A5058190462- Cardiac Ischemia and Reperfusion
- Anesthesia and Neurotoxicity Research
- Neuroscience and Neuropharmacology Research
- Receptor Mechanisms and Signaling
- Anesthesia and Sedative Agents
- Anesthesia and Pain Management
- Mitochondrial Function and Pathology
- Cardiac, Anesthesia and Surgical Outcomes
- Ion channel regulation and function
- Diabetes Treatment and Management
- Protein purification and stability
- Pancreatic function and diabetes
- Nitric Oxide and Endothelin Effects
- Cancer, Stress, Anesthesia, and Immune Response
- Neuropeptides and Animal Physiology
- Sphingolipid Metabolism and Signaling
- Neuroendocrine regulation and behavior
- Pain Mechanisms and Treatments
- Protein Kinase Regulation and GTPase Signaling
- Advanced MRI Techniques and Applications
- Cancer Cells and Metastasis
- Blood disorders and treatments
- Monoclonal and Polyclonal Antibodies Research
- Cardiac Arrest and Resuscitation
- Adipose Tissue and Metabolism
AbbVie (Germany)
2019-2025
University of Amsterdam
2010-2024
Amsterdam University Medical Centers
2019-2024
Metropolitan University
2024
University Hospital Heidelberg
2003-2014
Heidelberg University
2000-2014
Amsterdam UMC Location University of Amsterdam
2010-2014
Cardiovascular Institute of the South
2013
University Medical Center
2013
Mount Sinai Medical Center
2013
BACKGROUND/AIMS: Heart failure is characterized by chronic low-grade vascular inflammation, which in itself can lead to endothelial dysfunction. Clinical trials showed reductions heart failure-related hospitalizations of type 2 diabetic patients using sodium glucose co-transporter inhibitors (SGLT2i's). Whether and how SGLT2i's directly affect the endothelium under inflammatory conditions not completely understood. The aim study was investigate whether SGLT2i Empagliflozin (EMPA)...
Inflammation causing oxidative stress in endothelial cells contributes to heart failure development. Sodium/glucose cotransporter 2 inhibitors (SGLT2i's) were shown reduce hospitalization and stress. However, how inflammation causes cells, SGLT2i's can this is unknown. Here we hypothesized that 1) TNF-α activates the Na+/H+ exchanger (NHE) raises cytoplasmatic Na+ ([Na+]c), 2) increased [Na+]c reactive oxygen species (ROS) production, 3) empagliflozin (EMPA) reduces inflammation-induced ROS...
SGLT2i reduce cardiac hypertrophy, but underlying mechanisms remain unknown. Here we explore a role for serine/threonine kinases (STK) and sodium hydrogen exchanger 1(NHE1) activities in effects on hypertrophy. Isolated hearts from db/db mice were perfused with 1 µM EMPA, STK phosphorylation sites examined using unbiased multiplex analysis to detect the most affected STKs by EMPA. Subsequently, hypertrophy was induced H9c2 cells 50 phenylephrine (PE), of (p90 ribosomal S6 kinase (RSK)) NHE1...
N- methyl-d-aspartate (NMDA) receptors are important components of pain processing. Ketamine and Mg2+ block NMDA might therefore be useful analgesics, combinations ketamine provide more effective analgesia. We investigated their interactions at receptors. Xenopus oocytes, expressing NR1/NR2A or NR1/NR2B glutamate receptors, were studied. The effects Mg2+, racemic its isomers, the combination S(+)-ketamine on signaling determined. alone inhibited noncompetitively (half-maximal inhibitory...
Background Local anesthetics (LAs) have been shown to inhibit human polymorphonuclear neutrophil (hPMN) functions in vitro, but mechanisms are poorly understood. In this study the authors determined how LAs affect superoxide anion production of hPMNs primed with platelet-activating factor (PAF). The studied which pharmacologic properties important for action and assessed LA site within PAF signaling pathway. Methods Metabolic activity and/or activated were measured using cytochrome-c assay....
Mg2+ and ketamine interact superadditively at N- methyl-d-aspartate (NMDA) receptors, which may explain the clinical efficacy of combination. Because patients are usually exposed concomitantly to volatile anesthetics, we tested hypothesis that anesthetics with and/or recombinantly expressed NMDA receptors. NR1/NR2A or NR1/NR2B receptors were in Xenopus oocytes. We determined effects isoflurane, sevoflurane, desflurane on receptor signaling, alone combination S(+)-ketamine (4.1 μM NR1/NR2A,...
Background Several beneficial effects of local anesthetics (LAs) were shown to be due inhibition G protein-coupled receptor signaling. Differences in exposure time might explain discrepancies concentrations LAs required achieve these protective vivo and vitro (approximately 100-fold higher). Using Xenopus oocytes human neutrophils, the authors studied time-dependent on signaling characterized possible mechanisms sites action. Methods Measurement agonist-induced Ca2+-activated Cl currents,...
Rationale: Cardiomyocytes switch substrate utilization from fatty acid to glucose under ischemic conditions; however, it is unknown how perturbations in glycolytic enzymes affect cardiac response ischemia/reperfusion (I/R). Hexokinase (HK)II a HK isoform that expressed the heart and can bind mitochondrial outer membrane. Objective: We sought define HKII its binding mitochondria play role remodeling after I/R. Methods Results: first showed levels are reduced 2 days then subjected hearts of...
To facilitate subcutaneous dosing, biotherapeutics need to exhibit properties that enable high-concentration formulation and long-term stability in the buffer. For antibody–drug conjugates (ADCs), introduction of drug-linkers can lead increased hydrophobicity higher levels aggregation, which are both detrimental required for dosing. Herein we show how physicochemical ADCs could be controlled through drug-linker chemistry combination with prodrug payload, optimization these combinations...
Stable attachment of drug-linkers to the antibody is a critical requirement, and for maleimide conjugation cysteine, it achieved by ring hydrolysis succinimide ring. During ADC profiling in our in-house property screening funnel, we discovered that open form equilibrium with closed succinimide. Bromoacetamide (BrAc) was identified as optimal replacement, affords stable drug-linker while completely removing undesired open-closed equilibrium. Additionally, BrAc also offers multiple benefits...
Clinical studies suggest that intraoperative administration of the clinical remifentanil formulation Ultiva (GlaxoWellcome GmbH & Co, Bad Oldesloe, Germany) increases postoperative pain and analgesic requirements, but mechanisms remain unclear. N-methyl-D-aspartate (NMDA) receptors are thought to play a major role in development opiate tolerance. The authors hypothesized directly stimulates human NMDA receptors.To test this hypothesis, expressed NR1A/NR2A NR1A/NR2B Xenopus laevis oocytes by...
Local neurotoxicity of local anaesthetics is a well known phenomenon which determined by lipophilicity. Recent reports have indicated the relevance anaesthetic-induced cytotoxicity also in nonneuronal tissues. This study re-evaluates role lipophilicity anaesthetic cells. In addition, toxicities pipecoloxylidine S(-) enantiomers were investigated.Local was investigated vitro T-lymphoma cells (Jurkat). Cells incubated with each eight different anaesthetics, two esters and six amides. Annexin...
Local anesthetics (LAs) are widely known for inhibition of voltage-gated sodium channels underlying their antiarrhythmic and antinociceptive effects. However, LAs have significant immunomodulatory properties were shown to affect human neutrophil functions independent sodium-channel blockade. Previous studies suggest a highly selective interaction between the α-subunit G protein-coupled receptors Gq/G11 family as mechanism. Providing detailed structure function analysis, this study aimed...
Canagliflozin (CANA) shows anti-inflammatory and anti-oxidative effects on endothelial cells (ECs). In diabetes mellitus (DM), excessive reactive oxygen species (ROS) generation, increased intracellular calcium (Ca2+) enhanced extracellular signal regulated kinase (ERK) 1/2 phosphorylation are crucial precursors for inflammasome activation. We hypothesized that: (1) CANA prevents the TNF-α triggered ROS generation in ECs from diabetic donors turn suppresses activation; (2) effect of is...
Background Local anesthetics inhibit lipid mediator signaling (lysophosphatidate, thromboxane) by acting on intracellular domains of the receptor or G protein. On receptors for polar agonists, ligand-binding pocket could form an additional site interaction, possibly resulting in superadditive inhibition. The authors therefore investigated effects local m1 muscarinic functioning. Methods expressed isolation using Xenopus oocytes. Using a two-electrode voltage clamp, measured lidocaine, QX314...
Muscarinic m1 receptors are inhibited by local anaesthetics (LA) at n M concentrations. To elucidate in more detail the site(s) of LA interaction, we compared these findings with effects on m3 muscarinic receptors. We expressed Xenopus oocytes. Using two‐electrode voltage clamp, measured lidocaine, QX314 (permanently charged) and benzocaine uncharged) Ca 2+ ‐activated Cl − ‐currents ( I Cl(Ca) ), elicited acetyl‐β‐methylcholine bromide (MCh). also characterized interaction lidocaine [ 3...
ZusammenfassungHintergrund:
The activation of mitochondrial calcium-sensitive potassium (mBKCa) channels is crucially involved in cardioprotection induced by preconditioning. For milrinone (Mil)-induced preconditioning, the involvement mBKCa-channels and further signaling unknown. We hypothesize that (1) Mil-induced preconditioning concentration-dependent (2) mBKCa-channels, release reactive oxygen species (ROS), permeability transition pore (mPTP) could be involved. Isolated hearts male Wistar rats were perfused with...
For the investigation of biotransformation processes heteroelements in environment, both molecular and element-sensitive detection systems are used hyphenation to chromatographic separation. In this work, we studied potential our recently developed gas system with parallel electron impact mass spectrometry inductively coupled plasma (GC/EI-MS/ICP-MS) for non-target screening subsequent identification volatile arsenic compounds formed by fecal microorganisms. By combining strengths ICP-MS...
Background: Cardioprotective strategies against ischemia-reperfusion injury (IRI) that remain effective in the clinical arena need to be developed. Therefore, maintained efficacy of cardioprotective presence drugs routinely used clinically (e.g., opiates, benzodiazepines, P2Y 12 antagonist, propofol) identified preclinical models. Methods: Here, we examined promising compounds [fingolimod (Fingo), empagliflozin (Empa), melatonin (Mela) and nicotinamide riboside (NR)] administered i.v. as...