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Nahata M.,Tsumura Research Laboratories | Muto S.,Tomakomai City General Hospital | Oridate N.,Hokkaido University | Nakagawa K.,Hokkaido University | And 6 more authors.
American Journal of Physiology - Gastrointestinal and Liver Physiology | Year: 2012

Gastroesophageal reflux disease (GERD) is often associated with decreased upper gastrointestinal motility, and ghrelin is an appetite-stimulating hormone known to increase gastrointestinal motility. We investigated whether ghrelin signaling is impaired in rats with GERD and studied its involvement in upper gastrointestinal motility. GERD was induced surgically in Wistar rats. Rats were injected intravenously with ghrelin (3 nmol/ rat), after which gastric emptying, food intake, gastroduodenal motility, and growth hormone (GH) release were investigated. Furthermore, plasma ghrelin levels and the expression of ghrelin-related genes in the stomach and hypothalamus were examined. In addition, we administered ghrelin to GERD rats treated with rikkunshito, a Kampo medicine, and examined its effects on gastroduodenal motility. GERD rats showed a considerable decrease in gastric emptying, food intake, and antral motility. Ghrelin administration significantly increased gastric emptying, food intake, and antral and duodenal motility in sham-operated rats, but not in GERD rats. The effect of ghrelin on GH release was also attenuated in GERD rats, which had significantly increased plasma ghrelin levels and expression of orexigenic neuropeptide Y/agouti-related peptide mRNA in the hypothalamus. The number of ghrelin-positive cells in the gastric body decreased in GERD rats, but the expression of gastric preproghrelin and GH secretagogue receptor mRNA was not affected. However, when ghrelin was exogenously administered to GERD rats treated with rikkunshito, a significant increase in antral motility was observed. These results suggest that gastrointestinal dysmotility is associated with impaired ghrelin signaling in GERD rats and that rikkunshito restores gastrointestinal motility by improving the ghrelin response. Copyright © 2012 the American Physiological Society.


Yamada M.,Steel Memorial Muroran Hospital | Kuroda H.,Steel Memorial Muroran Hospital | Yoshida M.,Steel Memorial Muroran Hospital | Usami M.,Steel Memorial Muroran Hospital | And 10 more authors.
Japanese Journal of Cancer and Chemotherapy | Year: 2015

A 62-year-old woman developed B lymphoblastic leukemia (B-ALL) in April 2010, and achieved complete remission after hyper-CVAD/high-dose-MA therapy combined with rituximab. ALL recurred in December 2011, and remission was again achieved with the Japan Adult Leukemia Study Group (JALSG) ALL202 protocol combined with rituximab. Owing to a fever and rash that persisted from July 2012, the patient was examined again. On examination, redness was observed in the pharynx, and poorly defined oval erythemas were seen on the cheeks, posterior region of the neck, and upper arms. Blood test results showed high levels of ferritin, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP), and mild hepatosplenomegaly was identified on abdominal computed tomography (CT), indicative of an adult-onset Still's disease-like condition. Prednisolone therapy was initiated in August 2012, and remission was achieved. A second recurrence of ALL developed in September 2012, and although remission was again achieved using the JALSG ALL202 protocol, a third recurrence of ALL occurred in April 2013, and the patient could not be saved. In this case, adult-onset Still's disease-like erythema developed during the remission phase of ALL.


Takeda H.,Hokkaido University | Muto S.,Hokkaido University | Muto S.,Tomakomai City General Hospital | Nakagawa K.,Hokkaido University | And 8 more authors.
Methods in Enzymology | Year: 2012

Rikkunshito is a kampo herbal medicine which is widely used in Japan for the treatment of the upper gastrointestinal symptoms of patients with functional dyspepsia, gastroesophageal reflux disease, dyspeptic symptoms of postgastrointestinal surgery patients, and chemotherapy-induced dyspepsia in cancer patients. Recently, very unique characteristics of rikkunshito have been unveiled; oral administration of rikkunshito potentiates orexigenic action of ghrelin through several different mechanisms. In addition, several lines of evidence obtained from both animal and human studies indicate that rikkunshito can be an attractive and promising therapeutic option for the anorectic conditions including cisplatin-induced dyspepsia, anorexia of aging, stress-induced hypophagia, and cancer cachexia-anorexia syndrome. In this chapter, we highlight the orexigenic effect of rikkunshito with a special focus on its interaction with ghrelin signaling system. © 2012 Elsevier Inc. All rights reserved.


Sadakane C.,Hokkaido University | Sadakane C.,Tsumura and Co. | Muto S.,Hokkaido University | Muto S.,Tomakomai City General Hospital | And 8 more authors.
Biochemical and Biophysical Research Communications | Year: 2011

Rikkunshito (RKT), a Japanese traditional medicine, has been shown to stimulate food intake in rats with cisplatin-induced anorexia; however, the underlying mechanisms remain unknown. In this study, we investigated whether RKT is involved in the degradation of peripheral ghrelin. RKT inhibited decreases in plasma ghrelin level and enhanced acyl- to desacyl-ghrelin (A/D) ratio in cisplatin-treated rats. Several components of RKT demonstrated inhibitory activity against ghrelin deacylating enzymes. In addition, 10-gingerol, a component of RKT, inhibited exogenous ghrelin deacylation. Therefore, RKT may enhance plasma acyl-ghrelin level, at least in part, by inhibiting the circulating ghrelin degrading enzyme. © 2011 Elsevier Inc.


Nahata M.,Tsumura and Co. | Muto S.,Hokkaido University | Muto S.,Tomakomai City General Hospital | Nakagawa K.,Hokkaido University | And 9 more authors.
Psychoneuroendocrinology | Year: 2013

This study was conducted to clarify the role of serotonin (5-hydroxytryptamine, 5-HT) 2C receptor (5-HT2CR) signaling during novelty-induced hypophagia in aged mice. Male C57BL/6J mice [6-week-old (young) and 79-80-week-old (aged) mice] were exposed to a novel environment, and its effects on feeding behavior, stress hormones, and appetite-related factors were examined. Exposure of aged mice to a novel environment suppressed food intake and increased corticosterone secretion. These responses were marked compared with those in young mice. The expression in hypothalamic corticotropin-releasing factor (CRF), pituitary CRF1R and proopiomelanocortin mRNA in aged mice exposed to a novel environment was increased or tended to increase, compared to control mice. 5-HT2CR antagonist, SB242084 or rikkunshito administration attenuated the decrease in food intake and increased stress hormone levels in aged mice exposed to the environmental change. The 5-HT2CR mRNA expression in paraventricular nucleus was significantly enhanced, when aged mice was exposure to the novel environment. Thus, novelty-induced hypophagia in aged mice resulted, at least in part, from up-regulated hypothalamic 5-HT2CR function. In conclusion, 5-HT2CR signaling enhancement and the subsequent activation of the CRF neuron were involved in novelty-induced hypophagia in aged mice, and the 5-HT2CR antagonists offer a promising therapeutic option for depression. © 2013 Elsevier Ltd.


Saegusa Y.,Hokkaido University | Saegusa Y.,Tsumura and Co | Takeda H.,Hokkaido University | Muto S.,Hokkaido University | And 8 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2011

We hypothesized that anorexia induced by novelty stress caused by exposure to a novel environment may be due to activation of corticotropin-releasing factor (CRF) and subsequently mediated by decreasing peripheral ghrelin concentration via serotonin (5-HT) and melanocortin-4 receptors (MC4R). Each mouse was transferred from group-housed cages to individual cages to establish the novelty stress. We observed the effect of changes in feeding behavior in a novel environment using the method of transferring group-housed mice to individual cages. We investigated the effect of an intracerebroventricular injection of antagonists/ agonists of CRF1/2 receptors (CRF1/2Rs), 5-HT 1B/2C receptors (5-HT 1B/2CR), and MC4R to clarify the role of each receptor on the decrease in food intake. Plasma ghrelin levels were also measured. The novelty stress caused a reduction in food intake that was abolished by administering a CRF1R antagonist. Three hours after the novelty stress, appetite reduction was associated with reduced levels of neuropeptide Y/agouti-related peptide mRNA, increased levels of proopiomelanocortin mRNA in the hypothalamus, and a decrease in plasma ghrelin level. Administering a CRF1R antagonist, a 5-HT 1B/2CR antagonist, an MC4R antagonist, exogenous ghrelin, and an enhancer of ghrelin secretion, rikkunshito, resolved the reduction in food intake 3 h after the novelty stress by enhancing circulating ghrelin concentrations. We showed that anorexia during a novelty stress is a process in which CRF1R is activated at the early stage of appetite loss and is subsequently activated by a 5-HT 1B/2CR and MC4R stimulus, leading to decreased peripheral ghrelin concentrations. © 2011 the American Physiological Society.


Takeda H.,Hokkaido University | Muto S.,Hokkaido University | Muto S.,Tomakomai City General Hospital | Hattori T.,Tsumura and Co. | And 8 more authors.
Endocrinology | Year: 2010

Aging is associated with decreased food intake, a phenomenon termed the anorexia of aging. In this study, we sought to clarify changes in peripheral and central appetite-related factors in aged mice. Furthermore, we investigated the effects of rikkunshito, a traditional Japanese medicine, on age-related anorexia. C57BL/6J mice that were 6 or 75 wk old were studied. We investigated changes in food intake, ghrelin and leptin levels, and the expression of appetite-related genes with age. In addition, we verified the effects of ghrelin, rikkunshito, phosphodiesterase 3 (PDE3), and phosphoinositide 3-kinase inhibitors on appetite. Food intake was significantly decreased in 75-wk-old micecomparedwith the 6-wk-old mice. In 75-wk-old mice, plasma acylated ghrelin levels under fasting conditions were lower than in 6-wk-old mice, whereas leptin levels under feeding conditions were substantially higher. The expression levels of hypothalamic preproghrelin under feeding conditions and the expression levels of neuropeptide Y and agouti-related protein under fasting conditions were lower compared with those of the 6-wk-old mice. Ghrelin supplementation (33 μg/kg) failed to increase food intake in 75-wk-old mice. Conversely, oral administration of LY294002, a phosphoinositide 3-kinase inhibitor, and cilostamide, a PDE3 inhibitor, increased food intake in 75-wk-old mice. Moreover, rikkunshito increased food intake in aged mice. The components of rikkunshito (nobiletin, isoliquiritigenin, and heptamethoxyflavone) had inhibitory effects on PDE3. These results suggest that dysregulation of ghrelin secretion and ghrelin resistance in the appetite control system occurred in aged mice and that rikkunshito ameliorated aging-associated anorexia via inhibition of PDE3. Copyright © 2010 by The Endocrine Society.

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