PubMed Health⌕ Search

Biomedical subjects

Yong Sik Kim

Publications and source records attributed to Yong Sik Kim.

At least 19 recordsLinked to original sources
PubMed2007

IFN-gamma-induced BACE1 expression is mediated by activation of JAK2 and ERK1/2 signaling pathways and direct binding of STAT1 to BACE1 promoter in astrocytes.

Beta-site APP cleaving enzyme 1 (BACE1) is an essential enzyme for the production of beta amyloid. Since we found that injection of interferon-gamma (IFN-gamma) into young mouse brains increased BACE1 expression in astrocytes, we investigated molecular mechanisms underlying this process by cloning a putative BACE1 promoter. BACE1 promoter activity was differentially regulated by IFN-gamma in a region specific manner and down-regulated by an inhibitor of Janus kinase 2 (JAK2). A dominant negative mutant of signal transducer and activator of transcription 1 (STAT1) expression suppressed BACE1 promoter activity, and this was rescued by transfecting wild type STAT1. Electrophoretic mobility shift assay and promoter activity assays indicated that STAT1 binds directly to the putative STAT1 binding sequence of BACE1 promoter. Because IFN-gamma treatment induced STAT1 phosphorylation, we examined whether the expression of a suppressor of cytokine signaling (SOCS), negative regulator of JAK2, suppresses BACE1 promoter activity. The results show that SOCS1 or SOCS3 expression suppressed BACE1 promoter by blocking phosphorylation of Tyr701 residue in STAT1. Also, because IFN-gamma treatment specifically potentiated extracellular signal regulated MAP kinase (ERK) 1/2 activation, pretreatment of mitogen-activated or extracellular signal-regulated protein kinase (MEK) inhibitor, PD98059, significantly attenuated IFN-gamma-induced BACE1 promoter activity and protein expression through blocking phosphorylation of Ser727 residue in STAT1, suggesting that ERK1/2 is associated with IFN-gamma-induced STAT1 signaling cascade. Taken together, our results suggest that IFN-gamma activates JAK2 and ERK1/2 and then phosphorylated STAT1 binds to the putative STAT1 binding sequences in BACE1 promoter region to modulate BACE1 protein expression in astrocytes.

Alzheimer Disease↗
PubMed2006

Acupuncture inhibits microglial activation and inflammatory events in the MPTP-induced mouse model.

Using a mouse model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD), this study investigated on the neuroprotective effects of acupuncture by examining whether acupuncture contributed to inhibiting microglial activation and inflammatory events. C57BL/6 mice were treated with MPTP (30 mg/kg, i.p.) for 5 consecutive days. Acupuncture was then applied to acupoints Yanglingquan (GB34) and Taichong (LR3) starting 2 h after the first MPTP administration and then at 48 h intervals until the mice were sacrificed for analyses at 1, 3, and 7 days after the last MPTP injection. These experiments demonstrated that acupuncture inhibited the decreased of the tyrosine hydroxylase (TH) immunoreactivity (IR) and generated a neuroprotective effects in the striatum (ST) and the substantia nigra (SN) on days 1, 3, and 7 post-MPTP injections. Acupuncture attenuated the increase of macrophage antigen complex-1 (MAC-1), a marker of microglial activation, at 1 and 3 days and reduced the increases in cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression on days 1, 3, and 7. In MPTP group, striatal dopamine (DA) was measured by 46% at 7 days, whereas DA in the acupuncture group was 78%. On the basis of these results, we suggest that acupuncture could be used as a neuroprotective intervention for the purpose of inhibiting microglial activation and inflammatory events in PD.

Acupuncture↗
PubMed2006

Age-related changes in glycogen synthase kinase 3beta (GSK3beta) immunoreactivity in the central nervous system of rats.

Although glycogen synthase kinase 3beta (GSK3beta) is emerging as a prominent drug target in the treatment of neurodegenerative diseases such as Alzheimer's disease (AD) and stroke, very little is known about age-related changes in GSK3beta expression and GSK3beta phosphorylation. Therefore, we examined age-related changes in immunoreactivities for GSK3beta and phosphorylated GSK3beta (pGSK3beta) in the central nervous system. In aged rats, there were significant increases in GSK3beta immunoreactivity in the cell bodies and processes of pyramidal cells in most cortical regions. GSK3beta immunoreactivity was also significantly increased in the pyramidal layer of CA1-3 regions, and the granule cell layer of dentate gyrus. Age-related increases were prominent in lateral septal nuclei, compared to the medial septal nuclei. Interestingly, both GSK3beta and pGSK3beta was increased in the prefrontal cortex, while GSK3beta and pGSK3beta was differentially localized in the cerebellar cortex. The first demonstration of age-related alterations in immunoreactivities for GSK3beta and pGSK3beta in the basal forebrain area and cholinergic projection targets may provide useful data for investigating the pathogenesis of age-related neurodegenerative diseases including AD.

Aging↗
PubMed2006

Activation of extracellular signal-regulated kinase signaling by chronic electroconvulsive shock in the rat frontal cortex.

The effects of chronic electroconvulsive shock (ECS), given daily for 1, 5 and 10 days, on the activation of extracellular signal-regulated kinase (ERK) were studied in the rat frontal cortex. The phosphorylation of MEK1/2 and ERK1/2 increased through 5 days of ECS. Thereafter, a plateau was achieved. The expression of brain-derived neurotrophic factor was continuously increased for 10 days. Our data show that the effect of ECS on ERK1/2 signaling is increased with chronic treatment.

Animals↗
PubMed2006

Partial evidence of an association between epidermal growth factor A61G polymorphism and age at onset in male schizophrenia.

Epidermal growth factor (EGF) is a well-known neurotrophic factor regulating the development of various neuronal cells, including dopaminergic neurons, and dysfunction of EGF signals has been demonstrated as a risk factor for schizophrenia. Recently, several researchers have investigated associations including age at onset (AAO) with EGF A61G functional polymorphism, but the results of these studies have been controversial. Thus, we investigated whether A61G plays a role in predisposition to schizophrenia and its effects on AAO. Our subjects included 190 patients with schizophrenia and 347 controls. We assessed three different points of AAO: age at first occurrence of positive psychotic symptoms, medication, and hospitalization as a patient with schizophrenia. We found no differences in allele and genotype frequencies between patients and controls or associations between A61G and AAOs across stratified points in the entire sample and in each gender. However, we found significant gender differences in patients with the AA genotype in all stratified points of AAOs. Subset analyses of G allele distribution between clinical subsets with an AAO cutoff of 20 years revealed that male patients with early onset schizophrenia were more likely to exhibit the common AA homozygote than male patients with adulthood onset schizophrenia. In conclusion, although we were unable to support an association between EGF A61G and schizophrenia, the AA genotype might play a disease-modifying role differentially according to gender.

Adolescent↗
PubMed2006

The dysbindin gene (DTNBP1) and schizophrenia: no support for an association in the Korean population.

The dysbindin gene (DTNBP1) is located in chromosome 6p22.3, one of the regions of positive linkage for schizophrenia. A strong genetic association between DTNBP1 and schizophrenia has been replicated through many recent studies. In particular, dysbindin protein has been found to play a role in the glutamate neural transmission in the brain. In this study, we attempted to replicate the previously reported positive association between DTNBP1 and schizophrenia in the Korean population. Our sample included 194 patients with schizophrenia based on DSM-IV and 351 normal controls. We genotyped five SNPs including SNP A in promoter region of DTNBP1. The allele and genotype association were analyzed and the simulated haplotype was investigated as well. As the result, we could not find a significant association of DTNBP1 with schizophrenia in this Korean sample. Additional analysis of the subgroup of schizophrenia having familial loading of major psychiatric disorders did not show association, either. In summary, DTNBP1 is not likely to be a major susceptibility gene for schizophrenia in this Korean population. This result of no association also implies possible genetic heterogeneity of schizophrenia. Further studies with more dense SNPs of the whole gene sequence for various populations will be necessary to understand the genetic contribution of DTNBP1 for the development of schizophrenia.

Adult↗
PubMed2006

Haloperidol induces calcium ion influx via L-type calcium channels in hippocampal HN33 cells and renders the neurons more susceptible to oxidative stress.

Haloperidol is a classical neuroleptic drug that is still in clinical use and can lead to abnormal motor activity following repeated administration. However, there is little knowledge of how it triggers neuronal impairment. In this study, we report that it induced calcium ion influx via L-type calcium channels and that the elevation of calcium ions induced by haloperidol appeared to render hippocampal cells more susceptible to oxidative stress. Indeed, the level of cytotoxic reactive oxygen species (ROS) and the expression of pro-apoptotic Bax increased in response to oxidative stress in haloperidol-treated cells, and these effects were inhibited by verapamil, a specific L-type calcium channel blocker, but not by the T-type calcium channel blocker, mibefradil. These findings indicate that haloperidol induces calcium ion influx via L-type calcium channels and that this calcium influx influences neuronal fate.

Animals↗
PubMed2006

The effects of repeated administrations of MK-801 on ERK and GSK-3beta signalling pathways in the rat frontal cortex.

Repeated administrations of NMDA receptor antagonists induce behavioural changes which resemble the symptoms of schizophrenia in animals. ERK and GSK-3beta associated signalling pathways have been implicated in the pathogenesis of psychosis and in the action mechanisms of various psychotropic agents. Here, we observed the phosphorylations of ERK and GSK-3beta and related molecules in the rat frontal cortex after repeated intraperitoneal injections of MK-801, over periods of 1, 5, and 10 d. Repeated treatment with 0.5, 1, and 2 mg/kg MK-801 increased the phosphorylation levels of the MEK-ERK-p90RSK and Akt-GSK-3beta pathways and concomitantly and significantly increased CREB phosphorylation in the rat frontal cortex. However, single MK-801 treatment did not induce these significant changes. In addition, the immunoreactivities of HSP72, Bax, and PARP were not altered, which suggests that neuronal damage may not occur in the rat frontal cortex in response to chronic MK-801 treatment. These findings suggest that chronic exposure to MK-801 may induce pro-survival and anti-apoptotic activity without significant neuronal damage in the rat frontal cortex. Moreover, this adaptive change might be associated with the psychotomimetic action of MK-801.

Animals↗
PubMed2006

Investigation of genetic association between human Frizzled homolog 3 gene (FZD3) and schizophrenia: results in a Korean population and evidence from meta-analysis.

The neurodevelopmental hypothesis offers a promising approach through which to explore the pathogenesis of schizophrenia. Human Frizzled-3 protein is one of the major components of the Wnt signaling pathway and plays a crucial role in regulating early neurodevelopmental processes. Therefore, the human Frizzled homolog 3 (FZD3) gene, which encodes this protein, may be an excellent candidate gene for association studies of schizophrenia. To replicate the previously reported positive association between FZD3 and schizophrenia in Han Chinese and Japanese populations, we genotyped two single nucleotide polymorphism (SNP) markers of FZD3 in 241 unrelated schizophrenic patients and 192 control subjects. Fisher's exact test was used to compare the genotypic and allelic frequencies in the two groups. In addition, to integrate and evaluate the accumulated evidence published to date, we performed a meta-analysis on the published data, including our own. No evidence was found to support the association between either of the investigated SNP markers and schizophrenia in a Korean population. Moreover, the meta-analytic result did not support the association between several commonly investigated markers in FZD3 and schizophrenia. Failure to replicate previous positive association results could reflect various theoretical factors. Therefore, other sources of error have to be ruled out before coming to a conclusion. In the case of FZD3, it seems that repeated failures to replicate the original results by several independent research groups combine to provide evidence against an association between FZD3 and schizophrenia. Other candidate genes involved in early neurodevelopmental processes may deserve further investigation.

Alleles↗
PubMed2006

Clozapine, a neuroleptic agent, inhibits Akt by counteracting Ca2+/calmodulin in PTEN-negative U-87MG human glioblastoma cells.

Clozapine (CZP), a dibenzodiazepine derivative with a piperazinyl side chain, is in clinical use as an antipsychotic drug. This study investigated the effect of CZP on the modulation of the PI3K/Akt/GSK-3beta pathway in PTEN-negative U-87MG glioblastoma cells. Treatment with CZP rapidly inhibited the basal and EGF-induced phosphorylation of Akt. The inhibition of Akt resulted in the dephosphorylation of GSK-3beta and increased GSK-3beta kinase activity. A voltage-sensitive Ca(2+) channel blocker and calmodulin (CaM) antagonists inhibited Akt phosphorylation, whereas elevation of the intracellular Ca(2+) concentration prevented CZP-induced dephosphorylation of Akt and GSK-3beta, suggesting that Ca(2+)/CaM participates in the inhibition of Akt by CZP in U-87MG cells. In addition, similar to LY294002, CZP arrested cell cycle progression at G0/G1 phase, which was accompanied by decreased expression of cyclin D1. The reduction in the cyclin D1 level induced by CZP was abrogated by the inhibition of GSK-3beta, the inhibition of proteasome-dependent proteolysis, or an increase in the intracellular Ca(2+) concentration. These results suggest that the antipsychotic drug CZP modulates the PI3K/Akt/GSK-3beta pathway by counteracting Ca(2+)/CaM in PTEN-negative U-87MG glioblastoma cells.

Antipsychotic Agents↗
PubMed2006

KAI1/CD82 suppresses tumor invasion by MMP9 inactivation via TIMP1 up-regulation in the H1299 human lung carcinoma cell line.

We conducted a study on the mechanism of KAI1/CD82-mediated suppression of tumor invasiveness and metastasis, and examined its effect on MMP-9 activity and the TIMP1 levels in H1299 human non-small cell lung carcinoma cells. The H1299 human lung carcinoma cells were transfected with pcDNA3.1-CD82 and stable transfectant clones that had a high KAI1/CD82 expression were obtained. We performed Western blot analysis, cell invasion assay, gelatin zymography, and RT-PCR to assess the KAI1/CD82 expression and tumor invasiveness, the MMP-9 activity, the MMP-9 mRNA and protein levels, and the TIMP1 levels in the H1299/CD82 transfectant cells and compared the results with those of the control groups. The H1299/CD82 transfectants exhibited significant suppression of cell invasion, reduced MMP9 enzyme activity, elevated MMP9 mRNA and MMP-9 protein levels, and elevated TIMP1 levels. It may be postulated that KAI1/CD82 over-expression in the H1299 non-small cell lung carcinoma cells suppresses the tumor invasiveness and metastatic potential by inducing MMP9 inactivation via the up-regulation of TIMP1.

Carcinoma↗
PubMed2006

Limited ability of capsule endoscopy to detect normally positioned duodenal papilla.

BACKGROUND: The current power of capsule endoscopy (CE) to diagnose patients with obscure GI bleeding is 42% to 74.4%. OBJECTIVE: The aim of this study was to evaluate the diagnostic power of CE through its ability to detect duodenal papilla. DESIGN AND PATIENTS: A total of 112 consecutive CEs were retrospectively reviewed. All patients had undergone esophagogastroduodenoscopy and had their normal duodenal papilla confirmed. SETTING AND INTERVENTIONS: The CE findings were reviewed separately at a rate of 15 images/second by 2 experienced and competent capsule readers. MAIN OUTCOME MEASUREMENTS: The CE detection rate of duodenal papilla was calculated. In addition, the number of frames showing duodenal papilla was counted. RESULTS: Among the total CEs, 2 cases were excluded because the capsule could not traverse the second portion of duodenum. The most common indication was obscure GI bleeding. CE only detected duodenal papilla in 48 cases (43.6%). The mean number of frames of the visualizing duodenal papilla was 3.5 +/- 2.5 (range 1-13). LIMITATIONS: Choosing duodenal papilla as the reference may not be optimal because its position is difficult to identify. CONCLUSIONS: Our study conveys an important message on the present power of CE; we should carefully review CE findings at a slower review rate to raise the detection ability of the current-powered CE, when it is passing through several "difficult to identify" locations such as second portion of the duodenum. In addition, to raise the power of CE, technologic improvements of CE, such as an extracorporeal-controllable device or a multiside viewing capsule, are needed.

Adult↗
PubMed2006

Comparison of the characteristics of submucosal injection solutions used in endoscopic mucosal resection.

OBJECTIVE: Submucosal injection is used to prevent complications, such as perforation, during endoscopic mucosal resection (EMR). Since injection of normal saline produces mucosal elevation of short duration, repeated injection is needed for extensive resection. To overcome this limitation, various submucosal injection solutions have been developed but there are few data comparing their efficacy. This study was therefore conducted to compare the physical and chemical properties and the duration of mucosal elevation of various submucosal injection solutions. MATERIAL AND METHODS: A fresh transverse colon specimen acquired from a mongrel was used. Experiments were repeated four times. To compare the efficacy of mucosal elevation, 1 ml of each solution was injected into the submucosa: 0.9% NaCl, 20% mannitol, 0.1% sodium hyaluronate, 0.3% hydroxypropyl methylcellulose (HPMC), and 2% fibrinogen. Physical and chemical properties such as viscosity and osmolarity were compared. RESULTS: The heights of initial mucosal elevations were 6.52+/-0.26 mm, 6.87+/-0.05 mm, 6.92+/-0.09 mm, 6.90+/-0.08 mm, and 6.90+/-0.08 mm for normal saline, mannitol, sodium hyaluronate, HPMC, and fibrinogen, respectively. Whereas injection of normal saline took about 20 min and mannitol about 30 min for the initial elevation to be reduced to more than half the initial height, it took more than 60 min for all the other agents. A correlation was found between the duration of mucosal elevation and viscosity but not with osmolarity. CONCLUSIONS: The mucosal elevation lasted longer with sodium hyaluronate, HPMC, and fibrinogen than with mannitol or normal saline, and this seems to be due to the viscosity rather than the osmolarity of each solution.

Animals↗
PubMed2006

Identification of a new functional target of haloperidol metabolite: implications for a receptor-independent role of 3-(4-fluorobenzoyl) propionic acid.

Haloperidol, a dopamine D2 receptor blocker, is a classical neuroleptic drug that elicits extrapyramidal symptoms. Its metabolites include 3-(4-fluorobenzoyl) propionic acid (FBPA) and 4-(4-chlorophenyl)-4-piperidinol (CPHP). Until now, the biological significance of these metabolites has remained largely unknown. Here, we report that the administration of FBPA to mice effected a suppression of locomotor activity and induced catalepsy in a manner similar to that observed with haloperidol, whereas CPHP had no significant effects. Neither of these two metabolites, however, exhibited any ability to bind to the dopamine D2 receptor. FBPA blocked dopamine-induced extracellular signal-regulated kinase 1/2 phosphorylation, and it specifically affected mitogen-activated protein kinase kinase (MEK)1/2 activity in hippocampal HN33 cells. Moreover, FBPA was capable of direct interaction with MEK1/2, and inhibited its activity in vitro. We demonstrated the generation of haloperidol metabolites within haloperidol-treated cells by mass spectrometric analyses. Collectively, our results confirm the biological activity of FBPA, and provide initial clues as to the receptor-independent role of haloperidol.

Animals↗
PubMed2006

Surface and chemical properties of surface-modified UHMWPE powder and mechanical and thermal properties of its impregnated PMMA bone cement, IV: effect of MMA/accelerator on the surface modification of UHMWPE powder.

In our previous study, we manufactured a reinforced poly(methylmethacrylate) (PMMA) bone cement with 3 wt% of the surface-modified ultra high molecular weight polyethylene (UHMWPE) powder to improve its poor mechanical and thermal properties resulting from unreacted methylmethacrylate (MMA), the generation of bubble and shrinkage, and high curing temperature. In the present study, the effect of ratios of MMA and N,N'-dimethyl-p-toluidine (DMPT) solutions in redox polymerization system was investigated for the surface modification of UHMWPE powder. We characterized physical and chemical properties of surface-modified UHMWPE powder and reinforced bone cements by a scanning electron microscope, ultimate tensile strength (UTS) and curing temperature (Tmax). It was found that UTSs (41.3-51.3 MPa) of the reinforced PMMA bone cements were similar to those (44.5 MPa) of conventional PMMA bone cement (control), as well as significantly higher (P < 0.05) than those (33.8 MPa) of 3 wt% unmodified UHMWPE powder-impregnated bone cement. In particular, the UTS of redox polymerization system using MMA/DMPT solution was better than that of radical system using MMA/xylene solution. Also, Tmax of the reinforced PMMA bone cements decreased from 103 to 72-84 degrees C. From these results, we confirmed that the surface-modified UHMWPE powder can be used as reinforcing agent to improve the mechanical and thermal properties of conventional PMMA bone cement.

Biomechanical Phenomena↗
PubMed2006

The effects of long-term clozapine add-on therapy on the rehospitalization rate and the mood polarity patterns in bipolar disorders.

OBJECTIVE: We investigated the effect long-term clozapine add-on therapy has on rehospitalization rate and mood polarity patterns in patients with bipolar disorders. METHOD: Clinical data from medical records of 51 patients with bipolar disorder (DSM-IV) treated with clozapine add-on for more than 6 months at the Refractory Bipolar Disorders Clinic of Seoul National University Hospital were retrospectively analyzed. Patients had been registered from 1995 to 2004. Rehospitalization rates were compared before and after clozapine add-on. The clinical polarity of episodes resulting in hospitalizations was also compared. Twenty-seven bipolar patients treated with clozapine add-on for more than 3 years were further analyzed for long-term stability. RESULTS: The number of hospital days per year was reduced in 90.2% of patients after clozapine add-on. Total number and duration of hospitalizations per year decreased, and the effect size of clozapine add-on was substantially large (Wilcoxon z = -5.48, p < .01 for number of hospitalizations/year; Wilcoxon z = -5.32, p < .01 for hospital days/year; r = -0.54 and -0.53, respectively). Significant reductions were found in the number and duration of hospitalizations associated with manic, depressive, and hypomanic episodes. Number and duration of hospitalizations associated with mixed episodes did not show significant changes. The long-term efficacy of clozapine add-on was supported by continuous reduction in hospital days per year in the 27 selected patients. CONCLUSION: Long-term clozapine add-on therapy was effective in reducing the number and duration of rehospitalizations of bipolar patients resistant to conventional treatment. A significant reduction was found in rehospitalizations associated with manic, depressive, and hypomanic episodes, whereas mixed episode-associated rehospitalizations did not show significant changes.

Adolescent↗