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Tomohisa Hattori - One of the best experts on this subject based on the ideXlab platform.
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influence of food on the gastric motor effect of the kampo medicine Rikkunshito in rat
Neurogastroenterology and Motility, 2018Co-Authors: Miwa Nahata, Naoki Fujitsuka, Chiharu Sadakane, Y Mizuhara, J Watanabe, Tomohisa HattoriAbstract:Background Rikkunshito, one of the Kampo medicines, is widely prescribed as a remedy for various upper gastrointestinal syndromes. The effect of Rikkunshito is related to endogenous ghrelin and its active ingredient atractylodin enhances ghrelin receptor signaling. Kampo medicines are traditionally administered before or between meals; however, no definitive benefit of the timing of administration has been proven yet. To clarify the influence of food on the pharmacological action of Rikkunshito, we investigated the gastric motor activity and pharmacokinetic profiles of atractylodin after the administration of Rikkunshito in fasted and fed rats. Methods Phase III-like contractions in the gastric antrum after an injection of ghrelin were measured using a strain gauge force transducer. Rikkunshito was administered to rats during fasting or after a nutrient test meal. Ghrelin was injected 30 minutes later and gastric motility was evaluated. Furthermore, after Rikkunshito administration, the pharmacokinetic profiles of atractylodin in the plasma and brain of fasted and free-fed rats were assessed. Key Results Rikkunshito administration potentiated ghrelin-induced phase III-like contractions under fasting conditions. This effect was attenuated in animals fed a test meal. Atractylodin was detected pharmacokinetically in the plasma and brain after Rikkunshito administration in rats, and free-fed rats exhibited a decreased maximum concentration of plasma atractylodin and a delayed time to reach the maximum concentration. Conclusions & Inferences We show that the pharmacological action of Rikkunshito is influenced by food in rats. The efficacy of Rikkunshito may be associated with decreased absorption of its active ingredient atractylodin when food is in the stomach.
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Changes in plasma ghrelin levels and preproghrelin mRNA expression in aged female mice exposed to novelty stress.
2017Co-Authors: Chinami Matsumoto, Miwa Nahata, Tomohisa Hattori, Chiharu Sadakane, Chihiro Yamada, Hiroshi TakedaAbstract:Changes in the plasma levels of acylated ghrelin (A), desacylated ghrelin (B), gastric (left panel) and hypothalamic (right panel) preproghrelin mRNA expression (C) in the free-fed condition and the effects of a 5-HT2CR antagonist and endogenous ghrelin enhancer on plasma ghrelin levels in aged female mice exposed to novelty stress or not after an 18 h fast (D). The 5-HT2CR antagonist (SB242084; 6 mg/kg, PO), or ghrelin enhancer (Rikkunshito (RKT); 1000 mg/kg, PO) was administered to aged female mice immediately after stress exposure. Data are presented as the mean ± SEM, (A, B) young; fed n = 9, fasted n = 8, aged; fed n = 3, fasted n = 5, (C) young; n = 8, aged; n = 5, (D) n = 5. (A-C); *, p < 0.05, **, p < 0.01 vs. young control group, (D); #, p < 0.05 vs. distilled water (DW)-treated non-stressed group. *, p < 0.05 vs. DW-treated stressed group.
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Review Article Beneficial Effects of Rikkunshito, a Japanese Kampo Medicine, on Gastrointestinal Dysfunction and Anorexia in Combination with Western Drug: A Systematic Review
2016Co-Authors: Sachiko Mogami, Tomohisa HattoriAbstract:License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Kampo medicines are traditional herbal medicines which have been approved for medicinal use by the Japanese Ministry of Health and Welfare and are currently being used more and more, often in combination with Western drugs. Thus, the need for investigation of interactions between Kampo medicines and Western drugs is now widely recognized. Aim. To summarize the effects and drug interactions of Rikkunshito, a Kampomedicine often prescribed for upper gastrointestinal disorders and anorexia. Methods. Animal and human studies were systematically reviewed to identify published data on Rikkunshito. Results describing its effects were abstracted, with an emphasis on drug interactions. Results and Discussion. Rikkunshito ameliorates anorexia induced by anticancer drugs, improves quality of life scores, and can even prolong survival compared with monotherapy. Rikkunshito combined with proton pump inhibitor therapy is shown to be useful in the treatment of PPI-refractory gastroesophageal reflux disease patients and patients with gastrointestinal symptoms after endoscopic submucosal dissection. Rikkunshito reduces antidepressant-induced adverse events and improves quality of life without influencing antidepressant effects. Conclusions. Rikkunshito shows ameliorative effects on adverse reactions induced by variousWestern drugs and can achieve better results (e.g., anticancer drugs and proton pump inhibitor) without influencing the efficacy and bioavailability of Western drugs. 1
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RESEARCH ARTICLE Pharmacokinetic Profiles of Active Ingredients and Its Metabolites Derived from Rikkunshito, a Ghrelin Enhancer, in Healthy Japanese Volunteers: A Cross-Over, Randomized Study
2016Co-Authors: Hiroyuki Kitagawa, Tomohisa Hattori, Chiharu Sadakane, Masaya Munekage, Takashi Matsumoto, Miwako Fukutake, Katsuyuki Aoki, Kazuya Maemura, Yosio Kase, Yasuhito UezonoAbstract:Background Rikkunshito, a traditional Japanese (Kampo) medicine, has been used to treat upper gastro-intestinal disorders such as functional dyspepsia and gastroesophageal reflux. This study investigated the exposure and pharmacokinetics of the ingredients of Rikkunshito in healthy volunteers. Methods and Results First, an exploratory nonrandomized, open-label, one-period, noncrossover study using four healthy Japanese volunteers to detect 32 typical ingredients of Rikkunshito in plasma and urine. As a result, 18 or 21 of 32 ingredients was detected in plasma or urine samples after oral administration of Rikkunshito (7.5 g/day). Furthermore, a randomized, open-label, three-arm, three-period, crossover study using 21 subjects was conducted to determine the amounts of exposure and pharmacokinetic parameters of nine ingredients derived from rik-kunshito (atractylodin, atractylodin carboxylic acid, pachymic acid, 3,30,40,5,6,7,8-hepta-methoxyflavone, naringenin, nobiletin, liquiritigenin, isoliquiritigenin, and 18β-glycyrrhetini
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Rikkunshito ameliorates cancer cachexia partly through elevation of glucarate in plasma
Evidence-based Complementary and Alternative Medicine, 2015Co-Authors: Katsuya Ohbuchi, Naoki Fujitsuka, Tomohisa Hattori, Akio Inui, Shin Nishiumi, Masahiro Yamamoto, Takeshi Azuma, Masaru YoshidaAbstract:Cancer cachexia, which is characterized by decreased food intake, weight loss and systemic inflammation, increases patient's morbidity and mortality. We previously showed that Rikkunshito (RKT), a Japanese traditional herbal medicine (Kampo), ameliorated the symptoms of cancer cachexia through ghrelin signaling-dependent and independent pathways. To investigate other mechanisms of RKT action in cancer cachexia, we performed metabolome analysis of plasma in a rat model bearing the Yoshida AH-130 hepatoma. A total of 110 metabolites were detected in plasma and RKT treatment significantly altered levels of 23 of those metabolites in cachexia model rats. Among them, glucarate, which is known to have anticarcinogenic activity through detoxification of carcinogens via inhibition of β-glucuronidase, was increased in plasma following administration of RKT. In our AH-130 ascites-induced cachexia rat model, administration of glucarate delayed onset of weight loss, improved muscle atrophy, and reduced ascites content. Additionally, glucarate reduced levels of plasma interferon-γ (IFN-γ) in tumor-bearing rats and was also found to suppress LPS-induced IFN-γ expression in splenocytes in vitro. These results suggest that glucarate has anti-inflammatory activity via a direct effect on immune host cells and suggest that RKT may also ameliorate inflammation partly through the elevation of glucarate in plasma.
Hiroshi Takeda - One of the best experts on this subject based on the ideXlab platform.
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Changes in plasma ghrelin levels and preproghrelin mRNA expression in aged female mice exposed to novelty stress.
2017Co-Authors: Chinami Matsumoto, Miwa Nahata, Tomohisa Hattori, Chiharu Sadakane, Chihiro Yamada, Hiroshi TakedaAbstract:Changes in the plasma levels of acylated ghrelin (A), desacylated ghrelin (B), gastric (left panel) and hypothalamic (right panel) preproghrelin mRNA expression (C) in the free-fed condition and the effects of a 5-HT2CR antagonist and endogenous ghrelin enhancer on plasma ghrelin levels in aged female mice exposed to novelty stress or not after an 18 h fast (D). The 5-HT2CR antagonist (SB242084; 6 mg/kg, PO), or ghrelin enhancer (Rikkunshito (RKT); 1000 mg/kg, PO) was administered to aged female mice immediately after stress exposure. Data are presented as the mean ± SEM, (A, B) young; fed n = 9, fasted n = 8, aged; fed n = 3, fasted n = 5, (C) young; n = 8, aged; n = 5, (D) n = 5. (A-C); *, p < 0.05, **, p < 0.01 vs. young control group, (D); #, p < 0.05 vs. distilled water (DW)-treated non-stressed group. *, p < 0.05 vs. DW-treated stressed group.
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a new strategy using Rikkunshito to treat anorexia and gastrointestinal dysfunction
Evidence-based Complementary and Alternative Medicine, 2015Co-Authors: Yayoi Saegusa, Miwa Nahata, Tomohisa Hattori, Chihiro Yamada, Hiroshi TakedaAbstract:Because the clinical condition of gastrointestinal dysfunction, including functional dyspepsia, involves tangled combinations of pathologies, there are some cases of insufficient curative efficacy. Thus, traditional herbal medicines (Kampo medicines) uniquely developed in Japan are thought to contribute to medical treatment for upper gastrointestinal symptoms. Rikkunshito is a Kampo medicine often used to treat dyspeptic symptoms. Over the past few years, several studies have investigated the efficacy of Rikkunshito for dysmotility, for example, upper abdominal complaints, in animals and humans. Rikkunshito ameliorated the decrease in gastric motility and anorexia in cisplatin-treated rats, stress-loaded mice, and selective serotonin reuptake inhibitor-treated rats by enhancing plasma ghrelin levels via serotonin2B/2C receptor antagonism. In addition, Rikkunshito ameliorated the decrease in food intake in aged mice and stress-loaded decreased gastric motility via enhanced ghrelin receptor signaling. Several clinical studies revealed that Rikkunshito was effective in ameliorating upper gastrointestinal symptoms, including dyspepsia, epigastric pain, and postprandial fullness. In this review, we discuss these studies and propose additional evidence-based research that may promote the clinical use of Kampo medicines, particularly Rikkunshito, for treating anorexia and gastrointestinal dysfunction.
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A randomized, placebo-controlled, double-blind clinical trial of Rikkunshito for patients with non-erosive reflux disease refractory to proton-pump inhibitor: the G-PRIDE study
Journal of Gastroenterology, 2014Co-Authors: Kazunari Tominaga, Hiroshi Takeda, Mototsugu Kato, Yasuyuki Shimoyama, Eiji Umegaki, Ryuichi Iwakiri, Kenji Furuta, Koichi Sakurai, Takeo Odaka, Hiroaki KusunokiAbstract:Background The aim of this study was to investigate the efficacy of Rikkunshito (RKT), a traditional Japanese medicine, combined with proton pump inhibitor (PPI) in patients with PPI-refractory non-erosive reflux disease (NERD). Methods Patients with PPI-refractory NERD ( n = 242) were randomly assigned to the RKT group [rabeprazole (10 mg/day) + RKT (7.5 g/t.i.d.) for 8 weeks] or the placebo group (rabeprazole + placebo). After the 4- and 8-week treatments, we assessed symptoms and quality of life (QOL) using the Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (FSSG), Gastrointestinal Symptom Rating Scale (GSRS), and Short-Form Health Survey-8 (SF-8). Results There were no significant differences in FSSG and GSRS score improvement between these groups after the 4- and 8-week treatments. The mental component summary (MCS) scores of the SF-8 improved more in the RKT group (from 45.8 ± 8.1 to 48.5 ± 7.4) than in the placebo group (from 47.7 ± 7.1 to 48.4 ± 7.5) after the 4-week treatment ( P
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Effects of Rikkunshito (traditional Japanese medicine) on enteral feeding and the plasma ghrelin level in critically ill patients: a pilot study
Journal of Intensive Care, 2014Co-Authors: Mineji Hayakawa, Hiroshi Takeda, Takeshi Wada, Yuichiro Yanagida, Atsushi Sawamura, Satoshi GandoAbstract:Background Rikkunshito is a traditional Japanese medicine that has been widely prescribed for patients with various gastrointestinal symptoms. Recently, the prokinetic effects of Rikkunshito in patients with a variety of diseases have attracted attention in Japan. The prokinetic effects of Rikkunshito are believed to result from an increase of active ghrelin, which is most abundant in the stomach and which has a gastrokinetic function. The aim of the present pilot study was to investigate the effects of Rikkunshito on intragastric enteral feeding and plasma ghrelin levels in critically ill patients. Methods The study population consisted of critically ill patients who were projected to require intragastric tube feeding for more than 7 days. The patients were prospectively assigned to one of two treatment groups and were randomized to receive either Rikkunshito (2.5 g) or metoclopramide (10 mg) every 8 h. All patients received standard enteral nutrition. Patients in both groups were begun on intragastric tube feeding according to our institution’s feeding protocol. Results All patients were undergoing mechanical ventilation at the time of enrollment. The portions of enteral nutrition provided to the target amount and the quantity of gastric discharge were not statistically significantly different between the two groups. The Rikkunshito group reached 50% of the target amount of enteral feeding significantly earlier than the metoclopramide group, although the proportion of patients in whom enteral feeding was successful did not differ significantly between the two groups. Patients in the Rikkunshito group showed significantly higher plasma levels of active ghrelin compared to those in the metoclopramide group. Conclusions The administration of Rikkunshito increased the plasma level of active ghrelin, and induced prokinetic effects that were greater than those observed following treatment with metoclopramide in critically ill patients. Trial registration UMIN00000356
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effects of Rikkunshito traditional japanese medicine on enteral feeding and the plasma ghrelin level in critically ill patients a pilot study
Journal of intensive care, 2014Co-Authors: Mineji Hayakawa, Hiroshi Takeda, Takeshi Wada, Yuichiro Yanagida, Atsushi Sawamura, Yuichi Ono, Satoshi GandoAbstract:Rikkunshito is a traditional Japanese medicine that has been widely prescribed for patients with various gastrointestinal symptoms. Recently, the prokinetic effects of Rikkunshito in patients with a variety of diseases have attracted attention in Japan. The prokinetic effects of Rikkunshito are believed to result from an increase of active ghrelin, which is most abundant in the stomach and which has a gastrokinetic function. The aim of the present pilot study was to investigate the effects of Rikkunshito on intragastric enteral feeding and plasma ghrelin levels in critically ill patients. The study population consisted of critically ill patients who were projected to require intragastric tube feeding for more than 7 days. The patients were prospectively assigned to one of two treatment groups and were randomized to receive either Rikkunshito (2.5 g) or metoclopramide (10 mg) every 8 h. All patients received standard enteral nutrition. Patients in both groups were begun on intragastric tube feeding according to our institution’s feeding protocol. All patients were undergoing mechanical ventilation at the time of enrollment. The portions of enteral nutrition provided to the target amount and the quantity of gastric discharge were not statistically significantly different between the two groups. The Rikkunshito group reached 50% of the target amount of enteral feeding significantly earlier than the metoclopramide group, although the proportion of patients in whom enteral feeding was successful did not differ significantly between the two groups. Patients in the Rikkunshito group showed significantly higher plasma levels of active ghrelin compared to those in the metoclopramide group. The administration of Rikkunshito increased the plasma level of active ghrelin, and induced prokinetic effects that were greater than those observed following treatment with metoclopramide in critically ill patients. UMIN00000356
Naoki Fujitsuka - One of the best experts on this subject based on the ideXlab platform.
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influence of food on the gastric motor effect of the kampo medicine Rikkunshito in rat
Neurogastroenterology and Motility, 2018Co-Authors: Miwa Nahata, Naoki Fujitsuka, Chiharu Sadakane, Y Mizuhara, J Watanabe, Tomohisa HattoriAbstract:Background Rikkunshito, one of the Kampo medicines, is widely prescribed as a remedy for various upper gastrointestinal syndromes. The effect of Rikkunshito is related to endogenous ghrelin and its active ingredient atractylodin enhances ghrelin receptor signaling. Kampo medicines are traditionally administered before or between meals; however, no definitive benefit of the timing of administration has been proven yet. To clarify the influence of food on the pharmacological action of Rikkunshito, we investigated the gastric motor activity and pharmacokinetic profiles of atractylodin after the administration of Rikkunshito in fasted and fed rats. Methods Phase III-like contractions in the gastric antrum after an injection of ghrelin were measured using a strain gauge force transducer. Rikkunshito was administered to rats during fasting or after a nutrient test meal. Ghrelin was injected 30 minutes later and gastric motility was evaluated. Furthermore, after Rikkunshito administration, the pharmacokinetic profiles of atractylodin in the plasma and brain of fasted and free-fed rats were assessed. Key Results Rikkunshito administration potentiated ghrelin-induced phase III-like contractions under fasting conditions. This effect was attenuated in animals fed a test meal. Atractylodin was detected pharmacokinetically in the plasma and brain after Rikkunshito administration in rats, and free-fed rats exhibited a decreased maximum concentration of plasma atractylodin and a delayed time to reach the maximum concentration. Conclusions & Inferences We show that the pharmacological action of Rikkunshito is influenced by food in rats. The efficacy of Rikkunshito may be associated with decreased absorption of its active ingredient atractylodin when food is in the stomach.
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Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1
Molecular Psychiatry, 2016Co-Authors: Naoki Fujitsuka, Yasuhito Uezono, A Asakawa, A Morinaga, M S Amitani, H Amitani, G Katsuura, Y Sawada, Y Sudo, E MochikiAbstract:Caloric restriction (CR) is known to retard aging and delay functional decline as well as the onset of diseases in most organisms. Ghrelin is secreted from the stomach in response to CR and regulates energy metabolism. We hypothesized that in CR ghrelin has a role in protecting aging-related diseases. We examined the physiological mechanisms underlying the ghrelin system during the aging process in three mouse strains with different genetic and biochemical backgrounds as animal models of accelerated or normal human aging. The elevated plasma ghrelin concentration was observed in both klotho-deficient and senescence-accelerated mouse prone/8 (SAMP8) mice. Ghrelin treatment failed to stimulate appetite and prolong survival in klotho-deficient mice, suggesting the existence of ghrelin resistance in the process of aging. However, ghrelin antagonist hastened death and ghrelin signaling potentiators Rikkunshito and atractylodin ameliorated several age-related diseases with decreased microglial activation in the brain and prolonged survival in klotho-deficient, SAMP8 and aged ICR mice. In vitro experiments, the elevated sirtuin1 (SIRT1) activity and protein expression through the cAMP–CREB pathway was observed after ghrelin and ghrelin potentiator treatment in ghrelin receptor 1a-expressing cells and human umbilical vein endothelial cells. Furthermore, Rikkunshito increased hypothalamic SIRT1 activity and SIRT1 protein expression of the heart in the all three mouse models of aging. Pericarditis, myocardial calcification and atrophy of myocardial and muscle fiber were improved by treatment with Rikkunshito. Ghrelin signaling may represent one of the mechanisms activated by CR, and potentiating ghrelin signaling may be useful to extend health and lifespan.
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Rikkunshito ameliorates cancer cachexia partly through elevation of glucarate in plasma
Evidence-based Complementary and Alternative Medicine, 2015Co-Authors: Katsuya Ohbuchi, Naoki Fujitsuka, Tomohisa Hattori, Akio Inui, Shin Nishiumi, Masahiro Yamamoto, Takeshi Azuma, Masaru YoshidaAbstract:Cancer cachexia, which is characterized by decreased food intake, weight loss and systemic inflammation, increases patient's morbidity and mortality. We previously showed that Rikkunshito (RKT), a Japanese traditional herbal medicine (Kampo), ameliorated the symptoms of cancer cachexia through ghrelin signaling-dependent and independent pathways. To investigate other mechanisms of RKT action in cancer cachexia, we performed metabolome analysis of plasma in a rat model bearing the Yoshida AH-130 hepatoma. A total of 110 metabolites were detected in plasma and RKT treatment significantly altered levels of 23 of those metabolites in cachexia model rats. Among them, glucarate, which is known to have anticarcinogenic activity through detoxification of carcinogens via inhibition of β-glucuronidase, was increased in plasma following administration of RKT. In our AH-130 ascites-induced cachexia rat model, administration of glucarate delayed onset of weight loss, improved muscle atrophy, and reduced ascites content. Additionally, glucarate reduced levels of plasma interferon-γ (IFN-γ) in tumor-bearing rats and was also found to suppress LPS-induced IFN-γ expression in splenocytes in vitro. These results suggest that glucarate has anti-inflammatory activity via a direct effect on immune host cells and suggest that RKT may also ameliorate inflammation partly through the elevation of glucarate in plasma.
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ghrelin enhancer Rikkunshito improves postprandial gastric motor dysfunction in an experimental stress model
Neurogastroenterology and Motility, 2015Co-Authors: Y Harada, Naoki Fujitsuka, Tomohisa Hattori, Mitsuko Ochiai, Kenjiro Hayashi, Eriko Hosomi, Koji YakabiAbstract:Background Functional dyspepsia (FD) is one of the most common disorders of gastrointestinal (GI) diseases. However, no curable treatment is available for FD because the detailed mechanism of GI dysfunction in stressed conditions remains unclear. We aimed to clarify the association between endogenous acylated ghrelin signaling and gastric motor dysfunction and explore the possibility of a drug with ghrelin signal-enhancing action for FD treatment. Methods Solid gastric emptying (GE) and plasma acylated ghrelin levels were evaluated in an urocortin1 (UCN1) -induced stress model. To clarify the role of acylated ghrelin on GI dysfunction in the model, exogenous acylated ghrelin, an endogenous ghrelin enhancer, Rikkunshito, or an α2-adrenergic receptor (AR) antagonist was administered. Postprandial motor function was investigated using a strain gauge force transducer in a free-moving condition. Key Results Exogenous acylated ghrelin supplementation restored UCN1-induced delayed GE. Alpha2-AR antagonist and Rikkunshito inhibited the reduction in plasma acylated ghrelin and GE in the stress model. The action of Rikkunshito on delayed GE was blocked by co-administration of the ghrelin receptor antagonist. UCN1 decreased the amplitude of contraction in the antrum while increasing it in the duodenum. The motility index of the antrum but not the duodenum was significantly reduced by UCN1 treatment, which was improved by acylated ghrelin or Rikkunshito. Conclusions & Inferences The UCN1-induced gastric motility dysfunction was mediated by abnormal acylated ghrelin dynamics. Supplementation of exogenous acylated ghrelin or enhancement of endogenous acylated ghrelin secretion by Rikkunshito may be effective in treating functional GI disorders.
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Rikkunshito induces gastric relaxation via the β adrenergic pathway in suncus murinus
Neurogastroenterology and Motility, 2015Co-Authors: Anupom Mondal, Naoki Fujitsuka, Tomohisa Hattori, Takafumi Sakai, A Takehara, Sayaka Aizawa, Toru Tanaka, Ichiro SakataAbstract:Background Rikkunshito (RKT) is a gastroprotective herbal medicine. In this study, we investigated the role of RKT in the relaxation of the gastric body (fundus and corpus) and antrum. Methods We used Suncus murinus, a unique small model animal with similar gastrointestinal motility to humans and dogs. RKT was added at 0.1, 1.0, and 5.0 mg/mL to induce relaxation in vitro; the outcome measure was the intensity of relaxation. The number of spontaneous antral contractions in the absence or the presence of RKT was also counted. Key Results Rikkunshito induced the relaxation of the gastric body and antrum and decreased the number of spontaneous antral contractions in a dose-dependent manner. The responses to RKT (1.0 mg/mL) were not affected by pretreatment with atropine, N-nitro-l-arginine methyl ester, ritanserin, or ondansetron. On the other hand, timolol almost completely reversed the relaxation induced by RKT (1.0 mg/mL) on the gastric body and antrum and the occurrence of the spontaneous antral contractions. Both butoxamine, a β2-adrenoreceptor antagonist, and L 748337, a β3-adrenoreceptor antagonist, but not CGP 20712, a β1-adrenoreceptor antagonist, significantly reversed the RKT-induced (1.0 mg/mL) gastric relaxation. Conclusions & Inferences These results indicate that RKT stimulates and modulates gastric relaxation through β2- and β3-adrenergic, but not β1-adrenergic, pathways in S. murinus.
Yasuhito Uezono - One of the best experts on this subject based on the ideXlab platform.
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Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1
Molecular Psychiatry, 2016Co-Authors: Naoki Fujitsuka, Yasuhito Uezono, A Asakawa, A Morinaga, M S Amitani, H Amitani, G Katsuura, Y Sawada, Y Sudo, E MochikiAbstract:Caloric restriction (CR) is known to retard aging and delay functional decline as well as the onset of diseases in most organisms. Ghrelin is secreted from the stomach in response to CR and regulates energy metabolism. We hypothesized that in CR ghrelin has a role in protecting aging-related diseases. We examined the physiological mechanisms underlying the ghrelin system during the aging process in three mouse strains with different genetic and biochemical backgrounds as animal models of accelerated or normal human aging. The elevated plasma ghrelin concentration was observed in both klotho-deficient and senescence-accelerated mouse prone/8 (SAMP8) mice. Ghrelin treatment failed to stimulate appetite and prolong survival in klotho-deficient mice, suggesting the existence of ghrelin resistance in the process of aging. However, ghrelin antagonist hastened death and ghrelin signaling potentiators Rikkunshito and atractylodin ameliorated several age-related diseases with decreased microglial activation in the brain and prolonged survival in klotho-deficient, SAMP8 and aged ICR mice. In vitro experiments, the elevated sirtuin1 (SIRT1) activity and protein expression through the cAMP–CREB pathway was observed after ghrelin and ghrelin potentiator treatment in ghrelin receptor 1a-expressing cells and human umbilical vein endothelial cells. Furthermore, Rikkunshito increased hypothalamic SIRT1 activity and SIRT1 protein expression of the heart in the all three mouse models of aging. Pericarditis, myocardial calcification and atrophy of myocardial and muscle fiber were improved by treatment with Rikkunshito. Ghrelin signaling may represent one of the mechanisms activated by CR, and potentiating ghrelin signaling may be useful to extend health and lifespan.
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RESEARCH ARTICLE Pharmacokinetic Profiles of Active Ingredients and Its Metabolites Derived from Rikkunshito, a Ghrelin Enhancer, in Healthy Japanese Volunteers: A Cross-Over, Randomized Study
2016Co-Authors: Hiroyuki Kitagawa, Tomohisa Hattori, Chiharu Sadakane, Masaya Munekage, Takashi Matsumoto, Miwako Fukutake, Katsuyuki Aoki, Kazuya Maemura, Yosio Kase, Yasuhito UezonoAbstract:Background Rikkunshito, a traditional Japanese (Kampo) medicine, has been used to treat upper gastro-intestinal disorders such as functional dyspepsia and gastroesophageal reflux. This study investigated the exposure and pharmacokinetics of the ingredients of Rikkunshito in healthy volunteers. Methods and Results First, an exploratory nonrandomized, open-label, one-period, noncrossover study using four healthy Japanese volunteers to detect 32 typical ingredients of Rikkunshito in plasma and urine. As a result, 18 or 21 of 32 ingredients was detected in plasma or urine samples after oral administration of Rikkunshito (7.5 g/day). Furthermore, a randomized, open-label, three-arm, three-period, crossover study using 21 subjects was conducted to determine the amounts of exposure and pharmacokinetic parameters of nine ingredients derived from rik-kunshito (atractylodin, atractylodin carboxylic acid, pachymic acid, 3,30,40,5,6,7,8-hepta-methoxyflavone, naringenin, nobiletin, liquiritigenin, isoliquiritigenin, and 18β-glycyrrhetini
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Rikkunshito, a ghrelin potentiator, ameliorates anorexia-cachexia syndrome
Frontiers in Pharmacology, 2014Co-Authors: Naoki Fujitsuka, Yasuhito UezonoAbstract:Anorexia-cachexia syndrome develops during the advanced stages of various chronic diseases in which patients exhibit a decreased food intake, weight loss, and muscle tissue wasting. For these patients, this syndrome is a critical problem leading to an increased rate of morbidity and mortality. The present pharmacological therapies for treating anorexia-cachexia have limited effectiveness. The Japanese herbal medicine Rikkunshito is often prescribed for the treatment of anorexia and upper gastrointestinal disorders. Thus, Rikkunshito is expected to be beneficial for the treatment of patients with anorexia-cachexia syndrome. In this review, we summarize the effects of Rikkunshito and its mechanisms of action on anorexia-cachexia. Persistent loss of appetite leads to a progressive depletion of body energy stores, which is frequently associated with cachexia. Consequently, regulating appetite and energy homeostasis is critically important for treating cachexia. Ghrelin is mainly secreted from the stomach, and it plays an important role in initiating feeding, controlling gastrointestinal motility, and regulating energy expenditure. Recent clinical and basic science studies have demonstrated that the critical mechanism of Rikkunshito underlies endogenous ghrelin activity. Interestingly, several components of Rikkunshito target multiple gastric and central sites, and regulate the secretion, receptor sensitization, and degradation of ghrelin. Rikkunshito is effective for the treatment of anorexia, body weight loss, muscle wasting, and anxiety-related behavior. Furthermore, treatment with Rikkunshito was observed to prolong survival in an animal model of cachexia. The use of a potentiator of ghrelin signaling, such as Rikkunshito, may represent a novel approach for the treatment of anorexia-cachexia syndrome.
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Novel Therapeutics for Adverse Effects of Antitumor Therapy: The Promise of Multicomponent, Traditional Japanese Herbal Remedies
Journal of carcinogenesis & mutagenesis, 2014Co-Authors: Toru Kono, Hiroshi Takeda, Yoshio Kase, Mitsuo Shimada, Yasuhito UezonoAbstract:In contrast to conventional single-target drugs, multi-component Kampo medicines are designed to achieve therapeutic effects through multiple drug targets. This article will discuss recent advances in mechanistic studies and the clinical effects of five representative Kampo formulations (hangeshashinto, daikenchuto, goshajinkigan, yokukansan and Rikkunshito) for the treatment of adverse effects caused by anticancer drugs such as oral mucositis, diarrhea, neurotoxicity and abnormal behavior, for which western pharmaceuticals fail to adequately address.
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Reviewed by:
2014Co-Authors: Naoki Fujitsuka, Yasuhito Uezono, Ikuroh Ohsawa, Tokyo MetropolitanAbstract:Rikkunshito, a ghrelin potentiator, ameliorate
Takafumi Sakai - One of the best experts on this subject based on the ideXlab platform.
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Rikkunshito induces gastric relaxation via the β adrenergic pathway in suncus murinus
Neurogastroenterology and Motility, 2015Co-Authors: Anupom Mondal, Naoki Fujitsuka, Tomohisa Hattori, Takafumi Sakai, A Takehara, Sayaka Aizawa, Toru Tanaka, Ichiro SakataAbstract:Background Rikkunshito (RKT) is a gastroprotective herbal medicine. In this study, we investigated the role of RKT in the relaxation of the gastric body (fundus and corpus) and antrum. Methods We used Suncus murinus, a unique small model animal with similar gastrointestinal motility to humans and dogs. RKT was added at 0.1, 1.0, and 5.0 mg/mL to induce relaxation in vitro; the outcome measure was the intensity of relaxation. The number of spontaneous antral contractions in the absence or the presence of RKT was also counted. Key Results Rikkunshito induced the relaxation of the gastric body and antrum and decreased the number of spontaneous antral contractions in a dose-dependent manner. The responses to RKT (1.0 mg/mL) were not affected by pretreatment with atropine, N-nitro-l-arginine methyl ester, ritanserin, or ondansetron. On the other hand, timolol almost completely reversed the relaxation induced by RKT (1.0 mg/mL) on the gastric body and antrum and the occurrence of the spontaneous antral contractions. Both butoxamine, a β2-adrenoreceptor antagonist, and L 748337, a β3-adrenoreceptor antagonist, but not CGP 20712, a β1-adrenoreceptor antagonist, significantly reversed the RKT-induced (1.0 mg/mL) gastric relaxation. Conclusions & Inferences These results indicate that RKT stimulates and modulates gastric relaxation through β2- and β3-adrenergic, but not β1-adrenergic, pathways in S. murinus.
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Potentiation of ghrelin signaling attenuates cancer anorexia – cachexia and prolongs survival
Translational Psychiatry, 2011Co-Authors: Naoki Fujitsuka, Yasuhito Uezono, Kouichiro Minami, Udval Sedbazar, Yuko Maejima, Toshihiko Yada, Akihiro Asakawa, Takashi Yamaguchi, Akira Niijima, Takafumi SakaiAbstract:Cancer anorexia–cachexia syndrome is characterized by decreased food intake, weight loss, muscle tissue wasting and psychological distress, and this syndrome is a major source of increased morbidity and mortality in cancer patients. This study aimed to clarify the gut–brain peptides involved in the pathogenesis of the syndrome and determine effective treatment for cancer anorexia–cachexia. We show that both ghrelin insufficiency and resistance were observed in tumor-bearing rats. Corticotropin-releasing factor (CRF) decreased the plasma level of acyl ghrelin, and its receptor antagonist, α-helical CRF, increased food intake of these rats. The serotonin 2c receptor (5-HT2cR) antagonist SB242084 decreased hypothalamic CRF level and improved anorexia, gastrointestinal (GI) dysmotility and body weight loss. The ghrelin receptor antagonist (D-Lys3)-GHRP-6 worsened anorexia and hastened death in tumor-bearing rats. Ghrelin attenuated anorexia–cachexia in the short term, but failed to prolong survival, as did SB242084 administration. In addition, the herbal medicine Rikkunshito improved anorexia, GI dysmotility, muscle wasting, and anxiety-related behavior and prolonged survival in animals and patients with cancer. The appetite-stimulating effect of Rikkunshito was blocked by (D-Lys3)-GHRP-6. Active components of Rikkunshito, hesperidin and atractylodin, potentiated ghrelin secretion and receptor signaling, respectively, and atractylodin prolonged survival in tumor-bearing rats. Our study demonstrates that the integrated mechanism underlying cancer anorexia–cachexia involves lowered ghrelin signaling due to excessive hypothalamic interactions of 5-HT with CRF through the 5-HT2cR. Potentiation of ghrelin receptor signaling may be an attractive treatment for anorexia, muscle wasting and prolong survival in patients with cancer anorexia–cachexia.
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Potentiation of ghrelin signaling attenuates cancer anorexia–cachexia and prolongs survival
Translational Psychiatry, 2011Co-Authors: Naoki Fujitsuka, Yasuhito Uezono, Kouichiro Minami, Udval Sedbazar, Yuko Maejima, Toshihiko Yada, Akihiro Asakawa, Takashi Yamaguchi, Akira Niijima, Takafumi SakaiAbstract:Cancer anorexia–cachexia syndrome is characterized by decreased food intake, weight loss, muscle tissue wasting and psychological distress, and this syndrome is a major source of increased morbidity and mortality in cancer patients. This study aimed to clarify the gut–brain peptides involved in the pathogenesis of the syndrome and determine effective treatment for cancer anorexia–cachexia. We show that both ghrelin insufficiency and resistance were observed in tumor-bearing rats. Corticotropin-releasing factor (CRF) decreased the plasma level of acyl ghrelin, and its receptor antagonist, α-helical CRF, increased food intake of these rats. The serotonin 2c receptor (5-HT2cR) antagonist SB242084 decreased hypothalamic CRF level and improved anorexia, gastrointestinal (GI) dysmotility and body weight loss. The ghrelin receptor antagonist (D-Lys3)-GHRP-6 worsened anorexia and hastened death in tumor-bearing rats. Ghrelin attenuated anorexia–cachexia in the short term, but failed to prolong survival, as did SB242084 administration. In addition, the herbal medicine Rikkunshito improved anorexia, GI dysmotility, muscle wasting, and anxiety-related behavior and prolonged survival in animals and patients with cancer. The appetite-stimulating effect of Rikkunshito was blocked by (D-Lys3)-GHRP-6. Active components of Rikkunshito, hesperidin and atractylodin, potentiated ghrelin secretion and receptor signaling, respectively, and atractylodin prolonged survival in tumor-bearing rats. Our study demonstrates that the integrated mechanism underlying cancer anorexia–cachexia involves lowered ghrelin signaling due to excessive hypothalamic interactions of 5-HT with CRF through the 5-HT2cR. Potentiation of ghrelin receptor signaling may be an attractive treatment for anorexia, muscle wasting and prolong survival in patients with cancer anorexia–cachexia.
