In the present study, the transcriptional analysis of CD biopsies reveals profound alterations in the ileum transportome profile. More than 60 SLC transporters showed different expression pattern compared with the healthy donors, being mostly decreased. Changes were confirmed in almost all the eighteen altered SLCs analyzed by RT-PCR. The results obtained display alterations in amino acid transporters, purinome members, Zn transporters and metallothioneins. All together, these alterations which mainly involve transporters localized at the apical membrane of the enterocyte anticipate impaired amino acid uptake and purinergic responses. Remarkably, incubation of explants with specific commensal bacteria restored almost all CD transportome alterations.
Transportome Profiling Identifies Profound Alterations in Crohn's Disease Partially Restored by Commensal Bacteria.
Specimen part, Disease
View SamplesAdipose tissue plays an important role in storing excess nutrients and preventing ectopic lipid accumulation in other organs. Obesity leads to excess lipid storage in adipocytes, resulting in the generation of stress signals and the derangement of metabolic functions. SIRT1 is an important regulatory sensor of nutrient availability in many metabolic tissues. Here we report that SIRT1 functions in adipose tissue to protect from the development of inflammation and obesity under normal feeding conditions, and the progression to metabolic dysfunction under dietary stress. Genetic ablation of SIRT1 from adipose tissue leads to gene expression changes that highly overlap with changes induced by high fat diet in wild type mice, suggesting that dietary stress signals inhibit the activity of SIRT1. Indeed, we show that high fat diet induces the cleavage of SIRT1 in adipose tissue by the inflammation-activated caspase-1, providing a link between dietary stress and predisposition to metabolic dysfunction.
High-fat diet triggers inflammation-induced cleavage of SIRT1 in adipose tissue to promote metabolic dysfunction.
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View SamplesBackground: In the last decade, much attention has been drawn to probiotic bacteria in the context of inflammatory bowel disease (IBD), since the potential of certain strains to attenuate inflammation was demonstrated in several animal experiments and clinical studies. Data in humans elucidating the molecular mechanism of probiotic action are still scarce. To this end, we used an organ culture system of human colon mucosa and investigated the gene expression profiles after treatment with different probiotic bacteria in phorbol 12-myristate 13-acetate (PMA)/ionomycin (IO)) stimulated samples using whole genome microarrays. Moreover, we analyzed changes occurring in the intestinal explants cultured for 8 hours when compared to fresh, directly frozen mucosa, in order to infer the suitability of the system to study an inflammatory stimulus and likely antiinflammatory responses. Results: Culturing intestinal colon fragments during 8 hours elicited differential gene expression in 283 genes, 229 upregulated and 54 downregulated. Upregulated genes were predominantly related to apoptosis, whereas downregulated genes encoded mitochondrial proteins. No specific enrichment of genes related to inflammation or immune response could be detected, confirming the suitability of the system to further study the inmunomodulatory/anti-inflammatory properties of Lactobacillus casei BL23 (BL23), L.plantarum 299v (LP299v) and L.plantarum 299v (A-) (LP299v (A-)), a mutant strain with reduced adhesive properties to enterocytes. Intestinal explants were stimulated with PMA/IO for 3 hours and subsequently incubated with probiotic bacteria for 4 h. ANOVA analysis (p 0,01) revealed 205 differentially expressed genes between Control, PMA/IO (Inflamed), and the 3 bacterial treatments. Most importantly, a number of PMA/IO induced genes related to immune response and immune system process such as IL-2, IFN-, IL17A and pro-inflammatory cytokines CXCL9 and CXCL11 were downregulated by BL23, LP299v and LP299v (A-). The behaviour of the three Lactobacillus strains was quite similar, although their presence induced differential expression of a small number of genes in a strain dependent manner. Conclusion: The human colon organ culture was found to be a suitable model for the study of inflammatory/anti-inflammatory stimuli, and therefore it constitutes a valuable tool to determine the inmunomodulatory effect of probiotic bacteria. The global transcriptional profile evoked by strains BL23, LP299v and LP299v (A-) in artificially inflamed tissue indicated a clear homeostasis restoring effect, including a decrease of the signals produced by activated T cells.
Lactobacillus paracasei and Lactobacillus plantarum strains downregulate proinflammatory genes in an ex vivo system of cultured human colonic mucosa.
Specimen part
View SamplesBrdt is a testis specific member of a family of chromatin interacting proteins. All of the family members have been shown to regulate transcription. Brdt is highly expressed in round spermatids, and may play a role in transcriptional regulation in these cells.
The testis-specific double bromodomain-containing protein BRDT forms a complex with multiple spliceosome components and is required for mRNA splicing and 3'-UTR truncation in round spermatids.
Specimen part
View SamplesAnalysis of DZNep-induced gene expression changes in cultured podocytes. The hypothesis tested in the present study was that DZnep ultimately augments Txnip expression, increasing oxidative stress in podocytes. These results provide important information on the response of podocytes to histone methyltransferase inhibition and a possible mechanism for DZNep action in podocytes.
The Histone Methyltransferase Enzyme Enhancer of Zeste Homolog 2 Protects against Podocyte Oxidative Stress and Renal Injury in Diabetes.
Specimen part
View SamplesSIRT1 deacetylase functions in a variety of cells and tissues to mitigate age- and disease-induced damages. However, it remains unknown if SIRT1 also acts to prevent pathological changes that accrue in motor units, and specifically alpha-motor neurons, with advancing age and during the progression of amyotrophic lateral sclerosis (ALS). Here, we show that SIRT1 expression decreases in the spinal cord of wild type mice with advancing age. Using mouse models that overexpress or inactivate SIRT1 in motor neurons, we discovered that SIRT1 prevents age-related degeneration of motor neurons' presynaptic sites at neuromuscular junctions (NMJs). We also found that increasing SIRT1 in motor neurons delays degeneration of presynaptic sites at NMJs and extends the lifespan of SOD1G93A mice. Thus, SIRT1 has a similar effect on aging and ALS-affected motor neurons, two conditions in which a remarkable number of transcripts are similarly altered in the spinal cord. These include genes involved in inflammatory and immune responses and genes with known function at synapses. These findings show that SIRT1 functions to mitigate pathological changes induced by aging and ALS, two conditions with a surprising degree of overlap in the spinal cord. Overall design: Eight replicates spinal cords from mice aged 18-24 months, eight replicates of spinal cords from mice aged 3-4 months, 3 replicates of spinal cords from ALS symptomatic mice aged 5-6 months and 3 replicates of spinal cords from wt controls aged 5-6 months.
SIRT1 deacetylase in aging-induced neuromuscular degeneration and amyotrophic lateral sclerosis.
Cell line, Subject
View SamplesBackground
Glioblastoma models reveal the connection between adult glial progenitors and the proneural phenotype.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Reprogramming of the microRNA transcriptome mediates resistance to rapamycin.
Specimen part, Cell line
View SamplesThe mammalian target of rapamycin (mTOR) is a central regulator of cell proliferation. Inhibitors of mTOR are being evaluated as anti-tumor agents. Given the emerging role of microRNAs (miRNAs) in tumorgenesis we hypothesized that miRNAs could play important roles in the response of tumors to mTOR inhibitors. Rapamycin resistant myogenic cells developed by long-term rapamycin treatment showed extensive reprogramming of miRNAs expression, characterized by up-regulation of the mir-17~92 and related clusters and down-regulation of tumor-suppressor miRNAs. Antagonists of oncogenic miRNA families and mimics of tumor suppressor miRNAs (let-7) restored rapamycin sensitivity in resistant tumor cells. This study identified miRNAs as new downstream components of the mTOR-signaling pathway, which may determine the response of tumors to mTOR inhibitors.
Reprogramming of the microRNA transcriptome mediates resistance to rapamycin.
Specimen part, Cell line
View SamplesThe CHER-LOB randomized phase II study showed that the combination of lapatinib and trastuzumab plus chemotherapy increases the pathologic complete remission (pCR) rate as compared to chemotherapy plus either trastuzumab or lapatinib. An extensive biomarker programme was prospectively planned to identify potential predictors of sensitivity to different treatments and evaluate treatment effect on tumor biomarkers.
Prospective Biomarker Analysis of the Randomized CHER-LOB Study Evaluating the Dual Anti-HER2 Treatment With Trastuzumab and Lapatinib Plus Chemotherapy as Neoadjuvant Therapy for HER2-Positive Breast Cancer.
Specimen part, Disease, Disease stage
View Samples