A5082118776- Pharmacogenetics and Drug Metabolism
- Metabolomics and Mass Spectrometry Studies
- Computational Drug Discovery Methods
- Hormonal Regulation and Hypertension
- Animal testing and alternatives
- Inhalation and Respiratory Drug Delivery
- Thyroid Disorders and Treatments
- Estrogen and related hormone effects
- Effects and risks of endocrine disrupting chemicals
- Zebrafish Biomedical Research Applications
- Environmental Toxicology and Ecotoxicology
- Drug-Induced Hepatotoxicity and Protection
- Vitamin K Research Studies
- Aerosol Filtration and Electrostatic Precipitation
- Pregnancy and preeclampsia studies
- Pesticide Residue Analysis and Safety
- 3D Printing in Biomedical Research
- Renin-Angiotensin System Studies
- Birth, Development, and Health
- Cancer, Hypoxia, and Metabolism
- Protein Degradation and Inhibitors
- Selenium in Biological Systems
- Liver physiology and pathology
- Immunotoxicology and immune responses
- Chemical Safety and Risk Management
BASF (Germany)
2017-2024
BASF (United States)
2022
Robert Bosch (Germany)
2019-2020
University of Tübingen
2007-2010
Saarland University
2008-2009
Roche (Switzerland)
1997
The establishment of reliable and robust in vitro models for hazard assessment, a prerequisite moving away from animal testing, requires the evaluation model transferability reproducibility. Lung that can be exposed via air, by means an air-liquid interface (ALI) are promising evaluating safety nanomaterials (NMs) after inhalation exposure. We performed inter-laboratory comparison study to evaluate reproducibility lung consisting human bronchial cell line Calu-3 as monoculture and, increase...
17β-Estradiol (E2), the most potent female sex hormone, stimulates growth of mammary tumors and endometriosis via activation estrogen receptor α (ERα). 17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1), which is responsible for catalytic reduction weakly active estrone (E1) into E2, therefore discussed as a novel drug target. Recently, we have discovered 2,5-bis(hydroxyphenyl) oxazole to be inhibitor 17β-HSD1. In this paper, further structural optimizations were performed: 39...
While in vitro testing is used to identify hazards of chemicals, nominal assay concentrations may misrepresent potential vivo effects and do not provide dose–response data which can be for a risk assessment. We reverse dosimetry compare effect concentrations-to-in doses causing toxic related endocrine disruption. Ten compounds (acetaminophen, bisphenol A, caffeine, 17α-ethinylestradiol, fenarimol, flutamide, genistein, ketoconazole, methyltestosterone, trenbolone) have been tested the yeast...
Pyridine substituted naphthalenes (e.g., I-III) constitute a class of potent inhibitors aldosterone synthase (CYP11B2). To overcome the unwanted inhibition hepatic enzyme CYP1A2, we aimed at reducing number aromatic carbons these molecules because aromaticity has previously been identified to correlate positively with CYP1A2 inhibition. As hypothesized, tetrahydronaphthalene type molecular scaffold (1-11) exhibit decreased However, tetralone 9 turned out be cytotoxic human cell line U-937...
17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is responsible for the catalytic reduction of weakly active E1 to highly potent E2. E2 stimulates proliferation hormone-dependent diseases via activation estrogen receptor α (ERα). Because overexpression 17β-HSD1 in mammary tumors, this enzyme should be an attractive target treatment estrogen-dependent pathologies. Recently, we have reported on a series inhibitors: bis(hydroxyphenyl) azoles, thiophenes, and benzenes. In paper, different...
Disturbance of the thyroid hormone homeostasis has been associated with adverse health effects such as goiters and impaired mental development in humans tumors rats. In vitro silico methods for predicting small molecules on are currently being explored alternatives to animal experiments, but still an early stage development. The aim this work was a battery models set targets involved molecular initiating events homeostasis: deiodinases 1, 2, 3, peroxidase (TPO), receptor (TR), sodium/iodide...
The European Partnership for Alternative Approaches to Animal Testing (EPAA) convened a 'Blue Sky Workshop' on new ideas non-animal approaches predict repeated-dose systemic toxicity. aim of the Workshop was formulate strategic improve and increase applicability, implementation acceptance modern methods determine concluded that good progress is being made assess repeated dose toxicity without animals taking advantage existing knowledge in toxicology, thresholds toxicological concern, adverse...
Air-liquid interface (ALI) lung cell models cultured on permeable transwell inserts are increasingly used for respiratory hazard assessment requiring controlled aerosolization and deposition of any material ALI cells. The approach presented herein aimed to assess the insert-delivered dose aerosolized materials using VITROCELL® Cloud12 system, a commercially available aerosol-cell exposure system. An inter-laboratory comparison study was conducted with seven European partners having different...
Recently, we reported on the development of potent and selective inhibitors aldosterone synthase (CYP11B2) for treatment congestive heart failure myocardial fibrosis. A major drawback these nonsteroidal compounds was a strong inhibition hepatic drug-metabolizing enzyme CYP1A2. In present study, examined influence substituents in heterocycle lead structures with naphthalene molecular scaffold to overcome this unwanted side effect. With respect CYP11B2 inhibition, some induced dramatic...
The European Partnership for Alternative Approaches to Animal Testing (EPAA) convened a Partners' Forum Toxicokinetics and Read-Across provide an overview on research activities develop in vitro toxicokinetics methods physiologically-based kinetic (PBK) models find synergies enhance use of toxicokinetic data strengthen read-across. Currently, lacking often prevent the application Preferably, should be generated using silico tools anchored towards human relevance. In certain sectors, PBK...
Since 2020, the REACh regulation requires toxicological data on nanoforms of materials, including assessment their skin-sensitizing properties. Small molecules’ skin sensitization potential can be assessed by new approach methodologies (NAMs) addressing three key events (KE: protein interaction, activation dendritic cells, and keratinocytes) combined in a defined (DA) described OECD guideline 497. In present study, applicability NAMs (DPRA, LuSens, h-CLAT) to nine materials (eight inorganic...
A crucial component of a substance registration and regulation is the evaluation human prenatal developmental toxicity. Current toxicological tests are based on mammalian models, but these costly, time consuming may pose ethical concerns. The zebrafish embryo has evolved as promising alternative model to study However, implementation embryotoxicity test challenged by lacking information relevance observed morphological alterations in fish for Elucidating mechanism toxicity could help...
Abstract Angiogenesis is a key process in embryonic development, disruption of this can lead to severe developmental defects, such as limb malformations. The identification molecular perturbations representative antiangiogenesis zebrafish embryo (ZFE) may guide the assessment toxicity from an endpoint- mechanism-based approach, thereby improving extrapolation findings humans. Thus, aim study was discover changes characteristic and toxicity. We exposed ZFEs two antiangiogenic drugs (SU4312,...
There is a need for paradigm change in the methodology employed toxicological testing and assessment. It could be said that this well on its way, through an evolutionary progress analogous to of natural selection. Darwin’s Theory Evolution has defined idea evolution descendancy since last third 19th century. Increasingly, concept ‘evolution’ being applied beyond field biology. This Comment article discusses context ‘evolutionary pressure’ deliberates how process can help foster development,...
Introduction: Identifying substances which can disturb thyroid hormone (TH) signaling pathways is gaining importance and soon to be a regulatory requirement in the EU. The European Commission Joint Research Centre's (EC JRC) Union Reference Laboratory for alternatives animal testing (EURL ECVAM) coordinating validation of multiple vitro methods focusing on different modes action (MoA) resulting an test battery. Deiodinases (DIO) are regulators TH by activating or inactivating via...
Cell-based metabolomics provides multiparametric physiologically relevant readouts that can be highly advantageous for improved, biologically based decision making in early stages of compound development. Here, we present the development a 96-well plate LC-MS/MS-based targeted screening platform classification liver toxicity modes action (MoAs) HepG2 cells. Different parameters workflow (cell seeding density, passage number, cytotoxicity testing, sample preparation, metabolite extraction,...
Introduction: The European Union Reference Laboratory for alternatives to animal testing (EU RL ECVAM) coordinates the validation of multiple thyroid in vitro assays aiming set up an test battery. consists two independent parts: part 1 (Reproducibility assessment) which reproducibility method is evaluated by a small number described inhibitors and 2 (Predictivity where predictivity investigated blinded substances. deiodinases (DIO) are important regulators hormone (TH) metabolism potential...
Abstract Omics techniques have been increasingly recognized as promising tools for Next Generation Risk Assessment. Targeted metabolomics offer the advantage of providing readily interpretable mechanistic information about perturbed biological pathways. In this study, a high-throughput LC–MS/MS-based broad targeted system was applied to study nitrofurantoin metabolic dynamics over time and concentration provide mechanistic-anchored approach point departure (PoD) derivation. Upon exposure at...