A5050962059- Pharmacogenetics and Drug Metabolism
- Gene expression and cancer classification
- Drug Transport and Resistance Mechanisms
- Drug-Induced Hepatotoxicity and Protection
- Computational Drug Discovery Methods
- Molecular Biology Techniques and Applications
- Liver physiology and pathology
- 3D Printing in Biomedical Research
- bioluminescence and chemiluminescence research
- Liver Disease Diagnosis and Treatment
- Carcinogens and Genotoxicity Assessment
- Alcohol Consumption and Health Effects
- Mitochondrial Function and Pathology
- RNA Research and Splicing
- Diet, Metabolism, and Disease
- Peroxisome Proliferator-Activated Receptors
- thermodynamics and calorimetric analyses
- Adipose Tissue and Metabolism
- Eicosanoids and Hypertension Pharmacology
- RNA Interference and Gene Delivery
- Metabolomics and Mass Spectrometry Studies
- Animal testing and alternatives
- DNA and Nucleic Acid Chemistry
- Immune Response and Inflammation
- Pharmacological Receptor Mechanisms and Effects
Roche (Switzerland)
2010-2024
Roche (China)
2018
Drug Safety Research Unit
2004
École Polytechnique Fédérale de Lausanne
1998-2000
University of Zurich
1997-1998
Abstract Carbapenem-resistant Acinetobacter baumannii (CRAB) has emerged as a major global pathogen with limited treatment options 1 . No new antibiotic chemical class activity against A. reached patients in over 50 years Here we report the identification and optimization of tethered macrocyclic peptide (MCP) antibiotics potent antibacterial CRAB. The mechanism action this molecule involves blocking transport bacterial lipopolysaccharide from inner membrane to its destination on outer...
Microarray technology allows the simultaneous analysis of mRNA expression levels thousands genes. In field toxicogenomics, this could help to identify potentially unsafe compounds based on changes in patterns they induce. Rodent vivo and vitro systems are currently experimental models choice for predictive toxicology, especially early phases development. This study characterizes several hepatic profiles, comparing them gene liver tissue. The investigated comprise two rat cell lines (BRL3A...
Male rats were treated with various model compounds or the appropriate vehicle controls. Most substances either well-known hepatotoxicants showed hepatotoxicity during preclinical testing. The aim of present study was to determine if biological samples from can be classified based on gene expression profiles. In addition analysis using microarrays, a complete serum chemistry profile and liver kidney histopathology performed. We analyzed hepatic profiles supervised learning method (support...
Currently used hepatocyte cell systems for in vitro assessment of drug metabolism include hepatoma lines and primary human (PHH) cultures. We investigated the suit-ability validated vivo Basel phenotyping cocktail (caffeine [CYP1A2], efavirenz [CYP2B6], losartan [CYP2C9], omeprazole [CYP2C19], metoprolol [CYP2D6], midazolam [CYP3A4]) characterized four (HepG2 cells, HepaRG cryopreserved hepatocytes 2-dimensional [2D] culture or 3D-spheroid co-culture) regarding basal CYP inducibility. Under...
Phytanic acid, a metabolite of the chlorophyll molecule, is part human diet and present in normal serum at low micromolar concentrations. It was previously shown to be ligand 9-cis-retinoic acid receptor peroxisome proliferator-activated (PPAR) a. PPAR agonists are widely used treatment type 2 diabetes. Here, we report that phytanic not only transactivator PPARa, but it also acts via PPARb PPARg CV-1 cells have been cotransfected with respective full-length an acyl-CoA...
Recent evidence suggests that macrophages and/or other nonparenchymal cells may release important mediators contributing to the hepatic necrosis induced by high doses of acetaminophen (APAP). The nature and causative role these has remained elusive, however. To investigate proinflammatory cytokine, tumor factor (TNF) in initiation early propagation APAP-induced liver injury, we have used mice deficient both TNF closely related lymphotoxin-alpha (LT-alpha). Male TNF/LT-alpha knockout C57BL/6...
Male rats were treated with various model compounds or the appropriate vehicle controls. Most substances either well-known hepatotoxicants showed hepatotoxicity during preclinical testing. The aim of present study was to determine if biological samples from can be classified based on gene expression profiles. In addition analysis using microarrays, a complete serum chemistry profile and liver kidney histopathology performed. We analyzed hepatic profiles supervised learning method (support...
Abstract The impact of the surface‐active formulation ingredients Cremophor EL, Tween 80 and Solutol HS 15 on intrinsic clearance ( Cl int ) midazolam (MDZ) was investigated in rat hepatocytes microsomes. In with 0.003%, 0.03% 0.3% (w/v) already present incubation medium, significantly reduced a dose‐dependent manner by about 25%, 30% 50%, respectively. presence EL significant reduction respectively, observed at surfactant concentration. At 80, 50% 20%, A also experiments liver...
Single stranded oligonucleotides (SSO) represent a novel therapeutic modality that opens new space to address previously undruggable targets. In spite of their proven efficacy, the development promising SSO drug candidates has been limited by reported cases SSO-associated hepatotoxicity. The mechanisms induced liver toxicity are poorly understood, and up now no preclinical in vitro model established allows prediction hepatotoxicity risk given SSO. Therefore, assessment hepatic liability...
The phenotype of a living cell is determined by its pattern active signaling networks, giving rise to "molecular phenotype" associated with differential gene expression. Digital amplicon based RNA quantification sequencing useful technology for molecular phenotyping as novel tool characterize the state biological systems.We show here that activity networks can be assessed on set established key regulators and expression targets rather than entire transcriptome. We compiled panel 917 human...
Glucagon-like peptide 1 (GLP1) analogs have been associated with an increased incidence of thyroid C-cell hyperplasia and tumors in rodents. This effect may be due to a GLP1 receptor (GLP1R)-dependent mechanism. As the expression GLP1R is much lower primates than rodents, described proliferative lesions not relevant man. Here, we aimed establish primary cell cultures rat human evaluate function C-cells. In our experiments, was observed C-cells ( situ hybridization) but detected (mRNA protein...
Genomics technologies are used in several disciplines, including toxicology. However, these relatively new, and their applications require further investigations. When investigators apply to vitro experiments, two major issues need be clarified: a) can toxicity studies, combination with genomics analyses, predict the of a compound; b) generated toxicogenomics data reproducible between laboratories? These questions were addressed by an interlaboratory study laboratories four pharmaceutical...
We have analyzed gene expression and histopathology of rat liver treated with a histamine-3 receptor inverse agonist under development for the treatment obesity 24 h after single acute administration. While did not identify clear toxicity, analysis changes strongly suggested toxicity. This prediction was confirmed in 2-week repeat-dose study where prominent pathology occurred, while that lead to persisted. A subset these genes vitro both human hepatocytes reveal potential relevancy findings...
Long-term in vitro liver models are now widely explored for human hepatic metabolic clearance prediction, enzyme phenotyping, cross-species metabolism, comparison of low drugs, and induction studies. Here, we present studies using a long-term model, which show how metabolism active transport, drug-drug interactions, healthy diseased states, such as hepatitis B virus (HBV) infection, may be assessed single test system to enable effective data integration physiologically based pharmacokinetic...