Ji-Myung Kim

Effect of folate deficiency on placental DNA methylation in hyperhomocysteinemic rats

We report that the maternal folate status can influence folate-mediated one-carbon metabolism and DNA methylation in the placenta. Thirty-six female Sprague-Dawley rats were divided into the following three dietary groups: folate-supplemented (FS; 8 mg/kg folic acid, n=12), homocystine- and folate-supplemented (HFS; 0.3% homocystine and 8 mg/kg folic acid, n=12) and homocystine-supplemented and folate-deficient (HFD; 0.3% homocystine and no folic acid, n=12). The animals were fed their experimental diets from 4 weeks prior to mating until Day 20 of pregnancy (n=7-9 per group). The HFS diet increased the plasma homocysteine and placental DNA methylation but did not affect plasma folate, vitamin B-12, S-adenosyl methionine (SAM) or S-adenosyl homocysteine (SAH) levels, or the SAM/SAH ratio in the liver and placenta compared with the FS diet. The HFD diet induced severely low plasma folate concentrations, with plasma homocysteine levels increasing up to 100 micromol/L, and increased hepatic SAH and decreased placental SAM levels and SAM/SAH ratio in both tissues, with a concomitant decrease in placental DNA methylation. Placental DNA methylation was significantly correlated with placental (gamma=0.819), hepatic (gamma=0.7) and plasma (gamma=0.752) folate levels; plasma homocysteine level (gamma=-0.688); hepatic SAH level (gamma=-0.662) and hepatic SAM/SAH ratio (gamma=0.494). These results suggest that the maternal folate status in hyperhomocysteinemic rats influences the homeostasis of folate-mediated one-carbon metabolism and the methyl pool, which would, in turn, affect placental DNA methylation by altering the methylation potential of the liver.

S-Allyl-l-cysteine attenuates cerebral ischemic injury by scavenging peroxynitrite and inhibiting the activity of extracellular signal-regulated kinase

S-Allyl-l-cysteine (SAC) has been shown to reduce ischemic injury due to its antioxidant activity. However, the antioxidant property of SAC has been controversial. The present study investigated the neuroprotective mechanism of SAC in cerebral ischemic insults. SAC decreased the size of infarction after transient or global ischemic insults. While it did not alter the N-methyl-d-aspartate excitotoxicity, SAC significantly scavenged the endogenously or exogenously produced ONOO− and reduced ONOO− cytotoxicity. In contrast, SAC has much lower scavenging activity against H2O2, or NO. Further, SAC inhibited the activity of extracellular signal-regulated kinase (ERK) increased in cultured neurons exposed to oxygen-glucose deprivation or in rat brain tissue after transient middle cerebral artery occlusion. The neuroprotective effect of SAC was mimicked by the ERK inhibitor U0125. The present results indicate that SAC exert its neuroprotective effect by scavenging ONOO− and inhibiting the ERK signaling pathway activated during initial hypoxic/ischemic insults.

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.

Protective Effect of β-Caryophyllene, a Natural Bicyclic Sesquiterpene, Against Cerebral Ischemic Injury

β-Caryophyllene (trans-4,11,11-trimethyl-8-methylenebicyclo[7,2,0]undec-4-ene), found in various plants, is a natural bicyclic sesquiterpene with a low toxicity. Here, we show that a single intraperitoneal injection of β-caryophyllene (10 mg/kg) significantly reduced the cortical infarct volume by 67% when given immediately before middle cerebral artery occlusion (MCAO). Neurological deficits caused by MCAO were also significantly decreased by β-caryophyllene. β-Caryophyllene treatment of cortical cells exposed to oxygen-glucose deprivation revealed a significant protection in a dose-dependent manner. However, β-caryophyllene neither suppressed N-methyl-D-aspartate excitotoxicity in cultured cortical cells nor markedly decreased the oxidative stress measured in the cellular or acellular systems. By contrast, treatments with β-caryophyllene dose-dependently inhibited mRNA expression of inducible nitric oxide synthetase, interleukin (IL)-1β, IL-6, and cyclooxygenase 2 in C6 microglial cells, and decreased the level of nitric oxide and prostaglandin E₂ at a 100 μM concentration. All of these findings suggest that β-caryophyllene has a potent neuroprotective activity, and its neuroprotection may be partly related to the modulation of inflammatory mediators.

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.

Neuroprotective Effects of Several Korean Medicinal Plants Traditionally Used for Stroke Remedy

The neuroprotective effect of six aqueous extracts and one alcoholic extract prepared from seven medicinal plants that have been recorded as having therapeutic effects for stroke in Korean traditional medicine were studied using both in vitro and in vivo cerebral ischemia models. Among the extracts tested, the aqueous extracts of Acorus gramineus, Chrysanthemum indicum, and Pinus densiflora and the alcoholic extract of Vitis vinifera significantly increased the cell viability of SK-N-SH human neuroblastoma cells exposed to oxygen-glucose deprivation (P < .05). Following two-vessel occlusion in gerbils, extracts of P. densiflora and V. vinifera significantly increased the number of surviving cells/mm(2) of the CA1 region by 2.1-2.2-fold (P < .01). Oral or intraperitoneal administration of S-allyl cysteine, as a positive control, also markedly increased cell survival up to about 3.3-fold at the dosage of 300 mg/kg of body weight (P < .01). These results indicate that P. densiflora and V. vinifera exert neuroprotective effects against ischemic insults in both the in vitro and in vivo cerebral ischemia models and prompted us to further characterize the detailed mechanism of action and elucidate the active principles.

Dietary S-Allyl-L-cysteine Reduces Mortality with Decreased Incidence of Stroke and Behavioral Changes in Stroke-Prone Spontaneously Hypertensive Rats

S-Allyl-L-cysteine (SAC), an active organosulfur compound derived from garlic, was found to reduce mortality with lesser incidence of stroke and also to lower the overall stroke-related behavioral score in stroke-prone spontaneously hypertensive (SHRSP) rats by dietary administration. Consequently, the anti-stroke effect of dietary SAC was demonstrated in SHRSP rats.

Association between high sensitivity C-reactive protein and dietary intake in Vietnamese young women

BACKGROUND/OBJECTIVES High sensitivity C-reactive protein (hsCRP) is a strong independent predictor of future cardiovascular disease (CVD) risk. We evaluated the relationship between hsCRP and dietary intake in apparently healthy young women living in southern Vietnam. SUBJECTS/METHODS Serum hsCRP was measured and dietary intake data were obtained using the 1-day 24-hour recall method in women (n = 956; mean age, 25.0 ± 5.7 years) who participated in the International Collaboration Study for the Construction of Asian Cohort of the Korean Genome and Epidemiology Study (KoGES) in 2011. RESULTS Women in the high risk group (> 3 mg/L) consumed fewer fruits and vegetables, total plant food, potassium, and folate than those in the low risk group (< 1 mg/L). A multiple regression analysis after adjusting for covariates revealed a significant negative association between hsCRP and fruit and vegetable consumption. A logistic regression analysis showed that the odds ratio (OR) of having a high hsCRP level in women with the highest quartiles of consumption of fruits and vegetables [OR, 0.391; 95% confidence interval (CI), 0.190-0.807], potassium [OR, 0.425; 95% CI, 0.192-0.939] and folate [OR, 0.490; 95% CI, 0.249-0.964] were significantly lower than those in the lowest quartiles. CONCLUSIONS These results suggest that, in young Vietnamese women, an increased consumption of fruit and vegetables might be beneficial for serum hsCRP, a risk factor for future CVD events.

Intake of antioxidants and B vitamins is inversely associated with ischemic stroke and cerebral atherosclerosis

BACKGROUND/OBJECTIVES This study was conducted to examine relationships between dietary habits and intakes of antioxidants and B vitamins and the risk of ischemic stroke, and to compare dietary factors according to the presence of cerebral artery atherosclerosis and stroke subtypes. SUBJECTS/METHODS A total of 147 patients and 144 control subjects were recruited consecutively in the metropolitan area of Seoul, Korea. Sixty participants each in the case and control groups were included in analyses after 1:1 frequency matching. In addition, 117 acute ischemic stroke patients were classified into subtypes according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) guidelines. Dietary intake was measured using a semi-quantitative food frequency questionnaire composed of 111 food items and plasma lipid and homocysteine levels were analyzed. RESULTS When compared with control subjects, stroke patients had unfavorable dietary behaviors and lower intakes of fruits (73.1 ± 83.2 g vs. 230.9 ± 202.1 g, P < 0.001), vegetables (221.1 ± 209.0 g vs. 561.7 ± 306.6 g, P < 0.001), and antioxidants, including vitamins C, E, B6, β-carotene, and folate. The intakes of fruits, vegetables, vitamin C, and folate were inversely associated with the risk of ischemic stroke after adjusting for confounding factors. Intakes of vegetables, vitamins C, B6, B12, and folate per 1,000 kcal were lower in ischemic stroke with cerebral atherosclerosis than in those without. Overall vitamin B12 intake per 1,000 kcal differed according to the TOAST classification (P = 0.004), but no differences among groups existed based on the post-hoc test. CONCLUSIONS When compared with control subjects, ischemic stroke patients, particularly those with cerebral atherosclerosis, had unfavorable dietary intake, which may have contributed to the development of ischemic stroke. These results indicate that proper dietary recommendations are important for the prevention of ischemic stroke.

Associations of dietary intake and metabolic syndrome risk parameters in Vietnamese female marriage immigrants in South Korea: the KoGES follow-up study.

BACKGROUND/OBJECTIVES This study was conducted to compare the overall changes in dietary intake and metabolic syndrome risk parameters in Vietnamese marriage-based female immigrants over time. SUBJECTS/METHODS The subjects of this study were 581 Vietnamese marriage-based female immigrants, who were recruited from local clinical centers in Korea. Baseline data were collected from 2006-2011 and the follow-up data were collected from 2012-2014. Dietary food intake was assessed by a 1-day 24-hour recall method. RESULTS Compared to the baseline, the mean body weight, body mass index, waist circumference, high density lipoprotein (HDL)-cholesterol, systolic blood pressure and diastolic blood pressure increased while the fasting blood sugar, triglycerides and low density lipoprotein-cholesterol decreased at follow-up. The total consumption of foods such as vegetables/fruits/seaweeds/mushrooms, oil and fat, and eggs decreased during the follow-up period, whereas the consumption of sugars, beverages and meats increased. Partial correlation between the rate of change [(Follow-up - Baseline) / Baseline × 100] in metabolic syndrome risk parameters and food intake after controlling for confounding factors showed that the waist circumference was positively correlated with either the total plant food intake (r = 0.1042, P = 0.0129) or the total food intake (r = 0.0880, P = 0.0359). The plasma levels of total cholesterol (r = -0.1918, P = 0.0289) and HDL-cholesterol (r = -0.1424, P = 0.0007) were negatively correlated with the percentage of total intake from plant food, and HDL-cholesterol levels were positively correlated with the intake of total animal food (r = 0.0980, P = 0.0217). The serum C-reactive protein levels were positively correlated with the total intake of animal food (r = 0.2374, P < 0.0001) or the percentage of total intake from animal food (r = 0.1346, P = 0.0016). CONCLUSIONS These results suggest that the change rate of dietary intake such as total plant food or animal food is associated with the change rates of metabolic syndrome risk parameters.