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BACKGROUND: The current study aimed to assess the association between low maternal protein intake during pregnancy and child developmental delay at age 3 years. METHODS: This research used data obtained from the Japan Environment and Children's Study. In total, we analyzed 77,237 mother-child pairs. Dietary intake was assessed using the Food Frequency Questionnaire. Developmental outcomes at age 3 years were evaluated with the Japanese version of the Ages and Stages Questionnaire, Third Edition. A multivariate logistic regression analysis was performed to assess the association between maternal protein intake during pregnancy and child development delays at age 3 years. RESULTS: Based on the protein-to-total energy intake ratio during early pregnancy, the participants were categorized into three groups: <9.39% (>2 standard deviation below the mean), the severely low protein (SLP) group; 9.39-<13%, the low protein group; and ≥13%, the normal protein group. After adjusting for potential confounding factors, SLP intake was found to be significantly correlated with a higher risk of developmental delay according to the communication, fine motor and problem-solving skill domains. CONCLUSIONS: SLP intake caused by inadequate diet during early pregnancy was associated with a higher risk of child developmental delay at age 3 years. IMPACT: Animal studies have shown that maternal protein restriction during pregnancy and lactation causes abnormal brain development among offspring. Birth cohort studies to date have not assessed the effects of maternal low protein exposure during pregnancy on child development. Severely low protein intake during early pregnancy was associated with a higher risk of child developmental delay at age 3 years. Since nutritional imbalance in early pregnancy affects not only fetal growth but also postnatal neurodevelopment, nutritional management before pregnancy is considered important.
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Desarrollo Infantil , Exposición Materna , Embarazo , Humanos , Femenino , Animales , Desarrollo Fetal , Japón , DietaRESUMEN
BACKGROUND AND OBJECTIVES: Barley mixed rice, "Mugi gohan," is traditionally eaten with yam paste in Japan. Both ingredients contain dietary fiber and reportedly reduce postprandial hyperglycemia. However, evidence supporting the benefits of combining barley mixed rice with yam paste is limited. In this study, we evaluated whether ingesting a combination of barley mixed rice and yam paste affected postprandial blood glucose concentration and insulin secretion. METHODS AND STUDY DESIGN: This study followed an open-label, randomized controlled crossover design, following the unified protocol of the Japanese Association for the Study of Glycemic Index. Fourteen healthy subjects each consumed four different test meals: white rice only, white rice with yam paste, barley mixed rice, and barley mixed rice with yam paste. We measured their postprandial blood glucose and insulin concentrations after every meal, and we calculated the area under curve for glucose and insulin. RESULTS: Participants had significantly reduced area under curve for glucose and insulin after eating barley mixed rice with yam paste compared to when they ate white rice only. Participants had similar area under curve for glucose and insulin after eating barley mixed rice only, or eating white rice with yam paste. Participants had lower blood glucose concentrations 15 min after eating barley mixed rice only, whilst eating white rice with yam paste did not maintain lower blood glucose after 15 min. CONCLUSIONS: Eating barley mixed rice with yam paste decreases postprandial blood glucose concentrations and reduces insulin secretion.
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Glucemia , Dioscorea , Hordeum , Secreción de Insulina , Oryza , Adulto , Humanos , Estudios Cruzados , Pueblos del Este de Asia , Ingestión de Alimentos , Insulina , Comidas , Periodo PosprandialRESUMEN
Hepatitis C virus (HCV) infection causes liver pathologies, including hepatocellular carcinoma (HCC). Homeobox (HOX) gene products regulate embryonic development and are associated with tumorigenesis, although the regulation of HOX genes by HCV infection has not been clarified in detail. We examined the effect of HCV infection on HOX gene expression. In this study, HCV infection induced more than half of the HOX genes and reduced the level of histone H2A monoubiquitination on lysine 119 (K119) (H2Aub), which represses HOX gene promoter activity. HCV infection also promoted proteasome-dependent degradation of RNF2, which is an E3 ligase mediating H2A monoubiquitination as a component of polycomb repressive complex 1. Since full-genomic replicon cells but not subgenomic replicon cells exhibited reduced RNF2 and H2Aub levels and induction of HOX genes, we focused on the core protein. Expression of the core protein reduced the amounts of RNF2 and H2Aub and induced HOX genes. Treatment with LY-411575, which can reduce HCV core protein expression via signal peptide peptidase (SPP) inhibition without affecting other viral proteins, dose-dependently restored the amounts of RNF2 and H2Aub in HCV-infected cells and impaired the induction of HOX genes and production of viral particles but not viral replication. The chromatin immunoprecipitation assay results also indicated infection- and proteasome-dependent reductions in H2Aub located in HOX gene promoters. These results suggest that HCV infection or core protein induces HOX genes by impairing histone H2A monoubiquitination via a reduction in the RNF2 level.IMPORTANCE Recently sustained virologic response can be achieved by direct-acting antiviral (DAA) therapy in most hepatitis C patients. Unfortunately, DAA therapy does not completely eliminate a risk of hepatocellular carcinoma (HCC). Several epigenetic factors, including histone modifications, are well known to contribute to hepatitis C virus (HCV)-associated HCC. However, the regulation of histone modifications by HCV infection has not been clarified in detail. In this study, our data suggest that HCV infection or HCV core protein expression impairs monoubiquitination of histone H2A K119 in the homeobox (HOX) gene promoter via destabilization of RNF2 and then induces HOX genes. Several lines of evidence suggest that the expression of several HOX genes is dysregulated in certain types of tumors. These findings reveal a novel mechanism of HCV-related histone modification and may provide information about new targets for diagnosis and prevention of HCC occurrence.
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Genes Homeobox/genética , Hepacivirus/fisiología , Histonas/metabolismo , Ubiquitinación/fisiología , Línea Celular , Regulación de la Expresión Génica , Hepacivirus/metabolismo , Hepatitis C/genética , Hepatitis C/metabolismo , Hepatitis C/virología , Código de Histonas , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Interacciones Huésped-Patógeno , Humanos , Complejo Represivo Polycomb 1/genética , Complejo Represivo Polycomb 1/metabolismo , Regiones Promotoras Genéticas , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteínas del Núcleo Viral/metabolismoRESUMEN
Background: At its earliest stages, mammalian embryonic development is apparently simple but vulnerable. The environment during the preimplantation period, which only lasts a couple of days, has been implicated in adult health, extending to such early stages the concept of the developmental origin of health and disease (DOHaD). Methods: In this review, we first provide a brief history of assisted reproductive technology (ART) focusing on in vitro culture and its outcomes during subsequent development mainly in mice and humans. Further, we introduce the "MEM mouse," a novel type 2 diabetes mouse model generated by in vitro culture of preimplantation embryos in alpha minimum essential medium (αMEM). Main findings: The association between ART and its long-term effects has been carefully examined for its application in human infertility treatment. The "MEM mouse" develops steatohepatitis and kidney disease with diabetes into adulthood. Conclusion: The close association between the environment of preimplantation and health in postnatal life is being clarified. The approach by which severe mouse phenotypes are successfully induced by manipulating the environment of preimplantation embryos could provide new chronic disease animal models, which we call "modified ART-DOHaD" animal models. This will also offer insights into the mechanisms underlying their long-term effects.
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We examined whether peripheral leukocytes of mice derived from in vitro αMEM-cultured embryos and exhibiting type 2 diabetes had higher expression of inflammatory-related genes associated with the development of atherosclerosis. Also, we examined the impact of a barley diet on inflammatory gene expression. Adult mice were produced by embryo transfer, after culturing two-cell embryos for 48 h in either α minimal essential media (α-MEM) or potassium simplex optimized medium control media. Mice were fed either a barley or rice diet for 10 weeks. Postprandial blood glucose and mRNA levels of several inflammatory genes, including Tnfa and Nox2, in blood leukocytes were significantly higher in MEM mice fed a rice diet compared with control mice. Barley intake reduced expression of S100a8 and Nox2. In summary, MEM mice exhibited postprandial hyperglycemia and peripheral leukocytes with higher expression of genes related to the development of atherosclerosis, and barley intake reduced some gene expression.
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Aterosclerosis/dietoterapia , Blastocisto/efectos de los fármacos , Dieta/métodos , Hordeum/química , Hiperglucemia/dietoterapia , Efectos Tardíos de la Exposición Prenatal/dietoterapia , Animales , Aterosclerosis/genética , Aterosclerosis/metabolismo , Aterosclerosis/patología , Blastocisto/metabolismo , Blastocisto/patología , Glucemia/metabolismo , Calgranulina A/genética , Calgranulina A/metabolismo , Transferencia de Embrión , Embrión de Mamíferos , Femenino , Regulación de la Expresión Génica , Hiperglucemia/genética , Hiperglucemia/metabolismo , Hiperglucemia/patología , Leucocitos/metabolismo , Leucocitos/patología , Ratones , NADPH Oxidasa 2/genética , NADPH Oxidasa 2/metabolismo , Compuestos Orgánicos/efectos adversos , Oryza/química , Periodo Posprandial , Embarazo , Efectos Tardíos de la Exposición Prenatal/genética , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/patología , Técnicas de Cultivo de Tejidos , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Jejunal sodium/glucose co-transporter (Sglt1) displays circadian expression. The jejunum was collected every 4 h from mice, and we examined histone acetylation and binding of bromodomain-containing protein-4 (BRD4) around of the gene. Histone acetylation increased in the transcribed region of Sglt1 prior to induction of the gene. Furthermore, the binding of mRNA elongation factor around the gene showed circadian rhythm.
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Ritmo Circadiano/genética , Histonas/metabolismo , Yeyuno/metabolismo , Proteínas Nucleares/metabolismo , Factor B de Elongación Transcripcional Positiva/metabolismo , ARN Mensajero/metabolismo , Transportador 1 de Sodio-Glucosa/genética , Factores de Transcripción/metabolismo , Acetilación , Animales , Inmunoprecipitación de Cromatina , Expresión Génica , Masculino , Ratones Endogámicos C57BL , Regiones Promotoras Genéticas , Unión ProteicaRESUMEN
Epigenetic memories are acquired information included in the chromatin or DNA such as methylation and histone modifications. Recent studies suggest that epigenetic memories determine the types of differentiated cells in each tissue. Moreover, the development of metabolic diseases induced by environmental factors during development is controlled by epigenetic regulation rather than the genetic regulation such as DNA sequence-dependent transcriptional regulation. In general, the demethylation of CpG islands induces histone acetylation, associated changes from heterochromatin to euchromatin, and enhances transcriptional activation. Under the classical model of epigenetics, these changes are induced by the binding of transcriptional factors to cis-elements located on promoter/enhancer regions and the associated binding of histone acetyl-transferase and the transcription initiation complex. This model is dependent on epigenetics in the promoter/enhancer region and is used to explain the induction of genes by lipophilic nutrients such as vitamin A, vitamin D, and unsaturated fatty acid metabolites. However, recent studies have demonstrated that epigenetics in the gene body (transcribed region) also regulate transcription. This novel model postulates that histone acetylation and bromodomain-containing protein 4, which contains two bromodomains to bind acetylated histones, on the gene body enhance transcriptional elongation. Gene expression alterations induced by carbohydrate signals and changes to energy balance in the body accompanied by the intake of major nutrients are also regulated by this model. In this section, we introduce these epigenetic regulations and their relationship with nutrient intake and discuss the link between epigenetic regulation and the development of metabolic diseases.
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Epigénesis Genética/fisiología , Regulación de la Expresión Génica , Interacción Gen-Ambiente , Modelos Genéticos , Fenómenos Fisiológicos de la Nutrición , Animales , Metilación de ADN , Humanos , Regiones Promotoras GenéticasRESUMEN
PURPOSE: Recent studies suggest that nutritional status during developmental periods is associated with subsequent development of metabolic abnormalities. In this study, we examined whether malnutrition by fasting for 3 days during the suckling-weaning transient period induces subsequent development of metabolic abnormalities in rats. METHODS: Male Sprague-Dawley rats were fasted for 3 days during the suckling-weaning transient period. They are subsequently fed a high-fat, high-sucrose (HF) or low-fat, high-starch (LF) diet for 14 weeks from 17 weeks of age, and the liver and blood samples were collected for measuring mRNA and protein levels of metabolic genes and blood concentrations of glucose and insulin, respectively. RESULTS: Fasting for 3 days during the suckling-weaning transient period induced impaired glucose tolerance in rats fed the LF diet in adulthood. Liver triglycerides in rats fed the HF diet in adulthood increased to 140 % in rats fasted for 3 days during the suckling-weaning transient period compared with those non-fasted. Furthermore, liver expression of FBP1 and ACCα genes in adult rats fed the LF diet increased to 125 and 145 %, respectively, in rats fasted for 3 days during the suckling-weaning transient period compared to non-fasted rats. PEPCK1 protein expression levels in rats fed the LF diet were higher in rats fasted for 3 days during the suckling-weaning transient period than in non-fasted rats. CONCLUSION: Fasting for 3 days in rats during the suckling-weaning transient period enhances metabolic abnormalities in animals fed a HF or LF diet in adulthood by confounding metabolism of lipid and sugar in the liver.
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Fenómenos Fisiológicos Nutricionales de los Animales , Ayuno , Intolerancia a la Glucosa , Hígado/fisiopatología , Enfermedades Metabólicas/fisiopatología , Adiponectina/sangre , Animales , Animales Lactantes , Glucemia/metabolismo , Peso Corporal , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Dieta Alta en Grasa , Grasas de la Dieta , Modelos Animales de Enfermedad , Ácidos Grasos no Esterificados/sangre , Gluconeogénesis/genética , Insulina/sangre , Leptina/sangre , Lipogénesis/genética , Hígado/metabolismo , Masculino , Desnutrición/complicaciones , Desnutrición/fisiopatología , Enfermedades Metabólicas/etiología , Tamaño de los Órganos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Triglicéridos/sangre , DesteteRESUMEN
BACKGROUND: Inactivation of glucocorticoid hormones and p44/42 mitogen-activated protein kinase (MAPK) is thought to be important in small intestinal maturation and expression of genes related to intestinal differentiation and functions. METHODS: We investigated target genes induced by co-treatment for 48h with a glucocorticoid hormone agonist, dexamethasone (Dex), and a p44/42 MAPK inhibitor, PD98059 (PD), in a small intestine-like cell line (Caco-2) using microarray analysis. We also investigated whether expression changes of the target genes induced by the co-treatment are associated with histone modifications around these genes. RESULTS: Co-treatment of Caco-2 cells with Dex and PD enhanced several genes related to intestinal differentiation and functions such as SCNN1A, FXYD3, LCT and LOX. Induction of the SCNN1A gene was associated with increased presence of acetylated histone H3 and H4 and di-methylated histone H3 at lysine (K) 4 around the transcribed region of the gene, and induction of the FXYD3 gene was associated with increased presence of acetylated histones H3 and H4 from the promoter/enhancer to the transcribed region of the gene. Induction of LCT and LOX genes was associated with increased presence of acetylated histone H4 on the promoter/enhancer region of the genes. CONCLUSIONS: Histone acetylation and/or histone H3 K4 methylation around the promoter/enhancer or/and transcribed regions of target genes are associated with induction of the genes by co-treatment with Dex and PD in Caco-2 cells. GENERAL SIGNIFICANCE: The histone code is specific to each gene with respect to induction by glucocorticoid hormone and inhibition of p44/42 MAPK in Caco-2 cells.
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Biomarcadores/metabolismo , Dexametasona/farmacología , Flavonoides/farmacología , Código de Histonas/efectos de los fármacos , Código de Histonas/genética , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Acetilación , Antineoplásicos Hormonales/farmacología , Células CACO-2 , Inmunoprecipitación de Cromatina , Perfilación de la Expresión Génica , Humanos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Regiones Promotoras Genéticas , Inhibidores de Proteínas Quinasas/farmacología , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Neurodevelopmental disorders (NDs) are currently thought to be caused by either genetic defects or various environmental factors. Recent studies have demonstrated that congenital NDs can result not only from changes in DNA sequence in neuronal genes but also from changes to the secondary epigenomic modifications of DNA and histone proteins. Thus, epigenomic assays, as well as genomic assays, are currently performed for diagnosis of the congenital NDs. It is recently known that the epigenomic modifications can be altered by various environmental factors, which potentially cause acquired NDs. Furthermore these alterations can potentially be restored taking advantage of use of reversibility in epigenomics. Therefore, epigenome-based early diagnosis and subsequent intervention, by using drugs that restore epigenomic alterations, will open up a new era of preemptive medicine for congenital and acquired NDs.
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PURPOSE: Faster eating is positively associated with body mass index in apparently healthy Japanese populations. In the present study, we examined the associations between self-reported rate of eating and visceral and subcutaneous fat areas in apparently healthy middle-aged Japanese men. METHODS: We conducted a cross-sectional study of men who participated in health checkups in Japan. We removed participants who were diagnosed with metabolic diseases by the time of their health checkups. A total of 320 subjects aged 30-64 years (mean ± standard deviation, 47.4 ± 8.6 years) were selected. We compared the associations between rate of eating and various clinical parameters including visceral and subcutaneous fat areas, using analysis of covariance (ANCOVA), which was adjusted by age and lifestyle factors such as alcohol intake, energy intake, smoking, and physical activity. Multivariate logistic regression analyses (MLRA) were performed with visceral fat area (cm(2)) as the dependent variable and independent variables that included self-reported rate of eating. RESULTS: Tukey's multiple test following ANCOVA showed that self-reported rate of eating was positively associated with visceral fat area (cm(2)), but not with subcutaneous fat area (cm(2)). MLRA showed that the odds ratio of rate of eating for visceral fat area in tertile (T) 3 (>100 cm(2)) compared with T1 (≤70 cm(2)) was 1.99 (95% CI 1.40-2.90, P < 0.01), and the association remained after adjustment for the subcutaneous fat area. CONCLUSIONS: The present results show that self-reported faster eating is positively associated with visceral fat accumulation, independently of subcutaneous fat accumulation, in apparently healthy Japanese men.
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Adiposidad , Pueblo Asiatico , Conducta Alimentaria , Grasa Intraabdominal/anatomía & histología , Adulto , Consumo de Bebidas Alcohólicas , Índice de Masa Corporal , Peso Corporal , Estudios Transversales , Ingestión de Energía , Voluntarios Sanos , Humanos , Estilo de Vida , Modelos Logísticos , Masculino , Persona de Mediana Edad , Actividad Motora , Análisis Multivariante , Autoinforme , Grasa Subcutánea/anatomía & histologíaRESUMEN
Fasting for 3 days leads to reduction in the expression of GLUT5 and SGLT1 genes in jejunum. Re-feeding a high-sucrose diet in fasted rats enhanced mRNA levels and histone H3 acetylation on transcribed region of GLUT5 gene within 24 h, but not in SGLT1. Responsiveness of jejunal GLUT5 gene is associated with changes in histone H3 acetylation on transcribed region.
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Sacarosa en la Dieta/efectos adversos , Regulación de la Expresión Génica/efectos de los fármacos , Transportador de Glucosa de Tipo 5/genética , Histonas/metabolismo , Yeyuno/metabolismo , Inanición , Transcripción Genética/efectos de los fármacos , Acetilación/efectos de los fármacos , Animales , Yeyuno/efectos de los fármacos , Masculino , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Body mass index (BMI) is routinely used to ascertain health status, including activities of daily living (ADLs); however, the associations of ADLs with height and weight in older adults have not been elucidated. Therefore, we cross-sectionally investigated the correlations between ADLs and height, weight, and BMI in 155 participants aged 82 to 103 years and characterized the naïve Bayesian prediction for ADLs. Activities of daily living showed a significant negative correlation with height and weight and a positive correlation with age. In males, a shorter height was associated with an increased risk of falling and disability in phone calling independently, and losing weight was associated with an increased risk of disability in going out. Combining age, weight, and height improved the area under the receiver operating characteristic curve in the prediction of disability in going out and phone calling independently in males. Therefore, height and weight, not BMI, are potential predictors of ADL decline.
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Actividades Cotidianas , Estatura , Índice de Masa Corporal , Peso Corporal , Humanos , Masculino , Femenino , Anciano de 80 o más Años , Estudios Transversales , Japón , Teorema de Bayes , Anciano , Evaluación Geriátrica/métodos , Pueblos del Este de AsiaRESUMEN
Reactive oxygen species production might be prevented by xanthine oxidoreductase (XOR) inhibitors, which can cause glomerulosclerosis. We aimed to investigate whether topiroxostat, an XOR inhibitor, prevents diabetic kidney disease development in mice. Six-week-old control Institute of Cancer Research (ICR) mice and type 2 diabetic Nagoya Shibata Yasuda (NSY) mice were divided into the ICR group (ICR mice which received a lard-containing high-fat diet [HFD] based on the AIN-93G diet), NSY control group (NSY mice which received the same aforementioned diet), and NSY + topiroxostat group (NSY mice which received the same aforementioned diet with addition of 0.0012% topiroxostat). After 20 weeks, plasma biomarkers, XOR activity and oxidative stress levels, which were assessed using malondialdehyde (MDA), were measured through enzyme-linked immunosorbent assay or enzymatic methods. Renal pathology was evaluated using periodic acid-Schiff staining. Redox gene and protein expression were determined using RT-qPCR and western blotting, respectively. Plasma XOR activity was lower in NSY mice treated with topiroxostat than those without. Plasma cystatin C and creatinine levels did not differ between the ICR and NSY control groups or between the NSY control and NSY + topiroxostat groups. The NSY + topiroxostat group showed a smaller mesangial area than the NSY control group. The mRNA expression of Sod3, Prdx1, Gpx2, and Gpx3 was higher in the NSY + topiroxostat group than in the NSY control group. Renal MDA levels were lower in the NSY + topiroxostat group than in the NSY control group. Topiroxostat can reduce glomerulosclerosis, and the reduction is associated with renal oxidative markers.
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Recently, we have demonstrated that mice, cultured embryos in α-minimum essential medium (αMEM) and subsequent fed a high-fat, high-sugar diet, developed steatohepatitis. In this study, we investigated using these samples whether the expression of lipid droplet formation genes in the liver is higher in MEM mice, whether these expressions are regulated by histone acetylation, writers/readers of histone acetylation, and the transcriptional factors of endoplasmic reticulum stress. Mice were produced by two-cell embryos in αMEM or standard potassium simplex-optimized medium (control) in vitro for 48 h, and implanted into an oviduct for spontaneous delivery. MEM and control-mice were fed a high-fat, high-sugar diet for 18 wk, and then liver samples were collected and analyzed by histology, qRT-PCR, and chromatin immunoprecipitation assay. Gene expression of Cidea, Cidec, and Plin4 were higher in MEM mice and histone H3K9 acetylation, BRD4, and CBP were higher in MEM mice than in control mice around those genes. However, the binding of endoplasmic reticulum stress-related transcription factors (ATF4, CHOP and C/EBPα) around those genes in the liver, was not clearly differed between MEM mice and control mice. The increased expression of Cidea, Cidec and Plin4 in the liver, accompanied by the development of steatohepatitis in mice induced is positively associated with increased histone H3K9 acetylation and CBP and BRD4 binding around these genes.
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Estrés del Retículo Endoplásmico , Hígado Graso , Histonas , Gotas Lipídicas , Hígado , Animales , Histonas/metabolismo , Acetilación , Gotas Lipídicas/metabolismo , Ratones , Femenino , Hígado/metabolismo , Hígado Graso/metabolismo , Hígado Graso/genética , Hígado Graso/etiología , Factor de Transcripción Activador 4/metabolismo , Factor de Transcripción Activador 4/genética , Dieta Alta en Grasa/efectos adversos , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Factor de Transcripción CHOP/metabolismo , Factor de Transcripción CHOP/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Proteínas Potenciadoras de Unión a CCAAT/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Reguladoras de la Apoptosis/genéticaRESUMEN
Non-alcoholic steatohepatitis (NASH), caused by fat buildup, can lead to liver inflammation and damage. Elucidation of the spatial distribution of fibrotic tissue in the fatty liver in NASH can be immensely useful to understand its pathogenesis. Thus, we developed a novel serial section-3D (SS3D) technique that combines high-resolution image acquisition with 3D construction software, which enabled highly detailed analysis of the mouse liver and extraction and quantification of stained tissues. Moreover, we studied the underexplored mechanism of fibrosis progression in the fatty liver in NASH by subjecting the mice to a high-fat diet (HFD), followed by lipopolysaccharide (LPS) administration. The HFD/LPS (+) group showed extensive fibrosis compared with control; additionally, the area of these fibrotic regions in the HFD/LPS (+) group was almost double that of control using our SS3D technique. LPS administration led to an increase in Tnfα and Il1ß mRNA expression and the number of macrophages in the liver. On the other hand, transforming growth factor-ß1 (Tgfß1) mRNA increased in HFD group compared to that of control group without LPS-administration. In addition, COL1A1 levels increased in hepatic stellate cell (HSC)-like XL-2 cells when treated with recombinant TGF-ß1, which attenuated with recombinant latency-associated protein (rLAP). This attenuation was rescued with LPS-activated macrophages. Therefore, we demonstrated that fatty liver produced "latent-form" of TGF-ß1, which activated by macrophages via inflammatory cytokines such as TNFα and IL1ß, resulting in activation of HSCs leading to the production of COL1A1. Moreover, we established the effectiveness of our SS3D technique in creating 3D images of fibrotic tissue, which can be used to study other diseases as well.
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Dieta Alta en Grasa , Lipopolisacáridos , Cirrosis Hepática , Macrófagos , Enfermedad del Hígado Graso no Alcohólico , Factor de Crecimiento Transformador beta1 , Animales , Factor de Crecimiento Transformador beta1/metabolismo , Ratones , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Cirrosis Hepática/patología , Cirrosis Hepática/metabolismo , Dieta Alta en Grasa/efectos adversos , Masculino , Hígado/metabolismo , Hígado/patología , Ratones Endogámicos C57BL , Activación de Macrófagos , Imagenología Tridimensional/métodos , Modelos Animales de Enfermedad , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/patología , Interleucina-1beta/metabolismoRESUMEN
Obesity and ageing are the most important risk factors for sleep apnoea syndrome (SAS); however, the role of body mass index (BMI) on sleep status in healthy older adults is unclear. To explore sleep parameters according to BMI among active older adults, we cross-sectionally examined the relationship between sleep-related parameters and BMI in 32 Japanese adults aged from 83 to 95 years without long-term care who were unaware of having SAS. Correlation and linear regression analyses were performed. Moderate or severe SAS prevalence was high in both those with low (68.8%) and high (68.8%) BMI. A higher increase in apnoea-hypopnoea index (AHI) was negatively correlated with sleep depth in the high-BMI group. In the low-BMI group, the number of awakenings and age were positively correlated with AHI. Older adults may have SAS regardless of their BMI, and the sleep status of patients with SAS may vary by BMI.
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Hypertensive disorders of pregnancy (HDP) increase the risk of preterm births and cesarean delivery. This study aimed to investigate whether maternal blood leukocyte, monocyte, or neutrophil counts in the first trimester are related to the development of HDP. Data were collected from the Japan Environment and Children's Study, a large birth cohort study (n = 38,194) that recruited pregnant women in 15 Regional Centers across Japan (from January 2011 to March 2014). The odds ratios (ORs) for mild/severe HDP according to the cut-off value of leukocyte/neutrophil/monocyte counts by the receiver operating characteristic curve showed high ORs. Furthermore, pregnant women with the highest quartiles of leukocyte and monocyte counts had higher adjusted ORs (aORs) for mild (leukocyte: aOR = 1.27, 95% confidence interval [CI]: 1.02-1.58; monocyte: aOR = 1.30, 95% CI 1.04-1.63) and severe HDP (leukocyte: aOR = 1.51, 95% CI 1.08-2.13; monocyte: aOR = 1.44, 95% CI 1.03-2.01) compared with those with the lowest quartiles of those counts. In addition, pregnant women with the highest neutrophil counts had higher aOR for mild HDP (aOR = 1.26, 95% CI 1.02-1.56) compared with those with the lowest count. In conclusion, high leukocyte and monocyte counts in the first trimester are associated with the development of HDP. Thus, they may be used to predict subsequent HDP.
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Hipertensión Inducida en el Embarazo , Preeclampsia , Recién Nacido , Niño , Embarazo , Humanos , Femenino , Estudios de Cohortes , Hipertensión Inducida en el Embarazo/epidemiología , Neutrófilos , Monocitos , Japón/epidemiologíaRESUMEN
PURPOSE: The risk of metabolic syndrome (MetS) is assessed based on the presence of risk factors that include dyslipidemia, hyperglycemia, hypertension and obesity. In this study, we assessed the risk of MetS using principle component (PC) analysis of MetS diagnostic parameters and examined whether the resulting eigenvalues are associated with the circulating concentrations of inflammatory cytokines [interleukin (IL)-1ß and IL-6] and a marker for insulin sensitivity (adiponectin) in middle-aged Japanese men without treatment for metabolic diseases. MATERIALS: We conducted a cross-sectional study of 308 Japanese men without treatment for metabolic diseases aged 40-69 years who participated in health checkups in Japan. We calculated the PC1 score from the following MetS diagnostic parameters: body mass index (BMI), fasting blood glucose, diastolic blood pressure, triacylglycerol and high-density lipoprotein cholesterol. We compared the relationship between PC1 scores and other clinical parameters, including IL-1ß, IL-6 and adiponectin, by Spearman's rank correlation coefficient analyses and Jonckheere-Terpstra test. RESULTS: The associations for most clinical parameters were higher with the PC1 score than with other MetS diagnostic parameters. Homeostasis model assessment-insulin resistance, an index of insulin resistance, showed stronger associations with PC1 score than with MetS diagnostic parameters. Significant associations for IL-1ß, IL-6 and adiponectin were observed with the PC1 score, BMI and triacylglycerol; these associations were higher with the PC1 score than with BMI and triacylglycerol. CONCLUSIONS: The present results show that the PC1 score is closely associated with parameters of MetS, inflammation and insulin resistance.
Asunto(s)
Biomarcadores/sangre , Síndrome Metabólico/sangre , Síndrome Metabólico/diagnóstico , Análisis de Componente Principal/métodos , Adiponectina/sangre , Adulto , Anciano , Pueblo Asiatico , Glucemia/análisis , Índice de Masa Corporal , HDL-Colesterol/sangre , Estudios Transversales , Humanos , Insulina/sangre , Resistencia a la Insulina , Interleucina-1beta/sangre , Interleucina-6/sangre , Japón/epidemiología , Masculino , Persona de Mediana Edad , Factores de Riesgo , Triglicéridos/sangreRESUMEN
PURPOSE: Elevated circulating activities of alanine aminotransferase (ALT), a marker for liver injury, and the lifestyle of a higher rate of eating in healthy and preclinical subjects are associated with increased risk of obesity and diabetes. In this study, we examined the associations between self-reported rate of eating and circulating ALT activity in middle-aged apparently healthy Japanese men. METHODS: We conducted a cross-sectional study of 3,929 apparently healthy men aged 40-59 years (mean ± SD age, 49.2 ± 5.8 years; BMI, 23.5 ± 2.8 kg/m²) who participated in health checkups in Japan. We analyzed their clinical serum parameters and lifestyle factors, including self-reported rate of eating. Associations between self-reported rate of eating and liver injury markers [ALT, γ-glutamyl transpeptidase (GTP), and aspartate aminotransferase (AST)], other clinical parameters or lifestyle factors were determined using analysis of variance followed by Tukey's test. Multivariate logistic regression analyses (MLRA) were performed with ALT activity as the dependent variable and independent variables that included self-reported rate of eating. RESULTS: MLRA showed that ALT activity showed trends for higher self-reported rate of eating after adjustment for age, energy intake, and smoking status. The association between ALT activity and self-reported rate of eating disappeared after adjustment for BMI. CONCLUSION: The results of this study show that ALT activity is positively associated with self-reported rate of eating in middle-aged apparently healthy Japanese men.