Ontology highlight
ABSTRACT:
PROVIDER: PRJNA812427 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18455431_1.fastq.gz | Fastqsanger.gz | |||
| SRR18455431_2.fastq.gz | Fastqsanger.gz | |||
| SRR18455432_1.fastq.gz | Fastqsanger.gz | |||
| SRR18455432_2.fastq.gz | Fastqsanger.gz | |||
| SRR18455433_1.fastq.gz | Fastqsanger.gz |
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Project description:Five diatoms transcriptomes under iron limitation and oxidative stress
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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 robust transcriptional plasticity of liver mediated through xenobiotic receptors underlies its ability to respond rapidly and effectively to diverse chemical stressors. Thus, drug-induced gene expression changes in liver serve not only as biomarkers of liver injury, but also as mechanistic sentinels of adaptation in metabolism, detoxification and tissue protection from chemicals. Modern RNA sequencing methods offer an unmatched opportunity to quantitatively monitor these processes in parallel and to contextualize the spectrum of dose-dependent stress, adaptation, protection and injury responses induced in liver by drug treatments. Using this approach, we profiled the transcriptional changes in rat liver following daily oral administration of 95 different compounds, many of which are known to be associated with clinical risk for drug induced liver injury (DILI) by diverse mechanisms.
2020-02-24 | GSE144219 | GEO
Project description:Clinical reports describing increased liver toxicity in adult versus pediatric patients treated with the anti-leukemic drug asparaginase suggest that hepatic stress responses differ with age. We utilized RNA sequencing to comparatively examine the liver transcriptomes of juvenile (2 wk old) and adult (8 and 16 wk old) mice following chronic exposure to asparaginase. Liver RNA from 2 and 16 week old mice were sent Sulzberger Columbia Genome Center for cDNA library preparation and sequencing at the same time as liver RNA from 8 week old mice (GSE92364). Asparaginase exposure altered the liver transcriptomes only modestly whereas age had a massive global influence. Unbiased exploration into the effect of age on drug responses revealed that the integrated stress response (ISR) represented a common, core molecular signature regardless of age. ISR engagement in juveniles corresponded with transcriptional signatures of downregulated lipid biosynthesis and increased sequestration of iron. In contrast, adults showed ISR activation alongside upregulation of Saa1 and Saa2 inflammatory markers, serine/glycine metabolism, and folate cycle suggesting mitochondrial stress. We also observed sporadic enrichment in RNA gene signatures reflecting altered nucleotide metabolism of adults in response to the drug. Taken together, our data show that maturity to adulthood does not alter the ISR gene signature to asparaginase. Instead, age-related changes in cellular resource capacity and turnover may be the determining factor in guiding hepatic stress responses to asparaginase.
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