The dopamine b-hydroxylase (DBH) gene is expressed selec- tively in noradrenergic and adrenergic ... more The dopamine b-hydroxylase (DBH) gene is expressed selec- tively in noradrenergic and adrenergic neurons and neuroen- docrine cells in the nervous system. A cAMP response element (CRE) residing at 2181 to 2174 bp from the transcription start site of the human DBH gene seems to be essential for DBH transcription. Potential cis-regulatory motifs such as AP1 and YY1 occur proximal
The purpose of this study was to propose finite element (FE) modeling methods for predicting stre... more The purpose of this study was to propose finite element (FE) modeling methods for predicting stress distributions on teeth and mandible under chewing action. For FE model generation, CT images of skull were translated into 3D FE models, and static analysis was performed considering linear material behaviors and nonlinear geometrical effect. To find out proper boundary and loading conditions, parametric studies were performed with various areas and directions of restraints and loading. The loading directions are prescribed to be same as direction of masseter muscle, which was referred from anatomy chart and CT image. From the analysis, strain and stress distributions of teeth and mandible were obtained and compared with experimental data for model validation. As a result of FE analysis, the optimized boundary condition was chosen such that 8 teeth were fixed in all directions and condyloid process was fixed in all directions except for forward and backward directions. Also, fixing a ...
Endothelin-1 (ET-1) has been characterized as a potent vasoconstrictor secreted by the endotheliu... more Endothelin-1 (ET-1) has been characterized as a potent vasoconstrictor secreted by the endothelium, and play a major role in the regulation of vascular tone. It has been also known to participate in inflammatory reactions. The production of ET-1 by macrophages during infection and inflammation is related to tissue perfusion and leukocyte extravasation. The aim of this study is to investigate the role of IL-8/CXCL8, as a major inflammatory chemokine, for ET-1 expression in macrophges. Expression of ET-1 mRNA in mouse peritoneal macrophages (PeMφ) was weaker than that in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). However, expression of IL-8/CXCL8-induced ET-1 mRNA in PeMφ was much more stronger than that in SHR and WKY VSMCs. Maximum expression of ET-1 mRNA was observed at 50 ng/ml dose of IL-8/CXCL8 and occurred at 2 h after addition of IL-8/CXCL8. Expression of ET-1 by IL-8/CXCL8 was dependent on NF-κB activation and ERK1/2 phosphorylation. Baicalein, a 12-lipoxygenase (LO) inhibitor, inhibited the expression of IL-8/CXCL8-induced ET-1 mRNA. This inhibitory action of baicalein was mediated via ERK1/2 inactivation. Induction of 12-LO mRNA by IL-8/ CXCL8 and expression of ET-1 mRNA by 12-LO metabolite, 12(S)-HETE were also detected. The expression of IL-8/ CXCL8-induced ET-1 mRNA was not detected in PeMφ transfected with 12-LO siRNA. These results suggest that IL-8/CXCL8 can act as one of main inducers of ET-1 in vascular inflammatory reactions, and ET-1 expression by IL-8/CXCL8 is related to 12-LO pathway in PeMφ.
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 15, 1998
Dopamine beta-hydroxylase (DBH) catalyzes the conversion of dopamine to noradrenaline and is sele... more Dopamine beta-hydroxylase (DBH) catalyzes the conversion of dopamine to noradrenaline and is selectively expressed in noradrenergic and adrenergic neurons and neuroendocrine cells. Recent data from this laboratory showed that a paired-like homeodomain (HD) protein, Phox2a, interacts with the HD-binding site residing within a composite promoter of the human DBH gene, designated domain IV, in a cell-specific manner and directly controls noradrenergic-specific DBH promoter activity. In this report, we demonstrate that three additional protein-binding sites (i.e., domains I, II, and III) between domain IV and the TATA box are critical for intact DBH promoter activity in noradrenergic cells and that they activate DBH transcription in a highly concerted manner. Transient transfection assays of mutant DBH reporter constructs indicated that domain I was active in every cell line tested, whereas domain III was preferentially active in DBH-positive cells. Remarkably, mutation of domain II was...
Journal of immunology (Baltimore, Md. : 1950), 2014
Matrix metalloproteinases (MMPs) play important roles in normal brain development and synaptic pl... more Matrix metalloproteinases (MMPs) play important roles in normal brain development and synaptic plasticity, although aberrant expression of MMPs leads to brain damage, including blood-brain barrier disruption, inflammation, demyelination, and neuronal cell death. In this article, we report that MMP-8 is upregulated in LPS-stimulated BV2 microglial cells and primary cultured microglia, and treatment of MMP-8 inhibitor (M8I) or MMP-8 short hairpin RNA suppresses proinflammatory molecules, particularly TNF-α secretion. Subsequent experiments showed that MMP-8 exhibits TNF-α-converting enzyme (TACE) activity by cleaving the prodomain of TNF-α (A(74)/Q(75), A(76)/V(77) residues) and, furthermore, that M8I inhibits TACE activity more efficiently than TAPI-0, a general TACE inhibitor. Biochemical analysis of the underlying anti-inflammatory mechanisms of M8I revealed that it inhibits MAPK phosphorylation, NF-κB/AP-1 activity, and reactive oxygen species production. Further support for the p...
In the present study, we found that the natural compound arctigenin inhibited hydrogen peroxide-i... more In the present study, we found that the natural compound arctigenin inhibited hydrogen peroxide-induced reactive oxygen species (ROS) production in rat primary astrocytes. Since hemeoxygenase-1 (HO-1) plays a critical role as an antioxidant defense factor in the brain, we examined the effect of arctigenin on HO-1 expression in rat primary astrocytes. We found that arctigenin increased HO-1 mRNA and protein levels. Arctigenin also increases the nuclear translocation and DNA binding of Nrf2/c-Jun to the antioxidant response element (ARE) on HO-1 promoter. In addition, arctigenin increased ARE-mediated transcriptional activities in rat primary astrocytes. Further mechanistic studies revealed that arctigenin increased the phosphorylation of AKT, a downstream substrate of phosphatidylinositol 3-kinase (PI3K). Treatment of cells with a PI3K-specific inhibitor, LY294002, suppressed the HO-1 expression, Nrf2 DNA binding and ARE-mediated transcriptional activities in arctigenin-treated astro...
The receptor tyrosine kinase Mer plays a central role in inhibiting the inflammatory response of ... more The receptor tyrosine kinase Mer plays a central role in inhibiting the inflammatory response of immune cells to pathogens. We aimed to understand the function of Mer signaling in the resolution of sterile inflammation in experiments with a Mer-neutralizing antibody or with Mer-deficient (Mer(-/-)) mice in a model of sterile, zymosan-induced acute inflammation. We found that inhibition or deficiency of Mer enhanced local and systemic inflammatory responses. The exacerbated inflammatory responses induced by the lack of Mer signaling were associated with reduced abundance of the transcription factors liver X receptor α (LXRα) and LXRβ and decreased expression of their target genes in peritoneal macrophages, spleens, and lungs. Similarly, treatment of mice with a Mer/Fc fusion protein, which prevents the Mer ligand Gas6 (growth arrest-specific protein 6) from binding to Mer, exacerbated the inflammatory response and decreased the abundance of LXR. Coadministration of the LXR agonist T0...
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that regulate cell-matrix comp... more Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that regulate cell-matrix composition and are also involved in processing various bioactive molecules such as cell-surface receptors, chemokines, and cytokines. Our group recently reported that MMP-3, -8, and -9 are upregulated during microglial activation and play a role as proinflammatory mediators (Lee et al., 2010, 2014). In particular, we demonstrated that MMP-8 has tumor necrosis factor alpha (TNF-α)-converting enzyme (TACE) activity by cleaving the prodomain of TNF-α and that inhibition of MMP-8 inhibits TACE activity. The present study was undertaken to compare the effect of MMP-8 inhibitor (M8I) with those of inhibitors of other MMPs, such as MMP-3 (NNGH) or MMP-9 (M9I), in their regulation of TNF-α activity. We found that the MMP inhibitors suppressed TNF-α secretion from lipopolysaccharide (LPS)-stimulated BV2 microglial cells in an order of efficacy: M8I>NNGH>M9I. In addition, MMP inhibitors suppres...
The Journal of the Korean Rheumatism Association, 2008
Leflunomide is a new disease-modifying drug licensed for treatment of rheumatoid arthritis. Recen... more Leflunomide is a new disease-modifying drug licensed for treatment of rheumatoid arthritis. Recently, neuropathy has been reported with leflunomide. We report a case of peripheral neuropathy in rheumatoid arthritis treated with leflunomide. Nerve conduction study and electromyogram show sensory-motor polyneuropathy of both upper and lower limbs. Leflunomide medication was discontinued and cholestryamine washout was performed with some improvement in a couple of weeks.
The Journal of the Korean Rheumatism Association, 2008
Pachydermodactyly is a kind of benign fibromatosis in which asymptomatic symmetrical soft tissue ... more Pachydermodactyly is a kind of benign fibromatosis in which asymptomatic symmetrical soft tissue swellings occur on the proximal phalanges and the proximal interphalangeal joints of the hands. Although young women can also be affected, the young men are affected most commonly. There is no bony or articular abnormality on radiographic study. Histological examination of skin demonstrated epidermal hyperplasia, hyperkeratosis, acanthosis and thickened reticular dermis by deposition of collagen. It is important to recognize this disease identity without misdiagnosis for other rheumatologic diseases to avoid inappropriate and possibly toxic treatments. We report a case of pachydermodactyly and discuss the differential diagnosis.
Clinical and Experimental Reproductive Medicine, 2013
The aim of the present study was to examine the relationship among male age, strict morphology, a... more The aim of the present study was to examine the relationship among male age, strict morphology, and sperm chromatin structure and condensation. Methods: Sperm samples from a total of 100 men underwent semen analysis, and sperm chromatin structure and condensation were assessed with toluidine blue (TB) and aniline blue (AB) tests. Results: Prevalence of strict morphology of less than 4%, and abnormal sperm chromatin structure and condensation did not show any statistically significant differences according to male age (p=0.605, p=0.235, and p=0.080). No significant correlation was demonstrated among age of male partners, strict morphology, and abnormal sperm chromatin structure using TB and AB tests. However, abnormal sperm chromatin condensation was positively associated with sperm chromatin structure (r=0.594, p=0.000) and showed negative correlation with strict morphology (r =-0.219, p=0.029). Conclusion: The tests for sperm chromatin condensation showed a significant association with strict morphology. Further study is needed to elucidate the relationship between clinical outcome and sperm chromatin tests.
The Journal of the Korean Rheumatism Association, 2009
Uveitis is the most common extra-articular manifestation of ankylosing spondylitis, and this occu... more Uveitis is the most common extra-articular manifestation of ankylosing spondylitis, and this occurs in 30∼50% of the patients with ankylosing spondylitis. The main symptoms of ankylosing spondylitis are usually highly responsive to TNF inhibitors, but the effects of TNF inhibitors on uveitis are inconsistent. We report here on sixteen cases of new onset uveitis during etanercept therapy in patients with ankylosing spondylitis and they had no histories of uveitis. The symptoms of ankylosing spondyltiis, other than the uveitis, were well controlled during etanercept therapy. Six patients had histories of infliximab therapy before undergoing etanercept therapy, and uveitis did not develop during this infliximab therapy. Uveitis can develop during the course of ankylosing spondylitis, yet there is a possibility of a temporal relationship between etanercept therapy and uveitis.
Proper proximal contact is important for maintaining and stabilizing the dental arch. However, th... more Proper proximal contact is important for maintaining and stabilizing the dental arch. However, the proximal contact strength (PCS) is not a constant value and can be affected by a variety of factors. PURPOSE. This study examined the influences of postural changes on the posterior PCS. MATERIAL AND METHODS. Twelve adults with a normal occlusion and had not undergone prosthetic treatment or proximal restoration were participated in this study. A metal strip was inserted into the proximal surface and removed at a constant velocity. The contact strength was measured in every contact point between canine to second molar in both arches. The PCSs were obtained initially in the upright position, secondly in the supine position and finally in the upright position again. All measurements were repeated after a 2 hour period. Statistical analysis was carried out using the Friedman test (P < .05). RESULTS. Generally, a decrease in PCS occurred when the posture was changed from the initial upright to supine position, while it increased when the posture was changed from the supine to upright position. A significant change was observed in all areas except for between the canine-first premolar in the maxilla and between the first molarsecond molar in the mandible areas. CONCLUSION. The posterior PCS, which dentists generally believe to be a static feature of occlusion,
JC virus causes the fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML)... more JC virus causes the fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML) under immunosuppressive states such as AIDS. During the pathogenesis of AIDS, HIV-infected microglia secrete cytokines including interleukin-1 and tumor necrosis factor-a (TNF-a), which affect neuronal cells resulting in dysfunction of the CNS. We hypothesized that extracellular stimuli released from HIVinfected microglia may reactivate JC virus by affecting neighboring oligodendrocytes. In the present study, we found that phorbol myristate acetate (PMA) and interleukin-1h (IL-1h) dramatically increased JC virus transcription in glial cells. Site-directed mutagenesis and gel shift analyses revealed that PMA and IL-1h strongly induced nuclear factor-1 (NF-1) binding to the JC virus enhancer region, increasing transcriptional activity of the viral early promoter. Additionally, we demonstrated that protein kinase C (PKC) pathways were involved in the PMA/IL-1h-mediated up-regulation of the JC virus early promoter. These findings may represent one of the possible mechanisms for higher incidence of PML among AIDS patients.
The effect of rosiglitazone, an agonist of peroxisome proliferator-activated receptor-γ (PPARγ), ... more The effect of rosiglitazone, an agonist of peroxisome proliferator-activated receptor-γ (PPARγ), was investigated in a mouse parent-to-F1 GVHD model. Rosiglitazone inhibited mixed lymphocyte reactions, inducing enhanced apoptosis in CD4+, CD8+, and B220+ cells, but not in NK1.1+, Mac-1+, CD4+/CD25+ and CD3+/NK1.1+ cells. Rosiglitazone administration prevented GVHD in the liver, skin, spleen and intestine. Rosiglitazone inhibited GVHD-induced increases in serum levels of tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-6, and IL-12, and the GVHD-induced decreases in transforming growth factor-beta and IL-10. Immunophenotyping of splenic leukocytes demonstrated that while rosiglitazone treatment increased the population percentages of both donor and host CD4+/CD25+ and CD3+/NK1.1+ cells, the treatment resulted in lower fractions of both donor and host CD8+ cells. Rosiglitazone inhibited the GVHD-induced decreases in the expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), as well as the GVHD-induced increase in the splenic p-Akt and nuclear factor-kappa B expression. These results indicate that rosiglitazone and PPARγ activation may be useful in protecting the host from GVHD.
The expanded blastocysts, developed from 2PN-stage embryos, are generally divided into three cate... more The expanded blastocysts, developed from 2PN-stage embryos, are generally divided into three categories: a good blastocyst containing a large and distinguishable inner cell mass (ICM), a blastocyst with a small and distinct ICM, and a blastocyst with a poorly defined ICM. In this study, we introduce methods for the derivation of human embryonic stem cells (hESCs) depending on the quality of the blastocysts. An immunosurgical method was used for the good expanded blastocysts. This method, however, raises the probability of ICM loss in cases of hESC derivation from blastocysts with smaller or indistinct ICMs. Furthermore, this method is also associated with a risk of the contamination of the hESCs with animal pathogens. To overcome these shortcomings, the partial-or whole-embryo culture method was used. For blastocysts with no visible ICM, the whole-embryo culture method was used to establish hESCs via the seeding of the entire blastocyst without its zona pellucida directly on a STO feeder layer. However, trophectodermal overgrowth tends to hinder the expansion of the ICM during the initial steps of hESC derivation. Therefore, the partial-embryo culture method was developed to establish hESCs from blastocysts with smaller ICMs. The surgical isolation of the region containing the ICM with an ultra-fine glass pipette alleviates trophectoderm overgrowth. This method is also applicable to blastocysts with large and distinct ICMs, and the efficiency of this method is comparable to that of the immunosurgical method.
The objective of this study was to elucidate whether polymorphisms of the interleukin 23 receptor... more The objective of this study was to elucidate whether polymorphisms of the interleukin 23 receptor gene (IL23R) are associated with susceptibility to systemic lupus erythematosus (SLE) in a Korean population. We recruited 602 SLE patients and 991 healthy controls. Seven single nucleotide polymorphisms (rs1004819, rs7517847, rs10489629, rs2201841, rs1343151, rs11209032, and rs1495965) were selected for genotyping among previously reported variants used in a genome-wide association study of inflammatory bowel disease. Polymorphic sites were genotyped using the TaqMan assay. The genotype distributions of IL23R polymorphisms and haplotypes were compared between the SLE patients and healthy controls using multiple logistic regression models. None of the IL23R genetic variants differed significantly between SLE patients and healthy controls, which suggests that IL23R polymorphisms play no role in the susceptibility to SLE in the Korean population. Electronic supplementary material The online version of this article (doi:10.1007/s00296-009-0893-8) contains supplementary material, which is available to authorized users.
Microglial activation plays a pivotal role in the development and progression of neurodegenerativ... more Microglial activation plays a pivotal role in the development and progression of neurodegenerative diseases. Thus, antiinflammatory agents that control microglial activation can serve as potential therapeutic agents for neurodegenerative diseases. Here, we designed and synthesized a-galactosylceramide (a-GalCer) analogs to exert anti-inflammatory effects in activated microglia. We performed biological evaluations of 25 a-GalCer analogs and observed an interesting preliminary structure-activity relationship in their inhibitory influence on NO release and TNF-a production in LPS-stimulated BV2 microglial cells. After identification of 4d and 4e as hit compounds, we further investigated the underlying mechanism of their anti-inflammatory effects using RT-PCR analysis. We confirmed that 4d and 4e regulate the expression of iNOS, COX-2, IL-1b, and IL-6 at the mRNA level and the expression of TNF-a at the post-transcriptional level. In addition, both 4d and 4e inhibited LPS-induced DNA binding activities of NF-kB and AP-1 and phosphorylation of p38 MAPK without affecting other MAP kinases. When we examined the anti-inflammatory effect of a p38 MAPK-specific inhibitor, SB203580, on microglial activation, we observed an identical inhibitory pattern as that of 4d and 4e, not only on NO and TNF-a production but also on the DNA binding activities of NF-kB and AP-1. Taken together, these results suggest that p38 MAPK plays an important role in the anti-inflammatory effects of 4d and 4e via the modulation of NF-kB and AP-1 activities.
The anti-inflammatory effect of ginsenosides Rg3 and Rh2, which improves ischemic brain injury in... more The anti-inflammatory effect of ginsenosides Rg3 and Rh2, which improves ischemic brain injury induced by middle cerebral artery occlusion, was investigated in lipopolysaccharide (LPS) and IFN-gamma-induced murine BV-2 microglial cells. Ginsenoside Rh2 inhibited the production of NO, with an IC50 value of 17 microM. The inhibitory effect of Rh2 on NO correlates with the decreased protein and mRNA expression of an inducible NO synthase (iNOS) gene. Additionally, ginsenoside Rh2 inhibited the expression of COX-2, pro-inflammatory TNF-alpha and IL-1beta in BV-2 cells induced by LPS/IFN-gamma, while it increased the expression of the anti-inflammatory cytokine IL-10. Electrophoretic mobility shift assays revealed that ginsenoside Rh2 significantly inhibited the LPS/IFN-gamma-induced AP-1 DNA binding activity, while it enhanced the protein binding to CRE sequences. However, it did not affect NF-kappaB binding activity. Thus, the anti-inflammatory effect of Rh2 appears to depend on the AP-1 and protein kinase A (PKA) pathway. The anti-inflammatory effect of ginsenoside Rg3 against LPS/IFN-gamma-activated BV-2 cells was less potent than that of ginsenoside Rh2. These findings suggest that the in vivo anti-ischemic effect of ginsenoside Rg3 may originate from ginsenoside Rh2, which is a main metabolite of ginsenoside Rg3 by intestinal microflora, and that of ginsenoside Rh2 may be due to its anti-inflammatory effect in brain microglia.
This study shows that two cAMP elevating agents, dibutyryl-cAMP (dbcAMP) and forskolin, regulate ... more This study shows that two cAMP elevating agents, dibutyryl-cAMP (dbcAMP) and forskolin, regulate the expression of several cytokines and inducible nitric oxide synthase (iNOS) in a different manner. Both dbcAMP and forskolin repressed lipopolysaccharide (LPS)-induced TNF-a expression and enhanced anti-inflammatory cytokine IL-10 level in the BV2 microglia. In contrast, they differentially regulated the iNOS, IL-6 and IL-1b expression levels. DbcAMP increased the IL-1b level without affecting either the IL-6 or iNOS expression, whereas forskolin repressed the IL-6 and iNOS expression level without affecting IL-1b in the LPS-stimulated microglia. Treatment with H89, a specific inhibitor of protein kinase A (PKA), revealed that an enhancement in the IL-10 and IL-1b levels by dbcAMP or forskolin totally depends on the PKA pathway, while changes in the other cytokines and iNOS are independent or only partially dependent on the PKA pathway. These results suggest the diverse regulation of the inflammatory reactions depending on different cAMP elevating agents.
The dopamine b-hydroxylase (DBH) gene is expressed selec- tively in noradrenergic and adrenergic ... more The dopamine b-hydroxylase (DBH) gene is expressed selec- tively in noradrenergic and adrenergic neurons and neuroen- docrine cells in the nervous system. A cAMP response element (CRE) residing at 2181 to 2174 bp from the transcription start site of the human DBH gene seems to be essential for DBH transcription. Potential cis-regulatory motifs such as AP1 and YY1 occur proximal
The purpose of this study was to propose finite element (FE) modeling methods for predicting stre... more The purpose of this study was to propose finite element (FE) modeling methods for predicting stress distributions on teeth and mandible under chewing action. For FE model generation, CT images of skull were translated into 3D FE models, and static analysis was performed considering linear material behaviors and nonlinear geometrical effect. To find out proper boundary and loading conditions, parametric studies were performed with various areas and directions of restraints and loading. The loading directions are prescribed to be same as direction of masseter muscle, which was referred from anatomy chart and CT image. From the analysis, strain and stress distributions of teeth and mandible were obtained and compared with experimental data for model validation. As a result of FE analysis, the optimized boundary condition was chosen such that 8 teeth were fixed in all directions and condyloid process was fixed in all directions except for forward and backward directions. Also, fixing a ...
Endothelin-1 (ET-1) has been characterized as a potent vasoconstrictor secreted by the endotheliu... more Endothelin-1 (ET-1) has been characterized as a potent vasoconstrictor secreted by the endothelium, and play a major role in the regulation of vascular tone. It has been also known to participate in inflammatory reactions. The production of ET-1 by macrophages during infection and inflammation is related to tissue perfusion and leukocyte extravasation. The aim of this study is to investigate the role of IL-8/CXCL8, as a major inflammatory chemokine, for ET-1 expression in macrophges. Expression of ET-1 mRNA in mouse peritoneal macrophages (PeMφ) was weaker than that in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). However, expression of IL-8/CXCL8-induced ET-1 mRNA in PeMφ was much more stronger than that in SHR and WKY VSMCs. Maximum expression of ET-1 mRNA was observed at 50 ng/ml dose of IL-8/CXCL8 and occurred at 2 h after addition of IL-8/CXCL8. Expression of ET-1 by IL-8/CXCL8 was dependent on NF-κB activation and ERK1/2 phosphorylation. Baicalein, a 12-lipoxygenase (LO) inhibitor, inhibited the expression of IL-8/CXCL8-induced ET-1 mRNA. This inhibitory action of baicalein was mediated via ERK1/2 inactivation. Induction of 12-LO mRNA by IL-8/ CXCL8 and expression of ET-1 mRNA by 12-LO metabolite, 12(S)-HETE were also detected. The expression of IL-8/ CXCL8-induced ET-1 mRNA was not detected in PeMφ transfected with 12-LO siRNA. These results suggest that IL-8/CXCL8 can act as one of main inducers of ET-1 in vascular inflammatory reactions, and ET-1 expression by IL-8/CXCL8 is related to 12-LO pathway in PeMφ.
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 15, 1998
Dopamine beta-hydroxylase (DBH) catalyzes the conversion of dopamine to noradrenaline and is sele... more Dopamine beta-hydroxylase (DBH) catalyzes the conversion of dopamine to noradrenaline and is selectively expressed in noradrenergic and adrenergic neurons and neuroendocrine cells. Recent data from this laboratory showed that a paired-like homeodomain (HD) protein, Phox2a, interacts with the HD-binding site residing within a composite promoter of the human DBH gene, designated domain IV, in a cell-specific manner and directly controls noradrenergic-specific DBH promoter activity. In this report, we demonstrate that three additional protein-binding sites (i.e., domains I, II, and III) between domain IV and the TATA box are critical for intact DBH promoter activity in noradrenergic cells and that they activate DBH transcription in a highly concerted manner. Transient transfection assays of mutant DBH reporter constructs indicated that domain I was active in every cell line tested, whereas domain III was preferentially active in DBH-positive cells. Remarkably, mutation of domain II was...
Journal of immunology (Baltimore, Md. : 1950), 2014
Matrix metalloproteinases (MMPs) play important roles in normal brain development and synaptic pl... more Matrix metalloproteinases (MMPs) play important roles in normal brain development and synaptic plasticity, although aberrant expression of MMPs leads to brain damage, including blood-brain barrier disruption, inflammation, demyelination, and neuronal cell death. In this article, we report that MMP-8 is upregulated in LPS-stimulated BV2 microglial cells and primary cultured microglia, and treatment of MMP-8 inhibitor (M8I) or MMP-8 short hairpin RNA suppresses proinflammatory molecules, particularly TNF-α secretion. Subsequent experiments showed that MMP-8 exhibits TNF-α-converting enzyme (TACE) activity by cleaving the prodomain of TNF-α (A(74)/Q(75), A(76)/V(77) residues) and, furthermore, that M8I inhibits TACE activity more efficiently than TAPI-0, a general TACE inhibitor. Biochemical analysis of the underlying anti-inflammatory mechanisms of M8I revealed that it inhibits MAPK phosphorylation, NF-κB/AP-1 activity, and reactive oxygen species production. Further support for the p...
In the present study, we found that the natural compound arctigenin inhibited hydrogen peroxide-i... more In the present study, we found that the natural compound arctigenin inhibited hydrogen peroxide-induced reactive oxygen species (ROS) production in rat primary astrocytes. Since hemeoxygenase-1 (HO-1) plays a critical role as an antioxidant defense factor in the brain, we examined the effect of arctigenin on HO-1 expression in rat primary astrocytes. We found that arctigenin increased HO-1 mRNA and protein levels. Arctigenin also increases the nuclear translocation and DNA binding of Nrf2/c-Jun to the antioxidant response element (ARE) on HO-1 promoter. In addition, arctigenin increased ARE-mediated transcriptional activities in rat primary astrocytes. Further mechanistic studies revealed that arctigenin increased the phosphorylation of AKT, a downstream substrate of phosphatidylinositol 3-kinase (PI3K). Treatment of cells with a PI3K-specific inhibitor, LY294002, suppressed the HO-1 expression, Nrf2 DNA binding and ARE-mediated transcriptional activities in arctigenin-treated astro...
The receptor tyrosine kinase Mer plays a central role in inhibiting the inflammatory response of ... more The receptor tyrosine kinase Mer plays a central role in inhibiting the inflammatory response of immune cells to pathogens. We aimed to understand the function of Mer signaling in the resolution of sterile inflammation in experiments with a Mer-neutralizing antibody or with Mer-deficient (Mer(-/-)) mice in a model of sterile, zymosan-induced acute inflammation. We found that inhibition or deficiency of Mer enhanced local and systemic inflammatory responses. The exacerbated inflammatory responses induced by the lack of Mer signaling were associated with reduced abundance of the transcription factors liver X receptor α (LXRα) and LXRβ and decreased expression of their target genes in peritoneal macrophages, spleens, and lungs. Similarly, treatment of mice with a Mer/Fc fusion protein, which prevents the Mer ligand Gas6 (growth arrest-specific protein 6) from binding to Mer, exacerbated the inflammatory response and decreased the abundance of LXR. Coadministration of the LXR agonist T0...
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that regulate cell-matrix comp... more Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that regulate cell-matrix composition and are also involved in processing various bioactive molecules such as cell-surface receptors, chemokines, and cytokines. Our group recently reported that MMP-3, -8, and -9 are upregulated during microglial activation and play a role as proinflammatory mediators (Lee et al., 2010, 2014). In particular, we demonstrated that MMP-8 has tumor necrosis factor alpha (TNF-α)-converting enzyme (TACE) activity by cleaving the prodomain of TNF-α and that inhibition of MMP-8 inhibits TACE activity. The present study was undertaken to compare the effect of MMP-8 inhibitor (M8I) with those of inhibitors of other MMPs, such as MMP-3 (NNGH) or MMP-9 (M9I), in their regulation of TNF-α activity. We found that the MMP inhibitors suppressed TNF-α secretion from lipopolysaccharide (LPS)-stimulated BV2 microglial cells in an order of efficacy: M8I>NNGH>M9I. In addition, MMP inhibitors suppres...
The Journal of the Korean Rheumatism Association, 2008
Leflunomide is a new disease-modifying drug licensed for treatment of rheumatoid arthritis. Recen... more Leflunomide is a new disease-modifying drug licensed for treatment of rheumatoid arthritis. Recently, neuropathy has been reported with leflunomide. We report a case of peripheral neuropathy in rheumatoid arthritis treated with leflunomide. Nerve conduction study and electromyogram show sensory-motor polyneuropathy of both upper and lower limbs. Leflunomide medication was discontinued and cholestryamine washout was performed with some improvement in a couple of weeks.
The Journal of the Korean Rheumatism Association, 2008
Pachydermodactyly is a kind of benign fibromatosis in which asymptomatic symmetrical soft tissue ... more Pachydermodactyly is a kind of benign fibromatosis in which asymptomatic symmetrical soft tissue swellings occur on the proximal phalanges and the proximal interphalangeal joints of the hands. Although young women can also be affected, the young men are affected most commonly. There is no bony or articular abnormality on radiographic study. Histological examination of skin demonstrated epidermal hyperplasia, hyperkeratosis, acanthosis and thickened reticular dermis by deposition of collagen. It is important to recognize this disease identity without misdiagnosis for other rheumatologic diseases to avoid inappropriate and possibly toxic treatments. We report a case of pachydermodactyly and discuss the differential diagnosis.
Clinical and Experimental Reproductive Medicine, 2013
The aim of the present study was to examine the relationship among male age, strict morphology, a... more The aim of the present study was to examine the relationship among male age, strict morphology, and sperm chromatin structure and condensation. Methods: Sperm samples from a total of 100 men underwent semen analysis, and sperm chromatin structure and condensation were assessed with toluidine blue (TB) and aniline blue (AB) tests. Results: Prevalence of strict morphology of less than 4%, and abnormal sperm chromatin structure and condensation did not show any statistically significant differences according to male age (p=0.605, p=0.235, and p=0.080). No significant correlation was demonstrated among age of male partners, strict morphology, and abnormal sperm chromatin structure using TB and AB tests. However, abnormal sperm chromatin condensation was positively associated with sperm chromatin structure (r=0.594, p=0.000) and showed negative correlation with strict morphology (r =-0.219, p=0.029). Conclusion: The tests for sperm chromatin condensation showed a significant association with strict morphology. Further study is needed to elucidate the relationship between clinical outcome and sperm chromatin tests.
The Journal of the Korean Rheumatism Association, 2009
Uveitis is the most common extra-articular manifestation of ankylosing spondylitis, and this occu... more Uveitis is the most common extra-articular manifestation of ankylosing spondylitis, and this occurs in 30∼50% of the patients with ankylosing spondylitis. The main symptoms of ankylosing spondylitis are usually highly responsive to TNF inhibitors, but the effects of TNF inhibitors on uveitis are inconsistent. We report here on sixteen cases of new onset uveitis during etanercept therapy in patients with ankylosing spondylitis and they had no histories of uveitis. The symptoms of ankylosing spondyltiis, other than the uveitis, were well controlled during etanercept therapy. Six patients had histories of infliximab therapy before undergoing etanercept therapy, and uveitis did not develop during this infliximab therapy. Uveitis can develop during the course of ankylosing spondylitis, yet there is a possibility of a temporal relationship between etanercept therapy and uveitis.
Proper proximal contact is important for maintaining and stabilizing the dental arch. However, th... more Proper proximal contact is important for maintaining and stabilizing the dental arch. However, the proximal contact strength (PCS) is not a constant value and can be affected by a variety of factors. PURPOSE. This study examined the influences of postural changes on the posterior PCS. MATERIAL AND METHODS. Twelve adults with a normal occlusion and had not undergone prosthetic treatment or proximal restoration were participated in this study. A metal strip was inserted into the proximal surface and removed at a constant velocity. The contact strength was measured in every contact point between canine to second molar in both arches. The PCSs were obtained initially in the upright position, secondly in the supine position and finally in the upright position again. All measurements were repeated after a 2 hour period. Statistical analysis was carried out using the Friedman test (P < .05). RESULTS. Generally, a decrease in PCS occurred when the posture was changed from the initial upright to supine position, while it increased when the posture was changed from the supine to upright position. A significant change was observed in all areas except for between the canine-first premolar in the maxilla and between the first molarsecond molar in the mandible areas. CONCLUSION. The posterior PCS, which dentists generally believe to be a static feature of occlusion,
JC virus causes the fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML)... more JC virus causes the fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML) under immunosuppressive states such as AIDS. During the pathogenesis of AIDS, HIV-infected microglia secrete cytokines including interleukin-1 and tumor necrosis factor-a (TNF-a), which affect neuronal cells resulting in dysfunction of the CNS. We hypothesized that extracellular stimuli released from HIVinfected microglia may reactivate JC virus by affecting neighboring oligodendrocytes. In the present study, we found that phorbol myristate acetate (PMA) and interleukin-1h (IL-1h) dramatically increased JC virus transcription in glial cells. Site-directed mutagenesis and gel shift analyses revealed that PMA and IL-1h strongly induced nuclear factor-1 (NF-1) binding to the JC virus enhancer region, increasing transcriptional activity of the viral early promoter. Additionally, we demonstrated that protein kinase C (PKC) pathways were involved in the PMA/IL-1h-mediated up-regulation of the JC virus early promoter. These findings may represent one of the possible mechanisms for higher incidence of PML among AIDS patients.
The effect of rosiglitazone, an agonist of peroxisome proliferator-activated receptor-γ (PPARγ), ... more The effect of rosiglitazone, an agonist of peroxisome proliferator-activated receptor-γ (PPARγ), was investigated in a mouse parent-to-F1 GVHD model. Rosiglitazone inhibited mixed lymphocyte reactions, inducing enhanced apoptosis in CD4+, CD8+, and B220+ cells, but not in NK1.1+, Mac-1+, CD4+/CD25+ and CD3+/NK1.1+ cells. Rosiglitazone administration prevented GVHD in the liver, skin, spleen and intestine. Rosiglitazone inhibited GVHD-induced increases in serum levels of tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-6, and IL-12, and the GVHD-induced decreases in transforming growth factor-beta and IL-10. Immunophenotyping of splenic leukocytes demonstrated that while rosiglitazone treatment increased the population percentages of both donor and host CD4+/CD25+ and CD3+/NK1.1+ cells, the treatment resulted in lower fractions of both donor and host CD8+ cells. Rosiglitazone inhibited the GVHD-induced decreases in the expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), as well as the GVHD-induced increase in the splenic p-Akt and nuclear factor-kappa B expression. These results indicate that rosiglitazone and PPARγ activation may be useful in protecting the host from GVHD.
The expanded blastocysts, developed from 2PN-stage embryos, are generally divided into three cate... more The expanded blastocysts, developed from 2PN-stage embryos, are generally divided into three categories: a good blastocyst containing a large and distinguishable inner cell mass (ICM), a blastocyst with a small and distinct ICM, and a blastocyst with a poorly defined ICM. In this study, we introduce methods for the derivation of human embryonic stem cells (hESCs) depending on the quality of the blastocysts. An immunosurgical method was used for the good expanded blastocysts. This method, however, raises the probability of ICM loss in cases of hESC derivation from blastocysts with smaller or indistinct ICMs. Furthermore, this method is also associated with a risk of the contamination of the hESCs with animal pathogens. To overcome these shortcomings, the partial-or whole-embryo culture method was used. For blastocysts with no visible ICM, the whole-embryo culture method was used to establish hESCs via the seeding of the entire blastocyst without its zona pellucida directly on a STO feeder layer. However, trophectodermal overgrowth tends to hinder the expansion of the ICM during the initial steps of hESC derivation. Therefore, the partial-embryo culture method was developed to establish hESCs from blastocysts with smaller ICMs. The surgical isolation of the region containing the ICM with an ultra-fine glass pipette alleviates trophectoderm overgrowth. This method is also applicable to blastocysts with large and distinct ICMs, and the efficiency of this method is comparable to that of the immunosurgical method.
The objective of this study was to elucidate whether polymorphisms of the interleukin 23 receptor... more The objective of this study was to elucidate whether polymorphisms of the interleukin 23 receptor gene (IL23R) are associated with susceptibility to systemic lupus erythematosus (SLE) in a Korean population. We recruited 602 SLE patients and 991 healthy controls. Seven single nucleotide polymorphisms (rs1004819, rs7517847, rs10489629, rs2201841, rs1343151, rs11209032, and rs1495965) were selected for genotyping among previously reported variants used in a genome-wide association study of inflammatory bowel disease. Polymorphic sites were genotyped using the TaqMan assay. The genotype distributions of IL23R polymorphisms and haplotypes were compared between the SLE patients and healthy controls using multiple logistic regression models. None of the IL23R genetic variants differed significantly between SLE patients and healthy controls, which suggests that IL23R polymorphisms play no role in the susceptibility to SLE in the Korean population. Electronic supplementary material The online version of this article (doi:10.1007/s00296-009-0893-8) contains supplementary material, which is available to authorized users.
Microglial activation plays a pivotal role in the development and progression of neurodegenerativ... more Microglial activation plays a pivotal role in the development and progression of neurodegenerative diseases. Thus, antiinflammatory agents that control microglial activation can serve as potential therapeutic agents for neurodegenerative diseases. Here, we designed and synthesized a-galactosylceramide (a-GalCer) analogs to exert anti-inflammatory effects in activated microglia. We performed biological evaluations of 25 a-GalCer analogs and observed an interesting preliminary structure-activity relationship in their inhibitory influence on NO release and TNF-a production in LPS-stimulated BV2 microglial cells. After identification of 4d and 4e as hit compounds, we further investigated the underlying mechanism of their anti-inflammatory effects using RT-PCR analysis. We confirmed that 4d and 4e regulate the expression of iNOS, COX-2, IL-1b, and IL-6 at the mRNA level and the expression of TNF-a at the post-transcriptional level. In addition, both 4d and 4e inhibited LPS-induced DNA binding activities of NF-kB and AP-1 and phosphorylation of p38 MAPK without affecting other MAP kinases. When we examined the anti-inflammatory effect of a p38 MAPK-specific inhibitor, SB203580, on microglial activation, we observed an identical inhibitory pattern as that of 4d and 4e, not only on NO and TNF-a production but also on the DNA binding activities of NF-kB and AP-1. Taken together, these results suggest that p38 MAPK plays an important role in the anti-inflammatory effects of 4d and 4e via the modulation of NF-kB and AP-1 activities.
The anti-inflammatory effect of ginsenosides Rg3 and Rh2, which improves ischemic brain injury in... more The anti-inflammatory effect of ginsenosides Rg3 and Rh2, which improves ischemic brain injury induced by middle cerebral artery occlusion, was investigated in lipopolysaccharide (LPS) and IFN-gamma-induced murine BV-2 microglial cells. Ginsenoside Rh2 inhibited the production of NO, with an IC50 value of 17 microM. The inhibitory effect of Rh2 on NO correlates with the decreased protein and mRNA expression of an inducible NO synthase (iNOS) gene. Additionally, ginsenoside Rh2 inhibited the expression of COX-2, pro-inflammatory TNF-alpha and IL-1beta in BV-2 cells induced by LPS/IFN-gamma, while it increased the expression of the anti-inflammatory cytokine IL-10. Electrophoretic mobility shift assays revealed that ginsenoside Rh2 significantly inhibited the LPS/IFN-gamma-induced AP-1 DNA binding activity, while it enhanced the protein binding to CRE sequences. However, it did not affect NF-kappaB binding activity. Thus, the anti-inflammatory effect of Rh2 appears to depend on the AP-1 and protein kinase A (PKA) pathway. The anti-inflammatory effect of ginsenoside Rg3 against LPS/IFN-gamma-activated BV-2 cells was less potent than that of ginsenoside Rh2. These findings suggest that the in vivo anti-ischemic effect of ginsenoside Rg3 may originate from ginsenoside Rh2, which is a main metabolite of ginsenoside Rg3 by intestinal microflora, and that of ginsenoside Rh2 may be due to its anti-inflammatory effect in brain microglia.
This study shows that two cAMP elevating agents, dibutyryl-cAMP (dbcAMP) and forskolin, regulate ... more This study shows that two cAMP elevating agents, dibutyryl-cAMP (dbcAMP) and forskolin, regulate the expression of several cytokines and inducible nitric oxide synthase (iNOS) in a different manner. Both dbcAMP and forskolin repressed lipopolysaccharide (LPS)-induced TNF-a expression and enhanced anti-inflammatory cytokine IL-10 level in the BV2 microglia. In contrast, they differentially regulated the iNOS, IL-6 and IL-1b expression levels. DbcAMP increased the IL-1b level without affecting either the IL-6 or iNOS expression, whereas forskolin repressed the IL-6 and iNOS expression level without affecting IL-1b in the LPS-stimulated microglia. Treatment with H89, a specific inhibitor of protein kinase A (PKA), revealed that an enhancement in the IL-10 and IL-1b levels by dbcAMP or forskolin totally depends on the PKA pathway, while changes in the other cytokines and iNOS are independent or only partially dependent on the PKA pathway. These results suggest the diverse regulation of the inflammatory reactions depending on different cAMP elevating agents.
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