Conduritol B Epoxide treatment of MSCs and 293T cells
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: PRJNA110421
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE13675 | GEO | 2008/12/15
SECONDARY ACCESSION(S): PRJNA110421
REPOSITORIES: GEO
Similar Datasets
Project description:Conduritol B Epoxide treatment of MSCs and 293T cells
| PRJNA110421 | ENA
Project description:We characterized the transcriptomic profiles of cells from the substantia nigra (SN) of mice with co-injection with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and selective inhibitor of GCase activity (conduritol-β-epoxide, (CBE)) to mimic PD bearing GCase dysfunction (MPTP+CBE), mice treated with MPTP, mice treated with CBE and control mice treated with injec-tion of sodium chloride (NaCl) (vehicle).
2023-08-31 | E-MTAB-13244 | biostudies-arrayexpress
Project description:Most lysosomal storage diseases (LSDs) have a significant neurological component, including types 2 and 3 Gaucher disease (neuronal forms of Gaucher disease; nGD). No therapies are currently available for nGD since the recombinant enzymes used in the systemic form of Gaucher disease do not cross the blood-brain barrier. However, a number of promising approaches are currently being tested, including substrate reduction therapy (SRT), in which partial inhibition of the synthesis of the glycosphingolipids (GSLs) that accumulate in nGD lowers their accumulation. We now induce nGD in mice by injection with conduritol B-epoxide (CBE), an irreversible inhibitor of acid beta-glucosidase (GCase), the enzyme defective in nGD, with or without co-injection with GZ-667161, a prototype for SRT. Significant neuropathology, and a reduction in lifespan, was observed upon CBE injection, and this was largely reversed by co-injection with GZ-667161, along with a reduction in glucosylceramide and glucosylsphingosine levels. Analysis of gene expression by RNAseq revealed that GZ-667161 largely reversed the changes in genes and pathways that were differentially-expressed upon CBE injection, specifically pathways of GSL metabolism, lipoproteins and other lipid metabolic pathways, lipid droplets, astrocyte activation, neuronal function, and to some extent, neuroinflammation. Together, this demonstrates the efficacy of SRT to reverse the effects of substrate accumulation on pathological components and pathways in nGD brain.
2020-05-26 | GSE151133 | GEO
Project description:Genotoxic agents cause cellular DNA damage and stress responses, including transcriptional changes. Here we focused on the early transcriptional responses of human cells to benzo(a)pyrene diol epoxide (BPDE), which causes bulky DNA adduct damage. Human amnion epithelial FL cells were exposed to three doses of BPDE (5, 50, and 500 nM) and the vehicle control DMSO, and differential gene expression profiles were obtained 4 h after exposure using oligonucleotide microarrays followed by validation with quantitative real-time RT-PCR. Compared with a few genes affected by the low and medium-dose exposure, extensive and robust changes in gene expression were induced by the high-dose BPDE. We found that the expression of cell cycle-regulators, signaling molecules and transcription factors were significantly altered and important signaling pathways related to cell survival or apoptosis were affected by BPDE. Several genes and related regulatory pathways that were previously not known to be responsive to this genotoxic agent have now been implicated, which helps to draw the whole picture of how cells respond to environmental chemical exposure via transcriptional regulation. Experiment Overall Design: Human amnion epithelial FL cells were exposed to vehicle control (dimethyl sulfoxide) and increasing doses (5, 50, 500 nM) of anti-benzo(a)pyrene diol epoxide (anti-BPDE), respectively. The transcriptomes of the three treatments were compared to that of the control, respectively, to test the hypothesis that a characterized differential expression profile would be generated by exposure to various doses of this genotoxic agent.
2008-04-08 | E-GEOD-7675 | biostudies-arrayexpress
Project description:Great interest has been shown in understanding the pathology of Gaucher disease (GD) due to the recently-discovered genetic relationship with Parkinson’s disease. For such studies, suitable animal models of GD are required. Chemical induction of GD by inhibition of acid β-glucosidase (GCase) using the irreversible inhibitor, conduritol-B-epoxide (CBE), is particularly attractive, although few systematic studies examining the effect of CBE on development of symptoms associated with neurological forms of GD have been performed. We now demonstrate a correlation between the amount of CBE injected into mice and levels of accumulation of the GD substrates, glucosylceramide and glucosylsphingosine, and show that disease pathology, indicated by altered levels of pathological markers, depends on the dose of CBE and its time of injection. Gene array analysis shows a remarkable similarly in the gene expression profile of CBE-treated mice and a genetic GD mouse model, the Gbaflox/flox;nestin-Cre mouse, with 120 of the 144 genes up-regulated in CBE-treated mice also up regulated in Gbaflox/flox;nestin-Cre mice. Finally, we demonstrate that some aspects neuropathology and some behavioral abnormalities can be arrested upon cessation of CBE treatment during a specific time window. Together, our data demonstrate that injection of mice with CBE provides a rapid and relatively easy way to induce symptoms typical of neuronal forms of GD, which will prove particularly useful when examining the role of specific biochemical pathways in GD pathology, since CBE can be injected into mice defective in components of putative pathological pathways, alleviating the need for time consuming crossing of mice.
2016-08-30 | GSE78757 | GEO
Project description:Cellular responses to carcinogens are typically studied in transformed cell lines, which do not reflect the physiological status of normal tissues. To address this question, we have characterized the transcriptional program and cellular responses of normal human lung WI-38 fibroblasts upon exposure to the ultimate carcinogen benzo[a]pyrene diol epoxide (BPDE). Exposure to BPDE induces a strong inflammatory response in WI-38 primary fibroblasts. Whole-genome microarray analysis shows induction of several genes related to the production of inflammatory factors, including those that encode interleukins (ILs), growth factors, and enzymes related to prostaglandin synthesis and signaling. This is the first demonstration that a strong inflammatory response is triggered in primary fibroblasts in response to a reactive diol epoxide derived from a polycyclic aromatic hydrocarbon.
2010-01-01 | GSE19510 | GEO
Project description:Genotoxic agents cause cellular DNA damage and stress responses, including transcriptional changes. Here we focused on the early transcriptional responses of human cells to benzo(a)pyrene diol epoxide (BPDE), which causes bulky DNA adduct damage. Human amnion epithelial FL cells were exposed to three doses of BPDE (5, 50, and 500 nM) and the vehicle control DMSO, and differential gene expression profiles were obtained 4 h after exposure using oligonucleotide microarrays followed by validation with quantitative real-time RT-PCR. Compared with a few genes affected by the low and medium-dose exposure, extensive and robust changes in gene expression were induced by the high-dose BPDE. We found that the expression of cell cycle-regulators, signaling molecules and transcription factors were significantly altered and important signaling pathways related to cell survival or apoptosis were affected by BPDE. Several genes and related regulatory pathways that were previously not known to be responsive to this genotoxic agent have now been implicated, which helps to draw the whole picture of how cells respond to environmental chemical exposure via transcriptional regulation. Keywords: Dose response
2008-01-01 | GSE7675 | GEO
Project description:Vitamin K epoxide reductases (VKOR) constitute a major family of integral membrane thiol oxidoreductases. In humans, VKOR sustains blood coagulation and bone mineralization through the vitamin K cycle. Previous chemical models assumed that the catalysis of human VKOR (hVKOR) starts from a fully reduced active site. This state, however, constitutes only a minor cellular fraction (5.6%). Thus, how hVKOR catalysis is carried out in the cellular environment remains largely unknown. Here we use quantitative mass spectrometry (MS) and electrophoretic mobility analysis to show that KO forms a covalent complex with a cysteine mutant mimicking hVKOR in a partially oxidized state. Trapping of this covalent reaction intermediate suggests that the partially oxidized state is catalytically active in cells. To investigate this activity, we analyze the correlation between the cellular activity and the cellular cysteine status of hVKOR. We find that the partially oxidized hVKOR has a considerably lower activity than hVKOR with a fully reduced active site. Although there are more partially oxidized hVKOR than fully reduced hVKOR in cells, these two reactive states contribute about equally to the overall hVKOR activity, and hVKOR catalysis can initiate from either of these states. Overall, the combination of MS quantification and biochemical analyses reveal the catalytic mechanism of this integral membrane enzyme in a cellular environment.
2020-12-03 | PXD020676 | Pride
Project description:The type 1 interferon (IFN) response is part of the innate immune response and best known for its role in viral and bacterial infection. However, this pathway is also induced in sterile inflammation such as occurs in a number of neurodegenerative diseases, including neuronopathic Gaucher disease (nGD), a lysosomal storage disorder (LSD) caused by mutations in Gba1. Mice were injected with conduritol B-epoxide, an irreversible inhibitor of acid-beta glucosidase, the enzyme defective in nGD. Quadrat deficient MyTrMaSt mice, where four adaptors of pathogen recognition receptors (PRRs) are deficient, were used to determine the role of the IFN pathway in nGD pathology. Activation of inflammatory and other pathways was analyzed by a variety of methods including RNAseq. Elevation in the expression of PRRs associated with the IFN response was observed in CBE-injected mice. Ablation of upstream pathways leading to IFN production had no therapeutic benefit on the lifespan of nGD mice but attenuated neuroinflammation. Primary and secondary pathological pathways, i.e. those associated or not with mouse lifespan, were distinguished, and a set of ~210 genes including those related to sphingolipid, cholesterol and lipoprotein metabolism, along with a number of inflammatory pathways related to chemokines, TNF, TGF, complement, IL6 and damage associated pathogens were classified as primary pathological pathways, along with some lysosomal and neuronal genes. Although IFN signaling is the top elevated pathway in nGD, we demonstrate that this pathway is not related to mouse viability and is consequently defined as a secondary pathology pathway. By elimination, we defined a number of critical pathways that are directly related to brain pathology in nGD, which in addition to its usefulness in understanding pathophysiological mechanisms may also pave the way for development of novel therapeutic paradigms by targeting such pathways.
2020-09-01 | GSE150266 | GEO
Project description:An epoxide hydrolase inhibitor reduces neuroinflammation in a mouse model of Alzheimer’s disease
| PRJNA679618 | ENA