TGR5 (Gpbar1) is a G protein-coupled receptor responsive to bile acids (BAs), which is expressed in different non-parenchymal cells of the liver, including biliary epithelial cells, liver-resident macrophages, sinusoidal endothelial cells (LSECs) and activated hepatic stellate cells (HSCs). Mice with targeted deletion of TGR5 are more susceptible towards cholestatic liver injury induced by cholic acid-feeding and bile duct ligation, resulting in a reduced proliferative response and increased liver injury. Conjugated lithocholic acid (LCA) represents the most potent TGR5 BA ligand and LCA-feeding has been used as a model to rapidly induce severe cholestatic liver injury in mice. Thus, TGR5 knockout (KO) mice and wildtype littermates were fed a diet supplemented with 1%LCA for 84 hours. Liver injury and gene expression changes induced by the LCA-diet revealed an enrichment of pathways associated with inflammation, proliferation and matrix remodelling. Knockout of TGR5 in mice caused upregulation of endothelin-1 (ET-1) expression in the livers. Analysis of TGR5-dependent ET-1 signalling in isolated LSECs and HSCs demonstrated that TGR5 activation reduces ET-1 expression and secretion from LSECs and triggers internalization of the ET-1 receptor in HSCs dampening ET-1 responsiveness. Thus, we identified two independent mechanisms by which TGR5 inhibits ET-1 signalling and modulates portal pressure.
The G Protein-Coupled Bile Acid Receptor TGR5 (Gpbar1) Modulates Endothelin-1 Signaling in Liver.
Sex
View SamplesRats were given pulmonary embolism by i.v. injection of 25 micron polystyrene microspheres or 0.01% Tween20 solution as vehicle control
Differential effect of mild and severe pulmonary embolism on the rat lung transcriptome.
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View SamplesTime and dose related expression profiles of rat right heart tissue in microsphere bead model for Pulmonary embolism
Transcriptional profile of right ventricular tissue during acute pulmonary embolism in rats.
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View SamplesBromodomain and extra terminal domain (BET) inhibition reduces occupancy of BET-family proteins at promoter and enhancer sites resulting in changes in the transcription of specific genes.
Inhibition of BET bromodomain-dependent XIAP and FLIP expression sensitizes KRAS-mutated NSCLC to pro-apoptotic agents.
Specimen part, Cell line
View SamplesPulmonary vascular occlusions due to thromboemboli can result in pulmonary hypertension and right heart damage. Treatments to clear the vascular obstructions such as i.v. heparain or thrombolytics can resolve the hypertension but right ventricular damage often occurs first. Methods of protecting the right ventricle from hypertensive damage during the course of acute treatment to clear the thromboemboli are needed. Monocyte- and neutrophil-mediated inflammation and fibrosis are associated with chronic right ventricular damage but the pathways involved are not understood. A comprehesive survey of gene expression during chronic pulmonary embolism verses control rats has been conducted in this study.
Transcriptional changes in right ventricular tissues are enriched in the outflow tract compared with the apex during chronic pulmonary embolism in rats.
Sex
View SamplesWe analysed the genexpression of dental follicle cells (DFCs) after 3 days osteogenic differentiation with BMP2 after transfection with a DLX3 plasmid (pDLX3) and after transfection with an empty plasmid (pEV)
A protein kinase A (PKA)/β-catenin pathway sustains the BMP2/DLX3-induced osteogenic differentiation in dental follicle cells (DFCs).
Specimen part
View SamplesThe mechanisms of action of the combined targeted therapy bevacizumab erlotinib in late stage non-squamous non-small cell lung cancer was investigated by means of whole genome exon arrays.
24h-gene variation effect of combined bevacizumab/erlotinib in advanced non-squamous non-small cell lung cancer using exon array blood profiling.
Sex, Age, Specimen part, Time
View SamplesDuctal carcinoma in situ (DCIS) is a precursor lesion that can give rise to invasive breast cancer (IBC). It has been proposed that both the nature of the lesion and the tumor microenvironment play key roles in progression to IBC. Here, laser capture microdissected tissue samples from epithelium and stroma in normal breast, pure DCIS, and pure IBC were employed to define key gene expression profiles associated with disease progression.
Progression of ductal carcinoma in situ to invasive breast cancer is associated with gene expression programs of EMT and myoepithelia.
Specimen part, Subject
View SamplesThe goal of the experiment: To characterize the dynamic gene expression profile of engineered human skin in vitro and after grafting, and compare with expression profile of uninjured human skin.
Engineered human skin substitutes undergo large-scale genomic reprogramming and normal skin-like maturation after transplantation to athymic mice.
Specimen part
View SamplesBackground: Diverticular disease is a significant healthcare burden in the United States. Younger diverticulitis patients are at increased risk for recurrence. How the molecular pathophysiology differs from those that develop disease at an older age is not understood. We aimed to profile the colonic transcriptome from younger versus older diverticulitis patients to identify differential biological pathways contributing to disease. Methods: We performed RNA-seq on full-thickness sigmoid colon tissue obtained at the time of surgery on diverticulitis patients (n=26) diagnosed at a younger age (<42 years old) or at an older age (>65 years old). Viral reads were identified from the RNA-seq dataset and associated with clinical metadata and the host transcriptome. HHV-6 positivity was evaluated in diverticulitis patients by PCR and immunofluorescence. Patient sera was profiled for HHV-6 using qPCR and ELISA to detect anti-HHV-6 antibodies. Results: Using RNA-seq, diverticulitis patients were profiled for differential expression associated with age of diagnosis. A subset of younger diverticulitis patients (diverticulitis colonic transcriptome-viral signature (DCT-VS)) demonstrated increased expression of anti-viral response genes. We identified viral transcripts in the RNA-seq dataset and found HHV-6 transcripts negatively correlated with DCT-VS. Younger patients more frequently displayed evidence of HHV-6 infection through DNA analysis and immunofluorescence of colonic tissue. During acute disease, HHV-6 DNA was detected in the serum but was absent during disease quiescence. Conclusions: Patients diagnosed with diverticulitis at a younger age demonstrate reactivation of HHV-6 in the sigmoid colon that remains persistent. Future studies to assess the role of pathogenicity and the use of anti-virals for acute uncomplicated diverticulitis should be considered. Overall design: Examination of full-thickness sigmoid colon tissue from 26 diverticulitis patients, including 13 diagnosed at an younger age (<42 years old) and 13 diagnosed at an older age (>65 years old)
A differential host response to viral infection defines a subset of earlier-onset diverticulitis patients.
Sex, Specimen part, Race, Subject
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