E-GEOD-74903
Ontology highlight
ABSTRACT:
PROVIDER: E-GEOD-74903 | ExpressionAtlas | 2020-06-16
REPOSITORIES: ExpressionAtlas
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| E-GEOD-74903-analysis-methods.tsv | Tabular | |||
| E-GEOD-74903-atlasExperimentSummary.Rdata | Rdata | |||
| E-GEOD-74903-configuration.xml | Xml | |||
| E-GEOD-74903-percentile-ranks.tsv | Tabular | |||
| E-GEOD-74903.condensed-sdrf.tsv | Tabular |
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Project description:Assessing concordance of drug-induced transcriptional response in rodent liver and cultured hepatocytes
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Project description:Human liver organoids, an in vitro 3D culture system to recapitulate biological tissue, are expected to be used for drug discovery. However, Matrigel, the most widely used extracellular matrix for organoid culture, has concerns about safety and reproducibility since it is murine-derived. Morever, low hepatic functions of human liver organoids compared to primary human hepatocytes is considered a challenge. Herein, we attempted to culture human liver organoids, established from primary (cryopreserved) human hepatocytes (PHH), using HYDROX, a chemically defined 3D nanofiber. While proliferative capacity of human liver organoids was lost by HYDROX-culture, the gene expression level of a hepatocyte marker CYP3A4 and the CYP3A4 metabolic activity in HYDROX-cultured liver organoids were significantly improved, comparable to those of PHH. HYDROX-cultured liver organoids when treated with hepatotoxic drugs such as acetaminophen showed similar cell viability to that of PHH, suggesting that HYDROX-cultured liver organoids could be applied to drug-induced hepatotoxicity test. Furthermore, HYDROX-cultured liver organoids maintained its functions for up to 35 days and could be used to estimate chronic drug-induced hepatotoxicity such as those of fialuridine. Our findings demonstrated that human liver organoids obtained high liver functions by HYDROX-culture, meaning that HYDROX could contribute to drug discovery as a novel biomaterial.
2024-05-22 | GSE239375 | GEO
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 TNFα 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 IRE1α 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. We sought to determine the effect of co-exposure of certain drugs associated with idiosyncratic DILI with the cytokine TNFalpha to mimic drug exposure with inflammation signaling in HepG2 cells Human hepatoma HepG2 cells were obtained from American Type Culture Collection (ATCC, Wesel, Germany), cultured in DMEM supplemented with 10% (v/v) FBS, 25 U/mL penicillin and 25 µg/mL streptomycin and used for experiments between passage 5 and 20.
2014-01-22 | E-GEOD-54254 | biostudies-arrayexpress
Project description:Drug induced liver injury (DILI) is still a major reason for drug attrition during clinical trials and market-withdrawal of already approved drugs. DILI is difficult to predict in animal models, hence more suitable screening methods are needed to predict adverse effects in human. Here, transcriptomic data from short- and long-term cultured primary human hepatocytes exposed to the human hepatotoxin Chlorpromazine was analysed.
2013-08-05 | E-MTAB-1747 | biostudies-arrayexpress
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 M-oM-^AM-! (TNFM-oM-^AM-!) 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/TNFM-oM-^AM-!-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. 4 biological replicates of Diclofenac and 6 biological replicates of vehicle. 46 hours after isolation, cells were exposed to either 300 M-BM-5M DCF or the solvent DMSO for 24 hours.
2014-01-22 | E-GEOD-54256 | biostudies-arrayexpress
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:The effect of drugs, disease and other perturbations on mRNA levels are studied using gene expression microarrays or RNA-seq, with the goal of understanding molecular effects arising from the perturbation. Previous comparisons of reproducibility across laboratories have been limited in scale and focused on a single model. The use of model systems, such as cultured primary cells or cancer cell lines, assumes that mechanistic insights derived with would have been observed via in vivo studies. We examined the concordance of compound-induced transcriptional changes using data from several sources: rat liver and rat primary hepatocytes (RPH) from Drug Matrix (DM) and open TG-GATEs (TG), primary human hepatocytes (HPH) from TG, and mouse liver / HepG2 results from the Gene Expression Omnibus (GEO) repository. Gene expression changes for treatments were normalized to controls and analyzed with three methods: 1) gene level for 9071 high expression genes in rat liver, 2) gene set analysis (GSA) using canonical pathways and gene ontology sets, 3) weighted gene co-expression network analysis (WGCNA). Co-expression networks performed better than genes or GSA on a quantitative metric when comparing treatment effects within rat liver and rat vs. mouse liver. Genes and modules performed similarly at Connectivity Map-style analyses, where success at identifying similar treatments among a collection of reference profiles is the goal. Comparisons between rat liver and RPH, and those between RPH, HPH and HepG2 cells reveal low concordance for all methods. We investigate differences in the baseline state of cultured cells in the context of drug-induced perturbations in rat liver and highlight the striking similarity between toxicant-exposed cells in vivo and untreated cells in vitro. Gene expression studies in model systems are widely used for understanding the mechanism of drugs and other perturbations in biological systems. Other researchers have examined the reproducibility of microarray studies between laboratories, or comparing microarrays and/or RNA sequencing. However, no large scale studies have compared results from protocols which differ in minor details, or results generated in vivo vs. in vitro culture system thought to serve as useful models. The rat liver is by far the most extensively studied model evaluating effects of drugs and other perturbations, and existing data allowed us to assess the level of concordance between rat liver and rat primary hepatocytes cultured in collagen-coated plates (i.e. âflatâ culture) for hundreds of drugs. We found that the mouse liver serves as a better model of the rat liver than do rat primary hepatocytes, even after allowing for differences due to pharmacokinetics. The low concordance observed between rat liver and rat hepatocytes suggests that validating the utility of âomics data generated on emerging cell culture approaches (e.g. âorgan-on-a-chipâ, 3D-printed tissues) using rat cells and comparison to the rat liver may be necessary in order to gain confidence these approaches substantially improve on traditional culture models of human cells. To identify transcriptional changes in culture, rat primary hepatocytes (RPH) were isolated from three male Sprague Dawley rats. During the isolation and prior to perfusion, a lobe of liver was tied off to serve as the liver in situ reference sample. Cells were isolated and samples from the cell pellet (time zero) and cells cultured for 4, 24 and 48 hours. Three biological replicates were generated for each group (one from each rat). Each biological replicate was analyzed via 3 technical replicates, for a total of 9 array hybridizations per group.
2015-11-12 | E-GEOD-74903 | biostudies-arrayexpress
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 TNFα 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 IRE1α 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.
2014-01-22 | GSE54256 | GEO
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 TNFα 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 IRE1α 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.
2014-01-22 | GSE54255 | GEO
Project description:We investigated the effects of the flutamide (FLU) -induced liver injury in primary rat hepatocytes using our liver microfluidic biochips. Flutamide is used a non-steroidal anti-androgenic drug. Two flutamide concentrations, 10M-BM-5M and 100M-BM-5M, were used to expose the hepatocytes for 24h under perfusion. Primary rat hepatocytes were cultivated in microfluidic biochips and treated with 10 and 100M-BM-5M of flutamide for 24h
2013-12-01 | E-GEOD-44317 | biostudies-arrayexpress