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1.
Plant J ; 116(3): 650-668, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37531328

RESUMO

Circadian regulation produces a biological measure of time within cells. The daily cycle in the availability of light for photosynthesis causes dramatic changes in biochemical processes in photosynthetic organisms, with the circadian clock having crucial roles in adaptation to these fluctuating conditions. Correct alignment between the circadian clock and environmental day-night cycles maximizes plant productivity through its regulation of metabolism. Therefore, the processes that integrate circadian regulation with metabolism are key to understanding how the circadian clock contributes to plant productivity. This forms an important part of exploiting knowledge of circadian regulation to enhance sustainable crop production. Here, we examine the roles of circadian regulation in metabolic processes in source and sink organ structures of Arabidopsis. We also evaluate possible roles for circadian regulation in root exudation processes that deposit carbon into the soil, and the nature of the rhythmic interactions between plants and their associated microbial communities. Finally, we examine shared and differing aspects of the circadian regulation of metabolism between Arabidopsis and other model photosynthetic organisms, and between circadian control of metabolism in photosynthetic and non-photosynthetic organisms. This synthesis identifies a variety of future research topics, including a focus on metabolic processes that underlie biotic interactions within ecosystems.


Assuntos
Arabidopsis , Relógios Circadianos , Ritmo Circadiano/fisiologia , Arabidopsis/metabolismo , Ecossistema , Fotossíntese/fisiologia , Relógios Circadianos/fisiologia , Regulação da Expressão Gênica de Plantas
2.
Eur J Neurosci ; 60(2): 3901-3920, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38924210

RESUMO

Circadian clocks maintain diurnal rhythms of sleep-wake cycle of 24 h that regulate not only the metabolism of an organism but also many other periodical processes. There is substantial evidence that circadian regulation is impaired in Alzheimer's disease. Circadian clocks regulate many properties known to be disturbed in Alzheimer's patients, such as the integrity of the blood-brain barrier (BBB) as well as the diurnal glymphatic flow that controls waste clearance from the brain. Interestingly, an evolutionarily conserved transcription factor, that is, aryl hydrocarbon receptor (AhR), impairs the function of the core clock proteins and thus could disturb diurnal rhythmicity in the BBB. There is abundant evidence that the activation of AhR signalling inhibits the expression of the major core clock proteins, such as the brain and muscle arnt-like 1 (BMAL1), clock circadian regulator (CLOCK) and period circadian regulator 1 (PER1) in different experimental models. The expression of AhR is robustly increased in the brains of Alzheimer's patients, and protein level is enriched in astrocytes of the BBB. It seems that AhR signalling inhibits glymphatic flow since it is known that (i) activation of AhR impairs the function of the BBB, which is cooperatively interconnected with the glymphatic system in the brain, and (ii) neuroinflammation and dysbiosis of gut microbiota generate potent activators of AhR, which are able to impair glymphatic flow. I will examine current evidence indicating that activation of AhR signalling could disturb circadian functions of the BBB and impair glymphatic flow and thus be involved in the development of Alzheimer's pathology.


Assuntos
Doença de Alzheimer , Ritmo Circadiano , Sistema Glinfático , Receptores de Hidrocarboneto Arílico , Animais , Humanos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Barreira Hematoencefálica/metabolismo , Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Sistema Glinfático/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo
3.
Plant Cell Environ ; 47(2): 408-415, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37927244

RESUMO

Establishing the temperature dependence of respiration is critical for accurate predictions of the global carbon cycle under climate change. Diurnal temperature fluctuations, or changes in substrate availability, lead to variations in leaf respiration. Additionally, recent studies hint that the thermal sensitivity of respiration could be time-dependent. However, the role for endogenous processes, independent from substrate availability, as drivers of temporal changes in the sensitivity of respiration to temperature across phylogenies has not yet been addressed. Here, we examined the diurnal variation in the response of respiration to temperatures (R-T relationship) for different lycophyte, fern, gymnosperm and angiosperm species. We tested whether time-dependent changes in the R-T relationship would impact leaf level respiration modelling. We hypothesized that interactions between endogenous processes, like the circadian clock, and leaf respiration would be independent from changes in substrate availability. Overall, we observed a time-dependent sensitivity in the R-T relationship across phylogenies, independent of temperature, that affected modelling parameters. These results are compatible with circadian gating of respiration, but further studies should analyse the possible involvement of the clock. Our results indicate time-dependent regulation of respiration might be widespread across phylogenies, and that endogenous regulation of respiration is likely affecting leaf-level respiration fluxes.


Assuntos
Aclimatação , Respiração Celular , Respiração Celular/fisiologia , Aclimatação/fisiologia , Plantas , Temperatura , Respiração , Folhas de Planta/fisiologia
4.
Proc Natl Acad Sci U S A ; 118(11)2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33692123

RESUMO

The hippocampus's dorsal and ventral parts are involved in different operative circuits, the functions of which vary in time during the night and day cycle. These functions are altered in epilepsy. Since energy production is tailored to function, we hypothesized that energy production would be space- and time-dependent in the hippocampus and that such an organizing principle would be modified in epilepsy. Using metabolic imaging and metabolite sensing ex vivo, we show that the ventral hippocampus favors aerobic glycolysis over oxidative phosphorylation as compared to the dorsal part in the morning in control mice. In the afternoon, aerobic glycolysis is decreased and oxidative phosphorylation increased. In the dorsal hippocampus, the metabolic activity varies less between these two times but is weaker than in the ventral. Thus, the energy metabolism is different along the dorsoventral axis and changes as a function of time in control mice. In an experimental model of epilepsy, we find a large alteration of such spatiotemporal organization. In addition to a general hypometabolic state, the dorsoventral difference disappears in the morning, when seizure probability is low. In the afternoon, when seizure probability is high, the aerobic glycolysis is enhanced in both parts, the increase being stronger in the ventral area. We suggest that energy metabolism is tailored to the functions performed by brain networks, which vary over time. In pathological conditions, the alterations of these general rules may contribute to network dysfunctions.


Assuntos
Epilepsia/metabolismo , Hipocampo/metabolismo , Animais , Estudos de Casos e Controles , Ritmo Circadiano , Modelos Animais de Doenças , Metabolismo Energético , Epilepsia/fisiopatologia , Glicólise , Hipocampo/fisiopatologia , Masculino , Camundongos , Fosforilação Oxidativa , Probabilidade , Convulsões/metabolismo
5.
Artigo em Inglês | MEDLINE | ID: mdl-39319595

RESUMO

Circadian rhythms modulate the biology of many human tissues and are driven by a nearly 24-h transcriptional feedback loop. Dynamic DNA methylation may play a role in driving 24-h rhythms of gene expression in the human brain. However, little is known about the degree of circadian regulation between the DNA methylation and the gene expression in the peripheral tissues, including human blood. We hypothesized that 24-h rhythms of DNA methylation play a role in driving 24-h RNA expression in human blood. To test this hypothesis, we analyzed DNA methylation levels and RNA expression in blood samples collected from eight healthy males at six-time points over 24 h. We assessed 442,703 genome-wide CpG sites in methylation and 12,364 genes in expression for 24-h rhythmicity using the cosine model. Our analysis revealed significant rhythmic patterns in 6345 CpG sites and 21 genes. Next, we investigated the relationship between methylation and expression using powerful circadian signals. We found a modest negative correlation (ρ = -0.83, p = 0.06) between the expression of gene TXNDC5 and the methylation at the nearby CpG site (cg19116172). We also observed that circadian CpGs significantly overlapped with genetic risk loci of schizophrenia and autism spectrum disorders. Notably, one gene, TXNDC5, showed a significant correlation between circadian methylation and expression and has been reported to be association with neuropsychiatric diseases.

6.
J Neurochem ; 160(4): 454-468, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34919270

RESUMO

There is increasing evidence for a daily rhythm of µ-opioid receptor (MOR) efficacy and the development of alcohol dependence. Previous studies show that ß-arrestin 2 (bArr2) has an impact on alcohol intake, at least partially mediated via modulation of MOR signaling, which in turn mediates the alcohol rewarding effects. Considering the interplay of circadian rhythms on MOR and alcohol dependence, we aimed to investigate bArr2 in alcohol dependence at different time points of the day/light cycle on the level of bArr2 mRNA (in situ hybridization), MOR availability (receptor autoradiography), and MOR signaling (Damgo-stimulated G-protein coupling) in the nucleus accumbens of alcohol-dependent and non-dependent Wistar rats. Using a microarray data set we found that bArr2, but not bArr1, shows a diurnal transcription pattern in the accumbens of naïve rats with higher expression levels during the active cycle. In 3-week abstinent rats, bArr2 is up-regulated in the accumbens at the beginning of the active cycle (ZT15), whereas no differences were found at the beginning of the inactive cycle (ZT3) compared with controls. This effect was accompanied by a specific down-regulation of MOR binding in the active cycle. Additionally, we detect a higher receptor coupling during the inactive cycle compared with the active cycle in alcohol-dependent animals. Together, we report daily rhythmicity for bArr2 expression linked to an inverse pattern of MOR, suggesting an involvement for bArr2 on circadian regulation of G-protein coupled receptors in alcohol dependence. The presented data may have implications for the development of novel bArr2-related treatment targets for alcoholism.


Assuntos
Alcoolismo/genética , Ritmo Circadiano/genética , Receptores Opioides mu/efeitos dos fármacos , Receptores Opioides mu/genética , beta-Arrestina 2/genética , Alcoolismo/tratamento farmacológico , Animais , Regulação para Baixo , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacologia , Masculino , Análise em Microsséries , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Ratos , Ratos Wistar , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Recompensa
7.
J Biol Chem ; 295(11): 3518-3531, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32019867

RESUMO

Proper function of many physiological processes requires a robust circadian clock. Disruptions of the circadian clock can result in metabolic diseases, mood disorders, and accelerated aging. Therefore, identifying small molecules that specifically modulate regulatory core clock proteins may potentially enable better management of these disorders. In this study, we applied a structure-based molecular-docking approach to find small molecules that specifically bind to the core circadian regulator, the transcription factor circadian locomotor output cycles kaput (CLOCK). We identified 100 candidate molecules by virtual screening of ∼2 million small molecules for those predicted to bind closely to the interface in CLOCK that interacts with its transcriptional co-regulator, Brain and muscle Arnt-like protein-1 (BMAL1). Using a mammalian two-hybrid system, real-time monitoring of circadian rhythm in U2OS cells, and various biochemical assays, we tested these compounds experimentally and found one, named CLK8, that specifically bound to and interfered with CLOCK activity. We show that CLK8 disrupts the interaction between CLOCK and BMAL1 and interferes with nuclear translocation of CLOCK both in vivo and in vitro Results from further experiments indicated that CLK8 enhances the amplitude of the cellular circadian rhythm by stabilizing the negative arm of the transcription/translation feedback loop without affecting period length. Our results reveal CLK8 as a tool for further studies of CLOCK's role in circadian rhythm amplitude regulation and as a potential candidate for therapeutic development to manage disorders associated with dampened circadian rhythms.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Proteínas CLOCK/metabolismo , Ritmo Circadiano/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células HEK293 , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Modelos Biológicos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Frações Subcelulares/metabolismo , Fatores de Tempo
8.
Plant Cell Environ ; 44(2): 387-398, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33099776

RESUMO

Nighttime transpiration has been previously reported as a significant source of water loss in many species; however, there is a need to determine if this trait plays a key role in the response to drought. This study aimed to determine the magnitude, regulation and relative contribution to whole plant water-use, of nighttime stomatal conductance (gnight ) and transpiration (Enight ) in grapevine (Vitis vinifera L.). Our results showed that nighttime water loss was relatively low compared to daytime transpiration, and that decreases in soil and plant water potentials were mainly explained by daytime stomatal conductance (gday ) and transpiration (Eday ). Contrary to Eday , Enight did not respond to VPD and possible effects of an innate circadian regulation were observed. Plants with higher gnight also exhibited higher daytime transpiration and carbon assimilation at midday, and total leaf area, suggesting that increased gnight may be linked with daytime behaviors that promote productivity. Modeling simulations indicated that gnight was not a significant factor in reaching critical hydraulic thresholds under scenarios of either extreme drought, or time to 20% of soil relative water content. Overall, this study suggests that gnight is not significant in exacerbating the risk of water stress and hydraulic failure in grapevine.


Assuntos
Carbono/metabolismo , Transpiração Vegetal/fisiologia , Vitis/fisiologia , Transporte Biológico , Relógios Circadianos , Desidratação , Estômatos de Plantas/fisiologia , Água/metabolismo
9.
Proc Natl Acad Sci U S A ; 115(45): 11643-11648, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30348778

RESUMO

The circadian clock orchestrates 24-h rhythms in physiology in most living organisms. At the molecular level, the dogma is that circadian oscillations are based on a negative transcriptional feedback loop. Recent studies found the NAD+-dependent histone deacetylase, SIRT1, directly regulates acetylation status of clock components and influences circadian amplitude in cells. While Nakahata et al. [Nakahata Y, Kaluzova M (2008) Cell 134:329-340] reported that loss of SIRT1 increases amplitude through BMAL1 acetylation, Asher et al. [Asher G, Gatfield D (2008) Cell 134:317-328] reported that loss of SIRT1 decreases amplitude through an increase in acetylated PER2. To address this SIRT1 paradox, we developed a circadian enzymatic model. Predictions from this model and experimental validation strongly align with the findings of Asher et al., with PER2 as the primary target of SIRT1. Further, the model suggested SIRT1 influences BMAL1 expression through actions on PGC1α. We validated this finding experimentally. Thus, our computational and experimental approaches suggest SIRT1 positively regulates clock function through actions on PER2 and PGC1α.


Assuntos
Relógios Circadianos/genética , Retroalimentação Fisiológica , Modelos Biológicos , Proteínas Circadianas Period/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Sirtuína 1/genética , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Linhagem Celular , Simulação por Computador , Citocinas/genética , Citocinas/metabolismo , Regulação da Expressão Gênica , Genes Reporter , Humanos , Luciferases/genética , Luciferases/metabolismo , Camundongos , NAD/metabolismo , Nicotinamida Fosforribosiltransferase/genética , Nicotinamida Fosforribosiltransferase/metabolismo , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Osteoblastos/citologia , Osteoblastos/metabolismo , Proteínas Circadianas Period/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Transdução de Sinais , Sirtuína 1/metabolismo
10.
Mol Ecol ; 29(10): 1860-1872, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32293070

RESUMO

Domestication of animals imposes strong targeted selection for desired traits but can also result in unintended selection due to new domestic environments. Atlantic salmon (Salmo salmar) was domesticated in the 1970s and has subsequently been selected for faster growth in systematic breeding programmes. More recently, salmon aquaculture has replaced fish oils (FOs) with vegetable oils (VOs) in feed, radically changing the levels of essential long-chain polyunsaturated fatty acids (LC-PUFAs). Our aim here was to study the impact of domestication on metabolism and explore the hypothesis that the shift to VO diets has unintentionally selected for a domestication-specific lipid metabolism. We conducted a 96-day feeding trial of domesticated and wild salmon fed diets based on FOs, VOs or phospholipids, and compared transcriptomes and fatty acids in tissues involved in lipid absorption (pyloric caeca) and lipid turnover and synthesis (liver). Domesticated salmon had faster growth and higher gene expression in glucose and lipid metabolism compared to wild fish, possibly linked to differences in regulation of circadian rhythm pathways. Only the domesticated salmon increased expression of LC-PUFA synthesis genes when given VOs. This transcriptome response difference was mirrored at the physiological level, with domesticated salmon having higher LC-PUFA levels but lower 18:3n-3 and 18:2n-6 levels. In line with this, the VO diet decreased growth rate in wild but not domesticated salmon. Our study revealed a clear impact of domestication on transcriptomic regulation linked to metabolism and suggests that unintentional selection in the domestic environment has resulted in evolution of stronger compensatory mechanisms to a diet low in LC-PUFAs.


Assuntos
Domesticação , Metabolismo dos Lipídeos , Salmo salar , Transcriptoma , Animais , Óleos de Peixe , Metabolismo dos Lipídeos/genética , Salmo salar/genética
12.
Pediatr Nephrol ; 34(10): 1765-1776, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31338588

RESUMO

BACKGROUND: Reduced kidney volume (KV) following prematurity is a proxy for reduced nephron number and is associated with the development of hypertension and end-stage renal disease in adults. We investigated whether extreme prematurity affects KV, function, and blood pressure in school-aged children and if nephrocalcinosis (NC) developed during the neonatal period had additional effects. METHODS: We investigated 60 children at a mean age of 7.7 years: 20 born extremely preterm (EPT < 28 weeks gestational age with NC (NC+)), 20 born EPT without NC (NC-), and 19 born as full-term infants (control). We measured KV by ultrasound, collected blood and urine samples to evaluate renal function, and measured office and 24-h ambulatory blood pressure (ABPM). RESULTS: Children born EPT had significantly smaller kidneys (EPT (NC+ NC-) vs control (estimated difference, 11.8 (CI - 21.51 to - 2.09 ml), p = 0.018) and lower but normal cystatin C-based glomerular filtration rate compared with control (estimated difference, - 10.11 (CI - 0.69 to - 19.5), p = 0.035). KV and function were not different between NC+ and NC- groups. Change in KV in relation to BSA (KV/BSA) from the neonatal period to school age showed significantly more EPT children with neonatal NC having a negative evolution of KV (p = 0.01). Blood pressure was normal and not different between the 3 groups. Fifty percent of EPT had a less than 10% day-to-night decline in ABPM. CONCLUSIONS: Kidney growth and volume is affected by EPT birth with NC being a potential aggravating factor. Circadian blood pressure regulation seems abnormal in EPT-born children.


Assuntos
Pressão Sanguínea/fisiologia , Lactente Extremamente Prematuro/fisiologia , Rim/crescimento & desenvolvimento , Nefrocalcinose/complicações , Monitorização Ambulatorial da Pressão Arterial/estatística & dados numéricos , Estudos de Casos e Controles , Criança , Ritmo Circadiano/fisiologia , Feminino , Seguimentos , Taxa de Filtração Glomerular/fisiologia , Humanos , Recém-Nascido , Rim/diagnóstico por imagem , Rim/fisiopatologia , Testes de Função Renal , Masculino , Nefrocalcinose/sangue , Nefrocalcinose/fisiopatologia , Nefrocalcinose/urina , Tamanho do Órgão , Suécia , Ultrassonografia
13.
Int J Mol Sci ; 20(16)2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31416128

RESUMO

The functional and structural adaptations in cerebral arteries could be one of the fundamental causes in the occurrence of orthostatic intolerance after space flight. In addition, emerging studies have found that many cardiovascular functions exhibit circadian rhythm. Several lines of evidence suggest that space flight might increase an astronaut's cardiovascular risks by disrupting circadian rhythm. However, it remains unknown whether microgravity disrupts the diurnal variation in vascular contractility and whether microgravity impacts on circadian clock system. Sprague-Dawley rats were subjected to 28-day hindlimb-unweighting to simulate the effects of microgravity on vasculature. Cerebrovascular contractility was estimated by investigating vasoconstrictor responsiveness and myogenic tone. The circadian regulation of CaV1.2 channel was determined by recording whole-cell currents, evaluating protein and mRNA expressions. Then the candidate miRNA in relation with Ca2+ signal was screened. Lastly, the underlying pathway involved in circadian regulation of cerebrovascular contractility was determined. The major findings of this study are: (1) The clock gene BMAL1 could induce the expression of miR-103, and in turn modulate the circadian regulation of CaV1.2 channel in rat cerebral arteries at post-transcriptional level; and (2) simulated microgravity disrupted intrinsic diurnal oscillation in rat cerebrovascular contractility by altering circadian regulation of BMAL1/miR-103/CaV1.2 signal pathway.


Assuntos
Fatores de Transcrição ARNTL/genética , Canais de Cálcio Tipo L/metabolismo , Circulação Cerebrovascular/genética , Ritmo Circadiano , MicroRNAs/genética , Vasoconstrição/genética , Ausência de Peso , Fatores de Transcrição ARNTL/metabolismo , Animais , Linhagem Celular , Regulação da Expressão Gênica , Masculino , Modelos Biológicos , Ratos , Transdução de Sinais
14.
Plant J ; 92(1): 19-30, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28670834

RESUMO

The altered carbon assimilation pathway of crassulacean acid metabolism (CAM) photosynthesis results in an up to 80% higher water-use efficiency than C3 photosynthesis in plants making it a potentially useful pathway for engineering crop plants with improved drought tolerance. Here we surveyed detailed temporal (diel time course) and spatial (across a leaf gradient) gene and microRNA (miRNA) expression patterns in the obligate CAM plant pineapple [Ananas comosus (L.) Merr.]. The high-resolution transcriptome atlas allowed us to distinguish between CAM-related and non-CAM gene copies. A differential gene co-expression network across green and white leaf diel datasets identified genes with circadian oscillation, CAM-related functions, and source-sink relations. Gene co-expression clusters containing CAM pathway genes are enriched with clock-associated cis-elements, suggesting circadian regulation of CAM. About 20% of pineapple microRNAs have diel expression patterns, with several that target key CAM-related genes. Expression and physiology data provide a model for CAM-specific carbohydrate flux and long-distance hexose transport. Together these resources provide a list of candidate genes for targeted engineering of CAM into C3 photosynthesis crop species.


Assuntos
Ananas/genética , Carbono/metabolismo , Regulação da Expressão Gênica de Plantas , MicroRNAs/genética , Proteínas de Plantas/genética , Transcriptoma , Ananas/fisiologia , Relógios Circadianos , Fotossíntese , Estômatos de Plantas/genética , Estômatos de Plantas/fisiologia , RNA de Plantas/genética , Água/metabolismo
15.
Front Neuroendocrinol ; 36: 150-64, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25256348

RESUMO

Negative feedback regulation of glucocorticoid (GC) synthesis and secretion occurs through the function of glucocorticoid receptor (GR) at sites in the hypothalamic-pituitary-adrenal (HPA) axis, as well as in brain regions such as the hippocampus, prefrontal cortex, and sympathetic nervous system. This function of GRs in negative feedback coordinates basal glucocorticoid secretion and stress-induced increases in secretion that integrate GC production with the magnitude and duration of the stressor. This review describes the effects of GR loss along major sites of negative feedback including the entire brain, the paraventricular nucleus of the hypothalamus (PVN), and the pituitary. In genetic mouse models, we evaluate circadian regulation of the HPA axis, stress-stimulated neuroendocrine response and behavioral activity, as well as the integrated response of organism metabolism. Our analysis provides information on contributions of region-specific GR-mediated negative feedback to provide insight in understanding HPA axis dysregulation and the pathogenesis of psychiatric and metabolic disorders.


Assuntos
Marcação de Genes , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Receptores de Glucocorticoides/metabolismo , Animais , Hipotálamo/metabolismo , Camundongos , Receptores de Glucocorticoides/genética , Estresse Fisiológico/fisiologia
16.
Gastroenterology ; 148(5): 1012-1023.e14, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25701738

RESUMO

BACKGROUND & AIMS: Hyperhomocysteinemia is often associated with liver and metabolic diseases. We studied nuclear receptors that mediate oscillatory control of homocysteine homeostasis in mice. METHODS: We studied mice with disruptions in Nr0b2 (called small heterodimer partner [SHP]-null mice), betaine-homocysteine S-methyltransferase (Bhmt), or both genes (BHMT-null/SHP-null mice), along with mice with wild-type copies of these genes (controls). Hyperhomocysteinemia was induced by feeding mice alcohol (National Institute on Alcohol Abuse and Alcoholism binge model) or chow diets along with water containing 0.18% DL-homocysteine. Some mice were placed on diets containing cholic acid (1%) or cholestyramine (2%) or high-fat diets (60%). Serum and livers were collected during a 24-hour light-dark cycle and analyzed by RNA-seq, metabolomic, and quantitative polymerase chain reaction, immunoblot, and chromatin immunoprecipitation assays. RESULTS: SHP-null mice had altered timing in expression of genes that regulate homocysteine metabolism compared with control mice. Oscillatory production of S-adenosylmethionine, betaine, choline, phosphocholine, glyceophosphocholine, cystathionine, cysteine, hydrogen sulfide, glutathione disulfide, and glutathione, differed between SHP-null mice and control mice. SHP inhibited transcriptional activation of Bhmt and cystathionine γ-lyase by FOXA1. Expression of Bhmt and cystathionine γ-lyase was decreased when mice were fed cholic acid but increased when they were placed on diets containing cholestyramine or high-fat content. Diets containing ethanol or homocysteine induced hyperhomocysteinemia and glucose intolerance in control, but not SHP-null, mice. In BHMT-null and BHMT-null/SHP-null mice fed a control liquid, lipid vacuoles were observed in livers. Ethanol feeding induced accumulation of macrovesicular lipid vacuoles to the greatest extent in BHMT-null and BHMT-null/SHP-null mice. CONCLUSIONS: Disruption of Shp in mice alters timing of expression of genes that regulate homocysteine metabolism and the liver responses to ethanol and homocysteine. SHP inhibits the transcriptional activation of Bhmt and cystathionine γ-lyase by FOXA1.


Assuntos
Ritmo Circadiano , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Homocisteína/metabolismo , Hiper-Homocisteinemia/metabolismo , Fígado/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Betaína-Homocisteína S-Metiltransferase/genética , Betaína-Homocisteína S-Metiltransferase/metabolismo , Glicemia/metabolismo , Resina de Colestiramina , Ácido Cólico , Cistationina gama-Liase/genética , Cistationina gama-Liase/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Etanol , Regulação Enzimológica da Expressão Gênica , Intolerância à Glucose/sangue , Intolerância à Glucose/metabolismo , Homeostase , Homocisteína/sangue , Hiper-Homocisteinemia/sangue , Hiper-Homocisteinemia/induzido quimicamente , Hiper-Homocisteinemia/genética , Hiper-Homocisteinemia/prevenção & controle , Camundongos Knockout , RNA Mensageiro/metabolismo , Receptores Citoplasmáticos e Nucleares/deficiência , Receptores Citoplasmáticos e Nucleares/genética , Fatores de Tempo , Ativação Transcricional
17.
Mol Hum Reprod ; 21(8): 662-71, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25939854

RESUMO

Circadian genes are expressed in virtually all cells and tissues, and circadian rhythms influence many bodily processes, including reproductive physiology. The expression of hMTNR1B is suppressed during pregnancy until late in term (much like the oxytocin receptor), at which time it is up-regulated to allow for the nocturnal melatonin/oxytocin synergy, which promotes strong nocturnal contractions. Little is currently known about the regulation of hMNTR1b, nor about its functional significance in the myometrium. We, therefore, aimed to elucidate some of the transcription factors that regulate hMNTR1b gene expression in the human myometrium and to determine if hMNTR1b is under circadian control. In this study, we used immortalized and primary myometrial cells that were assessed for circadian gene expression rhythms using real-time bioluminometry and quantitative PCR. Chromatin immunoprecipitation examined the binding of the clock gene product brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like protein 1 (BMAL1) to the promoter of the hMTNR1B gene. Overexpression studies tested the role of circadian locomotor output cycles kaput (CLOCK) and its partner BMAL1 in regulating hMTNR1B expression. We confirmed circadian clock gene expression in both immortalized human myometrial cells and primary myometrial cell cultures. We further showed that the hBMAL1 protein binds to an E-box motif in the proximal promoter of the hMTNR1B gene. Overexpression studies demonstrated that the BMAL1/CLOCK complex activates expression of hMTNR1B leading to a circadian rhythm in phase with the E-box driven clock gene hPER2 (Period 2). These results indicate, for the first time, the presence of a functional circadian clock in the human myometrium with the hMTNR1B gene as a clock controlled target. Further investigations could open new vistas for understanding the regulation of uterine contractions and the timing of human labor.


Assuntos
Ritmo Circadiano/fisiologia , Regulação da Expressão Gênica , Miócitos de Músculo Liso/metabolismo , Miométrio/metabolismo , Receptor MT2 de Melatonina/genética , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Relógios Circadianos/genética , Relógios Circadianos/fisiologia , Ritmo Circadiano/genética , Feminino , Humanos , Melatonina/metabolismo , Miométrio/citologia , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Receptor MT2 de Melatonina/metabolismo
18.
Biochem Soc Trans ; 43(6): 1127-32, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26614649

RESUMO

NAD, as well as its phosphorylated form, NADP, are best known as electron carriers and co-substrates of various redox reactions. As such they participate in approximately one quarter of all reactions listed in the reaction database KEGG. In metabolic pathway analysis, the total amount of NAD is usually assumed to be constant. That means that changes in the redox state might be considered, but concentration changes of the NAD moiety are usually neglected. However, a growing number of NAD-consuming reactions have been identified, showing that this assumption does not hold true in general. NAD-consuming reactions are common characteristics of NAD(+)-dependent signalling pathways and include mono- and poly-ADP-ribosylation of proteins, NAD(+)-dependent deacetylation by sirtuins and the formation of messenger molecules such as cyclic ADP-ribose (cADPR) and nicotinic acid (NA)-ADP (NAADP). NAD-consuming reactions are thus involved in major signalling and gene regulation pathways such as DNA-repair or regulation of enzymes central in metabolism. All known NAD(+)-dependent signalling processes include the release of nicotinamide (Nam). Thus cellular NAD pools need to be constantly replenished, mostly by recycling Nam to NAD(+). This process is, among others, regulated by the circadian clock, causing complex dynamic changes in NAD concentration. As disturbances in NAD homoeostasis are associated with a large number of diseases ranging from cancer to diabetes, it is important to better understand the dynamics of NAD metabolism to develop efficient pharmacological invention strategies to target this pathway.


Assuntos
Vias Biossintéticas , Relógios Circadianos/fisiologia , Retroalimentação Fisiológica/fisiologia , NAD/metabolismo , Acetilação , Animais , Humanos , Modelos Biológicos , Oxirredução , Sirtuína 1/metabolismo
19.
NPJ Biol Timing Sleep ; 1(1): 8, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39363957

RESUMO

Sleep timing and quantity disturbances persist in tauopathy patients. This has been studied in transgenic models of primary tau neuropathology using traditional electroencephalograms (EEGs) and more recently, the PiezoSleep Mouse Behavioral Tracking System. Here, we generated a primary tauopathy model using an intracerebroventricular injection of human mutant hSyn-P301L-tau, using adeno-associated virus of serotype 8 (AAV8). We discovered distinctions in sleep architecture with altered quantity and timing in AAV8-P301L tau expressing mice of both sexes using the noninvasive PiezoSleep System. The AAV8-P301L tau mice exhibit striking age-related increases in sleep duration specifically at the active phase onset, suggesting a critical and sensitive time-of-day for tauopathy related sleep disturbances to occur. Since our findings show sleep behavior changes at specific transitional periods of the day, tau neuropathology may impact normal diurnal variation in biological processes, which should be explored using the AAV8-P301L tauopathy model.

20.
Front Plant Sci ; 15: 1332192, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38699537

RESUMO

The desert riparian forests are susceptible to meteorological changes and contribute significantly to the net ecosystem productivity (NEP) variations of arid ecosystems. However, the responsive patterns of their NEP variations to the meteorological variabilities remain inadequately comprehended. To address this gap, we utilized seven years of eddy covariance flux measurements in a representative desert riparian forest to investigate the NEP variations and its response to changing meteorological factors across diverse temporal scales. The results revealed significant periodic variations in half-hourly NEP, with dominant cycles spanning from five hours to one year, with a principal oscillation period of one day. Key meteorological factors including global solar radiation (Rg), relative humidity (RH), air temperature (Ta), soil temperature (Ts), and vapor pressure deficit (VPD) exhibited synchronization with NEP on daily scales. This synchronization, coupled with the observed one-day periodic NEP variations, provides robust evidence supporting the existence of a circadian rhythm in the ecosystem carbon exchange of desert riparian forest regulated by meteorological conditions. Seasonal patterns were significant in the impact of Rg phase, Ta diurnal amplitude, and VPD diurnal amplitude on NEP diurnal amplitude and phase. The NEP diurnal amplitude significantly, directly, and positively affected daily NEP in both the dormant and growing seasons, whereas its phase yielded significant negative effects (P< 0.05). The averages, amplitudes, and phases of diurnal meteorological conditions controlled the daily NEP by regulating NEP diurnal amplitude and phase. These findings provide evidence that the variability in circadian rhythms, caused by the increase in diurnal Ta and VPD, significantly impact the daily NEP at an ecosystem scale. This study enriches our comprehension of the meteorological mechanisms governing diurnal and seasonal carbon uptake dynamics within desert riparian forests, providing fresh insights into the direct and indirect roles of climate change in shaping patterns of ecosystem carbon exchange.

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