薬理と治療

Objectives This study aims to investigate the diabetes prevention effects and the mechanisms by ingestion of black tea for 3 weeks in a type 2 diabetes model KK-Ay mice. Methods The KK-Ay mice were provided black tea for 3 weeks and were examined for weight gain and diabetes condition. In addition, Gene microarray analysis was performed and gene expression in liver cells was analyzed to investigate the effect of black tea ingestion on diabetic pathology and its mechanism. Results Black tea suppressed increase of body weight, accumulation of visceral fat, and blood glucose and insulin levels. In addition, we confirmed an improvement in insulin resistance via suppression of elevated blood glucose and insulin levels. Moreover, as a result of investigating liver gene expression by DNA microarray and real-time PCR analysis, a decreased in the expression of Fos and Jun, which are proteins comprising activator protein 1 （AP-1）. Conclusions This study suggests that long-term ingestion of black tea reduces Fos and Jun gene expression levels and is involved in suppressing worsening of diabetes.

This study aimed at assessing the potential toxicity and the approximate lethal dose of the test substance, acetic acid bacteria（Gluconacetobacter hansenii）, following a single oral administration in 6-week-old male and female Sprague-Dawley（Crl: CD（SD））rats. The test groups consisted of five animals（male and female）in each per group, namely, a dosing group administered with acetic acid bacteria at 2000 mg╱kg and a control group administered with water. All animals were monitored for clinical signs and changes in the body for a 14 day observation period after dosing, after which the animals were subjected to gross necropsy at the end of the observation period. No rats in the dosing group died during the observation period, and no effects on clinical signs, body weight, or necroscopic findings were observed in the dosing group. The approximate lethal dose of the test substance, acetic acid bacteria, was greater than 2000 mg╱kg in male and female rats under the conditions of this study.

This study was conducted to assess the cumulative toxicity of the test substance, acetic acid bacteria（Gluconacetobacter hansenii）, when administered once daily for 4 weeks to 6-week-old Sprague-Dawley（Crl: CD（SD））rats by oral gavage method. The rats were distributed into two groups each consisting of 10 male and 10 female rats. Group 1 was the control group and received water only, whereas Group 2 received the test substance at a dose level of 2000mg╱kg╱day.No animal deaths were reported during the observation period. No test substance-related toxic effects in clinical signs, body weight, food consumption, urinalysis, hematology, clinical chemistry, organ weights, necropsy, and histopathological findings were observed. The no-observed-adverse-effect level of acetic acid bacteria was concluded to be higher than 2000mg╱kg╱day for both male and female rats under the conditions of this study.

Acetic acid bacteria（Gluconacetobacter hansenii）were evaluated for potential genotoxic effects using the bacterial reverse mutation test（Ames test）and the in vitro mammalian chromosomal aberration test using Chinese hamster lung cells. The Ames test was carried out using Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 and the Escherichia coli strain WP2uvrA（pKM101）. It showed that the test cells did not induce gene mutations or chromosomal aberrations in any strains under varying metabolic conditions. Thus, acetic acid bacteria do not exert genotoxic potential under the experimental conditions tested here.

Objectives The aim of this study was to examine the effect of enzyme-treated lemon-derived hesperidin（LEH）on healthy Japanese subjects experiencing daily facial swelling. Methods This randomized, double-blind, crossover, placebo-controlled study enrolled healthy Japanese subjects（n＝88）who were experiencing daily facial swelling. Participants were randomly assigned into the LEH and placebo groups（n＝44 per group）using a computerized random-number generator and ingested either one LEH tablet or one placebo tablet per day after dinner. The study design incorporated a two-week intervention period followed by a washout period of two weeks. Subjective symptoms of facial swelling were evaluated by a visual analog scale as the primary outcome. Additionally, subjective symptoms associated with facial skin texture, face volume（assessed by photo-analysis）, calf volume and circumference, and blood pressure were evaluated as secondary outcomes. Results The per-protocol set comprised 43 participants in each group. Among the subjective symptoms, the LEH ingestion contributed to the alleviation of swelling of the face and eye contours in the morning. Additionally, swelling of the eye contours and dullness of the skin under the eyes in the evening were improved by LEH intake. No adverse effects were associated with LEH observed. Conclusions Intake of LEH tablets for two weeks improved facial swelling in the morning. LEH may also improve puffy eyes, dullness under the eyes and calf swelling. Trial registration UMIN-CTR: UMIN000031609 Foundation SAPPORO HOLDINGS LTD.

Background/Objectives To evaluate the influence of the long-term ingestion of corn syrup solids containing maltobionic acid（maltobionic acid calcium salt）on the bone mineral density（BMD）and safety of healthy Japanese women. Methods This was a randomized, double-blind, placebo-controlled, parallel-group study. Thirty-four healthy Japanese women aged 50-69 years who were at least 1 year past the onset of natural menopause were allocated into two groups: one in which participants ingested 8 g of corn syrup solids containing maltobionic acid calcium salt and another in which participants ingested 8 g of placebo（hydrous crystalline maltose and calcium carbonate） group per day for 24 weeks. BMD measurements（dual-energy X-ray absorptiometry method）and bone metabolism parameter measurements were evaluated by a peripheral blood test, while safety was evaluated by a physical examination, a peripheral blood test, a urinalysis, subjective symptoms, and a medical questionnaire. Results All 34 subjects completed the study with no adverse events related to the test food. Fifteen subjects were excluded before the efficacy analysis because of conflict with control criteria; the remaining 19 subjects were analyzed. Consumption of corn syrup solids containing maltobionic acid was maintained, and BMD, bone area, and bone mineral content （BMC）were improved. Conclusions These results indicate that corn syrup solids containing maltobionic acid might contribute to the prevention of osteoporosis（. UMIN︱CTR ID：UMIN 000025401）

Objectives We examined an intestine-conditioning activity of the dietary fiber-containing food. Methods We performed a double-blind, randomized, placebo-controlled, cross-over study to evaluate the effect of the test food which contained indigestible dextrin, Bacillus coagulans and fructooligosaccharide, on intestinal microflora and defecation frequency. The subjects were 45 healthy human volunteers, who tended to be constipation, and they were divided into three groups. On each of the 3 experimental periods, they took a placebo food or test food（low dose or high dose）for 2 weeks. Thirty nine subjects were eligible for analysis because 6 subjects were withdrawn from the study. Results The defecation frequency in both of low and high dose groups were increased significantly compared with those in placebo group. The occupancy rate of Bifidobacterium in feces in high dose group were higher than those in placebo group. No adverse events were observed, which were caused by the ingestion of the test food. Conclusion These results showed that the dietary fiber-containing food has intestinal-condition improving effect on healthy subjects（. UMIN Trial ID：UMIN 000031693）

Objective To determine whether orally supplemented 5-aminolevulinic acid（ALA） improves age-related damaged skin properties in healthy middle-aged and older women. Methods This randomized, double-blind, placebo-controlled study included 138 healthy women aged 50-64 years（most women were aged above 55 years） who were bothered about skin dryness. The participants were randomly assigned to receive either placebo or ALA supplement （50 mg ALA phosphate╱day）for 12 weeks and the groups were compared（the primary analysis）. We assessed the effects of ALA supplementation on the stratum corneum hydration （SCH）of the cheek and volar forearm, as well as three skin viscoelasticity parameters measured using a Cutometer®（R2, R5, and R7）on the cheek after 4, 8, and 12 weeks of treatment. Efficacy evaluation was also conducted in 122 selected participants who did not show a conflict with any efficacy analysis exclusion criteria（the secondary analysis）. Results Data from either of the efficacy analyses and both efficacy analyses showed that ALA supplementation increased the SCH levels on the cheek and volar forearm and improved the values of all three skin viscoelasticity parameters on the cheek over the treatment period. Additionally, intergroup differences in the magnitude of changes in the SCH levels at week 12 and the values of R5 and R7 parameters at weeks 8 and 12 significantly favored ALA supplementation. The supplement was well-tolerated, and no clinically problematic side effects or laboratory abnormalities were observed during the treatment. Conclusion Our findings indicate that ALA supplementation is effective for improving skin hydration and skin elasticity in middle-aged and older women. This study is registered with UMIN Clinical Trials Registry（ID: UMIN000030195）

Objective The study was conducted to explore the effects of a wasabi root extract product rich in 6-（methylsulfinyl）hexyl isothiocyanate named “Wasabi Sulfinyl（WS）”on neurocognitive functions in the cognitively intact elderly. Methods Fifty cognitively intact elderly adults with memory complaints between the ages of 45 and 69 years were enrolled in this randomized double-blind, placebo-controlled trial and randomized to receive 100 mg WS or placebo daily for a period of 8 weeks. Efficacy on neurocognitive functions were assessed using a battery of four neuropsychological tests, which were examined at baseline before treatment started and after 4 and 8 weeks of treatment. Statistical analyses followed the per-protocal principle. Results All subjects completed the study although four were excluded from the efficacy analysis due to adverse event or protocol violation. Analysis of the fully evaluable population indicated that there were no significant differences between WS and placebo groups on any outcome measure. However, there were trends favoring WS in almost all parameters of the Group version of the Stroop Color Word Test（G-SCWT）, of which the magnitude of improve ment of correct responses in the Stroop interference task and the interference rate reached near-significant levels（P＝0.083 and 0.091, respectively）at the end of 8-week treatment. Moreover, post-hoc subgroup analyses indicated that a subset of nonexercisers exhibited significantly better performance in both reverse-Stroop control task and Stroop interference task of the G-SWCT at week 8. During the study no WS-induced side effects were observed. Conclusion The results showed that WS may have some beneficial effects on attention╱processing-related cognitive performance in cognitively intact middle-aged and older adults. Post-hoc analyses of subgroups suggest that nonexercisers subjects were more likely respond to WS. （UMIN-CTR/UMIN000027407）

Objectives Stress and fatigue are generally experienced in everyday life. In this study, we examined the influence of drinking coffee with reduced levels of an oxidative component （hydroxyhydroquinone［HHQ］）on stress and fatigue caused by a transient mental workload in healthy volunteers. Methods Fifteen healthy men aged 30 to 40 years drank oxidative component-reduced coffee （high chlorogenic acids and low HHQ coffee）or placebo coffee（low chlorogenic acids and low HHQ coffee）daily for 4 weeks. Body weight, blood pressure, fatigue level, and autonomic nerve activity were measured and blood was collected on the test day before drinking the test beverage and after 4 weeks of drinking the test beverage. On the test day, stress and fatigue loads were induced by 1 hour of calculation work and personal computer work, and the degree of fatigue before and after the loading was evaluated. This study was conducted in a double-blind crossover manner. Results Feelings of overall fatigue, physical fatigue, subjective stress, and irritability after the workload were significantly reduced by 4 weeks of ingesting oxidized component-reduced coffee. In addition, the mental work capacity evaluated by the calculation work was significantly increased by ingesting the oxidized component-reduced coffee. Conclusion These findings suggest that ingesting an oxidative component-reduced coffee may reduce stress and fatigue caused by transient mental workload.

Objective The purpose of this randomized, placebo-controlled, double-blind, parallel-group study is to evaluate the influence of 12weeks ingestion of dietary supplement of low molecular fish collagen peptide to the knee joint pain and discomfort. Methods Fifty healthy adult male and female with the uncomfortable feeling of knee joint, were divided into active test and placebo groups. Subjects ingested active test dietary supplement（containing about 5 g fish collagen peptide）or placebo dietary supplement（not containing fish collagen peptide. maltodextrin powder）daily for 12 weeks. Knee joint pain and discomfort was assessed by changes in VAS survey and the questionnaire survey on knee joint function, at weeks 0, 4, 8, 12, and after 4 weeks from the end of 12 weeks ingestion. Results Each subject was determined the knee of the stronger pain （right or left）at the time of the screening and was followed the trend of that VAS value for 16 weeks. The VAS value of the low-molecular fish collagen group markedly decreased after initiation and the difference from the placebo group was significant after 4 weeks. The VAS value of the low-molecular fish collagen group decreased to 40.7％ of the 0-week value at 12 weeks, whereas the decrease in the placebo group was 60.8％. Furthermore, even at 4 weeks after the end of ingestion, the VAS value of the low-molecular fish collagen group remained significantly lower value than at the start, and the value was equivalent to that at 12 weeks. On the other hand, in the placebo group, the 16-week VAS value increased to 76.1％ of the 0-week value after the end of ingestion. The difference between this value and the 0-week value was not significant. The VAS value of another knee（non-target knee）, and a questionnaire survey also showed the same results as above. No test food related adverse events were observed during the study, except one case（placebo group）of diarrhea due to overdose ingestion. Therefore, it was suggested that ingestion of this food for 12 weeks was safe and useful for improving knee joint pain and discomfort. Conclusion Dietary supplement containing low︱molecular fish collagen peptide improved knee joint pain and discomfort（. UMIN︱CTR ID：000029871）

Objectives Foods containing aged garlic extract are thought to have an effect on fatigue during the rainy season and summer in Japan. The present study elucidated the suppressive effects of these foods on fatigue during winter and spring. Methods This randomized, double-blind, placebo-controlled parallel study included 52 healthy adult volunteers（male, n＝19; female, n＝33）who consumed a placebo or test food for eight weeks. Subjective mood（fatigue）was evaluated using the visual analogue scale and volunteers completed the stress arousal checklist and a questionnaire about cold sensation. Body temperature and salivary α︱amylase activities were also measured. The safety of this food was also evaluated by physical examinations and blood tests. Results The scores for fatigue and stress were significantly decreased after eight weeks of test food intake compared with the placebo. Salivary α-amylase activities in the test food group were significantly lower than those in the placebo group after eight weeks of intake. Sensitivity to cold improved and body temperature increased. There were no problems with safety. Conclusions Foods containing aged garlic extract can decrease fatigue and stress during winter and spring. The present results suggest that the mechanisms of action are the suppression of sympathetic nerve activity and improvement of blood circulation. Trial Registration UMIN-CTR: UMIN000024713

In order to evaluate the effect of Rice Power®（rice fermented extract）No. 6 on sebum secretion of the face, an open comparison test was conducted with healthy Japanese males and females aged 20 to 59 years old. Specific gel containing Rice Power® No. 6 was topically applied on the face twice a day for 28 days, and both the amount of sebum secretion and water content of the facial skin were measured before and after the application. Simultaneously, we obtained answers from applicants whether and how bodily sensation of the face changes or not during the test period. The results showed that Rice Power® No. 6 gel suppressed the sebum secretion along with the application. However, the skin humidity was either maintained or increased through the test period. With the decrease of sebum secretion, bodily sensation changed, especially the reduction of shininess on the face was observed. Therefore, it was revealed that Rice Power® No. 6 has a certain suppressive effect on the sebum secretion without harmful effect on the skin. Moreover, there is a correlation between the amount of sebum secretion and bodily sensation effect.