Hwayoung Lee

Effects of dietary folic acid supplementation on cerebrovascular endothelial dysfunction in rats with induced hyperhomocysteinemia

This study shows, for the first time, that hyperhomocysteinemia induces endothelial dysfunction in a rat brain, and that this can be alleviated by dietary folic acid supplementation. Our experiments examined the effects of folic acid supplementation on the endothelial nitric oxide synthase (eNOS) expression in the hyperhomocysteinemic rat brain, and related the observed changes in eNOS expression to the expression of the cell adhesion molecule and the glucose transporter protein. The animals were raised on an experimental diet containing 0.3% homocystine for 2 weeks and then they were placed either on a 0.3% homocystine, 0.3% homocystine with 8 mg/kg folic acid, or folic acid (8 mg/kg) diet for 2 weeks. The cerebrovascular eNOS activity was examined immunohistochemically. Cerebral levels of eNOS, glucose transporter-1 (GLUT-1), and the vascular cell adhesion molecule-1 (VCAM-1) proteins were evaluated by Western blot analysis. At 4 weeks, the homocystine diet induced a fourfold increase in plasma homocysteine (control: 6.5+/-0.4 micromol/l, homocystine: 26.2+/-2.5 micromol/l), and a reduction in the cerebral eNOS and GLUT-1 expression levels with a concomitant increase in the level of VCAM-1 expression. Dietary folic acid supplementation caused a significant decrease in the plasma homocysteine levels, a concomitant increase in the hyperhomocysteinemia-induced reduction in the cerebral eNOS and GLUT-1 expression levels, and a decrease in the hyperhomocysteinemia-induced VCAM-1 expression levels.

Short-term hyperhomocysteinemia-induced oxidative stress activates retinal glial cells and increases vascular endothelial growth factor expression in rat retina.

Hyperhomocysteinemia is associated with an increase in the incidence of vascular diseases, including retinal vascular diseases. We examined the effects of high plasma levels of homocysteine on retinal glial cells and vascular endothelial growth factor (VEGF) expression. Male Sprague-Dawley rats were fed either a 3.0 g/kg homocystine diet or a control diet for 2 week. The homocystine-diet group had higher plasma levels of homocysteine and thiobarbituric acid reactive substances (TBARSs) and lower plasma levels of folate, retinol, α-tocopherol, and retinal expression of CuZn superoxide dismutase (SOD) than the controls. The rats fed the homocystine-diet showed an increase in vimentin, glial fibrillary acidic protein (GFAP), and VEGF immunoreactivity in the retina as compared to the controls. The increase in vimentin immunoreactivity in the hyperhomocysteinemic rats was correlated with changes in GFAP immunoreactivity in astrocytes within the ganglion cell layer. We found for the first time that short-term hyperhomocysteinemia-induced oxidative stress activates retinal glial cells and increases VEGF expression in the retina.

Ultra-long antagonism of kappa opioid agonist-induced diuresis by intracisternal nor-binaltorphimine in monkeys.

Kappa opioid receptor (KOR) agonists such as U-50488H and bremazocine are analgesics and diuretics. In monkeys, the selective KOR antagonist, nor-binaltorphimine (nor-BNI), produces a long-lasting antagonism of the antinociceptive effects of U-50488H but not those of bremazocine, suggesting that KOR-mediated antinociception may occur through two distinct KORs. The aim of this study was to characterize the antagonist effect of nor-BNI against the diuretic effects of U-50488H and bremazocine in monkeys. Urine outputs were collected over 3 h subsequent to i.m. administration of KOR agonists. Both U-50488H (0.032-1 mg/kg) and bremazocine (0.00032-0.01 mg/kg) dose-dependently increased urine output and the diuretic effect reached a plateau at higher doses. The maximum effect of either U-50488H or bremazocine was approximately 15 ml/kg/3 h of urine. Pretreatment with intracisternal nor-BNI 0.32 mg significantly blocked both U-50488H (0.18 mg/kg)- and bremazocine (0.0032 mg/kg)-induced diuresis for 20 weeks. However, the same dose of nor-BNI 0.32 mg given subcutaneously was not effective. These results demonstrate that central KOR mediate KOR agonist-induced diuresis in monkeys. More important, this study provides functional evidence for a homogenous population of KOR underlying KOR-mediated diuresis and illustrates a unique pharmacological profile of nor-BNI-induced ultra-long KOR antagonism in vivo.

The Association Between Fetal and Postnatal Growth Status and Serum Levels of Uric Acid in Children at 3 Years of Age

BACKGROUND Recent studies suggest that uric acid plays a causal role in the development of hypertension in relation to birth weight. The aim of the study was to elucidate the effect of prenatal and/or postnatal growth status on serum uric acid levels in children at 3 years of age. METHODS A total of 178 children from the birth cohort at Ewha Womans University Hospital were followed. Anthropometric characteristics, blood pressure, and serum uric acid were measured at 3 years of age. RESULTS The level of serum uric acid was significantly higher in hypertensive children (3.8 mg/dl) than in nonhypertensive children (3.4 mg/dl). Preterm birth and lower placental weight were the preterm factors significantly associated with increased serum uric acid in early childhood. In addition, current weight, body mass index, and change-in-weight s.d. score from birth to current were also associated with serum uric acid level. Both the first- and fourth-quartile groups for weight and weight gain presented higher levels of serum uric acid. We found that the highest uric acid level belonged to the group of preterm or low birth weight (LBW) and higher change in weight s.d. score. Children who were born at full term or with a normal birth weight and lower change in weight s.d. score had the lowest serum uric acid levels. CONCLUSION Preterm birth and a subsequent high rate of postnatal weight gain are risk factors for increased serum uric acid levels in early childhood.

Association of vitamin D concentrations with adiposity indices among preadolescent children in Korea

Abstract Background and Objective: We aimed to investigate the association between serum 25-hydroxyvitamin D (25(OH)D) and anthropometric indicators of adiposity among Korean preadolescent children aged 7–9 years. Subjects and Methods: Children aged 7 to 9 from the Ewha Birth & Growth Cohort were followed up from July to August 2011. Serum 25(OH)D concentration was measured using radio immunoassay. We assessed the magnitude of cross-sectional association with vitamin D concentrations and indicators of adiposity [body mass index (BMI), waist circumference (WC), mid-arm circumference (MAC), body fat mass (BFM), percent body fat (PBF), and triceps skinfold thickness (TSF)] using multiple linear and logistic regression analyses adjusted for sex, age, birth order, maternal education, and fruit/fruit juice intake. Results: Thirty-two (16%) out of a total of 205 children showed an optimal level of serum 25(OH)D, but most children did not reach a sufficient level (<30 ng/mL) even in summer. The level of 25(OH)D was inversely associated with BMI (β=–0.10, p<0.01), WC (β=–0.28, p<0.01), and BFM (β=–0.12, p=0.02) after adjusting for confounding factors and showed marginal boundary with PBF (β=–0.20, p=0.06) and TSF (β=–0.11, p=0.08). Regarding the risk of overweight, a 13% protective effect per 1 ng/mL increase of 25(OH)D was shown even after adjusting for relevant confounding factors (adjusted odds ratio=0.87, 95% confidence interval 0.78–0.98). Conclusions: We found that the 25(OH)D concentrations were inversely associated with adiposity indices in preadolescent children. This study suggests that adequate vitamin D intake in growing children is crucial to maintain an optimal vitamin D level to prevent obesity and obesity-related health problems later in life.

Mendelian Randomization Analysis of the Effect of Maternal Homocysteine During Pregnancy, as Represented by Maternal MTHFR C677T Genotype, on Birth Weight

Background We used Mendelian randomization analysis to investigate the causal relationship between maternal homocysteine level, as represented by maternal methylenetetrahydrofolate reductase (MTHFR) C677T genotype, with the birth weight of offspring. Methods We recruited women at 24 to 28 weeks’ gestation who visited Ewha Womans University Hospital for prenatal care during the period from August 2001 to December 2003. A total of 473 newborns with a gestational age of at least 37 weeks were analyzed in this study. We excluded twin births and children of women with a history of gestational diabetes, gestational hypertension, or chronic renal disease. The association of maternal homocysteine concentration with the birth weight of infants was analyzed using 2-stage regression. Results MTHFR C677T genotype showed a dose–response association with homocysteine concentration for each additional T allele (Ptrend < 0.01). Birth weight decreased from 120 to 130 grams as maternal homocysteine level increased, while controlling for confounding factors; however, the association was of marginal significance (P = 0.06). Conclusions Our results suggest an adverse relationship between maternal homocysteine level and birth weight. A reduction in homocysteine levels might positively affect birth outcomes.

The preventive effect of breast-feeding for longer than 6 months on early pubertal development among children aged 7–9 years in Korea

OBJECTIVE The present study was performed to investigate whether breast-feeding is associated with early pubertal development among children 7-9 years old in Korea. DESIGN Children were divided into those who did and did not receive breast-feeding for 6 months or longer in accordance with the recommendations of the WHO. Pubertal status was determined by clinical examination using Tanner staging. SETTING Prospective observational study. SUBJECTS We conducted a follow-up study of children aged 7-9 years in 2011 who had taken part in the Ewha Birth & Growth Cohort study. RESULTS Fifty (22.8%) of the total of 219 children were in early puberty, with the proportion being slightly higher for girls (24.1%) than boys (21.4%). Children who had entered early puberty were taller, weighed more and had a higher concentration of insulin-like growth factor 1. Moreover, the change in weight Z-score from birth to follow-up was significantly lower in children who were breast-fed than in those who were not (weight Z-score change: 0.32 (sd 1.59) v. 0.77 (sd 1.61), respectively, P=0.04). Comparison of breast-feeding by puberty status indicated a preventive association with early puberty in children who were breast-fed for 6 months or longer (OR=0.37; 95% CI 0.18, 0.74). This association remained significant after adjustment for relevant covariates. CONCLUSIONS These results demonstrate a beneficial association between breast-feeding and early pubertal development, especially in those breast-fed for 6 months or longer. The study suggests that interventions would need to start early in life to prevent early pubertal development.

Effect of Urinary Bisphenol A on Androgenic Hormones and Insulin Resistance in Preadolescent Girls: A Pilot Study from the Ewha Birth & Growth Cohort

To assess the effect of urinary bisphenol A (BPA) on repeated measurements of androgenic hormones and metabolic indices, we used multivariate analysis of variance (MANOVA) adjusted for potential confounders at baseline. During July to August 2011, 80 preadolescent girls enrolled in the Ewha Birth & Growth Cohort study participated in a follow-up study and then forty-eight of them (60.0%) came back one year later. Baseline levels of estradiol and androstenedione were higher in the BPA group than in the non-BPA group. One year later, girls in the high BPA exposure group showed higher levels of androstenedione, testosterone, estradiol, and insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) index, than those in the other groups (p < 0.05). In MANOVA, estradiol and androstenedione showed significant differences among groups, while dehydroepiandrosterone, insulin, and HOMA-IR showed marginally significant differences. Exposure to BPA may affect endocrine metabolism in preadolescents. However, further investigation is required to elucidate the mechanisms linking BPA with regulation of androgenic hormones.

Is the association between ACE genes and blood pressure mediated by postnatal growth during the first 3 years

Unlike the defined role of angiotensin-converting enzyme (ACE) gene in adult hypertension, ACE gene did not show direct influence on childhood blood pressure (BP), rather, seemed to be related to childhood growth with age-dependent characteristics. Thus, we examined intermediate effects of postnatal growth between the ACE polymorphisms and BP. We analyzed data from 257 children born in 2001-04 at Ewha Womans University Hospital in Seoul, Korea, and followed them up until 3 years of age. Children with excessive adiposity had higher BP, as rapid growers did to no-change and decelerated growers. The ACE II genotype was associated with greater growth acceleration than the DD genotype (II: 46.8% vs. DD: 23.9%), and with a higher BP. The interactions between ACE genotype and adiposity at age 3 were significant on the BP levels. The highest BP increase with the same degree of adiposity was observed in those with the II genotype [β (SE) for BMI: 1.9 (0.9), p=0.04]; particularly, only rapid grown II carriers demonstrated statistical significance on this linear association. These results suggested that ACE polymorphisms and BP association are mediated by postnatal growth. Further studies are required to determine the age-specific ACE genetic effects and its undefined biological mechanism.

Effects of Adrenal Androgen Levels on Bone Age Advancement in Prepubertal Children: Using the Ewha Birth and Growth Cohort Study

Bone age (BA) advancement in prepubertal children may be associated with earlier onset of puberty and obesity. This study aimed to define the effects of adrenal androgen levels on the advancement of BA in prepubertal children, independent of obesity. During July and August 2011, we examined BA in 200 prepubertal children aged 7–9 years who were part of the Ewha Birth & Growth Cohort Study. BA was assessed by the Greulich-Pyle method. An index of BA advancement was calculated as the ratio of BA to chronological age (CA) (BA/CA), and this ratio was classified into 3 tertiles. We analyzed the relationship between BA advancement and anthropometric characteristics and adrenal hormone levels. The number of overweight children increased from the first group to the third group (PTrend = 0.03). The levels of adrenal androgens showed a significant positive correlation with the tertile groups after adjusting for age and sex (testosterone: r = 0.26, P < 0.001; dehydroepiandrosterone: r = 0.21, P < 0.001; androstenedione: r = 0.20, P < 0.001). Further, after controlling for body mass index (BMI), sex, and age, the BA/CA was found to be positively correlated with androstenedione (β = 0.04, R2 = 3.7%) and testosterone levels (β = 0.05, R2 = 4.7%). Based on our results, it is suggested that adrenal androgen levels are associated with BA advancement independent of BMI.