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Concentration Dependent Manner (concentration + dependent_manner)
Selected AbstractsPROPERTIES OF CYSTEINE PROTEINASE INHIBITORS FROM BLACK GRAM AND RICE BEANJOURNAL OF FOOD BIOCHEMISTRY, Issue 3 2001SOOTTAWAT BENJAKUL ABSTRACT Cysteine proteinase inhibitors (CPI) were purified to 59 and 54 fold from black gram (Vignaraungo (L.) Hepper) and rice bean (Vignaumbellata Thunb.), respectively, by using heal treatment, followed by chromatography on a carboxymethyl (CM)-papain-Sepharose affinity column. The purified inhibitors were highly inhibitory to papain and Pacific whiting cathepsin L in a concentration dependent manner. They were detected as a dark band on tricine-SDS-PAGE gel stained for inhibitory activity. The apparent molecular weights of purified CPI from black gram and rice bean seeds were estimated to be 12, 000 daltons. The purified inhibitors were thermostable up to 90C and active in the neutral and alkaline pH ranges. [source] INHIBITION OF GEL WEAKENING OF THREADFIN BREAM SURIMI USING THAI LEGUME SEED PROTEINASE INHIBITORSJOURNAL OF FOOD BIOCHEMISTRY, Issue 5 2000SOOTTAWAT BENJAKUL ABSTRACT Partially purified proteinase inhibitors from cowpea (Vigna unguiculata (L) Wasp), pigeon pea (Cajanus cajan (L.) Millsp.) and bdmbara groundnuts (Voandzeia subterranea (L.) Thou) effectively inhibited sarcoplasmic modori-inducing proteinase extracted from threadfin bream muscle in a concentration dependent manner. Incorporation of these proteinase inhibitors into threadfin bream surimi partially inhibited autolytic degradation and increased the gel force and deformation. Combination of setting and incorporating proteinase inhibitors from cowpea and bambara groundnut var. HY at the level of 30 Kcunits/g resulted in an increase in gel force and deformation by 60% and 26%, respectively. However, the lightness and whiteness of surimi gels decreased slightly when the proteinase inhibitor was added at a level of 30 kunits/g. [source] Tuna Pepsin: Characteristics and Its Use for Collagen Extraction from the Skin of Threadfin Bream (Nemipterus spp.)JOURNAL OF FOOD SCIENCE, Issue 5 2008S. Nalinanon ABSTRACT:, Pepsin from the stomach of albacore tuna, skipjack tuna, and tongol tuna was characterized. Pepsin from all tuna species showed maximal activity at pH 2.0 and 50 °C when hemoglobin was used as a substrate. Among the stomach extract of all species tested, that of albacore tuna showed the highest activity (40.55 units/g tissue) (P < 0.05). Substrate-Native-PAGE revealed that pepsin from albacore tuna and tongol tuna consisted of 2 isoforms, whereas pepsin from skipjack tuna had only 1 form. The activity was completely inhibited by pepstatin A, while EDTA (ethylenediaminetetraacetic acid), SBTI (soybean trypsin inhibitor), and E-64 (1-(L -trans-epoxysuccinyl-leucylamino)-4-guanidinobutane) exhibited negligible effect. The activity was strongly inhibited by SDS (sodium dodecyl sulfate) (0.05% to 0.1%, w/v). Cysteine (5 to 50 mM) also showed an inhibitory effect in a concentration dependent manner. ATP, molybdate, NaCl, MgCl2, and CaCl2 had no impact on the activity. When tuna pepsin (10 units/g defatted skin) was used for collagen extraction from the skin of threadfin bream for 12 h, the yield of collagen increased by 1.84- to 2.32-fold and albacore pepsin showed the comparable extraction efficacy to porcine pepsin. The yield generally increased with increasing extraction time (P < 0.05). All collagen obtained with the aid of tuna pepsin showed similar protein patterns compared with those found in acid-solubilized collagen. Nevertheless, pepsin from skipjack tuna caused the degradation of , and , components. All collagens were classified as type I with large portion of ,-chain. However, proteins with molecular weight (MW) greater than 200 kDa were abundant in acid-solubilized collagen. [source] Toxic effect of blood components on perinatal rat subventricular zone cells and oligodendrocyte precursor cell proliferation, differentiation and migration in cultureJOURNAL OF NEUROCHEMISTRY, Issue 5 2009Packiasamy A. R. Juliet Abstract The germinal matrix of human brain gives rise to oligodendrocytes and astrocytes after mid-gestation. Hemorrhage in the germinal matrix of premature infants is associated with suppressed cell proliferation. We hypothesize that soluble blood constituents have an adverse effect on the proliferation of cultured rat subventricular zone (SVZ) cells and the proliferation, migration, and differentiation of oligodendrocyte progenitor cells (OPC). Using caspase 3 activation and lactate dehydrogenase release assays, rat plasma, serum, thrombin, and kallikrein killed SVZ cells when grown in the presence (but not absence) of platelet derived growth factor. Plasma and serum killed OPC at 1 : 1 to 1 : 100 dilutions. Using a bromodeoxyuridine incorporation assay OPC proliferation was reduced by plasma, serum, thrombin and plasmin. Blood proteins also suppressed OPC migration in a concentration dependent manner. However, differentiation of OPC into myelin basic protein expressing cells was suppressed only by thrombin. We conclude that soluble blood components, particularly thrombin, have an adverse effect on maturing SVZ cells and OPC derived from newborn rat brain. [source] Potentiation of PGE2 -mediated cAMP production during neuronal differentiation of human neuroblastoma SK-N-BE(2)C cellsJOURNAL OF NEUROCHEMISTRY, Issue 2 2001Se-Young Choi The prostaglandin-evoked cAMP production was studied in human neuroblastoma SK-N-BE(2)C cells during neuronal differentiation induced by all- trans retinoic acid. The incubation with 5 µm all- trans retinoic acid for 4,6 days promoted neurite outgrowth of cells. After differentiation, prostaglandin E2 (PGE2)-induced cAMP production was dramatically increased, whereas forskolin- and AlF -induced cAMP productions were not changed. The increase reached maximum after 4-days of incubation with all- trans retinoic acid. The differentiation caused an increase in the maximal response and a decrease in the half-maximal effective concentration of the PGE2 -induced cAMP production. In addition, the binding of [3H]PGE2 to membrane receptors was enhanced in differentiated cells. However, the order of potency of the various prostaglandins (PGE1 = PGE2 > PGD2 = PGF2, = PGI2) in cAMP production did not change during the differentiation, suggesting that mainly E-prostanoid (EP) receptors were involved. Butaprost, an EP2 receptor specific agonist, increased the cAMP level in a concentration dependent manner and had a similar potentiating effect on cAMP production as PGE2 upon differentiation. Northern blot analysis using the human cDNA probes shows that the EP2 mRNA level was about seven times higher in differentiated cells, while the dopamine ,-hydroxylase (DBH) mRNA completely disappeared. Our results, thus, suggest that elevated gene expression of the prostanoid EP2 receptor results in an increase in the PGE2 -evoked cAMP production in SK-N-BE(2)C cells during neuronal differentiation. [source] Titanium particles induce the immediate early stress responsive chemokines IL-8 and MCP-1 in osteoblastsJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 3 2002Elizabeth A. Fritz Abstract Exposure of human osteoblasts to ultrafine titanium (Ti) particles has been shown to alter osteoblast gene expression. We previously reported that Ti particles can increase IL-6 release and suppress the gene expression of procollagens ,1[I] and ,1[III] in human osteoblasts. In this study, we now demonstrate that Ti particles can rapidly induce the chemotactic cytokines interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1), two immediate early stress responsive chemokines important for the activation and chemotaxis of neutrophils and macrophages, respectively. In MG-63 osteosarcoma cells and bone marrow derived primary osteoblasts Ti particles selectively increased the steady state levels of IL-8 and MCP-1 mRNA in a time and concentration dependent manner. The increased chemokine mRNA correlated with increased secretion of IL-8 and MCP-1 protein. Actinomycin D, a potent RNA polymerase II inhibitor, blocked the Ti particle induction of IL-8 and MCP-1 mRNA expression, whereas cycloheximide, which inhibits protein synthesis, failed to inhibit chemokine gene expression suggesting Ti particles directly target activation of chemokine gene transcription. Consistent with a transcriptional mechanism not involving new protein synthesis, we demonstrate that Ti particles induce the binding of the p65 and p50 subunits of the latent transcription factor NF-,B to the IL-8 gene promoter. Taken together, these data demonstrate that Ti particles can activate transcription of the stress responsive chemokine genes IL-8 and MCP-1 in human osteoblasts. © 2002 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved. [source] Omalizumab decreases nonspecific airway hyperresponsiveness in vitroALLERGY, Issue 2 2007P. Berger Background:, In asthmatic patients, both symptoms and hyperresponsiveness are related to immunoglobulin E (IgE) concentration in serum. The anti-IgE monoclonal antibody omalizumab improved the control of asthma, but its effect on airway hyperresponsiveness is controversial. Passive sensitization reproduced in vitro a bronchial hyperresponsiveness, an increase in IgE bearing cells, and a mast cell degranulation. This study was designed to examine the effect of omalizumab on passive sensitization-induced hyperresponsiveness, alterations in IgE positive inflammatory cells and mast cell degranulation within the bronchial wall. Methods:, Proximal (3,5 mm diameter) and distal (0.5,1.5 mm diameter) human bronchi dissected out from 10 lung specimens were incubated in normal or asthmatic serum containing various concentrations of omalizumab. Contractile responses to histamine or Dermatophagoides pteronyssinus (D. pter) were recorded using an organ bath system and expressed as percentage of maximal contractile response to acetylcholine (ACh). Immunohistochemistry was performed using monoclonal antibodies directed against IgE or tryptase. Mast cells were classified as fully granulated (type I), partly (type II) or largely degranulated (type III). Results:, The specific bronchial hyperresponsiveness to D. pter and the nonspecific bronchial hyperresponsiveness to histamine following passive sensitization were significantly inhibited by omalizumab in both distal and proximal airways. Passive sensitization-induced increase in IgE positive cells was also abolished by omalizumab in a concentration dependent manner. Mast cell degranulation which was inhibited by omalizumab was positively correlated with the contractile response to D. pter. Conclusions:, Omalizumab blocks specific and nonspecific bronchial hyperresponsiveness. Anti-IgE also decreases IgE bearing cell number and mast cell degranulation. [source] EGF-induced EGF-receptor and MAP kinase phosphorylation in goat cumulus cells during in vitro maturationMOLECULAR REPRODUCTION & DEVELOPMENT, Issue 4 2005Laurence Gall Abstract EGF has been shown to influence meiotic maturation and development competence of oocyte in various mammalian species. We previously reported, in goat, that the EGF receptor (EGF-R) was present both on cumulus cells and oocytes. Here, EGF-induced signaling was investigated during the in vitro maturation process in goat cumulus,oocyte complexes (COCs). Cumulus cells and oocytes were subjected to Western immunoblotting analysis using anti-MAP kinase, anti-phosphotyrosine, anti-phospho MAP kinase, and anti-phospho EGF-R antibodies. We demonstrated that treatment with EGF during the in vitro maturation process induced rapid tyrosine phosphorylation of EGF-R in a time and concentration dependent manner in cumulus cells. A similar pattern of activation by phosphorylation was observed for MAP kinase upon EGF stimulation. AG 1478, an inhibitor of the EGF kinase, suppressed EGF-stimulated phosphorylation of EGF-R and also affected the MAP kinase activation. Treatment with the MEK inhibitor PD 98059 abolished EGF-induced MAP kinase activation. We did not observe oocyte EGF-R phosphorylation in our experiments during the in vitro maturation process. Our data indicate, in goat cumulus cells, that activation of EGF-R by EGF triggers signaling through the MAP kinase pathway during in vitro maturation. This supports the hypothesis that the major site of action for EGF, that regulates oocyte maturation, is the cumulus cell. Mol. Reprod. Dev. © 2005 Wiley-Liss, Inc. [source] Estradiol-antagonistic activity of phenolic compounds from leguminous plants,PHYTOTHERAPY RESEARCH, Issue 3 2008B. Pinto Abstract Natural flavonoids are currently receiving much attention because of their estrogenic and antiestrogenic properties. Six isoflavones (isoprunetin, isoprunetin 7- O - , - d -glucopyranoside, isoprunetin 4,,7-di- O - , - d -glucopyranoside, genistein, genistein 7-O- , - d -glucopyranoside, daidzein), four flavones (luteolin, luteolin 7-O- , - d -glucopyranoside, luteolin 4,-O- , - d -glucopyranoside, licoflavone C), isolated from Genista morisii and G. ephedroides (two Leguminosae plants of the Mediterranean area) together with two structurally related pterocarpans, bitucarpin A and erybraedyn C, isolated from Bituminaria bituminosa (Leguminosae), were tested for the antagonist activity by a yeast based estrogen receptor assay (Saccharomyces cerevisiae RMY326 ER-ERE). Most compounds inhibited the estradiol-induced transcriptional activity in a concentration dependent manner. In particular, for the flavone luteolin 77% inhibition of the induced , -galactosidase activity was observed. Interestingly, licoflavone C exhibited a dose-dependent antagonistic activity at concentrations up to 10,4 m, but stimulated , -galactosidase expression at higher concentrations resulting in a U-shaped-like dose-response curve. Copyright © 2007 John Wiley & Sons, Ltd. [source] The Chinese herbal preparation Qing Yi Tang (QYT) improves intestinal myoelectrical activity and Increases intestinal transit during acute pancreatitis in RodentsPHYTOTHERAPY RESEARCH, Issue 4 2007Yong-Yu Li Abstract The aim was to investigate alterations of intestinal motility in models of acute pancreatitis and to investigate the effects of the Chinese herbal preparation Qing Yi Tang (QYT) on these alterations. Upper gastrointestinal transit was evaluated in mice following induction of mild acute pancreatitis (MAP) using caerulein. Myoelectrical activity was recorded in rats after induction of severe acute pancreatitis (SAP) using sodium deoxycholate (SDOC). The contractility of jejunum segments was evaluated in the presence of SDOC, lipopolysaccharide (LPS) and trypsin. QYT accelerated the transit in MAP mice in a concentration dependent manner. Slow wave activity of smooth muscle in rat stomach and jejunum remained unchanged following SAP, but the spiking activity was significantly decreased, with bursts of 7.2 ± 2.6/10 min compared with 47.9 ± 13.2/10 min without SAP (p < 0.01). QYT reversed this decrease. Additionally, the amplitudes of slow waves and spikes were enhanced by QYT in SAP rats. The tension and amplitude of spontaneous contractile activity was reduced by SDOC and LPS and increased by trypsin. Gastrointestinal (GI) transit is altered by SAP but not by MAP. The Chinese herbal preparation QYT improves disturbed motility in AP by stimulating myoelectrical activity and accelerating GI transit. Copyright © 2007 John Wiley & Sons, Ltd. [source] Myocardium distribution of sertindole and its metabolite dehydrosertindole in guinea-pigsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2006Mireille Canal-Raffin Abstract Sertindole, like other atypical antipsychotics, has been shown to increase the action potential duration and QT interval in a concentration dependent manner, in in vitro electrophysiological studies. However, this does not always translate into increased duration of the QT interval, increased risk of torsade de pointes or sudden death in clinical practice. The reasons for these apparent discrepancies are unclear and many studies have underscored the importance of the interpretation of in vitro electrophysiological data in the context of other pharmacodynamic (e.g. cardiac ion channels target, receptor affinity) and pharmacokinetic parameters (total plasma drug concentration and drug distribution). To address the possible relevance of the concentrations used in experimental studies, the myocardium distribution of sertindole and its metabolite was determined after single and repeated intraperitoneal administration to guinea-pigs. The data suggest that the plasma concentration appears to predict the concentration in the myocardium and that the myocardium concentrations of sertindole are 3.1 times higher than plasma concentrations. Using these data, the relevance of in vitro electrophysiological studies to clinical plasma concentrations has been appraised. Copyright © 2006 John Wiley & Sons, Ltd. [source] Population pharmacokinetics of intravenously and orally administered docetaxel with or without co-administration of ritonavir in patients with advanced cancerBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2010Stijn L. W. Koolen WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Docetaxel is an approved drug for the treatment of cancer of various primary origins. , An oral docetaxel regimen is warranted because of patient convenience and the opportunity to investigate more schedule intensive treatment regimens. , Co-administration of ritonavir significantly enhanced the apparent oral bioavailability of docetaxel. WHAT THIS STUDY ADDS , This study demonstrates that ritonavir increased the absorption of docetaxel after oral administration. , Furthermore, we showed that the clearance of docetaxel was inhibited in a concentration dependent manner. , The developed model will be used for further development of an oral docetaxel regimen. AIM Docetaxel has a low oral bioavailability due to affinity for P-glycoprotein and cytochrome P450 (CYP) 3A4 enzymes. Inhibition of the CYP3A4 enzymes by ritonavir resulted in increased oral bioavailability. The aim of this study was to develop a population pharmacokinetic (PK) model and to evaluate and quantify the influence of ritonavir on the PK of docetaxel. METHODS Data from two clinical trials were included in the data analysis, in which docetaxel (75 mg m,2 or 100 mg) had been administered intravenously or orally (10 mg or 100 mg) with or without co-administration of oral ritonavir (100 mg). Population modelling was performed using non-linear mixed effects modelling. A three-compartment model was used to describe the i.v. data. PK data after oral administration, with or without co-administration of ritonavir, were incorporated into the model. RESULTS Gut bioavailability of docetaxel increased approximately two-fold from 19 to 39% (CV 13%) with ritonavir co-administration. The hepatic extraction ratio and the elimination rate of docetaxel were best described by estimating the intrinsic clearance. Ritonavir was found to inhibit in a concentration dependent manner the intrinsic clearance of docetaxel, which was described by an inhibition constant of 0.028 µg ml,1 (CV 36%). A maximum inhibition of docetaxel clearance of more then 90% was reached. CONCLUSIONS A PK model describing both the PK of orally and intravenously administered docetaxel in combination with ritonavir, was successfully developed. Co-administration of ritonavir lead to increased oral absorption and reduced elimination rate of docetaxel. [source] Vascular and Biology 05BRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue S1 2002L. Yea Background: Tight junctions govern the permeability of endothelial and epithelial cells. Changes in tight junction function are thus an early and key event in cancer metastasis and tissue permeability. This study sought to determine the role of oestrogen in the regulation of tight junctions and expression of occludin in endothelial cells. Methods: Human vascular endothelial cell line was incubated with 17-,-oestradiol at different concentrations (from 10,11m to 10,7m) over 1,24 h. Expression of occludin mRNA was determined using RT-PCR, and change of occludin protein using Western blotting. Transendothelial resistance (TER) was measured with an EVOM, and transendothelial cell permeability was determined using fluorescence labelled dextran (FITC-dextran 10) with a multichannel fluorescence reader. Results: 17-,-oestradiol reduced the expression of occludin mRNA in a time and concentration dependent manner with an obvious effect starting from 4 h. Reduced level of occludin protein was similarly seen after treatment with 17-,-oestradiol. Incubation of HECV with 17-,-oestradiol resulted in an increase in paracellular permeability by 9.9 ± 8.9 per cent at 10,10m (P > 0.05 versus control), 42.1 ± 15.2 per cent at 10,9m (P < 0.05 versus control), and 40.1 ± 22.4 per cent at 10,8m (P < 0.05, versus control). A decrease in the transendothelial cell resistance (TER) was seen with oestradiol (a reduction by 18.6 ± 16.6 per cent (P > 0.05 versus control), 31.5 ± 10.6 per cent (P < 0.01), or 44.4 ± 18.4 per cent (P < 0.01), at concentration 10,10, 10,9, 10,8m, respectively. Conclusions: This study shows a perturbation of tight junction functions in endothelial cells by oestrogen, which may have implications in the aetiology of mastalgia and vascular spread of breast cancer. [source] The novel ruthenium,, -linolenic complex [Ru2(aGLA)4Cl] inhibits C6 rat glioma cell proliferation and induces changes in mitochondrial membrane potential, increased reactive oxygen species generation and apoptosis in vitroCELL BIOCHEMISTRY AND FUNCTION, Issue 1 2010Geise Ribeiro Abstract The present study reports the synthesis of a novel compound with the formula [Ru2(aGLA)4Cl] according to elemental analyses data, referred to as Ru2GLA. The electronic spectra of Ru2GLA is typical of a mixed valent diruthenium(II,III) carboxylate. Ru2GLA was synthesized with the aim of combining and possibly improving the anti-tumour properties of the two active components ruthenium and , -linolenic acid (GLA). The properties of Ru2GLA were tested in C6 rat glioma cells by analysing cell number, viability, lipid droplet formation, apoptosis, cell cycle distribution, mitochondrial membrane potential and reactive oxygen species. Ru2GLA inhibited cell proliferation in a time and concentration dependent manner. Nile Red staining suggested that Ru2GLA enters the cells and ICP-AES elemental analysis found an increase in ruthenium from <0.02 to 425,mg/Kg in treated cells. The sub-G1 apoptotic cell population was increased by Ru2GLA (22,±,5.2%) when analysed by FACS and this was confirmed by Hoechst staining of nuclei. Mitochondrial membrane potential was decreased in the presence of Ru2GLA (44,±,2.3%). In contrast, the cells which maintained a high mitochondrial membrane potential had an increase (18,±,1.5%) in reactive oxygen species generation. Both decreased mitochondrial membrane potential and increased reactive oxygen species generation may be involved in triggering apoptosis in Ru2GLA exposed cells. The EC50 for Ru2GLA decreased with increasing time of exposure from 285,µM at 24,h, 211,µM at 48,h to 81,µM at 72,h. In conclusion, Ru2GLA is a novel drug with antiproliferative properties in C6 glioma cells and is a potential candidate for novel therapies in gliomas. Copyright © 2009 John Wiley & Sons, Ltd. [source] Inward relocation of exogenous phosphatidylserine triggered by IGF-1 in non-apoptotic C2C12 cells is concentration dependentCELL BIOCHEMISTRY AND FUNCTION, Issue 6 2005Cyril Rauch Abstract The plasma membrane is composed of two leaflets that are asymmetric with regard to their phospholipid composition with phosphatidylserine (PS) predominantly located within the inner leaflet whereas other phospholipids such as phosphatidylcholine (PC) are preferentially located in the outer leaflet. An intimate relationship between cellular physiology and the composition of the plasma membrane has been demonstrated, with for example apoptosis requiring PS exposure for macrophage recognition. In skeletal muscle development, differentiation also requires PS exposure in myoblasts to create cell,cell contact areas allowing the formation of multinucleate myotubes. Although it is clearly established that membrane composition/asymmetry plays an important role in cellular physiology, the role of cytokines in regulating this asymmetry is still unclear. When incubated with myoblasts, insulin-like growth factor I (IGF-1) has been shown to promote proliferation versus differentiation in a concentration dependent manner and therefore, may be a potential candidate regulating cell membrane asymmetry. We show, in non-apoptotic C2C12 cells, that relocation of an exogenous PS analogue, from the outer into the inner leaflet, is accelerated by IGF-1 in a concentration-dependent manner and that maintenance of membrane asymmetry triggered by IGF-1 is however independent of the PI3K inhibitor wortmannin. Copyright © 2005 John Wiley & Sons, Ltd. [source] Effects of retinoids and thiazolidinediones on proliferation, insulin release, insulin mRNA, GLUT 2 transporter protein and mRNA of INS-1 cellsCELL BIOCHEMISTRY AND FUNCTION, Issue 3 2001J. Blumentrath Abstract Both 9-cis-retinoic acid (9cRA) and all-trans-retinoic acid (ATRA) are active metabolites of vitamin A (retinol). There exists an interaction between retinoid receptors and peroxisome proliferator-activated receptors (PPAR,). To define their functions in an insulin secreting system the effects of ATRA, 9cRA and the PPAR, agonist rosiglitazone on cell proliferation, insulin release and glucose transporter (GLUT) 2 of INS-1 cells were tested. Retinoic acid receptor (RAR-, and -,) and retinoid X receptor (RXR-, and -,) proteins are present (immunoblots). Both 9cRA and ATRA inhibit INS-1 cell proliferation ([3H]-thymidine assay) in a concentration dependent manner. Both 9cRA and ATRA increased insulin release, but only ATRA ralsed the GLUT 2 mRNA in a bell-shaped concentration response curve after 48,h. The insulinotropic effect of one compound is not significantly superimposed by the other indicating that the same binding sites are used by 9cRA and ATRA. The acute and chronic effects of the PPAR, agonist rosiglitazone on insulin release were additionally determined since glitazones act as transcription factors together with RXR agonists. At high concentrations (100,,m) rosiglitazone inhibited glucose (8.3,mm) stimulated insulin secretion (acute experiment over 60,min). Insulin secretion, however, was increased during a 24,h treatment at a concentration of 10,,m and again inhibited at 100,,m. Changes in preproinsulin mRNA expression were not observed. Rosiglitazone (100,,m) increased GLUT 2 mRNA paralleled by an increase of GLUT 2 protein, but only after 24,h of treatment. This data indicate that RAR and RXR mediate insulin release. The changes in GLUT 2 have no direct impact on insulin release; the inhibition seen at high concentrations of either compound is possibly the result of the observed inhibition of cell proliferation. Effects of rosiglitazone on preproinsulin mRNA and GLUT 2 (mRNA and protein) do not play a role in modulating insulin secretion. With the presence of an RXR receptor agonist the effect of rosiglitazone on insulin release becomes stimulatory. Thus the effects of RAR-, RXR agonists and rosiglitazone depend on their concentrations, the duration of their presence and are due to specific interactions. Copyright © 2001 John Wiley & Sons, Ltd. [source] | ||||||||||||||||