Transcription profiling of PBMCs from slightly obese human males given diclofenac or a placebo to study modulation of inflammation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Marjan van Erk
PROVIDER: E-TABM-740 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Publications
Insight in modulation of inflammation in response to diclofenac intervention: a human intervention study.
van Erk Marjan J MJ Wopereis Suzan S Rubingh Carina C van Vliet Trinette T Verheij Elwin E Cnubben Nicole H P NH Pedersen Theresa L TL Newman John W JW Smilde Age K AK van der Greef Jan J Hendriks Henk F J HF van Ommen Ben B
BMC medical genomics 20100223
<h4>Background</h4>Chronic systemic low-grade inflammation in obese subjects is associated with health complications including cardiovascular diseases, insulin resistance and diabetes. Reducing inflammatory responses may reduce these risks. However, available markers of inflammatory status inadequately describe the complexity of metabolic responses to mild anti-inflammatory therapy.<h4>Methods</h4>To address this limitation, we used an integrative omics approach to characterize modulation of inf ...[more]
Similar Datasets
Project description:Diclofenac is a widely used analgesic drug that can cause serious adverse drug reactions. We used Saccharomyces cerevisiae as model eukaryote to elucidate the molecular mechanisms of diclofenac toxicity and resistance. Although most yeast cells died during initial diclofenac treatment, some survived and started growing again. Microarray analysis of the adapted cells identified three major processes involved in diclofenac detoxification and tolerance. Especially pleiotropic drug resistance genes and genes under control of Rlm1p, a transcription factor in the protein kinase C (PKC) pathway, were upregulated in diclofenac-adapted cells. Genes involved in ribosome biogenesis and rRNA processing were downregulated, as well as zinc-responsive genes. Five independent yeast cultures were incubated with 100 µM diclofenac for 75 hours. Every 24h, cultures were diluted to OD600 ~0.1 in YNB containing 100 µM diclofenac. Five independent control cultures were grown in the absence of diclofenac.
2011-05-17 | E-GEOD-29331 | biostudies-arrayexpress
Project description:Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) which has been shown to increase the susceptibility of various bacteria to antimicrobials and demonstrated to have broad antimicrobial activity. This study describes transcriptome alterations in S. aureus strain COL grown with diclofenac and characterizes the effects of this NSAID on antibiotic susceptibility in laboratory, clinical and diclofenac reduced-susceptibility (DcRS) mutant S. aureus strains.
2011-07-18 | E-GEOD-30724 | biostudies-arrayexpress
Project description:Diclofenac (DCL) is a non-steroidal anti-inflammatory drug. Its use can be associated with serious adverse drug reactions most notable myocardial infarction and drug-induced liver injury (DILI). The molecular causes leading to DILI remains unclear and it seems to be multifactorial. The aims of this study is to identify the molecular mechanisms involving immune mediated inflammatory reactions and its link to DILI through whole genome gene expression profiling. Diclofenac was given to mice at 30 mg/kg for 1, 3 and 14 days. Microarray experiments were performed with RNA extracts from liver samples. The performed gene expression studies showed >600 significantly regulated genes after single and repeated dosing for 3 and 14 days. The functional annotation revealed several genes were regulated in common coding for inflammatory, immune, stress and acute-phase responses. Immunohistochemistry, qRT-PCR as well as Western blotting were performed to evidence the regulation of key molecules in affected livers. In conclusion, the present study provides evidence for a mechanism of diclofenac induced liver injury that involves pro-inflammatory cytokine and acute phase responses. C57BL6- mice (males, 8 weeks old) (n=5) were administered daily by intraperitoneal injection of 30 mg/kg diclofenac sodium for up to 14 days. Control mice (n=5) were treated corresponding quantities of saline. The mice were euthanized at 24h (day 1), 72h (day 3) or 14 days after vehicle or diclofenac administration. The whole genome gene expression profiling studies of liver samples were performed to define the molecular mechanism of diclofenac induced immune mediated liver injury.
2016-08-09 | E-GEOD-75277 | biostudies-arrayexpress
Project description:Idiosyncratic drug-induced liver injury (iDILI) is a major cause of acute liver failure resulting in liver transplantation or death. Prediction and diagnosis of iDILI remain a great challenge, as current models provide unsatisfying results in terms of sensitivity, specificity and prognostic value. The absence of appropriate tools for iDILI detection also impairs the development of reliable biomarkers. Here, we report on a new method for identification of drug-specific biomarkers. We combined the advantages of monocyte-derived hepatocyte-like (MH) cells, able to mimic individual characteristics, with those of a novel mass spectrometry (MS)-based proteomics technology to assess potential biomarkers for Diclofenac-induced DILI. We found over 2700 proteins differentially regulated in MH cells derived from individual patients. Herefrom, we identified integrin beta 3 (ITGB3) to be specifically upregulated in Diclofenac-treated MH cells from Diclofenac-DILI patients compared to control groups. Finally, we validated ITGB3 by flow cytometry analysis of whole blood and histological staining of liver biopsies derived from patients diagnosed with Diclofenac-DILI. In summary, our results show that biomarker candidates can be identified by proteomics analysis of MH cells. Application of this method to a broader range of drugs in the future will exploit its full potential for the development of drug-specific biomarkers.
2018-07-23 | PXD008918 | Pride
Project description:Drug-induced liver injury (DILI) is an important clinical problem. Here we used a genomics approach to establish the critical drug-induced toxicity pathways that act in synergy with the pro-inflammatory cytokine tumor necrosis factor (TNF) to cause cell death of liver HepG2 cells. Transcriptomics of the cell injury stress response pathways initiated by two hepatoxicants, diclofenac and carbamazepine, revealed the endoplasmic reticulum (ER) stress/translational initiation signaling and Nrf2 antioxidant signaling as two major affected pathways, which was similar to that observed for the majority of ~80 DILI compounds in primary human hepatocytes. The ER stress was primarily related to PERK and ATF4 activation and subsequent expression of CHOP, which was all independent of TNFM-NM-1 signaling. Identical ATF4 dependent transcriptional programs were observed in primary human hepatocytes as well as primary precision cut human liver slices. Targeted RNA interference studies revealed that while ER stress signaling through IRE1M-NM-1 and ATF6 acted cytoprotective, activation of the ER stress protein kinase PERK and subsequent expression of CHOP was pivotal for the onset of drug/TNF-induced apoptosis. While inhibition of the Nrf2-dependent adaptive oxidative stress response enhanced the drug/TNF cytotoxicity, Nrf2 signaling did not affect CHOP expression. Both hepatotoxic drugs enhanced expression of the translational initiation factor EIF4A1, which was essential for CHOP expression and drug/TNF-mediated cell killing. Our data support a model in which enhanced drug-induced translation initiates PERK-mediated CHOP signaling in an EIF4A1 dependent manner, thereby sensitizing towards caspase-8-dependent TNF induced apoptosis. Liver slices (diameter 4 mm, thickness 250 M-BM-5m) were pre-incubated at 37M-BM-0C for 1h individually in a well containing 1.3 ml WilliamsM-bM-^@M-^Y medium E with glutamax-1 (Gibco, Paisley, UK), supplemented with 25 mM D-glucose and 50 M-BM-5g/ml gentamicin (Gibco, Paisley, UK) (WEGG medium) in a 12-well plate with shaking (90 times/min) under saturated carbogen atmosphere.
2014-01-22 | E-GEOD-54255 | biostudies-arrayexpress
Project description:Acute myeloid leukemia is a heterogeneous disease with regard to the underlying genetic and molecular pathophysiology. Non-steroidal anti-inflammatory drugs (NSAIDs) exert significant anti-proliferative effects in various malignant cells in vitro and in vivo. Hence, these agents can be utilized to study potential disease specific anti-proliferative pathways. In this study, a total number of 42 bone marrow derived CD34+ cells from de novo AML patients and the AML cell lines THP-1 and HL-60 were treated with the NSAIDs Sulindac sulfide and Diclofenac. We examined viability, apoptosis, differentiation and addressed the molecular mechanisms involved. We found a consistent induction of apoptosis and to some extent myeloid differentiation in NSAID treated AML cells. Comprehensive protein and gene expression profiling of Diclofenac treated AML cells revealed transcriptional activation of GADD45M-NM-1 and its downstream MAPK/JNK pathway as well as increased protein levels of the Caspase-3 precursor. This points towards a role of the c-Jun NH2-terminal kinase (JNK) in NSAID mediated apoptosis. This was dependent on JNK activity as addition of a specific JNK-inhibitor abrogated apoptosis. Furthermore, the AP-1 transcription factor family membersM-bM-^@M-^Y c-Jun, JunB and Fra-2 were transcriptionally activated in NSAID treated AML cells. Re-expression of these transcription factors led to activation of GADD45M-NM-1 with induction of apoptosis. Mechanistically, we demonstrate that NSAIDs induce apoptosis in AML through a novel pathway involving increased expression of AP-1 heterodimers, which by itself is sufficient to induce GADD45M-NM-1 expression with consecutive activation of JNK and induction of apoptosis. HL-60 and THP-1 AML cells were treated with 100 M-BM-5M Diclofenac or DMSO as control for 48 hours. Each experiment was performed in duplicate. After this treatment total RNA of the cells was harvested and analysed by means of gene expression profiling with the Affymetrix HU-133A array.
2011-03-26 | E-GEOD-28185 | biostudies-arrayexpress
Project description:Diclofenac is a widely used analgesic drug that can cause serious adverse drug reactions. We used Saccharomyces cerevisiae as model eukaryote to elucidate the molecular mechanisms of diclofenac toxicity and resistance. Although most yeast cells died during initial diclofenac treatment, some survived and started growing again. Microarray analysis of the adapted cells identified three major processes involved in diclofenac detoxification and tolerance. Especially pleiotropic drug resistance genes and genes under control of Rlm1p, a transcription factor in the protein kinase C (PKC) pathway, were upregulated in diclofenac-adapted cells. Genes involved in ribosome biogenesis and rRNA processing were downregulated, as well as zinc-responsive genes.
2011-05-17 | GSE29331 | GEO
Project description:Diclofenac is widely used as nonsteroidal anti-inflammatory drug leaving residues in the environment. To investigate effects on terrestrial ecosystems, we measured dissipation rate in soil and investigated ecotoxicological and transcriptome-wide responses in Folsomia candida. Exposure for 4 weeks to diclofenac reduced both survival and reproduction of F. candida in a dose-dependent manner. At concentrations ≥200 mg/kg soil diclofenac remained stable in the soil during a 21-day incubation period. Microarrays examined transcriptional changes at low and high diclofenac exposure concentrations. The results indicated that development and growth were severely hampered and immunity-related genes, mainly directed against bacteria and fungi, were significantly up-regulated. Furthermore, neural metabolic processes were significantly affected only at the high concentration. We conclude that diclofenac is toxic to non-target soil invertebrates, although its mode of action is different from the mammalian toxicity. The genetic markers proposed in this study may be promising early markers for diclofenac ecotoxicity.
2014-10-01 | GSE59589 | GEO
Project description:Gene expression analysis of diclofenac-treated rat cardiomyocytes vs non-treated rat cardiomyocytes. Goal of study is to identify changes on genes expression induced by diclofenac. The data analysis focused on genes that might be related to cardiotoxicity; genes expression ion channels and pathways.
2016-02-13 | GSE77880 | GEO
Project description:Gene expression analysis of diclofenac-treated rat cardiomyocytes vs non-treated rat cardiomyocytes. Goal of study is to identify changes on genes expression induced by diclofenac. The data analysis focused on genes that might be related to cardiotoxicity; genes expression ion channels and pathways. two control samples vs 6 diclofenac-treated samples. Variables of treatment included two time points (6h or 24h) and three reference concentrations (1, 1/5 and 1/25). Each group had 3 replicates.
2016-02-13 | E-GEOD-77880 | biostudies-arrayexpress