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 SamplesGene expression profiles of paired normal adjacent mucosa and tumor samples from 98 individuals and 50 healthy colon mucosae, were obtained through Affymetrix Human Genome U219 Arrays. This dataset is in the context of the COLONOMICS project and to query additional information you can visit the project website www.colonomics.org.
Discovery and validation of new potential biomarkers for early detection of colon cancer.
Sex, Age, Disease, Subject
View SamplesThe gastrointestinal (GI) tract can have significant impact on the regulation of the whole body metabolism and may contribute to the development of obesity and diabetes. To systemically elucidate the role of the GI tract in obesity, we performed a transcriptomic analyses in different parts of the GI tract of two obese mouse models: ob/ob and high-fat diet (HFD) fed mice. Compared to their lean controls, both obese mouse groups had significant amount of gene expression changes in the stomach (ob/ob: 959; HFD: 542), much more than the number of changes in the intestine. Despite the difference in genetic background, the two mouse models shared 296 similar gene expression changes in the stomach. Among those genes, some had known associations to obesity, diabetes and insulin resistance. In addition, the gene expression profile strongly suggested an increased gastric acid secretion in both obese mouse models, probably through an activation of the gastrin pathway. In conclusion, our data reveal a previously unknown dominant connection between the stomach and obesity.
Significant obesity-associated gene expression changes occur in the stomach but not intestines in obese mice.
Specimen part
View SamplesWe used Affymetrix microarrays to investigate gene expression changes in the liver of wild-type C57BL-6 mice exposed to a high-fat diet that might have been caused by the oral consumption of the probiotic B. pseudocatenulatum CECT 7765.
Hepatic molecular responses to Bifidobacterium pseudocatenulatum CECT 7765 in a mouse model of diet-induced obesity.
Specimen part
View SamplesIdentification of TLR4 as one of the most abundant RNA species in pericytes with respect to MSC, and corroboration of TLR4 expression on the cell surface, led us to obtain a comprehensive overview of the expression program of lipopolysaccharide (LPS) stimulated pericytes. Microarray analyisis demonstrated the significant upregulation of 76 annotated genes including transcripts for adhesion molecules, inflammation mediators, pro-angiogenic factors, transcription factors and anti-apoptotic proteins.
Lipopolysaccharide activates Toll-like receptor 4 (TLR4)-mediated NF-κB signaling pathway and proinflammatory response in human pericytes.
Specimen part, Treatment
View SamplesPericytes and mesenchymal stem cells (MSC) are ontogenically related, and in fact no phenotypic differences were observed by flow cytometry using a panel of surface antigen markers. Global gene expression profiles of human pericytes and MSC revealed that 43 genes were expressed more than 10 fold in pericytes as compared to MSC.
Lipopolysaccharide activates Toll-like receptor 4 (TLR4)-mediated NF-κB signaling pathway and proinflammatory response in human pericytes.
Specimen part
View SamplesBACKGROUND: p53 is an important tumor suppressor with a known role in the later stages of colorectal cancer, but its relevance to the early stages of neoplastic initiation remains somewhat unclear. Although p53-dependent regulation of Wnt signalling activity is known to occur, the importance of these regulatory mechanisms during the early stages of intestinal neoplasia has not been demonstrated.
A limited role for p53 in modulating the immediate phenotype of Apc loss in the intestine.
Specimen part
View SamplesTo characterize how symbiotic bacteria affect the lolecular and cellular mechanisms of epithelial homeostasis, human colonic Caco-2 cells
Epithelial cell proliferation arrest induced by lactate and acetate from Lactobacillus casei and Bifidobacterium breve.
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View SamplesWe sought to find a gene-expression multigene predictor of response to infliximab therapy in Rheumatoid Arthritis patients. Using internal and external cross-validation systems we have built and validated an 8-gene predictor for response to infliximab.
An eight-gene blood expression profile predicts the response to infliximab in rheumatoid arthritis.
Sex, Specimen part, Disease, Disease stage
View SamplesIn order to identify the developmental changes controlling the switch from disease susceptibility to resistance, we performed global gene expression analysis on non-infected and infected intestinal tissues taken from 4-day- and 7-day-old animals.
Maturation of paneth cells induces the refractory state of newborn mice to Shigella infection.
Age
View Samples