The relationship between premorbid intelligence and symptoms of severe anorexia nervosa restricting type.

The purposes of this study were as follows: to compare premorbid IQ with present IQ in patients with more severe anorexia nervosa restricting type (AN-R) and to investigate the relationship between decreasing IQ and symptoms in patients with severe AN-R. Twenty-two participants were recruited (12 were AN-R patients; 10 were healthy controls). The average BMI in AN-R patients and healthy controls was 12.65 and 19.82, respectively. We assessed the outcomes using the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III), the Japanese Adult Reading Test, The Eating Disorders Inventory-2 (EDI-2), Beck Depression Scale-2 (BDI-2) and State-Trait Anxiety Index. In two-way ANOVA, there were significant interactions for the FIQ and PIQ. Only in the AN-R group, a significant single main effect of time was evidenced for the FIQ and PIQ. In the AN-R group, a significantly high positive correlation was found between changes in the PIQ and the body dissatisfaction subscale of the EDI-2. These findings raise the possibility that in patients with severe AN-R, an excessive decrease in body weight induces decreased PIQ; as a result, they have worse dissatisfaction with their body shape.

A randomized phase II study of nutritional and exercise treatment for elderly patients with advanced non-small cell lung or pancreatic cancer: the NEXTAC-TWO study protocol.

BACKGROUND: Most advanced elderly cancer patients experience fatigue, anorexia, and declining physical function due to cancer cachexia, for which effective interventions have not been established. We performed a phase I study of a new nonpharmacological multimodal intervention called the nutritional and exercise treatment for advanced cancer (NEXTAC) program and reported the excellent feasibility of and compliance with this program in elderly patients with advanced cancer who were at risk for cancer cachexia. We report here the background, hypothesis, and design of the next-step multicenter, randomized phase II study to evaluate the efficacy of the program, the NEXTAC-TWO study. METHODS: Patients with chemo-naïve advanced non-small cell lung cancer or pancreatic cancer, age ≥ 70 years, performance status ≤2, with adequate organ function and without disability according to the modified Katz index will be eligible. In total, 130 participants will be recruited from 15 Japanese institutions and will be randomized into either the intervention group or a control group. Computer-generated random numbers are allocated to each participant. Stratification factors include performance status (0 to 1 vs. 2), site of primary cancer (lung vs. pancreas), stage (III vs. IV), and type of chemotherapy (cytotoxic vs. others). Interventions and assessment will be performed 4 times every 4 ± 2 weeks from the date of randomization. Interventions will consist of nutritional counseling, nutritional supplements (rich in branched-chain amino acids), and a home-based exercise program. The exercise program will include low-intensity daily muscle training and lifestyle education to promote physical activity. The primary endpoint is disability-free survival. It is defined as the period from the date of randomization to the date of developing disability or death due to any cause. This trial also plans to evaluate the improvements in nutritional status, physical condition, quality of life, activities of daily living, overall survival, and safety as secondary endpoints. Enrollment began in August 2017. The study results will demonstrate the efficacy of multimodal interventions for elderly cancer patients and their application for the maintenance of physical and nutritional conditions in patients with cancer cachexia. This work is supported by a grant-in-aid from the Japan Agency for Medical Research and Development. DISCUSSION: This is the first randomized trial to evaluate the efficacy and safety of a multimodal intervention specific for elderly patients with advanced cancer. TRIAL REGISTRATION: Registered at August 23, 2017. Registry number: UMIN000028801 .

Oral aversion to dietary sugar, ethanol and glycerol correlates with alterations in specific hepatic metabolites in a mouse model of human citrin deficiency.

Mice carrying simultaneous homozygous mutations in the genes encoding citrin, the mitochondrial aspartate-glutamate carrier 2 (AGC2) protein, and mitochondrial glycerol-3-phosphate dehydrogenase (mGPD), are a phenotypically representative model of human citrin (a.k.a., AGC2) deficiency. In this study, we investigated the voluntary oral intake and preference for sucrose, glycerol or ethanol solutions by wild-type, citrin (Ctrn)-knockout (KO), mGPD-KO, and Ctrn/mGPD double-KO mice; all substances that are known or suspected precipitating factors in the pathogenesis of human citrin deficiency. The double-KO mice showed clear suppressed intake of sucrose, consuming less with progressively higher concentrations compared to the other mice. Similar observations were made when glycerol or ethanol were given. The preference of Ctrn-KO and mGPD-KO mice varied with the different treatments; essentially no differences were observed for sucrose, while an intermediate intake or similar to that of the double-KO mice was observed for glycerol and ethanol. We next examined the hepatic glycerol 3-phosphate, citrate, citrulline, lysine, glutamate and adenine nucleotide levels following forced enteral administration of these solutions. A strong correlation between the simultaneous increased hepatic glycerol 3-phosphate and decreased ATP or total adenine nucleotide content and observed aversion of the mice during evaluation of their voluntary preferences was found. Overall, our results suggest that the aversion observed in the double-KO mice to these solutions is initiated and/or mediated by hepatic metabolic perturbations, resulting in a behavioral response to increased hepatic cytosolic NADH and a decreased cellular adenine nucleotide pool. These findings may underlie the dietary predilections observed in human citrin deficient patients.

A perspective on metabolic surgery from a gastroenterologist.

Type 2 diabetes (T2D) and obesity are important public health problems. The global prevalence of diabetes mellitus is 8.8%. Interventional diabetology and obesitology have been recently advocated as treatment options for T2D and obesity. The roles of metabolic surgery such as Roux-en-Y gastric bypass, sleeve gastrectomy, gastric banding, and biliopancreatic diversion are focused. Different types of metabolic surgeries have different glucose-lowering and weight loss effects. Endoscopic treatments include the intra-gastric balloon (to restrict the gastric volume) and duodenal-jejunal bypass liner (DJBL, as a malabsorptive procedure). Anatomic changes in the gastrointestinal tract may cause alterations in gut hormones, bile acids, adipokines, inflammatory cytokines, hepatokines, myokines, gut microbiota, and even unidentified factors. Modulating gut hormones, including foregut (ghrelin, glucose-dependent insulinotropic polypeptide) and hindgut (glucagon-like peptide-1, peptide YY) hormones, through metabolic surgeries improves glycemic homeostasis. Metabolic surgeries reduce pro-inflammatory cytokines and increase anti-inflammatory cytokines. Metabolic surgeries also regulate one's appetite through the new establishment of jejunal nutrient sensing. Therefore, the effects of metabolic surgery and DJBL implantation emphasize the crucial role of the small intestine in glucose homeostasis. Removing diabetogenic or obesogenic factors from the duodenum and/or jejunum may help to solve the problems of diabetes and obesity in the future.

The Role of Ghrelin and Ghrelin Signaling in Aging.

With our aging society, more people hope for a long and healthy life. In recent years, researchers have focused on healthy longevity factors. In particular, calorie restriction delays aging, reduces mortality, and extends life. Ghrelin, which is secreted during fasting, is well known as an orexigenic peptide. Because ghrelin is increased by caloric restriction, ghrelin may play an important role in the mechanism of longevity mediated by calorie restriction. In this review, we will discuss the role of orexigenic peptides with a particular focus on ghrelin. We conclude that the ghrelin-growth hormone secretagogue-R signaling pathway may play an important role in the anti-aging mechanism.

Mechanism for increased hepatic glycerol synthesis in the citrin/mitochondrial glycerol-3-phosphate dehydrogenase double-knockout mouse: Urine glycerol and glycerol 3-phosphate as potential diagnostic markers of human citrin deficiency.

The mitochondrial aspartate-glutamate carrier isoform 2 (citrin) and mitochondrial glycerol-3-phosphate dehydrogenase (mGPD) double-knockout mouse has been a useful model of human citrin deficiency. One of the most prominent findings has been markedly increased hepatic glycerol 3-phosphate (G3P) following oral administration of a sucrose solution. We aimed to investigate whether this change is detectable outside of the liver, and to explore the mechanism underlying the increased hepatic G3P in these mice. We measured G3P and its metabolite glycerol in plasma and urine of the mice under various conditions. Glycerol synthesis from fructose was also studied using the liver perfusion system. The citrin/mGPD double-knockout mice showed increased urine G3P and glycerol under normal, fed conditions. We also found increased plasma glycerol under fasted conditions, while oral administration of different carbohydrates or ethanol led to substantially increased plasma glycerol. Fructose infusion to the perfused liver of the double-knockout mice augmented hepatic glycerol synthesis, and was accompanied by a concomitant increase in the lactate/pyruvate (L/P) ratio. Co-infusion of either pyruvate or phenazine methosulfate, a cytosolic oxidant, with fructose corrected the high L/P ratio, leading to reduced glycerol synthesis. Overall, these findings suggest that hepatic glycerol synthesis is cytosolic NADH/NAD(+) ratio-dependent and reveal a likely regulatory mechanism for hepatic glycerol synthesis following a high carbohydrate load in citrin-deficient patients. Therefore, urine G3P and glycerol may represent potential diagnostic markers for human citrin deficiency.

Guidelines for parenteral fluid management for terminal cancer patients.

BACKGROUND: Japan's first guidelines for parenteral fluid management for terminal cancer patients were issued in 2006. These guidelines focused on the fluid levels to administer to patients with a remaining life expectancy of 1-2 months. However, recent refinement of the concept of cachexia is prompting caregivers worldwide to rethink parenteral fluid management for terminal cancer patients. OBJECTIVE: Our objective was to develop guidelines for parenteral fluid management for terminal cancer patients with a remaining life expectancy of 1 month, a point when cachexia generally begins to severely adversely affect the body. METHODS: The Japanese Society for Palliative Medicine appointed a Guidelines Working Practitioner Group consisting of a multidisciplinary team of specialists. In response to 26 clinical questions on parenteral fluid management for terminal cancer patients, the Working Group used the Delphi method to reach consensus on the recommendability and evidence level of 89 relevant manuscripts identified through a systematic literature review. The Working Group then had an outside committee reviews the draft guidelines validity before authoring the final version. RESULTS: The resulting clinically aligned guidelines contain specific recommendations (25 recommendations on physical suffering/remaining life expectancy, 10 nursing-related recommendations and 4 ethical recommendations) assessed using the Delphi method and by an outside committee. CONCLUSIONS: Japanese Society for Palliative Medicine released a revised edition of the Guidelines for Parenteral Fluid Management for Terminal Cancer Patients, which are based on medical evidence and consider the pathologic features of cachexia. We recommend that caregivers carefully evaluate the clinical usefulness of the guidelines.

Molecular Cloning of Ghrelin and Characteristics of Ghrelin-Producing Cells in the Gastrointestinal Tract of the Common Marmoset (Callithrix jacchus).

Ghrelin was first isolated from human and rat as an endogenous ligand for the growth hormone secretagogue receptor (GHS-R). In the present study, we determined the ghrelin cDNA sequence of the common marmoset (Callithrix jacchus), a small-bodied New World monkey, and investigated the distribution of ghrelin-producing cells in the gastrointestinal tract and localization profiles with somatostatin-producing cells. The marmoset ghrelin cDNA coding region was 354 base pairs, and showed high homology to that in human, rhesus monkey, and mouse. Marmoset ghrelin consists of 28 amino acids, and the N-terminal region is highly conserved as found in other mammalian species. Marmoset preproghrelin and mature ghrelin have 86.3% and 92.9% homology, respectively, to their human counterparts. Quantitative RT-PCR analysis showed that marmoset ghrelin mRNA is highly expressed in the stomach, but it is not detected in other tissues of the gastrointestinal tract. In addition, a large number of ghrelin mRNA-expressing cells and ghrelin-immunopositive cells were detected in the mucosal layer of the stomach, but not in the myenteric plexus. Moreover, all the ghrelin cells examined in the stomach were observed to be closed-type. Double staining showed that somatostatin-immunopositive cells were not co-localized with ghrelin-producing cells; however, a subset of somatostatin-immunopositive cells is directly adjacent to ghrelin-immunopositive cells. These findings suggest that the distribution of ghrelin cells in marmoset differs from that in rodents, and thus the marmoset may be a more useful model for the translational study of ghrelin in primates. In conclusion, we have clarified the expression and cell distribution of ghrelin in marmoset, which may represent a useful model in translational study.

Good appearance of food gives an appetizing impression and increases cerebral blood flow of frontal pole in healthy subjects.

We investigated the effect of food appearance on appetite and on left-frontal pole blood flow in healthy young subjects. The iEat, a new form of foods with good appearance and greater softness was hypothesized to have the better effects to the subjects than blender-processed foods. The effect on appetite and left-frontal pole blood flow using hemoencephalography was assessed while participants were viewing the slideshows of two kinds of foods respectively. The slideshows were used to control the showing time and other variables. The pictures of iEat foods stimulated both of them more than the blender-processed ones. The measurement of cerebral blood flow could be a useful method to monitor the cognitive and emotional aspects of feeding behavior that are important for humans. Like iEat, the foods that look as good as ordinary food yet are softer can be used for people with poor appetite and eating difficulties to ordinary food.

Activation of imidazoline-I3 receptors ameliorates pancreatic damage.

Agmatine, an endogenous ligand of imidazoline receptors, is reported to exhibit anti-hyperglycaemic and many other effects. It has been established that the imidazoline I3 receptor is involved in insulin secretion. The current study characterizes the role of the imidazoline I3 receptor in the protection of pancreatic islets. The activity effect of agmatine against on streptozotocin (STZ)-induced (5 mmol/L) rat ß cell apoptosis was examined by using ApoTox-Glo triplex assay, live/dead cell double staining assay, flow cytometric analysis, and western blot. Imidazoline I3 receptors antagonist KU14R and the phospholipase C inhibitor named U73122 were treated in ß cells to investigate the potential signalling pathways. The serum glucose and recovery of insulin secretion were measured in STZ-treated rats after continuously injected agmatine. The apoptosis in rat ß cells was reduced by agmatine in a dose-dependent manner, cell viability was improved after treatment with agmatine and these effects were suppressed after the blockade of KU14R and U73122. Western blot analysis confirmed that agmatine could decrease caspase-3 expression and increase the p-BAD levels. In STZ-treated rats, injection of agmatine for 4 weeks may significantly lower the serum glucose and recovery of insulin secretion. This improvement of pancreatic islets induced by agmatine was deleted by KU14R in vivo. Agmatine can activate the imidazoline I3 receptor linked with the phospholipase C pathway to induce cell protection against apoptosis induced by a low dose of STZ. This finding provides new insight into the prevention of early stage pancreatic islet damage.

Relationship between the severity of pre-frailty and the degree of adaptation of Ninjin'yoeito (NYT) on pre-frailty.

With the global trend towards longer life expectancies, there's an increasing emphasis on not just living longer, but also maintaining health and wellbeing into older age. This study explores the efficacy of Ninjin'yoeito (NYT) in the early stages of frailty, a critical period for preventive interventions. Taking account of the knowledge gap regarding the association between early frailty and NYT, we use data from workplace health checkups to examine the relationship between pre-frailty severity and NYT adaption. The objective of our research is to enhance the comprehension of early treatments using NYT to prevent the progression of frailty. A total of 314 employees of the Kyoto Industrial Health Association who received workplace health checkups between November 2021 and March 2023 and consented to this study were included in the analysis. Information on gender, age, body mass index (BMI), NYT-specific symptoms assessment, the Japanese version of the General Health Questionnaire-12 (GHQ-12), and the Kihon Checklist (KCL) were obtained. The correlation analysis revealed that there was a strong positive correlation between the number of applicable NYT indications and the GHQ-12 score (r = 0.5992, p < 0.0001). Similarly, a moderate positive correlation was observed between the number of applicable NYT indications and the KCL score (r = 0.5030, p < 0.0001). In the multivariate analysis, both GHQ-12 (ß = 0.49, SE = 0.06, t = 7.66, 95% CI: 0.36 to 0.62, p = 0.000) and KCL (ß = 0.54, SE = 0.12, t = 4.29, 95% CI: 0.29 to 0.79, p = 0.000) showed significant positive associations with the variance in the number of applicable NYT indications, indicating that higher scores on these measures were related to a greater number of indications. NYT has the potential to be utilized not only as a therapeutic intervention for frailty, but also as a preventive measure.

The barriers to interprofessional care for cancer cachexia among Japanese healthcare providers: A nationwide survey.

BACKGROUND: Cancer cachexia is a severe complication of advanced malignancy, with few therapeutic options. To promote interprofessional care for cancer cachexia, healthcare providers' needs should be addressed in detail. This pre-planned subgroup analysis of the Global Educational Needs Evaluation: a systemic interprofessional study in cancer cachexia (GENESIS-CC) survey aimed to identify barriers to interprofessional care of cancer cachexia in Japan. METHODS: A nationwide survey was electronically conducted for healthcare providers in oncological or general healthcare facilities from January to March 2021 in Japan. The Japanese Regional Advisory Board developed a barrier scoring system with 33 from the 58 original survey items to quantify six domains of barriers: (1) lack of confidence, (2) lack of knowledge, (3) barriers in personal practice, (4) barriers in perception, (5) barriers in team practice and (6) barriers in education. The largest possible barrier score was set at 100 points. We compared the scores by profession. RESULTS: A total of 1227 valid responses were obtained from 302 (24.6%) physicians, 252 (20.5%) pharmacists, 236 (19.2%) nurses, 218 (17.8%) dietitians, 193 (15.7%) rehabilitation therapists and 26 (2.0%) other professionals. Overall, 460 (37.5%) were not very or at all confident about cancer cachexia care, 791 (84.1%) agreed or strongly agreed that care was influenced by reimbursement availability and 774 (81.9%) did not have cancer cachexia as a mandatory curriculum. The largest mean barrier score (± standard deviation) was 63.7 ± 31.3 for education, followed by 55.6 ± 21.8 for team practice, 43.7 ± 32.5 for knowledge, 42.8 ± 17.7 for perception and 36.5 ± 16.7 for personal practice. There were statistically significant interprofessional differences in all domains (P < 0.05), especially for pharmacists and nurses with the highest or second highest scores in most domains. CONCLUSIONS: There is a need to improve the educational system and team practices of cancer cachexia for most Japanese healthcare providers, especially pharmacists and nurses. Our study suggests the need to reform the mandatory educational curriculum and reimbursement system on cancer cachexia to promote interprofessional care for cancer cachexia in Japan.

Comparison between single-muscle evaluation and cross-sectional area muscle evaluation for predicting the prognosis in patients with oral squamous cell carcinoma: a retrospective cohort study.

Introduction: The most effective method of assessing sarcopenia has yet to be determined, whether by single muscle or by whole muscle segmentation. The purpose of this study was to compare the prognostic value of these two methods using computed tomography (CT) images in patients with oral squamous cell carcinoma (OSCC). Materials and methods: Sex- and age-adjusted Cox proportional hazards models were employed for each parameter of sarcopenia related to overall survival, disease-free survival, and disease-specific survival. Harrell's concordance index was calculated for each model to assess discriminatory power. Results: In this study including 165 patients, a significant correlation was found between the CT-based assessment of individual muscles and their cross-sectional area. Single muscle assessments showed slightly higher discriminatory power in survival outcomes compared to whole muscle assessments, but the difference was not statistically significant, as indicated by overlapping confidence intervals for the C-index between assessments. To further validate our measurements, we classified patients into two groups based on intramuscular adipose tissue content (P-IMAC) of the spinous process muscle. Analysis showed that the higher the P-IMAC value, the poorer the survival outcome. Conclusion: Our findings indicate a slight advantage of single-muscle over whole-muscle assessment in prognostic evaluation, but the difference between the two methods is not conclusive. Both assessment methods provide valuable prognostic information for patients with OSCC, and further studies involving larger, independent cohorts are needed to clarify the potential advantage of one method over the other in the prognostic assessment of sarcopenia in OSCC.

Impact of Helicobacter pylori eradication on circulating adiponectin in humans.

BACKGROUND: The relationship between Helicobacter pylori infection and metabolic syndrome is not well understood. Adiponectin is an adipose-derived protein considered to play a significant role in the development of metabolic syndrome. The aim of this study was to clarify the influence of H. pylori infection on circulating adiponectin in humans. METHODS: In a prospective study, 456 patients underwent endoscopy and H. pylori testing. All of the 338 H. pylori -positive patients received eradication therapy. Treatment was successful in 241 patients. Circulating adiponectin and other metabolic parameters were measured at baseline in all patients and 12 weeks after eradication therapy in those initially positive for H. pylori. RESULTS: Circulating adiponectin levels were not different between H. pylori -positive and H. pylori -negative patients. In the group with successful eradication, levels of total adiponectin and each multimer form were significantly increased after therapy. Conversely, the levels of total adiponectin and high-molecular-weight adiponectin, but not middle-molecular-weight and low-molecular-weight adiponectin, were increased in the group with unsuccessful eradication after the therapy. CONCLUSIONS: Eradication therapy of H. pylori increased circulating adiponectin levels in Japanese individuals and could be beneficial for preventing metabolic syndrome conditions.

Cancer cachexia pathophysiology and translational aspect of herbal medicine.

About half of all cancer patients show a syndrome of cachexia, characterized by anorexia and loss of adipose tissue and skeletal muscle mass. Numerous cytokines have been postulated to play a role in the etiology of cancer cachexia. Cytokines can elicit effects that mimic leptin signaling and suppress orexigenic ghrelin and neuropeptide Y signaling, inducing sustained anorexia and cachexia not accompanied by the usual compensatory response. Furthermore, cytokines have been implicated in the induction of cancer-related muscle wasting. In particular, tumor necrosis factor-alpha, interleukin-1, interleukin-6 and interferon-gamma have been implicated in the induction of cancer-related muscle wasting. Cytokine-induced skeletal muscle wasting is probably a multifactorial process, which involves a depression in protein synthesis, an increase in protein degradation or a combination of both. Cancer patients suffer from the reduction in physical function, tolerance to anti-cancer therapy and survival, while many effective chemotherapeutic agents for cancer are burdened by toxicities that can reduce patient's quality of life or hinder their effective use. Herbal medicines have been widely used to help improve such conditions. Recent studies have shown that herbal medicines such as rikkunshito enhance ghrelin signaling and consequently improve nausea, appetite loss and cachexia associated with cancer or cancer chemotherapy, which worsens the quality of life and life expectancy of the patients. The multicomponent herbal medicines capable of targeting multiple sites could be useful for future drug discovery. Mechanistic studies and identification of active compounds could lead to new discoveries in biological and biomedical sciences.

Ghrelin and cachexia in chronic kidney disease.

Ghrelin is a growth hormone (GH) secretagogue and a potent orexigenic factor that stimulates feeding by interacting with hypothalamic feeding-regulatory nuclei. Its multifaceted effects are potentially beneficial as a treatment in human disease states. In both adult and pediatric chronic kidney disease (CKD) patients, decreased appetite plays a major role in wasting, which in turn is linked to morbidity and mortality; wasting has also been linked to high levels of leptin and proinflammatory cytokines. The beneficial effects of ghrelin treatment in CKD are potentially mediated by multiple concurrent actions, including the stimulation of appetite-regulating centers, anti-inflammatory effects, and direct kidney effects. Further evaluation of this appetite-regulating hormone in CKD is needed to confirm previous findings and to determine the underlying mechanisms.

Anamorelin in Japanese patients with cancer cachexia: an update.

PURPOSE OF REVIEW: Anamorelin was approved for production and marketing in Japan on 22 January 2021 for cancer cachexia in non-small-cell lung cancer, gastric cancer, pancreatic cancer, and colorectal cancer. The authors describe the updates of anamorelin for cancer cachexia in Japan. RECENT FINDINGS: Recent evidence showed that anamorelin improved lean body mass, body weight, and appetite in patients with cancer cachexia in clinical practice. Anamorelin does not increase body weight in the severe-weight-loss group in cachectic patients with pancreatic cancer. Several case reports showed that anamorelin can cause cardiac adverse drug reactions. Among the cardiac adverse reactions, fatal arrhythmias should be monitored carefully even if it is the first dose. Anamorelin combined with nutrition, physical activity, and exercise may be more useful than anamorelin alone for treating cancer cachexia. An interim analysis from post-marketing all-case surveillance was performed; however, details have not yet been published. When anamorelin cannot be used for cancer cachexia, Kampo medicines can be considered as an option. SUMMARY: Anamorelin has changed the clinical practice of cancer cachexia in Japan. The authors hope that anamorelin is available for other disease-related cachexia along with appropriate multidisciplinary interventions.

Comparative study of the effects of the three kinds of Kampo-hozai: Ninjinyoeito, Hochuekkito, and Juzentaihoto on anxious and low sociability behavior using NPY-knockout zebrafish.

Ninjinyoeito, Hochuekkito, and Juzentaihoto are the three types of Kampo-hozai used to support the treatment of various diseases by energizing patients through improved mental health. While Kampo-hozais are clinically used to improve mental energy decline, a comparison between their effects on neuropsychiatric symptoms like anxiety and sociability and the strength of their effects has not been conducted. Therefore, this study compared the effects of Ninjinyoeito, Hochuekkito, and Juzentaihoto on psychiatric symptoms using neuropeptide Y knockout (NPY-KO) zebrafish, a suitable animal model for anxiety and low sociability. Neuropeptide Y knockout zebrafish were fed a Ninjinyoeito, Hochuekkito, or Juzentaihoto-supplemented diet for 4 days. Then, sociability was analyzed using a three-Chambers test and anxiety-like behavior was evaluated using the cold stress and novel tank tests. The results showed that Ninjinyoeito treatment improved the low sociability of neuropeptide Y knockout, while Hochuekkito and Juzentaihoto did not. Neuropeptide Y knockout exhibited anxiety-like behaviors, such as freezing and swimming in the wall area under cold stress, but Ninjinyoeito treatment improved these behaviors. However, these anxiety-like behaviors were not improved by Hochuekkito and Juzentaihoto. Ninjinyoeito treatment also improved anxiety-like behaviors of neuropeptide Y knockout in the novel tank test. However, no improvement was shown in the Hochuekkito and Juzentaihoto groups. This trend was also confirmed in the low water stress test using wild-type zebrafish. This study exhibits that among the three types of Kampo-hozai, Ninjinyoeito is the most effective in psychiatric disorders associated with anxiety and low sociability.

Alteration of antral and proximal colonic motility induced by chronic psychological stress involves central urocortin 3 and vasopressin in rats.

Because of the difficulties in developing suitable animal models, the pathogenesis of stress-induced functional gastrointestinal disorders is not well known. Here we applied the communication box technique to induce psychological stress in rats and then examined their gastrointestinal motility. We measured upper and lower gastrointestinal motility induced by acute and chronic psychological stress and examined the mRNA expression of various neuropeptides in the hypothalamus. Chronic psychological stress disrupted the fasted motility in the antrum and accelerated motility in the proximal colon. mRNA expression of AVP, oxytocin, and urocortin 3 was increased by chronic psychological stress. Intracerebroventricular (ICV) injection of urocortin 3 disrupted the fasted motility in the antrum, while ICV injection of Ucn3 antiserum prevented alteration in antral motility induced by chronic psychological stress. ICV injection of AVP accelerated colonic motility, while ICV injection of SSR 149415, a selective AVP V1b receptor antagonist, prevented alteration in proximal colonic motility induced by chronic psychological stress. Oxytocin and its receptor antagonist L 371257 had no effect on colonic motility in either the normal or chronic psychological stress model. These results suggest that chronic psychological stress induced by the communication box technique might disrupt fasted motility in the antrum via urocortin 3 pathways and accelerates proximal colonic motility via the AVP V1b receptor in the brain.