Journal of Translational Medicine最新文献

{"title":"Health-related quality of life in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post COVID-19 Condition: a systematic review.","authors":"Breanna Weigel, Maira Inderyas, Natalie Eaton-Fitch, Kiran Thapaliya, Sonya Marshall-Gradisnik","doi":"10.1186/s12967-025-06131-z","DOIUrl":"10.1186/s12967-025-06131-z","url":null,"abstract":"<p><strong>Purpose: </strong>Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Post COVID-19 Condition (PCC) are debilitating, chronic multi-systemic illnesses that require multidisciplinary care. However, people with ME/CFS (pwME/CFS) and people with PCC (pwPCC) are often precluded from accessing necessary disability and social support services. These unmet care needs exacerbate the existing illness burdens experienced by pwME/CFS and pwPCC. To deliver appropriate care and optimise health outcomes for pwME/CFS and pwPCC, the development of evidence-based healthcare policies that recognise the disabling impacts of these illnesses must be prioritised. This systematic review summarises the health-related quality of life (HRQoL) of pwME/CFS and pwPCC when compared with healthy controls (HCs) to elucidate the impacts of these illnesses and guide healthcare policy reform.</p><p><strong>Methods: </strong>CINAHL, Embase, MEDLINE, PubMed, PsycINFO and the Web of Science Core Collection were systematically searched from 1st January 2003 to 23rd July 2024. Eligible publications included observational studies capturing quantitative HRQoL data among pwME/CFS or pwPCC when compared with HCs. The use of validated patient-reported outcome measures (PROMs) was mandatory. Eligible studies were also required to employ the most stringent diagnostic criteria currently available, including the Canadian Consensus Criteria or International Consensus Criteria for ME/CFS and the World Health Organization case definition for PCC (PROSPERO ID: CRD42024501309).</p><p><strong>Results: </strong>This review captured 16 studies, including eight studies among pwME/CFS, seven studies among pwPCC and one study among both illness cohorts. Most participants were female and middle-aged. All pwPCC had experienced prolonged COVID-19 symptoms for at least three months. When compared with HCs, all HRQoL domains were significantly impaired among pwME/CFS and pwPCC. Both illnesses had a salient impact on physical health, including pain and ability to perform daily and work activities. While direct comparisons between pwME/CFS and pwPCC were limited by inconsistencies in the PROMs employed, comparable impact trends across HRQoL domain scores were observed.</p><p><strong>Conclusion: </strong>ME/CFS and PCC have similar, profound impacts on HRQoL that warrant access to multidisciplinary disability and social support services. Future research must harmonise HRQoL data collection and prioritise longitudinal investigations among pwME/CFS and pwPCC to characterise PCC subgroups (including those fulfilling ME/CFS criteria) and predictors of prognosis.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"318"},"PeriodicalIF":6.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615889","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":"MiR-451a attenuates hepatic steatosis and hepatitis C virus replication by targeting glycerol kinase.","authors":"Swagata Majumdar, Deeya Roy Chowdhury, Bidhan Chandra Chakraborty, Abhijit Chowdhury, Simanti Datta, Soma Banerjee","doi":"10.1186/s12967-025-06286-9","DOIUrl":"10.1186/s12967-025-06286-9","url":null,"abstract":"<p><strong>Background: </strong>Lipotoxicity is one of the causes for the progression of fatty liver in chronic hepatitis (CH) towards end-stage liver diseases. The role of miRNAs in the signalling pathways of lipid metabolism has been studied, but their direct targets in this pathway have not been identified yet. Here, we have characterized a downregulated miRNA in CH namely miR-451a, which has a direct impact on the lipid metabolism pathway.</p><p><strong>Methods: </strong>Liver tissue samples and blood were collected from CHC/CHB patients and normal individuals. Huh7 and SNU449 cell lines were used for in vitro assays. Expressions of miRNA/mRNAs and proteins were confirmed by qRT-PCR and immuno-blot analysis. Oil Red O staining, Colorimetric, and Fluorometric assay kit were used to quantify triglyceride (TG) and cholesterol from tissue and serum, respectively. Target prediction and pathway analysis were performed using Targetscan, miRWalk, and DAVID respectively. 3'UTR-Luciferase assay and Co-immuno-precipitation were conducted to determine direct interaction between miRNA-mRNA and protein-protein, respectively. Unpaired two-tailed Student's t-test and Mann-Whitney test were employed as required using GraphPad prism. P < 0.05 was considered as significant.</p><p><strong>Results: </strong>The miRNA, miR-451a was selected as one of the downregulated miRNAs in progressive liver disease stages of CHC and CHB. Target identification and pathway analysis of this miRNA revealed that lipid metabolism pathway gene, glycerol kinase (GK), could be the target of this miRNA. Subsequent 3'UTR Luciferase assay and immuno-blot analysis confirmed the binding of miR-451a to GK. Though both hepatitis viruses, HCV and HBV, could alter the lipid metabolism pathways, intracellular TG and cholesterol content were observed to be significantly higher upon HCV infection only. It also suppressed the expression of miR-451a, resulting in overshooting of GK expression. GK interacted positively with the transcription factor SREBP1, which led to overexpression of Fatty acid synthase, Acetyl- CoA Carboxylase, and Stearoyl-CoA desaturase. As a result, intracellular fatty acids, TG, and cholesterol synthesis and accumulation heightened but trafficking dropped, resulting in hypo-cholesterolemia in blood. While, restoration of miR-451a impeded lipid accumulation, reduced steatohepatitis and suppressed HCV replication as well.</p><p><strong>Conclusion: </strong>These findings suggest that the alteration in the hepatic lipid profile upon HCV/HBV infection is attributed to the downregulation of miR-451a, which has the potential to restrict the expression of GK and SREBP1 in the TG biosynthesis pathway, implying that supplementation of miR-451a may be a potential therapeutic strategy for impeding CHC.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"322"},"PeriodicalIF":6.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11907786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625066","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":"Gender differences in eating habits and sports preferences across age groups: a cross-sectional study.","authors":"Stefania Gorini, Elisabetta Camajani, Edda Cava, Alessandra Feraco, Andrea Armani, Isaac Amoah, Tiziana Filardi, Xinyan Wu, Rocky Strollo, Massimiliano Caprio, Elvira Padua, Mauro Lombardo","doi":"10.1186/s12967-025-06311-x","DOIUrl":"10.1186/s12967-025-06311-x","url":null,"abstract":"<p><strong>Background: </strong>Gender differences in dietary habits, physical activity and body composition are key determinants of health and disease risk. Although these differences are well documented, their variation across age groups remains poorly explored. This study examines gender-specific patterns in eating behaviours, sport preferences and body composition metrics, with the aim of providing evidence for tailored public health interventions.</p><p><strong>Methods: </strong>A cross-sectional study was conducted on 2,276 participants (1,349 females and 927 males) aged 18-75 years. Recruitment combined an online survey and clinical assessments. Body composition was evaluated with bioelectrical impedance analysis (BIA) and eating habits were investigated with detailed weekly food diaries. Gender differences between five age groups were statistically analysed using chi-square and t-tests (p ≤ 0.05). The study protocol was approved by the Lazio Area 5 Ethics Committee.</p><p><strong>Results: </strong>Significant differences in body composition were observed between genders: men had a higher lean mass and basal metabolic rate, whereas women showed a higher fat mass in all age groups. Eating habits varied significantly: men preferred salty and protein-rich foods, consumed alcohol more frequently and showed a higher prevalence of meal skipping and uncontrolled eating behaviour. Women showed greater meal regularity, a preference for sweet tastes and a higher likelihood of eating alone in the older age groups. Sports participation differs markedly in the age group 30-39 years, in which men were predominantly involved in team sports, while women favoured strength training and skill activities.</p><p><strong>Conclusions: </strong>This study highlights the strong gender disparities in dietary and lifestyle behaviour, which evolve with age. These findings underline that tailored public health strategies, responding to gender-specific requirements, are needed to promote healthier lifestyles and reduce inequalities. Future studies should use longitudinal designs to explore causal relationships.</p><p><strong>Registered clinical studies: </strong>The study is registered on ClinicalTrials.gov (NCT06661330; registered 22 October 2024, retrospectively). Available at: https://clinicaltrials.gov/study/NCT06661330 .</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"312"},"PeriodicalIF":6.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11900493/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615884","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":"Mechanical forces in the tumor microenvironment: roles, pathways, and therapeutic approaches.","authors":"Yanli Zhang, Qi Fu, Wenyue Sun, Qiujuan Yue, Ping He, Dong Niu, Min Zhang","doi":"10.1186/s12967-025-06306-8","DOIUrl":"10.1186/s12967-025-06306-8","url":null,"abstract":"<p><p>Tumors often exhibit greater stiffness compared to normal tissues, primarily due to increased deposition within the tumor stroma. Collagen, proteoglycans, laminin, and fibronectin are key components of the extracellular matrix (ECM), interacting to facilitate ECM assembly. Enhanced fiber density and cross-linking within the ECM result in elevated matrix stiffness and interstitial fluid pressure, subjecting tumors to significant physical stress during growth. This mechanical stress is transduced intracellularly via integrins, the Rho signaling pathway, and the Hippo signaling pathway, thereby promoting tumor invasion. Additionally, mechanical pressure fosters glycolysis in tumor cells, boosting energy production to support metastasis. Mechanical cues also regulate macrophage polarization, maintaining an inflammatory microenvironment conducive to tumor survival. In summary, mechanical signals within tumors play a crucial role in tumor growth and invasion. Understanding these signals and their involvement in tumor progression is essential for advancing our knowledge of tumor biology and enhancing therapeutic approaches.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"313"},"PeriodicalIF":6.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11899831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615897","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":"Dietary and circulating omega-6 fatty acids and their impact on cardiovascular disease, cancer risk, and mortality: a global meta-analysis of 150 cohorts and meta-regression.","authors":"Reza Sadeghi, Mostafa Norouzzadeh, Minoo HasanRashedi, Sanaz Jamshidi, Hamid Ahmadirad, Mahdi Alemrajabi, Mohammadreza Vafa, Farshad Teymoori","doi":"10.1186/s12967-025-06336-2","DOIUrl":"10.1186/s12967-025-06336-2","url":null,"abstract":"<p><strong>Background: </strong>Despite the significant increase in omega-6 fatty acid consumption, evidence regarding their health impacts remains inconsistent. This study performs an umbrella review and updated meta-analysis to evaluate the association between dietary and circulating omega-6 levels and the risks of cardiovascular diseases (CVDs), cancer, and mortality.</p><p><strong>Methods: </strong>A systematic search was conducted in PubMed, Scopus, and Web of Science until January 2024 to identify eligible meta-analyses of prospective observational studies. The Cochrane risk of bias and GRADE tools were used to assess the risk of bias and certainty of the evidence, respectively.</p><p><strong>Results: </strong>Analysis of 150 publications revealed that higher dietary intake and circulating levels of omega-6 were associated with lower risks of CVDs, cancer incidence, and all-cause mortality in the general population, particularly for coronary heart disease and stroke. While omega-6 intake was linked to lower risks of lung and prostate cancers, it was associated with higher risks of ovarian and endometrial cancers. Subgroup analyses revealed that these protective associations were more pronounced in cohort studies and absent in populations with pre-existing health conditions.</p><p><strong>Conclusions: </strong>Higher dietary intake and circulating levels of omega-6 fatty acids were associated with lower risks of CVDs, cancers, and all-cause mortality. However, the associations vary by cancer type and are less evident in individuals with pre-existing health conditions. These findings highlight the potential benefits of omega-6 fatty acids for public health while underscoring the need for further research to address specific risks and underlying mechanisms.</p><p><strong>Trial registration: </strong>Registration number (PROSPERO): CRD42024522842.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"314"},"PeriodicalIF":6.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11899657/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615881","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":"Decreased complement 4 and interleukin-10 as biomarkers in aqueous humour for non-exudative age-related macular degeneration: a case control study.","authors":"Juliane Schikora, Aaron Dort, Hannah N Wolf, Mihály Józsi, Richard B Pouw, Thomas Bertelmann, Dirk Bahlmann, Christian van Oterendorp, Nicolas Feltgen, Hans Hoerauf, Diana Pauly, Jannis Klemming","doi":"10.1186/s12967-024-05909-x","DOIUrl":"10.1186/s12967-024-05909-x","url":null,"abstract":"<p><strong>Background: </strong>The development of age-related macular degeneration (AMD) is influenced by risk factors that contribute to inflammatory processes, cellular stress responses, and a dysregulation of the complement system. Given the incomplete understanding of the pathogenesis of AMD and the necessity for novel therapeutics, biomarker studies investigating aqueous humour from the anterior chamber of the eye serve as a valuable tool. This pilot study aimed to assess inflammatory mediators and complement components in aqueous humour of non-exudative AMD patients in comparison with a control group.</p><p><strong>Methods: </strong>The aqueous humour of 12 non-exudative AMD patients and 21 control subjects was collected during cataract surgery. Levels of 78 inflammatory proteins and complement components were measured using multiplex immunoassays. The influence of sex or smoking on the AMD status was assessed using Pearson's chi-square test. Biomarker levels between AMD patients vs. controls, smokers vs. non-smokers, and females vs. males were compared. Parametric datasets were analysed using independent-means t-test, while non-parametric data analysis was conducted utilising Wilcoxon's rank-sum test. Spearman's correlation investigated associations between drusen volume and biomarker levels, as well as biomarker levels and subject age.</p><p><strong>Results: </strong>All examined 78 immunological factors were detectable in aqueous humour. The proteins were categorised into high, medium, and low level groups. Aqueous humour contained high levels of complement proteins, including iC3b, FH/FHL-1, C4B, and FI. Non-exudative AMD patients exhibited decreased levels of C4 (P = 0.020), IL-10 (P = 0.033), and FI (P = 0.082). A positive correlation was observed between drusen volume and CCL4 levels (r_S = 0.78, P = 0.013). Furthermore, smokers demonstrated significantly increased levels of pro-inflammatory proteins (CCL7, IL-7; P = 0.027, P = 0.030). MMP-1 was positively correlated with age (r_S = 0.44, P = 0.010), while sex differences were observed in FB (P = 0.027) and C4B (P = 0.036) levels.</p><p><strong>Conclusions: </strong>This pilot study presents an initial overview of inflammation-associated biomarkers in the aqueous humour, highlighting potential roles for C4 and IL-10 in the development of non-exudative AMD. A larger, more-focused follow-up study is in progress to further investigate biomarkers localised to the eye and refine our understanding of AMD.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"317"},"PeriodicalIF":6.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615878","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":"IP6K2 mutations as a novel mechanism of resistance to oncolytic virus therapy.","authors":"Zhijian Huang, Xiangqian Zhao, Zirong Jiang, Xiaoting Qiu, Xinhao Sun, Dawei Wang, Hucheng Zhang, Qi Chen, Ruirong Tan, Yangkun Shen","doi":"10.1186/s12967-025-06265-0","DOIUrl":"10.1186/s12967-025-06265-0","url":null,"abstract":"<p><strong>Background: </strong>Oncolytic virus therapy (OVT) represents a promising frontier in cancer treatment. Despite its efficacy in clinical trials, variability in patient response, particularly resistance development, highlights the need for tailored therapeutic strategies.</p><p><strong>Methods: </strong>The Inositol Hexakisphosphate Kinase 2 (IP6K2) gene knock out was carried by CRISPR/Cas9 system. The evaluation of biomarkers of apoptosis and relevant pathways was conducted to be assessed. Attachment assay was conducted to verify the binding ability of virus to the host cells. Cell proliferation and apoptosis was assessed. Subcutaneous xenograft model was used to evaluate IP6K2 knock out influence in vivo. cBioPortal and TCGA database were applied to analyze genomic alterations in pan-cancer.</p><p><strong>Results: </strong>IP6K2 was essential for effective Herpes Simplex Virus Type1 (HSV-1) replication and subsequent cell apoptosis, acting through the tumor Protein p53 (p53) and Cyclin-Dependent Kinase Inhibitor 1 A (p21) signaling axis. The tumor model demonstrated that tumors lacking IP6K2 exhibited resistance to HSV-1 oncolysis, resulting in diminished therapeutic outcomes. Analysis of cBioPortal and TCGA databases corroborated the potential resistance stemming from IP6K2 mutations across various cancer types, underscoring the necessity for pre-treatment IP6K2 status assessment.</p><p><strong>Conclusions: </strong>This study underscores the role of IP6K2 as potential markers of resistance, which opens avenues for precision medicine approaches in OVT.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"311"},"PeriodicalIF":6.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11900485/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615892","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":"Notch signaling in the tumor immune microenvironment of colorectal cancer: mechanisms and therapeutic opportunities.","authors":"Jiachun Sun, Yi Chen, Ziyi Xu, Weizheng Wang, Penghui Li","doi":"10.1186/s12967-025-06282-z","DOIUrl":"10.1186/s12967-025-06282-z","url":null,"abstract":"<p><p>Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide, driven by a complex interplay of genetic, environmental, and immune-related factors. Among the pivotal pathways implicated in CRC tumorigenesis, the Notch signaling pathway is instrumental in governing cell fate decisions, tissue renewal, homeostasis, and immune cell development. As a highly conserved mechanism, Notch signaling not only modulates tumor cell behavior but also shapes the immune landscape within the tumor microenvironment (TME). Aberrant Notch signaling in CRC fosters immune evasion and tumor progression through its effects on the balance and functionality of immune cells, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Elevated Notch pathway activation correlates with advanced clinicopathological features and poorer clinical outcomes, highlighting its relevance as both a prognostic biomarker and a therapeutic target. Therapeutic approaches aimed at inhibiting the Notch pathway, such as γ-secretase inhibitors (GSIs) or monoclonal antibodies (mAbs) in combination with other therapies, have demonstrated promising efficacy in preclinical and clinical settings. This review examines the impact of Notch signaling on CRC immunity, elucidating its regulatory mechanisms within immune cells and its role in promoting tumor progression. Additionally, this review discusses therapeutic strategies targeting Notch signaling, including GSIs, mAbs, and potential combination therapies designed to overcome resistance and improve patient outcomes. By elucidating the multifaceted role of Notch within the CRC TME, this review underscores its potential as a target for innovative therapeutic strategies.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"315"},"PeriodicalIF":6.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11900264/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615831","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":"Metabolic expression profiling analysis reveals pyruvate-mediated EPHB2 upregulation promotes lymphatic metastasis in head and neck squamous cell carcinomas.","authors":"Jingjing Miao, Boyu Chen, Lu Zhang, Zhongming Lu, Rui Wang, Chunyang Wang, Xingyu Jiang, Qi Shen, Yue Li, Dongni Shi, Ying Ouyang, Xiangfu Chen, Xiaowu Deng, Siyi Zhang, Hequn Zou, Shuwei Chen","doi":"10.1186/s12967-025-06305-9","DOIUrl":"10.1186/s12967-025-06305-9","url":null,"abstract":"<p><p>Lymphatic metastasis is a well-known factor for initiating distant metastasis of head and neck squamous cell carcinoma (HNSCC), which caused major death in most patients with cancer. Meanwhile, metabolic reprogramming to support metastasis is regarded as a prominent hallmark of cancers. However, how metabolic disorders drive in HNSCC remains unclear. We firstly established a new classification of HNSCC patients based on metabolism gene expression profiles from the TCGA and GEO database, and identified an enriched carbohydrate metabolism subgroup which was significantly associated with lymphatic metastasis and worse clinical outcome. Moreover, we found that highly activated pyruvate metabolism endowed tumors with EPHB2 upregulation and promoted tumor lymphangiogenesis independently of VEGF-C/VEGFR3 signaling pathway. Mechanically, high nuclear acetyl-CoA production from pyruvate metabolism promoted histone acetylation, which in turn transcriptionally upregulated EPHB2 expression and secretion in tumor cells. EPHB2 bound with EFNB1 in lymphatic endothelial cells promoted YAP/TAZ cytoplasmic retention, which alleviated YAP/TAZ-mediated prospero homeobox protein 1 (PROX1) transcriptional repression, and then triggered tumor lymphangiogenesis. Importantly, combined treatment with EFNB1-Fc and VEGFR3 inhibitor synergistic abrogated lymphangiogenesis in vitro and in vivo, suggesting that targeting EPHB2 might be a potential strategy to patients with no or slight response to VEGFR3 inhibitor. These findings uncover the mechanism by which pyruvate metabolism is linked to lymphatic metastasis of tumor and provides a promising therapeutic strategy for the prevention of HNSCC metastasis.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"316"},"PeriodicalIF":6.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11899055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615898","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":"The FKBPL-based therapeutic peptide, AD-01, protects the endothelium from hypoxia-induced damage by stabilising hypoxia inducible factor-α and inflammation.","authors":"Sahar Ghorbanpour, Siân Peta Cartland, Hao Chen, Sanchit Seth, Rupert C Ecker, Claire Richards, Dunja Aksentijevic, Matthew P Padula, Louise Cole, Majid Ebrahimi Warkiani, Mary Meltem Kavurma, Lana McClements","doi":"10.1186/s12967-025-06118-w","DOIUrl":"10.1186/s12967-025-06118-w","url":null,"abstract":"<p><strong>Background: </strong>Endothelial dysfunction is a hallmark feature of cardiovascular disease (CVD), yet the underlying mechanisms are still poorly understood. This has impeded the development of effective therapies, particularly for peripheral artery disease. FK506-binding protein like (FKBPL) and its therapeutic peptide mimetic, AD-01, are crucial negative regulators of angiogenesis, however their roles in CVD are unknown. In this study, we aimed to elucidate the FKBPL-mediated mechanisms involved in regulating endothelial dysfunction induced by hypoxia or inflammation, and to determine whether AD-01 can effectively restore endothelial function under these conditions.</p><p><strong>Methods: </strong>Hindlimb ischemia was induced in mice by ligating the proximal and distal ends of the right femoral artery, and, after three days, the gastrocnemius muscle was collected for immunofluorescence staining, and RNA extraction. A 3D in vitro microfluidics model was developed to determine the endothelial cell migration and impact of FKBPL following treatments with: (i) 24 µM FKBPL targeted siRNA, (ii) 1 mM hypoxia inducible factor (HIF-1)α activator (DMOG), (iii) 50% (v/v) macrophage conditioned media (MCM), ± 100 nM AD-01. Unbiased, untargeted proteomic analysis was conducted via LC-MS/MS to identify protein targets of AD-01.</p><p><strong>Results: </strong>FKBPL expression is substantially downregulated in mice after hindlimb ischemia (p < 0.05, protein; p < 0.001, mRNA), correlating with increased neovascularization and altered vascular adhesion molecule expression. In our real-time advanced 3D microfluidics model, hypoxia suppressed FKBPL (p < 0.05) and VE-cadherin (p < 0.001) expression, leading to increased endothelial cell number and migration (p < 0.001), which was restored by AD-01 treatment (p < 0.01). Under inflammatory conditions, FKBPL (p < 0.01) and HIF-1α (p < 0.05) expression was elevated, correlating with increased endothelial cell migration (p < 0.05). Unlike hypoxia, AD-01 did not influence endothelial cell migration under inflammatory conditions, but normalized FKBPL (p < 0.001), HIF-1α (p < 0.05) and CD31 (P < 0.05), expression, in 3D microfluidic cell culture. Proteomic analysis revealed that AD-01 treatment in hypoxia enhanced the abundance of tissue remodelling and vascular integrity proteins including collagen alpha-1(XIX) chain and junctional cadherin associated-5 (JCAD) proteins.</p><p><strong>Conclusions: </strong>FKBPL represents an important novel mechanism in hypoxia and inflammation-induced angiogenesis. The FKBPL-based therapeutic peptide, AD-01, could be a viable treatment option for CVD-related endothelial cell dysfunction.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"309"},"PeriodicalIF":6.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11895374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605028","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}