Current gene therapy最新文献

{"title":"MARVELD3 as a Prognostic Biomarker in Esophageal Cancer and its Relationship with m6A Modification, Cuproptosis, and the ceRNA Regulatory Network.","authors":"Wenbo Fan, Chunyao Huang, Zhulin Wang, Shaowu Sun, Kaiyuan Li, Xu Liu, Zelong Wang, Tianliang Zhao, Guoqing Zhang, Xue Pan","doi":"10.2174/0115665232472353260717043837","DOIUrl":"https://doi.org/10.2174/0115665232472353260717043837","url":null,"abstract":"<p><strong>Introduction: </strong>The present study analyzed the specific function of MARVEL domaincontaining protein 3 (MARVELD3) in esophageal cancer (EC).</p><p><strong>Methods: </strong>MARVELD3 expression and its association with clinicopathological features in EC samples were analyzed using data from the TCGA and GEO databases. Enrichment analysis was performed on differentially expressed genes (DEGs) in samples with high and low MARVELD3 expression. Furthermore, the relationships of MARVELD3 with immune infiltration, response to immune therapy, N6-methyladenosine (m6A) modification, cuproptosis, and ceRNA regulatory network were explored.</p><p><strong>Results: </strong>In EC, MARVELD3 exhibited high expression, which was significantly correlated with the T-stage and histological type. ROC curve analysis demonstrated a high prediction accuracy of MARVELD3 for tumor prognosis. Moreover, immune infiltration analysis showed a close relationship between MARVELD3 and the immune microenvironment and immune cells in EC. Additionally, MARVELD3, the m6A modification-related gene YTHDF1, and the cuproptosis-related gene CDK5RAP1 were closely correlated. Furthermore, the predicted ceRNA regulatory network THRBIT1/ hsa-miR-23a-3p/MARVELD3 and LINC00261/hsa-miR-23a-3p/MARVELD3 axes may be involved in the pathogenesis of EC and its progression.</p><p><strong>Discussion: </strong>This study analyzed the involvement of MARVELD3 in EC and revealed its relationship with m6A modification and cuproptosis and its relevant ceRNA regulatory network.</p><p><strong>Conclusion: </strong>MARVELD3 may be a potential biomarker for EC and was closely linked to immune infiltration, response to immune therapy, m6A modification, cuproptosis, and ceRNA regulatory networks in EC.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148599975","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}

{"title":"Gene/Genome Editing in Cardiovascular Biology and Disease.","authors":"Tushar Verma, Ravi Pratap Singh, Mahima Chaudhary, Pramod Kumar Sharma, Dharmendra Kumar","doi":"10.2174/0115665232453929260206091608","DOIUrl":"https://doi.org/10.2174/0115665232453929260206091608","url":null,"abstract":"<p><strong>Introduction: </strong>Cardiovascular diseases continue to be the leading cause of death worldwide. Traditional medicines relieve symptoms and slow the advancement of the disease, but fail to fix genetic problems at their roots. Cardiovascular science has dramatically changed thanks to advancements in genome editing tools, such as CRISPR/Cas9 and its successor technologies. These types of genome editing tools enable researchers and physicians to precisely and programmatically manipulate specific genetic loci related to cardiovascular diseases, offering hope for developing new curative therapies.</p><p><strong>Methods: </strong>This article is based on a complete review of peer-reviewed literature published between 2020 and 2025. A systematic search of databases (PubMed, Web of Science, Scopus, and others) for literature using the keywords (genome editing; CRISPR/Cas9; base editing; prime editing; cardiovascular disease; cardiomyopathy; atherosclerosis; etc.) was completed.</p><p><strong>Results: </strong>CRISPR/Cas9 makes it easy and fast to create genetically modified cardiac model organisms to evaluate pathogenic variation. Using base editing is an effective way to perform precise single- nucleotide corrections, particularly with respect to PCSK9 targeting and its association with long-lasting reductions in LDL cholesterol levels in humans. Prime editing extends this capability to complex mutations, including RBM20 in dilated cardiomyopathy. Early-stage clinical trials targeting transthyretin amyloidosis demonstrate the feasibility of in vivo genome editing. Secondgeneration cardiotropic AAV vectors and lipid nanoparticles continue to improve cardiac delivery and safety profiles.</p><p><strong>Discussion: </strong>Genome editing shifted cardiovascular research from associative genetics toward causal intervention. Next-generation editors reduce double-strand break-associated risks, enhancing clinical suitability. Still remaining challenges include efficient delivery in a tissue-specific manner, off-target effects, immunity, and ethical considerations related to permanent genomic modification.</p><p><strong>Conclusion: </strong>Genome editing is a paradigm-shifting development within the field of cardiology that promises a long-term genetic remedy. Yet further optimization and development within genome editing and its guidelines will be important for making such a paradigm shift successful.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148520209","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}

{"title":"Advancing siRNA Therapeutics with Pharmacometrics: A Review of Modeling Approaches and Clinical Applications.","authors":"Jueun Kang, Hyeonwoo Yim, Hyunsuk Jeong, Seunghoon Han, Suein Choi, Sungpil Han","doi":"10.2174/0115665232465559260526165502","DOIUrl":"https://doi.org/10.2174/0115665232465559260526165502","url":null,"abstract":"<p><p>Small interfering RNA (siRNA) therapeutics represent a paradigm shift in targeting previously undruggable diseases through specific gene silencing. Since the FDA's first approval of patisiran in 2018, the field has expanded rapidly, with eight approved drugs and numerous clinical candidates. However, the atypical pharmacokinetic-pharmacodynamic (PK-PD) profile of siRNAs, characterized by rapid plasma elimination, prolonged tissue retention, and temporal dissociation between exposure and effect, has created distinct obstacles for conventional dose-finding strategies. This review examines how model-informed drug development, particularly pharmacometric modeling, has emerged as an essential tool in the advancement of siRNA therapeutics. Population PK-PD models for all FDA-approved siRNA drugs are systematically described, demonstrating that mechanistic and semi-mechanistic approaches inform preclinical-to-clinical translation, optimize dosing regimens, and support regulatory decisions. Key modeling frameworks include: (1) mechanistic models incorporating asialoglycoprotein receptor (ASGPR)-mediated uptake, RNA-induced silencing complex (RISC) loading, and mRNA degradation kinetics; (2) minimal physiologically-based PK-PD models for interspecies scaling; and (3) exposure-response models addressing the disconnect between plasma PK and pharmacological activity. This review also discusses how quantitative pharmacology addresses developmental challenges, including first-in-human dose selection, optimal dosing intervals, organ impairment effects, and interindividual variability. This pharmacometric perspective provides a quantitative framework for rational development of safe and effective siRNA therapeutics across diverse patient populations.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396177","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}

{"title":"Identifying Basement Membrane-Related Diagnostic Biomarkers for Rheumatoid Arthritis Through Machine Learning.","authors":"Lingtian Min, Chengji Zhang, Long Xu, Jielin Deng, Haihu Wang, Shiqi Ren, Cheng Chen","doi":"10.2174/0115665232468196260521104934","DOIUrl":"https://doi.org/10.2174/0115665232468196260521104934","url":null,"abstract":"<p><strong>Introduction: </strong>Rheumatoid Arthritis (RA) is a common autoimmune disease. The Basement Membrane (BM) plays a critical structural role in tissues such as the kidneys and joints, and is often implicated in immune-related diseases. This study aims to explore the complex interactions between RA and the BM, and to identify potential diagnostic biomarkers.</p><p><strong>Methods: </strong>The data used in this study were sourced from the Gene Expression Omnibus (GEO) database. We screened Differentially Expressed Genes (DEGs) related to BM by comparing RA tissue with normal tissue. Consensus clustering analysis was performed based on the features of the BM in RA tissue samples. Functional enrichment analyses, including Gene Ontology (GO) and KEGG pathway analysis, were performed on genes common to the different clusters. Three machine learning algorithms were used to screen for biomarkers, including LASSO, Random Forest (RF), and Support Vector Machine Recursive Feature Elimination (SVM-RFE). The screening results were validated using the GSE77298 dataset and confirmed via qRT-PCR. In addition, molecular docking technology was applied to predict the binding potential between Schisandrin (SCH) and the candidate biomarkers SEL1L3 and SLAMF8.</p><p><strong>Results: </strong>By integrating RA transcriptome data with BM-related genes, we identified two BMassociated molecular subtypes of RA, both of which exhibit distinct immune cell infiltration characteristics. By further implementing a combination of LASSO, RF, and SVM-RFE, SEL1L3 and SLAMF8 were identified as candidate diagnostic biomarkers. In the external validation set (GSE77298) and qRT-PCR experiments, both exhibited significant upregulation in RA tissue and excellent diagnostic efficacy. The AUC of SEL1L3 and SLAMF8 was 0.987 and 0.970, respectively, and molecular docking suggests that SCH binds stably to both.</p><p><strong>Discussion: </strong>The research results indicate that molecular changes related to BM may play an important role in the pathogenesis of RA, particularly through immune regulation and tissue remodeling. Identifying different subtypes of BM-related RA highlights the heterogeneity of RA and may help improve disease classification and personalized diagnosis. SEL1L3 and SLAMF8 can serve as promising biomarkers for early RA detection and provide new insights into BM-related immune mechanisms.</p><p><strong>Conclusion: </strong>SEL1L3 and SLAMF8 are the first BM-associated RA diagnostic markers identified, providing new targets for early RA diagnosis and investigation of its molecular mechanisms.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148374876","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}

{"title":"A Multi-Gene Myofibroblast Framework Stratifies Prognostic and Immune Landscapes in HCC.","authors":"Li Bai, Qingmiao Shi, Leiya Fu","doi":"10.2174/0115665232483062260630052508","DOIUrl":"https://doi.org/10.2174/0115665232483062260630052508","url":null,"abstract":"<p><strong>Introduction: </strong>Myofibroblasts play a critical role in the progression of hepatocellular carcinoma (HCC), a major subtype of primary liver cancer.</p><p><strong>Methods: </strong>Bulk RNA-seq data were analyzed to identify core genes of relevant cell subpopulations. Next, cell clustering was performed based on public scRNA-seq data of HCC. Using the R package CellChat, receptor-ligand communication networks between myofibroblasts and other cell subtypes were characterized. Hub genes within HCC myofibroblast subpopulations were screened via hdWGCNA. Subsequently, differentially expressed genes (DEGs) from the bulk analysis were intersected with these hub genes. Machine learning algorithms were employed to select key genes to construct a nomogram. Finally, correlations in immune cell infiltration were analyzed.</p><p><strong>Results: </strong>Six major cell subpopulations were identified from the scRNA-seq data, with prominent crosstalk observed between myofibroblasts and hepatocytes. Using hdWGCNA, 10 myofibroblastassociated co-expression modules were obtained, five of which were identified as functionally key modules. By intersecting the module hub genes with HCC-related DEGs, 15 overlapping genes were obtained. From these, four key genes were ultimately selected by machine learning algorithms: plasmalemma vesicle-associated protein (PLVAP), retinol binding protein 7 (RBP7), NADH dehydrogenase (Ubiquinone) 1 Alpha subcomplex subunit 4-like 2 (NDUFA4L2), and tropomyosin 2 (Beta) (TPM2). A nomogram integrating 6 imaging-histological features and PLVAP expression exhibited robust prediction capacity. All gene expressions were positively correlated with the infiltration of regulatory T cells (Tregs) and macrophage M0 and negatively correlated with the infiltration of neutrophils and monocytes.</p><p><strong>Discussion: </strong>Myofibroblasts participate in extensive intercellular crosstalk in the HCC microenvironment, suggesting the potential value of myofibroblast-related biomarkers in HCC therapy.</p><p><strong>Conclusion: </strong>In this study, hub genes associated with myofibroblast programs in HCC were identified using scRNA-seq and hdWGCNA.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148374884","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}

{"title":"Single-cell Transcriptomics Inference of Neutrophil-mast Cell Communication Programs in Periodontitis.","authors":"Lina Liu, Miaomiao Xue","doi":"10.2174/0115665232490192260613183947","DOIUrl":"https://doi.org/10.2174/0115665232490192260613183947","url":null,"abstract":"<p><strong>Introduction: </strong>Neutrophil dysregulation is one of the main features of periodontitis (PD). This study delineated neutrophil heterogeneity and predicted potential communication of mast cells within the microenvironment of PD using computational single-cell transcriptomics.</p><p><strong>Methods: </strong>We analyzed a public scRNA-seq dataset (GSE171213) from gingival tissues of healthy controls, PD patients, and post-treatment patients. Data processing, clustering, and annotation were performed using Seurat and Harmony packages. Cell-cell communication was computationally inferred using CellChat and NicheNet packages, and transcriptional regulatory programs were predicted via SCENIC. HMC-1.2 mast cells were treated with TGFB1 and assessed for proliferation, migration, the level of VEGFA, IL-6, and TNF-α.</p><p><strong>Results: </strong>Ten cell types in PD were identified. Two distinct transcriptional states of neutrophils were identified based on gene expression profiles. Cell-cell communication analysis predicted that Subtype 2, which was enriched for inflammatory and effector genes, exhibited stronger putative interactions with mast cells via ligand-receptor pairs such as IL6-(IL6R+IL6ST) and SEMA4D- PLXNB2. NicheNet-based analysis further inferred that neutrophil-derived TGFB1, OSM, and IL1B were associated with mast-cell target gene programs related to proliferation, migration, angiogenesis, and inflammatory responses. Finally, in vitro cell experiments indicated that TGFB1 inhibited proliferation but promoted migration and the expression of VEGFA, IL-6, and TNF-α. However, all effects were reversed by SB431542, confirming TGFBR1 dependence.</p><p><strong>Discussion: </strong>This study delineated neutrophil transcriptional heterogeneity in PD and identified neutrophil- mast cell communication axes as a contributor to the inflammatory microenvironment in PD.</p><p><strong>Conclusion: </strong>Through computational analysis of single-cell transcriptomics, this study described two neutrophil states and their predicted interaction network with mast cells in PD, providing testable hypotheses for future mechanistic and translational studies.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148276435","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}

{"title":"GULP1 in Ovarian Cancer: Expression, Biological Function, and Clinical Significance.","authors":"Zongzong Sun, Xinjun Hu, Di Huang, Yingfan Wang","doi":"10.2174/0115665232491888260612113741","DOIUrl":"https://doi.org/10.2174/0115665232491888260612113741","url":null,"abstract":"<p><strong>Introduction: </strong>As an engulfment adapter for apoptotic clearance, GULP1 is related to tumor progression, but its role in ovarian cancer (OVCA) remains unclear.</p><p><strong>Methods: </strong>GULP1 expression, copy number variations (CNVs), and their correlations were analyzed using datasets collected from The Cancer Genome Atlas (TCGA)-OVCA and the Gene Expression Profiling Interactive Analysis (GEPIA). Gene set enrichment analysis (GSEA), immune infiltration assessment, and drug sensitivity prediction were conducted to identify pathways enriched by GULP1 and to explore its potential association with drug sensitivity. The binding affinity of candidate drugs to GULP1 was evaluated through molecular docking. Finally, cellular assays were performed to explore the biological functions of GULP1 in OVCA cells.</p><p><strong>Results: </strong>GULP1 was downregulated in OVCA, particularly in advanced stages. The GULP1 expression was associated with enrichment of hypoxia, EMT, angiogenesis, and TGFβ signaling, which were correlated with immune evasion. LFM-A13 demonstrated binding affinity for GULP1 (ΔG = -5.85 kcal/mol). Overexpression of GULP1 inhibited migration and invasion of A2780 and SK-OV-3 cells. Conversely, GULP1 knockdown exerted the opposite effects.</p><p><strong>Discussion: </strong>This study explored the role of GULP1 in OVCA and analyzed its correlation with the immune microenvironment and key pathways. Molecular docking predicted LFM-A13 as a potential therapeutic agent for OVCA; however, its efficacy remains to be clinically verified.</p><p><strong>Conclusion: </strong>The current findings reveal GULP1 as a novel biomarker for OVCA progression and immune escape, highlighting its role in modulating the tumor microenvironment (TME). Targeting GULP1 with LFM-A13 may offer a potential strategy for OVCA precision therapy.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148270641","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}

{"title":"Single‑cell Transcriptomic Profiling of Bone Marrow Mesenchymal Stem Cells Reveals Lineage Heterogeneity and Dysregulated Osteoblast Genes in Osteoporosis Versus Osteoarthritis.","authors":"Houlei Wang, Chenyang Zhuang, Tianle Ma, Hong Lin","doi":"10.2174/0115665232482401260522115907","DOIUrl":"https://doi.org/10.2174/0115665232482401260522115907","url":null,"abstract":"<p><strong>Introduction: </strong>Osteoporosis (OP) and osteoarthritis (OA) are two skeletal disorders characterized by disrupted bone homeostasis. Transplantation of bone marrow mesenchymal stem cells (BM-MSCs) has emerged as a promising therapeutic strategy for both conditions; however, the precise molecular mechanisms mediating their beneficial effects remain poorly defined.</p><p><strong>Methods: </strong>The GSE147287 dataset containing scRNA-seq data from BM-MSCs from OA and OP patients was obtained. Dimensionality reduction and cell clustering were performed using the Seurat R package, pseudotime trajectory analysis was carried out with the Monocle 2 package, and transcription factor (TF)-target gene regulatory networks were inferred using the GENIE3 R package. RT-qPCR quantified mRNA levels in a rat OP model, which was established via bilateral ovariectomy.</p><p><strong>Results: </strong>Nine distinct BM-MSC subtypes were classified. OP samples had higher osteocytes and neutrophils and lower macrophages, chondroblasts, monocytes, and plasma B cells than OA samples. Chondroblasts (4 clusters), 2/3 linked to autophagy, may drive OA-to-OP progression. Osteoblasts (the largest OP-OA difference) showed reduced osteoblast differentiation, downregulated Wnt pathway genes, and upregulated ossification genes in late stages. In the rat model, CAT, CHRDL1, RUNX1, ETS1, FOXO3, and TAL1 were dysregulated.</p><p><strong>Discussion: </strong>OP and OA exhibit distinct BM-MSC lineage heterogeneity. OA-to-OP progression involves enhanced oxidative phosphorylation and reduced autophagy. Downregulated RUNX1 (inhibiting NF-κB/IL-6) and Wnt pathway in OP were consistent with previous findings, showing the potential to serve as biomarkers for predicting disease progression and therapy response.</p><p><strong>Conclusion: </strong>This study preliminarily examined BM-MSC lineage heterogeneity in OP and OA, clarifying the dynamic development, transcriptional regulation, and biological functions of chondrocytes and osteoblasts in these two bone diseases.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148197627","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}

{"title":"Surface Functionalization of 3D-Printed Porous Ti-6Al-4V Scaffolds with PDA‑mHA-Col I Composite Coating Drives Macrophage Polarization toward the M2 Phenotype and Promotes Immunomodulation: An In Vitro Study.","authors":"Xu Han, Hailong Yuan, Yi Xiao, Zhen Tang, Gang Tian, Jianyong Gao, Qi Cai, Lisong Lin, Xiaogang Xu","doi":"10.2174/0115665232490888260525103922","DOIUrl":"https://doi.org/10.2174/0115665232490888260525103922","url":null,"abstract":"<p><strong>Objective: </strong>To devise a bioactive surface functionalization approach for 3D-printed Ti- 6Al-4V scaffolds that influences macrophage polarization towards the pro-reparative M2 phenotype, therefore enhancing immunomodulation and facilitating good implant-soft tissue integration.</p><p><strong>Methods: </strong>Porous Ti-6Al-4V scaffolds were produced by selective laser melting and then covered with a polydopamine-multi-element-doped hydroxyapatite-type I collagen (PDA-mHA-Col I) composite. The scaffolds' physicochemical characteristics were characterized. Murine RAW264.7 macrophages were cocultured with uncoated (T) or coated (TPMC) scaffolds. Cell viability, proliferation, apoptosis, adhesion, and polarization were assessed via CCK-8 tests, EdU staining, flow cytometry, phalloidin staining, ELISA, and qRT-PCR. The NF-κB, PI3K/Akt, and STAT6 signaling pathways were examined using Western blotting and targeted inhibitors.</p><p><strong>Results: </strong>The PDA-mHA-Col I coating improved surface hydrophilicity while maintaining mechanical characteristics. XPS verified effective collagen immobilization, exhibiting a surface nitrogen concentration of 13.03%. The coating demonstrated stability after 7 days in PBS, retaining a nitrogen content of 11.74% and negligible titanium exposure. In comparison to the T group, the TPMC scaffold markedly enhanced macrophage adhesion, proliferation, and spreading, while diminishing apoptosis. It prompted M2 polarization, as shown by reduced expression of M1 markers (iNOS, CD86) and pro-inflammatory cytokines (TNF-α, IL-6), with elevated expression of M2 markers (Arg-1, CD206) and anti-inflammatory cytokines (IL-10, TGF-β1). The TPMC scaffold suppressed the phosphorylation of NF-κB p65 while simultaneously activating PI3K/Akt and STAT6 signaling pathways. The inhibition of PI3K or STAT6 somewhat mitigated the increase of M2 markers.</p><p><strong>Discussion: </strong>The coating created a pro-healing milieu by inhibiting inflammatory signals and stimulating pro-reparative pathways, thus tackling a significant obstacle in oral and maxillofacial bone repair.</p><p><strong>Conclusions: </strong>The PDA-mHA-Col I composite coating facilitates macrophage M2 polarization by concurrently inhibiting NF-κB and activating PI3K/Akt/STAT6 signaling, presenting a viable immunomodulatory approach for oral and maxillofacial bone restoration.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148197583","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}

{"title":"A Telomere-Maintenance Three-Gene Model for the Prognostic Prediction in Intrahepatic Cholangiocarcinoma and Multi-Cohort Validation.","authors":"Lihua Wang, Wenjing Zhao, Zhongfeng Cui, Guangming Li","doi":"10.2174/0115665232492924260525110747","DOIUrl":"https://doi.org/10.2174/0115665232492924260525110747","url":null,"abstract":"<p><strong>Introduction: </strong>Intrahepatic cholangiocarcinoma (iCCA) is characterized by heterogeneity and poor survival. It remains unclear how telomere maintenance programs influence the prognosis and immune microenvironment in iCCA, and clinically applicable, telomere‑anchored transcriptomic tools are currently lacking.</p><p><strong>Methods: </strong>Transcriptomes and survival data from TCGA-CHOL, GSE107943, and E-MTAB-6389 cohorts were integrated (n=135). Telomere maintenance gene (TMG) scores were calculated using GSVA and subsequently used for WGCNA module identification. Functional enrichment was analyzed with clusterProfiler (FDR-adjusted P < 0.05). A prognostic model was constructed using univariate Cox and LASSO-Cox regression analyses, and validated by Kaplan-Meier (KM) curve and time-dependent ROC. Immune features were inferred by MCPcounter, CIBERSORT, and ssGSEA algorithms. Drug sensitivity was predicted by pRRophetic, and the resulting IC50 estimates were then correlated with the RiskScore.</p><p><strong>Results: </strong>The TMG score was inversely correlated with the ESTIMATE score (Spearman ρ=-0.2439, P=0.0044). WGCNA identified a TMG-associated module enriched for cellcycle/ mitotic and microtubule functions. Three key TMGs (PTTG1, TSPYL5, PLLP) were integrated to develop a RiskScore that can consistently stratify overall survival (OS) in both the integrated set and all external cohorts, demonstrating a robust accuracy for 1-, 3-, and 5-year prognostic prediction. High-RiskScore tumors exhibited reduced immune infiltration across multiple deconvolution frameworks. The RiskScore was negatively correlated with predicted IC50 for several agents (e.g., pyrimethamine, GNF-2, NSC-87877, CGP-082996, KIN001-135), suggesting higher drug sensitivity in high-risk cases.</p><p><strong>Discussion: </strong>We identified a three-gene, telomere-related risk score for iCCA, which can effectively predict patients' survival and distinguish immune-cold, high-proliferation phenotypes. Potential targeted drugs for high-risk patients were predicted and supported by mechanistic validation.</p><p><strong>Conclusion: </strong>A compact telomere-anchored three-gene RiskScore was developed to predict the prognosis, immune contexture, and therapy sensitivity for iCCA.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148136902","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}