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1.
Chemosphere ; 239: 124752, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31514010

RESUMO

The online biomonitoring of aquatic accidental pollution is very important to realize the assessment of complex toxicity. However, the monitoring results would be affected greatly by the internal physio-ecological changes of test organisms, and circadian rhythms might contribute greatly to this kind of effects. In the present study, the behavior responses of zebrafish (Danio rerio) to different concentrations of Deltamethrin, Atrazine, and Thallium (Tl) in 15 days were investigated using an online behavior monitoring system. The results showed that the average behavior strength (BS) value of dark period (0.71 ±â€¯0.16) was lower than that of light period (0.88 ±â€¯0.09) in the control group. Similar pattern was observed in all other treatments with negative relationship between exposure concentrations and mean BS values. It is concluded that the 24 h circadian rhythms in the behavior responses of zebrafish (Danio rerio) could be observed clearly in the online biomonitoring system, and the online monitoring results would be affected obviously in the characteristics of behavior periodicity abnormal and time delay. Therefore, it is suggested that internal physio-ecological characteristics of organisms must be considered once they have the chance to play roles in bio-induced technologies. More investigations are warranted to clear the effects of internal physio-ecological changes on the exported results.


Assuntos
Comportamento Animal/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Qualidade da Água , Peixe-Zebra/fisiologia , Animais , Atrazina/toxicidade , Nitrilos/toxicidade , Piretrinas/toxicidade , Tálio/toxicidade
2.
J Agric Food Chem ; 67(43): 11969-11976, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31583884

RESUMO

Our present study focused on the regulating effect of oolong tea polyphenols (OTPs) on the circadian rhythm of liver and intestinal microbiome. OTP significantly alleviated the disrupted diurnal oscillation and phase shift of the specific intestinal microbiota and liver clock genes in mice induced by constant dark (CD) treatment. Transcriptomics revealed that 1114 genes in the control group and 647 genes in the CD group showed circadian rhythm while 723 genes were rhythmic in the CD-OTP group. The Gene Ontology (GO) database provided significant differences in differentially expressed genes (DEGs) in response to OTP treatment. In addition, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriched the most DEGs after OTP intervention including "Focal adhesion" (9 DEGs) and "PI3K-Akt signaling pathway" (9 DEGs). The present study provided a global view that OTP may alleviate the circadian rhythm disorder of the host, contributing to the improvement of microecology and health.


Assuntos
Camellia sinensis/química , Ritmo Circadiano/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Intestinos/microbiologia , Fígado/metabolismo , Extratos Vegetais/administração & dosagem , Polifenóis/administração & dosagem , Adulto , Animais , Feminino , Ontologia Genética , Humanos , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transcriptoma/efeitos dos fármacos
3.
Ecotoxicol Environ Saf ; 183: 109556, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31509926

RESUMO

Dydrogesterone (DDG) is a synthetic progestin used in contraception and hormone replacement therapy. Our previous transcriptome data showed that the response to light stimulus, photoperiodism and rhythm related gene ontology (GO) terms were significantly enriched in the brain of zebrafish after chronic exposure to DDG. Here we investigated the effects of DDG on the eye of zebrafish. Zebrafish were exposed to DDG at three concentration levels (3.39, 33.1, and 329 ng L-1) for 120 days. Based on our previous transcriptome data, the transcription of genes involved in visual cycle and circadian rhythm network was examined by qPCR analysis. In the visual cycle network, exposure to all concentrations of DDG significantly decreased transcription of grk7a, aar3a and guca1d, while increased the transcription of opn1mw4 and opn1sw2 at the low concentration. Importantly, exposure to all concentrations of DDG down-regulated the transcription of rep65a that encodes a critical enzyme to catalyze the conversion from all-trans-retinal to 11-cis-retinal in the eye of male zebrafish. In the circadian rhythm network, DDG enhanced the transcription of clocka, arntl2 and nifil3-5 at all three concentrations, while it decreased the transcription of cry5, per1b, nr1d2b and si:ch211.132b12.7. In addition, DDG decreased the transcription of tefa in both males and females. Moreover, histological analysis showed the exposure to 329 ng L-1 of DDG decreased the thickness of retinal ganglion cell in the eye of male zebrafish. These results indicated that DDG exposure could affect the transcription of genes in visual cycle and circadian rhythm network in the eyes of zebrafish. This suggests that DDG has potential negative impact on the normal eye function.


Assuntos
Ritmo Circadiano/efeitos dos fármacos , Didrogesterona/toxicidade , Retina/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Animais , Ritmo Circadiano/genética , Relação Dose-Resposta a Droga , Feminino , Masculino , Retina/metabolismo , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/metabolismo
4.
Emergencias (Sant Vicenç dels Horts) ; 31(4): 227-233, ago. 2019. graf, tab
Artigo em Espanhol | IBECS | ID: ibc-182762

RESUMO

Objetivos: Este estudio analiza el control del ritmo en los servicios de urgencias (SUH) y sus resultados en pacientes con fibrilación auricular (FA) de reciente comienzo, para identificar áreas de mejora en el manejo. Método: Estudio multicéntrico, observacional, prospectivo y transversal desarrollado en 124 SUH representativos del sistema sanitario español basado en el registro HERMES-AF (estrategias de manejo en el servicio de urgencias hospitalario de la FA) del 23 de mayo al 5 de junio de 2011. Se incluyeron pacientes con FA sintomática con menos de 48 h de evolución en los cuales se tomó la decisión de restaurar el ritmo sinusal. Resultados: Se incluyeron 337 pacientes, se optó por cardioversión farmacológica en 311 pacientes (92,3%), y por cardioversión eléctrica en 52 (15%), la mitad de los casos tras fracaso de los fármacos. Se obtuvo ritmo sinusal (RS) en 278 pacientes (82,5%) y el alivio de los síntomas en 297 (94%), con una tasa de efectos adversos del 0,9%, ninguno grave. Amiodarona se asoció de manera independiente a una menor tasa de RS al alta (OR = 0,442; IC 95% 0,238-0,823; p = 0,01), al contrario que la cardioversión eléctrica (OR = 4,0; IC 95% 1,2-13,3; p = 0,024). Los fármacos I-C se asociaron con una mayor proporción de altas en < 6 h (OR 2,6; IC 95% 1,6-4,3; p < 0,001) y amiodarona con más estancias prolongadas de > 24 h (OR 2,7, IC 95% 1,5-4,8; p < 0,003). Conclusiones: En los SUH, la restauración del RS en la FA de reciente comienzo es segura, efectiva y asocia beneficios clínicos para los pacientes. Reemplazar amiodarona por técnicas más efectivas y rápidas como la cardioversión eléctrica o los fármacos I-C es un área de mejora de la calidad asistencial


Objectives: To analyze heart rate control in hospital emergency departments and outcomes in patients with recent onset atrial fibrillation (AF) so that targets for improvement can be identified. Methods: Multicenter, prospective observational cross-sectional study in a representative sample of 124 hospitals of the Spanish health services, based on records in the HERMES-AF database (Hospital Emergency Department Management Strategies for AF) for May 23 to June 5, 2011. Patients with symptomatic AF within 48 hours of onset were enrolled when the decision was made to attempt restoration of sinus rhythm. Results: We included 337 patients. Chemical cardioversion was used in 311 (92.3%) and electrical cardioversion in 52 (15%), after drugs had failed in half the cases. Sinus rhythm was restored in 278 patients (82.5%), and symptoms resolved in 94%. Adverse effects were recorded in 0.9% but none were serious. Amiodarone was independently associated with a lower rate of restored sinus rhythm (odds ratio [OR], 0.442; 95% CI, 0.238-0.823; P=.01) than electrical cardioversion (OR, 4.0; 95% CI, 1.2-13.3; P=.024). The use of class Ic antiarrhythmic agents was associated with a higher percentage of discharges in less than 6 hours (OR, 2.6; 95% CI, 1.6-4.3; P<.001), and amiodarone was associated with hospital stays longer than 24 hours (OR, 2.7; 95% CI, 1.5-4.8; P<.003). Conclusions: Emergency department restoration of sinus rhythm in patients with AF is safe, effective, and associated with clinical benefits. Quality of care could be improved by replacing the use of amiodarone with faster and more effective treatments such as electrical cardioversion or the use of class Ic agents


Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Cardioversão Elétrica/métodos , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/terapia , Serviços Médicos de Emergência , Ritmo Circadiano/efeitos dos fármacos , Sistema de Registros/normas , Cardioversão Elétrica/tendências , Estudos Prospectivos , Estudos Transversais , Espanha , Antiarrítmicos/administração & dosagem , Sistemas de Saúde/organização & administração
5.
BMC Endocr Disord ; 19(1): 78, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31337371

RESUMO

BACKGROUND: Hypoglycaemia, especially nocturnal, remains the main limiting factor of achieving good glycaemic control in type 1 diabetes. The effect of first generation long-acting insulin analogues in reducing nocturnal hypoglycaemia is well documented in patient with type 1 diabetes. The effect of the newer long-acting insulin degludec on risk of nocturnal hypoglycaemia remains undocumented in patients with type 1 diabetes and recurrent severe nocturnal hypoglycaemia. The HypoDeg trial is designed to investigate whether insulin degludec in comparison with insulin glargine U100 is superior in limiting the occurrence of nocturnal hypoglycaemia in patients with recurrent nocturnal severe hypoglycaemia. This paper reports the study design of the HypoDeg trial. METHODS/DESIGN: A Danish investigator-initiated, prospective, randomised, open, blinded endpoint (PROBE), multicentre, two-year cross-over study investigating the effect of insulin degludec versus insulin glargine U100 on frequency of nocturnal hypoglycaemia in patients with type 1 diabetes and one or more episodes of nocturnal severe hypoglycaemia during the preceding two years as the major inclusion criteria. Patients are randomised (1:1) to basal therapy with insulin degludec or insulin glargine. Insulin aspart is used as bolus therapy in both treatment arms. DISCUSSION: In contrast to most other insulin studies the HypoDeg trial includes only patients at high risk of hypoglycaemia. The HypoDeg trial will compare treatment with insulin degludec to insulin glargine U100 in terms of risk of nocturnal hypoglycaemic episodes in patients with type 1 diabetes with the greatest potential to benefit from near-physiological insulin replacement therapy. www.clinicaltrials.gov : NCT02192450.


Assuntos
Ritmo Circadiano/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemia/epidemiologia , Hipoglicemiantes/uso terapêutico , Insulina de Ação Prolongada/uso terapêutico , Índice de Gravidade de Doença , Adolescente , Adulto , Idoso , Biomarcadores/análise , Glicemia/análise , Estudos Cross-Over , Esquema de Medicação , Feminino , Seguimentos , Humanos , Hipoglicemia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Adulto Jovem
6.
Environ Toxicol ; 34(11): 1255-1262, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31298479

RESUMO

Progesterone (P4) is a biologically active steroid hormone that is involved in the regulation of oocyte growth and maturation, as well as development of the endometrium and implantation in the uterus of humans. It can also stimulate oocyte maturation in female fish, as well as spermatogenesis and sperm motility in male fish. Thus, P4 has been extensively used in human and animal husbandry as a typical progestin. However, P4 remaining in the water environment will pose a potential hazard to aquatic organisms. For example, it can interfere with sex differentiation and reproduction in aquatic vertebrates such as fish. Therefore, we investigated the effects of prolonged progesterone exposure on the expression of genes related to circadian rhythm signaling and the hypothalamic-pituitary-gonadal (HPG) axes in Yellow River Carp, which may have a potential impact on their sex differentiation. Our results suggested that P4 exposure altered the expression of genes related to circadian rhythm signaling, which can lead to disorders in the endocrine system and regulate the HPG axes-related activities. Furthermore, the expression of genes related to the HPG axes was also altered, which might affect gonadal development and the reproductive systems of Yellow River Carp. In addition, these changes may provide a plausible mechanism for the observed shifts in their sex ratio toward females.


Assuntos
Ritmo Circadiano/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Progesterona/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Carpas/crescimento & desenvolvimento , Carpas/metabolismo , Feminino , Gônadas/efeitos dos fármacos , Gônadas/patologia , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Diferenciação Sexual/efeitos dos fármacos , Razão de Masculinidade , Transcrição Genética/efeitos dos fármacos
7.
J Physiol Sci ; 69(5): 791-798, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31301005

RESUMO

Serum testosterone concentration decreases with age in humans and rodents. Accordingly, old male mice show changes in locomotor activity rhythms: a lengthened free-running period and decreased activity levels among others. To investigate whether testosterone replacement improves the age-related decline in circadian rhythmicity, we examined the effects of testosterone on the circadian rhythms of wheel running activity in old male mice. Intact male C57BL/6J mice (18-22 months old) were subcutaneously implanted with silicone tubes packed with testosterone propionate (TP) or cholesterol. TP treatment significantly decreased the daily wheel running revolutions in a normal light/dark (LD) cycle and in constant darkness (DD), but did not affect the free-running period. The same experiment performed on young male gonadectomized mice (3-5 months old) demonstrated that TP treatment significantly increased activity levels in both LD and DD. These results suggest that testosterone replacement exacerbates the age-related decline in circadian rhythmicity.


Assuntos
Ritmo Circadiano/efeitos dos fármacos , Testosterona/farmacologia , Animais , Escuridão , Luz , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Fotoperíodo
8.
J Agric Food Chem ; 67(31): 8510-8519, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31294559

RESUMO

Acrylamide, mainly formed in Maillard browning reaction during food processing, causes defects in liver circadian clock and mitochondrial function by inducing oxidative stress. Resveratrol is a polyphenol that has powerful antioxidant and anti-inflammatory activity. However, the preventive effects of resveratrol on acrylamide-triggered oxidative damage and circadian rhythm disorders are unclear at the current stage. The present research revealed that resveratrol pretreatment prevented acrylamide-induced cell death, mitochondrial dysfunction, and inflammatory responses in HepG2 liver cells. Acrylamide significantly triggered disorders of circadian genes transcription and protein expressions including Bmal1 and Cry 1 in primary hepatocytes, which were prevented by resveratrol pretreatment. Moreover, we found that the beneficial effects of resveratrol on stimulating Nrf2/NQO-1 pathway and mitochondrial respiration complex expressions in acrylamide-treated cells were Bmal1-dependent. Similarly, the inhibitory effects of resveratrol on inflammation signaling NF-κB were Cry1-dependent. In conclusion, these results demonstrated resveratrol could be a promising compound in suppressing acrylamide-induced hepatotoxicity and balancing the circadian clock.


Assuntos
Fatores de Transcrição ARNTL/imunologia , Acrilamida/toxicidade , Transtornos Cronobiológicos/imunologia , Criptocromos/imunologia , Hepatócitos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Resveratrol/farmacologia , Fatores de Transcrição ARNTL/genética , Animais , Transtornos Cronobiológicos/tratamento farmacológico , Transtornos Cronobiológicos/genética , Transtornos Cronobiológicos/fisiopatologia , Ritmo Circadiano/efeitos dos fármacos , Criptocromos/genética , Células Hep G2 , Hepatócitos/imunologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/genética , Mitocôndrias/imunologia
9.
Chemosphere ; 235: 280-287, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31260868

RESUMO

Thifluzamide as a fungicide is toxic to brain of zebrafish embryos. Brain can regulate biological rhythms. To clarify whether thifluzamide would influence circadian rhythms, zebrafish embryos were treated with thifluzamide (0, 0.19, 1.90 and 2.85 mg/L) for 4 days. Exposure to thifluzamide induced pronounced changes in embryo brain and melatonin levels. The mRNA levels of genes related to circadian rhythms were apparently altered. Among these, the transcripts of cry1ba and clock1 were extremely correlated with exposure concentrations. Importantly, the content of cry1 showed no apparent changes, but the clock level was dramatically increased. Moreover, consistent with the inhibition of development and behavior, the levels of GH and DA were significantly inhibited. In addition, the expression levels of genes related to development, behavior and reproduction were significantly changed by thifluzamide. Therefore, we speculated that circadian disruption due to thifluzamide exposure were primarily attributed to increases in expression of clock1a and contents of clock, which might be at least in part responsible for abnormal development and behavior of zebrafish. In addition, our research will provide important insights into the grouped assessment of SDHI pesticides in future.


Assuntos
Anilidas/toxicidade , Ritmo Circadiano/efeitos dos fármacos , Tiazóis/toxicidade , Peixe-Zebra/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Ritmo Circadiano/genética , Proteínas de Ligação a DNA/metabolismo , Relação Dose-Resposta a Droga , Embrião não Mamífero , Fungicidas Industriais/toxicidade , Melatonina/metabolismo , RNA Mensageiro/metabolismo , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/metabolismo
10.
Behav Processes ; 165: 23-28, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31132444

RESUMO

Circadian rhythms organize behavior and physiological processes to be appropriate to the predictable cycle of daily events. These rhythms are entrained by stimuli that provide time of day cues (zeitgebers), such as light, which regulates the sleep-wake cycle and associated rhythms. But other events, including meals, social cues, and bouts of locomotor activity, can act as zeitgebers. Recent evidence shows that most organs and tissues contain cells that are capable of some degree of independent circadian cycling, suggesting the circadian system is broadly and diffusely distributed. Within laboratory studies of behavior, circadian rhythms tend to be treated as a complication to be minimized, but they offer a useful model of predictable shifts in behavioral tendencies. In the present review, we summarize the evidence that formed the basis for a hypothesis that drugs of abuse can entrain circadian rhythms and describe the outcome of a series of experiments designed to test that hypothesis. We propose that such drug-entrained rhythms may contribute to demonstrated daily variations in drug metabolism, tolerance, and sensitivity to drug reward. Of particular importance, these rhythms may be evoked by a single episode of drug taking, strengthen with repeated episodes, and re-emerge after long periods of abstinence, thereby contributing to drug abuse, addiction, and relapse.


Assuntos
Ritmo Circadiano/efeitos dos fármacos , Comportamento Alimentar/fisiologia , /farmacologia , Animais , Encéfalo/fisiopatologia , Ritmo Circadiano/fisiologia , Sinais (Psicologia) , Tolerância a Medicamentos , Habituação Psicofisiológica/fisiologia , Humanos , Taxa de Depuração Metabólica/fisiologia , Motivação/efeitos dos fármacos , Motivação/fisiologia , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/psicologia
11.
Expert Opin Pharmacother ; 20(11): 1341-1349, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31046480

RESUMO

INTRODUCTION: Insomnia in Major Depressive Disorder (MDD) is highly prevalent and associated with increased suffering and functional impairment. Effective, evidence-based treatments for insomnia in MDD are an unmet need in clinical practice. AREAS COVERED: Herein, the authors provide a review of the clinical correlates, putative neurobiological mechanisms and treatment options for the management of insomnia in individuals with MDD. EXPERT OPINION: Sleep disturbances in MDD should be recognized as at least one of the following: (1) a domain of depressive psychopathology; (2) a consequence of rhythm disruptions; (3) a manifestation of comorbidities of sleep disturbances; (4) a manifestation of the influence of sex hormones in the brain in MDD; (5) a general medical comorbidity; and (6) a side effect of antidepressant medications. Assessment of insomnia in clinical practices is routinely performed with the use of non-structured interviews. Other methods such as standardized questionnaires and sleep diaries, along with complementary methods such as actigraphy and polysomnography are more scarcely applied. Smartphones and personal devices offer a promising strategy with the use of passive, long lasting, and ecologically valid assessments despite the lack of studies specifically targeting insomnia in individuals with MDD. New therapeutic approaches are essential, including novel targets such as orexins/hypocretins and the endocannabinoid system.


Assuntos
Antidepressivos/efeitos adversos , Transtorno Depressivo Maior/patologia , Inibidores de Captação de Serotonina/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Ritmo Circadiano/efeitos dos fármacos , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/tratamento farmacológico , Prática Clínica Baseada em Evidências , Humanos , Orexinas/antagonistas & inibidores , Orexinas/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Distúrbios do Início e da Manutenção do Sono/etiologia
12.
Environ Int ; 128: 146-157, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31055201

RESUMO

It has been documented that 3, 3', 4, 4', 5-pentachlorobiphenyl (PCB126) elicits diverse detrimental effects on human health including metabolic syndrome and non-alcoholic fatty-liver disease (NAFLD), through a wide array of non-carcinogenic mechanisms, which require further detailed investigations. The circadian clock system consists of central clock machinery (located in the suprachiasmatic nucleus in the hypothalamus) and the peripheral clocks (located in nearly all peripheral tissues). Peripheral clocks in the liver play fundamental roles in maintaining liver homeostasis, including the regulation of energy metabolism and the expression of enzymes that fine-tune the absorption and metabolism of xenobiotics. However, the molecular basis of whether PCB126 disrupts liver homeostasis (e.g., glucose and lipid metabolism) by dysregulating the circadian clock system is still unknown. Thus, we performed a set of comprehensive analyses of glucose and lipid metabolism in the liver tissues from low-dose PCB126-treated mice. Our results demonstrated that PCB126 diminished glucose and cholesterol levels in serum and elevated glucose and cholesterol levels in the liver. Moreover, PCB126 compromised PGC1α and PDHE1α, which are the driving force for mitochondrial biogenesis and entry of pyruvate into the tricarboxylic acid (TCA) cycle, respectively, and resulted in the accumulation of glucose, glycogen and pyruvate in the liver after PCB126 exposure. Additionally, PCB126 blocked hepatic cholesterol metabolism and export pathways, leading to an elevated localization of hepatic cholesterol. Mechanistic investigations illustrated that PCB126 greatly altered the expression profile of core clock genes and their target rhythm genes involved in orchestrating glucose and cholesterol metabolism. Together, our results demonstrated that a close correlation between PCB126-disturbed glucose and lipid metabolism and disordered physiological oscillation of circadian genes.


Assuntos
Ritmo Circadiano/efeitos dos fármacos , Glucose/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Bifenilos Policlorados/farmacologia , Animais , Metabolismo Energético/efeitos dos fármacos , Homeostase , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos
13.
J Pineal Res ; 67(2): e12586, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31077613

RESUMO

Disruption of circadian time structure and suppression of circadian nocturnal melatonin (MLT) production by exposure to dim light at night (dLAN), as occurs with night shift work and/or disturbed sleep-wake cycles, is associated with a significantly increased risk of breast cancer and resistance to tamoxifen and doxorubicin. Melatonin inhibition of human breast cancer chemoresistance involves mechanisms including suppression of tumor metabolism and inhibition of kinases and transcription factors which are often activated in drug-resistant breast cancer. Signal transducer and activator of transcription 3 (STAT3), frequently overexpressed and activated in paclitaxel (PTX)-resistant breast cancer, promotes the expression of DNA methyltransferase one (DNMT1) to epigenetically suppress the transcription of tumor suppressor Aplasia Ras homolog one (ARHI) which can sequester STAT3 in the cytoplasm to block PTX resistance. We demonstrate that breast tumor xenografts in rats exposed to dLAN and circadian MLT disrupted express elevated levels of phosphorylated and acetylated STAT3, increased DNMT1, but reduced sirtuin 1 (SIRT1) and ARHI. Furthermore, MLT and/or SIRT1 administration blocked/reversed interleukin 6 (IL-6)-induced acetylation of STAT3 and its methylation of ARH1 to increase ARH1 mRNA expression in MCF-7 breast cancer cells. Finally, analyses of the I-SPY 1 trial demonstrate that elevated MT1 receptor expression is significantly correlated with pathologic complete response following neo-adjuvant therapy in breast cancer patients. This is the first study to demonstrate circadian disruption of MLT by dLAN driving intrinsic resistance to PTX via epigenetic mechanisms increasing STAT3 expression and that MLT administration can reestablish sensitivity of breast tumors to PTX and drive tumor regression.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Melatonina/farmacologia , Paclitaxel/farmacologia , Fator de Transcrição STAT3/metabolismo , Proteínas Supressoras de Tumor/biossíntese , Proteínas rho de Ligação ao GTP/biossíntese , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ritmo Circadiano/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Ratos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Chemosphere ; 228: 649-655, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31063912

RESUMO

Circadian rhythms are fundamental to behavior and physiology of organisms. Flutolanil as a fungicide is toxic to zebrafish embryos. The aims of this study were to determine whether flutolanil would influence circadian rhythms of zebrafish and the mechanism involved. Zebrafish embryos were exposed to flutolanil (0, 0.125, 0.5 and 2 mg/L) for 4 days. Here we report that flutolanil increased the melatonin levels of zebrafish. The mRNA levels of genes related to circadian rhythms were significantly altered. The clock level was significantly increased, but the content of cry1 showed no apparent changes. Moreover, our findings that the level of GH was significantly decreased were consistent with the abnormal development of zebrafish embryos. The expression levels of genes related to development, behavior and reproduction were significantly altered by flutolanil. These results indicate that flutolanil disturbed circadian rhythms of zebrafish primarily by affecting the positive elements, which were at least in partial responsible for abnormal development and behavior of zebrafish. And we speculate that flutolanil is toxic to zebrafish embryos at least in part via dysregulation of circadian rhythms involving clock.


Assuntos
Anilidas/toxicidade , Ritmo Circadiano/efeitos dos fármacos , Melatonina/metabolismo , Peixe-Zebra/embriologia , Animais , Comportamento Animal/efeitos dos fármacos , Proteínas CLOCK/genética , Ritmo Circadiano/genética , Criptocromos/genética , Ecotoxicologia/métodos , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/fisiologia , Fungicidas Industriais/toxicidade , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/fisiologia , Proteínas de Peixe-Zebra/genética
15.
Int Immunopharmacol ; 73: 108-117, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31082723

RESUMO

Circadian rhythm disruption (CRD) is regarded as a risk factor for inflammatory bowel disease (IBD), and it was reported to suppress the level of melatonin, which execute anti-inflammatory effects. High mobility group box 1 protein (HMGB1) is a member of the damage-associated molecular pattern (DAMP) family and has been verified as an IBD-associated inflammatory cytokine that mediates the TLR4-NF-κB pathway. However, no exact mechanism has been illustrated among melatonin, disrupted circadian rhythm and inflammatory bowel disease, as well as regarding the effect of melatonin on HMGB1. In the present study, we aimed to explore the role of relationship with HMGB1. CRD aggravated DSS-induced colitis by worsening colonic inflammation and tissue injury, as well as by enhancing HMGB1 translocation, which could be reversed by ethyl pyruvate, an HMGB1 antagonist. Moreover, melatonin treatment attenuated these disorders and the shuttling of HMGB1 in the intestinal epithelial cells (IECs), the effect of which could be partly reversed by the melatonin antagonist luzindole. The protective role of melatonin may be tightly related to the translocation of HMGB1 in IECs. Accordingly, these results suggested that melatonin may be a new therapeutic beneficial option in IBD patients, especially for those with circadian rhythm disruption.


Assuntos
Ritmo Circadiano/efeitos dos fármacos , Colite/tratamento farmacológico , Melatonina/uso terapêutico , Animais , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Colo/patologia , Sulfato de Dextrana , Proteína HMGB1/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Masculino , Melatonina/farmacologia , Camundongos Endogâmicos C57BL
16.
Clin Neuropharmacol ; 42(3): 80-87, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31082833

RESUMO

This review describes the characteristics of a number of pathologies, which are considered from the point of view of chronobiology, that is, the way in which biological processes are expressed throughout the 24-hour day. This perspective is a relatively new way of thinking about disease and additionally about how to treat diseases. It has called attention to the importance of not only the quantity of a drug that is administered but also when it is administered. In addition, the review presents an overview of the emerging clinical strategies known as chronotherapeutics, that is, the effects of the daily scheduling of drug administration and the consequences of the activity and efficacy of therapies that are applied in this manner. This article also reviews innovative ways in which physicians are applying time-specified drug treatment (chronopharmacology) for sleep disorders. Here, we present a systematic description of chronopharmacology as well as definitions of key terms that, we believe, will be helpful for newcomers to the field. It is hoped that greater awareness of this new perspective on pharmacology will promote its adoption by researchers and clinicians.


Assuntos
Fenômenos Cronobiológicos/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Cronoterapia Farmacológica , Transtornos do Sono-Vigília/tratamento farmacológico , Humanos
17.
EMBO J ; 38(12)2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-31126958

RESUMO

Autophagy and energy metabolism are known to follow a circadian pattern. However, it is unclear whether autophagy and the circadian clock are coordinated by common control mechanisms. Here, we show that the oscillation of autophagy genes is dependent on the nutrient-sensitive activation of TFEB and TFE3, key regulators of autophagy, lysosomal biogenesis, and cell homeostasis. TFEB and TFE3 display a circadian activation over the 24-h cycle and are responsible for the rhythmic induction of genes involved in autophagy during the light phase. Genetic ablation of TFEB and TFE3 in mice results in deregulated autophagy over the diurnal cycle and altered gene expression causing abnormal circadian wheel-running behavior. In addition, TFEB and TFE3 directly regulate the expression of Rev-erbα (Nr1d1), a transcriptional repressor component of the core clock machinery also involved in the regulation of whole-body metabolism and autophagy. Comparative analysis of the cistromes of TFEB/TFE3 and REV-ERBα showed an extensive overlap of their binding sites, particularly in genes involved in autophagy and metabolic functions. These data reveal a direct link between nutrient and clock-dependent regulation of gene expression shedding a new light on the crosstalk between autophagy, metabolism, and circadian cycles.


Assuntos
Autofagia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/fisiologia , Relógios Circadianos , Metabolismo Energético , Nutrientes/fisiologia , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/efeitos dos fármacos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Sítios de Ligação , Células Cultivadas , Relógios Circadianos/efeitos dos fármacos , Relógios Circadianos/genética , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/fisiologia , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Regulação da Expressão Gênica , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/fisiologia , Nutrientes/farmacologia , Fatores de Transcrição/efeitos dos fármacos , Fatores de Transcrição/genética , Fatores de Transcrição/fisiologia
18.
J Pineal Res ; 67(1): e12583, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31033013

RESUMO

Light significantly improves alertness during the night (Cajochen, Sleep Med Rev, 11, 2007 and 453; Ruger et al., AJP Regul Integr Comp Physiol, 290, 2005 and R1413), but results are less conclusive at daytime (Lok et al., J Biol Rhythms, 33, 2018 and 589). Melatonin and core body temperature levels at those times of day may contribute to differences in alerting effects of light. In this experiment, the combined effect of daytime exogenous melatonin administration and light intensity on alertness, body temperature, and skin temperature was studied. The goal was to assess whether (a) alerting effects of light are melatonin dependent, (b) soporific effects of melatonin are mediated via the thermoregulatory system, and (c) light can improve alertness after melatonin-induced sleepiness during daytime. 10 subjects (5 females, 5 males) received melatonin (5 mg) in dim (10 lux) and, on a separate occasion, in bright polychromatic white light (2000 lux). In addition, they received placebo both under dim and bright light conditions. Subjects participated in all four conditions in a balanced order, yielding a balanced within-subject design, lasting from noon to 04:00 pm. Alertness and performance were assessed half hourly, while body temperature and skin temperature were measured continuously. Saliva samples to detect melatonin concentrations were collected half hourly. Melatonin administration increased melatonin concentrations in all subjects. Subjective sleepiness and distal skin temperature increased after melatonin ingestion. Bright light exposure after melatonin administration did not change subjective alertness scores, but body temperature and proximal skin temperature increased, while distal skin temperature decreased. Light exposure did not significantly affect these parameters in the placebo condition. These results indicate that (a) exogenous melatonin administration during daytime increases subjective sleepiness, confirming a role for melatonin in sleepiness regulation, (b) bright light exposure after melatonin ingestion significantly affected thermoregulatory parameters without altering subjective sleepiness, therefore temperature changes seem nonessential for melatonin-induced sleepiness, (c) subjective sleepiness was increased by melatonin ingestion, but bright light administration was not able to improve melatonin-induced sleepiness feelings nor performance. Other (physiological) factors may therefore contribute to differences in alerting effects of light during daytime and nighttime.


Assuntos
Regulação da Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Luz , Melatonina/administração & dosagem , Adulto , Feminino , Humanos , Masculino , Melatonina/metabolismo
19.
Neuroscience ; 408: 327-338, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30978380

RESUMO

Rapid changes in the light-dark cycle cause circadian desynchronization between rhythms of spike-wave discharges (SWDs) and motor activity in genetic epileptic rats, and this is accompanied by an increase in epileptic activity. Given the close relationship between absence seizures and sleep-wake states, the present study assessed firstly a putative relationship between vigilance rhythms and SWDs during re-synchronization, and secondly sleep-wake patterns responsible for increased epileptic activity. Lastly, in a view of existing evidence that melatonin and its agonists accelerate re-synchronization, the effects of different doses of agomelatine upon the speed of re-synchronization of different sleep-wake states and SWDs were investigated. Simultaneous electroencephalographic and electromyographic recordings were made in symptomatic WAG/Rij rats, before, during and 10 days following an 8 h light phase delay. Agomelatine was orally administered acutely and sub-chronically, during 10 post-shift days. The magnitude of the advance after the shift and the speed of re-synchronization were specific for various rhythms. Most prominent change was the increase in REM sleep duration during the dark phase. A post-shift increase in passive wakefulness and a reduction in deep slow-wave sleep coincided with an aggravation of SWDs during the light phase. Agomelatine showed neither an effect on sleep-wake parameters and SWDs, nor affected re-synchronization. The same speed of re-synchronization of SWDs and light slow-wave sleep suggests that both are controlled by a common circadian mechanism. The redistribution of SWDs and their increase in the light phase after the shift may be of importance for patients with absence epilepsy planning long trans-meridian flight across time zones.


Assuntos
Acetamidas/farmacologia , Ritmo Circadiano/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Sono/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Eletroencefalografia , Eletromiografia , Masculino , Ratos
20.
Neurobiol Learn Mem ; 161: 169-174, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31022446

RESUMO

Studies investigating effects of acute stress on Prospective Memory (PM) so far yielded heterogeneous findings. Although results were commonly attributed to stress-induced changes in cortisol, past research did not disentangle effects of cortisol from the effects of sympathetic nervous system (SNS) activation and cognitive reappraisal. The present study therefore aimed at investigating the mere effect of cortisol on PM tasks that differently involve prefrontal brain regions (nonfocal vs. focal PM tasks) via a placebo-controlled oral pharmacological intake of 10 mg hydrocortisone mimicking physiological responses to stress. Contrary to our prediction, enhanced levels of cortisol did not affect PM accuracy and monitoring costs, neither for the focal nor the nonfocal PM tasks. These results suggest that changes of cortisol levels do not underlie potential stress effects on PM. Further exploratory results revealed that PM performance was higher in the 3 pm than in the 1 pm placebo group. This means that PM performance, independently of effects of cortisol, seem to vary throughout the day.


Assuntos
Adaptação Psicológica/fisiologia , Ritmo Circadiano/fisiologia , Glucocorticoides/farmacologia , Hidrocortisona/farmacologia , Memória Episódica , Desempenho Psicomotor/fisiologia , Estresse Psicológico/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Adaptação Psicológica/efeitos dos fármacos , Adulto , Ritmo Circadiano/efeitos dos fármacos , Método Duplo-Cego , Feminino , Glucocorticoides/administração & dosagem , Humanos , Hidrocortisona/administração & dosagem , Masculino , Desempenho Psicomotor/efeitos dos fármacos , Estresse Psicológico/metabolismo , Sistema Nervoso Simpático/metabolismo , Adulto Jovem
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