Considering the numerous complex and different pathological mechanisms involved in Alzheimers disease (AD) progression, treatments targeting a single cause may lead to limited benefits. The goal of this study was the identification of a novel mode of action for this unmet need. Pharmacological tool compounds: suberoylanilide hydroxamic acid (SAHA) and tadalafil, targeting histone deacetylases (HDAC) and phosphodiesterase 5 (PDE5) respectively, were utilized simultaneously for in-vitro and in-vivo Proof-of-Concept (PoC). A synergistic effect was observed in the amelioration of AD signs using the combination therapy in Tg2576 mice. Finally, a therapeutic agent, CM-414, inhibiting simultaneously HDAC2/6 and PDE5 was generated and tested in Tg2576 mice. CM-414 reversed cognitive impairment, reduced amyloid and tau pathology, and rescued dendritic spine density loss in the hippocampus in AD mice. Importantly, the effect obtained was present after a 4-weeks wash-out period.
Concomitant histone deacetylase and phosphodiesterase 5 inhibition synergistically prevents the disruption in synaptic plasticity and it reverses cognitive impairment in a mouse model of Alzheimer's disease.
Specimen part
View SamplesRegulatory T cells (Treg) are pivotal for the maintenance of peripheral tolerance by controlling self-reactive, chronic and homeostatic T cell responses. We now report that the increase in Treg suppressive function observed in lymphopenic mice correlates with the degree of lymphopenia and is caused by a higher frequency of a novel subpopulation of CD103posICOSpos cells among peripheral Treg that differentially express multiple Treg signature genes.
A subpopulation of CD103(pos) ICOS(pos) Treg cells occurs at high frequency in lymphopenic mice and represents a lymph node specific differentiation stage.
Sex, Age, Specimen part
View SamplesOur results indicate that oxidation of TAF10 by LOXL2 induces its release from its promoters, leading to a block in TFIID-dependent gene transcription. Since TFIID complex is crucial for the expression of Nanog, Klf4, Sox2 and Oct4 and for maintaining the pluripotent state of embryonic stem cells, TAF10 oxidation by LOXL2 leads to inactivation of the pluripotency genes and a loss of pluripotent capacity in embryonic stem cells. Moreover, in vivo results demonstrate an essential role of LOXL2 in neural differentiation during zebrafish development: in the absence of LOXL2 the neural progenitor gene Sox2 is aberrantly overexpressed and neural differentiation is impaired.
LOXL2 Oxidizes Methylated TAF10 and Controls TFIID-Dependent Genes during Neural Progenitor Differentiation.
Specimen part
View SamplesObjective: We hypothesized that type 1 diabetes (T1D) is accompanied by changes in gene expression in peripheral blood mononuclear cells (PBMCs) due to dysregulation of adaptive and innate immunity, counterregulatory responses to immune dysregulation, insulin deficiency and hyperglycemia. Research Design and Methods: Microarray analysis was performed on PBMCs from 43 patients with newly diagnosed T1D, 12 patients with newly diagnosed type 2 diabetes (T2D) and 24 healthy controls. One and four month follow-up samples were obtained from 20 of the T1D patients.
Gene expression in peripheral blood mononuclear cells from children with diabetes.
Sex, Age, Treatment, Race
View SamplesGlucocorticoids (GCs) and protein kinase A (PKA)-activating agents (beta-adrenergic receptor agonists) are mainstream asthma therapies based on their ability to prevent or reverse excessive airway smooth muscle (ASM) constriction. Their abilities to regulate another important feature of asthma - excessive ASM growth are poorly understood. Recent studies have suggested that GCs render agents of inflammation such as interleukin 1beta and tumor necrosis factor alpha mitogenic to ASM, via suppression of (antimitogenic) induced cyclooxygenase-2-dependent PKA activity. To further explore the mechanistic basis of these observations, we assessed the effects of epidermal growth factor and interleukin 1beta stimulation, and the modulatory effects of GC treatment and PKA inhibition, on the ASM transcriptome by microarray analysis.
Glucocorticoid- and protein kinase A-dependent transcriptome regulation in airway smooth muscle.
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View SamplesSubstantia nigra pars compacta (SNpc) is highly sensitive to normal aging and selectively degenerates in Parkinson's disease. However, ventral tegmental area (VTA), a region adjacent to SNpc, is less affected in PD. Until now, molecular mechanisms behind VTA aging have not been fully investigated using high throughput techniques.
Age-mediated transcriptomic changes in adult mouse substantia nigra.
Specimen part
View SamplesSubstantia nigra pars compacta (SNpc) is highly sensitive to normal aging and selectively degenerates in Parkinson's disease. Until now, molecular mechanisms behind SNpc aging have not been fully investigated using high throughput techniques.
Age-mediated transcriptomic changes in adult mouse substantia nigra.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Age-mediated transcriptomic changes in adult mouse substantia nigra.
Specimen part
View SamplesmicroRNAs (miRNAs) regulate virtually all biological processes, but little is known of their role in germinal center (GC) B cells. While the GC reaction is crucial to ensure a competent immune response, GC B cells are also the origin of most human lymphomas. Here we report that miR-217 is specifically upregulated in GC B cells. Gain- and loss-of-function mouse models reveal that miR-217 functions as a positive modulator of the GC response through the regulation of a DNA repair gene network. Moreover, we show that miR-217 overexpression promotes mature B cell lymphomagenesis. Therefore miR-217 provides a novel molecular link between the normal GC response and B cell transformation Overall design: 4 samples were analyzed by RNAseq: 1) naïve (CD19+Fas-GL7-) B cells from miR-217TG, 2) GC (CD19+Fas+GL7+) B cells from miR-217TG, 3) naïve (CD19+Fas-GL7-) B cells from littermate controls and 4) GC (CD19+Fas+GL7+) B cells from littermate controls. Samples were isolated by cell sorting from pooled Peyer’s patches (4-6 animals per genotype). Two independent experiments were performed.
miR-217 is an oncogene that enhances the germinal center reaction.
Specimen part, Subject
View SamplesThis dataset was used to establish whole blood transcriptional modules (n=260) that represent groups of coordinately expressed transcripts that exhibit altered abundance within individual datasets or across multiple datasets. This modular framework was generated to reduce the dimensionality of whole blood microarray data processed on the Illumina Beadchip platform yielding data-driven transcriptional modules with biologic meaning.
Interferon signature in the blood in inflammatory common variable immune deficiency.
Disease
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