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A Novel Statistical Algorithm for Gene Expression Analysis Differentiates PXR-Dependent and Independent Mechanisms of Toxicity

ABSTRACT: The objective of the present study is to examine the potential role of the pregnane x receptor (PXR) in mice treated with an small molecule inhibitor for beta-secretase (CMP013) Two groups of mice, C57Bl/6 (PXR+/+) and PXR-knockout C57Bl/6NTac (PXR-/-), were administered either CMP013 or vehicle. There were five animals per treatment group for each strain. After 96 h, all animals were euthanized, and liver samples were collected for RNA. extraction.

ORGANISM(S): Mus musculus

SUBMITTER: Sandra Tran

PROVIDER: E-GEOD-23780 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Effect of phenobarbital on CAR and PXR regulated genes involved in drug metabolism and cholesterol homeostasis

Project description:The nuclear receptors CAR (constitutive androstane receptor) and PXR (pregnane X receptor) mediate the effects of phenobarbital (PB) on gene transcription. To investigate the relative role of CAR and PXR in the induction response, cDNA arrays were generated containing 120 genes which are known to be regulated with these or related nuclear receptors (genes involved in drug metabolism, cholesterol biosynthesis, sterol synthesis/transport, heme synthesis). Samples from livers of wild type and CAR-/-, PXR-/- or CAR/PXR-/- knockout mice were tested after treatment with PB for gene expression within the European Framework V program “Steroltalk” (www.steroltalk.net). Results from these experiments unexpectedly revealed that if CAR and PXR are deleted, PB increases the expression of several other nuclear receptors and genes involved in drug metabolism and cholesterol biosynthesis. Animals were injected i.p. 100mg/kg phenobarbital or vehicle (5% DMSO in corn oil). After 12h they were sacrificed and total RNA was isolated from the livers. Pools of untreated samples were mixed in each genetic variant group (wild type and CAR-/-, PXR-/- or CAR/PXR-/-) with the phenobarbital treated ones and hybridized to Sterolgene V1 arrays.

2008-08-23 | E-GEOD-12489 | biostudies-arrayexpress

A Novel Statistical Algorithm for Gene Expression Analysis Differentiates PXR-Dependent and Independent Mechanisms of Toxicity

Project description:The objective of the present study is to examine the potential role of the pregnane x receptor (PXR) in mice treated with an small molecule inhibitor for beta-secretase (CMP013)

2010-08-25 | GSE23780 | GEO

Phenobarbital and TCPOBOP effects on CAR and PXR regulated genes involved in drug metabolism and cholesterol homeostasis

Project description:This SuperSeries is composed of the following subset Series: GSE12489: Effect of phenobarbital on CAR and PXR regulated genes involved in drug metabolism and cholesterol homeostasis GSE12509: Effect of TCPOBOP on CAR and PXR regulated genes involved in drug metabolism and cholesterol homeostasis Refer to individual Series

2008-08-23 | E-GEOD-12529 | biostudies-arrayexpress

Effect of PCN on CAR and PXR regulated genes involved in circadian rhythm, drug metabolism and cholesterol homeostasis

Project description:The nuclear receptor PXR (Pregnane X rreceptor) mediates the effects of pregnenolone-16alpha-carbonitrile (PCN) on gene transcription. The relative role of PXR and also CAR to the induction response by PCN was studied on cDNA arrays containing 320 (Steroltalk V2) genes (genes involved in cyrcadian rhythm, drug metabolism, cholesterol biosynthesis, sterol synthesis/transport, heme synthesis). Samples from livers of wild type and CAR-/-, PXR-/- or CAR/PXR-/- knockout mice were tested after treatment with PCN for gene expression within the European Framework V program âSteroltalkâ (www.steroltalk.net). Results from these experiments show the complex role of PXR receptor in the expression of genes involved in cyrcadian rhythm, drug metabolism and cholesterol biosynthesis. Animals were injected i.p. 40mg/kg PCN or vehicle (5% DMSO in corn oil). After 12h they were sacrificed and total RNA was isolated from the livers. Pools of untreated samples were mixed in each genetic variant group (wild type and CAR-/-, PXR-/- or CAR/PXR-/-) with the PCN treated ones and hybridized to Steroltalk V2 arrays.

2010-05-16 | E-GEOD-12537 | biostudies-arrayexpress

Effect of TCPOBOP on CAR and PXR regulated genes involved in drug metabolism and cholesterol homeostasis

Project description:The nuclear receptor CAR (constitutive androstane receptor) mediates the effects of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) on gene transcription. To investigate the relative role of CAR and also PXR in the induction response, cDNA arrays were generated containing 120 (Sterolgene V1) genes which are known to be regulated with these or related nuclear receptors (genes involved in drug metabolism, cholesterol biosynthesis, sterol synthesis/transport, heme synthesis). Samples from livers of wild type and CAR-/-, PXR-/- or CAR/PXR-/- knockout mice were tested after treatment with TCPOBOP for gene expression within the European Framework V program “Steroltalk” (www.steroltalk.net). Results from these experiments show the complex role of CAR receptor in the expression of genes involved in drug metabolism and cholesterol biosynthesis. Animals were injected i.p. 10mg/kg TCPOBOP or vehicle (5% DMSO in corn oil). After 12h they were sacrificed and total RNA was isolated from the livers. Pools of untreated samples were mixed in each genetic variant group (wild type and CAR-/-, PXR-/- or CAR/PXR-/-) with the TCPOBOP treated ones and hybridized to Sterolgene V1 arrays.

2008-08-23 | E-GEOD-12509 | biostudies-arrayexpress

Effects of PXR activation on the macrophage transcriptome

Project description:Purpose: To explore the role of PXR signaling in regulating macrophage transcriptome related to atherogenesis Methods: Peritoneal macrophages were isolated from LDLR knockout mice with myeloid specific PXR deficiency (PXRΔMyeLDLR-/-) and their littermates (PXRF/FLDLR-/-). Then the macrophages were treated with a PXR ligand PCN or DMSO control for 12 hr. Total RNA was extracted for RNAseq Results: PCN-mediated PXR activation induced 439 differentially expressed genes (DEGs) with false discovery rate (FDR) < 5% and fold change >1.5 in control macrophages. By contrast, PCN only induced 38 DEFs in PXR-deficient macrophages. Conclusions: These results indicate that PXR signaling may affect many genes in macrophages related atherosclerosis development.

2020-02-22 | GSE145719 | GEO

Pregnane X Receptor (PXR) protects against cisplatin-induced acute kidney injury

Project description:Background: Cisplatin-induced acute kidney injury (CAKI) has been recognized as one of the most serious side effects of cisplatin. Pregnane X receptor (PXR) is a ligand-dependent nuclear receptor and serves as a master regulator of xenobiotic detoxification. Increasing evidence also suggests PXR has many nonxenobiotic functions including the regulation of cell proliferation, inflammatory response and glucose and lipid metabolism. Methods: In this study, we aimed to investigate the role of PXR in cisplatin-induced nephrotoxicity. CAKI model was performed in wild-type or PXR knockout mice. Pregnenolone 16α-carbonitrile (PCN), a mouse PXR specific agonist, was used for PXR activation. The renal function, biochemical, histopathological and molecular alterations were examined in mouse blood, urine or renal tissues. Whole transcriptome analysis was performed by RNA sequencing. Dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays were applied to determine the regulation of PXR on its target genes. Results: We found that PXR activation significantly attenuated CAKI as reflected by improved renal function, reduced renal tubular apoptosis, ameliorated oxidative and endoplasmic reticulum stress, and suppressed inflammatory factor expression. RNA sequencing analysis revealed that the renoprotective effect of PXR was associated with multiple crucial signaling pathways. In particular, PXR protected against cisplatin-induced AKI by the activation of PI3K/AKT pathway and the induction of multidrug and toxin extrusion 1 (MATE1), an important transporter mediating cellular excretion of cisplatin, in the kidney. Conclusions: Our results demonstrate that PXR activation can preserve renal function in cisplatin-induced AKI and suggest a possibility of PXR as a novel therapeutic target for cisplatin-induced nephrotoxicity.

2023-03-20 | GSE147256 | GEO

Transcriptional profiling of C57BL-mice with humanized CAR/PXR or CAR/PXR-knockout treated with DCB and CPA

Project description:To investigate the role of the nuclear receptors CAR (constitutive androstane receptor) and PXR (Pregnane X receptor) in mediating the effects of non-genotoxic carcinogens, groups of mice humanised or deleted for CAR and PXR were treated with 1,4-Dichlorobenzene or cyproterone acetate for 3d and liver tissue harvested for expression profiling. Control groups were treated with appropriate vehicles.

2018-04-27 | GSE68365 | GEO

Genome wide comparison of the inducible transcriptomes of CAR, PXR and PPARÎ± in primary human hepatocytes

Project description:To identify the CAR-, PXR- and PPARÎ±-specific genome-wide expression changes, hepatocyte cultures from six individual donors were treated with the prototypical ligands for CAR (CITCO), PXR (rifampicin) and PPARÎ± (WY14,643) as well as DMSO (vehicle control). Afterwards, the mRNA expression in these samples was determined utilizing AffymetrixÂ® microarrays. Primary human hepatocytes (PHH) from 6 donors were treated for 24 h with 10ÂµM of rifampicin, 50ÂµM of WY14,643, 1ÂµM of CITCO and 0.1% of DMSO (vehicle).

2016-03-24 | E-GEOD-76148 | biostudies-arrayexpress

Protein S-nitrosylation Restricts Xenobiotic Receptor PXR Hyperactivity and Ameliorates Acetaminophen-induced Liver Injury in Mice

Project description:Drug-induced liver injury (DILI), especially acetaminophen overdose, is the leading cause of acute liver failure. Pregnane X receptor (PXR) is a nuclear receptor and the master regulator of drug metabolism. Aberrant activation of PXR plays a pathogenic role in the acetaminophen hepatotoxicity. Here, we aimed to examine the PXR S-nitrosylation (SNO) in response to acetaminophen. We found that PXR was S-nitrosylated in hepatocytes and the mouse livers after exposure to acetaminophen or S-nitrosoglutathione (GSNO). Mass-spectrometry and site-directed mutagenesis identified the cysteine 307 as the primary residue for SNO-modification. In hepatocytes, SNO suppressed both agonist (rifampicin and SR12813)-induced and constitutively active PXR (VP-PXR) activations. Furthermore, in acetaminophen overdosed mouse livers, PXR protein was decreased at the centrilobular regions overlapping with increased SNO. In PXR-deficient (PXR-/-) mice, replenishing the livers with the SNO-deficient PXR significantly aggravated hepatic necrosis and apoptosis, increased HMGB1 release, and exacerbated liver injury and inflammation. Particularly, we demonstrated that S-nitrosoglutathione reductase (GSNOR) inhibitor N6022 promoted hepatoprotection by increasing the levels of PXR S-nitrosylation. In conclusion, PXR is post-translationally modified by S-nitrosylation in hepatocytes in response to acetaminophen. This modification mitigated the acetaminophen-induced PXR hyperactivity. It may serve as a new target for therapeutical intervention.

2024-03-06 | GSE243679 | GEO

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