Comput Methods Programs Biomed. 2025 Jul 8;270:108916. doi: 10.1016/j.cmpb.2025.108916. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: This study explores an extension of the classic Hawk and Dove evolutionary game model by considering the influence of environmental or external resources on the players' fitness. This allows us to model the resulting heterogeneous population dynamics, which is of great importance for simulating cancer population growth and optimizing anti-cancer therapies.

METHODS: To model population heterogeneity, we are using an extension of classical spatial evolutionary game theory by introducing multidimensional spatial evolutionary games (MSEG). This allows for the study of genetic heterogeneity on a multidimensional lattice. The classic Hawk and Dove model is modified to reflect the impact of external resources. Various types and shapes of resource functions were included in the payoff matrix and then simulated to examine their impact on the model's dynamics and population heterogeneity.

RESULTS: The results are presented in time-dependent plots for both mean-field and spatial models. Additionally, spatial 2D and 3D matrices are presented to show the spatial distribution of both phenotypes analyzed in the extended Hawk and Dove model. The results reveal significant differences between the mean-field and spatial models for the same parameter values. Furthermore, differences are observed when comparing models with different resource functions.

CONCLUSION: The two-phenotype model was used to show the influence of external, time- and phenotype-specific resource functions on the dynamics of the game's phenotypes. Moreover, the study highlights that spatial models, which provide more accurate information about population heterogeneity, can yield significantly different results compared to mean-field models.

PMID:40652752 | DOI:10.1016/j.cmpb.2025.108916

Discov Oncol. 2025 Jul 13;16(1):1324. doi: 10.1007/s12672-025-03101-1.

ABSTRACT

BACKGROUND: The genetic mechanisms underlying non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) remain understudied. While numerous genes associated with these lymphoid tumors have been identified, little research has focused on the genetic networks that directly drive NHL and HL pathogenesis.

METHODS: We conducted integrative genomic analyses, including a transcriptome-wide association study (TWAS), a proteome-wide association study (PWAS), and a summary-data-based Mendelian randomization (SMR), to identify causal genes for NHL and HL. TWAS and PWAS were performed using FUSION software by integrating GWAS data with gene and protein expression weights from large-scale datasets. The SMR analysis utilized cis-eQTL data to assess causal relationships between gene expression and lymphoma risk. Associations were deemed significant at p < 0.05.

RESULTS: The PWAS identified 106 proteins associated with NHL and 67 proteins associated with HL. The TWAS revealed 172 genes linked to NHL risk and 448 genes linked to HL risk. Finally, the SMR analysis highlighted 270 genes associated with NHL risk; there was with no evidence of heterogeneity in the HEIDI test, which supports pleiotropic effects. Key genes that influence NHL risk include KRT1, ERAP2, RMDN1, FAS, and C5, while UNC5B was identified as a significant causal gene for HL. Locus and effect plots were used to validate these findings by highlighting causal variants associated with lymphoma risks.

CONCLUSION: In this study, KRT1, ERAP2, RMDN1, FAS, C5, and UNC5B were identified as potential causal factors in lymphoma risk, underscoring mechanisms such as immune modulation and tumor suppression and providing insights into future therapeutic targets.

PMID:40652422 | DOI:10.1007/s12672-025-03101-1

J Proteome Res. 2025 Jul 13. doi: 10.1021/acs.jproteome.5c00285. Online ahead of print.

ABSTRACT

Early colorectal cancer (CRC) detection among inflammatory bowel disease improves treatment outcomes and survival. A sensitive and specific serum-based tool can bridge the gap between patient presentation and invasive colonoscopy, thereby enhancing early diagnosis. We screened serum biomarkers in colonoscopy-positive (CP, cancer) and colonoscopy-negative (CN, other bowel diseases) individuals, as well as in healthy controls (n = 20 each), to identify CRC-specific markers. Using data-independent acquisition-mass spectrometry, three proteins were identified as uniquely altered in the CP group compared with CN. We found that a serum protein called brain-specific angiogenesis inhibitor I-associated protein 3 was significantly overexpressed in CRC patients, which can distinguish CP patients from CN patients. Additionally, 19 neoantigen peptides specific to the CRC serum proteome were identified. Further validation in an independent set of samples (n = 10 per group) using parallel reaction monitoring was performed for the potential biomarker and neoantigen identified. These proteins were combined with carcinoembryonic antigen into a multiprotein panel, which enhanced diagnostic performance (AUC = 0.758), yielding 67% sensitivity, 64% specificity, and 65% accuracy. These findings support the potential of a targeted serum-based panel for preselecting symptomatic individuals for colonoscopic evaluation. However, further studies are needed in a larger cohort to evaluate clinical utility.

PMID:40652393 | DOI:10.1021/acs.jproteome.5c00285

Microbiome. 2025 Jul 12;13(1):162. doi: 10.1186/s40168-025-02139-1.

ABSTRACT

BACKGROUND: Mobile genetic elements (MGEs) drive horizontal gene transfer and microbial evolution, spreading adaptive genes across microbial communities. While extensively studied in other ecosystems, the role of MGEs in shaping ruminant gastrointestinal microbiomes-especially their impact on diversity, adaptation, and dietary responsiveness-remains largely unexplored. This study systematically profiles MGE distribution and functionality across gastrointestinal regions in multiple ruminant species to advance our understanding of microbial adaptation.

RESULTS: Across 2458 metagenomic samples from eight ruminant species, we identified 4,764,110 MGEs-a ~ 216-fold increase over existing MGE databases. These elements included integrative and conjugative elements, integrons, insertion sequences, phages, and plasmids, with mobilization patterns largely confined to closely related microbial lineages. The distribution of MGEs varied by GIT regions, often reflecting nutritional gradients. In a validation cohort, GH1-carrying plasmids enriched in carbohydrate-active enzymes were found to predominate in the stomach, showing notable responsiveness to forage-based diets. All annotated MGEs have been compiled into a publicly accessible database, rumMGE ( https://rummge.liulab-njau.com ), to support further research.

CONCLUSIONS: This study substantially expands the catalog of known MGEs in ruminants, revealing their diverse roles in microbial evolution and functional adaptation to dietary changes. The findings provide a valuable resource for advancing research on microbial functionality and offer insights with potential applications for enhancing ruminant health and productivity, through strategies aimed at modulating the microbiome in agricultural contexts. Video Abstract.

PMID:40652256 | DOI:10.1186/s40168-025-02139-1

NPJ Syst Biol Appl. 2025 Jul 12;11(1):76. doi: 10.1038/s41540-025-00554-6.

NO ABSTRACT

PMID:40651992 | DOI:10.1038/s41540-025-00554-6

Cell Stem Cell. 2025 Jul 4:S1934-5909(25)00231-0. doi: 10.1016/j.stem.2025.06.009. Online ahead of print.

ABSTRACT

ADP-heptose (ADP-Hep), a metabolite produced by gram-negative bacteria, is detected in the host cytosol by the kinase ALPK1, which engages TIFA-dependent innate immune responses. However, the function of ALPK1-TIFA signaling in primary cells and in physiological settings remains poorly understood. Here, we showed that, in the intestinal epithelium, ALPK1 and TIFA were mainly expressed by the intestinal stem cell (ISC) pool, where they controlled the replacement of homeostatic ISCs by new revival stem cells (revSCs) following injury. Mechanistically, ADP-Hep triggered pro-inflammatory nuclear factor κB (NF-κB) signaling and tumor necrosis factor (TNF)-dependent ISC apoptosis, which initiated a transforming growth factor β (TGF-β)- and YAP-dependent revSC program. Single-cell transcriptomics and lineage-tracing experiments identified Paneth cells as a cell of origin for revSC induction in response to ADP-Hep. In vivo, revSC emergence following irradiation or dextran-sodium-sulfate-induced injury was blunted in Tifa-/- mice. Together, our work reveals that ALPK1-TIFA signaling contributes to ISC turnover in response to bacterial detection in the intestine.

PMID:40651470 | DOI:10.1016/j.stem.2025.06.009

EBioMedicine. 2025 Jul 11;118:105839. doi: 10.1016/j.ebiom.2025.105839. Online ahead of print.

ABSTRACT

BACKGROUND: Cyanotic congenital heart disease (CCHD) affects over 3 million individuals globally and can progress to heart failure. Mitochondrial dysfunction is well established in adult heart failure and is also a central feature of CCHD. CCHD cyanosis itself contributes to further mitochondrial dysfunction. Systems biology methods detail the epigenomic, transcriptomic, and metabolomic profile of biological samples. This systematic review highlights CCHD systems biology literature related to mitochondrial dysfunction.

METHODS: OVID/Medline was searched between January 2010 and June 2025. Studies implementing untargeted systems biology methods in CCHD tissue or plasma were included. Genes with differential expression between CCHD and unaffected controls were pooled and analysed using GO term functional enrichment for pathway analysis, transcription factor and kinase enrichment, and metabolic pathways.

FINDINGS: From 31 included studies (genomic: n = 5, epigenomic: n = 3, transcriptomic: n = 23, proteomic: n = 2, metabolomic: n = 3, lipidomic: n = 1), we identified 8 pathogenic/likely pathogenic single nucleotide polymorphisms, 73 differentially methylated genes, 4170 differentially expressed genes, 173 differentially expressed proteins between CCHD versus unaffected controls. Several genes involved in mitochondrial respiratory chain (NDUFV1, NDUFV2, NDUFA5, NDUFS3, COX5A, COQ7) were identified.

INTERPRETATION: CCHD pathogenesis and progression are associated with mitochondrial dysfunction through changes in metabolism, fission, and fusion.

FUNDING: Vanier CIHR Scholarship, UHN Research Studentship, and Ontario Graduate Scholarship. Translational Biology and Engineering Program seed operating funds and research funding from the Heart and Stroke Foundation of Canada.

PMID:40651188 | DOI:10.1016/j.ebiom.2025.105839

Bioinformatics. 2025 Jul 12:btaf394. doi: 10.1093/bioinformatics/btaf394. Online ahead of print.

ABSTRACT

MOTIVATION: Modelling gene expression is a central problem in systems biology. Single-cell technologies have revolutionised the field by enabling sequencing at the resolution of individual cells. This results in a much richer data compared to what is obtained by bulk technologies, offering new possibilities and challenges for gene regulatory network inference.

RESULTS: In this work we introduce GRIT-a method to fit a differential equation model and to infer gene regulatory networks from single-cell data using the theory of optimal transport. The idea consists in tracking the evolution of the cell distribution over time and finding the system whose temporal marginals minimise the transport cost with the observations. GRIT is finally used to identify genes and pathways affected by two Parkinson's disease associated mutations.

AVAILABILITY AND IMPLEMENTATION: Matlab implementation of the method and code for data generation are at gitlab.com/uniluxembourg/lcsb/systems-control/grit together with a user guide. A snapshot of the code used for the results of this article is at doi : 10.5281/zenodo.15582432.

SUPPLEMENTARY INFORMATION: Supplementary material consisting of supplementary notes, figures, and tables is available at Bioinformatics online.

PMID:40650986 | DOI:10.1093/bioinformatics/btaf394

Bioinformatics. 2025 Jul 12:btaf398. doi: 10.1093/bioinformatics/btaf398. Online ahead of print.

ABSTRACT

SUMMARY: Legionella pneumophila has significantly contributed to multiple cases of pneumonia with a high rate of mortality globally. Its ability to exploit host mechanisms through several expressed virulence factors poses challenges for diagnosis, treatment, and outbreak control. To address this, we developed LegionProfiler, a computational tool that swiftly identifies virulence factor protein domains within genome assemblies of Legionella pneumophila serogroup 1 isolates and classifies them into high- or low-virulence groups. LegionProfiler automates the probing of genome assemblies for virulence-associated protein domains and determines the isolate's potential to cause severe pneumonia infection. The LegionProfiler workflow is made available through a user-friendly interface to enhance technical control of infectious sources and adds important insights to the general epidemiology of clinical isolates. It could also support the development of targeted therapeutic strategies that will improve patient treatment.

AVAILABILITY AND IMPLEMENTATION: LegionProfiler is freely accessible as a web service at https://legionprofiler.uni-muenster.de, and can also be run locally in a Docker container. The source code can be found at https://imigitlab.uni-muenster.de/heiderlab/legionprofiler or at Zenodo (DOI:10.5281/zenodo.15592325).

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:40650928 | DOI:10.1093/bioinformatics/btaf398

STAR Protoc. 2025 Jul 11;6(3):103932. doi: 10.1016/j.xpro.2025.103932. Online ahead of print.

ABSTRACT

Variational autoencoders (VAEs) can be used to model the gene expression space of single-cell RNA sequencing (scRNA-seq) data. Here, we present a protocol for using single-cell variational inference of dose response (scVIDR), a VAE designed to model single-cell gene expression for dose-dependent chemical perturbations. We describe steps to access the scVIDR code and data using a containerization application called Docker. We then detail procedures for training the sVIDR model and predicting gene expression. For complete details on the use and execution of this protocol, please refer to Kana et al.1.

PMID:40650899 | DOI:10.1016/j.xpro.2025.103932

Int J Legal Med. 2025 Jul 12. doi: 10.1007/s00414-025-03560-9. Online ahead of print.

ABSTRACT

Assigning a developmental stage is the most subjective step in dental age estimation. Therefore, clear stage definitions and proper observer calibrations are essential or high reliability and reproducibility. In this study, the reliability of the Demirjian method was assessed among 8 experts in DAE. The sample used were panoramic radiographs consisting of 50 healthy patients aged between 15 and 13.99 years old. Seven permanent teeth on the left side in both maxilla and mandible were selected to be examined. Further reference to both reliability and reproducibility will be referred as "reliability". The intra- and inter-rater reliability was assessed using Cohen's Kappa and Gwet's AC1/AC2 value for the overall tooth type, and specific tooth reliability. The intra-rater reliability gives an excellent reliability within observers ranging from 0.86 to 1. The inter-rater reliability was 0.962, with no difference between maxilla (0.950) and mandible region (0.954). Additionally, it was observed that canines and premolars have a lower agreement (0.934) compared to incisors and molars. Further detailed analysis for each tooth gives the lowest reliability to FDI 32 (0.868). Although the Demirjian staging method offers robust reliability for DAE with an emphasis on standardized protocols and examiner calibration, the performance of staging varies across different tooth types.

PMID:40650710 | DOI:10.1007/s00414-025-03560-9

Int J Mol Sci. 2025 Jul 1;26(13):6356. doi: 10.3390/ijms26136356.

ABSTRACT

Transmembrane channel-like (TMC) proteins are essential for hearing and balance; however, the molecular mechanisms that regulate their proper folding and membrane targeting remain poorly understood. Here, we establish Caenorhabditis elegans as a genetically tractable model to dissect TMC-1 trafficking by combining CRISPR knock-in strains, super-resolution microscopy, and genome-wide forward genetic screening. We show that TMC-1 robustly localizes to the plasma membrane in both neurons and muscle cells and identify a conserved valine (V803) in transmembrane domain 9 (TM9) as critical for its biogenesis and trafficking. Structural analyses guided by AlphaMissense and AlphaFold uncover two evolutionarily conserved functional hotspots, one in the extracellular loop adjacent to TM9 and the other in the TMC signature motif, which are interconnected by an evolutionarily conserved disulfide bond. Disrupting this bond in worm TMC-1 abolishes its cell-surface localization and destabilizes the mechanotransduction channel complex. Together, these findings provide a structural framework for interpreting deafness-causing mutations in human TMC1 and highlight disulfide-bond-linked hotspots as key molecular determinants of TMC protein biogenesis and trafficking.

PMID:40650136 | DOI:10.3390/ijms26136356

Int J Mol Sci. 2025 Jun 28;26(13):6267. doi: 10.3390/ijms26136267.

ABSTRACT

Circadian rhythms govern cellular metabolism, redox balance, and endocrine signaling in numerous tissues. However, chronic disturbance of these biological rhythms, mediated by modern lifestyle factors including shift work, sleep irregularity, and prolonged light exposure, has been increasingly associated with oxidative stress, metabolic dysregulation, and the pathogenesis of chronic diseases. This review discusses recent mechanistic advances that link circadian misalignment with tissue-specific metabolic reprogramming and impaired proteostasis, focusing on metabolic inflammation and associated pathologies. Emerging work reveals a close interdependence between the circadian clock and proteasome-mediated protein turnover and highlights this interplay's importance in maintaining redox homeostasis. Furthermore, circadian modulation of the activity of the inflammasome complex is suggested to represent an important, but largely unexplored, risk factor in the pathobiology of both malignancy and metabolic syndrome. Recently, researchers have proposed them as novel endocrine regulators of systemic energy balance and inflammation, with a focus on their circadian regulation. In addition, the emerging domains of chrono-epigenetics and tissue-specific programming of the clock pathways may serve to usher in novel therapies through precision medicine. Moving ahead, circadian-based therapeutic approaches, including time-restricted feeding, chronopharmacology, and metabolic rewiring, have high potential for re-establishing physiological domain homeostasis linked to metabolic inflammation pathologies. Elucidating this reciprocal relationship between circadian biology and cellular stress pathways may one day facilitate the generation of precise interventions aiming to alleviate the health burden associated with circadian disruption.

PMID:40650041 | DOI:10.3390/ijms26136267

Int J Mol Sci. 2025 Jun 28;26(13):6240. doi: 10.3390/ijms26136240.

ABSTRACT

Asthma is a chronic and heterogeneous inflammatory airway disease with diverse clinical endotypes and limited curative treatment options. Recent systems biology analyses identified four potential molecular triggers-AKT1, MAPK13, STAT1, and TLR4-as candidate regulators of asthma-associated signaling pathways. This study aimed to validate the expression of these four proteins and their downstream signaling elements in peripheral blood mononuclear cells (PBMCs) from patients with allergic asthma (AA), nonallergic asthma (NA), and healthy controls (HC), to explore their potential as biomarkers or therapeutic targets. For that, PBMC samples were collected from 45 AA patients, 17 NA patients, and 15 HC subjects. Gene and protein expression of AKT1, MAPK13, STAT1, and TLR4 were quantified using RT-qPCR and Western blotting. Expression patterns were compared across groups and stratified by asthma severity. Correlations with clinical parameters (FEV1, FVC, FeNO, IgE, eosinophil counts) and treatment regimens were also assessed. All four target genes showed significantly reduced expression in asthma patients compared to controls (p < 0.001), with the most marked downregulation in NA patients. At the protein level, MAPK13 and TLR4 showed significant differential expression. Stratification by severity revealed a stepwise reduction in gene expression in AA patients, correlating with disease severity, whereas NA patients showed uniformly low expression regardless of severity. Multiple pathway-related genes, including RELA, SMAD3, NFATC1, and ALOX5, were also downregulated, particularly in NA patients. Notably, differential correlations were observed between gene expression and lung function parameters in AA vs. NA groups. In conclusion, this study supports the potential involvement of AKT1, MAPK13, STAT1, and TLR4 in asthma pathogenesis and highlights differences between allergic and nonallergic asthma at the molecular level. These proteins and their associated pathways may serve as future targets for biomarker development or endotype-specific therapies. Further studies in larger and more diverse cohorts, including functional validation, are warranted.

PMID:40650018 | DOI:10.3390/ijms26136240

Int J Mol Sci. 2025 Jun 23;26(13):6017. doi: 10.3390/ijms26136017.

ABSTRACT

The essential micronutrient zinc is known to inhibit gastric acid secretion (GAS), where its homeostasis is strictly regulated. We hypothesized that the gastric bitter taste receptors, TAS2Rs, regulate the following: (i) zinc-modulated proton secretory activity (PSA) as a key mechanism of GAS and (ii) zinc homeostasis in immortalized parietal cells. To confirm this hypothesis, human gastric tumor cells (HGT-1) were exposed to 100-1000 µM of zinc salts for 30 min in order to quantitate their TAS2R-dependent PSA and intracellular zinc concentration using a fluorescence-based pH sensor and ICP-MS, respectively. Thereby, we identified TAS2R43 as a key player in parietal cell PSA and zinc homeostasis, with both conclusions being verified by a CRISPR-Cas9 knockout approach. Moreover, by regulating the zinc importer protein ZIP14, TAS2R43 proved to perform a protective role against excessive zinc accumulation in immortalized parietal cells.

PMID:40649796 | DOI:10.3390/ijms26136017

Cancers (Basel). 2025 Jun 23;17(13):2102. doi: 10.3390/cancers17132102.

ABSTRACT

Cancer research faces significant biological, technological, and systemic limitations that hinder the development of effective therapies and improved patient outcomes. Traditional preclinical models, such as 2D and 3D cell cultures, murine xenografts, and organoids, often fail to reflect the complexity of human tumor architecture, microenvironment, and immune interactions. This discrepancy results in promising laboratory findings not always translating effectively into clinical success. A core obstacle is tumor heterogeneity, characterized by diverse genetic, epigenetic, and phenotypic variations within tumors, which complicates treatment strategies and contributes to drug resistance. Hereditary malignancies and cancer stem cells contribute strongly to generating this complex panorama. Current early detection technologies lack sufficient sensitivity and specificity, impeding timely diagnosis. The tumor microenvironment, with its intricate interactions and resistance-promoting factors, further promotes treatment failure. Additionally, we only partially understand the biological processes driving metastasis, limiting therapeutic advances. Overcoming these barriers involves not only the use of new methodological approaches and advanced technologies, but also requires a cultural effort by researchers. Many cancer studies are still essentially observational. While acknowledging their significance, it is crucial to recognize the shift from deterministic to indeterministic paradigms in biomedicine over the past two to three decades, a transition facilitated by systems biology. It has opened the doors of deep metabolism where the functional processes that control and regulate cancer progression operate. Beyond biological barriers, systemic challenges include limited funding, regulatory complexities, and disparities in cancer care access across different populations. These socio-economic factors exacerbate research stagnation and hinder the translation of scientific innovations into clinical practice. Overcoming these obstacles requires multidisciplinary collaborations, advanced modeling techniques that better emulate human cancer, and innovative technologies for early detection and targeted therapy. Strategic policy initiatives must address systemic barriers, promoting health equity and sustainable research funding. While the complexity of cancer biology and systemic challenges are formidable, ongoing scientific progress and collaborative efforts inspire hope for breakthroughs that can transform cancer diagnosis, treatment, and survival outcomes worldwide.

PMID:40647400 | DOI:10.3390/cancers17132102

Foods. 2025 Jun 28;14(13):2303. doi: 10.3390/foods14132303.

ABSTRACT

Houttuynia cordata is a culinary herb from Asia. Its edible rhizomes and leaves have a fishy aroma, the molecular background of which was unknown. A comparative aroma extract dilution analysis applied to fresh rhizomes and leaves resulted in 44 and 41 odorants, respectively, 38 of which were present with FD factors ≥1 in both samples. The odorant with the highest FD factors, whether in the rhizomes or leaves, was identified as metallic, soapy, fishy smelling 3-oxododecanal. Toward clarifying its tautomeric composition, quantum calculations suggested a predominance of the enol forms in the plant. However, the form perceived at the sniffing port during GC-O remained unclear.

PMID:40647055 | DOI:10.3390/foods14132303

Biotechnol Biofuels Bioprod. 2025 Jul 11;18(1):73. doi: 10.1186/s13068-025-02672-z.

ABSTRACT

Advancing biomethane production from anaerobic digestion (AD) is essential for building a more reliable and resilient bioenergy system. However, incomplete conversion of lignocellulose-rich agricultural waste remains a key limitation, often leaving energy-dense residues in the digestate by-product. In this study, we introduce a novel application of chelator-mediated Fenton (CMF) post-treatment to recover untapped biomethane potential from these recalcitrant residues, representing a significant departure from conventional pre-treatment strategies. By systematically varying pH, iron-chelator concentration, and hydrogen peroxide dosage, we identified reaction conditions (pH 6-8, 5 mM Fe2+-dihydroxybenzene, 3-4 wt.% H2O2) that enhanced lignocellulose deconstruction and increased dissolved organic carbon (DOC) availability for methanogenesis. CMF post-treatment led to up to a tenfold increase in biomethane potential compared to untreated controls. Microbial community analysis revealed enrichment of cellulolytic species, suggesting enhanced hydrolytic activity as a driver of improved conversion. Application of the CMF post-treatment method to isolated poplar lignin further demonstrated its versatility for diverse lignocellulosic substrates. These findings position CMF post-treatment as a promising strategy to enhance AD efficiency and valorize digestate.

PMID:40646625 | DOI:10.1186/s13068-025-02672-z

Cardiovasc Diabetol. 2025 Jul 11;24(1):283. doi: 10.1186/s12933-025-02823-4.

ABSTRACT

AIMS: Diabetes is a leading cause of mortality worldwide, primarily due to cardiovascular diseases (CVD). Arterial stiffness is a CVD predictor and is associated with increased mortality in diabetic individuals. In diabetes, the formation and accumulation of methylglyoxal (MGO), a highly reactive glycolysis by product and a major precursor in advanced glycation endproducts (AGEs) formation, has been implicated in CVD. In this study, we investigated the role of endogenous MGO in arterial stiffening in a mouse model of type 1 diabetes (T1D) overexpressing the MGO-detoxifying enzyme glyoxalase-1 (GLO1).

METHODS AND RESULTS: Diabetes was induced in C57BL/6 J mice through 5-day streptozotocin injections. 17-week-old control, diabetic, and GLO1-overexpressing diabetic mice were used. Fasting glucose in diabetes and GLO1/diabetes was higher than control. Plasma, urine, and aortic MGO, AGEs, and cross-links were determined using ultra-performance liquid chromatography tandem mass spectrophotometry. MGO was increased in plasma and urine in diabetic mice, while GLO1 decreased MGO in urine. The AGE cross-link pentosidine in aorta was increased in diabetes and ameliorated by GLO1. Tail-cuff blood pressure and carotid-femoral pulse wave velocity were measured preceding euthanasia, and did not differ between groups. Descending thoracic aorta ex vivo passive biaxial arterial wall biomechanics were measured and diabetes showed elevated ex vivo PWV, which was attenuated by GLO1 overexpression. Material viscoelasticity was decreased in diabetes and normalised by GLO1 overexpression. Second harmonic generation imaging demonstrated a predominant axial orientation of diabetic collagen fibres, while GLO1/diabetes led to a uniform orientation. When comparing GLO1/diabetes and diabetes, bulk RNA sequencing revealed 137 differentially expressed genes affecting extracellular matrix organisation, cell-cell and cell-matrix communication and interaction pathways.

CONCLUSION: In an animal model of T1D, GLO1 overexpression attenuates arterial stiffening at the underlying material levels, by modifying collagen ultrastructure and viscoelastic properties. Targeting MGO may provide a novel approach to prevent arterial T1D stiffening.

PMID:40646595 | DOI:10.1186/s12933-025-02823-4

Respir Res. 2025 Jul 11;26(1):243. doi: 10.1186/s12931-025-03322-6.

ABSTRACT

BACKGROUND: The best described endotype of COPD is alpha-1 antitrypsin (AAT) deficiency, due to a genetic abnormality in the SERPINA1 gene. Common deficient PI variants are the Z and S variants. Homozygotes for the Z allele (PI*ZZ individuals) carry the genotype most commonly associated with severe AAT deficiency (AATD), but a highly prevalent endotype is the heterozygous state (PI*MZ individuals). The effect of PI*MZ status on exacerbations and health care utilization is unknown.

STUDY DESIGN AND METHODS: Cleveland electronic health record data was examined to compare healthcare utilization between PI*MZ and PI*MM individuals. Three outcomes were assessed: moderate COPD exacerbation (defined as short-term steroid prescription), any emergent care (defined as an express care, urgent care, or emergency department visit), and any hospitalization. Models were adjusted for age, sex, race, BMI, smoking status, comorbidity count, liver disease, zip code median income.

RESULTS: 4,148 individuals had the PI*MM genotype and 308 PI*MZ. PI*MZ was associated with increased risk for moderate COPD exacerbations (HR [95% CI]: 1.66 [1.27, 2.17]) and hospitalizations (HR [95% CI]: 1.44 [1.19, 1.75]) compared to PI*MM. The risk of hospitalization was higher among PI*MZ individuals with AAT levels < 90 mg/dL (HR [95% CI]: 1.59 [1.14, 2.23]) but not in those with AAT levels > 90 mg/dL, as compared to PI*MM.

INTERPRETATION: Given the high prevalence, PI*MZ represents a COPD phenotype that is associated with worse outcomes, inviting additional investigation to identify predictive biomarkers of worse disease and treatable traits. Future prospective studies to better characterize the longitudinal course and healthcare utilization among individuals with a PI*MZ genotype.

PMID:40646587 | DOI:10.1186/s12931-025-03322-6