Effect of mRNA formulated with lipid nanoparticles on the transcriptomic and epigenetic profiles of F4/80+ liver-associated macrophages

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Янв. 7, 2025

Delivery of an mRNA formulated with lipid nanoparticles (LNPs) induces robust humoral and cell-mediated branches the immune response. Depending on LNP formula, encoding proteins can be detected in liver upon intramuscular administration mRNA/LNP mice. This study investigated impact liver-associated macrophages at transcriptomic epigenetic levels a mouse model. An ovalbumin (OVA) LNPs, was administered intramuscularly, OVA-specific antibody serum Day 7. F4/80+ were isolated subjected to RNA sequencing, which identified 554 genes whose expression altered compared those PBS control group. The involved macrophage inflammatory functions, such as Tnf, Il6 Marco, upregulated. Gene ontology enrichment analysis revealed that IL-6/JAK/STAT3 TNFα/NF-κB hallmarks significantly enriched, mRNA/LNP-exposed characterized M1-like cells based profiles. Enrichment active histone mark H3K4me3 showed clusters loci highly increased group, indicating mRNA/LNPs cis-regulatory regions Marco marks, correlated well their transcription. Taken together, our data indicated via route influences gene profiles macrophages, reflecting its ability induce

Язык: Английский

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Infant RSV infection desensitizes β2-adrenergic receptor via CXCL11-CXCR7 signaling in airway smooth muscle

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 15, 2025

ABSTRACT Rationale Airflow obstruction refractory to β2 adrenergic receptor (β2AR) agonists is an important clinical feature of infant respiratory syncytial virus (RSV) bronchiolitis, with limited treatment options. This resistance often linked poor drug delivery and potential viral infection airway smooth muscle cells (ASMCs). Whether RSV inflammation causes β2AR desensitization in ASMCs unknown. Objectives To investigate the interaction signaling pathway Methods Infant precision-cut lung slices (PCLSs) mouse pup models were subjected physiological assays. Virus-free, conditioned media from RSV-infected bronchial epithelial air-liquid interface (ALI) culture nasopharyngeal aspirates (NPA) infants severe bronchiolitis collected applied PCLSs ASMCs. Cytokines these samples profiled assessed for effects on expression, cell surface distribution, relaxant function Measurements Main Results Conditioned NPA induced similar as infection. Cytokine profiling identified CXCL11 one most elevated signals following activated its CXCR7 a complex promote phosphorylation, internalization, degradation. Blockade partially restored relaxation response Conclusions The CXCL11-CXCR7 plays critical role during represents therapeutic target alleviating airflow bronchiolitis.

Язык: Английский

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Shear-Stress Initiates Signal Two of NLRP3 Inflammasome Activation in LPS-Primed Macrophages through Piezo1

ACS Applied Materials & Interfaces, Год журнала: 2025, Номер unknown

Опубликована: Янв. 21, 2025

The innate immune system is tightly regulated by a complex network of chemical signals triggered pathogens, cellular damage, and environmental stimuli. While it well-established that changes in the extracellular environment can significantly influence response to pathogens damage-associated molecules, there remains limited understanding how stimuli specifically impact activation NLRP3 inflammasome, key component immunity. Here, we demonstrated shear stress act as Signal 2 inflammasome pathway treating LPS-primed immortalized bone marrow-derived macrophages (iBMDMs) with several physiologically relevant magnitudes induce activation. We within 1.0 50 dyn/cm2 were able ASC speck formation, while was sufficient significant calcium signaling, gasdermin-D cleavage, caspase-1 activity, IL-1β secretion, all hallmarks Utilizing knockout iBMDMs, primarily activated result exposure. Quantitative polymerase chain reaction (qPCR), ELISA, small molecule inhibitor study aided us demonstrating expression Piezo1, NLRP3, gasdermin-D, IL-1β, CCL2 secretion upregulated iBMDMs treated stress. This provides foundation for further interconnected pathogenesis chronic inflammatory diseases ability play role their progression.

Язык: Английский

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Joint fluid multi-omics improves diagnostic confidence during evaluation of children with presumed septic arthritis

Pediatric Rheumatology, Год журнала: 2025, Номер 23(1)

Опубликована: Янв. 24, 2025

An accurate diagnosis of septic versus reactive or autoimmune arthritis remains clinically challenging. A multi-omics strategy comprising metagenomic and proteomic technologies were undertaken for children diagnosed with presumed to advance clinical diagnoses care affected individuals. Twelve suspected prospectively enrolled compare standard tests a rapid approach. The combined bacterial 16S rRNA metagenomics, single cell transcriptomics, proteomics on knee joint fluid specimens. diagnostic value the was ascertained relative culture PCR-negative results. Ten primary two acute hematogenous osteomyelitis (AHO) assessed. Joint cultures positive 6/12 (50%) patients, consistent elevated inflammatory markers (IL-4, IL-6, IL-17A, TNF-a, etc.). Metagenomic sequencing results 100% concordant Six patients culture- PCR-negative. Multiomics analyses 6 negative established that 2/6 culture-negative had potential Juvenile idiopathic (JIA) 1 post-Streptococcal Reactive Arthritis. without any bacteremia autoantibodies (IgGs) in joint-fluid targeting several nuclear antigens (i.e., dsDNA, histones, Jo-1, scl-70, Ro/SS-A, SmDs, CENP-A along non-nuclear i.e. Albumin, Collagens, Myosin, Laminin, etc. Single transcriptomics confirmed an abundance CD4+ follicular helper T (Tfh), CD8 + cells B autoantibody subjects. combination DNA (p = 0.006), cytokine assays 0.009) profiling 0.02) significantly distinct between those infections. This improved confidence 9 12 (75%) children, key treatment decisions. multiomics approach rapidly identified conditions, improving strategies presumptive arthritis.

Язык: Английский

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Bioinformatics analysis of coronary microvascular dysfunction in rats based on single-cell RNA sequencing

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Фев. 11, 2025

Coronary microvascular dysfunction serves as one of the etiological factors for ischemic heart disease and represents a novel therapeutic direction coronary artery diseases; however, research on its pathogenesis remains inconsistent. This study aims to explore single-cell gene expression profiles in rats with using RNA sequencing, particular focus in-depth analysis endothelial cell characteristics. By establishing rat model dysfunction, we collected cardiac apical tissue prepare suspensions further analyzed them bioinformatics methods. From total 55,419 cells, identified 28 distinct clusters, cells fibroblasts being predominant types. Compared NC group, proportion CMD group was significantly reduced, while number increased. Through classified into normal phenotype mesenchymal proliferative lymphatic originating from cells. Additionally, exhibited an increase immune enhanced inflammatory response, increased oxidative stress. These findings may provide potential targets treatment dysfunction.

Язык: Английский

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Comparative Analysis Between Olink‐PEA and Alamar‐NULISA Proteomic Technologies Applied to a Critically Ill COVID‐19 Cohort

PROTEOMICS, Год журнала: 2025, Номер unknown

Опубликована: Фев. 10, 2025

ABSTRACT We aim to verify and validate low‐abundant plasma proteins from severe COVID‐19 cases controls through a comparative analysis between Olink Alamar performances. Eighty‐three 44 were measured for proteomics using three panels one panel, which share 94 targets. CV, pairwise correlation of intensity signals, detectability range compared across platforms. Statistical comparisons performed FDR‐adjusted linear models with age as covariate construct differential protein abundance volcano plots per platform heatmaps our cohort five public cohorts. Overall, ( n = 94) showed strong correlations among r 0.82) 0.7). 60/94 had mutual significance on both platforms; 54 concordant effect direction, six opposite direction (IL‐6R, IL‐1R2, KITLG, TSLP, IL‐17C, IL‐4R). verified 80 60 targets controls, respectively, along Olink. Compared cohorts by Olink, data consistent findings 28 proteins, 27 validated Alamar.

Язык: Английский

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Different Transcriptome Signatures of the Lymphatic and the Blood Vessels From Rat Mesentery Reveal Distinct Function Characteristics

Microcirculation, Год журнала: 2025, Номер 32(2)

Опубликована: Фев. 1, 2025

ABSTRACT Objective Lymphatic vessels and blood have some similarities in structure, but they distinct contraction characteristics functions. Revealing the detailed transcriptional differences of lymphatic, artery vein are required for circulation research. Methods The tissues mesenteric artery, were collected from Wistar rats. transcriptome signatures these RNA‐seq (RNA sequencing) analyzed using bioinformatic methods. Results GO (gene ontology) enrichment showed three gene expression patterns extracellular matrix, cell adhesion molecule binding, receptor ligand activity, contractile fiber. genes involved contractility also differently expressed, which enriched into KEGG (Kyoto Encyclopedia Genes Genomes) pathways cytoskeleton muscle cells, vascular smooth contraction, renin‐angiotensin system. Through PPI (protein–protein interaction) analysis, we identified 43 expressed hub tissues. Thirty‐four transcription factors cofactors as important normal function Furthermore, screened out 20 potential marker each tissue. Conclusions Our study described vein, shedding light on mechanisms These results provided therapeutic targets diseases markers lymphatic vessel studies.

Язык: Английский

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Acute hypoxia modulate macrophage phenotype accompanied with transcriptome re-programming and metabolic re-modeling

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Фев. 17, 2025

Introduction Macrophages, which tend to aggregate in the hypoxic regions of tissues, have a significant impact on disease progression and outcome because their plastic responsiveness hypoxia, particularly early stages. Understanding macrophages’participation hypoxia-related disorders requires demonstrating acute hypoxia survival, phenotype, function. Methods Here we conducted systematic evaluation macrophage responses over 24 48 h including cell growth activity, inflamatory response, polarization transcriptional metabolic changes. Results We found that suppresses proliferation phagocytosis function with parallel change transcriptome re-programming re-modeling. Although macrophages accumulate heterogeneity based oxygen concentration culture period, genes involved chemotaxis, glycolytic process were commonly altered during hypoxia. Furthermore, pro-inflammatory response was activated concomitantly an enhanced anti-inflammatory regulatory mechanism characterized by increased M2 population metabolite itaconic acid. Aside from glycolysis, key intermediates pentose phosphate pathway significantly increased, such as fructose 1,6-bisphosphate (fold change: 7.8), 6-phosphogluconate 6.1), ribose 5-phosphate 3.9), indicated important compensatory regulation rules for Discussion These findings highlight viability phagocytosis, while modifies metabolome specific inflammatory pathways facilitate adaptation conditions.

Язык: Английский

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Histone demethylase LSD1 promotes castration‐resistant prostate cancer by causing widespread gene expression derangements

IUBMB Life, Год журнала: 2025, Номер 77(3)

Опубликована: Март 1, 2025

Abstract Lysine‐specific demethylase 1 (LSD1), a histone crucial for embryonic development and tissue differentiation, has an undefined role in prostate cancer (PCa), especially castration‐resistant PCa. The present study represents pioneering endeavor to comprehensively dissect the function of LSD1 within PCa landscape. Our investigations revealed that attenuation expression exerts multiple inhibitory effects on cells. Specifically, it curtails proliferation colony‐forming ability PC‐3 cells, concomitantly promotes apoptosis, impedes cell invasion. Notably, knockdown triggers significant perturbations profiles pivotal proteins, such as prostate‐specific antigen (PSA), forkhead box A1 (FOXA1), NKX3.1, thereby shedding new light underlying molecular mechanisms governing progression. Leveraging bioinformatics analysis transcriptome sequencing, we unearthed precipitates widespread gene dysregulation, with 3166 genes exhibiting differential patterns, which turn impact broad spectrum cellular processes. Importantly, identified modulates methylation modification H3 lysine 4 monomethylation (H3K4me1) promoter region matrix metallopeptidase 13 (MMP13), orchestrating its expression. In both orthotopic metastatic tumor models, well vitro cultures, inhibitor GSK2879552 demonstrated potent efficacy suppressing To sum up, this not only uncovers oncogenic but also validates therapeutic promise GSK2879552, furnishing novel perspectives prospective targets clinical management

Язык: Английский

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Cytokine storm polymorphisms in nonvaccinated COVID-19 patients

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 17, 2025

Abstract Cytokines and chemokines are essential for establishing an appropriate immune response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Variations in the genes encoding cytokines strongly influence pathogenic challenges disease outcomes. This study was carried out determine associations of polymorphisms TNF -α , IL-6 IL-8, IL-10 CCL5 with COVID-19 severity. A total 627 unvaccinated patients were classified according WHO We evaluated levels IFN-α, IFN-γ, TNF-α, IL-1R, IL-6, IL-7, IL-10, CCL2, CCL3, CXCL8, CXCL10 GCSF serum compared among severity groups stratified by polymorphism alleles. revealed a significant increase IL-2, CCL-2 dead group. However, higher moderate group than mild Logistic regression analysis that five associated increased risk COVID-19: (rs1800610) allele (OR=1.50; 95% CI: 1.01–2.24); (rs1800796) C (OR=1.64; 1.05–2.57); (rs1800871) T (OR=1.94; 1.24–3.04) (rs1800872) (OR=1.87; 1.21–2.89); (rs3817656) G (OR= 1.64; 1.02–2.65)). The (rs1800871 rs1800872) (rs1800796 rs18049563) gene also Increases carriers rs1049953. In contrast, not any SNPs.

Язык: Английский

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