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PubMed2026

A Novel Splice Variant in the COL1A1 Gene Leads to Exon 46 Skipping and Osteogenesis Imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI) is a clinical and genetic disorder characterised by bone fragility, growth deficiency and skeletal deformity. Ninety per cent of OI cases are attributable to autosomal dominant variants in the COL1A1 and COL1A2 genes. METHODS: Candidate variants were identified and verified through trio whole-exome sequencing (trio-WES), copy number variation sequencing (CNV-seq) and Sanger sequencing. Minigene splicing assays were performed in HeLa and HEK293T cells with pcDNA3.1 and pcMINI-C vectors to investigate the function of the candidate variants. A systematic review of COL1A1 splicing variants and the corresponding genotype-phenotype spectrum was performed. RESULTS: Trio-WES revealed a novel heterozygous variant in the C-terminal region of the COL1A1 gene: NM_000088.4:c.3423+5G>A. Sanger sequencing confirmed the variant in both the proband (II-2) and her foetus (III-1) who were clinically suspected of having OI. The c.3423+5G>A variant causes complete skipping of Exon 46, as demonstrated by a minigene splicing assay. We retrieved 419 COL1A1 splicing variants from PubMed, excluded 15 without phenotypic data and 2 linked to Ehlers-Danlos syndrome and stratified the remaining 402 variants into three types on the basis of splice site location: (1) Variants at canonical splicing sites (77.8%, 313/402) mostly cause mild phenotypes, whereas a minority may be severe. (2) Intron variants in other locations, such as splice region variants (17.9%, 72/402), usually cause mild clinical phenotypes, and deep intronic splice variants (0.4%, 2/402) that may result in severe phenotypes. (3) Other variants (3.7%, 15/402), such as exon variants or fragment loss, are extremely rare. We also preliminarily discuss the mechanisms underlying phenotypic variability and the characteristics of C-terminal variants. CONCLUSIONS: This intron variant in COL1A1 was classified as likely pathogenic and was confirmed to disrupt COL1A1 expression. The summary analysis results also revealed a correlation among splicing variants, C-terminal region variants and disease, suggesting that variant location provides a useful framework for prognosis prediction.

Female↗

PubMed2026

TCGA-based identification of prognostic biomarkers and candidate traditional Chinese medicine compounds in papillary thyroid carcinoma: An observational study.

This study aimed to identify prognostic genes associated with papillary thyroid carcinoma (PTC) and explore candidate traditional Chinese medicine (TCM) compounds using integrated bioinformatics and molecular docking. In this observational study, PTC gene expression profiles and clinical data were obtained from The Cancer Genome Atlas. Differentially expressed genes were screened using differential-expression sequencing (DESeq2), followed by protein-protein interaction network analysis to identify hub genes. Their expression, diagnostic value, immune relevance, prognostic significance, protein-level validation, and single-cell distribution were assessed using gene expression profiling interactive analysis, receiver operating characteristic analysis, immune infiltration analysis, Kaplan-Meier survival analysis, the human protein atlas, and single-cell RNA-sequencing data. Candidate TCM compounds were predicted using symptom mapping (SymMap) and the TCM Systems Pharmacology Database and Analysis Platform, and molecular docking was performed to evaluate potential ligand-target interactions. Five hub genes, colony-stimulating factor 2, apolipoprotein E, fibronectin 1 (FN1), collagen type I alpha 1 chain (COL1A1), and intercellular adhesion molecule 1, were identified and found to be significantly upregulated in PTC tissues, with diagnostic value in receiver operating characteristic analysis. Immune infiltration analysis showed associations with macrophages, dendritic cells, and T helper 1 cells, whereas single-cell analysis demonstrated heterogeneous expression across immune and stromal cell populations, including fibroblasts. Higher FN1 and COL1A1 expression was associated with poorer outcomes. Immunohistochemistry supported the expression patterns, while single-cell analysis provided exploratory cell-type-level context for the cellular distribution of selected genes. Ginseng and Smilax glabra were predicted as common candidate TCMs, and docking suggested favorable binding between their active compounds and selected hub targets. Colony-stimulating factor 2, apolipoprotein E, FN1, COL1A1, and intercellular adhesion molecule 1 may be biologically relevant hub genes in PTC, while FN1 and COL1A1 may have prognostic value. Predicted TCM compounds provide preliminary computational evidence for possible compound-target interactions, requiring experimental and clinical validation.

Female↗

PubMed2026

Integrative pooled transcriptomic analysis reveals shared and distinct molecular signatures in adult T-cell leukemia/lymphoma and peripheral T-cell lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) and peripheral T-cell lymphomas (PTCLs) are aggressive neoplasms of mature T cells with poor prognosis and limited therapies. ATLL originates from HTLV-1 infection, while PTCL comprises heterogeneous subtypes without a defined etiologic factor. Comparative molecular profiling of these malignancies remains limited. We conducted an integrative pooled transcriptomic analysis of publicly available Gene Expression Omnibus (GEO) microarray datasets to compare ATLL, PTCL, and normal T-cell samples. Differential expression, functional enrichment, and protein-protein interaction (PPI) network analyses were performed using STRING, Cytoscape, and Gephi. Key hub genes and functional modules were further analyzed through KEGG and Enrichr databases. Comparative analyses revealed upregulation of extracellular matrix (ECM) components (COL1A1, COL3A1, FN1, SPARC, THBS1) and immune-regulatory molecules (CD163, CXCL12-CXCR4, complement subunits). Shared pathways included ECM-receptor interaction, focal adhesion, and PI3K-Akt signaling. PTCL showed enrichment in coagulation and angiogenesis, while ATLL displayed distinct enrichment of cytoskeletal, chemokine, immune-regulatory, and signaling-associated pathways. PPI networks identified ECM and chemokine signaling as key hubs, with subtype-specific modules related to immune regulation, proliferation, and metabolism. This integrative approach uncovers common and distinct oncogenic programs in ATLL and PTCL, emphasizing ECM remodeling and immune modulation as shared hallmarks. Hub genes such as COL1A1, FN1, and CXCL12-CXCR4 may represent candidate molecular signatures that warrant validation in independent patient cohorts and functional studies before their clinical utility can be established.

Humans↗

PubMed2026

Biogenic Silver Nanoparticles from the Cell-Free Supernatant of Mychonastes sp. B1: Antibacterial and Antibiofilm Effects, and Wound Healing Activity Supported by Gene and Protein Expression Analysis.

The biogenic synthesis of silver nanoparticles (AgNPs) using microalgae provides a sustainable alternative to conventional physicochemical methods. In this study, AgNPs were synthesized from the cell-free supernatant of the freshwater microalga Mychonastes sp. B1 and characterized by ultraviolet-visible spectroscopy (UV-Vis), transmission electron microscopy (TEM), dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR), and field-emission scanning electron microscopy with energy-dispersive X-ray spectroscopy (FE-SEM/EDS). The nanoparticles were predominantly spherical (15-55 nm), highly stable (ζ =  - 42.8 mV), and appeared to be capped by extracellular polymeric substances. The biogenic AgNPs (GS-AgNPs) exhibited potent antibacterial activity, with minimum inhibitory concentrations (MICs) of 2.0 µg/mL against Staphylococcus aureus and 2.5 µg/mL against Pseudomonas aeruginosa, and significantly (p < 0.05) inhibited biofilm formation. Fibroblast viability remained at or above 80% at AgNP concentrations up to 1.5 µg/mL, which promoted cell migration and increased wound closure by 8.1% at 24 h (p < 0.05). Exposure to 1.5 µg/mL AgNPs significantly upregulated extracellular matrix markers (Col1a1 2.3-fold, Fn1 3.3-fold at mRNA level; COL1A1 2.1-fold, FN1 2.7-fold at the protein level). These findings indicate that GS-AgNPs possess antimicrobial and wound healing properties, highlighting their potential as biocompatible nanomaterials for biomedical applications.

Silver↗

PubMed2026

Dynamic transcriptomic landscape from bulk RNA-seq reveals critical mmu-miR-181a-5p/hif1a and mmu-miR-101a-3p/col1a1 modules for deep second-degree burn wound healing.

Burn injuries constitute a significant global health challenge, with deep partial-thickness burns (deep second-degree) posing particular clinical concerns due to prolonged healing and high scarring risks stemming from reticular dermis damage. Current therapeutic strategies remain largely empirical, reflecting limited understanding of stage-specific regulatory mechanisms. This study systematically investigated the molecular basis of deep partial-thickness burn repair by establishing murine models and performing RNA-seq analysis across healing phases (0, 3, 7, 14 days post-burn, dpb). Integrated bioinformatics revealed pivotal ceRNA and PPI networks, identifying hif1a (hypoxia-responsive immunomodulator) and col1a1 (ECM remodeling hub) as nodal regulators. Mechanistically, mmu-miR-101a-3p and mmu-miR-181a-5p were validated as post-transcriptional repressors of col1a1 and hif1a, respectively. Our work pioneers the discovery of the mmu-miR-181a-5p/hif1a and mmu-miR-101a-3p/col1a1 axes as master regulators of burn repair, offering novel therapeutic targets. The multi-omics dataset and molecular networks established herein provide a foundational resource for wound healing research.

MicroRNAs↗

PubMed2026

Acidic transcription factors position the genome at nuclear speckles through transcription-dependent and -independent mechanisms.

A small fraction of the genome reproducibly positions near nuclear speckles (NSs), increasing the expression and/or splicing efficiency of NS-associated genes. How specific genomic regions in mammalian cells are targeted to NSs remains unclear. Here, we demonstrate the establishment of genome-wide NS association without active transcription. We show that DNA sequences derived from NS-associated regions, when integrated as transgenes, are autonomously targeted to NSs. By systematically dissecting one such genomic locus, the COL1A1-SGCA locus, we identified redundant NS-targeting cis-regulatory elements, including an ∼600-bp fragment with 17 binding motifs for 8 transcription factors (TFs). Four NS-targeting TFs within this fragment contain acidic activation domains (AADs) that provide both chromatin-context and transcription-dependent NS targeting, properties that appear to be common among several other tested AADs. A subset of acidic activator TFs contains an additional, transcription-independent NS-targeting activity. Our findings establish diverse and partially redundant NS-targeting activities, which may facilitate dynamic gene positioning at the NS periphery for context-specific transcriptional responses.

Transcription, Genetic↗

PubMed2026

Severe Early-Onset Fetal Growth Restriction: The Yield of Antenatal and Postnatal Genetic Testing.

OBJECTIVES: We evaluated the diagnostic yield of karyotype (KT) and chromosomal microarray (CMA) with isolated severe FGR diagnosed before 32 weeks' gestation. Exome and genome sequencing (ES/GS) level data were available in a subset of this population. METHOD: We performed a retrospective review of singleton pregnancies (delivered 2022-2025) with estimated fetal weight or abdominal circumference < 3rd percentile before 32 weeks' gestation, no sonographic structural anomalies, and diagnostic testing (KT, CMA, ES, or GS) via amniocentesis or cord blood. Cases with abnormal cell-free DNA were excluded. RESULTS: Forty cases were included (mean diagnosis 26.8 weeks). Testing was performed via amniocentesis in 42% and cord blood in 58%. All KT (27/40) were normal. CMA (39/40) identified one pathogenic CNV (2.5%) and three (7.5%) variants of uncertain significance (VUS). Four (10%) showed ≥ 1 region of absence of heterozygosity (AOH) > 10Mb; one revealed maternal uniparental disomy of chromosome 6. Sequencing (N = 10) detected one VUS in COL1A1. Acute viral infection was not observed in any of the cases. CONCLUSIONS: CMA was diagnostic in 2/39 (5.1%) cases, a pathogenic CNV implicating the SHOX gene, and maternal UPD 6, which were consistent with FGR. There was a remarkable rate (10%) of AOH. Further investigation, including placental studies and genome sequencing, may elucidate whether AOH is a contributing factor for FGR.

Humans↗

PubMed2026

Desmoplakin loss in alveolar epithelium drives Wnt/β-Catenin-mediated extracellular matrix remodeling and fibrotic signaling in vitro.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic interstitial lung disease characterized by aberrant extracellular matrix (ECM) remodeling, epithelial dysfunction, and limited therapeutic options. Genetic studies implicate Desmoplakin (DSP), a desmosomal adhesion protein, in IPF susceptibility; however, its mechanistic role remains unclear. This study aimed to investigate the role of DSP in regulating fibrotic and ECM remodeling pathways in alveolar epithelial cells. METHODS AND RESULTS: DSP was silenced using siRNA in adenocarcinoma-derived human alveolar epithelial A549 cells. DSP loss induced epithelial-to-mesenchymal transition, enhanced cell migration, and increased epithelial permeability, along with upregulation of fibrotic and ECM-associated genes. Pathway enrichment analysis of DSP interactors (STRING database) identified the Wnt/β-catenin signaling as a potential key pathway. Mechanistic validation using cycloheximide chase assays, qPCR, western blotting, immunofluorescence, and luciferase-reporter assays suggested that DSP loss destabilizes desmosomal complexes, promoting plakoglobin (γ-catenin) degradation while reducing β-catenin turnover. This was associated with increased nuclear accumulation of β-catenin and enhanced TCF/LEF-dependent transcription, leading to elevated expression of ECM-related genes, including COL1A1 and MMP9. DSP overexpression suppressed Wnt/β-catenin signaling and fibrotic gene expression, while pharmacological inhibition of this pathway attenuated DSP-dependent increases in ECM-associated gene expression. CONCLUSION: These findings suggest that DSP may function as a regulator of alveolar epithelial homeostasis and extracellular matrix remodeling in an in vitro epithelial model. Loss of DSP is associated with activation of Wnt/β-catenin-mediated fibrotic signaling, correlating with reduced plakoglobin stability. This study provides mechanistic insight into epithelial-matrix crosstalk in vitro and identifies a candidate pathway that may contribute to ECM dysregulation in IPF, the disease relevance of which will require validation in primary human alveolar epithelial cells and in vivo models.

Humans↗

PubMed2026

Normoalbuminuric and albuminuric diabetic kidney disease exhibit divergent renal proteomic characteristics: implications for management.

BACKGROUND: The pathogenesis of diabetic kidney disease (DKD) is complex. Normoalbuminuric diabetic kidney disease (NADKD) is a special subtype of DKD that often progresses insidiously without detectable albuminuria, posing diagnostic and therapeutic challenges. Its pathogenesis remains unclear. Proteomic analysis of renal tissues may offer insights into its pathogenesis and identify biomarkers. METHODS: Clinicopathological data from 295 biopsy-proven DKD patients were collected and classified into normoalbuminuric (UACR < 30 mg/g, n = 25), microalbuminuric (UACR 30-300 mg/g, n = 26), and macroalbuminuric (UACR > 300 mg/g, n = 244) groups. Laser microdissection combined with mass spectrometry (LMD/MS) was used to analyze glomerular and proximal tubule proteomics in 5 patients per DKD subgroup and 5 control subjects. Associations with clinical features were examined. RESULTS: Glomerular proteomic analysis revealed that oxidative stress and metabolic pathways (UQCRC1) were upregulated in NADKD group, whereas the complement and coagulation cascades (C3, C5, C6, C9, CFH, CFHR1) were significantly upregulated in the microalbuminuric and macroalbuminuric DKD groups. The proximal tubule proteomics analysis showed that oxidative phosphorylation-related proteins (SDHA, CYCS, UQCRQ) were upregulated in NADKD, and collagen I related proteins (COL1A1, COL1A2) were significantly upregulated. CONCLUSION: Oxidative stress and mitochondrial dysfunction are involved in the progression of NADKD, lesions predominantly located in the tubulointerstitium. The complement pathway participates in the pathogenesis and progression of albuminuric DKD (ADKD). These divergent molecular profiles suggest that NADKD and ADKD may reflect different pathophysiological mechanisms and have important implications for therapeutic strategies in diabetes management.

Humans↗

PubMed2025

Colorectal Liver Metastasis Pathomics Model: Integrating Single-Cell and Spatial Transcriptome Analysis With Pathomics for Predicting Liver Metastasis in Colorectal Cancer.

The liver is the primary target organ for hematologic metastasis of colorectal cancer (CRC), and CRC liver metastasis (CRLM) often precludes radical resection, making it the leading cause of death in patients with CRC. To improve the identification and prediction of liver metastasis risk, we identified a cell type of liver metastasis--triggering malignant cells (LMTMCs) through integrating single-cell RNA sequencing and spatial transcriptome analysis. Multiomics cell communication analysis indicated that the interaction between fibroblasts and LMTMCs through the COL1A1-CD44/SDC4 and LAMA4-CD44 signaling axes could promote CRLM. By applying the one-class logistic regression algorithm, we developed a CRLM scoring system in the bulk RNA-sequencing data according to the abundance of LMTMCs in each individual. Using the grouping labels derived from the CRLM scoring system in the bulk data and the corresponding whole-slide images without any manual annotations at the region or pixel level, processed via slide-level weakly supervised learning, a deep-learning model based on the ResNet18 architecture, called Colorectal Liver Metastasis Pathomics Model, was developed to predict the risk of liver metastasis in patients with CRC. The Colorectal Liver Metastasis Pathomics Model achieved an area under the curve of 0.84 at the internal test set of The Cancer Genome Atlas-CRC histology images. In the external independent validation sets, namely the Affiliated Hospital of Southwest Medical University and the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University cohorts, the areas under the curve were 0.89 and 0.72, respectively, indicating effective classification performances. This study provided new insights and tools for the early identification of CRLM and demonstrated the potential of combining multiomics with deep learning-based pathomics in cancer research.

Humans↗

PubMed2026

Colchicine attenuates cardiac hypertrophy by targeting the macrophage-driven Interleukin-6 suppression.

Hypertrophic cardiomyopathy (HCM), the most prevalent inherited cardiovascular disease, is strongly linked to progressive heart failure and sudden cardiac death (SCD). However, its underlying pathogenic mechanisms remain incompletely understood, and effective therapeutic strategies are still lacking. Here, we established two murine HCM models harboring high SCD risk-associated mutations. Single-cell RNA sequencing revealed immune activation and enhanced fibrotic remodeling in the myocardium of these models. Therefore, we hypothesized that colchicine, a widely used anti-inflammatory drug known to reduce cardiovascular events in multiple cardiac disorders, may also represent a promising therapeutic candidate for HCM. As we expected, colchicine treatment attenuated pathological remodeling in our study, as evidenced by reduced cardiomyocyte hypertrophy, decreased fibrosis, and downregulation of cardiac stress markers (Anp, Bnp) and fibrotic mediators (Ctgf, Col1a1, Col3a1). In addition, colchicine attenuated pro-inflammatory macrophage populations and suppressed IL-6 expression, thereby contributing to the preservation of cardiac function. These findings provide the first preclinical evidence that colchicine alleviates myocardial inflammation and fibrosis in HCM, underscoring its potential as a novel therapeutic strategy to reduce fibrosis, lower SCD risk, and improve patient outcomes.

Animals↗

PubMed2026

Spatial Proteomics of the Normal Breast Collagen Stroma: Links to Density and Body Mass Index.

Collagen breast stroma can become a breast cancer risk factor, yet proteomic regulation of normal breast stroma remains poorly defined. This study evaluates the spatial regulation of the collagen proteome from normal breast tissue. Normal breast tissue sections from the Susan G. Komen tissue bank were used (n = 40), with data including genetic ancestry (n = 20 African ancestry; n = 20 European ancestry), body-mass-index (BMI), age, and mammogram density by the Breast Imaging Reporting and Data System (BI-RADS). 10-plex cell marker staining showed CD44 and COL1A1 markers modulated with BMI. Collagen fiber widths by second harmonic generation microscopy contrasted in BMI categories by genetic ancestry. Targeted extracellular matrix proteomics mass spectrometry imaging showed the collagen alpha-1(I) chain proteome was spatially heterogeneous across the normal breast microenvironment with site-specific post-translational modification of proline hydroxylation. Signatures computationally extracted from stroma-rich regions reported that 47 collagen peptides distinguished BI-RADS categories (area under the receiver operating curve >0.7; p-value >0.05). Multivariate modeling of collagen peptides, fiber metrics, and clinical features supported a strong positive association with BMI as a determinant of collagen alterations in the normal breast. This study provides a foundation for larger studies investigating the clinical value of spatial collagen proteome alterations in human breast.

Humans↗

PubMed2026

Decoding regional keratinization in human oral mucosa through high-resolution spatial transcriptomics.

Oral mucosa exhibits region-specific keratinization, essential for periodontal health, yet the spatial and molecular mechanisms driving these differences remain poorly understood. This study aimed to generate a high-resolution spatial transcriptomic atlas of the human oral mucosa around the mucogingival junction, to reveal stromal-epithelial interactions, that distinguish keratinized from non-keratinized programs. Formalin-fixed paraffin-embedded specimens from the mucogingival junction area of two healthy donors were analyzed with the 10 × Genomics Visium HD platform, yielding two keratinized and two non-keratinized regions. Spatial clustering, pseudotime trajectory inference, cell-type integration with a single-cell reference, and ligand-receptor network analysis were applied to delineate epithelial and stromal compartments. Sixteen reproducible clusters, recapitulating tissue architecture, were identified and revealed distinct transcriptional signatures, distinguishing gingiva from lining mucosa. Pseudotime analysis revealed bifurcating epithelial lineages, originating from a shared basal progenitor layer into keratinized and non-keratinized programs. Gingival keratinization was driven by stromal collagen ligands (COL1A1, COL1A2, COL6A1, COL6A2) engaging epithelial receptors (CD44, SDC1), further reinforced within the epithelium by desmosomal adhesion via DSG1-DSC2/3. Gingival keratinization emerges from integrated stromal collagen signaling and epithelial adhesion. This spatially resolved framework advances understanding of oral mucosal specialization and provides a foundation for biologically guided regenerative therapies.

Humans↗

PubMed2025

Newly identified single-nucleotide polymorphism associated with the transition from nonalcoholic fatty liver disease to liver fibrosis: results from a nested case-control study in the UK biobank.

BACKGROUND: Genetic factors may have a significant influence on the likelihood of liver fibrosis in individuals with nonalcoholic fatty liver disease (NAFLD). The present study was conducted to explore how single-nucleotide polymorphism (SNP) impacts the development of fibrosis in those suffering from NAFLD. MATERIALS AND METHODS: Utilizing the UK Biobank dataset, we conducted a nested case-control analysis among NAFLD participants, defining the case group as those with liver fibrosis and cirrhosis during follow-up. For our in vitro investigations, we employed the LX-2 human hepatic stellate cell line. Our procedures included cultivating these cells, employing SAMM50-rs2073080 plasmid techniques to enhance the expression of recently discovered SNPs, and conducting biochemical assays. To quantify gene expression, we used real-time PCR with fluorescence detection. RESULTS: The study analyzed data from 5467 participants (1094 cases and 4373 controls). Genome-wide association analysis identified nine significant loci, including the novel rs2073080 variant, strongly associated with NAFLD-associated hepatic fibrosis. In vitro TGF-β modeling revealed significant upregulation of α-SMA and COL1A1, confirming model effectiveness. Oxidative stress markers like elevated malondialdehyde (MDA) and reduced catalase (CAT) and superoxide dismutase (SOD) levels indicated liver damage in the TGF-β group. SAMM50-rs2073080 was upregulated in the NAFLD-associated fibrosis model. In vitro experiments on LX-2 cells showed that SAMM50-rs2073080 overexpression led to increased fibrosis, as indicated by higher cellular MDA levels and lower CAT and SOD levels, compared to the vector group. CONCLUSION: Our research highlights a significant association of SAMM50-rs2073080 with the progression of NAFLD to hepatic fibrosis, and the in vitro experiments further corroborated these findings.

Humans↗

PubMed2026

Inhibition of EED enhances osteogenic differentiation and bone formation: a potential therapeutic strategy for osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a heterogeneous group of inherited connective tissue disorders primarily caused by dominant mutations in COL1A1 or COL1A2 that impair type I procollagen folding and secretion. Misfolded collagen accumulates in the endoplasmic reticulum (ER), triggering ER stress and osteoblast dysfunction, and bone fragility. Current pharmacologic therapy focuses on inhibiting bone resorption but has limited efficacy and does not address the underlying biology of the disease. The epigenetic regulator polycomb-repressive complex 2 (PRC2) has emerged as an important regulator of bone formation. Genetic and pharmacologic disruption of PRC2 enhanced osteogenic differentiation in WT cells. Here, we demonstrate that inhibition of the PRC2 through targeting its essential component embryonic ectoderm development (EED) enhances osteogenic differentiation, improves bone architecture in male Col1a2 +/G610C OI mouse models, modulates the integrated stress response (ISR), and improves ER morphology in OI cells. These findings identify EED inhibition as a novel epigenetic strategy to restore collagen homeostasis and improve skeletal integrity in OI.

ER stress↗

PubMed2024

Multiple urinary peptides are associated with hypertension: a link to molecular pathophysiology.

OBJECTIVES: Hypertension is a common condition worldwide; however, its underlying mechanisms remain largely unknown. This study aimed to identify urinary peptides associated with hypertension to further explore the relevant molecular pathophysiology. METHODS: Peptidome data from 2876 individuals without end-organ damage were retrieved from the Human Urinary Proteome Database, belonging to general population (discovery) or type 2 diabetic (validation) cohorts. Participants were divided based on systolic blood pressure (SBP) and diastolic BP (DBP) into hypertensive (SBP ≥140 mmHg and/or DBP ≥90 mmHg) and normotensive (SBP <120 mmHg and DBP <80 mmHg, without antihypertensive treatment) groups. Differences in peptide abundance between the two groups were confirmed using an external cohort ( n  = 420) of participants without end-organ damage, matched for age, BMI, eGFR, sex, and the presence of diabetes. Furthermore, the association of the peptides with BP as a continuous variable was investigated. The findings were compared with peptide biomarkers of chronic diseases and bioinformatic analyses were conducted to highlight the underlying molecular mechanisms. RESULTS: Between hypertensive and normotensive individuals, 96 (mostly COL1A1 and COL3A1) peptides were found to be significantly different in both the discovery (adjusted) and validation (nominal significance) cohorts, with consistent regulation. Of these, 83 were consistently regulated in the matched cohort. A weak, yet significant, association between their abundance and standardized BP was also observed. CONCLUSION: Hypertension is associated with an altered urinary peptide profile with evident differential regulation of collagen-derived peptides. Peptides related to vascular calcification and sodium regulation were also affected. Whether these modifications reflect the pathophysiology of hypertension and/or early subclinical organ damage requires further investigation.

Humans↗

PubMed2024

Desmoplakin mutations in cardiac fibroblasts cause TGFβ1-mediated pathological fibrogenesis in desmoplakin cardiomyopathy via beclin-1 regulation.

BACKGROUND: Pathological fibrosis is a major finding in cardiovascular diseases and can result in arrhythmia and heart failure. Desmosome gene mutations can lead to arrhythmogenic cardiomyopathy (ACM). Among ACM, pathogenic desmoplakin ( DSP ) variants cause a distinctive cardiomyopathy with excessive cardiac fibrosis that could precede ventricular dysfunction. DSP variants are also linked to other fibrotic diseases. Whether DSP plays any role in pathological fibrosis remain unknown. METHODS: Mesenchymal stromal cells (MSCs) are resident fibroblast-like cells that are responsible for fibrogenesis in most organs, including hearts. We first used unbiased genome-wide analyses to generate cardiac fibroblasts-like, induced pluripotent stem cell-derived MSCs from normal donors and ACM patients with DSP mutations. We then studied the fibrogenic responses of cardiac MSCs to transforming growth factor beta-1 (TGF-β1) using Western/Co-IP, autophagy assay, gene knockdowns/over-expressions, genomic analyses, mouse DSP knockdown models, immunostaining, and qPCR. RESULTS: TGFβ1 induced excessive accumulations of vimentin (VIM)/fibrillar collagens, and over-activated fibrotic genes in DSP- mutant MSCs when compared to normal MSCs. In normal MSCs, VIMs bind to wild-type DSP during normal fibrogenesis after TGFβ1. DSP- mutant MSCs exhibited a haplo-insufficient phenotype with increased DSP-unbound VIMs that sequestered beclin-1 (BECN1) from activating autophagy and caveolin-1 (CAV1)-mediated endocytosis. Decreased autophagy caused collagen accumulations and diminished CAV1 endocytosis resulted in abnormal CAV1 plaque formation that over-activated fibrotic genes [ COL1A1, COL3A1, and fibronectin ( FN )] via heightened p38 activities after TGFβ1. Genome-wide analysis and DSP knockdown in mouse fibroblasts confirmed this novel role of DSP mutations in pathological fibrosis. Overexpression of VIM-binding domains of DSP could suppress pathological fibrosis by increasing collagen autophagic degradation and decreasing fibrotic gene expressions. CONCLUSIONS: Our data reveal that DSP deficiency in MSCs/fibroblasts leads to exaggerated fibrogenesis in DSP-cardiomyopathy by decreasing BECN1 availability for autophagy and CAV1-endocytosis. Overexpression of VIM binding domains of DSP could be a new strategy to treat pathological fibrosis.

Journal Article↗

PubMed2026

Desmoplakin Mutations in Cardiac Fibroblasts Cause TGFβ1-Mediated Pathological Fibrogenesis in Desmoplakin Cardiomyopathy Via Beclin-1 Regulation.

BACKGROUND: Pathological fibrosis is a major finding in cardiovascular diseases and can result in arrhythmia and heart failure. Desmosome gene mutations can lead to arrhythmogenic cardiomyopathy. Among arrhythmogenic cardiomyopathies, pathogenic DSP (desmoplakin) variants cause a distinctive cardiomyopathy with excessive cardiac fibrosis that could precede ventricular dysfunction. DSP variants are also linked to other fibrotic diseases. Whether DSP plays any role in pathological fibrosis remains unknown. METHODS: Mesenchymal stromal cells (MSCs) are resident fibroblast-like cells that are responsible for fibrogenesis in most organs, including the heart. We first used RNA-seq genome-wide analyses to generate cardiac fibroblast-like, induced pluripotent stem cell-derived MSCs from normal donors and patients with arrhythmogenic cardiomyopathy and DSP mutations. We then studied the fibrogenic responses of cardiac MSCs to TGFβ1 (transforming growth factor β1) using Western/Co-IP, autophagy assays, gene knockdowns/over-expressions, genomic analyses, mouse DSP knockdown models, immunostaining, and qPCR. RESULTS: TGFβ1 induced excessive accumulation of VIM (vimentin)/fibrillar collagens and over-activated fibrotic genes in DSP-mutant MSCs when compared with normal MSCs. In normal MSCs, VIMs bind to wild-type DSP during normal fibrogenesis after TGFβ1. DSP-mutant MSCs exhibited a haplo-insufficient phenotype with increased DSP-unbound VIMs that sequestered BECN1 (beclin-1) from activating autophagy and CAV1 (caveolin-1)-mediated endocytosis. Decreased autophagy caused collagen accumulation, and diminished CAV1 endocytosis resulted in abnormal CAV1 plaque formation that over-activated fibrotic genes (COL1A1, COL3A1, and fibronectin [FN]) via heightened p38 activity after TGFβ1. Genome-wide analysis and DSP knockdown in mouse fibroblasts confirmed this novel role of DSP mutations in pathological fibrosis. Overexpression of VIM-binding domains of DSP could suppress pathological fibrosis by increasing collagen autophagic degradation and decreasing fibrotic gene expression. CONCLUSIONS: Our data reveal that DSP deficiency in MSCs/fibroblasts leads to exaggerated fibrogenesis in DSP-cardiomyopathy by decreasing BECN1 availability for autophagy and CAV1-endocytosis. Overexpression of VIM binding domains of DSP could be a new strategy to treat pathological fibrosis.

Animals↗