排序方式: 共有17条查询结果,搜索用时 15 毫秒
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Normand Podechard Olivier Fardel Michel Corolleur Marc Bernard Valrie Lecureur 《Toxicology in vitro》2009,23(6):1139-1144
Polycyclic aromatic hydrocarbons (PAHs) such as benzo(a)pyrene (BP) are environmental contaminants exerting various toxic effects. PAHs have notably been found to inhibit adipogenesis in rodent species. To determine whether a similar process concerns human cells, we have analyzed the effects of BP towards differentiation of human cultured mesenchymal stem cells (MSC) into adipocytes, triggered by a pro-adipogenic culture medium. BP was found to markedly prevent formation of lipid vesicles, cellular lipid accumulation and up-regulation of adipogenic markers such as fatty acid binding protein-4 and glyceraldehyde-3-phosphate dehydrogenase, which represent major hallmarks of human MSC-derived adipocytes. The aryl hydrocarbon receptor (AhR), known to mediate most of the toxic effects of PAHs, was demonstrated to be present and functional in human MSC. 2,3,7,8-tetrachlorodibenzo-p-dioxin, an AhR agonist like BP, was found to inhibit lipid accumulation in human MSC cultured with adipogenic medium, in contrast to the PAH benzo(e)pyrene, known to not, or only poorly, interact with AhR. Moreover, BP inhibitory effect toward lipid accumulation in MSC exposed to adipogenic medium was fully counteracted by co-treatment with the AhR antagonist α-naphtoflavone. Taken together, these data indicate that environmental PAHs like BP can likely inhibit human adipogenesis in an AhR-dependent manner. 相似文献
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Fardel O Payen L Sparfel L Vernhet L Lecureur V 《Annales pharmaceutiques fran?aises》2002,60(6):380-385
Membrane transport proteins play a major role in hepato-biliary secretion of xenobiotics. Some of them, especially OATPs and OCT1, are present at the vascular pole of hepatocytes and mediate uptake of xenobiotics into parenchymal liver cells from blood whereas others, such as P-glycoprotein and MRP2, are ABC transporters present at the canalicular domain of hepatocytes and responsible for the transmembrane passage into bile of drugs or their metabolites. Many endogenous or exogenous factors, including drug metabolizing enzyme inducers, alter expression of hepatic transporters whose activity can moreover be inhibited by various structurally-unrelated compounds. Such changes of expression and/or activity of membrane transport proteins may contribute to some drug interactions. 相似文献
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Podechard N Tekpli X Catheline D Holme JA Rioux V Legrand P Rialland M Fardel O Lagadic-Gossmann D Lecureur V 《Toxicology letters》2011,206(3):289-299
1-Nitropyrene (1-NP) is a nitro-polycyclic aromatic hydrocarbon (nitro-PAH) present in diesel exhaust and bound to particular matter in urban air. We show that 1-NP and the referent PAH benzo(a)pyrene (BP) induce apoptosis and a lipid accumulation dependent on cytochrome P450 1A1-metabolites in mouse hepatoma cells, whereas 1-amino-pyrene had no effect. The caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp(O-Me) fluoromethyl ketone (Z-VAD-fmk), inhibits 1-NP-induced apoptosis, but failed to alter 1-NP-triggered lipid accumulation determined by Nile red staining. We further show that cholesterol and fatty acid contents are modified after nitro-PAH exposure and that 1-NP-induced cholesterol level is partially involved in related apoptosis. In parallel, the activity of the stearoyl-CoA desaturase 1 (SCD1), determined by fatty acid analysis, and its expression are reduced by 1-NP. The role of SCD1 in 1-NP-induced apoptosis is demonstrated in cells down-expressing SCD1, in which an increased apoptosis is observed, whereas the SCD1 overexpression elicits the opposite effects. In contrast, changes in SCD1 gene expression have no effect on the induced lipid accumulation. Moreover, 1-NP increases the activity of the AMP-dependent protein kinase (AMPK) leading to a caspase-independent apoptosis. Overall, our study demonstrates that the 1-NP-induced apoptosis is caspase- and AMPK-dependent, and is associated to a decrease of SCD1 expression which results in an alteration of lipid homeostasis. 相似文献
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Potassium antimonyl tartrate induces reactive oxygen species-related apoptosis in human myeloid leukemic HL60 cells 总被引:5,自引:0,他引:5
Potassium antimonyl tartrate (PAT), like arsenic trioxide (As2O3), has recently been shown to exert cytotoxicity towards acute promyelocytic leukemia (APL) cells. In the present study, we demonstrated that PAT treatment also inhibited cell growth of four acute myeloid leukemia (AML) cell lines, i.e., HL60, K562, KG1a and U937, that do not derive from APL. PAT, like As2O3, was further shown to induce apoptosis in HL60 cells as assessed by Hoechst 33342 staining and microscopical detection. Such an apoptotic process was associated with loss of mitochondrial potential and enhanced cellular production of reactive oxygen-related species; it was potentiated by co-treatment with buthionine sulfoximine, a pro-oxidant compound acting through inhibition of glutathione synthesis, and abolished in response to the antioxidant N-acetylcysteine, thus outlining that the toxicity of PAT, similarly to that of As2O3, is modulated by the cellular redox status. Pan-caspase inhibitors failed to inhibit PAT-triggered apoptosis of HL60 cells whereas they fully blocked that linked to As2O3, suggesting that PAT, unlike As2O3, does not require caspase activity for inducing apoptosis. PAT and As2O3 also differently affected intracellular pH, a key parameter commonly altered during apoptotic processes. Such data therefore indicate that PAT can exert cytotoxicity towards AML cells not deriving from APL such as HL60 cells, through inducing an apoptotic process which exhibits some similarities and some differences with that triggered by As2O3. 相似文献
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Cloning and expression of murine sister of P-glycoprotein reveals a more discriminating transporter than MDR1/P-glycoprotein 总被引:3,自引:0,他引:3
Lecureur V Sun D Hargrove P Schuetz EG Kim RB Lan LB Schuetz JD 《Molecular pharmacology》2000,57(1):24-35
Sister of P-glycoprotein (SPGP), a novel murine cDNA and member of the ATP-binding cassette superfamily highly homologous to P-glycoprotein (Pgp), was cloned. Moreover, its genomic clone was isolated and localized to chromosome 2 by fluorescence in situ hybridization. SPGP was functionally evaluated relative to MDR1 after subcloning SPGP cDNA into a retroviral bicistronic vector capable of expressing both SPGP and the green fluorescent protein. LLC-PK1 and MDCKII cells were transduced with this retrovirus and SPGP-positive clones were isolated. Drug uptake and efflux was compared in cells ectopically expressing either SPGP or human MDR1. SPGP cells had decreased uptake of taurocholate and vinblastine compared with LLC-PK1 cells. Additional studies revealed that vinblastine efflux was accelerated by SPGP compared with LLC-PK1. Further comparison revealed that although MDR1 easily impaired uptake of vincristine, daunomycin, paclitaxel, and digoxin, SPGP had no effect on uptake of these drugs. However, further studies demonstrated that, like MDR1, SPGP effluxed calcein-acetoxymethyl ester (AM). Unlike MDR1, SPGP was incapable of effluxing rhodamine 123. Although cyclosporine A and reserpine blocked calcein-AM transport by MDR1, these drugs had either minimal or no effect, respectively, on blocking SPGP efflux of calcein-AM. In contrast, ditekiren, a linear hexapeptide, readily and preferentially inhibited SPGP efflux of calcein-AM. Further studies with three structural analogs of ditekiren revealed that one analog inhibited SPGP efflux of calcein-AM, although not as potently as ditekiren. These are the first studies to reveal that SPGP has distinct transport properties compared with MDR1. 相似文献
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Podechard N Lecureur V Le Ferrec E Guenon I Sparfel L Gilot D Gordon JR Lagente V Fardel O 《Toxicology letters》2008,177(2):130-137
Benzo(a)pyrene (BP) is an environmental contaminant known to favor airway inflammation likely through up-regulation of pro-inflammatory cytokines. The present study was designed to characterize its effects toward interleukin-8 (IL-8), a well-established pulmonary inflammatory cytokine. In primary human macrophages, BP was shown to induce IL-8 expression at both mRNA and secretion levels in a dose-dependent manner. Such an up-regulation was likely linked to aryl hydrocarbon receptor (AhR)-activation since BP-mediated IL-8 induction was reduced after AhR expression knock-down through RNA interference. Moreover, electrophoretic mobility shift assays (EMSAs) and chromatin immunoprecipitation experiments showed BP-triggered binding of AhR to a consensus xenobiotic responsive element (XRE) found in the human IL-8 promoter. Finally, BP administration to mice led to over-expression of keratinocyte chemoattractant (KC), the murine functional homologue of IL-8, in lung. It also triggered the recruitment of neutrophils in bronchoalveolar lavage (BAL) fluids, which was however fully abolished in the presence of a chemical antagonist of the KC/IL-8 receptors CXCR1/CXCR2, thus supporting the functional and crucial involvement of KC in BP-induced lung inflammation. Overall, these data highlight an AhR-dependent regulation of IL-8 in response to BP that likely contributes to the airway inflammatory effects of this environmental chemical. 相似文献
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Inflammation Research - To determine whether inflammatory hepatocytes may constitute primary targets for ruxolitinib, a Janus kinase (JAK) inhibitor, its effects towards expression of hepatic... 相似文献