, Miaorong Yu, Guoqing Hu, Yong Gan
{"title":"The new era of siRNA therapy: Advances in cancer treatment","authors":"Zhuan Zhang,&nbsp;Miaorong Yu,&nbsp;Guoqing Hu,&nbsp;Yong Gan","doi":"10.1002/ctm2.70363","DOIUrl":"https://doi.org/10.1002/ctm2.70363","url":null,"abstract":"&lt;p&gt;Small interfering RNAs (siRNAs) have emerged as a groundbreaking tool in therapeutics, offering precise and efficient silencing of disease-related genes. Through the RNA interference (RNAi) mechanism, siRNAs operate through the RNAi pathway, selectively degrading target messenger RNAs (mRNAs) and thereby preventing the synthesis of aberrant or harmful proteins.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; This exquisite specificity allows siRNAs to target previously ‘undruggable’ proteins, offering significant potential for treating a wide spectrum of diseases, including genetic disorders, chronic diseases, and cancers.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Recent progress in siRNA technology has resulted in the clinical approval of groundbreaking therapies like Onpattro&lt;sup&gt;®&lt;/sup&gt;, Amvuttra&lt;sup&gt;®&lt;/sup&gt;, and Givlaari&lt;sup&gt;®&lt;/sup&gt;, with over 130 siRNA candidates currently in clinical investigation.&lt;span&gt;&lt;sup&gt;3, 4&lt;/sup&gt;&lt;/span&gt; These therapies have already demonstrated remarkable efficacy in conditions such as transthyretin-mediated amyloidosis and acute hepatic porphyria, highlighting the broad therapeutic potential of this approach.&lt;/p&gt;&lt;p&gt;Despite these achievements, the broader application of siRNA therapeutics faces significant hurdles. Key limitations include siRNA instability in biological fluids, inefficient intracellular delivery, immunogenicity, and off-target effects, all of which can compromise therapeutic efficacy.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Overcoming these hurdles necessitates the development of innovative delivery systems that protect siRNA from degradation, promote efficient cellular uptake, and facilitate cytosolic release.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; Our study introduces a significant advance in siRNA-based therapeutics through the engineering of cholesterol-enriched exosomes (Chol/MEs).&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; By enhancing the cholesterol content in the exosomal membrane, we created a delivery platform that enables siRNA to bypass endosomal entrapment and directly enter the cytosol via membrane fusion. This mechanism substantially improves intracellular delivery, leading to enhanced gene silencing and therapeutic efficacy. In preclinical tumour models, Chol/MEs loaded with PLK1 siRNA demonstrated superior tumour growth inhibition, reducing bioluminescence intensity to a remarkable 0.05-fold of that observed in the PBS control group. This gene silencing efficiency significantly outperformed that of conventional transfection agents, Lipofectamine 2000 and RNAiMAX. Importantly, the biocompatibility and reduced immunogenicity of Chol/MEs address critical limitations of existing delivery technologies, offering a safer and more effective approach for siRNA-based therapies.&lt;/p&gt;&lt;p&gt;Synthetic lethality has emerged as a promising strategy in cancer therapy, exploiting specific genetic vulnerabilities in tumour cells.&lt;span&gt;&lt;sup&gt;8, 9&lt;/sup&gt;&lt;/span&gt; This approach involves the simultaneous disruption of two genes, where the inactivation of any gene alone is nonlethal, but their com","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 6","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70363","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144244390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Targeting the MDK/c-Myc complex to overcome temozolomide resistance in glioma 靶向MDK/c-Myc复合物克服胶质瘤中替莫唑胺耐药性
IF 7.9 1区 医学
Clinical and Translational Medicine Pub Date : 2025-06-04 DOI: 10.1002/ctm2.70359
Xiaonan Xi, Xiaojing Ding, Qianqian Wang, Ning Liu, Bangmao Wang, Genbei Wang, Weilong Zhong, Yaxin Lu
{"title":"Targeting the MDK/c-Myc complex to overcome temozolomide resistance in glioma","authors":"Xiaonan Xi,&nbsp;Xiaojing Ding,&nbsp;Qianqian Wang,&nbsp;Ning Liu,&nbsp;Bangmao Wang,&nbsp;Genbei Wang,&nbsp;Weilong Zhong,&nbsp;Yaxin Lu","doi":"10.1002/ctm2.70359","DOIUrl":"https://doi.org/10.1002/ctm2.70359","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Temozolomide (TMZ), which is an alkylating agent, is the standard chemotherapeutic drug used for glioma treatment. However, the development of resistance to TMZ limits its efficacy. Thus, identifying novel therapeutic targets is necessary.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this study, the levels of midkine (MDK) and c-Myc expression in glioma patient samples downloaded from TCGA were analyzed. Their interactions were also demonstrated through microthermometry and immunocoprecipitation. Furthermore, proteomics technology and Western blot showed that MDK interacted with c-Myc and influenced its ubiquitination, thereby activating a prosurvival signalling pathway and epithelial–mesenchymal transition mechanism, which contributed to TMZ resistance. To target the MDK/c-Myc complex, we screened for a small-molecule inhibitor (ACT001) that specifically disrupts the interaction between MDK and c-Myc. Treatment with ACT001 greatly sensitized TMZ-resistant glioma cells to TMZ, promoting cell death and inhibiting cell proliferation. Moreover, combination therapy with ACT001 and TMZ showed synergistic effects that inhibit tumour growth in glioma xenograft models and glioma in situ models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>ACT001 facilitated the degradation of c-Myc by focusing on the MDK/c-Myc complex and controlled the Wnt/β-catenin signalling pathway via MDK, ultimately halting the advancement of glioma. When combined with TMZ, ACT001 showed good therapeutic potential for the treatment of glioma.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Focusing on the MDK/c-Myc complex could be an effective approach to combat resistance to TMZ in glioma. Therapy with ACT001 may be a novel approach to improve the efficacy of TMZ-based chemotherapy in patients with glioma. Further preclinical and clinical studies are warranted to validate the therapeutic potential of targeting the MDK/c-Myc complex in glioma treatment.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 6","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70359","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144213771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
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