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1.
Mol Cell Endocrinol ; 559: 111809, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36283500

RESUMO

An internal circadian clock regulates timing of systemic energy homeostasis. The central clock in the hypothalamic suprachiasmatic nucleus (SCN) directs local clocks in peripheral tissues such as liver, muscle, and adipose tissue to synchronize metabolism with food intake and rest/activity cycles. Aryl hydrocarbon receptor (AhR) interacts with the molecular circadian clockworks. Activation of AhR dampens rhythmic expression of core clock genes, which may lead to metabolic dysfunction. Given the importance of appropriately-timed adipose tissue function to regulation of energy homeostasis, this study focused on mechanisms by which AhR may influence clock-controlled adipose tissue activity. We hypothesized that AhR activation in adipose tissue would impair lipolysis by dampening adipose rhythms, leading to a decreased lipolysis rate during fasting, and subsequently, altered serum glucose concentrations. Levels of clock gene and lipolysis gene transcripts in mouse mesenchymal stem cells (BMSCs) differentiated into mature adipocytes were suppressed by the AhR agonist ß-napthoflavone (BNF), in an AhR dependent manner. BNF altered rhythms of core clock gene and lipolysis gene transcripts in C57bl6/J mice. BNF reduced serum free fatty acids, glycerol and liver glycogen. Chromatin immunoprecipitation indicated that BNF increased binding of AhR to E-Box elements in clock gene and lipolysis gene promoters. These data establish a link between AhR activation and impaired lipolysis, specifically by altering adipose tissue rhythmicity. In response to the decreased available energy from impaired lipolysis, the body increases glycogenolysis, thereby degrading more glycogen to provide necessary energy.


Assuntos
Relógios Circadianos , Receptores de Hidrocarboneto Arílico , Camundongos , Animais , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Ritmo Circadiano/fisiologia , Lipólise , Relógios Circadianos/genética , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Camundongos Endogâmicos C57BL
2.
Synapse ; 77(1): e22250, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36085433

RESUMO

The suprachiasmatic nucleus (SCN) is the most important circadian clock in mammals. The SCN synchronizes to environmental light via the retinohypothalamic tract (RHT), which is an axon cluster derived from melanopsin-expressing intrinsic photosensitive retinal ganglion cells. Investigations on the development of the nonimage-forming pathway and the RHT are scarce. Previous studies imply that light stimulation during postnatal development is not needed to make the RHT functional at adult stages. Here, we examined the effects of light deprivation (i.e., constant darkness (DD) rearing) during postnatal development on the expression in the ventral SCN of two crucial proteins for the synchronization of circadian rhythms to light: the presynaptic vesicular glutamate transporter type 2 (vGluT2) and the GluN2B subunit of the postsynaptic NMDA receptor. We found that animals submitted to DD conditions exhibited a transitory reduction in the expression of vGluT2 (at P12-19) and of GluN2B (at P7-9) that was compensated at older stages. These findings support the hypothesis that visual stimulation during early ages is not decisive for normal development of the RHT-SCN pathway.


Assuntos
Receptores de N-Metil-D-Aspartato , Núcleo Supraquiasmático , Proteína Vesicular 2 de Transporte de Glutamato , Animais , Ratos , Ritmo Circadiano/fisiologia , Mamíferos/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Células Ganglionares da Retina/metabolismo , Núcleo Supraquiasmático/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo
3.
Methods Mol Biol ; 2583: 149-156, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36418732

RESUMO

Diverse metabolic disorders can disrupt brain growth, and analyzing metabolism in animal models of microcephaly may reveal new mechanisms of pathogenesis. The metabolism of functioning cells in a living organism is constantly changing in response to a changing environment, circadian rhythms, consumed food, drugs, progressing sicknesses, aging, and many other factors. Metabolic profiling can give important insights into the working machinery of the cell. However, a frozen snapshot of the interconnected, complex network of reactions gives very limited information about this system. Flux analysis using stable isotope labels enables more robust metabolic studies that consider interrogate metabolite processing and changes in molecular concentrations over time.


Assuntos
Doenças Metabólicas , Microcefalia , Camundongos , Animais , Ritmo Circadiano/fisiologia , Isótopos , Doenças Metabólicas/metabolismo , Metabolômica
4.
Front Endocrinol (Lausanne) ; 13: 960351, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36387856

RESUMO

The suprachiasmatic nucleus (SCN) synchronizes the physiological rhythms to the external light-dark cycle and tunes the dynamics of circadian rhythms to photoperiod fluctuations. Changes in the neuronal network topologies are suggested to cause adaptation of the SCN in different photoperiods, resulting in the broader phase distribution of neuron activities in long photoperiods (LP) compared to short photoperiods (SP). Regulated by the SCN output, the level of glucocorticoids is elevated in short photoperiod, which is associated with peak disease incidence. The underlying coupling mechanisms of the SCN and the interplay between the SCN and the HPA axis have yet to be fully elucidated. In this work, we propose a mathematical model including a multiple-cellular SCN compartment and the HPA axis to investigate the properties of the circadian timing system under photoperiod changes. Our model predicts that the probability-dependent network is more energy-efficient than the distance-dependent network. Coupling the SCN network by intra-subpopulation and inter-subpopulation forces, we identified the negative correlation between robustness and plasticity of the oscillatory network. The HPA rhythms were predicted to be strongly entrained to the SCN rhythms with a pro-inflammatory high-amplitude glucocorticoid profile under SP. The fast temporal topology switch of the SCN network was predicted to enhance synchronization when the synchronization is not complete. These synchronization and circadian dynamics alterations might govern the seasonal variation of disease incidence and its symptom severity.


Assuntos
Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Núcleo Supraquiasmático/fisiologia , Fotoperíodo , Ritmo Circadiano/fisiologia
5.
Int J Mol Sci ; 23(21)2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36361737

RESUMO

Circadian rhythms significantly affect metabolism, and their disruption leads to cardiometabolic diseases and fibrosis. The clock repressor Rev-Erb is mainly expressed in the liver, heart, lung, adipose tissue, skeletal muscles, and brain, recognized as a master regulator of metabolism, mitochondrial biogenesis, inflammatory response, and fibrosis. Fibrosis is the response of the body to injuries and chronic inflammation with the accumulation of extracellular matrix in tissues. Activation of myofibroblasts is a key factor in the development of organ fibrosis, initiated by hormones, growth factors, inflammatory cytokines, and mechanical stress. This review summarizes the importance of Rev-Erb in ECM remodeling and tissue fibrosis. In the heart, Rev-Erb activation has been shown to alleviate hypertrophy and increase exercise capacity. In the lung, Rev-Erb agonist reduced pulmonary fibrosis by suppressing fibroblast differentiation. In the liver, Rev-Erb inhibited inflammation and fibrosis by diminishing NF-κB activity. In adipose tissue, Rev- Erb agonists reduced fat mass. In summary, the results of multiple studies in preclinical models demonstrate that Rev-Erb is an attractive target for positively influencing dysregulated metabolism, inflammation, and fibrosis, but more specific tools and studies would be needed to increase the information base for the therapeutic potential of these substances interfering with the molecular clock.


Assuntos
Relógios Circadianos , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares , Humanos , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Fatores de Transcrição , Ritmo Circadiano/fisiologia , Fibrose , Inflamação
6.
Int J Mol Sci ; 23(21)2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36361751

RESUMO

Disturbances in circadian rhythms are known to affect immune functions. However, the long-term impact of abnormal circadian rhythms on the immune-related functions of the spleen are poorly understood. Hence, we aimed to investigate the immune-related functions of spleen in Per1/Per2 double-knockout (DKO) and wild-type (WT) mice aged 4, 9, and 14 months. Compared to the WT mice, the DKO mice had smaller spleen white pulp (WP) and lymphocyte germinal area, as well as fewer immune cells with age-these differences were especially clear. The spleen lymphocyte mortality, malondialdehyde (MDA) levels, reactive oxygen species (ROS) levels, and ferritin-binding receptor (TFR1) levels were significantly higher in the 14-month-old DKO mice than in WT mice of the same age. Transcriptome analysis showed that most of the differentially expressed mRNAs were enriched in DNA damage repair-related pathways. In DKO mice, spleen cells showed up-regulation of pro-ferroptosis genes, such as Cd36,Atm, and Acsl4, and down-regulation of anti-ferroptosis genes, such as GPX4. We found that long-term abnormalities in the circadian rhythm can induce DNA damage and ferroptosis in mouse spleen.


Assuntos
Proteínas Circadianas Period , Baço , Camundongos , Animais , Proteínas Circadianas Period/genética , Baço/metabolismo , Ritmo Circadiano/fisiologia , Fatores de Transcrição/metabolismo , Linfócitos/metabolismo , Imunidade , Camundongos Knockout
7.
F1000Res ; 11: 1016, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36226040

RESUMO

Background: Impairment of the circadian clock has been associated with numerous diseases, including sleep disorders and metabolic disease. Although small-molecules that modulate clock function may form the basis of drug discovery of clock-related diseases, only a few compounds that selectively target core clock proteins have been identified. Three scaffolds were previously discovered as small-molecule activators of the clock protein Cryptochrome (CRY), and they have been providing powerful tools to understand and control the circadian clock system. Identifying new scaffolds will expand the possibilities of drug discovery. Methods: A methylbenzimidazole derivative TH401 identified from cell-based circadian screens was characterized. Effects of TH401 on circadian rhythms were evaluated in cellular assays. Functional assays and X-ray crystallography were used to elucidate the effects of the compound on CRY1 and CRY2 isoforms. Results: TH401 lengthened the period of circadian rhythms and stabilized both CRY1 and CRY2. The compound repressed Per2 reporter activity, which was reduced by Cry1 or Cry2 knockout and abolished by Cry1/Cry2 double knockout, indicating the dependence on CRY isoforms. Thermal shift assays showed slightly higher interaction of TH401 with CRY2 over CRY1. The crystal structure of CRY1 in complex with TH401 revealed a conformational change of the gatekeeper W399, which is involved in isoform-selectivity determination. Conclusions: The present study identified a new small-molecule TH401 that targets both CRY isoforms. This compound has expanded the chemical diversity of CRY activators, and will ultimately aid in the development of therapeutics against circadian clock-related disorders.


Assuntos
Relógios Circadianos , Criptocromos , Animais , Criptocromos/química , Criptocromos/metabolismo , Ritmo Circadiano/fisiologia , Relógios Circadianos/fisiologia , Mamíferos/metabolismo , Isoformas de Proteínas
8.
Front Public Health ; 10: 1036886, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36388285

RESUMO

Introduction: Using wrist-wearable sensors to ecological transient assessment may provide a more valid assessment of physical activity, sedentary time, sleep and circadian rhythm than self-reported questionnaires, but has not been used widely to study the association with mild cognitive impairment and their characteristics. Methods: 31 normal cognitive ability participants and 68 MCI participants were monitored with tri-axial accelerometer and nocturnal photo volumetric pulse wave signals for 14 days. Two machine learning algorithms: gradient boosting decision tree and eXtreme gradient boosting were constructed using data on daytime physical activity, sedentary time and nighttime physiological functions, including heart rate, heart rate variability, respiratory rate and oxygen saturation, combined with subjective scale features. The accuracy, precision, recall, F1 value, and AUC of the different models are compared, and the training and model effectiveness are validated by the subject-based leave-one-out method. Results: The low physical activity state was higher in the MCI group than in the cognitively normal group between 8:00 and 11:00 (P < 0.05), the daily rhythm trend of the high physical activity state was generally lower in the MCI group than in the cognitively normal group (P < 0.05). The peak rhythms in the sedentary state appeared at 12:00-15:00 and 20:00. The peak rhythms of rMSSD, HRV high frequency output power, and HRV low frequency output power in the 6h HRV parameters at night in the MCI group disappeared at 3:00 a.m., and the amplitude of fluctuations decreased; the amplitude of fluctuations of LHratio nocturnal rhythm increased and the phase was disturbed; the oxygen saturation was between 90 and 95% and less than 90% were increased in all time periods (P < 0.05). The F1 value of the two machine learning algorithms for MCI classification of multi-feature data combined with subjective scales were XGBoost (78.02) and GBDT (84.04). Conclusion: By collecting PSQI Scale data combined with circadian rhythm characteristics monitored by wrist-wearable sensors, we are able to construct XGBoost and GBDT machine learning models with good discrimination, thus providing an early warning solution for identifying family and community members with high risk of MCI.


Assuntos
Ritmo Circadiano , Disfunção Cognitiva , Humanos , Idoso , Ritmo Circadiano/fisiologia , Disfunção Cognitiva/psicologia , Aprendizado de Máquina , Comportamento Sedentário , Sono
9.
Proc Natl Acad Sci U S A ; 119(45): e2211142119, 2022 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-36322771

RESUMO

Ultradian rhythms in metabolism and physiology have been described previously in mammals. However, the underlying mechanisms for these rhythms are still elusive. Here, we report the discovery of temperature-sensitive ultradian rhythms in mammalian fibroblasts that are independent of both the cell cycle and the circadian clock. The period in each culture is stable over time but varies in different cultures (ranging from 3 to 24 h). We show that transient, single-cell metabolic pulses are synchronized into stable ultradian rhythms across contacting cells in culture by gap junction-mediated coupling. Coordinated rhythms are also apparent for other metabolic and physiological measures, including plasma membrane potential (Δψp), intracellular glutamine, α-ketoglutarate, intracellular adenosine triphosphate (ATP), cytosolic pH, and intracellular calcium. Moreover, these ultradian rhythms require extracellular glutamine, several different ion channels, and the suppression of mitochondrial ATP synthase by α-ketoglutarate, which provides a key feedback mechanism. We hypothesize that cellular coupling and metabolic feedback can be used by cells to balance energy demands for survival.


Assuntos
Relógios Circadianos , Ritmo Ultradiano , Animais , Ácidos Cetoglutáricos , Glutamina , Ciclo Celular , Ritmo Circadiano/fisiologia , Mamíferos
10.
Medicina (Kaunas) ; 58(11)2022 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-36422221

RESUMO

Background and Objectives: The purpose of this study was to investigate the effects of a 12-week concurrent training (CT) (i.e., aerobic plus resistance exercise) on short-term blood pressure variability (BPV) and BP values in hypertensive patients with non-dippper BP nocturnal pattern and underlying coronary artery disease. Material and Methods: The study included 72 consecutive patients who were divided into two groups according to the nocturnal BP pattern: dipping pattern (33 pts) and non-dipping (39 pts). Before starting CT and at 12 weeks, patients underwent the six minute walk test, ergometric test, assessment of 1-repetiton maximum (1 RM), and 24/h BP monitoring (24-h ABPM). Results: After CT, exercise capacity increased in both groups in a similar fashion. Twenty-four/h systolic BPV and daytime systolic BPV decreased significantly in the dipping group while they were unchanged in the non-dipping group (between groups changes: -1.0 ± 0.4 mmHg and -1.3 ± 0.9 mmHg; p = 0.02 and p = 0.006, respectively). Twenty-four/h systolic BP and daytime systolic BP decreased significantly in the dipping group while they were unchanged in the non-dipping group (between groups changes: -7.1 ± 2.6 mmHg and -7.8 ± 2.4 mmHg; p = 0.004 and p = 0.002, respectively). Nighttime systolic BP and BPV was unchanged in both groups. Twenty-four/h diastolic BP presented small but not significant changes in both groups. Conclusions: The effects of CT on BPV and BP were blunted in hypertensive subjects with a non-dipping BP pattern.


Assuntos
Hipertensão , Treinamento de Força , Humanos , Gravidez , Feminino , Pressão Sanguínea/fisiologia , Ritmo Circadiano/fisiologia , Hipertensão/complicações , Hipertensão/terapia , Monitorização Ambulatorial da Pressão Arterial
11.
PLoS Genet ; 18(11): e1010487, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36367867

RESUMO

Proper timing of rhythmic locomotor behavior is the consequence of integrating environmental conditions and internal time dictated by the circadian clock. Rhythmic environmental input like daily light and temperature changes (called Zeitgeber) reset the molecular clock and entrain it to the environmental time zone the organism lives in. Furthermore, depending on the absolute temperature or light intensity, flies exhibit their main locomotor activity at different times of day, i.e., environmental input not only entrains the circadian clock but also determines the phase of a certain behavior. To understand how the brain clock can distinguish between (or integrate) an entraining Zeitgeber and environmental effects on activity phase, we attempted to entrain the clock with a Zeitgeber different from the environmental input used for phasing the behavior. 150 clock neurons in the Drosophila melanogaster brain control different aspects of the daily activity rhythms and are organized in various clusters. During regular 12 h light: 12 h dark cycles at constant mild temperature (LD 25°C, LD being the Zeitgeber), so called morning oscillator (MO) neurons control the increase of locomotor activity just before lights-on, while evening oscillator (EO) neurons regulate the activity increase at the end of the day, a few hours before lights-off. Here, using 12 h: 12 h 25°C:16°C temperature cycles as Zeitgeber, we attempted to look at the impact of light on phasing locomotor behavior. While in constant light and 25°C:16°C temperature cycles (LLTC), flies show an unimodal locomotor activity peak in the evening, during the same temperature cycle, but in the absence of light (DDTC), the phase of the activity peak is shifted to the morning. Here, we show that the EO is necessary for synchronized behavior in LLTC but not for entraining the molecular clock of the other clock neuronal groups, while the MO controls synchronized morning activity in DDTC. Interestingly, our data suggest that the influence of the EO on the synchronization increases depending on the length of the photoperiod (constant light vs 12 h of light). Hence, our results show that effects of different environmental cues on clock entrainment and activity phase can be separated, allowing to decipher their integration by the circadian clock.


Assuntos
Relógios Circadianos , Drosophila melanogaster , Animais , Temperatura , Drosophila melanogaster/genética , Ritmo Circadiano/fisiologia , Fotoperíodo , Relógios Circadianos/genética
12.
Nat Commun ; 13(1): 6068, 2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-36241650

RESUMO

Diurnal (i.e., 24-hour) oscillations of the gut microbiome have been described in various species including mice and humans. However, the driving force behind these rhythms remains less clear. In this study, we differentiate between endogenous and exogenous time cues driving microbial rhythms. Our results demonstrate that fecal microbial oscillations are maintained in mice kept in the absence of light, supporting a role of the host's circadian system rather than representing a diurnal response to environmental changes. Intestinal epithelial cell-specific ablation of the core clock gene Bmal1 disrupts rhythmicity of microbiota. Targeted metabolomics functionally link intestinal clock-controlled bacteria to microbial-derived products, in particular branched-chain fatty acids and secondary bile acids. Microbiota transfer from intestinal clock-deficient mice into germ-free mice altered intestinal gene expression, enhanced lymphoid organ weights and suppressed immune cell recruitment. These results highlight the importance of functional intestinal clocks for microbiota composition and function, which is required to balance the host's gastrointestinal homeostasis.


Assuntos
Relógios Circadianos , Microbiota , Fatores de Transcrição ARNTL/genética , Animais , Ácidos e Sais Biliares , Relógios Circadianos/genética , Ritmo Circadiano/fisiologia , Ácidos Graxos , Homeostase , Humanos , Camundongos
13.
Clin Nutr ESPEN ; 51: 50-71, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36184249

RESUMO

BACKGROUND AND AIMS: The rising prevalence of obesity is a major international concern and is associated with a substantial burden of disease. Disrupted circadian behaviours, including late and extended eating patterns, are identified as risk factors for obesity. The circadian rhythm synchronises metabolic functions between and within tissues, optimising physiology to integrate with environmental and behavioural cycles. Cellular circadian rhythms also separate poorly compatible processes and enable adaptive integration of energy metabolism with autophagy. The timing of nutritional input is a key and easily controllable variable that influences circadian function. Misalignment of nutritional input with the centrally generated circadian rhythm may dampen and disrupt circadian metabolic function. This review seeks to provide a mechanistic overview of nutritional circadian entrainment and its downstream metabolic effects. The aims are: to characterise the key cellular and physiological mechanisms involved in the nutritional entrainment of circadian rhythms; and to explore the perturbation of these pathways by misaligned nutritional inputs, with relevance to obesity-associated dysmetabolism. METHODS: A systematic two-tranche search strategy was employed. Searches were conducted within PubMed between March and December 2020. Included studies were formally evaluated for quality. Evidence was extracted and coded into key themes. RESULTS: 142 records were screened and 50 accepted. The evidence analysed was moderate-to-high quality and enabled the detailed characterisation of cellular pathways involved in nutritional circadian entrainment. Results indicated that diverse nutritional input pathways converge upon key nutrient/redox sensors and nutritionally sensitive core clock genes, which integrate with circadian metabolic pathways, allowing bidirectional communication between circadian clock function and metabolism. Versus alignment, nutritional misalignment was causally associated with dampening and alteration of core clock rhythms, between-tissue rhythmic decoupling, dysmetabolism, and obesity. Signalling through key circadian nodes, such as NAD+/SIRT, was indicated to have importance in these metabolic changes. Misaligned nutritional inputs were associated with altered core circadian temporal dynamics of metabolism and autophagy, and different time division between insulin-sensitive and insulin-resistant metabolic states. Time-restricted feeding protocols aligned with the natural circadian rhythm (light-dark cycle) relatively strengthened circadian oscillatory patterns and protected against diet-induced obesity. CONCLUSIONS: This review suggests potential value in further investigating circadian-normalising nutritional interventions for obesity, such as circadian-aligned time-restricted feeding.


Assuntos
Ritmo Circadiano , Sirtuínas , Ritmo Circadiano/fisiologia , Humanos , Insulina , NAD , Obesidade
14.
PLoS One ; 17(10): e0276372, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36256675

RESUMO

In mammals, the center of the circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Many studies have suggested that there are multiple regions generating different circadian periods within the SCN, but the exact localization of the regions has not been elucidated. In this study, using a transgenic rat carrying a destabilized luciferase reporter gene driven by a regulatory element of Per2 gene (Per2::dLuc), we investigated the regional variation of period lengths in horizontal slices of the SCN. We revealed a distinct caudal medial region (short period region, SPR) and a rostro-lateral region (long period region, LPR) that generate circadian rhythms with periods shorter than and longer than 24 hours, respectively. We also found that the core region of the SCN marked by dense VIP (vasoactive intestinal peptide) mRNA-expressing neurons covered a part of LPR, and that the shell region of the SCN contains both SPR and the rest of the LPR. Furthermore, we observed how synchronization is achieved between regions generating distinct circadian periods in the SCN. We found that the longer circadian rhythm of the rostral region appears to entrain the circadian rhythm in the caudal region. Our findings clarify the localization of regionality of circadian periods and the mechanism by which the integrated circadian rhythm is formed in the SCN.


Assuntos
Proteínas Circadianas Period , Peptídeo Intestinal Vasoativo , Ratos , Animais , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Peptídeo Intestinal Vasoativo/genética , Peptídeo Intestinal Vasoativo/metabolismo , Núcleo Supraquiasmático/metabolismo , Ritmo Circadiano/fisiologia , Luciferases/metabolismo , Ratos Transgênicos , RNA Mensageiro , Mamíferos/genética
15.
BMC Plant Biol ; 22(1): 472, 2022 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-36195835

RESUMO

BACKGROUND: To adapt the periodic fluctuation of environmental factors, plants are subtle to monitor the natural variation for the growth and development. The daily activities and physiological functions in coordination with the natural variation are regulated by circadian clock genes. The circadian emission of floral scents is one of the rhythmic physiological activities controlled by circadian clock genes. Here, we study the molecular mechanism of circadian emission pattern of ocimene and linalool compounds in Oncidium Sharry Baby (Onc. SB) orchid. RESULTS: GC-Mass analysis revealed that Onc. SB periodically emitted ocimene and linalool during 6 to 14 o'clock daily. Terpene synthase, one of the key gene in the terpenoid biosynthetic pathway is expressed in coordination with scent emission. The promoter structure of terpene synthase revealed a circadian binding sequence (CBS), 5'-AGATTTTT-3' for CIRCADIAN CLOCK ASSOCIATED1 (CCA1) transcription factor. EMSA data confirms the binding affinity of CCA1. Transactivation assay further verified that TPS expression is regulated by CCA1. It suggests that the emission of floral scents is controlled by CCA1. CONCLUSIONS: The work validates that the mechanism of circadian emission of floral scents in Onc. Sharry Baby is controlled by the oscillator gene, CCA1(CIRCADIAN CLOCK ASSOCIATED 1) under light condition. CCA1 transcription factor up-regulates terpene synthase (TPS) by binding on CBS motif, 5'-AGATTTTT-3' of promoter region to affect the circadian emission of floral scents in Onc. SB.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Relógios Circadianos , Orchidaceae , Monoterpenos Acíclicos , Alquil e Aril Transferases , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Relógios Circadianos/genética , Ritmo Circadiano/fisiologia , Regulação da Expressão Gênica de Plantas , Odorantes , Orchidaceae/genética , Orchidaceae/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
16.
Curr Psychiatry Rep ; 24(11): 623-634, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36227449

RESUMO

PURPOSE OF REVIEW: We present a review of research on the role of melatonin in the management of sleep and circadian disorders, stressing current overall view of the knowledge across psychiatric disorders. RECENT FINDINGS: Dysregulation of sleep and circadian rhythms has been established in several psychiatric and neurocognitive disorders for long. Recent research confirms this finding consistently across disorders. The secretion of melatonin in schizophrenia and neurocognitive disorders is reduced due to a smaller volume and enlarged calcification of the pineal gland. On the other hand, melatonin dysregulation in bipolar disorder may be more dynamic and caused by light-sensitive melatonin suppression and delayed melatonin secretion. In both cases, exogenous melatonin seems indicated to correct the dysfunction. However, a very limited number of well-designed trials with melatonin to correct sleep and circadian rhythms exist in psychiatric disorders, and the evidence for efficacy is robust only in autism, attention deficit hyperactivity disorder (ADHD), and neurocognitive disorders. This topic has mainly not been of interest for recent work and well-designed trials with objective circadian parameters are few. Overall, recent studies in psychiatric disorders reported that melatonin can be effective in improving sleep parameters such as sleep onset latency, sleep efficiency, and sleep quality. Recent meta-analysis suggests that optimal dosage and dosing time might be important to maximize the efficacy of melatonin. The knowledge base is sufficient to propose well-designed, larger trials with circadian parameters as inclusion and outcome criteria. Based on the partly fragmentary information, we propose testing efficacy in disorders with neurocognitive etiopathology with later and higher dosing, and affective and anxiety disorders with lower and earlier dosing of melatonin. Melatonin is promising for the correction of sleep and circadian abnormalities in psychiatric disorders. However, research results on its effect are still few and need to be accumulated. For effective use of melatonin, it is necessary to consider the appropriate dosage and administration time, depending on the individual abnormality of sleep and circadian rhythms.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtorno Bipolar , Melatonina , Transtornos do Sono-Vigília , Humanos , Melatonina/uso terapêutico , Sono/fisiologia , Ritmo Circadiano/fisiologia , Transtornos do Sono-Vigília/tratamento farmacológico
17.
Proc Natl Acad Sci U S A ; 119(44): e2209933119, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36279450

RESUMO

Circadian clocks are synchronized by external timing cues to align with one another and the environment. Various signaling pathways have been shown to independently reset the phase of the clock. However, in the body, circadian clocks are exposed to a multitude of potential timing cues with complex temporal dynamics, raising the question of how clocks integrate information in response to multiple signals. To investigate different modes of signal integration by the circadian clock, we used Circa-SCOPE, a method we recently developed for high-throughput phase resetting analysis. We found that simultaneous exposure to different combinations of known pharmacological resetting agents elicits a diverse range of responses. Often, the response was nonadditive and could not be readily predicted by the response to the individual signals. For instance, we observed that dexamethasone is dominant over other tested inputs. In the case of signals administered sequentially, the background levels of a signal attenuated subsequent resetting by the same signal, but not by signals acting through a different pathway. This led us to examine whether the circadian clock is sensitive to relative rather than absolute levels of the signal. Importantly, our analysis revealed the involvement of a signal-specific fold-change detection mechanism in the clock response. This mechanism likely stems from properties of the signaling pathway that are upstream to the clock. Overall, our findings elucidate modes of input integration by the circadian clock, with potential relevance to clock resetting under both physiological and pathological conditions.


Assuntos
Relógios Circadianos , Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Transdução de Sinais , Sinais (Psicologia) , Dexametasona/farmacologia
18.
Front Endocrinol (Lausanne) ; 13: 1001316, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36277693

RESUMO

A circadian rhythm is an internalized timing system that synchronizes the cellular, behavioral, and physiological processes of organisms to the Earth's rotation. Because all physiological activities occur at a specific time, circadian rhythm disturbances can lead to various pathological disorders and diseases. Growing evidence has shown that the circadian clock is tightly connected to male fertility, and circadian perturbations contribute to infertility. The night shiftwork, insufficient sleep, and poor sleep quality are common causes of circadian disturbances, and many studies have reported that they impair sperm quality and increase the risk of male infertility. However, research on the impacts of light, body temperature, and circadian/circannual rhythms is relatively lacking, although some correlations have been demonstrated. Moreover, as the index of sperm quality was diverse and study designs were non-uniform, the conclusions were temporarily inconsistent and underlying mechanisms remain unclear. A better understanding of whether and how circadian disturbances regulate male fertility will be meaningful, as more scientific work schedules and rational lifestyles might help improve infertility.


Assuntos
Relógios Circadianos , Infertilidade , Masculino , Humanos , Ritmo Circadiano/fisiologia , Sêmen , Fertilidade
19.
Int J Mol Sci ; 23(20)2022 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-36293015

RESUMO

Omega-3 fatty acids (ω-3 FAs) are well-known for their actions on immune/inflammatory and neurological pathways, functions that are also under circadian clock regulation. The daily photoperiod represents the primary circadian synchronizer ('zeitgeber'), although diverse studies have pointed towards an influence of dietary FAs on the biological clock. A comprehensive literature review was conducted following predefined selection criteria with the aim of updating the evidence on the molecular mechanisms behind circadian rhythm regulation by ω-3 FAs. We collected preclinical and clinical studies, systematic reviews, and metanalyses focused on the effect of ω-3 FAs on circadian rhythms. Twenty animal (conducted on rodents and piglets) and human trials and one observational study providing evidence on the regulation of neurological, inflammatory/immune, metabolic, reproductive, cardiovascular, and biochemical processes by ω-3 FAs via clock genes were discussed. The evidence suggests that ω-3 FAs may serve as non-photic zeitgebers and prove therapeutically beneficial for circadian disruption-related pathologies. Future work should focus on the role of clock genes as a target for the therapeutic use of ω-3 FAs in inflammatory and neurological disorders, as well as on the bidirectional association between the molecular clock and ω-3 FAs.


Assuntos
Relógios Circadianos , Ácidos Graxos Ômega-3 , Animais , Humanos , Suínos , Ritmo Circadiano/fisiologia , Fotoperíodo , Ácidos Graxos Ômega-3/farmacologia , Estudos Observacionais como Assunto
20.
Int J Mol Sci ; 23(20)2022 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-36293048

RESUMO

Sleep is a fundamental, evolutionarily conserved, plastic behavior that is regulated by circadian and homeostatic mechanisms as well as genetic factors and environmental factors, such as light, humidity, and temperature. Among environmental cues, temperature plays an important role in the regulation of sleep. This review presents an overview of thermoreception in animals and the neural circuits that link this process to sleep. Understanding the influence of temperature on sleep can provide insight into basic physiologic processes that are required for survival and guide strategies to manage sleep disorders.


Assuntos
Ritmo Circadiano , Sono , Animais , Ritmo Circadiano/fisiologia , Temperatura , Sono/fisiologia , Homeostase/fisiologia , Plásticos
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