RESUMEN
Congenital heart defects with heterotaxia are associated with pregestational diabetes mellitus. To provide insight into the mechanisms underlying such diabetes-related heart defects, we examined the effects of high-glucose concentrations on formation of the left-right axis in mouse embryos. Expression of Pitx2, which plays a key role in left-right asymmetric morphogenesis and cardiac development, was lost in the left lateral plate mesoderm of embryos of diabetic dams. Embryos exposed to high-glucose concentrations in culture also failed to express Nodal and Pitx2 in the left lateral plate mesoderm. The distribution of phosphorylated Smad2 revealed that Nodal activity in the node was attenuated, accounting for the failure of left-right axis formation. Consistent with this notion, Notch signal-dependent expression of Nodal-related genes in the node was also down-regulated in association with a reduced level of Notch signaling, suggesting that high-glucose concentrations impede Notch signaling and thereby hinder establishment of the left-right axis required for heart morphogenesis.
Asunto(s)
Tipificación del Cuerpo/genética , Corazón/fisiología , Hiperglucemia/fisiopatología , Animales , Glucemia/química , Modelos Animales de Enfermedad , Células Madre Embrionarias/citología , Femenino , Regulación del Desarrollo de la Expresión Génica , Glucosa/química , Glucosa/metabolismo , Células HEK293 , Cardiopatías Congénitas/fisiopatología , Humanos , Mesodermo/fisiología , Ratones , Microscopía Electrónica de Rastreo , Morfogénesis/genética , Fosforilación , Receptores Notch/metabolismo , Transducción de Señal , Factores de TiempoRESUMEN
GPCRs are involved in numerous physiologic functions and are important drug targets. Although the epithelial barrier is important for protection from invading pathogens, the correlation between GPCRs and epithelial barrier function remains unknown. Leukotriene B4 (LTB4) receptor type 2 (BLT2), mainly expressed in epithelial cells, is a GPCR for 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT) and LTB4. In our study, BLT2 localized at the lateral membrane in BLT2-overexpressing Madin-Darby canine kidney (MDCK) II cells and in the small intestine of BLT2-transgenic mice. BLT2-deficient mice exhibited higher transepidermal water loss and were more sensitive to epicutaneous sensitization. MDCK-BLT2 cells recovered transepithelial electrical resistance (TER) after a calcium switch faster than did MDCK-Mock cells, and 12-HHT stimulation accelerated TER recovery only in MDCK-BLT2 cells. Quantitative PCR and immunoblot analyses revealed that the 12-HHT/BLT2 axis up-regulated claudin-4 (CLDN4) expression in MDCK-BLT2 cells and human primary keratinocytes, and CLDN4 knockdown abolished 12-HHT-dependent TER recovery. Acceleration of TER recovery and induction of CLDN4 expression by 12-HHT stimulation were abolished by inhibition of Gαi protein or p38 MAPK. These results show that 12-HHT/BLT2 enhances epithelial barrier function by increasing CLDN4 expression via the Gαi protein-p38 MAPK pathway.
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Sistema de Señalización de MAP Quinasas/fisiología , Receptores de Leucotrieno B4/metabolismo , Piel/metabolismo , Uniones Estrechas/metabolismo , Animales , Claudina-4/biosíntesis , Claudina-4/genética , Perros , Ácidos Grasos Insaturados/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Células de Riñón Canino Madin Darby , Ratones , Ratones Noqueados , Receptores de Leucotrieno B4/genética , Piel/citología , Uniones Estrechas/genética , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Nivolumab, an anti-programmed death-1 antibody, is a breakthrough treatment for several malignancies. Its specific adverse effects caused by autoimmunity are termed immune-related adverse events, which involve several endocrine dysfunctions. Herein, we report two cases of isolated adrenocorticotropic hormone (ACTH) deficiency induced by nivolumab for the treatment of metastatic malignant melanoma. Case 1 was a 39-year-old man and Case 2 was a 50-year-old woman, both of whom presented with progressive melanoma. After 13 courses of nivolumab administration, both cases were diagnosed with adrenal insufficiency. Despite their basal serum ACTH and cortisol levels being low with little response to corticotropin-releasing hormone loading, other anterior pituitary hormone levels were preserved. Based on these endocrinological data, isolated ACTH deficiency was diagnosed. Magnetic resonance imaging showed normal pituitary glands, excluding hypophysitis. Finally, hydrocortisone replacement enabled the patients to continue nivolumab treatment. Therefore, it is important to consider isolated ACTH syndrome as a possible and potentially severe immune-related adverse event of nivolumab, even when head magnetic resonance imaging of affected cases does not show enlargement. We should not misdiagnose hidden immune-related adverse events behind general complaints of malignancies such as general malaise and appetite loss, to allow successful treatment using this beneficial immune checkpoint inhibitor.
Asunto(s)
Hormona Adrenocorticotrópica/deficiencia , Anticuerpos Monoclonales/efectos adversos , Autoinmunidad , Enfermedades del Sistema Endocrino/inducido químicamente , Enfermedades del Sistema Endocrino/inmunología , Enfermedades Genéticas Congénitas/inducido químicamente , Enfermedades Genéticas Congénitas/inmunología , Hipoglucemia/inducido químicamente , Hipoglucemia/inmunología , Hormona Adrenocorticotrópica/inmunología , Adulto , Autoinmunidad/efectos de los fármacos , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , NivolumabRESUMEN
The node triggers formation of the left-right axis in mouse embryos by establishing local asymmetry of Nodal and Cerl2 expression. We found that Wnt3 is expressed in perinodal crown cells preferentially on the left side. The enhancer responsible for Wnt3 expression was identified and found to be regulated by Foxa2 and Rbpj under the control of Notch signaling. Rbpj binding sites suppress enhancer activity in pit cells of the node, thereby ensuring crown cell-specific expression. In addition, we found that the expression of Gdf1 and Cerl2 is also regulated by Notch signaling, suggesting that such signaling may induce the expression of genes related to left-right asymmetry as a set. Furthermore, Cerl2 expression became symmetric in response to inhibition of Wnt-ß-catenin signaling. Our results suggest that Wnt signaling regulates the asymmetry of Cerl2 expression, which likely generates a left-right difference in Nodal activity at the node for further amplification in lateral plate mesoderm.
Asunto(s)
Tipificación del Cuerpo , Vía de Señalización Wnt/fisiología , Animales , Femenino , Factor Nuclear 3-beta del Hepatocito/fisiología , Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas/fisiología , Péptidos y Proteínas de Señalización Intercelular/fisiología , Ratones , Ratones Endogámicos ICR , Proteína Wnt3/fisiologíaRESUMEN
The mouse inner ear develops from a simple epithelial pouch, the otocyst, with the dorsal and ventral portions giving rise to the vestibule and cochlea, respectively. The otocyst undergoes a morphological change to generate flattened saclike structures, known as outpocketings, in the dorsal and lateral regions. The semicircular canals of the vestibule form from the periphery of the outpocketings, with the central region (the fusion plate) undergoing de-epithelialization and disappearing. However, little is known of the mechanism that orchestrates formation of the semicircular canals. We now show that the area of canonical Wnt signaling changes dynamically in the dorsal otocyst during its morphogenesis. The genes for several Wnt ligands were found to be expressed in the dorsal otocyst according to specific patterns, whereas those for secreted inhibitors of Wnt ligands were expressed exclusively in the ventral otocyst. With the use of whole-embryo culture in combination with potent modulators of canonical Wnt signaling, we found that forced persistence of such signaling resulted in impaired formation both of the lateral outpocketing and of the fusion plates of the dorsal outpocketing. Canonical Wnt signaling was found to suppress Netrin1 expression and to preserve the integrity of the outpocketing epithelium. In addition, inhibition of canonical Wnt signaling reduced the size of the otocyst, likely through suppression of cell proliferation and promotion of apoptosis. Our stage-specific functional analysis suggests that strict regulation of canonical Wnt signaling in the dorsal otocyst orchestrates the process of semicircular canal formation.
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Oído Interno/citología , Regulación del Desarrollo de la Expresión Génica/fisiología , Morfogénesis/fisiología , Canales Semicirculares/embriología , Proteínas Wnt/metabolismo , Vía de Señalización Wnt/fisiología , Animales , Oído Interno/embriología , Técnica del Anticuerpo Fluorescente , Hibridación in Situ , Ratones , Ratones Endogámicos ICR , Factores de Crecimiento Nervioso/metabolismo , Netrina-1 , Estadísticas no Paramétricas , Proteínas Supresoras de Tumor/metabolismoRESUMEN
The node at the anterior tip of the primitive streak serves as an initial generator of the left-right (L-R) axis in mammalian embryos. We now show that a small disturbance in molecular signaling at the node is responsible for the L-R reversal of visceral organs in the inv mutant mouse. In the node of wild-type embryos, the expression of Nodal and Cerl2 (Dand5), which encodes an inhibitor of Nodal, is asymmetric, with the level of Nodal expression being higher on the left side and that of Cerl2 expression higher on the right. In inv/inv embryos, however, a localized reduction in the level of Cerl2 expression results in upregulation of the Nodal signal and a consequent induction of Lefty expression in the node. The ectopic expression of Lefty1 delays the onset of Nodal expression in the lateral plate mesoderm. L-R asymmetry of Cerl2 expression in the node also becomes reversed in a manner dependent on the Nodal signal. Nodal expression in the lateral plate mesoderm then appears on the right side, probably reflecting the balance between Nodal and Cerl2 in the node. The inhibition of Cerl2 expression by the Nodal signal suggests a mechanism for amplification of the cue for L-R asymmetry provided by nodal flow and for stabilization of asymmetric gene expression around the node. In inv/inv embryos, this system may function in reverse as a result of ectopic production of Lefty, which inhibits the Nodal signal on the left side in a manner dependent on leftward nodal flow.
Asunto(s)
Tipificación del Cuerpo/fisiología , Proteína Nodal/metabolismo , Organizadores Embrionarios/metabolismo , Transducción de Señal/fisiología , Animales , Tipificación del Cuerpo/genética , Cruzamientos Genéticos , Regulación del Desarrollo de la Expresión Génica , Inmunohistoquímica , Hibridación in Situ , Ratones , Ratones Transgénicos , Modelos Biológicos , Proteína Nodal/genética , Técnicas de Cultivo de ÓrganosRESUMEN
RATIONALE: During embryogenesis, the CXC chemokine ligand (CXCL)12 acts on endothelial cells to control cardiac development and angiogenesis. Although biological functions of CXCL12 are exerted in part through activation of the small GTPase Rac, the pathway leading from its receptor CXC chemokine receptor (CXCR)4 to Rac activation remains to be determined. OBJECTIVE: DOCK180 (dedicator of cytokinesis), an atypical Rac activator, has been implicated in various cellular functions. Here, we examined the role of DOCK180 in cardiovascular development. METHODS AND RESULTS: DOCK180 associates with ELMO (engulfment and cell motility) through the N-terminal region containing a Src homology 3 domain. We found that targeted deletion of the Src homology 3 domain of DOCK180 in mice leads to embryonic lethality with marked reduction of DOCK180 expression at the protein level. These mutant mice, as well as DOCK180-deficient mice, exhibited multiple cardiovascular abnormalities resembling those seen in CXCR4-deficient mice. In DOCK180 knocked down endothelial cells, CXCL12-induced Rac activation was impaired, resulting in a marked reduction of cell motility. CONCLUSIONS: These results suggest that DOCK180 links CXCR4 signaling to Rac activation to control endothelial cell migration during cardiovascular development.
Asunto(s)
Factores de Intercambio de Guanina Nucleótido/fisiología , Corazón/embriología , Corazón/crecimiento & desarrollo , Receptores CXCR4/fisiología , Proteínas de Unión al GTP rac/metabolismo , Animales , Línea Celular , Movimiento Celular/fisiología , Endotelio Vascular/embriología , Endotelio Vascular/crecimiento & desarrollo , Endotelio Vascular/fisiología , Activación Enzimática/fisiología , Factores de Intercambio de Guanina Nucleótido/deficiencia , Humanos , Ratones , Ratones Noqueados , Ratones Transgénicos , Transducción de Señal/fisiologíaRESUMEN
Fgf signaling plays pivotal roles in mouse gastrulation and left-right axis formation. However, although genetic analyses have revealed important aspects of Fgf signaling in these processes, the temporal resolution of genetic studies is low. Here, we combined whole-embryo culture with application of chemical compounds to inhibit Fgf signaling at specific time points. We found that sodium chlorate and PD173074 are potent inhibitors of Fgf signaling in early mouse embryos. Fgf signaling is required for the epithelial-to-mesenchymal transition of the primitive streak before the onset of gastrulation. Once gastrulation begins, Fgf signaling specifies mesodermal fates via the Ras/MAPK downstream cascade. Finally, Fgf signaling on the posterior side of the embryo during gastrulation induces Nodal expression in the node via Tbx6-Dll1, the initial event required for Nodal expression in the left lateral plate mesoderm.
Asunto(s)
Factores de Crecimiento de Fibroblastos/metabolismo , Transducción de Señal/genética , Animales , Embrión de Mamíferos , Femenino , Factores de Crecimiento de Fibroblastos/genética , Gastrulación , Mesodermo/metabolismo , Ratones , Ratones Endogámicos ICR , EmbarazoRESUMEN
Leukotriene B4 (LTB4) receptor 1 (BLT1) is a chemotactic G protein-coupled receptor expressed by leukocytes, such as granulocytes, macrophages, and activated T cells. Although there is growing evidence that BLT1 plays crucial roles in immune responses, its role in dendritic cells remains largely unknown. Here, we identified novel DC subsets defined by the expression of BLT1, namely, BLT1hi and BLT1lo DCs. We also found that BLT1hi and BLT1lo DCs differentially migrated toward LTB4 and CCL21, a lymph node-homing chemoattractant, respectively. By generating LTB4-producing enzyme LTA4H knockout mice and CD11c promoter-driven Cre recombinase-expressing BLT1 conditional knockout (BLT1 cKO) mice, we showed that the migration of BLT1hi DCs exacerbated allergic contact dermatitis. Comprehensive transcriptome analysis revealed that BLT1hi DCs preferentially induced Th1 differentiation by upregulating IL-12p35 expression, whereas BLT1lo DCs accelerated T cell proliferation by producing IL-2. Collectively, the data reveal an unexpected role for BLT1 as a novel DC subset marker and provide novel insights into the role of the LTB4-BLT1 axis in the spatiotemporal regulation of distinct DC subsets.
Asunto(s)
Células Dendríticas/metabolismo , Hipersensibilidad/patología , Inflamación/patología , Receptores de Leucotrieno B4/metabolismo , Piel/patología , Animales , Biomarcadores/metabolismo , Diferenciación Celular/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Quimiocina CCL21/farmacología , Células Dendríticas/efectos de los fármacos , Dermatitis Atópica/complicaciones , Dermatitis Atópica/inmunología , Dermatitis Atópica/patología , Hipersensibilidad/complicaciones , Hipersensibilidad/inmunología , Inflamación/complicaciones , Inflamación/inmunología , Interleucina-12/biosíntesis , Leucotrieno B4/metabolismo , Ganglios Linfáticos/efectos de los fármacos , Ratones Endogámicos C57BL , Células TH1/efectos de los fármacos , Células TH1/inmunología , Transcriptoma/genéticaRESUMEN
An 82-year-old woman was admitted to the hospital with dyspnea and fatigue. She had been given amlodipine, furosemide, candesartan, pravastatin and roxatidine acetate for two months in an other hospital. Chest CT showed patchy consolidations throughout the entire lungs. We suspected drug-induced pneumonia, and treated her with prednisolone under mechanical ventilation. The pulmonary consolidations eventually improved, but on the 15th hospital day the patient developed thrombocytopenia and disseminated intravascular coagulation (DIC). Heparin flushes had been performed since the first hospital day. After these were stopped, her platelet count became normal and the patient recovered from DIC. The clinical course, and the fact that testing for heparin-induced thrombocytopenia (HIT) antibodies was positive, supported the diagnosis of HIT and DIC. We report a rare case of HIT and DIC during treatment for drug-induced pneumonia.
Asunto(s)
Coagulación Intravascular Diseminada/inducido químicamente , Heparina/efectos adversos , Neumonía/inducido químicamente , Neumonía/complicaciones , Trombocitopenia/inducido químicamente , Anciano de 80 o más Años , Femenino , HumanosRESUMEN
The endocardium is the endothelial component of the vertebrate heart and plays a key role in heart development. Where, when, and how the endocardium segregates during embryogenesis have remained largely unknown, however. We now show that Nkx2-5+ cardiac progenitor cells (CPCs) that express the Sry-type HMG box gene Sox17 from embryonic day (E) 7.5 to E8.5 specifically differentiate into the endocardium in mouse embryos. Although Sox17 is not essential or sufficient for endocardium fate, it can bias the fate of CPCs toward the endocardium. On the other hand, Sox17 expression in the endocardium is required for heart development. Deletion of Sox17 specifically in the mesoderm markedly impaired endocardium development with regard to cell proliferation and behavior. The proliferation of cardiomyocytes, ventricular trabeculation, and myocardium thickening were also impaired in a non-cell-autonomous manner in the Sox17 mutant, likely as a consequence of down-regulation of NOTCH signaling. An unknown signal, regulated by Sox17 and required for nurturing of the myocardium, is responsible for the reduction in NOTCH-related genes in the mutant embryos. Our results thus provide insight into differentiation of the endocardium and its role in heart development.
Asunto(s)
Diferenciación Celular , Embrión de Mamíferos/embriología , Endocardio/embriología , Regulación del Desarrollo de la Expresión Génica , Proteínas HMGB/biosíntesis , Factores de Transcripción SOXF/biosíntesis , Transducción de Señal , Células Madre/metabolismo , Animales , Embrión de Mamíferos/citología , Endocardio/citología , Proteínas HMGB/genética , Mesodermo/citología , Mesodermo/embriología , Ratones , Ratones Transgénicos , Receptores Notch/genética , Receptores Notch/metabolismo , Factores de Transcripción SOXF/genética , Células Madre/citologíaRESUMEN
BACKGROUND: A clustering of insulin resistance, hypertension, and dyslipidemia has been labeled as metabolic syndrome. Asians have a lower frequency of obesity than do Caucasians but have an increasing tendency toward metabolic syndrome. METHODS: We conducted a cross-sectional study of individuals aged 30-60 years. We analyzed the health data of 596 Japanese and Mongolians for metabolic syndrome based on the Third Report of the National Cholesterol Educational Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III) definition and the three modified ATP III definitions. RESULTS: The prevalence of metabolic syndrome using ATP III criteria was 6% for the Japanese and 12% for the Mongolians, a remarkable lower prevalence relative to the reported prevalence in the United States. With the exception of visceral obesity, the prevalences of individual metabolic abnormalities within each of the two Asian groups were similar to each other and to reported rates of prevalence in the United States. CONCLUSIONS: A universal metabolic syndrome definition is inappropriate for comparisons of metabolic syndrome among Asian ethnic groups. We believe that the ATP III index for visceral obesity should be adjusted for Asian populations.
Asunto(s)
Pueblo Asiatico , Hipercolesterolemia/epidemiología , Hipercolesterolemia/terapia , Síndrome Metabólico/epidemiología , Síndrome Metabólico/terapia , Adulto , Estudios Transversales , Femenino , Humanos , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/etnología , Masculino , Síndrome Metabólico/diagnóstico , Síndrome Metabólico/etnología , Persona de Mediana Edad , Guías de Práctica Clínica como Asunto , PrevalenciaRESUMEN
OBJECTIVE: Asians have a unique feature characterized by a low frequency of obesity, but a high frequency of diabetes and metabolic syndrome. It is important to develop simple and reliable anthropometric measurement tools for multiple metabolic disorders, but the cut-off values of anthropometric measurements for Asians have been less clear than those for Caucasians. RESEARCH DESIGN: Data from 361 Japanese and 252 Mongolians aged 30-60 years were investigated for the relationship between multiple metabolic disorders parameters and anthropometric measurements. Pearson's correlation coefficients and receiver operating characteristic (ROC) analysis were done. RESULTS: Mongolians of both genders had significantly higher values for all anthropometric measurements than did the Japanese. The Japanese anthropometric measurements showed the highest correlation coefficient of the area under the curve (AUC) from an ROC analysis for HDL-C and triglyceride, while the Mongolians showed the highest values for HOMA-IR. BMI and waist circumference (WC) for both ethnic groups showed relatively higher AUCs for the multiple metabolic disorders parameters. Optimal cut-off values predicting multiple metabolic disorders in the Japanese were estimated at 24 BMI and 82 cm WC (men) and 23 BMI and 73 cm WC (women); for the Mongolian, 27 BMI and 92 cm WC (men) and 27 BMI and 84 cm WC (women). CONCLUSIONS: There were great differences in diagnostic accuracy for the anthropometric measurements by ethnicity, and a relatively lower magnitude of differences by kind of anthropometric measurement. The present study suggests that BMI and WC were useful for predicting multiple metabolic disorders in non-diabetic Mongolians and Japanese, while the use of plasma triglyceride and HDL-cholesterol levels in combination with BMI and WC may enhance the ability of predicting metabolic parameters in the Japanese.
Asunto(s)
Antropometría/métodos , Pueblo Asiatico , Enfermedades Metabólicas/epidemiología , Adulto , Consumo de Bebidas Alcohólicas , Glucemia/metabolismo , Presión Sanguínea , Tamaño Corporal , Colesterol/sangre , Ejercicio Físico , Femenino , Humanos , Insulina/sangre , Japón , Lipoproteínas/sangre , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , FumarRESUMEN
A clustering of insulin resistance, hypertension and dyslipidemia has been labeled as the metabolic syndrome. Asians have a lower frequency of obesity than do Caucasians, but have an increasing tendency toward metabolic syndrome. Most data on metabolic syndrome are based on studies from Western countries with only limited information derived from Asian populations. We conducted a cross-sectional study of individuals aged 30-60 yr in workplace settings. We examined and analyzed the health data of 1,384 Japanese, Koreans and Mongolians for metabolic syndrome based on the modified definitions of the working definition proposed by the Third Report of the National Cholesterol Educational Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III definition). The prevalence of metabolic syndrome using the ATP III-BMI30 and ATP III-BMI25 definitions was 7% and 12% for Japanese, 7% and 13% for Koreans, and 12% and 16% for Mongolians, respectively. With the exception of obesity, the prevalences of individual metabolic abnormalities within each of the three Asian groups were similar to each other and to reported rates of prevalence in the U.S.A. Nevertheless, the values of sensitivity and specificity by the metabolic syndrome definitions are remarkably different relative to ethnicity. A universal metabolic syndrome definition is inappropriate for comparisons of metabolic syndrome among Asian ethnic groups. We believe that the ATP III-BMI25 definition is suitable for the determination of metabolic syndrome among Japanese and Koreans, and that the ATP III-BMI30 is more appropriate for Mongolians.
Asunto(s)
Estilo de Vida , Enfermedades Metabólicas/etnología , Obesidad/epidemiología , Adulto , Antropometría , Estudios Transversales , Femenino , Humanos , Hipertensión/epidemiología , Japón/epidemiología , Corea (Geográfico)/epidemiología , Masculino , Enfermedades Metabólicas/clasificación , Enfermedades Metabólicas/diagnóstico , Persona de Mediana Edad , Mongolia/epidemiología , Prevalencia , Sensibilidad y Especificidad , Distribución por SexoRESUMEN
Obesity occurs less frequently in Japanese than in various other ethnic populations. A person with abnormal glucose tolerance is often found to have one or more of the other cardiovascular disease risk factors, such as obesity, hypertension and hyperlipidemia. This clustering has been labeled as metabolic syndrome (WHO, 1998). It was suggested that Japanese, categorized as having normal weight (BMI of less than 25.0), as defined by the WHO (2000), have an increasing tendency toward metabolic syndrome. Our objective was to analyze metabolic syndrome in "Overweight" with BMI of 23.0-24.9 in Japanese workers, and to assess the suitability for Asians of the Regional Office for the Western Pacific Region of WHO criteria pertaining to obesity (WPRO criteria, 2000). We conducted a cross-sectional study in the workplace setting and investigated the relationship between BMI classification based on WPRO criteria and metabolic syndrome by gender and age group (18-44 yr vs. 45-60 yr). Three hundred seventy-nine men and 432 women Japanese workers participated in this study. BMI were categorized as 20% "Overweight" (23.0-24.9 BMI), 20% "Obese I" (25.0-29.9 BMI) and 2% "Obese II" (over 30.0 BMI), based on WPRO criteria. Graded increases in BMI were positively associated with body fat percentage, waist circumference, hip circumference and waist/hip ratio in both genders and age groups. A progressively increasing BMI category in the elder group aged 45-60 yr in both genders was positively related with parameters constituting metabolic syndrome. Graded increases in BMI classes in elder workers based on WPRO criteria were positively associated with prevalence of metabolic syndrome, and "Overweight" elder women had significantly higher prevalence of metabolic syndrome. The present investigation, based on the increasing risks of "Overweight" with a BMI of 23.0-24.9, suggests that WPRO criteria are suitable for Japanese workers aged over 45 yr.
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Índice de Masa Corporal , Síndrome Metabólico/prevención & control , Obesidad/diagnóstico , Salud Laboral , Adolescente , Adulto , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Organización Mundial de la SaludRESUMEN
Epiblast stem cells (EpiSCs) are primed pluripotent stem cells and can be derived from postimplantation mouse embryos. We now show that the absence of canonical Wnt/ß-catenin signaling is essential for maintenance of the undifferentiated state in mouse EpiSCs and in the epiblast of mouse embryos. Attenuation of Wnt signaling with the small-molecule inhibitor XAV939 or deletion of the ß-catenin gene blocked spontaneous differentiation of EpiSCs toward mesoderm and enhanced the expression of pluripotency factor genes, allowing propagation of EpiSCs as a homogeneous population. EpiSCs were efficiently established and propagated from single epiblast cells in the presence of both XAV939 and the Rho kinase (ROCK) inhibitor Y27632. Cell transplantation revealed that EpiSCs were able to contribute to primordial germ cells and descendants of all three germ layers in a host embryo, suggesting that they maintained pluripotency, even after prolonged culture with XAV939. Such an improvement in the homogeneity of pluripotency achieved with the use of a Wnt inhibitor should prove advantageous for manipulation of primed pluripotent stem cells.
Asunto(s)
Implantación del Embrión , Células Madre Embrionarias/citología , Estratos Germinativos/citología , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Amidas/farmacología , Animales , Diferenciación Celular/efectos de los fármacos , Células Madre Embrionarias/efectos de los fármacos , Células Madre Embrionarias/trasplante , Eliminación de Gen , Estratos Germinativos/efectos de los fármacos , Estratos Germinativos/metabolismo , Mesodermo/citología , Mesodermo/efectos de los fármacos , Ratones , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/efectos de los fármacos , Piridinas/farmacología , Transducción de Señal/efectos de los fármacos , Trasplante de Células Madre , beta Catenina/deficiencia , beta Catenina/genéticaAsunto(s)
Pueblo Asiatico/estadística & datos numéricos , Índice de Masa Corporal , Obesidad/diagnóstico , Antropometría/métodos , Asia/etnología , HDL-Colesterol/sangre , Impedancia Eléctrica , Humanos , Síndrome Metabólico/sangre , Síndrome Metabólico/diagnóstico , Síndrome Metabólico/etnología , Obesidad/sangre , Obesidad/etnología , Triglicéridos/sangre , Población Blanca/estadística & datos numéricosRESUMEN
The effects of dietary consumption of mulberry (Morus alba L.) leaves and their major flavonol glycoside, quercetin 3-(6-malonylglucoside) (Q3MG), on the development of atherosclerotic lesions, in relation to the susceptibility of plasma LDL to oxidative modification, was studied in LDL receptor-deficient (LDLR-/-) mice. Male mice aged 8 wk were randomly assigned to 4 groups (control, quercetin, Q3MG, and mulberry). The control group was fed an atherogenic-diet containing 3 g cholesterol and 15 g cocoa butter/100 g. The other experimental groups were fed the same atherogenic diet supplemented with 0.05 g quercetin/100 g for the quercetin group, 0.05 g Q3MG/100 g for the Q3MG group, and 3 g dried mulberry-leaf powder/100 g for the mulberry group. The mice were fed their respective diets for 8 wk. The susceptibility of LDL to oxidative modification was significantly decreased in the Q3MG- and mulberry-treated mice, as evidenced by the 44.3 and 42.2% prolongation of the lag phase for conjugated diene formation compared with that of the control mice. The atherosclerotic lesion area in both the Q3MG- and mulberry-treated mice was significantly reduced by 52% compared with that of the controls. However, in the quercetin group, no protective effects were observed against LDL oxidation or atherosclerotic lesion formation. In conclusion, mulberry leaves attenuated the atherosclerotic lesion development in LDLR-/- mice through enhancement of LDL resistance to oxidative modification, and these antioxidative and antiatherogenic protective effects were attributed mainly to Q3MG, the quantitatively major flavonol glycoside in mulberry leaves.
Asunto(s)
Arteriosclerosis/prevención & control , Morus , Fitoterapia , Hojas de la Planta , Quercetina/análogos & derivados , Quercetina/uso terapéutico , Receptores de LDL/fisiología , Administración Oral , Animales , Aorta/efectos de los fármacos , Aorta/patología , Lípidos/sangre , Hígado/anatomía & histología , Hígado/efectos de los fármacos , Masculino , Ratones , Ratones Noqueados , Estructura Molecular , Extractos Vegetales/farmacología , Receptores de LDL/deficiencia , Receptores de LDL/genética , Aumento de PesoRESUMEN
The IL1R is composed of two kinds of molecule, type I (IL1R I) and type II (IL1R2). IL1R1 contributes to IL-1 signaling, whereas the IL1R2 has no signaling property and acts as a decoy for IL-1. In this study, we developed a bovine IL1R2-specific sandwich ELISA to examine the sIL1R2 concentration in serum and milk from dairy cows. The concentration of colostral IL-1beta was examined to estimate the correlation to sIL1R2. The results showed that the sIL1R2 concentration in sera and milk changes with the stages of lactation. The serum sIL1R2 concentrations were 5.56+/-0.69 ng/ml (colostrum), 3.14+/-0.72 ng/ml (the early stage of lactation) and 5.76+/-1.25 ng/ml (the late stage of lactation). The milk sIL1R2 concentrations were 1.83+/-0.47 ng/ml (colostrum), 0.73+/-0.22 ng/ml (the early stage of lactation) and 2.92+/-0.56 ng/ml (the late stage of lactation). The concentrations of IL1R2 in sera and milk were significantly higher at the late stage of lactation and colostrum than that of the early stage of lactation. The reduction rates of sIL1R2 levels from the colostrum to the early stage of lactation were 43.6% (serum) and 61% (whey). IL-1beta was detected in all the colostrum (995.9+/-346.6 ng/ml). Significant correlation was observed between the levels of colostral IL-1beta and IL1R2 (r=0.75).