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Nonalcoholic steatohepatitis (NASH) occurs worldwide and is characterized by lipid accumulation in hepatocytes, hepatic inflammation, fibrosis, and an increased risk of cirrhosis. Although a major proportion of NASH patients exhibit obesity and insulin resistance, 20% lack a high body mass and are categorized as "non-obese NASH". Time-restricted feeding (TRF), limiting daily food intake within certain hours, improves obesity, lipid metabolism, and liver inflammation. Here, we determined whether TRF affects NASH pathology induced by a choline-deficient high-fat diet (CDAHFD), which does not involve obesity. TRF ameliorated the increase in epididymal white adipose tissue and plasma alanine transaminase and aspartate transaminase levels after 8 weeks of a CDAHFD. Although gene expression of TNF alpha in the liver was suppressed by TRF, it did not exhibit a suppressive effect on hepatic lipid accumulation, gene expression of cytokines and macrophage markers (Mcp1, IL1b, F4/80), or fibrosis, as evaluated by Sirius red staining and western blot analysis of alpha-smooth muscle actin. A CDAHFD-induced increase in gene expression related to fibrogenesis (Collagen 1a1 and TGFß) was neither suppressed by TRF nor that of alpha-smooth muscle actin but was increased by TRF. Our results indicated that TRF has a limited suppressive effect on CDAHFD-induced NASH pathology.
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Deficiencia de Colina , Enfermedad del Hígado Graso no Alcohólico , Humanos , Animales , Ratones , Enfermedad del Hígado Graso no Alcohólico/patología , Colina/metabolismo , Dieta Alta en Grasa/efectos adversos , Actinas/metabolismo , Deficiencia de Colina/metabolismo , Hígado/metabolismo , Cirrosis Hepática/patología , Inflamación/patología , Fibrosis , Obesidad/complicaciones , Lípidos/efectos adversos , Ratones Endogámicos C57BL , Modelos Animales de EnfermedadRESUMEN
Disturbances in sleep-wake and circadian rhythms may reportedly precede the onset of cognitive symptoms in the early stages of Alzheimer's disease (AD); however, the underlying mechanisms of these AD-induced sleep disturbances remain unelucidated. To specifically evaluate the involvement of amyloid ß (Aß) oligomers in AD-induced sleep disturbances, we examined circadian and sleep phenotypes using an Aß-GFP transgenic (Aß-GFP Tg) mouse characterized by intracellular accumulation of Aß oligomers. The circadian rhythm and free-running period of wheel running activity were identical between Aß-GFP Tg and littermate wild-type mice. The durations of rapid eye movement (REM) sleep were elongated in Aß-GFP Tg mice; however, the durations of non-REM sleep and wakefulness were unaffected. The Aß-GFP Tg mice exhibited shifts in the electroencephalogram (EEG) power spectra toward higher frequencies in the inactive light phase. These findings suggest that the intracellular accumulation of Aß oligomers might be associated with sleep quality; however, its impact on circadian systems is limited.
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Obesity and diabetes mellitus are associated with increased risk of arterial thrombosis and venous thromboembolism. Tsumura Suzuki Obese Diabetes (TSOD) mice are useful models for elucidating the molecular mechanisms of these diseases. We investigated normoglycemic [Ng]-TSOD mice with a metabolic abnormality that was accompanied by a coagulative and fibrinolytic state with a phenotype that distinctly differed from that of standard TSOD mice. As in TSOD mice, plasminogen activation inhibitor-1 (PAI-1) that inhibits fibrinolysis was substantially augmented in Ng-TSOD mice, suggesting that they are hypofibrinolytic. However, blood clotting parameters were within the normal range in Ng-TSOD mice. These findings indicated that Ng-TSOD mice are novel models with a hypofibrinolytic phenotype that is not associated with hyperglycemia.
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Diabetes Mellitus , Hiperglucemia , Animales , Ratones , Hiperglucemia/complicaciones , Ratones Obesos , Obesidad/complicaciones , FenotipoRESUMEN
Angelica keiskei Koidzumi (Ashitaba) is a traditional folk medicine and health supplement in Japan. Ashitaba yellow stem exudate (AYE) contains abundant chalcones and thus has the potential to treat and prevent many pathological states such as cancer, inflammation, obesity, diabetics, thrombosis, and hypertension. Levels of plasminogen activator inhibitor 1 (PAI-1), a key regulator of the fibrinolytic system, increase with age in mouse plasma. Therefore, we aimed to determine the effects of AYE on plasma thrombotic parameters in aging mice. Long-term (52 weeks) AYE supplementation significantly decreased age-induced increases of PAI-1 in mouse plasma. Supplementation with AYE decreased levels of the acute-phase and fibrinolytic protein plasma plasminogen, and significantly decreased those of tumor necrosis factor α. These results suggested that continuous intake of AYE throughout life decreases age-induced systemic inflammation and prevents thrombotic tendencies without affecting body weight gain in aged mice. Our findings showed that supplementing diets with AYE might help to prevent thrombotic diseases in elderly individuals.
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Angelica , Trombosis , Humanos , Animales , Ratones , Anciano , Inhibidor 1 de Activador Plasminogénico , Aumento de Peso , Inflamación/tratamiento farmacológico , Trombosis/tratamiento farmacológico , Trombosis/prevención & control , Exudados y Transudados , Suplementos DietéticosRESUMEN
Disordered sleep is a global social problem and an established significant risk factor for psychological and metabolic diseases. We profiled non-targeted metabolites in saliva from mouse models of chronic sleep disorder (CSD). We identified 288 and 55 metabolites using CE-FTMS and LC-TOFMS, respectively, among which concentrations of 58 (CE-FTMS) and three (LC-TOFMS) were significantly changed by CSD. Pathway analysis revealed that CSD significantly suppressed glycine, serine and threonine metabolism. Arginine and proline metabolic pathways were among those that were both upregulated and downregulated. Pathways of alanine, aspartate and glutamate metabolism, genetic information processing, and the TCA cycle tended to be downregulated, whereas histidine metabolism tended to be upregulated in mice with CSD. Pyruvate, lactate, malate, succinate and the glycemic amino acids alanine, glycine, methionine, proline, and threonine were significantly decreased, whereas 3-hydroxybutyric and 2-hydroxybutyric acids associated with ketosis were significantly increased, suggesting abnormal glucose metabolism in mice with CSD. Increases in the metabolites histamine and kynurenic acid that are associated with the central nervous system- and decreased glycine, might be associated with sleep dysregulation and impaired cognitive dysfunction in mice with CSD. Our findings suggested that profiling salivary metabolites could be a useful strategy for diagnosing CSD.
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Fabaceae , Saliva , Masculino , Animales , Ratones , Sueño , Psicofisiología , Alanina , Enfermedad Crónica , Modelos Animales de Enfermedad , MetabolomaRESUMEN
Ketogenic diets (KDs) affect the circadian rhythms of behavior and clock gene expression in experimental animals. However, these diets were designed to simulate a fasting state; thus, whether these effects are caused by diet-induced ketogenesis or persistent starvation is difficult to distinguish. The present study aimed to define the effects of a KD containing medium-chain triglycerides (MCT-KD) that increase blood ketone levels without inducing carbohydrate starvation, on circadian rhythms and sleep regulation. Mice were fed with a normal diet (CTRL) or MCT-KD for 2 weeks. Blood ß-hydroxybutyrate levels were significantly increased up to 2 mM by the MCT-KD, whereas body weight gain and blood glucose levels were identical between the groups, suggesting that ketosis accumulated without carbohydrate starvation in the MCT-KD mice. Circadian rhythms of wheel-running activity and core body temperature were almost identical, although wheel-running was slightly reduced in the MCT-KD mice. The circadian expression of the core clock genes, Per1, Per2, Bmal1, and Dbp in the hypothalamus, heart, liver, epididymal adipose tissues, and skeletal muscle were almost identical between the CTRL and MCT-KD mice, whereas the amplitude of hepatic Per2 and adipose Per1 expression was increased in MCT-KD mice. The MCT-KD reduced the duration of rapid-eye-movement (REM) sleep without affecting the duration of non-REM sleep and the duration of wakefulness. These findings suggested that the impact of ketone bodies on circadian systems are limited, although they might reduce locomotor activity and REM sleep duration.
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Dieta Cetogénica , Ratones , Animales , Duración del Sueño , Fenotipo , Cuerpos Cetónicos , Triglicéridos , CarbohidratosRESUMEN
Chronic sleep disorders (CSD) comprise a potential risk factor for metabolic and cardiovascular diseases, obesity and stroke. Thus, the identification of biomarkers for CSD is an important step in the early prevention of metabolic dysfunctions induced by sleep dysfunction. Diagnostic saliva samples can be easily and noninvasively collected. Thus, we aimed to identify whole microRNA (miRNA) profiles of saliva in control and psychophysiologically stressed CSD mouse models and compare them at Zeitgeber time (ZT) 0 (lights on) and ZT12 (lights off). The findings of two-way ANOVA revealed that the expression of 342 and 109 salivary miRNAs was affected by CSD and the time of day, respectively. Interactions were found in 122 miRNAs among which, we identified 197 (ZT0) and 62 (ZT12) upregulated, and 40 (ZT0) and seven (ZT12) downregulated miRNAs in CSD mice. We showed that miR-30c-5p, which is elevated in the plasma of patients with hypersomnia, was upregulated in the saliva of CSD mice collected at ZT0. The miRNAs, miR-10a-5p, miR-146b-5p, miR-150-5p, and miR-25-3p are upregulated in the serum of humans with poor sleep quality, and these were also upregulated in the saliva of CSD mice collected at ZT0. The miRNAs miR-30c, miR146b-5p, miR150, and miR-25-5p are associated with cardiovascular diseases, and we found that plasma concentrations of brain natriuretic peptides were significantly increased in CSD mice. The present findings showed that salivary miRNA profiles could serve as useful biomarkers for predicting CSD.
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Enfermedades Cardiovasculares , MicroARNs , Trastornos del Sueño-Vigilia , Humanos , Masculino , Ratones , Animales , Estrés Psicológico , MicroARNs/genética , Biomarcadores , Modelos Animales de Enfermedad , SueñoRESUMEN
Identification of early biomarkers of stress is important for preventing mood and anxiety disorders. Saliva is an easy-to-collect and non-invasive diagnostic target. The aim of this study was to characterize the changes in salivary whole microRNAs (miRNAs) and metabolites in mice subjected to subchronic and mild social defeat stress (sCSDS). In this study, we identified seven upregulated and one downregulated miRNAs/PIWI-interacting RNA (piRNA) in the saliva of sCSDS mice. One of them, miR-208b-3p, which is reported as a reliable marker for myocardial infarction, was upregulated in the saliva of sCSDS mice. Histological analysis showed frequent myocardial interstitial fibrosis in the heart of such mice. In addition, gene ontology and pathway analyses suggested that the pathways related to energy metabolism, such as the oxidative phosphorylation and the pentose phosphate pathway, were significantly related to the miRNAs affected by sCSDS in saliva. In contrast, salivary metabolites were not significantly changed in the sCSDS mice, which is consistent with our previous metabolomic study on the plasma of sCSDS mice. Taken in the light of previous studies, the present study provides novel potential stress biomarkers for future diagnosis using saliva.
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MicroARNs , Derrota Social , Ratones , Animales , MicroARNs/genética , MicroARNs/metabolismo , Ratones Endogámicos C57BL , Estrés Psicológico/genética , Estrés Psicológico/metabolismo , Metaboloma , Modelos Animales de Enfermedad , Biomarcadores/metabolismoRESUMEN
Duchenne muscular dystrophy (DMD) is a myopathy characterized by progressive muscle weakness caused by a mutation in the dystrophin gene on the X chromosome. We recently showed that a medium-chain triglyceride-containing ketogenic diet (MCTKD) improves skeletal muscle myopathy in a CRISPR/Cas9 gene-edited rat model of DMD. We examined the effects of the MCTKD on transcription profiles in skeletal muscles of the model rats to assess the underlying mechanism of the MCTKD-induced improvement in DMD. DMD rats were fed MCTKD or normal diet (ND) from weaning to 9 months, and wild-type rats were fed with the ND, then tibialis anterior muscles were sampled for mRNA-seq analysis. Pearson correlation heatmaps revealed a one-node transition in the expression profile between DMD and wild-type rats. A total of 10,440, 11,555 and 11,348 genes were expressed in the skeletal muscles of wild-type and ND-fed DMD rats the MCTKD-fed DMD rats, respectively. The MCTKD reduced the number of DMD-specific mRNAs from 1624 to 1350 and increased the number of mRNAs in common with wild-type rats from 9931 to 9998. Among 2660 genes were differentially expressed in response to MCTKD intake, the mRNA expression of 1411 and 1249 of them was respectively increased and decreased. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses suggested that the MCTKD significantly suppressed the mRNA expression of genes associated with extracellular matrix organization and inflammation. This suggestion was consistent with our previous findings that the MCTKD significantly suppressed fibrosis and inflammation in DMD rats. In contrast, the MCTKD significantly increased the mRNA expression of genes associated with oxidative phosphorylation and ATP production pathways, suggesting altered energy metabolism. The decreased and increased mRNA expression of Sln and Atp2a1 respectively suggested that Sarco/endoplasmic reticulum Ca2+-ATPase activation is involved in the MCTKD-induced improvement of skeletal muscle myopathy in DMD rats. This is the first report to examine transcription profiles in the skeletal muscle of CRISPR/Cas9 gene-edited DMD model rats and the effect of MCTKD feeding on it.
RESUMEN
OBJECTIVE: The regular consumption of whole grains is linked to a lower likelihood of developing metabolic disorders. We previously found that chronic supplementation with wheat alkylresorcinols (ARs) prevents obesity and its associated metabolic symptoms induced by a high-fat high-sucrose diet (HFHSD) in mice. The aim of this study was to examine the time-of-day-dependence of these effects in mice. METHODS: Eight-wk-old male C57 BL/6 J mice were individually housed under a 12-h light/dark cycle (Zeitgeber time; ZT0, lights on; ZT12, lights off) and given access to a HFHSD from ZT12-16 (activity onset) and ZT20-24 (activity offset) to respectively represent breakfast and dinner times for 3 wk. Thereafter, the HFHSD was replaced with the same diet containing 0.4% ARs at either ZT12-16 or ZT20-24 for 8 wk. Control mice received the HFHSD without ARs at both feeding times. RESULTS: Supplementation with ARs significantly suppressed feed efficiency when given at breakfast, but not at dinner. ARs consumed at breakfast increased fecal lipid content and decreased the expression of Fat/Cd36 in enterocytes that enhances lipid uptake, but did not affect hepatic and blood lipid levels. The consumption of ARs at breakfast also upregulated the expression of Irs1, a key gene for insulin signaling in white adipose tissue and attenuated elevated blood leptin levels induced by the diet. This led to high scores for the homeostasis model assessment of insulin sensitivity, and the adiponectin/leptin ratio, a negative index of adipose tissue dysfunction. CONCLUSIONS: These findings suggested that ARs ameliorate feed efficiency by decreasing dietary lipid absorption more effectively at the time of activity onset than offset. Further studies are needed to elucidate the molecular mechanism of the time-of-day-dependent effects of ARs on diet-induced metabolic disorders.
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Leptina , Enfermedades Metabólicas , Ratones , Masculino , Animales , Triticum , Dieta Alta en Grasa/efectos adversos , Enfermedades Metabólicas/metabolismo , Grasas de la Dieta , Ratones Endogámicos C57BL , Sacarosa , Suplementos DietéticosRESUMEN
Duchenne muscular dystrophy (DMD) is an X-linked recessive myopathy caused by dystrophin mutations. Although respiratory management has improved the prognosis of patients with DMD, inevitable progressive cardiomyopathy is a current leading cause of premature death. Recently, we showed that a medium-chain triglyceride containing ketogenic diet (MCTKD) improves skeletal muscle function and pathology in a CRISPR/Cas9 gene-edited rat model with DMD. In this study, we sought to clarify whether MCTKD also improves the cardiomyopathy in these rats. DMD rats were fed either the MCTKD or normal diet (ND) from ages of 3 weeks to 9 months old. Compared with the ND-fed rats, MCTKD-fed rats showed significantly prolonged QRS duration, decreased left ventricular fractional shortening, an increased heart weight/body weight ratio, and progression of cardiac fibrosis. In contrast to our previous study which found that MCTKD improved skeletal myopathy, the current study showed unexpected exacerbation of the cardiomyopathy. Further studies are needed to explore the underlying mechanisms for these differences and to explore modified dietary options that improve skeletal and cardiac muscles simultaneously.
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Cardiomiopatías , Dieta Cetogénica , Distrofia Muscular de Duchenne , Animales , Sistemas CRISPR-Cas , Cardiomiopatías/patología , Modelos Animales de Enfermedad , Distrofina/genética , Distrofina/metabolismo , Edición Génica , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/patología , Ratas , TriglicéridosRESUMEN
Duchenne muscular dystrophy (DMD) is an intractable genetic disease associated with progressive skeletal muscle weakness and degeneration. Recently, it was reported that intraperitoneal injections of ketone bodies partially ameliorated muscular dystrophy by increasing satellite cell (SC) proliferation. Here, we evaluated whether a ketogenic diet (KD) with medium-chain triglycerides (MCT-KD) could alter genetically mutated DMD in model rats. We found that the MCT-KD significantly increased muscle strength and fiber diameter in these rats. The MCT-KD significantly suppressed the key features of DMD, namely, muscle necrosis, inflammation, and subsequent fibrosis. Immunocytochemical analysis revealed that the MCT-KD promoted the proliferation of muscle SCs, suggesting enhanced muscle regeneration. The muscle strength of DMD model rats fed with MCT-KD was significantly improved even at the age of 9 months. Our findings suggested that the MCT-KD ameliorates muscular dystrophy by inhibiting myonecrosis and promoting the proliferation of muscle SCs. As far as we can ascertain, this is the first study to apply a functional diet as therapy for DMD in experimental animals. Further studies are needed to elucidate the underlying mechanisms of the MCT-KD-induced improvement of DMD.
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Dieta Cetogénica , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiología , Distrofia Muscular de Duchenne/dietoterapia , Distrofia Muscular de Duchenne/fisiopatología , Triglicéridos/química , Triglicéridos/farmacología , Animales , Peso Corporal/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Fibrosis/dietoterapia , Fibrosis/patología , Inflamación/dietoterapia , Inflamación/patología , Cetonas/sangre , Cetosis , Masculino , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Distrofia Muscular de Duchenne/patología , Necrosis/dietoterapia , Necrosis/patología , Ratas , Células Satélite del Músculo Esquelético/citología , Células Satélite del Músculo Esquelético/efectos de los fármacos , Triglicéridos/uso terapéuticoRESUMEN
OBJECTIVES: The body clock controls diurnal rhythms of nutrient digestion, absorption, and metabolism. Fish oil (FO) contains abundant ω-3 polyunsaturated fatty acids (PUFA), including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), that are thought to lower triglyceride (TG) levels. This randomized, placebo-controlled, double-blind, parallel-group trial aimed to confirm the effects of the time of FO intake on TG in healthy Japanese adults. METHODS: Twenty healthy Japanese adults (age, 20-60 y) were assigned to either a group that consumed sausages enriched with FO (DHA 1010 mg; EPA 240 mg) in the morning and a placebo (DHA 40 mg; EPA 15 mg) in the evening (BF-FO) or another group that consumed FO-enriched sausages in the evening and the placebo in the morning (DN-FO). Serum lipid parameters, fatty acid (FA) composition, and messenger RNA expression of lipogenic genes in circulating blood cells were evaluated in fasting blood samples before, as well as after 4 and 8 wk of FO intake. RESULTS: Serum concentrations of TG and total saturated FA were significantly decreased in the BF-FO group, whereas those of ω-3 PUFA were significantly and identically increased in both groups. Serum concentrations of ω-6 PUFA were significantly decreased in the BF-FO but not the DN-FO group. Messenger RNA expression of the lipogenic genes ACLY, SCD, and FASN were similarly reduced in both groups. CONCLUSIONS: These findings suggested that the timing of FO intake affects both serum FA concentrations and TG metabolism in normolipidemic humans. The mechanisms of these effects of FO on lipid metabolism require further investigation.
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Ácidos Grasos Omega-3 , Aceites de Pescado , Adulto , Ácidos Docosahexaenoicos , Método Doble Ciego , Ácido Eicosapentaenoico , Ácidos Grasos , Humanos , Persona de Mediana Edad , Proyectos Piloto , Adulto JovenRESUMEN
Maternal fructose consumption during pregnancy and lactation is associated with metabolic dysregulation in offspring. We tested the hypothesis that fish oil (FO) supplementation during pregnancy and lactation improves fructose-induced metabolic dysregulation in postpartum dams and offspring mice. We therefore aimed to determine the effects of FO supplementation on metabolic disruption in neonatal mice and dams induced by a maternal high-fructose diet (HFrD). The weight of the offspring of dams fed with HFrD on postnatal day 5 was significantly low, but this was reversed by adding FO to the maternal diet. Feeding dams with HFrD significantly increased plasma concentrations of triglycerides, uric acid, and total cholesterol, and decreased free fatty acid concentrations in offspring. Maternal supplementation with FO significantly suppressed HFrD-induced hypertriglyceridemia and hyperuricemia in the offspring. Maternal HFrD induced remarkable mRNA expression of the lipogenic genes Srebf1, Fasn, Acc1, Scd1, and Acly in the postpartum mouse liver without affecting hepatic and plasma lipid levels. Although expression levels of lipogenic genes were higher in the livers of postpartum dams than in those of nonmated mice, HFrD feeding increased the hepatic lipid accumulation in nonmated mice but not in postpartum dams. These findings suggest that although hepatic lipogenic activity is higher in postpartum dams than nonmated mice, the lipid consumption is enhanced in postpartum dams during pregnancy and lactation. Maternal FO supplementation obviously suppressed the expression of these lipogenic genes. These findings coincide with reduced plasma triglyceride concentrations in the offspring. Therefore, dietary FO apparently ameliorated maternal HFrD-induced dyslipidemia in offspring by suppressing maternal lipogenic gene expression and/or neonatal plasma levels of uric acid.
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Azúcares de la Dieta/administración & dosificación , Suplementos Dietéticos , Aceites de Pescado/administración & dosificación , Fructosa/administración & dosificación , Hiperlipidemias/prevención & control , Lipogénesis/genética , Hígado/metabolismo , Animales , Animales Recién Nacidos , Femenino , Regulación de la Expresión Génica , Hiperlipidemias/etiología , Lactancia , Metabolismo de los Lípidos , Lípidos/sangre , Ratones , Periodo Posparto , Embarazo , Ácido Úrico/sangreRESUMEN
Sleep disturbances can contribute to cognitive decline and neuropsychiatric disorders. However, the underlying mechanisms of these processes are poorly understood. The present study evaluated the effects of a chronic sleep disorder (CSD) on long-term memory formation and anxiety-like behavior in our originally established mouse model of psychophysiological stress-induced CSD characterized by disrupted circadian rhythms of wheel-running activity and sleep-wake cycles. Model mice are continuously exposed to mild stress imposed by perpetually staying on a running-wheel to avoid water. The findings of novel object recognition (NORT) and open field (OFT) tests showed that CSD impaired recognition memory and elicited anxiety-like behavior, respectively. These results suggested that the CSD impaired cognitive function and emotional status. Thus, this CSD model could be useful for studying the underlying mechanisms of neurobehavioral difficulties caused by sleep disorders. We then examined the hippocampal mRNA expression of genes associated with learning and memory, and anxiety and depression. The CSD increased the mRNA expression of Crhr1, Ngf and Phlpp1, and suppressed that of Ace, Egr2 and Slc6a4. Based on the functions of these genes, we inferred that the increase in Crhr1 mRNA was associated with the pathogenesis of psychiatric conditions, whereas mRNA levels of the other five genes were directed towards symptom relief. Upregulating hippocampal Crhr1 expression might contribute in part to the activation of corticotropin-releasing hormone (CRH)-CRH receptor1 signaling that mediates CSD-evoked mental disorders.
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Ansiedad/etiología , Disfunción Cognitiva/etiología , Memoria a Largo Plazo , Trastornos del Sueño-Vigilia/complicaciones , Animales , Ansiedad/fisiopatología , Enfermedad Crónica , Ritmo Circadiano , Disfunción Cognitiva/fisiopatología , Modelos Animales de Enfermedad , Masculino , Ratones , Prueba de Campo Abierto , Trastornos del Sueño-Vigilia/fisiopatología , Estrés Psicológico/complicaciones , Estrés Psicológico/fisiopatologíaRESUMEN
OBJECTIVES: Cocoa contains many chemical compounds that affect the physiological functions of experimental animals and humans. The present study used a mouse model characterized by disrupted circadian rhythms of locomotor activity and sleep-wake cycles to determine whether natural cocoa improves chronic sleep disorders (CSDs) induced by psychophysiological stress. METHODS: Mice were fed a high-fat, high-sucrose diet supplemented with 2.0% natural cocoa and stressed for 30 d to induce CSDs. RESULTS: Dietary cocoa restored the amplitude reduction of day-night activity rhythms by improving reduced nocturnal wheel-running activities during CSDs. Electroencephalography revealed that dietary cocoa significantly ameliorated CSD-induced increases in wakefulness during the first half of the inactive phase and in nonrapid eye movement sleep during the first half of the active phase. The attenuation of circadian rapid eye movement sleep rhythms and increased electroencephalography slow-wave activity (a marker of nonrapid eye movement sleep intensity) induced by CSDs improved in mice supplemented with cocoa. Dietary cocoa notably did not affect wheel-running activity rhythms or sleep-wake cycles under normal conditions. Dietary cocoa significantly increased the hypothalamic mRNA expression of Hspa1 a that encodes HSP70 and is associated with sleep regulation. Furthermore, Hspa1 a expression was not induced by CSDs in mice supplemented with cocoa. CONCLUSIONS: These findings suggest that dietary cocoa exerts beneficial effects on insomnia and circadian sleep disorders induced by psychophysiological stress.
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Ritmo Circadiano , Trastornos del Sueño-Vigilia , Animales , Dieta , Locomoción , Ratones , Sueño , VigiliaRESUMEN
Acute or chronic effects of consuming or skipping breakfast on cognitive performance in humans are controversial. To evaluate the effects of chronically skipping breakfast (SB) on hippocampus-dependent long-term memory formation, we examined hippocampal gene expression and applied the novel object recognition test (NORT) after two weeks of repeated fasting for six hours from lights off to mimic SB in mice. We also examined the effects of SB on circadian rhythms of locomotor activity, food intake, core body temperature (CBT) and sleep-wake cycles. Skipping breakfast slightly but significantly decreased total daily food intake without affecting body weight gain. Locomotor activity and CBT significantly decreased during the fasting period under SB. The degree of fasting-dependent CBT reduction gradually increased and then became stabilized after four days of SB. Electroencephalographic data revealed that repeated SB significantly decreased the duration of wakefulness and increased that of rapid eye movement (REM) and of non-REM (NREM) sleep during the period of SB. Furthermore, total daily amounts of wakefulness and NREM sleep were significantly decreased and increased, respectively, under SB, suggesting that SB disrupts sleep homeostasis. Skipping breakfast significantly suppressed mRNA expression of the memory-related genes, Camk2a, Fkbp5, Gadd45b, Gria1, Sirt1 and Tet1 in the hippocampus. Recognition memory assessed by NORT was impaired by SB in accordance with the gene expression profiles. These findings suggested that chronic SB causes dysregulated CBT, sleep-wake cycles and hippocampal gene expression, which results in impaired long-term memory formation.
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Temperatura Corporal/fisiología , Desayuno/fisiología , Ingestión de Alimentos/fisiología , Hipocampo/metabolismo , Memoria/fisiología , Vigilia/fisiología , Animales , Antígenos de Diferenciación/genética , Antígenos de Diferenciación/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Ritmo Circadiano/fisiología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Ayuno , Regulación de la Expresión Génica , Homeostasis , Masculino , Memoria a Largo Plazo/fisiología , Ratones , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , ARN Mensajero , Receptores AMPA/genética , Receptores AMPA/metabolismo , Sirtuina 1/genética , Sirtuina 1/metabolismo , Sueño REM/fisiología , Proteínas de Unión a Tacrolimus/genética , Proteínas de Unión a Tacrolimus/metabolismoRESUMEN
Ketogenic diets (KD) that are very high in fat and low in carbohydrates are thought to simulate the metabolic effects of starvation. We fed mice with a KD for seven days to assess the underlying mechanisms of muscle wasting induced by chronic starvation. This diet decreased the weight of the gastrocnemius (Ga), tibialis anterior (TA) and soleus (Sol) muscles by 23%, 11% and 16%, respectively. The size of Ga, TA, Sol muscle fibers and the grip strength of four limbs also significantly declined by 20%, 28%, 16% and 22%, respectively. The muscle atrophy-related genes Mafbx, Murf1, Foxo3, Lc3b and Klf15 were upregulated in the skeletal muscles of mice fed with the KD. In accordance with the reduced expression of anabolic genes such as Igf1, surface sensing of translation (SUnSET) analyses of fast-twitch Ga, TA and Sol muscles revealed that the KD suppressed muscle protein synthesis. The mRNA expression of oxidative stress-responsive genes such as Sod1 was significantly increased in all muscles examined. In addition to hypercorticosteronemia, hypoinsulinemia and reduced IGF-1, oxidative stress might also be involved in KD-induced muscle atrophy. Feeding mice with a KD is a novel experimental animal model of muscle-wasting induced by chronic starvation.
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Dieta Cetogénica/efectos adversos , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Biosíntesis de Proteínas , Proteolisis , Animales , Femenino , Ratones , Ratones Endogámicos ICR , Músculo Esquelético/patología , Atrofia Muscular/etiología , Atrofia Muscular/patologíaRESUMEN
To investigate whether heat-killed Lactobacillus curvatus CP2998 (CP2998) inhibits glucocorticoid-induced myotube atrophy which is associated with the ubiquitin-proteasome system, mouse skeletal muscle C2C12 myotubes were treated with dexamethasone (DEX) in the presence or absence of CP2998. DEX exposure significantly decreased myotube diameters and increased mRNA expression levels of MuRF1 and MAFbx, E3 ubiquitin ligases. CP2998 treatment restored myotube diameters and dose dependently decreased mRNA expression levels of these E3 ubiquitin ligases. CP2998 treatment also inhibited DEX-induced glucocorticoid dependent transcription. Our results suggest that CP2998 prevents DEX-induced muscle atrophy by suppressing glucocorticoid receptor activation.
Asunto(s)
Proteínas Bacterianas/administración & dosificación , Dexametasona/efectos adversos , Glucocorticoides/efectos adversos , Lactobacillus/aislamiento & purificación , Atrofia Muscular/prevención & control , Animales , Técnicas de Cultivo de Célula , Relación Dosis-Respuesta a Droga , Alimentos Fermentados/microbiología , Ratones , Fibras Musculares Esqueléticas/efectos de los fármacos , Proteínas Musculares/metabolismo , Atrofia Muscular/inducido químicamente , ARN Mensajero/metabolismo , Proteínas Ligasas SKP Cullina F-box/metabolismo , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Actograms are well-established methods used for visualizing periodic activity of animals in chronobiological research. They help in the understanding of the overall characteristics of rhythms and are instrumental in defining the direction of subsequent detailed analysis. Although there exists specialized software for creating actograms, new users such as students and researchers from other fields often find it inconvenient to use. In this study, we demonstrate a fast and easy method to create actograms using Microsoft Excel. As operations in Excel are simple and user-friendly, it takes only a few minutes to create an actogram. Using this method, it is possible to obtain a visual understanding of the characteristics of rhythms not only from typical activity data, but also from any kind of time-series data such as body temperature, blood sugar level, gene expressions, sleep electroencephalogram, heartbeat, and so on. The actogram thus created can also be converted to the "heatogram" shown by color temperature. As opposed to conventional chronograms, this new type of chronogram facilitates easy understanding of rhythmic features in a more intuitive manner. This method is therefore convenient and beneficial for a broad range of researchers including students as it aids in the better understanding of periodic phenomena from a large amount of time-series data.