Liver transcriptional critical balance induced by acetaminophen is prevented by chronic copper loading
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens Cebus capucinus
PROVIDER: GSE93937 | GEO | 2017/12/01
SECONDARY ACCESSION(S): PRJNA362864
REPOSITORIES: GEO
Similar Datasets
Project description:This SuperSeries is composed of the following subset Series:; GSE5593: Acetaminophen (APAP) Rat Blood Training Gene Expression Data Set; GSE5594: Acetaminophen (APAP) Rat Blood Test Gene Expression Data Set; GSE5595: Acetaminophen (APAP) Rat Liver Test Gene Expression Data Set; The Supplementary files (appended below) contain the mapping for the decoding of blinded samples. Experiment Overall Design: Refer to individual Series
2008-06-14 | E-GEOD-5652 | biostudies-arrayexpress
Project description:Acetaminophen (APAP) is one of the most widely consumed and prescribed drugs. APAP overdose is one of the leading causes of intrinsic drug-induced liver injury (DILI), acute liver failure (ALF), and liver transplantation in the Western world. Mg2+, essential for health, plays a role in virtually every process within the human cell. The cellular transporter family cyclin M, also known as CNNM, plays a key role in Mg2+ transport across the cell membranes in different organs. Here, we identified that the expression of CNNM4 is elevated in the liver of patients with APAP-induced liver injury (AILI), with a concomitant disturbance in serum Mg2+ levels. We demonstrated that, in the liver, APAP interferes with the Mg2+ mitochondrial reservoir via CNNM4, which affects ATP production and ROS generation, further boosting endoplasmic reticulum (ER) stress of the hepatocytes. Importantly, the CNNM4 mutant T495I showed no effect. Finally, a shift in localization of CNNM4 from membrane to ER was shown under APAP toxicity. Therapeutic targeting of Cnnm4 in the liver with nanoparticles and GalNAc-formulated siRNA provides efficient protection from AILI by restoring hepatocyte Mg2+ homeostasis and by inducing hepatocyte restoration. Our results suggest that inhibition of Cnnm4 may represent an alternative route for the treatment of DILI..
2023-03-11 | PXD036682 | Pride
Project description:Toxicogenomics (tgx) is used as a tool to identify mechanisms and markers of necrosis in C57BL/6 mice treated by oral gavage using acetaminophen (APAP), isoniazid (INZ), and paraquat (PQ). Critical doses for tgx analysis were derived from a 25 day dose range finding study. For tgx analysis, livers of mice were collected 1 and 2 days after a single compound dose of 168.75, 225, and 300 mg/kg bw for APAP; 12.5, 25, and 50 mg/kg bw for PQ; and 22, 44, and 88 mg/kg bw for INZ. All samples were diluted in water.
2014-12-16 | GSE51969 | GEO
Project description:Basic PBPK (Physiologically Based PharmacoKinetic) model of Acetaminophen.
This is a basic model of Acetaminophen (APAP, Paracetamol) pharmacokinetics in humans. Many of the model parameters
(compartment volumes, volumetric flow rates, etc.) are scaled allometrically based on the body weight (BW) raised to the
3/4 power. Because of that, the assigned values of many of the parameters are recalculated at run time and are different
than the default values for the particular entity (e.g., the volume of a compartment and the volumetric flow rate between compartments).
APAP dose is initially given in grams (APAP_Dose_gram), which is converted to moles via the APAP molecular weight (APAP_MW).
APAP quantities throughout the rest of the models are given in moles.
The base parameters are for a 70Kg human and a pharmacological oral dose of 1.4 gram of APAP. Metabolism is modelled as a single ODE in the liver compartment and the metabolite does not leave that compartment.
This model is loosely based on the model of Wambaugh and Shaw (PLoS Comput Biol. 2010 Apr 22;6(4):e1000756. doi: 10.1371/journal.pcbi.1000756. Pubmed ID: PMID- 20421935) with the following changes:
The lung lumen compartment was omitted.
A kidney compartment was added.
Glomerular Filtration is from the kidney compartment.
The APAP dose was changed to 1.4g.
The gut adsorption rate constant (KGutabs), tissue partition coefficients and liver metabolism rate constant (CLmetabolism) were fit using the human in vivo
data of Critchley (Critchley, J. A., Critchley, L. A. H., Anderson, P. J., and Tomlinson, B. 2005 Journal of clinical pharmacy and therapeutics, 30(2), 179-184).
To model the extensive re-adsorption of APAP from the kidney tubules back into the blood the QGfr value is modified. This was done by
changing the scaling parameter QGFR_ref value from 0.31 to 0.039, resulting in a decrease in the QGfr value of 8 fold (from 7.2 L/hr to 0.91 L/hr).
The parameters in this file are the REFSIM
parameters from our publication.
2024-09-02 | BIOMD0000000619 | BioModels
Project description:Genetic disruption of thioredoxin reductase 1 protects against acetaminophen (APAP) toxicity. To determine the role of the thioredoxin system on xenobiotic metabolism we challeneged wildtype and txnrd1liver-null mice with acetaminophen.
2013-06-08 | GSE37874 | GEO
Project description:Overdose of acetaminophen (APAP) is the major cause of acute liver failure in the Western world with very limited treatment options. Previous studies from our groups and others have shown that timely activation of liver regeneration is a critical determinant of transplant-free survival of APAP-induced acute liver failure (ALF) patients. We used affy microarrays to explore the mechanisms of transcriptional expression in YAP-KO mice after 300mg/kg APAP overdose.
2021-10-04 | GSE183119 | GEO
Project description:Acetaminophen (APAP), a widely used analgesic and antipyretic that is considered to be relatively safe at recommended doses, is the leading cause of drug-induced liver failure in the United States. 3M-bM-^@M-^Y-Hydroxyacetanilide (AMAP), a regioisomer of acetaminophen is useful as a comparative tool for studying APAP-induced toxicity since it is non-toxic relative to APAP. TGF-alpha transgenic mouse hepatocytes were treated with both isomers to investigate mitogen-activated protein kinase cascades in order to differentiate their toxicological outcomes. Mitogen-activated protein kinase (MAPK) cascade expression and activation were measured using microarray and Bioplex technologies, respectively. APAP treatment led to c-Jun N-terminal kinase (JNK) activation, whereas AMAP treatment led to the activation of extracellular-signal-regulated protein kinase (ERK). The microarray data suggested APAP treatment may upregulate gene expression at multiple levels of the JNK cascade including a JNK-related scaffold protein. Expression data was related to phosphoprotein levels using the Bioplex system. APAP treatment led to a significant activation of JNK compared to its regioisomer. In contrast, microarray analysis of AMAP showed a slight upregulation of ERK gene activity. Furthermore, Bioplex data showed AMAP treatment led to significant ERK phosphorylation compared to APAP. Cell viability assays confirmed that APAP-induced activation of JNK was related to higher rates of cell death, whereas activation of ERK by AMAP may be cytoprotective. 27 arrays, 9 experimental groups, 2hr AMAP, 2hr APAP, 2hr Control, 6hr AMAP, 6hr APAP, 6hr Control, 24hr AMAP, 24hr APAP, 24hr Control.
2010-07-06 | E-GEOD-18614 | biostudies-arrayexpress
Project description:Toxicogenomics (tgx) is used as a tool to identify mechanisms and markers of necrosis in C57BL/6 mice treated by oral gavage using acetaminophen (APAP), isoniazid (INZ), and paraquat (PQ). Critical doses for tgx analysis were derived from a 25 day dose range finding study. For tgx analysis, livers of mice were collected 1 and 2 days after a single compound dose of 168.75, 225, and 300 mg/kg bw for APAP; 12.5, 25, and 50 mg/kg bw for PQ; and 22, 44, and 88 mg/kg bw for INZ. All samples were diluted in water. For the toxicogenomics study, samples were as followed: five mice per low, medium, and high dose group at 1 day, and five mice in the high dose group at 2 days. One set of vehicle controls (n=5) per day was used. The total number of samples was 70.
2014-12-16 | E-GEOD-51969 | biostudies-arrayexpress
Project description:Genetic disruption of thioredoxin reductase 1 protects against acetaminophen (APAP) toxicity. To determine the role of the thioredoxin system on xenobiotic metabolism we challeneged wildtype and txnrd1liver-null mice with acetaminophen. Adult male wildtype and txnrd1 liver-null mice (C57BL6/J) were treated with either saline (PBS) or 100mg/kg APAP. Liver RNA was harvested eight hours after challenge and processed for microarray analysis. Comparison of 2 treatment conditions in 2 genotypes, biological replicates in triplicate.
2013-06-08 | E-GEOD-37874 | biostudies-arrayexpress
Project description:To investigate the molecular mechanisms of the inflammation-mediated exacerbation of increased acetaminophen (APAP) toxicity.
2020-10-04 | GSE104601 | GEO