A5073113809- Drug Transport and Resistance Mechanisms
- Drug-Induced Hepatotoxicity and Protection
- Cancer, Hypoxia, and Metabolism
- Glioma Diagnosis and Treatment
- Liver Diseases and Immunity
- Pharmacological Effects and Toxicity Studies
- Mitochondrial Function and Pathology
- Liver Disease Diagnosis and Treatment
- Galectins and Cancer Biology
- Liver physiology and pathology
- Glycosylation and Glycoproteins Research
- Endoplasmic Reticulum Stress and Disease
- Mast cells and histamine
- Epigenetics and DNA Methylation
- Pediatric Hepatobiliary Diseases and Treatments
- Genetics and Neurodevelopmental Disorders
- Cancer Research and Treatments
- Pluripotent Stem Cells Research
- Hepatitis B Virus Studies
- RNA modifications and cancer
- Alkaline Phosphatase Research Studies
- Immune cells in cancer
- Cancer, Lipids, and Metabolism
- Antibiotic Resistance in Bacteria
- Polyamine Metabolism and Applications
Centre National de la Recherche Scientifique
2022-2025
Université de Bordeaux
2024-2025
Institut de Biochimie et Génétique Cellulaires
2022-2024
Jewish General Hospital
2020-2024
uOttawa Brain and Mind Research Institute
2024
McGill University
2019-2024
University of Ottawa
2022-2024
Inserm
2009-2019
Université de Rennes
2015-2019
Centre Hospitalier Universitaire de Rennes
2019
Abstract Intrahepatic cholestasis represents a frequent manifestation of drug-induced liver injury; however, the mechanisms underlying such injuries are poorly understood. In this study human HepaRG and primary hepatocytes, we found that bile canaliculi (BC) underwent spontaneous contractions, which essential for acid (BA) efflux require alternations in myosin light chain (MLC2) phosphorylation/dephosphorylation. Short exposure to 6 cholestatic compounds revealed BC constriction dilation...
The role of hepatobiliary transporters in drug-induced liver injury remains poorly understood. Various vivo and vitro biological approaches are currently used for studying hepatic transporters; however, appropriate localization functional activity these essential normal biliary flow drug transport. Human hepatocytes (HHs) considered as the most suitable cell model but erratic availability inter-donor variations limit their use. In this work, we aimed to compare influx efflux differentiated...
Glioblastoma contains a rare population of self-renewing brain tumor stem cells (BTSCs) which are endowed with properties to proliferate, spur the growth new tumors, and at same time, evade ionizing radiation (IR) chemotherapy. However, drivers BTSC resistance therapy remain unknown. The cytokine receptor for oncostatin M (OSMR) regulates proliferation glioblastoma tumorigenesis. Here, we report our discovery mitochondrial OSMR that confers IR via regulation oxidative phosphorylation,...
Of the hepatic cell lines developed for in vitro studies of functions as alternatives to primary human hepatocytes, many have lost major liver-like functions, but not HepaRG cells. The increasing use latter worldwide raises need establishing reference functional status early biobanked Using deep proteome and secretome analyses, levels master regulators phenotype structural elements ensuring biliary polarity were found be close those hepatocytes. cells proved highly differentiated, with...
Abstract Lactate is a central metabolite in brain physiology but also contributes to tumor development. Glioblastoma (GB) the most common and malignant primary adults, recognized by angiogenic invasive growth, addition its altered metabolism. We show herein that lactate fuels GB anaplerosis replenishing tricarboxylic acid (TCA) cycle absence of glucose. dehydrogenases (LDHA LDHB), which we found spatially expressed tissues, catalyze interconversion pyruvate lactate. However, ablation both...
Alteration of bile acid (BA) profiles and secretion by cholestatic drugs represents a major clinical issue. Species differences exist in BA composition, synthesis, regulation; however presently, there is no vitro reproducible cell model to perform studies on BAs humans. We have evaluated the capacity human HepaRG line synthesize, conjugate, secrete BAs, analyzed changes content profile after cyclosporine A (CsA) treatment. Our data show that cells produced normal at daily levels comparable,...
Intrahepatic cholestasis represents 20%–40% of drug-induced injuries from which a large proportion remains unpredictable. We aimed to investigate mechanisms underlying and improve its early detection using human HepaRG cells set 12 cholestatic drugs six noncholestatic drugs. In this study, we analyzed bile canaliculi dynamics, Rho kinase (ROCK)/myosin light chain (MLCK) pathway implication, efflux inhibition taurocholate [a predominant salt export pump (BSEP) substrate], expression the major...
Histamine potentiates activation of native and recombinant <i>N</i>-methyl-d-aspartate receptors (NMDARs), but its mechanisms action physiological functions in the brain remain controversial. Using four different models, we have further investigated histamine-induced potentiation various NMDAR-mediated responses. In single cultured hippocampal neurons, histamine potentiated NMDA currents. It also NMDA-induced increase intracellular calcium absence, as well with saturating concentrations,...
Brain tumor stem cells (BTSCs) and intratumoral heterogeneity represent major challenges in glioblastoma therapy. Here, we report that the LGALS1 gene, encoding carbohydrate binding protein, galectin1, is a key regulator of BTSCs resistance to Genetic deletion alters BTSC gene expression profiles results downregulation sets associated with mesenchymal subtype glioblastoma. Using combination pharmacological genetic approaches, establish inhibition signaling impairs self-renewal, suppresses...
The penicillinase-resistant antibiotics (PRAs), especially the highly prescribed flucloxacillin, caused frequent liver injury via mechanisms that remain largely non-elucidated. We first showed independently of cytotoxicity, could exhibit cholestatic effects in human hepatocytes absence an immune reaction, were typified by dilatation bile canaliculi associated with impairment Rho-kinase signaling pathway and reduced acid efflux. Then, we analyzed sequential molecular events involved...
The plant homeodomain zinc-finger protein, PHF6, is a transcriptional regulator, and PHF6 germline mutations cause the X-linked intellectual disability (XLID) Börjeson-Forssman-Lehmann syndrome (BFLS). mechanisms by which regulates transcription how its BFLS remain poorly characterized. Here, we show genome-wide binding of in developing cortex vicinity genes involved central nervous system development neurogenesis. Characterization mice harbouring patient reveals an increase embryonic neural...
We previously reported that some <i>N</i>-methyl-d-aspartate (NMDA)-receptor antagonists enhanced histamine neuron activity in rodents. Here, we have investigated the effects of memantine, an NMDA-receptor antagonist used for treatment Alzheimer9s disease, on histaminergic neurotransmission. In vitro, memantine antagonized native NMDA receptors with a micromolar potency but had no effect at recombinant human receptors. vivo, single administration increased activity, as shown by 60% increase...
Drug-induced intrahepatic cholestasis is characterized by cellular accumulation of bile acids (BAs), whose mechanisms remain poorly understood. The present study aimed to analyze early and progressive alterations BA profiles induced cyclosporine A, chlorpromazine, troglitazone, tolcapone, trovafloxacin, tacrolimus after 4-hour, 24-hour, 6-day treatments differentiated HepaRG cells. In BA-free medium, the potent cholestatic drugs troglitazone reduced endogenous synthesis 24 hours, whereas...
Several endothelin receptor antagonists (ERAs) have been developed for the treatment of pulmonary arterial hypertension (PAH). Some them related to clinical cases hepatocellular injury (sitaxentan [SIT]) and/or cholestasis (bosentan [BOS]). We aimed determine if ambrisentan (AMB) and macitentan (MAC), in addition BOS SIT, could potentially cause liver damage man by use human HepaRG cells. Our results showed that like BOS, MAC-induced cytotoxicity cholestatic disorders characterized bile...
Drug-induced cholestasis is mostly intrahepatic and characterized by alterations of bile canaliculi dynamics morphology as well accumulation acids (BAs) in hepatocytes. However, little information exists on first changes BA content profile induced cholestatic drugs human liver. In this study, we aimed to analyze the effects a large set noncholestatic presence physiological serum concentrations 60-fold higher levels 9 main BAs cellular using HepaRG were measured cell layers (cells +...
Abstract Previous studies have shown that gut‐derived bacterial endotoxins contribute in the progression of simple steatosis to steatohepatitis, although mechanism(s) remains inaccurate date. As hepatic stellate cells (HSC) play a pivotal role accumulation excessive extracellular matrix (ECM), leading collagen deposition, fibrosis, and perpetuation inflammatory response, an vitro model was developed investigate crosstalk between HSC hepatocytes (human hepatoma cell) pretreated with...
Abstract Glioblastoma (GB) remains one of the most treatment refractory and fatal tumour in humans. GB contains a population self-renewing stem cells, brain cells (BTSC) that are highly resistant to therapy at origin relapse. Here, we report, for first time, mubritinib potently impairs stemness growth patient-derived BTSCs harboring different oncogenic mutations. Mechanistically, by employing bioenergetic assays rescue experiments, provide compelling evidence acts on complex I electron...
Abstract BACKGROUND Glioblastoma (GB) is the most aggressive tumor of central nervous system, with a median survival less than 15 months after diagnosis. The standard care consists in surgical resection followed by radio-chemotherapy. However, patients are subject to high rate recurrence, explained an enriched immune environment myeloid cells, which represent up 70% weight and have immunosuppressive and/or pro-tumoral properties. GB possesses highly invasive properties due its hypoxic acidic...