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11.
The effect of dexamethasone-induced alteration of adrenocortical activity was assessed in two species of New World primates: Saimiri sciureus and Callicebus moloch. Basal and stress levels of corticosteroids were determined following treatment with three doses of dexamethasone (0, 50, or 500 μg/kg). Saimiri showed substantially higher basal levels of corticosteroids than did Callicebus and a greater incremental corticosteroid response to physical restraint. Dexamethasone was found to reduce basal corticosteroids in both species, although this effect was greater for Callicebus than for Saimiri Moreover, the adrenocortical response to physical restraint was reduced by dexamethasone treatment in Callicebus but not in Saimiri. The pattern of results suggests that the species differ in the mechanisms mediating adrenocortical activity. 相似文献
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Maaike Schilperoort Jan Kroon Sander Kooijman Annelies E. Smit Max Gentenaar Kathrin Mletzko Felix N. Schmidt Leo van Ruijven Bjrn Busse Alberto M. Pereira Natasha M. AppelmanDijkstra Nathalie Bravenboer Patrick C.N. Rensen Onno C. Meijer Elizabeth M. Winter 《Aging cell》2021,20(10)
Glucocorticoid (GC)‐induced osteoporosis is a widespread health problem that is accompanied with increased fracture risk. Detrimental effects of anti‐inflammatory GC therapy on bone have been ascribed to the excess in GC exposure, but it is unknown whether there is also a role for disruption of the endogenous GC rhythm that is inherent to GC therapy. To investigate this, we implanted female C57Bl/6J mice with slow‐release corticosterone (CORT) pellets to blunt the rhythm in CORT levels without inducing hypercortisolism. Flattening of CORT rhythm reduced cortical and trabecular bone volume and thickness, whilst bone structure was maintained in mice injected with supraphysiologic CORT at the time of their endogenous GC peak. Mechanistically, mice with a flattened CORT rhythm showed disrupted circadian gene expression patterns in bone, along with changes in circulating bone turnover markers indicative of a negative balance in bone remodelling. Indeed, double calcein labelling of bone in vivo revealed a reduced bone formation in mice with a flattened CORT rhythm. Collectively, these perturbations in bone turnover and structure decreased bone strength and stiffness, as determined by mechanical testing. In conclusion, we demonstrate for the first time that flattening of the GC rhythm disrupts the circadian clock in bone and results in an osteoporotic phenotype in mice. Our findings indicate that at least part of the fracture risk associated with GC therapy may be the consequence of a disturbed GC rhythm, rather than excess GC exposure alone, and that a dampened GC rhythm may contribute to the age‐related risk of osteoporosis. 相似文献
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《Cytotherapy》2014,16(4):535-544
Background aimsMultiple sclerosis (MS) is considered to be a T-cell–mediated disease. Although MS remits with corticosteroid treatment, the disease relapses on discontinuation of therapy. Human amniotic epithelial cells (hAEC) from the placenta are readily accessible in large quantities and have anti-inflammatory properties. Previously we reported that hAEC given near disease onset ameliorated clinical signs and decreased myelin oligodendrocyte glycoprotein (MOG)-specific immune responses in MOG-induced experimental autoimmune encephalomyelitis (EAE), an experimental MS model.MethodsTo examine the therapeutic effect of hAEC in a clinically relevant setting, we first treated MOG peptide–induced EAE mice with a corticosteroid, prednisolone, in drinking water to induce remission. hAEC were then infused intravenously into the remitted mice. Anti-MOG antibodies in serum were detected by enzyme-linked immunoassay. Splenocyte proliferation was assessed by 3H-thymidine incorporation. Immune cell subpopulations in spleens and lymph nodes and secreted cytokines in splenocyte culture were quantified by flow cytometry. Central nervous system histology was examined with the use of hematoxylin and eosin, Luxol fast blue and immunostaining.ResultsWith cessation of prednisolone treatment, hAEC delayed EAE relapse for 7 days, and, after another 7 days, largely remitted disease in six of eight responder mice. Splenocyte proliferation was suppressed, anti-MOG35–55 antibodies in serum were decreased and interleukin-2 and interleukin-5 production by splenocytes were elevated after hAEC treatment. In the central nervous system, hAEC-treated mice had decreased demyelination and fewer macrophages in the inflammatory infiltrates. hAEC treatment also increased CD4+CD25+FoxP3+ regulatory T cells in inguinal lymph nodes.ConclusionsThese data demonstrate that the therapeutic effects of hAEC after corticosteroid treatment in an MS model probably are the consequence of peripheral immunoregulation. We suggest that hAEC may have potential as a cell therapy for remitted MS. 相似文献
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《Bioorganic & medicinal chemistry letters》2014,24(13):2871-2876
A multivalent approach focused on amine-based secondary binding groups was applied to the discovery of long-acting inhaled β2-agonists. Addition of amine moieties to the neutral secondary binding group of an existing β2-agonist series was found to provide improved in vivo efficacy, but also led to the formation of biologically active aldehyde metabolites which were viewed as a risk for the development of these compounds. Structural simplification of the scaffold and blocking the site of metabolism to prevent aldehyde formation afforded a potent series of dibasic β2-agonists with improved duration of action relative to their monobasic analogs. Additional optimization led to the discovery of 29 (TD-4306), a potent and selective β2-agonist with potential for once-daily dosing. 相似文献
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《Bioorganic & medicinal chemistry letters》2014,24(12):2625-2630
A series of potent β2-adrenoceptor agonists incorporating a biarylamine secondary binding group was identified. The previously reported milveterol (5), identified by a multivalent approach and containing a typical β2-agonist primary binding group linked via a phenethylamine linker to a hydrophilic secondary binding group, served as an initiation point. A more hydrophobic set of secondary binding groups was explored, prepared rapidly from a common intermediate by Buchwald–Hartwig amination. TD-5471 (25), a potent and selective full agonist of the human β2-adrenoceptor, was identified as the most promising agent. It is potent, with slow onset in an in vitro guinea pig trachea model and shows a dose-dependent and long duration of action in an in vivo guinea pig model of bronchoprotection. TD-5471 is structurally differentiated from milveterol and its long duration of action is consistent with a correlation with hydrophobicity observed in other long-acting β2-agonist discovery programs. 相似文献
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Behavioral and adrenocortical responses of rhesus (Macaca mulatta), bonnet (M. radiata), and crabeating (M. fascicularis) macaques were compared in their home cages, during exposure to novelty and during physical restraint. Both behavioral and adrenocortical responses differentiated species in each condition. In all conditions, post-test corticosteroid levels were highest for crabeaters and lowest for rhesus. Rhesus were the most active behaviorally, and bonnets were the most passive, while crabeaters exhibited the greatest signs of behavioral disturbance. Relationships between adrenocortical and behavioral responses varied between groups. Both adrenocortical and behavioral profiles were in accord with the behavior of these three species under more natural conditions. The role of psychophysiological responses in general behavioral dispositions toward the environment is discussed. It is concluded that behavioral dispositions, inclusive of psychophysiological responses, may vary qualitatively even among closely related primate species. 相似文献
19.
目的:观察在哮喘缓解期阶梯治疗中,哮喘控制测试(asthma control test,ACT)与最大呼气峰流速(PEF)作用的相关性,帮助支气管哮喘患者更加准确、简便的进行自我监测,提高患者的依从性。方法:选择我院哮喘专病门诊就诊的78例哮喘患者,吸入糖皮质激素(ICS)进行缓解期的阶梯治疗。要求每日早、晚监测PEF,并记录到哮喘日记上。每月哮喘专病门诊复诊一次,了解PEF值、PEF占个人预计值的百分比(PEFpred%),PEFpred%个人预计值80%为哮喘控制,PEFpred%个人预计值80%为哮喘未控制,同时进行ACT问卷,计算得分,20分为哮喘未控制;20~25分为哮喘控制。结果:ACT评分20~25分组与ACT评分20分组PEFpred%比较,差异有统计学意义(P0.01)。PEFpred%个人预计值80%组与PEFpred%个人预计值80%组ACT评分比较,差异有统计学意义(P0.01)。ACT评分与PEFpred%具有线性相关关系,P0.001。结论:在哮喘缓解期阶梯治疗中,ATC评分与PEF具有良好的相关性,对于没有条件或不能监测PEF的哮喘患者可以用ACT评分作为评估哮喘控制的指标,指导阶梯治疗。 相似文献
20.
Diaz D Chara L Chevarria J Carballido J Esteban E Navas V Monserrat J Prieto A de la Hera A Alvarez-Mon M 《Cancer immunology, immunotherapy : CII》2009,58(2):235-245
The peripheral blood lymphocytes of eight patients with metastatic renal cell carcinoma, and of eight healthy volunteers were
analyzed by four-color flow cytometry to characterize the immunophenotypic alterations manifested, determine the prevalence
of lymphocyte apoptosis, and detect evidence of the systemic effect of inhaled IL-2. The T, B and NK lymphocytes of untreated
patients were found to have undergone profound changes characterized by an increase in susceptibility to both spontaneous
and mitogen-induced ex vivo apoptosis, a modified distribution of the main lymphocyte populations in the peripheral blood,
and alterations in activation status. An increase in the proportion of regulatory T cells was also seen in these patients.
Treatment with inhaled IL-2, however, normalized the rate of apoptosis in all the lymphocyte subpopulations studied, as well
as their distribution and activation status. These findings demonstrate that inhaled IL-2 has systemic immunomodulatory effects. 相似文献