International Journal of Molecular Sciences最新文献

Lysine lactylation represents a novel post-translational modification (PTM) involved in cellular functions including glycolysis and macrophage polarisation. It differs in form and mechanism from other PTMs such as acetylation, methylation, phosphorylation, ubiquitination, and SUMOylation. As a recently discovered modification, lactylation has been implicated in the progression of multiple diseases. Recent studies further indicate lactylation's association with multiple ocular pathologies. This review systematically summarises and discusses lactylation's involvement in prevalent eye diseases, including myopia, retinopathy, ocular melanoma, uveitis, and macular degeneration. We further collate emerging data suggesting lactylation signalling pathways may represent potential therapeutic targets for ocular pathologies. This review aims to provide a comprehensive overview for holistic intervention strategies and multidimensional assessment across various ocular conditions, while offering valuable insights for future research and development from a lactylation perspective.

Periodontitis is a chronic infectious disease characterized by the destruction of the tooth-supporting tissues, including the gingiva, periodontal ligament, and alveolar bone, which may ultimately lead to tooth loss. However, blood-based biomarkers reflecting systemic inflammation in periodontitis remain poorly defined. We analyzed plasma proteomic data from the UK Biobank using Olink Explore proteomics to identify systemic protein signatures distinguishing chronic periodontitis patients (n = 90) from healthy controls (n = 2234). Among 2151 proteins passing quality control, 29 proteins showed significant differential expression (FDR < 1.0 × 10^-5). Growth differentiation factor 15 (GDF15) exhibited the strongest upregulation (mean NPX: -0.183 to 0.157, effect size = 0.337, FDR = 2.82 × 10^-12), followed by N-terminal pro-B-type natriuretic peptide (NT-proBNP) (effect size = 0.594), Interleukin-6 (IL-6) (effect size = 0.450), and Insulin-like growth factor binding protein-(4IGFBP4) (effect size = 0.269). Multiple TNF receptor superfamily members (TNFRSF1A/1B, TNFRSF10A/10B) and proteins involved in extracellular matrix remodeling (COL6A3, ADAM12) and vascular stress (ADM) were significantly elevated. In contrast, EGFR and DNER showed decreased expression. Protein-protein interaction network analysis revealed IL-6 as a central hub protein forming a tightly interconnected cluster with TNF receptor family members. These findings indicate systemic plasma protein profiles associated with chronic periodontitis within this population-based cohort. The identified proteins may provide a basis for future evaluation of blood-based biomarkers for chronic periodontitis, pending further validation.

Gastrointestinal acute graft-versus-host disease (GI aGvHD) remains a leading cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Current diagnostic methods rely on invasive procedures with limited sensitivity. While circulating biomarkers have been proposed, little is known about the local transcriptomic landscape within inflamed GI tissue. We performed integrated profiling of mRNA and microRNA expression in colonoscopically resected GI biopsies from n = 8 HSCT patients, including n = 3 with histologically confirmed GI aGvHD and n = 5 without. Using NanoString nCounter technology, we quantified 770 immune-related mRNAs and 799 mature human microRNAs. Differential expression analysis, pathway enrichment, cell type deconvolution, and machine learning-based biomarker prioritisation were conducted to define disease-specific molecular signatures. GI aGvHD was marked by upregulation of inflammatory genes (e.g., IL1B, IL17RA, HLA-DRA) and immune-regulatory microRNAs (e.g., miR-155-3p, miR-223-3p), alongside downregulation of epithelial and anti-inflammatory markers (ST6GAL1, THBS1, miR-1915-3p, miR-145-5p). Enrichment analyses revealed activation of IL2/STAT5, JAK/STAT3, TCR signalling, and antigen presentation pathways. Machine learning identified LCN2, CXCL13, and miR-1269b as top-ranked biomarker candidates. Cell deconvolution showed increased M0 macrophage and decreased dendritic cell signatures in aGvHD tissue. This is the first study to integrate mRNA and microRNA profiling in GI tissue using NanoString technology to characterise the immune and epithelial transcriptomic landscape of aGvHD. Our findings reveal dysregulated immune pathways, altered myeloid cell populations, and novel biomarker candidates, offering tissue-specific insights into disease pathogenesis and potential diagnostic targets. Larger validation studies and functional assays are warranted to confirm clinical utility.

Pregnanolone glutamate (PG) is a synthetic neurosteroid analog showing promise for treating ischemic brain injury, yet its blood-brain barrier (BBB) transport and metabolic fate remain unclear. We investigated the pharmacokinetics of PG in postnatal day 12 rats of both sexes subjected to endothelin-1 (ET-1)-induced focal hippocampal ischemia. Animals received PG (1 mg/kg intraperitoneal (i.p.)) or vehicle; serum and hippocampal steroidomes were profiled 60 min post-administration using gas chromatography-tandem mass spectrometry (GC-MS/MS) (hippocampus: n = 16 PG+, n = 27 PG-; multi-tissue subset: n = 6 PG+, n = 21 PG-). Our data revealed a "dual-fate" mechanism: PG undergoes systemic hydrolysis as a prodrug, as suggested by the tissue distribution pattern at 60 min post-administration, but also crosses the BBB intact, with significant parent conjugate accumulation in the hippocampus (42.3 pmol/g). The brain functioned as a "metabolic sink", passively accumulating metabolites generated in peripheral organs-such as 17-hydroxypregnanolone-despite local absence of synthesizing enzymes (e.g., CYP17A1). Crucially, PG induced "metabolic segregation" within the central nervous system (CNS): the pharmacological 5β-pathway was saturated (~170-fold pregnanolone increase), while endogenous neuroprotective 5α-pathway (allopregnanolone) homeostasis remained preserved, contrasting with peripheral metabolic saturation. Preferential hippocampal accumulation of 3-oxo and 3β-isomers suggests autonomous regulatory buffering via oxidative 17β-hydroxysteroid dehydrogenase (HSD17B) enzymes, protecting against excessive GABAergic inhibition. This unique pharmacokinetic profile-combining metabolic segregation with active central buffering-defines PG as a dual-mechanism delivery system that generates central neuroactive metabolites-several with previously established GABAergic and neuroprotective activity-without disrupting endogenous neurosteroidogenesis, positioning it as a promising neurotherapeutic candidate minimizing physiological steroid homeostasis disruption. Importantly, the present study characterizes the pharmacokinetic and metabolic fate of PG; the neuroprotective efficacy of PG was demonstrated in our prior functional studies using the same model.

In the original publication [...].

Extracellular matrix (ECM) remodeling is a hallmark of colorectal cancer progression, yet the transcriptional mechanisms coordinating collagen deposition and matrix metalloproteinase activation remain incompletely understood. We performed integrated computational analysis of 680 samples across normal mucosa, adenoma, and carcinoma stages to characterize discoidin domain receptor (DDR)-mediated transcriptional networks during tumorigenesis. Stage-stratified correlation analysis of fourteen pathway genes revealed profound divergence between DDR1 and DDR2; DDR1 correlations remained weak across all stages, while DDR2 correlations strengthened 2.59-fold from normal to carcinoma. DDR2-COL11A1 exhibited the most dramatic coupling intensification, increasing from R2=0.007 in normal tissue to R2=0.549 in carcinoma, accompanied by 1.99-fold COL11A1 upregulation. Remarkably, pathway activation occurred despite stable DDR2 expression, indicating enhanced transcriptional coupling efficiency rather than receptor upregulation as the primary mechanism. Deep neural network classification achieved 93.14% accuracy distinguishing disease stages, with SHAP analysis independently validating DDR2-COL11A1 as the most important gene interaction for cancer classification. These findings establish DDR2-specific transcriptional coupling as a functionally important mechanism in colorectal cancer progression and identify COL11A1 as a critical downstream target, suggesting novel therapeutic strategies targeting coupling efficiency rather than receptor abundance.

This study evaluated entomopathogenic nematodes (EPNs) isolated from a cacao agroforestry system in the Peruvian Amazon, focusing on their molecular characterization and efficacy against Spodoptera frugiperda (Lepidoptera: Noctuidae) larvae. Thirteen EPN isolates were obtained from 50 soil samples using the Galleria mellonella baiting technique. Mortality assays revealed significant differences among isolates at 24, 48, and 72 h, with isolates 11N-A4 and 8N-B1 being the most virulent, achieving maximum mortalities of 100% and 96.3% at 72 h, respectively. Median lethal time (LT₅₀) values indicated rapid action of these isolates on G. mellonella larvae, with 33.3 h for 11N-A4 and 32.4 h for 8N-B1. Molecular identification using ITS, D2-D3 (LSU), and COI markers confirmed the isolates as Heterorhabditis sp. (11N-A4) and Heterorhabditis amazonensis (8N-B1). In bioassays with S. frugiperda larvae, both EPNs exhibited dose- and time-dependent mortality. H. amazonensis showed rapid action, reaching 100% mortality at the highest dose (60 IJs/larvae) within 48 h, whereas Heterorhabditis sp. displayed a gradual, sustained increase, attaining 91% mortality at 72 h. Median lethal dose (LD₅₀) and LT₅₀ values reflected the efficiency of both isolates, with Heterorhabditis sp. achieving lower LD₅₀ at later stages and shorter LT₅₀ at low-to-intermediate doses. These findings highlight the potential of Heterorhabditis sp. and H. amazonensis as effective biocontrol agents adapted to local conditions and represent the first report of H. amazonensis in Peru. Further studies under field conditions are required to confirm their suitability for incorporation into integrated pest management strategies in the Peruvian Amazon.

The choroid plexus (CP) has traditionally been regarded as a cerebrospinal fluid-producing structure; however, increasing evidence indicates that it functions as a dynamic regulatory interface involved in immune surveillance, metabolic homeostasis, and brain clearance. Neuroimaging studies consistently report CP enlargement across aging and diverse neurological and neuropsychiatric disorders, yet the underlying cellular mechanisms remain poorly integrated. In this review, we synthesize morphological, molecular, and imaging evidence to propose a sequential degenerative model of the CP epithelium. This model comprises: (1) regulated epithelial cell loss via apical extrusion, (2) compensatory hypertrophy of residual cells, (3) mitochondrial remodeling with oncocytic-like change, and (4) progressive blood-cerebrospinal fluid barrier dysfunction. At the molecular level, alterations in epithelial adhesion systems-particularly SPINT1-mediated protease regulation and E-cadherin-based adherens junction stability-may initiate epithelial instability. Hypertrophic epithelial cells exhibit increased mitochondrial burden, reflected by Tom20 expression, which may initially support metabolic adaptation but ultimately contribute to oxidative stress and functional decline. At the macroscopic level, the cumulative effects of cell loss, hypertrophy, and mitochondrial remodeling likely underlie CP enlargement detectable by magnetic resonance imaging. This framework positions CP enlargement as an imaging-visible manifestation of epithelial stress and provides a structural-molecular basis for interpreting CP alterations in brain aging and neurodegenerative disorders.

Cancer-associated thrombosis (CAT) is a major cause of morbidity and mortality in oncology, arising from complex interactions between tumor biology, host factors, and anticancer therapies. Growing evidence indicates that biological sex and gender-related factors modulate both thrombotic risk and clinical expression of venous thromboembolism (VTE) in patients with cancer. In this narrative review, we summarize current epidemiological, biological, and clinical data on sex- and gender-related differences in CAT across solid and hematologic malignancies. Men generally exhibit a higher overall incidence of VTE, whereas women may experience earlier, treatment-associated thrombotic events, with variability according to cancer type, stage, and therapy. Biological factors linked to coagulation and inflammation differ between sexes and may contribute to these patterns, although mechanistic evidence remains incomplete. Sex-related disparities also emerge in treatment-associated complications, including bleeding risk and abnormal uterine bleeding in anticoagulated women of reproductive age. In contrast, evidence for sex differences in oncohematology-associated thrombosis is limited and inconsistent. Gender-related inequalities in clinical trial participation further constrain the interpretation of available data. Overall, current evidence supports sex as a clinically relevant modifier of CAT risk, underscoring the need for systematic sex- and gender-informed research, to improve mechanistic understanding, and sex-stratified reporting to advance precision medicine in thrombosis and oncology.

Hepatocellular carcinoma (HCC) progression is shaped by crosstalk between the tumor immune microenvironment (TME) and metabolic reprogramming. This study aims to characterize a macrophage-lactylation molecular axis in HCC and to develop a quantitative prognostic stratification model. Using the TCGA-LIHC cohort, differentially expressed genes were intersected with Paeoniflorin (PF)-related targets, HCC disease targets, and macrophage-/lactylation-related genes to identify candidate genes. Prognostic genes were selected through Cox and LASSO-Cox analyses to construct a risk score model, followed by survival analysis and ROC curve evaluation. Immune infiltration was assessed using ESTIMATE and ssGSEA algorithms, and PF-protein binding interactions were explored via molecular docking and molecular dynamics simulations. Intersection analysis identified eight key genes, and prognostic model genes (HNRNPU, LDHA, and NPM1) were used to construct the prognostic model. High-risk patients exhibited significantly poorer overall survival (p < 0.001), with 1- and 3-year AUC values ranging from 0.70 to 0.90. HNRNPU was positively correlated with activated CD4 T cells (r = 0.385) and negatively correlated with eosinophils (r = -0.498). Molecular docking indicated favorable binding of PF to the model proteins, with the highest predicted affinity observed for LDHA (Vina score = -8.9 kcal/mol), and molecular dynamics simulations suggested the formation of a stable LDHA-PF complex during the later stage of the simulation. We propose a prognostic risk model for HCC constructed using three prognostic model genes and provide computational evidence linking PF to key molecular nodes such as LDHA. External cohort validation and experimental studies are warranted.