Cebus capucinus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA362864 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Using a Cebus capucinus model and after chronic copper oral administration, we assessed a global transcriptional liver adaptations induced by acutely challenging the animals with a unique high dose of oral acetaminophen (APAP).
2017-12-01 | GSE93937 | GEO
Project description:Copper is an essential trace element, but can become toxic when present in abundance. The severe effects of copper-metabolism imbalance are illustrated by the inherited disorders Wilson disease and Menkes disease. The Labrador retriever dog breed is a novel non-rodent model for copper-storage defects displaying identical phenotypic alterations and carrying mutations in genes known to be involved in copper transport. Besides disease initiation and progression of copper accumulation, the molecular mechanisms and pathways involved in copper accumulation and eventually progression towards copper associated chronic hepatitis still remains unclear. Using liver tissue of Labrador retrievers in different stages of copper-associated hepatitis, expression levels targeted at candidate genes as well as transcriptome microarrays, have shed light on involved molecular pathways. At the initial phase, viz. increased hepatic copper levels, transcriptomic alterations in livers revealed enrichment for cell adhesion, developmental, inflammatory, and cytoskeleton pathways. Upregulation of targeted MT1A and COMMD1 mRNA shows the livers first response to rising intrahepatic copper concentrations. In livers with copper-associated hepatitis mainly an activation of inflammatory pathways is detected. Once the hepatitis is in the chronic stage, transcriptional differences are found in cell adhesion adaptations and cytoskeleton remodelling. In view of the high similarities in hepatopathies between men and dog extrapolation of these dog data into human biomedicine seems feasible.
2017-05-02 | GSE86932 | 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:The gene expression profiles were analyzed of HuH-7 cells treated with cytotoxic agents, such as acetaminophen, arsenic or copper, along with cells that were treated for potential benefits with either caffeine or exosomes isolated from pooled human sera
2019-12-02 | GSE76139 | GEO
Project description:Acetaminophen is the primary cause of acute liver toxicity in Europe/USA. Therefore, the FDA reconsiders recommendations concerning safe acetaminophen dosage/use. Current tests for liver toxicity are no ideal predictive markers for liver injury. Here, ‘omics techniques (global analysis of metabolomic/gene expression responses) may provide additional insight. To better understand acetaminophen-induced responses at low dose, we evaluated effects of (sub-)therapeutic acetaminophen doses on metabolite formation/global gene-expression changes (including, for the first time, miRNA) in blood/urine samples from healthy human volunteers.
2011-07-07 | GSE30418 | GEO
Project description:Liver injury is a core pathological process in the majority of liver diseases, yet the genetic factors predisposing individuals to its initiation and progression remain poorly understood. Here we show that asialoglycoprotein receptor 1 (ASGR1), a lectin specifically expressed in the liver, is downregulated in patients with liver fibrosis or cirrhosis and male mice with liver injury. ASGR1 deficiency exacerbates while its overexpression mitigates acetaminophen-induced acute and CCl4-induced chronic liver injuries in male mice. Mechanistically, ASGR1 binds to an endoplasmic reticulum stress mediator GP73 and facilitates its lysosomal degradation. ASGR1 depletion increases circulating GP73 levels and promotes the interaction between GP73 and BIP to activate endoplasmic reticulum stress, leading to liver injury. Neutralization of GP73 not only attenuates ASGR1 deficiency-induced liver injuries but also improves survival in mice received a lethal dose of acetaminophen. Collectively, these findings identify ASGR1 as a potential genetic determinant of susceptibility to liver injury and propose it as a therapeutic target for the treatment of liver injury.
2023-11-26 | GSE232677 | GEO
Project description:Homeostatic plasticity, a form of synaptic plasticity, maintains the fine balance between overall excitation and inhibition in developing and mature neuronal networks. Although the synaptic mechanisms of homeostatic plasticity are well characterized, the associated transcriptional program remains poorly understood. We show that the Kleefstra syndrome-associated protein, EHMT1, plays a critical and cell-autonomous role in synaptic scaling by responding to attenuated neuronal firing or sensory drive. Chronic activity deprivation increased the amount of neuronal dimethylated H3 at lysine 9 (H3K9me2), the catalytic product of EHMT1 and an epigenetic marker for gene repression. Genetic knockdown and pharmacological blockade of EHMT1 or EHMT2 prevented the increase of H3K9me2 and synaptic scaling up. Furthermore, BDNF repression was preceded by EHMT1/2-mediated H3K9me2 deposition at the Bdnf promoter during synaptic scaling up, both in vivo or in vivo. These findings suggest that changes in chromatin state through H3K9me2 governs a repressive program to achieve synaptic scaling. 12 samples (4 conditions in biological triplicate), 3 wt, 3 wt tetradotoxin treated, 3 k.d., 3 k.d. tetradotoxin treated
2016-06-30 | E-GEOD-68960 | biostudies-arrayexpress
Project description:Sluka2016 - Acetaminophen metabolism
Liver metabolism of Acetaminophen: Acetaminophen (APAP) is
metabolized in the liver in both Phase I and Phase II reactions.
Phase II reactions convert APAP to APAP-glucuronide and
APAP-sulfate. Phase I reactions involve Cytochrome P450 mediated
(mostly Cyp450-2E1 and -1A2) conversion of APAP to
N-acetyle-p-quinoneimine (NAPQI), which goes on to react with
cellular nucleophiles such as glutathione (GSH). At high doses of
APAP significant GSH depletion in hepatocyte occurs resulting in
cell necrosis and and in extreme cases death.
This model is described in the article:
A Liver-Centric Multiscale
Modeling Framework for Xenobiotics.
Sluka JP, Fu X, Swat M, Belmonte JM,
Cosmanescu A, Clendenon SG, Wambaugh JF, Glazier JA.
PLoS ONE 2016; 11(9): e0162428
Abstract:
We describe a multi-scale, liver-centric in silico modeling
framework for acetaminophen pharmacology and metabolism. We
focus on a computational model to characterize whole body
uptake and clearance, liver transport and phase I and phase II
metabolism. We do this by incorporating sub-models that span
three scales; Physiologically Based Pharmacokinetic (PBPK)
modeling of acetaminophen uptake and distribution at the whole
body level, cell and blood flow modeling at the tissue/organ
level and metabolism at the sub-cellular level. We have used
standard modeling modalities at each of the three scales. In
particular, we have used the Systems Biology Markup Language
(SBML) to create both the whole-body and sub-cellular scales.
Our modeling approach allows us to run the individual
sub-models separately and allows us to easily exchange models
at a particular scale without the need to extensively rework
the sub-models at other scales. In addition, the use of SBML
greatly facilitates the inclusion of biological annotations
directly in the model code. The model was calibrated using
human in vivo data for acetaminophen and its sulfate and
glucuronate metabolites. We then carried out extensive
parameter sensitivity studies including the pairwise
interaction of parameters. We also simulated population
variation of exposure and sensitivity to acetaminophen. Our
modeling framework can be extended to the prediction of liver
toxicity following acetaminophen overdose, or used as a general
purpose pharmacokinetic model for xenobiotics.
This model is hosted on
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2024-09-02 | BIOMD0000000624 | BioModels
Project description:Acetaminophen overdose is the most common cause of acute liver injury (ALI) or acute liver failure in the USA. Its pathogenetic mechanisms are incompletely understood. Additional studies are warranted to identify new genetic risk factors for more mechanistic insights and new therapeutic target discoveries. The objective of this study was to explore the role and mechanisms of nicotinamide phosphoribosyltransferase (NAMPT) in acetaminophen-induced ALI. C57BL/6 Nampt gene wild type (Nampt+/+)-, heterozygous knockout (Nampt+/-)-, and overexpression (NamptOE)-mice were treated with overdose of acetaminophen, followed by histological, biochemical, and transcriptomic evaluation of liver injury. The mechanism of Nampt in acetaminophen -induced hepatocytic toxicity was also explored in cultured primary hepatocytes. Three lines of evidence have convergently demonstrated that acetaminophen overdose triggers the most severe oxidative stress and necrosis, and the highest expression of key necrosis driving genes in Nampt+/- mice, while the effects in NamptOE mice were least severe relative to Nampt+/+ mice. These findings support that NAMPT protects against acetaminophen induced ALI.
2018-04-03 | GSE110787 | GEO
Project description:Liver injury results in rapid regeneration through hepatocyte proliferation and hypertrophy. However, after acute severe injury, such as acetaminophen poisoning, effective regeneration may fail. We investigated how senescence underlies this regenerative failure. In human acute liver disease, and murine models, p21-dependent hepatocellular senescence was proportionate to disease severity and was associated with impaired regeneration. In an acetaminophen injury model a transcriptional signature associated with the induction of paracrine senescence is observed within twenty four hours, and is followed by one of impaired proliferation. In genetic models of hepatocyte injury and senescence we observed transmission of senescence to local uninjured hepatocytes. Spread of senescence depended upon macrophage derived TGFβ1 ligand. In acetaminophen poisoning inhibition of TGFβ receptor 1 (TGFβR1) improved survival. TGFβR1 inhibition reduced senescence and enhanced liver regeneration even when delivered after the current therapeutic window. This mechanism, in which injury induced senescence impairs regeneration, is an attractive therapeutic target for acute liver failure.
2019-03-20 | GSE111828 | GEO