RESUMEN
BACKGROUND: Rikkunshito (RKT), a traditional Japanese medicine, can relieve epigastric discomfort and anorexia in patients with functional dyspepsia. RKT enhances the orexigenic hormone, ghrelin. Ghrelin regulates food motivation by stimulating the appetite control center in the hypothalamus and the brain mesolimbic dopaminergic pathway (MDPW). However, the effect of RKT on MDPW remains unclear. Here, we aimed to investigate the central neural mechanisms underlying the orexigenic effects of RKT, focusing on the MDPW. METHODS: We examined the effects of RKT on food intake and neuronal c-Fos expression in restraint stress- and cholecystokinin octapeptide-induced anorexia in male rats. KEY RESULTS: RKT treatment significantly restored stress- and cholecystokinin octapeptide-induced decreased food intake. RKT increased c-Fos expression in the ventral tegmental area (VTA), especially in tyrosine hydroxylase-immunoreactive neurons, and nucleus accumbens (NAc). The effects of RKT were suppressed by the ghrelin receptor antagonist [D-Lys3]-GHRP-6. RKT increased the number of c-Fos/orexin-double-positive neurons in the lateral hypothalamus (LH), which project to the VTA. The orexin receptor antagonist, SB334867, suppressed RKT-induced increase in food intake and c-Fos expression in the LH, VTA, and NAc. RKT increased c-Fos expression in the arcuate nucleus and nucleus of the solitary tract of the medulla, which was inhibited by [D-Lys3]-GHRP-6. CONCLUSIONS & INFERENCES: RKT may restore appetite in subjects with anorexia through ghrelin- and orexin-dependent activation of neurons regulating the brain appetite control network, including the hypothalamus and MDPW.
RESUMEN
Cholecystokinin (CCK) had been the first gastrointestinal hormone known to exert anorexic effects. CCK had been inferred to contribute to the onset of functional dyspepsia (FD) symptoms. To understand the pathophysiology of FD, the roles of stress have to be clarified. In this study, we aimed to clarify the influence of stress on the action of cholecystokinin (CCK) on appetite and gastric emptying. Using rats, stress was simulated by giving restraint stress or intraperitoneal injection of the stress-related peptide hormone urocortin 1 (UCN1). The effects of CCK and restraint stress, alone or in combination, on food intake and gastric motility were examined, and c-Fos expression in the neurons of appetite control network in the central nervous system was assessed by immunohistochemical staining. CCK inhibited food intake and gastric emptying in a dose-dependent manner. Food intake for 1 h was significantly lower with UCN1 (2 nmol/kg) than with the saline control. Restraint stress amplified the suppressive effects of CCK on food intake for 1 h and on gastric emptying. With regard to brain function, the CCK induced c-Fos expression in the neurons of the nucleus tractus solitarius and paraventricular nucleus of the hypothalamus was markedly and significantly amplified by the addition of restraint stress with CCK. The results suggested that stress might amplify the anorexic effects of CCK through activation of the nuclei that comprise the brain neuronal network for satiation; this might play a role in the pathogenesis of the postprandial distress syndromes of functional dyspepsia.
Asunto(s)
Apetito/efectos de los fármacos , Colecistoquinina/farmacología , Vaciamiento Gástrico/efectos de los fármacos , Neuronas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Estrés Psicológico/fisiopatología , Animales , Encéfalo/citología , Encéfalo/metabolismo , Dispepsia/etiología , Ingestión de Alimentos/efectos de los fármacos , Masculino , Neuronas/metabolismo , Ratas Sprague-Dawley , Urocortinas/farmacologíaRESUMEN
Recapitulative animal models of idiopathic pulmonary fibrosis (IPF) and related diseases are lacking, which inhibits our ability to fully clarify the pathogenesis of these diseases. Although lung fibrosis in mouse models is often induced by bleomycin, silica-induced lung fibrosis is more sustainable and more progressive. Therefore, in this study, we sought to elucidate the mediator(s) responsible for the pathogenesis of lung fibrosis, through the use of a mouse model of silica-induced lung fibrosis. With a single nasal administration of 16 mg of silica, lung inflammation (assessed by elevated cellular components in the BAL fluids [BALFs]) and lung fibrosis (assessed by lung histology and lung hydroxyproline levels) were induced and sustained for as long as 24 weeks. Of the mediators measured in the BALFs, IL-9 was characteristically elevated gradually, and peaked at 24 weeks after silica administration. Treatment of silica-challenged mice with anti-IL-9-neutralizing antibody inhibited lung fibrosis, as assessed by lung hydroxyproline level, and suppressed the levels of major mediators, including IL-1ß, IL-6, IL-12, CCL2, CXCL1, and TNF-α in BALFs. Moreover, human lung specimens from patients with IPF have shown high expression of IL-9 in alveolar macrophages, CD4-positive cells, and receptors for IL-9 in airway epithelial cells. Collectively, these data suggest that IL-9 plays an important role in the pathogenesis of lung fibrosis in diseases such as IPF.
Asunto(s)
Fibrosis Pulmonar Idiopática/patología , Interleucina-9/metabolismo , Neumonía/tratamiento farmacológico , Fibrosis Pulmonar/tratamiento farmacológico , Dióxido de Silicio/toxicidad , Anciano , Animales , Anticuerpos/farmacología , Líquido del Lavado Bronquioalveolar , Estudios de Casos y Controles , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Fibrosis Pulmonar Idiopática/metabolismo , Mediadores de Inflamación/metabolismo , Interleucina-9/inmunología , Masculino , Ratones Endogámicos C57BL , Neumonía/inducido químicamente , Neumonía/patología , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/patología , Receptores de Interleucina-9/metabolismoRESUMEN
BACKGROUND: Viral infections are the most common triggers of asthma exacerbation, but the key molecules involved in this process have not been fully identified. Although cysteinyl leukotrienes (cysLTs) have been postulated as the key mediators, their precise roles remain largely unclear. To investigate the roles of cysLTs in virus-induced asthma exacerbation, we developed a murine model using a viral double-stranded RNA analog, polyinosinic-polycytidylic acid (poly I:C), and analyzed the effect of leukotriene receptor antagonist (LTRA) administration. METHODS: A/J mice were immunized with ovalbumin (OVA) + alum (days 0, 28, 42, and 49), followed by intranasal challenge with OVA (phase 1: days 50-52) and poly I:C (phase 2: days 53-55). Montelukast was administered during poly I:C challenge (phase 2) in the reliever model or throughout the OVA and poly I:C challenges (phases 1 and 2) in the controller model. Airway responsiveness to acetylcholine chloride was assessed, and bronchoalveolar lavage (BAL) was performed on day 56. RESULTS: Administration of poly I:C to OVA-sensitized and -challenged mice increased the number of eosinophils and levels of IL-13, IL-9, CCL3, and CXCL1 in BAL fluid (BALF) and tended to increase airway responsiveness. Montelukast significantly attenuated the poly I:C-induced increase in the number of eosinophils and levels of IL-13, IL-9, and CCL3 in BALF and airway hyperresponsiveness in both the reliever and controller models. CONCLUSIONS: This is the first report showing that LTRA functionally suppressed the pathophysiology of a virus-induced asthma exacerbation model, suggesting the importance of cysLTs as a potential treatment target.
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Antiasmáticos/farmacología , Asma/etiología , Asma/metabolismo , Antagonistas de Leucotrieno/farmacología , ARN Bicatenario/efectos adversos , Acetatos/farmacología , Compuestos de Alumbre/efectos adversos , Animales , Asma/tratamiento farmacológico , Asma/patología , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Ciclopropanos , Cisteína/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Eosinófilos/efectos de los fármacos , Eosinófilos/inmunología , Eosinófilos/metabolismo , Inmunización , Mediadores de Inflamación/metabolismo , Leucotrienos/metabolismo , Masculino , Ratones , Ovalbúmina/efectos adversos , Poli I-C/administración & dosificación , Quinolinas/farmacología , ARN Viral/efectos adversos , Hipersensibilidad Respiratoria/tratamiento farmacológico , Hipersensibilidad Respiratoria/etiología , Hipersensibilidad Respiratoria/metabolismo , Hipersensibilidad Respiratoria/patología , SulfurosRESUMEN
An 80-year-old woman with rheumatoid arthritis and a past history of tuberculosis presented with exertional dyspnea and edema of both legs. Chest X-ray performed on admission showed bilateral pleural effusion. Thoracoscopy under local anesthesia was performed, and vasodilation and non-specific yellowish inflammatory changes were noted in the pleura. A pathological examination showed chronic fibrosing pleuritis in addition to chronic pleural inflammatory changes with lymphoid aggregates. The nails on all fingers and toes were thickened and displayed yellow discoloration, and the edema was resistant to diuretics. Lymphoscintigraphy was conducted, which showed lymphatic drainage abnormalities. The patient was ultimately diagnosed as having yellow nail syndrome.
Asunto(s)
Anestesia Local/métodos , Toracoscopía/métodos , Síndrome de la Uña Amarilla/diagnóstico , Anciano de 80 o más Años , Artritis Reumatoide/complicaciones , Femenino , Humanos , Derrame Pleural/patología , Síndrome de la Uña Amarilla/complicacionesRESUMEN
BACKGROUND: Viral infection is one of the risk factors for asthma exacerbation. However, which pathogens are related to asthma exacerbation in adults remains unclear. OBJECTIVE: The relation between various infections and adult asthma exacerbations was investigated in clinical practice. METHODS: The study subjects included 50 adult inpatients due to asthma exacerbations and 20 stable outpatients for comparison. The pathogens from a nasopharyngeal swab were measured by multiplex PCR analysis. RESULTS: Asthma exacerbations occurred after a common cold in 48 inpatients. The numbers of patients with viral, bacterial, or both infections were 16, 9, and 9, respectively. The dominant viruses were rhinoviruses, respiratory syncytial virus, influenza virus, and metapneumovirus. The major bacteria were S. pneumoniae and H. influenzae. Compared to pathogen-free patients, the patients with pathogens were older and non-atopic and had later onset of disease, lower FeNO levels, lower IgE titers, and a higher incidence of comorbid sinusitis, COPD, or pneumonia. Compared to stable outpatients, asthma exacerbation inpatients had a higher incidence of smoking and comorbid sinusitis, COPD, or pneumonia. Viruses were detected in 50% of stable outpatients, but a higher incidence of rhinovirus, respiratory syncytial virus, and metapneumovirus infections was observed in asthma exacerbation inpatients. H. influenzae was observed in stable asthmatic patients. Other bacteria, especially S. pneumoniae, were important in asthma exacerbation inpatients. CONCLUSION: Viral or bacterial infections were observed in 70% of inpatients with an asthma exacerbation in clinical practice. Infection with S. pneumoniae was related to adult asthma exacerbation.
Asunto(s)
Asma/microbiología , Asma/virología , Infecciones Bacterianas/complicaciones , Virosis/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Asma/complicaciones , Asma/epidemiología , Comorbilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nasofaringe/microbiología , Nasofaringe/virología , Neumonía/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/epidemiologíaRESUMEN
Takotsubo cardiomyopathy is a transient left-ventricular dysfunction that typically occurs in elderly women due to emotional or physical stress. An 85-y-old woman underwent flexible bronchoscopy to evaluate her malignant lymphoma. After flexible bronchoscopy, she experienced takotsubo cardiomyopathy diagnosed by left ventriculography and subsequent generalized tonic-clonic seizure diagnosed by electroencephalography. Magnetic resonance imaging of her brain after 1 d showed post-convulsive encephalopathy. We believe that these 2 consecutive incidents were caused by the physical stress of the flexible bronchoscopy.
Asunto(s)
Encefalopatías/etiología , Broncoscopía/efectos adversos , Convulsiones/etiología , Cardiomiopatía de Takotsubo/etiología , Anciano de 80 o más Años , Femenino , Humanos , Linfoma/diagnóstico , Estrés FisiológicoRESUMEN
The autonomic nervous system (ANS) conveys neuronal input from the brain to the stomach. We investigated mechanisms through which urocortin 1 (UCN1) injected intracerebroventricularly (ICV, 300 pmol/rat) inhibits circulating ghrelin in rats. This was achieved by assessing (1) the induction of c-fos gene expression as a marker of neuronal activation in specific hypothalamic and caudal brainstem regulating ANS; (2) the influence of vagotomy and pharmacological blockade of central and peripheral α- and ß-adrenergic receptor (AR) on ICV UCN1-induced reduction of plasma ghrelin levels (determined by ELISA); and (3) the relevance of this pathway in the feeding response to a fast in rats. UCN1 increased c-fos mRNA expression in key brain sites influencing sympathetic activity namely the hypothalamic paraventricular and ventromedial nuclei, locus coeruleus, nucleus of the solitary tract, and rostral ventrolateral medulla, by 16-, 29-, 6-, 37-, and 13-fold, respectively. In contrast, the dorsal motor nucleus of the vagus had little c-fos mRNA expression and ICV UCN1 induced a similar reduction in acylated ghrelin in the sham-operated (31%) and vagotomized (41%) rats. An intraperitoneal (IP) injection of either a non-selective α- or selective α2-AR antagonist reduced, while a selective α2-AR agonist enhanced ICV UCN1-induced suppression of plasma acylated ghrelin levels. In addition, IP injection of a non-selective ß- or selective ß1-AR agonist blocked, and selective ß1-AR antagonist augmented, the ghrelin response to ICV UCN1. The IP injections of a selective α1- or non-selective ß or ß2-AR antagonists, or any of the pretreatments given ICV had no effect. ICV UCN1 reduced the 2-h food intake in response to a fast by 80%, and this effect was partially prevented by a selective α2-AR antagonist. These data suggest that ICV UCN1 reduces plasma ghrelin mainly through the brain sympathetic component of the ANS and peripheral AR specifically α2-AR activation and inactivation of ß1-AR. The α2-AR pathway contributes to the associated reduction in food intake.
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Encéfalo/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Ghrelina/sangre , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Adrenérgicos beta 1/metabolismo , Urocortinas/farmacología , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Antagonistas de Receptores Adrenérgicos beta 1/farmacología , Animales , Encéfalo/metabolismo , Masculino , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Sprague-Dawley , VagotomíaRESUMEN
This study was conducted to determine the mechanisms by which serotonin (5-hydroxytryptamine, 5-HT) receptors are involved in the suppression of food intake in a rat stress model and to observe the degree of activation in the areas of the brain involved in feeding. In the stress model, male Sprague-Dawley rats (8 weeks old) were given intracerebroventricular injections of urocortin (UCN) 1. To determine the role of the 5-HT2c receptor (5-HT2cR) in the decreased food intake in UCN1-treated rats, specific 5-HT2cR or 5-HT2b receptor (5-HT2bR) antagonists were administered. Food intake was markedly reduced in UCN1-injected rats compared with phosphate buffered saline treated control rats. Intraperitoneal administration of a 5-HT2cR antagonist, but not a 5-HT2bR antagonist, significantly inhibited the decreased food intake. To assess the involvement of neural activation, we tracked the expression of c-fos mRNA as a neuronal activation marker. Expression of the c-fos mRNA in the arcuate nucleus, ventromedial hypothalamic nucleus (VMH) and rostral ventrolateral medulla (RVLM) in UNC1-injected rats showed significantly higher expression than in the PBS-injected rats. Increased c-fos mRNA was also observed in the paraventricular nucleus (PVN), the nucleus of the solitary tract (NTS), and the amygdala (AMG) after injection of UCN1. Increased 5-HT2cR protein expression was also observed in several areas. However, increased coexpression of 5-HT2cR and c-fos was observed in the PVN, VMH, NTS, RVLM and AMG. Whereas, pro-opiomelanocortin mRNA expression was not changed. In an UNC1-induced stress model, 5-HT2cR expression and activation was found in brain areas involved in feeding control.
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Anorexia/metabolismo , Hipotálamo/metabolismo , Receptor de Serotonina 5-HT2C/metabolismo , Aminopiridinas/farmacología , Animales , Anorexia/inducido químicamente , Ingestión de Energía/efectos de los fármacos , Conducta Alimentaria , Expresión Génica , Indoles/farmacología , Masculino , Bulbo Raquídeo/metabolismo , Proopiomelanocortina/genética , Proopiomelanocortina/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Quinolinas/farmacología , Ratas , Ratas Sprague-Dawley , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , UrocortinasRESUMEN
BACKGROUND: Apelin is a peptide that was originally isolated from bovine stomach extract and has been demonstrated to be an endogenous ligand for orphan receptor APJ. Both apelin and the APJ receptor are widely distributed in the whole body. Apelin is supposed to have important regulatory roles in the function of many organs such as in the cardiovascular system; however, the mechanism of apelin function has not been elucidated. In this study, we studied the action of apelin in acid secretion and demonstrated its mechanism of action. METHODS: Gastric lumen-perfused rats were prepared and their stomachs were perfused with a saline solution using a peristaltic pump. Apelin-12, 36 or Pyr(1)-apelin-13, were intravenously injected to examine their effects on acid secretion in rats. In some experiments, rats were pretreated with famotidine (0.33 mg/kg) or atropine sulfate (0.1mg/kg) intravenously injected 5 or 15 min before apelin injection. Furthermore, isolated vascularly perfused rat stomachs were prepared to examine the effect of apelin on histamine release, which was assayed in the effluent by radioimmunoassay. Messenger RNA of histidine decarboxylase (HDC) in gastric mucosa of isolated stomach was measured by real-time RT-PCR. RESULTS: Apelin-12 (20-100 µg/kg) dose-dependently increased gastric acid secretion, with a maximum of 203% at 100 µg/kg (n=5). Neither Pyr(1)-apelin-13 nor apelin-36 caused a significant increase in acid secretion. Famotidine completely blocked the stimulatory action of apelin on acid secretion. Apelin-12 (100 µg/20 ml/10 min) markedly increased histamine release from isolated vascularly perfused rat stomachs by 278%, and also increased the mRNA of HDC by 480% of the control. Atropine sulfate did not abolish the effect of apelin on the secretion of gastric acid. Apelin-12 amplified an increase of acid secretion stimulated by gastrin injection. CONCLUSION: These results indicate that apelin-12 stimulates gastric acid secretion through an increase in histamine release and synthesis from gastric mucosa, suggesting that apelin might play a role in the secretion of gastric acid or serve as a regulating factor of the secretion of gastric acid.
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Ácido Gástrico/metabolismo , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Liberación de Histamina/efectos de los fármacos , Péptidos y Proteínas de Señalización Intercelular/farmacología , Animales , Relación Dosis-Respuesta a Droga , Mucosa Gástrica/cirugía , Histamina/biosíntesis , Histidina Descarboxilasa/genética , Histidina Descarboxilasa/metabolismo , Humanos , Técnicas In Vitro , Masculino , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Although it is known that urocortin 1 (UCN) acts on both corticotropin-releasing factor receptors (CRF(1) and CRF(2)), the mechanisms underlying UCN-induced anorexia remain unclear. In contrast, ghrelin, the endogenous ligand for the growth hormone secretagogue receptor, stimulates food intake. In the present study, we examined the effects of CRF(1) and CRF(2) receptor antagonists (CRF(1)a and CRF(2)a) on ghrelin secretion and synthesis, c-fos mRNA expression in the caudal brain stem, and food intake following intracerebroventricular administration of UCN. Eight-week-old, male Sprague-Dawley rats were used after 24-h food deprivation. Acylated and des-acylated ghrelin levels were measured by enzyme-linked immunosorbent assay. The mRNA expressions of preproghrelin and c-fos were measured by real-time RT-PCR. The present study provided the following important insights into the mechanisms underlying the anorectic effects of UCN: 1) UCN increased acylated and des-acylated ghrelin levels in the gastric body and decreased their levels in the plasma; 2) UCN decreased preproghrelin mRNA levels in the gastric body; 3) UCN-induced reduction of plasma ghrelin and food intake were restored by CRF(2)a but not CRF(1)a; 4) UCN-induced increase of c-fos mRNA levels in the caudal brain stem containing the nucleus of the solitary tract (NTS) was inhibited by CRF(2)a; and 5) UCN-induced reduction of food intake was restored by exogenous ghrelin and rikkunshito, an endogenous ghrelin secretion regulator. Thus, UCN increases neuronal activation in the caudal brain stem containing NTS via CRF(2) receptors, which may be related to UCN-induced inhibition of both ghrelin secretion and food intake.
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Ingestión de Alimentos/efectos de los fármacos , Ghrelina/metabolismo , Receptores de Hormona Liberadora de Corticotropina/fisiología , Urocortinas/farmacología , Animales , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Medicamentos Herbarios Chinos/farmacología , Ácido Gástrico/metabolismo , Vaciamiento Gástrico/efectos de los fármacos , Vaciamiento Gástrico/fisiología , Ghrelina/farmacología , Infusiones Intraventriculares , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Vías Secretoras/efectos de los fármacos , Urocortinas/administración & dosificación , Urocortinas/metabolismoRESUMEN
Although chemotherapy with cisplatin is a widely used and effective cancer treatment, the undesirable gastrointestinal side effects associated with it, such as nausea, vomiting, and anorexia, markedly decrease patients' quality of life. To elucidate the mechanism underlying chemotherapy-induced anorexia, focusing on the hypothalamic ghrelin secretion-anorexia association, we measured hypothalamic ghrelin secretion in fasted and cisplatin-treated rats. Hypothalamic ghrelin secretion changes after vagotomy or administration of cisplatin. Cisplatin + rikkunshito, a serotonin 2C receptor antagonist or serotonin 3 receptor antagonist, was investigated. The effects of intracerebroventricular (icv) administration of ghrelin or the serotonin 2C receptor antagonist SB242084 on food intake were also evaluated in cisplatin-treated rats. Hypothalamic ghrelin secretion significantly increased in 24-h-fasted rats compared to freely fed rats and was markedly reduced 24 and 48 h after cisplatin treatment in cisplatin-treated rats compared to saline-treated rats, although their plasma ghrelin levels were comparable. In cisplatin-treated rats, icv ghrelin administration reversed the decrease in food intake, vagotomy partially restored hypothalamic ghrelin secretion, and hypothalamic serotonin 2C receptor mRNA expression increased significantly. Administration of rikkunshito (an endogenous ghrelin enhancer) or a serotonin 2C receptor antagonist reversed the decrease in hypothalamic ghrelin secretion and food intake 24 h after cisplatin treatment. Cisplatin-induced anorexia is mediated through reduced hypothalamic ghrelin secretion. Cerebral serotonin 2C receptor activation partially induces decrease in hypothalamic ghrelin secretion, and rikkunshito suppresses cisplatin-induced anorexia by enhancing this secretion.
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Anorexia/inducido químicamente , Cisplatino/farmacología , Ghrelina/metabolismo , Hipotálamo/efectos de los fármacos , Aminopiridinas/administración & dosificación , Aminopiridinas/farmacología , Animales , Anorexia/metabolismo , Anorexia/patología , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Cisplatino/efectos adversos , Regulación hacia Abajo/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Medicamentos Herbarios Chinos/farmacología , Ingestión de Alimentos/efectos de los fármacos , Ghrelina/administración & dosificación , Hipotálamo/metabolismo , Indoles/administración & dosificación , Indoles/farmacología , Inyecciones Intraventriculares , Masculino , Ratas , Ratas Sprague-Dawley , Vías Secretoras/efectos de los fármacos , Antagonistas de la Serotonina/administración & dosificación , Antagonistas de la Serotonina/farmacologíaRESUMEN
BACKGROUND: Ghrelin, a growth-hormone-releasing peptide, has two major molecular forms: acylated (acyl) and desacylated (desacyl). Recent studies suggest different roles for these two forms. In the present study, we compared desacyl and acyl ghrelin with regard to acid secretion and histamine production in the rat stomach. METHODS: We performed in vivo experiments using gastric lumen-perfused rats. The effects of the two forms of ghrelin on gastrin (gastrin-17)-stimulated acid secretion were also examined. Furthermore, to examine the effects of ghrelin on histamine production, histidine decarboxylase messenger ribonucleic acid in the gastric corpus mucosa was measured by reverse transcription-polymerase chain reaction. RESULTS: Intravenous administration of acyl ghrelin at 20 µg/kg increased gastric acid secretion to 4.8 times greater than control levels. However, desacyl ghrelin had no effect on acid secretion, even at 200 µg/kg. Acyl ghrelin enhanced gastrin-stimulated acid secretion while desacyl ghrelin did not. Vagotomy markedly inhibited the enhancement of gastrin-stimulated acid secretion by acyl ghrelin. Acyl ghrelin increased histidine decarboxylase messenger ribonucleic acid concentration by 2.3 times compared with basal levels at 1 h after administration and by 2.7 times at 2 h after administration; desacyl ghrelin had no such effect. Synergism between acyl ghrelin and gastrin was seen regarding histidine decarboxylase messenger ribonucleic acid concentration. CONCLUSIONS: The results indicate that acyl ghrelin stimulates gastric acid secretion via a mechanism involving activation of the vagus nerve and histamine release and synthesis and that desacyl ghrelin has no action on gastric acid secretion. Furthermore, the results demonstrate synergism between gastrin and acyl ghrelin in terms of gastric acid secretion via a mechanism involving histamine release and synthesis.
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Ácido Gástrico/metabolismo , Ghrelina/farmacología , Histamina/biosíntesis , Estómago/efectos de los fármacos , Acilación , Animales , Relación Dosis-Respuesta a Droga , Mucosa Gástrica/metabolismo , Gastrinas/administración & dosificación , Ghrelina/administración & dosificación , Ghrelina/química , Histamina/metabolismo , Histidina Descarboxilasa/metabolismo , Humanos , Masculino , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Factores de Tiempo , Nervio Vago/metabolismoRESUMEN
Circulating ghrelin concentration regulates appetite behavior, but no study thus far has focused on the role of central ghrelin in anorexia after chemotherapy. To clarify the action mechanisms of rikkunshito (RKT), a traditional Japanese medicine, on cisplatin-induced anorexia, we attempted to elucidate its effect on hypothalamic ghrelin receptor expression in cisplatin-induced anorexia. We first examined the effects of an intracerebroventricular (ICV) injection of exogenous ghrelin on food intake with or without cisplatin treatment, and the effects of cisplatin or m-chlorophenylpiperazine (mCPP), a 5-HT2C receptor agonist, on hypothalamic growth hormone secretagogue receptor 1a (GHS-R1a) mRNA expression. To identify the mechanism of cisplatin-induced decrease in hypothalamic GHS-R1a mRNA expression, we evaluated the effects of SB242084HCl, a 5-HT2C receptor antagonist, and RKT on hypothalamic GHS-R1a gene expression, along with the effect of coadministration of a GHS-R1a antagonist on decreased food intake. Compared to vehicle controls, an ICV-injected rat ghrelin failed to inhibit the decrease in food intake in cisplatin-treated rats. Hypothalamic GHS-R1a gene expression was significantly reduced after cisplatin or mCPP treatment, and the induced decrease was reversed by SB242084HCl or RKT, but not granisetron or ondansetron, both of which are 5-HT3 receptor antagonists. Their suppressive effect on the decrease in food intake was abolished by coadministration of the GHS-R1a antagonist. Administration of RKT or SB242084HCl reversed the decrease in food intake induced by mCPP injection. The improvement by RKT on decreased food intake after cisplatin treatment was partly mediated by hesperidin and isoliquiritigenin, components of RKT. Cisplatin-induced anorexia may worsen because of decreased hypothalamic GHS-R1a gene expression. A 5-HT2C receptor antagonist and RKT suppressed cisplatin-induced anorexia by inhibiting reduction of GHS-R1a signal transduction in the hypothalamus.
Asunto(s)
Anorexia/inducido químicamente , Anorexia/tratamiento farmacológico , Cisplatino/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Ghrelina/metabolismo , Hipotálamo/metabolismo , Antagonistas del Receptor de Serotonina 5-HT2 , Animales , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/genética , Mucosa Gástrica/metabolismo , Granisetrón/farmacología , Hipotálamo/efectos de los fármacos , Masculino , Oligopéptidos/genética , Ondansetrón/farmacología , Quinoxalinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Ghrelina/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estómago/efectos de los fármacosRESUMEN
PURPOSE: We attempted to clarify the significance of atrophic change of gastric mucosa for reduction of plasma ghrelin concentration irrespective of Helicobacter pylori (Hp) infection. METHODS: Plasma acylated (acyl-)ghrelin concentration in 220 subjects, both with and without atrophic gastritis, was measured with an enzyme immunoassay kit. The extent of atrophic change of gastric mucosa was assessed and graded endoscopically. Hp infection was determined by assay of the anti-Hp antibody with an ELISA assay kit. RESULTS: Plasma acyl-ghrelin concentration was significantly lower in the Hp positive than the Hp negative group, and Hp eradication significantly increased plasma acyl-ghrelin concentrations in Hp positive subjects. Plasma acyl-ghrelin was significantly lower in subjects with severely atrophic gastritis than in those with mild or moderate atrophic gastritis, irrespective of Hp infection or age group (<60 years old or > or = 60 years old). In male subjects with a normal body mass index, plasma acyl-ghrelin concentrations in subjects with severely atrophic gastritis were significantly lower than those in subjects with mildly or moderately atrophic gastritis, suggesting that the results of the study are independent of emaciation or obesity. Logistic regression analysis showed that gastric atrophy is the key factor that modulates plasma acyl-ghrelin levels. CONCLUSIONS: The results suggest that plasma acyl-ghrelin concentration decreases in accordance with the extent of atrophic change in gastric mucosa irrespective of Hp infection, indicating that the low plasma acyl-ghrelin level of subjects with Hp infection is mainly caused by the progress of atrophic changes in gastric mucosa.
Asunto(s)
Mucosa Gástrica/patología , Gastritis Atrófica/sangre , Ghrelina/sangre , Infecciones por Helicobacter/sangre , Helicobacter pylori , Antibacterianos/uso terapéutico , Anticuerpos Antibacterianos/sangre , Índice de Masa Corporal , Ensayo de Inmunoadsorción Enzimática , Femenino , Mucosa Gástrica/metabolismo , Mucosa Gástrica/microbiología , Gastritis Atrófica/microbiología , Gastritis Atrófica/patología , Gastroscopía , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/patología , Helicobacter pylori/inmunología , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND/PURPOSE: Natural orifice translumenal endoscopic surgery (NOTES) is a novel concept using an endoscope via a translumenal access for abdominal surgery. This study was designed to evaluate the feasibility and technical aspects of NOTES cholecystectomy from our experience on humans and animals. METHODS: NOTES cholecystectomies were performed in 12 animal experiments, including 8 pigs (6 by transgastric and 2 by transvaginal accesses) and 4 dogs (4 transvaginal accesses), and a human female cadaver. RESULTS: The entire gallbladder could be removed under direct vision in all experiments. The average time was 60 min by transgastric and 40 min by transvaginal in animals. It was 87 min for human transvaginal cholecystectomy. In all animal and human procedures, there was no major complication concerning the operation. DISCUSSION: The transvaginal route may be the easiest route for abdominal NOTES. Percutaneous endoscopic gastrostomy (PEG) allowed the safe performance of a controlled gastric perforation and shortened the time. The hybrid method allowed performance of a safe procedure and shortened the time. CONCLUSIONS: Transvaginal and transgastric NOTES cholecystectomy is technically feasible and safe in both humans and animals. New instrumentation needs to be developed to perform a pure NOTES cholecystectomy without transabdominal assistance.
Asunto(s)
Colecistectomía Laparoscópica/métodos , Laparoscopios , Estómago , Vagina , Animales , Cadáver , Colecistectomía Laparoscópica/efectos adversos , Cicatriz/prevención & control , Modelos Animales de Enfermedad , Perros , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Factores de Riesgo , Porcinos , Resultado del TratamientoRESUMEN
The present study surveyed activation of central neurons following peripheral administration of apelin-12 (AP12), an apelin peptide homologue, by examining the distribution of neurons expressing c-Fos protein. AP12 is known to induce gastric acid secretion among other physiological functions such as regulation of circulation. It was recently reported that apelin counteracted the effect of arginine vasopressin (AVP) in the maintenance of body fluid homeostasis. We attempted to clarify which neurons in the central nervous system express c-Fos protein after intraperitoneal injection of AP12. Intraperitoneally administered AP12 induced expression of c-Fos protein in several nuclei throughout the brain. In the paraventricular nucleus of the hypothalamus (PAH), lateral hypothalamic area (LH), paraventricular nucleus of the thalamus (PVT), periaqueductal gray matter (PAG), bed nucleus of the stria terminalis (BNST), locus coeruleus (LC), lateral parabrachial nucleus (Pbl), the complex of the solitary tract nucleus (NTS) and dorsal motor nucleus of the vagus nerve (DMX), numbers of neurons expressing c-Fos protein were much higher in test than in control experiments. These findings suggest that AP12 stimulates central neurons that may play roles in the regulation of gastric acid, and hypothalamic neurons that may play roles in the maintenance of body fluid homeostasis as well as other physiological functions.
Asunto(s)
Encéfalo/citología , Péptidos y Proteínas de Señalización Intercelular/farmacología , Neuronas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Animales , Encéfalo/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Ratas , Ratas WistarRESUMEN
In this study, we surveyed central neurons that might be activated after peripheral administration of a gut-brain peptide ghrelin, by examining neurons expressing c-Fos protein. First, we examined the relationship between the dose of ghrelin and the amount of gastric acid secreted. Ghrelin induced a significant increase in the amount of gastric acid secretion in a dose-dependent manner. Secondly, we examined central neurons that expressed c-Fos protein after intravenous injection of ghrelin. We found that intravenously injected ghrelin induced the neural expression of c-Fos protein in several nuclei and circumventricular organs in the brain. These results suggest that ghrelin released into the circulation may stimulate central neurons that have some role in the control mechanism for gastric acid secretion.
Asunto(s)
Encéfalo/metabolismo , Ácido Gástrico/metabolismo , Mucosa Gástrica/metabolismo , Neuronas/metabolismo , Hormonas Peptídicas/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Animales , Núcleo Arqueado del Hipotálamo/efectos de los fármacos , Núcleo Arqueado del Hipotálamo/metabolismo , Área Postrema/efectos de los fármacos , Área Postrema/metabolismo , Biomarcadores/metabolismo , Encéfalo/anatomía & histología , Encéfalo/efectos de los fármacos , Recuento de Células , Relación Dosis-Respuesta a Droga , Conducta Alimentaria/efectos de los fármacos , Conducta Alimentaria/fisiología , Mucosa Gástrica/inervación , Ghrelina , Inmunohistoquímica , Inyecciones Intravenosas , Masculino , Neuronas/efectos de los fármacos , Hormonas Peptídicas/farmacología , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Ratas , Ratas Wistar , Núcleo Solitario/efectos de los fármacos , Núcleo Solitario/metabolismo , Órgano Subfornical/efectos de los fármacos , Órgano Subfornical/metabolismo , Nervio Vago/efectos de los fármacos , Nervio Vago/metabolismoRESUMEN
Ghrelin, a novel growth hormone-releasing peptide, is present in the rat and human stomach and is known to stimulate acid secretion and stomach motility. However, the mechanism of action of ghrelin is not fully understood. In the present study, we attempted to elucidate the role of histamine in ghrelin-induced acid secretion in rat stomach. Intravenous administration of ghrelin at 0.8 to 20 microg/kg dose dependently increased gastric acid secretion, as measured by the gastric lumen perfusion method. The maximum response was almost equal to that of gastrin (20 microg/kg). These actions were abolished by bilateral subdiaphragmatic vagotomy. Famotidine (0.33 mg/kg) also completely inhibited the effects of ghrelin. Furthermore, ghrelin increased histidine decarboxylase (HDC) messenger RNA (mRNA) levels, as measured by real-time reverse transcription-polymerase chain reaction using LightCycler. The action of ghrelin on HDC mRNA was abolished by vagotomy. Ghrelin did not affect histamine release from isolated vascularly perfused rat stomach. Taken together, these results suggest that ghrelin stimulates gastric acid secretion via a mechanism involving activation of vagal efferent nerve and histamine release from gastric enterochromaffin-like cells.
Asunto(s)
Ácido Gástrico/metabolismo , Mucosa Gástrica/metabolismo , Histamina/metabolismo , Hormonas Peptídicas/farmacología , Animales , Famotidina/farmacología , Ghrelina , Hormona del Crecimiento , Antagonistas de los Receptores H2 de la Histamina/farmacología , Histidina Descarboxilasa/genética , Masculino , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estómago/efectos de los fármacos , Estómago/inervación , VagotomíaRESUMEN
BACKGROUND: Recent studies have demonstrated relationships between cytokines and gastric acid secretion. The present study was performed in rats to elucidate the effects of interleukin-8 (IL-8) on gastric acid secretion through an increase in histamine release from the stomach. METHODS: The experiments were performed in gastric lumen-perfused rats for the study of acid secretion and in totally isolated vascularly perfused rat stomach preparations for the study of histamine release. The histamine in the effluent was determined by radioimmunoassay. RESULTS: IL-8 (500 ng) significantly enhanced gastrin-stimulated acid secretion. IL-8, at a concentration of 500 ng/20 ml per 10 min, did not alter basal histamine release, but at 100 ng/20 ml and 500 ng/20 ml it dose-dependently increased gastrin-stimulated histamine release. CONCLUSIONS: IL-8 enhances gastrin-stimulated acid secretion and histamine release from the rat stomach, which may explain the enhancing effect of IL-8 on gastric acid secretion.