Search Results (31,698)

This study evaluated the effects of dietary supplementation with a commercial lactoferrin–osteopontin complexes preparation (LF-OPN; LF:OPN mass ratio 8:1; 240 mg/kg body weight) on growth, immune indices, antioxidant status, intestinal barrier-related markers, fecal microbiota, short-chain fatty acids (SCFAs), peripheral lymphocyte subsets, and the whole-blood transcriptome of growing British Shorthair kittens. Sixteen kittens were randomly assigned to either a basal diet group (CON) or a group supplemented with LF-OPN complexes (LFT) for 28 days. LF-OPN supplementation did not significantly affect body weight or average daily gain. On D28, the LFT group had a higher serum immunoglobulin M concentration and a lower tumor necrosis factor-α concentration (p < 0.05). Serum superoxide dismutase and glutathione peroxidase activities and total antioxidant capacity were higher, whereas malondialdehyde was lower (p < 0.05) in the LFT group (p < 0.01). Fecal 16S rRNA gene sequencing revealed no significant difference in alpha diversity; howerer, LEfSe identified selective taxonomic difference, including higher relative abundances of Holdemanella and Erysipelotrichaceae and lower relative abundances of Enterobacteriaceae and Escherichia-Shigella in the LFT group. Fecal short-chain fatty acid concentrations were unchanged. Flow cytometry revealed a higher proportions of peripheral CD4+ lymphocytes and a higher CD4+/CD8+ ratio in the LFT group (p < 0.01), whereas the CD8+ proportion was unchanged. Whole-blood RNA sequencing identified 283 differentially expressed genes (199 upregulated and 84 downregulated), with enrichment of immune-related pathways including hematopoietic cell lineage, antigen processing and presentation, cytokine–cytokine receptor interaction, NF-κB signaling, and IL-17 signaling, but these findings were not independently validated. The tested LF-OPN preparation was well tolerated and was associated with elevated antioxidant status, altered immune indices, and selective modulation of the fecal microbiota in growing kittens. The study does not establish synergy or identify the individual contributions of either protein. Full article

Klebsiella pneumoniae infection following H9N2 Influenza A virus (IAV) infection causes severe pneumonia. But the underlying pathogenic mechanisms of H9N2 IAV and K. pneumoniae co-infection are complex and need to be further explored. In this study, the lung transcriptomes of mice with H9N2 IAV and K. pneumoniae co-infection were characterized by transcriptomic profiling. As a result, GO enrichment analysis revealed that the differential genes were primarily involved in the activation of immune responses, cellular components of membranes and extracellular spaces, and defense responses against pathogen infections. According to KEGG enrichment, the differentially expressed genes (DEGs) were concentrated in TLR signaling pathways, RLR signaling pathways, TNF signaling pathways and NLRP3 signaling pathways. Furthermore, in vitro cell models were established to investigate the innate immune responses induced by H9N2 IAV and K. pneumoniae CPS co-stimulation. K. pneumoniae CPS stimulation influenced the cytokine profiles of mink lung epithelial cells infected with H9N2 IAV, worsened cell viability, and aggravated apoptosis, indirectly inhibiting H9N2 IAV replication. The findings demonstrated that K. pneumoniae superinfection modulated the innate immune responses induced by H9N2 IAV infection, contributing to its pathogenesis. Full article

Fracture healing depends on coordinated osteogenesis and restoration of the vascular microenvironment. Endothelial cells support skeletal repair through angiogenesis, tissue perfusion and angiocrine signaling that regulates osteoprogenitor recruitment and differentiation. This narrative review examines endothelial dysfunction (ED) as a potential systemic contributor to impaired fracture healing by integrating evidence from vascular biology, experimental models and clinical studies. ED is characterized by reduced nitric oxide (NO) bioavailability, oxidative stress, inflammation and impaired vascular repair. These changes may disrupt angiogenic–osteogenic coupling through altered hypoxia-inducible factor 1-alpha subunit (HIF-1α)/vascular endothelial growth factor (VEGF) signaling, endothelial Notch activity, platelet-derived growth factor (PDGF)-mediated vascular remodeling and endothelial progenitor cell (EPC) mobilization. Conditions associated with endothelial dysfunction, including diabetes, aging, chronic kidney disease (CKD), smoking, obesity and chronic inflammatory disease, are also linked to delayed union, nonunion and poorer orthopedic outcomes. Cardiovascular disease and perioperative cardiovascular instability may further impair perfusion and physiological reserve during repair. However, the available evidence is predominantly experimental or observational, and direct causal evidence in fracture patients remains limited. Prospective studies combining standardized endothelial assessments with fracture-healing outcomes are needed to clarify clinical relevance and identify potential therapeutic targets. Full article

Mesenchymal stem cells (MSCs) have become a focus of regenerative medicine research due to their potential utility in treating a variety of musculoskeletal disorders. Multiple qualities make them an ideal candidate to address musculoskeletal structural degeneration and inflammation, including their multi-lineage differentiation capacity, relative ease of extraction, and paracrine signaling capabilities. This narrative review examines the literature surrounding MSC-related therapies in musculoskeletal disorders, with a particular emphasis on mechanical and cellular factors affecting therapeutic efficacy. Multiple clinical and preclinical studies find that MSCs bolster tissue repair through a combination of extracellular matrix remodeling, inflammatory modulation, and regenerative signaling pathways. In addition, mechanotransduction signaling pathways have been discovered that convert mechanical tensile shear stress, compression, and strain forces into regulatory signals for matrix remodeling and tissue proliferation. Additional studies suggest that MSC efficacy and optimization are greatly influenced by a cell’s mechanical environment within the body. Further understanding of these mechanical factors can greatly bolster emerging regenerative therapies increasingly being utilized for musculoskeletal conditions. Full article

Telomere length (TL) is an important indicator of embryo quality and is associated with subsequent developmental outcomes. However, little is known about the factors that regulate TL during embryonic development. Because in vitro-produced embryos typically exhibit shorter TL than in vivo-developed embryos, this study aimed to identify factors that regulate TL in bovine embryos. Candidate regulators were identified by integrating RNA-seq data from bovine blastocysts with normal or short TL and information on factors present in oviductal fluid. Ingenuity Pathway Analysis of differentially expressed genes identified angiotensin II (Ang II), transforming growth factor-beta 1 (TGFB1), and epidermal growth factor (EGF) as candidate regulators. The effects of supplementing these factors in the culture medium were then evaluated with respect to embryonic development, TL, telomerase activity, and DNA methylation. All three factors improved embryonic development. Ang II and TGFB1 increased TL at the blastocyst stage and reduced global DNA methylation levels at both the 8-cell and blastocyst stages. Transcriptomic analysis further suggested that Ang II and TGFB1 modulated pathways related to chromatin remodeling and telomere maintenance. These findings identify Ang II and TGFB1 as important regulators of telomere length during bovine preimplantation development and suggest that their effects are mediated, at least in part, through epigenetic remodeling. Full article

Compartment-specific induced pluripotent stem cell (iPSC)-derived cardiomyocytes provide a powerful resource to study cellular and molecular underpinnings of congenital heart disease (CHD) and acquired cardiovascular disease (CVD). Human heart development requires coordinated and complex regulation of key signaling pathways including Notch, BMP, Wnt, Nodal, and Shh during each step of heart morphogenesis. Compartment-specific cardiac cells for modeling the various structures in the heart can be generated by fine tuning these signaling pathways in a sequential manner thereby mimicking spatiotemporal regulation during embryonic heart morphogenesis. In this review, we provide a brief overview of key signaling pathways that are responsible for forming the distinct structures of the heart originating from the first heart field (FHF) and second heart field (SHF). We then summarize recent differentiation protocols that leverage key heart-development related signaling molecules to generate compartment-specific cardiomyocytes and organoids for disease modeling and therapeutic development in cardiovascular disease. Full article

Multiple sclerosis (MS) is an immune-mediated central nervous system disease with mapped genetic risk loci but unresolved cross-layer regulatory mechanisms. We harmonised 30 primary public MS datasets spanning bulk transcriptomics (552 samples, 367 MS/185 healthy control [HC]), DNA methylation arrays (475 samples, 244 MS/231 HC) with sorted-cell whole-genome bisulfite sequencing (WGBS) assessment, single-cell RNA sequencing (RNA-seq; 517,533 cells from 81 donors), and cerebrospinal fluid (CSF) and brain white-matter proteomes, and UK Biobank Pharma Proteomics Project (UK Biobank-PPP) plasma proteomic statistics (407 MS/39,979 HC) for external validation. We prioritised MS-associated genes showing inverse-concordant, cohort-level methylation–expression associations and orthogonal support across layers. After harmonised reprocessing and per-stratum differential testing, a bulk-RNA × methylation inverse-concordance filter followed by an independent proteomic and/or donor-level single-cell anchor identified two Tier-1 candidates (IKZF1’s anchor is a candidate-panel-adjusted donor-level pseudobulk association, not transcriptome-wide significance): ITGB2 and IKZF1. ITGB2 showed the strongest cross-layer support: RNA down-regulation, promoter hypermethylation and reduced plasma abundance in UK Biobank MS cases, a pattern consistent with altered leukocyte-integrin adhesion. Pathway and network analyses linked the candidates predominantly to leukocyte and lymphocyte activation and differentiation, leukocyte-integrin adhesion, and interferon and cytokine-signalling immune modules. These findings nominate MS-relevant regulatory candidates and provide a reusable multi-omics framework for hypothesis generation and validation. Full article

Crop straw is an abundant lignocellulosic resource, but its efficient bioconversion is hindered by the recalcitrant structure of plant cell walls. This study integrated degradation phenotyping, enzyme activity assays, whole-genome analysis, and comparative transcriptomics to link the wheat-straw degradation performance of strain XH2 with its enzymatic and molecular responses. Strain XH2 was isolated from fully decomposed compost collected in Anhui Province, China, selected based on the formation of a distinct hydrolysis halo on CMC-Congo red agar, and deposited in the China Center for Type Culture Collection (CCTCC) under accession number CCTCC M 2025519. Morphological, cultural, phylogenetic, and genomic analyses identified strain XH2 as Streptomyces thermocarboxydus. Its degradation capacity was evaluated during 28 days of cultivation by measuring straw degradation, lignocellulosic components, scanning electron microscopy (SEM), and extracellular enzyme activities. S. thermocarboxydus XH2 caused marked disruption of the wheat-straw surface and achieved a degradation rate of 31.45%. Cellulose and hemicellulose contents decreased from 41.10% to 28.87% and from 30.72% to 16.85%, respectively, whereas lignin decreased from 8.28% to 6.30%. Endoglucanase activity, filter paper activity (FPase, an indicator of total cellulase activity), and xylanase activity peaked on day 7, reaching 35.99, 17.68, and 37.01 U/mL, respectively. Genome analysis revealed multiple genes encoding cellulases and hemicellulases. Comparative transcriptomic analysis after 72 h of cultivation in wheat-straw medium identified 1614 differentially expressed genes relative to Gause No. 1 medium, with major enrichment in ABC transporters and fructose and mannose metabolism. Most genes associated with polysaccharide degradation were upregulated. These findings link the degradation phenotype of S. thermocarboxydus XH2 to its enzymatic and molecular responses and support its further evaluation as a candidate for wheat-straw bioconversion under greenhouse and field conditions. Full article

Lung cancer is characterized by profound molecular and clinical heterogeneity and remains the leading cause of cancer-related mortality worldwide. Its initiation and progression are shaped by complex genetic and epigenetic alterations that perturb key biological processes, including cell proliferation, apoptosis, metabolic reprogramming, invasion, metastasis, and immune evasion. Increasing evidence indicates that dysregulated alternative splicing (AS) represents a critical post-transcriptional regulatory mechanism involved in lung cancer pathogenesis. Although AS abnormalities are not the sole drivers of tumorigenesis, they contribute to malignant transformation, tumor progression, therapeutic resistance, and phenotypic plasticity, providing opportunities for biomarker development and therapeutic targeting. This review summarizes the multifaceted roles of AS in lung cancer biology, highlighting its contributions to tumor evolution, metastatic dissemination, and treatment resistance. Furthermore, subtype-specific AS landscapes between major lung cancer subtypes are discussed to elucidate their distinct molecular mechanisms and therapeutic implications. Representative AS-generated isoforms, including cluster of differentiation 44 variants (CD44v), are further discussed as examples of how aberrant splicing events regulate cancer stemness, tumor progression, and therapeutic responses. The regulatory mechanisms underlying CD44v generation, including upstream splicing factors and downstream signaling pathways, are also summarized. Collectively, this review highlights the emerging role of aberrant AS regulation in lung cancer and emphasizes its potential implications for biomarker discovery and precision therapeutic strategies targeting splicing dysregulation. Full article

Alzheimer’s disease (AD) has a complex pathogenesis, involving molecular and neuroimmune dysregulation, but the causal drivers linking transcriptomic changes to immune remodeling are not yet clear. In a discovery cohort, differential expression analysis was performed, and it was independently validated in two external cohorts. Key genes were prioritized via LASSO/logistic regression, functionally annotated, and causally linked to AD using two-sample MR. The neuroimmune landscape was mapped by ssGSEA, and top candidates were validated in vitro. RGS1 is a key node in neuroinflammation and cytoskeletal dynamics, which is prioritized by the algorithmic intersection. MR analysis suggested a potential causal association between genetically predicted RGS1 expression and AD risk. RGS1 was consistently upregulated in both discovery and validation cohorts (AUC: 0.61–0.67) and was confirmed in vitro. Immune deconvolution showed that AD-specific enrichment profiles occur, and RGS1 is strongly correlated with activated CD4+ T cells and pro-inflammatory chemokines. RGS1 is identified as a robust key gene that may contribute to immune microenvironment dysregulation in AD, and combining discovery-validation transcriptomics, causal inference, and experimental validation, we find that RGS1 is a potential immunomodulatory target. Full article

Background and Objectives: Oxidized LDL (oxLDL) and Toll-like receptor (TLR) signaling are implicated in inflammatory bone loss and periodontitis, but their cooperative effects on osteoclastogenesis remain unclear. We investigated whether TLR2/4 stimulation regulates the transcription of LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1), a receptor for oxLDL, and whether oxLDL enhances TLR-mediated osteoclastogenic responses in the absence of exogenous RANKL. Materials and Methods: Mouse bone marrow cells (BMCs) were differentiated into bone marrow macrophages (BMMs) with M-CSF and stimulated with TLR ligands (Pam3CSK4 for TLR2 and Lipid A for TLR4) and/or oxLDL, with or without exogenous RANKL. Raw264.7 cells were stimulated with TLR ligands or Porphyromonas gingivalis lipopolysaccharide (LPS). LOX-1 transcriptional activity and osteoclastogenic responses were evaluated using luciferase assays, quantitative RT-PCR, and tartrate-resistant acid phosphatase (TRAP) staining. Results: In Raw264.7 cells, stimulation with Pam3CSK4, Lipid A, or LPS significantly increased LOX-1 promoter activity. In BMCs, Pam3CSK4 significantly increased LOX-1 and MyD88 mRNA expression on day 1, whereas expression decreased by day 3; these changes were suppressed by a TLR2 inhibitor. Lipid A significantly increased LOX-1 and MyD88 mRNA expression on day 3, and the increase in LOX-1 expression was inhibited by a TLR4 inhibitor. Functionally, Pam3CSK4 or Lipid A alone increased mononuclear TRAP-positive cells but did not induce multinucleated TRAP-positive cells. In contrast, co-stimulation of oxLDL with either Pam3CSK4 or Lipid A promoted multinucleated TRAP-positive cell formation even in the absence of exogenous RANKL. Conclusions: TLR2/4 stimulation transiently enhanced LOX-1 transcription and expression in association with increased MyD88 expression. TLR ligands cooperated with oxLDL to promote multinucleated TRAP-positive cell formation in the absence of exogenous RANKL, suggesting that inflammatory and metabolic signals may act synergistically during osteoclastogenesis. These findings improve our understanding of how dyslipidemia-associated factors may contribute to inflammatory bone-resorptive diseases, including periodontitis. Full article

Abdominal aortic aneurysm (AAA) is a progressive vascular disease in which no pharmacological therapy has consistently reduced expansion or rupture risk, highlighting the need to better define reproducible molecular programs in human aneurysmal tissue. Publicly available human abdominal aortic tissue microarray datasets were identified using the Search, Tag, Analyze Resource for Gene Expression Omnibus (STARGEO) platform. Three independent datasets comprising 324 total samples, including 278 aneurysmal abdominal aortic tissue samples and 46 non-aneurysmal control samples, were included. Transcriptomic meta-analysis identified 2331 differentially expressed genes in AAA tissue relative to non-aneurysmal controls. Upregulated genes were enriched for immune and inflammatory signaling, oxidative stress regulation, and extracellular matrix remodeling. Downregulated genes included regulators of vascular smooth muscle cell structure, cell–matrix adhesion, cytoskeletal organization, and metabolic homeostasis. Human AAA tissue demonstrates a reproducible inflammatory–oxidative transcriptional program characterized by leukocyte recruitment, cytokine amplification, innate immune sensing, redox remodeling, protease-mediated extracellular matrix degradation, and suppression of vascular smooth muscle cell and matrix maintenance programs. These findings support a model of AAA as an immune–redox remodeling disease in which inflammatory, oxidative, proteolytic, structural, and failed resolution pathways converge to destabilize the aortic wall. Full article

Background/Objectives: Glioblastoma (GBM) is the most lethal primary brain malignancy in adults, with a median overall survival of approximately 15 months. Temozolomide (TMZ) resistance develops in virtually all patients, and no second-line regimen has improved outcomes over the past two decades. The DNA methyltransferase inhibitor decitabine (DAC) has attracted interest as a chemosensitizer, but whether it directly reverses the TMZ-resistance transcriptome or operates through distinct, complementary mechanisms has not been tested at multi-omics resolution. Methods: We performed an integrative six-layer multi-omics analysis across five public GEO datasets (bulk RNA-seq, EPIC 850K methylation, and 21,676 single cells) re-purposed from studies conducted for unrelated aims, formally tested DAC-mediated reversal of the TMZ-resistance transcriptome across 11,707 genes, mapped pharmacogenomic targets with DGIdb v5, and built an exploratory, hypothesis-generating 11-gene prognostic model internally validated in TCGA-GBM (n = 166) and externally tested in the independent CPTAC-GBM cohort (n = 96). Results: DAC reprogrammed transcription across 1114–1882 differentially expressed genes per cohort and reactivated 146 direct epigenetic targets, identifying INPP5D/SHIP1 as the top-ranked direct epigenetic-reactivation target. Genome-wide reversal analysis across 11,707 co-detected genes showed a negligible effect (Spearman ρ = 0.073), but single-cell analysis revealed significant per-cell attenuation of MES-like and stem-like programs (Δ = −0.071 and −0.135, respectively; both p < 0.001). The 11-gene risk model achieved a Harrell’s C-index of 0.706 (apparent); after correcting for the two-stage gene selection with a full-pipeline bootstrap, the optimism-corrected C-index was 0.63, and external validation in an independent cohort (CPTAC-GBM, n = 96) showed only near-chance discrimination (C-index 0.55), indicating that the signature does not generalize and is exploratory. Pharmacogenomic mapping yielded 734 unique therapeutic agents (230 FDA-approved) across 69 druggable targets after excluding AR. Most of these agents are not GBM-directed, so this catalog-level mapping is hypothesis-generating rather than a set of therapeutic recommendations. Conclusions: DAC does not broadly reverse the TMZ-resistant transcriptome but acts through three complementary mechanisms: epigenetic reactivation of INPP5D/SHIP1, cancer-testis-antigen and type I interferon induction, and per-cell attenuation of mesenchymal–stem-like transcriptional intensity, supporting hypotheses for rationally designed DAC-based combination therapy in TMZ-resistant GBM. Full article

Background and Clinical Significance: Proliferative fasciitis (PF) is an infrequent benign fibroblastic/myofibroblastic proliferation that may closely resemble a soft tissue sarcoma, creating a diagnostic dilemma out of proportion to its biological behaviour. Because no single clinical, histological or immunohistochemical feature is diagnostic, accurate classification depends on the integration of complementary findings. We describe a challenging case of PF involving the lower leg and present a practical clinicopathological approach to its evaluation. Case Presentation: A 34-year-old man presented with a painless subcutaneous nodule on the lateral aspect of the left lower leg, discovered incidentally. Clinical examination suggested a benign superficial soft-tissue lesion, and because no features raised suspicion for malignancy, complete excision was performed without preoperative imaging. Gross examination revealed a 1.9 × 1.6 × 0.7 cm fascial-based lesion composed of spindle cells and scattered ganglion-like cells within a variably myxoid stroma. Focal nuclear pleomorphism, typical mitotic activity (2 mitoses/10 high-power fields), and limited extension into adjacent adipose tissue broadened the differential diagnosis. Immunohistochemistry demonstrated focal SMA positivity, weak focal desmin and S100 expression, absence of CD31 and CD34 staining, and a low Ki-67 proliferative index (approximately 2–3%). Negative surgical margins, together with integration of the clinical presentation, gross findings, histomorphology, and immunophenotype, supported the diagnosis of proliferative fasciitis. The patient remains free of local recurrence four months after surgery. Conclusions: PF should be considered in the differential diagnosis of superficial spindle-cell proliferations showing deceptively aggressive histological features. Careful clinicopathological correlation remains the cornerstone of diagnosis and helps distinguish this benign entity from its malignant mimics. The clinicopathological framework proposed in this report may assist pathologists in the systematic evaluation of similar diagnostically challenging lesions. Full article

Breast cancer is a highly heterogeneous malignancy in which fatty acid metabolism plays a critical yet insufficiently characterized role in tumor progression, immune evasion, and treatment resistance. To address this gap, we performed a comprehensive re-analysis of single-cell transcriptomic data from 62 breast cancer patients using the Non-negative Matrix Factorization (NMF) algorithm to delineate tumor cell subpopulations at single-cell resolution. Through Gene Set Enrichment Analysis (GSEA), we identified the tumor cell subgroup most significantly associated with fatty acid metabolism. Subsequent Slingshot trajectory analysis revealed STARD10 as a key regulatory gene in fatty acid metabolic reprogramming along tumor cell differentiation trajectories. In vitro functional experiments further validated that STARD10 plays a functional role in modulating fatty acid metabolism in breast cancer cells. These findings establish STARD10 as a novel molecular marker and potential therapeutic target in breast cancer, offering new insights into the metabolic mechanisms underlying tumor heterogeneity and disease progression. Full article