RESUMEN
AIM: Rikkunshito is a traditional Japanese medicine used for delayed gastric emptying in intensive care units in Japan. This study aimed to investigate whether standard- or high-dose rikkunshito can improve the achievement of enteral calorie target among critically ill adults. METHODS: This open-label, single-center, pilot randomized controlled trial was carried out from March 2018 until December 2018 and enrolled critically ill adult patients requiring enteral nutrition by gastric tube for at least 5 days. Patients were randomized into the control group, the standard-dose rikkunshito group (2.5 g three times daily), and the high-dose rikkunshito group (5 g three times daily). Intervention was given for 5 days. The primary outcome measure was the percentage of enteral calorie intake achieved in the target at the fifth day after randomization. RESULTS: The cohort comprised 26 patients; of these, 9, 8, and 9 were included in the control group, the standard-dose group, and the high-dose group, respectively. Twenty-one patients (81%) were included in the primary analysis. The percentage of enteral calorie intake achieved in the target at the fifth day was 59% (interquartile range [IQR], 39-63%), 40% (IQR, 26-61%), and 62% (IQR, 17-83%) in the control, the standard-dose, and the high-dose groups, respectively (P = 0.42). The number of adverse events did not differ significantly between the groups (control group, 4 [44%]; standard-dose group, 3 [38%]; and high-dose group, 4 [44%], P = 1.00). CONCLUSIONS: Standard- or high-dose rikkunshito did not improve the achievement of enteral calorie target in critically ill adults.
RESUMEN
C-type natriuretic peptide (CNP) and its receptor are abundantly distributed in the brain, especially in the arcuate nucleus (ARC) of the hypothalamus associated with regulating energy homeostasis. To elucidate the possible involvement of CNP in energy regulation, we examined the effects of intracerebroventricular administration of CNP on food intake in mice. The intracerebroventricular administration of CNP-22 and CNP-53 significantly suppressed food intake on 4-h refeeding after 48-h fasting. Next, intracerebroventricular administration of CNP-22 and CNP-53 significantly decreased nocturnal food intake. The increment of food intake induced by neuropeptide Y and ghrelin was markedly suppressed by intracerebroventricular administration of CNP-22 and CNP-53. When SHU9119, an antagonist for melanocortin-3 and melanocortin-4 receptors, was coadministered with CNP-53, the suppressive effect of CNP-53 on refeeding after 48-h fasting was significantly attenuated by SHU9119. Immunohistochemical analysis revealed that intracerebroventricular administration of CNP-53 markedly increased the number of c-Fos-positive cells in the ARC, paraventricular nucleus, dorsomedial hypothalamus, ventromedial hypothalamic nucleus, and lateral hypothalamus. In particular, c-Fos-positive cells in the ARC after intracerebroventricular administration of CNP-53 were coexpressed with α-melanocyte-stimulating hormone immunoreactivity. These results indicated that intracerebroventricular administration of CNP induces an anorexigenic action, in part, via activation of the melanocortin system.
Asunto(s)
Regulación del Apetito , Hipotálamo/metabolismo , Melanocortinas/agonistas , Péptido Natriurético Tipo-C/metabolismo , Neuronas/metabolismo , Receptores de Melanocortina/agonistas , Transducción de Señal , Animales , Regulación del Apetito/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Ghrelina/antagonistas & inhibidores , Ghrelina/metabolismo , Hipotálamo/citología , Hipotálamo/efectos de los fármacos , Inyecciones Intraventriculares , Masculino , Melanocortinas/antagonistas & inhibidores , Melanocortinas/metabolismo , Hormonas Estimuladoras de los Melanocitos/farmacología , Ratones , Ratones Endogámicos C57BL , Péptido Natriurético Tipo-C/administración & dosificación , Péptido Natriurético Tipo-C/antagonistas & inhibidores , Proteínas del Tejido Nervioso/administración & dosificación , Proteínas del Tejido Nervioso/agonistas , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/metabolismo , Neuronas/citología , Neuronas/efectos de los fármacos , Neuropéptido Y/antagonistas & inhibidores , Neuropéptido Y/metabolismo , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Precursores de Proteínas/administración & dosificación , Precursores de Proteínas/antagonistas & inhibidores , Precursores de Proteínas/metabolismo , Receptores de Melanocortina/antagonistas & inhibidores , Receptores de Melanocortina/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , alfa-MSH/metabolismoRESUMEN
Ghrelin was initially identified as an endogenous ligand for the GH secretagogue receptor. When administrated exogenously, ghrelin stimulates GH release and food intake. Previous reports in ghrelin-null mice, which do not exhibit impaired growth nor appetite, question the physiologic role of ghrelin in the regulation of the GH/IGF-I axis. In this study, we generated a transgenic mouse that expresses human diphtheria toxin (DT) receptor (DTR) cDNA in ghrelin-secretion cells [ghrelin-promoter DTR-transgenic (GPDTR-Tg) mice]. Administration of DT to this mouse ablates ghrelin-secretion cells in a controlled manner. After injection of DT into GPDTR-Tg mice, ghrelin-secreting cells were ablated, and plasma levels of ghrelin were markedly decreased [nontransgenic littermates, 70.6 +/- 10.2 fmol/ml vs. GPDTR-Tg, 5.3 +/- 2.3 fmol/ml]. To elucidate the physiological roles of circulating ghrelin on GH secretion and somatic growth, 3-wk-old GPDTR-Tg mice were treated with DT twice a week for 5 wk. The GH responses to GHRH in male GPDTR-Tg mice were significantly lower than those in wild-type mice at 5 wk of age. However, those were normalized at 8 wk of age. In contrast, in female mice, there was no difference in GH response to GHRH between GPDTR-Tg mice and controls at 5 or 8 wk of age. The gender-dependent differences in response to GHRH were observed in ghrelin-ablated mice. However, GPDTR-Tg mice did not display any decreases in IGF-I levels or any growth retardation. Our results strongly suggest that circulating ghrelin does not play a crucial role in somatic growth.
Asunto(s)
Ghrelina/sangre , Hormona Liberadora de Hormona del Crecimiento/metabolismo , Hormona del Crecimiento/metabolismo , Crecimiento/fisiología , Factores de Edad , Análisis de Varianza , Animales , Densidad Ósea/fisiología , Ingestión de Alimentos/genética , Femenino , Ghrelina/genética , Hormona del Crecimiento/genética , Hormona Liberadora de Hormona del Crecimiento/genética , Hormona Liberadora de Hormona del Crecimiento/farmacología , Hipotálamo/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Ratones , Ratones Transgénicos , Hipófisis/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores SexualesRESUMEN
Previous study showed that mulberry (Morus Alba L.) leaf (ML) ameliorates atherosclerosis in apoE(-/-) mice. Although the adipocytokine dysregulation is an important risk factor for atherosclerotic cardiovascular disease, the effect of ML on metabolic disorders related to adipocytokine dysregulation and inflammation has not been studied. Therefore, we studied the effects of ML in metabolic disorders and examined the mechanisms by which ML ameliorates metabolic disorders in db/db mice. We treated db/db mice with ML, pioglitazone, or both for 12 weeks and found that ML decreased blood glucose and plasma triglyceride. Co-treatment with ML and pioglitazone showed additive effects compared with pioglitazone. Moreover, their co-treatment attenuated the body weight increase observed under the pioglitazone treatment. ML treatment also increased the expression of adiponectin, and decreased the expression of TNF-alpha, MCP-1, and macrophage markers in white adipose tissue (WAT). Furthermore, ML decreased lipid peroxides and the expression of NADPH oxidase subunits in WAT and liver. Their co-treatment enhanced these effects. Thus, ML ameliorates adipocytokine dysregulation at least in part through inhibiting oxidative stress in WAT of db/db mice, and that ML may be a basis for a pharmaceutical for the treatment of the metabolic syndrome as well as reducing adverse effects of pioglitazone.
Asunto(s)
Adipoquinas/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Antioxidantes/farmacología , Diabetes Mellitus/tratamiento farmacológico , Hipoglucemiantes/farmacología , Morus , Obesidad/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Tiazolidinedionas/farmacología , Adiponectina/metabolismo , Tejido Adiposo Blanco/metabolismo , Adiposidad/efectos de los fármacos , Animales , Glucemia/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Quimiocina CCL2/metabolismo , Colesterol/sangre , Diabetes Mellitus/metabolismo , Modelos Animales de Enfermedad , Quimioterapia Combinada , Metabolismo Energético/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Lipólisis/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Mutantes , NADPH Oxidasas/metabolismo , Obesidad/metabolismo , Pioglitazona , Extractos Vegetales/farmacología , Hojas de la Planta , Subunidades de Proteína , Factores de Tiempo , Triglicéridos/sangre , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
We developed and analyzed two types of transgenic mice: rat insulin II promoter-ghrelin transgenic (RIP-G Tg) and rat glucagon promoter-ghrelin transgenic mice (RGP-G Tg). The pancreatic tissue ghrelin concentration measured by C-terminal radioimmunoassay (RIA) and plasma desacyl ghrelin concentration of RIP-G Tg were about 1000 and 3.4 times higher than those of nontransgenic littermates, respectively. The pancreatic tissue n-octanoylated ghrelin concentration measured by N-terminal RIA and plasma n-octanoylated ghrelin concentration of RIP-G Tg were not distinguishable from those of nontransgenic littermates. RIP-G Tg showed suppression of glucose-stimulated insulin secretion. Arginine-stimulated insulin secretion, pancreatic insulin mRNA and peptide levels, beta cell mass, islet architecture, and GLUT2 and PDX-1 immunoreactivity in RIP-G Tg pancreas were not significantly different from those of nontransgenic littermates. Islet batch incubation study did not show suppression of insulin secretion of RIP-G Tg in vitro. The insulin tolerance test showed lower tendency of blood glucose levels in RIP-G Tg. Taking lower tendency of triglyceride level of RIP-G Tg into consideration, these results may indicate that the suppression of insulin secretion is likely due to the effect of desacyl ghrelin on insulin sensitivity. RGP-G Tg, in which the pancreatic tissue ghrelin concentration measured by C-RIA was about 50 times higher than that of nontransgenic littermates, showed no significant changes in insulin secretion, glucose metabolism, islet mass, and islet architecture. The present study raises the possibility that desacyl ghrelin may have influence on glucose metabolism.
Asunto(s)
Glucagón/genética , Insulina/genética , Hormonas Peptídicas/genética , Regiones Promotoras Genéticas , Animales , Arginina/química , Northern Blotting , Peso Corporal , ADN Complementario/metabolismo , Biblioteca de Genes , Ghrelina , Glucosa/metabolismo , Proteínas de Homeodominio/metabolismo , Inmunohistoquímica , Insulina/metabolismo , Secreción de Insulina , Intrones , Islotes Pancreáticos/metabolismo , Metabolismo de los Lípidos , Ratones , Ratones Transgénicos , Modelos Genéticos , Páncreas/metabolismo , Hormonas Peptídicas/metabolismo , Péptidos/química , ARN Mensajero/metabolismo , Radioinmunoensayo , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Transactivadores/metabolismoRESUMEN
Ghrelin, a 28-amino acid acylated peptide, displays strong GH-releasing activity in concert with GHRH. The fatty acid modification of ghrelin is essential for the actions, and des-acyl ghrelin, which lacks the modification, has been assumed to be devoid of biological effects. Some recent reports, however, indicate that des-acyl ghrelin has effects on cell proliferation and survival. In the present study, we generated two lines of transgenic mice bearing the preproghrelin gene under the control of chicken beta-actin promoter. Transgenic mice overexpressed des-acyl ghrelin in a wide variety of tissues, and plasma des-acyl ghrelin levels reached 10- and 44-fold of those in control mice. They exhibited lower body weights and shorter nose-to-anus lengths, compared with control mice. The serum GH levels tended to be lower, and the serum IGF-I levels were significantly lower in both male and female transgenic mice than control mice. The responses of GH to administered GHRH were normal, whereas those to administered ghrelin were reduced, especially in female transgenic mice, compared with control mice. These data suggest that overexpressed des-acyl ghrelin may modulate the GH-IGF-I axis and result in small phenotype in transgenic mice.