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Abstract 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

IntroductionThe 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 methodsSex- 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.ResultsIn 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.ConclusionOur 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.

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 (β = 0.49, SE = 0.06, t = 7.66, 95% CI: 0.36 to 0.62, p = 0.000) and KCL (β = 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.

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.

Abstract Fractalkine is one of the CX3C chemokine family, and it is widely expressed in the brain including the hypothalamus. In the brain, fractalkine is expressed in neurons and binds to a CX3C chemokine receptor 1 (CX3CR1) in microglia. The hypothalamus regulates energy homeostasis of which dysregulation is associated with obesity. Therefore, we examined whether fractalkine-CX3CR1 signalling involved in regulating food intake and hypothalamic inflammation associated with obesity pathogenesis. In the present study, fractalkine significantly reduced food intake induced by several experimental stimuli and significantly increased brain-derived neurotrophic factor (BDNF) mRNA expression in the hypothalamus. Moreover, tyrosine receptor kinase B (TrkB) antagonist impaired fractalkine-induced anorexigenic actions. In addition, compared with wild-type mice, CX3CR1-deficient mice showed a significant increase in food intake and a significant decrease in BDNF mRNA expression in the hypothalamus. Mice fed a high-fat diet (HFD) for 16 weeks showed hypothalamic inflammation and reduced fractalkine mRNA expression in the hypothalamus. Intracerebroventricular administration of fractalkine significantly suppressed HFD-induced hypothalamic inflammation in mice. HFD intake for 4 weeks caused hypothalamic inflammation in CX3CR1-deficient mice, but not in wild-type mice. These findings suggest that fractalkine-CX3CR1 signalling induces anorexigenic actions via activation of the BDNF-TrkB pathway and suppresses HFD-induced hypothalamic inflammation in mice.

Background: Better prognostic biomarkers for oral squamous cell carcinoma (OSCC) must be developed, particularly within the realm of clinically and frequently administered tests, to advise appropriate clinical therapy and follow-up. In this study, we retrospectively investigated which of the several inflammation-nutrition indicators might predict the prognosis of patients with OSCC.Methods: The preoperative neutrophil-lymphocyte ratio (NLR), lymphocyte–monocyte ratio (LMR), platelet–lymphocyte ratio (PLR), CRP-albumin ratio (CAR), Glasgow prognostic score (GPS), modified GPS (mGPS), prognostic nutritional index (PNI), controlling nutrition status (CONUT), and modified CONUT (mCONUT) were retrospectively evaluated using blood samples collected 1–5 days before surgery. To estimate the effect on the prognosis of tumor progression, the mean values of the markers between stages I/II and III/IV were used for subgroup analysis. The multivariate Cox proportional hazards model included all independent variables significantly associated with survival in the univariate analysis to determine the independent variables.Results: A total of 112 patients (69 males and 43 females) with primary OSCC who underwent surgical treatment at our hospital were included. There were statistically significant differences in the mean values of monocytes, platelets, and albumin between stages I/II and III/IV. According to the multivariate Cox proportional hazards regression, a low PNI was associated with shorter overall survival (OS) and disease-free survival (DFS); women were associated with shorter DFS.Conclusion: The pretreatment PNI had excellent predictive value for the 5-year OS and DFS of patients with OSCC. Future large-scale prospective studies with a high sample size are needed to verify our findings in OSCC patients.

With the recent aging of society, the prevention of frailty has become an important issue because people desire both a long and healthy lifespan. Klotho-hypomorphic (kl/kl) mice are known to show phenotypes of premature aging. Ninjin’yoeito (NYT) is a traditional Japanese Kampo medicine used to treat patients with vulnerable constitution, fatigue or physical exhaustion caused by aging and illness. Recent studies have reported the potential efficacy of NYT against frailty. We therefore evaluated the effect of NYT on the gait function, activity, the histopathological status of organs and survival using kl/kl mice as a model of aging-related frailty. Two sets of 28-day-old male kl/kl mice were assigned to the vehicle (non-treated; NT), 3% or 5% NYT dietary groups. One set of groups (NT, n = 18; 3% NYT, n = 11; 5% NYT, n = 11) was subjected to the analysis of free walking, rotarod, and spontaneous activity tests at approximately 58 days old. Thereafter, we measured triceps surae muscles weight and myofiber cross-sectional area (CSA), and quantified its telomere content. In addition, we evaluated bone strength and performed histopathological examinations of organs. Survival was measured in the second set of groups (NT, 3% NYT and 5% NYT group, n = 8 each). In the walking test, several indicators such as gait velocity were improved in the NYT 3% group. Similar results were obtained for the latency to fall in the rotarod test and spontaneous motor activity. Triceps muscle mass, CSA and its telomere content were significantly improved in the NYT 3% group. Bone density, pulmonary alveolus destruction and testicular atrophy were also significantly improved in the NYT 3% group. Survival rate and body weight were both significantly improved in the NYT3% group compared with those in the NT group. Continuous administration of NYT from the early stage of aging improved not only gait performance, but also the survival in the aging-related frailty model. This effect may be associated with the improvements in aging-related organ changes such as muscle atrophy. Intervention with NYT against the progression of frailty may contribute to a longer, healthier life span among the elderly individuals.

Sociability is an essential component of the linkage structure in human and other vertebrate communication. Low sociability is defined as a poor social approach, including social withdrawal and apathy, and is implicated in a variety of psychiatric disorders. Ninjinyoeito (NYT), a traditional Japanese herbal medicine, has been used in the medical field. This study aimed to determine the effect of NYT on low sociality in NPY-KO zebrafish. NPY-KO zebrafish were fed a 3% NYT-supplemented diet for 4 days and subjected to behavioral tests. In the mirror test, NPY-KO zebrafish fed a control diet showed avoidance behavior toward their mirror counterparts. In contrast, the treatment of NPY-KO zebrafish with NYT significantly increased their interaction with their counterparts in the mirror. In addition, a 3-chambers test was conducted to confirm the effect of NYT on the low sociality of NPY-KO zebrafish. NPY-KO zebrafish fed the control diet showed less interaction with fish chambers, while NYT treatment increased the interaction. Phosphorylation of ERK, a marker of neuronal activity, was significantly reduced in the whole brain of NYT-fed NPY-KO zebrafish, compared to the control diet. NYT treatment significantly suppressed hypothalamic-pituitary-adrenal-related genes (gr, pomc, and crh) and sympathetic-adrenal-medullary-related genes (th1, th2, and cck) in NPY-KO zebrafish. NYT administration significantly reduced mRNA levels of gad1b compared to the control diet, suggesting the involvement of GABAergic neurons in NYT-induced improvement of low sociability. Furthermore, the expression of CREB was suppressed when NPY-KO zebrafish were fed NYT. Next, we attempted to identify the effective herb responsible for the NYT-induced improvement of low sociability. NPY-KO zebrafish were fed an experimental diet containing the target herb for 4 days, and its effect on sociability was evaluated using the 3-chambers test. Results showed that Cinnamon Bark and Polygala Root treatments significantly increased time spent in the fish tank area compared to the control diet, while the other 10 herbs did not. We confirmed that these two herbs suppressed the activity of HPA-, SAM-, and GABAergic neurons, as well as NYT-treated zebrafish, accompanied by downregulation of CREB signaling. This study suggests the potential use of NYT as a drug for sociability disorders.

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.

Background: Red rice koji (RRK), prepared by growing Monascus 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.

The effects of degalactosylated whey protein on lipopolysaccharide (LPS)-induced inflammatory responses in mice were observed in comparison with intact whey protein. Intraperitoneal administration of both intact and degalactosylated whey proteins for 5 days did not affect body weight and food intake in mice. On day 6, intraperitoneal administration of LPS induced a marked decrease in body weight 4 h later. The LPS-induced decrease in body weight was significantly suppressed by the administration of degalactosylated whey protein, but not intact whey protein. Administration of LPS also significantly increase plasma tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels, which were significantly suppressed by the administration of degalactosylated whey protein, but not intact whey protein. Moreover, the application of degalactosylated whey protein to RAW264.7 cells significantly reduced mRNA expression of toll-like receptor 4 (TLR4) and significantly increased mRNA expression of mitogen-activated protein kinase phosphatase-1 (MKP-1). The marked increased expression of TNF-α and IL-1β in response to LPS in RAW264.7 cells was significantly suppressed by the application of degalactosylated whey protein. These results suggest that degalactosylated whey protein suppresses the effects of LPS in part by decreasing in TLR4 and increasing in MKP-1.

Abstract 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.

Atractylenolide-III (AIII), a sesquiterpene compound isolated from the rhizome of Atractylodes macrocephala, has been reported to have anti-inflammatory effects in the peripheral organs. However, its effects on brain inflammation remain elusive. The present study investigated the effects of AIII on the response to lipopolysaccharide (LPS) in mouse microglia and clarified the underlying mechanism. In this study, treatment of MG6 cells with AIII (100 μM) significantly decreased the mRNA expression and protein levels of toll-like receptor 4 (TLR4). In addition, pretreatment of MG6 cells and primary cultured microglia cells with AIII (100 μM) significantly decreased the mRNA expression and protein levels of tumor necrosis factor-α, interleukin-1β, interleukin-6, inducible nitric oxide synthase, and cyclooxygenase-2 induced by LPS (5 ng/mL) without cytotoxicity. Subsequently, pretreatment with AIII significantly suppressed the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun NH2-terminal kinase (JNK) after LPS stimulation in MG6 cells. These results showed that AIII downregulated TLR4 expression, leading to suppression of the p38 MAPK and JNK pathways, which in turn inhibited the production of pro-inflammatory cytokines and enzymes in LPS-stimulated microglia. Our findings, therefore, suggest the potential for AIII as a therapeutic agent for the treatment of brain inflammation, particularly in microglia-associated inflammation.

Abstract 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.

Abstract 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.

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.

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 Ca2+ concentration ([Ca2+]i) 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 [Ca2+]i increases in ghrelin-unresponsive vs. ghrelin-responsive NPY neurons. Single ARC neurons were subjected to [Ca2+]i measurement and subsequent immunostaining for NPY. Ghrelin failed to increase [Ca2+]i in 42% of ARC NPY neurons. Ninjin'yoeito (10 μg/ml)-induced increases in [Ca2+]i were abolished in Ca2+ free condition in ghrelin-responsive and ghrelin-unresponsive ARC NPY neurons. Ninjin'yoeito-induced [Ca2+]i increases were inhibited by N-type Ca2+ channel blocker ω-conotoxin in the majority (17 of 20), while by L-type Ca2+ channel blocker nitrendipine in the minority (2 of 23), of ghrelin-responsive neurons. In contrast, Ninjin'yoeito-induced [Ca2+]i 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 Ca2+ channels in the majority of ghrelin-responsive and ghrelin-unresponsive neurons, respectively, to increase [Ca2+]i. We suggest ARC N- and L-type Ca2+ channels as potential targets for activating, respectively, ghrelin-responsive, and unresponsive NPY neurons to treat anorexia.

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.

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.

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.

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.

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.

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, S.C.) 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

Background. Alcohol consumption is a lifestyle factor associated with type 2 diabetes. This relationship is reportedly different depending on the type of alcohol beverage. The purpose of this study was to examine the acute effects of traditional Japanese alcohol beverages on biochemical parameters, physical and emotional state, and sleep patterns. Methods. Six healthy subjects (three men and three women; age, 28.8 ± 9.5 years; body mass index, 21.4 ± 1.6 kg/m2) consumed three different types of alcohol beverages (beer, shochu, and sake, each with 40 g ethanol) or mineral water with dinner on different days in the hospital. Blood samples were collected before and 1, 2, and 12 h after drinking each beverage, and assessments of physical and emotional state were administered at the same time. In addition, sleep patterns and brain waves were examined using polysomnography. Results. Blood glucose levels at 1 h and the 12-h area under the curve (AUC) value after drinking shochu were significantly lower than that with water and beer. The 12-h blood insulin AUC value after drinking shochu was significantly lower than that with beer. Blood glucose × insulin level at 1 h and the 2-h blood glucose × insulin AUC value with shochu were significantly lower than that with beer. The insulinogenic indexes at 2 h with beer and sake, but not shochu, were significantly higher than that with water. The visual analogue scale scores of physical and emotional state showed that the tipsiness levels with beer, shochu, and sake at 1 h were significantly higher than that with water. These tipsiness levels were maintained at 2 h. The polysomnography showed that the rapid eye movement (REM) sleep latency with shochu and sake were shorter than that with water and beer. Conclusions. Acute consumption of alcohol beverages with a meal resulted in different responses in postprandial glucose and insulin levels as well as REM sleep latency. Alcohol beverage type should be taken into consideration for people with impaired glucose tolerance.

Adipocyte-derived leptin is a hormone associated with the regulation of energy homeostasis, including glucose metabolism. Hyperleptinemia, induced by the consumption of energy-enriched diets, inhibits leptin transport across the blood-brain barrier, and thereby produces leptin insufficiency in the hypothalamus. As a result of sustained leptin insufficiency, the hypothalamic restraint on pancreatic insulin secretion is lost. Additionally, both glucose metabolism and energy expenditure are also diminished, and both type 1 and type 2 diabetes are induced. A replication-deficient recombinant adeno-associated virus vector engineered to encode the leptin gene (rAVV-LEP) has been used in models of diabetes as a novel therapeutic approach. After rAVV-LEP injection in ob/ob mice, hypothalamic leptin expression was increased, body weight was suppressed, and hyperinsulinemia was ameliorated. Additionally injection of rAVV-LEP into the hypothalamus suppressed the expression of orexigenic neuropeptide Y (NPY) and enhanced anorexigenic pro-opiomelanocortin (POMC) in the arcuate nucleus (ARC) in rats. It is proposed that central leptin gene therapy should be tested clinically to reduce the worldwide epidemic of obesity, diabetes, and shortened life span. In this article, the information has been assembled from published review articles on this topic.

Leptin has a crucial role in regulating food intake and maintaining metabolic homeostasis. Although little is known about the process of leptin secretion, insulin, which has an important role in the metabolism of glucose and lipids, is believed to regulate leptin secretion through a posttranscriptional mechanism in the short term, and via glucose metabolism in the long term. The gastric mucosa secretes leptin, but this mechanism has not been completely elucidated. Understanding the mechanism of insulin-regulated leptin secretion could lead to the development of new treatment methods for obesity and its comorbidities, which are serious public health concerns.

Objective. Allantoin is the primary active compound in yams (Dioscorea spp.). Recently, allantoin has been demonstrated to activate imidazoline 3 (I3) receptors located in pancreatic tissues. Thus, the present study aimed to investigate the role of allantoin in the effect to improve damage induced in pancreatic β-cells by streptozotocin (STZ) via the I3 receptors.Research Design and Methods. The effect of allantoin on STZ-induced apoptosis in pancreatic β-cells was examined using the ApoTox-Glo triplex assay, live/dead cell double staining assay, flow cytometric analysis, and Western blottings. The potential mechanism was investigated using KU14R: an I3 receptor antagonist, and U73122: a phospholipase C (PLC) inhibitor. The effects of allantoin on serum glucose and insulin secretion were measured in STZ-treated rats.Results. Allantoin attenuated apoptosis and cytotoxicity and increased the viability of STZ-induced β-cells in a dose-dependent manner; this effect was suppressed by KU14R and U73112. Allantoin decreased the level of caspase-3 and increased the level of phosphorylated B-cell lymphoma 2 (Bcl-2) expression detected by Western blotting. The improvement in β-cells viability was confirmed using flow cytometry analysis. Daily injection of allantoin for 8 days in STZ-treated rats significantly lowered plasma glucose and increased plasma insulin levels. This action was inhibited by treatment with KU14R.Conclusion. Allantoin ameliorates the damage of β-cells induced by STZ. The blockade by pharmacological inhibitors indicated that allantoin can activate the I3 receptors through a PLC-related pathway to decrease this damage. Therefore, allantoin and related analogs may be effective in the therapy for β-cell damage.

Oxidative stress is involved in cancer development. Hydrogen (H2) is a potent antioxidant and exhibits anti-inflammatory and potentially anticancer-like activities. This study aimed to investigate the role of H2 incombination with 5-fluorouracil (5-FU) in cancer treatment both in vitro and in vivo using the colon 26 cell line. The survival rate was determined using the Kaplan–Meier survival test, and cell viability was assessed using cell viability imaging kit and the MTT assay, and activation of the cell apoptosis pathway (Phosphorylated adenosine monophosphate activated protein kinase (p-AMPK), Apoptosis-inducing factor (AIF) and Caspase 3) were characterized by western blots. Hydrogen water administration improved the survival of mice with colon 26-induced cancer. Furthermore, hydrogen water enhanced cell apoptosis in cancer cells, resulting in a marked increase in the expression of p-AMPK, AIF and Caspase 3 in colon 26 cells. Hydrogen water also increased the inhibitory effect of 5-FU on colon 26 cells with spect to cell survival rate and anticancer functions. Additionally, high-content hydrogen water exhibited stronger antioxidative and anticancer activity than did the natural hydrogen water. In conclusion, high-content hydrogen water can inhibit colon cancer, particularly in combination with 5-fluorouracil.

Rikkunshito, a traditional Japanese (Kampo) medicine, has been used to treat upper gastrointestinal disorders such as functional dyspepsia and gastroesophageal reflux. This study investigated the exposure and pharmacokinetics of the ingredients of rikkunshito in healthy volunteers.First, an exploratory nonrandomized, open-label, one-period, noncrossover study using four healthy Japanese volunteers to detect 32 typical ingredients of rikkunshito in plasma and urine. As a result, 18 or 21 of 32 ingredients was detected in plasma or urine samples after oral administration of rikkunshito (7.5 g/day). Furthermore, a randomized, open-label, three-arm, three-period, crossover study using 21 subjects was conducted to determine the amounts of exposure and pharmacokinetic parameters of nine ingredients derived from rikkunshito (atractylodin, atractylodin carboxylic acid, pachymic acid, 3,3',4',5,6,7,8-heptamethoxyflavone, naringenin, nobiletin, liquiritigenin, isoliquiritigenin, and 18β-glycyrrhetinic acid) after oral administration of rikkunshito at three different doses (2.5, 5.0, or 7.5 g/day) during each period. The pharmacokinetic profiles of the nine ingredients in plasma were characterized. The geometric means (95% confidence interval) for the Cmax of the ingredients at a dose of 7.5 g were 1570 (1210-2040), 14,300 (12,200-16,800), 91.0 (71.8-115), 105 (75.6-144), 1150 (802-1650), 35.9 (24.6-52.5), 800 (672-952), 42.8 (30.4-60.3), and 55,600 (39,600-78,100) pg/mL, respectively, and for the AUC0-last were 1760 (1290-2390), 12700 (11,100-14,600), 1210 (882-1650), 225 (157-322), 4630 (2930-7320), 35.7 (20.4-62.7), 4040 (3260-5010), 122 (88.2-168), and 832,000 (628,000-1,100,000) pg·h/mL respectively.We identified the ingredients of rikkunshito that are absorbed in humans. Furthermore, we determined the pharmacokinetics of nine ingredients derived from rikkunshito. This information will be useful for elucidating the pharmacological effects of rikkunshito.Japan Pharmaceutical Information Center #CTI-121801 and -142522.

Rice koji is considered a readily accessible functional food that may have health-promoting effects. We investigated whether white, yellow, and red koji have the anti-obesity effect in C57BL/6J mice fed a high-fat diet (HFD), which is a model for obesity. Mice were fed HFD containing 10% (w/w) of rice koji powder or steamed rice for 4 weeks. Weight gain, epididymal white adipose tissue, and total adipose tissue weight were significantly lower in all rice koji groups than in the HFD-rice group after 4 weeks. Feed efficiency was significantly reduced in the yellow koji group. Blood glucose levels were significantly lower in the white and red koji groups with HOMA-R and leptin levels being reduced in the white koji group. White and red koji increased glucose uptake and GLUT4 protein expression in L6 myotube cells. These results showed that all rice koji have the anti-obesity or anti-diabetes effects although the mechanisms may differ depending on the type of rice koji consumed.

BACKGROUND AND AIMS: Phosphatase and tensin homolog (PTEN) is a phosphoinositide phosphatase that regulates crucial cellular functions, including insulin signaling, lipid and glucose metabolism, as well as survival and apoptosis. Silymarin is the active ingredient in milk thistle and exerts numerous effects through the activation of PTEN. However, the effect of silymarin on the development of insulin resistance remains unknown. METHODS: Wistar rats fed fructose-rich chow or normal chow were administered oral silymarin to identify the development of insulin resistance using the homeostasis model assessment of insulin resistance and hyperinsulinemic- euglycemic clamping. Changes in PTEN expression in skeletal muscle and liver were compared using western blotting analysis. Further investigation was performed in L6 cells to check the expression of PTEN and insulin-related signals. PTEN deletion in L6 cells was achieved by small interfering ribonucleic acid transfection. RESULTS: Oral administration of silymarin at a dose of 200 mg/kg once daily induced insulin resistance in normal rats and enhanced insulin resistance in fructose-rich chow-fed rats. An increase of PTEN expression was observed in the skeletal muscle and liver of rats with insulin resistance. A decrease in the phosphorylation of Akt in L6 myotube cells, which was maintained in a high-glucose condition, was also observed. Treatment with silymarin aggravated high-glucose-induced insulin resistance. Deletion of PTEN in L6 cells reversed silymarin-induced impaired insulin signaling and glucose uptake. CONCLUSIONS: Silymarin has the ability to disrupt insulin signaling through increased PTEN expression. Therefore, silymarin should be used carefully in type-2 diabetic patients.

Musclin is a novel skeletal muscle-derived secretory factor found in the signal sequence trap of mouse skeletal muscle cDNAs. Musclin possesses a region homologous to the natriuretic peptide family. Thus, musclin is found to bind with the natriuretic peptide clearance receptors. However, the role of musclin in vascular regulation remains unclear. In this study, we aim to investigate the direct effect of musclin on vascular tone and to analyze its role in hypertension using the spontaneously hypertensive rats (SHR). In aortic strips isolated from SHR, musclin induced contractions in a dose-dependent manner. We found that the musclin-induced vasoconstriction was more marked in SHR than in normal rats (WKY). Moreover, this contraction was reduced by blockade of natriuretic peptide receptor C using the ab14355 antibody. Therefore, mediation of the natriuretic peptide receptor in musclin-induced vasoconstriction can be considered. In addition, similar to the natriuretic peptide receptor, expression of the musclin gene in blood vessels was higher in SHR than in WKY. Injection of musclin markedly increased the blood pressure in rats that can be inhibited by anti-musclin antibodies. Musclin-induced vasoconstriction was more pronounced in SHR than in WKY as in its expression. Taken together, these results suggest that musclin is involved in blood pressure regulation. The higher expression of musclin in hypertension indicates that musclin could be used as a new target for the treatment of hypertension in the future.

BACKGROUND: Microglia of the central nervous system act as sentinels and rapidly react to infection or inflammation. The pathophysiological role of bone marrow-derived microglia is of particular interest because they affect neurodegenerative disorders and neuropathic pain. The hypothesis of the current study is that chronic psychological stress (chronic PS) induces the infiltration of bone marrow-derived microglia into hypothalamus by means of chemokine axes in brain and bone marrow. METHODS AND FINDINGS: Here we show that bone marrow-derived microglia specifically infiltrate the paraventricular nucleus (PVN) of mice that received chronic PS. Bone marrow derived-microglia are CX3CR1(low)CCR2(+)CXCR4(high), as distinct from CX3CR1(high)CCR2(-)CXCR4(low) resident microglia, and express higher levels of interleukin-1β (IL-1β) but lower levels of tumor necrosis factor-α (TNF-α). Chronic PS stimulates the expression of monocyte chemotactic protein-1 (MCP-1) in PVN neurons, reduces stromal cell-derived factor-1 (SDF-1) in the bone marrow and increases the frequency of CXCR4(+) monocytes in peripheral circulation. And then a chemokine (C-C motif) receptor 2 (CCR2) or a β3-adrenoceptor blockade prevents infiltration of bone marrow-derived microglia in the PVN. CONCLUSION: Chronic PS induces the infiltration of bone marrow-derived microglia into PVN, and it is conceivable that the MCP-1/CCR2 axis in PVN and the SDF-1/CXCR4 axis in bone marrow are involved in this mechanism.

Hydrogen (H(2)) acts as a therapeutic antioxidant. However, there are few reports on H(2) function in other capacities in diabetes mellitus (DM). Therefore, in this study, we investigated the role of H(2) in glucose transport by studying cultured mouse C2C12 cells and human hepatoma Hep-G2 cells in vitro, in addition to three types of diabetic mice [Streptozotocin (STZ)-induced type 1 diabetic mice, high-fat diet-induced type 2 diabetic mice, and genetically diabetic db/db mice] in vivo. The results show that H(2) promoted 2-[(14)C]-deoxy-d-glucose (2-DG) uptake into C2C12 cells via the translocation of glucose transporter Glut4 through activation of phosphatidylinositol-3-OH kinase (PI3K), protein kinase C (PKC), and AMP-activated protein kinase (AMPK), although it did not stimulate the translocation of Glut2 in Hep G2 cells. H(2) significantly increased skeletal muscle membrane Glut4 expression and markedly improved glycemic control in STZ-induced type 1 diabetic mice after chronic intraperitoneal (i.p.) and oral (p.o.) administration. However, long-term p.o. administration of H(2) had least effect on the obese and non-insulin-dependent type 2 diabetes mouse models. Our study demonstrates that H(2) exerts metabolic effects similar to those of insulin and may be a novel therapeutic alternative to insulin in type 1 diabetes mellitus that can be administered orally.

In developed countries, the transition from school to work has radically changed over the past two decades. It has become prolonged, complicated and individualized (Bynner et al., 1997; Walther et al., 2004). Young people used to transition directly from school to stable employment, or with a very short unemployed period. In many European countries, this situation has been changing since the eighties: overall youth unemployment has increased, and many young people experience long periods of unemployment, government training schemes and part-time or temporary jobs. In Japan, this change has taken a decade later to appear, becoming prevalent by the late nineties (Inui, 2003). The transiting process has become not only precarious for young people, but also difficult for society to precisely understand the risks and problems. Traditionally, we have been able to recognize young people's situation by a simple category: in education, employed, in training or unemployed. However, these categories no longer accurately represent young people's state. In Japan, most young people used to move from school directly to full-time employment through the new graduate recruitment system (Inui, 1993). Therefore, in official statistics such as the School Basic Survey, 'employed' includes only those who are in regular employment, while those who are in part-time or temporary work are covered by the categories 'jobless' and 'others'. However, with the increase in non-full-time jobs in the nineties, these categories have become less useful for describing the actual employment conditions of young people. Indeed, this is why, in the late of nineties, the Japanese Ministry of Education changed the category name from 'jobless' to 'others'.

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 crosssectional 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. [ABSTRACT FROM AUTHOR]