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2.
Gynecol Endocrinol ; 37(10): 898-901, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34355625

RESUMEN

OBJECTIVE: Hysterosalpingography (HSG) performed with an iodine contrast media can cause thyroid dysfunction, including thyrotoxicosis and hypothyroidism. We investigated the association between the serum levels of thyroid-stimulating hormone receptor antibody (TRAb), an indicator of Graves' disease, and abnormal thyroid function after performing HSG. METHODS: The screening of TRAb was conducted in 362 patients who first visited the Tawara IVF Clinic between April and September 2018. The association between TRAb levels and the effects of HSG examinations on thyroid function were evaluated. RESULTS: Of the 362 patients, 2 (0.55%) had high levels (>2.0 IU/L) of TRAb, whereas 18 (5.0%) had intermediate TRAb levels, ranging from 0.3 to 1.9 IU/L. Of the 98 women (including 7 of the 18 women with TRAb level 0.3-1.9 IU/L, and 91 of the 342 women with TRAb level <0.3 IU/L) who had undergone HSG, two women developed overt thyrotoxicosis after HSG, and the frequency was significantly higher (p = .0044) in the group with intermediate levels of TRAb (28.6%, 2 of 7) than that in the group with low TRAb levels (<0.3 IU/L; 0.0%, 0 of 91). CONCLUSIONS: These findings indicate that increased serum levels of TRAb are significantly associated with the development of thyrotoxicosis after HSG.


Asunto(s)
Medios de Contraste/efectos adversos , Histerosalpingografía/efectos adversos , Inmunoglobulinas Estimulantes de la Tiroides/sangre , Yodo/efectos adversos , Enfermedades de la Tiroides/inmunología , Glándula Tiroides/fisiopatología , Adulto , Estudios de Casos y Controles , Femenino , Enfermedad de Graves/inmunología , Humanos , Infertilidad/diagnóstico por imagen , Enfermedades de la Tiroides/etiología , Enfermedades de la Tiroides/fisiopatología , Pruebas de Función de la Tiroides
3.
J Physiol Sci ; 71(1): 18, 2021 Jun 16.
Artículo en Inglés | MEDLINE | ID: mdl-34134629

RESUMEN

We examined whether the chemogenetic activation of endogenous arginine vasopressin (AVP) affects central nesfatin-1/NucB2 neurons, using a transgenic rat line that was previously generated. Saline (1 mL/kg) or clozapine-N-oxide (CNO, 1 mg/mL/kg), an agonist for hM3Dq, was subcutaneously administered in adult male AVP-hM3Dq-mCherry transgenic rats (300-370 g). Food and water intake were significantly suppressed after subcutaneous (s.c.) injection of CNO, with aberrant circadian rhythmicity. The percentages of Fos expression in nesfatin-1/NucB2-immunoreactive neurons were significantly increased in the hypothalamus and brainstem at 120 min after s.c. injection of CNO. Suppressed food intake that was induced by chemogenetic activation of endogenous AVP was ablated after intracerebroventricularly administered nesfatin-1/NucB2-neutralizing antibody in comparison with vehicle, without any alteration of water intake nor circadian rhythmicity. These results suggest that chemogenetic activation of endogenous AVP affects, at least in part, central nesfatin-1/NucB2 neurons and may exert anorexigenic effects in the transgenic rats.


Asunto(s)
Depresores del Apetito/farmacología , Arginina Vasopresina/fisiología , Clozapina/análogos & derivados , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Nucleobindinas/metabolismo , Transducción de Señal , Animales , Apetito/efectos de los fármacos , Apetito/fisiología , Clozapina/farmacología , Ingestión de Líquidos/fisiología , Ingestión de Alimentos/fisiología , Masculino , Nucleobindinas/fisiología , Ratas Transgénicas , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología
4.
Sci Rep ; 10(1): 13671, 2020 08 13.
Artículo en Inglés | MEDLINE | ID: mdl-32792584

RESUMEN

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of hepatic triglycerides (TG) and hyperglycemia arising due to persistent insulin resistance, and is profoundly linked to obesity. However, there is currently no established treatment for NAFLD in obese human subjects. We previously isolated Helz2, the expression of which was upregulated in human and mouse NAFLD, and its deletion activated the hepatic expression of functional leptin receptor long form (Leprb) and suppressed NAFLD development and body weight (BW) gain in obese mice. A high-throughput assay of small-molecule drugs revealed that guanabenz acetate (Ga), originally used to treat hypertension, possesses a high affinity constant against HELZ2, and its administration activates LEPRB expression in HepG2 cells in vitro. The chronic oral administration of Ga shows the selective leptin sensitization in the liver via upregulation of hepatic Leprb expression, which affects expression of genes involved in lipogenesis and fatty acid ß-oxidation and diminishes hepatocyte hypertrophy with droplets enriched in TG in high-fat diet-induced obese mice. This activity significantly improves insulin resistance to decrease hyperglycemia and hepatocyte and adipocyte weights, resulting in BW reduction without reducing food intake. Regarding drug repositioning, Ga has the potential to effectively treat NAFLD and hyperglycemia in obese patients.


Asunto(s)
Guanabenzo/administración & dosificación , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Proteínas Nucleares/metabolismo , Obesidad/tratamiento farmacológico , Receptores de Leptina/metabolismo , Administración Oral , Animales , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Reposicionamiento de Medicamentos , Regulación de la Expresión Génica , Guanabenzo/farmacología , Células Hep G2 , Humanos , Lipogénesis/efectos de los fármacos , Ratones , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Proteínas Nucleares/antagonistas & inhibidores , Obesidad/inducido químicamente , Obesidad/metabolismo
5.
Peptides ; 128: 170308, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32229144

RESUMEN

Since its discovery in 2006 by Oh-I and colleagues, NUCB2/nesfatin-1 encoded by nucleobindin-2 (NUCB2) has drawn sustained attention as reflected in over 500 publications. Among those, more than half focused on the alterations of food intake, body weight and metabolism (glucose, fat) induced by nesfatin-1 and/or NUCB2/nesfatin-1. In the current review we discuss the existing literature focusing on NUCB2/nesfatin-1's influence on food intake, body weight and glucose as well as fat metabolism and highlight gaps in knowledge.


Asunto(s)
Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Nucleobindinas/metabolismo , Nucleobindinas/farmacología , Animales , Grasas/metabolismo , Glucosa/metabolismo , Humanos , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo
6.
J Physiol Sci ; 69(5): 733-739, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31228099

RESUMEN

Nesfatin-1 is a hypothalamic anorexigenic peptide processed from nucleobindin 2 (NUCB2). Central and peripheral administration of NUCB2/nesfatin-1 enhances glucose metabolism and insulin release. NUCB2/nesfatin-1 is also localized in pancreatic islets, while its function remains unknown. To explore the role of pancreatic ß-cell-produced NUCB2/nesfatin-1, we developed pancreatic ß-cell-specific NUCB2 knockout (ßNUCB2 KO) mice and NUCB2 gene knockdown (shNUCB2) MIN6 ß-cell line. In ßNUCB2 KO mice, casual blood glucose was elevated from 12 weeks of age. In a glucose tolerance test at 12 weeks, insulin secretion at 15 min was reduced and blood glucose at 2 h increased in ßNUCB2 KO mice fasted 8 h. In islets isolated from ßNUCB2 KO mice, high glucose-stimulated insulin secretion (GSIS) was impaired. In shNUCB2 MIN6 cells, GSIS was reduced and UCP-2 mRNA expression was elevated. These results show impaired GSIS possibly associated with UCP-2 overexpression in NUCB2-silenced ß-cells, suggesting that ß-cell-produced NUCB2/nesfatin-1 maintains GSIS and thereby glycemia.


Asunto(s)
Glucemia/metabolismo , Índice Glucémico/fisiología , Secreción de Insulina/fisiología , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Nucleobindinas/metabolismo , Proteína Desacopladora 2/metabolismo , Animales , Línea Celular , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa/métodos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratas
7.
Endocr J ; 65(5): 547-556, 2018 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-29618670

RESUMEN

Patients with adrenal insufficiency require appropriate glucocorticoid replacement therapy; however, reliable biological parameters for optimizing glucocorticoid supplementation are limited. The physician has to rely primarily on clinical judgment, carefully taking into account signs and symptoms potentially suggestive of over- or under-replacement. We have found that some patients who are viewed as receiving sufficient doses of glucocorticoids occasionally exhibit morning headache or morning discomfort, which may be caused by unrecognized nocturnal hypoglycemia. Our aim in this study was to evaluate the usefulness of continuous glucose monitoring (CGM) for detecting unrecognized hypoglycemia and optimizing glucocorticoid replacement therapy in adult patients with central hypoadrenalism. Six patients with central hypoadrenalism of various etiologies were included in this study. All patients exhibited occasional morning headache or discomfort. We performed CGM to measure plasma glucose levels in all patients, and CGM identified unrecognized hypoglycemia episodes at midnight and early in the morning in five patients (83%). The CGM findings were used to fine-tune the dosing and regimens of glucocorticoid replacement and to re-evaluate glucose levels to avoid further unrecognized hypoglycemic events. This optimization of hydrocortisone supplementation prevented additional nocturnal hypoglycemia incidences in all cases. The addition of L-thyroxine with hydrocortisone continued to provide favorable glycemic control. Occasional symptoms also improved after maintenance in all patients. These findings demonstrated that CGM may represent a powerful tool for identifying unrecognized hypoglycemia and for optimizing supplementary hormones in patients with central hypoadrenalism, thereby improving their quality of life.


Asunto(s)
Insuficiencia Suprarrenal/sangre , Automonitorización de la Glucosa Sanguínea , Glucemia , Glucocorticoides/uso terapéutico , Terapia de Reemplazo de Hormonas , Hipoglucemia/diagnóstico , Adolescente , Insuficiencia Suprarrenal/complicaciones , Insuficiencia Suprarrenal/tratamiento farmacológico , Adulto , Anciano , Femenino , Humanos , Hidrocortisona/uso terapéutico , Hipoglucemia/sangre , Hipoglucemia/complicaciones , Masculino , Persona de Mediana Edad , Calidad de Vida , Adulto Joven
8.
Thyroid ; 28(1): 50-59, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29037117

RESUMEN

BACKGROUND: There are currently no reliable biomarkers to predict relapse in Graves' disease (GD). In the present study, we investigated novel diagnostic biomarkers to predict the long-term remission of or relapse in GD. METHODS: A DNA microarray analysis was performed to examine gene expression in the peripheral leukocytes of a frequently relapsing patient with GD and a patient in long-term remission after the discontinuation of antithyroid drugs (ATDs). Based on the DNA microarray analysis, we focused on Sialic acid-binding immunoglobulin-like lectin1 (SIGLEC1) as a candidate novel biomarker to predict GD relapse. Three hundred and fifty-eight patients with GD in the thyroid clinics of four different hospitals in Japan were included in a cross-sectional study to establish whether SIGLEC1 mRNA levels distinguish GD relapse experience from long-term remission. An additional 55 patients with GD were enrolled in a prospective study to clarify whether SIGLEC1 mRNA levels at ATD discontinuation predict GD relapse. RESULTS: SIGLEC1 mRNA levels were significantly higher in patients with GD relapse experience than in those in long-term remission. Based on the receiver operating characteristic analysis, we found that high SIGLEC1 mRNA levels (≥258.9 copies) significantly distinguished GD relapse experience from long-term remission (p < 0.0001; sensitivity 66.7%, specificity 70.1%). In the prospective study, when the optimal cutoff value from the receiver operating characteristic curve analysis was applied to SIGLEC1 mRNA positivity at ATD discontinuation, SIGLEC1-positive patients (≥258.9 copies) showed a significantly higher cumulative risk of relapse than SIGLEC1-negative patients (<258.9 copies) (p = 0.022, the log-rank test). CONCLUSIONS: SIGLEC1 mRNA levels have potential as a novel predictive biomarker for GD relapse.


Asunto(s)
Enfermedad de Graves/diagnóstico , Lectina 1 Similar a Ig de Unión al Ácido Siálico/sangre , Tirotropina/sangre , Tiroxina/sangre , Triyodotironina/sangre , Adulto , Biomarcadores/sangre , Estudios Transversales , Femenino , Enfermedad de Graves/sangre , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Recurrencia , Factores de Riesgo , Adulto Joven
9.
Peptides ; 95: 10-15, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28697955

RESUMEN

The anorexigenic neuropeptide NEFA/nucleobindin 2 (NUCB2)/nesfatin-1-containing neurons are distributed in the brain regions involved in feeding regulation. In spite of the growing knowledge of its physiological functions through extensive studies, its molecular mechanism of reaction, including its receptor, remains unknown. NUCB2/nesfatin-1 is also involved in various peripheral regulations, including glucose homeostasis. In pancreatic beta-cells, NUCB2/nesfatin-1 is reported to enhance glucose-stimulated insulin secretion (GSIS) but its exact mechanism remains unknown. To clarify this mechanism, we measured the effect of nesfatin-1 on the electrical activity of pancreatic beta-cells. Using mouse primary beta cells, we measured changes in the ATP-sensitive K+ (KATP) channel current, the voltage-gated K+ (Kv) channel current, and insulin secretion upon application of nesfatin-1. Nesfatin-1 inhibited the Kv channel, but KATP channel activity was unaffected. Nesfatin-1 enhanced insulin secretion to a same level as Kv channel blocker tetraethylammonium (TEA). The effect was not further enhanced when nesfatin-1 and TEA were applied simultaneously. The inhibition binding assay with [125I]nesfatin-1 in Kv2.1 channels, major contributor of Kv current in beta cell, expressing HEK239 cells indicated the binding of nesfatin-1 on Kv2.1 channel. Because Kv channel inhibition enhances insulin secretion under high glucose conditions, our present data suggest a possible mechanism of nesfatin-1 on enhancing GSIS through regulation of ion channels rather than its unidentified receptor.


Asunto(s)
Proteínas de Unión al Calcio/administración & dosificación , Proteínas de Unión al ADN/administración & dosificación , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Proteínas del Tejido Nervioso/administración & dosificación , Animales , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Glucosa/metabolismo , Homeostasis/efectos de los fármacos , Secreción de Insulina , Células Secretoras de Insulina/efectos de los fármacos , Canales KATP/metabolismo , Ratones , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Nucleobindinas , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio con Entrada de Voltaje/metabolismo , Tetraetilamonio/farmacología
10.
Sci Rep ; 7: 45819, 2017 04 04.
Artículo en Inglés | MEDLINE | ID: mdl-28374855

RESUMEN

Fibroblast growth factor 21 (FGF21), liver-derived hormone, exerts diverse metabolic effects, being considered for clinical application to treat obesity and diabetes. However, its anorexigenic effect is debatable and whether it involves the central mechanism remains unclarified. Moreover, the neuron mediating FGF21's anorexigenic effect and the systemic energy state supporting it are unclear. We explored the target neuron and fed/fasted state dependence of FGF21's anorexigenic action. Intracerebroventricular (ICV) injection of FGF21 markedly suppressed food intake in fed mice with elevated blood glucose. FGF21 induced c-Fos expression preferentially in hypothalamic paraventricular nucleus (PVN), and increased mRNA expression selectively for nucleobindin 2/nesfatin-1 (NUCB2/Nesf-1). FGF21 at elevated glucose increased [Ca2+]i in PVN NUCB2/Nesf-1 neurons. FGF21 failed to suppress food intake in PVN-preferential Sim1-Nucb2-KO mice. These findings reveal that FGF21, assisted by elevated glucose, activates PVN NUCB2/Nesf-1 neurons to suppress feeding under fed states, serving as the glycemia-monitoring messenger of liver-hypothalamic network for integrative regulation of energy and glucose metabolism.


Asunto(s)
Glucemia , Factores de Crecimiento de Fibroblastos/farmacología , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Saciedad/fisiología , Animales , Proteínas de Unión al Calcio/metabolismo , Proteínas de Unión al ADN/metabolismo , Ingestión de Alimentos , Infusiones Intraventriculares , Masculino , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Nucleobindinas , Núcleo Hipotalámico Paraventricular/metabolismo , Proteínas Proto-Oncogénicas c-fos
11.
J Diabetes Investig ; 8(5): 677-686, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28129466

RESUMEN

AIMS/INTRODUCTION: To explore the relationships between periodontitis and microvascular complications as well as glycemic control in type 2 diabetes patients. MATERIALS AND METHODS: This multicenter, hospital-based, cross-sectional study included 620 patients with type 2 diabetes. We compared the prevalence and severity of periodontitis between patients with ≥1 microvascular complication and those without microvascular complications. We also compared the prevalence and severity of periodontitis among patients with different degrees of glycemic control. RESULTS: After adjusting for confounding factors, multiple logistic regression analysis showed that the severity of periodontitis was significantly associated with the number of microvascular complications (odds ratio 1.3, 95% confidence interval 1.1-1.6), glycated hemoglobin ≥8.0% (64 mmol/mol; odds ratio 1.6; 95% confidence interval 1.1-2.3), and older age (≥50 years; odds ratio 1.7; 95% confidence interval 1.1-2.6). However, the prevalence of periodontitis was not significantly associated with the number of microvascular complications, but was associated with male sex, high glycated hemoglobin (≥8.0% [64 mmol/mol]), older age (≥40 years), longer duration of diabetes (≥15 years) and fewer teeth (≤25). Furthermore, propensity score matching for age, sex, diabetes duration and glycated hemoglobin showed that the incidence of severe periodontitis was significantly higher among patients with microvascular complications than among those without microvascular complications (P < 0.05). CONCLUSIONS: The number of microvascular complications is a risk factor for more severe periodontitis in patients with type 2 diabetes, whereas poor glycemic control is a risk factor for increased prevalence and severity of periodontitis.


Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Periodontitis/complicaciones , Periodontitis/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Estudios Transversales , Femenino , Humanos , Masculino , Microvasos/fisiopatología , Persona de Mediana Edad , Factores de Riesgo , Índice de Severidad de la Enfermedad
12.
Cell Signal ; 28(11): 1694-702, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27478065

RESUMEN

Expression of adaptor protein, phosphotyrosine interaction, pleckstrin homology domain, and leucine zipper containing 1 (APPL1) promoted glucose transporter 4 (GLUT4) translocation and glucose uptake in adipose and muscle tissues in response to stimulation with insulin, adiponectin, or exercise. In response to mechanical stretch, knockdown of APPL1 in C2C12 myotubes suppressed glucose uptake. APPL1-induced increased glucose uptake was mediated by protein kinase C (PKC) ζ but not AKT, AMPK, or calmodulin-dependent protein kinase. In myotubes overexpressing APPL1, PKCζ was phosphorylated and translocated to the plasma membrane (PM) in response to mechanical stretch. Phosphorylated PKCζ co-immunoprecipitated with protein phosphatase 2A (PP2A) under basal conditions, but dissociated upon myotube stretching. Moreover, stretch-induced phosphorylated PKCζ co-immunoprecipitated with non-muscle myosin IIa. Blebbistatin, an inhibitor of myosin II ATPase activity, suppressed APPL1-mediated stretch-induced glucose uptake and PKCζ translocation. Taken together these data demonstrate that in response to mechanical stretch, APPL1 enhances glucose uptake by modulating the activation and localization of PKCζ, as well as its functional interaction with both PP2A and myosin IIa. These findings support a new function for non-muscle myosin IIa in differentiated myotubes.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Glucosa/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Miosina Tipo IIA no Muscular/metabolismo , Proteína Quinasa C/metabolismo , Estrés Mecánico , Adenilato Quinasa/metabolismo , Animales , Línea Celular , Membrana Celular/metabolismo , Desoxiglucosa/metabolismo , Transportador de Glucosa de Tipo 4/metabolismo , Ratones , Fosforilación , Proteína Fosfatasa 2/metabolismo , Transporte de Proteínas
13.
Endocrinology ; 157(6): 2322-32, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27105386

RESUMEN

Nesfatin-1, derived from nucleobindin-2 (NUCB2), is expressed in the hypothalamus, including the paraventricular nucleus (PVN), an integrative center for energy homeostasis. However, precise role of the NUCB2/nesfatin-1 in PVN remains less defined. The present study aimed to clarify physiological and/or pathophysiological roles of endogenous NUCB2/nesfatin-1 in PVN by using adeno-associated virus vectors encoding short hairpin RNAs targeting NUCB2 in mice. PVN-specific NUCB2 knockdown primarily increased food intake and decreased plasma oxytocin level specifically in light phase, leading to increased body weight gain without affecting energy expenditure. Furthermore, high-salt diet increased the systolic blood pressure, plasma arginine vasopressin (AVP) and AVP mRNA expression in PVN, and all these changes were blunted by PVN-specific NUCB2 knockdown. These results reveal that the endogenous NUCB2/nesfatin-1 in PVN regulates PVN AVP and oxytocin and consequently the fluid and energy balance.


Asunto(s)
Proteínas de Unión al Calcio/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Oxitocina/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Vasopresinas/metabolismo , Adiposidad/genética , Adiposidad/fisiología , Animales , Western Blotting , Proteínas de Unión al Calcio/genética , Calorimetría , Proteínas de Unión al ADN/genética , Conducta Alimentaria/fisiología , Inmunohistoquímica , Resistencia a la Insulina/genética , Resistencia a la Insulina/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas del Tejido Nervioso/genética , Nucleobindinas , ARN Interferente Pequeño/genética
14.
Diabetes ; 64(11): 3725-36, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26310564

RESUMEN

Nesfatin-1 acts on the hypothalamus and regulates the autonomic nervous system. However, the hypothalamic mechanisms of nesfatin-1 on the autonomic nervous system are not well understood. In this study, we found that intracerebroventricular (ICV) administration of nesfatin-1 increased the extracellular signal-regulated kinase (ERK) activity in rats. Furthermore, the activity of sympathetic nerves, in the kidneys, liver, and white adipose tissue (WAT), and blood pressure was stimulated by the ICV injection of nesfatin-1, and these effects were abolished owing to pharmacological inhibition of ERK. Renal sympathoexcitatory and hypertensive effects were also observed with nesfatin-1 microinjection into the paraventricular hypothalamic nucleus (PVN). Moreover, nesfatin-1 increased the number of phospho (p)-ERK1/2-positive neurons in the PVN and coexpression of the protein in neurons expressing corticotropin-releasing hormone (CRH). Pharmacological blockade of CRH signaling inhibited renal sympathetic and hypertensive responses to nesfatin-1. Finally, sympathetic stimulation of WAT and increased p-ERK1/2 levels in response to nesfatin-1 were preserved in obese animals such as rats that were fed a high-fat diet and leptin receptor-deficient Zucker fatty rats. These findings indicate that nesfatin-1 regulates the autonomic nervous system through ERK signaling in PVN-CRH neurons to maintain cardiovascular function and that the antiobesity effect of nesfatin-1 is mediated by hypothalamic ERK-dependent sympathoexcitation in obese animals.


Asunto(s)
Proteínas de Unión al Calcio/farmacología , Proteínas de Unión al ADN/farmacología , Hipotálamo/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteínas del Tejido Nervioso/farmacología , Neuronas/metabolismo , Sistema Nervioso Simpático/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/inervación , Animales , Presión Sanguínea/efectos de los fármacos , Dieta Alta en Grasa , Hipotálamo/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/inervación , Hígado/efectos de los fármacos , Hígado/inervación , Masculino , Neuronas/efectos de los fármacos , Nucleobindinas , Fosforilación , Ratas , Ratas Zucker , Sistema Nervioso Simpático/efectos de los fármacos
15.
Case Rep Endocrinol ; 2015: 416145, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25664188

RESUMEN

Amiodarone is used commonly and effectively in the treatment of arrhythmia; however, it may cause thyrotoxicosis categorized into two types: iodine-induced hyperthyroidism (type 1 amiodarone-induced thyrotoxicosis (AIT)) and destructive thyroiditis (type 2 AIT). We experienced a case of type 2 AIT, in which high-dose steroid was administered intravenously, and we finally decided to perform total thyroidectomy, resulting in a complete cure of the AIT. Even though steroid had been administered to the patient (maximum 80 mg of prednisolone), the operation was performed safely and no acute adrenal crisis as steroid withdrawal syndrome was found after the operation. Few cases of type 2 AIT that underwent total thyroidectomy with high-dose steroid administration have been reported. The current case suggests that total thyroidectomy should be taken into consideration for patients with AIT who cannot be controlled by medical treatment and even in those under high-dose steroid administration.

16.
J Clin Gastroenterol ; 49(2): 127-31, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24583745

RESUMEN

BACKGROUND: Although the potential advantages of the Endocut mode (E-mode) of endoscopic sphincterotomy (EST) over the conventional blended cut mode (C-mode) have been reported, the problems, including the small sample size and retrospective analysis, that occurred in previous studies make it difficult to conclude the advantage of the E-mode regarding the safety and efficacy. We performed a prospective randomized controlled study to compare these modes. METHODS: A total of 360 patients with choledocholithiasis or stenosis of the bile duct were randomly assigned to one of the modes. To avoid the technical bias due to multiple operators or institutions, the main operator and the institution were restricted to only one experienced doctor and 3 institutions at his place of employment, respectively. We defined pancreatitis, bleeding, and perforation as complications of EST. Besides, bleeding includes endoscopically evident bleeding that was defined as visible during the procedure of sphincterotomy and temporary slight oozing. RESULTS: The complications occurred in 20 (11.2%) patients from the E-mode group: pancreatitis in 6 (3.4%) and endoscopically evident bleeding in 14 (7.8%). In contrast, the complications occurred in 25 (13.8%) patients from the C-mode group: pancreatitis in 7 (3.9%) and endoscopically evident bleeding in 18 (9.9%), although these findings were not statistically significant. Overall, there were no severe complications. There were no significant differences in completion ratio of EST and the time taken for the sphincterotomy between both groups. CONCLUSIONS: The E-mode could not surpass the C-mode in safety and efficacy under the operation by a single endoscopist.


Asunto(s)
Coledocolitiasis/cirugía , Colestasis/cirugía , Esfinterotomía Endoscópica/métodos , Adulto , Anciano , Anciano de 80 o más Años , Coledocolitiasis/diagnóstico , Colestasis/diagnóstico , Constricción Patológica , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/etiología , Estudios Prospectivos , Esfinterotomía Endoscópica/efectos adversos , Resultado del Tratamiento , Adulto Joven
17.
Biochem Biophys Res Commun ; 456(4): 913-8, 2015 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-25534851

RESUMEN

An adipokine leptin plays a central role in the regulation of feeding and energy homeostasis via acting on the hypothalamus. However, its downstream neuronal mechanism is not thoroughly understood. The neurons expressing nucleobindin-2 (NUCB2)-derived nesfatin-1 in the hypothalamic paraventricular nucleus (PVN) have been implicated in feeding and energy homeostasis. The present study aimed to explore the role of PVN NUCB2/nesfatin-1 in the leptin action, by using adeno-associated virus (AAV) vectors encoding shRNA targeting NUCB2 (AAV-NUCB2-shRNA). Leptin directly interacted and increased cytosolic Ca(2+) in single neurons isolated from the PVN, predominantly in NUCB2/nesftin-1-immunoreactive neurons. Treatment with leptin in vivo and in vitro markedly increased NUCB2 mRNA expression in the PVN. Peripheral and central injections of leptin failed to significantly inhibit food intake in mice receiving AAV-NUCB2. These results indicate that PVN NUCB2/nesfatin-1 is directly targeted by leptin, and mediates its anorexigenic effect.


Asunto(s)
Anorexia/metabolismo , Proteínas de Unión al Calcio/metabolismo , Proteínas de Unión al ADN/metabolismo , Leptina/farmacología , Proteínas del Tejido Nervioso/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Animales , Anorexia/genética , Proteínas de Unión al Calcio/genética , Proteínas de Unión al ADN/genética , Dependovirus/metabolismo , Metabolismo Energético/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Homeostasis/efectos de los fármacos , Leptina/administración & dosificación , Masculino , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/genética , Neuronas/metabolismo , Nucleobindinas , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/metabolismo
18.
World J Gastroenterol ; 20(43): 16227-35, 2014 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-25473177

RESUMEN

AIM: To investigate the mechanism and in vivo effects of MK-0626, a dipeptidyl peptidase-4 inhibitor, on hepatic steatosis using ob/ob mice. METHODS: We analyzed obese (ob/ob) 8-wk-old male mice that had been randomly divided into two groups of ob/ob mice (n = 16 each) and were treated with 1.5 or 3 mg/kg MK-0626 and two control groups of untreated ob/ob mice and lean littermates (n = 16 each). All mice were fed a normal chow diet with or without MK-0626 for either four or eight weeks. Blood samples were collected, and total hepatectomy was performed. RESULTS: The administration of dietary MK-0626 ameliorated the hepatic lipid accumulation in ob/ob mice treated with 3 mg/kg MK-0626 (3 MK), P < 0.05, vs untreated ob/ob mice (ob/ob). The MK-0626 treatment reduced the serum alanine aminotransferase levels (both treatment groups, P < 0.05 vs ob/ob) and glucoses/insulin levels/calculated HOMA scores (1.5 MK, P < 0.05 vs ob/ob; 3 MK, P < 0.01 vs ob/ob) and increased the serum adiponectin levels (3 MK, P < 0.05 vs ob/ob) in a dose-dependent manner. The MK-0626 treatment increased the mRNA expression of peroxisome proliferator-activated receptor α/microsomal triglyceride transfer protein (1.5 MK, P < 0.05 vs ob/ob; 3 MK, P < 0.01 vs ob/ob) but reduced the sterol regulatory element binding transcription factor-1c/fatty acid synthase/stearoyl-CoA desaturase-1 (both treatment groups, P < 0.01 vs ob/ob). The MK-0626 treatment increased the activity of AMP-activated protein kinase (AMPK) (both treatment groups, P < 0.01 vs ob/ob). CONCLUSION: MK-0626 could attenuate hepatic steatosis through enhancing AMPK activity, inhibiting hepatic lipogenic gene expression, enhancing triglyceride secretion from liver and increasing serum adiponectin levels.


Asunto(s)
Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Hígado Graso/prevención & control , Hígado/efectos de los fármacos , Obesidad/tratamiento farmacológico , Triazoles/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Adiponectina/sangre , Animales , Biomarcadores/sangre , Citoprotección , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Activación Enzimática , Hígado Graso/sangre , Hígado Graso/enzimología , Hígado Graso/etiología , Hígado Graso/genética , Hígado Graso/patología , Regulación de la Expresión Génica , Lipogénesis/efectos de los fármacos , Lipogénesis/genética , Hígado/enzimología , Hígado/patología , Masculino , Ratones Obesos , Obesidad/sangre , Obesidad/complicaciones , Obesidad/enzimología , Obesidad/genética , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Triglicéridos/sangre
19.
Endocr J ; 61(9): 933-9, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25168660

RESUMEN

The physiology of insulin signaling under normal and disease conditions is well studied in classical insulin target tissues, but not in podocytes. To examine insulin stimulation of podocyte GLUT4 translocation, we established a protocol involving treatment with the PPARα agonist fenofibrate to induce E11 podocyte differentiation within 48 hours rather than 7-10 days, which is required for differentiation under the reported protocol. This allowed us to transiently introduce GLUT4 reporter cDNA and RNAi and thereby to examine the regulatory pathway involved. Here we demonstrate that treatment with 200 µM fenofibrate for 36 hours following transfection had a dramatic effect on podocyte morphology, induced several podocyte specific protein expression markers (G protein-coupled receptor 137B, chloride intracellular channel 5, and nephrin) and resulted in insulin-stimulated GLUT4 translocation. In addition, Nucleobindin-2 was found to constitutively associate with Septin 7 (the repressor of GLUT4 translocation), and knockdown of Nucleobindin-2 was found to completely abrogate insulin-stimulated GLUT4 translocation. Together, these data suggest that Nucleobindin-2 may repress Septin7-induced inhibition of insulin-stimulated GLUT4 translocation in podocytes.


Asunto(s)
Proteínas de Unión al Calcio/fisiología , Proteínas de Unión al ADN/fisiología , Fenofibrato/farmacología , Transportador de Glucosa de Tipo 4/metabolismo , Proteínas del Tejido Nervioso/fisiología , Podocitos/efectos de los fármacos , Animales , Diferenciación Celular/efectos de los fármacos , Línea Celular , Insulina/fisiología , Ratones , Nucleobindinas , Podocitos/metabolismo , Septinas/metabolismo
20.
Biochem Biophys Res Commun ; 451(1): 24-9, 2014 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-25019984

RESUMEN

Emerging evidence has indicated that the transcription and processing of precursor mRNA (pre-mRNA) are functionally coupled to modulate gene expression. In collaboration with coregulators, several steroid hormone receptors have previously been shown to directly affect alternative pre-mRNA splicing coupled to hormone-induced gene transcription; however, the roles of the thyroid hormone receptor (TR) and its coregulators in alternative splicing coordinated with transcription remain unknown. In the present study, we constructed a luciferase reporter and CD44 alternative splicing (AS) minigene driven by a minimal promoter carrying 2 copies of the palindromic thyroid hormone-response element. We then examined whether TR could modulate pre-mRNA processing coupled to triiodothyronine (T3)-induced gene transcription using luciferase reporter and splicing minigene assays in HeLa cells. In the presence of cotransfected TRß1, T3 increased luciferase activities along with the inclusion of the CD44 variable exons 4 and 5 in a dose- and time-dependent manner. In contrast, cotransfected TRß1 did not affect the exon-inclusion of the CD44 minigene driven by the cytomegalovirus promoter. T3-induced two-exon inclusion was significantly increased by the cotransfection of the TR-associated protein, 150-kDa, a subunit of the TRAP/Mediator complex that has recently been shown to function as a splicing factor. In contrast, T3-induced two-exon inclusion was significantly decreased by cotransfection of the polypyrimidine tract-binding protein-associated splicing factor, which was previously shown to function as a corepressor of TR. These results demonstrated that liganded TR in cooperation with its associating cofactors could modulate alternative pre-mRNA splicing coupled to gene transcription.


Asunto(s)
Empalme Alternativo , Receptores de Hormona Tiroidea/genética , Elementos de Respuesta , Transcripción Genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Exones , Células HeLa/efectos de los fármacos , Humanos , Receptores de Hialuranos/genética , Luciferasas/genética , Factor de Empalme Asociado a PTB , Regiones Promotoras Genéticas , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Receptores de Hormona Tiroidea/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Triyodotironina/farmacología
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