Estrogen Receptor-1 Genetic Polymorphisms for the Risk of Premature Ovarian Failure and Early Menopause

Background: The aim of this study was to investigate the role of the estrogen receptor 1 (ESR1) genetic polymorphisms for early menopause that was classified as premature ovarian failure (POF) and early menopause (EM) and to examine whether the associations of ESR1 genetic variants are different for POF and EM. Methods: We selected 100 POF cases and matched 100 EM cases and 200 normal menopause (NM) controls from the Korean Multi-Center Cohort. Among them, we restricted idiopathic POF and EM cases vs NM controls by excluding POF/EM cases with medical/surgical causes. The XbaI (rs9340799) and PvuII (rs2234693) in the ESR1 gene were genotyped. The single-nucleotide polymorphism (SNP) and haplotype effects were analyzed by multivariate logistic regression and haplotype analysis. Also nominal polytomous logistic regression was used to find whether ESR1 genetic variants are differently associated with POF and EM. Results: The global p values for idiopathic POF and EM were 0.08 and 0.39 (SNP-based), and <0.001 and 0.12 (haplotype-based), respectively. The XbaI genetic variant containing the X allele was marginally significantly associated with a reduced risk of idiopathic POF (OR=0.6, 95% CI 0.3-1.0). The P-x haplotype and diplotypes significantly decreased the risk of idiopathic POF (OR=0.5, 95% CI 0.2-0.9; OR 0.4, 95% CI 0.2-0.9, respectively). In contrast from POF, the P-x haplotypes and diplotypes insignificantly increased the risk for both idiopathic EM (p(polytomous)=0.009 for P-x haplotype; p(polytomous)=0.02 for P-x diplotypes). Conclusion: Our results suggest that the ESR1 gene including PvuII and XbaI polymorphisms may modify the risk of idiopathic premature ovarian failure (POF) but not idiopathic early menopause (EM) risk.Bretherick KL, 2008, FERTIL STERIL, V89, P318, DOI 10.1016/j.fertnstert.2007.03.008Chang SH, 2007, MATURITAS, V58, P19, DOI 10.1016/j.maturitas.2007.04.001Kitamura I, 2007, BONE, V40, P1623, DOI 10.1016/j.bone.2007.02.016Molvarec A, 2007, HYPERTENS RES, V30, P205Hsieh YY, 2007, MOL HUM REPROD, V13, P117, DOI 10.1093/molehr/gal099Dvornyk V, 2006, MATURITAS, V54, P19, DOI 10.1016/j.maturitas.2005.08.005Onland-Moret NC, 2005, CANCER CAUSE CONTROL, V16, P1195, DOI 10.1007/s10552-005-0307-5Popat RA, 2005, NEUROLOGY, V65, P383Schuit SCE, 2005, EUR J ENDOCRINOL, V153, P327, DOI 10.1530/eje.1.01973Kok HS, 2005, HUM REPROD, V20, P536, DOI 10.1093/humrep/deh600Ioannidis JPA, 2004, JAMA-J AM MED ASSOC, V292, P2105van der Klift M, 2004, J BONE MINER RES, V19, P1172, DOI 10.1359/JBMR.040215Schuit SCE, 2004, JAMA-J AM MED ASSOC, V291, P2969Wasserman L, 2004, INT J OBESITY, V28, P49, DOI 10.1038/sj.ijo.0802481van Meurs JBJ, 2003, HUM MOL GENET, V12, P1745, DOI 10.1093/hmg/ddg176Gorai I, 2003, J CLIN ENDOCR METAB, V88, P799, DOI 10.1210/jc.2002-020353Laml T, 2002, HUM REPROD UPDATE, V8, P483Herrington DM, 2002, CIRCULATION, V105, P1879, DOI 10.1161/01.CIR.0000016173.98826.88Kobayashi N, 2002, MATURITAS, V41, P193YOO KY, 2002, ASIAN PAC J CANCER P, V3, P85de Bruin JP, 2001, HUM REPROD, V16, P2014Pelletier G, 2000, J CLIN ENDOCR METAB, V85, P4835Weiderpass E, 2000, CARCINOGENESIS, V21, P623Yan G, 2000, J WOMEN HEALTH GEN-B, V9, P275Lorentzon M, 1999, J CLIN ENDOCR METAB, V84, P4597Weel AEAM, 1999, J CLIN ENDOCR METAB, V84, P3146Drummond AE, 1999, MOL CELL ENDOCRINOL, V151, P57, DOI 10.1016/S0303-7207(99)00038-6Christin-Maitre S, 1998, MOL CELL ENDOCRINOL, V145, P75Torgerson DJ, 1997, EUR J OBSTET GYN R B, V74, P63vanderSchouw YT, 1996, LANCET, V347, P714Kobayashi S, 1996, J BONE MINER RES, V11, P306NELSON LM, 1996, REPROD ENDOCRINOLOGY, P1394KAPRIO J, 1995, HUM BIOL, V67, P739CRAMER DW, 1995, FERTIL STERIL, V64, P740EXCOFFIER L, 1995, MOL BIOL EVOL, V12, P921NELSON LM, 1994, J CLIN ENDOCR METAB, V79, P1470CAPLAN GA, 1994, J ROY SOC MED, V87, P200PALMER JR, 1992, AM J EPIDEMIOL, V136, P408BAGUR AC, 1992, CALCIFIED TISSUE INT, V51, P4FRANCESCHI S, 1991, INT J CANCER, V49, P57MEYER JM, 1991, AM J MED GENET, V39, P148TRELOAR SA, 1990, AM J HUM GENET, V47, P137SNOWDON DA, 1989, AM J PUBLIC HEALTH, V79, P709

Estrogen receptor-α gene haplotype is associated with primary knee osteoarthritis in Korean population

Estrogen and estrogen receptors (ERs) are known to play important roles in the pathophysiology of osteoarthritis (OA). To investigate ER-α gene polymorphisms for its associations with primary knee OA, we conducted a case–control association study in patients with primary knee OA (n = 151) and healthy individuals (n = 397) in the Korean population. Haplotyping analysis was used to determine the relationship between three polymorphisms in the ER-α gene (intron 1 T/C, intron 1 A/G and exon 8 G/A) and primary knee OA. Genotypes of the ER-α gene polymorphism were determined by PCR followed by restriction enzyme digestion (PvuII for intron 1 T/C, XbaI for intron 1 A/G, and BtgI for exon 8 G/A polymorphism). There was no significant difference between primary knee OA patients and healthy control individuals in the distribution of any of the genotypes evaluated. However, we found that the allele frequency for the exon 8 G/A BtgI polymorphism (codon 594) was significantly different between primary knee OA patients and control individuals (odds ratio = 1.38, 95% confidence interval = 1.01–1.88; P = 0.044). In haplotype frequency estimation analysis, there was a significant difference between primary knee OA patients and control individuals (degrees of freedom = 7, χ(2 )= 21.48; P = 0.003). Although the number OA patients studied is small, the present study shows that ER-α gene haplotype may be associated with primary knee OA, and genetic variations in the ER-α gene may be involved in OA

Impact of Glutathione S-Transferase M1 and T1 Gene Polymorphisms on the Smoking-Related Coronary Artery Disease

Glutathione S-transferase (GST) plays a key role in the detoxification of xenobiotic atherogen generated by smoking. To analyze the effect of GSTM1/T1 gene polymorphisms on the development of smoking-related coronary artery disease (CAD), 775 Korean patients who underwent coronary angiography were enrolled. The subjects were classified by luminal diameter stenosis into group A (>50%), B (20-50%), or C (<20%). GSTM1 and GSTT1 gene polymorphisms were analyzed using multiplex polymerase chain reaction (PCR) for GSTM1/T1 genes and CYP1A1 gene for internal control. Of 775 subjects, 403 patients belonged to group A. They had higher risk factors for CAD than group B (N=260) and group C (N=112). The genotype frequencies of null GSTM1 and GSTT1 showed no significant differences among 3 groups. Considering the effect of GSTM1 gene polymorphisms on the smoking-related CAD, smokers with GSTM1 null genotype had more increased risk for CAD than non-smoker with GSTM1 positive genotype (odds ratios [OR], 2.07, confidence interval [CI], 1.06-4.07). Also the effect of GSTT1 gene polymorphism on smoking-related CAD showed the same tendency as GSTM1 gene (OR, 2.00, CI, 1.05-3.84). This effect of GSTM1/T1 null genotype on smoking-related CAD was augmented when both gene polymorphisms were considered simultaneously (OR, 2.76, CI, 1.17-6.52). We concluded that GSTM1/T1 null genotype contributed to the pathogenesis of smoking-related CAD to some degree

The association of PBX1 polymorphisms with overweight/obesity and metabolic alterations in the Korean population

Pre-B-cell leukemia transcription factor 1 (PBX1), which is located on chromosome 1q23, was recently reported to be associated with type 2 diabetes mellitus. We examined whether single nucleotide polymorphisms (SNPs) of the PBX1 gene are associated with overweight/obesity in a Korean population. We genotyped 66 SNPs in the PBX1 gene and investigated their association with clinical phenotypes found in 214 overweight/obese subjects and 160 control subjects using the Affymetrix Targeted Genotyping chip array. Seven SNPs (g.+75186C>T, g.+78350C>A, g.+80646C>T, g.+138004C>T, g.+185219G>A, g.+191272A>C, and g.+265317T>A) were associated with the risk of obesity in three models (codominant, dominant, and recessive) (P=0.007-0.05). Haplotype 1 (CAC) and 3 (TAC) of block 3 and haplotype 2 (GGAAT) of block 10 were also strongly associated with the risk of obesity. In the control group, subjects that had homozygote for the major allele for both g.+185219G>A and g.+191272A>C showed lower high density lipoprotein-cholesterol (HDL-C) level compared to those possessing the minor allele, suggesting that the association between the homozygote for the major allele for both g.+185219G>A and g.+191272A>C and HDL-C is attributable to the increased risk of obesity. This study suggests that the PBX1 gene is a possible risk factor in overweight/obese patients

Study of Pharmacodynamic and Pharmacokinetic Interaction of Bojungikki-Tang with Aspirin in Healthy Subjects and Ischemic Stroke Patients

Background. Bojungikki-tang (BJIKT) is a widely used traditional herbal formula in China, Japan, and Korea. There have been reports that several herbs among BJIKT have interactions with antiplatelet drugs, such as aspirin. This study aimed to assess whether BJIKT interacts with aspirin in terms of pharmacokinetics (PK) and pharmacodynamics (PD) in healthy subjects and ischemic stroke patients. Methods. The phase I interaction trial was a randomized, open-label, crossover study of 10 healthy male subjects, and the phase III interaction trial was a randomized, placebo-controlled, parallel study of 43 ischemic stroke patients. Each participant randomly received aspirin + BJIKT or aspirin + placebo. For PK analysis, plasma acetyl salicylic acid (ASA) and salicylic acid (SA) were evaluated, and, for PD analysis, platelet aggregation and plasma thromboxane B2 (TxB2) were measured. Results. In the PK parameters, mean area under curve, maximum concertation, and peak concentration time of ASA and SA were not different between two groups in healthy subjects and ischemic stroke patients. In the PD profiles, TxB2 concentrations and platelet aggregation were not affected by coadministration of BJIKT in healthy subjects and ischemic stroke patients. Conclusions. These results suggest that coadministration of BJIKT with aspirin may not result in herb-drug interaction

Global analysis of ginsenoside Rg1 protective effects in β-amyloid-treated neuronal cells

Background: A number of reports have described the protective effects of ginsenoside Rg1 (Rg1) in Alzheimer's disease (AD). However, the protective mechanisms of Rg1 in AD remain elusive. Methods: To investigate the potential mechanisms of Rg1 in β-amyloid peptide-treated SH-SY5Y cells, a comparative proteomic analysis was performed using stable isotope labeling with amino acids in cell culture combined with nano-LC-MS/MS. Results: We identified a total of 1,149 proteins in three independent experiments. Forty-nine proteins were significantly altered by Rg1 after exposure of the cells to β-amyloid peptides. The protein interaction network analysis showed that these altered proteins were clustered in ribosomal proteins, mitochondria, the actin cytoskeleton, and splicing proteins. Among these proteins, mitochondrial proteins containing HSD17B10, AARS2, TOMM40, VDAC1, COX5A, and NDUFA4 were associated with mitochondrial dysfunction in the pathogenesis of AD. Conclusion: Our results suggest that mitochondrial proteins may be related to the protective mechanisms of Rg1 in AD

Bioactive Fraction of Aronia melanocarpa Fruit Inhibits Adipogenic Differentiation of Cultured 3T3-L1 Cells

Obesity is caused by excessive fat cells and the overgrowth of adipocytes and is a major risk factor for several chronic illnesses. Aronia melanocarpa fruit is rich in anthocyanins and polyphenols and has protective effects against various diseases. In this study, we examined the effect of Aronia extract (Aronia bioactive fraction, ABF®) on the biomarkers of the adipogenic pathway during adipocyte differentiation of 3T3-L1 cells. Lipid accumulation was verified by Oil Red O staining. mRNA and protein expression of lipoprotein lipase (LPL), CCAAT/enhancer-binding protein α (C/EBPα), peroxisome proliferator-activated receptor γ (PPARγ), fatty acid-binding protein 2 (FABP2), and fatty acid synthase (FAS) were assayed by RT-qPCR and Western blot analyses. Adiponectin and leptin secretion were measured using enzyme-linked immunosorbent assays. ABF® treatment downregulated lipid accumulation based on Oil Red O staining. ABF®-treated cells exhibited decreased mRNA and protein expression of LPL, C/EBPα, PPARγ, FABP2, and FAS. Moreover, ABF® treatment significantly increased adiponectin secretion and decreased leptin secretion. In conclusion, ABF® has anti-adipogenic effects on the differentiation of 3T3-L1 cells and may be used as an anti-obesity nutraceutical

Proteomic analysis reveals that the protective effects of ginsenoside Rb1 are associated with the actin cytoskeleton in β-amyloid-treated neuronal cells

Background: The ginsenoside Rb1 (Rb1) is the most abundant compound in the root of Panax ginseng. Recent studies have shown that Rb1 has a neuroprotective effect. However, the mechanisms underlying this effect are still unknown. Methods: We used stable isotope labeling with amino acids in cell culture, combined with quantitative mass spectrometry, to explore a potential protective mechanism of Rb1 in β-amyloid-treated neuronal cells. Results: A total of 1,231 proteins were commonly identified from three replicate experiments. Among these, 40 proteins were significantly changed in response to Rb1 pretreatment in β-amyloid-treated neuronal cells. Analysis of the functional enrichments and protein interactions of altered proteins revealed that actin cytoskeleton proteins might be linked to the regulatory mechanisms of Rb1. The CAP1, CAPZB, TOMM40, and DSTN proteins showed potential as molecular target proteins for the functional contribution of Rb1 in Alzheimer's disease (AD). Conclusion: Our proteomic data may provide new insights into the protective mechanisms of Rb1 in AD

Pharmacokinetic Comparison of Ginsenosides between Fermented and Non-Fermented Red Ginseng in Healthy Volunteers

Fermentation of red ginseng (RG) produces fermented red ginseng (FRG), thereby increasing the relative amount of downstream ginsenosides, including compound Y (CY), F2, Rh2, compound K (CK), compound O, protopanaxadiol (PPD), and protopanaxatriol (PPT). These downstream ginsenosides have beneficial pharmacological effects, and are easily absorbed by the human body. Based on these expectations, a randomized, single-dose, two-period, crossover clinical trial was planned to compare the pharmacokinetic characteristics of seven types (Rb1, CY, F2, CK, Rh2, PPD, and PPT) of ginsenoside components after FRG and RG administration. The safety and tolerability profiles were assessed in this clinical trial. Sixteen healthy Korean male subjects were administered 6 g of FRG or RG. All ginsenosides except Rb1 showed higher systemic exposure after FRG administration than after RG administration, based on comparisons of ginsenoside Cmax and area under the concentration–time curve (AUC) between FRG and RG. CK, the main ginsenoside component produced during the fermentation process, had 69.23/74.53-fold higher Cmax/AUClast after administration of FRG than RG, and Rh2 had 20.27/18.47-fold higher Cmax/AUClast after administration of FRG than RG. In addition, CY and F2 were detected in FRG; however, all plasma concentrations of CY and F2, except in one subject, were below the lower limit of quantification in RG. There were no clinically significant findings with respect to clinical laboratory tests, blood pressures, or adverse events. Therefore, regular administration of FRG may exert better pharmacological effects than RG