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1.
Journal of Liver Cancer ; : 108-116, 2019.
Artículo en Inglés | WPRIM | ID: wpr-765719

RESUMEN

BACKGROUND/AIMS: Programmed death receptor 1 (PD-1) is a promising new target for treatment of patients with hepatocellular carcinoma (HCC). A high expression level of programmed death-ligand 1 (PD-L1) is a possible prognostic indicator for poor outcome in other malignancies. Here, we investigated the clinical significance of PD-1 and PD-L1 in patients with HCC. METHODS: We enrolled patients with HCC who underwent surgical resection at Severance Hospital between 2012 and 2017 and investigated the levels of PD-L1 in HCC tissues (tPD-L1) and PD-L1/PD-1 in serum (sPD-L1/sPD-1). We also aimed to determine whether expression levels correlated with clinical and histological features. RESULTS: A total of 72 patient samples were analyzed. The median sPD-L1 and sPD-1 levels were 25.72 and 341.44 pg/mL, respectively. A positive correlation was detected between tPD-L1 and sPD-1 levels (R²=0.426, P50% reduction in sPD-1 levels was observed immediately after nivolumab administration. However, sPD-1 level was not associated directly with prognosis in patients with advanced HCC. CONCLUSIONS: The results demonstrated that PD-L1 and PD-1 levels changed according to the immunotherapy. However, no significant association with clinical outcome in patients with HCC was detected.


Asunto(s)
Humanos , Carcinoma Hepatocelular , Estudios de Seguimiento , Inmunoterapia , Mortalidad , Pronóstico
2.
Artículo en Coreano | WPRIM | ID: wpr-725002

RESUMEN

OBJECTIVES: Mechanisms of clinical synergistic effects, induced by co-treatments of lithium and valproate, are unclear. Extracellular signal-regulated kinase (ERK) has been suggested to play important roles in mechanisms of the action of mood stabilizers. In this study, effects of co-treatments of lithium and valproate on the ERK1/2 signal pathway and its down-stream transcription factors, ELK1 and C-FOS, were investigated in vitro. METHODS: PC12 cells, human pheochromocytoma cells, were treated with lithium chloride (30 mM), valproate (1 mM) or lithium chloride + valproate. The phosphorylation of ERK1/2 was analyzed with immunoblot analysis. Transcriptional activities of ELK1 and C-FOS were analyzed with reporter gene assay. RESULTS: Single treatment of lithium and valproate increased the phosphorylation of ERK and transcriptional activities of ELK1 and C-FOS, respectively. Combined treatments of lithium and valproate induced more robust increase in the phosphorylation of ERK1/2 and transcriptional activities of ELK1 and C-FOS, compared to those in response to single treatment of lithium or valproate. CONCLUSIONS: Co-treatments of lithium and valproate induced synergistic increase in the phosphorylation of ERK1/2 and transcriptional activities of its down-stream transcription factors, ELK1 and C-FOS, compared to effects of single treatment. The findings might suggest potentiating effects of lithium and valproate augmentation treatment strategy.


Asunto(s)
Animales , Humanos , Genes Reporteros , Cloruro de Litio , Litio , Células PC12 , Feocromocitoma , Fosforilación , Fosfotransferasas , Transducción de Señal , Factores de Transcripción , Ácido Valproico
3.
Psychiatry Investigation ; : 339-346, 2012.
Artículo en Inglés | WPRIM | ID: wpr-58436

RESUMEN

OBJECTIVE: To compare verbal and visual memory performances between patients with bipolar I disorder (BD I) and patients with bipolar II disorder (BD II) and to determine whether memory deficits were mediated by impaired organizational strategies. METHODS: Performances on the Korean-California Verbal Learning Test (K-CVLT) and the Rey-Osterrieth Complex Figure Test (ROCF) in 37 patients with BD I, 46 patients with BD II and 42 healthy subjects were compared. Mediating effects of impaired organization strategies on poor delayed recall was tested by comparing direct and mediated models using multiple regression analysis. RESULTS: Both patients groups recalled fewer words and figure components and showed lower Semantic Clustering compared to controls. Verbal memory impairment was partly mediated by difficulties in Semantic Clustering in both subtypes, whereas the mediating effect of Organization deficit on the visual memory impairment was present only in BD I. In all mediated models, group differences in delayed recall remained significant. CONCLUSION: Our findings suggest that memory impairment may be one of the fundamental cognitive deficits in bipolar disorders and that executive dysfunctions can exert an additional influence on memory impairments.


Asunto(s)
Humanos , Trastorno Bipolar , Función Ejecutiva , Memoria , Trastornos de la Memoria , Negociación , Semántica , Aprendizaje Verbal
4.
Artículo en Inglés | WPRIM | ID: wpr-57563

RESUMEN

Microglial cells are the resident innate immune cells that sense pathogens and tissue injury in the central nervous system (CNS). Microglial activation is critical for neuroinflammatory responses. The synthetic compound 2-hydroxy-3',5,5'-trimethoxychalcone (DK-139) is a novel chalcone-derived compound. In this study, we investigated the effects of DK-139 on Toll-like receptor 4 (TLR4)-mediated inflammatory responses in BV2 microglial cells. DK-139 inhibited lipopolysaccharide (LPS)-induced TLR4 activity, as determined using a cell-based assay. DK-139 blocked LPS-induced phosphorylation of IkappaB and p65/RelA NF-kappaB, resulting in inhibition of the nuclear translocation and trans-acting activity of NF-kappaB in BV2 microglial cells. We also found that DK-139 reduced the expression of NF-kappaB target genes, such as those for COX-2, iNOS, and IL-1beta, in LPS-stimulated BV2 microglial cells. Interestingly, DK-139 blocked LPS-induced Akt phosphorylation. Inhibition of Akt abrogated LPS-induced phosphorylation of p65/RelA, while overexpression of dominant-active p110CAAX enhanced p65/RelA phosphorylation as well as iNOS and COX2 expression. These results suggest that DK-139 exerts an anti-inflammatory effect on microglial cells by inhibiting the Akt/IkappaB kinase (IKK)/NF-kappaB signaling pathway.


Asunto(s)
Animales , Ratas , Sitios de Unión , Línea Celular , Chalconas/química , Ciclooxigenasa 2/metabolismo , Quinasa I-kappa B/metabolismo , Inflamación/tratamiento farmacológico , Interleucina-1beta/metabolismo , Lipopolisacáridos/inmunología , Microglía/efectos de los fármacos , Simulación de Dinámica Molecular , FN-kappa B/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II/metabolismo , Fosforilación/efectos de los fármacos , Unión Proteica , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Transducción de Señal , Receptor Toll-Like 4/antagonistas & inhibidores , Factor de Transcripción ReIA/metabolismo
5.
Artículo en Inglés | WPRIM | ID: wpr-93418

RESUMEN

The early growth response gene 2 (EGR2) is located at chromosome 10q21, one of the susceptibility loci in bipolar disorder (BD). EGR2 is involved in cognitive function, myelination, and signal transduction related to neuregulin-ErbB receptor, Bcl-2 family proteins, and brain-derived neurotrophic factor. This study investigated the genetic association of the EGR2 gene with BD and schizophrenia (SPR) in Korea. In 946 subjects (350 healthy controls, 352 patients with BD, and 244 with SPR), nine single nucleotide polymorphisms (SNPs) in the EGR2 gene region were genotyped. Five SNPs showed nominally significant allelic associations with BD (rs2295814, rs61865882, rs10995315, rs2297488, and rs2297489), and the positive associations of all except rs2297488 remained significant after multiple testing correction. Linkage disequilibrium structure analysis revealed two haplotype blocks. Among the common identified haplotypes (frequency > 5%), 'T-G-A-C-T (block 1)' and 'A-A-G-C (block 2)' haplotypes were over-represented, while 'C-G-G-T-T (block 1)' haplotype was under-represented in BD. In contrast, no significant associations were found with SPR. Although an extended analysis with a larger sample size or independent replication is required, these findings suggest a genetic association of EGR2 with BD. Combined with a plausible biological function of EGR2, the EGR2 gene is a possible susceptibility gene in BD.


Asunto(s)
Adulto , Femenino , Humanos , Masculino , Trastorno Bipolar/genética , Proteína 2 de la Respuesta de Crecimiento Precoz/genética , Predisposición Genética a la Enfermedad/genética , Genotipo , Haplotipos/genética , Corea (Geográfico) , Desequilibrio de Ligamiento/genética , Polimorfismo de Nucleótido Simple/genética , Esquizofrenia/genética
6.
Artículo en Inglés | WPRIM | ID: wpr-48090

RESUMEN

BACKGROUND: Neck flexion has been shown to increase cranial spread of contrast agent when a small fixed volume was injected into the high thoracic epidural space. The purpose of this study was to evaluate the effect of volume of contrast medium on its distribution through the high thoracic epidural space during neck extension and flexion using the rabbit model. METHODS: An epidural catheter was introduced into the epidural space of New Zealand white rabbits with the tip located at the T3-4 intervertebral level. The neck was extended or flexed (n = 8 for each group), and the contrast medium was injected with the volume increasing by increments of 0.1 ml/kg, up to 0.3 ml/kg. The spread of contrast medium was determined by counting the number of vertebral body units using lateral epidurographic images. RESULTS: In both groups, the total spread of contrast medium was similar, increasing continuously with injected volume. The cranial spread was greater in the flexion group than the extension group. However, the caudal spread was greater in the extension than in the flexion group. In the extension group, the contrast medium spread caudally about twice as far as it spread cranially, but there was no statistically significant difference between cranial and caudal spread in the flexion group. CONCLUSIONS: In the high thoracic epidural space of rabbit, the contrast medium of varying doses showed limited cranial spread. The flexion of the neck increased cranial spread and extension of the neck increased caudal spread.


Asunto(s)
Conejos , Catéteres , Espacio Epidural , Cuello
7.
Artículo en Inglés | WPRIM | ID: wpr-94334

RESUMEN

2-Chloro-10-[3(-dimethylamino)propyl]phenothiazinemonohydrochloride (chlorpromazine) is a phenothiazine derivative used clinically to control psychotic disorders. It also exhibits an anticancer activity. Treatment with chlorpromazine (CPZ) results in cell-cycle arrest at the G2/M phase in rat C6 glioma cells. CPZ reduces the expression of cell cycle-related proteins, such as cyclin D1, cyclin A, and cyclin B1, but causes an increase in the p21(Waf1/Cip1) level. The molecular mechanism by which CPZ regulates p21(Waf1/Cip1) expression is unknown. Here, we provide evidence that CPZ activates the p21(Waf1/Cip1) gene promoter via induction of the transcription factor early growth response-1 (Egr-1) independently of p53 in C6 cells. A point mutation in the Egr-1-binding motif within the p21(Waf1/Cip1) promoter abrogated promoter inducibility due to CPZ. Forced expression of Egr-1 enhanced p21(Waf1/Cip1) promoter activity. In contrast, knockdown of endogenous Egr-1 by small interference RNA attenuated CPZ-induced p21(Waf1/Cip1) promoter activity. A chromatin immunoprecipitation assay demonstrated that Egr-1 binds to the p21(Waf1/Cip1) gene promoter. Further analysis showed that the ERK and JNK MAP kinases are required for induction of Egr-1 by CPZ. Finally, stable silencing of Egr-1 expression lead to attenuated CPZ-inducible p21(Waf1/Cip1) expression and inhibited G2/M phase cell-cycle arrest. These results demonstrate that a functional link between ERK and JNK MAP kinase pathways and p21(Waf1/Cip1) induction via Egr-1 contributes to CPZ-induced anticancer activity in C6 glioma cells.

8.
Artículo en Inglés | WPRIM | ID: wpr-167143

RESUMEN

Expression of protein kinase C-delta (PKC delta) is up-regulated by apoptosis-inducing stimuli. However, very little is known about the signaling pathways that control PKC delta gene transcription. In the present study, we demonstrate that JNK stimulates PKC delta gene expression via c-Jun and ATF2 in response to the anticancer agent doxorubicin (DXR) in mouse lymphocytic leukemia L1210 cells. Luciferase reporter assays showed that DXR-induced activation of the PKC delta promoter was enhanced by ectopic expression of JNK1, c-Jun, or ATF2, whereas it was strongly reduced by expression of dominant negative JNK1 or by treatment with the JNK inhibitor SP600125. Furthermore, point mutations in the core sequence of the c-Jun/ATF2 binding site suppressed DXR-induced activation of the PKC delta promoter. Our results suggest an additional role for a JNK signaling cascade in DXR-induced PKC delta gene expression.


Asunto(s)
Animales , Ratones , Factor de Transcripción Activador 2/fisiología , Antracenos/farmacología , Antibióticos Antineoplásicos/farmacología , Apoptosis , Línea Celular Tumoral , Doxorrubicina/farmacología , Proteína Quinasa 8 Activada por Mitógenos/fisiología , Mutación , Regiones Promotoras Genéticas , Proteína Quinasa C-delta/genética , Proteínas Proto-Oncogénicas c-jun/antagonistas & inhibidores , Transducción de Señal/fisiología , Transcripción Genética
9.
Artículo en Inglés | WPRIM | ID: wpr-106417

RESUMEN

The early growth response-1 gene (egr-1) encodes a zinc-finger transcription factor Egr-1 and is rapidly inducible by a variety of extracellular stimuli. Anisomycin (ANX), a protein synthesis inhibitor, stimulates mitogen-activated protein kinase (MAPK) pathways and thereby causes a rapid induction of immediate-early response genes. We found that anisomycin treatment of U87MG glioma cells resulted in a marked, time-dependent increase in levels of Egr-1 protein. The results of Northern blot analysis and reporter gene assay of egr-1 gene promoter (Pegr-1) activity indicate that the ANX- induced increase in Egr-1 occurs at the transcriptional level. Deletion of the serum response element (SRE) in the 5'-flanking region of egr-1 gene abolished ANX-induced Pegr-1 activity. ANX induced the phosphorylation of the ERK1/2, JNK, and p38 MAPKs in a time-dependent manner and also induced transactivation of Gal4-Elk-1, suggesting that Elk-1 is involved in SRE-mediated egr-1 transcription. Transient transfection of dominant-negative constructs of MAPK pathways blocked ANX-induced Pegr-1 activity. Furthermore, pretreatment with specific MAPK pathway inhibitors, including the MEK inhibitor U0126, the JNK inhibitor SP600125, and the p38 kinase inhibitor SB202190, completely inhibited ANX-inducible expression of Egr-1. Taken together, these results suggest that all three MAPK pathways play a crucial role in ANX-induced transcriptional activation of Pegr-1 through SRE-mediated transactivation of Elk


Asunto(s)
Humanos , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteína Elk-1 con Dominio ets/genética , Activación Transcripcional/efectos de los fármacos , Elemento de Respuesta al Suero , Inhibidores de Proteínas Quinasas/farmacología , Biosíntesis de Proteínas/efectos de los fármacos , Regiones Promotoras Genéticas/genética , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteínas Quinasas JNK Activadas por Mitógenos/genética , Quinasas MAP Reguladas por Señal Extracelular/genética , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Línea Celular Tumoral , Anisomicina/farmacología
10.
Artículo en Inglés | WPRIM | ID: wpr-119638

RESUMEN

The early growth response gene-1 (Egr-1) is a tumor suppressor which plays an important role in cell growth, differentiation and apoptosis. Egr-1 has been shown to be down-regulated in many types of tumor tissues. Trifluoperazine (TFP), a phenothiazine class of antipsychotics, restored serum-induced Egr-1 expression in several cancer cell lines. We investigated the effect of Egr-1 expression on the TFP-induced inhibition of cell growth. Ectopic expression of Egr-1 enhanced the TFP-induced antiproliferative activity and downregulated cyclin D1 level in U87MG glioma cells. Our results suggest that antipsychotics TFP exhibits antiproliferative activity through up-regulation of Egr-1.


Asunto(s)
Humanos , Ciclo Celular , Proliferación Celular/efectos de los fármacos , Ciclina D1/metabolismo , Proteínas de Unión al ADN/genética , Expresión Génica , Glioma/metabolismo , Proteínas Inmediatas-Precoces/genética , Regiones Promotoras Genéticas/efectos de los fármacos , Factores de Transcripción/genética , Trifluoperazina/farmacología , Células Tumorales Cultivadas
11.
Artículo en Coreano | WPRIM | ID: wpr-97031

RESUMEN

OBJECTIVE: cDNA microarray is a convenient molecular technology that enables to search for gene expression in large scale. To explore the effect of antipsychotics on the gene expression in the brain, we applied cDNA microarray and searched for differentially expressed genes in the olanzapine-treated rat frontal cortex. METHODS: We administered olanzapine (4 mg/kg/day, IP) to S-D rats for 14days, and dissected the frontal cortex to examine. We analyzed altered gene expression from microarray, and screened up- or down-regulated genes. Their changes were confirmed by RT-PCR. RESULTS: Three down-regulated and one up-regulated genes were screened by triplicate cDNA microarray analysis. Among them, translocase of the inner mitochondrial membrane 23 (TIM23) was confirmed in RT-PCR. The expression of TIM23 mRNA was significantly increased in olanzapine-treated rat frontal cortex. CONCLUSION: This is the first report of up-regulated gene expression of TIM23 by antipsychotics in the rat brain. TIM23 is the essential component of mitochondrial biogenesis. From this result, we suggest that antipsychotic effect may be related to the improvement of mitochondrial dysfunction in the brain.


Asunto(s)
Animales , Ratas , Antipsicóticos , Encéfalo , ADN Complementario , Expresión Génica , Membranas Mitocondriales , Biogénesis de Organelos , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero , Esquizofrenia
12.
Artículo en Inglés | WPRIM | ID: wpr-13044

RESUMEN

Phospholipase Cgamma1 (PLCgamma1) plays an important role in controlling cellular proliferation and differentiation. PLCgamma1 is overexpressed in some tumors, and its overexpression induces solid tumors in nude mice. However, the regulatory mechanisms underlying PLCgamma1-induced cell proliferation are not fully understood. Here we show that overexpression of PLCgamma1 highly phosphorylated glycogen synthase kinase-3beta (GSK-3beta) at serine-9 in 3Y1 fibroblasts. Inhibition of protein kinase C (PKC)s with GF109203X abrogated GSK-3beta phosphorylation by PLCgamma1. We also found that steady-state level of cyclin D1 protein, but not cyclin D1 mRNA, was highly elevated in response to serum stimulation in PLCgamma1-transfected cells as compared with vector-transfected cells. Since GSK-3beta is involved in cyclin D1 proteolysis in response to mitogenic stimulation, PLCgamma1-mediated GSK-3beta phosphorylation may function as a regulation of cyclin D1 accumulation in PLCgamma1-overexpressing cells.


Asunto(s)
Animales , Ratas , Ciclina D1/metabolismo , Factor de Crecimiento Epidérmico/farmacología , Fibroblastos , Expresión Génica , Glucógeno Sintasa Quinasa 3/química , Mitógenos/farmacología , Fosfolipasas de Tipo C/genética , Fosforilación/efectos de los fármacos , Fosfoserina/metabolismo , Proteína Quinasa C/antagonistas & inhibidores , Transducción de Señal
13.
Artículo en Coreano | WPRIM | ID: wpr-196396

RESUMEN

PURPOSE: It has been demonstrated that PLC-gamma1 is overexpressed in many tumor cells, and that overexpression of Phospholipase C (PLC)-gamma1 is associated with tumor progression. In order to understand the effect of the PLC-gamma1 overexpression on the regulation of cell cycle regulators following DNA damage, we analyzed the expression level of PCNA, cyclin B1, and p21 Waf1 after ultraviolet C (UVC) irradiation in PLC-gamma1-transfected PC12 cells. MATERIALS AND METHODS: PC12 and 3Y1 cells, transfected with empty vector or rat PLC-gamma1 cDNA, were used for this study. Following UVC irradiation, cell cycle progression was analyzed by flow cytometry and protein expression was detected by Western blotting. RESULTS: Waf1 protein was markedly down-regulated, whereas PCNA and cyclin B1 was up-regulated in PLC-gamma1 overexpressed-cells as compared to the vector transfected-cells. When the cells were irradiated with UVC, PCNA was slightly increased within 3-hours of the UV irradiation and then was markedly decreased in Vector/ PC12 cells, while it remained high until 37 hour after UVC in PLC-gamma1/PC12 cells. In contrast, cyclin B1 was gradually decreased following UVC irradiation in both cells. CONCLUSION: The overexpression of PLC-gamma1 affects the expression level of PCNA after UVC irradiation. We proposed that the overexpression of PLC-gamma1 may contribute to the UV-induced genomic instability by up-regulating the expression of PCNA.


Asunto(s)
Animales , Ratas , Western Blotting , Ciclo Celular , Ciclina B1 , Ciclinas , Daño del ADN , ADN Complementario , Citometría de Flujo , Inestabilidad Genómica , Células PC12 , Fosfolipasas , Antígeno Nuclear de Célula en Proliferación , Fosfolipasas de Tipo C
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