Hak Chul Jang

EGb761, a Ginkgo Biloba Extract, Is Effective Against Atherosclerosis In Vitro, and in a Rat Model of Type 2 Diabetes

Background EGb761, a standardized Ginkgo biloba extract, has antioxidant and antiplatelet aggregation and thus might protect against atherosclerosis. However, molecular and functional properties of EGb761 and its major subcomponents have not been well characterized. We investigated the effect of EGb761 and its major subcomponents (bilobalide, kaemferol, and quercetin) on preventing atherosclerosis in vitro, and in a rat model of type 2 diabetes. Methods and Results EGb761 (100 and 200 mg/kg) or normal saline (control) were administered to Otsuka Long-Evans Tokushima Fatty rats, an obese insulin-resistant rat model, for 6 weeks (from 3 weeks before to 3 weeks after carotid artery injury). Immunohistochemical staining was performed to investigate cell proliferation and apoptosis in the injured arteries. Cell migration, caspase-3 activity and DNA fragmentation, monocyte adhesion, and ICAM-1/VCAM-1 levels were explored in vitro. Treatment with EGb761 dose-dependently reduced intima-media ratio, proliferation of vascular smooth muscle cells (VSMCs) and induced greater apoptosis than the controls. Proliferation and migration of VSMCs in vitro were also decreased by the treatment of EGb761. Glucose homeostasis and circulating adiponectin levels were improved, and plasma hsCRP concentrations were decreased in the treatment groups. Caspase-3 activity and DNA fragmentation increased while monocyte adhesion and ICAM-1/VCAM-1 levels decreased significantly. Among subcomponents of EGb761, kaemferol and quercetin reduced VSMC migration and increased caspase activity. Conclusions EGb761 has a protective role in the development of atherosclerosis and is a potential therapeutic agent for preventing atherosclerosis.

Long-term oral exposure to bisphenol A induces glucose intolerance and insulin resistance

Bisphenol A (BPA) is a widely used endocrine disruptor. Recent epidemiologic results have suggested an association between exposure to BPA and cardiovascular disease, type 2 diabetes, and obesity. We investigated the in vivo effects of long-term oral exposure to BPA on insulin resistance and glucose intolerance. In the present study, 4- to 6-week-old male mice on a high-fat diet (HFD) were treated with 50 μg/kg body weight per day of BPA orally for 12 weeks. Long-term oral exposure to BPA along with an HFD for 12 weeks induced glucose intolerance in growing male mice. Intraperitoneal glucose tolerance tests showed that the mice that received an HFD and BPA exhibited a significantly larger area under the curve than did those that received an HFD only (119.9±16.8 vs. 97.9±18.2 mM/min, P=0.027). Body weight, percentage of white adipose tissue, and percentage of body fat did not differ between the two groups of mice. However, treatment with BPA reduced Akt phosphorylation at position Thr308 and GSK3β phosphorylation at position Ser9 in skeletal muscle. BPA tended to decrease serum adiponectin levels and to increase serum interleukin 6 and tumor necrosis factor α, although these findings were not statistically significant. Treatment with BPA did not induce any detrimental changes in the islet area or morphology or the insulin content of β cells. In conclusion, long-term oral exposure to BPA induced glucose intolerance and insulin resistance in growing mice. Decreased Akt phosphorylation in skeletal muscle by way of altered serum adipocytokine levels might be one mechanism by which BPA induces glucose intolerance.

A common mutation in cholesteryl ester transfer protein gene and plasma HDL cholesterol level before and after hormone replacement therapy in Korean postmenopausal women

Background Plasma cholesteryl ester transfer protein (CETP) functions to transfer cholesteryl ester from HDL to trigiyceride-rich lipoproteins and regulates plasma HDL cholesterol level. A common mutation, the exon 15 A to G substitution at codon 442 (D442G) results in reduced plasma CETP activity and increased plasma HDL cholesterol level. Meanwhile, hormone replacement therapy (HRT) in postmenopausal women increases plasma HDL cholesterol level. Methods We investigated the frequency of D442G mutation and its effect on plasma HDL cholesterol level in Korean women. We also examined if the mutation has any effect on an increase in plasma HDL cholesterol level during HRT. Results Two hundred and twenty eight women aged over 40 years were recruited in this study. Of 228 women, 22 (9.6%) were identified as having the D442G mutation; 21 heterozygotes and 1 homozygote. The subjects with the mutation had higher plasma HDL cholesterol levels than those without the mutation (61.6±17.3 vs. 55.1±14.0 mg/dL, p<0.05). After 12 month HRT, HDL cholesterol increased by 6.4% (3.6±13.2 mg/dL, p<0.05) and D442G mutation did not have any significant effect on the change of plasma HDL cholesterol level. Conclusion D442G mutation is common in Korean postmenopausal women and it is associated with increased plasma HDL cholesterol level. HRT for postmenopausal women increased plasma HDL cholesterol level in similar amounts regardless of the presence or absence of D442G mutation.

Subclinical hypothyroidism in addition to common risk scores for prediction of cardiovascular disease: a 10-year community-based cohort study

OBJECTIVE This study was carried out to determine whether serum TSH levels improve the prediction of cardiovascular risk in addition to common clinical risk scores, given the association between subclinical hypothyroidism (SCH) and cardiovascular disease (CVD). DESIGN We carried out an observational study in a prospective cohort. METHODS The study included a total of 344 SCH and 2624 euthyroid participants aged over 40 years and who were without previously recorded CVDs were included in this study analysis. We measured thyroid function and traditional risk factors at baseline and estimated the 10-year cumulative incidence of CVD in a gender-stratified analysis. RESULTS During 10 years of follow-up, 251 incident cardiovascular events were recorded. The elevation of serum TSH levels significantly increased the CV risk independent of conventional risk factors in men. In the atherosclerotic CVD (ASCVD) risk score or the Reynolds risk score (RRS) model, the addition of serum TSH levels had no effect on model discrimination as measured by the area under the curve in either women or men. Adding serum TSH did not improve the net reclassification improvement in either women (3.48% (P=0.29) in the ASCVD, -0.89% (P=0.75) in the RRS, respectively) or men (-1.12% (P=0.69), 3.45% (P=0.20), respectively) and only mildly affected the integrated discrimination Improvement in the ASCVD-adjusted model (0.30% in women and 0.42% in men, both P=0.05). CONCLUSIONS In the context of common risk scoring models, the additional assessment of serum TSH levels provided little incremental benefit for the prediction of CV risk.

Nonassociation of interleukin-1 receptor antagonist genotypes with bone mineral density, bone turnover status, and estrogen responsiveness in Korean postmenopausal women

Interleukin-1 receptor antagonist (IL-1ra), a natural inhibitor of interleukin-1 (IL-1), completely inhibits the stimulatory effects of IL-1 on bone resorption. Bioactivity of IL-1 increases in the estrogen-deficient state with an increased IL-1:IL-1ra ratio and decreases after estrogen replacement therapy with a decreased IL-1:IL-1ra ratio. An association was found between an 86 basepair variable number tandem-repeat (VNTR) polymorphism of the IL-1ra gene and an increased production of IL-1ra in a cultured monocyte system. The IL-1ra VNTR polymorphism, therefore, is an attractive candidate gene for osteoporosis susceptibility as well as hormone responsiveness after estrogen replacement. We examined the association of this VNTR polymorphism with bone mass, bone turnover, and the change of bone mineral density (BMD) after 1 year of hormone replacement therapy (HRT). The frequencies of the five alleles were as follows: A1, 90.8% (410 bp, four repeats); A2, 7.2% (240 bp, two repeats); A3, 1.6% (500 bp, five repeats); A4, 0.4% (326 bp, three repeats); and A5, 0% (595 bp, six repeats), in 714 healthy ethnically Korean postmenopausal women, aged 41-74 years (55.2 +/- 6.3 years mean +/- SD). Spine (L2-4) and femoral neck BMD were not significantly different among IL-1ra genotypes, and no significant genotypic differences were found in bone markers. There were no differences in genotypic proportions when we categorized the subjects into a high-loss group and a normal-loss group with regard to levels of bone marker. No significant genotypic differences were found in changes in lumbar and femoral neck BMD and those in bone markers before and after 1 year of HRT in 312 women. Our data suggest that these IL-1ra polymorphisms are not associated with BMD, bone turnover, or the change of BMD after 1 year of HRT in Korean women.

A case of gastric cancer initially presenting with polydipsia.

Metastatic brain tumors from gastric cancer are extremely rare. A 61-year-old Korean woman, initially presenting with polydipsia and polyuria, was found to have metastatic lesions in the brain by MRI. We performed several diagnostic procedures to determine the origin of the brain metastases. She was revealed to have a soft tissue mass of the right adrenal gland and fungating ulcers in the stomach. Histologic studies of both the adrenal gland mass and gastric tissues revealed malignant tumors composed of anaplastic cells. Based on the electron microscopy study, the malignant tumor of the right adrenal gland was a metastatic lesion from the anaplastic carcinoma of stomach. Therefore, the malignant tumors of the brain were assumed to have originated from the gastric cancer. This case report is presented to make clinicians aware of the possibility that diabetes insipidus (polydipsia) may present as an initial manifestation of brain metastases.