19 results on '"Jan-Hendrik Reinders"'
Search Results
2. Potent dihydroquinolinone dopamine D2 partial agonist/serotonin reuptake inhibitors for the treatment of schizophrenia
- Author
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Jean Zhang, Ping Zhou, Tikva Carrick, Albert J. Robichaud, Rolf Feenstra, Jan-Hendrik Reinders, Dianne Kowal, Chris G. Kruse, Martina A.W. van der Neut, Yinfa Yan, David P. Rotella, Mark H. Pausch, Margaret Lai, and Karen L. Marquis
- Subjects
Serotonin reuptake inhibitor ,Clinical Biochemistry ,Pharmaceutical Science ,Pharmacology ,Quinolones ,Biochemistry ,Partial agonist ,Reuptake ,Structure-Activity Relationship ,Dopamine receptor D2 ,Drug Discovery ,Moiety ,Animals ,Molecular Biology ,biology ,Chemistry ,Receptors, Dopamine D2 ,Organic Chemistry ,Disease Models, Animal ,Norepinephrine transporter ,Dopamine Agonists ,Receptor, Serotonin, 5-HT1A ,biology.protein ,Schizophrenia ,Molecular Medicine ,Pharmacophore ,Endogenous agonist ,Selective Serotonin Reuptake Inhibitors ,Antipsychotic Agents - Abstract
A dihydroquinolinone moiety was found to be a potent serotonin reuptake inhibitor pharmacophore when combined with certain amines. This fragment was coupled with selected D2 ligands to prepare a series of dual acting compounds with attractive in vitro profiles as dopamine D2 partial agonists and serotonin reuptake inhibitors. Structure–activity studies revealed that the linker plays a key role in contributing to D2 affinity, function, and SRI activity.
- Published
- 2010
3. Tetrahydrocarbazole-based serotonin reuptake inhibitor/dopamine D2 partial agonists for the potential treatment of schizophrenia
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Jean Zhang, Julie A. Brennan, Chris G. Kruse, Jan-Hendrik Reinders, Dianne Kowal, Geraldine Ruth Mcfarlane, Feenstra Roelof W, Sara Núñez-García, Andrew C. McCreary, Karen L. Marquis, Radka Graf, Mark H. Pausch, Alexander Greenfield, Margaret Lai, Albert J. Robichaud, Farhana Pruthi, Tikva Carrick, David P. Rotella, Cristina Grosanu, Steven M. Grauer, Rajiah A. Denny, Kelly Sullivan, Rachel Navarra, and Martina A.W. van der Neut
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medicine.medical_treatment ,Serotonin reuptake inhibitor ,Clinical Biochemistry ,Carbazoles ,Pharmaceutical Science ,Pharmacology ,Serotonin 5-HT1 Receptor Antagonists ,Biochemistry ,Partial agonist ,chemistry.chemical_compound ,In vivo ,Dopamine receptor D2 ,Drug Discovery ,medicine ,Animals ,Antipsychotic ,Neurotransmitter ,Molecular Biology ,Receptors, Dopamine D2 ,Organic Chemistry ,Rats ,Disease Models, Animal ,chemistry ,Dopamine Agonists ,Receptor, Serotonin, 5-HT1A ,Schizophrenia ,Molecular Medicine ,Serotonin ,Reuptake inhibitor ,Selective Serotonin Reuptake Inhibitors - Abstract
A 5-fluoro-tetrahydrocarbazole serotonin reuptake inhibitor (SRI) building block was combined with a variety of linkers and dopamine D2 receptor ligands in an attempt to identify potent D2 partial agonist/SRI molecules for treatment of schizophrenia. This approach has the potential to treat a broader range of symptoms compared to existing therapies. Selected compounds in this series demonstrate high affinity for both targets and D2 partial agonism in cell-based and in vivo assays.
- Published
- 2009
4. Principal component analysis differentiates the receptor binding profiles of three antipsychotic drug candidates from current antipsychotic drugs
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Jeroen T.B.M. Tolboom, Hein K. A. C. Coolen, Jan-Hendrik Reinders, Jeffrey C. Glennon, Josephus H. M. Lange, and Chris G. Kruse
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Drug ,Indoles ,medicine.drug_class ,Pyridines ,media_common.quotation_subject ,medicine.medical_treatment ,Atypical antipsychotic ,Phthalimides ,Pharmacology ,Weight Gain ,Piperazines ,Radioligand Assay ,Basal Ganglia Diseases ,Metabolic Diseases ,Receptors, Biogenic Amine ,Drug Discovery ,Monoaminergic ,medicine ,Humans ,Biogenic Monoamines ,Receptor ,Antipsychotic ,media_common ,Principal Component Analysis ,Chemistry ,Typical antipsychotic ,Benzoxazines ,Hyperprolactinemia ,Principal component analysis ,Molecular Medicine ,Antipsychotic Agents - Abstract
The receptor binding affinities of the three drug candidates 1 (SLV310), 2 (SLV313), and 3 (SLV314) were positioned against the results from nine (a)typical antipsychotic drugs. The receptor binding data from sixteen monoaminergic receptors served as the input in a principal component analysis (PCA). The PCA outcome revealed a unique binding profile of 1, 2, and 3 as compared with the reference compounds 4-8 and 10-12. The weight gain inducing antipsychotics 6-8 clustered in the PCA by scoring strongly negative for factor 1. The hyperprolactinaemia related antipsychotics 4, 5, 10, and 12 clustered by their negative scores for factor 2.
- Published
- 2007
5. In vitro characterization of SLV308 (7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolone, monohydrochloride): a novel partial dopamine D2 and D3 receptor agonist and serotonin 5-HT1A receptor agonist
- Author
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Jan-Hendrik Reinders, Jeffrey C. Glennon, Guus J. M. van Scharrenburg, Mayke B. Hesselink, Feenstra Roelof W, Long Stephen K, Martina A.W. van der Neut, Andrew C. McCreary, and Eric Ronken
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Agonist ,Male ,medicine.medical_specialty ,Quinpirole ,medicine.drug_class ,Recombinant Fusion Proteins ,CHO Cells ,Pharmacology ,Partial agonist ,Binding, Competitive ,Piperazines ,Cellular and Molecular Neuroscience ,Radioligand Assay ,Dopamine receptor D1 ,Dopamine receptor D3 ,Internal medicine ,Dopamine receptor D2 ,Cricetinae ,medicine ,Cyclic AMP ,Inverse agonist ,Animals ,Humans ,Drug Interactions ,Rats, Wistar ,Lisuride ,Benzoxazoles ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Receptors, Dopamine D2 ,Colforsin ,Receptors, Dopamine D3 ,Brain ,Parkinson Disease ,Serotonin 5-HT1 Receptor Agonists ,Rats ,Serotonin Receptor Agonists ,Endocrinology ,Dopamine receptor ,Guanosine 5'-O-(3-Thiotriphosphate) ,Dopamine Agonists ,Receptor, Serotonin, 5-HT1A ,Endogenous agonist - Abstract
Present Parkinson's disease treatment strategies are far from ideal for a variety of reasons; it has therefore been suggested that partial dopamine receptor agonism might be a potential therapeutic approach with potentially fewer side effects. In the present study, we describe the in vitro characterization of the nonergot ligand SLV308 (7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolonemonohydrochloride). SLV308 binds to dopamine D(2), D(3), and D(4) receptors and 5-HT(1) (A) receptors and is a partial agonist at dopamine D(2) and D(3) receptors and a full agonist at serotonin 5-HT(1) (A) receptors. At cloned human dopamine D(2,L) receptors, SLV308 acted as a potent but partial D(2) receptor agonist (pEC(50) = 8.0 and pA(2) = 8.4) with an efficacy of 50% on forskolin stimulated cAMP accumulation. At human recombinant dopamine D(3) receptors, SLV308 acted as a partial agonist in the induction of [(35)S]GTPgammaS binding (intrinsic activity of 67%; pEC(50) = 9.2) and antagonized the dopamine induction of [(35)S]GTPgammaS binding (pA(2) = 9.0). SLV308 acted as a full 5-HT(1) (A) receptor agonist on forskolin induced cAMP accumulation at cloned human 5-HT(1) (A) receptors but with low potency (pEC(50) = 6.3). In rat striatal slices SLV308 concentration-dependently attenuated forskolin stimulated accumulation of cAMP, as expected for a dopamine D(2) and D(3) receptor agonist. SLV308 antagonized the inhibitory effect of quinpirole on K(+)-stimulated [(3)H]-dopamine release from rat striatal slices (pA(2) = 8.5). In the same paradigm, SLV308 had antagonist properties in the presence of quinpirole (pA(2) = 8.5), but the partial D(2) agonist terguride had much stronger antagonistic properties. In conclusion, SLV308 combines high potency partial agonism at dopamine D(2) and D(3) receptors with full efficacy low potency serotonin 5-HT(1) (A) receptor agonism and is worthy of profiling in in vivo models of Parkinson's disease.
- Published
- 2006
6. Principal Component Analysis Differentiates the Receptor Binding Profiles of Three Antipsychotic Drug Candidates from Current Antipsychotic Drugs.
- Author
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Jos H. M. Lange, Jan-Hendrik Reinders, Jeroen T. B. M. Tolboom, Jeffrey C. Glennon, Hein K. A. C. Coolen, and Chris G. Kruse
- Subjects
- *
RADIOLIGAND assay , *ANTIPSYCHOTIC agents , *WEIGHT gain , *CELL receptors - Abstract
The receptor binding affinities of the three drug candidates 1(SLV310), 2(SLV313), and 3(SLV314) were positioned against the results from nine (a)typical antipsychotic drugs. The receptor binding data from sixteen monoaminergic receptors served as the input in a principal component analysis (PCA). The PCA outcome revealed a unique binding profile of 1, 2, and 3as compared with the reference compounds 4−8and 10−12. The weight gain inducing antipsychotics 6−8clustered in the PCA by scoring strongly negative for factor 1. The hyperprolactinaemia related antipsychotics 4, 5, 10, and 12clustered by their negative scores for factor 2. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
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7. In vitro and in vivo inhibition of chicken brain neurotoxic esterase by leptophos analogs
- Author
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Jan Hendrik Reinders, Robert A. Metcalf, Larry G. Hansen, and Robert L. Metcalf
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Oxon ,biology ,Health, Toxicology and Mutagenesis ,General Medicine ,Esterase ,In vitro ,chemistry.chemical_compound ,chemistry ,Biochemistry ,In vivo ,Oral administration ,Enzyme inhibitor ,biology.protein ,Pi ,Leptophos ,Agronomy and Crop Science - Abstract
Inhibition of chicken brain neurotoxic esterase (NTE) by a series of O -halogenated-phenyl- O -alkyl phenylphosphonates was studied in vitro . The “apparent” activity was found to consist of “true” NTE (sensitive to mipafox) plus a minor mipafox-resistant component. The pI 50 of O -(2,6-dichlorophenyl) O -methyl phenylphosphonate for “true” NTE was 6.65, whereas it was about 3 for mipafox-resistant hydrolysis of phenyl valerate. This compound is suitable as an alternative to mipafox in the assay of “true” NTE, whereas the use of leptophos oxon gives a less accurate measure. The ethoxy analogs are about as potent in vitro as the corresponding methoxy compounds. Leptophosoxon and ethoxyleptophosoxon are more potent in vitro inhibitors than desbromoleptophosoxon. Within a like group of chlorinated phenylphosphonates, a reasonable correlation between in vitro neurotoxic esterase inhibition of the oxon and in vivo delayed neurotoxic potential by the corresponding phosphonothionate exists. In vivo inhibition of “apparent” NTE from chicken brain, studied 24 hr after an oral dose, is dose dependent for leptophos, ethoxyleptophos, and desbromoleptophos, the latter one being a very potent in vivo inhibitor. Ethoxyleptophos and leptophos have about equal in vivo esterase inhibitory properties. For desbromoleptophos and leptophos there is good agreement between the minimum dose causing delayed neurotoxicity and the dose leading to substantial inhibition of “apparent” NTE; ethoxyleptophos, on the other hand, inhibits the esterase at a dose much lower than the one which is neurotoxic. Several possible explanations for this discrepancy are considered.
- Published
- 1983
8. Comparison of secretion and subcellular localization of von Willebrand protein with that of thrombospondin and fibronectin in cultured human vascular endothelial cells
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J. A. Van Mourik, Jan Hendrik Reinders, N. R. Hunter, H. A. A. Van Heugten, P. G. De Groot, Mervin D. Gonsalves, Joke Zandbergen, and J. Dawes
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Von Willebrand factor type C domain ,Umbilical Veins ,Endothelium ,Fluorescent Antibody Technique ,Cell Fractionation ,Von Willebrand factor ,von Willebrand Factor ,Thrombospondin 1 ,Centrifugation, Density Gradient ,medicine ,Humans ,Thrombospondins ,Molecular Biology ,Cells, Cultured ,Glycoproteins ,Thrombospondin ,biology ,Cell Biology ,Blood Coagulation Factors ,Extracellular Matrix ,Fibronectins ,Cell biology ,Organoids ,Fibronectin ,Endothelial stem cell ,medicine.anatomical_structure ,Biochemistry ,biology.protein ,Tetradecanoylphorbol Acetate - Abstract
Cultured human vascular endothelial cells synthesize von Willebrand protein, thrombospondin and fibronectin. These proteins are secreted in the culture medium and incorporated into the extracellular matrix. We have compared the subcellular localization and the secretion of these proteins in response to stimulants in cultured human umbilical vein endothelial cells. Density gradient centrifugation using colloidal silica showed that the storage and secretion organelle with von Willebrand protein did not contain thrombospondin or fibronectin. Indirect immunofluorescence microscopy indicated that thrombospondin and fibronectin are not located in the rod-shaped organelles containing von Willebrand protein. Thrombin, ionophore A23187 and phorbol myristate acetate did not affect secretion of thrombospondin and fibronectin, while von Willebrand protein secretion was stimulated upon incubation of cells with these agents for 30 min. Prolonged incubation of cultured endothelial cells after a 1-h treatment with phorbol myristate acetate resulted in an increased secretion of von Willebrand protein into the conditioned medium; in contrast, accumulation of thrombospondin and fibronectin in endothelial cell-conditioned medium was decreased. These findings indicate that, unlike in platelets, these major endothelial proteins are not located in the same subcellular compartments. Von Willebrand protein is distinguished from thrombospondin and fibronectin both by its unique subcellular localization and its secretion rate in response to stimuli.
- Published
- 1985
9. Perturbation of human endothelial cells by thrombin or PMA changes the reactivity of their extracellular matrix towards platelets
- Author
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Jan Hendrik Reinders, J. J. Sixma, and P G de Groot
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Blood Platelets ,Von Willebrand factor type C domain ,Umbilical Veins ,Platelet Aggregation ,Endothelium ,Thrombin ,Von Willebrand factor ,Cell–cell interaction ,medicine ,Humans ,Platelet ,Cells, Cultured ,biology ,Articles ,Cell Biology ,Extracellular Matrix ,Cell biology ,Fibronectin ,Endothelial stem cell ,Kinetics ,medicine.anatomical_structure ,Biochemistry ,biology.protein ,Tetradecanoylphorbol Acetate ,medicine.drug - Abstract
In this study we have examined the influence of perturbation of endothelial cells on the amounts of fibronectin and von Willebrand factor in their extracellular matrix and the consequences of a changed composition of the matrix on platelet adhesion. For this purpose, we have used an in vitro perfusion system with which we can investigate the interactions of platelets in flowing blood with cultured endothelial cells and their extracellular matrix (Sakariassen, K. S., P. A. M. M. Aarts, P. G. de Groot, W. P. M. Houdgk, and J. J. Sixma, 1983, J. Lab. Clin Med. 102:522-535). Treatment of endothelial cells with 0.1-1.0 U/ml thrombin for 2 h increased the reactivity of the extracellular matrix, isolated after the thrombin treatment, towards platelets by approximately 50%. The increased reactivity did not depend on de novo protein synthesis but was inhibited by 3-deazaadenosine, an inhibitor of phospholipid methylation, which also inhibits the stimulus-induced instantaneous release of von Willebrand factor from endothelial cells. However, no changes in the amounts of von Willebrand factor and fibronectin in the matrix were detected. Thrombin may change the organization of the matrix proteins, not the composition. When endothelial cells were perturbed with the phorbol ester PMA or thrombin for 3 d, the adhesion of platelets to the extracellular matrix of treated cells was strongly impaired. This impairment coincided with a decrease in the amounts of von Willebrand factor and fibronectin present in the matrix. These results indicate that, after perturbation, endothelial cells regulate the composition of their matrix, and that this regulation has consequences for the adhesion of platelets.
- Published
- 1987
10. Contents, Vol. 18, 1988
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Evan Kaiser, Grazia Conforti, Raymond R. Schleef, David J. Loskutoff, David M. Stern, Klaus T. Preissner, Jan A. van Mourik, K.S. Pettersen, Patricia F. E. M. Nievelstein, Jan Hendrik Reinders, Michael R. Buchanan, Jan J. Sixma, C L Verweij, JC Giltay, Peter P. Nawroth, T A Haas, Gayle L. Crozier, Victor W.M. van Hinsbergh, Adriana Zanetti, Philip G. de Groot, Elisabetta Dejana, and H. Prydz
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medicine.medical_specialty ,Pathology ,business.industry ,Physiology (medical) ,General surgery ,Medicine ,Hematology ,business - Published
- 1988
11. Polar secretion of von Willebrand factor by endothelial cells
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H.-J. M. Brinkman, Marijke F van Buul-Wortelboer, Jan A. van Mourik, Jan Hendrik Reinders, and Willem G. van Aken
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Umbilical Veins ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Stimulation ,In Vitro Techniques ,Matrix (biology) ,Umbilical vein ,Von Willebrand factor ,hemic and lymphatic diseases ,Internal medicine ,von Willebrand Factor ,medicine ,Humans ,Secretion ,Molecular Biology ,biology ,Cell Biology ,Cell biology ,Endothelial stem cell ,Secretory protein ,Endocrinology ,Cell culture ,cardiovascular system ,biology.protein ,Endothelium, Vascular ,Subcellular Fractions ,circulatory and respiratory physiology - Abstract
Human umbilical vein endothelial cells cultured on a collagen lattice were used to study the polarity of von Willebrand factor (vWF) secretion. Endothelial cells cultured under these conditions allow direct measurements of substances released at both the apical and basolateral surface. The constitutive secretion of vWF was compared to the release of vWF from their storage granules after stimulation (regulated secretion). The basal, constitutive release of vWF occurs into both the apical and subendothelial direction. The rate of accumulation of vWF to the subendothelial direction is about three times higher than the amount of vWF secreted into the lumenal medium per unit of time. However, upon stimulation of confluent endothelial cell monolayers with phorbol myristate acetate, endothelial cells predominantly secrete vWF at the lumenal surface. Under these conditions, vWF does not accumulate in the collagen matrix. Thus, endothelial cells are able to organize themselves into a polarized monolayer, in such a way that vWF secreted by the regulated pathway accumulates at the lumenal site, whereas resting endothelial cells release vWF predominantly at the opposite, basolateral surface.
- Published
- 1989
12. Cigarette smoke impairs endothelial cell prostacyclin production
- Author
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Jan Hendrik Reinders, J. A. Van Mourik, P. G. De Groot, and Herm Jan M Brinkman
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Nicotine ,medicine.medical_specialty ,Programmed cell death ,Cell Survival ,Prostaglandin ,Prostacyclin ,6-Ketoprostaglandin F1 alpha ,Arachidonic Acids ,Pathogenesis ,chemistry.chemical_compound ,Von Willebrand factor ,Smoke ,Internal medicine ,Tobacco ,von Willebrand Factor ,medicine ,Humans ,Endothelium ,Calcimycin ,Cells, Cultured ,Arachidonic Acid ,biology ,Chemistry ,Thrombin ,Epoprostenol ,Endothelial stem cell ,Plants, Toxic ,Endocrinology ,Biochemistry ,Prostaglandins ,biology.protein ,Tetradecanoylphorbol Acetate ,lipids (amino acids, peptides, and proteins) ,Cyclooxygenase ,Cardiology and Cardiovascular Medicine ,Cadmium ,medicine.drug - Abstract
Production of prostacyclin by endothelial cells is considered to be important in rendering the vessel wall nonthrombogenic. Cigarette smoking is an important risk factor in the pathogenesis of atherosclerosis. Here we show that the incubation of cultured human endothelial cells with a cigarette smoke condensate impaired the basal prostacyclin release. Also, the enhanced release of prostacyclin provoked by phorbol myristate acetate was inhibited by cigarette smoke condensate. Furthermore, cigarette smoke condensate impaired the thrombin-induced prostacyclin production. The production of prostacyclin from exogenous arachidonate was not affected by cigarette smoke condensate, indicating that cigarette smoke condensate constituents exert their inhibitory properties on the level of arachidonate mobilization from cellular phospholipids, rather than on cyclooxygenase or prostaglandin synthetase. The effects noted for cigarette smoke condensate could not be attributed to the cigarette smoke constituents nicotine and cadmium. While inhibiting the endothelial cell prostacyclin production significantly, cigarette smoke condensate did not cause cell death or impairment of secretory function, as measured by the release of von Willebrand factor. This in vitro study shows that impairment of an endothelial cell function is related to a risk factor for atherosclerosis.
- Published
- 1986
13. Isolation of a storage and secretory organelle containing Von Willebrand protein from cultured human endothelial cells
- Author
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Cornelia Loesberg, Mervin D. Gonsalves, Philip G. de Groot, Jan Hendrik Reinders, Joke Zandbergen, and Jan A. van Mourik
- Subjects
Von Willebrand factor type C domain ,Umbilical Veins ,Endothelium ,Cell Fractionation ,symbols.namesake ,Von Willebrand factor ,von Willebrand Factor ,Organelle ,Centrifugation, Density Gradient ,medicine ,Humans ,Molecular Biology ,Calcimycin ,Cells, Cultured ,biology ,Endoplasmic reticulum ,Cell Biology ,Golgi apparatus ,Molecular biology ,Blood Coagulation Factors ,Organoids ,Endothelial stem cell ,medicine.anatomical_structure ,Biochemistry ,biology.protein ,symbols ,Tetradecanoylphorbol Acetate ,Cell fractionation - Abstract
Von Willebrand protein was synthesized and secreted by human endothelial cells in culture. Ca2+ ionophore A23187 and phorbol myristate acetate stimulated the release of Von Willebrand protein from the cultured cells. Stimulated release was accompanied by the disappearance of rod-like structures from the cultured endothelial cells immunostained for Von Willebrand protein, suggesting the existence of a storage organelle for Von Willebrand protein in these cells (Loesberg, C., Gonsalves, M.D., Zandbergen, J., Willems, C., Van Aken, W.G., Stel, H.V., Van Mourik, J.A. and De Groot, P.G. (1983) Biochim. Biophys. Acta 763, 160-168). Cultured human endothelial cells were fractionated on a density gradient of colloidal silica. Von Willebrand protein was found in two organelle populations: a buoyant one sedimenting with a variety of cell organelle marker enzymes, including those of the Golgi apparatus, mitochondria, lysosomes, peroxisomes, endoplasmic reticulum and plasma membrane fragments (peak density of this fraction: 1.08 g X ml-1), and a dense one with a peak density of 1.12 g X ml-1. The dense organelles containing Von Willebrand protein were apparently free of other organelles. Stimulating Von Willebrand protein release with phorbol myristate acetate or Ca2+ ionophore A23187 resulted in a decrease or even complete disappearance of Von Willebrand protein from the high-density organelle fraction, implying a role of this organelle in the stimulus-induced release of Von Willebrand protein. The Von Willebrand protein content of the buoyant fraction was lowered to some extent or did not change upon incubation of the cells with ionophore A23187 and phorbol myristate acetate. Restoration of Von Willebrand protein content of the dense organelle fraction after stimulation occurred within 2 days; this was accompanied by recurrence of immunostaining of rod-shaped structures in cells and an increase in cellular Von Willebrand protein. The excretion of restored Von Willebrand protein could be stimulated again.
- Published
- 1984
14. In vitro neurotoxic esterase assay using leptophos oxon analogs as inhibitors
- Author
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Robert L. Metcalf, Larry G. Hansen, and Jan Hendrik Reinders
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Carboxylic Ester Hydrolases ,Insecticides ,Stereochemistry ,Leptophos oxon ,Neurotoxic esterase ,Brain ,General Medicine ,Toxicology ,In vitro ,chemistry.chemical_compound ,Structure-Activity Relationship ,Leptophos ,Organophosphorus Compounds ,Biochemistry ,chemistry ,Structure–activity relationship ,Animals ,Chickens - Abstract
In comparing neurotoxic esterase (NTE) inhibition properties of a series of phenylphosphonates, it was discovered that certain compounds including leptophos inhibited mipafox-insensitive phenylvalerate hydrolases. This leads to erroneous values for NTE inhibition which can be corrected by a differential assay: the total amount of mipafox-insensitive activity is determined with O-(2,6-dichlorophenyl)O-methyl phenylphosphonate and subtracted from the apparent NTE determined with the test compound before calculating pI50's.
- Published
- 1983
15. Storage and secretion of von Willebrand factor by endothelial cells
- Author
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Jan Hendrik Reinders, J. A. Van Mourik, J. J. Sixma, and P. G. De Groot
- Subjects
Von Willebrand factor type C domain ,Organelles ,Platelet Aggregation ,Vesicle ,Hematology ,Biology ,Molecular biology ,Umbilical vein ,Extracellular matrix ,Endothelial stem cell ,Microscopy, Electron ,Biochemistry ,Von Willebrand factor ,Ristocetin ,hemic and lymphatic diseases ,Physiology (medical) ,von Willebrand Factor ,Weibel–Palade body ,biology.protein ,Centrifugation, Density Gradient ,Humans ,Tetradecanoylphorbol Acetate ,Secretion ,Endothelium ,Cells, Cultured - Abstract
Endothelial cells synthesize and store von Willebrand factor. We have studied the storage and secretion of von Willebrand factor in cultured human umbilical vein endothelial cells. In particular, we were interested in the nature of the storage compartment and the effects of perturbation on the storage and secretion processes. The storage compartment for von Willebrand factor was isolated from homogenates of endothelial cells. By an immunostaining technique the isolated vesicles stained for von Willebrand factor. The staining pattern was similar to that of Weibel-Palade bodies in intact endothelial cells. We concluded that the storage compartment containing von Willebrand factor is identical to the Weibel-Palade body. The von Willebrand factor of the isolated storage vesicles is predominantly constructed of polypeptide chains with a Mr of 220 kD. On the other hand, von Willebrand factor continuously secreted by endothelial cells is constructed of both a 220 kD and a larger precursor (apparent Mr of 275 kD) subunit. The storage vesicles contain von Willebrand factor that supports ristocetin-induced platelet aggregation. Thus, endothelial cells store fully processed, biologically active von Willeband factor within Weibel-Palade bodies. Short-term ( < 1 h) treatment of endothelial cells with the perturbing phorbol ester 4β-phorbol-12-myristate-13-acetate (PMA) results in release of cellular stored von Willebrand factor. 24–48 h after exposure to PMA the endothelial cell distribution of von Willeband factor is changed distinctly. While the contents of the von Willebrand factor storage sites in the cells are gradually restored within 48 h, enhanced amounts of von WiUebrand factor are secreted into the medium. The number as well as the size of von Willebrand factor storage granules in the endothelial cells increase after exposure to phorbol ester, as determined by immunofiuorescence microscopy. Phorbol ester treated cells release stored von Willebrand factor 48 h after they have been stimulated. PMA decreases the von Willebrand factor contents of the extracellular matrix; the deposition of von Willebrand factor in the subendothelium is blocked by PMA, whereas the degradation of matrix von Willebrand factor is not affected. Thus, perturbation of endothelial cells changes the cellular distribution of von Willebrand factor.
- Published
- 1988
16. PERTURBATION OF CULTURED ENDOTHELIAL CELLS ALTERS CELLULAR VON WILLEBRAND FACTOR DISTRIBUTION
- Author
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Ph G de Groot, Jan Hendrik Reinders, C L Verweii, and J A V Mourlk
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Von Willebrand factor ,biology ,Chemistry ,hemic and lymphatic diseases ,cardiovascular system ,biology.protein ,Biophysics ,Perturbation (astronomy) ,circulatory and respiratory physiology - Abstract
Endothelial cells, cultured from human umbilical veins, synthesize von Willebrand Factor (vWF), that is stored by the cells in Weibel-Palade bodies, secreted into the medium and incorporated into the extracellular matrix underneath the cells. We have studied the influence of perturbation by phorbol esters and thrombin on the cellular distribution of vWF. Short-term (< 1 hour) treatment of endothelial cells with phorbol ester PMA or thrombin resulted in the release of cellular stored vWF. Long-term treatment with perturbants evoked a distinct change in the endothelial cell distribution of vWF, evident 24 to 48 hours after exposure. While the contents of the vWF storage vesicles were gradually restored within 48 hours, enhanced amounts of vWF were secreted into the medium. However, PMA did not increase the endothelial cell contents of mRNA encoding for vWF. The number as well as the size of vWF storage granules in the cells increased after exposure to perturbants. The perturbed cells responded to stimuli in releasing stored vWF, the amounts secreted were even greater than those in control cells. The extracellular matrix lost its vWF contents as the result of PMA or thrombin treatment, by blocking deposition of vWF in the matrix, not by enhancing degradation of matrix vWF. In perfusion experiments, the adhesion of washed platelets onto the isolated matrix of perturbed cells was considerable less than that in controls. Addition of vWF to the perfusate overcame this impairment. Thus, perturbation of endothelial cells changes the cellular distribution of vWF.Supported in part by ZWO grants 13-30-31 and 13-90-91 and Netherlands Heart Foundation grant 28.004.
- Published
- 1987
17. Effects of dietary antioxidants on the biotransformation and porphyrinogenic action of hexachlorobenzene in two strains of rats
- Author
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Jutta Seidel, Jan-Hendrik Reinders, Anjo Strik, G. Koss, and Felix Debets
- Subjects
medicine.medical_specialty ,Porphyrins ,Chlorobenzenes ,Toxicology ,Antioxidants ,Hepatic porphyria ,chemistry.chemical_compound ,Basal (phylogenetics) ,Cytochrome P-450 Enzyme System ,Species Specificity ,In vivo ,Internal medicine ,medicine ,Hexachlorobenzene ,Animals ,Life Science ,Biotransformation ,Toxicologie ,Glutathione Transferase ,Rats, Inbred Strains ,General Medicine ,Glutathione ,medicine.disease ,Ascorbic acid ,In vitro ,Diet ,Rats ,Endocrinology ,Porphyria ,chemistry ,Biochemistry ,Liver ,Microsomes, Liver ,Female - Abstract
Groups of female Agus or Wistar rats were given hexachlorobenzene (HCB) (50 mg/kg body wt.) in olive oil by stomach tube every other day. HCB-treated animals were fed either on a basal powdered diet without extra added antioxidants or on the same basal diet supplemented with 0.15% ascorbic acid and 0.12% DL-α-tocopherolacetate. One of the HCB-treated Agus groups and one control group of Agus rats (both on a low-antioxidant diet) received by stomach tube 25 mg/kg body wt. of 3,5-di- tert -butyl-4-hydroxytoluene (BHT) every other day. Autopsies were made after 1, 2, 5 and 8 weeks. The Agus rats were highly porphyric after 8 weeks of HCB treatment, whereas the Wistar rats showed no symptoms of hepatic porphyria within that period. HCB significantly decreased the hepatic glutathione concentration in Wistar and Agus rats. Agus rats were found to possess lower levels of hepatic glutathione than Wistar rats. Moreover, the induction of ethoxyresorufin O -deethylase activity was 1.5–1.7-fold higher in the HCB-treated Agus rats than in the corresponding Wistar rats; whereas Agus rats showed less induction of glutathione- S -transferase activity. The ratio of the excreted amounts of phenolic metabolites to the sulfur-containing metabolites increased from about 0.05, after the 1st week, to 0.3 after the 8th week. There was no difference in the accumulation of HCB in the liver between the two strains. However, Agus rats were found to possess significantly higher concentrations of HCB metabolites in their livers than the Wistar rats; in addition, the capacity for methylating the thiophenolic metabolites in vivo appeared to be greater in the former strain. Wistar rats fed on a low-antioxidant diet excreted 2–3 times less HCB and metabolites than Wistar rats kept on a diet rich in antioxidants. The difference between Agus and Wistar rats in their susceptibility to the porphyrinogenic effect of HCB is discussed in the light of the above findings. In contrast to earlier observations in vitro, dietary antioxidants could not protect against the porphyrinogenic action of HCB in vivo. The dietary antioxidants even stimulated the onset of porphyria in HCB-fed Agus rats. The results point to an important role of glutathione and its transferring enzyme system in the inactivation of a reactive metabolite of HCB. This reactive species is suggested to be responsible for the disturbance of the hepatic heme synthesis.
- Published
- 1981
18. Perturbation of cultured human vascular endothelial cells by phorbol ester or thrombin alters the cellular von Willebrand factor distribution
- Author
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Richard C. Vervoorn, Jan Hendrik Reinders, Jan A. van Mourik, Cornelis L. Verweij, and Philip G. de Groot
- Subjects
Von Willebrand factor type C domain ,medicine.medical_specialty ,Physiology ,Clinical Biochemistry ,Phorbol ester ,Umbilical vein ,Extracellular matrix ,Thrombin ,Von Willebrand factor ,hemic and lymphatic diseases ,Internal medicine ,Phorbol Esters ,von Willebrand Factor ,medicine ,Humans ,RNA, Messenger ,Cells, Cultured ,Phorbol 12,13-Dibutyrate ,Messenger RNA ,biology ,Chemistry ,Cell Biology ,Molecular biology ,Extracellular Matrix ,Endothelial stem cell ,Endocrinology ,biology.protein ,Tetradecanoylphorbol Acetate ,Endothelium, Vascular ,circulatory and respiratory physiology ,medicine.drug ,Subcellular Fractions - Abstract
We have studied the influence of perturbation of cultured human umbilical vein endothelial cells on the distribution of the von Willebrand factor. As shown previously, short-term (less than 1 hr) treatment of endothelial cells with the phorbol ester 4 beta-phorbol 12-myristate 13-acetate (PMA) or thrombin resulted in the release of cellular stored von Willebrand factor. Long-term treatment with PMA or thrombin evoked a distinct change in the endothelial cell distribution of von Willebrand factor, evident 24 to 48 hrs after exposure. Whereas the contents of the von Willebrand factor storage sites in the cells were gradually restored within 48 hrs, enhanced amounts of von Willebrand factor were secreted into the medium. However, PMA did not increase the endothelial cell contents of mRNA encoding for von Willebrand factor. The number as well as the size of von Willebrand factor storage granules in the endothelial cells increased after exposure to the phorbol ester, as determined by immunofluorescence microscopy. A second treatment with PMA or thrombin, 48 hrs after cells had been stimulated with these agents, resulted again in the instantaneous release of von Willebrand factor. PMA and thrombin caused a decrease in the von Willebrand factor contents of the extracellular matrix. Pulse-chase experiments revealed that PMA blocked the deposition of von Willebrand factor in the subendothelium, whereas PMA did not affect the degradation of matrix von Willebrand factor. Thus, perturbation of endothelial cells changes the cellular distribution of von Willebrand factor.
- Published
- 1987
19. Subject Index, Vol. 18, 1988
- Author
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Evan Kaiser, K.S. Pettersen, T A Haas, Grazia Conforti, Victor W.M. van Hinsbergh, Raymond R. Schleef, Philip G. de Groot, Peter P. Nawroth, Michael R. Buchanan, Jan Hendrik Reinders, Jan J. Sixma, Klaus T. Preissner, JC Giltay, Jan A. van Mourik, C L Verweij, Adriana Zanetti, David M. Stern, Elisabetta Dejana, Patricia F. E. M. Nievelstein, David J. Loskutoff, Gayle L. Crozier, and H. Prydz
- Subjects
medicine.medical_specialty ,Index (economics) ,business.industry ,Physiology (medical) ,Physical therapy ,medicine ,Subject (documents) ,Hematology ,business ,Surgery - Published
- 1988
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