2-Ethylpyrazine Induces Vasodilatation by Releasing Nitric Oxide in the Endothelium.

Oxygen transportation and regulation of some physiological processes are facilitated by blood flow. Furthermore, blood flow is regulated by various factors such as nitric oxide (NO) and the autonomic nerve system. In modern life, many people suffer from chilliness (hiesho) because of mental stress and an excessive use air-conditioning systems, which induces vasoconstriction in the peripheral skin. In this study, we focused on pyrazine derivatives, particularly compounds that are used as food flavoring materials, and investigated their effects on vascular function and blood flow. We examined the vasodilatory effect of pyrazine derivatives in the rat thoracic aorta and found 2-ethylpyrazine (2-EP) to be the most active pyrazine compound. Additionally, we found that 2-EP induces vasodilatation through the activities of endothelium-derived relaxing factors. 2-EP activates NO synthesis through the effect of endothelial NO synthase in the endothelium. As a result, cyclic GMP levels rise in smooth muscle cells and vasodilatation is induced. We also confirmed that 2-EP increases peripheral blood flow in rats. From these results, we concluded that 2-EP induces vasodilatation by inducing the release of NO and increasing peripheral blood flow.

Fecal Lipid Excretion after Consumption of a Black Tea Polyphenol Containing Beverage-Randomized, Placebo-Controlled, Double-Blind, Crossover Study.

Obesity is a serious medical condition worldwide. Inhibition of lipid absorption is very important in preventing obesity. In a previous study, we found that postprandial elevation of triacylglycerol was suppressed by the intake of black tea polyphenol (BTP). We also reported that BTP caused lipid excretion into feces in an animal study. The present study is a clinical trial that examined lipid excretion. In this randomized, placebo-controlled, double-blind, crossover study, in the first test period participants were asked to drink either a beverage containing 55 mg BTP or a control beverage without BTP 3 times a day for 10 d. After an 11-d interval, for the second test period, they then drank the alternate test beverage 3 times a day for 10 d. During the test periods, the participants were asked to eat meals standardized according to calorie and fat content. Stool samples were obtained during the last 3 d of each test period for fecal lipid measurements. Total lipid excretion increased from 5.51±1.73 to 6.87±1.91 g/3 d after BTP intake in comparison with intake of the control beverage. These results indicated that BTP increased lipid excretion.

Roasted Barley Extract (Mugicha) Containing Cyclo(D-Phe-L-Pro) Prevents a Decrease in Skin Temperature in Cold Conditions: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study.

Roasted barley extract (RBE) is a traditional Japanese beverage. Previously, we reported the effects of RBE containing cyclo(d-Phe-l-Pro) on blood flow in animals and humans and investigated rapid skin temperature recovery from cold-water immersion in women. The present randomized, double-blind study investigated the effects of RBE containing cyclo(d-Phe-l-Pro) on men's and women's skin temperature in excessively air-cooled conditions. Participants felt cold in the test room (25.5±0.5ºC). They ingested an RBE or placebo beverage and remained in the air-conditioned room for 100 min. Skin temperature of the left foot was measured every 5 min using infrared thermography. We evaluated effect of RBE administration by paired t-test. The skin temperature of the RBE group remained higher than that of the placebo group. The skin temperature changes 100 min after RBE or placebo ingestion were -3.67±1.14ºC and -4.59±0.89ºC, respectively in all participants. We also did subclass analysis focusing on men or women. In a previous study, RBE efficacy for skin temperature in men was not clearly demonstrated. RBE consumption was also effective not only in female participants but also in male participants. The skin temperature changes 100 min after RBE or placebo ingestion were -3.65±0.64ºC and -4.55±0.32ºC, respectively in male participants. Therefore, RBE containing cyclo(d-Phe-l-Pro) prevented skin temperature decreases in excessively air-cooled conditions in both men and women.

Roasted Barley Extract Affects Blood Flow in the Rat Tail and Increases Cutaneous Blood Flow and Skin Temperature in Humans.

Roasted barley extract (RBE, "Mugicha") is a traditional Japanese beverage reported to improve blood viscosity and affect food functionality. RBE is suggested to contain 2,5-diketopiperazines, which are the functional component with neuroprotective and immunostimulatory effects that are produced in food through roasting. In this study, we investigated the effects of RBE on blood circulation, both clinically and in rats. At first, we confirmed five 2,5-diketopiperazine derivatives in RBE by LC-MS analysis. Secondarily, we revealed that RBE affects blood flow in the rat tail and compared the efficacy on rat tail blood flow among five 2,5-diketopiperazines in RBE. Especially, cyclo(d-Phe-l-Pro) was the most effective in increasing blood flow in the rat tail. We also researched the mechanism of cyclo(d-Phe-l-Pro) with rat aorta study. As a result, we confirmed that cyclo(d-Phe-l-Pro) has an effect on vasodilatation through the release of nitric oxide in the vascular endothelium. Finally, we also confirmed that RBE affects cutaneous blood flow and increases skin temperature in humans.

Roasted Barley Extract (Mugi-cha) Containing Cyclo(d-Phe-l-Pro) Prevents Lowering of the Cutaneous Blood Flow and Skin Temperature under Air Conditioning: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study.

Roasted barley extract (RBE), also known as mugi-cha, is a well-known healthy non-caffeinated beverage, and its health functionality has been widely reported. Our previous clinical study showed that RBE affects the cutaneous blood flow and skin temperature after cold-water immersion and that cyclo(d-Phe-l-Pro) is responsible for its effect. In this study, we investigated whether cyclo(d-Phe-l-Pro)-containing RBE prevents the decrease in the cutaneous blood flow and skin temperature. Subjects remained in the air-conditioned room while ingesting RBE or a placebo. We measured the cutaneous blood flow and skin temperature. We evaluated the effect of RBE administration by two-way repeated measures analysis of variance. A total of 15 subjects were enrolled. The change in cutaneous blood flow in the RBE and placebo groups was -0.79 ± 0.38 and -2.03 ± 0.35 mL min-1 100 g-1, respectively ( p value of 0.041). The change in the skin temperature in the RBE and placebo groups was -1.85 ± 0.35 and -3.02 ± 0.30 °C, respectively ( p value of <0.001). We also did subclass analysis with cold-feeling subjects. For the seven subjects who had cold sensation, the change in the cutaneous blood flow in the RBE and placebo groups was -0.48 ± 0.58 and -2.56 ± 0.48 mL min-1 100 g-1, respectively ( p value of 0.008). The change in the skin temperature in the RBE and placebo groups was -1.46 ± 0.74 and -2.89 ± 0.39 °C, respectively ( p value of 0.009). Thus, RBE containing cyclo(d-Phe-l-Pro) prevents the decrease in the cutaneous blood flow and skin temperature under air conditioning.

A randomized, double-masked, placebo-controlled crossover trial on the effects of L-ornithine on salivary cortisol and feelings of fatigue of flushers the morning after alcohol consumption.

BACKGROUND: Residual alcohol effects on physiological and psychological symptoms are commonly experienced the morning after alcohol consumption. The purpose of this study was to assess the effects of L-ornithine on subjective feelings and salivary stress markers the morning after alcohol consumption and to investigate whether L-ornithine acutely accelerates ethanol metabolism. METHODS: This study had a randomized, placebo-controlled, double-masked crossover design. Subjects were all healthy Japanese adults with the 'flusher' phenotype for alcohol tolerance. In experiment 1, 11 subjects drank 0.4 g/kg body weight alcohol 1.5 h before their usual bedtime. Half an hour after drinking, they ingested either a placebo or 400 mg ornithine. The next morning on awakening, subjects completed a questionnaire containing a visual analog scale (VAS), the Oguri-Shirakawa-Azumi sleep inventory MA version (OSA-MA), and a profile of mood states (POMS) and collected a saliva sample for measurement of salivary stress markers (cortisol, secretory immunoglobulin A, and α-amylase). In experiment 2, placebo or 400 mg ornithine were administrated to 16 subjects both before and after drinking, and the feeling of drunkenness, breath ethanol concentration and one-leg standing time were repeatedly investigated until 180 min after alcohol consumption. RESULTS: There were significant decreases in "awareness", "feeling of fatigue" and "lassitude" VAS scores and in "anger-hostility" and "confusion" POMS scores and a significant increase in "sleep length" in the OSA-MA test. Salivary cortisol concentrations on awakening were reduced after ornithine supplementation. There were no differences between ornithine and placebo in any of the subjective or physiological parameters of acute alcohol metabolism. CONCLUSIONS: Taking 400 mg ornithine after alcohol consumption improved various negative feelings and decreased the salivary stress marker cortisol the next morning. These effects were not caused by an increase in acute alcohol metabolism.

Identification and characterization of genes involved in glutathione production in yeast.

Glutathione is a major peptide protecting cells against oxidative stress. To study the cellular processes affecting intracellular glutathione production, we screened Saccharomyces cerevisiae mutant collections and identified new eight yeast deletion mutants that produced more than 1.2-fold higher levels of intracellular glutathione: chc1, cst6, ddc1, def1, pep12, rts1, ubp6, and yih1. Furthermore, overexpression of the DEF1 and CYS4 genes led to a higher production of glutathione, similar to overexpression of GSH1. A multiplier effect on activation of glutathione synthesis was observed by a combination of overexpression of GSH1 and deletion of one of the eight genes. Metabolome analysis of the def1, pep12, and ubp6 deletion mutant, and DEF1-overexpressing strains showed that levels of intracellular methionine and oxidized glutathione were higher than in the control strains, suggesting that methionine biosynthesis was activated and the oxidative stress response was increased in these glutathione-overproductive strains. Moreover, overexpression of GSH1, CYS4, and DEF1 also increased glutathione production in Candida utilis. Taken together, these results will significantly contribute to more effective industrial production of glutathione using yeasts.

Isohumulones, bitter acids derived from hops, activate both peroxisome proliferator-activated receptor alpha and gamma and reduce insulin resistance.

The peroxisome proliferator-activated receptors (PPARs) are dietary lipid sensors that regulate fatty acid and carbohydrate metabolism. The hypolipidemic effects of fibrate drugs and the therapeutic benefits of the thiazolidinedione drugs are due to their activation of PPARalpha and -gamma, respectively. In this study, isohumulones, the bitter compounds derived from hops that are present in beer, were found to activate PPARalpha and -gamma in transient co-transfection studies. Among the three major isohumulone homologs, isohumulone and isocohumulone were found to activate PPARalpha and -gamma. Diabetic KK-Ay mice that were treated with isohumulones (isohumulone and isocohumulone) showed reduced plasma glucose, triglyceride, and free fatty acid levels (65.3, 62.6, and 73.1%, respectively, for isohumulone); similar reductions were found following treatment with the thiazolidinedione drug, pioglitazone. Isohumulone treatment did not result in significant body weight gain, although pioglitazone treatment did increase body weight (10.6% increase versus control group). C57BL/6N mice fed a high fat diet that were treated with isohumulones showed improved glucose tolerance and reduced insulin resistance. Furthermore, these animals showed increased liver fatty acid oxidation and a decrease in size and an increase in apoptosis of their hypertrophic adipocytes. A double-blind, placebo-controlled pilot study for studying the effect of isohumulones on diabetes suggested that isohumulones significantly decreased blood glucose and hemoglobin A1c levels after 8 weeks (by 10.1 and 6.4%, respectively, versus week 0). These results suggest that isohumulones can improve insulin sensitivity in high fat diet-fed mice with insulin resistance and in patients with type 2 diabetes.