Publications by authors named "Akio Inui"

216 Publications

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

Int J Med Sci 2021 4;18(7):1566-1569. Epub 2021 Feb 4.

Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

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.
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http://dx.doi.org/10.7150/ijms.53907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976560PMC
February 2021

Ninjinyoeito improves anxiety behavior in neuropeptide Y deficient zebrafish.

Neuropeptides 2021 Mar 6;87:102136. Epub 2021 Mar 6.

Department of Food Life Science, Faculty of Fisheries, Kagoshima University, Kagoshima, Japan; The United Graduate School of Agricultural Sciences, Kagoshima University, Kagoshima, Japan. Electronic address:

Anxiety induced by excess mental or physical stress is deeply involved in the onset of human psychiatric diseases such as depression, bipolar disorder, and panic disorder. Recently, Kampo medicines have received focus as antidepressant drugs for clinical use because of their synergistic and additive effects. Thus, we evaluated the anxiolytic activity of Ninjinyoeito (NYT) using neuropeptide Y-knockout (NPY-KO) zebrafish that exhibit severe anxiety responses to acute stress. Adult NPY-KO zebrafish were fed either a 3% NYT-supplemented or normal diet (i.e., the control diet) for four days and were then examined via behavioral tests. After short-term cold stress (10 °C, 2 s) was applied, control-fed NPY-KO zebrafish exhibited anxiety behaviors such as freezing, erratic movement, and increased swimming time along the tank wall. On the other hand, NYT-fed NPY-KO zebrafish significantly suppressed these anxiety behaviors, accompanied by a downregulation of tyrosine hydroxylase levels and phosphorylation of extracellular signal-regulated kinases in the brain. To understand the responsible component(s) in NYT, twelve kinds of herbal medicines that composed NYT were tested in behavioral trials with the zebrafish. Among them, nine significantly reduced freezing behavior in NPY-KO zebrafish. In particular, Schisandra fruit induced the most potent effect on abnormal zebrafish behavior, even in the lower amount (0.3% equivalent to NYT), followed by Atractylodes rhizome and Cinnamon bark. Subsequently, four lignans uniquely found in Schisandra fruit (i.e., gomisin A, gomisin N, schizandrin, and schizandrin B) were investigated for their anxiolytic activity in NPY-KO zebrafish. As a result, schizandrin was identified as a responsible compound in the anxiolytic effect of NYT. These results suggest that NYT has a positive effect on mental stress-induced anxiety and may be a promising therapeutic for psychiatric diseases.
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http://dx.doi.org/10.1016/j.npep.2021.102136DOI Listing
March 2021

Impaired brain fractalkine-CX3CR1 signaling is implicated in cognitive dysfunction in diet-induced obese mice.

BMJ Open Diabetes Res Care 2021 Feb;9(1)

Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Introduction: A diet high in saturated fat is well known to affect neuronal function and contribute to cognitive decline in experimental animals and humans. Fractalkine released from neurons acts on its receptor, CX3C chemokine receptor 1 (CX3CR1), in the microglia to regulate several brain functions. The present study addressed whether fractalkine-CX3CR1 signaling in the brain, especially the hippocampus, contributes to the cognitive deficits observed in diet-induced obese (DIO) mice.

Research Design And Methods: Mice were given 60% high-fat diet for 16 weeks. The expression of fractalkine and CX3CR1 in the hippocampus, amygdala and prefrontal cortex of DIO mice was analyzed. Cognitive ability in the Y-maze test and hippocampal glutamate receptors and synaptic markers were observed in DIO and CX3CR1 antagonist-treated mice. Regulation of fractalkine and CX3CR1 expression in the hippocampus was examined following administration of a selective insulin-like growth factor-1 (IGF-1) receptor inhibitor and a tyrosine receptor kinase B (TrkB) antagonist in normal mice.

Results: DIO mice exhibited significant cognitive deficits in the Y-maze test and decrease in fractalkine and CX3CR1 in the hippocampus and amygdala compared with mice fed a control diet (CD mice). Administration of the CX3CR1 antagonist 18a in normal mice induced significant cognitive deficits in the Y-maze test. DIO mice and CX3CR1 antagonist-treated mice exhibited significant decreases in protein levels of NMDA (N-methyl-D-aspartate) receptor subunit (NR2A), AMPA (α-amino-5-methyl-3-hydroxy-4-isoxazole propionate) receptor subunit (GluR1) and postsynaptic density protein 95 in the hippocampus compared with their respective controls. Furthermore, plasma IGF-1 and hippocampal brain-derived neurotrophic factor were significantly decreased in DIO mice compared with CD mice. Administration of a selective IGF-1 receptor inhibitor and a TrkB antagonist in normal mice significantly decreased fractalkine and CX3CR1 in the hippocampus.

Conclusions: These findings indicate that the cognitive decline observed in DIO mice is due, in part, to reduced fractalkine-CX3CR1 signaling in the corticolimbic system.
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http://dx.doi.org/10.1136/bmjdrc-2020-001492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878130PMC
February 2021

Antagonism for NPY signaling reverses cognitive behavior defects induced by activity-based anorexia in mice.

Psychoneuroendocrinology 2021 Apr 25;126:105133. Epub 2021 Jan 25.

Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Patients with AN often express psychological symptoms such as body image distortion, cognitive biases, abnormal facial recognition, and deficits in working memory. However, the molecular mechanisms underlying the impairment of cognitive behaviors in AN remain unknown. In the present study, we measured cognitive behavior using novel object recognition (NOR) tasks and mRNA expressions in hypothalamic neuropeptides in female C57BL/6J mice with activity-based anorexia (ABA). Additionally, we evaluated the effects of antagonists with intracerebroventricular (icv) administration on the impairment of cognitive behavior in NOR tasks. Our results showed that NOR indices were lowered, subsequently increasing mRNA levels of agouti-related peptide (AgRP) and neuropeptide Y (NPY), and c-Fos- and AgRP- or NPY-positive cells in the hypothalamic arcuate nucleus in ABA mice. We also observed that icv administration of anti-NPY antiserum (2 µl), anti-AgRP antibody (0.1 μg), and Y5 receptor antagonist CPG71683 (15 nmol) significantly reversed the decreased NOR indices. Therefore, our results suggest that increased NPY and AgRP signaling in the brain might contribute to the impairment of cognitive behavior in AN.
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http://dx.doi.org/10.1016/j.psyneuen.2021.105133DOI Listing
April 2021

The regulatory approval of anamorelin for treatment of cachexia in patients with non-small cell lung cancer, gastric cancer, pancreatic cancer, and colorectal cancer in Japan: facts and numbers.

J Cachexia Sarcopenia Muscle 2021 Feb 31;12(1):14-16. Epub 2020 Dec 31.

Pharmacological Department of Herbal Medicine, Kagoshima University Graduate School of Medical & Dental Sciences, Kagoshima, Japan.

Anamorelin is a ghrelin receptor agonist that can be administered orally and thought to improve cancer cachexia by improving appetite and increasing serum insulin-like growth factor-1. Anamorelin was not approved for use in Europe. In contrast, the use of anamorelin for cancer cachexia in four types of cancer (non-small cell lung cancer, gastric cancer, pancreatic cancer, and colorectal cancer) was approved in Japan on 11 December 2020. Phase 2 trial (ONO-7643-04) for the treatment of patients with non-small cell lung cancer and cachexia resulted in 1.56 kg lean body mass increase assessed by dual-energy X-ray absorptiometry (DXA). Another study for advanced and unresectable gastrointestinal (colorectal, gastric, or pancreatic) cancer showed 1.89 ± 0.36 kg improvement in lean body mass. Skeletal lean body mass assessed by DXA is important for diagnosing sarcopenia and cachexia in Asia. The approval of anamorelin is expected to change clinical practice of cancer cachexia in Japan and hopefully in other countries. In the past, cachexia was rarely diagnosed in Japan, because it was often thought that cachexia meant terminal stage. The dissemination of clinical findings on anamorelin from Japan, as well as the creation of consensus papers and clinical practice guidelines for cachexia in Japan and Asia, will be required to promote international expansion in the future.
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http://dx.doi.org/10.1002/jcsm.12675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890143PMC
February 2021

Red rice extract alleviates hyperglycemia by increasing glucose uptake and glucose transporter type 4 levels in skeletal muscle in two diabetic mouse models.

Food Nutr Res 2020 8;64. Epub 2020 Oct 8.

Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Background: Red rice (RRK), prepared by growing species on steamed rice, has been reported to lower blood glucose levels in diabetic animal models. However, the action mechanism is not yet completely understood.

Objective: The objective of this study was to examine the mechanism underlying the hypoglycemic action of RRK extract in two diabetic animal models: the insulin-deficiency mice, where the insulin deficiency was induced by streptozotocin (STZ), and insulin-resistance mice, where the insulin resistance was induced by a high-fat diet (HFD).

Design: Low (12.5 mg/kg body weight [BW]) and high (50.0 mg/kg BW) doses of RRK extract were orally administered to the mice for 10 successive days (0.25 mL/day/mouse). The protein expression levels of glucose transporter type 4 (GLUT4) in the skeletal muscle and glucose transporter type 2 (GLUT2) in the liver were measured. Blood glucose (BG) levels of STZ-treated mice in insulin tolerance test (ITT) and BG and insulin levels of HFD-fed mice in intraperitoneal glucose tolerance test (IPGTT) were investigated.

Results: In the STZ-treated mice, oral administration of RRK extract lowered BG levels and food intake but increased plasma 1,5-anhydroglucitol level. Moreover, the RRK extract lowered the BG levels of STZ-treated mice as measured by ITT. In the HFD-fed mice, we confirmed that the orally administered RRK extract lowered the BG and the homeostasis model assessment index for insulin resistance. Furthermore, the RRK extract lowered the BG and insulin levels of HFD-fed mice in IPGTT. Regarding the protein levels of GLUT, the orally administered RRK extract increased the GLUT4 level in the skeletal muscle; however, the RRK extract did not alter the GLUT2 level in the liver of either the STZ-treated or the HFD-fed mice.

Discussion: Our study demonstrates that RRK extract can improve impaired glucose tolerance in mouse models of diabetes by enhancing GLUT4 expression in skeletal muscle.

Conclusion: These results suggest that RRK extract could potentially be a functional food for the treatment of diabetes mellitus.
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http://dx.doi.org/10.29219/fnr.v64.4226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672486PMC
October 2020

Reduced brain fractalkine-CX3CR1 signaling is involved in the impaired cognition of streptozotocin-treated mice.

IBRO Rep 2020 Dec 15;9:233-240. Epub 2020 Sep 15.

Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Patients with diabetes mellitus are predisposed to cognitive impairment. Fractalkine-CX3CR1 in the brain signaling represents a primary neuron-microglia inter-regulatory system for several brain functions including learning and memory processes. The present study addressed whether fractalkine-CX3CR1 signaling in the hippocampus contributes to the cognitive deficits observed in streptozotocin (STZ)-treated mice. Our results showed that STZ-treated mice exhibited significant cognitive deficits in the Y-maze test, and a decrease in fractalkine and CX3CR1 levels in the hippocampus. Moreover, intracerebroventricular injection of the CX3CR1 antagonist 18a in normal mice induced significant cognitive deficits in the Y-maze test. STZ-treated mice showed a significant increase in plasma corticosterone levels and a decrease in plasma and hippocampal levels of insulin-like growth factor-1 (IGF-1). Therefore, we examined the effects of corticosterone and IGF-1 on regulation of fractalkine and CX3CR1 expression. Dexamethasone (DEX) application significantly decreased the mRNA expression of fractalkine in primary neuron and astrocyte cultures, and of CX3CR1 in primary microglia cultures. On the other hand, IGF-1 application significantly increased the mRNA expression of fractalkine in primary neuron cultures and CX3CR1 in primary microglia cultures. In addition, administration of DEX and the IGF-1 receptor tyrosine kinase inhibitor picropodophyllin significantly reduced the mRNA expression of fractalkine and CX3CR1 in the hippocampus. These findings indicate that impaired cognition in STZ-treated mice is associated with reduced fractalkine-CX3CR1 signaling in the hippocampus which may be induced by an increase in corticosterone and a decrease in IGF-1.
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http://dx.doi.org/10.1016/j.ibror.2020.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509139PMC
December 2020

Ninjin'yoeito Targets Distinct Ca Channels to Activate Ghrelin-Responsive vs. Unresponsive NPY Neurons in the Arcuate Nucleus.

Front Nutr 2020 17;7:104. Epub 2020 Jul 17.

Division of Integrative Physiology, Center for Integrative Physiology, Kansai Electric Power Medical Research Institute, Kobe, Japan.

Appetite loss or anorexia substantially deteriorates quality of life in various diseases, and stand upstream of frailty. Neuropeptide Y (NPY) in the hypothalamic arcuate nucleus (ARC) and ghrelin released from stomach are potent inducers of appetite. We previously reported that Ninjin'yoeito, a Japanese kampo medicine comprising twelve herbs, restores food intake, and body weight in cisplatin-treated anorectic mice. Furthermore, Ninjin'yoeito increased cytosolic Ca concentration ([Ca]) in not only ghrelin-responsive but ghrelin-unresponsive NPY neurons in ARC. The cellular lineage/differentiation of ghrelin-unresponsive neuron is less defined but might alter along with aging and diet. This study examined the occupancy of ghrelin-unresponsive neurons among ARC NPY neurons in adult mice fed normal chow, and explored the mechanisms underlying Ninjin'yoeito-induced [Ca] increases in ghrelin-unresponsive vs. ghrelin-responsive NPY neurons. Single ARC neurons were subjected to [Ca] measurement and subsequent immunostaining for NPY. Ghrelin failed to increase [Ca] in 42% of ARC NPY neurons. Ninjin'yoeito (10 μg/ml)-induced increases in [Ca] were abolished in Ca free condition in ghrelin-responsive and ghrelin-unresponsive ARC NPY neurons. Ninjin'yoeito-induced [Ca] increases were inhibited by N-type Ca channel blocker ω-conotoxin in the majority (17 of 20), while by L-type Ca channel blocker nitrendipine in the minority (2 of 23), of ghrelin-responsive neurons. In contrast, Ninjin'yoeito-induced [Ca] increases were inhibited by nitrendipine in the majority (14 of 17), while by ω-conotoxin in the minority (8 of 24), of ghrelin-unresponsive neurons. These results indicate that ghrelin-unresponsive neurons occur substantially among NPY neurons of ARC in adult mice fed normal chow. Ninjin'yoeito preferentially target N-type and L-type Ca channels in the majority of ghrelin-responsive and ghrelin-unresponsive neurons, respectively, to increase [Ca]. We suggest ARC N- and L-type Ca channels as potential targets for activating, respectively, ghrelin-responsive, and unresponsive NPY neurons to treat anorexia.
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http://dx.doi.org/10.3389/fnut.2020.00104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379896PMC
July 2020

Editorial: Frailty and Herbal Medicines- From Molecular Mechanisms to Clinical Efficacy.

Front Nutr 2020 15;7:41. Epub 2020 Apr 15.

Pharmacological Department of Herbal Medicine, Kagoshima University Graduate School of Medicine and Dental Sciences, Kagoshima, Japan.

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http://dx.doi.org/10.3389/fnut.2020.00041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174580PMC
April 2020

Neuropeptide Y deficiency induces anxiety-like behaviours in zebrafish (Danio rerio).

Sci Rep 2020 04 3;10(1):5913. Epub 2020 Apr 3.

Department of Pharmacological Sciences of Herbal Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.

Neuropeptide Y (NPY) controls energy homeostasis including orexigenic actions in mammalians and non-mammalians. Recently, NPY has attracted attention as a mediator of emotional behaviour and psychosomatic diseases. However, its functions are not fully understood. We established npy gene-deficient (NPY-KO) zebrafish (Danio rerio) to assess the relationship between NPY and emotional behaviours. The NPY-KO zebrafish exhibited similar growth, but pomc and avp mRNA levels in the brain were higher as compared to wild-type fish. NPY-KO zebrafish exhibited several anxiety-like behaviours, such as a decrease in social interaction in mirror test and decreased locomotion in black-white test. The acute cold stress-treated NPY-KO zebrafish exhibited anxiety-like behaviours such as remaining stationary and swimming along the side of the tank in the mirror test. Moreover, expression levels of anxiety-associated genes (orx and cck) and catecholamine production (gr, mr, th1 and th2) were significantly higher in NPY-KO zebrafish than in wild-type fish. We demonstrated that NPY-KO zebrafish have an anxiety phenotype and a stress-vulnerability like NPY-KO mice, whereby orx and/or catecholamine signalling may be involved in the mechanism actions.
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http://dx.doi.org/10.1038/s41598-020-62699-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125123PMC
April 2020

Weight loss induced by whole grain-rich diet is through a gut microbiota-independent mechanism.

World J Diabetes 2020 Feb;11(2):26-32

Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan.

The prevalence of overweight and obesity has increased worldwide. Obesity is a well-known risk factor of type 2 diabetes mellitus and cardiovascular disease and raises public health concerns. Many dietary guidelines encourage the replacement of refined grains with whole grains (WGs) to enhance body weight management. Current evidence regarding interrelationships among WGs, body weight, and gut microbiota is limited and inconclusive. In this editorial, we comment on the article by Roager et al published in the recent issue of the 2019; 68(1): 83-93. In the study, obese patients (25 < body mass index < 35 kg/m) were randomly assigned to receive two 8-wk dietary controlling periods with WGs and refined grain-rich diet. The results showed significantly decreased body weight in the WG group. Either the composition of gut microbiota or short-chain fatty acids, the leading end product of fermentation of non-digestible carbohydrate by gut microbiota, did not differ between the two groups. The study highly indicated that a WG-rich diet reduced body weight independent of gut microbiota. We then raised some plausible mechanisms of how WGs might influence body weight and demonstrated more literature in line with WGs enhance body weight control through a microbiota-independent pathway. Possible mechanisms include: (1) The abundant dietary fiber contents of WGs increase satiety, satiation, energy excretion from stool, and energy expenditure simultaneously decreasing energy absorption and fat storage; (2) The plentiful amount of polyphenols of WGs improve energy expenditure by hampering adipocyte maturation and function; (3) The sufficient magnesium and zinc of WGs guarantee lean body mass growth and decrease fat mass; (4) The effect of WGs on brown adipose tissue is a key component of non-shivering thermogenesis; and (5) The increase of adiponectin by WGs enhances glucose utilization, lipid oxidation, and energy expenditure.
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http://dx.doi.org/10.4239/wjd.v11.i2.26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6969707PMC
February 2020

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.

BMC Cancer 2019 May 31;19(1):528. Epub 2019 May 31.

Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.

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 .
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http://dx.doi.org/10.1186/s12885-019-5762-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544995PMC
May 2019

Helicobacter pylori Vacuolating Cytotoxin A Causes Anorexia and Anxiety via Hypothalamic Urocortin 1 in Mice.

Sci Rep 2019 04 12;9(1):6011. Epub 2019 Apr 12.

Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Helicobacter pylori (Hp) infection is related to the pathogenesis of chronic gastric disorders and extragastric diseases. Here, we examined the anorexigenic and anxiogenic effects of Hp vacuolating cytotoxin A (VacA) through activation of hypothalamic urocortin1 (Ucn1). VacA was detected in the hypothalamus after peripheral administration and increased Ucn1 mRNA expression and c-Fos-positive cells in the hypothalamus but not in the nucleus tractus solitarius. c-Fos and Ucn1-double positive cells were detected. CRF1 and CRF2 receptor antagonists suppressed VacA-induced anxiety and anorexia, respectively. VacA activated single paraventricular nucleus neurons and A7r5 cells; this activation was inhibited by phospholipase C (PLC) and protein kinase C (PKC) inhibitors. VacA causes anorexia and anxiety through the intracellular PLC-PKC pathway, migrates across the blood-brain barrier, and activates the Ucn1-CRF receptor axis.
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http://dx.doi.org/10.1038/s41598-019-42163-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461611PMC
April 2019

Ninjin-yoeito activates ghrelin-responsive and unresponsive NPY neurons in the arcuate nucleus and counteracts cisplatin-induced anorexia.

Neuropeptides 2019 Jun 6;75:58-64. Epub 2019 Mar 6.

Center for Integrative Physiology, Division of Integrative Physiology, Kansai Electric Power Medical Research Institute, Kobe 650-0047, Japan; Division of System Neuroscience, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, Tochigi 320-0498, Japan; Pharmacological Department of Herbal Medicine, Kagoshima University Graduate School of Medical & Dental Sciences, Kagoshima 890-8544, Japan. Electronic address:

Reduced appetite or anorexia substantially deteriorates quality of life in various diseases including cancer, depression and heart failure. Furthermore, reduced appetite may stand upstream of sarcopenia and frailty. All these diseases are heavy burdens in the modern medicine and society. Therefore, the means that counteracts reduced appetite has been awaited, however, effective and well evidenced substance is not currently available. Ninjin-yoeito, a Japanese kampo medicine comprising twelve herbs has been used to treat anorexia. However, underlying mechanism is little known. Neuropeptide Y (NPY) and ghrelin are the most potent central and peripheral inducers of appetite, respectively. This study sought to determine whether Ninjin-yoeito influences NPY and/or ghrelin-responsive neurons in the hypothalamic arcuate nucleus (ARC), a feeding center. We isolated single neurons from ARC of mice and measured cytosolic Ca concentration ([Ca]) with fura-2 fluorescence imaging, followed by immunocytochemical identification of NPY neurons. Ninjin-yoeito (1-10 μg/ml) increased [Ca] in ARC neurons, the majority (80%) of which was immunoreactive to NPY. One fraction of these Ninjin-yoeito-responsive NPY neurons also responded to ghrelin, while another fraction did not. Furthermore, oral administration of Ninjin-yoeito (1 g/kg/day) counteracted the reductions in food intake and body weight by cisplatin, an anti-cancer drug, in mice. These results demonstrate that Ninjin-yoeito directly targets both ghrelin-responsive and unresponsive NPY neurons in ARC and preserves food intake and body weight in cisplatin-treated anorectic mice. Ninjin-yoeito's signaling through ghrelin-responsive and ghrelin-unresponsive NPY pathways may provide strong mechanistic basis for this medicine for treating anorectic conditions associated with cancer, depression, heart failure, sarcopenia, frailty and aging.
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http://dx.doi.org/10.1016/j.npep.2019.03.001DOI Listing
June 2019

Rubiscolin-6 activates opioid receptors to enhance glucose uptake in skeletal muscle.

J Food Drug Anal 2019 01 14;27(1):266-274. Epub 2018 Aug 14.

Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. Electronic address:

Rubiscolin-6 is an opioid peptide derived from plant ribulose bisphosphate carboxylase/oxygenase (Rubisco). It has been demonstrated that opioid receptors could control glucose homeostasis in skeletal muscle independent of insulin action. Therefore, Rubiscolin-6 may be involved in the control of glucose metabolism. In the present study, we investigated the effect of rubiscolin-6 on glucose uptake in skeletal muscle. Rubiscolin-6-induced glucose uptake was measured using the fluorescent indicator 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxyglucose (2-NBDG) in L6 and C2C12 cell lines. The protein expressions of glucose transporter 4 (GLUT4) and AMP-activated protein kinase (AMPK) in L6 cells were observed by Western blotting. The in vivo effects of rubiscolin-6 were characterized in streptozotocin (STZ)-induced diabetic rats. Rubiscolin-6 induced a concentration-dependent increase in glucose uptake levels. The increase of phospho-AMPK (pAMPK) and GLUT4 expressions were also observed in L6 and C2C12 cells. Effects of rubiscolin-6 were blocked by opioid receptor antagonists and/or associated signals inhibitors. Moreover, Rubiscolin-6 produced a dose-dependent reduction of blood glucose and increased GLUT4 expression in STZ-induced diabetic rats. In conclusion, rubiscolin-6 increases glucose uptake, potentially via an activation of AMPK to enhance GLUT4 translocation after binding to opioid receptors in skeletal muscle.
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http://dx.doi.org/10.1016/j.jfda.2018.06.012DOI Listing
January 2019

Herbal Medicine Ninjin'yoeito in the Treatment of Sarcopenia and Frailty.

Front Nutr 2018 12;5:126. Epub 2018 Dec 12.

Pharmacological Department of Herbal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Frailty and sarcopenia have recently gained considerable attention in terms of preventive care in Japan, which has an ever-increasing aging population. Sarcopenia is defined as atrophy of skeletal muscles caused by the age-related decrease in growth hormone/insulin-like growth factor and sex hormones. The Japanese Ministry of Health, Labor and Welfare reports that frailty can lead to impairment of both mental and physical functioning. Chronic diseases such as diabetes and dementia may underlie frailty. It is important to prevent progression of frailty and extend the healthy lifespan. In herbal medicine practice, including Japanese Kampo medicine, "Mibyo," a presymptomatic state, has long been recognized and may be applicable to frailty. Kampo medicines may include several medicinal plants and are thought to have the potential to improve symptoms of frailty, such as loss of appetite and body weight, fatigue, and sarcopenia, as well as anxiety, depression, and cognitive decline. Ninjin'yoeito (Ren Shen Yang Ying Tang) is the most powerful Kampo medicine and has been widely applied to palliative care of cancer patients. This review includes recent anti-aging studies and describes the effects and mechanisms of Ninjin'yoeito (Ren Shen Yang Ying Tang) when used for frailty or to extend a healthy life expectancy.
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http://dx.doi.org/10.3389/fnut.2018.00126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299011PMC
December 2018

Improvement of Diabetes Mellitus Symptoms by Intake of Ninjin'yoeito.

Front Nutr 2018 27;5:112. Epub 2018 Nov 27.

Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Diabetes mellitus is a well-known common disease and one of the most serious social problems in the worldwide. Although various types of drugs are developed, the number of patients suffering from diabetes mellitus is still increasing. Ninjin'yoeito (NYT) is one of formulas used in Japanese traditional herbal medicines for improving various types of metabolic disorders. However, the effect of NYT on diabetes mellitus has not yet been investigated. In the present study, we tried to clarify the action of NYT on the serum glucose level in streptozotocin (STZ)-induced diabetic mice. We found that intake of NYT decreased the serum glucose level and increased insulin sensitivity in STZ-induced diabetic mice. NYT treatment also improved acidification of the interstitial fluid around skeletal muscles found in STZ-induced diabetic mice, while the interstitial fluid acidification has been reported to cause insulin resistance. Furthermore, in the proximal colon of STZ-induced diabetic mice, NYT treatment showed a tendency to increase the expression of sodium-coupled monocarboxylate transporter 1 (SMCT1), which has ability to absorb weak organic acids (pH buffer molecules) resulting in improvement of the interstitial fluid acidification. Based on these observations, the present study suggests that NYT is a useful formula to improve hyperglycemia and insulin resistance via elevation of interstitial fluid pH in diabetes mellitus, which might be caused by increased absorption of pH buffer molecules (SMCT1 substrates, weak organic acids) mediated through possibly elevated SMCT1 expression in the proximal colon.
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http://dx.doi.org/10.3389/fnut.2018.00112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277701PMC
November 2018

Ninjinyoeito Improves Behavioral Abnormalities and Hippocampal Neurogenesis in the Corticosterone Model of Depression.

Front Pharmacol 2018 26;9:1216. Epub 2018 Oct 26.

Pharmacological Department of Herbal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Ninjinyoeito (NYT), a traditional Chinese medicine consisting of 12 herbs, is designed to improve fatigue, cold limbs, anorexia, night sweats, and anemia. Recently, NYT was reported to improve cognitive outcome and depression in patients with Alzheimer's disease. However, little is known about how NYT alleviates depression and cognitive dysfunction. In this study, we investigated the effects and mechanisms of NYT in a corticosterone (CORT)-induced model of depression. Chronic NYT treatment ameliorated the depressive-like behaviors induced by CORT treatment in three types of behavioral tests. In addition, chronic NYT treatment also improved memory disruptions induced by CORT in both the Y-maze and novel object recognition tests, without affecting locomotor activity. Furthermore, we also showed that NYT treatment attenuated the CORT-induced reduction in cell proliferation and immature neuronal cell numbers in mouse hippocampal dentate gyrus. These results suggest that NYT has therapeutic effects on CORT-induced behavioral abnormalities and inhibition of hippocampal neurogenesis.
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http://dx.doi.org/10.3389/fphar.2018.01216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6212574PMC
October 2018

Feasibility of early multimodal interventions for elderly patients with advanced pancreatic and non-small-cell lung cancer.

J Cachexia Sarcopenia Muscle 2019 02 18;10(1):73-83. Epub 2018 Oct 18.

Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Background: Combinations of exercise and nutritional interventions might improve the functional prognosis for cachectic cancer patients. However, high attrition and poor compliance with interventions limit their efficacy. We aimed to test the feasibility of the early induction of new multimodal interventions specific for elderly patients with advanced cancer Nutrition and Exercise Treatment for Advanced Cancer (NEXTAC) programme.

Methods: This was a multicentre prospective single-arm study. We recruited 30 of 46 screened patients aged ≥70 years scheduled to receive first-line chemotherapy for newly diagnosed, advanced pancreatic, or non-small-cell lung cancer. Physical activity was measured using pedometers/accelerometer (Lifecorder , Suzuken Co., Ltd., Japan). An 8 week educational intervention comprised three exercise and three nutritional sessions. The exercise interventions combined home-based low-intensity resistance training and counselling to promote physical activity. Nutritional interventions included standard nutritional counselling and instruction on how to manage symptoms that interfere with patient's appetite and oral intake. Supplements rich in branched-chain amino acids (Inner Power , Otsuka Pharmaceutical Co., Ltd., Japan) were provided. The primary endpoint of the study was feasibility, which was defined as the proportion of patients attending ≥4 of six sessions. Secondary endpoints included compliance and safety.

Results: The median patient age was 75 years (range, 70-84). Twelve patients (40%) were cachectic at baseline. Twenty-nine patients attended ≥4 of the six planned sessions (96.7%, 95% confidence interval, 83.3 to 99.4). One patient dropped out due to deteriorating health status. The median proportion of days of compliance with supplement consumption and exercise performance were 99% and 91%, respectively. Adverse events possibly related to the NEXTAC programme were observed in five patients and included muscle pain (Grade 1 in two patients), arthralgia (Grade 1 in one patient), dyspnoea on exertion (Grade 1 in one patient), and plantar aponeurositis (Grade 1 in one patient).

Conclusions: The early induction of multimodal interventions showed excellent compliance and safety in elderly patients with newly diagnosed pancreatic and non-small-cell lung cancer receiving concurrent chemotherapy. We are now conducting a randomized phase II study to measure the impact of these interventions on functional prognosis.
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http://dx.doi.org/10.1002/jcsm.12351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438328PMC
February 2019

The Effectiveness of Cognitive Behavioral Therapy With Mindfulness and an Internet Intervention for Obesity: A Case Series.

Front Nutr 2018 27;5:56. Epub 2018 Jun 27.

Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

It is difficult for obese (body mass index of more than 30) and overweight (body mass index of 25-30) people to reduce and maintain their weight. The aim of this case series was to examine the effectiveness of a new cognitive behavioral therapy (CBT) program that combines mindfulness exercises (e.g., the raisin exercise and breathing exercises) and an online intervention to prevent dropout and subsequent weight gain in overweight participants. This case series included three participants, for whom previous weight reduction programs had been unsuccessful. All participants completed the program (60-min, group sessions provided weekly for 9 weeks) and an 18-month follow-up assessment. Results showed that all participants succeeded in losing weight (loss ranged from 5.30 to 8.88% of their total body weight). Although rebound weight gain is commonly observed in the first year following initial weight loss, the follow-up assessment showed that participants achieved further weight loss during the 18-month follow-up period. These results suggest that a CBT program that comprises mindfulness and an online intervention may be an effective method for weight loss and maintenance, and may prevent dropout in obese and overweight individuals.

Trial Registration: This case series was registered at www.umin.ac.jp with identifier UMIN000029664.
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http://dx.doi.org/10.3389/fnut.2018.00056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036279PMC
June 2018

The Role of Ghrelin and Ghrelin Signaling in Aging.

Int J Mol Sci 2017 Jul 12;18(7). Epub 2017 Jul 12.

Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan.

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.
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http://dx.doi.org/10.3390/ijms18071511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536001PMC
July 2017

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

Mol Genet Metab 2017 04 14;120(4):306-316. Epub 2017 Feb 14.

Department of Molecular Metabolism and Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan.

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.
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http://dx.doi.org/10.1016/j.ymgme.2017.02.004DOI Listing
April 2017

A perspective on metabolic surgery from a gastroenterologist.

J Pharmacol Sci 2017 Feb 19;133(2):61-64. Epub 2017 Jan 19.

Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Rd., Taipei, 112, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, 155, Section 2, Linong Street, Taipei, 112, Taiwan; Taiwan Association for the Study of Small Intestinal Diseases, 5, Fuxing Street, Guishan District, Taoyuan, 33305, Taiwan. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jphs.2017.01.001DOI Listing
February 2017

A Sexually Dimorphic Area of the Dorsal Hypothalamus in Mice and Common Marmosets.

Endocrinology 2016 Dec 11;157(12):4817-4828. Epub 2016 Oct 11.

Division of Life Science (Y.M., C.K.-T.-T., T.T., H.I., I.S., T.S., S.T.), Graduate School of Science and Engineering, Saitama University, Sakura-ku, Saitama 338-8570, Japan; Drug Safety Research Laboratories (S.Y., F.I., A.A.), Shin Nippon Biomedical Laboratories, Ltd, Kagoshima 891-1394, Japan; Department of Anatomy and Neurobiology (K.-I.M., M.K.), Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; Department of Psychosomatic Internal Medicine (G.K., A.I.), Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; and Laboratory of Behavioral Neuroendocrinology (S.O.), University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.

We found a novel sexually dimorphic area (SDA) in the dorsal hypothalamus (DH) of mice. The SDA-DH was sandwiched between 2 known male-biased sexually dimorphic nuclei, the principal nucleus of the bed nucleus of the stria terminalis and the calbindin-sexually dimorphic nucleus, and exhibited a female-biased sex difference in neuronal cell density. The density of neurons in the SDA-DH was increased in male mice by orchidectomy on the day of birth and decreased in female mice by treatment with testosterone, dihydrotestosterone, or estradiol within 5 days after birth. These findings indicate that the SDA-DH is defeminized under the influence of testicular testosterone, which acts via both directly by binding to the androgen receptor, and indirectly by binding to the estrogen receptor after aromatization. We measured the activity of SDA-DH neurons with c-Fos, a neuronal activity marker, in female mice during maternal and sexual behaviors. The number of c-Fos-expressing neurons in the SDA-DH of female mice was negatively correlated with maternal behavior performance. However, the number of c-Fos-expressing neurons did not change during female sexual behavior. These findings suggest that the SDA-DH contains a neuronal cell population, the activity of which decreases in females exhibiting higher performance of maternal behavior, but it may contribute less to female sexual behavior. Additionally, we examined the brain of common marmosets and found an area that appears to be homologous with the mouse SDA-DH. The sexually dimorphic structure identified in this study is not specific to mice and may be found in other species.
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http://dx.doi.org/10.1210/en.2016-1428DOI Listing
December 2016

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

Zoolog Sci 2016 Oct;33(5):497-504

2 Area of Life-NanoBio, Division of Strategy Research, Graduate School of Science and Engineering,Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama 338-8570, Japan.

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.
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http://dx.doi.org/10.2108/zs160020DOI Listing
October 2016

A Role of Ginseng and Its Constituents in the Treatment of Central Nervous System Disorders.

Evid Based Complement Alternat Med 2016 18;2016:2614742. Epub 2016 Aug 18.

Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan.

Ginseng, a perennial plant belonging to the Panax genus of the Araliaceae family, has been used in China, Korea, and Japan as a traditional herbal medicine for thousands of years. Ginseng is recorded to have exhibited a wide variety of beneficial pharmacological effects and has become a popular and worldwide known health supplement and drug. The protective effects of ginseng on central nervous system are discussed in this review. Ginseng species and ginsenosides and their intestinal metabolism and bioavailability are concisely introduced. The molecular mechanisms of the effects of ginseng on central nervous system, mainly focused on the neuroprotection properties of ginseng, memory, and learning enhanced properties, and the effects on neurodegenerative disorders are presented. Thus, ginseng and its constituents are of potential merits in the treatment of cerebral disorders.
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http://dx.doi.org/10.1155/2016/2614742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5007341PMC
September 2016

Guidelines for parenteral fluid management for terminal cancer patients.

Jpn J Clin Oncol 2016 Nov;46(11):986-992

Department of Pain Management & Palliative Care Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.

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.
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http://dx.doi.org/10.1093/jjco/hyw105DOI Listing
November 2016

Increased Ghrelin but Low Ghrelin-Reactive Immunoglobulins in a Rat Model of Methotrexate Chemotherapy-Induced Anorexia.

Front Nutr 2016 26;3:23. Epub 2016 Jul 26.

Nutrition, Gut and Brain Laboratory, INSERM UMR1073, Rouen, France; Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Normandy University, Rouen, France.

Background And Aims: Cancer chemotherapy is commonly accompanied by mucositis, anorexia, weight loss, and anxiety independently from cancer-induced anorexia-cachexia, further aggravating clinical outcome. Ghrelin is a peptide hormone produced in gastric mucosa that reaches the brain to stimulate appetite. In plasma, ghrelin is protected from degradation by ghrelin-reactive immunoglobulins (Ig). To analyze possible involvement of ghrelin in the chemotherapy-induced anorexia and anxiety, gastric ghrelin expression, plasma levels of ghrelin, and ghrelin-reactive IgG were studied in rats treated with methotrexate (MTX).

Methods: Rats received MTX (2.5 mg/kg, subcutaneously) for three consecutive days and were killed 3 days later, at the peak of anorexia and weight loss. Control rats received phosphate-buffered saline. Preproghrelin mRNA expression in the stomach was analyzed by in situ hybridization. Plasma levels of ghrelin and ghrelin-reactive IgG were measured by immunoenzymatic assays and IgG affinity kinetics by surface plasmon resonance. Anxiety- and depression-like behaviors in MTX-treated anorectic and in control rats were evaluated in the elevated plus-maze and the forced-swim test, respectively.

Results: In MTX-treated anorectic rats, the number of preproghrelin mRNA-producing cells was found increased (by 51.3%, p < 0.001) as well were plasma concentrations of both ghrelin and des-acyl-ghrelin (by 70.4%, p < 0.05 and 98.3%, p < 0.01, respectively). In contrast, plasma levels of total IgG reactive with ghrelin and des-acyl-ghrelin were drastically decreased (by 87.2 and 88.4%, respectively, both p < 0.001), and affinity kinetics of these IgG were characterized by increased small and big Kd, respectively. MTX-treated rats displayed increased anxiety- but not depression-like behavior.

Conclusion: MTX-induced anorexia, weight loss, and anxiety are accompanied by increased ghrelin production and by a decrease of ghrelin-reactive IgG levels and affinity binding properties. Such changes of ghrelin-reactive IgG may underlie their decreased ghrelin-transporting capacities compromising ghrelin orexigenic and anxiolytic effects and contributing to chemotherapy-induced loss of appetite.
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http://dx.doi.org/10.3389/fnut.2016.00023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4960292PMC
August 2016

Rosmarinic acid ameliorates hyperglycemia and insulin sensitivity in diabetic rats, potentially by modulating the expression of PEPCK and GLUT4.

Drug Des Devel Ther 2016 7;10:2193-202. Epub 2016 Jul 7.

Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Background: Rosmarinic acid (RA) is a natural substance that may be useful for treating diabetes mellitus. The present study investigated the effects of RA on glucose homeostasis and insulin regulation in rats with streptozocin (STZ)-induced type 1 diabetes or high-fat diet (HFD)-induced type 2 diabetes.

Methods: Glucose homeostasis was determined using oral glucose tolerance tests and postprandial glucose tests, and insulin activity was evaluated using insulin tolerance tests and the homeostatic model assessment for insulin resistance. Additionally, the protein expression levels of PEPCK and GLUT4 were determined using Western blot analysis.

Results: RA administration exerted a marked hypoglycemic effect on STZ-induced diabetic rats and enhanced glucose utilization and insulin sensitivity in HFD-fed diabetic rats. These effects of RA were dose-dependent. Meanwhile, RA administration reversed the STZ- and HFD-induced increase in PEPCK expression in the liver and the STZ- and HFD-induced decrease in GLUT4 expression in skeletal muscle.

Conclusion: RA reduces hyperglycemia and ameliorates insulin sensitivity by decreasing PEPCK expression and increasing GLUT4 expression.
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http://dx.doi.org/10.2147/DDDT.S108539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940010PMC
May 2017

[Programs for Continuing Medical Education: A session; 8. Stress and internal disease].

Authors:
Akio Inui

Nihon Naika Gakkai Zasshi 2016 Mar;105(3):464-70

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http://dx.doi.org/10.2169/naika.105.464DOI Listing
March 2016