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Dose-dependent Decrease (dose-dependent + decrease)
Kinds of Dose-dependent Decrease Selected AbstractsEffects of in utero exposure to 2,2,,4,4,,5,5,-hexachlorobiphenyl (PCB 153) on somatic growth and endocrine status in rat offspringCONGENITAL ANOMALIES, Issue 4 2008Kenichi Kobayashi ABSTRACT Exposure to polychlorobiphenyl (PCB) mixtures at an early stage of development has been reported to affect endocrine glands; however, little is known about the precise toxicological properties of individual PCB. The present study was undertaken to determine whether prenatal exposure to 2,2,,4,4,,5,5,-hexachlorobiphenyl (PCB 153), a di- ortho -substituted non-coplanar congener, affects postnatal development in rat offspring. Pregnant Sprague-Dawley rats (Crj: CD (SD) IGS) were given PCB 153 (0, 16, or 64 mg/kg/day) orally from gestational day (GD) 10 through GD 16, and developmental parameters in the male and female offspring were examined. We found no dose-dependent changes in body weight, body length (nose,anus length), tail length, or the weights of kidneys, testes, ovaries and uterus in offspring at 1 or 3 weeks of age. Liver weights were increased in the PCB 153,treated groups, although we observed a significant difference only in males. Anogenital distance was unaffected in the PCB 153,treated groups. We observed a significant dose-dependent decrease in the plasma concentrations of thyroxine and tri-iodothyronine, whereas those of thyroid-stimulating hormone were not significantly changed. In addition, there were no dose-dependent changes in plasma concentrations of growth hormone and insulin-like growth factor-I in any dose group. These findings suggest that prenatal exposure to PCB 153 (GD 10,16, 16,64 mg/kg/day) may alter the thyroid status in rat offspring to some extent without affecting somatic growth or its related hormonal parameters. [source] Structure,activity relationships of isoeugenol-based chlorophenylpiperazine derivatives on serotonergic/adrenergic receptor, platelet aggregation, and lipid peroxidationDRUG DEVELOPMENT RESEARCH, Issue 5 2010Kuo-Ping Shen Abstract Three isoeugenol-based eugenosedin chlorphenylpiperazine derivatives, Eu-A, Eu-B, and Eu-C, were synthesized and tested for their serotonergic, adrenergic antagonist, antioxidant, and anti-aggregation activities. In radioligand binding assays, all three agents displayed significant binding affinities on ,1, ,2, ,1, 5-HT1B, and 5-HT2A receptors. In human platelet, they inhibited epinephrine and 5-HT-induced aggregation, and in human platelet with ,2 and 5-HT2A receptors they had a competitive binding effect. Eu-B and Eu-C were more potent than Eu-A. All compounds had antioxidant effects derived from aryloxypropanolamine. Eu- A, Eu-B, or Eu-C (1, 3, 5,mg/kg iv) given to normotensive Wistar rats produced a dose-dependent decrease in mean arterial blood pressure and heart rate and when injected into the cisternum, Eu-A, Eu-B, or Eu-C (0.3, 0.03,µmol) increased blood pressure within 15,min. Pretreatment with any of the three agents inhibited clonidine (38,pmol)-induced hypotension. In vitro experiments, Eu-A, Eu-B, or Eu-C (1, 10, and 100,µM) competitively antagonized norepinephrine-, clonidine-, and 5-HT (10,8,10,4,M)-induced vasocontraction in isolated rat aorta, and competitively antagonized isoproterenol (10,8,10,4,M)-induced positive inotropic effects in a concentration-dependent manner in the isolated rat left atrium. In isolated rabbit ear arteries sensitized with 16,mM K+, all three agents antagonized 5-nonyloxytryptamine- and 5-HT-induced vasocontractions. These findings show that Eu-A, Eu-B, and Eu-C possess functional ,1, ,2, ,1, 5-HT1B, and 5-HT2A receptor blocking activities. In conclusion, the changes in the position of chloride at phenylpiperazine influenced the serotonergic receptor, adrenoceptor antagonistic activities, but not anti-aggregation and antioxidant activities. Drug Dev Res 71:1,9, 2010. © 2010 Wiley-Liss, Inc. [source] Influence of dietary 2,4,6-trinitrotoluene exposure in the northern bobwhite (Colinus virginianus)ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 1 2002Robert M. Gogal Jr. Abstract The risk to wildlife from exposure to the explosive, 2,4,6-trinitrotoluene (TNT) has been a concern at numerous military installations where it has been found in the soil. To date, no published data are available describing effects of TNT exposure in an avian species. Subchronic dietary exposure to TNT was therefore evaluated in a species of management concern at military installations, the northern bobwhite (Colinus virginianus). Adult male and female quail (n = 5/sex/dose) were given commercial feed containing 3,000, 1,500, 750, and 100 mg/kg TNT for 90 d following the determination of an acute lethal dose and a 14-d range finding study. Dietary TNT intake caused a dose-dependent decrease in total red blood cell counts, packed cell volume, total plasma protein, blood prolymphocytes, and blood lymphocytes. An increased trend in late apoptotic/necrotic blood leukocytic cells was also observed in TNT-exposed birds, as was hemosiderosis in the liver. With the exception of hemosiderosis, these trends were statistically significant yet of questionable biological significance. Since treatment-related responses in this preliminary study were variable, a conservative interpretation is suggested. However, since these treatments had concentrations that were a log-fold or more than doses in similar studies using mammals, these data suggest that northern bobwhite are less sensitive to oral exposures of TNT than mammals. [source] PRECLINICAL STUDY: Different effects of chronic phencyclidine on brain-derived neurotrophic factor in neonatal and adult rat brainsADDICTION BIOLOGY, Issue 2 2006Jun'ichi Semba ABSTRACT The N-methyl-D-aspartate (NMDA) receptor and brain-derived neurotrophic factor (BDNF) are both known to play major roles in the normal development of the brain. We have hypothesized that the chronic blockade of NMDA with phencyclidine (PCP) may have a different effect on BDNF synthesis at different stages of development. In an acute experiment, rat pups and adult rats were injected with PCP (2.5, 5 or 10 mg/kg) at postnatal day (PD) 15 or 49, respectively. In a chronic experiment, rat pups were injected daily from PD 5 to PD 14 with PCP (2.5, 5 or 10 mg/kg), while adult rats were injected daily with the same dose from PD 39 to PD 48. BDNF levels in the hippocampus, striatum and frontal cortex were determined by ELISA assay 24 hours after the last injection. Chronic PCP treatment of neonatal rats induced a dose-dependent decrease in BDNF in the hippocampus but not in the frontal cortex and striatum. Single injection of PCP to rat pups showed a slight reduction of BDNF in the hippocampus but only at higher doses. In contrast to neonatal brain, neither acute nor chronic injection of PCP influenced BDNF in adult brain. These findings suggest that chronic blockade of NMDA receptor in the early neonatal period has an inhibitory effect on BDNF synthesis in the hippocampus and may impair normal neurodevelopment in rat pups. [source] Glutamate regulates retinal progenitors cells proliferation during developmentEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2006Rodrigo A. P. Martins Abstract The precise coordination of cell cycle exit and cell fate specification is essential for generating the correct proportion of retinal cell types during development. The decision to exit the cell cycle is regulated by intrinsic and extrinsic cues. There is growing evidence that neurotransmitters can regulate cell proliferation and cell fate specification during the early stages of CNS development prior to the formation of synaptic connections. We found that the excitatory neurotransmitter glutamate regulates retinal progenitor cell proliferation during embryonic development of the mouse. AMPA/kainate and N -methyl- d -aspartate receptors are expressed in embryonic retinal progenitor cells. Addition of exogenous glutamate leads to a dose-dependent decrease in cell proliferation without inducing cell death or activating the p53 pathway. Activation of AMPA/kainate receptors induced retinal progenitor cells to prematurely exit the cell cycle. Using a replication-incompetent retrovirus to follow the clonal expansion of individual retinal progenitor cells, it was observed that blockade of AMPA/kainate receptors increased the proportion of large clones, showing that modulation of endogenous glutamatergic activity can have long-term consequences on retinal cell proliferation. Real time reverse transcriptase-polymerase chain reaction and immunoblot analyses demonstrated that glutamate does not alter the levels of the mRNA and proteins that regulate the G1/S-phase transition. Instead, the activity of the Cdk2 kinase is reduced in the presence of glutamate. These data indicate that glutamate regulates retinal progenitor cell proliferation by post-translational modulation of cyclin/Cdk2 kinase activity. [source] Voltage-gated sodium channel isoform-specific effects of pompilidotoxinsFEBS JOURNAL, Issue 4 2010Emanuele Schiavon Pompilidotoxins (PMTXs, , and ,) are small peptides consisting of 13 amino acids purified from the venom of the solitary wasps Anoplius samariensis (,-PMTX) and Batozonellus maculifrons (,-PMTX). They are known to facilitate synaptic transmission in the lobster neuromuscular junction, and to slow sodium channel inactivation. By using ,-PMTX, ,-PMTX and four synthetic analogs with amino acid changes, we conducted a thorough study of the effects of PMTXs on sodium current inactivation in seven mammalian voltage-gated sodium channel (VGSC) isoforms and one insect VGSC (DmNav1). By evaluating three components of which the inactivating current is composed (fast, slow and steady-state components), we could distinguish three distinct groups of PMTX effects. The first group concerned the insect and Nav1.6 channels, which showed a large increase in the steady-state current component without any increase in the slow component. Moreover, the dose-dependent increase in this steady-state component was correlated with the dose-dependent decrease in the fast component. A second group of effects concerned the Nav1.1, Nav1.2, Nav1.3 and Nav1.7 isoforms, which responded with a large increase in the slow component, and showed only a small steady-state component. As with the first group of effects, the slow component was dose-dependent and correlated with the decrease in the fast component. Finally, a third group of effects concerned Nav1.4 and Nav1.5, which did not show any change in the slow or steady-state component. These data shed light on the complex and intriguing behavior of VGSCs in response to PMTXs, helping us to better understand the molecular determinants explaining isoform-specific effects. [source] Alcohol intoxication effects on visual perception: An fMRI studyHUMAN BRAIN MAPPING, Issue 1 2004Vince D. Calhoun Abstract We examined the effects of two doses of alcohol (EtOH) on functional magnetic resonance imaging (fMRI) activation during a visual perception task. The Motor-Free Visual Perception Test,Revised (MVPT-R) provides measures of overall visual perceptual processing ability. It incorporates different cognitive elements including visual discrimination, spatial relationships, and mental rotation. We used the MVPT-R to study brain activation patterns in healthy controls (1) sober, and (2) at two doses of alcohol intoxication with event-related fMRI. The fMRI data were analyzed using a general linear model approach based upon a model of the time course and a hemodynamic response estimate. Additionally, a correlation analysis was performed to examine dose-dependent amplitude changes. With regard to alcohol-free task-related brain activation, we replicate our previous finding in which SPM group analysis revealed robust activation in visual and visual association areas, frontal eye field (FEF)/dorsolateral prefrontal cortex (DLPFC), and the supplemental motor area (SMA). Consistent with a previous study of EtOH and visual stimulation, EtOH resulted in a dose-dependent decrease in activation amplitude over much of the visual perception network and in a decrease in the maximum contrast-to-noise ratio (in the lingual gyrus). Despite only modest behavior changes (in the expected direction), significant dose-dependent activation increases were observed in insula, DLPFC, and precentral regions, whereas dose-dependent activation decreases were observed in anterior and posterior cingulate, precuneus, and middle frontal areas. Some areas (FEF/DLPFC/SMA) became more diffusely activated (i.e., increased in spatial extent) at the higher dose. Alcohol, thus, appears to have both global and local effects upon the neural correlates of the MVPT-R task, some of which are dose dependent. Hum. Brain Mapping 21:15,26, 2004. © 2003 Wiley-Liss, Inc. [source] A Nonprostanoid EP4 Receptor Selective Prostaglandin E2 Agonist Restores Bone Mass and Strength in Aged, Ovariectomized RatsJOURNAL OF BONE AND MINERAL RESEARCH, Issue 4 2006Hua Zhu Ke MD Abstract CP432 is a newly discovered, nonprostanoid EP4 receptor selective prostaglandin E2 agonist. CP432 stimulates trabecular and cortical bone formation and restores bone mass and bone strength in aged ovariectomized rats with established osteopenia. Introduction: The purpose of this study was to determine whether a newly discovered, nonprostanoid EP4 receptor selective prostaglandin E2 (PGE2) agonist, CP432, could produce bone anabolic effects in aged, ovariectomized (OVX) rats with established osteopenia. Materials and Methods: CP432 at 0.3, 1, or 3 mg/kg/day was given for 6 weeks by subcutaneous injection to 12-month-old rats that had been OVX for 8.5 months. The effects on bone mass, bone formation, bone resorption, and bone strength were determined. Results: Total femoral BMD increased significantly in OVX rats treated with CP432 at all doses. CP432 completely restored trabecular bone volume of the third lumbar vertebral body accompanied with a dose-dependent decrease in osteoclast number and osteoclast surface and a dose-dependent increase in mineralizing surface, mineral apposition rate, and bone formation rate-tissue reference in OVX rats. CP432 at 1 and 3 mg/kg/day significantly increased total tissue area, cortical bone area, and periosteal and endocortical bone formation in the tibial shafts compared with both sham and OVX controls. CP432 at all doses significantly and dose-dependently increased ultimate strength in the fifth lumber vertebral body compared with both sham and OVX controls. At 1 and 3 mg/kg/day, CP432 significantly increased maximal load in a three-point bending test of femoral shaft compared with both sham and OVX controls. Conclusions: CP432 completely restored trabecular and cortical bone mass and strength in established osteopenic, aged OVX rats by stimulating bone formation and inhibiting bone resorption on trabecular and cortical surfaces. [source] Effect of Osteoblast-Targeted Expression of Bcl-2 in Bone: Differential Response in Male and Female Mice,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 8 2005Alexander G Pantschenko Abstract Transgenic mice (Col2.3Bcl-2) with osteoblast-targeted human Bcl-2 expression were established. Phenotypically, these mice were smaller than their wildtype littermates and showed differential effects of the transgene on bone parameters and osteoblast activity dependent on sex. The net effect was an abrogation of sex differences normally observed in wildtype mice and an inhibition of bone loss with age. Ex vivo osteoblast cultures showed that the transgene had no effect on osteoblast proliferation, but decreased bone formation. Estrogen was shown to stimulate endogenous Bcl-2 message levels. These studies suggest a link between Bcl-2 and sex regulation of bone development and age-related bone loss. Introduction: Whereas Bcl-2 has been shown to be an important regulator of apoptosis in development, differentiation, and disease, its role in bone homeostasis and development is not well understood. We have previously showed that the induction of glucocorticoid-induced apoptosis occurred through a dose-dependent decrease in Bcl-2. Estrogen prevented glucocorticoid-induced osteoblast apoptosis in vivo and in vitro by preventing the decrease in Bcl-2 in osteoblasts. Therefore, Bcl-2 may be an important regulator of bone growth through mechanisms that control osteoblast longevity and function. Materials and Methods: Col2.3Bcl-2 mice were developed carrying a 2.3-kb region of the type I collagen promoter driving 1.8 kb of human Bcl-2 (hBcl-2). Tissue specific expression of hBcl-2 in immunoassays validated the transgenic animal model. Histomorphometry and DXA were performed. Proliferation, mineralization, and glucocorticoid-induced apoptosis were examined in ex vivo cultures of osteoblasts. The effect of estrogen on mouse Bcl-2 in ex vivo osteoblast cultures was assayed by RT-PCR and Q-PCR. Results and Conclusions: Two Col2.3Bcl-2 (tg/+) founder lines were established and appeared normal except that they were smaller than their nontransgenic wildtype (+/+) littermates at 1, 2, and 6 months of age, with the greatest differences at 2 months. Immunohistochemistry showed hBcl-2 in osteoblasts at the growth plate and cortical surfaces. Nontransgenic littermates were negative. Western blots revealed hBcl-2 only in type I collagen-expressing tissues. Histomorphometry of 2-month-old mice showed a significant decrease in tg/+ calvaria width with no significant differences in femoral trabecular area or cortical width compared with +/+. However, tg/+ males had significantly more trabecular bone than tg/+ females. Female +/+ mice showed increased bone turnover with elevated osteoblast and osteoclast parameters compared with +/+ males. Col2.3Bcl-2 mice did not show such significant differences between sexes. Male tg/+ mice had a 76.5 ± 1.5% increase in ObS/BS with no significant differences in bone formation rate (BFR) or mineral apposition rate (MAR) compared with male +/+ mice. Transgenic females had a significant 48.4 ± 0.1% and 20.1 ± 5.8% decrease in BFR and MAR, respectively, compared with +/+ females. Osteoclast and osteocyte parameters were unchanged. By 6 months, femurs from female and male +/+ mice had lost a significant amount of their percent of trabecular bone compared with 2-month-old mice. There was little to no change in femoral bone in the tg/+ mice with age. Ex vivo cultures of osteoblasts from +/+ and Col2.3Bcl-2 mice showed a decrease in mineralization, no effect on proliferation, and an inhibition of glucocorticoid-induced apoptosis in Col2.3Bcl-2 cultures. Estrogen was shown to increase mouse Bcl-2 transcript levels in osteoblast cultures of wildtype mice, supporting a role for Bcl-2 in the sex-related differences in bone phenotype regulated by estrogen. Therefore, Bcl-2 differentially affected bone phenotype in male and female transgenic mice, altered bone cell activity associated with sex-related differences, and decreased bone formation, suggesting that apoptosis is necessary for mineralization. In addition, Bcl-2 targeted to mature osteoblasts seemed to delay bone development, producing a smaller transgenic mouse compared with wildtype littermates. These studies suggest that expression of Bcl-2 in osteoblasts is important in regulating bone mass in development and in the normal aging process of bone. [source] Role of Gastrointestinal Hormones in Postprandial Reduction of Bone Resorption,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 12 2003Dennis B Henriksen Abstract Collagen type I fragments, reflecting bone resorption, and release of gut hormones were investigated after a meal. Investigations led to a dose escalation study with glucagon like peptide-2 (GLP-2) in postmenopausal women. We found a dose-dependent effect of GLP-2 on the reduction of bone resorption. Introduction: The C-terminal telopeptide region of type I collagen as measured in serum (s-CTX) can be used to assess bone resorption. This marker of bone resorption has a significant circadian variation that is influenced by food intake. However, the mediator of this variation has not been identified. Materials and Methods: We studied the release of the gut hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2; a representative of the intestinal proglucagon-derived peptides) after ingestion of glucose, fat, protein, and fructose, as well as their effects after parenteral administration in relation to bone turnover processes in healthy volunteers. Furthermore, we studied the effect on bone turnover of a single subcutaneous injection of GLP-2 in four different dosages (100, 200, 400, or 800 ,g GLP-2) or placebo in 60 postmenopausal women (mean age, 61 ± 5 years). Results: All macronutrients significantly (p < 0.05) reduced bone resorption as assessed by s-CTX (39,52% from baseline), and only the glucagon-like peptides were secreted in parallel. Parenteral administration of GIP and GLP-1 did not result in a reduction of the s-CTX level, whereas GLP-2 caused a statistically significant and dose-dependent reduction in the s-CTX level from baseline compared with placebo (p < 0.05). Urine DPD/creatinine, a marker of bone resorption, was significantly reduced by 25% from baseline in the 800-,g GLP-2 group (p < 0.01). An area under the curve (AUC0,8h) analysis for s-CTX after GLP-2 injection confirmed the dose-dependent decrease (ANOVA, p = 0.05). The s-osteocalcin level was unaffected by the GLP-2 treatment. Conclusion: These studies exclude both GIP and GLP-1 as key mediators for the immediate reduction in bone resorption seen after a meal. The dose-dependent reduction of bone resorption markers found after subcutaneous injection of GLP-2 warrants further investigation into the mechanism and importance of GLP-2 for the bone turnover processes. [source] Gap junctional communication in human osteoclasts in vitro and in vivoJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 6a 2008A. F. Schilling Abstract Bone-forming cells are known to be coupled by gap junctions, formed primarily by connexin43 (Cx43). The role of Cx43 in osteoclasts has so far only been studied in rodents, where Cx43 is important for fusion of mononuclear precursors to osteoclasts. Given the potential importance for human diseases with pathologically altered osteoclasts, we asked whether a similar influence of Cx43 can also be observed in osteoclasts of human origin. For this purpose, Cx43 mRNA expression was studied in a time course experiment of human osteoclast differentiation by RT-PCR. Localization of Cx43 in these cells was determined by immunohistochemistry and confocal microscopy. For the assessment of the effect of gap junction inhibition on cell fusion, gap junctions were blocked with heptanol during differentiation of the cells and the cells were then evaluated for multinuclearity. Paraffin sections of healthy bone and bone from patients with Paget's disease and giant cell tumour of the bone were used to study Cx43 expression in vivo. We found mRNA and protein expression of Cx43 in fully differentiated osteoclasts as well as in precursor cells. This expression decreased in the course of differentiation. Consistently, we found a lower expression of Cx43 in osteoclasts than in bone marrow precursor cells in the histology of healthy human bone. Blockade of gap junctional communication by heptanol led to a dose-dependent decrease in multinuclearity, suggesting that gap junctional communication precedes cell fusion of human osteoclasts. Indeed, we found a particularly strong expression of Cx43 in the giant osteoclasts of patients with Paget's disease and giant cell tumour of the bone. These results show that gap junctional communication is important for fusion of human mononuclear precursor cells to osteoclasts and that gap junctional Cx43 might play a role in the regulation of size and multinuclearity of human osteoclasts in vivo. [source] Salvianolic acid B attenuates plasminogen activator inhibitor type 1 production in TNF-, treated human umbilical vein endothelial cellsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2005Zhe Zhou Abstract Plasminogen activator inhibitor type 1 (PAI-1), which plays a role in the development of atherosclerosis, is produced by endothelial cells following stimulation with various inflammatory cytokines such as tumor necrosis factor (TNF-,). In the present study, we investigated the effects of a potent water-soluble antioxidant, salvianolic acid B (SalB; derived from the Chinese herb, Salviamiltiorrhiza), on the expression of PAI-1 in TNF-,-treated human umbilical vein endothelial cells (HUVECs). We found that SalB inhibited TNF-,-induced PAI-1 mRNA production and protein secretion in HUVECs. Treatment with SalB (0.05 and 0.15 µM) notably attenuated TNF-, induced expression of PAI-1 to 90.5% and 74.6%, respectively, after 12 h, and to 75.1% and 64.2%, respectively, after 18 h. We also observed a dose-dependent decrease in PAI-1 protein production in the presence of SalB. We then used pathway inhibitors to investigate which step of the TNF-, induced signaling pathway was targeted by SalB. We found that the c-Jun N-terminal kinase (JNK) inhibitor, SP600125, increased the inhibitory effects of SalB on TNF-,-induced PAI-1 secretion, whereas the nuclear factor-,B (NF-,B) inhibitor, emodin, and the extracellular signal-regulated kinase (ERK) inhibitor, PD98059, did not. A gel shift assay further showed that SalB inhibited the TNF-,-activated NF-,B and AP-1 DNA binding activities in a dose-dependent manner. Collectively, these results indicate that the NF-,B and ERK-AP-1 pathways are possible targets of SalB in the regulation of TNF-,-stimulated PAI-1 production in HUVECs. © 2005 Wiley-Liss, Inc. [source] Venous air embolism induces both platelet dysfunction and thrombocytopeniaACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 6 2009S. T. SCHÄFER Background: In vitro, air bubbles can induce platelet activation and platelet to air bubble binding. We therefore tested in vivo the hypothesis that venous air embolism (VAE) induces (1) platelet dysfunction and (2) thrombocytopenia. Methods: Adult swine (60.8±3.9 kg; n=8) were anaesthetized, mechanically ventilated, and placed in a semi-upright position. Air boli (0.5,80 ml) were injected randomly via an ear vein, and arterial blood was sampled after cumulative air dosages of 0, 80, 160, and 240 ml. Coagulation was assessed by impedance aggregometry, rotational thrombelastometry, whole blood count, plasmatic coagulation variables, and fibrinogen, d -dimer, protein C, and antithrombin plasma concentrations, respectively. Results: VAE induced a 47% decrease in platelet count (303 vs. 160 nl,1; P<0.001) over the dose range assessed, with haematocrit being unaltered. Furthermore, VAE-impaired platelet aggregation induced by adenosine diphosphate, arachidonic acid, collagen, and the thromboxan analogue U46619 over the dose range assessed independent of thrombocytopenia. (P<0.05 vs. baseline). In contrast, rotational thrombelastometry alone was quite insensitive in detecting VAE-induced coagulation changes, showing only at near lethal air dosages a prolonged clot formation time following activation with tissue factor, contact activator, and during spontaneous coagulation (P<0.05 vs. baseline). Conclusions: VAE induces both a dose-dependent decrease in platelet count and a marked decrease in platelet aggregation, independent of thrombocytopenia (P<0.05 vs. baseline). [source] Antifibrinolytic agents reduce tissue plasminogen activator-mediated neuronal toxicity in vitroACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 3 2009H.-Y. SUN Introduction: Serine proteases and their inhibitors play an important role in physiological homeostasis including neuronal activity, hemostasis, and wound healing. Tissue plasminogen activator (tPA) is involved in normal neuronal plasticity and memory formation but can also be neurotoxic. We hypothesized that the serine protease inhibitor aprotinin confers neuronal protection by inhibiting tPA activity. Methods: Using cultured rat dopaminergic neuroblasts (N27 line), tPA-induced cytotoxicity was quantitated by an MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and flow cytometry using propidium iodide DNA staining. The anti-apoptotic effects of aprotinin and other protease inhibitors were also evaluated using these systems. Results: Treatment of cultured neuroblasts with tPA (10,20 ,g/ml) caused a dose-dependent decrease in cell viability (71.3±2.4 at 10 ,g/ml down to 52.7±2.5% at 20 ,g/m tPA, 24-h treatment), which was potentiated in the absence of serum in the culture medium (59.5±6.3% at 10 ,g/ml down to 47.9±4.7% at 20 ,g/ml). Aprotinin was effective in ameliorating cell death when administered 30 min before tPA exposure as shown by increased cell viability (91.8±0.6% at tPA at 20 ,g/ml), but this protection was significantly reduced when aprotinin was administered after tPA. The efficacy of aprotinin as a neuroprotectant was equivalent or superior to other direct tPA antagonist peptides Glu-Gly-Arg-chlormethylketone (EGRck) and Phe-Pro-Arg-chlormethylketone (FPRck) in this setting. Conclusion: These data suggest that one of the mechanisms of neuroprotection afforded by aprotinin may be inhibition of tPA-mediated neurotoxicity. [source] Regulated interactions of the norepineprhine transporter by the actin and microtubule cytoskeletonsJOURNAL OF NEUROCHEMISTRY, Issue 5 2008Alexis M. Jeannotte Abstract One role of the actin cytoskeleton is to maintain the structural morphology and activity of the pre-synaptic terminal. We sought to determine if the actin cytoskeleton plays a role in regulating interactions between the norepinephrine transporter (NET) and alpha-Synuclein (,-Syn), two proteins expressed in the pre-synaptic terminal. In cells transfected with either 0.5 ,g/mL or 3 ,g/mL of ,-Syn and 1 ,g/mL of NET DNA, treatment with cytochalasin D, an actin depolymerizing agent, caused a dose-dependent decrease and increase, respectively, in [3H]-NE uptake. Protein interactions between NET, ,-actin, and ,-Syn were modified, along with levels of surface transporters. Treatment of primary brainstem neurons and frontal cortex synaptosomes with cytochalasin D caused a 115% and 28% increase, respectively, in NET activity. Depolymerization of both actin and microtubules did not alter NET activity in cells with 0.5 ,g/mL ,-Syn, but caused an increase in [3H]-NE uptake in cells transfected with 3 ,g/mL of ,-Syn and primary neurons. This is the first direct demonstration of NET activity being regulated via actin and modulated by interactions with ,-Syn. [source] Glucocorticoids and the Development of Agonistic Behaviour during Puberty in Male Golden HamstersJOURNAL OF NEUROENDOCRINOLOGY, Issue 12 2005J. C. Wommack Abstract During puberty, the agonistic behaviour of male golden hamsters undergoes a transition from play fighting to adult aggression. Repeated exposure to social stress early in puberty accelerates this transition. The present study investigated the possible role of glucocorticoids on the maturation of agonistic behaviour. First, we compared serum cortisol levels following a 20-min restraint stress during early puberty, mid-puberty or adulthood. Across puberty, animals exhibited a two-fold increase in post-restraint cortisol levels. We also compared corticotrophin-releasing hormone (CRH) immunoreactive fibres projecting to the median eminence between animals in early puberty and adulthood. The CRH fibre density was two-fold greater in adults compared to juveniles. Furthermore, we investigated the effects of stress hormones on the maturation of agonistic behaviour. Male hamsters were injected daily with dexamethasone, a corticosteroid receptor type II agonist (0, 10 or 40 µg/100 g), early in puberty from postnatal day 31 (P-31) to P-36. When paired with a smaller and younger intruder on P-37, attack frequency did not differ between groups. However, dexamethasone-treated animals showed a dose-dependent decrease in the percentage of play-fighting attacks and an increase in the percentage of adult attacks. In summary, puberty can be described as a period of increasing hypothalamic-pituitary-adrenal activity in male golden hamsters. Moreover, increasing glucocorticoid levels influence the maturation of agonistic behaviour. These data shed new light on the neuroendocrine mechanisms that regulate the maturation of social behaviours during puberty. [source] Vasopressin Preferentially Depresses Excitatory Over Inhibitory Synaptic Transmission in the Rat Supraoptic Nucleus In VitroJOURNAL OF NEUROENDOCRINOLOGY, Issue 4 2000Kombian1 Endogenous arginine-vasopressin (AVP) in the supraoptic nucleus is known to decrease the firing rate of some supraoptic nucleus neurones. To determine a possible mechanism by which this locally released AVP produces this change in neuronal excitability, we investigated the effects of AVP on evoked excitatory (e.p.s.c.) and inhibitory post-synaptic (i.p.s.c.) responses recorded in magnocellular neurones in a hypothalamic slice preparation, using the perforated-patch recording technique. Our data show that AVP produces a dose-dependent decrease in the evoked e.p.s.c. in about 80% of magnocellular neurones tested with an estimated EC50 of about 0.9 ,M. The maximum decrease in e.p.s.c. amplitude was about 31% of control and was obtained with an AVP concentration of 2 ,M. The AVP-induced synaptic depression was blocked by Manning Compound (MC), a non-selective antagonist of oxytocin (OXT) and vasopressin (AVP) receptors, but not by a selective OXT receptor antagonist. It was not mimicked by desmopressin (ddAVP), a V2-receptor subtype agonist. By contrast, AVP used at the same concentration (2 ,M), had no global effect on pharmacologically isolated i.p.s.c.s in the majority of magnocellular neurones tested. These results show that AVP acts in the supraoptic nucleus to reduce excitatory synaptic transmission to magnocellular neurones by activating a non-OXT receptor, presumably the V1 receptor subtype. [source] Polymethylmethacrylate particles impair osteoprogenitor viability and expression of osteogenic transcription factors Runx2, osterix, and Dlx5JOURNAL OF ORTHOPAEDIC RESEARCH, Issue 5 2010Richard Chiu Abstract Polymethylmethacrylate (PMMA) particles have been shown to inhibit the differentiation of osteoprogenitor cells, but the mechanism of this inhibitory effect has not been investigated. We hypothesize that the inhibitory effects of PMMA particles involve impairment of osteoprogenitor viability and direct inhibition of transcription factors that regulate osteogenesis. We challenged MC3T3-E1 osteoprogenitors with PMMA particles and examined the effects of these materials on osteoprogenitor viability and expression of transcription factors Runx2, osterix, Dlx5, and Msx2. MC3T3-E1 cells treated with PMMA particles over a 72-h period showed a significant reduction in cell viability and proliferation as indicated by a dose- and time-dependent increase in supernatant levels of lactate dehydrogenase, an intracellular enzyme released from dead cells, a dose-dependent decrease in cell number and BrdU uptake, and the presence of large numbers of positively labeled Annexin V-stained cells. The absence of apoptotic cells on TUNEL assay indicated that cell death occurred by necrosis, not apoptosis. MC3T3-E1 cells challenged with PMMA particles during the first 6 days of differentiation in osteogenic medium showed a significant dose-dependent decrease in the RNA expression of Runx2, osterix, and Dlx5 on all days of measurement, while the RNA expression of Msx2, an antagonist of Dlx5-induced osteogenesis, remained relatively unaffected. These results indicate that PMMA particles impair osteoprogenitor viability and inhibit the expression of transcription factors that promote osteoprogenitor differentiation. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:571,577, 2010 [source] Full-length bovine spp24 [spp24 (24-203)] inhibits BMP-2 induced bone formation,JOURNAL OF ORTHOPAEDIC RESEARCH, Issue 6 2008Chananit Sintuu Abstract Secreted phosphoprotein 24 kDa (spp24) is a bone matrix protein. It contains a TGF-, receptor II homology 1 (TRH1) domain. A cyclic, synthetic 19 amino acid peptide (bone morphogenetic protein binding peptide or BBP) based on the sequence of the TRH1 domain enhances BMP-2 induced osteogenesis. Many observations suggest that different size forms of this protein have very different effects (inhibiting or enhancing) on BMP-2 induced osteogenesis. Using the stable recombinant Met(His)6 -tagged secretory form of full-length (fl) bovine spp24 [Met(His)6 -spp24 (residues 24,203)] and transgenic (TG) mice expressing fl bovine spp24 (residues 1,203), we have demonstrated that spp24 inhibits BMP-2 induced bone formation. The effects of Met(His)6 -spp24 (24,203) were determined in the ectopic bone-forming bioassay in male mice. Implantation of 5 µg of BMP-2 stimulated bone formation, assessed densitometrically as bone area and mineral content. When Met(His)6 -spp24 (24,203) was implanted with BMP-2, it elicited a dose-dependent decrease in BMP-2-medicated ectopic bone formation. When added at a 50-fold excess (w/w), Met(His)6 -spp24 (24,203) completely ablated the effects of BMP-2, while addition of a 10-fold excess had no effect. Constitutive expression of fl bovine spp24 (1,203) under the control of the osteocalcin promoter in TG female mice reduced femoral and vertebral bone mineral density at 3 months of age and reduced femoral BMD at 8 months of age, but had no effects in male mice, which can exhibit less osteocalcin-promoter driven gene transcription than females. Histomorphometric analysis demonstrated that bone volume and trabecular thickness were lower in TG female mice at 3 months of age than in sex- and age-matched wild type (WT) controls. Thus, fl spp24 and its secretory isoform (Met(His)6 -spp24 [24,203]), which contain a BMP-binding or TRH1 motif, inhibit ectopic bone formation in male mice and adversely affects BMD and histological parameters related to bone mass and formation in female mice expressing the human transgene. Under these conditions, fl spp24 acts as a BMP antagonist in vivo. © 2008 Orthopaedic Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:753,758, 2008 [source] Acute and Chronic Alcohol Exposure Impair the Phagocytosis of Apoptotic Cells and Enhance the Pulmonary Inflammatory ResponseALCOHOLISM, Issue 10 2010Darren M. Boé Background:, Alcohol abuse increases the risk for acute respiratory distress syndrome (ARDS). Efferocytosis, the clearance of apoptotic cells, is important in the resolution of inflammation and is regulated by RhoA and rho kinase (ROCK) activation. The effects of alcohol on pulmonary Rho pathway activation and efferocytosis have not been determined. We hypothesize that acute and chronic alcohol exposure impair pulmonary efferocytosis, leading to heightened inflammation during ARDS. Methods:, For in vivo experiments, C57BL/6 mice received either a single intraperitoneal injection of alcohol or chronic ethanol-in-water for 8 weeks prior to intratracheal instillation of apoptotic cells or lipopolysaccharide (LPS). Bronchoalveolar lavage (BAL) was performed for cells counts, calculation of the phagocytic index (PI), and Rho activity measurements. For in vitro studies, primary alveolar macrophages were cultured in alcohol (25,100 mM) and then co-cultured with apoptotic cells. RhoA activity was determined following alcohol exposure, and the PI was determined before and after treatment with the ROCK inhibitor, Y27632. Results:, Acute alcohol exposure was associated with impaired efferocytosis. Following LPS exposure, acute alcohol exposure was also associated with increased BAL neutrophils. Chronic alcohol exposure alone did not alter efferocytosis. However, following exposure to LPS, chronic alcohol exposure was associated with both impaired efferocytosis and increased BAL neutrophils. In vitro alcohol exposure caused a dose-dependent decrease in efferocytosis. Despite the fact that RhoA activity was decreased by alcohol exposure and RhoA inhibition did not alter the effects of alcohol on efferocytosis, treatment with the Rho kinase inhibitor, Y27632, reversed the effects of alcohol on efferocytosis. Conclusions:, Acute alcohol exposure impairs pulmonary efferocytosis, whereas exposure to chronic alcohol is only associated with impaired efferocytosis following LPS-induced lung injury. Both forms of alcohol exposure are associated with increased alveolar neutrophil numbers in response to LPS. The acute effects of alcohol on efferocytosis appear to be mediated, at least in part, by RhoA-independent activation of ROCK. Further studies are needed to dissect the differences between the effects of acute and chronic alcohol exposure on efferocytosis and to determine the effects of alcohol on alternative activators of ROCK. [source] Pluchea lanceolata attenuates cadmium chloride induced oxidative stress and genotoxicity in Swiss albino miceJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 9 2005Tamanna Jahangir Cadmium intoxication induces lipid peroxidation and causes oxidative damage to various tissues by altering antioxidant defence system enzymes. At 24h after treatment with a single intraperitoneal dose of cadmium chloride (5 mg kg,1), Swiss albino mice showed a significant increase in the levels of malanodialdehyde and xanthine oxidase (P<0.001), and a concomitant depletion of renal glutathione, catalase (P<0.001) and other antioxidant enzymes. CdCl2 also led to a simultaneous increase in micronuclei formation (P<0.001) and chromosomal aberrations (P<0.05) in mouse bone marrow cells. Oral pre-treatment with Pluchea lanceolata extract at doses of 100 and 200 mg kg,1 for 7 consecutive days before CdCl2 intoxication caused a significant reduction in malanodialdehyde formation and xanthine oxidase activity (P<0.001). A significant restoration of the activity of antioxidant defence system enzymes such as catalase, glutathione peroxidase (P<0.05), glutathione- S -transferase and glutathione reductase (P<0.001) was observed. A significant dose-dependent decrease in chromosomal aberrations and micronuclei formation was also observed (P<0.05). The results indicate that pre-treatment with P. lanceolata attenuates cadmium chloride induced oxidative stress and genotoxicity by altering antioxidant enzymes and reducing chromatid breaks and micronuclei formation. [source] The Glycine Reuptake Inhibitor Org 25935 Interacts With Basal and Ethanol-Induced Dopamine Release in Rat Nucleus AccumbensALCOHOLISM, Issue 7 2009Helga Höifödt Lidö Background:, The mesolimbic dopamine (DA) projection from the ventral tegmental area to nucleus accumbens (nAc), a central part of the reward system, is activated by ethanol (EtOH) and other drugs of abuse. We have previously demonstrated that the glycine receptor in the nAc and its amino acid agonists may be implicated in the DA activation and reinforcing properties of EtOH. We have also reported that the glycine transporter 1 inhibitor, Org 25935, produces a robust and dose-dependent decrease in EtOH consumption in Wistar rats. The present study explores the interaction between EtOH and Org 25935 with respect to DA levels in the rat nAc. Methods:, The effects of Org 25935 (6 mg/kg, i.p.) and/or EtOH (2.5 g/kg, i.p.) on accumbal DA levels were examined by means of in vivo microdialysis (coupled to HPLC-ED) in freely moving male Wistar rats. The effect of Org 25935 on accumbal glycine output was also investigated. Results:, Systemic Org 25935 increased DA output in a subpopulation of rats (52% in Experiment 1 and 38% in Experiment 2). In Experiment 2, EtOH produced a significant increase in DA levels in vehicles (35%) and in Org 25935 nonresponders (19%), whereas EtOH did not further increase the DA level in rats responding to Org 25935 (2%). The same dose of Org 25935 increased glycine levels by 87% in nAc. Conclusions:, This study demonstrates that Org 25935, probably via increased glycine levels, (i) counteracts EtOH-induced increases of accumbal DA levels and (ii) increases basal DA levels in a subpopulation of rats. The results are in line with previous findings and it is suggested that the effects observed involve interference with accumbal GlyRs and are related to the alcohol consumption modulating effect of Org 25935. [source] Heritability of the Blood Pressure Response to Acute Ethanol Exposure in Five Inbred Strains of MiceALCOHOLISM, Issue 10 2000Daniel C. Hatton Background: Chronic alcohol consumption is a major risk factor for hypertension. There is evidence in humans that the susceptibility to alcohol-related hypertension may vary based on genotype. As a first step in investigating the genetic basis for alcohol-related hypertension, the current study was designed to assess the heritability of the blood pressure response to acute ethanol exposure by using AKR/J (AK), C57BL/6J (B6), DBA/2J (D2), Balb/cJ (Balb), and A/J (A) mice. Methods: Mean arterial pressure (MAP) was recorded continuously for 24 hr in freely moving mice from an indwelling femoral catheter before we tested the effects of saline or ethanol (2 g/kg ip) on blood pressure. Results: Relative to saline, ethanol caused a pressor response that peaked within 10 min, followed by a decline in MAP. Strain A mice had a significantly greater pressor response to ethanol than other strains and did not show a decline in MAP below baseline. All other strains showed a progressive fall in blood pressure below baseline across the 60 min measurement interval. Heritability was estimated to be 0.62 for the pressor response and 0.64 for the maximal depressor response. Repeated doses of ethanol at 1 hr intervals in A and B6 mice (0,2,1.5,1.5,1.5 g/kg ip) resulted in a dose-dependent increase in MAP in A mice for the first three doses and a dose-dependent decrease in MAP in B6 mice that was independent of blood ethanol concentrations. Conclusion: The results indicate that there is a significant genetic component to the acute blood pressure response to ethanol. [source] Growth inhibitory effects of pegylated IFN ,-2b on human liver cancer cells in vitro and in vivoLIVER INTERNATIONAL, Issue 8 2006Hirohisa Yano Abstract: Purpose: We investigated the effects of pegylated IFN-,2b (PEG-IFN-,2b) on the growth of human liver cancer cells. Methods: The effect of PEG-IFN-,2b on the proliferation of 13 liver cancer cell lines was investigated in vitro. Chronological changes in growth and IFN-, receptor-2 (IFNAR-2) expression were monitored in hepatocellular carcinoma (HCC) cells (HAK-1B) cultured with PEG-IFN-,2b. After HAK-1B cells were transplanted into nude mice, various doses of PEG-IFN-,2b or IFN-,2b were administered, and tumor volume, weight, histology, and IFNAR-2 expression were examined. Results: PEG-IFN-,2b inhibited the growth of nine cell lines with apoptosis in a dose- and time-dependent manner. Continuous contact with PEG-IFN-,2b induced time-dependent growth inhibition and down-regulation of IFNAR-2 expression. PEG-IFN-,2b induced a dose-dependent decrease in tumor volume and weight, a significant increase of apoptotic cells, and a decrease in IFNAR-2 expression in the tumor. The clinical dose for chronic hepatitis C was also effective. The antitumor effect of PEG-IFN-,2b was significantly stronger than that of non-PEG-IFN-,2b in vivo. Conclusions: Continuous contact with PEG-IFN-,2b induces strong antitumor effects and the down-regulation of IFNAR-2 in HCC cells. The data suggest potential clinical application of PEG-IFN-,2b for the prevention and treatment of HCC. [source] Secretin induces variable inhibition of motility in different parts of the Australian possum sphincter of OddiNEUROGASTROENTEROLOGY & MOTILITY, Issue 5 2001B. O. Al-Jiffry The sphincter of Oddi (SO) may not function as a single structure. We aimed to determine the response of the proximal and distal segments of the bile duct (BD-SO) and pancreatic duct (PD-SO) components of the SO to secretin, with and without neural blockade with tetrodotoxin (TTX). In anaesthetized Australian possums, separate manometry catheters were placed in the proximal and distal BD-SO or PD-SO segments to record motility. Secretin, 50,1000 ng kg,1, was administered, followed by TTX, and re-administration of secretin, 500 and 1000 ng kg,1. Changes in the motility index (MI, frequency × mean amplitude) were determined. Statistical analysis utilized repeated-measures ANOVA. Secretin produced a dose-dependent decrease in MI from the proximal and distal BD-SO and PD-SO (all P < 0.001). The maximum inhibition, at 1000 ng kg,1, was 21 ± 4%, 33 ± 6% and 42 ± 5% of control (mean ± SEM), for proximal and distal BD-SO, and distal PD-SO, respectively. The proximal PD-SO MI, however, was inhibited to 62 ± 6% of control, at 1000 ng kg,1. TTX enhanced the secretin-induced response to the same level at the four sites (P < 0.02). We conclude that secretin inhibits the motility of the possum SO in a nonuniform manner and is modulated by neural activity. [source] Coronary and systemic hemodynamic effects of clevidipine, an ultra-short-acting calcium antagonist, for treatment of hypertension after coronary artery surgeryACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 2 2000N. Kieler-Jensen Background: The aim was to evaluate the use of clevidipine, a new vascular selective, ultra-short-acting calcium antagonist for blood pressure control after coronary artery bypass grafting (CABG). Methods: The effects of clevidipine on central hemodynamics, myocardial blood flow and metabolism were studied at two different phases after CABG. In phase 1 (n=13), the hypertensive phase, the effects of clevidipine were compared to those of sodium nitroprusside (SNP) when used to control postoperative hypertension. In phase 2 (n=9), the normotensive phase, a clevidipine dose-response relationship was established. Results: At a target mean arterial pressure (MAP) of 75 mmHg, systemic vascular resistance (SVR) and heart rate (HR) were lower, preload, stroke volume (SV) and pulmonary vascular resistance (PVR) were higher, while there were no differences in myocardial lactate metabolism or oxygen extraction with clevidipine compared to SNP. In the normotensive phase, clevidipine induced a dose-dependent decrease in MAP (,19%), SVR (,27%) and PVR (,15%), accompanied by an increase in SV (10%), but no reflex increase in HR or changes in cardiac preload. Clevidipine caused a direct coronary vasodilation, as indicated by a decrease in myocardial oxygen extraction from 54% to 45%. Myocardial lactate metabolism was unaffected by clevidipine. The blood clearance of clevidipine was 0.05 l ,· ,min,1 ,· ,kg,1, the volume of distribution at steady state was 0.08 l ,· ,kg,1 and the initial and terminal half-lives were <1 min and 4 min, respectively. Conclusions: Clevidipine rapidly reduced MAP and induced a systemic, pulmonary and coronary vasodilation with no effect on venous capacitance vessels or HR. Clevidipine caused no adverse effects on myocardial lactate metabolism. Clevidipine thus appears suitable to control blood pressure after CABG. [source] Effect of UV irradiation on type I collagen fibril formation in neutral collagen solutionsPHOTODERMATOLOGY, PHOTOIMMUNOLOGY & PHOTOMEDICINE, Issue 3 2001Julian M. Menter Background: Collagens have the well-known ability to spontaneously self-associate to form fibrils at physiological temperature and neutral pH in vitro and in vivo. Because solar UV may photochemically alter collagen, the kinetics of fibril formation may be modified. Thus, we have begun a systematic study of the effect of various UV wavebands on fibril formation. Methods: Citrate-soluble calf skin collagen (Elastin Products) was dissolved at 0.05% in 0.5 M HOAc, dialyzed over 2 days into two changes of 0.0327 M phosphate buffer, pH 7.0 at 4 °C, and centrifuged at 48 000×g. Photolysis was carried out at 4 °C with either (a) UVC (UVG,11 lamp), (b) filtered solar-simulating radiation (SSR) or UVA (SSR or UVL,21 lamp filtered with a 2.0 mm Schott WG 345 filter). Gelation was commenced by rapidly raising the temperature from 8 °C to 33 °C. Nucleation and growth were followed by turbidimetric measurements at 400 nm. Results: UVC radiation (0,17.3 J/cm2) resulted in a dose-dependent decrease in the rate of fibril growth. Under these conditions, concomitant collagen cross-linking and degradation occurred. Fibril nucleation, a prerequisite for growth, was rapid (threshold , 2 min) and was not affected by UVC, UVA or SSR. SSR (0,1320 J/cm2) caused a small decrease in growth rate and in the degree of fibril formation. UVA radiation (0,1080 J/cm2) had a similar effect. "Direct" photochemical damage thus paralleled absorption via various collagen chromophores, with UVC>SSR,UVA. The presence of riboflavin (RF) resulted in ground-state interactions that markedly altered both nucleation and growth kinetics. Irradiation with 29.6 J/cm2 UVA in the presence of RF photosensitizer caused relatively minor additional changes in fibrillation kinetics. Conclusions: These results collectively indicate that fibril formation is markedly dependent on specific ground state interactions and relatively insensitive to nonspecific UV damage. On the other hand, fibrils thus formed from photochemically altered collagen may have altered structural properties that could have subtle but unfavorable effects on the local dermal milieu in vivo. Notwithstanding, the relative insensitivity of fibrillogenesis to non-specific photochemical damage probably represents a favorable adaptation, overall, which tends to conserve the mechanical integrity of the skin. [source] Effects of cuminaldehyde on melanoma cellsPHYTOTHERAPY RESEARCH, Issue 6 2008Teruhiko Nitoda Abstract Cuminaldehyde (4-isopropylbenzaldehyde) suppressed melanin formation in cultured murine B16-F10 melanoma cells in a dose-dependent decrease up to 0.25 mm without affecting cell growth. Approximately 30% suppression in melanin production resulted when the cells were cultured with 0.25 mm of cuminaldehyde. This activity was not noticeable with cultured human A375 melanoma cells. Copyright © 2008 John Wiley & Sons, Ltd. [source] Dose-Dependent Immunohistochemical Changes in Rat Cornea and Retina after Oral Methylphenidate AdministrationANATOMIA, HISTOLOGIA, EMBRYOLOGIA, Issue 2 2009E. Tunc Summary Methylphenidate hydrochloride (MPH), more commonly known as Ritalin, is a piperidine derivative and is the drug most often used to treat attention deficit/hyperactivity disorder, one of the most common behavioural disorders of children and young adults. The aim of this study was to investigate dose-dependent immunohistochemical Dopamine 2 receptor (D2) expression and apoptosis in the rat cornea and cornea. In this study, 27 female pre-pubertal Wistar albino rats, divided into three different dose groups (5, 10 and 20 mg/kg) and their control groups, were used. They were treated orally with methylphenidate dissolved in saline solution for 5 days per week during 3 months. At the end of the third month, after perfusion fixation, eye tissue was removed. Paraffin sections were collected for immunohistochemical and terminal deoxynucleotidyl-transferase-mediated dUTP-biotin nick end labelling assay studies. In our study, we observed that the cornea D2 receptor reactivity showed a dose-related increase after MPH treatment, especially in basal cells of the epithelium and a dose-dependent decrease in the retinal ganglion cell which was statistically meaningful. Analysis of the cornea thickness results showed no meaningful difference between groups. Apoptotic cell number showed a meaningful increase in the high dose treated group compared to the other groups of the study. The data suggest that Ritalin has degenerative effect on the important functional part of the eye, such as cornea and retina and its activating dopaminergic mechanism via similar neuronal paths, functionally and structurally, to induce morphological changes. As a result, we believe that this morphological changes negatively effecting functional organization of the affected cornea and retina. [source] Microsomal UDP-Glucuronyltransferase in Rat Liver: Oxidative ActivationBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 6 2005María Eugenia Letelier In this work, we characterize Fe3+/ascorbate-induced activation of UDPGT activity prior to solubilization with Triton X-100 and after the oxidation process provoked the solubilization of the enzyme. We observed a time-dependent increase in UDPGT activity up to 20 min. incubation of the microsomes with Fe3+/ascorbate (3-times); after 20 min. incubation, however, we observed a time-dependent decrease in this activity to basal levels after 4 hr incubation. Treatment of microsomes with 0.1% Triton X-100 (5 min.) lead to a similar increase in UDPGT activity; higher detergent concentrations produced a dose-dependent decrease in this activity to basal levels with 1% Triton X-100. Interestingly, UDPGT activity was susceptible to activation only when associated to microsomal membranes and the loss of activation correlated with the solubilization of this activity. UDPGT activation by either Fe3+/ascorbate or Triton X-100 was correlated with an increase in p -nitrophenol apparent Km and Vmax values. This activation was prevented or reversed by the reducing agents glutathione, cysteine or dithiothreitol when it was induced by the Fe3+/ascorbate. Furthermore, the latter provoked a significant decrease in microsomal thiol content, effect not observed after treatment with Triton X-100. Our results suggest that the main mechanism responsible for Fe3+/ascorbate-induced UDPGT activation is likely to be the promotion of protein sulfhydryl oxidation; this mechanism appears to be different from detergent-induced UDPGT activation. [source] | |||||||||||||