Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Stagnation of social activity due to the COVID-19 pandemic probably reduces motivation to maintain a healthy diet. It is important to report on the dietary changes observed in older adults during a period of restriction on outings and to clarify the relationship between dietary variety and frailty. This one-year follow-up study examined the association between frailty and dietary variety during the COVID-19 pandemic. METHODS: Baseline and follow-up surveys were conducted in August 2020 and August 2021, respectively. The follow-up survey was distributed by mail to 1635 community-dwelling older adults aged ≥65 years. Of the 1235 respondents, 1008 respondents who were non-frail at baseline are included in this study. Dietary variety was examined using a dietary variety score developed for older adults. Frailty was assessed using a five-item frailty screening tool. The outcome was frailty incidence. RESULTS: In our sample, 108 subjects developed frailty. A linear regression analysis revealed a significant association between dietary variety score and frailty score (β, -0.032; 95% CI, -0.064 to -0.001; p = 0.046). This association was also significant in Model 1, adjusted for sex and age, (β, -0.051; 95% CI, -0.083 to -0.019; p = 0.002) and in a multivariate analysis that added adjustments for living alone, smoking, alcohol use, BMI, and existing conditions to Model 1 (β, -0.045; 95% CI, -0.078 to -0.012; p = 0.015). CONCLUSIONS: A low dietary variety score was associated with an increased frailty score during the COVID-19 pandemic. The restricted daily routine caused by the COVID-19 pandemic will probably continue to have a long-term effect in terms of reduced dietary variety. Thus, vulnerable populations, such as older adults, might require dietary support.

DOI： 10.3390/nu15051145

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Objectives: This study aimed to investigate the influences of living arrangements on the association between dietary variety and frailty by gender in community-dwelling older people. Design: A cross-sectional study. Setting: Nishinomiya city, Hyogo prefecture, Japan. Participants: A total of 4,996 randomly selected community-dwelling older people aged 65 years and older and living in Nishinomiya City. Measurements: Survey questionnaires were distributed via mail. The frailty score was evaluated by the 5-item frailty screening index. Dietary variety was assessed using the dietary variety score developed for the general older Japanese population. Results: A total of 2,764 community-dwelling participants aged ≥ 65 years responded to the questionnaires. After excluding missing data, 1,780 participants were included in the study analysis. The frailty scores in older men living alone were significantly higher than those in older men living with someone (P < 0.001). The dietary variety scores in older men living alone were significantly lower than those in older men living with someone (P < 0.001). However, differences in the frailty and dietary variety scores between living alone and living with someone were not were observed in older women (P = 0.360 and P = 0.265, respectively). In the multivariable regression analysis, the associations between dietary variety score and frailty score in living alone (β= −0. 271, P = 0.011) were stronger than those in living with someone in the case of older men (β= −0.131, P = 0.045). Similar associations between dietary variety and frailty were presented in older women living alone than in those living with someone (β −0.114, P = 0.002; β −0.088, P = 0.012, respectively). Conclusions: Older men who live alone had higher frailty score and lower dietary variety. The associations between dietary variety and frailty were different according to living arrangements in both older men and older women.

DOI： 10.14283/jfa.2021.49

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Language：Japanese   Publisher：JAPANESE SOCIETY OF HEALTH EDUCATION AND PROMOTION  

Objective: We aimed to investigate associations between “competencies for living” and eating behaviors/attitudes at home and at school among elementary school children in the upper grades.

Methods: A homework survey based on a cross-sectional research design was conducted using a self-administered questionnaire provided to 971 children in the 4th, 5th, and 6th grades of elementary schools in K City, Hyogo Prefecture in July 2019. We examined each student’s situation at home during dinner, their relationship with family, their eating behaviors/attitudes related to school meals, the contents of conversations during dinner, and the nature of their help with meals. Analyses were performed separately for boys and girls, as there was a difference in the distribution of items assessing eating behaviors/attitudes. Multiple regression analysis using the forced entry method was performed with the competencies for living score as the dependent variable and children’s eating behaviors/attitudes as the independent variable. Using this same method, we examined the contents of conversations and student help with meal preparation/clean up for associations with competencies for living.

Results: Children’s competencies for living was positively associated with conversation with family at dinner in both boys and girls (boys: standardized regression coefficient β=0.20 P=0.002) (girls: β=0.12 P=0.044), and meal time conversations included matters related to school (boys: β=0.25 P=0.003) (girls: β=0.17 P=0.031). In boys, a positive association between competencies for living and helping with meals was observed. Competencies for living was also associated with eating attitudes, including not refusing the food they do not like in school meals (boys) and liking vegetables (girls).

Conclusion: The associations between children’s competencies for living and some aspects of eating behaviors/attitudes at home and school differed between boys and girls. The eating behavior that correlated with competencies for living in both boys and girls was conversation with family at dinner.

DOI： 10.11260/kenkokyoiku.30.283

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Language：English   Publisher：(一社)日本予防医学会  

70歳以上の独居高齢者を対象に、生活満足度や主観的健康感に関する質問票調査を行った。質問への回答者2027名のうち1915名(男性388名、女性1527名、平均78.3±5.7歳)のデータを解析した。1614名(84.3%)は生活満足度が高いと回答し、301名(157%)は低いと回答した。生活満足度は性別、年齢、独居歴、主観的健康感、人生の楽しみ、社会参加、自宅で調理する頻度、生活環境(経済的自律)と関連していた。主観的健康感が低い者の生活満足の粗オッズ比は有意に高かった。多変量解析で主観的健康感が低い者の生活満足の調整オッズ比は有意に高かった。性別および年齢層により層別解析しても生活満足度と主観的健康感の間に同様の関連性がみられた。以上の結果から、独居高齢者では生活満足度が独立して主観的健康感と関連すると考えられた。

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BACKGROUND: The coronavirus disease 2019 (COVID-19) has adversely affected social contact and physical activity. This study investigated the correlation between physical activity, social contact, and sedentary time among adults aged 65 years and above during the COVID-19 pandemic. METHODS: This study was conducted in N City, H Prefecture, Japan. The authors randomly selected 4,996 adults, aged 65 years and above (mean age 74.1 ± 6.1 years), living in N City, and survey forms were distributed by mail in mid-August 2020. Altogether, 1,925 participants were included in this study. The survey comprised questions concerning the participants' sex, height, weight, age, smoking and drinking habits, living arrangements, social contact assessments, physical activity levels, and sedentary time. Moreover, linear regression analysis was utilized to investigate the associations between the variables. RESULTS: The reported median physical activity was 1272 metabolic equivalent of task-min/week (interquartile range 528-2628), and the reported median sedentary time was 360 min/week (interquartile range 240-600). COVID-19 "somewhat," "quite a lot," or "completely" hindered the frequency of in-person contact with friends among 75.5% of the respondents and hampered the frequency of virtual contact with friends among 38.8% of the respondents. Physical activity was associated significantly with in-person contact indicators: "interaction with friends" (B = -0.111; 95%CI: -0.187, -0.035; p = 0.004) and "social participation" (B = -0.163; 95%CI: -0.248, -0.079; p < 0.001). These associations remained significant for both multivariate analysis Models 1 (sex and age) and 2 (addition of body mass index [BMI], alcohol use, smoking, living alone, and the number of illnesses to Model 1). Additionally, sedentary time was significantly associated with the social contact variable of "interaction with friends" (B = 0.04; 95%CI: 0.016, 0.064; p = 0.001). This association remained significant in both multivariate analysis models. CONCLUSIONS: Significant associations were confirmed between reduced social contact, decreased physical activity, and more sedentary behavior among older adults due to COVID-19. Hence, continuous monitoring and support for social activities among susceptible older adults in extraordinary circumstances are essential.

DOI： 10.1186/s12877-022-03188-z

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Language：Japanese   Publisher：JAPANESE SOCIETY OF HEALTH EDUCATION AND PROMOTION  

Objective: The objective of this study was to clarify the relationship between the competencies for living possessed by children in upper grades of elementary school and their parents’ attitudes and behaviors regarding eating habits.

Methods: A questionnaire survey was conducted among children who were in the fourth, fifth, and sixth grades of elementary school, and their parents concerning both the children’s competencies for living and parental attitudes and behaviors regarding eating habits. The relationship was examined through multiple regression analysis using a stepwise method, with scores for competencies for living (psychosocial ability, moral ability, and physical ability) as dependent variables, and the parental attitudes and behaviors regarding eating habits were examined as independent variables.

Results: The scores for competencies for living were related to parental concern about children’s lack of exercise (β=−0.15 P=0.001), parents’ perceptions of children skipping breakfast (β=−0.10 P=0.018), and the teaching of mealtime greetings (β=0.10 P=0.016) as the parental attitudes and behaviors. Similar associations were found for moral ability and physical ability. The scores for psychosocial ability were also related to parents skipping breakfast and the time they spent preparing breakfast.

Conclusion: Parental concern about children’s lack of exercise and parental perceptions regarding children skipping breakfast were negative factors for children’s competencies for living, while teaching mealtime greetings was a positive factor. It was suggested that improving parental attitude and behavior regarding eating habits may promote the development of children’s competencies for living.

DOI： 10.11260/kenkokyoiku.30.3

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Other Link： https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20K02598/

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: This study investigated the relationship between social activities and frailty during the restriction on outings due to COVID-19. DESIGN: A cross-sectional study. SETTING AND SUBJECTS: This study was conducted in City Nishinomiya of Prefecture Hyogo, in Japan. A mail survey was carried out among women aged 65 years or older in May 2020. A population of 293 women aged 65 years or older living in the community was recruited for the study and 213 of them were analyzed. MEASUREMENTS: The survey included questions on sex, age, height, weight, and social activity. Social activity consisted of participation in social organizations and their frequency, as well as frequency of interaction with family and friends. The survey also asked if regular social activity had been impeded by COVID-19. RESULTS: A significant association was found between frailty and hindered interaction with friends (β: 0.176, p = .014). Multivariate linear regression analysis confirmed that this association was also significant in Model 1 (β: 0.158, p = .025), and Model 2 (β: 0.148, p = .034). CONCLUSIONS: No association between being hindered in social activity and frailty was found in older women living in the community during the restriction on outings due to COVID-19.

DOI： 10.5770/cgj.24.507

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OBJECTIVES: To investigate the relationship between diet and frailty in community-dwelling older adults during the period of restriction on outings due to novel coronavirus disease 2019 (COVID-19). METHOD: A mail survey targeting adults aged 65 years or older, including questions on sex, age, height, weight, and social participation, was conducted in May 2020. The participants' dietary variety score and frailty score were then calculated. RESULTS: Overall, 322 women aged 65 years or older and who were living in the community were recruited for the study; 253 were finally analyzed. The mean age of the 253 participants was 80.0 ± 6.4 years. The dietary variety score and frailty scores were significantly correlated in the linear regression analysis (β: -0.224, p < .001). In the multivariate regression analysis, these factors remained significantly correlated in Model 1, which was adjusted for age (β: -0.229, p < .001), and Model 2, which was adjusted for age, body mass index, and other confounding factors (β: -0.208, p = .001). DISCUSSION: Diet was correlated with frailty in older adults living in the community during the period of restriction on outings due to COVID-19.

DOI： 10.1093/geronb/gbaa218

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BACKGROUND AND OBJECTIVES: Sleep disturbance is a common health problem in the elderly population. We examined the association between dietary variety and subjective sleep quality in community-dwelling elderly Japanese women. METHODS AND STUDY DESIGN: This cross-sectional study recruited 160 community-dwelling elderly women aged ≥65 years. Subjective sleep quality and dietary variety were assessed by Pittsburgh Sleep Quality Index (PSQI) and dietary variety score (DVS), respectively. DVS was calculated from the eating frequency of 10 food groups. Sleep disturbance was defined as PSQI score of ≥6. RESULTS: The DVS in subjects with sleep disturbance was significantly lower than that of those without the disturbance (4.1±2.1 vs 5.3±2.1, p<0.01). In the multivariable regression model, the PSQI score was negatively correlated with the DVS score in age-adjusted model (standardized coefficient; -0.234, p<0.01). In the further adjusted model that included depression levels, the negative association between PSQI score and DVS score was retained (standardized coefficient; -0.211, p<0.05). Among 10 food groups comprising DVS, the eating frequency of soybean and soybean products was the determinant of sleep disturbance in the stepwise liner regression analysis. In the further model that contained DVS, DVS was the independent determinant of sleep disturbance, while the eating frequency of soybean and soybean products was excluded. CONCLUSIONS: A worse sleep quality was associated with lower DVS in elderly Japanese women. Diet comprising various food groups was better for sleep quality than consuming only a particular food in the elderly.

DOI： 10.6133/apjcn.202106_30(2).0012

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1177/1010539521998861

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Obesity modifies the association between sodium and potassium intake and blood pressure. However, the impact of obesity on the relationship between the sodium-potassium balance and cardiovascular risk in type 2 diabetes (T2DM) patients remains unclear. We investigated the relationship between the 24-h urinary sodium-to-potassium ratio and serum asymmetric dimethylarginine (ADMA) level, which is a cardiovascular risk factor, in Japanese T2D patients with or without obesity. This cross-sectional study included 243 patients with T2DM who were hospitalized for diabetes education. Urinary sodium-to-potassium ratios were calculated from 24-h urine collection. The subjects were divided into two groups according to their BMIs (<25 and ≥25). The serum ADMA levels positively correlated with the urinary sodium-to-potassium ratios in non-obese patients, but not in obese patients. Multivariate linear regression analyses showed that the serum ADMA levels positively correlated with the urinary sodium-to-potassium ratios after adjustment for other confounders in non-obese patients. This correlation was observed in non-obese patients with hypertension, but not in those without hypertension. Measurement of the pulse wave velocity and intima-media thickness revealed that elevation of the serum ADMA levels was significantly associated with an increase in the degree of atherosclerotic progression in subjects with T2DM. Additionally, an assessment of dietary intake showed that the consumption of dairy products as well as of green and yellow vegetables was negatively associated with urinary sodium-to-potassium ratios in patients with T2DM. In conclusion, elevation of serum ADMA may be positively associated with the urinary sodium-to-potassium ratio in Japanese non-obese patients with T2DM.

DOI： 10.1038/s41440-018-0098-1

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Objectives: The purpose of this study was to assess the relationship between economic security and self-rated health for elderly Japanese residents living alone. Design: A secondary analysis of a cross-sectional study. Setting: N City, H. Prefecture, Japan. Participants: Survey questionnaires were distributed to 2,985 elderly residents living alone, aged ≥70 years, of which, 1,939 (65.0%) were returned and treated as valid responses. Measurements: The survey included questions about gender, age, number of years spent in N City, self-rated health, economic security, number of years spent living alone, reason for living alone, life satisfaction, cooking frequency, frequency of seeing a doctor, long-term care service usage, as well as whether they enjoyed their lives, participated in social organizations. Results: Of the respondents, 1,563 (80.6%) reported that they were economically secure, and 376 (19.4%) responded that they were insecure. The odds ratio predicting poor self-rated health for the economically insecure participants was significantly high (odds ratio: 3.19, 95%, Confidence Interval (CI): 2.53−4.02, and P < 0.001). Similarly, the adjusted odds ratio for poor self-rated health was significantly high for the economically insecure participants in multivariate analyses controlling for factors such as age, gender, cooking frequency, and social participation (adjusted odds ratio: 2.21, 95%, CI: 1.70−2.88, and P < 0.001). Furthermore, a similar trend was observed in stratified analyses based on gender and age groups. Conclusion: Economic security predicted self-rated health independently of confounders, including social participation and cooking frequency, among the elderly Japanese living alone in communities.

DOI： 10.1007/s12603-017-0994-0

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Language：Japanese   Publisher：(一社)日本臨床栄養協会  

重篤な疾患を有さない健康な高齢女性148名(平均78.0±6.0歳)を対象とした。平均血中25-OH-ビタミンD(25-OHD)濃度は23.4±5.4g/mlであった。血中25-OHD濃度によってビタミンD欠乏群(20ng/ml未満)29.1%、ビタミンD不足群(20以上30ng/ml未満)57.4%、ビタミンD正常群(30ng/ml以上)13.5%であった。血中25-OHD濃度を4分位に分け、最小値群は、最大値群に比べ有意に年齢が高く、四肢の骨格筋指数SMIや握力と骨量が低値傾向を示した。血中のカルシウムと亜鉛の濃度、ヘマトクリット値は、最小値群が最大値群に比べ有意に低値を示し、血清アルブミンは最小値群が最大値群に比べ低値傾向を示した。単相関では、血中25-OHD濃度と年齢との間に負の相関関係、握力、骨量との間に正の相関関係を認めた。単相関において、血中25-OHD濃度と血中のアルブミンとカルシウム、亜鉛の濃度、ヘマトクリット値において、それぞれ正の相関関係、血中シスタチンCとの間に負の相関関係を認めた。年齢とともに、血中亜鉛濃度が血中25-OHD濃度の独立した規定因子として抽出された。

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Language：Japanese   Publisher：[出版社不明]  

１人暮らし高齢者において、栄養状態が高齢者の社会参加の継続性にどのような影響を与えるかは明らかでない。2008年度の西宮市主催の「ふれあい昼食会」に参加した１人暮らし高齢者で、文書による同意が得られ、5年間経過観察可能であった135名を対象とした。途中で昼食会に参加しなくなった高齢者を脱落群、継続参加した高齢者を非脱落群とした。脱落群は47.4%と高率に存在し、脱落群は非脱落群に比し年齢が高く、Mini Nutritional Assessment（MNA）評価における低栄養の割合が高値を示した。Log-rank検定から80歳以上群は80歳未満群に比し、低栄養群は栄養状態良好群に比し、それぞれ有意に参加継続期間が短いことが分かった。また、Cox比例ハザードモデルによる多変量解析から、参加継続性の関連因子として、年齢とMNAによる低栄養がそれぞれ抽出された。男女全体に対し、女性では年齢と握力が関連因子として抽出された。以上より、１人暮らし高齢者において、年齢とともに低栄養が社会参加の継続性に関連する重要な因子であることが示唆された。
Objective: We examined whether nutritional status affects the continuity of social participation in Japanese elderly people who live alone.Methods: In retrospective observational study, physical measurements and mini nutritional assessment（MNA） were performed in 135 elderly participants to Fureai-luncheon party （2008-2012） who live alone.Results: Frequency of dropout group was 47.4% for 5 years and subjects in dropout group were older and with higher incidence of malnourished status by MNA as compared with those in non-dropout group. Both age and malnutrition were independently associated with a higher risk of dropout from social participation.Conclusion: This study showed that malnutrition and age are two independent risk factors for dropout from social participation in Japanese elderly people who live alone.

DOI： 10.14993/00002177

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The mineralocorticoid receptor (MR) and its downstream signaling play an important role in hypertensive renal injury. The interaction of advanced glycation end products (AGE) with their receptor (RAGE) is involved in the progression of renal disease. However, the pathological crosstalk between AGE-RAGE axis and MR system in kidney derangement remains unclear. We screened DNA-aptamer directed against RAGE (RAGE-apt) in vitro and examined its effects on renal injury in uninephrectomized deoxycorticosterone acetate (DOCA)/salt-induced hypertensive mice. RAGE, GTP-bound Rac-1 (Rac1), and MR were co-localized in the podocytes of DOCA mice. The deletion of RAGE gene significantly inhibited mesangial matrix expansion and tubulointerstitial fibrosis in DOCA mice, which was associated with the reduction of glomerular oxidative stress, MR, Rac1, and urinary albumin excretion (UAE) levels. RAGE-apt attenuated the increase in carboxymethyllysine (CML), RAGE, nitrotyrosine, Rac1, and MR levels in the kidneys and reduced UAE in DOCA mice. Aldosterone (Aldo) increased nitrotyrosine, CML, and RAGE gene expression in murine podocytes, whereas CML stimulated MR and Rac1 levels, which were blocked by RAGE-apt. The present study indicates the crosstalk between the AGE-RAGE axis and Aldo-MR system, suggesting that RAGE-apt may be a novel therapeutic tool for the treatment of MR-associated renal diseases.

DOI： 10.1038/s41598-018-21176-5

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Erythropoietin-resistant anemia is associated with adverse cardiovascular events in patients with ESRD, but the underlying mechanism remains unclear. Here, we evaluated the role of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA). In 54 patients with advanced CKD, erythrocyte but not plasma ADMA levels independently associated with low hemoglobin values, although levels of both types of ADMA were elevated compared with those in healthy volunteers. Furthermore, erythrocyte ADMA level associated with the erythropoietin resistance index in patients receiving a weekly injected dose of erythropoiesis-stimulating agents standardized for hemoglobin levels and body weight, whereas it correlated with the erythropoietin demand index (plasma erythropoietin units divided by the hemoglobin value) in patients not receiving erythropoiesis-stimulating agents. Compared with sham-operated controls, wild-type mice with 5/6 subtotal nephrectomy (Nx), a remnant kidney model with advanced CKD, had decreased hemoglobin, hematocrit, and mean corpuscular volume values but increased erythrocyte and plasma ADMA and plasma erythropoietin levels. In comparison, dimethylarginine dimethlaminohydrolase-1 transgenic (DDAH-1 Tg) mice, which efficiently metabolized ADMA, had significant improvements in all of the values except those for erythropoietin after 5/6 Nx. Additionally, wild-type Nx mice, but not DDAH-1 Tg Nx mice, had reduced splenic gene expression of erythropoietin receptor and erythroferrone, which regulates iron metabolism in response to erythropoietin. This study suggests that erythrocyte ADMA accumulation contributes to impaired response to erythropoietin in predialysis patients and advanced CKD mice via suppression of erythropoietin receptor expression.

DOI： 10.1681/ASN.2016111184

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BACKGROUND: Depression is highly prevalent in uremic patients undergoing hemodialysis (HD). We previously found that low free-carnitine levels are associated with depression severity in male patients undergoing HD. However, whether L-carnitine supplementation improves the depression state in male patients undergoing HD remains unclear. METHODS: Sixteen male patients undergoing HD were orally administered 900 mg L-carnitine daily or intravenously administered 1000 mg L-carnitine immediately after undergoing HD for 3 months. The depression state and various types of carnitine levels were evaluated using the self-rating depression scale (SDS) and tandem mass spectrometry, respectively, at baseline and 3 months after treatment. RESULTS: L-carnitine supplementation significantly increased serum levels of free and other acylcarnitine types, associated with improved SDS scores in male patients undergoing HD. Univariate analysis revealed that low baseline butyryl- and isovaleryl-/2-methylbutyryl-carnitine levels were significantly correlated with SDS scores after treatment. Multiple regression analysis revealed that butyryl-carnitine levels were a sole independent predictor of SDS scores after treatment (r2 = 0.533). CONCLUSION: L-carnitine supplementation for 3 months improved the depression state in uremic male patients undergoing HD. Thus, low butyryl-carnitine levels may predict the clinical response to L-carnitine supplementation in male patients undergoing HD and who have mild depression.

DOI： 10.2174/1570180814666170216102632

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高齢者では慢性腎臓病（CKD）患者は増加するが、内皮型一酸化窒素合成酵素（eNOS）遺伝子G894T多型と高齢者の腎機能との関連は明らかではない。本研究は、地域在住女性高齢者109名を対象に、G894T多型と腎機能との関連を検討した。eNOS遺伝子G894T多型（rs1799983）はTaqMan PCR法で解析した。Tアリル群はGG群に比し、eGFRが有意に低値であり、CKD患者割合が有意に高かった。さらに、Tアリル群においてのみ、eGFRとHDL-Cとの間に有意な正の相関、炎症指標TNF-αとの間に負の相関関係を認めた。Tアリル群において清涼飲料水を飲む習慣がある場合、HDL-Cは有意に低値を示したが、この関連はGG群では認められなかった。以上より、eNOS遺伝子G894T多型は、女性高齢者においてeGFRに関連すること、環境因子との相互作用によりeGFRに影響を与える可能性が示唆された。
Prevalence of chronic kidney diseases （CKD） is high in elderly. Although nitric oxide （NO） is an important regulator of renal function, relation between G894T polymorphic variant of endothelial NO synthase （eNOS） gene and renal function in the elderly is unclear. We investigated the association between G894T and renal function in 109 of community-dwelling elderly Japanese women. G894T polymorphic variants （rs1799983） are assessed by the TaqMan PCR method. T allele （GT and TT）group showed lower estimated glomerular filtration rate （eGFR） and a higher incidence of CKD（eGFR<60 ml/min/1.73m２） compared to those in GG genotype group. eGFR was associated with HDL-C and inversely associationed with TNF-α only in the T allele group. Additionally HDL-C was positively correlated with sweetened soft drink consumption habit in the T allele group, but not in the GG group. In conclusion, G894T polymorphism might be associated with eGFR and might interact with environmental factors to influence eGFR in community-dwelling elderly Japanese women.

DOI： 10.14993/00002176

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BACKGROUND: Maternal exposure to overnutrition during fetal development contributes to metabolic and renal damage in offspring. Adiponectin plays a protective role against obesity-related renal injury. However, role of adiponectin in renal injury of offspring exposed to maternal overnutrition remains unknown. We addressed the issue. METHODS: Female Sprague-Dawley rats were fed either a standard (N) or a high-fat and high-fructose (HFF)-diet for 6 weeks before mating, and kept each diet during the gestation and lactation period. After 4 weeks postpartum, all the offspring were fed N diet, and followed by 12 weeks. Kidney weight, urinary albumin excretion, blood pressure, and blood chemistry, including adiponectin and malondialdehyde, a marker of oxidative stress, were evaluated in the offspring. RESULTS: Compared with N-offspring, serum adiponectin levels of 1-day- and 4-week-old HFF-offspring were significantly lower, the latter of which was inversely associated with malondialdehyde. Kidney weight was significantly decreased in 1-day-old HFF-offspring, whereas increased in 4-week-old HFF-offspring. Urinary albumin excretion levels of HFF-offspring at 8, 12, and 16-week old were significantly higher than those of N-offspring at the same age, whose levels at 16-week old were inversely correlated with plasma adiponectin. Compared with N-offspring, HFF-offspring at 16-week old exhibited glomerulosclerosis, hyperglycemia, and high mean blood pressure associated with reduced podocin and increased transforming growth factor-β1 expression in the kidneys. CONCLUSIONS: Our present study suggests that exposure to maternal HFF-diet during fetal and early postnatal development induces hypoadiponectinemia in offspring, which might cause renal injury and metabolic derangements later in life.

DOI： 10.1007/s10157-016-1265-9

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Mitochondrial dysfunction causes increased oxidative stress and depletion of ATP, which are involved in the etiology of a variety of renal diseases, such as CKD, AKI, and steroid-resistant nephrotic syndrome. Antioxidant therapies are being investigated, but clinical outcomes have yet to be determined. Recently, we reported that a newly synthesized indole derivative, mitochonic acid 5 (MA-5), increases cellular ATP level and survival of fibroblasts from patients with mitochondrial disease. MA-5 modulates mitochondrial ATP synthesis independently of oxidative phosphorylation and the electron transport chain. Here, we further investigated the mechanism of action for MA-5. Administration of MA-5 to an ischemia-reperfusion injury model and a cisplatin-induced nephropathy model improved renal function. In in vitro bioenergetic studies, MA-5 facilitated ATP production and reduced the level of mitochondrial reactive oxygen species (ROS) without affecting activity of mitochondrial complexes I-IV. Additional assays revealed that MA-5 targets the mitochondrial protein mitofilin at the crista junction of the inner membrane. In Hep3B cells, overexpression of mitofilin increased the basal ATP level, and treatment with MA-5 amplified this effect. In a unique mitochondrial disease model (Mitomice with mitochondrial DNA deletion that mimics typical human mitochondrial disease phenotype), MA-5 improved the reduced cardiac and renal mitochondrial respiration and seemed to prolong survival, although statistical analysis of survival times could not be conducted. These results suggest that MA-5 functions in a manner differing from that of antioxidant therapy and could be a novel therapeutic drug for the treatment of cardiac and renal diseases associated with mitochondrial dysfunction.

DOI： 10.1681/ASN.2015060623

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OBJECTIVES: Food or supplement-derived L-carnitine is changed to trimethylamine (TMA) by interstinal microbiota, which is further metabolized to trimethylamine-N-oxide (TMAO), being involved in the promotion of atherosclerosis in animal models. Meanwhile, carnitine deficiency has played a role in accelerated atherosclerosis in hemodialysis (HD) patients. However, effects of oral L-carnitine supplementation on circulating levels of TMAO and markers of vascular injury and oxidative stress in patients on HD remain unclear. In this study, we addressed the issue. METHODS: Thirty-one HD patients with carnitine deficiency were treated with oral L-carnitine (900 mg/d) for 6 months. At baseline and after treatment, clinical variables including circulating levels of carnitine fractions, TMA, TMAO, advanced glycation end products (AGE), soluble forms of intracellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and malondialdehyde (MDA) were measured. RESULTS: Oral L-carnitine supplementation significantly increased total, free, acyl carnitine, and plasma TMA and TMAO levels, whereas it decreased markers of vascular injury and oxidative stress such as sICAM-1, sVCAM-1, and MDA levels. TMA and TMAO levels at baseline were correlated with each other, and free carnitine was independently associated with TMAO levels. Furthermore, change in AGE values from baseline ([INCREMENT]AGE) was positively correlated with [INCREMENT]sICAM-1 (P = 0.043) and was a sole independent determinant of [INCREMENT]sICAM-1 (R = 0.133, P = 0.043). CONCLUSIONS: This study demonstrated that although oral L-carnitine supplementation was associated with increased TMAO levels, it might be beneficial on vascular injury in patients on HD. Vasculoprotective properties of L-carnitine supplementation in HD patients might be ascribed partly to its inhibitory actions on AGE.

DOI： 10.1097/FJC.0000000000000197

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Language：English   Publisher：(公社)日本栄養・食糧学会  

Gly m Bd 28K (Gm28K), a soybean allergen, is formed as a preproprotein consisting of a predicted signal peptide, Gm28K, and the 23-kDa peptide (Gm23K). Gm28K and Gm23K are found in the protein-storage vacuoles (PSVs) of developing soybean seeds. However, the complete structure of Gm28K has not yet been identified and its processing and transport to the vacuoles has never been clarified. In the present study, we elucidated the 5'-nucleotide sequence of cDNA encoding the Gm28K precursor and identified a putative signal peptide (SP) with 24 N-terminal amino acid residues. We expressed peptides from the Gm28K precursor as fusion proteins with enhanced green fluorescent protein (EGFP) in tobacco BY2 suspension-cultured cells. BY2 cells transformed by an expression vector for SP-EGFP-Gm28-Gm23K (SP-EGFP-Gm28-Gm23K/BY2 cells) and SP-Gm28-Gm23K-EGFP/BY2 cells produced the EGFP fused-Gm28K precursor, and the EGFP-fluorescence in their vacuoles were recorded. In the experiments with SP-EGFP/BY2 and SP-EGFP-Gm28K/BY2 cells, large amounts of the EGFP segments were secreted into the medium. On the other hand, the fluorescence of EGFP in SP-EGFP-Gm23K/BY2 cells was shown to accumulate only in the endoplasmic reticulum without secretion into the medium. These findings show that the SP signals the precursor to enter the lumen of the endoplasmic reticulum and that both the Gm28K and Gm23K components may be involved in the transport from the endoplasmic reticulum (ER) lumen via the Golgi to the vacuoles in a proprotein form.

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2014&ichushi_jid=J04559&link_issn=&doc_id=20140513430009&doc_link_id=1390282681301589632&url=https%3A%2F%2Fcir.nii.ac.jp%2Fcrid%2F1390282681301589632&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_3.gif

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Ischemia/reperfusion injury is the leading cause of acute tubular necrosis. Nitric oxide has a protective role against ischemia/reperfusion injury; however, the role of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, in ischemia/reperfusion injury remains unclear. ADMA is produced by protein arginine methyltransferase (PRMT) and is mainly degraded by dimethylarginine dimethylaminohydrolase (DDAH). Here we examined the kinetics of ADMA and PRMT and DDAH expression in the kidneys of ischemia/reperfusion-injured mice. After the injury, DDAH-1 levels were decreased and renal and plasma ADMA values were increased in association with renal dysfunction. Renal ADMA was correlated with 8-hydroxy-2'-deoxyguanosine, a marker of oxidative stress. An antioxidant, N-acetylcysteine, or a proteasomal inhibitor, MG-132, restored these alterations. Infusion of subpressor dose of ADMA exacerbated renal dysfunction, capillary loss, and tubular necrosis in the kidneys of ischemia/reperfusion-injured wild mice, while damage was attenuated in DDAH transgenic mice. Thus, ischemia/reperfusion injury-induced oxidative stress may reduce DDAH expression and cause ADMA accumulation, which may contribute to capillary loss and tubular necrosis in the kidney.

DOI： 10.1038/ki.2013.398

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Inflammation is involved in renal fibrosis, a final common pathway for kidney diseases. To clarify how JAK/STAT/SOCS system was involved in renal fibrosis, UUO was induced in BALB/c or SOCS3(+/-) mice in the presence or absence of JAK inhibitor-incorporated nanoparticle (pyridine6-PGLA). UUO increased pSTAT3 and subsequently elevated SOCS3 levels in the obstructed kidneys. pSTAT3 levels were further increased in SOCS3(+/-) mice. UUO-induced renal fibrosis was markedly suppressed in SOCS3(+/-) mice, while it was aggravated by pre-treatment with pyridine6-PGLA. Although there were no differences in renal mRNA levels of TGF-β and collagens between wild and SOCS3(+/-) mice, MMP-2 activity was enhanced in SOCS3(+/-) UUO mice. Activated MMP-2 was completely suppressed by pyridine6-PGLA-pre-treatment. TNF-α one of JAK/STAT activators, increased pSTAT3 levels and subsequently induced MMP-2 activation in proximal tubular cells. These results suggest that JAK/STAT3 signaling may play a role in repair process of renal fibrosis in UUO partly via MMP-2 activation.

DOI： 10.1016/j.clim.2013.11.003

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Cardiorenal syndrome (CRS) is a condition in which there is a complex interrelationship between cardiovascular disease (CVD) and chronic kidney disease (CKD). Impairment of one organ could accelerate pathological processes in the other, which in turn accelerates the progression of failure of both. Although clinical studies hint at a specific bidirectional interaction between cardiovascular system and kidney, insight into the pathogenesis of CRS remains unknown. One possible factor that could explain this link is endothelial dysfunction (ED). ED is not only involved in initiation and progression of atherosclerosis, but also contributes to progression of renal injury. Asymmetric dimethylarginine (ADMA) is an endogenous NO synthase inhibitor found in the plasma and cells. Plasma ADMA levels are increased in CKD patients and known to be an independent biomarker and predictor for future cardiovascular events as well as the progression of CKD. These findings indicate that accumulated ADMA-mediated ED may play important roles in CRS in CKD patients. In this review, we discuss the roles of ADMA in the development of ED, especially focusing on its roles in CRS.

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Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, plays a role in endothelial dysfunction, an initial step of atherosclerosis. Advanced glycation end products (AGEs) also contribute to accelerated atherosclerosis. However, a pathophysiological crosstalk between ADMA and AGEs remains unclear. In this study, we investigated the relationship between ADMA and AGE level in patients with end-stage renal disease (ESRD) due to diabetic nephropathy. We also examined whether and how AGEs increased ADMA generation by cultured endothelial cells (ECs). Plasma ADMA levels were positively associated with serum AGE level and were inversely correlated with endothelial function determined by flow-mediated vasodilatation. AGEs dose dependently increased reactive oxygen species (ROS) generation in ECs, which was blocked by antisense DNA raised against receptor for AGEs (RAGE). Furthermore, AGEs decreased messenger RNA (mRNA) level of dimethylarginine dimethylaminohydrolase (DDAH)-II, an enzyme for ADMA degradation, reduced its total enzymatic activity and resultantly increased ADMA, all of which were completely blocked by an antioxidant, N-acetylcysteine. These results suggest that the AGE-RAGE-mediated ROS generation could be involved in endothelial dysfunction in diabetic ESRD patients partly by increasing the ADMA generation via suppression of DDAH activity in ECs.

DOI： 10.1177/1479164113486662

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.foodchem.2011.10.011

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

We produced a monoclonal antibody (mAb) against N(G),N(G)-dimethyl-L-arginine (asymmetric dimethylarginine: ADMA), an endogenous competitive inhibitor of nitric oxide synthase (NOS), and developed an enzyme-linked immunosorbent assay (ELISA). The competitive ELISA method using the mAb determined 5 nM-100 nM ADMA, and ADMA levels in human plasma and urine were found to be 0.78 µM and 51.3 µmol/g of creatinine respectively.

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

N(G), N(G)-Dimethyl-L-arginine (asymmetric dimethylarginine: ADMA) is an endogenous competitive inhibitor of nitric oxide synthase (NOS). Plasma ADMA concentrations have been reported to increase in connection with diseases associated with an impaired endothelial L-arginine/NO pathway. In this study, we investigated the metabolism of ADMA in circulating blood cell populations to elucidate the regulatory mechanism of elevation of plasma ADMA, a novel risk factor for cardiovascular disease. We found by RT-PCR and Western blot analyses that protein arginine methyltransferase (PRMT)1 and dimethylarginine dimethylaminohydrolase (DDAH)-1, responsible for the biosynthesis and degradation of ADMA respectively, are expressed in erythrocytes (ECs), leukocytes, and platelets. We also identified a major ADMA-containing protein in ECs as catalase, confirmed by GST-pull down assay to bind to PRMT1 in vitro. This is the first report that the ADMA-metabolizing system, including the arginine methylation of proteins and the breakdown of free ADMA, occurs in circulating blood cell-populations, and that catalase in ECs might be a potential protein targeted by PRMT1.

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Tropomyosin had been identified as a major allergen in shrimp. The digestion and absorption of tropomyosin (Pen j 1) from kuruma prawn were investigated by ex vivo, in vitro, and in vivo techniques in order to elucidate the relationship between the allergenicity of the allergen and its gastrointestinal behavior. Pen j 1 transported the Caco-2 monolayer in a dose-dependent manner, and also enhanced the permeability of lucifer yellow, a marker of paracellular transportation, at high concentrations of the allergen. Studies with everted sacs revealed that Pen j 1 was rapidly degraded to small peptides (MW<3.5 kDa) and amino acids by intestinal proteases and absorbed from enterocytes. Furthermore, Pen j 1 orally administered to rats tended to remain in the stomach rather than in the small intestine, after which the allergen moved to the epithelial cells. These observations suggest that Pen j 1 may be absorbed via the gastric mucosa prior to its digestion in the intestines.

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Language：Japanese  

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