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1.
Cell Prolif ; 53(1): e12727, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31747713

RESUMO

OBJECTIVE: Chondrogenesis and endochondral ossification in mandibular condyle play crucial roles in maxillofacial morphogenesis and function. Circadian regulator brain and muscle arnt-like 1 (BMAL1) is proven to be essential for embryonic and postnatal development. The goal of this study was to define the functions of BMAL1 in the embryonic and postnatal growth of mandibular condylar cartilages (MCC). MATERIALS AND METHODS: Micro-CT, TUNEL staining and EdU assay were performed using BMAL1-deficient mice model, and in vitro experiments were performed using rat chondrocytes isolated from MCC. RNA sequencing in mandibular condyle tissues from Bmal1-/- mice and the age-matched wild-type mice was used for transcriptional profiling at different postnatal stages. RESULTS: The expression levels of BMAL1 decrease gradually in MCC. BMAL1 is proved to regulate sequential chondrocyte differentiation, and its deficiency can result in the impairment of endochondral ossification of MCC. RNA sequencing reveals hedgehog signalling pathway is the potential target of BMAL1. BMAL1 regulates hedgehog signalling and affects its downstream cascades through directly binding to the promoters of Ptch1 and Ihh, modulating targets of hedgehog signalling which is indispensable for endochondral ossification. Importantly, the short stature phenotypes caused by BMAL1 deficiency can be rescued by hedgehog signalling activator. CONCLUSIONS: Collectively, these results indicate that BMAL1 plays critical roles on chondrogenesis and endochondral ossification of MCC, giving a new insight on potential therapeutic strategies for facial dysmorphism.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Cartilagem/embriologia , Diferenciação Celular/fisiologia , Condrócitos/metabolismo , Ritmo Circadiano/fisiologia , Côndilo Mandibular/embriologia , Transdução de Sinais/fisiologia , Animais , Cartilagem/citologia , Condrócitos/citologia , Condrogênese/fisiologia , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Côndilo Mandibular/citologia , Camundongos , Camundongos Knockout , Receptor Patched-1/genética , Receptor Patched-1/metabolismo
2.
Nature ; 574(7777): 254-258, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31534216

RESUMO

Group 3 innate lymphoid cells (ILC3s) are major regulators of inflammation, infection, microbiota composition and metabolism1. ILC3s and neuronal cells have been shown to interact at discrete mucosal locations to steer mucosal defence2,3. Nevertheless, it is unclear whether neuroimmune circuits operate at an organismal level, integrating extrinsic environmental signals to orchestrate ILC3 responses. Here we show that light-entrained and brain-tuned circadian circuits regulate enteric ILC3s, intestinal homeostasis, gut defence and host lipid metabolism in mice. We found that enteric ILC3s display circadian expression of clock genes and ILC3-related transcription factors. ILC3-autonomous ablation of the circadian regulator Arntl led to disrupted gut ILC3 homeostasis, impaired epithelial reactivity, a deregulated microbiome, increased susceptibility to bowel infection and disrupted lipid metabolism. Loss of ILC3-intrinsic Arntl shaped the gut 'postcode receptors' of ILC3s. Strikingly, light-dark cycles, feeding rhythms and microbial cues differentially regulated ILC3 clocks, with light signals being the major entraining cues of ILC3s. Accordingly, surgically or genetically induced deregulation of brain rhythmicity led to disrupted circadian ILC3 oscillations, a deregulated microbiome and altered lipid metabolism. Our work reveals a circadian circuitry that translates environmental light cues into enteric ILC3s, shaping intestinal health, metabolism and organismal homeostasis.


Assuntos
Encéfalo/efeitos da radiação , Ritmo Circadiano/efeitos da radiação , Homeostase/efeitos da radiação , Intestinos/imunologia , Intestinos/efeitos da radiação , Luz , Linfócitos/imunologia , Linfócitos/efeitos da radiação , Fatores de Transcrição ARNTL/deficiência , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Relógios Biológicos/genética , Relógios Biológicos/efeitos da radiação , Encéfalo/fisiologia , Ritmo Circadiano/genética , Ritmo Circadiano/imunologia , Ritmo Circadiano/fisiologia , Sinais (Psicologia) , Comportamento Alimentar/efeitos da radiação , Feminino , Microbioma Gastrointestinal/efeitos da radiação , Imunidade Inata/efeitos da radiação , Intestinos/citologia , Metabolismo dos Lipídeos , Linfócitos/metabolismo , Masculino , Camundongos , Fotoperíodo
3.
Nat Commun ; 10(1): 4107, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511530

RESUMO

Influenza is a leading cause of respiratory mortality and morbidity. While inflammation is essential for fighting infection, a balance of anti-viral defense and host tolerance is necessary for recovery. Circadian rhythms have been shown to modulate inflammation. However, the importance of diurnal variability in the timing of influenza infection is not well understood. Here we demonstrate that endogenous rhythms affect survival in influenza infection. Circadian control of influenza infection is mediated by enhanced inflammation as proven by increased cellularity in bronchoalveolar lavage (BAL), pulmonary transcriptomic profile and histology and is not attributable to viral burden. Better survival is associated with a time dependent preponderance of NK and NKT cells and lower proportion of inflammatory monocytes in the lung. Further, using a series of genetic mouse mutants, we elucidate cellular mechanisms underlying circadian gating of influenza infection.


Assuntos
Ritmo Circadiano/fisiologia , Infecções por Orthomyxoviridae/complicações , Infecções por Orthomyxoviridae/fisiopatologia , Pneumonia/complicações , Pneumonia/fisiopatologia , Fatores de Transcrição ARNTL/deficiência , Fatores de Transcrição ARNTL/metabolismo , Animais , Antígenos Ly , Feminino , Vírus da Influenza A/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/metabolismo , Células Mieloides/metabolismo , Células T Matadoras Naturais/imunologia , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/virologia , Fenótipo , Pneumonia/virologia , Fatores de Tempo , Transcriptoma/genética , Replicação Viral
4.
Nutrients ; 11(9)2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31546853

RESUMO

BACKGROUND: Dietary factors have significant effects on the brain, modulating mood, anxiety, motivation and cognition. To date, no attention has been paid to the consequences that the combination of ethanol (EtOH) and a high-fat diet (HFD) have on learning and mood disorders during adolescence. The aim of the present work was to evaluate the biochemical and behavioral consequences of ethanol binge drinking and an HFD consumption in adolescent mice. METHODS: Animals received either a standard diet or an HFD (ad libitum vs. binge pattern) in combination with ethanol binge drinking and were evaluated in anxiety and memory. The metabolic profile and gene expression of leptin receptors and clock genes were also evaluated. RESULTS: Excessive white adipose tissue and an increase in plasma insulin and leptin levels were mainly observed in ad libitum HFD + EtOH mice. An upregulation of the Lepr gene expression in the prefrontal cortex and the hippocampus was also observed in ad libitum HFD groups. EtOH-induced impairment on spatial memory retrieval was absent in mice exposed to an HFD, although the aversive memory deficits persisted. Mice bingeing on an HFD only showed an anxiolytic profile, without other alterations. We also observed a mismatch between Clock and Bmal1 expression in ad libitum HFD animals, which were mostly independent of EtOH bingeing. CONCLUSIONS: Our results confirm the bidirectional influence that occurs between the composition and intake pattern of a HFD and ethanol consumption during adolescence, even when the metabolic, behavioral and chronobiological effects of this interaction are dissociated.


Assuntos
Bulimia , Dieta Hiperlipídica , Etanol/toxicidade , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Adiposidade , Animais , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Hipocampo/metabolismo , Aprendizagem/fisiologia , Leptina/sangue , Masculino , Camundongos , Transtornos do Humor/etiologia , Transtornos do Humor/metabolismo , Córtex Pré-Frontal/metabolismo , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Ganho de Peso
5.
Endocrinology ; 160(10): 2215-2229, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31398249

RESUMO

The circadian glucocorticoid (GC) rhythm is dependent on a molecular clock in the suprachiasmatic nucleus (SCN) and an adrenal clock that is synchronized by the SCN. To determine whether the adrenal clock modulates GC responses to stress, experiments used female and male Cyp11A1Cre/+::Bmal1Fl/Fl knockout [side-chain cleavage (SCC)-KO] mice, in which the core clock gene, Bmal1, is deleted in all steroidogenic tissues, including the adrenal cortex. Following restraint stress, female and male SCC-KO mice demonstrate augmented plasma corticosterone but not plasma ACTH. In contrast, following submaximal scruff stress, plasma corticosterone was elevated only in female SCC-KO mice. Adrenal sensitivity to ACTH was measured in vitro using acutely dispersed adrenocortical cells. Maximal corticosterone responses to ACTH were elevated in cells from female KO mice without affecting the EC50 response. Neither the maximum nor the EC50 response to ACTH was affected in male cells, indicating that female SCC-KO mice show a stronger adrenal phenotype. Parallel experiments were conducted using female Cyp11B2 (Aldosterone Synthase)Cre/+::Bmal1Fl/Fl mice and adrenal cortex-specific Bmal1-null (Ad-KO) mice. Plasma corticosterone was increased in Ad-KO mice following restraint or scruff stress, and in vitro responses to ACTH were elevated in adrenal cells from Ad-KO mice, replicating data from female SCC-KO mice. Gene analysis showed increased expression of adrenal genes in female SCC-KO mice involved in cell cycle control, cell adhesion-extracellular matrix interaction, and ligand receptor activity that could promote steroid production. These observations underscore a role for adrenal Bmal1 as an attenuator of steroid secretion that is most prominent in female mice.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Córtex Suprarrenal/metabolismo , Corticosterona/sangue , Glucocorticoides/metabolismo , Fatores de Transcrição ARNTL/genética , Hormônio Adrenocorticotrópico , Animais , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo , Feminino , Genótipo , Masculino , Camundongos , Camundongos Knockout , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Fatores Sexuais , Estresse Fisiológico
6.
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
7.
Molecules ; 24(16)2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31408938

RESUMO

Resveratrol (RES) possesses anti-inflammatory and anti-oxidant activities, and it can prevent liver lipid metabolism disorders in obese and diabetic individuals. This study elucidated the mechanisms of brain and muscle Arnt-like protein-1 (Bmal1) in the protective effects of RES against liver lipid metabolism disorders. The results indicated that RES ameliorated free fatty acid (FFA)-induced (oleic acid (OA): palmitic acid (PA) = 2:1) glycolipid metabolic disorders in hepatocytes. Simultaneously, RES partially reverted the relatively shallow daily oscillations of FFA-induced circadian clock gene transcription and protein expression in HepG2 cells. RES also attenuated FFA-triggered reactive oxygen species (ROS) secretion and restored mitochondrial membrane potential consumption, as well as the restoration of mitochondrial respiratory complex expression. This study provides compelling evidence that RES controls intracellular lipid metabolic imbalance in a Bmal1-dependent manner. Overall, RES may serve as a promising natural nutraceutical for the regulation of lipid metabolic disorders relevant to the circadian clock.


Assuntos
Fatores de Transcrição ARNTL/genética , Relógios Circadianos/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Resveratrol/farmacologia , Fatores de Transcrição ARNTL/antagonistas & inibidores , Fatores de Transcrição ARNTL/metabolismo , Animais , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Relógios Circadianos/genética , Criptocromos/genética , Criptocromos/metabolismo , Regulação da Expressão Gênica , Células Hep G2 , Hepatócitos/citologia , Hepatócitos/metabolismo , Homeostase/genética , Humanos , Metabolismo dos Lipídeos/genética , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ácido Oleico/antagonistas & inibidores , Ácido Oleico/farmacologia , Ácido Palmítico/antagonistas & inibidores , Ácido Palmítico/farmacologia , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Cultura Primária de Células , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
8.
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
9.
Environ Toxicol ; 34(11): 1255-1262, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31298479

RESUMO

Progesterone (P4) is a biologically active steroid hormone that is involved in the regulation of oocyte growth and maturation, as well as development of the endometrium and implantation in the uterus of humans. It can also stimulate oocyte maturation in female fish, as well as spermatogenesis and sperm motility in male fish. Thus, P4 has been extensively used in human and animal husbandry as a typical progestin. However, P4 remaining in the water environment will pose a potential hazard to aquatic organisms. For example, it can interfere with sex differentiation and reproduction in aquatic vertebrates such as fish. Therefore, we investigated the effects of prolonged progesterone exposure on the expression of genes related to circadian rhythm signaling and the hypothalamic-pituitary-gonadal (HPG) axes in Yellow River Carp, which may have a potential impact on their sex differentiation. Our results suggested that P4 exposure altered the expression of genes related to circadian rhythm signaling, which can lead to disorders in the endocrine system and regulate the HPG axes-related activities. Furthermore, the expression of genes related to the HPG axes was also altered, which might affect gonadal development and the reproductive systems of Yellow River Carp. In addition, these changes may provide a plausible mechanism for the observed shifts in their sex ratio toward females.


Assuntos
Ritmo Circadiano/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Progesterona/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Carpas/crescimento & desenvolvimento , Carpas/metabolismo , Feminino , Gônadas/efeitos dos fármacos , Gônadas/patologia , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Diferenciação Sexual/efeitos dos fármacos , Razão de Masculinidade , Transcrição Genética/efeitos dos fármacos
10.
Genome Res ; 29(8): 1262-1276, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31249065

RESUMO

Organisms use endogenous clocks to adapt to the rhythmicity of the environment and to synchronize social activities. Although the circadian cycle is implicated in aging, it is unknown whether natural variation in its function contributes to differences in lifespan between populations and whether the circadian clock of specific tissues is key for longevity. We have sequenced the genomes of Drosophila melanogaster strains with exceptional longevity that were obtained via multiple rounds of selection from a parental strain. Comparison of genomic, transcriptomic, and proteomic data revealed that changes in gene expression due to intergenic polymorphisms are associated with longevity and preservation of skeletal muscle function with aging in these strains. Analysis of transcription factors differentially modulated in long-lived versus parental strains indicates a possible role of circadian clock core components. Specifically, there is higher period and timeless and lower cycle expression in the muscle of strains with delayed aging compared to the parental strain. These changes in the levels of circadian clock transcription factors lead to changes in the muscle circadian transcriptome, which includes genes involved in metabolism, proteolysis, and xenobiotic detoxification. Moreover, a skeletal muscle-specific increase in timeless expression extends lifespan and recapitulates some of the transcriptional and circadian changes that differentiate the long-lived from the parental strains. Altogether, these findings indicate that the muscle circadian clock is important for longevity and that circadian gene variants contribute to the evolutionary divergence in longevity across populations.


Assuntos
Fatores de Transcrição ARNTL/genética , Relógios Circadianos/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Genoma de Inseto , Longevidade/genética , Músculo Esquelético/metabolismo , Proteínas Circadianas Period/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Evolução Biológica , Ritmo Circadiano/genética , DNA Intergênico/genética , DNA Intergênico/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Genética Populacional , Genômica , Músculo Esquelético/crescimento & desenvolvimento , Proteínas Circadianas Period/metabolismo , Polimorfismo Genético , Transcriptoma , Sequenciamento Completo do Genoma
11.
Yale J Biol Med ; 92(2): 251-258, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31249486

RESUMO

Bmal1 is the only single circadian clock gene that is essential for rhythmic gene expression in the mammalian circadian timing system. Genetic approaches targeting Bmal1 expression have been used to further assess its role in the circadian clock and to test for behavioral effects of clock disruption. In particular, disruptions in circadian clock function have been implicated in human mood disorders, and clock gene manipulation in mice may provide valuable models for studying depression-like behavior. In this review, we explore various approaches to manipulating Bmal1 in mouse models and review their effects on the brain's master circadian pacemaker, on circadian rhythmicity in other brain regions, and on circadian and mood-related behavior.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Encéfalo/fisiologia , Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Fatores de Transcrição ARNTL/genética , Animais , Encéfalo/metabolismo , Regulação da Expressão Gênica , Humanos , Camundongos Knockout , Modelos Biológicos , Fatores de Tempo
12.
Yakugaku Zasshi ; 139(6): 861-866, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31155526

RESUMO

Brown adipose tissue is a critical regulator of metabolic health, and contributes to thermogenesis by uncoupling oxidative phosphorylation through the action of mitochondrial uncoupling protein 1 (Ucp1). Recent studies have shown that cold exposure and the stimulation of ß3-adrenergic receptors induce the development of brown cell-like "beige" adipocytes in white adipose tissue. Brown and/or beige adipocyte-mediated thermogenesis suppresses high-fat diet-associated obesity. Therefore, the development of brown/beige adipocytes may prevent obesity and metabolic diseases. In the present study, we elucidated whether naturally occurring compounds contribute to regulating the cellular differentiation of brown/beige adipocytes. We screened for the up-regulated expression of Ucp1 during beige adipogenesis using extracts of crude herbal drugs frequently used in Kampo prescriptions (therapeutic drugs in Japanese traditional medicine). This screening revealed that the extract prepared from Citri Unshiu Pericarpium [the peel of Citrus unshiu (Swingle) Marcov.] increased the expression of Ucp1 in beige adipocytes. We also focused on the function of clock genes in regulating brown/beige adipogenesis. Therefore, another aim of the present study was to evaluate naturally occurring compounds that regulate brain and muscle Arnt-like 1 (Bmal1) gene expression. In this review, we focus on naturally occurring compounds that affect regulatory processes in brown/beige adipogenesis, and discuss better preventive strategies for the management of obesity and other metabolic disorders.


Assuntos
Fatores de Transcrição ARNTL , Adipócitos Bege/fisiologia , Adipócitos Marrons/fisiologia , Adipogenia/efeitos dos fármacos , Adipogenia/genética , Diferenciação Celular , Medicamentos de Ervas Chinesas/farmacologia , Proteína Desacopladora 1 , Fatores de Transcrição ARNTL/metabolismo , Fatores de Transcrição ARNTL/fisiologia , Animais , Relógios Biológicos/genética , Temperatura Baixa , Dieta Hiperlipídica/efeitos adversos , Expressão Gênica , Humanos , Medicina Kampo , Doenças Metabólicas/prevenção & controle , Obesidade/etiologia , Obesidade/prevenção & controle , Fosforilação Oxidativa , Receptores Adrenérgicos beta 3/metabolismo , Termogênese , Proteína Desacopladora 1/metabolismo
13.
Integr Cancer Ther ; 18: 1534735419836494, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30943793

RESUMO

From an epidemiological standpoint, disruptions to circadian rhythms have been shown to contribute to the development of various disease pathologies, including breast cancer. However, it is unclear how altered circadian rhythms are related to malignant transformations at the molecular level. In this article, a series of isogenic breast cancer cells representing disease progression was used to investigate the expression patterns of core circadian clock proteins BMAL1 and PER2. Our model is indicative of 4 stages of breast cancer and includes the following cells: MCF10A (non-malignant), MCF10AT.Cl2 (pre-malignant), MCF10Ca1h (well-differentiated, malignant), and MCF10Ca1a (poorly differentiated, malignant). While studies of circadian rhythms in cancer typically use low-resolution reverse transcription polymerase chain reaction assays, we also employed luciferase reporters BMAL1:Luc and PER2:Luc in real-time luminometry experiments. We found that across all 4 cancer stages, PER2 showed relatively stable oscillations compared with BMAL1. Period estimation using both wavelet-based and damped-sine-fitting methods showed that the periods are distributed over a wide circadian range and there is no clear progression in mean period as cancer severity progresses. Additionally, we used the K-nearest neighbors algorithm to classify the recordings according to cancer line, and found that cancer stages were largely differentiated from one another. Taken together, our data support that there are circadian discrepancies between normal and malignant cells, but it is difficult and insufficient to singularly use period evaluations to differentiate them. Future studies should employ other progressive disease models to determine whether these findings are representative across cancer types or are specific to this series.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteínas Circadianas Period/metabolismo , Mama/metabolismo , Mama/patologia , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Células Cultivadas , Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Progressão da Doença , Feminino , Células HEK293 , Humanos
14.
Hum Cell ; 32(3): 275-284, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30941700

RESUMO

This study aimed to characterize the pathophysiology, including possible correlations, of clock gene expression and erythropoietin (EPO) production in the acute stage of blood hemorrhage. Specimens of human cortical tissues (right and left kidneys) and cardiac blood were collected at autopsy from 52 cases following mortality due to acute-stage blood hemorrhage following sharp instrument injury. BMAL1 and PER2 mRNA levels were determined by reverse transcription-polymerase chain reaction; BMAL1 and PER2 protein levels were assessed using immunohistochemistry; BMAL1 protein levels were quantitatively measured by western blotting; and serum EPO levels were measured by chemiluminescent enzyme immunoassay. Separately, a rat model of hemorrhagic conditions was generated and used to confirm the results obtained with autopsy-derived specimens. A positive correlation was observed between BMAL1 protein and serum EPO levels, but not between BMAL1 mRNA levels and serum EPO levels. We also noted that Per2 mRNA expression became elevated in humans who survived for > 3 h after acute hemorrhagic events, with subsequent decreases in serum EPO levels. The rat model showed that even short (30-min) intervals of blood loss yielded increases in both Bmal1 mRNA and serum EPO levels; longer (60-min) intervals resulted in increases in Per2 mRNA expression along with decreases in serum EPO. Thus, the acute-stage human hemorrhage cases and the rat hemorrhage model yielded similar tendencies for clock gene expression and EPO secretion. In conclusion, our results indicated that clock genes are involved in the regulation of EPO production during the early stages of hypoxia/ischemia resulting from the acute hemorrhagic events.


Assuntos
Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Eritropoetina/metabolismo , Expressão Gênica , Hemorragia/genética , Hemorragia/metabolismo , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Choque Hemorrágico/genética , Choque Hemorrágico/metabolismo , Doença Aguda , Animais , Modelos Animais de Doenças , Humanos , Masculino , Mudanças Depois da Morte , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Fatores de Tempo
15.
J Biol Chem ; 294(17): 7046-7056, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-30862677

RESUMO

ELOVL3 is a very long-chain fatty acid elongase, and its mRNA levels display diurnal rhythmic changes exclusively in adult male mouse livers. This cyclical expression of hepatic Elovl3 is potentially controlled by the circadian clock, related hormones, and transcriptional factors. It remains unknown, however, whether the circadian clock, in conjunction with androgen signaling, functions in maintaining the rhythmic expression of Elovl3 in a sexually dimorphic manner. Under either zeitgeber or circadian time, WT mouse livers exhibited a robust circadian rhythmicity in the expression of circadian clock genes and Elovl3 In contrast, male Bmal1 -/- mice displayed severely weakened expression of hepatic circadian clock genes, resulting in relatively high, but nonrhythmic, Elovl3 expression levels. ChIP assays revealed that NR1D1 binds to the Elovl3 promoter upon circadian change in WT mouse livers in vivo, and a diminished binding was observed in male Bmal1 -/- mouse livers. Additionally, female mouse livers exhibited constant low levels of Elovl3 expression. Castration markedly reduced Elovl3 expression levels in male mouse livers but did not disrupt circadian variation of Elovl3 Injection of female mice with 5α-dihydrotestosterone induced Elovl3 rhythmicity in the liver. In AML12 cells, 5α-dihydrotestosterone also elevated Elovl3 expression in a time-dependent manner. In contrast, flutamide efficiently attenuated this induction effect. In conclusion, a lack of either the circadian clock or androgen signaling impairs hepatic Elovl3 expression, highlighting the observation that coordination between the circadian clock and androgen signaling is required to sustain the rhythmic expression of Elovl3 in mouse liver.


Assuntos
Androgênios/metabolismo , Relógios Circadianos , Fígado/enzimologia , Transdução de Sinais , Fatores de Transcrição ARNTL/metabolismo , Animais , Feminino , Regulação da Expressão Gênica , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Regiões Promotoras Genéticas , Triglicerídeos/metabolismo
16.
Int Immunopharmacol ; 70: 362-371, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30852291

RESUMO

To date, little information is available on the effects of circadian oscillation on immune regulation in lower vertebrates, such as teleost fish. In the present study, regulation of circadian oscillation of inflammatory cytokine TNF-α gene expression by clock gene was investigated using model fish medaka (Oryzias latipes). Firstly, structural analysis of clock genes was performed, which revealed that medaka BMAL1 and CLOCK1 conserve functionally important domains, such as basic helix-loop-helix (bHLH) and period-aryl hydrocarbon receptor nuclear translocator-single-minded (PAS), seen in their counterparts in other vertebrates. Expression of medaka Bmal1, Clock1, and Per1 genes was confirmed in central and peripheral tissues. Moreover, the expression of these clock genes and TNF-α genes in medaka acclimated to a 12:12 light (L) - dark (D) cycle showed circadian oscillation. In addition, higher expression of TNF-α gene was detected in medaka embryo cells (OLHdrR-e3) overexpressing Bmal1 and Clock1 genes. It was suggested that this increase was mediated by transcriptional regulation by clock proteins, which target E-box sequence in the cis-element of TNF-α gene as was detected by luciferase reporter gene assay. Moreover, in vitro head kidney stimulation with LPS at different zeitgeber time (ZT) under LD12:12 condition affected the degree of TNF-α gene expression, which shows high and low responsiveness to LPS stimulation at ZT18 and ZT10, respectively. These results suggested that fish TNF-α exhibited circadian oscillation regulated by clock proteins and its responsiveness against immune-stimulation depends on time zone.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Proteínas CLOCK/metabolismo , Relógios Circadianos/genética , Proteínas de Peixes/metabolismo , Regulação da Expressão Gênica , Oryzias/fisiologia , Fator de Necrose Tumoral alfa/genética , Fatores de Transcrição ARNTL/genética , Animais , Proteínas CLOCK/genética , Proteínas de Peixes/genética , Humanos , Camundongos , Modelos Animais , Oryzias/genética , Filogenia , Peixe-Zebra
17.
Genes Dev ; 33(5-6): 294-309, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30804225

RESUMO

The mammalian circadian clock relies on the transcription factor CLOCK:BMAL1 to coordinate the rhythmic expression of thousands of genes. Consistent with the various biological functions under clock control, rhythmic gene expression is tissue-specific despite an identical clockwork mechanism in every cell. Here we show that BMAL1 DNA binding is largely tissue-specific, likely because of differences in chromatin accessibility between tissues and cobinding of tissue-specific transcription factors. Our results also indicate that BMAL1 ability to drive tissue-specific rhythmic transcription is associated with not only the activity of BMAL1-bound enhancers but also the activity of neighboring enhancers. Characterization of physical interactions between BMAL1 enhancers and other cis-regulatory regions by RNA polymerase II chromatin interaction analysis by paired-end tag (ChIA-PET) reveals that rhythmic BMAL1 target gene expression correlates with rhythmic chromatin interactions. These data thus support that much of BMAL1 target gene transcription depends on BMAL1 capacity to rhythmically regulate a network of enhancers.


Assuntos
Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Regulação da Expressão Gênica/genética , Motivos de Aminoácidos/genética , Animais , Cromatina/metabolismo , Ritmo Circadiano/genética , Elementos Facilitadores Genéticos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , Regiões Promotoras Genéticas/genética , Ligação Proteica , RNA Polimerase II/metabolismo
18.
J Cell Sci ; 132(3)2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30709969

RESUMO

Cell-autonomous circadian clocks coordinate tissue homeostasis with a 24-hourly rhythm. The molecular circadian clock machinery controls tissue- and cell type-specific sets of rhythmic genes. Disruptions of clock mechanisms are linked to an increased risk of acquiring diseases, especially those associated with aging, metabolic dysfunction and cancer. Despite rapid advances in understanding the cyclic outputs of different tissue clocks, less is known about how the clocks adapt to their local niche within tissues. We have discovered that tissue stiffness regulates circadian clocks, and that this occurs in a cell-type-dependent manner. In this Review, we summarise new work linking the extracellular matrix with differential control of circadian clocks. We discuss how the changes in tissue structure and cellular microenvironment that occur throughout life may impact on the molecular control of circadian cycles. We also consider how altered clocks may have downstream impacts on the acquisition of diseases.


Assuntos
Relógios Circadianos/genética , Ritmo Circadiano/genética , Matriz Extracelular/metabolismo , Retroalimentação Fisiológica , Regulação da Expressão Gênica , Mecanotransdução Celular , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Microambiente Celular/genética , Criptocromos/genética , Criptocromos/metabolismo , Células Eucarióticas/citologia , Células Eucarióticas/metabolismo , Matriz Extracelular/química , Homeostase/genética , Humanos , Mamíferos , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo
19.
J Agric Food Chem ; 67(19): 5413-5422, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30685977

RESUMO

l-Theanine, a unique amino acid in tea leaves, is known to have beneficial effects on stress relief, tumor suppression, and prevention of hypertension and cardiovascular diseases (CADs). The disruption of the circadian rhythm has been implied in the pathogenesis of CADs. However, it is unknown whether l-theanine has a modulatory effect on the vascular circadian rhythm. In this research, we have established a circadian gene expression model in rat vascular smooth muscle cells by dexamethasone induction. l-Theanine treatment enhanced the expression amplitude of clock genes, including Bmal1, Cry1, Rev-erbα, and Per2. Moreover, pairwise comparisons of the RNA-sequencing data showed that l-theanine is able to upregulate a ray of the rhythm genes and differentially expressed genes that are involved in vasoconstriction and actin cytoskeleton regulation pathways. Our data suggest that l-theanine changes the circadian gene rhythm involving in the process of vascular smooth muscle restructure.


Assuntos
Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Dexametasona/efeitos adversos , Glutamatos/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Transcrição Genética/efeitos dos fármacos , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Células Cultivadas , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/metabolismo , Criptocromos/genética , Criptocromos/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Ratos , Análise de Sequência de RNA
20.
FEBS Lett ; 593(4): 423-432, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30659595

RESUMO

Glucocorticoids have various medical uses but are accompanied by side effects. The glucocorticoid receptor (GR) has been reported to regulate the clock genes, but the underlying mechanisms are incompletely understood. In this study, we focused on the suppressive effect of the GR on the expression of Rev-erbα (Nr1d1), an important component of the clock regulatory circuits. Here we show that the GR suppresses Rev-erbα expression via the formation of a complex with CLOCK and BMAL1, which binds to the E-boxes in the Nr1d1 promoter. In this GR-CLOCK-BMAL1 complex, the GR does not directly bind to DNA, which is referred to as tethering. These findings provide new insights into the role of the GR in the control of circadian rhythm.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Proteínas CLOCK/metabolismo , Dexametasona/administração & dosagem , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Receptores de Glucocorticoides/metabolismo , Animais , Ritmo Circadiano/efeitos dos fármacos , Dexametasona/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Células Hep G2 , Humanos , Masculino , Camundongos , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/química , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Regiões Promotoras Genéticas , Receptores de Glucocorticoides/agonistas
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