Biomedical subjects
Publications and source records attributed to H-S Kim.
In this short review the methods of preparation of novel 1,2,4,5-tetraoxacycloalkanes and the related peroxides are summarized, with the emphasis on the usefulness of 1,1-bishydroperoxides as the precursor. Also, their antimalarial activities in vitro and in vivo are discussed.
1. We studied amobarbital's effects on membrane properties and currents, and electrically evoked inhibitory postsynaptic currents (IPSCs) mediated by gamma-aminobutyric acid (GABA) in rat thalamic slices. Using concentration-response relationships, we compared amobarbital's effects in nociceptive nuclei and non-nociceptive nucleus reticularis thalami (nRT). 2. Amobarbital decreased input resistance by activating GABA(A) receptors. Amobarbital produced a larger decrease in ventrobasal than nRT neurons. 3. Amobarbital depressed burst and tonic firing. Depression of burst firing was more effective, particularly in ventrobasal and intralaminar neurons. Depression was reversed by GABA(A) antagonists, and surmountable by increasing current injection, implicating a receptor-mediated shunt mechanism. 4. Amobarbital did not affect the tetrodotoxin-isolated low threshold Ca(2+) spike during GABA(A) blockade. Amobarbital reduced excitability without altering outward leak, or hyperpolarisation-activated inward currents. 5. Amobarbital increased mean conductance and burst duration of single GABA(A) channels. Consistent with this, amobarbital increased amplitude and decay time of IPSCs with distinct EC(50)s, implicating actions at two GABA(A) receptor sites. 6. Activation of GABA(A) receptors by low concentrations, fast IPSC amplitude modulation, and failure to affect intrinsic currents distinguished amobarbital's mechanism of action from previously characterised barbiturates. The selective actions of amobarbital on GABA(A) receptor may have relevance in explaining anaesthetic and analgesic uses.
OBJECTIVE: To determine whether chronic central administration of ghrelin can block the effects of leptin on food intake, adiposity, and plasma concentrations of metabolic parameters and hormones. DESIGN: Intracerebroventricular (ICV) infusions of leptin (5 microg/day) for 7 days, with or without ghrelin (1.2 microg/day), in rats. Rats administered leptin plus ghrelin were divided into ad lib-fed and food-restricted groups. MEASUREMENT: Body weight and food intake were monitored daily. Following killing on day 8, epididymal fat weight and fasting plasma concentrations of glucose, insulin, leptin, ghrelin, IGF-1, and adiponectin were determined. RESULTS: ICV infusion of leptin decreased food intake by 39% and fat weight by 41%. Leptin decreased plasma concentrations of glucose, insulin, and leptin and increased plasma ghrelin levels. Central coadministration of ghrelin blocked the effects of leptin. Most of the effects of ghrelin were diminished by food restriction but ghrelin effect on adiposity and plasma insulin concentrations remained in food-restricted rats. CONCLUSION: Chronic central administration of ghrelin reversed the effects of leptin, primarily by altering food intake, but ghrelin may have regulatory effects on adiposity and plasma insulin levels independent of feeding effect.
Three different extraction methods were evaluated: Soxhlet extraction, accelerated solvent extractor extraction and alkali digestion with high-resolution gas chromatography/high-resolution mass spectrometry, for the analysis of edible freshwater fish and frogs. The recovery efficiencies for the different extraction methods were also compared. Using these extraction methods, the concentrations and spatial distributions of these compounds in freshwater fish and frogs (n = 99), collected from 31 locations on four major river systems (Han, Nakdong, Kum and Youngsan) and two wetlands in South Korea, were examined. The concentrations of total polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) in all the freshwater fish and frog samples were analysed. The toxic equivalency (TEQ) concentration of PCDD/Fs in fish ranged from 0 (n.d.) to 1.309 pg I-TEQ g(-1) wet weight. Detailed concentrations for different types of fish were as follows (pg I-TEQ g(-1) wet weight): 0 (n.d.)-1.309 for crucian (mean 0.331, n = 28), 0.004-0.743 for carp (0.244, n = 10), 0.004-0.592 for dace (0.198, n = 8), 0.187-0.400 for cornet fish (0.287, n = 3), 0.164-0.410 for Korean piscivorous chub (0.303, n = 6), 0.105-0.516 for bass (0.310, n = 2), 0.451-0.812 for mullet (0.631, n = 2), 0.082 for long-nosed barbell, 0.100 for common Korean bitterling and 0.995 for dark chub. The total TEQ concentration ranged from 0 (n.d.) to 1.258 pg I-TEQ g(-1) wet weight for the two kinds of frogs (n = 36) investigated: 0 (n.d.)-1.258 pg I-TEQ g(-1) (mean 0.346, n = 29) for the bullfrog and from 0 (n.d.)-0.474 pg I-TEQ g(-1) (0.185, n = 7) for the mountain frog.
We examined the structural genes (gag, pol and env) of the human endogenous retrovirus (HERV-W) family from 12 normal human tissues and 18 human cancer cell lines using RT-PCR. For the gag and pol genes, their expression patterns showed tissue or cell specificity, depending on the samples, whereas the env gene was expressed in all tissues and cancer cells examined. To identify active HERV-W elements in tissues and cancer cells, the RT-PCR products were cloned and sequenced. Ninety-five clones for the env gene, 55 clones for the pol gene and 17 clones for the gag gene of the HERV-W family were isolated from human tissues and sequenced, while 85 clones for the env gene, 61 clones for the pol gene and no clones for the gag gene of the HERV-W family were isolated and sequenced from cancer cells. Among these clones, 50 clones from tissues and 44 from cancer cells showed putative amino acids of the HERV-W env gene, while only two clones from cancer cells showed putative amino acids of the HERV-W pol gene. Phylogenetic analysis indicated that several clones identified previously from human monochromosomes had sister relationships with the clones from the different tissues and cancer cells. These data suggest that HERV-W elements are actively expressed in human tissues and cancer cells. These active HERV-W elements deserve further investigation as potential causative agents of various human diseases including cancers.
OBJECTIVE: To examine the effects of two polymorphisms of the endothelial constitutive nitric oxide synthase (ecNOS) gene, 4a/4b(A:B) located in intron 4 and Glu298Asp(G:T) located in exon 7, on the development of acute coronary syndromes (ACS). METHODS: 164 patients with ACS and 142 control participants were investigated for genotype and conventional risk factors. Genotype was determined by polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS: Genotype and allele frequencies of the A:B polymorphism in the ACS group (0.15:0.85 for AA+AB:BB, 0.09:0.91 for A:B) differed from those in the control group (0.26:0.74 for AA+AB:BB, 0.15:0.85 for A:B). However, genotype and allele frequencies of the G:T polymorphism in the ACS group (0.22:0.78 for TT+TG:GG, 0.11:0.89 for T:G) were similar to those in the control group (0.17:0.83 for TT+TG:GG, 0.09:0.91 for T:G). Multiple logistic regression analysis showed that the non-BB (AA+AB) and the non-BB+GG genotypes were significant protective factors against ACS (odds ratios 0.49 and 0.34, 95% confidence intervals 0.26 to 0.93 and 0.14 to 0.83, respectively). In addition, linear association analysis showed that the percentage of ACS patients was significantly lower in the genotype group non-BB+GG than in the genotype group BB+non-GG (39.6% v 62.7%, p = 0.01). CONCLUSIONS: The non-BB genotype of the ecNOS 4a/4b gene polymorphism is a protective factor against the development of ACS. The GG genotype of the ecNOS Glu298Asp polymorphism exerts a benefit in addition to the non-BB genotype in the Korean population.
A human endogenous retrovirus, HERV-W, has recently been identified on human chromosome 7 and contains a single complete open reading frame putatively encoding an envelope protein. Its env gene was expressed in various tissues, and mainly in human placenta. We investigated env gene of the HERV-W family in the Macaca fuscata (Japanese monkey). The env gene expression was detected in various tissues (testis, prostate, kidney, cerebellum, thymus, placenta, intestine, stomach, ovary) of the Japanese monkey by RT-PCR. Southern blot analysis indicated that the monkey genome contained at least 15 copies of the HERV-W family. Using the PCR approach with the monkey genome, thirteen env fragments of the HERV-W family were identified and analyzed. These env fragments from monkey showed a high degree of sequence similarity (91-94%) to that of human HERV-W (AF072506). Putative amino acid sequences of the env fragments indicated multiple frameshifts and termination codons by deletion/insertion or point mutation in all clones identified in this study. Phylogenetic analysis of the env fragments derived from the monkey genome with those of the human genome showed a random sister relationship.
Human endogenous retrovirus HC2 is an incomplete provirus containing the entire gag and pol genes and a 3' LTR, whereas the 5' LTR and env gene are missing. We investigated expression of the HC2 pol gene in the squirrel monkey ( Saimiri sciureus) by RT-PCR. The pol gene was expressed in cerebellum, liver, lung, and spleen of the squirrel monkey, but not in six other tissues tested. RT-PCR products were cloned and sequenced resulting in seven sequences that were analyzed. These sequences showed 73.7-89.2% sequence similarity to HC2 pol genes present in the human genome. No frameshifts or termination codons caused by deletion/insertion or point mutation were found in clones SM-HC27-1 and SM-HC27-4 isolated from squirrel monkey lung tissues. Phylogenetic analysis showed that HC2 pol elements from the squirrel monkey were randomly clustered with those in human genome and the genomes of other nonhuman primates, indicating that substantial evolution of the HC2 elements occurred prior to primate speciation with additional evolution of the elements, independent of each other, after speciation.
Cholesteryl ester transfer protein (CETP) is a key protein involved in high-density lipoprotein cholesterol (HDL-C) metabolism. It is known to affect plasma HDL-C levels, and its genetic regulation may be involved in the development of coronary artery disease (CAD). The aim of this study was to determine the frequency of the CETP Taq1B polymorphism in Koreans, and to investigate its relationship with plasma HDL-C levels and CAD. One-hundred and nineteen patients with significant CAD and 106 controls were examined with respect to their genotypes, lipid profiles and other risk factors of CAD. The genotype frequencies of B1B1:B1B2:B2B2 in males and females were 35.5%:50%:14.5% and 34.7%:42.6%:22.7%, respectively, which is comparable to previous reports in other ethnic groups. The B1B1 homozygote was associated with significantly lower HDL-C levels in females (p = 0.049) and non-smoking males (p = 0.037). After controlling for gender, body mass index (BMI) and smoking, the TaqIB polymorphism was still significantly associated with HDL-C levels (p = 0.046) and explained 5.4% of the HDL-C variation in this study. By univariate analysis, the B1B1 homozygote was a significant predictor of CAD (p = 0.043), and this was confirmed by multivariate analysis with traditional risk factors, i.e. the B1B1 homozygote was an independent predictor of CAD (p = 0.026, odds ratio = 1.97, 95% confidence interval: 1.08-3.57). In conclusion, the B1B1 homozygote of the CETP Taq1B polymorphism is associated with low HDL-C levels in females and non-smoking males, and may be an independent genetic risk factor of CAD in the Korean population.
The 55-amino acid (a.a.) preS2 region of the hepatitis B virus (HBV) envelope protein is highly immunogenic, and antibodies against this epitope confer seroprotection against HBV infections. Accordingly, various experimental and clinical studies for developing and evaluating HBV vaccines that include this particular epitope have been reported. However, a pitfall in using preS2 epitopes as part of a vaccinating antigen is that polymerized human serum albumin (pHSA), which is a normal constituent of the human serum, binds to and makes complexes with this particular region. Consequently, it is most likely that the antigen epitope is masked by serum pHSA and subsequently not detected by the immune system. To overcome these limitations, a novel single a.a substitute of the preS2 region was designed that corresponds to a tyrosine to serine exchange at position 140 of preS2. Competitive enzyme-linked immunosorbent assay showed that this substitution completely abolishes pHSA-binding activities in the mutated preS2 peptide, and CD spectra analysis revealed that this property might have been induced by slight conformational changes in its secondary structure. Nevertheless, the original B-cell epitope was still preserved in the mutated preS2 as determined by experimental immunization in mice. In this regard, the preS2(120-145/Y140S) sequence may be an HBV vaccine where epitopes, with intrinsic properties have been deleted without affecting the immunogenicity of the epitope itself. It is expected that the inclusion of this point mutated preS2 epitope will improve the efficacy of conventional preS2-containing HBV vaccines.
Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are cardiac hormones that regulate blood pressure and volume, and exert their biological actions via the natriuretic peptide receptor-A gene (Npr1). Mice lacking Npr1 (Npr(-/-)) have marked cardiac hypertrophy and fibrosis disproportionate to their increased blood pressure. This study examined the relationships between ANP and BNP gene expression, immunoreactivity and fibrosis in cardiac tissue, circulating ANP levels, and ANP and BNP mRNA during embryogenesis in Npr1(-/-) mice. Disruption of the Npr1 signaling pathway resulted in augmented ANP and BNP gene and ANP protein expression in the cardiac ventricles, most pronounced for ANP mRNA in females [414 +/- 57 in Npr1(-/-) ng/mg and 124 +/- 25 ng/mg in wild-type (WT) by Taqman assay, P < 0.001]. This increased expression was highly correlated to the degree of cardiac hypertrophy and was localized to the left ventricle (LV) inner free wall and to areas of ventricular fibrosis. In contrast, plasma ANP was significantly greater than WT in male but not female Npr1(-/-) mice. Increased ANP and BNP gene expression was observed in Npr1(-/-) embryos from 16 days of gestation. Our study suggests that cardiac ventricular expression of ANP and BNP is more closely associated with local hypertrophy and fibrosis than either systemic blood pressure or circulating ANP levels.