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91.
P Malherbe E Borroni L Gobbi H Knust M Nettekoven E Pinard O Roche M Rogers-Evans JG Wettstein J-L Moreau 《British journal of pharmacology》2009,156(8):1326-1341
Background and purpose:
The OX2 receptor is a G-protein-coupled receptor that is abundantly found in the tuberomammillary nucleus, an important site for the regulation of the sleep-wake state. Herein, we describe the in vitro and in vivo properties of a selective OX2 receptor antagonist, N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulphonyl)-amino]-N-pyridin-3-ylmethyl-acetamide (EMPA).Experimental approach:
The affinity of [3H]EMPA was assessed in membranes from HEK293-hOX2-cells using saturation and binding kinetics. The antagonist properties of EMPA were determined by Schild analysis using the orexin-A-or orexin-B-induced accumulation of [3H]inositol phosphates (IP). Quantitative autoradiography was used to determine the distribution and abundance of OX2 receptors in rat brain. The in vivo activity of EMPA was assessed by reversal of [Ala11,D-Leu15]orexin-B-induced hyperlocomotion during the resting phase in mice and the reduction of spontaneous locomotor activity (LMA) during the active phase in rats.Key results:
[3H]EMPA bound to human and rat OX2-HEK293 membranes with KD values of 1.1 and 1.4 nmol·L−1 respectively. EMPA competitively antagonized orexin-A-and orexin-B-evoked accumulation of [3H]IP at hOX2 receptors with pA2 values of 8.6 and 8.8 respectively. Autoradiography of rat brain confirmed the selectivity of [3H]EMPA for OX2 receptors. EMPA significantly reversed [Ala11,D-Leu15]orexin-B-induced hyperlocomotion dose-dependently during the resting phase in mice. EMPA, injected i.p. in rats during the active phase, reduced LMA dose-dependently. EMPA did not impair performance of rats in the rotarod procedure.Conclusions and implications:
EMPA is a high-affinity, reversible and selective OX2 receptor antagonist, active in vivo, which should prove useful for analysis of OX2 receptor function. 相似文献92.
Background and purpose:
The sarcoplasmic reticulum (SR), regulates the cytoplasmic Ca2+ concentration ([Ca2+]cyto) in vascular smooth muscle. Release from the SR is controlled by two intracellular receptor/channel complexes, the ryanodine receptor (RyR) and the inositol 1,4,5-trisphosphate receptor (IP3R). These receptors may be regulated by the accessory FK506-binding protein (FKBP) either directly, by binding to the channel, or indirectly via FKBP modulation of two targets, the phosphatase, calcineurin or the kinase, mammalian target of rapamycin (mTOR).Experimental approach:
Single portal vein myocytes were voltage-clamped in whole cell configuration and [Ca2+]cyto measured using fluo-3. IP3Rs were activated by photolysis of caged IP3 and RyRs activated by hydrostatic application of caffeine.Key results:
FK506 which displaces FKBP from each receptor (to inhibit calcineurin) increased the [Ca2+]cyto rise evoked by activation of either RyR or IP3R. Rapamycin which displaces FKBP (to inhibit mTOR) also increased the amplitude of the caffeine-evoked, but reduced the IP3-evoked [Ca2+]cyto rise. None of the phosphatase inhibitors, cypermethrin, okadaic acid or calcineurin inhibitory peptide, altered either caffeine- or IP3-evoked [Ca2+]cyto release; calcineurin did not contribute to FK506-mediated potentiation of RyR- or IP3R-mediated Ca2+ release. The mTOR inhibitor , like rapamycin, decreased IP3-evoked Ca2+ release. LY294002Conclusions and implications:
Ca2+ release in portal vein myocytes, via RyR, was modulated directly by FKBP binding to the channel; neither calcineurin nor mTOR contributed to this regulation. However, IP3R-mediated Ca2+ release, while also modulated directly by FKBP may be additionally regulated by mTOR. Rapamycin inhibition of IP3-mediated Ca2+ release may be explained by mTOR inhibition. 相似文献93.
Attachment insecurities (anxiety and avoidance) are often associated with relationship dissatisfaction, but the mediators have been unclear. We examined the mediating role of perceived conflict in 274 French‐Canadian couples who completed measures of attachment insecurities, perception of conflict, and relationship satisfaction. Partners' own attachment anxiety and avoidance predicted their experience of conflict. In addition, women's anxiety predicted men's experience of conflict, and men's avoidance predicted women's experience of conflict. The associations between attachment insecurities and relationship dissatisfaction were partially mediated by conflict. 相似文献
94.
Sonya L. Cyr Isabelle Angers Loic Guillot Ioana Stoica-Popescu Michèle Lussier Salman Qureshi David S. Burt Brian J. Ward 《Vaccine》2009
An intranasal vaccine composed of Toll-like receptor 2 (TLR2) ligand Neisseria meningitidis outer membrane proteins and Toll-like receptor 4 (TLR4) ligand Shigella flexneri lipopolysaccharide (LPS) (Protollin) and enriched respiratory syncytial virus (RSV) proteins (eRSV) has been demonstrated to promote balanced Th1/Th2 responses without eosinophil recruitment and to protect against challenge in mouse models. We used TLR2, TLR4 and myeloid differentiation factor 88 (MyD88) knock-out (-/-) mice to investigate the roles of these signalling pathways on immunogenicity, protection and pulmonary infiltrates following RSV immunization and challenge. Antigen-specific systemic and mucosal antibody production was significantly impaired only in TLR4-/- mice following Protollin–eRSV immunization. In contrast, an intact MyD88 pathway was crucial to elicit a balanced type 1:type 2 immune response, characterized by increased splenocyte production of antigen-induced IFNγ and IL-10 with concomitant reduction of IL5, IgG2a isotype switching and abrogation of pulmonary eosinophil recruitment following challenge. MyD88-dependent signalling also contributed to neutrophil recruitment to the lungs following immunization with eRSV antigen, in the presence or absence of Protollin, compared to a mock antigen or vaccine. Both TLR4 and MyD88-signalling were required for optimal protection against challenge. The upregulation of early signalling molecules IFN-β, TNFα, CD40 and CD86 were studied in splenocytes isolated from naïve TLR2, TLR4 and MyD88-/- mice following stimulation with vaccine components. Splenocytes from TLR4-/- mice displayed reduced IFN-β while those of MyD88-/- mice elicited less TNFα and lower expression of CD40 and CD86 on CD11c+ cells. Together, our results suggest that optimal immunogenicity and protection against RSV without risk of enhanced pulmonary inflammation requires intact TLR4/MyD88-dependent signalling. 相似文献
95.
M. Arborati D. Benchorba I. Lesieur JG Bizot-Espiard B. Guardiola-Lemaitre MJ Chapman and E. Ninio 《Fundamental & clinical pharmacology》1997,11(1):68-77
Summary— Cholesteryl esters in the hydrophobic core of low-density lipoprotein (LDL) particles constitute a major molecular target during copper-mediated oxidation. To facilitate the rapid analysis and quantitation of the oxidative degradation of LDL cholesteryl esters, we describe a new approach based on light scattering detection following separation by HPLC. We have applied this approach to the evaluation of the protective capacity of a new synthetic antioxidant, S20478, during oxidation of LDL in the presence of copper ions. HPLC separation of cholesterol and the four major molecular species of cholesteryl esters (C16:0, C18:1, C18:2 and C20:4) of LDL was achieved in a single run of 20 min with high sensitivity (50 ng) and low background. Time course studies of the oxidative modification of LDL (ratio LDL protein: copper, 100 μg/mL: 1μM) revealed that the content of unsaturated cholesteryl esters (C20:4 and C18:2) decreased (–30% and –15%, respectively) within 90 min of copper-mediated oxidation, while only minor degradation (up to 15%) of monounsaturated (C18:1) and saturated (C16:0) esters occurred. At 24 hours of oxidation, only traces (< 5%) of the C20:4 and C18:2 esters were detectable; whereas 52% of the C18:1 ester remained (P < 0.01). Of the saturated esters, only minor proportions (35% or less) underwent oxidative modification. In addition, some 81% of free cholesterol was conserved as the native sterol. The synthetic antioxidant, S20478 (50 μM) was capable of inhibiting the initiation and the propagation of copper-mediated LDL oxidation as determined by the time- and dose-dependant inhibition of the formation of conjugated dienes and thiobarbituric acid-reactive substances, as well as the conservation of the net electrical charge of LDL; indeed S20478 conserved cholesteryl esters in their native form up to 24 hours. However, after prolonged exposure to copper ions (48 hours), only 47% of the unsaturated esters remained (C18:2, P < 0.05). Nonetheless, S20478 (10 μM) was more efficient in inhibiting copper-mediated LDL oxidation as compared to probucol at the same concentration. These findings suggest that S20478 may be of potential interest in a new antioxidant approach to therapeutic stabilisation and regression of atherosclerotic plaques. Moreover, this method should prove useful in the assessment of the integrity of native LDL, and provides a new chemical marker of the degree of LDL oxidation. 相似文献
96.
1. Ouabain is known to have natriuretic effects only at high doses, and therefore if endogenously produced ouabain has a role in the regulation of sodium excretion, the renal response to ouabain must be increased substantially in certain physiological situations. The aim of this study is to determine whether treatment with the mineralocorticoid, aldosterone, potentiates that natriuretic response to ouabain. 2. Six conscious sheep received renal arterial infusion of either vehicle or aldosterone (3 μg/h). Forty hours after commencement of infusion ouabain was infused into the renal artery at 400 μg/h for 60min. A second infusion of ouabain was administered on the 6th day of aldosterone treatment. 3. In the absence of aldosterone, the effects on sodium excretion produced by ouabain infusion at 400 μg/h into the renal artery were variable and not statistically significant. Ouabain infusion after 40 h of aldosterone treatment increased sodium excretion from 40 ± 14 to 676 ± 69 μmol/min in the second hour following cessation of ouabain infusion (P< 0.001). Ouabain infusion after 6 days of aldosterone treatment increased sodium excretion similarly. Ouabain-stimulated sodium excretion was significantly greater during aldosterone treatment compared to vehicle treatment (P<0.05). In contrast, no enhancement of effect was observed after acute treatment with aldosterone. 4. These results demonstrate potentiation of the natriuretic response to ouabain infusion by chronic mineralocorticoid treatment and suggest a potential role of endogenous digitalislike factor in the physiological control of sodium homeo stasisaldo sterone, endogenous digitalis-like factor, ouabain, sodium excretion. 相似文献
97.
Maria Teresa Hernandez Hannelore C Sauerwein Isabelle Jambaqué Elaine De Guise Francine Lussier Anne Lortie Olivier Dulac Maryse Lassonde 《Neuropsychologia》2002,40(4):384-400
Frontal lobe dysfunction in adults has been associated with impairments of planning abilities, working memory, impulse control, attention and certain aspects of motor coordination. However, very few studies have attempted to assess these functions in children suffering from frontal lobe epilepsy. The aim of the present study was to determine whether some or all of the components of the frontal lobe syndrome are present in children with this disorder. For this purpose, a neuropsychological test battery was administered to 32 unresected epileptic children, aged 8-16 years: 16 with frontal lobe epilepsy (FLE), eight with temporal lobe epilepsy (TLE) and eight with generalized epilepsy whose principal manifestations were typical absences (GEA). The performances of the three epileptic groups were further compared to normative data derived from 200 French-speaking, healthy children aged 7-16 years, except for standardized tests for which the norms provided in the manual were used. The three epilepsy groups did not differ with respect to conceptual shift and recency memory. However, the FLE children showed deficits in planning and impulse control. Furthermore, they had significantly more coordination problems and exhibited greater rigidity than the other epilepsy groups on the motor tests. These problems were more marked in younger FLE children (8-12 years). The latter were also more impaired on verbal fluency measures. No differences were observed with respect to gender, localization of the epileptic abnormality (unilateral versus bilateral) or medication (monotherapy versus polytherapy). The findings reveal similarities between the neuropsychological profiles of FLE children and adults with frontal lobe lesions. 相似文献
98.
99.
庆大霉素在小鼠的时辰毒性及时辰药代动力学 总被引:1,自引:0,他引:1
本文研究了庆大霉素对小鼠的毒性及其药代动力学的昼夜节律性变化。雄性ICR小鼠自实验前两周置于标准的明期和暗期下饲养,自由进食进水。毒性实验剂量为庆大霉素290mg/kg,Sc:药代动力学实验剂量为45 mg/kg,Sc。结果表明,庆大霉素毒性及药代动力学因用药时间不同呈明显的昼夜节律性变化。明期中点用药毒性最大,血药浓度最高,AUC值最大:暗期用药毒性小,血药浓度低,AUC值小。提示了庆大霉素毒性的昼夜节律变化与其药代动力学的的昼夜节律变化有密切关系。 相似文献
100.