Kaori Endoh

Bilobalide in Ginkgo biloba extract is a major substance inducing hepatic CYPs.

In a search for substances related to the marked induction of hepatic cytochrome P450 (CYP) by ginkgo biloba extract (GBE), mice were given either GBE (1000 mg kg−1) or fractions of GBE for 5 days. The content and activity of CYPs were induced markedly by a bilobalide‐rich fraction, but not by flavonoid‐rich fractions. The level of induction by the bilobalide‐rich fraction was almost the same as that induced by the unfractionated GBE, suggesting that bilobalide is largely responsible for the CYPs induction. To confirm these findings, mice were given various doses of bilobalide (10.5, 21 and 42 mg kg−1), or GBE (1000 mg kg−1, containing bilobalide at 42 mg kg−1). Treatment with bilobalide induced CYPs markedly and in a dose‐dependent manner, and the level of induction was quite similar between bilobalide (42 mg kg−1) and GBE. Treatment with GBE and with bilobalide greatly induced pentoxyresorufin O‐dealkylase activity. These findings indicate that bilobalide is the major substance in GBE that induces hepatic CYPs.

Low folate status increases chromosomal damage by X-ray irradiation

Purpose: To examine how folate status influences chromosomal damage following X-ray irradiation. Material and methods: In an animal study, mice were fed either a low, basal, or high folic acid diet (0, 2, or 40 mg/kg diet, respectively) for 4 weeks, and then given total body irradiation (TBI) at 0.5 Gy. In a human study, subjects were supplemented with folic acid (800 μg/day) for 2 weeks and their peripheral blood was irradiated at 0.5 Gy in vitro. Chromosomal damage was determined by micronucleus assay. Results: In an animal study, TBI-induced chromosomal damage was higher and folate concentration was lower in the bone marrow of the low folic acid group compared to the other two diet groups. The chromosomal damage and folate concentration were comparable between the basal and high folic acid groups. TBI administered to mice decreased folate in the plasma, erythrocyte and bone marrow. In a human study, supplementation with folic acid increased plasma folate, but did not influence either plasma homocysteine or X-ray-induced chromosomal damage in lymphocytes. Conclusion: Low folate status increases susceptibility to X-ray-induced chromosomal damage, but excessive folic acid supplementation under normal conditions yields no further protection due to folate saturation in the target tissue.

Vulnerability of folate in plasma and bone marrow to total body irradiation in mice

Purpose: To examine how folate status in a body is influenced by oxidative stress. Material and methods: Mice were given total body irradiation (TBI) by X-ray, and changes in the concentration of folate were compared to those in vitamins C and E. Results: In a time-dependent study, folate in plasma and bone marrow decreased from 5 h until 120 h post-TBI at 3 Gy. Folate in plasma and bone marrow decreased in a dose-dependent manner at 24 h. Marked decreases of vitamins C and E were also detected in bone marrow, but not in plasma even at 10 Gy of TBI. The susceptibility of plasma folate by irradiation was confirmed by an in vitro exposure study. Neither vitamins C and E nor folate were decreased in the liver by TBI. Conclusion: It is suggested that folate is vulnerable to oxidative stress, and folate may need to be evaluated, particularly for TBI or radiotherapy.

Interactions between Psychological Stress and Drinking Status in Relation to Diet among Middle-Aged Men and Women: A Large-Scale Cross-Sectional Study in Japan

The aim of this study was to investigate the interaction between psychological stress (PS) and drinking status in relation to diet among middle-aged Japanese men and women in a large-scale cross-sectional study. The study population included 5,587 middle-aged Japanese men and 2,718 middle-aged Japanese women who underwent annual health checkups. The subjects were divided into 2 groups (non-drinkers and drinkers) and classified as having low, moderate, or high self-reported PS levels. Energy-adjusted food and nutrient consumption was assessed with a validated food frequency questionnaire. Using a general linear model, food and nutrient consumption was estimated for each self-reported PS level in the 2 groups (non-drinkers and drinkers) and the interactions between self-reported PS levels and drinking status were calculated. In men, pork and beef; squid, octopus, shrimp, and clams; eggs; mushrooms; Japanese-style sweets; ice cream; bread; Chinese noodles; coffee; and soda as foods and protein, animal protein, fat, animal fat, carbohydrate, monounsaturated fatty acid, polyunsaturated fatty acid (PUFA), n-3 PUFA, n-6 PUFA, cholesterol, vitamin D, vitamin B2, vitamin B6, vitamin B12, niacin, pantothenic acid, magnesium, phosphorus, and zinc as nutrients significantly interacted with self-reported PS levels and drinking status (p for interaction <0.05 for all). No specific interactions were found in women. These findings suggest interactions between PS levels and drinking status with consumption of some foods and nutrients, especially macronutrient intake, in men but not in women.

Low folate status enhanced benzene-induced cytogenetic damage in bone marrow of mice : A relationship between dietary intake and tissue levels of folate

Abstract We examined the protective effect of dietary folate on benzene-induced chromosomal damage in bone marrow of mice regarding folate levels in diet and tissue. Male mice were fed either a deficient, basal, or high folate diet (0, 2, or 8 mg/kg diet, respectively) for 4 wk followed by a single dose of benzene. Plasma folate levels corresponded to those of dietary intake. Meanwhile, bone marrow, erythrocyte, and liver folate were decreased to 40% in the deficient group and almost saturated in the high group. Plasma homocysteine levels negatively correlated to levels of tissue folate. Chromosomal damage, evaluated by micronucleus assay, was not affected by folate status alone but was markedly enhanced by benzene, particularly in the deficient group (P < 0.05 vs. the basal and high groups). The activities of hepatic drug-metabolizing enzymes did not enhance benzene metabolism in the deficient groups, indicating that enhanced chromosomal damage was solely due to the low folate status. These results suggest that a low folate status can increase the risk of benzene-induced chromosomal damage in bone marrow, but excess folate intake does not enhance protection, as it is saturated in tissue.

Genetic Variants of RAMP2 and CLR are Associated with Stroke

Aim: Stroke is associated closely with vascular homeostasis, and several complex processes and interacting pathways, which involve various genetic and environmental factors, contribute to the risk of stroke. Although adrenomedullin (ADM) has a number of physiological and vasoprotective functions, there are few studies of the ADM receptor system in humans. The ADM receptor comprises a calcitonin-receptor-like receptor (CLR) and receptor activity-modifying proteins (RAMPs). We analyzed single nucleotide polymorphisms (SNPs) in the RAMP2 and CLR genes to determine their association with stroke in the light of gene-environment interactions. Methods: Using cross-sectional data from the Japan Multi-Institutional Collaborative Cohort Study in the baseline surveys, 14,087 participants from 12 research areas were genotyped. We conducted a hypothesis-based association between stroke prevalence and SNPs in the RAMP2 and CLR genes based on data abstracted from two SNPs in RAMP2 and 369 SNPs in CLR. We selected five SNPs from among the CLR variants (rs77035639, rs3815524, rs75380157, rs574603859, and rs147565266) and one RAMP2 SNP (rs753152), which were associated with stroke, for analysis. Results: Five of the SNPs (rs77035639, rs3815524, rs75380157, rs147565266, and rs753152) showed no significant association with obesity, ischemic heart disease, hypertension, dyslipidemia, and diabetes. In the logistic regression analysis, rs574603859 had a lower odds ratio (0.238; 95% confidence interval, 0.076–0.745, adjusted for age, sex, and research area) and the other SNPs had higher odds ratios for association with stroke. Conclusions: This was the first study to investigate the relationships between ADM receptor genes (RAMP2 and CLR) and stroke in the light of gene-environment interactions in human.

Association of genetic risk score and chronic kidney disease in a Japanese population: Genetic risk score and chronic kidney disease

Chronic kidney disease (CKD) is a public health problem worldwide including Japan. Recent genome‐wide association studies have discovered CKD susceptibility variants. We developed a genetic risk score (GRS) based on CKD‐associated variants and assessed a possibility that the GRS can improve the discrimination capability for the prevalence of CKD in a Japanese population. The present study consists of 11 283 participants randomly selected from 12 Japan Multi‐Institutional Collaborative Cohort Study sites. Individual GRS was constructed combining 18 single‐nucleotide polymorphisms identified in a Japanese population. Participants with eGFR <60 mL/min per 1.73 m2 was defined as case (stage 3 CKD or higher) in this study. Logistic regression analysis was used to examine the association between the GRS and CKD risk with adjustment for sex, age, hypertension and type 2 diabetes mellitus. The frequency of individuals with CKD was 8.3%, which was relatively low compared with those previously reported in a Japanese population. The odds ratio of having CKD was 1.120 (95% confidence interval: 1.042–1.203) per 10 GRS increment in the fully adjusted model (P = 0.002). The C‐statistic was significantly increased in the model with the GRS, comparing with the model without the GRS (0.720 vs 0.719, Pdifference = 0.008). Increment of the GRS was associated with increased risk of CKD. Additionally, the GRS significantly improved the discriminatory ability of CKD prevalence in a Japanese population; however, the improvement of discriminatory ability brought about by the GRS seemed to be small compared with that of non‐genetic CKD risk factors.

A genome-wide association study of coping behaviors suggests FBXO45 is associated with emotional expression

Individuals use coping behaviors to deal with unpleasant daily events. Such behaviors can moderate or mediate the pathway between psychosocial stress and health‐related outcomes. However, few studies have examined the associations between coping behaviors and genetic variants. We conducted a genome‐wide association study (GWAS) on coping behaviors in 14088 participants aged 35 to 69 years as part of the Japan Multi‐Institutional Collaborative Cohort Study. Five coping behaviors (emotional expression, emotional support seeking, positive reappraisal, problem solving and disengagement) were measured and analyzed. A GWAS analysis was performed using a mixed linear model adjusted for study area, age and sex. Variants with suggestive significance in the discovery phase (N = 6403) were further examined in the replication phase (N = 7685). We then combined variant‐level association evidence into gene‐level evidence using a gene‐based analysis. The results showed a significant genetic contribution to emotional expression and disengagement, with an estimation that the 19.5% and 6.6% variance in the liability‐scale was explained by common variants. In the discovery phase, 12 variants met suggestive significance (P < 1 × 10−6) for association with the coping behaviors and perceived stress. However, none of these associations were confirmed in the replication stage. In gene‐based analysis, FBXO45, a gene with regulatory roles in synapse maturation, was significantly associated with emotional expression after multiple corrections (P < 3.1 × 10−6). In conclusion, our results showed the existence of up to 20% genetic contribution to coping behaviors. Moreover, our gene‐based analysis using GWAS data suggests that genetic variations in FBXO45 are associated with emotional expression.

Genome-Wide Association Study of Renal Function Traits: Results from the Japan Multi-Institutional Collaborative Cohort Study

Background: Chronic kidney disease (CKD) is a rapidly growing, worldwide public health problem. Recent advances in genome-wide-association studies (GWAS) revealed several genetic loci associated with renal function traits worldwide. Methods: We investigated the association of genetic factors with the levels of serum creatinine (SCr) and the estimated glomerular filtration rate (eGFR) in Japanese population-based cohorts analyzing the GWAS imputed data with 11,221 subjects and 12,617,569 variants, and replicated the findings with the 148,829 hospital-based Japanese subjects. Results: In the discovery phase, 28 variants within 4 loci (chromosome [chr] 2 with 8 variants including rs3770636 in the LDL receptor related protein 2 gene locus, on chr 5 with 2 variants including rs270184, chr 17 with 15 variants including rs3785837 in the BCAS3 gene locus, and chr 18 with 3 variants including rs74183647 in the nuclear factor of activated T-cells 1 gene locus) reached the suggestive level of p < 1 × 10–6 in association with eGFR and SCr, and 2 variants on chr 4 (including rs78351985 in the microsomal triglyceride transfer protein gene locus) fulfilled the suggestive level in association with the risk of CKD. In the replication phase, 25 variants within 3 loci (chr 2 with 7 variants, chr 17 with 15 variants and chr 18 with 3 variants) in association with eGFR and SCr, and 2 variants on chr 4 associated with the risk of CKD became nominally statistically significant after Bonferroni correction, among which 15 variants on chr 17 and 3 variants on chr 18 reached genome-wide significance of p < 5 × 10–8 in the combined study meta-analysis. The associations of the loci on chr 2 and 18 with eGFR and SCr as well as that on chr 4 with CKD risk have not been previously reported in the Japanese and East Asian populations. Conclusion: Although the present GWAS of renal function traits included the largest sample of Japanese participants to date, we did not identify novel loci for renal traits. However, we identified the novel associations of the genetic loci on chr 2, 4, and 18 with renal function traits in the Japanese population, suggesting these are transethnic loci. Further investigations of these associations are expected to further validate our findings for the potential establishment of personalized prevention of renal disease in the Japanese and East Asian populations.

Actual Daily Intakes of Tea Catechins and Thier Estimation According to Four Season 3 Day Weighed Dietary Records and a Short Food Frequency Questionnaire among Japanese Men and Women

Background: Tea catechins are considered to be important preventive factors of cancer on several organs; however, the relationships of the actual daily intakes (ADIs) on the preventive effects have not been adequately addressed. We measured the ADIs of tea catechins as annual averages derived from every their ingested cups recorded by each subject, and the estimation models were established considering tea origin. Methods: Fifty-nine Japanese men and women completed four season 3 day weighed dietary records (WDRs) and a food frequency questionnaire (FFQ), and samples of green, oolong and black teas, ingested during a total 12 days were collected for the analysis. The ADIs of the total and composed catechins of all tea samples were measured by a high-performance liquid chromatography. The estimation models for the ADIs (R2: coefficient of determination) based on the WDRs and FFQ were established with multiple regression analysis using appropriate confounding factors. V Results: The ADIs of total catechins and epigallocatechin gallate (EGCg) were 110 and 21.4 mg/day in men and 157 and 34.7 mg/day in women, respectively. The total catechins ADIs were positively associated with green tea consumption based on WDRs and FFQ (adjusted R2 =0.421 and 0.341 for men and 0.346 and 0.238 for women, p<0.05 for all, respectively). Likewise, the EGCg ADIs were associated with green tea intake derived from WDRs and FFQ, respectively. Conclusions: We revealed the ADIs of total catechins and EGCg as annual averages could establish their estimation models. These provide reference information to clarify their relationships with cancer risks.