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1.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(9): 1128-1132, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31657338

RESUMO

OBJECTIVE: To investigate the effect of circadian heart rate variation on short-term and long-term mortality in intensive care unit (ICU) patients. METHODS: A retrospective cohort study was conducted. A total of 32 536 ICU patients were recorded from 2001 to 2008 published by Multiparameter Intelligent Monitoring in Intensive Care II (MIMIC-II v2.6) in April 2011. The circadian heart rate variation was defined as the ratio of mean nighttime (23:00 to 07:00) heart rate to mean daytime (07:00 to 23:00) heart rate. The 28-day mortality and 1-year mortality were defined as outcome events. The information such as age, gender, ethnicity, first sequential organ failure assessment (SOFA) score, first simplified acute physiology score I (SAPS I), usage of sedatives and catecholamines within 24 hours admission of ICU, clinical complications [hypertension, chronic obstructive pulmonary disease (COPD), diabetes with or without complications, congestive heart failure, liver disease, renal failure, etc.], and the complete heart rate records within 24 hours after ICU admission were collected. Cox proportional risk regression models were used to investigate the association between circadian heart rate variation and 28-day mortality and 1-year mortality in ICU patients. Besides, subgroup analysis was also performed in patients with different first SOFA scores. RESULTS: Totally 15 382 ICU patients in MIMIC-II database were enrolled, excluding the patients without heart rate records or death records, using pacemaker with arrhythmia, without SOFA or SAPS I score records. Finally, 9 439 patients were enrolled in the study cohort. (1) Cox regression analysis of the whole patient showed that the higher circadian heart rate variation was correlated with the increased 28-day mortality [hazard ratio (HR) = 1.613, 95% confidence interval (95%CI) was 1.338-1.943, P < 0.001] and 1-year mortality (HR = 1.573, 95%CI was 1.296-1.908, P < 0.001). After adjustment for demographic factors (age, gender and ethnicity), severity of illness (SOFA and SAPS I scores), clinical complications (hypertension, COPD, diabetes with or without complications, congestive heart failure, liver disease, renal failure, etc.), and influence of medications (sedatives and catecholamines), the night-day heart rate ratio was also correlated with 28-day mortality (HR = 1.256, 95%CI was 1.018-1.549, P = 0.033) and 1-year mortality (HR = 1.249, 95%CI was 1.010-1.545, P = 0.040). (2) According to the SOFA score (median value of 5), the patients were divided into two subgroups, in which 5 478 patients with SOFA score ≤ 5 and 3 961 patients with SOFA score > 5. Cox regression subgroup analysis showed that circadian heart rate variation was related with higher 28-day mortality (HR = 1.430, 95%CI was 1.164-1.756, P = 0.001) and 1-year mortality (HR = 1.393, 95%CI was 1.123-1.729, P = 0.003) in patients with SOFA score > 5. After adjustment for covariates, the 28-day mortality (HR = 1.279, 95%CI was 1.032-1.584, P = 0.025) and 1-year mortality (HR = 1.255, 95%CI was 1.010-1.558, P = 0.040) also increased with the increasing of night-day heart rate ratio in patients with SOFA score > 5. However, the relationships did not exist in patients with SOFA score ≤ 5. CONCLUSIONS: In ICU patients, the 28-day mortality and 1-year mortality increase with the higher circadian heart rate variation, which indicates that the circadian heart rate variation in ICU patients is positively correlated with the short-term and long-term mortality, especially in patients with relatively severe illness.


Assuntos
Relógios Circadianos , Frequência Cardíaca/fisiologia , Unidades de Terapia Intensiva , Mortalidade/tendências , Cuidados Críticos , Humanos , Escores de Disfunção Orgânica , Prognóstico , Estudos Retrospectivos
2.
Sheng Li Xue Bao ; 71(5): 783-791, 2019 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-31646332

RESUMO

Circadian rhythms widely exist in living organisms, and they are regulated by the biological clock. Growing evidence has shown that circadian rhythms are tightly related to the physiological function of the cardiovascular system, including blood pressure, heart rate, metabolism of cardiomyocytes, function of endothelial cells, and vasoconstriction and vasodilation. In addition, disruption of circadian rhythms has been considered as one of the important risk factors for cardiovascular diseases, such as myocardial infarction. This review summarizes the recent research advances in the relationship between circadian clock and cardiovascular diseases, hoping to improve treatment strategies for patients with cardiovascular diseases according to the theory of biological clock.


Assuntos
Doenças Cardiovasculares/fisiopatologia , Relógios Circadianos , Ritmo Circadiano , Pressão Sanguínea , Células Endoteliais/citologia , Frequência Cardíaca , Humanos , Miócitos Cardíacos/metabolismo , Vasoconstrição , Vasodilatação
3.
Nature ; 574(7776): 43-44, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31576028
4.
Genes Dev ; 33(17-18): 1136-1158, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31481537

RESUMO

Circadian rhythms are driven by a transcription-translation feedback loop that separates anabolic and catabolic processes across the Earth's 24-h light-dark cycle. Central pacemaker neurons that perceive light entrain a distributed clock network and are closely juxtaposed with hypothalamic neurons involved in regulation of sleep/wake and fast/feeding states. Gaps remain in identifying how pacemaker and extrapacemaker neurons communicate with energy-sensing neurons and the distinct role of circuit interactions versus transcriptionally driven cell-autonomous clocks in the timing of organismal bioenergetics. In this review, we discuss the reciprocal relationship through which the central clock drives appetitive behavior and metabolic homeostasis and the pathways through which nutrient state and sleep/wake behavior affect central clock function.


Assuntos
Relógios Circadianos/fisiologia , Metabolismo Energético/genética , Hipotálamo/metabolismo , Neurônios/fisiologia , Animais , Ritmo Circadiano/fisiologia , AMP Cíclico/metabolismo , Comportamento Alimentar/fisiologia , Humanos , Transdução de Sinais
5.
BMC Evol Biol ; 19(1): 174, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462236

RESUMO

BACKGROUND: A number of non-visual responses to light in vertebrates, such as circadian rhythm control and pupillary light reflex, are mediated by melanopsins, G-protein coupled membrane receptors, conjugated to a retinal chromophore. In non-mammalian vertebrates, melanopsin expression is variable within the retina and extra-ocular tissues. Two paralog melanopsin genes were classified in vertebrates, Opn4x and Opn4m. Snakes are highly diversified vertebrates with a wide range of daily activity patterns, which raises questions about differences in structure, function and expression pattern of their melanopsin genes. In this study, we analyzed the melanopsin genes expressed in the retinas of 18 snake species from three families (Viperidae, Elapidae, and Colubridae), and also investigated extra-retinal tissue expression. RESULTS: Phylogenetic analysis revealed that the amplified gene belongs to the Opn4x group, and no expression of the Opn4m was found. The same paralog is expressed in the iris, but no extra-ocular expression was detected. Molecular evolutionary analysis indicated that melanopsins are evolving primarily under strong purifying selection, although lower evolutionary constraint was detected in snake lineages (ω = 0.2), compared to non-snake Opn4x and Opn4m (ω = 0.1). Statistical analysis of selective constraint suggests that snake phylogenetic relationships have driven stronger effects on melanopsin evolution, than the species activity pattern. In situ hybridization revealed the presence of melanopsin within cells in the outer and inner nuclear layers, in the ganglion cell layer, and intense labeling in the optic nerve. CONCLUSIONS: The loss of the Opn4m gene and extra-ocular photosensitive tissues in snakes may be associated with a prolonged nocturnal/mesopic bottleneck in the early history of snake evolution. The presence of melanopsin-containing cells in all retinal nuclear layers indicates a globally photosensitive retina, and the expression in classic photoreceptor cells suggest a regionalized co-expression of melanopsin and visual opsins.


Assuntos
Proteínas de Répteis/genética , Retina/metabolismo , Opsinas de Bastonetes/genética , Serpentes/genética , Animais , Relógios Circadianos , Evolução Molecular , Regulação da Expressão Gênica , Filogenia , Opsinas de Bastonetes/fisiologia , Serpentes/classificação , Serpentes/fisiologia , Visão Ocular
6.
J Agric Food Chem ; 67(36): 10089-10096, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31423784

RESUMO

Circadian rhythms are closely associated with metabolic homeostasis. Metabolic disorders can be alleviated by many bioactive components through controlling of clock gene expressions. Capsaicin has been demonstrated with many beneficial effects including anti-obesity and anti-insulin resistance activities, yet whether the rhythmic expression of circadian clock genes are involved in the regulation of redox imbalance and glucose metabolism disorder by capsaicin remains unclear. In this work, the insulin resistance was induced in HepG2 cells by treatment of glucosamine. Glucose uptake levels, reactive oxygen species, H2O2 production, and mitochondrial membrane potential (MMP) were measured with/without capsaicin cotreatment. The mRNA and protein expressions of core circadian clock genes were evaluated by RT-qPCR and western blot analysis. Our study revealed that circadian misalignment could be ameliorated by capsaicin. The glucosamine-induced cellular redox imbalance and glucose metabolism disorder were ameliorated by capsaicin in a Bmal1-dependent manner.


Assuntos
Capsaicina/administração & dosagem , Relógios Circadianos/efeitos dos fármacos , Transtornos do Metabolismo de Glucose/tratamento farmacológico , Resistência à Insulina , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/metabolismo , Glucose/metabolismo , Transtornos do Metabolismo de Glucose/genética , Transtornos do Metabolismo de Glucose/metabolismo , Transtornos do Metabolismo de Glucose/fisiopatologia , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Insulinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxirredução/efeitos dos fármacos
7.
Environ Pollut ; 252(Pt B): 1455-1463, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31265956

RESUMO

Circadian rhythm is believed to play important roles in atherosclerosis. The gut microbiota is found to be closely related to atherogenesis, and shows compositional and functional circadian oscillation. However, it's still unclarified whether circadian clock and intestinal microbiota are involved in the progression of atherosclerosis induced by environmental pollutant acrolein. Herein, patients with atherosclerosis showed higher MMP9, a promising biomarker for atherosclerosis, and lower Bmal1 and Clock expression in the plasma. Interestingly, acrolein exposure contributed to the increased MMP9, decreased Clock and Bmal1, and activated MAPK pathways in human umbilical vein endothelial cells (HUVECs). We found that knockdown of Clock or Bmal1 lead to upregulation of MMP9 in HUVECs, and that Clock and Bmal1 expression was elevated while MAPK pathways were blocked. Atherosclerotic apolipoproteinE-deficient mice consumed a high-fat diet were used and treated with acrolein (3 mg/kg/day) in the drinking water for 12 weeks. Upregulation of MMP9, and downregulation of Clock and Bmal1 were also observed in plasma of the mice. Besides, acrolein feeding altered gut microbiota composition at a phylum level especially for an increased Firmicutes and a decreased Bacteroidetes. Additionally, gut microbiota showed correlation with atherosclerotic plaque, MMP9 and Bmal1 levels. Therefore, our findings indicated that acrolein increased the expression of MMP9 through MAPK regulating circadian clock, which was associated with gut microbiota regulation in atherosclerosis. Circadian rhythms and gut microbiota might be promising targets in the prevention of cardiovascular disease caused by environmental pollutants.


Assuntos
Fatores de Transcrição ARNTL/sangue , Aterosclerose/patologia , Proteínas CLOCK/sangue , Ritmo Circadiano/fisiologia , Microbioma Gastrointestinal/fisiologia , Metaloproteinase 9 da Matriz/metabolismo , Fatores de Transcrição ARNTL/genética , Acroleína , Adulto , Animais , Apolipoproteínas E/genética , Aterosclerose/induzido quimicamente , Proteínas CLOCK/genética , Linhagem Celular , Relógios Circadianos/fisiologia , Dieta Hiperlipídica , Regulação para Baixo , Feminino , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Knockout
8.
Nature ; 571(7764): 183-192, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31292558

RESUMO

For several decades, understanding ageing and the processes that limit lifespan have challenged biologists. Thirty years ago, the biology of ageing gained unprecedented scientific credibility through the identification of gene variants that extend the lifespan of multicellular model organisms. Here we summarize the milestones that mark this scientific triumph, discuss different ageing pathways and processes, and suggest that ageing research is entering a new era that has unique medical, commercial and societal implications. We argue that this era marks an inflection point, not only in ageing research but also for all biological research that affects the human healthspan.


Assuntos
Envelhecimento/fisiologia , Pesquisa Biomédica , Envelhecimento Saudável/fisiologia , Rejuvenescimento/fisiologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Relógios Circadianos , Ensaios Clínicos como Assunto , Envelhecimento Saudável/efeitos dos fármacos , Envelhecimento Saudável/genética , Humanos , Inflamação , Longevidade/efeitos dos fármacos , Longevidade/genética , Longevidade/fisiologia , Mitocôndrias/metabolismo , Estado Nutricional , Estresse Oxidativo , Transdução de Sinais
9.
Cell Mol Life Sci ; 76(19): 3801-3826, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31222374

RESUMO

The skin is the interface between the organism and the external environment, acting as its first barrier. Thus, this organ is constantly challenged by physical stimuli such as UV and infrared radiation, visible light, and temperature as well as chemicals and pathogens. To counteract the deleterious effects of the above-mentioned stimuli, the skin has complex defense mechanisms such as: immune and neuroendocrine systems; shedding of epidermal squamous layers and apoptosis of damaged cells; DNA repair; and pigmentary system. Here we have reviewed the current knowledge regarding which stimuli affect the molecular clock of the skin, the consequences to skin-related biological processes and, based on such knowledge, we suggest some therapeutic targets. We also explored the recent advances regarding the molecular clock disruption in melanoma, its impact on the carcinogenic process, and its therapeutic value in melanoma treatment.


Assuntos
Relógios Circadianos , Melanoma/etiologia , Neoplasias Cutâneas/etiologia , Fenômenos Fisiológicos da Pele , Animais , Humanos , Melanoma/tratamento farmacológico , Pele/metabolismo , Neoplasias Cutâneas/tratamento farmacológico
10.
J Agric Food Chem ; 67(32): 8735-8739, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31244204

RESUMO

The circadian clock is an intrinsic mechanism of biological adaptation to the cyclical changes of the environment. The circadian rhythm disorders affect the life activities of organisms. A variety of phytochemicals (e.g., polyphenols, flavonoids, alkaloids, and melatonin) reportedly can regulate the expression and rhythm of circadian clock genes and stabilize the internal environment. This perspective focuses on the relationship of circadian clock genes with oxidative stress, inflammatory response, and metabolic disorders and emphasizes the regulation of phytochemicals on the circadian clock. Potential mechanisms and applications of supplemental phytochemicals to improve metabolic disorders and circadian rhythm disorders are also discussed.


Assuntos
Relógios Circadianos , Doenças Metabólicas/fisiopatologia , Compostos Fitoquímicos/metabolismo , Animais , Humanos , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Estresse Oxidativo , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo
11.
Sheng Wu Gong Cheng Xue Bao ; 35(5): 795-804, 2019 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-31222998

RESUMO

The cyanobacterial circadian clock has three relatively independent parts: the input path, the core oscillator, and the output path. The core oscillator is composed of three clock proteins: KaiA, KaiB, and KaiC. The interactions among these three proteins generate a rhythmic signal and convey the input signals to the output signals to maintain the accuracy and stability of the oscillation of downstream signals. Based on the cyanobacterial circadian clock and the structure, function, and interaction of the clock proteins of the core oscillator, combining the recent results from our laboratory, this review summarized the recent progresses of the molecular mechanism of KaiA in regulating KaiC's enzymatic activity, mediating phase reset of the oscillator, and competing with CikA for the binding site of KaiB.


Assuntos
Proteínas de Bactérias , Relógios Circadianos , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano , Cianobactérias , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Relógios Circadianos/genética , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/metabolismo , Cianobactérias/genética , Ativação Enzimática/genética
12.
Nat Commun ; 10(1): 2543, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186426

RESUMO

The circadian clock is known to regulate plant innate immunity but the underlying mechanism of this regulation remains largely unclear. We show here that mutations in the core clock component LUX ARRHYTHMO (LUX) disrupt circadian regulation of stomata under free running and Pseudomonas syringae challenge conditions as well as defense signaling mediated by SA and JA, leading to compromised disease resistance. RNA-seq analysis reveals that both clock- and defense-related genes are regulated by LUX. LUX binds to clock gene promoters that have not been shown before, expanding the clock gene networks that require LUX function. LUX also binds to the promoters of EDS1 and JAZ5, likely acting through these genes to affect SA- and JA-signaling. We further show that JA signaling reciprocally affects clock activity. Thus, our data support crosstalk between the circadian clock and plant innate immunity and imply an important role of LUX in this process.


Assuntos
Arabidopsis/genética , Relógios Circadianos/genética , Imunidade Vegetal/genética , Arabidopsis/microbiologia , Relógios Circadianos/fisiologia , Resistência à Doença/genética , Regulação da Expressão Gênica de Plantas , Mutação , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Estômatos de Plantas/fisiologia , Pseudomonas syringae/fisiologia , Análise de Sequência de RNA
13.
Chem Biol Interact ; 308: 288-293, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31150629

RESUMO

Hypaconitine is an active and highly toxic constituent derived from Aconitum species. Here we aimed to determine the chronotoxicity of hypaconitine in mice, and to investigate a potential role of metabolism in hypaconitine chronotoxicity. Cardiac toxicity was assessed by measuring CK (creatine kinase) and LDH (lactate dehydrogenase) levels after hypaconitine administration to wild-type and Bmal1-/- (a clock disrupted model) mice at different times of day. The mRNA and protein levels of Cyp3a11 in mouse livers were determined by qPCR and western blotting, respectively. In vitro metabolism was assessed using liver microsomes. Pharmacokinetic study of hypaconitine was performed with wild-type mice. We observed injection time-dependent toxicity (i.e., a more severe toxicity during the light phase than the dark phase) for hypaconitine in mice. The chronotoxicity was attributed to a difference in systemic exposure of hypaconitine caused by time of day-dependent metabolism. Furthermore, circadian metabolism of hypaconitine was accounted for by the diurnal expression of Cyp3a11, a major enzyme for hypaconitine detoxification in the liver. Moreover, Bmal1 ablation in mice abolished the daily rhythm of Cyp3a11 expression and abrogated the time-dependency of hypaconitine toxicity. In conclusion, circadian Cyp3a11 metabolism contributed to chronotoxicity of hypaconitine in mice. This metabolism-based chronotoxicity would facilitate the formulation of best timing for drug administration.


Assuntos
Aconitina/análogos & derivados , Relógios Circadianos , Citocromo P-450 CYP3A/metabolismo , Fígado/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Fatores de Transcrição ARNTL/deficiência , Fatores de Transcrição ARNTL/genética , Aconitina/metabolismo , Aconitina/farmacocinética , Aconitina/toxicidade , Animais , Creatina Quinase/sangue , Citocromo P-450 CYP3A/genética , Células HEK293 , Meia-Vida , Humanos , Fígado/metabolismo , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microssomos Hepáticos/metabolismo , RNA Mensageiro/metabolismo
14.
Nat Rev Endocrinol ; 15(7): 393-405, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31073218

RESUMO

Feeding, which is essential for all animals, is regulated by homeostatic mechanisms. In addition, food consumption is temporally coordinated by the brain over the circadian (~24 h) cycle. A network of circadian clocks set daily windows during which food consumption can occur. These daily windows mostly overlap with the active phase. Brain clocks that ensure the circadian control of food intake include a master light-entrainable clock in the suprachiasmatic nuclei of the hypothalamus and secondary clocks in hypothalamic and brainstem regions. Metabolic hormones, circulating nutrients and visceral neural inputs transmit rhythmic cues that permit (via close and reciprocal molecular interactions that link metabolic processes and circadian clockwork) brain and peripheral organs to be synchronized to feeding time. As a consequence of these complex interactions, growing evidence shows that chronodisruption and mistimed eating have deleterious effects on metabolic health. Conversely, eating, even eating an unbalanced diet, during the normal active phase reduces metabolic disturbances. Therefore, in addition to energy intake and dietary composition, appropriately timed meal patterns are critical to prevent circadian desynchronization and limit metabolic risks. This Review provides insight into the dual modulation of food intake by homeostatic and circadian processes, describes the mechanisms regulating feeding time and highlights the beneficial effects of correctly timed eating, as opposed to the negative metabolic consequences of mistimed eating.


Assuntos
Encéfalo/metabolismo , Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Ingestão de Alimentos/fisiologia , Ingestão de Energia , Comportamento Alimentar/fisiologia , Feminino , Humanos , Hipotálamo/metabolismo , Masculino , Sensibilidade e Especificidade
15.
Zoolog Sci ; 36(2): 95-104, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31120643

RESUMO

Most animals exhibit circadian rhythms in various physiological and behavioral functions regulated by circadian clock that resides in brain and in many peripheral tissues. Temperature cycle is an important time cue for entrainment, even in mammals, since the daily change in body temperature is thought to be used for phase regulation of clocks in peripheral tissues. However, little is known about the mechanisms by which temperature resets the clock. In the present study, we investigated the effect of temperature on circadian activity rhythm and clock gene transcription by using the cricket, Gryllus bimaculatus. We show that temperature cycle can entrain both behavioral and transcriptional rhythms of clock genes, such as period, timeless, cryptochrome2 and cycle in the circadian pacemaker tissue, optic lobe. Under temperature cycle, phase of evening peak of locomotor activity occurred 1 h before the warm-to-cold phase transition, which is associated with earlier peaks of mRNA expression rhythm of the clock genes than that under light/dark cycles. When the temperature cycle was advanced by 6 h, behavioral rhythms re-entrained to newly phased temperature cycle after ∼16 transient cycles. The mRNA oscillation of period and timeless gained stable rhythm under phase advanced temperature cycles with a lesser number of transient cycles than cryptochrome2 and cycle. These results suggest that temperature cycle can entrain behavioral and molecular rhythms in cricket and clock genes vary in sensitivity to temperature. It is thus likely that clock genes play differential roles in resetting the clock with environmental temperature changes.


Assuntos
Relógios Circadianos/genética , Ritmo Circadiano/fisiologia , Gryllidae/fisiologia , Atividade Motora , Temperatura Ambiente , Animais , Gryllidae/genética , Gryllidae/metabolismo , Masculino , Lobo Óptico de Animais não Mamíferos , RNA Mensageiro/genética
16.
Int J Mol Sci ; 20(9)2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31071906

RESUMO

Circadian rhythms regulate over 40% of protein-coding genes in at least one organ in the body through mechanisms tied to the central circadian clock and to cell-intrinsic auto-regulatory feedback loops. Distinct diurnal differences in regulation of regeneration have been found in several organs, including skin, intestinal, and hematopoietic systems. Each regenerating system contains a complex network of cell types with different circadian mechanisms contributing to regeneration. In this review, we elucidate circadian regeneration mechanisms in the three representative systems. We also suggest circadian regulation of global translational activity as an understudied global regulator of regenerative capacity. A more detailed understanding of the molecular mechanisms underlying circadian regulation of tissue regeneration would accelerate the development of new regenerative therapies.


Assuntos
Relógios Circadianos/genética , Ritmo Circadiano/genética , Regeneração/genética , Ribossomos/genética , Animais , Sistema Hematopoético/crescimento & desenvolvimento , Humanos , Intestinos/crescimento & desenvolvimento , Pele/crescimento & desenvolvimento
17.
Int J Mol Sci ; 20(9)2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-31086108

RESUMO

The circadian clock is an endogenous oscillator that controls daily rhythms in metabolism, physiology, and behavior. Although the timekeeping components differ among species, a common design principle is a transcription-translation negative feedback loop. However, it is becoming clear that other mechanisms can contribute to the generation of 24 h rhythms. Peroxiredoxins (Prxs) exhibit 24 h rhythms in their redox state in all kingdoms of life. In mammalian adrenal gland, heart and brown adipose tissue, such rhythms are generated as a result of an inactivating hyperoxidation reaction that is reduced by coordinated import of sulfiredoxin (Srx) into the mitochondria. However, a quantitative description of the Prx/Srx oscillating system is still missing. We investigate the basic principles that generate mitochondrial Prx/Srx rhythms using computational modeling. We observe that the previously described delay in mitochondrial Srx import, in combination with an appropriate separation of fast and slow reactions, is sufficient to generate robust self-sustained relaxation-like oscillations. We find that our conceptual model can be regarded as a series of three consecutive phases and two temporal switches, highlighting the importance of delayed negative feedback and switches in the generation of oscillations.


Assuntos
Relógios Circadianos/fisiologia , Animais , Ritmo Circadiano/fisiologia , Simulação por Computador , Humanos , Modelos Teóricos , Oxirredução , Peroxirredoxinas/metabolismo , Transdução de Sinais/fisiologia
18.
Mol Cells ; 42(4): 301-312, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31091556

RESUMO

Post-transcriptional regulation underlies the circadian control of gene expression and animal behaviors. However, the role of mRNA surveillance via the nonsense-mediated mRNA decay (NMD) pathway in circadian rhythms remains elusive. Here, we report that Drosophila NMD pathway acts in a subset of circadian pacemaker neurons to maintain robust 24 h rhythms of free-running locomotor activity. RNA interference-mediated depletion of key NMD factors in timeless-expressing clock cells decreased the amplitude of circadian locomotor behaviors. Transgenic manipulation of the NMD pathway in clock neurons expressing a neuropeptide PIGMENT-DISPERSING FACTOR (PDF) was sufficient to dampen or lengthen free-running locomotor rhythms. Confocal imaging of a transgenic NMD reporter revealed that arrhythmic Clock mutants exhibited stronger NMD activity in PDF-expressing neurons than wild-type. We further found that hypomorphic mutations in Suppressor with morphogenetic effect on genitalia 5 (Smg5 ) or Smg6 impaired circadian behaviors. These NMD mutants normally developed PDF-expressing clock neurons and displayed daily oscillations in the transcript levels of core clock genes. By contrast, the loss of Smg5 or Smg6 function affected the relative transcript levels of cAMP response element-binding protein B (CrebB ) in an isoform-specific manner. Moreover, the overexpression of a transcriptional repressor form of CrebB rescued free-running locomotor rhythms in Smg5-depleted flies. These data demonstrate that CrebB is a rate-limiting substrate of the genetic NMD pathway important for the behavioral output of circadian clocks in Drosophila.


Assuntos
Relógios Circadianos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/genética , Mutação , Degradação do RNAm Mediada por Códon sem Sentido , Transativadores/metabolismo , Animais , Animais Geneticamente Modificados , Proteínas CLOCK/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Endorribonucleases/genética , Endorribonucleases/metabolismo , Neurônios/metabolismo , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Processamento Pós-Transcricional do RNA , Transdução de Sinais
19.
Plant Mol Biol ; 101(1-2): 1-19, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31062216

RESUMO

KEY MESSAGE: The circadian clock controls many molecular activities, impacting experimental interpretation. We quantify the genome-wide effects of time-of-day on the heat-shock response and the effects of "diurnal bias" in stress experiments. Heat stress has significant adverse effects on plant productivity worldwide. Most experiments examining heat stress are performed during daytime hours, generating a 'diurnal bias' in the pathways and regulatory mechanisms identified. Such bias may confound downstream interpretations and limit our understanding of the full response to heat stress. Here we show that the transcriptional and physiological responses to a sudden heat shock in Arabidopsis are profoundly sensitive to the time of day. We observe that plant tolerance and acclimation to heat shock vary throughout the day and are maximal at dusk. Consistently, over 75% of heat-responsive transcripts show a time of day-dependent response, including many previously characterized heat-response genes. This temporal sensitivity implies a complex interaction between time and temperature where daily variations in basal transcription influence thermotolerance. When we examined these transcriptional responses, we uncovered novel night-response genes and cis-regulatory elements, underpinning new aspects of heat stress responses not previously appreciated. Exploiting this temporal variation can be applied to most environmental responses to understand the underlying network wiring. Therefore, we propose that using time as a perturbagen is an approach that will enhance our understanding of plant regulatory networks and responses to environmental stresses.


Assuntos
Arabidopsis/fisiologia , Relógios Circadianos/genética , Redes Reguladoras de Genes , Genoma de Planta/genética , Proteínas de Choque Térmico/genética , Resposta ao Choque Térmico/genética , Aclimatação , Arabidopsis/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas/genética , Temperatura Alta , Plântula/genética , Plântula/fisiologia , Estresse Fisiológico , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
20.
Cell Tissue Res ; 377(1): 81-94, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31073908

RESUMO

Mood state alterations are often accompanied by disruptions of daily rhythms of physiology. Circadian rhythms of physiology are controlled by a central clock harbored in the suprachiasmatic nucleus (SCN), which is functionally dependent on the rhythmic expression of several clock genes. The molecular clockwork has been identified in other extra-SCN brain regions, some of which are implicated in the regulation of motivational and emotional states, although their specific circadian role is not fully known. In mood disorders, alterations of the molecular clock have been reported. Thus, functional expression of circadian genes in the brain is compromised in mood diseases. In the present review, we describe the current evidence that implicates the clock gene alterations as an important factor in the development of mood-related disorders. Furthermore, we describe the possible role of other brain clocks, beyond the SCN, in the circadian control of mood. The comprehension of the circadian neural and genetic mechanisms underlying mood alterations might guide towards the identification of optimal drug and non-drug therapies for the cure of depression and other mood disorders.


Assuntos
Relógios Circadianos/genética , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Ritmo Circadiano/genética , Habenula/metabolismo , Transtornos do Humor/genética , Transtornos do Humor/fisiopatologia , Animais , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/metabolismo , Drosophila melanogaster , Feminino , Humanos , Masculino , Camundongos , Ratos , Núcleo Supraquiasmático/metabolismo
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