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Biomedical subjects

K Lee

Publications and source records attributed to K Lee.

At least 109 records · Page 6Linked to original sources
PubMed2001

Glial cell line-derived neurotrophic factor (GDNF) gene and schizophrenia: polymorphism screening and association analysis.

The glial cell line-derived neurotrophic factor (GDNF) is an important neurotrophic and potential differentiation factor for dopaminergic systems. Both the dopamine theory and the neurodevelopmental hypothesis of schizophrenia suggest that alterations of GDNF functions could be involved in the pathogenesis of schizophrenia. Using polymerase chain reaction and single strand conformational polymorphism analysis, we searched for polymorphisms in the GDNF gene in 50 patients with schizophrenia. No evidence was obtained, however, for the presence of polymorphisms in the DNA sequence encoding GDNF mature peptide in our patients. We then examined a trinucleotide repeat (AGG)(n) polymorphism in the 3'-UTR of the GDNF gene for allelic association in a Japanese sample of 99 schizophrenic patients and 98 control subjects. There was no significant difference in the overall distribution of the allele between the two groups. When each allele was examined separately, the allele (AGG)(10) was more common in schizophrenic patients than in control subjects, but this finding was not significant when multiple testing was taken into account in the analysis. Overall, we obtained no solid evidence for the involvement of the GDNF gene in the pathogenesis of schizophrenia, although further studies in larger numbers of subjects will be required to conclude whether the trinucleotide repeat polymorphism is associated with the development of schizophrenia.

Adult↗
PubMed2001

Palladium-catalyzed cross-coupling reactions of in situ generated allylindium reagents with aryl halides.

[reaction: see text] In situ generated allylindium reagents from the reaction of 1 equiv of indium with 1.5 equiv of allyl halides could be effective cross-coupling partners in palladium-catalyzed cross-coupling reactions to aryl halides. The best results were obtained with 2% Pd(2)dba(3)CHCl(3) and 16% Ph(3)P in the presence of 3 equiv of LiCl in DMF at 100 degrees C.

Journal Article↗
PubMed2001

A novel nucleophilic substitution of in situ generated 3-tert-butyldimethyl- silyloxyalk-2-enylsulfonium salts with allylindium reagents.

[reaction: see text] In situ generated 3-tert-butyldimethylsilyloxyalk-2-enylsulfonium salts derived from the reaction of alpha,beta-enones with dimethyl sulfide in the presence of TBSOTf undergo a novel nucleophilic substitution with in situ generated allylindium reagents from indium and allyl halides to give silyl enol ethers of delta,epsilon-unsaturated ketones, which correspond to Michael addition products, in good yields.

Journal Article↗
PubMed2001

Expression of voltage-gated calcium channel subunits in rat dorsal root ganglion neurons.

In the present study, we have used in situ hybridisation to examine the distribution of calcium channel subunits in rat dorsal root ganglion (DRG) neurons. Within DRG neurons, the calcium channel alpha subunit mRNAs alpha(1A), alpha(1B), alpha(1C), alpha(1D), alpha(1E), alpha(1I) and alpha(1S) were readily detected in small (<25 microm), medium (25-45 microm) and large (>45 microm) diameter neurons. alpha(1F) was present at very low levels in these neurons whilst alpha(1G) was virtually undetectable. The calcium channel auxiliary subunits alpha(2)delta(1) and alpha(2)delta(2) showed a complementary pattern of distribution to that of alpha(2)delta(3) in DRG neurons. alpha(2)delta(1) and alpha(2)delta(2) transcripts were expressed predominantly in small c-type sensory neurons and were present at lower levels in large Abeta-type sensory neurons. In contrast, alpha(2)delta(3) mRNA was present in high quantities in the large-diameter cells but was expressed at lower levels in small-diameter neurons of the DRG. The present study provides an insight into the molecular profile of calcium channel alpha(1) and alpha(2)delta subunits in the neurons responsible for transmitting sensory information.

Animals↗
PubMed2001

MMTV promoter hypomethylation is linked to spontaneous and MNU associated c-neu expression and mammary carcinogenesis in MMTV c-neu transgenic mice.

The erbB family of receptor tyrosine kinases is frequently implicated in neoplasia. Amplification and overexpression of erbB2/neu has been found in 20 to 40% of human breast cancers. Previous studies using MMTV/c-neu transgenic mice have linked rat neu overexpression to mammary tumor development. In this study, we provide evidence that rat neu overexpression in mammary tumors of MMTV/c-neu transgenic mice is always associated with demethylation of the MMTV promoter, whereas the normal mammary glands of these transgenic mice always contain specific methylated regions of the MMTV promoter. In addition, after exposure to N-methyl-N-nitrosourea (MNU), the latency of mammary tumor development is significantly reduced and again is also associated with MMTV promoter demethylation. Thus, the transition from methylation to hypomethylation of the MMTV promoter induces high-level expression of c-neu and appears to be a prerequisite for transformation from normal to malignant mammary epithelium, either spontaneously or after carcinogen exposure. Expression of transgenic c-neu from the demethylated MMTV promoter appears to be an early event that allows outgrowth of mammary epithelium predisposed to malignant transformation.

Alkylating Agents↗
PubMed2001

Barrier crossing of a semiflexible ring polymer.

Motivated by the dynamics of a membrane in response to an external force, we study the thermally activated crossing of a semiflexible ring polymer over a potential barrier. For the bistable potential of Kramers type smoothly varying over a long length scale, we calculate the crossing rate using the multidimensional Kramers' rate theory and the functional integral method. We find that, due to its conformational fluctuation, the rate for a flexible ring is much larger than that for a stiff ring. For a sufficiently long chain length or a sufficiently weak bending modulus, the ring undergoes a compact-stretch transition. The stretched conformation of the chain results in a decrease of the activation energy and so the further increase of the rate. This result implies that the soft matter conformational flexibility and adaptability facilitate the barrier crossing.

Journal Article↗
PubMed2001

Synthesis and purine receptor affinity of 6-oxopurine nucleosides and nucleotides containing (N)-methanocarba-pseudoribose rings.

6-Oxopurine derivatives containing a northern (N) methanocarba modification (i.e., fused cyclopropane and cyclopentane rings in place of the ribose) were synthesized and the adenosine receptor affinity measured. Guanine or hypoxanthine was coupled at the 7-position, or 1,3-dibutylxanthine was coupled at the 9-position. The pseudoribose ring was also substituted at the 5'-position with an N-methyluronamide or with phosphate groups.

Calcium↗
PubMed2001

Additive effects of intra-accumbens infusion of the cAMP-specific phosphodiesterase inhibitor, rolipram and cocaine on brain stimulation reward.

Evidence from cocaine self-administration studies suggests that increasing the activity of cyclic AMP (cAMP) pathways within the nucleus accumbens may produce a reduction in cocaine's reinforcing effects. Rolipram may increase intra-cellular levels of cAMP by selectively inhibiting Type IV phosphodiesterases, enzymes that catalyze cAMP breakdown. The present study was undertaken to test the hypothesis that infusion of rolipram into the nucleus accumbens would decrease cocaine-induced enhancement of the sensitivity of brain stimulation reward (BSR) pathways. BSR thresholds were determined in rats after the systemic administration of cocaine (4 mg/kg IP) and the infusion of rolipram (0.2 microg/side) into the nucleus accumbens both alone and in combination. Thresholds also were determined after the systemic administration of rolipram alone and, as a positive control, for amphetamine (10 microg/side) infused into the nucleus accumbens. BSR thresholds were significantly lowered below baseline levels following d-amphetamine administration suggesting that cannulae were in place to allow perfusion of reward pathways. Compared to values for saline alone, thresholds were lower after the injection of cocaine (4 mg/kg IP) or the infusion of rolipram (0.2 microg/side) into the nucleus accumbens. Treatment with the combination of cocaine and intra-nucleus accumbens rolipram produced a greater lowering of the BSR threshold than did administration of either rolipram or cocaine alone. Systemic administration of rolipram (0.5 mg/kg IP) either blocked the effects of BSR or raised BSR thresholds and produced stimulation-induced head jerking in most of the test animals. These results suggest that infusion into the nucleus accumbens of rolipram, an agent that putatively elevates cAMP levels in this structure, can enhance the sensitivity of reward pathways to BSR and can augment cocaine's actions on these pathways.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2001

Beta3, a novel auxiliary subunit for the voltage gated sodium channel is upregulated in sensory neurones following streptozocin induced diabetic neuropathy in rat.

In the present study we have used in situ hybridization to examine the changes in mRNA expression of the voltage gated sodium channel subunits beta1 and beta3, which occur in response to streptozocin induced diabetic neuropathy. Under control conditions beta1 mRNA was detected throughout the spinal cord and in large dorsal root ganglion (DRG) Abeta fibres whilst beta3 mRNA was expressed exclusively in the layers I/II and X of the spinal cord and in small DRG c-fibres. Following streptozocin treatment, the expression of beta1 mRNA remained unchanged in both the spinal cord and DRG whilst beta3 message was significantly increased in both the spinal cord and in medium diameter Adelta type DRG neurones. In conclusion, the present study illustrates that the development of the neuropathic pain state is associated with distinct changes in the pattern of beta3 subunit expression and that these changes appear to be specific to the neuropathic pain state induced.

Animals↗
PubMed2001

Hoxa3 and pax1 regulate epithelial cell death and proliferation during thymus and parathyroid organogenesis.

The thymus and parathyroid glands in mice develop from a thymus/parathyroid primordium that forms from the endoderm of the third pharyngeal pouch. We investigated the molecular mechanisms that promote this unique process in which two distinct organs form from a single primordium, using mice mutant for Hoxa3 and Pax1. Thymic ectopia in Hoxa3(+/-)Pax1(-/-) compound mutants is due to delayed separation of the thymus/parathyroid primordium from the pharynx. The primordium is hypoplastic at its formation, and has increased levels of apoptosis. The developing third pouch in Hoxa3(+/-)Pax1(-/-) compound mutants initiates normal expression of the parathyroid-specific Gcm2 and thymus-specific Foxn1 genes. However, Gcm2 expression is reduced at E11.5 in Pax1(-/-) single mutants, and further reduced or absent in Hoxa3(+/-)Pax1(-/-) compound mutants. Subsequent to organ-specific differentiation from the shared primordium, both the parathyroids and thymus developed defects. Parathyroids in compound mutants were smaller at their formation, and absent at later stages. Parathyroids were also reduced in Pax1(-/-) mutants, revealing a new function for Pax1 in parathyroid organogenesis. Thymic hypoplasia at later fetal stages in compound mutants was associated with increased death and decreased proliferation of thymic epithelial cells. Our results suggest that a Hoxa3-Pax1 genetic pathway is required for both epithelial cell growth and differentiation throughout thymus and parathyroid organogenesis.

Animals↗
PubMed2001

The nonexpression of CD36 on reticulocytes and mature red blood cells does not modify the clinical course of patients with sickle cell anemia.

It is thought that an increase in the adhesion of circulating reticulocytes to the vascular endothelium may initiate the vascular occlusion underlying the painful crises and organ failures typical of sickle cell disease (SCD). At least 2 receptors, usually present on reticulocytes, seem to be involved in this adhesion process: glycoprotein CD36 (glycoprotein IV) and integrin alpha(4)beta(1) (very late activation antigen--4). Recently, a high frequency of the platelet CD36--deficient phenotype was reported in black Africans. The frequency of this deficiency was similar in subjects with and without SCD. The role of CD36 in vaso-occlusion was then investigated by comparing the clinical course in 2 groups of black Africans homozygous for hemoglobin S, with and without CD36 deficiency, but similar in age, sex, geographical origin, number of alpha-globin genes, and beta-globin gene haplotype. Flow cytometry showed that CD36 was absent from the circulating red blood cells and reticulocytes of platelet CD36--deficient individuals but present on those from patients with normal platelet CD36 expression, and that alpha(4)beta(1) integrin levels were similar on the reticulocytes of the 2 groups. Neither clinical severity, as evaluated by the frequency and characteristics of vaso-occlusive events, nor biological data differed significantly in the 2 groups of patients. Finally, although CD36 has been suggested to play a critical role in the pathogenesis of vaso-occlusion, this study, despite including only a small number of patients, supports the idea that the modulation of expression of a single type of adhesion molecule is insufficient to counteract the pathological process leading to vaso-occlusion in SCD patients. (Blood. 2001;98:966-971)

Adolescent↗
PubMed2001

The effect of exposure to a commercial 2,4-D formulation during gestation on the immune response in CD-1 mice.

Pregnant CD-1 mice were administered a commercial 2,4-dichlorophenoxyacetic acid (2,4-D) formulation on days 6-16 days of gestation, in drinking water at concentrations ranging from 0 to 1.0% of the formulated product, equivalent to approximately 0-650 mg/kg per day expressed as the amine derivative. The effect of 2,4-D on immune function was evaluated in offspring 7 weeks after birth. The dams tolerated repeated 2,4-D exposure in drinking water without difficulty. The offspring exhibited decreased body weight with minor reductions in the kidney weights in the 0.1 and 1.0% 2,4-D treatment groups. A generalized suppression of lymphocyte stimulation by concanavalin A (Con A) was observed at high dose of commercial 2,4-D formulation (1.0%). Cytometric studies of the lymphocyte subpopulations demonstrated an increased relative count of B cells and reduced T cytotoxic or suppressor cells in the 1.0% formulation. The humoral immune response, antibody production against sheep red blood cells and peritoneal macrophage phagocytic function, were not altered by 2,4-D. Since the immune alterations in the offspring were observed many weeks after exposure, it appears as though 2,4-D exposure during gestation causes permanent changes in cell types associated with immune function. Since 2,4-D is not considered a persistent chemical, it is unlikely that 2,4-D residues are contributing significantly to the observed immune alterations. The immune alterations were observed only in the higher treatment groups. Therefore, the impact on human and animal health from an immune perspective, which would be encountered following normal application in the environment, would be minimal.

2,4-Dichlorophenoxyacetic Acid↗
PubMed2001

Developmental expression of the novel voltage-gated sodium channel auxiliary subunit beta3, in rat CNS.

1. We have compared the mRNA distribution of sodium channel alpha subunits known to be expressed during development with the known auxiliary subunits Nabeta1.1 and Nabeta2.1 and the novel, recently cloned subunit, beta3. 2. In situ hybridisation studies demonstrated high levels of Nav1.2, Nav1.3, Nav1.6 and beta3 mRNA at embryonic stages whilst Nabeta1.1 and Nabeta2.1 mRNA was absent throughout this period. 3. Nabeta1.1 and Nabeta2.1 expression occurred after postnatal day 3 (P3), increasing steadily in most brain regions until adulthood. beta3 expression differentially decreased after P3 in certain areas but remained high in the hippocampus and striatum. 4. Emulsion-dipped slides showed co-localisation of beta3 with Nav1.3 mRNA in areas of the CNS suggesting that these subunits may be capable of functional interaction. 5. Co-expression in Xenopus oocytes revealed that beta3 could modify the properties of Nav1.3; beta3 changed the equilibrium of Nav1.3 between the fast and slow gating modes and caused a negative shift in the voltage dependence of activation and inactivation. 6. In conclusion, beta3 is shown to be the predominant beta subunit expressed during development and is capable of modulating the kinetic properties of the embryonic Nav1.3 subunit. These findings provide new information regarding the nature and properties of voltage-gated sodium channels during development.

Aging↗
PubMed2001

Oxidative modification of tryptophan 43 in the heme vicinity of the F43W/H64L myoglobin mutant.

The F43W/H64L myoglobin mutant was previously constructed to investigate the effects of electron-rich tryptophan residue in the heme vicinity on the catalysis, where we found that Trp-43 in the mutant was oxidatively modified in the reaction with m-chloroperbenzoic acid (mCPBA). To identify the exact structure of the modified tryptophan in this study, the mCPBA-treated F43W/H64L mutant has been digested stepwise with Lys-C achromobacter and trypsin to isolate two oxidation products by preparative fast protein liquid chromatography. The close examinations of the (1)H NMR spectra of peptide fragments reveal that two forms of the modified tryptophan must have 2,6-disubstituted indole substructures. The (13)C NMR analysis suggests that one of the modified tryptophan bears a unique hydroxyl group in stead of the NH(2) group at the amino-terminal. The results together with mass spectrometry (MS)/MS analysis (30 Da increase in mass of Trp-43) indicate that oxidation products of Trp-43 are 2,6-dihydro-2,6-dioxoindole and 2,6-dihydro-2-imino-6-oxoindole derivatives. Our finding is the first example of the oxidation of aromatic carbons by the myoglobin mutant system.

Catalysis↗
PubMed2001

Transport of cyclic nucleotides and estradiol 17-beta-D-glucuronide by multidrug resistance protein 4. Resistance to 6-mercaptopurine and 6-thioguanine.

Human multidrug resistance protein 4 (MRP4) has recently been determined to confer resistance to the antiviral purine analog 9-(2-phosphonylmethoxyethyl)adenine and methotrexate. However, neither its substrate selectivity nor physiological functions have been determined. Here we report the results of investigations of the in vitro transport properties of MRP4 using membrane vesicles prepared from insect cells infected with MRP4 baculovirus. It is shown that expression of MRP4 is specifically associated with the MgATP-dependent transport of cGMP, cAMP, and estradiol 17-beta-D-glucuronide (E(2)17 beta G). cGMP, cAMP, and E(2)17 beta G are transported with K(m) and V(max) values of 9.7 +/- 2.3 microm and 2.0 +/- 0.3 pmol/mg/min, 44.5 +/- 5.8 microm and 4.1 +/- 0.4 pmol/mg/min, and 30.3 +/- 6.2 microm and 102 +/- 16 pmol/mg/min, respectively. Consistent with its ability to transport cyclic nucleotides, it is demonstrated that the MRP4 drug resistance profile extends to 6-mercaptopurine and 6-thioguanine, two anticancer purine analogs that are converted in the cell to nucleotide analogs. On the basis of its capacity to transport cyclic nucleotides and E(2)17 beta G, it is concluded that MRP4 may influence diverse cellular processes regulated by cAMP and cGMP and that its substrate range is distinct from that of any other characterized MRP family member.

3T3 Cells↗
PubMed2001

Chern-Simons theories on the noncommutative plane.

We investigate U(N) Chern-Simons theories on the noncommutative plane. We show that for the theories to be consistent quantum mechanically, the coefficient of the Chern-Simons term should be quantized kappa = n/2pi with an integer n. This is a surprise for the U(1) gauge theory. When uniform background charge density rho(e) is present, the quantization rule changes to kappa+rho(e)straight theta = n/2pi with the noncommutative parameter straight theta. With the exact expression for the angular momentum, we argue in the U(1) theory that charged particles in the symmetric phase carry fractional spin 1/2n and vortices in the broken phase carry half-integer or integer spin -n/2.

Journal Article↗
PubMed2001

Reversal of drug resistance mediated by multidrug resistance protein (MRP) 1 by dual effects of agosterol A on MRP1 function.

We previously isolated agosterol A (AG-A) from a marine Spongia sp. and found that it completely reversed colchicine resistance in P-glycoprotein (Pgp)-over-expressing KB-C2 cells and vincristine resistance in multidrug-resistance protein (MRP)1-over-expressing CV60 cells. However, a tri-deacetylated derivative of AG-A (IAG-A) showed almost no activity in reversing Pgp- or MRP1-mediated drug resistance. In this study, we examined the mechanisms by which AG-A reverses MRP1-mediated drug resistance by investigating the interaction between agosterols and MRP1 in MRP1-over-expressing human KB carcinoma (KB/MRP) cells. [3H]-Leukotriene C4 (LTC4), [3H]-2,4-dinitrophenyl-S-glutathione uptake into membrane vesicles prepared from KB/MRP cells and intracellular [3H]-vincristine accumulation and efflux in KB/MRP cells were measured with or without AG-A and/or inactive IAG-A. AG-A reduced MRP1-mediated [3H]-LTC4 transport in a dose-dependent manner, but IAG-A did not. Inhibition by AG-A was competitive, with a K(i) value of 31 microM. AG-A at 10 microM enhanced the accumulation of [3H]-vincristine in KB/MRP cells to the level of that in control cells in the absence of the agent. Likewise, ATP-dependent efflux of [3H]-vincristine from KB/MRP cells was enhanced compared with KB-3-1 cells and inhibited by AG-A. In addition, AG-A reduced intracellular levels of glutathione, a compound required for MRP1-mediated transport of some anti-cancer drugs. These findings suggest that AG-A reverses MRP1-mediated drug resistance by directly inhibiting the capacity of MRP1 to transport drugs. In addition, the capacity of AG-A to reduce cellular glutathione levels may contribute to the modulating activity of MRP1.

ATP Binding Cassette Transporter, Subfamily B, Mem↗