Induction of plasminogen activator inhibitor 1 gene expression in adipocytes by thiazolidinediones.
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3T3 Cells↗
Biomedical subjects
A Takada
Publications and source records attributed to A Takada.
Tissue-type plasminogen activator is involved in the process of neuronal death induced by oxygen-glucose deprivation in culture.
Effect of tissue-type plasminogen activator (tPA) on oxygen-glucose deprivation (OGD) was studied in cultured cortical neurons prepared from tPA gene knockout (tPA-KO) and wild-type (Wt) mice. Three hours of OGD induced 45% and 23% of neuronal death in Wt and tPA-KO mice, respectively. Neuronal death in tPA-KO mice was increased to 42% by additional tPA. Six hours of OGD induced 80% and 40% of neuronal death in Wt and tPA-KO mice, respectively, whereas the addition of tPA increased to 62% in tPA-KO mice. These results suggest that tPA is directly involved in the process of neuronal death induced by ischemia-mimic stress without involving vascular or circulatory components.
Animals↗
Plasminogen-binding activity of neuraminidase determines the pathogenicity of influenza A virus.
When expressed in vitro, the neuraminidase (NA) of A/WSN/33 (WSN) virus binds and sequesters plasminogen on the cell surface, leading to enhanced cleavage of the viral hemagglutinin. To obtain direct evidence that the plasminogen-binding activity of the NA enhances the pathogenicity of WSN virus, we generated mutant viruses whose NAs lacked plasminogen-binding activity because of a mutation at the C terminus, from Lys to Arg or Leu. In the presence of trypsin, these mutant viruses replicated similarly to wild-type virus in cell culture. By contrast, in the presence of plasminogen, the mutant viruses failed to undergo multiple cycles of replication while the wild-type virus grew normally. The mutant viruses showed attenuated growth in mice and failed to grow at all in the brain. Furthermore, another mutant WSN virus, possessing an NA with a glycosylation site at position 130 (146 in N2 numbering), leading to the loss of neurovirulence, failed to grow in cell culture in the presence of plasminogen. We conclude that the plasminogen-binding activity of the WSN NA determines its pathogenicity in mice.
Animals↗
Ebola virus glycoprotein: proteolytic processing, acylation, cell tropism, and detection of neutralizing antibodies.
Using the vesicular stomatitis virus (VSV) pseudotype system, we studied the functional properties of the Ebola virus glycoprotein (GP). Amino acid substitutions at the GP cleavage site, which reduce glycoprotein cleavability and viral infectivity in some viruses, did not appreciably change the infectivity of VSV pseudotyped with GP. Likewise, removal of two acylated cysteine residues in the transmembrane region of GP showed no discernible effects on infectivity. Although most filoviruses are believed to target endothelial cells and hepatocytes preferentially, the GP-carrying VSV showed greater affinity for epithelial cells than for either of these cell types, indicating that Ebola virus GP does not necessarily have strong tropism toward endothelial cells and hepatocytes. Finally, when it was used to screen for neutralizing antibodies against Ebola virus GP, the VSV pseudotype system allowed us to detect strain-specific neutralizing activity that was inhibited by secretory GP (SGP). This finding provides evidence of shared neutralizing epitopes on GP and SGP molecules and indicates the potential of SGP to serve as a decoy for neutralizing antibodies.
Acylation↗
Infectivity-enhancing antibodies to Ebola virus glycoprotein.
Ebola virus causes severe hemorrhagic fever in primates, resulting in mortality rates of up to 100%, yet there are no satisfactory biologic explanations for this extreme virulence. Here we show that antisera produced by DNA immunization with a plasmid encoding the surface glycoprotein (GP) of the Zaire strain of Ebola virus enhances the infectivity of vesicular stomatitis virus pseudotyped with the GP. Substantially weaker enhancement was observed with antiserum to the GP of the Reston strain, which is much less pathogenic in humans than the Ebola Zaire and Sudan viruses. The enhancing activity was abolished by heat but was increased in the presence of complement system inhibitors, suggesting that heat-labile factors other than the complement system are required for this effect. We also generated an anti-Zaire GP monoclonal antibody that enhanced viral infectivity and another that neutralized it, indicating the presence of distinct epitopes for these properties. Our findings suggest that antibody-dependent enhancement of infectivity may account for the extreme virulence of the virus. They also raise issues about the development of Ebola virus vaccines and the use of passive prophylaxis or therapy with Ebola virus GP antibodies.
Animals↗
Sudden death due to cardiovascular disorders: a review of the studies on the medico-legal cases in Tokyo.
The Tokyo Metropolitan Government has a medical examiner system, in which all cadavers classified as "unusual death" in the city of Tokyo should be examined, and if necessary, autopsied to determine the cause of death. Of about 10,000 unusual deaths examined per year, two thirds are usually determined to have died of natural causes. The most common cause of sudden natural death is ischemic heart disease, especially acute myocardial infarction. Pathological examination, however, proves acute myocardial ischemia in only one third of autopsies. Subarachnoid hemorrhage and intracerebral hemorrhage, acute myocarditis and cardiomyopathies and aortic dissection/aneurysm as well as pulmonary thromboembolism are frequent causes of death in medical examiner cases. Both pathological and socio-medical problems associated with these diseases are discussed.
Aortic Aneurysm↗
Mucosal vaccination against influenza: protection of pigs immunized with inactivated virus and ether-split vaccine.
Effective vaccinations against swine influenza reduce the economic loss of pig industries, and also may minimize the possibility of emergence of new pandemic viruses, since pigs are intermediate hosts to generate reassortant viruses among avian and mammalian influenza viruses. In this study, we showed that intranasal immunization of pigs with formalin-inactivated or ether-split influenza vaccine (A/Aichi/2/68) induced virus-specific IgG, IgM, and IgA antibodies in their nasal secretions and sera, resulting in complete protection from virus challenge. Antibody response to the challenge virus was not observed in the immunized pigs, suggesting that the replication of the virus in the primary targets, respiratory epithelial cells, was inhibited. The present results indicate that intranasal immunization of pigs with inactivated vaccines is effective to control swine influenza, and also provide a good model, as well as a mouse model, to evaluate an intranasal application of influenza vaccine for humans.
Administration, Intranasal↗
The expression of exercise-induced tPA activity in blood is regulated by the basal level of PAI-1.
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Adult↗
Importance of GlcUAbeta1-3GalNAc(4S,6S) in chondroitin sulfate E for t-PA- and u-PA-mediated Glu-plasminogen activation.
Chondroitin sulfate E (CSE) markedly enhanced plasminogen activation by tissue plasminogen activators (t-PAs) and urinary plasminogen activator (u-PA) in vitro; in the presence of 10 microg/ml of CSE, the potentiation factors of single chain of t-PA, two chain of t-PA and u-PA were 400, 140 and 130, respectively. Though the potentiation activity of CSE gradually decreased when it was depolymerized by chondroitinase ABC, the specific disaccharide from CSE still showed significant activity. Glycosaminoglycan (GAG) from sea cucumber, which possesses a very similar core structure to CSE, but has additional sulfated fucose branches exhibit very weak activity. These results suggested that the minimal structural requirement in CSE to enhance plasminogen activation by plasminogen activators is GlcUAbeta1-3GalNAc(4S,6S) and that additional branching sugars abolish the activity.
Animals↗
Downregulation of beta1 integrins by Ebola virus glycoprotein: implication for virus entry.
Filoviruses, including Ebola virus, are cytotoxic. To investigate the role of the Ebola virus glycoprotein (GP) in this cytopathic effect, we transiently expressed the GP in human kidney 293T cells. Expression of wild-type GP, but not the secretory form of the molecule lacking a membrane anchor, induced rounding and detachment of the cells, as did a chimeric GP containing its ectodomain and influenza virus hemagglutinin transmembrane-cytoplasmic domain. These results indicate that the GP ectodomain and its anchorage to the membrane are required for GP-induced morphologic changes in host cells. Since cell rounding and detachment could be associated with reduced levels of cell adhesion molecules, we also studied the expression of integrins, which are major molecules for adhesion to extracellular matrices, and found that the beta1 integrin group is downregulated by the GP. This result was further extended by experiments in which anti-beta1 monoclonal antibodies or purified integrins inhibited the infectivity of vesicular stomatitis virus pseudotyped with the GP. We suggest that integrins, especially the beta1 group, might interact with the GP and perhaps be involved in Ebola virus entry into cells.
Cell Line↗
Papillary fibroelastoma of the aortic valve: a sudden death case of coronary embolism with myocardial infarction.
Papillary fibroelastoma is a rare benign tumor, occasionally causing angina or sudden death. We report an autopsy case of an aortic valve papillary fibroelastoma with coronary artery embolism. The patient was a 68-year-old Japanese man who had collapsed suddenly in his house. He was a heavy drinker and had a history of liver disease but no notable cardiac event. The autopsy revealed extensive transmural infarction of the inferior wall of the left and right cardiac ventricles. The distal portion of the right coronary artery (segment 4, NYHA) was completely occluded by tumor emboli of the fibroelastoma. At the site of closure of the aortic non-coronary cusp, there was a typical papillary fibroelastoma, which was considered to have originated the coronary embolization.
Aged↗
Association between LDLR polymorphism and diseases in the Japanese population: aging and distribution of the polymorphism.
A number of DNA polymorphisms have been found to be associated with the pathophysiology of some common disease. If the LDLR polymorphism is directly or indirectly related to some fatal disease, the distribution of the polymorphism may vary with age. We therefore investigated the aging-associated distribution of the LDLR polymorphism. Blood samples were collected from Japanese cadavers (aged 0-91) at autopsy. The LDLR polymorphism was detected using a AmpliType PM PCR Typing kit. When the LDLR genotype was examined in cadavers divided according to age into 0-29 year group, 30-59 year group, and 60-91 year group, there were significant differences in genotype among the three age groups and between the 0-29 year group and 60-91 year group. The LDLR-A genotype tended to be lower in the older cadavers. The present study revealed that there were aging-dependent differences in the distribution of the LDLR polymorphism in autopsy samples, suggesting that a common mutation involved in the occurrence of fatal diseases may be present near the LDLR-A polymorphism locus.
Adolescent↗
Relevance of tissue factor and tissue factor pathway inhibitor for hypercoagulable state in the lungs of patients with idiopathic pulmonary fibrosis.
We investigated the role of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in the lungs of patients with idiopathic pulmonary fibrosis (IPF). Bronchoalveolar lavage (BAL) fluid was obtained from 22 patients with IPF, and the levels of TF and TFPI antigen were measured by ELISA. The TF and TFPI levels in BAL fluid supernatant were significantly higher in IPF patients than in normal controls. In addition, both levels were significantly higher in advanced cases than in nonadvanced cases. There was a significant correlation between the TF and TFPI levels. Localization of TF and TFPI antigens was investigated by immunohistochemical staining. Both antigens were mainly localized in hyperplastic cuboidal epithelial cells, suggesting that the widespread distribution of these cells contributed to the increase of TF and TFPI antigen levels in the lungs of IPF patients. To assess whether TF activity is counterbalanced by TFPI in the lungs of IPF patients, we examined procoagulant activity and TF activity. It was found, however, that both procoagulant and TF activities were significantly higher in the BAL fluid supernatant of IPF patients than in that of normal controls, which suggested that TFPI was actually increased, but the increase was insufficient to counterbalance TF, leading to the development of a hypercoagulable state in the lungs of IPF patients.
Adult↗
Previous exposure to footshock stress attenuates nicotine-induced serotonin release in rat striatum during the subsequent stress.
We have analyzed the effects of chronic or repeated footshock stress on the release of serotonin (5-hydroxytryptamine: 5-HT) in the striatum of rats that received nicotine by using a microdialysis technique. Neither local infusion of nicotine alone nor stress application alone changed 5-HT release. Local infusion of 1 mM nicotine to the striatum, however, significantly increased 5-HT release in the striatum to 145.9 +/- 30.8 pg/dialysate during simultaneous stress application. These increases of extracellular 5-HT release induced by the combination of nicotine and stress application were also observed in rats that had received daily chronic footshock. However, the previously administered footshock induced the reduced release of 5-HT from the striatum to 33.5 +/- 8. 6 (repeated footshock) and 10.0 +/- 3.6 pg/dialysate (daily footshock) when footshock was given together with nicotine infusion. These results suggest that previous exposure to stress attenuated the nicotine-induced 5-HT release in the striatum during the subsequent stress.
Animals↗
Serotonergic neurons projecting to hippocampus activate locomotion.
Although the role of brain serotonergic neurons in locomotion has been extensively studied, their influence may vary depending upon the terminal areas. Thus, using microdialysis and microinjection techniques, we examined the relationship between serotonin (5-HT) levels in striatum, hippocampus or prefrontal cortex (PFC) and motor activity in rats. The systemic injection (10 mg/kg i.p.) of monoamine oxidase inhibitor, tranylcypromine (TC), significantly elevated 5-HT levels in the striatum, hippocampus and PFC accompanied by a parallel increase in motor activity of the rats. This effect was mimicked by microinfusions of TC (1.0 mM) or 5-HT (1. 0 mM) into the hippocampus and to some extent into PFC (the response delayed in time), but not into striatum. The increase in motor activity produced by local infusions of TC either into the hippocampus or PFC could be prevented by pretreatment with 10 microM tetrodotoxin infused into the hippocampus. However, tetrodotoxin infused to PFC failed to prevent hyperlocomotion produced by intrahippocampal infusion of TC, although the response was delayed in time. Thus, we conclude that serotonergic neurons projecting to the hippocampus are involved in locomotor activity and PFC serotonergic fibers may facilitate hippocampal control of locomotion.
Animals↗
Transcriptional activation of JC virus by human T-lymphotropic virus type I Tax protein in human neuronal cell lines.
Polyomavirus JC (JCV) causes the human demyelinating disease, progressive multifocal leukoencephalopathy (PML). The recent demonstration of cases of PML in association with human T-lymphotropic virus type I (HTLV-I) infection prompted us to examine whether the HTLV-I-encoded regulatory protein Tax activates JCV transcription. By employing a dual luciferase assay, we initially found that the expression of Tax activated the transcriptional potential of both early and late promoters of JCV in human neuronal but not in non-neuronal cells. We subsequently analyzed the mechanism of Tax-induced activation of the JCV promoter in neuronal cells with the following results: 1) the JCV promoter that lacks the NF-kappaB-binding motif could not be activated by Tax; 2) the overexpression of IkappaBalpha abolished Tax-induced transcriptional activation of the JCV promoter; 3) a Tax mutant (M22) lacking the potential for activation via the NF-kappaB pathway did not activate the JCV promoter. Furthermore, Tax enhances the gene expression of JCV T antigen and VP1. We examined mechanisms of the cell-specific activation of the JCV promoter by Tax. Electrophoretic mobility shift assay demonstrated the presence of Tax-bound protein(s) that were specifically present in non-neuronal cells. This study is the first demonstration of the activation of JCV promoter by HTLV-I Tax in an NF-kappaB-dependent manner.
Base Sequence↗
Interspecies transmission of influenza viruses: H5N1 virus and a Hong Kong SAR perspective.
This account takes stock of events and involvements, particularly on the avian side of the influenza H5N1 'bird flu' incident in Hong Kong SAR in 1997. It highlights the role of the chicken in the many live poultry markets as the source of the virus for humans. The slaughter of chicken and other poultry across the SAR seemingly averted an influenza pandemic. This perspective from Hong Kong SAR marks the coming-of-age of acceptance of the role of avian hosts as a source of pandemic human influenza viruses and offers the prospect of providing a good baseline for influenza pandemic preparedness in the future. Improved surveillance is the key. This is illustrated through the H9N2 virus which appears to have provided the 'replicating' genes for the H5N1 virus and which has since been isolated in the SAR from poultry, pigs and humans highlighting its propensity for interspecies transmission.
Animals↗
Differential effects of nicotine against stress-induced changes in dopaminergic system in rat striatum and hippocampus.
A number of studies have shown an increase in nicotine self-administration among smokers when exposed to stress. Since it is well known that nicotine or stress alter the dopaminergic system, we examined the effect of chronic nicotine administration on the dopamine level and its metabolism in the striatum and the hippocampus during stressful conditions in rats. Nicotine (0.4 mg/kg, i.p. for 14 days) increased the dopamine level in the striatum (P<0. 05) and decreased it in the hippocampus (P<0.05) in comparison with the effect of saline. Three hours of water-immersion restraint stress sharply elevated the dopamine level (P<0.05) and reduced the 3-methoxytyramine level (P ranged from 0.05 to 0.001 depending on the area and time point) in both brain regions studied, while dihydroxyphenylacetic acid and homovanilic acid levels were not altered. Nicotine pretreatment attenuated some of these changes in a region- and time-dependent manner. However, stress induced a decrease in dopamine turnover in the hippocampus (P<0.05) but not in the striatum, and nicotine failed to prevent this effect. Stress-induced alterations gradually returned toward normal during the 48-h observation period, and in some cases this was facilitated by nicotine. Thus, we demonstrated differential, region- and time-dependent protective effects of chronic nicotine administration against stress-induced changes in dopamine levels and release in brain regions critically affected by stress.
Animals↗