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1.
J Pharmacol Sci ; 144(3): 129-138, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32921394

RESUMO

The traditional Japanese (Kampo) medicines yokukansan (YKS) and yokukansankachimpihange (YKSCH) have similar formulas and the same indications. In animals or cultured cells, the neuropharmacological actions of YKS are sometimes more beneficial than those of YKSCH. Since both drugs are used to treat sleep disorders in Japan, we examined the ameliorative effects of YKS and YKSCH on circadian rhythm disturbance and compared their efficacy using a mouse model of circadian rhythm disruption. Ramelteon was used as the positive control. Ramelteon treatment significantly reversed decreased running wheel activity during the advanced dark phase, indicating facilitation of circadian adaptation. YKS treatment also reversed the activity in the early period of drug treatment; however, it was not statistically significant. YKSCH treatment significantly reversed the decreased activity during the advanced dark phase. Plasma melatonin (MT) levels were significantly increased in the YKSCH but not in the YKS group. The ameliorative effect of YKSCH on rhythm disruption was significantly inhibited by coadministration of the MT2 receptor antagonist. Therefore, the therapeutic effect of YKSCH on circadian rhythm disruption would be attributable, to elevated endogenous MT levels. Taken together, YKS and YKSCH have different pharmacological properties and may be more precisely prescribed depending on patients' psychological symptoms.


Assuntos
Adaptação Biológica/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Kampo , Melatonina/metabolismo , Fitoterapia , Transtornos do Sono-Vigília/tratamento farmacológico , Animais , Masculino , Melatonina/sangue , Camundongos Endogâmicos C3H , Transtornos do Sono-Vigília/etiologia , Transtornos do Sono-Vigília/fisiopatologia
2.
J Int Med Res ; 48(9): 300060520958594, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32962495

RESUMO

OBJECTIVE: Coronavirus disease 2019 (COVID-19) shows a wide range of severity, ranging from an asymptomatic presentation to a severe illness requiring intensive care unit admission. Identification of a strategy to manage the severity of this disease will not only help to reduce its case fatality but also help to remove some of the burden from the already overwhelmed health care systems. While successful management of symptoms in general is important, identifying measures to modify the severity of the illness is a key factor in the fight against this pandemic. METHODS: This paper presents a short literature review to suggest a new treatment modality for COVID-19. RESULTS: COVID-19 is less severe and rarely fatal in children than in adults, which could be caused by greater fluctuations of plasma epinephrine in children. Our literature survey endorses this hypothesis according to both the epidemiological and immunological findings. CONCLUSION: Application of epinephrine pulses with a specific amplitude may be considered an intervention to minimize the severity of COVID-19.


Assuntos
Linfócitos T CD8-Positivos/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Epinefrina/uso terapêutico , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Adulto , Fatores Etários , Doenças Assintomáticas , Biomarcadores/sangue , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Criança , Ritmo Circadiano/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Esquema de Medicação , Epinefrina/sangue , Epinefrina/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Modelos Imunológicos , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Prognóstico , Índice de Gravidade de Doença
3.
Ecotoxicol Environ Saf ; 205: 111050, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32827960

RESUMO

Ammonia toxicity to respiratory system in pig faming is of particular concern, but the molecular mechanism remains still unclear. The present study was devoted to assess the impacts of the ammonia exposure on the lung tissues based on a pig study using 80 ppm ammonia exposing to piglets for different days. The histology analysis revealed ammonia exposure induced lung injury and inflammatory response, as indicated by epithelial-mesenchymal transition (EMT), significant thickening of alveolar septa, infiltration of inflammatory cells and excessive mucus production. The transcriptome analysis revealed many more up-regulated genes in exposure groups when compared with the control group, and these genes were significantly enriched in the GO term of extracellular exosome, proteolysis, and regulation of circadian rhythm. The study discovered the induction of seven genes (CRY2, CIART, CREM, NR1D1, NR1D2, PER1 and PER3) that encode repressors of circadian clock. One gene (ARNTL) that encodes activator of circadian clock was down-regulated after ammonia exposure. The results of this study suggest that ammonia exposure disturbed the pulmonary circadian clock gene expression, which may establish new evidence for further understanding the toxicity of ammonia to lungs.


Assuntos
Amônia/toxicidade , Relógios Circadianos/efeitos dos fármacos , Lesão Pulmonar , Amônia/metabolismo , Animais , Relógios Circadianos/genética , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Pulmão/metabolismo , Suínos , Fatores de Transcrição/genética , Regulação para Cima
4.
Nature ; 583(7816): 421-424, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32641825

RESUMO

The suprachiasmatic nucleus (SCN) serves as the body's master circadian clock that adaptively coordinates changes in physiology and behaviour in anticipation of changing requirements throughout the 24-h day-night cycle1-4. For example, the SCN opposes overnight adipsia by driving water intake before sleep5,6, and by driving the secretion of anti-diuretic hormone7,8 and lowering body temperature9,10 to reduce water loss during sleep11. These responses can also be driven by central osmo-sodium sensors to oppose an unscheduled rise in osmolality during the active phase12-16. However, it is unknown whether osmo-sodium sensors require clock-output networks to drive homeostatic responses. Here we show that a systemic salt injection (hypertonic saline) given at Zeitgeber time 19-a time at which SCNVP (vasopressin) neurons are inactive-excited SCNVP neurons and decreased non-shivering thermogenesis (NST) and body temperature. The effects of hypertonic saline on NST and body temperature were prevented by chemogenetic inhibition of SCNVP neurons and mimicked by optogenetic stimulation of SCNVP neurons in vivo. Combined anatomical and electrophysiological experiments revealed that osmo-sodium-sensing organum vasculosum lamina terminalis (OVLT) neurons expressing glutamic acid decarboxylase (OVLTGAD) relay this information to SCNVP neurons via an excitatory effect of γ-aminobutyric acid (GABA). Optogenetic activation of OVLTGAD neuron axon terminals excited SCNVP neurons in vitro and mimicked the effects of hypertonic saline on NST and body temperature in vivo. Furthermore, chemogenetic inhibition of OVLTGAD neurons blunted the effects of systemic hypertonic saline on NST and body temperature. Finally, we show that hypertonic saline significantly phase-advanced the circadian locomotor activity onset of mice. This effect was mimicked by optogenetic activation of the OVLTGAD→ SCNVP pathway and was prevented by chemogenetic inhibition of OVLTGAD neurons. Collectively, our findings provide demonstration that clock time can be regulated by non-photic physiologically relevant cues, and that such cues can drive unscheduled homeostatic responses via clock-output networks.


Assuntos
Relógios Circadianos/fisiologia , Vias Neurais , Neurônios/metabolismo , Sódio/metabolismo , Núcleo Supraquiasmático/fisiologia , Ácido gama-Aminobutírico/metabolismo , Animais , Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/fisiologia , Relógios Circadianos/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/fisiologia , Ingestão de Líquidos/efeitos dos fármacos , Glutamato Descarboxilase/metabolismo , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Vias Neurais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Optogenética , Organum Vasculosum/citologia , Organum Vasculosum/efeitos dos fármacos , Organum Vasculosum/enzimologia , Organum Vasculosum/fisiologia , Concentração Osmolar , Solução Salina Hipertônica/administração & dosagem , Solução Salina Hipertônica/metabolismo , Solução Salina Hipertônica/farmacologia , Sódio/administração & dosagem , Sódio/farmacologia , Núcleo Supraquiasmático/citologia , Núcleo Supraquiasmático/efeitos dos fármacos , Vasopressinas/metabolismo
5.
PLoS One ; 15(7): e0236318, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726319

RESUMO

Lately, Drosophila has been favored as a model in sleep and circadian rhythm research due to its conserved mechanism and easily manageable operation. These studies have revealed the sophisticated parameters in whole-day sleep profiles of Drosophila, drawing connections between Drosophila sleep and human sleep. In this study, we tested several sleep deprivation protocols (mechanical shakes and light interruptions) on Drosophila and delineated their influences on Drosophila sleep. We applied a daytime light-deprivation protocol (DD) mimicking jet-lag to screen drugs that alleviate sleep deprivation. Characteristically, classical sleep-aid compounds exhibited different forms of influence: phenobarbital and pentobarbital modified total sleep time, while melatonin only shortened the latency to sleep. Such results construct the basis for further research on sleep benefits in other treatments in Drosophila. We screened seven herb extracts, and found very diverse results regarding their effect on sleep regulation. For instance, Panax notoginseng and Withania somnifera extracts displayed potent influence on total sleep time, while Melissa officinalis increased the number of sleep episodes. By comparing these treatments, we were able to rank drug potency in different aspects of sleep regulation. Notably, we also confirmed the presence of sleep difficulties in a Drosophila Alzheimer's disease (AD) model with an overexpression of human Abeta, and recognized clear differences between the portfolios of drug screening effects in AD flies and in the control group. Overall, potential drug candidates and receipts for sleep problems can be identified separately for normal and AD Drosophila populations, outlining Drosophila's potential in drug screening tests in other populations if combined with the use of other genetic disease tools.


Assuntos
Extratos Vegetais/farmacologia , Privação do Sono/tratamento farmacológico , Transtornos do Sono-Vigília/tratamento farmacológico , Sono/fisiologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/genética , Animais , Ritmo Circadiano/efeitos dos fármacos , Modelos Animais de Doenças , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/genética , Drosophila melanogaster/fisiologia , Regulação da Expressão Gênica/genética , Humanos , Melatonina/farmacologia , Mutação , Panax notoginseng/química , Fenobarbital/farmacologia , Extratos Vegetais/química , Sono/efeitos dos fármacos , Sono/genética , Privação do Sono/genética , Privação do Sono/fisiopatologia , Transtornos do Sono-Vigília/genética , Transtornos do Sono-Vigília/fisiopatologia , Withania/química
6.
PLoS One ; 15(7): e0236315, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32706791

RESUMO

The natural product nobiletin is a small molecule, widely studied with regard to its therapeutic effects, including in cancer cell lines and tumors. Recently, nobiletin has also been shown to affect circadian rhythms via their enhancement, resulting in protection against metabolic syndrome. We hypothesized that nobiletin's anti-oncogenic effects, such as prevention of cell migration and formation of anchorage independent colonies, are correspondingly accompanied by modulation of circadian rhythms. Concurrently, we wished to determine whether the circadian and anti-oncogenic effects of nobiletin differed across cancer cell lines. In this study, we assessed nobiletin's circadian and therapeutic characteristics to ascertain whether these effects depend on cell line, which here also varied in terms of baseline circadian rhythmicity. Three cell culture models where nobiletin's effects on cell proliferation and migration have been studied previously were evaluated: U2OS (bone osteosarcoma), which possesses robust circadian rhythms; MCF7 (breast adenocarcinoma), which has weak circadian rhythms; and MDA-MB-231 (breast adenocarcinoma), which is arrhythmic. We found that circadian, migration, and proliferative effects following nobiletin treatment were subtle in the U2OS and MCF7 cells. On the other hand, changes were clear in MDA-MB-231s, where nobiletin rescued rhythmicity and substantially reduced oncogenic features, specifically two-dimensional cell motility and anchorage-independent growth. Based on these results and those previously described, we posit that the effects of nobiletin are indeed cell-type dependent, and that a positive correlation may exist between nobiletin's circadian and therapeutic effects.


Assuntos
Antineoplásicos Fitogênicos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Flavonas , Adenocarcinoma/tratamento farmacológico , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Flavonas/farmacologia , Flavonas/uso terapêutico , Humanos , Osteossarcoma/tratamento farmacológico
7.
Adv Pharmacol ; 89: 195-235, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616207

RESUMO

As a field, psychiatry is undergoing an exciting paradigm shift toward early identification and intervention that will likely minimize both the burden associated with severe mental illnesses as well as their duration. In this context, the rapid-acting antidepressant ketamine has revolutionized our understanding of antidepressant response and greatly expanded the pharmacologic armamentarium for treatment-resistant depression. Efforts to characterize biomarkers of ketamine response support a growing emphasis on early identification, which would allow clinicians to identify biologically enriched subgroups with treatment-resistant depression who are more likely to benefit from ketamine therapy. This chapter presents a broad overview of a range of translational biomarkers, including those drawn from imaging and electrophysiological studies, sleep and circadian rhythms, and HPA axis/endocrine function as well as metabolic, immune, (epi)genetic, and neurotrophic biomarkers related to ketamine response. Ketamine's unique, rapid-acting properties may serve as a model to explore a whole new class of novel rapid-acting treatments with the potential to revolutionize drug development and discovery. However, it should be noted that although several of the biomarkers reviewed here provide promising insights into ketamine's mechanism of action, most studies have focused on acute rather than longer-term antidepressant effects and, at present, none of the biomarkers are ready for clinical use.


Assuntos
Biomarcadores/metabolismo , Encéfalo/metabolismo , Ketamina/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Ritmo Circadiano/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Humanos , Ketamina/farmacologia
8.
Psychopharmacology (Berl) ; 237(8): 2555-2568, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32533210

RESUMO

RATIONALE: Selective serotonin reuptake inhibitor (SSRI) antidepressants are increasingly prescribed during pregnancy. Changes in serotonergic signaling during human fetal development have been associated with changes in brain development and with changes in affective behavior in adulthood. The suprachiasmatic nucleus (SCN) is known to be modulated by serotonin and it is therefore assumed that SSRIs may affect circadian rhythms. However, effects of perinatal SSRI treatment on circadian system functioning in the offspring are largely unknown. OBJECTIVE: Our aim was to investigate the effects of perinatal exposure to the SSRI fluoxetine (FLX) on circadian behavior, affective behavior, and 5-HT1A receptor sensitivity in female rats. In addition, we studied the expression of clock genes and the 5-HT1A receptor in the SCN, as they are potentially involved in underlying mechanisms contributing to changes in circadian rhythms. RESULTS: Perinatal FLX exposure shortened the free-running tau in response to the 5-HT1A/7 agonist 8-OH-DPAT. However, FLX exposure did not alter anxiety, stress coping, and 5-HT1A receptor sensitivity. No differences were found in 5-HT1A receptor and clock genes Per1, Per2, Cry1, and Cry2 SCN gene expression. CONCLUSIONS: Perinatal FLX exposure altered the response to a phase-shifting challenge in female rats, whether this may pose health risks remains to be investigated.


Assuntos
Adaptação Psicológica/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Fluoxetina/farmacologia , Inibidores de Captação de Serotonina/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Adaptação Psicológica/fisiologia , Animais , Antidepressivos/farmacologia , Ritmo Circadiano/fisiologia , Feminino , Ratos , Ratos Transgênicos , Ratos Wistar , Serotonina/metabolismo , Núcleo Supraquiasmático/efeitos dos fármacos , Núcleo Supraquiasmático/fisiologia
9.
Artigo em Inglês | MEDLINE | ID: mdl-32357113

RESUMO

Cell-autonomous circadian clocks have emerged as temporal orchestrators of numerous biological processes. For example, the cardiomyocyte circadian clock modulates transcription, translation, posttranslational modifications, ion homeostasis, signaling cascades, metabolism, and contractility of the heart over the course of the day. Circadian clocks are composed of more than 10 interconnected transcriptional modulators, all of which have the potential to influence the cardiac transcriptome (and ultimately cardiac processes). These transcriptional modulators include BMAL1 and REV-ERBα/ß; BMAL1 induces REV-ERBα/ß, which in turn feeds back to inhibit BMAL1. Previous studies indicate that cardiomyocyte-specific BMAL1-knockout (CBK) mice exhibit a dysfunctional circadian clock (including decreased REV-ERBα/ß expression) in the heart associated with abnormalities in cardiac mitochondrial function, metabolism, signaling, and contractile function. Here, we hypothesized that decreased REV-ERBα/ß activity is responsible for distinct phenotypical alterations observed in CBK hearts. To test this hypothesis, CBK (and littermate control) mice were administered with the selective REV-ERBα/ß agonist SR-9009 (100 mg·kg-1·day-1 for 8 days). SR-9009 administration was sufficient to normalize cardiac glycogen synthesis rates, cardiomyocyte size, interstitial fibrosis, and contractility in CBK hearts (without influencing mitochondrial complex activities, nor normalizing substrate oxidation and Akt/mTOR/GSK3ß signaling). Collectively, these observations highlight a role for REV-ERBα/ß as a mediator of a subset of circadian clock-controlled processes in the heart.


Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Miocárdio/metabolismo , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/agonistas , Fatores de Transcrição ARNTL/metabolismo , Animais , Ritmo Circadiano/efeitos dos fármacos , Expressão Gênica , Regulação da Expressão Gênica , Coração/efeitos dos fármacos , Camundongos , Camundongos Knockout , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Pirrolidinas/farmacologia , Tiofenos/farmacologia
10.
PLoS One ; 15(5): e0233863, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32470053

RESUMO

Adaptive regulation of epithelial transporters to nutrient intake is essential to decrease energy costs of their synthesis and maintenance, however such regulation is understudied. Previously we demonstrated that the transport function of the basolateral amino acid uniporter LAT4 (Slc43a2) is increased by dephosphorylation of serine 274 (S274) and nearly abolished by dephosphorylation of serine 297 (S297) when expressed in Xenopus oocytes. Phosphorylation changes in the jejunum of food-entrained mice suggested an increase in LAT4 transport function during food expectation. Thus, we investigated further how phosphorylation, expression and localization of mouse intestinal LAT4 respond to food-entrained diurnal rhythm and dietary protein content. In mice entrained with 18% protein diet, LAT4 mRNA was not submitted to diurnal regulation, unlike mRNAs of luminal symporters and antiporters. Only in duodenum, LAT4 protein expression increased during food intake. Concurrently, S274 phosphorylation was decreased in all three small intestinal segments, whereas S297 phosphorylation was increased only in jejunum. Interestingly, during food intake, S274 phosphorylation was nearly absent in ileum and accompanied by strong phosphorylation of mTORC1 target S6. Entraining mice with 8% protein diet provoked a shift in jejunal LAT4 localization from the cell surface to intracellular stores and increased S274 phosphorylation in both jejunum and ileum during food anticipation, suggesting decreased transport function. In contrast, 40% dietary protein content led to increased LAT4 expression in jejunum and its internalization in ileum. Ex vivo treatments of isolated intestinal villi fraction demonstrated that S274 phosphorylation was stimulated by protein kinase A. Rapamycin-sensitive insulin treatment and amino acids increased S297 phosphorylation, suggesting that the response to food intake might be regulated via the insulin-mTORC1 pathway. Ghrelin, an oscillating orexigenic hormone, did not affect phosphorylation of intestinal LAT4. Overall, we show that phosphorylation, expression and localization of intestinal mouse LAT4 responds to diurnal and dietary stimuli in location-specific manner.


Assuntos
Sistema L de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Ritmo Circadiano , Proteínas na Dieta/farmacologia , Alimentos , Intestinos/fisiologia , Aminoácidos/metabolismo , Animais , Antiporters/metabolismo , Ritmo Circadiano/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Grelina/administração & dosagem , Grelina/farmacologia , Insulina/metabolismo , Intestino Delgado/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos Endogâmicos C57BL , Microvilosidades/efeitos dos fármacos , Microvilosidades/metabolismo , Fosforilação/efeitos dos fármacos , Fosfosserina/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Frações Subcelulares/metabolismo , Simportadores/metabolismo , Serina-Treonina Quinases TOR/metabolismo
11.
Chem Biol Interact ; 325: 109132, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32437693

RESUMO

BACKGROUND: Alcohol increases the risk of developing colon cancer (CRC), in part via tissue inflammation and impaired barrier integrity. Circadian dyssynchrony (CD) is an understudied but common lifestyle associated factor that increases the risk of multi-organ tissue injury and number of malignancies including CRC. Our prior studies showed that the shift in light-dark cycle exacerbates barrier dysfunction and colonic inflammation in the setting of alcohol treatment, and increases the risk of CRC. Here we studied the interaction of alcohol with an abnormal eating pattern on markers of CD and colonic barrier integrity. METHOD: Mice were subjected to day (rest-phase = wrong-time WT) or night-time (active-phase = right-time RT) access to food in combination with access to water or 15% alcohol for total duration of 10 weeks. The food and liquid intake was measured. The locomotor activity data was recorded throughout the study, using a beam-break system. Mice were euthanized at two time points (ZT2 and ZT14). Time variation in the expression of the molecular marker of circadian clock (per2 gene) was measured in the central (hypothalamus) and intestinal (colon) tissue. Colonic protein expression of barrier markers (Occludin and Claudin-1) was studied. RESULTS: No significant differences were present in the weight gain and alcohol intake among the groups over the study period. We observed an interaction of WT eating with alcohol on behavioral markers of circadian rhythm. Compared to the RT + Water treated animals ("reference group"), combination of WT eating and alcohol consumption (WT + Alcohol) significantly changed the per2 oscillatory pattern, that was different between the colon and hypothalamus, indicative of worsening circadian dyssynchrony. This was associated with an overall impaired expression of barrier integrity markers in the colon. CONCLUSIONS: Alcohol induces circadian dyssynchrony which is worsened by abnormal food timing, associated with impaired barrier integrity in the colon. Future studies on the interaction of alcohol and food timing could provide further insights into alcohol associated CRC pathophysiology.


Assuntos
Ritmo Circadiano/efeitos dos fármacos , Colo/efeitos dos fármacos , Colo/patologia , Ingestão de Alimentos/fisiologia , Etanol/efeitos adversos , Consumo de Bebidas Alcoólicas/patologia , Consumo de Bebidas Alcoólicas/fisiopatologia , Animais , Biomarcadores/metabolismo , Colo/lesões , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Tempo
12.
Sleep Med Clin ; 15(2): 301-310, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32386703

RESUMO

This article focuses on melatonin and other melatonin receptor agonists, and specifically their circadian phase shifting and sleep-enhancing properties. The circadian system and circadian rhythm sleep-wake disorders are briefly reviewed, followed by a summary of the circadian phase shifting, sleep-enhancing properties, and possible safety concerns associated with melatonin and other melatonin receptor agonists. The recommended use of melatonin, including dose and timing, in the latest American Academy of Sleep Medicine Clinical Practice Guidelines for the treatment of intrinsic circadian rhythm disorders is also reviewed. Lastly, the practical aspects of treatment and consideration of clinical treatment outcomes are discussed.


Assuntos
Ritmo Circadiano/efeitos dos fármacos , Hipnóticos e Sedativos/uso terapêutico , Melatonina/uso terapêutico , Transtornos do Sono do Ritmo Circadiano/tratamento farmacológico , Sono/efeitos dos fármacos , Humanos , Hipnóticos e Sedativos/farmacologia , Melatonina/farmacologia , Resultado do Tratamento
13.
Georgian Med News ; (299): 93-100, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32242853

RESUMO

Despite significant progress in treatment of rheumatoid arthritis (RA), a considerable part of patients remains resistant to the current therapy, apparently for the reasons of undefined mechanisms of its pathogenesis. Recently, the disturbances of circadian regulation of inflammatory processes in RA have been highlighted as important ones. Endothelial nitric oxide synthase (NOS3) and soluble toll-like receptors 2 (sTLR2) take part in the regulation of angiogenesis, osteoclastogenesis, immune responses but their circadian rhythms and predictive significance in RA patients are still unknown. Aim - to estimate the associations between efficacy of treatment and the circadian rhythms of NOS3 and sTLR2, and NOS3 polymorphism in females with rheumatoid arthritis, Ukraine. 97 RA patients (100% female) aged 46.3±8.89 years with disease duration 8.44±6.52 years were examined. All patients as a disease-modifying therapy received methotrexate (MTX) orally in a dose ≤15 mg/week, folic acid 5 mg/week, NSAIDs and corticosteroids (CS) ≤10 mg/day by prednisone. Doses of MTX, NSAIDs and CS were stable 4 weeks prior to the enrolment and during the whole period of study. The efficacy end points included DAS28, RAID and American College of Rheumatology response criteria (ACR20/50/70). Serum levels of NOS3 and sTLR2 were determined at 08:00 and 20:00 using Cloud-Clone Corp kits (USA). NOS3 T-786С polymorphism was determined by Real-Time PCR. The SPSS22 software package was used for statistical processing of the results. The study was performed in accordance to the bioethical standards. After 12-week treatment among RA patients were revealed 52.6% ACR 20 responders and 47.4% non-responders. Opposite diurnal variation of NOS3 and sTLR2 serum levels were found in RA patients. There were significant differences in NOS3/sTLR2 ratio at 08:00 accordingly to NOS3 T786C genotype. The disturbances in daily variability of NOS3 or sTLR2 serum levels were more significant in non-responders compare to responders. Decrease of NOS3/sTLR2 ratio was a predictor of non-response to treatment in RA patients (ß=0.366, р=0.000). In RA patients the disturbances of circadian rhythms of endothelial nitric oxide synthase or toll-like receptors 2 expression are associated with an increase of resistance to disease-modifying therapy with methotrexate.


Assuntos
Artrite Reumatoide/terapia , Ritmo Circadiano/efeitos dos fármacos , Quimioterapia Combinada/métodos , Óxido Nítrico Sintase Tipo III/sangue , Receptor 2 Toll-Like/sangue , Adulto , Artrite Reumatoide/sangue , Artrite Reumatoide/genética , Feminino , Humanos , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo III/metabolismo , Prednisona/uso terapêutico , Resultado do Tratamento , Ucrânia
14.
Prog Cardiovasc Dis ; 63(3): 249-262, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32275926

RESUMO

The presence of hypertension (HTN) in patients with diabetes mellitus (DM) further worsens cardiovascular disease (CVD) prognosis. In addition, masked HTN and abnormal circadian blood pressure (BP) variability are common among patients with DM. Clinical trial data show that sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve CVD prognosis and prevent progression of renal dysfunction in high-risk patients with type 2 DM (T2DM). Consistent reductions in 24-hour, daytime and nocturnal BP have been documented during treatment with SGLT2i in patients with DM and HTN, and these reductions are of a magnitude that is likely to be clinically significant. SGLT2i agents also appear to have beneficial effects on morning, evening and nocturnal home BP. Greater reductions in BP during treatment with SGLT2i have been reported in patient subgroups with higher body mass index, and in those with higher baseline BP. Other documented beneficial effects of SGLT2i include reductions in arterial stiffness and the potential to decrease the apnea-hypopnea index in patients with DM and obstructive sleep apnea. Recent guidelines highlight the important role of SGLT2i as part of the pharmacological management of patients with DM and HTN, and recommend consideration of SGLT2i early in the clinical course to reduce all-cause and CVD mortality in patients with T2DM and CVD. Overall, available data support a role for SGLT2i as effective BP-lowering agents in patients with T2DM and poorly controlled HTN, irrespective of baseline glucose control status. Sustained improvements in 24-hour BP and the 24-hour BP profile are likely to contribute to the CVD benefits of SGLT2i treatment.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipertensão/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Monitorização Ambulatorial da Pressão Arterial , Diabetes Mellitus Tipo 2/mortalidade , Diabetes Mellitus Tipo 2/fisiopatologia , Humanos , Hipertensão/mortalidade , Hipertensão/fisiopatologia , Fatores de Proteção , Medição de Risco , Fatores de Risco , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
15.
Int Rev Immunol ; 39(4): 153-162, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32347747

RESUMO

The current COVID-19 pandemic is one of the most devastating events in recent history. The virus causes relatively minor damage to young, healthy populations, imposing life-threatening danger to the elderly and people with diseases of chronic inflammation. Therefore, if we could reduce the risk for vulnerable populations, it would make the COVID-19 pandemic more similar to other typical outbreaks. Children don't suffer from COVID-19 as much as their grandparents and have a much higher melatonin level. Bats are nocturnal animals possessing high levels of melatonin, which may contribute to their high anti-viral resistance. Viruses induce an explosion of inflammatory cytokines and reactive oxygen species, and melatonin is the best natural antioxidant that is lost with age. The programmed cell death coronaviruses cause, which can result in significant lung damage, is also inhibited by melatonin. Coronavirus causes inflammation in the lungs which requires inflammasome activity. Melatonin blocks these inflammasomes. General immunity is impaired by anxiety and sleep deprivation. Melatonin improves sleep habits, reduces anxiety and stimulates immunity. Fibrosis may be the most dangerous complication after COVID-19. Melatonin is known to prevent fibrosis. Mechanical ventilation may be necessary but yet imposes risks due to oxidative stress, which can be reduced by melatonin. Thus, by using the safe over-the-counter drug melatonin, we may be immediately able to prevent the development of severe disease symptoms in coronavirus patients, reduce the severity of their symptoms, and/or reduce the immuno-pathology of coronavirus infection on patients' health after the active phase of the infection is over.


Assuntos
Antioxidantes/administração & dosagem , Betacoronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Melatonina/administração & dosagem , Medicamentos sem Prescrição/administração & dosagem , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Fatores Etários , Idoso , Envelhecimento/imunologia , Animais , Betacoronavirus/patogenicidade , Quirópteros/imunologia , Quirópteros/virologia , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Humanos , Fotoperíodo , Pneumonia Viral/imunologia , Pneumonia Viral/virologia
16.
Chemosphere ; 253: 126762, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32302915

RESUMO

17ß-trenbolone (17ß-TBOH) is one of the dominant metabolites of trenbolone acetate, which is widely applied in beef cattle operations around the globe. The effects of environmental concentrations of 17ß-trenbolone on the early development of zebrafish embryos have received very little attention. Melatonin could regulate sleep-wake cycle and plays a protective role in various adverse conditions. Here, environmentally realistic concentrations of 17ß-trenbolone (1 ng/L, 10 ng/L, 50 ng/L) has been exposure to zebrafish embryos at 2 h postfertilization (hpf). The results showed that 10 ng/L and 50 ng/L 17ß-trenbolone disturbed the distribution of caudal primary motoneurons and downregulated expression of motoneuron development related genes along with locomotion decreasing. While melatonin could recover the detrimental effects caused by 17ß-trenbolone. Interestingly, 17ß-trenbolone exposure increased waking activity and decreased rest even in a low dose (1 ng/L). Moreover, it upregulated hypocretin/orexin (Hcrt) signaling which promotes wakefulness. Melatonin restored the insomnia-like alternation induced by 17ß-trenbolone exposure. Collectively, we conclude that 17ß-trenbolone disturbed motoneuron development and altered sleep/wake behavior, while melatonin could alleviate the deleterious influence on motoneuron development and recover the circadian rhythm.


Assuntos
Comportamento Animal/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Melatonina/farmacologia , Atividade Motora/efeitos dos fármacos , Distúrbios do Início e da Manutenção do Sono/prevenção & controle , Acetato de Trembolona/toxicidade , Peixe-Zebra , Animais , Bovinos , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/genética , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/fisiologia , Desenvolvimento Embrionário/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Neurônios Motores/efeitos dos fármacos , Orexinas/genética , Fenótipo , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente
17.
Invest Ophthalmol Vis Sci ; 61(3): 26, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32182332

RESUMO

Purpose: Elevated IOP can cause the development of glaucoma. The circadian rhythm of IOP depends on the dynamics of the aqueous humor and is synchronized with the circadian rhythm pacemaker, that is, the suprachiasmatic nucleus. The suprachiasmatic nucleus resets peripheral clocks via sympathetic nerves or adrenal glucocorticoids. However, the detailed mechanisms underlying IOP rhythmicity remain unclear. The purpose of this study was to verify this regulatory pathway. Methods: Adrenalectomy and/or superior cervical ganglionectomy were performed in C57BL/6J mice. Their IOP rhythms were measured under light/dark cycle and constant dark conditions. Ocular administration of corticosterone or norepinephrine was also performed. Localization of adrenergic receptors, glucocorticoid receptors, and clock proteins Bmal1 and Per1 were analyzed using immunohistochemistry. Period2::luciferase rhythms in the cultured iris/ciliary bodies of adrenalectomized and/or superior cervical ganglionectomized mice were monitored to evaluate the effect of the procedures on the local clock. The IOP rhythm of retina and ciliary epithelium-specific Bmal1 knockout mice were measured to determine the significance of the local clock. Results: Adrenalectomy and superior cervical ganglionectomy disrupted IOP rhythms and the circadian clock in the iris/ciliary body cultures. Instillation of corticosterone and norepinephrine restored the IOP rhythm. ß2-Adrenergic receptors, glucocorticoid receptors, and clock proteins were strongly expressed within the nonpigmented epithelia of the ciliary body. However, tissue-specific Bmal1 knock-out mice maintained their IOP rhythm. Conclusions: These findings suggest direct driving of the IOP rhythm by the suprachiasmatic nucleus, via the dual corticosterone and norepinephrine pathway, but not the ciliary clock, which may be useful for chronotherapy of glaucoma.


Assuntos
Ritmo Circadiano/fisiologia , Corticosterona/farmacologia , Pressão Intraocular/fisiologia , Norepinefrina/farmacologia , Sistema Nervoso Simpático/fisiologia , Fatores de Transcrição ARNTL/metabolismo , Administração Oftálmica , Adrenalectomia , Animais , Células Cultivadas , Corpo Ciliar/efeitos dos fármacos , Corpo Ciliar/metabolismo , Ritmo Circadiano/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Ganglionectomia , Imuno-Histoquímica , Iris/efeitos dos fármacos , Iris/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Circadianas Period/metabolismo , Fotoperíodo , Receptores Adrenérgicos beta 2/metabolismo , Receptores de Glucocorticoides/metabolismo , Gânglio Cervical Superior/cirurgia , Tonometria Ocular
18.
Sci Rep ; 10(1): 4043, 2020 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-32132552

RESUMO

Status epilepticus (SE) is a prevalent disorder associated with significant morbidity, including the development of epilepsy and mortality. Cardiac arrhythmias (i.e. inappropriate sinus tachycardia and bradycardia, asystole, and atrioventricular blocks) are observed in patients following SE. We characterized ictal (during a seizure) and interictal (between seizure) cardiac arrhythmogenesis following SE using continuous electrocardiography and video electroencephalography (vEEG) recordings throughout a 14-day monitoring period in an intrahippocampal chemoconvulsant mouse model that develops epilepsy. We quantified heart rhythm abnormalities and examined whether the frequency of cardiac events correlated with epileptiform activity, circadian (light/dark) cycle, the presence of seizures, and survival during this period of early epileptogenesis (the development of epilepsy) following SE. Shortly following SE, mice developed an increased interictal heart rate and heart rhythm abnormalities (i.e. sinus pause and sinus arrhythmias) when compared to control mice. Heart rhythm abnormalities were more frequent during the light cycle and were not correlated with increased epileptiform activity or seizure frequency. Finally, SE animals had early mortality, and a death event captured during vEEG recording demonstrated severe bradycardia prior to death. These cardiac changes occurred within 14 days after SE and may represent an early risk factor for sudden death following SE.


Assuntos
Arritmias Cardíacas , Ritmo Circadiano/efeitos dos fármacos , Eletroencefalografia , Ácido Caínico/efeitos adversos , Estado Epiléptico , Animais , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/patologia , Arritmias Cardíacas/fisiopatologia , Modelos Animais de Doenças , Ácido Caínico/farmacologia , Masculino , Camundongos , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/fisiopatologia
19.
Nature ; 579(7800): 609-614, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32040955

RESUMO

The neuromodulator melatonin synchronizes circadian rhythms and related physiological functions through the actions of two G-protein-coupled receptors: MT1 and MT2. Circadian release of melatonin at night from the pineal gland activates melatonin receptors in the suprachiasmatic nucleus of the hypothalamus, synchronizing the physiology and behaviour of animals to the light-dark cycle1-4. The two receptors are established drug targets for aligning circadian phase to this cycle in disorders of sleep5,6 and depression1-4,7-9. Despite their importance, few in vivo active MT1-selective ligands have been reported2,8,10-12, hampering both the understanding of circadian biology and the development of targeted therapeutics. Here we docked more than 150 million virtual molecules to an MT1 crystal structure, prioritizing structural fit and chemical novelty. Of these compounds, 38 high-ranking molecules were synthesized and tested, revealing ligands with potencies ranging from 470 picomolar to 6 micromolar. Structure-based optimization led to two selective MT1 inverse agonists-which were topologically unrelated to previously explored chemotypes-that acted as inverse agonists in a mouse model of circadian re-entrainment. Notably, we found that these MT1-selective inverse agonists advanced the phase of the mouse circadian clock by 1.3-1.5 h when given at subjective dusk, an agonist-like effect that was eliminated in MT1- but not in MT2-knockout mice. This study illustrates the opportunities for modulating melatonin receptor biology through MT1-selective ligands and for the discovery of previously undescribed, in vivo active chemotypes from structure-based screens of diverse, ultralarge libraries.


Assuntos
Ritmo Circadiano/fisiologia , Ligantes , Receptores de Melatonina/agonistas , Receptores de Melatonina/metabolismo , Animais , Ritmo Circadiano/efeitos dos fármacos , Escuridão , Avaliação Pré-Clínica de Medicamentos , Agonismo Inverso de Drogas , Feminino , Humanos , Luz , Masculino , Camundongos , Camundongos Knockout , Simulação de Acoplamento Molecular , Receptor MT1 de Melatonina/agonistas , Receptor MT1 de Melatonina/deficiência , Receptor MT1 de Melatonina/genética , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/agonistas , Receptor MT2 de Melatonina/deficiência , Receptor MT2 de Melatonina/genética , Receptor MT2 de Melatonina/metabolismo , Receptores de Melatonina/deficiência , Receptores de Melatonina/genética , Bibliotecas de Moléculas Pequenas/farmacologia , Especificidade por Substrato/genética
20.
Planta ; 251(2): 52, 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31950281

RESUMO

MAIN CONCLUSION: Our study demonstrated that the species respond non-linearly to increases in CO2 concentration when exposed to decadal changes in CO2, representing the year 1987, 2025, 2051, and 2070, respectively. There are several lines of evidence suggesting that the vast majority of C3 plants respond to elevated atmospheric CO2 by decreasing their stomatal conductance (gs). However, in the majority of CO2 enrichment studies, the response to elevated CO2 are tested between plants grown under ambient (380-420 ppm) and high (538-680 ppm) CO2 concentrations and measured usually at single time points in a diurnal cycle. We investigated gs responses to simulated decadal increments in CO2 predicted over the next 4 decades and tested how measurements of gs may differ when two alternative sampling methods are employed (infrared gas analyzer [IRGA] vs. leaf porometer). We exposed Populus tremula, Popolus tremuloides and Sambucus racemosa to four different CO2 concentrations over 126 days in experimental growth chambers at 350, 420, 490 and 560 ppm CO2; representing the years 1987, 2025, 2051, and 2070, respectively (RCP4.5 scenario). Our study demonstrated that the species respond non-linearly to increases in CO2 concentration when exposed to decadal changes in CO2. Under natural conditions, maximum operational gs is often reached in the late morning to early afternoon, with a mid-day depression around noon. However, we showed that the daily maximum gs can, in some species, shift later into the day when plants are exposed to only small increases (70 ppm) in CO2. A non-linear decreases in gs and a shifting diurnal stomatal behavior under elevated CO2, could affect the long-term daily water and carbon budget of many plants in the future, and therefore alter soil-plant-atmospheric processes.


Assuntos
Atmosfera/química , Dióxido de Carbono/farmacologia , Fisiologia/métodos , Estômatos de Plantas/efeitos dos fármacos , Estômatos de Plantas/fisiologia , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/efeitos da radiação , Raios Infravermelhos , Luz , Estômatos de Plantas/efeitos da radiação , Análise de Regressão
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