Objective Telmisartan, an angiotensin II type 1 (AT1) receptor blocker, and amlodipine, a calcium channel blocker, are antihypertensive agents clinically used as monotherapy or in combination. They exert beneficial cardiovascular effects independently of blood pressure lowering and classic mechanisms of action. In this study, we investigate molecular mechanisms responsible for the off-target effects of telmisartan and telmisartan-amlodipine in endothelial cells (EC), using an unbiased approach.
Telmisartan exerts pleiotropic effects in endothelial cells and promotes endothelial cell quiescence and survival.
Specimen part, Disease, Treatment
View SamplesmiR-29 can target many gene transcripts encoding extracellular matrix proteins. To unravel novel targets, we used microarray analysis to detect global gene expression changes when inhibiting endogenous miR-29.
Ten-eleven translocation (Tet) and thymine DNA glycosylase (TDG), components of the demethylation pathway, are direct targets of miRNA-29a.
Specimen part, Treatment
View SamplesThe homeobox containing gene Arx is expressed during ventral telencephalon development and it is required for correct GABAergic interneuron tangential migration from the ganglionic eminences to the olfactory bulbs, cerebral cortex and striatum. Its human ortholog is associated with a variety of neurological clinical manifestations whose syntoms are compatible with a loss of cortical interneurons and altered basal ganglia related-activities in humans. Herein, we reported the identification by global expression profiling of a group of genes whose expression is consistently altered in Arx mutant ganglionic eminences. Following analysis revealed the striking ectopic expression in the ganglionic eminences of a number of genes normally not, or only marginally, expressed in the ventral telencephalon. Among them, we functionally analyzed Ebf3, whose ectopic expression in ventral telencephalon is preventingneuronal tangential migration. Further, we showed that Arx is sufficient to repress Ebf3 endogenous expression and that its silencing in Arx mutant tissue might marginally rescue tangential cell movements. Together, these data provide an initial analysis of the molecular pathways regulated by Arx and how their networking might regulate those specific cellular processes during telencephalon development strongly altered by loss of Arx.
Arx acts as a regional key selector gene in the ventral telencephalon mainly through its transcriptional repression activity.
No sample metadata fields
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The Tbr2 Molecular Network Controls Cortical Neuronal Differentiation Through Complementary Genetic and Epigenetic Pathways.
Specimen part
View SamplesThe abscence of TBR2 gene in human leads to microcephaly. This condition is mimicked by the specific ablation of the murine gene in developing cerebral cortex. Herein we compared gene expression in control and Tbr2 cKO in E14.5 cerebral cortices. This approach represents a useful tool to identify the molecular mechanisms at the basis of the phenotype.
The Tbr2 Molecular Network Controls Cortical Neuronal Differentiation Through Complementary Genetic and Epigenetic Pathways.
Specimen part
View SamplesDirect cell reprogramming has enabled the direct conversion of skin fibroblasts into functional neurons and oligodendrocytes using a minimal set of cell lineage-specific transcription factors. This approach has substantial advantages since it is rapid and simple, generating the cell type of interest in a single step. However, it remains unknown whether this technology can be applied for directly reprogramming skin cells into astrocytes, the third neural lineage. Astrocytes play crucial roles in neuronal homeostasis and their dysfunctions contribute to the origin and progression of multiple human diseases. Herein, we carried out a screening using several transcription factors involved in defining the astroglial cell fate and identified NFIA, NFIB and SOX9 to be sufficient to convert with high efficiency embryonic and post-natal mouse fibroblasts into astrocytes (iAstrocytes). We proved both by gene expression profiling and functional tests that iAstrocytes are comparable to native brain astrocytes. This protocol can be then employed to generate functional iAstrocytes for a wide range of experimental applications.
Direct conversion of fibroblasts into functional astrocytes by defined transcription factors.
Specimen part
View SamplesAnalysis of mobilized peripheral blood CD34+ cells from a healthy volunteer under erythroid differentiation conditions with and without stimulation to the BMP or Wnt signaling pathways. For erythroid differentiation, expanded CD34+ cells were placed in Stemspan SFEM medium supplemented with 2% pen/strep, 20ng/ml SCF, 1U/ml Epo, 5ng/ml IL3, 2uM dexamethasone, and 1uM beta-estradiol. Arrays were performed 2 hours after addition of cytokines. For signaling pathway stimulation, cells were exposed to 0.5uM BIO (a GSK3 inhibitor) for Wnt pathway activation, 25ng/ml rhBMP4 for BMP pathway activation, or vehicle control for 2 hours. Three biological replicates were performed per treatment group.
Lineage regulators direct BMP and Wnt pathways to cell-specific programs during differentiation and regeneration.
Specimen part, Disease
View SamplesWe mated mice with floxed alleles of both Apc and Pten, to mice with floxed alleles for Arid1a, to obtain female mice with both copies of all three genes floxed. At 7 to 8 weeks of age the right ovarian bursal cavites of the mice were injected with 50 million plaque-forming units of adenovirus expressing Cre recombinase, which causes the floxed genes to be knocked out. Tumor tissue from 3 mice for each group was obtained at necropsy, RNA purified, and targets for Affymetrix arrays synthesized from the mRNAs. We used Affymetrix Mouse Genome 430 2.0 arrays, which hold 45101 probe-sets. Raw data was processed with Robust Multi-array Average algorithm (RMA). Data is log2-transformed transcript abundance estimates. We performed T-tests to compare the 3 vs 3 arrays. We supply a supplementary excel workbook that holds the same data as the data matrix file, but also holds the probe-set annotation at the time we analyzed the data, and some very simple statistical calculations, which select subsets of the probe-sets as differentially expressed. Consumers should consider obtaining more up-to-date probe-set annotation for the array platform. We have also supplied a second supplementary tar archive holding software and files to 1) perform permutation testing of the probe-set selection in order to estimate false discovery rates for the probe-sets we selected as differentially expressed, 2) perform enrichment testing of GO terms, and 3) to perform enrichment testing of KEGG pathways and 3000 curated gene sets from version 4 of the Molecular Signatures Database (MSigDB). The software is in "C".
Arid1a inactivation in an Apc- and Pten-defective mouse ovarian cancer model enhances epithelial differentiation and prolongs survival.
Sex
View SamplesTransplantation of GABAergic interneurons (INs) can sustain long-standing benefits in animal models of epilepsy and other neurological disorders. In a therapeutic perspective, a renewable source of functional GABAergic INs is needed. Here, we identified five factors (Foxg1, Sox2, Ascl1, Dlx5 and Lhx6) able to convert fibroblasts directly into induced GABAergic INs (iGABA-INs), displaying the molecular signature of telencephalic INs. The selected factors recapitulate in fibroblasts the activation of transcriptional networks required for the specification of GABAergic fate during telencephalon development. iGABA-INs exhibited progressively maturing firing patterns comparable to those of cortical INs, had synaptic currents and released GABA. Importantly, upon grafting in the hippocampus, iGABA-INs survived, matured and their optogenetic stimulation triggered GABAergic transmission and inhibited the activity of connected granule cells. The five factors also converted human cells into functional GABAergic neurons. These properties define iGABA-INs as a promising tool for disease modeling and cell-based therapeutic approaches. Overall design: Comparison of iGABA-INs transcriptional profile with those of starting fibroblasts and GAD67-GFP+ cortical interneurons.
Rapid Conversion of Fibroblasts into Functional Forebrain GABAergic Interneurons by Direct Genetic Reprogramming.
Specimen part, Cell line, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Synthesis and anticancer properties of water-soluble zinc ionophores.
No sample metadata fields
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