Carbon monoxide (CO) abrogates TNF-alpha mediated inflammatory responses in endothelial cells, yet, the underlying mechanism hereof is still elusive. We sought to explore potential mechanisms by which CO down-regulates VCAM-1 expression on TNF-alpha stimulated human umbilical vein endothelial cells (HUVEC). By genome-wide gene expression profiling and pathway analysis we studied the relevance of particular pathways for the anti-inflammatory effect of CO. In CO-releasing molecules-3 (CORM-3) stimulated HUVEC, significant changes in gene expression were found for genes implicated in the proteasome and porphyrine pathways. Although proteasome activities were increased by CORM-3, proteasome inhibitors did not abolish CORM-3s effect. Likewise, HO-1 inhibitors did not abrogate the ability of CORM-3 to down-regulate VCAM-1 expression. MAPK p38 was inhibited by CORM-3. Accordingly, VCAM-1 expression was down-regulated by the p38 inhibitor SB203580. Down-regulation of VCAM-1 by CORM-3 only occurred at concentrations that partly inhibit ATP production. Sodium azide and oligomycin paralleled the effect of CORM-3 in this regard. In conclusion, down-regulation of VCAM-1 by CORM-3 seems to be mediated via inhibition of p38 and mitochondrial respiration. Although CORM-3 up-regulates several genes in the ubiquitin proteasome sytem (UPS) or porphyrin pathway, there is no evidence that these changes are involved in the anti-inflammatory properties of CORM-3.
No associated publication
Cell line, Treatment
View SamplesThe goal of the study was to identify the effects of TGF-beta on primary human macrophages maturated under different conditions.
Activation of a TGF-beta-specific multistep gene expression program in mature macrophages requires glucocorticoid-mediated surface expression of TGF-beta receptor II.
No sample metadata fields
View SamplesLymph node vs. tonsil
Differential expression of a gene signature for scavenger/lectin receptors by endothelial cells and macrophages in human lymph node sinuses, the primary sites of regional metastasis.
No sample metadata fields
View SamplesProfiling CD34+ BCR-ABL+ cells of CML patients in chronic phase or blast crisis to identify differentially expressed stage-specific genes.
Gene expression profiling of CD34+ cells identifies a molecular signature of chronic myeloid leukemia blast crisis.
Sex, Age, Specimen part, Disease, Disease stage
View Samplesusing peripheral blood monocytes to identify marker genes for an extensively grown coronary collateral circulation.
Non-invasive gene-expression-based detection of well-developed collateral function in individuals with and without coronary artery disease.
Sex, Age
View SamplesSpecific microRNA (miRNA) signatures have been associated with different cytogenetic subtypes in acute leukemias. This finding prompted us to investigate potential associations between genetic abnormalities in multiple myeloma (MM) and singular miRNA expression profiles. Moreover, global gene expression profiling was also analyzed to find correlated miRNA-gene expression and select miRNA target genes that show such correlation. For this purpose, we analyzed the expression level of 365 miRNAs and the gene expression profiling in sixty newly diagnosed MM patients, selected to represent the most relevant recurrent genetic abnormalities. Supervised analysis showed significantly deregulated miRNAs in the different cytogenetic subtypes as compared to normal PC. Interestingly, miR-1 and miR-133a clustered on the same chromosomal loci, were specifically overexpressed in the cases with t(14;16). The analysis of the relationship between miRNA expression and their respective target genes showed a conserved inverse correlation between several miRNAs deregulated in MM cells and CCND2 expression level. These results illustrate, for the first time, that miRNA expression pattern in MM is associated with genetic abnormalities, and that the correlation of the expression profile of miRNA and their putative mRNA targets is useful to find statistically significant protein-coding genes in MM pathogenesis associated to changes in specific miRNAs.
Deregulation of microRNA expression in the different genetic subtypes of multiple myeloma and correlation with gene expression profiling.
Specimen part, Disease
View SamplesThe tumoral clone of Waldenstrms macroglobulinemia (WM) shows a wide morphological heterogeneity which ranges from B-lymphocytes (BL) to plasma cells (PC). By means of genome-wide expression profiling we have been able to identify genes exclusively deregulated in BL and PC from WM, but with a similar expression pattern in their corresponding cell-counterparts from CLL and MM, as well as normal individuals. The differentially expressed genes have important functions in B-cell differentiation and oncogenesis. Thus, two of the genes down-regulated in WM-BL were IL4R, which plays a relevant role in CLL B cell survival, and BACH2 that participates in the development of class-switched PC. Interestingly, one of the up-regulated genes in WM-BL was IL6. A set of 4 genes was able to discriminate clonal B-lymphocytes from WM and CLL: LEF1 (WNT/catenin pathway), MARCKS, ATXN1 and FMOD. We also found deregulation of genes involved in plasma cell differentiation such as PAX5 which was overexpressed in WM-PC, and IRF4 and BLIMP1 which were underexpressed. In addition, three of the target genes activated by PAX5 -CD79, BLNK and SYK- were up-regulated in WM-PC. In summary, these results indicate that both PC and BL from WM are genetically different from the MM and CLL cell-counterpart.
Gene expression profiling of B lymphocytes and plasma cells from Waldenström's macroglobulinemia: comparison with expression patterns of the same cell counterparts from chronic lymphocytic leukemia, multiple myeloma and normal individuals.
No sample metadata fields
View SamplesGene expression profile of acute myeloid leukemia.
Gene expression profile reveals deregulation of genes with relevant functions in the different subclasses of acute myeloid leukemia.
No sample metadata fields
View SamplesCytokine genes are targets of multiple epigenetic mechanisms in T lymphocytes. 5-azacytidine (5-azaC) is a nucleoside-based DNA methyltransferases (DNMT) inhibitor which induces demethylation and gene reactivation. In the current study, we analyzed the effect of 5-azaC in T-cell function and observed that 5-azaC inhibits T-cell proliferation and activation, blocking cell cycle in G0-G1 phase and decreasing the production of proinflammatory cytokines such as TNF and IFN. This effect was not due to a pro-apoptotic effect of the drug but to the down-regulation of genes involved in T-cell cycle progression and activation such as CCNG2, MTCP1, CD58, and ADK and up-regulation of genes which induce cell growth arrest, such as DCUN1D2, U2AF2, GADD45B or p53. In spite of being also up-regulated, we did not find any effect of 5-azaC on the methylation pattern of FOXP3. Finally, the administration of 5-azaC at 60 and 84 hours post-transplant prevented the development of GVHD leading to a significant increase in survival in a fully mismatched BMT mouse model. In conclusion, the current study shows the effect of 5-azaC in T-lymphocytes and illustrates its role in the allogeneic transplantation setting as an immunomodulatory drug, describing new pathways which must be explored in order to prevent graft-versus-host disease.
Immunomodulatory effect of 5-azacytidine (5-azaC): potential role in the transplantation setting.
Specimen part, Treatment, Time
View SamplesMicroRNAs have been demonstrated to be deregulated in multiple myeloma (MM). We have previously reported the downregulation of miR-214 in MM compared to normal plasma cells. In the present study, we have explored the functional role of miR-214 in myeloma pathogenesis. Ectopic expression of miR-214 reduced cell growth and induced apoptosis of myeloma cells. In order to identify the potential direct target genes of miR-214 which could be involved in the biological pathways regulated by this miRNA, gene expression profiling of H929 myeloma cell line transfected with precursor miR-214 was carried out. Functional analysis revealed significant enrichment for DNA replication, cell cycle phase and DNA binding. We show that miR-214 directly down-regulates the expression of PSMD10, which encodes the oncoprotein gankyrin, and ASF1B, a histone chaperone required for DNA replication, by binding to their 3'-UTR. In addition, gankyrin inhibition induced an increase of P53 mRNA levels and subsequent up-regulation in CDKN1A (p21Waf1/Cip1) and BAX transcripts, which are direct transcriptional targets of p53. In conclusion, we demonstrate that miR-214 function as a tumor suppressor in myeloma by a positive regulation of p53 and inhibition of DNA replication.
Restoration of microRNA-214 expression reduces growth of myeloma cells through positive regulation of P53 and inhibition of DNA replication.
Cell line
View Samples