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Biomedical subjects

D Kang

Publications and source records attributed to D Kang.

At least 73 records · Page 4Linked to original sources
PubMed1999

Variations in urinary 1-hydroxypyrene glucuronide in relation to smoking and the modification effects of GSTM1 and GSTT1.

The measurement of the pyrene metabolite, 1-hydroxypyrene, in human urine has been used to assess recent exposure to polycyclic aromatic hydrocarbons (PAH). The objective of this study was to see whether genetic polymorphisms in metabolic enzymes could explain some of the variation in urinary 1-hydroxypyrene glucuronide (1-OHPG) excretion in relation to smoking. Forty-seven male hospital workers, who were not occupationally exposed to PAH, participated in this study. The urine samples were analyzed for 1-OHPG utilizing immunoaffinity chromatography and synchronous fluorescence spectroscopy. The analysis of GSTM1 and GSTT1 polymorphism was performed by PCR. The 1-OHPG concentration in the urine of the hospital workers was 0.57 +/- 0.85 micromol/mol creatinine, and ranged from 0.02 to 5.04 mciromol/mol creatinine. Cigarette smoking was significantly correlated with urinary 1-OHPG (r = 0.3976, P = 0.0056). The 1-OHPG excretion in GSTM1-deficient smokers was higher than that in GSTM1-positive smokers. On the other hand, 1-OHPG excretion was higher in GSTT1-positive smokers than in GSTT1-deficient smokers. It is important to note the variability of individual PAH metabolite excretion due to different GSTM1 and GSTT1 genotypes.

Adult↗
PubMed1999

Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium.

Oxidative stress in the myocardium may play an important role in the pathogenesis of congestive heart failure (HF). However, the cellular sources and mechanisms for the enhanced generation of reactive oxygen species (ROS) in the failing myocardium remain unknown. The amount of thiobarbituric acid reactive substances increased in the canine HF hearts subjected to rapid ventricular pacing for 4 weeks, and immunohistochemical staining of 4-hydroxy-2-nonenal ROS-induced lipid peroxides was detected in cardiac myocytes but not in interstitial cells of HF animals. The generation of superoxide anion was directly assessed in the submitochondrial fractions by use of electron spin resonance spectroscopy with spin trapping agent, 5, 5'-dimethyl-1-pyrroline-N-oxide, in the presence of NADH and succinate as a substrate for NADH-ubiquinone oxidoreductase (complex I) and succinate-ubiquinone oxidoreductase (complex II), respectively. Superoxide production was increased 2.8-fold (P<0.01) in HF, which was due to the functional block of electron transport at complex I. The enzymatic activity of complex I decreased in HF (274+/-13 versus 136+/-9 nmol. min(-1). mg(-1) protein, P<0.01), which may thus have caused the functional uncoupling of the respiratory chain and the deleterious ROS production in HF mitochondria. The present study provided direct evidence for the involvement of ROS in the mitochondrial origin of HF myocytes, which might be responsible for both contractile dysfunction and structural damage to the myocardium.

Animals↗
PubMed1999

Mitochondrial DNA replication in human T lymphocytes is regulated primarily at the H-strand termination site.

The most unique feature in the replication of mitochondrial DNA (mtDNA) is that most of the newly synthesized heavy strands (H-strands) terminate prematurely, resulting in the formation of displacement loop (D-loop) strands. Only the H-strand which proceeds past the termination site is a true nascent H-strand leading to the overall replication on a circular mtDNA molecule. The physiological significance of the D-loop formation has long been unclear. To examine the role of premature termination in mtDNA replication, we therefore developed a method for selectively measuring both the total amount of nascent H-strands and the amount of true nascent H-strands using ligation-mediated polymerase chain reaction, which, for the first time, enabled us to estimate the frequency of premature termination. The stimulation of cell proliferation with interleukin 2 and phytohemagglutinin in human peripheral T lymphocytes caused an increase in the net replication rate of mtDNA. In stimulated cells, in comparison to resting ones, the amount of true nascent H-strands increased approx. 2.6-fold while the total amount of nascent H-strands remained unchanged, indicating that premature termination decreased while the initiation of replication remained the same. Our findings thus demonstrate the first clear example that premature termination plays a primary role in the up-regulation of the net rate of mtDNA replication in human cells.

Aphidicolin↗
PubMed1999

Evidence for functional conservation of a mammalian homologue of the light-responsive plant protein COP1.

Identified in Arabidopsis as a repressor of light-regulated development, the COP1 (constitutively photomorphogenic 1) protein is characterized by a RING-finger motif and a WD40 repeat domain [1]. The subcellular localization of COP1 is light-dependent. COP1 acts within the nucleus to repress photomorphogenic development, but light inactivates COP1 and diminishes its nuclear abundance [2]. Here, we report the identification of a mammalian COP1 homologue that contains all the structural features present in Arabidopsis COP1 (AtCOP1). When expressed in plant cells, a fusion protein comprising mammalian COP1 and beta-glucuronidase (GUS) responded to light by changing its subcellular localization pattern in a manner similar to AtCOP1. Whereas the mammalian COP1 was unable to rescue the defects of Arabidopsis cop1 mutants, expression of the amino-terminal half of mammalian COP1 in Arabidopsis interfered with endogenous COP1 function, resulting in a hyperphotomorphogenic phenotype. Therefore, the regulatory modules in COP1 proteins that are responsible for the signal-dependent subcellular localization are functionally conserved between higher plants and mammals, suggesting that mammalian COP1 may share a common mode of action with its plant counterpart in regulating development and cellular signaling.

Animals↗
PubMed1999

The Alzheimer-related gene presenilin 1 facilitates notch 1 in primary mammalian neurons.

The normal functional neurobiology of the Alzheimer's disease (AD) related gene presenilin 1 (PS1) is unknown. One clue comes from a genetic screen of Caenorhabditis elegans, which reveals that the presenilin homologue sel-12 facilitates lin-12 function [D. Levitan, I. Greenwald, Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene, Nature 377 (1995) 351-355]. The mammalian homologue of lin-12, Notch1, is a transmembrane receptor that plays an important role in cell fate decisions during development, including neurogenesis, but does not have a known function in fully differentiated cells. To better understand the potential role of Notch1 in mammalian postmitotic neurons and to test the hypothesis that Notch and PS 1 interact, we studied the effect of Notch1 transfection on neurite outgrowth in primary cultures of hippocampal/cortical neurons. We demonstrate that Notch1 inhibits neurite extension, and thus has a function in postmitotic mature neurons in the mammalian CNS. Furthermore, we present evidence demonstrating that there is a functional interaction between PS1 and Notch1 in mammalian neurons, analogous to the sel-12/lin-12 interaction in vulval development in C. elegans [D. Levitan, T. Doyle, D. Brousseau, M. Lee, G. Thinakaran, H. Slunt, S. Sisodia, I. Greenwald, Assessment of normal and mutant human presenilin function in Caenorhabditis elegans, Proc. Natl. Acad. Sci. U.S.A. 93 (1996) 14940-14944; D. Levitan, I. Greenwald, Effect of Sel-12 presenilin on Lin-12 localization and function in Caenorhabditis elegans, Development, 125 (1998) 3599-3606]. The inhibitory effect of Notch1 on neurite outgrowth is markedly attenuated in neurons from PS1 knockout mice, and enhanced in neurons from transgenic mice overexpressing wild type PS1, but not mutant PS1. These data suggest that PS1 facilitates Notch1 function in mammalian neurons, and support the hypothesis that a functional interaction exists between PS1 and Notch1 in postmitotic mammalian neurons.

Alzheimer Disease↗
PubMed1999

R-Loop in the replication origin of human mitochondrial DNA is resolved by RecG, a Holliday junction-specific helicase.

Stable RNA-DNA hybrids (R-loops) prime the initiation of replication in Escherichia coli cells. The R-loops are resolved by Escherichia coli RecG protein, a Holliday junction specific helicase. A stable RNA-DNA hybrid formation in the mitochondrial D-loop region is also implicated in priming the replication of mitochondrial DNA. Consistent with this hypothesis, the 3' ends of the mitochondrial R-loop formed by in vitro transcription are located close to the initiation sites of the mitochondrial DNA replication. This mitochondrial R-loop is resolved by RecG in a dose-dependent manner. Since the resolution by RecG requires ATP, the resolution is dependent on the helicase activity of RecG. A linear RNA-DNA heteroduplex is not resolved by RecG, suggesting that RecG specifically recognizes the higher structure of the mitochondrial R-loop. This is the first example that R-loops of an eukaryotic origin is sensitive to a junction-specific helicase. The resolution of the mitochondrial R-loop by RecG suggests that the replication-priming R-loops have a common structural feature recognized by RecG.

Bacterial Proteins↗
PubMed1999

Nucleic acid-binding properties of low-density lipoproteins: LDL as a natural gene vector.

The role of apo B-100 as a transcription factor is indicated by the presence of regions in its primary structure that are similar to the DNA-binding domains of the transcription factors ISGF3gamma, STATs, IRFs, and SREBPs as well as by the presence of 11 RNA-binding KH domains. The Apo B-100 sequence also contains numerous bipartite nuclear localization sequences (NLS). A modified gel shift assay was used to show binding of highly purified preparations of human LDLs to fragmented genomic DNA, plasmid DNA, synthetic oligonucleotides (ISRE, 5'-GGGAAACCGAAACTG and E/C, E-box motif and CCAAT, adipocyte-specific genes promoter site), and total RNA from human liver. LDL was observed to bind preferentially to plasmid DNA containing the hCMV IE2 promoter region. In experiments using human liver total RNA, RNA for five different genes was recovered from LDL and VLDL bands. Gene transfection experiments using human skin fibroblast cells were used to study the gene transfer capacity of LDL. Cells transfected with a pEGFP-N1 plasmid DNA and LDL expressed functional GFP, as indicated by fluorescence, at approximately 3 hrs after transfection. Our results strongly support an alternative role for apo B-100, in toto or perhaps as functional fragments, in the control of gene expression and as gene transfer vector.

Amino Acid Motifs↗
PubMed1999

1-Methyl-4-phenylpyridinium ion (MPP+) selectively inhibits the replication of mitochondrial DNA.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine is known to cause Parkinsonism in its neurotoxic form, 1-methyl-4-phenylpyridinium ion (MPP+). We have previously reported that MPP+ decreases the content of mitochondrial DNA (mtDNA) independently of the inhibition of complex I in human cells [Miyako, K., Kai, Y., Irie, T., Takeshige, K., and Kang, D. (1997) J. Biol. Chem. 272, 9605-9608]. Here we study the mechanism causing the decrease in mtDNA. MPP+ inhibits the incorporation of 5-bromo-2'-deoxyuridine into mtDNA but not into nuclear DNA, indicating that MPP+ inhibits the replication of mtDNA but not that of the nuclear genome. The replication of mtDNA is initiated by the synthesis of the heavy strand switched from the transcription of the light strand. MPP+ decreases the nascent heavy strands per mtDNA and increases the transcript of the ND6 gene, encoded on light strand, per mtDNA. The amount of mitochondrial transcription factor A is not decreased. These data suggest that the transcription is not inhibited and therefore the transition from transcription to replication of mtDNA is lowered in the MPP+-treated cells. Electron microscopy shows that the number of mitochondria is not decreased in the MPP+-treated cells, suggesting that MPP+ does not affect the overall biogenesis of mitochondria. Thus, MPP+ selectively inhibits the replication of mtDNA.

1-Methyl-4-phenylpyridinium↗
PubMed1999

Expression and differential intracellular localization of two major forms of human 8-oxoguanine DNA glycosylase encoded by alternatively spliced OGG1 mRNAs.

We identified seven alternatively spliced forms of human 8-oxoguanine DNA glycosylase (OGG1) mRNAs, classified into two types based on their last exons (type 1 with exon 7: 1a and 1b; type 2 with exon 8: 2a to 2e). Types 1a and 2a mRNAs are major in human tissues. Seven mRNAs are expected to encode different polypeptides (OGG1-1a to 2e) that share their N terminus with the common mitochondrial targeting signal, and each possesses a unique C terminus. A 36-kDa polypeptide, corresponding to OGG1-1a recognized only by antibodies against the region containing helix-hairpin-helix-PVD motif, was copurified from the nuclear extract with an activity introducing a nick into DNA containing 8-oxoguanine. A 40-kDa polypeptide corresponding to a processed form of OGG1-2a was detected in their mitochondria using antibodies against its C terminus. Electron microscopic immunocytochemistry and subfractionation of the mitochondria revealed that OGG1-2a locates on the inner membrane of mitochondria. Deletion mutant analyses revealed that the unique C terminus of OGG1-2a and its mitochondrial targeting signal are essential for mitochondrial localization and that nuclear localization of OGG1-1a depends on the NLS at its C terminus.

Alternative Splicing↗
PubMed1999

Large-scale optimization of neuron arbors.

At the global as well as local scales, some of the geometry of types of neuron arbors-both dendrites and axons-appears to be self-organizing: Their morphogenesis behaves like flowing water, that is, fluid dynamically; waterflow in branching networks in turn acts like a tree composed of cords under tension, that is, vector mechanically. Branch diameters and angles and junction sites conform significantly to this model. The result is that such neuron tree samples globally minimize their total volume-rather than, for example, surface area or branch length. In addition, the arbors perform well at generating the cheapest topology interconnecting their terminals: their large-scale layouts are among the best of all such possible connecting patterns, approaching 5% of optimum. This model also applies comparably to arterial and river networks.

Axons↗
PubMed1999

Anticlinic coupling between layers of an antiferroelectric liquid crystal.

The anticlinic interlayer coupling coefficient U was evaluated as a function of temperature for a pitch-compensated liquid crystal by optical observation of the electric field-induced optic mode. U was found to exhibit an unusual "S-shaped" dependence on temperature, with values ranging between 0.4x10(4) and 2.2x10(4) erg cm(-3) over a 10 degrees C temperature range below the smectic-A-smectic-C(*)(A) phase-transition temperature. The results are in good agreement with estimates for U based upon the threshold field for the onset of solitary waves, and provide strong support in the low-field regime for the single Fourier component model proposed by Li et al. [Phys. Rev. B 52, R13 075 (1995)].

Journal Article↗
PubMed1999

Pretransitional behavior above the nematic-isotropic phase transition of an auxetic trimer liquid crystal.

Static light scattering and electric field-induced Kerr measurements were performed above the nematic-isotropic phase transition of a terminal-lateral-lateral-terminal negative Poisson ratio trimer. For both measurements the inverse susceptibility was observed to be nearly linear with temperature, a result inconsistent with our previously reported Kerr data [Phys. Rev. E 58, 2041 (1998)].

Journal Article↗
PubMed1999

[Estimation of healthy reference intervals for elderly people through the use of outpatient data].

It is important to determine transferable reference intervals as well as uniformity in measured values for inter-regional and inter-institutional availability of clinical test results. For that purpose, the National Committee for Clinical Laboratory Standards (NCCLS) issued forth guidelines in 1995. Some regional institutions in Japan are making efforts to determine normal reference intervals based on these guidelines. We, the Fukuoka Five Hospitals Group, have selected 3,375 healthy reference individuals and have determined the normal reference intervals for the age groups of 20-29, 30-39, 40-49, and 50-59 years old. The rapidly increasing percentage of elderly people gives rise to ever increasing health-care needs for the elderly, which requires normal reference intervals for older age groups. However, we were unable to collect the required number of the reference individuals above 60 years of age. To obtain reference intervals with adequate reliability and usefulness temporally, we made use of the laboratory data of outpatients at Kyushu University Hospital, and were then easily able to collect the required number of elderly individuals. By performing a very simple selection from among the outpatients, our outpatient group became virtually indistinguishable from the group of healthy reference individuals established by us, with regard to many clinical tests, thus enabling us to estimate reference intervals for older age groups. This approach could be adopted in other regions.

Adult↗
PubMed1999

Increased 8-oxo-dGTPase in the mitochondria of substantia nigral neurons in Parkinson's disease.

There is growing evidence for the involvement of oxidative stress and mitochondrial respiratory failure in nigral neuronal death in Parkinson's disease (PD). We report increased immunoreactivity of 8-oxo-dGTPase (8-oxo-7, 8-dihydrodeoxyguanosine triphosphatase [hMTH1]), an enzyme known to play an important role in controlling spontaneous mutagenesis, and 8-oxo-7, 8-deoxyguanosine (8-oxo-dG) in the mitochondria of the substantia nigra of 6 PD patients. Our results suggest that hMTH1 might be a useful marker of oxidative stress and can be used to explore the relation between such oxidative stress and genomic instability.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1999

[Health-related quality of life in hypertensive patients].

OBJECTIVES: To explore the health-related quality of life (HRQOL) for hypertensive patients (HBP) and to provide reasonable evidence for evaluating the effectiveness of antihypertensive therapy in clinical practice. METHODS: A cross-sectional study was used to survey 106 patients with HBP and 127 nomotensives using SF-36 short form of quality of life in the community. The cutoff point score of HRQOL was decided by receiver operating characteristic (ROC) Curve analysis. There were 60 patients with BP > or = 160/95 mm Hg who had been treated by antihypertensive drugs for 6 months. Before and after the treatment, their HRQOL was measured and evaluated, and the relationship between the change of HRQOL and antihypertensive effect was evaluated. RESULTS: Apart from physical function and pain, other 7 domains were significantly lower in the hypertensive group than in the normotensive group, which included social function, role limitations attributed to both physical and emotional problems, mental health, activity or fatigue and overall evaluation of health (P < 0.05-0.001). A cutoff point of HRQOL was decided using ROC analysis in which the 290 score was the best one for diagnostic HRQOL with the sensitivity of 80% and a specificity of 70%. The target rate of the antihypertensive care and the improved rate of HRQOL for 60 patients with HBP were 63% and 75% separately for a 6-month treatment. CONCLUSION: The HRQOL of these hypertensives was significantly lower than that in the normotensives in the study. The measurement of HRQOL was more useful to evaluate the antihypertensive effectiveness in clinical practice.

Aged↗
PubMed1998

A peptidoglycan recognition protein in innate immunity conserved from insects to humans.

Innate nonself recognition must rely on common structures of invading microbes. In a differential display screen for up-regulated immune genes in the moth Trichoplusia ni we have found mechanisms for recognition of bacterial cell wall fragments. One bacteria-induced gene encodes a protein that, after expression in the baculovirus system, was shown to be a peptidoglycan recognition protein (PGRP). It binds strongly to Gram-positive bacteria. We have also cloned the corresponding cDNA from mouse and human and shown this gene to be expressed in a variety of organs, notably organs of the immune system-i.e., bone marrow and spleen. In addition, purified recombinant murine PGRP was shown to possess peptidoglycan affinity. From our results and the sequence homology, we conclude that PGRP is a ubiquitous protein involved in innate immunity, conserved from insects to humans.

Amino Acid Sequence↗
PubMed1998

Interaction of apolipoprotein E epsilon 4 with other genetic and non-genetic risk factors in late onset Alzheimer disease: problems facing the investigator.

The Apolipoprotein E4 allele (Apo-epsilon4) is the major susceptibility gene for late onset Alzheimer Disease (AD) but epidemiological data suggest that the effect of this allele is modified in different individuals by genetic or environmental factors. Age and head injury are major non-genetic factors modifying the Apo-epsilon4 risk. There is conflicting data as to whether alleles of other chaperon proteins (such as alpha-1-antichymotrypsin (ACT)) or Apo-epsilon4 receptors (such as the VDRL receptor) modify the Apo-epsilon4 risk for AD. We analyze problems posed by genetic association studies including those of multiple comparisons and selection of controls, the latter problem exacerbated by the wide variations in Apolipoprotein E allele frequencies observed in different groups and localities.

Alzheimer Disease↗