EBioMedicine最新文献

{"title":"Systematic design of DMBT1-derived peptides correlating physicochemical properties and sequence motifs with siRNA delivery and efficacy in cancer therapy.","authors":"Martina Tuttolomondo, Mikkel Green Terp, Nazmie Kalisi, Stefan Vogel, Henrik Jørn Ditzel","doi":"10.1016/j.ebiom.2025.105977","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105977","url":null,"abstract":"<p><strong>Background: </strong>Molecules driving the cancer process are frequently difficult to target with traditional small-molecule drugs. Small interfering RNAs (siRNAs) offer high specificity, but their clinical translation is hindered by inefficient delivery and rapid degradation. We previously identified DMBT1-derived cell-penetrating peptides (CPPs) that encapsulate siRNA and improve serum stability in vitro.</p><p><strong>Methods: </strong>We designed 37 DMBT1-derived peptides using a rational, high-throughput pipeline to enhance siRNA encapsulation, stability, and delivery. Binding, uptake, and silencing were assessed in A375 and MCF7 cells. Regression and motif discovery analyses were applied to link peptide physicochemical features with encapsulation efficiency, serum stability, and gene silencing.</p><p><strong>Findings: </strong>Twenty-seven peptides showed improved siRNA binding and 20 achieved robust uptake in serum. We identified a conserved motif, SWGRVRVLRGDKW, enriched in complexes achieving >75% knockdown, associated with efficient cytosolic release. HE25 emerged as the lead peptide, delivering BRAF^V600E-siRNA and significantly reducing A375 proliferation in vitro. In female NOG CIEA mice xenografts, HE25 suppressed tumour growth, while repeated intravenous dosing in BALB/c mice confirmed biosafety.</p><p><strong>Interpretation: </strong>Targeted optimisation combined with motif-based design establishes a framework for developing next-generation CPPs. The identification of a conserved motif driving efficient delivery highlights new opportunities for advancing siRNA therapeutics in cancer and beyond.</p><p><strong>Funding: </strong>This work was supported by Novo Nordisk Foundation, Villum Foundation, Lundbeck Foundation, A.P. Møller Foundation, Dagmar Marshalls Foundation, Neye Foundation, Fabrikant Einar Willumsens Mindelegat, and Direktør Michael Hermann Nielsens Mindelegat.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"121 ","pages":"105977"},"PeriodicalIF":10.8,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145354077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The circulating dihydrotestosterone/testosterone ratio is increased by gut microbial 5α-reductase activity in females.","authors":"Claes Ohlsson, Lei Li, Karin Horkeby, Lina Lawenius, Hannah Colldén, Klara Sjögren, Gabriel Baldanzi, Gunnar Engström, Johan Ärnlöv, Marju Orho-Melander, Tove Fall, Louise Grahnemo","doi":"10.1016/j.ebiom.2025.105978","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105978","url":null,"abstract":"<p><strong>Background: </strong>Dihydrotestosterone (DHT), the most potent ligand to the androgen receptor, is synthesised from testosterone (T) by 5α-reductase type 1 and 2. While type 1 is expressed in several non-reproductive tissues in both sexes, men also express high levels of the high-affinity type 2 isoform in reproductive tissues; yet women have a higher circulating DHT to T (DHT/T) ratio than men. We hypothesised that the high DHT/T ratio in women is caused by high gut microbiota (GM) 5α-reductase activity or altered β-glucuronidase-induced androgen reabsorption from the gut.</p><p><strong>Methods: </strong>We used a large cross-sectional subsample of the Swedish CArdioPulmonary bioImage Study (2897 women and 4338 men, 50-65 years of age) with GM composition and functionality determined by metagenome sequencing and circulating androgens determined by liquid chromatography-tandem mass spectrometry.</p><p><strong>Findings: </strong>We confirmed that women had higher (+194%) circulating DHT/T ratio than men. The relative abundance of microbial genes for 5α-reductase type 1 (P = 3 × 10^-4), but not β-glucuronidase, was positively associated with the DHT/T ratio in women. In women, the GM relative abundances of Odoribacter splanchnicus and Parabacteroides distasonis were positively associated with the relative abundance of microbial genes for 5α-reductase type 1 (P < 2 × 10^-149) and the circulating DHT/T ratio (O. splanchnicus P = 3 × 10^-6; P. distasonis P = 5 × 10^-5). In mechanistic studies, we observed very high DHT/T ratio in intestinal content of female conventionally-raised but not germ-free mice. In female mice, the DHT/T ratio was 86.9% higher in serum from the portal vein than in inferior vena cava (P = 0.007).</p><p><strong>Interpretation: </strong>These findings demonstrate that the circulating DHT/T ratio is increased by GM 5α-reductase activity in females. We propose that the GM acts as an endocrine organ influencing the androgenic status in females.</p><p><strong>Funding: </strong>See Acknowledgements.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"121 ","pages":"105978"},"PeriodicalIF":10.8,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145344129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The tectorial membrane has a critical role in metabolic age-related hearing loss.","authors":"Sonal Prasad, Marja Pitkänen, Anders Fridberger","doi":"10.1016/j.ebiom.2025.105976","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105976","url":null,"abstract":"<p><strong>Background: </strong>Millions of older adults have age-related hearing loss (ARHL), a disorder where potassium-secreting cells in the cochlea's lateral wall often degenerate. The degeneration reduces the force that drives ions into the sensory cells during sound stimulation, which is traditionally thought to explain the loss of hearing. Here we describe previously unknown mechanisms underlying this metabolic form of ARHL.</p><p><strong>Methods: </strong>Fluorescence spectroscopy and live-cell imaging was used in Dunkin-Hartley guinea pigs of either sex to investigate the effects of lateral wall dysfunction on the hearing organ and its accessory structures. Critical findings were confirmed by studying samples of human temporal bones.</p><p><strong>Findings: </strong>Lateral wall dysfunction caused calcium levels in the inner ear to decline, a change that was most pronounced in the tectorial membrane, an accessory structure crucial for transmitting acoustic stimuli to sensory cell stereocilia. This calcium depletion deprived the sensory cells of an essential ion. Additionally, the tectorial membrane detached from stereocilia, significantly impairing their ability to respond to sound. Sound-evoked responses were further decreased by sustained contraction of the entire hearing organ.</p><p><strong>Interpretation: </strong>These findings establish the tectorial membrane as a key factor in metabolic ARHL, which needs to be considered when developing better diagnostic tools or treatments.</p><p><strong>Funding: </strong>Swedish Research Council grants 2017-06092 and 2022-00548, Swedish Brain foundation grant FO2023-0171 and US National Institutes of Health grant R01DC000141-44.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"121 ","pages":"105976"},"PeriodicalIF":10.8,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pre-admission fine particulate matter exposure is associated with invasive pulmonary aspergillosis in patients with severe pneumonia, results from two multicenter cohort studies.","authors":"Hua Zhou, Shupeng Zhu, Yujing Li, Xindie Ren, Yancheng Zhu, Xiyao Chen, Anqi Jiao, Haidong Kan, John S Ji, Weijun Li, Chunyu Wang, Hongliu Cai, Hongyu Wang, Xiaohan Huang, Kangchen Li, Yinghe Xu, Wenxiao Zhang, Peng Shen, Xuwei He, Lin Zhong, Nan Wang, Fengqi Liu, Jin-Fu Xu, Chao Jiang, Lingtong Huang","doi":"10.1016/j.ebiom.2025.105971","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105971","url":null,"abstract":"<p><strong>Background: </strong>Aspergillus, the causative pathogen of invasive pulmonary aspergillosis (IPA)-a highly lethal infectious disease-produces spores with diameters that fall within the fine particulate matter (PM_2.5) range and are frequently detected in ambient PM_2.5 samples. In this study, we investigated whether pre-admission exposure to PM_2.5 is associated with an increased risk of IPA in patients with severe pneumonia.</p><p><strong>Methods: </strong>Daily PM_2.5 levels for the six months before admission were obtained from a multicenter retrospective cohort and a multicenter prospective cohort. Multivariable logistic regression was used to assess whether pre-admission PM_2.5 exposure is an independent risk factor of IPA in both cohorts. Pooled concentration-response curves determined the dose-response relationship. Mediation analysis was used to assess whether the presence of Aspergillus acts as a mediator between PM_2.5 exposure and 28-day mortality.</p><p><strong>Findings: </strong>Among 2287 patients, higher average daily PM_2.5 exposure over six-month before admission was independently associated with an increased risk of IPA. For every 10 μg/m³ increase in average daily PM_2.5 exposure during the six months before admission, the risk of IPA increased by 21% (95% CI: 10%-32%). The dose-response relationship was linear, and results remained robust across subgroups and sensitivity analyses. Mediation analysis showed that Aspergillus positivity was found to mediate 21.26% (95% CI: 4.5%-48%; P = 0.008) of the relationship between daily PM_2.5 exposure in the 90 days preceding admission and 28-day mortality.</p><p><strong>Interpretation: </strong>In this study, we evaluate the association between pre-admission PM_2.5 exposure and IPA. Our findings demonstrate that higher concentrations of PM_2.5 prior to admission are associated with an increased risk of IPA among ICU-admitted patients with severe pneumonia. In addition, our findings suggest that Aspergillus mediate the association between PM_2.5 exposure and mortality in this population.</p><p><strong>Funding: </strong>This work was supported by National Science and Technology Major Project of China (2025ZD0549000), National Natural Science Foundation of China (grant no. 82202356, 82341109, and 82173645), the Zhejiang Provincial Natural Science Fund (grant no. LTGY24H190001), \"Pioneer\" and \"Leading Goose\" R&D Program of Zhejiang (grant no. 2025C02090).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"121 ","pages":"105971"},"PeriodicalIF":10.8,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Delphi study on valuing DNA sequencing in oncology: a European stakeholder developed framework for assessing next generation sequencing and comprehensive genomic profiling diagnostics.","authors":"Augustovski Federico, Chavez Danitza, Haig Madeleine, Main Caitlin, Argento Fernando, Colaci Carla, Mills Mackenzie, Alfie Verónica, Pichon-Riviere Andrés, Alcaraz Andrea, Kanavos Panos","doi":"10.1016/j.ebiom.2025.105947","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105947","url":null,"abstract":"<p><strong>Background: </strong>Advanced genomic technologies like Next Generation Sequencing and Comprehensive Genomic Profiling are pivotal for the prevention, management and treatment of cancer by identifying crucial genetic markers. However, their adoption in Europe is inconsistent, partly due to the lack of a validated approach to assessing their value.</p><p><strong>Methods: </strong>A multi-phase mixed-methods approach was implemented, integrating a systematic review and multi-stakeholder consensus-generating Delphi exercise to derive a comprehensive set of value criteria and arrive at a value assessment framework. This value assessment framework adapted an existing Latin American-focused diagnostic framework to the European context. The Delphi included representatives from the broader stakeholder community (patient advocacy, industry, decision-makers, health technology assessment, regulators, academia, and physicians). Over four rounds, participants refined and rated the significance of these criteria in the context of the assessment of the specified technologies in oncology, particularly for reimbursement decisions. Responses were analysed in terms of stability and level of consensus in order to generate a final value assessment framework.</p><p><strong>Findings: </strong>34 individuals participated in all rounds of the Delphi exercise. The final value assessment framework includes 8 distinct value criteria, including: clinical impact; test performance and quality; quality of scientific evidence; non-clinical impact; impact on health system integration, organisation and delivery of care; economic aspects; ethical and governance concerns; and health system priorities. Within these criteria, a total of 27 distinct sub-criteria were identified, 23 of which had consensus as 'important' or 'very important' in assessing value.</p><p><strong>Interpretation: </strong>The resultant value assessment framework is validated by a wide range of key European stakeholders and enables systematic assessment of Next Generation Sequencing and Comprehensive Genomic Profiling technologies used in oncology diagnostics within the European setting. The framework includes aspects that are not adequately considered in current health technology assessment and goes beyond existing value assessment frameworks through the inclusion of newer criteria such as data governance concerns.</p><p><strong>Funding: </strong>Funding was provided by the Precision Cancer Consortium with an unrestricted educational grant.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"121 ","pages":"105947"},"PeriodicalIF":10.8,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Testosterone and pre-androgens by age and menopausal stage at midlife: findings from a cross-sectional study.","authors":"Yuanyuan Wang, Rakibul M Islam, Molly Bond, Susan R Davis","doi":"10.1016/j.ebiom.2025.105972","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105972","url":null,"abstract":"<p><strong>Background: </strong>Whether testosterone and the pre-androgens, androstenedione and dehydroepiandrosterone (DHEA) change at menopause remains uncertain.</p><p><strong>Methods: </strong>The Australian Women's Midlife Years Study recruited a nationally representative sample of 8096 women aged 40-69 years, between 27th October 2023 and 19th March 2024. Participants were excluded from providing a blood sample if pregnant, breastfeeding, using medications that affect sex hormone concentrations, or living over 100 km from a collection centre. Sex steroids were measured by liquid chromatography-tandem mass spectrometry and menopausal status was determined by the Stages of Reproductive Ageing Workshop (STRAW) + 10 criteria.</p><p><strong>Findings: </strong>Blood samples were provided by 1435 of the 5031 invited participants. After excluding participants with no menopause stage classification, abnormal thyroid function, hyperprolactinemia, bilateral oophorectomy, and an unreported pregnancy, 1104 participants, mean (SD) age 56.5 (8.5) years, were included in the main analysis. Median testosterone concentrations declined between the ages of 40-44 and 55-59 years (median (interdecile range) 0.56 (0.29-1.01) nmol/L vs 0.42 (0.21-0.79) nmol/L, p = 0.001 adjusted for BMI and smoking), reached a nadir at the age of 58-59 years, followed by a modest increase, and did not differ between the youngest group and participants aged 60-64 or 65-69 years. Median androstenedione and DHEA concentrations declined from the age of 40-44 years to 65-69 years, by 51% and 33%, respectively. Testosterone and DHEA concentrations did not vary by menopausal stage in participants aged 48-53 years, whereas androstenedione concentrations were significantly higher in premenopausal, compared with postmenopausal individuals (median (IQR) 1.94 (1.42-2.54) nmol/L vs 1.63 (1.01-2.02) nmol/L, p = 0.001).</p><p><strong>Interpretation: </strong>Testosterone concentrations declined from the age of 40 years, reaching a nadir at approximately 58-59 years followed by a modest increase, with no impact of natural menopause. These data do not support menopause per se as an indication for testosterone supplementation.</p><p><strong>Funding: </strong>This research was supported by a National Health and Medical Research Council (NHMRC) Leadership 3 Investigator Grant award SRD (2016627).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"121 ","pages":"105972"},"PeriodicalIF":10.8,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Manganese-based nanozymes for the dynamic regulation of the osteogenic microenvironment.","authors":"Xinlin Li, Binmian Shi, Yupu Lu, Yameng Yu, Peng Yu, Yufeng Zheng, Dandan Xia","doi":"10.1016/j.ebiom.2025.105958","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105958","url":null,"abstract":"<p><p>In recent years, manganese-based nanozymes (MBNs)-featuring the combined advantages of nanomaterial properties, manganese-specific characteristics, and multi-enzyme mimetic activities-have demonstrated revolutionary potential in modulating the osteogenic microenvironment. This work systematically reviews the multidimensional regulatory pathways by which MBNs modulate the osteogenic microenvironment, including dynamic regulation of reactive oxygen species (ROS), remodelling of the immune microenvironment, synergistic promotion of neurovascularisation, antibacterial activity and infection control, and regulation of osteogenic cell fate. Additionally, the review outlines their specific applications in various pathological contexts, such as infected bone defects, osteosarcoma, osteoporosis, and periodontitis. Finally, the current challenges hindering the clinical translation of MBNs are critically analysed, and precision-oriented strategies for their development are proposed. These insights are pivotal for advancing the clinical translation of MBNs, particularly in treating refractory bone defects.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"121 ","pages":"105958"},"PeriodicalIF":10.8,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145307300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patterns of altered in vivo brain metabolism in patients with amyotrophic lateral sclerosis (ALS) and asymptomatic C9orf72 mutation carriers: a cross-sectional ¹H and ³¹P magnetic resonance spectroscopic 7T imaging study.","authors":"Henk-Jan Westeneng, Abram D Nitert, Kevin van Veenhuijzen, Carrie Wismans, Graziella Donatelli, Harold H G Tan, Wytse van Hoek, Michael A van Es, Dennis W J Klomp, Alex A Bhogal, Jan H Veldink, Jannie P Wijnen, Leonard H van den Berg","doi":"10.1016/j.ebiom.2025.105963","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105963","url":null,"abstract":"<p><strong>Background: </strong>Processes leading to the onset of neurodegeneration in amyotrophic lateral sclerosis (ALS) are largely unknown. To gain insight into disease mechanisms, we measured brain metabolism in vivo in asymptomatic C9orf72 mutation carriers and patients with ALS.</p><p><strong>Methods: </strong>We enroled 15 asymptomatic family members with (AFM C9+) and 18 without a C9orf72 mutation (AFM C9-), 4 patients with ALS with (ALS C9+) and 35 without this mutation (ALS C9-), and 25 population-based controls (CO). Two-dimensional proton (¹H) and whole-brain phosphorus (³¹P) magnetic resonance spectroscopic imaging (MRSI) data were obtained using a 7T MR scanner. 11 brain metabolites were compared between groups using weighted Bayesian linear multilevel models.</p><p><strong>Findings: </strong>Compared to AFM C9-, AFM C9+ showed evidence of neuronal dysfunction (decreased total N-acetyl aspartate/total creatine (tNAA/tCr)), widespread increased membrane breakdown product (glycerol phosphorylethanolamine/phosphocreatine (GPE/PCr)), glutamate excitotoxicity (increased glutamate + glutamine/tNAA (Glx/tNAA)) and, in frontoparietal regions, an increase in the glycogen precursor uridine diphosphoglucose/PCr (UDPG/PCr). Compared to AFM C9+, neuronal dysfunction and membrane breakdown are similar in ALS C9+, but glutamate excitotoxicity and increased glycogen precursor are more severe and widespread, also involving the primary motor region. Moreover, lower total adenosine triphosphate/PCr (tATP/PCr) emerged in ALS C9+, and signs of disturbed membrane synthesis, intracellular second messenger system and glial pathology (myo-inositol + glycine/tCr (mI + Gly/tCr)). ALS C9- is characterised by glutamate excitotoxicity, increased tATP/PCr, and lower phospholipid levels.</p><p><strong>Interpretation: </strong>¹H and ³¹P 7T MRSI can detect evolving patterns of altered brain metabolism in asymptomatic mutation carriers and patients with ALS. Abnormalities in patients with ALS C9+ appeared to be different from those in patients with ALS C9-. Metabolic markers, measured in vivo, can serve as biomarkers for inclusion or stratification as well as for drug-target engagement in clinical trials. This method can facilitate identification of new and personalised drug targets to prevent or treat this devastating disease.</p><p><strong>Funding: </strong>ALS Foundation Netherlands.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"121 ","pages":"105963"},"PeriodicalIF":10.8,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145307294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating multi-modal omics to identify therapeutic atherosclerosis pathways for coronary heart disease.","authors":"Sophie C de Ruiter, Marion van Vugt, Chris Finan, Diederick E Grobbee, Dominique P V de Kleijn, Gerard Pasterkamp, Hester M den Ruijter, Ernest Diez Benavente, Sanne A E Peters, A Floriaan Schmidt","doi":"10.1016/j.ebiom.2025.105966","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105966","url":null,"abstract":"<p><strong>Background: </strong>Urinary metabolism breakdown products reflect metabolic changes in atherosclerosis-relevant tissues and may contain relevant therapeutic leads. We integrated data on urinary metabolism breakdown products, plasma proteins, atherosclerotic plaque tissue, and single-cell expression to identify druggable metabolic pathways for coronary heart disease (CHD).</p><p><strong>Methods: </strong>Mendelian randomisation was employed to interrogate findings from independent genome-wide association studies on 954 urinary metabolism breakdown products, 1562 unique proteins, and 181,522 CHD cases, establishing directionally concordant associations. Using the Athero-Express Biobank, concordant plasma proteins were linked to plaque vulnerability using protein and mRNA expression in plaque. Single-cell RNA sequencing data obtained from carotid plaque samples were used to test for differential expression of concordant proteins across plaque cell types.</p><p><strong>Findings: </strong>In total, 29 urinary metabolism breakdown products associated with CHD, predominantly originating from amino acid metabolism (n = 12) or unclassified origin (n = 9). We identified 113 plasma proteins with directionally concordant associations with these urinary metabolism breakdown products and CHD. Of the 110 proteins available in plaque, 16 were associated with plaque vulnerability. This included positive control proteins targeted by drugs indicated for CHD, such IL6R (targeted by tocilizumab) and AT1B2 (targeted by digoxin), as well as a potential repurposing opportunity C1S (targeted by sutimlimab).</p><p><strong>Interpretation: </strong>We have identified amino acid metabolism as an important contributing pathway to CHD risk. These metabolism pathways were linked to 16 prioritised proteins relevant for CHD with involvement in atherosclerotic plaques, providing important insights for drug development.</p><p><strong>Funding: </strong>SR and SP are supported by a VIDI Fellowship (project number 09150172010050) from the Dutch Organisation for Health Research and Development (ZonMW) awarded to SP. AFS is supported by BHF grant PG/22/10989, the UCL BHF Research Accelerator AA/18/6/34223, the UCL BHF Centre of Research Excellence RE/24/130013, MR/V033867/1, the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and the EU Horizon scheme (AI4HF 101080430 and DataTools4Heart 101057849). MV is supported by a postdoc talent grant from the Amsterdam Cardiovascular Sciences. This work was funded by UK Research and Innovation (UKRI) under the UK government's Horizon Europe funding guarantee EP/Z000211/1, and by the Rosetrees CF-2-2023-M-2/122. This publication is part of the project \"Computational medicine for cardiac disease\" with file number 2023.022 of the research programme \"Computing Time on National Computer Facilities\" which is (partly) financed by the Dutch Research Council (NWO).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"121 ","pages":"105966"},"PeriodicalIF":10.8,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145307309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alterations of the nasal and oral microbiota in multiple sclerosis.","authors":"Shuqi Li, Federico Montini, Anya Song, Valerie Willocq, Emily Chan, Rebecca Shamah, Mira Weiner, Bonnie I Glanz, Howard L Weiner, Laura M Cox","doi":"10.1016/j.ebiom.2025.105959","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105959","url":null,"abstract":"<p><strong>Background: </strong>While changes in the gut microbiota have been reported in multiple sclerosis (MS), little is known about the nasal and oral microbiota, which are important modulators of the mucosal immune system. The gingival microbiota can drive systemic inflammation, the pharyngeal microbiota can lead to autoimmune-mediated neurologic diseases, and altered nasal bacterial toxigenic genes are reported in active MS.</p><p><strong>Methods: </strong>We investigated nasal, gingival, and oropharyngeal microbiota from 69 MS to 40 healthy control subjects by 16S rRNA sequencing and identified site-specific microbiota differences in both the nasal and oral microbiota related to relapsing and progressive MS. We identified microbes associated with MS diagnosis, disease progression, disease modifying therapy, smoking, and anatomical site using linear regression analysis while controlling for confounding factors and subject demographics.</p><p><strong>Findings: </strong>We identified site-specific microbiota differences in both the nasal and oral microbiota related to relapsing and progressive MS. Using baseline microbiota samples and clinical outcomes over time, we identified potential beneficial microbes, including Dolosigranulum pigrum in the nasal microbiota and Prevotella sp. in the oral microbiota, as well as potential detrimental Streptococcus sp. in the oral microbiota.</p><p><strong>Interpretation: </strong>Taken together, our data suggest that nasal and oral microbiota are altered in MS, are linked to the disease course and provide an avenue to better understand MS pathogenesis and treatment.</p><p><strong>Funding: </strong>This work was supported by the Nancy Davis Race to Erase MS Young Investigator Award (LMC), NIH/NINDS R01NS087226 (HLW), Water Cove Charitable Foundation (HLW), and the Clara E. and John H. Ware Jr. Foundation (HLW, LMC).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":" ","pages":"105959"},"PeriodicalIF":10.8,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145299263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}