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OPTN as a therapeutic target for acetaminophen-induced liver injury by activating mitophagy

ABSTRACT: Acetaminophen (APAP) is a leading cause of acute liver failure in Western countries result from the accumulation of damaged mitochondria. However, there is no related clinically useful therapeutic intervention. Optineurin (OPTN) is a multifunctional protein involved in autophagy, oxidative stress, as well as nuclear factor κB (NF-κB) and IRF3 signaling, and OPTN mutations are associated with several human diseases.Here, to study the role of OPTN in APAP induced liver injury, we performed RNA-seq analysis of isolated control and Optn-/- mouse liver tissues.

ORGANISM(S): Mus musculus

PROVIDER: GSE195753 | GEO | 2024/08/21

REPOSITORIES: GEO

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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 BioModels Database and identified by: BIOMD0000000624. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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OPTN as a therapeutic target for acetaminophen-induced liver injury by activating mitophagy

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