Showing papers by "Dong-Kug Choi published in 2005"

Ablation of the Inflammatory Enzyme Myeloperoxidase Mitigates Features of Parkinson's Disease in Mice

Abstract: Parkinson's disease (PD) is characterized by a loss of ventral midbrain dopaminergic neurons, which can be modeled by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Inflammatory oxidants have emerged as key contributors to PD- and MPTP-related neurodegeneration. Here, we show that myeloperoxidase (MPO), a key oxidant-producing enzyme during inflammation, is upregulated in the ventral midbrain of human PD and MPTP mice. We also show that ventral midbrain dopaminergic neurons of mutant mice deficient in MPO are more resistant to MPTP-induced cytotoxicity than their wild-type littermates. Supporting the oxidative damaging role of MPO in this PD model are the demonstrations that MPO-specific biomarkers 3-chlorotyrosine and hypochlorous acid-modified proteins increase in the brains of MPTP-injected mice. This study demonstrates that MPO participates in the MPTP neurotoxic process and suggests that inhibitors of MPO may provide a protective benefit in PD.

Integrative role of cPLA2 with COX-2 and the effect of non-steriodal anti-inflammatory drugs in a transgenic mouse model of amyotrophic lateral sclerosis

Abstract: Cyclooxygenase-2 (COX-2) is a key molecule in the inflammatory pathway in amyotrophic lateral sclerosis (ALS). Cytosolic phospholipase A (cPLA2) is an important enzyme providing substrate for cyclooxygenases. We therefore examined cPLA2 expression in human ALS and mutant Cu/Zn superoxide dismutase (SOD1) transgenic mice and its relation to COX-2. Immunohistochemistry and real-time RT-PCR revealed elevated cPLA2 protein and its mRNA levels in the lumbar spinal cord of mutant SOD1 mice. COX-2 immunoreactivity was increased in lumbar spinal cord sections from both familial ALS (FALS) and sporadic ALS (SALS) as compared to controls, and cPLA2 immunoreactivity was increased in a patient with FALS. Oral administration of the non-selective cyclooxygenase (COX) inhibitor, sulindac, extended the survival (by 10%) of G93A SOD1 mice as compared to littermate controls. Sulindac, as well as the selective COX-2 inhibitors, rofecoxib and celecoxib reduced cPLA2 immunoreactivity in the lumbar spinal cord of G93A transgenic mice. Sulindac treatment preserved motor neurons, and reduced microglial activation and astrocytosis, in the spinal cord of G93A SOD1 transgenic mice. These results suggest that cPLA2 plays an important role in supplying arachidonic acid to the COX-2 driven inflammatory pathway in ALS associated with SOD1 mutations.

The Time‐Dependent Serial Gene Response to Zeocin Treatment Involves Caspase‐Dependent Apoptosis in HeLa Cells

Abstract: Zeocin, a member of the bleomycin/phleomycin family of antibiotics, is known to bind DNA and to induce apoptosis in cervical cancer cells, but the mechanism underlying this apoptotic response is poorly understood. The present study was undertaken to elucidate time-dependent serial transcript patterns in the HeLa cervical carcinoma cell line, following treatment with Zeocin. The HeLa cell proliferation rate was found to gradually decrease following Zeocin exposure, in a time-and dose-dependent manner. RNA transcript level measurements, for time-dependent serial gene expression profiling, were determined at 0, 6, 12, 18 and 24 hr using a 0.5 k apoptosis functional microarray chip. Further statistical analysis, using a significance test at a 95% confidence level, for transcripts with a greater than 2-fold change on the array chips, identified 49 up-regulated and 57 down-regulated genes. Our gene expression profile data indicate that Zeocin treatment induces an initial release of cytochrome c, the down-regulation of Bcl-X (L), ENDOG, DAXX and MDM2, and the up-regulation of CASP and BID. This suggests that a p53-independent mitochondrial caspase cascade pathway is primarily involved in Zeocin-induced apoptosis. Such caspasedependent cytotoxic activity also implies that this cell death pathway occurs via the caspase 8 and BID genes. However, disruption of either FAS or TNFR1 signaling did not interfere with the Zeocin induced apoptotic response in our experimental system. We hypothesize that Zeocin could be active against cervical cancer cell resistance to conventional chemotherapy and postulate that Zeocin is a novel candidate for the development of new chemotherapeutic treatments of gynecological cancers.

A computational approach to the inference of sphingolipid pathways from the genome of Aspergillus fumigatus.

Abstract: A growing body of evidence suggests that sphingolipids are important bioactive molecules, in addition to being critical structural components of cellular membranes. These molecules have been implicated in regulating cell growth, differentiation, angiogenesis, apoptosis, and senescence. Many of the enzymes involved in sphingolipid biosynthesis are the targets of fungal toxins, thus underscoring the importance of this pathway. An international consortium has made considerable progress in sequencing the genome of Aspergillus fumigatus, one of the most common mold pathogens of humans; however, most genes have not yet been annotated. Here, we have identified genes involved in the sphingolipid pathway of A. fumigatus by comparative analysis with four other fungal species and the gene prediction program GlimmerM. Our results shows that A. fumigatus has most of the sphingolipid pathway genes found in other fungi, except for the CSG2 and IPT1 genes; the former is involved in the mannosylation of inositol phosphorylceramide (IPC) to mannose-inositol-phosphorylceramide and the latter involved in the synthesis of mannose-(inositol-P)2-ceramide from mannose-inositol-phosphorylceramide.

Differential effects of ethanol on glial signal transduction initiated by lipopolysaccharide and interferon‐γ

Abstract: Although the pathogenic effects of alcohol abuse on brain are well established, its specific effects on the intracellular signal transduction pathways of glial cells in the central nervous system (CNS) are poorly understood. In this study, we evaluated how ethanol affects the glial signal transduction associated with inflammatory activation. Lipopolysaccharide (LPS), gangliosides, and interferon (IFN)-gamma induced the inflammatory activation of glia, which was differentially influenced by ethanol: 1) ethanol inhibited LPS- or gangliosides-induced, but not IFNgamma-induced, glial activation as demonstrated by the production of nitric oxide and the expression of inflammatory genes such as interleukin-1beta, tumor necrosis factor-alpha, IP-10, and CD86; 2) nuclear factor (NF)-kappaB or JAK/STAT1 pathway was necessary for LPS- or IFNgamma-induced glial activation, respectively; 3) ethanol inhibited LPS-induced NF-kappaB activation; and 4) ethanol did not significantly affect IFNgamma-induced STAT1/IRF-1 activation. Based on these results, ethanol seems to inhibit selectively some parts of the glial signal transduction pathways that are associated with inflammatory activation, which may lead to the deregulation of CNS inflammatory responses.

Exploring the Phospholipid Biosynthetic Pathways of Aspergillus fumigatus by Computational Genome Analysis

Abstract: Aspergillus fumigatus causes a wide range of diseases that include mycotoxicosis, allergic reactions and systematic diseases (invasive aspergillosis) with high mortality rates. In recent years, considerable progress in the genome sequencing of this fungus has been made by an international consortium, which includes the Wellcome Trust Sanger Institute (UK) and the Institute for Genome Research (USA). A tenfold whole genome shotgun sequence assembly of A. fumigatus has been made publicly available. In this study, it was attempted to identify the genes related to the phospholipid biosynthesis from the A. fumigatus genome by a gene prediction program (GlimmerM) and to reconstruct the metabolic pathway for phospholipids of A. fumigatus. Fifteen genes related to phospholipid pathway were identified in the A. fumigatus genomic sequence. The open reading frames predicted by GlimmerM showed a high amino acid sequence similarity with the other fungal phospholipid biosynthetic genes and well-conserved functional domains. The obtained results also demonstrated that the reconstructed pathway of A. fumigatus in phospholipid biosynthesis was very similar to that of other fungi such as Saccharomyces cerevisiae, Schizosaccharomyces pombe, Candida albicans, and Neurospora crassa. Therefore it is postulated that the antifungal drugs targeted for the biosynthesis of phospholipids could also be effective against A. fumigatus.

Immunoregulatory Effects of Phellinus linteus (Berk. et Curt) Teng Extract on the Cytokine Production, T Cell Population and Immunoglobulin E Level in Murine Mesenteric Lymph Node Lymphocytes

Abstract: Phellinus linteus (PL), one of the immune-regulatory substances, is recognized to play the role in the metabolic process on inflammation and immunity. It has been traditionally used in the oriental medicine to treat inflammatory related disease. The purpose of this study was to evaluate the effects of water extracts of PL on the mesenteric lymph node lymphocytes immune function in the ICR male mice. Control mice received vehicle only. The PL treated mice were administered the respective extract by oral gavages for 4 weeks. IgE concentrations in serum and MLN lymphocytes were significantly lower in PL treated mice than in control mice. PL increased the proportion of T cells in MLN lymphocytes. PL significantly decreased Th2 cytokine concentrations and mRNA expression levels in cytokine secretions. Therefore, water extracts of PL modulate inflammatory parameters through regulation of immunoglobulin production resulting from decreased Th2 cytokine secretion and mRNA expression levels and reduce pro-inflammatory cytokine secretion and mRNA expression in MLN lymphocytes.