SEARCH · PubMed Health

Results for “Jagged-1 Protein”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

4 recordsLinked to original sources

PubMed2026

Characterization of stem cells from exfoliated deciduous teeth from a patient with Alagille syndrome carrying a JAG1 mutation.

PURPOSE: Alagille syndrome (ALGS) is an autosomal dominantly inherited disorder primarily caused by mutations in the Jagged Canonical Notch Ligand 1 (JAG1) gene. Although many pluripotent stem cells are well established, no patient-derived stem cells from exfoliated deciduous teeth (SHED) have been developed. In this study, we aimed to establish SHED from an ALGS patient carrying a heterozygous JAG1mut mutation. METHODS: We isolated SHED from a deciduous tooth of an ALGS patient with a heterozygous JAG1 mutation (ALGS-SHED) by the colony-forming unit-fibroblast (CFU-F) method. We then compared the characteristics of ALGS-SHED and healthy donor-derived control SHED (CONT-SHED). RESULTS: ALGS-SHED displayed mesenchymal stem cell features as indicated by CFU-F formation, immunophenotype, and mesenchymal multipotency into adipocytes, chondrocytes, and osteoblasts. ALGS-SHED showed reduced population doubling capacity and exhibited induced chondrogenic potency and diminished osteogenic potency, but similar hepatic potency. ALGS-SHED damaged in situ potency to form bile duct-like tubular structures in the livers of chronically CCl4-injured mice. CONCLUSIONS: We successfully established ALGS-SHED from an ALGS patient carrying a heterozygous JAG1 mutation. Our established ALGS-SHED may represent a potential model for studying ALGS involving a JAG1 mutation.

Alagille Syndrome↗

PubMed2024

Androgen Effects on Alcohol-induced Liver Fibrosis Are Controlled by a Notch-dependent Epigenetic Switch.

BACKGROUND & AIMS: Alcohol-associated liver disease (ALD) is a major cause of alcohol-related mortality. Sex is an important variable; however, the mechanism behind sex differences is not yet established. METHODS: Kdm5b flox/flox Kdm5c flox male mice were subjected to gonadectomy or sham surgery. Mice were fed a Western diet and 20% alcohol in the drinking water for 18 weeks. To induce knockout, mice received 2 × 1011 genome copies of AAV8-CMV-Cre or AAV8-control. To test the role of Notch, mice were treated with 10 mg/kg of avagacestat for 4 weeks. RESULTS: We found that Kdm5b/Kdm5c knockout promoted alcohol-induced liver disease, whereas gonadectomy abolished this effect, suggesting that male sex hormones promote liver disease in the absence of KDM5 demethylases. In contrast, in the thioacetamide-induced fibrosis model, male sex hormones showed a protective effect regardless of genotype. In human liver disease samples, we found that androgen receptor expression positively correlated with fibrosis levels when KDM5B levels were low and negatively when KDM5B was high, suggesting that a KDM5B-dependent epigenetic state defines the androgen receptor role in liver fibrosis. Using isolated cells, we found that this difference was due to the differential effect of testosterone on hepatic stellate cell activation in the absence or presence of KDM5B/KDM5C. Moreover, this effect was mediated by KDM5-dependent suppression of Notch signaling. In KDM5-deficient mice, Notch3 and Jag1 gene expression was induced, facilitating testosterone-mediated induction of Notch signaling and stellate cell activation. Inhibiting Notch with avagacestat greatly reduced liver fibrosis and abolished the effect of Kdm5b/Kdm5c loss. CONCLUSIONS: Male sex hormone signaling can promote or prevent alcohol-associated liver fibrosis depending on the KDM5-dependent epigenetic state.

Animals↗

PubMed2026

Oncolytic HSV-1-Mediated JAG1 Blockade Induces Glioma Senescence-Associated Secretory Phenotype to Increase Macrophage Activation and Cetuximab-Mediated Senolysis.

UNLABELLED: Oncolytic HSV-1 (oHSV) treatment induces Notch signaling and myelosuppression in the tumor microenvironment (TME) of preclinical cancer models. Clinically, the Notch ligand JAG1 was upregulated in patients with recurrent high-grade glioma treated with the oHSV CAN-3110 and correlated with poor prognosis. To better understand endogenous JAG1-mediated signaling in glioma cells and tumor-associated macrophages (TAM), we engineered a JAG1-antagonizing oHSV (OD-0J1) and interrogated its impact on cancer and myeloid cells in the TME. OD-0J1 antagonized JAG1-mediated Notch signaling and suppressed tumor growth in athymic nude and humanized mice, an effect reliant on Notch signaling in tumor cells. Kinome profiling revealed that OD-0J1 treatment suppressed CDK1, resulting in activation of the G2-M cell cycle checkpoint. Cell cycle arrest led to senescence and correlated with increased reactive oxygen species, p62, and autophagosome accumulation and senescence-associated β-galactosidase activity. OD-0J1-induced senescence resulted in increased production of inflammatory chemokines and damage-associated molecular patterns (DAMP), such as IL1β, HMGB1, and extracellular ATP. Coculturing macrophages with OD-0J1-infected tumor cells led to stimulation of chemotactic and proinflammatory pathways, as well as increased Fc receptor activation. Single-cell RNA sequencing and flow cytometric analysis of F4/80+ cells isolated from tumors showed a shift from tumor-supporting TAMs to inflammatory macrophages upon OD-0J1 treatment. Heightened EGFR activation in senescent cells was a mechanism to escape cell death, which created a unique opportunity for cetuximab as a senolytic agent. Combination therapy reduced EGFR signaling and induced macrophage-mediated antibody-dependent cellular cytotoxicity, thereby increasing the antitumor therapeutic efficacy of OD-0J1. SIGNIFICANCE: Leveraging JAG1 antagonism in the context of oncolytic virotherapy rewires macrophage polarization within the tumor microenvironment, which has wide implications for sensitizing tumors to antibodies, senolytic agents, and BiTE therapies.

Humans↗

PubMed2025

A model of Notch signalling control of angiogenesis: Evidence of a role for Notch ligand heterodimerization.

The ubiquitous Notch receptor signalling network is essential for tissue growth and maintenance. Operationally, receptor activity is regulated by two principal, counterposed mechanisms: intercellular Notch transactivation triggered by interactions between receptors and ligands expressed in neighbouring cells; intracellular cis inhibition mediated by ligands binding to receptors expressed in the same cell. Moreover, different Notch receptor/ligand combinations are known to elicit distinct molecular and cellular responses, and together, these phenomena determine the strength, the duration and the specificity of Notch receptor signalling. To date, it has been assumed that these processes involve discrete ligand homomers and not heteromeric complexes composed of more than one ligand species. In this study, we explore the molecular basis of the opposing actions of the Notch ligands, DLL4 and JAG1, which control angiogenic sprouting. Through a combination of experimental approaches and mathematical modelling, we provide evidence that two mechanisms could underpin this process: 1) DLL4 rather than JAG1 induces efficient Notch1 receptor transactivation; 2) JAG1 directly blocks DLL4-dependent cis-inhibition of Notch signalling through the formation of a JAG1/DLL4 complex. We propose a new model of Notch signalling that recapitulates the formation of tip and stalk cells, which is necessary for sprouting angiogenesis.

Signal Transduction↗