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1.
J Pharmacol Toxicol Methods ; 127: 107504, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38678804

RESUMO

We developed a novel, stress-free blood sampling method for minipigs, allowing continuous cortisol monitoring over 24 h. Baseline cortisol levels exhibited both ultradian and diurnal rhythms. During nighttime, smaller ultradian rhythms overlaid a lower baseline cortisol, which increased in sleeping pigs before lights were turned on. Additionally, we developed an analytical tool based on the R package "pracma" to quantify ultradian peak and circadian components of the cortisol profiles. To validate our model, we investigated the effects of Verucerfont, a CRH receptor antagonist, and Venlafaxine, a serotonin-norepinephrine reuptake inhibitor. Verucerfont reduced cortisol levels during the first 9 h without affecting diurnal rhythm. Cortisol peak parameters decreased, with a 31% reduction in overall area under the curve (AUC) and a 38% reduction in ultradian average AUC. Ultradian peaks decreased from 7 to 4.5, with 34% lower amplitude. Venlafaxine maintained plasma concentrations within the targeted human effective range. This method enables us to enhance our understanding of cortisol regulation and provide valuable insights for the impact of investigation drugs on the diurnal and ultradian rhythms of cortisol.


Assuntos
Ritmo Circadiano , Hidrocortisona , Porco Miniatura , Cloridrato de Venlafaxina , Animais , Suínos , Hidrocortisona/sangue , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/fisiologia , Cloridrato de Venlafaxina/farmacologia , Ritmo Ultradiano/efeitos dos fármacos , Ritmo Ultradiano/fisiologia , Coleta de Amostras Sanguíneas/métodos , Área Sob a Curva , Masculino , Feminino
2.
J Cell Biochem ; 119(2): 1453-1462, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28771862

RESUMO

Biological clocks, time-keeping systems, enable the living organisms to synchronize their biochemical processes with their environment. Among these molecular oscillators, ultradian oscillators have been identified with volatility less than 24 h. Transcription factor Hes1, a member of the basic Helix-loop-Helix (bHLH) protein family, has an oscillation duration of 2 h in vertebrates. Due to the pivotal role of oxidative stress in many human diseases, we evaluated the effect(s) of oxidative stress on Hes1 oscillator, its upstream regulators, and its downstream cell cycle regulators. NIH/3T3 mouse fibroblast cells were treated with sublethal (250 µM) and lethal (1000 µM) doses of H2 O2 for 30 min. H2 O2 generated a delay in p-Stat3 and Socs3 mRNAs followed by suppression of Hes1 protein. These events were accompanied by simultaneous upregulation of p21 and downregulation of cyclinD1, resulting in a temporary arrest of the cell cycle. In conclusion, the elimination of Hes1 protein oscillation by H2 O2 may represent a defense mechanism against oxidative stress in fibroblast cells.


Assuntos
Fibroblastos/citologia , Peróxido de Hidrogênio/farmacologia , Fator de Transcrição STAT3/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Fatores de Transcrição HES-1/metabolismo , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Ciclina D1/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Células NIH 3T3 , Fosforilação , Ritmo Ultradiano/efeitos dos fármacos
3.
Mol Cell Endocrinol ; 439: 46-53, 2017 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-27769714

RESUMO

In this paper we report differential decoding of the ultradian corticosterone signal by glucocorticoid target tissues. Pulsatile corticosterone replacement in adrenalectomised rats resulted in different dynamics of Sgk1 mRNA production, with a distinct pulsatile mRNA induction profile observed in the pituitary in contrast to a non-pulsatile induction in the prefrontal cortex (PFC). We further report the first evidence for pulsatile transcriptional repression of a glucocorticoid-target gene in vivo, with pulsatile regulation of Pomc transcription in pituitary. We have explored a potential mechanism for differences in the induction dynamics of the same transcript (Sgk1) between the PFC and pituitary. Glucocorticoid receptor (GR) activation profiles were strikingly different in pituitary and prefrontal cortex, with a significantly greater dynamic range and shorter duration of GR activity detected in the pituitary, consistent with the more pronounced gene pulsing effect observed. In the prefrontal cortex, expression of Gilz mRNA was also non-pulsatile and exhibited a significantly delayed timecourse of increase and decrease when compared to Sgk1, additionally highlighting gene-specific regulatory dynamics during ultradian glucocorticoid treatment.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/farmacologia , Especificidade de Órgãos/genética , Ritmo Ultradiano/genética , Animais , Corticosterona/farmacologia , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/metabolismo , Masculino , Especificidade de Órgãos/efeitos dos fármacos , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Ritmo Ultradiano/efeitos dos fármacos
4.
Ann Med ; 48(1-2): 17-27, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26679264

RESUMO

INTRODUCTION: Disturbances of circadian rhythms are a key symptom of mood and anxiety disorders. Selective serotonin reuptake inhibitors (SSRIs) - commonly used antidepressant drugs - also modulate aspects of circadian rhythmicity. However, their potential to restore circadian disturbances in depression remains to be investigated. MATERIALS AND METHODS: The effects of the SSRI fluoxetine on genetically based, depression-related circadian disruptions at the behavioral and molecular level were examined using mice selectively bred for high anxiety-related and co-segregating depression-like behavior (HAB) and normal anxiety/depression behavior mice (NAB). RESULTS: The length of the circadian period was increased in fluoxetine-treated HAB as compared to NAB mice while the number of activity bouts and light-induced entrainment were comparable. No difference in hippocampal Cry2 expression, previously reported to be dysbalanced in untreated HAB mice, was observed, while Per2 and Per3 mRNA levels were higher in HAB mice under fluoxetine treatment. DISCUSSION: The present findings provide evidence that fluoxetine treatment normalizes disrupted circadian locomotor activity and clock gene expression in a genetic mouse model of high trait anxiety and depression. An interaction between the molecular mechanisms mediating the antidepressant response to fluoxetine and the endogenous regulation of circadian rhythms in genetically based mood and anxiety disorders is proposed.


Assuntos
Ansiedade/tratamento farmacológico , Transtorno Depressivo/tratamento farmacológico , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Ritmo Ultradiano/efeitos dos fármacos , Animais , Ansiedade/genética , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/fisiologia , Criptocromos/metabolismo , Transtorno Depressivo/genética , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Luz , Camundongos
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