RESUMO
Circadian rhythm (CR) disturbances are among the most commonly observed symptoms during major depressive disorder, mostly in the form of disrupted sleeping patterns. However, several other measurable parameters, such as plasma hormone rhythms and differential expression of circadian clock genes (ccgs), are also present, often referred to as circadian phase markers. In the recent years, CR disturbances have been recognized as an essential aspect of depression; however, most of the known animal models of depression have yet to be evaluated for their eligibility to model CR disturbances. In this study, we investigate the potential of adrenocorticotropic hormone (ACTH)-treated animals as a disease model for research in CR disturbances in treatment-resistant depression. For this purpose, we evaluate the changes in several circadian phase markers, including plasma concentrations of corticosterone, ACTH, and melatonin, as well as gene expression patterns of 13 selected ccgs at 3 different time points, in both peripheral and central tissues. We observed no impact on plasma corticosterone and melatonin concentrations in the ACTH rats compared to vehicle. However, the expression pattern of several ccgs was affected in the ACTH rats compared to vehicle. In the hippocampus, 10 ccgs were affected by ACTH treatment, whereas in the adrenal glands, 5 ccgs were affected and in the prefrontal cortex, hypothalamus and liver 4 ccgs were regulated. In the blood, only 1 gene was affected. Individual tissues showed changes in different ccgs, but the expression of Bmal1, Per1, and Per2 were most generally affected. Collectively, the results presented here indicate that the ACTH animal model displays dysregulation of a number of phase markers suggesting the model may be appropriate for future studies into CR disturbances.
Assuntos
Hormônio Adrenocorticotrópico , Relógios Circadianos , Corticosterona , Modelos Animais de Doenças , Animais , Masculino , Ratos , Relógios Circadianos/genética , Relógios Circadianos/fisiologia , Corticosterona/sangue , Hormônio Adrenocorticotrópico/sangue , Transtorno Depressivo Resistente a Tratamento/genética , Transtorno Depressivo Resistente a Tratamento/metabolismo , Ritmo Circadiano/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Ratos Wistar , MelatoninaAssuntos
Transtorno Depressivo Maior , MicroRNAs , Fator A de Crescimento do Endotélio Vascular , Adolescente , Humanos , Biomarcadores/sangue , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/genética , Perfilação da Expressão Gênica , MicroRNAs/sangue , MicroRNAs/genética , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
The aim of this study was to examine the effects of the OPG-RANKL-TRAIL system on proliferation, regulation of calcification-associated genes and calcification of human vascular smooth muscle cells (HVSMCs). Small interfering (si)RNA-mediated knockdown of OPG was followed by treatment of HVSMCs with recombinant RANKL or TRAIL. Regulation of a calcification-associated gene set was assayed by pathway analysis of microarray results. The lack of OPG in HVSMCs or treatment with RANKL or TRAIL did not affect proliferation of HVSMCs. In addition, OPG, RANKL or TRAIL did not modify the regulation of a calcification-associated gene set. Finally, in the long term calcification assay, we found that cells isolated from seven different human donors showed a great variability in the response to RANKL and insulin. However, overall RANKL and/or insulin did not affect the development of calcification of HVSMCs. These studies indicate that OPG knockdown does not alter the calcification process in HVSMCs.