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2.
Nat Commun ; 12(1): 864, 2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33558539

RESUMO

Circadian clocks allow organisms to synchronize their physiological processes to diurnal variations. A phase response curve allows researchers to understand clock entrainment by revealing how signals adjust clock genes differently according to the phase in which they are applied. Comprehensively investigating these curves is difficult, however, because of the cost of measuring them experimentally. Here we demonstrate that fundamental properties of the curve are recoverable from the singularity response, which is easily measured by applying a single stimulus to a cellular network in a desynchronized state (i.e. singularity). We show that the singularity response of Arabidopsis to light/dark and temperature stimuli depends on the properties of the phase response curve for these stimuli. The measured singularity responses not only allow the curves to be precisely reconstructed but also reveal organ-specific properties of the plant circadian clock. The method is not only simple and accurate, but also general and applicable to other coupled oscillator systems as long as the oscillators can be desynchronized. This simplified method may allow the entrainment properties of the circadian clock of both plants and other species in nature.


Assuntos
Arabidopsis/fisiologia , Relógios Circadianos/fisiologia , Arabidopsis/efeitos da radiação , Relógios Circadianos/efeitos da radiação , Luz , Especificidade de Órgãos/efeitos da radiação , Temperatura
3.
Nat Commun ; 12(1): 377, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33452240

RESUMO

Circadian clocks coordinate mammalian behavior and physiology enabling organisms to anticipate 24-hour cycles. Transcription-translation feedback loops are thought to drive these clocks in most of mammalian cells. However, red blood cells (RBCs), which do not contain a nucleus, and cannot perform transcription or translation, nonetheless exhibit circadian redox rhythms. Here we show human RBCs display circadian regulation of glucose metabolism, which is required to sustain daily redox oscillations. We found daily rhythms of metabolite levels and flux through glycolysis and the pentose phosphate pathway (PPP). We show that inhibition of critical enzymes in either pathway abolished 24-hour rhythms in metabolic flux and redox oscillations, and determined that metabolic oscillations are necessary for redox rhythmicity. Furthermore, metabolic flux rhythms also occur in nucleated cells, and persist when the core transcriptional circadian clockwork is absent in Bmal1 knockouts. Thus, we propose that rhythmic glucose metabolism is an integral process in circadian rhythms.


Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Eritrócitos/metabolismo , Glicólise/fisiologia , Via de Pentose Fosfato/fisiologia , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Células Cultivadas , Fibroblastos , Técnicas de Inativação de Genes , Voluntários Saudáveis , Humanos , Masculino , Metabolômica , Camundongos , Oxirredução , Cultura Primária de Células
4.
Nat Commun ; 11(1): 4410, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32879310

RESUMO

The hypothalamic suprachiasmatic (SCN) clock contains several neurochemically defined cell groups that contribute to the genesis of circadian rhythms. Using cell-specific and genetically targeted approaches we have confirmed an indispensable role for vasoactive intestinal polypeptide-expressing SCN (SCNVIP) neurons, including their molecular clock, in generating the mammalian locomotor activity (LMA) circadian rhythm. Optogenetic-assisted circuit mapping revealed functional, di-synaptic connectivity between SCNVIP neurons and dorsomedial hypothalamic neurons, providing a circuit substrate by which SCNVIP neurons may regulate LMA rhythms. In vivo photometry revealed that while SCNVIP neurons are acutely responsive to light, their activity is otherwise behavioral state invariant. Single-nuclei RNA-sequencing revealed that SCNVIP neurons comprise two transcriptionally distinct subtypes, including putative pacemaker and non-pacemaker populations. Altogether, our work establishes necessity of SCNVIP neurons for the LMA circadian rhythm, elucidates organization of circadian outflow from and modulatory input to SCNVIP cells, and demonstrates a subpopulation-level molecular heterogeneity that suggests distinct functions for specific SCNVIP subtypes.


Assuntos
Ritmo Circadiano/fisiologia , Neurônios/metabolismo , Núcleo Supraquiasmático , Animais , Mapeamento Encefálico , Relógios Circadianos/fisiologia , Locomoção/fisiologia , Camundongos , Optogenética/métodos , Núcleo Supraquiasmático/citologia , Núcleo Supraquiasmático/metabolismo
5.
Nat Commun ; 11(1): 4448, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895370

RESUMO

Substance abuse disorders are linked to alteration of circadian rhythms, although the molecular and neuronal pathways implicated have not been fully elucidated. Addictive drugs, such as cocaine, induce a rapid increase of dopamine levels in the brain. Here, we show that acute administration of cocaine triggers reprogramming in circadian gene expression in the striatum, an area involved in psychomotor and rewarding effects of drugs. This process involves the activation of peroxisome protein activator receptor gamma (PPARγ), a nuclear receptor involved in inflammatory responses. PPARγ reprogramming is altered in mice with cell-specific ablation of the dopamine D2 receptor (D2R) in the striatal medium spiny neurons (MSNs) (iMSN-D2RKO). Administration of a specific PPARγ agonist in iMSN-D2RKO mice elicits substantial rescue of cocaine-dependent control of circadian genes. These findings have potential implications for development of strategies to treat substance abuse disorders.


Assuntos
Relógios Circadianos/efeitos dos fármacos , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Cocaína/efeitos adversos , Núcleo Accumbens/efeitos dos fármacos , PPAR gama/metabolismo , Receptores de Dopamina D2/metabolismo , Administração Oral , Animais , Relógios Circadianos/fisiologia , Cocaína/administração & dosagem , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Dopamina/metabolismo , Injeções Intraperitoneais , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Knockout , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Núcleo Accumbens/fisiopatologia , PPAR gama/agonistas , Pioglitazona/administração & dosagem , Receptores de Dopamina D2/genética , Recompensa , Transdução de Sinais
6.
Nat Commun ; 11(1): 4291, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32855407

RESUMO

The annual photoperiod cycle provides the critical environmental cue synchronizing rhythms of life in seasonal habitats. In 1936, Bünning proposed a circadian-based coincidence timer for photoperiodic synchronization in plants. Formal studies support the universality of this so-called coincidence timer, but we lack understanding of the mechanisms involved. Here we show in mammals that long photoperiods induce the circadian transcription factor BMAL2, in the pars tuberalis of the pituitary, and triggers summer biology through the eyes absent/thyrotrophin (EYA3/TSH) pathway. Conversely, long-duration melatonin signals on short photoperiods induce circadian repressors including DEC1, suppressing BMAL2 and the EYA3/TSH pathway, triggering winter biology. These actions are associated with progressive genome-wide changes in chromatin state, elaborating the effect of the circadian coincidence timer. Hence, circadian clock-pituitary epigenetic pathway interactions form the basis of the mammalian coincidence timer mechanism. Our results constitute a blueprint for circadian-based seasonal timekeeping in vertebrates.


Assuntos
Fatores de Transcrição ARNTL/genética , Relógios Circadianos/fisiologia , Fotoperíodo , Hipófise/fisiologia , Ovinos/fisiologia , Fatores de Transcrição ARNTL/metabolismo , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Epigênese Genética , Regulação da Expressão Gênica , Masculino , Melatonina/genética , Melatonina/metabolismo , Estações do Ano
7.
Metabolism ; 111S: 154337, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32795560

RESUMO

All living organisms including humans, experience changes in the light exposure generated by the Earth's rotation. In anticipation of this unavoidable geo-physical variability, and to generate an appropriate biochemical response, species of many phyla, including mammals have evolved a nearly 24-hour endogenous timing device known as the circadian clock (CC), which is self-sustained, cell autonomous and is present in every cell type. At the heart of the 'clock' functioning resides the CC-oscillator, an elegantly designed transcriptional-translational feedback system. Notably, the core components of the CC-oscillator not only drive daily rhythmicity of their own synthesis, but also generate circadian phase-specific variability in the expression levels of thousands of target genes through transcriptional, post-transcriptional and post-translational mechanisms. Thereby, this 'clock'-system provides proper chronological coordination in the functioning of cells, tissues and organs. The CC governs many physiologically critical functions. Among these functions, the key role of the CC in maintaining metabolic homeostasis deserves special emphasis. Indeed, the several features of the modern lifestyle (e.g. travel-induced jet lag, rotating shift work, energy-dense food) which, force disruption of circadian rhythms have recently emerged as a major driver to global health problems like obesity, cardiovascular disease and metabolic liver disease such as non-alcoholic fatty liver disease (NAFLD). Here we review, the CC-dependent pathways in different tissues which play critical roles in mediating several critical metabolic functions under physiological conditions and discuss their impact for the development of metabolic disease with a focus on the liver.


Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Animais , Homeostase/fisiologia , Humanos , Doenças Metabólicas/patologia
8.
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
9.
Chronobiol Int ; 37(7): 961-973, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32519912

RESUMO

Maternal circadian rhythms provide highly important input into the entrainment and programming of fetal and newborn circadian rhythms. The light-dark cycle is an important regulator of the internal biological clock. Even though pregnant women spend a greater part of the day at home during the latter stages of pregnancy, natural light exposure is crucial for the fetus. The current recommended COVID-19 lockdown might dramatically alter normal environmental lighting conditions of pregnant women, resulting in exposure to extremely low levels of natural daylight and high-intensity artificial light sources during both day and night. This article summarizes the potential effects on pregnant woman and their fetuses due to prolonged exposure to altered photoperiod and as consequence altered circadian system, known as chronodisruption, that may result from the COVID-19 lockdown.


Assuntos
Betacoronavirus/patogenicidade , Ritmo Circadiano/fisiologia , Infecções por Coronavirus/virologia , Pneumonia Viral/virologia , Complicações Infecciosas na Gravidez/virologia , Relógios Circadianos/fisiologia , Feminino , Feto/virologia , Humanos , Melatonina/metabolismo , Melatonina/farmacologia , Pandemias , Gravidez
10.
Mol Cell ; 78(5): 805-807, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32502419

RESUMO

The amplitude of circadian rhythms dampens with age, but Levine et al. (2020) now show that nicotinamide adenine dinucleotide (NAD+) can restore robust circadian gene expression and behavior in aged mice through SIRT1-dependent deacetylation of the core clock protein PER2.


Assuntos
Ritmo Circadiano/genética , Proteínas Circadianas Period/metabolismo , Fatores de Transcrição ARNTL/genética , Fatores Etários , Animais , Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Citocinas/metabolismo , Humanos , Camundongos , NAD/metabolismo , Proteínas Circadianas Period/genética , Sirtuína 1/metabolismo , Sirtuínas/metabolismo
11.
Nature ; 582(7812): 395-398, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32494010

RESUMO

Neuroprotectant strategies that have worked in rodent models of stroke have failed to provide protection in clinical trials. Here we show that the opposite circadian cycles in nocturnal rodents versus diurnal humans1,2 may contribute to this failure in translation. We tested three independent neuroprotective approaches-normobaric hyperoxia, the free radical scavenger α-phenyl-butyl-tert-nitrone (αPBN), and the N-methyl-D-aspartic acid (NMDA) antagonist MK801-in mouse and rat models of focal cerebral ischaemia. All three treatments reduced infarction in day-time (inactive phase) rodent models of stroke, but not in night-time (active phase) rodent models of stroke, which match the phase (active, day-time) during which most strokes occur in clinical trials. Laser-speckle imaging showed that the penumbra of cerebral ischaemia was narrower in the active-phase mouse model than in the inactive-phase model. The smaller penumbra was associated with a lower density of terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive dying cells and reduced infarct growth from 12 to 72 h. When we induced circadian-like cycles in primary mouse neurons, deprivation of oxygen and glucose triggered a smaller release of glutamate and reactive oxygen species, as well as lower activation of apoptotic and necroptotic mediators, in 'active-phase' than in 'inactive-phase' rodent neurons. αPBN and MK801 reduced neuronal death only in 'inactive-phase' neurons. These findings suggest that the influence of circadian rhythm on neuroprotection must be considered for translational studies in stroke and central nervous system diseases.


Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Modelos Animais de Doenças , Neurônios/patologia , Neuroproteção , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/prevenção & controle , Animais , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Isquemia Encefálica/prevenção & controle , Glucose/deficiência , Humanos , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Infarto da Artéria Cerebral Média/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxigênio , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Acidente Vascular Cerebral/fisiopatologia , Pesquisa Médica Translacional , Falha de Tratamento
12.
Science ; 368(6492): 754-759, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32409472

RESUMO

The blood stage of the infection of the malaria parasite Plasmodium falciparum exhibits a 48-hour developmental cycle that culminates in the synchronous release of parasites from red blood cells, which triggers 48-hour fever cycles in the host. This cycle could be driven extrinsically by host circadian processes or by a parasite-intrinsic oscillator. To distinguish between these hypotheses, we examine the P. falciparum cycle in an in vitro culture system and show that the parasite has molecular signatures associated with circadian and cell cycle oscillators. Each of the four strains examined has a different period, which indicates strain-intrinsic period control. Finally, we demonstrate that parasites have low cell-to-cell variance in cycle period, on par with a circadian oscillator. We conclude that an intrinsic oscillator maintains Plasmodium's rhythmic life cycle.


Assuntos
Relógios Circadianos/fisiologia , Eritrócitos/parasitologia , Interações Hospedeiro-Parasita/fisiologia , Estágios do Ciclo de Vida , Malária Falciparum/sangue , Malária Falciparum/parasitologia , Plasmodium falciparum/crescimento & desenvolvimento , Animais , Relógios Circadianos/genética , Expressão Gênica , Genes de Protozoários/fisiologia , Interações Hospedeiro-Parasita/genética , Camundongos , Plasmodium falciparum/genética , Transcriptoma
13.
Proc Natl Acad Sci U S A ; 117(20): 10888-10896, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32354999

RESUMO

Casein kinase 1 (CK1) plays a central role in regulating the period of the circadian clock. In mammals, PER2 protein abundance is regulated by CK1-mediated phosphorylation and proteasomal degradation. On the other hand, recent studies have questioned whether the degradation of the core circadian machinery is a critical step in clock regulation. Prior cell-based studies found that CK1 phosphorylation of PER2 at Ser478 recruits the ubiquitin E3 ligase ß-TrCP, leading to PER2 degradation. Creation of this phosphodegron is regulated by a phosphoswitch that is also implicated in temperature compensation. However, in vivo evidence that this phosphodegron influences circadian period is lacking. Here, we generated and analyzed PER2-Ser478Ala knock-in mice. The mice showed longer circadian period in behavioral analysis. Molecularly, mutant PER2 protein accumulated in both the nucleus and cytoplasm of the mouse liver, while Per2 messenger RNA (mRNA) levels were minimally affected. Nuclear PER1, CRY1, and CRY2 proteins also increased, probably due to stabilization of PER2-containing complexes. In mouse embryonic fibroblasts derived from PER2-Ser478Ala::LUC mice, three-phase decay and temperature compensation of the circadian period was perturbed. These data provide direct in vivo evidence for the importance of phosphorylation-regulated PER2 stability in the circadian clock and validate the phosphoswitch in a mouse model.


Assuntos
Relógios Circadianos/fisiologia , Mutação , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Animais , Comportamento Animal , Caseína Quinase I/metabolismo , Núcleo Celular/metabolismo , Ritmo Circadiano/fisiologia , Feminino , Regulação da Expressão Gênica , Fígado , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Fosforilação , RNA Mensageiro/metabolismo , Transcriptoma , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Contendo Repetições de beta-Transducina/metabolismo
14.
Proc Natl Acad Sci U S A ; 117(20): 10935-10945, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32355000

RESUMO

The circadian clock in eukaryotes controls transcriptional and posttranscriptional events, including regulation of the levels and phosphorylation state of translation factors. However, the mechanisms underlying clock control of translation initiation, and the impact of this potential regulation on rhythmic protein synthesis, were not known. We show that inhibitory phosphorylation of eIF2α (P-eIF2α), a conserved translation initiation factor, is clock controlled in Neurospora crassa, peaking during the subjective day. Cycling P-eIF2α levels required rhythmic activation of the eIF2α kinase CPC-3 (the homolog of yeast and mammalian GCN2), and rhythmic activation of CPC-3 was abolished under conditions in which the levels of charged tRNAs were altered. Clock-controlled accumulation of P-eIF2α led to reduced translation during the day in vitro and was necessary for the rhythmic synthesis of select proteins in vivo. Finally, loss of rhythmic P-eIF2α levels led to reduced linear growth rates, supporting the idea that partitioning translation to specific times of day provides a growth advantage to the organism. Together, these results reveal a fundamental mechanism by which the clock regulates rhythmic protein production, and provide key insights into how rhythmic translation, cellular energy, stress, and nutrient metabolism are linked through the levels of charged versus uncharged tRNAs.


Assuntos
Relógios Circadianos/fisiologia , Fator de Iniciação 2 em Eucariotos/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , Animais , Ritmo Circadiano , Fator de Iniciação 2 em Eucariotos/genética , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Regulação Fúngica da Expressão Gênica , Neurospora crassa/crescimento & desenvolvimento , Neurospora crassa/metabolismo , Fosforilação , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , eIF-2 Quinase/metabolismo
15.
Am J Physiol Heart Circ Physiol ; 318(6): H1487-H1508, 2020 06 01.
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
16.
PLoS One ; 15(5): e0233386, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32437460

RESUMO

Salt is an essential nutrient; however, excessive salt intake is a prominent public health concern worldwide. Various physiological functions are associated with circadian rhythms, and disruption of circadian rhythms is a prominent risk factor for cardiovascular diseases, cancer, and immune disease. Certain nutrients are vital regulators of peripheral circadian clocks. However, the role of a high-fat and high-salt (HFS) diet in the regulation of circadian gene expression is unclear. This study aimed to investigate the effect of an HFS diet on rhythms of locomotor activity, caecum glucocorticoid secretion, and clock gene expression in mice. Mice administered an HFS diet displayed reduced locomotor activity under normal light/dark and constant dark conditions in comparison with those administered a normal diet. The diurnal rhythm of caecum glucocorticoid secretion and the expression levels of glucocorticoid-related genes and clock genes in the adrenal gland were disrupted with an HFS diet. These results suggest that an HFS diet alters locomotor activity, disrupts circadian rhythms of glucocorticoid secretion, and downregulates peripheral adrenal gland circadian clock genes.


Assuntos
Ritmo Circadiano/fisiologia , Dieta Hiperlipídica , Glucocorticoides/biossíntese , Atividade Motora/fisiologia , Cloreto de Sódio na Dieta , Glândulas Suprarrenais/metabolismo , Animais , Relógios Circadianos/fisiologia , Masculino , Camundongos , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo
17.
Mol Cell ; 78(5): 835-849.e7, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32369735

RESUMO

Disrupted sleep-wake and molecular circadian rhythms are a feature of aging associated with metabolic disease and reduced levels of NAD+, yet whether changes in nucleotide metabolism control circadian behavioral and genomic rhythms remains unknown. Here, we reveal that supplementation with the NAD+ precursor nicotinamide riboside (NR) markedly reprograms metabolic and stress-response pathways that decline with aging through inhibition of the clock repressor PER2. NR enhances BMAL1 chromatin binding genome-wide through PER2K680 deacetylation, which in turn primes PER2 phosphorylation within a domain that controls nuclear transport and stability and that is mutated in human advanced sleep phase syndrome. In old mice, dampened BMAL1 chromatin binding, transcriptional oscillations, mitochondrial respiration rhythms, and late evening activity are restored by NAD+ repletion to youthful levels with NR. These results reveal effects of NAD+ on metabolism and the circadian system with aging through the spatiotemporal control of the molecular clock.


Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano/genética , Proteínas Circadianas Period/metabolismo , Fatores de Transcrição ARNTL/genética , Fatores Etários , Envelhecimento/genética , Animais , Proteínas CLOCK/genética , Ritmo Circadiano/fisiologia , Citocinas/metabolismo , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NAD/metabolismo , Proteínas Circadianas Period/genética , Sirtuína 1/metabolismo , Sirtuínas/metabolismo
18.
Rev Neurol (Paris) ; 176(5): 361-365, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32241570

RESUMO

BACKGROUND: Twenty-five percent of the global population lives in one of the more than 70 countries that observe daylight saving time (DST). These people are exposed to 1hour of time transition twice a year, influencing the circulatory system. We aimed to analyze the incidence of thrombolysis to treat acute ischemic stroke in relation to clock changes in Hungary over a 10-year period. METHODS: The number of thrombolytic treatments performed within the period between 2006 and 2015 was analyzed. Anonymized nationwide data on the dates and exact daily numbers of thrombolysis interventions were provided by the National Health Insurance Fund. We compared the mean number of thrombolytic treatments on the day before with that on the day after each transition, and also between the preceding and following one week and month. RESULTS: Our data including the last days of each month suggested a significant increase in thrombolysis numbers both in spring and in autumn on the day and the week after the clock change. However, when the last days of each month were excluded from analysis (as this in itself was associated with a 7-fold increase in stroke incidence in our earlier study), no significant difference in the number of thrombolysis treatments between the days and weeks before and after the clock change was detectable. The long-term, monthly analysis also did not reveal a significant difference. CONCLUSIONS: Our findings reflect that psychosocial factors, such as the approach of the last day of the month override the intrinsic effect of disturbances of the circadian rhythm on stroke incidence.


Assuntos
Isquemia Encefálica/epidemiologia , Isquemia Encefálica/terapia , Fotoperíodo , Estações do Ano , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/terapia , Terapia Trombolítica/estatística & dados numéricos , Relógios Circadianos/fisiologia , Feminino , Fibrinolíticos/uso terapêutico , Humanos , Hungria/epidemiologia , Incidência , Masculino , Terapia Trombolítica/métodos , Fatores de Tempo
19.
Adv Exp Med Biol ; 1260: 193-265, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32304036

RESUMO

Worldwide, individuals are living longer due to medical and scientific advances, increased availability of medical care and changes in public health policies. Consequently, increasing attention has been focused on managing chronic conditions and age-related diseases to ensure healthy aging. The endogenous circadian system regulates molecular, physiological and behavioral rhythms orchestrating functional coordination and processes across tissues and organs. Circadian disruption or desynchronization of circadian oscillators increases disease risk and appears to accelerate aging. Reciprocally, aging weakens circadian function aggravating age-related diseases and pathologies. In this review, we summarize the molecular composition and structural organization of the circadian system in mammals and humans, and evaluate the technological and societal factors contributing to the increasing incidence of circadian disorders. Furthermore, we discuss the adverse effects of circadian dysfunction on aging and longevity and the bidirectional interactions through which aging affects circadian function using examples from mammalian research models and humans. Additionally, we review promising methods for managing healthy aging through behavioral and pharmacological reinforcement of the circadian system. Understanding age-related changes in the circadian clock and minimizing circadian dysfunction may be crucial components to promote healthy aging.


Assuntos
Envelhecimento/patologia , Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Doença , Longevidade/fisiologia , Animais , Envelhecimento Saudável/fisiologia , Humanos
20.
Zoolog Sci ; 37(2): 177-192, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32282149

RESUMO

There are few model fish that are both edible and suitable for use in the laboratory. The Japanese loach (Misgurnus anguillicaudatus) is a traditional food in Japan, but is highly neglected despite its great nutritional value. To understand its circadian system and photic input pathway for synchronization of physiological activities to environmental light-dark cycles, we measured locomotor activity under light-dark and constant dark (DD) conditions. Locomotor activity was found to be higher in the nighttime than daytime, and its rhythmicity was weakened under DD conditions. The nocturnal activity of the Japanese loach is mainly controlled by environmental light, rather than the circadian clock. We explored the circadian regulation and light-responsiveness of clock gene expression in the eyes of loaches. The daily expression profiles of its mRNA revealed that most of the examined Cry and Per genes were likely regulated by internal circadian and/or environmental light signals. Among the Opsin genes transcribed in the eye, we detected the retinal photopigment porphyropsin at the protein level, which was lower than in mice. This property of loach eyes prompted us to analyze the locomotor activities of eye-enucleated fish. As a result, they still showed nocturnal circadian activity. Thus, it is likely that extraocular photoreceptive tissue(s) also contribute to the photic input pathway, although loach eyes are a circadian photosensitive tissue. This suggests that the loach mainly uses not its vision but other stimuli, such as mechanical or chemical stimuli, detected by barbels, to coordinate its nocturnal behavior.


Assuntos
Relógios Circadianos/genética , Cipriniformes/genética , Animais , Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Cipriniformes/fisiologia , Olho/química , Olho/metabolismo , Feminino , Proteínas de Peixes/metabolismo , Regulação da Expressão Gênica , Luz , Locomoção/fisiologia , Masculino , Fenômenos Fisiológicos Oculares , RNA Mensageiro
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