Refine
Has Fulltext
- yes (293)
Is part of the Bibliography
- yes (293)
Year of publication
Document Type
- Journal article (220)
- Doctoral Thesis (50)
- Book article / Book chapter (14)
- Conference Proceeding (6)
- Review (2)
- Preprint (1)
Language
- English (293) (remove)
Keywords
- Toxikologie (119)
- DNA damage (15)
- Adenosine receptors (9)
- Adenosinrezeptor (8)
- oxidative stress (7)
- DNS-Schädigung (6)
- GPCR (6)
- Genotoxicity (6)
- DNA (5)
- DNA binding (5)
- G-Protein gekoppelte Rezeptoren (5)
- Micronuclei (5)
- Pharmakologie (5)
- Adenylate cyclase (4)
- FRET (4)
- Fluoreszenz-Resonanz-Energie-Transfer (4)
- G proteins (4)
- Medizin (4)
- Oxidativer Stress (4)
- micronuclei (4)
- mycotoxin (4)
- 1 (3)
- Biotransformation (3)
- Carcinogen (3)
- Carcinogenesis (3)
- Carcinogenicity (3)
- Carcinogens (3)
- DNA-Schaden (3)
- ERK1/2 (3)
- Enzyme induction (3)
- Ernährung (3)
- G protein-coupled receptors (3)
- Pneumolysin (3)
- apoptosis (3)
- cAMP (3)
- cytoskeleton (3)
- genotoxicity (3)
- heart failure (3)
- inflammation (3)
- liver (3)
- metabolism (3)
- nephrotoxicity (3)
- signal transduction (3)
- transcription factors (3)
- 18F-FDG (2)
- 5-Azacytidine (2)
- A1 adenosine receptors (2)
- Adenosin (2)
- Adrenerger Rezeptor (2)
- Aldosteron (2)
- Ames test (2)
- Angiotensin II (2)
- Bakteriengift (2)
- Benzene (2)
- Carcinogenität (2)
- DNA Binding (2)
- DNA Schaden (2)
- DNA repair (2)
- Diethylstilbestrol (2)
- Dose response (2)
- Dose-response relationship (2)
- Electropermeabilization (2)
- Estrogen (2)
- FCS (2)
- Förster Resonanz Energie Transfer (2)
- G-Protein gekoppelter Rezeptor (2)
- G-protein (2)
- Genotoxizität (2)
- HPLC-MS (2)
- Herzhypertrophie (2)
- Hirnhautentzündung (2)
- Hormone (2)
- In vitro (2)
- Inhalation (2)
- Insulin (2)
- Kleinkern (2)
- Leber (2)
- Meningitis (2)
- Micronucleus (2)
- Muscarinrezeptor (2)
- Mutagenität (2)
- Myokarditis (2)
- N-formyl peptides (2)
- Niere (2)
- PET (2)
- Pharmakokinetik (2)
- Pharmazie (2)
- QIVIVE (2)
- RKIP (2)
- Radioligand binding (2)
- Rat (2)
- Reproductive toxicity (2)
- Risk Assessment (2)
- Salmonella/microsome assay (2)
- Silicones (2)
- Toxicology (2)
- Toxin (2)
- actin (2)
- actinomycetes (2)
- adenosine receptors (2)
- aldosterone (2)
- barbiturates (2)
- biased signaling (2)
- binding (2)
- biomedicine, general (2)
- cGMP (2)
- calcium (2)
- cancer risk (2)
- carcinogen (2)
- carcinogenicity (2)
- cardiac hypertrophy (2)
- cell biology (2)
- comet assay (2)
- cytokinins (2)
- dialysis (2)
- differentiation (2)
- environmental health (2)
- familial DCM (2)
- fluorescence (2)
- fluorescence resonance energy transfer (2)
- genomic damage (2)
- heart (2)
- iPSC-cardiomyocytes (2)
- immunohistochemistry (2)
- in-vivo (2)
- insulin (2)
- kidneys (2)
- lymphocytes (2)
- mast cells (2)
- medicine (2)
- membrane skeleton (2)
- meningitis (2)
- mercapturic acid (2)
- mutagenicity (2)
- myocarditis (2)
- occupational medicine/industrial medicine (2)
- pharmacogenetics (2)
- pharmacokinetics (2)
- pharmacology/toxicology (2)
- phosphorylation (2)
- pneumolysin (2)
- positron emission tomography (2)
- rat brain membranes (2)
- receptors (2)
- resveratrol (2)
- risk assessment (2)
- therapy (2)
- toxicity (2)
- uremic toxins (2)
- vitamin B6 (2)
- yam (2)
- (Mouse L-cell) (1)
- (Rat brain membrane) (1)
- (Rat liver) (1)
- (Salmonella) (1)
- 1H-NMR-Spectroscopy (1)
- 2 (1)
- 2',7'-dichlorofluorescin (1)
- 2-Acetylaminofluorene (1)
- 2-Dichloroethane (1)
- 2-Dioxetane (1)
- 2-Generation reproduction (1)
- 2-acetylaminofluorene (1)
- 3 (1)
- 3-pentafluoropropene (1)
- 3-tetrafluoropropene (1)
- 3R (1)
- 4'-hydroxylation (1)
- 4-(p-nitrobenzyl)pyridine (1)
- 6-benzylaminopurine (1)
- 7,8-dihydroxyflavone (7,8-DHF) (1)
- 8-Hydroxy-deoxyguanosine (1)
- A(2B) receptors (1)
- A1 (1)
- A1 Adenosine receptors (1)
- A2B adenosine receptor (1)
- A2BAR (1)
- A<sub>2</sub> Adenosine receptor (1)
- AMPK (1)
- API-Massenspektrometrie (1)
- AUM (1)
- A\(_{2A}\) adenosine receptor antagonist (1)
- Acetylcysteinderivate (1)
- Acrylamid (1)
- Acrylamide (1)
- Actin (1)
- Actin cytoskeleton (1)
- Adenosine receptor (1)
- Adenosine receptor antagonists (1)
- Adrenergic receptor (1)
- Adverse outcome pathway (AOP) (1)
- Aflatoxin (1)
- Aflatoxin B1 (1)
- Aldosteronantagonist (1)
- Alkylation (1)
- Alzheimers disease (1)
- Amino acid composition (1)
- Amino acids (1)
- Aminosäuren (1)
- Anabolieagent (1)
- Angiotensin-II-Blocker (1)
- Angst (1)
- Aniline derivatives (1)
- Animal model (1)
- Anthocyane (1)
- Anthraquinone glycosides (1)
- Antibodies (1)
- Antikörper (1)
- Anxiety (1)
- Apoptose (1)
- Apoptosis (1)
- Aryl hydrocarbon rnonooxygenase (1)
- Astrozyt (1)
- Atria (1)
- Aufmerksamkeits-Defizit-Syndrom (1)
- Autofocus (1)
- Azole (1)
- Azoles (1)
- B cells (1)
- BETA(2)-adrenergic receptor (1)
- BRET (1)
- Background DNA damage (1)
- Bacterial Toxins (1)
- Bacterial meningitis (1)
- Bakterielle Hirnhautentzündung (1)
- Bakterien (1)
- Barbiturat (1)
- Barbiturates (1)
- Barth syndrome (1)
- Bcl-2 (1)
- Benfotiamin (1)
- Benzefuran dioxetane (1)
- Benzefuran epoxide (1)
- Benzo(a)pyrene-DNA binding (1)
- Berenil (1)
- Beta(1)-adrenergic receptor (1)
- Beta(2)-adrenergic receptor (1)
- Beta-1-Rezeptor (1)
- Beta-1-receptor (1)
- Beta-Adrenergic Receptor (1)
- Beta-Adrenozeptor (1)
- Bioluminescence resonance energy transfer (1)
- Biomarker (1)
- Biomarkers (1)
- Biosensor (1)
- Bisphenol A (1)
- Bromodeoxyuridine labeling (1)
- Brustkrebs (1)
- C1q/TNF related protein (CTRP) (1)
- CAMP production (1)
- CFC replacements (1)
- CIB1 (1)
- CRISPR Cas9 (1)
- CRISPR/Cas9 (1)
- CXCR4 (1)
- CYP19 (1)
- CYP51 (1)
- CaMKII (1)
- Calcium (1)
- Cancer prevention (1)
- Carcinogen risk Individual susceptibili (1)
- Carcinogenic potency (1)
- Cardiac myocyte ; Beta-Receptor ; Muscarinic receptor ; cAMP ; G-protein ; Serum (1)
- Cardiomyocyte (1)
- Cell adhesion (1)
- Cell death and comet assay (1)
- Cell transformation (1)
- Chemical carcinogenesis (1)
- Chemokine (1)
- Chemokine receptors (1)
- Chemotactic receptors (1)
- Chlorfluorkohlenstoffe (1)
- Choline deficiency (1)
- Cholinesteraseinhibitor (1)
- Chromosome aberration (1)
- Chromosome distribution (1)
- Chronic heart-failure (1)
- Clonidin (1)
- Colon cancer (1)
- Comet Assay (1)
- Comet assay (1)
- Covalent DNA binding (1)
- Covalent binding (1)
- Covalent binding index (1)
- Covalent binding index - Diethylstilbestrol (1)
- Cyclic AMP (1)
- Cyclo-AMP (1)
- Cyclo-GMP (1)
- Cytochrom P450 (1)
- Cytochrome b5 (1)
- Cytologie (1)
- DAMGO (1)
- DCM genetic background (1)
- DES (1)
- DNA Damage (1)
- DNA adduct . Repair endonuclease (1)
- DNA adducts (1)
- DNA binching (1)
- DNA damage response (1)
- DNA metabolism (1)
- DNA methylation (1)
- DNA transfection (1)
- DNA-Addukte (1)
- DNS-Bindung (1)
- DNS-Strangbruch (1)
- Depression (1)
- Dermatologie (1)
- Di (1)
- Dietary process-related contaminants (1)
- Diisononyl phthalate (1)
- Dilated cardiomyopathy (1)
- Dioscorea (1)
- Dose response relationships (1)
- Dosis-Wirkungs-Beziehung (1)
- Drug resistance (1)
- Dualstere Liganden (1)
- Dualsteric Ligands (1)
- ERK signaling (1)
- ERK-Kaskade (1)
- ERK-cascade (1)
- Electric Field (1)
- Electrical breakdown (1)
- Electrophiles (1)
- Elektrofusion (1)
- Elektroporation (1)
- Emodin (1)
- Endogenous genotoxicity (1)
- Entzündung (1)
- Epoxide hydrolase (1)
- Erk1/2 (1)
- Ersatzstoff (1)
- Estrone (1)
- Ethionine (1)
- Eukaryotic cell (1)
- Excitotoxicity (1)
- External exposure assessment (1)
- Extrakorporale Dialyse (1)
- FCKW-Ersatzstoffe (1)
- FPG protein (1)
- FRET sensors (1)
- Fabry Disease (FD) (1)
- Fischer 344 rats (1)
- Flow cytometry (1)
- Fluorescence (1)
- Fluorescence Correlation Spectroscopy (1)
- Fluorescence Microscopy (1)
- Fluorescence resonance energy transfer (1)
- Fluorescence-resonance-energy-transfer (1)
- Fluoreszenz (1)
- Fluoreszenzkorrelationsspektroskopie (1)
- Fluoreszenzmikroskopie (1)
- Fluorkohlenwasserstoffe (1)
- Fluoxetin (1)
- Fluoxetine (1)
- Friedreich’s ataxia (1)
- Fumonisin B1 (1)
- Fumonisine (1)
- Fungizid (1)
- Furan (1)
- Förster Resonance Energy Transfer (1)
- G Protein-Coupled Receptor (1)
- G protein coupled receptor (1)
- G protein coupled receptor (GPCR) (1)
- G protein-coupled receptor (1)
- G protein-coupled receptor kinase (1)
- G-protein coupled receptor (1)
- G-protein-coupled receptors (1)
- GABA-receptor complex (1)
- GC-MS (1)
- GC/MS (1)
- GPCR dimerisation (1)
- GPCR signaling (1)
- GPCRs (1)
- GTP-bindende Proteine (1)
- Gastric carcinogenesis (1)
- Gb3 and lyso-Gb3 biomarkers (1)
- Gene Transfer (1)
- Gene transfer (1)
- Genetic instability (1)
- Genomschaden (1)
- Genotyp (1)
- Gentoxikologie (1)
- Glutathion S-Konjugat (1)
- Glutathione Stransferase (1)
- Guanin Nukleotid Austauschfaktor (1)
- Guaninnucleotid-Austauschfaktoren (1)
- Guanylatcyclase (1)
- HCN channel (1)
- HCN-Kanal (1)
- HFC245fa (1)
- HIV (1)
- HIV infection (1)
- HPLC-MS/MS method (1)
- HeLa cells (1)
- Heart failure (1)
- Hemmung der Proliferation schnell wachsender Krebszellen (1)
- Herpesviren (1)
- High-thropughput screening (1)
- High-throughput screening (1)
- Hintergrund-DNA-Schaden (1)
- Hochdurchsatz-Screening (1)
- Hoechst 33258 dye (1)
- Homocystein (1)
- Hsp90 (1)
- Human platelets (1)
- Hybridoma (1)
- Häm (1)
- I1 Imidazolin Bindungsstelle (1)
- I1 imidazoline binding site (1)
- Immunization (1)
- Immunologie (1)
- In vitro testing (1)
- In vitro toxicity testing (1)
- In vivo (1)
- In-silico Modell (1)
- Inflammation (1)
- Inhibition (1)
- Ischemia/reperfusion (1)
- K + -channels (1)
- Kanzerogenese (1)
- Kardiomyozyt (1)
- Kidneys (1)
- Kinetochore (1)
- Kinetochores (1)
- Knockout (1)
- Kongestive Herzmuskelkrankheit (1)
- Krebs (1)
- Krebs <Medizin> (1)
- L5178Y cells (1)
- LC-MS (1)
- LC-MS/MS (1)
- LTB4 receptor (1)
- Latrophilin (1)
- Leukocyte/endothelium interaction (1)
- Ligand <Biochemie> (1)
- Lung (1)
- MAP-Kinase (1)
- MMQ cells (1)
- Magenkrebs (1)
- MammaJian mutagenicity test (1)
- Massenspektrometrie (1)
- Mastzelle (1)
- Maus (1)
- Mechanism of action (1)
- Melanocortin 4 receptor (MC4R) (1)
- Melanocyte stimulating hormones MSH (1)
- Merkaptolaktat (1)
- Merkaptursäure (1)
- Merkaptursäuren (1)
- Metabolic activation (1)
- Metabolism (1)
- Metabolism saturation (1)
- Metabolismus (1)
- Metabonomics (1)
- Metabonomix (1)
- Methylphenidat (1)
- Microcirculation (1)
- Micronucleus formation (1)
- Micronucleus test (1)
- Microscopy (1)
- Mikrokerne (1)
- Mitosis (1)
- Molekularpharmakologie (1)
- Multivariate Analyse (1)
- Mutagenicity (1)
- Mutagenicity assay (1)
- Mutagenitätstest (1)
- Mutagens (1)
- Mutation assay (1)
- Mykotoxin (1)
- N-methyl-N-nitrosourea (1)
- N1E 115 cells (1)
- NADPH-Oxidase (1)
- Na\(_V\)1.8 (1)
- Neomycin Resistance (1)
- Nephrotoxicity (1)
- Nephrotoxizität (1)
- Nervennetz (1)
- Nervenzelle (1)
- Nitrosation (1)
- Nitrosativer Stress (1)
- Nitrosierung (1)
- OXPHOS (1)
- Oxidative Stress (1)
- Oxidative stress (1)
- Oxygen radical (1)
- PBPK/PBTK model (1)
- PDE (1)
- PDE2 (1)
- PDXP inhibitors (1)
- PKA (1)
- PTH1R (1)
- Parathormon (1)
- Partial Agonists (1)
- Partialagonismus (1)
- Patulin (1)
- Peptides (1)
- Perforine (1)
- PhD thesis pharmacology (1)
- Pharmakogenetik (1)
- Phosphatase (1)
- Phosphatasen (1)
- Phosphodiesterase (1)
- Phosphoglykolat-Phosphatase (1)
- Phosphoglykolatphosphatase (1)
- Photoaffinity labelling (1)
- Physiologically based kinetic models (1)
- Physiologie (1)
- Phänotyp (1)
- Pointmutation (1)
- Pore (1)
- Pore formation (1)
- Pore-formation (1)
- Porenbildung (1)
- Prevalence (1)
- Prognostic impact (1)
- Prolactin (1)
- Propenderivate (1)
- Protein binding (1)
- Protein coding (1)
- Proteinaddukte (1)
- Proteinbindung (1)
- Proteintyrosinphosphatase (1)
- Protonen-NMR-Spektroskopie (1)
- Quantitative risk assessment (1)
- RAMP (1)
- RBM20 mutations (1)
- ROS (1)
- Radiation inactivation (1)
- Radicals (1)
- Radioligand binding - 86Rb + -efflux (1)
- Radioligands (1)
- Radioligauds (1)
- Raf kinase inhibitor protein (1)
- Raman micro-spectroscopy (1)
- Rat Iiver microsomes (1)
- Rat liver peroxisome (1)
- Ratte (1)
- Reactive intermediates (1)
- Reaktive Zwischenstufe (1)
- Receptor (1)
- Receptor dynamics (1)
- Regulation (1)
- Regulator of G protein signaling 2 (1)
- Renin-Angiotensin-System (1)
- Resveratrol (1)
- Rgs2 (1)
- Riot control agents (1)
- Risikoanalyse (1)
- Risikobewertung (1)
- Risk assessment (1)
- Risk estimation (1)
- Risk-factors (1)
- SCN5a (1)
- ST-elevation myocardial infarction (1)
- Salmonella typhimurium (1)
- Sensitivity (1)
- Sensor (1)
- Short-term tests (1)
- Signal transduction (1)
- Species Differences (1)
- Species differences (1)
- Spermatogenesis (1)
- Speziesunterschiede (1)
- Spontaneous tumours (1)
- Src (1)
- Stable Transformation (1)
- Statin (1)
- Stickstoffoxidsynthase (1)
- Streptococcus pneumoniae (1)
- Streptomyces (1)
- Stress (1)
- Structureactivity relationship (1)
- Styrol (1)
- Systembiologie (1)
- T cells (1)
- TK6 cells (1)
- Target size (1)
- Theophylline (1)
- Thymidine glycol (1)
- Tiermodell (1)
- Toxicokinetics (1)
- Toxikokinetik (1)
- Toxizität (1)
- Toxizitätstest (1)
- Transfection (1)
- Transgenic mouse (1)
- Transgenie mice (1)
- Transkriptionsfaktoren (1)
- Trenbolone (1)
- Trifluorpropionsäure (1)
- Tumorzelle (1)
- Tyrosin (1)
- Tyrosin phosphatase (1)
- Unscheduled DNA synthesis (1)
- Urämische Toxine (1)
- Uterine tumors (1)
- Valvular heart-desease (1)
- Venerologie (1)
- Volume distribution (1)
- Wachstumskonus (1)
- Water resources (1)
- Xanthines (1)
- Zell-Adhäsion (1)
- Zelladhäsion (1)
- Zelle (1)
- Zellkultur (1)
- Zellskelett (1)
- Zellteilung (1)
- Zelltransport (1)
- [3H]PIA binding (1)
- absorption (1)
- activation (1)
- active zone (1)
- acute slices (1)
- adduct (1)
- adenine (1)
- adenosine (1)
- adenosine 3',5'-cyclic monophosphate (1)
- adenylate cyclase (1)
- adenylyl cyclase signaling cascade (1)
- adenylyl-cyclase isoforms (1)
- adhesion GPCR (1)
- adiponectin (1)
- adipose tissue (1)
- adrenerge Rezeptoren (1)
- adrenergic receptors (1)
- adult cardiac myocytes (1)
- adverse outcome pathway (1)
- adverse outcome pathway (AOP) (1)
- aflatoxin (1)
- aflatoxin B1 (1)
- ageing (1)
- agonists (1)
- alkylation (1)
- allelic variant (1)
- alpha2-KO Maus (1)
- alpha2-KO mouse (1)
- alpha2-Rezeptor (1)
- alpha2-receptor (1)
- alternative methods (1)
- amine (1)
- amino acid (1)
- antagonists (1)
- anthocyanins (1)
- anti-Parkinson agents (1)
- anti-inflammatory agents (1)
- antibacterial/antiviral drug (1)
- antibodies (1)
- antibody/autoantibody (1)
- antioxidants (1)
- aortocaval fistula model (1)
- aromatic amides (1)
- arrhythmia (1)
- arrhythmogenesis (1)
- assay (1)
- association (1)
- astrocytes (1)
- atopic eczema (1)
- atrial natriuretic peptide (1)
- avaliação de risco (1)
- bacterial meningitis (1)
- bariatric surgery (1)
- base excision repair (incision activity) (1)
- beta2-adrenoceptor knockout (1)
- beta3 CL 316,243 (1)
- binding affinity (1)
- bioactive compounds (1)
- biofilms (1)
- biological techniques (1)
- biology (1)
- biomarker (1)
- biomarker of exposure (1)
- biomarkers (1)
- biotransformation (1)
- bisphenol a (1)
- blood coagulation factor XIII (1)
- blood plasma (1)
- blood pressure (1)
- blood samples (1)
- bone marrow (1)
- brain damage (1)
- brain membranes (1)
- calcitonin gene-related peptide (1)
- calmodulin (1)
- cancer (1)
- cardiac magnetic resonance imaging (1)
- cardiac myocyte ; muscarinic K current ; G-protein ; Albumin ; serum (1)
- cardiac remodelling (1)
- cardiomyocyte (1)
- cardiomyocytes (1)
- cardiovascular diseases (1)
- caveolin-1 (1)
- cell adhesion (1)
- cell culture (1)
- cell fate (1)
- cell fusion (1)
- cell proliferation (1)
- cell signalling (1)
- cell staining (1)
- cellular-trafficking (1)
- chalcone (1)
- chemotactic receptors (1)
- chemotaxis (1)
- child health (1)
- cholesterol depletion (1)
- cholesterol-dependent cytolysin (1)
- cholinesterase (1)
- cholinesterase inhibitors (1)
- chronic heart failure (1)
- chronic kidney disease (1)
- chronophin (1)
- cisplatin (1)
- classification (1)
- classification and labeling (1)
- clonidine (1)
- co-culture (1)
- coated vesicles (1)
- cognitive impairment (1)
- coherent anti-Stokes Raman scattering (CARS) microscopy (1)
- compartments (1)
- conduction disease (1)
- conformational auto-epitope (1)
- conjugated mycotoxins (1)
- constitutive activity (1)
- contact lens (1)
- continuous (1)
- contractility (1)
- coumarin (1)
- coupled (1)
- coupled receptor (1)
- covalent (1)
- covalent binding (1)
- creatinine (1)
- crystal structure (1)
- cyclic AMP (1)
- cyclic dipeptide (1)
- cyclic nucleotides such as cyclic adenosine monophosphate (1)
- cyclic peptides/cyclopeptides (1)
- cyclic-AMP (1)
- cyclic-gmp (1)
- cyclopeptide therapy (1)
- cytochrome P450 2C9 (1)
- cytochrome P450s (1)
- cytochrome p450 (1)
- cytogenetic effects (1)
- cytome biomarkers (1)
- cytosol (1)
- cytotoxic (1)
- dCIRL (1)
- danio rerio (1)
- definition (1)
- dendritic spines (1)
- desensitization (1)
- detrusor muscle (1)
- developmental biology (1)
- diabetes (1)
- diagnosis (1)
- dicyclohexyl phthalate (1)
- diet (1)
- dilated cardiomyopathy with ataxia (1)
- disrupting chemicals (1)
- disruptor endócrino (1)
- docking (1)
- domains (1)
- dormancy (1)
- dose (1)
- down-regulation (1)
- drug (1)
- dualsteric ligands (1)
- dunce (1)
- eccentric hypertrophy (1)
- ectodomain cleavage (1)
- efficient intervention points (1)
- endocrine disruptor (1)
- endogenous (1)
- energy-transfer (1)
- environmental phenols (1)
- enzyme-linked immunoassays (1)
- estrogen receptor (1)
- ethanol (1)
- etoposide (1)
- etox database (1)
- eugenol (1)
- exposição humana (1)
- exposure (1)
- extrapolation (1)
- fatty liver (1)
- fentanyl (1)
- fetal testis (1)
- fluorescence correlation spectroscopy (1)
- fluorescence detection (1)
- fluorescence imaging (1)
- fluorescence recovery after photobleaching (1)
- fluorescent probes (1)
- fluorocarbons (1)
- food contact materials (1)
- food safety (1)
- food security (1)
- formyl peptides (1)
- fumonisin B1 (1)
- functional clustering (1)
- fungi (1)
- furan (1)
- gastrointestinal cancer (1)
- general medicine (1)
- genetics (1)
- genotoxic (1)
- genotypes (1)
- genotyping (1)
- glucuronide (1)
- glutamate (1)
- glutathion S-conjugate (1)
- glycolytic flux control (1)
- gprotein (1)
- gravidez (1)
- growth cone (1)
- guanine nucleotide exchange factor (1)
- hA<sub>3</sub>AR (1)
- hOCT1 (1)
- haematopoietic stem cells (1)
- halo olefines (1)
- haloacid dehalogenase (1)
- healing and remodelling processes (1)
- heme (1)
- heterogeneous population (1)
- hiPSC-CM (1)
- hidden mycotoxins (1)
- histamine release (1)
- homeostasis (1)
- homocysteine (1)
- homodimerization (1)
- hormone receptors (1)
- human (1)
- human A(3) (1)
- human biomonitoring (1)
- human exposure (1)
- human lung (1)
- hydrofluorocarbons (1)
- hypertension (1)
- hypertonic solution (1)
- identification (1)
- impact pharmacogenetics (1)
- in vitro (1)
- in vivo (1)
- in-silico model (1)
- individual (1)
- indolylpyrimidylpiperazines (1)
- induced pluripotent stem cell cardiomyocytes (1)
- induced pluripotent stem cells (1)
- induzierte Phosphatasen MKP-1 und MKP-2 (1)
- inflammatory diseases (1)
- inhalation (1)
- inhibitors (1)
- insulin signaling (1)
- internalization (1)
- international union (1)
- intracellular calcium release (1)
- intracellular loop (1)
- intrinsic metabolism (1)
- ionic look (1)
- ischemic stroke (1)
- isoproterenol (1)
- key event relationship (1)
- kidney (1)
- kinases (1)
- laminopathy (1)
- lamivudine (1)
- late Na\(^+\) current (I\(_{NaL}\)) (1)
- legislation (1)
- life (1)
- ligand binding (1)
- lipid rafts (1)
- lipidomics (1)
- listeriolysin O (1)
- live imaging (1)
- liver microsomes (1)
- living vells (1)
- long-read sequencing (1)
- lovastatin (1)
- lysosomal disruption (1)
- lysosomal storage disorders (1)
- lösliche Guanylylcyclase (1)
- mTOR-inhibitor RAD-001 (1)
- maintenance of genomic integrity (1)
- male rats (1)
- mammalian genomics (1)
- marine sponges (1)
- masked mycotoxins (1)
- mass spectrometry (1)
- matrix metalloproteinase (1)
- maturation strategies (1)
- mechanotransduction (1)
- membrane (1)
- membrane transporters (1)
- memory B cells (1)
- mercaptolactic acid (1)
- mercapturic acids (1)
- metabolites (1)
- metabonomics (1)
- metabotropic signalling (1)
- micronucleus assay (1)
- micronucleus test (1)
- microvessel permeability (1)
- mild (1)
- mitochondria (1)
- mitochondrial DNA polymerase γ (1)
- mitochondrial cardiomyopathy (1)
- mitotic disturbance (1)
- modelo PBPK/PBTK (1)
- modified mycotoxins (1)
- molecular biology (1)
- molecular dynamics (1)
- molecular modeling (1)
- molecular modelling (1)
- monogenetic cardiomyopathies (1)
- mortality (1)
- mouse lymphoma L5178Y (1)
- mouse models DNA damage (1)
- mucosa (1)
- multivariate analysis (1)
- multivariate data analysis (1)
- muscarinic acetylcholine receptor (1)
- mutagen (1)
- mutant mice (1)
- mutation triggers (1)
- mycotoxin derivates (1)
- mycotoxin metabolites (1)
- mycotoxins (1)
- n-hexyl phthalate (1)
- nanopore (1)
- natural (1)
- neocortex (1)
- neurodegenerative diseases (1)
- neuronal dendrites (1)
- neurons (1)
- neutrophils (1)
- nitric-oxide (1)
- nitrosation (1)
- nitrosative stress (1)
- nitroso compound (1)
- no (1)
- nutritional composition (1)
- o-Chlorobenzylidene malononitrile (1)
- obesity (1)
- occurrence (1)
- ochratoxin A (1)
- octopamine (1)
- oligomerization (1)
- opioid ligands (1)
- opioid receptor (1)
- optimal drug combination (1)
- optimal drug targeting (1)
- optimal pharmacological modulation (1)
- optimal treatment strategies (1)
- organ toxicity (1)
- oxidativer Stress (1)
- p53 (1)
- parathyroid hormone (1)
- parathyroid hormone 1 receptor (1)
- partial agonists (1)
- performance liquid-chromatography (1)
- peripheral nerve (1)
- peripheral-blood lymphocytes (1)
- personalized treatment (1)
- perspectives (1)
- pharmacology (1)
- phenotyping (1)
- phosphoglycolate phosphatase (1)
- phosphoinositides (1)
- photoaffinity labelling (1)
- plasma membrane (1)
- poly(ADP-ribosyl)ation (1)
- pore formation (1)
- pore-forming toxin (1)
- potent (1)
- pregnancy (1)
- primary aromatic amine (1)
- protein (1)
- protein adducts (1)
- protein alkylation (1)
- protein design (1)
- protein-coupled receptors (1)
- protein-coupled-receptors (1)
- psoriasis (1)
- purine derivatives (1)
- pyridoxal phosphatase (1)
- pyridoxal phosphatase (PDXP) (1)
- pyrrolizidine alkaloids (1)
- quantitative assessments (1)
- radiation (1)
- radii (1)
- radioligand (1)
- radioligand binding (1)
- rat pheochromocytoma cells (1)
- rats (1)
- reactive metabolites (1)
- reaktive Metabolite (1)
- receptor binding (1)
- receptor pharmacology (1)
- receptor solubilization (1)
- receptor-G protein coupling (1)
- receptor-G protein coupling. (1)
- reduction of ERK1/2 phosphorylation (1)
- reduction of cells proliferation (1)
- regulation (1)
- relaxation (1)
- renal toxicity (1)
- repeated dose (1)
- reproductive and developmental toxicity (1)
- risk (1)
- risk-assesment (1)
- sensor (1)
- sensory physiology (1)
- serum (1)
- sex (1)
- sexual development (1)
- signaling microdomain (1)
- simulated digestion (1)
- single-molecule imaging (1)
- single-molecule microscopy (1)
- solid-phase extraction (1)
- solubilization (1)
- soluble guanylyl cyclase (1)
- sponges (1)
- spontaneously hypersensitive-rats (1)
- staphilococci (1)
- statins (1)
- stomach (1)
- streptomyces (1)
- sub-Saharan Africa (1)
- subtypes (1)
- sugars (1)
- susceptibility (1)
- synapses (1)
- synaptic plasticity (1)
- tMCAO (1)
- tandem mass-spectrometry (1)
- targets (1)
- testosterone production (1)
- tetrafluoropropene (1)
- therapeutic potential (1)
- thyroid hormone (1)
- tissue (1)
- tolbutamide substrate (1)
- toxicity testing (1)
- toxicocinética (1)
- toxicokinetics (1)
- toxicology (1)
- trans-1 (1)
- trans-Golgi network (1)
- transgenic animals (1)
- triazolotriazine derivatives (1)
- trifluoropropionic acid (1)
- tuber (1)
- tumour (1)
- tyrosine phosphatase (1)
- ultrastructure (1)
- urea (1)
- variocosities (1)
- vav2 (1)
- vitamin-D-receptor (1)
- volume overload (1)
- warfarin polymorphisms (1)
- weight of evidence (1)
- yellow fluorescent protein (1)
- µ-Opioid receptor (1)
- β-adrenergic receptors (1)
- β1-adrenoceptor/β1-adrenergic receptor (1)
- βAR (1)
Institute
- Institut für Pharmakologie und Toxikologie (293) (remove)
Sonstige beteiligte Institutionen
- Johns Hopkins School of Medicine (1)
- Johns Hopkins School of Medicine, Baltimore, MD, U.S. (1)
- Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V. (1)
- Max Delbrück Center for Molecular Medicine (1)
- Max-Delbrück-Center für molekulare Medizin, Berlin (1)
- Pharmakologie, Universität Bonn (1)
- Pharmazie, Universität Mailand (1)
μ‐Opioid receptors (μ‐ORs) play a critical role in the modulation of pain and mediate the effects of the most powerful analgesic drugs. Despite extensive efforts, it remains insufficiently understood how μ‐ORs produce specific effects in living cells. We developed new fluorescent ligands based on the μ‐OR antagonist E‐p‐nitrocinnamoylamino‐dihydrocodeinone (CACO), that display high affinity, long residence time and pronounced selectivity. Using these ligands, we achieved single‐molecule imaging of μ‐ORs on the surface of living cells at physiological expression levels. Our results reveal a high heterogeneity in the diffusion of μ‐ORs, with a relevant immobile fraction. Using a pair of fluorescent ligands of different color, we provide evidence that μ‐ORs interact with each other to form short‐lived homodimers on the plasma membrane. This approach provides a new strategy to investigate μ‐OR pharmacology at single‐molecule level.
Metabolism and signaling of cytokinins was first established in plants, followed by cytokinin discoveries in all kingdoms of life. However, understanding of their role in mammalian cells is still scarce. Kinetin is a cytokinin that mitigates the effects of oxidative stress in mammalian cells. The effective concentrations of exogenously applied kinetin in invoking various cellular responses are not well standardized. Likewise, the metabolism of kinetin and its cellular targets within the mammalian cells are still not well studied. Applying vitality tests as well as comet assays under normal and hyper-oxidative states, our analysis suggests that kinetin concentrations of 500 nM and above cause cytotoxicity as well as genotoxicity in various cell types. However, concentrations below 100 nM do not cause any toxicity, rather in this range kinetin counteracts oxidative burst and cytotoxicity. We focus here on these effects. To get insights into the cellular targets of kinetin mediating these pro-survival functions and protective effects we applied structural and computational approaches on two previously testified targets for these effects. Our analysis deciphers vital residues in adenine phosphoribosyltransferase (APRT) and adenosine receptor (A2A-R) that facilitate the binding of kinetin to these two important human cellular proteins. We finally discuss how the therapeutic potential of kinetin against oxidative stress helps in various pathophysiological conditions.
Aims
Chronic heart failure (CHF) can be caused by autoantibodies stimulating the heart via binding to first and/or second extracellular loops of cardiac β1-adrenoceptors. Allosteric receptor activation depends on conformational features of the autoantibody binding site. Elucidating these features will pave the way for the development of specific diagnostics and therapeutics. Our aim was (i) to fine-map the conformational epitope within the second extracellular loop of the human β\(_1\)-adrenoceptor (β1ECII) that is targeted by stimulating β\(_1\)-receptor (auto)antibodies and (ii) to generate competitive cyclopeptide inhibitors of allosteric receptor activation, which faithfully conserve the conformational auto-epitope.
Methods and results
Non-conserved amino acids within the β\(_1\)EC\(_{II}\) loop (compared with the amino acids constituting the ECII loop of the β\(_2\)-adrenoceptor) were one by one replaced with alanine; potential intra-loop disulfide bridges were probed by cysteine–serine exchanges. Effects on antibody binding and allosteric receptor activation were assessed (i) by (auto)antibody neutralization using cyclopeptides mimicking β1ECII ± the above replacements, and (ii) by (auto)antibody stimulation of human β\(_1\)-adrenoceptors bearing corresponding point mutations. With the use of stimulating β\(_1\)-receptor (auto)antibodies raised in mice, rats, or rabbits and isolated from exemplary dilated cardiomyopathy patients, our series of experiments unmasked two features of the β\(_1\)EC\(_{II}\) loop essential for (auto)antibody binding and allosteric receptor activation: (i) the NDPK\(^{211–214}\) motif and (ii) the intra-loop disulfide bond C\(^{209}\)↔C\(^{215}\). Of note, aberrant intra-loop disulfide bond C\(^{209}\)↔C\(^{216}\) almost fully disrupted the functional auto-epitope in cyclopeptides.
Conclusions
The conformational auto-epitope targeted by cardio-pathogenic β\(_1\)-receptor autoantibodies is faithfully conserved in cyclopeptide homologues of the β\(_1\)EC\(_{II}\) loop bearing the NDPK\(^{211–214}\) motif and the C\(^{209}\)↔C\(^{215}\) bridge while lacking cysteine C216. Such molecules provide promising tools for novel diagnostic and therapeutic approaches in β\(_1\)-autoantibodypositive CHF.
Ochratoxin A (OTA) is a widespread food contaminant, with exposure estimated to range from 0.64 to 17.79 ng/kg body weight (bw) for average consumers and from 2.40 to 51.69 ng/kg bw per day for high consumers. Current exposure estimates are, however, associated with considerable uncertainty. While biomarker-based approaches may contribute to improved exposure assessment, there is yet insufficient data on urinary metabolites of OTA and their relation to external dose to allow reliable estimates of daily intake. This study was designed to assess potential species differences in phase II biotransformation in vitro and to establish a correlation between urinary OTA-derived glucuronides and mercapturic acids and external exposure in rats in vivo. In vitro analyses of OTA metabolism using the liver S9 of rats, humans, rabbits and minipigs confirmed formation of an OTA glucuronide but provided no evidence for the formation of OTA-derived mercapturic acids to support their use as biomarkers. Similarly, OTA-derived mercapturic acids were not detected in urine of rats repeatedly dosed with OTA, while indirect analysis using enzymatic hydrolysis of the urine samples prior to LC–MS/MS established a linear relationship between urinary glucuronide excretion and OTA exposure. These results support OTA-derived glucuronides but not mercapturic acids as metabolites suitable for biomonitoring.
ERK1/2 are known key players in the pathophysiology of heart failure, but the members of the ERK cascade, in particular Raf1, can also protect the heart from cell death and ischemic injury. An additional autophosphorylation (ERK1 at Thr208, ERK2 at Thr188) empowers ERK1/2 translocation to the nucleus and phosphorylation of nuclear targets which take part in the development of cardiac hypertrophy. Thereby, targeting this additional phosphorylation is a promising pharmacological approach.
In this thesis, an in silico model of ERK cascade in the cardiomyocyte is introduced. The model is a semi-quantitive model and its behavior was tested with different softwares (SQUAD and CellNetAnalyzer). Different phosphorylation states of ERK1/2 as well as different stimuli can be reproduced. The different types of stimuli include hypertrophic as well as non-hypertrophic stimuli. With the introduced in-silico model time courses and synergistic as well as antagonistic receptor stimuli combinations can be predicted. The simulated time courses were experimentally validated. SQUAD was mainly used to make predictions about time courses and thresholds, whereas CNA was used to analyze steady states and feedback loops.
Furthermore, new targets of ERK1/2 which partially contribute, also in the formation of cardiac hypertrophy, were identified and the most promising of them were illuminated. Important further targets are Caspase 8, GAB2, Mxi-2, SMAD2, FHL2 and SPIN90.
Cardiomyocyte gene expression data sets were analyzed to verify involved components and to find further significantly altered genes after induced hypertrophy with TAC (transverse aortic constriction). Changes in the ultrastructure of the cardiomyocyte are the final result of induced hypertrophy.
Cyclic adenosine monophosphate (cAMP), the ubiquitous second messenger produced upon stimulation of GPCRs which couple to the stimulatory GS protein, orchestrates an array of physiological processes including cardiac function, neuronal plasticity, immune responses, cellular proliferation and apoptosis. By interacting with various effector proteins, among others protein kinase A (PKA) and exchange proteins directly activated by cAMP (Epac), it triggers signaling cascades for the cellular response. Although the functional outcomes of GSPCR-activation are very diverse depending on the extracellular stimulus, they are all mediated exclusively by this single second messenger. Thus, the question arises how specificity in such responses may be attained. A hypothesis to explain signaling specificity is that cellular signaling architecture, and thus precise operation of cAMP in space and time would appear to be essential to achieve signaling specificity. Compartments with elevated cAMP levels would allow specific signal relay from receptors to effectors within a micro- or nanometer range, setting the molecular basis for signaling specificity. Although the paradigm of signaling compartmentation gains continuous recognition and is thoroughly being investigated, the molecular composition of such compartments and how they are maintained remains to be elucidated. In addition, such compartments would require very restricted diffusion of cAMP, but all direct measurements have indicated that it can diffuse in cells almost freely.
In this work, we present the identification and characterize of a cAMP signaling compartment at a GSPCR. We created a Förster resonance energy transfer (FRET)-based receptor-sensor conjugate, allowing us to study cAMP dynamics in direct vicinity of the human glucagone-like peptide 1 receptor (hGLP1R). Additional targeting of analogous sensors to the plasma membrane and the cytosol enables assessment of cAMP dynamics in different subcellular regions. We compare both basal and stimulated cAMP levels and study cAMP crosstalk of different receptors. With the design of novel receptor nanorulers up to 60nm in length, which allow mapping cAMP levels in nanometer distance from the hGLP1R, we identify a cAMP nanodomain surrounding it. Further, we show that phosphodiesterases (PDEs), the only enzymes known to degrade cAMP, are decisive in constraining cAMP diffusion into the cytosol thereby maintaining a cAMP gradient. Following the discovery of this nanodomain, we sought to investigate whether downstream effectors such as PKA are present and active within the domain, additionally studying the role of A-kinase anchoring proteins (AKAPs) in targeting PKA to the receptor compartment. We demonstrate that GLP1-produced cAMP signals translate into local nanodomain-restricted PKA phosphorylation and determine that AKAP-tethering is essential for nanodomain PKA.
Taken together, our results provide evidence for the existence of a dynamic, receptor associated cAMP nanodomain and give prospect for which key proteins are likely to be involved in its formation. These conditions would allow cAMP to exert its function in a spatially and temporally restricted manner, setting the basis for a cell to achieve signaling specificity. Understanding the molecular mechanism of cAMP signaling would allow modulation and thus regulation of GPCR signaling, taking advantage of it for pharmacological treatment.
Background: Phosphodiesterases (PDE) critically regulate myocardial cAMP and cGMP levels. PDE2 is stimulated by cGMP to hydrolyze cAMP, mediating a negative crosstalk between both pathways. PDE2 upregulation in heart failure contributes to desensitization to β-adrenergic overstimulation. After isoprenaline (ISO) injections, PDE2 overexpressing mice (PDE2 OE) were protected against ventricular arrhythmia. Here, we investigate the mechanisms underlying the effects of PDE2 OE on susceptibility to arrhythmias. Methods: Cellular arrhythmia, ion currents, and Ca\(^{2+}\)-sparks were assessed in ventricular cardiomyocytes from PDE2 OE and WT littermates. Results: Under basal conditions, action potential (AP) morphology were similar in PDE2 OE and WT. ISO stimulation significantly increased the incidence of afterdepolarizations and spontaneous APs in WT, which was markedly reduced in PDE2 OE. The ISO-induced increase in I\(_{CaL}\) seen in WT was prevented in PDE2 OE. Moreover, the ISO-induced, Epac- and CaMKII-dependent increase in I\(_{NaL}\) and Ca\(^{2+}\)-spark frequency was blunted in PDE2 OE, while the effect of direct Epac activation was similar in both groups. Finally, PDE2 inhibition facilitated arrhythmic events in ex vivo perfused WT hearts after reperfusion injury. Conclusion: Higher PDE2 abundance protects against ISO-induced cardiac arrhythmia by preventing the Epac- and CaMKII-mediated increases of cellular triggers. Thus, activating myocardial PDE2 may represent a novel intracellular anti-arrhythmic therapeutic strategy in HF.
Introduction: Familial dilated cardiomyopathy (DCM) is clinically variable and has been associated with mutations in more than 50 genes. Rapid improvements in DNA sequencing have led to the identification of diverse rare variants with unknown significance (VUS), which underlines the importance of functional analyses. In this study, by investigating human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we evaluated the pathogenicity of the p.C335R sodium voltage-gated channel alpha subunit 5 (SCN5a) variant in a large family with familial DCM and conduction disease. Methods: A four-generation family with autosomal dominant familial DCM was investigated. Next-generation sequencing (NGS) was performed in all 16 family members. Clinical deep phenotyping, including endomyocardial biopsy, was performed. Skin biopsies from two patients and one healthy family member were used to generate human-induced pluripotent stem cells (iPSCs), which were then differentiated into cardiomyocytes. Patch-clamp analysis with Xenopus oocytes and iPSC-CMs were performed. Results: A SCN5a variant (c.1003T>C; p.C335R) could be detected in all family members with DCM or conduction disease. A novel truncating TTN variant (p.Ser24998LysfsTer28) could also be identified in two family members with DCM. Family members with the SCN5a variant (p.C335R) showed significantly longer PQ and QRS intervals and lower left ventricular ejection fractions (LV-EF). All four patients who received CRT-D were non-responders. Electrophysiological analysis with Xenopus oocytes showed a loss of function in SCN5a p.C335R. Na\(^+\) channel currents were also reduced in iPSC-CMs from DCM patients. Furthermore, iPSC-CM with compound heterozygosity (SCN5a p.C335R and TTNtv) showed significant dysregulation of sarcomere structures, which may be contributed to the severity of the disease and earlier onset of DCM. Conclusion: The SCN5a p.C335R variant is causing a loss of function of peak INa in patients with DCM and cardiac conduction disease. The co-existence of genetic variants in channels and structural genes (e.g., SCN5a p.C335R and TTNtv) increases the severity of the DCM phenotype.
G-protein-coupled receptors (GPCRs) regulate diverse physiological processes in the human body and represent prime targets in modern drug discovery. Engagement of different ligands to these membrane-embedded proteins evokes distinct receptor conformational rearrangements that facilitate subsequent receptor-mediated signalling and, ultimately, enable cellular adaptation to altered environmental conditions. Since the early 2000s, the technology of resonance energy transfer (RET) has been exploited to assess these conformational receptor dynamics in living cells and real time. However, to date, these conformational GPCR studies are restricted to single-cell microscopic setups, slowing down the discovery of novel GPCR-directed therapeutics. In this work, we present the development of a novel generalizable high-throughput compatible assay for the direct measurement of GPCR activation and deactivation. By screening a variety of energy partners for fluorescence (FRET) and bioluminescence resonance energy transfer (BRET), we identified a highly sensitive design for an α2A-adrenergic receptor conformational biosensor. This biosensor reports the receptor’s conformational change upon ligand binding in a 96-well plate reader format with the highest signal amplitude obtained so far. We demonstrate the capacity of this sensor prototype to faithfully quantify efficacy and potency of GPCR ligands in intact cells and real time. Furthermore, we confirm its universal applicability by cloning and validating five further equivalent GPCR biosensors. To prove the suitability of this new GPCR assay for screening purposes, we measured the well-accepted Z-factor as a parameter for the assay quality. All tested biosensors show excellent Z-factors indicating outstanding assay quality. Furthermore, we demonstrate that this assay provides excellent throughput and presents low rates of erroneous hit identification (false positives and false negatives). Following this phase of assay development, we utilized these biosensors to understand the mechanism and consequences of the postulated modulation of parathyroid hormone receptor 1 (PTHR1) through receptor activity-modifying protein 2 (RAMP2). We found that RAMP2 desensitizes PTHR1, but not the β2-adrenergic receptor (β2AR), for agonist-induced structural changes. This generalizable sensor design offers the first possibility to upscale conformational GPCR studies, which represents the most direct and unbiased approach to monitor receptor activation and deactivation. Therefore, this novel technology provides substantial advantages over currently established methods for GPCR ligand screening. We feel confident that this technology will aid the discovery of novel types of GPCR ligands, help to identify the endogenous ligands of so-called orphan GPCRs and deepen our understanding of the physiological regulation of GPCR function.
Prerequisite to any biological laboratory assay employing living animals is consideration about its necessity, feasibility, ethics and the potential harm caused during an experiment. The imperative of these thoughts has led to the formulation of the 3R-principle, which today is a pivotal scientific standard of animal experimentation worldwide. The rising amount of laboratory investigations utilizing living animals throughout the last decades, either for regulatory concerns or for basic science, demands the development of alternative methods in accordance with 3R to help reduce experiments in mammals. This demand has resulted in investigation of additional vertebrate species displaying favourable biological properties. One prominent species among these is the zebrafish (Danio rerio), as these small laboratory ray-finned fish are well established in science today and feature outstanding biological characteristics. In this review, we highlight the advantages and general prerequisites of zebrafish embryos and larvae before free-feeding stages for toxicological testing, with a particular focus on cardio-, neuro, hepato- and nephrotoxicity. Furthermore, we discuss toxicokinetics, current advances in utilizing zebrafish for organ toxicity testing and highlight how advanced laboratory methods (such as automation, advanced imaging and genetic techniques) can refine future toxicological studies in this species.