Dairy foods are postulated to have beneficial effects on blood pressure, body fat, serum lipids, and the incidence of type 2 diabetes. To evaluate the effects of the consumption of milk and dairy products, we performed a randomized dietary intervention trial for 24 wk in Japanese men, aged 20 to 60 y, with 2 or more components of the metabolic syndrome (Clinical trial registration: UMIN000006353). Subjects were randomized to a control group (n=98) that received dietary intervention focused on weight control supervised by registered dietitians, and a dairy-consumption group (n=102) that received both dietary intervention and regular home dairy delivery of 400 g/d for 24 wk. Co-primary endpoints included waist circumference, blood pressure, fasting blood sugar (FBS), and serum lipids. The dietary intervention decreased energy intake from 2,150 to 1,850 kcal/d in both groups (p<0.01). Mean rates of compliance with the dairy-consumption intervention were over 90%, resulting in increased calcium intake in the dairy-consumption group from 329 to 667 mg/d (p<0.01). Co-primary endpoints improved in both groups, but the degree of improvement was smaller in the dairy-consumption group (one-sided p=0.99). Subgroup analyses specified in the study protocol identified weight and leisure-time physical activity (LTPA) as significant effect modifiers. Differences in changes in systolic blood pressure compared with the control group were 28.0 mmHg (95% CI, 214.0 to 21.9, interaction; p<0.01) in the normal weight group and 25.8 mmHg (211.4 to 20.2, interaction; p=0.02) in the moderate-to-high LTPA group, indicating lower systolic blood pressure in the dairy-consumption group among participants in these subgroups. In conclusion, although effects on the co-primary endpoints of dairy consumption were not shown, dairy consumption lowered systolic blood pressure in the subgroups with normal weight and moderate-to-high LTPA and lowered FBS in the subgroup with normal weight.

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In diabetic patients, glucolipotoxicity induces multiple defects in β-cells. Furthermore, increasing evidence also confirms the direct interaction between the adipocytes and β-cells. The beneficial efficacy of vitamin C (Vc) on β-cells is rarely investigated. In this study, INS-1 832/13 β-cells were cultured with high levels of glucose and free fatty acid (FFA) or cocultured with 3T3-L1 adipocytes in the presence or absence of Vc. Vc decreased glucolipotoxicity-induced cell mass loss by reducing apoptosis and reactive oxidative species (ROS). After treatment with elevated glucose and FFA, β-cell secretion dysfunction was evidenced and was partially improved by 1, 10 and 50 μg/mL Vc treatment. In the coculture system, impaired secretion function was also moderately normalized upon addition of 10 and 50 μg/mL Vc to the coculture medium (p<0.05). Vc at 50 μg/mL significantly (p<0.05) inhibited the fatty acid release from adipocytes to the coculture medium. Meanwhile, the elevated ROS of cocultured β-cells was decreased in the presence of Vc (1 to 50 μg/mL). In both induction methods, intracellular TGs in both β-cells and adipocytes were decreased by Vc treatment; however, Vc did not affect the intracellular insulin level. Moreover, IL-6 and adiponectin levels in the coculture medium remained under the levels of the control group. The positive effects of Vc might be due to the antioxidant capacity and TG inhibitory effect of Vc.

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Thyroid and glucocorticoid hormones and several transcriptional factors such as caudal type homeobox (CDX)-2 and hepatocyte nuclear factor (HNF)-1α are important for the differentiation of small intestinal absorptive cells and the consequent expression of genes related to the digestion/absorption of carbohydrates. In this study, we investigated whether thyroid and glucocorticoid hormones enhanced the expression of lactase-phlorizin hydrolase (LPH) gene, an intestine-specific gene that encodes an enzyme for lactose digestion, in small intestinal stem-like IEC-6 cells co-transfected with CDX-2 and HNF-1α using a retrovirus system. Changes in expression of intestine-specific genes caused by treatment with thyroid and/or glucocorticoid hormones were monitored in empty vector-transfected cells and in CDX-2/HNF-1α co-transfected cells by qRT-PCR. Stable co-transfection with CDX-2 and HNF-1α evoked the expression of the LPH gene in IEC-6 cells. Furthermore, treatment with a thyroid hormone, triiodothyronine, and a glucocorticoid receptor agonist, dexamethasone, significantly enhanced expression of the LPH, CDX-2 and HNF-1α genes in CDX-2/HNF-1α co-transfected IEC-6 cells. These results suggest that thyroid and glucocorticoid hormones synergistically enhance expression of the LPH gene in CDX-2/HNF-1α co-transfected IEC-6 cells.

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Japanese cuisine has provided satisfying meals by fully utilizing the characteristic aroma and taste of katsuodashi (dried bonito broth), though it is not rich in sugars or fats. Katsuodashi is a very basic and indispensable element in Japanese cuisine, and is a hot water extract of katsuobushi (dried bonito). It has been reported that a dextrin solution containing natural dried bonito broth has a significant reinforcement effect, and has been suggested that the olfactory stimulation is important for the reinforcement effect. We examined various source materials for broth and identified an optimal method of aroma extraction by two-bottle choice and conditioned place preference tests in mice. By two-bottle choice tests, a solution containing arabushi (a type of katsuobushi) aroma extract obtained by a supercritical CO₂ extraction method showed a significantly high preference. The conditioned place preference test showed the dashi-taste solution with arabushi supercritical CO₂ extract had a reinforcement effect. Our results suggest that the arabushi extract obtained by supercritical CO₂ extraction contains components responsible for preference and reinforcement effects in mice; it could become conducive to making Japanese cuisine more satisfying and palatable.

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Picolinic acid (PiA) is an endogenous metabolite of tryptophan that has been reported to possess a wide range of physiological actions. We investigated the effects of dietary PiA on the metabolism of tryptophan to nicotinamide in growing rats. Feeding an ordinary diet containing 1% PiA to growing rats (6 wk) caused death within a few days. Toxicity of PiA was higher than that of analogs such as nicotinic acid and quinolinic acid. Feeding an ordinary diet containing 0.05% and 0.1% PiA did not elicit decreased intake of food or loss in body weight. PiA did not affect the in vitro liver activities of quinolinic acid phosphoribosyltransferase or α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSDase, a Zn-dependent enzyme). Concentrations of NAD and NADP in the liver and blood were not affected by PiA. PiA administration did not affect tryptophan metabolites such as anthranilic acid, kynurenic acid, and xanthurenic acid. However, quinolinic acid and subsequent metabolites such as nicotinamide and its catabolites were increased by administration of a diet containing 0.05% PiA but not by a 0.1% PiA diet. These results suggest that the in vivo activity of ACMSDase is controlled by the Zn level. Therefore, a small amount of PiA has a beneficial effect for conversion of tryptophan to nicotinamide, but an excessive amount of PiA can be very toxic.

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We compared the effects of three persimmon cultivars, one nonastringent-type fruit (Fuyu) and two astringent-type fruits (Hiratanenashi and Hachiya), on the lipid and glucose metabolism of high-fat diet-fed mice. Persimmon samples prepared from young fruits of the three cultivars contained around 80% dietary fiber and differed in their bile acid-binding abilities and tannin contents. C57BL/6J mice were fed a modified AIN76 high-fat diet supplemented with 2% of each persimmon sample instead of cellulose for 10 wk. All cultivars significantly accelerated fecal bile acid secretion, depending on the bile acid-binding ability of the cultivars. Hiratanenashi and Hachiya, the cultivars with a strong bile acid-binding ability, prevented any increase in fasting blood glucose and plasma nonesterified fatty acid levels. Hachiya, the cultivar with the highest tannin content, also tended to prevent an increase in plasma non-high-density lipoprotein cholesterol levels. However, Fuyu, the cultivar with the lowest bile acid-binding ability and tannin content, had no effect on lipid or glucose metabolism. These effects linked to expression of the genes related to lipid and energy metabolism, including the cytochrome P450 7A1 gene in the liver and the uncoupling protein 3 gene in the brown adipose tissue. These results indicate that the beneficial effects of these cultivars on lipid and glucose metabolism are closely related to their bile acid-binding ability and tannin content.

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To investigate the effects of Active Hexose Correlated Compound (AHCC) supplementation and the mechanism action of AHCC in patients with alcohol-induced mildly elevated liver enzyme levels, participants were randomly allocated to the placebo, 1 g AHCC, or 3 g AHCC group and took the supplement for 12 wk. Subjects visited the hospital for clinical and biochemical measurements, for examination of adverse events, to return unused supplements, and to obtain their next supplements. Biochemical tests including liver enzymes, a questionnaire survey, and anthropometric measurements were collected at baseline and every 4 wk thereafter. Adherence and adverse events were evaluated. After 12 wk of supplementation, the percentage change in alanine aminotransferase (ALT) level was significantly different between the placebo (4.02±59.07%) and both AHCC groups (1 g AHCC: 223.89±20.59%, 3 g AHCC: 224.09±30.73%) (p=0.04). Serum levels of tumor necrosis factor-α (p<0.05) and interleukin-1β (p<0.01) were significantly lower, while those of adiponectin were higher in both AHCC groups than in the placebo group (p<0.01). AHCC supplementation for 12 wk may improve the levels of liver enzymes and circulating pro-inflammatory and anti-inflammatory cytokines in patients with alcohol-induced liver enzyme elevation with mildly elevated liver enzyme levels.

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The prognosis of patients with hepatocellular carcinoma (HCC) is poor and the development of effective treatments for this malignancy, including combination chemotherapy, is required. This study examined the possible combined inhibitory effects of bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, and acyclic retinoid (ACR), which can prevent the development of HCC, on the growth of Huh7 human HCC cells. Xenograft tumors were produced by subcutaneously injecting Huh7 cells into nude mice. Starting 1 wk after the tumor cell injection, the mice were treated with bevacizumab alone (5 mg/kg body weight, subcutaneous injection, twice a week), ACR alone (given in a diet containing 0.03%), or their combination for 6 wk, and the effects of these regimens on xenograft growth were examined. Combined treatment with bevacizumab plus ACR significantly suppressed the growth of Huh7 xenografts. The combination of these agents significantly inhibited the phosphorylation of the Akt protein in tumor tissues. With combination therapy, the population of Ki-67-positive cells in xenografts decreased, while that of TUNEL-positive cells increased. The combination of bevacizumab and ACR exerts growth-suppressing effects on HCC cells by inhibiting cell proliferation and inducing apoptosis. This combination might be an effective regimen for the treatment of HCC.

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Oral immunotherapy for food allergy has been the focus of a lot of attention recently. The patients have to eat allergenic food instead of eliminating it in this therapy and there is no established standard method yet. To promote clear understanding and improvement of oral immunotherapy, the present study using B10.A mice investigated the effect of multiple oral administration of a model antigen, egg-white lysozyme, on both the antibody response and the anaphylactic reaction induced by subsequent administration of lysozyme. Various doses of egg-white lysozyme (0–100 mg/mouse) were administered to mice intragastrically for 6 d; then additional lysozyme was administered via the intraperitoneal route in all groups. Lysozyme-specific antibody responses were promptly induced by the first oral administration and enhanced by intraperitoneal administration. An anaphylactic reaction was further induced in these sensitized mice by intragastric administration of lysozyme, and the symptoms of shock were compared in order to evaluate the effects of pretreatment. Interestingly, the decrease in rectal temperature which is one of the common anaphylactic symptoms in mice was suppressed in all of the oral pre-administration groups, and the effects were highest in the group that received 20 mg. Consequently, this study using B10.A mice has shown that sensitization can be induced by intragastric administration of lysozyme instead of oral tolerance; however, anaphylactic shock induced by subsequent intragastric administration of lysozyme is suppressed. This mouse model would be useful for assessing the method of oral immunotherapy.

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