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Biomedical subjects

A Tanaka

Publications and source records attributed to A Tanaka.

At least 91 records · Page 5Linked to original sources
PubMed2001

Recombinant annexin II modulates impaired fibrinolytic activity in vitro and in rat carotid artery.

Fibrinolytic activity has been reported to be decreased in atherosclerosis. Recently, annexin II was identified as a coreceptor on endothelial cells for plasminogen and tissue plasminogen activator. In this study, we examined whether recombinant annexin II (rAN II) protein can modulate fibrinolytic activity on vascular endothelium in vitro and in vivo. The effect of rAN II on human umbilical vein endothelial cells (HUVECs) was measured. Addition of a fluorescent plasmin substrate revealed that HUVECs treated with rAN II exhibited significantly more plasmin generation than those treated with BSA. Moreover, rAN II treatment of HUVECs restored plasmin generation impaired by plasminogen activator inhibitor-1 or homocysteine pretreatment. In a rat carotid artery thrombus model, the patency of thrombosed carotid arteries was significantly enhanced by rAN II injection, in contrast to BSA injection, without systemic blood coagulation dysregulation. We found that rAN II enhanced plasmin generation on vascular endothelium in vitro and reduced thrombus formation in vivo, and concluded that enhancement of endothelial fibrinolytic activity by annexin II could modulate the hypercoagulable state of atherosclerosis. Further study of rAN II in vitro and in vivo may lead to the establishment of novel therapeutic approaches to thrombogenic vascular disease.

Animals↗
PubMed2001

Relationship between plasma insulin concentration and plasma remnant lipoprotein response to an oral fat load in patients with type 2 diabetes.

OBJECTIVES: The goal of this study was to evaluate the relative effects of hyperglycemia and hyperinsulinemia on postprandial remnant lipoprotein (RLP) concentrations in newly diagnosed type 2 diabetics. BACKGROUND: Increases in fasting RLP concentration have been described in type 2 diabetics, as well as in insulin-resistant nondiabetics. Given the atherogenicity of RLPs, we have extended these observations by assessing postprandial RLP concentrations and observing that hyperglycemia was necessary for the increase in RLP concentrations. METHODS: Patients with type 2 diabetes were subdivided on the basis of their plasma insulin response to oral glucose into hyperinsulinemic (H-DM) and normoinsulinemic (N-DM) groups of 15 patients each. Plasma triglyceride (TG), RLP-TG and RLP cholesterol (RLP-C) concentrations were determined before and 2 and 4 h after an oral fat load in these patients and 10 control (CTL) subjects. RESULTS: Plasma TG, RLP-TG and RLP-C concentrations peaked 2 h after the fat load in the CTL group, returning to baseline within 4 h. In contrast, concentrations of these variables increased throughout the 4-h study in both groups of patients with type 2 diabetes. Total integrated plasma RLP-TG and RLP-C responses above baseline after the oral fat load were significantly higher in the H-DM group compared with the CTL (p = 0.019 and 0.009, respectively) or N-DM (p = 0.026 and 0.029, respectively) groups. Post-heparin lipoprotein lipase activities and apo E phenotypes were similar in the H-DM and N-DM groups. CONCLUSIONS: Remnant lipoprotein response to an oral fat load is significantly increased in hyperinsulinemic patients with type 2 diabetes. These changes may increase the risk of coronary heart disease in these individuals.

Adult↗
PubMed2001

Inability of IL-12 to down-regulate IgE synthesis due to defective production of IFN-gamma in atopic NC/Nga mice.

NC/Nga mice raised in nonsterile circumstances spontaneously suffer from atopic dermatitis-like skin lesions with IgE hyperproduction. We investigated effects of rIL-12 on the IgE production in NC/Nga mice. rIL-12 administration was successful to suppress the increase of IgE levels in BALB/c mice immunized with OVA and aluminum hydroxide, but failed to abrogate that in NC/Nga mice. Both in vivo and in vitro IFN-gamma production induced by rIL-12 was less in NC/Nga mice than in BALB/c mice. Addition of rIFN-gamma to rIL-4 and LPS completely abrogated IgE production by B cells of BALB/c mice, but was insufficient to suppress it by B cells of NC/Nga mice. In splenic cells pretreated with Con A, STAT4 was phosphorylated at the tyrosine residue by addition of rIL-12, which was more weakly inducible in NC/Nga mice than in BALB/c mice. Finally, we examined the preventive ability of rIL-12 on the clinical aspects of atopic dermatitis in NC/Nga mice. rIL-12 administration resulted in exacerbation of development of the skin lesions and IgE production in NC/Nga mice raised in nonsterile circumstances. These results suggest that defective production of IFN-gamma by T cells less sensitive to IL-12 and low responsiveness of B cells to IFN-gamma may contribute to IgE hyperproduction in NC/Nga mice, and that IL-12 may have no ability to improve the clinical aspects of NC/Nga mice.

Animals↗
PubMed2001

Pathogenesis of laryngeal narrowing in patients with multiple system atrophy.

1. We do not fully understand the pathogenesis of nocturnal laryngeal stridor in patients with multiple system atrophy (MSA). Recent studies suggest that inspiratory thyroarytenoid (TA) muscle activation has a role in the development of the stridor. 2. The breathing pattern and firing timing of TA muscle activation were determined in ten MSA patients, anaesthetized with propofol and breathing through the laryngeal mask airway, while the behaviour of the laryngeal aperture was being observed endoscopically. 3. Two distinct breathing patterns, i.e. no inspiratory flow limitation (no-IFL) and IFL, were identified during the measurements. During IFL, significant laryngeal narrowing was observed leading to an increase in laryngeal resistance and end-tidal carbon dioxide concentration. Development of IFL was significantly associated with the presence of phasic inspiratory activation of TA muscle. Application of continuous positive airway pressure suppressed the TA muscle activation. 4. The results indicate that contraction of laryngeal adductors during inspiration narrows the larynx leading to development of inspiratory flow limitation accompanied by stridor in patients with MSA under general anaesthesia.

Aged↗
PubMed2001

Extensive neuronal localization and neurotrophic function of fibroblast growth factor 8 in the nervous system.

Fibroblast growth factor (FGF) 8 has been well established to play a critical role in the early development of the central nervous system (CNS). We report here extensive neuronal localization and neurotrophic function of FGF8 in the nervous system. In sections of mouse embryos at E10.5, FGF8 was immunohistochemically found in neurons at the marginal zones of the CNS and in the dorsal root ganglia (DRG). Neuronal localization of FGF8 was marked at later embryonic stages and in adults, involving most of the central and peripheral neurons, including intermuscular enteric neurons, DRGs, and paraaortic sympathetic ganglia. Functionally, FGF8 promoted neurite outgrowth in human neuroblastoma SK-N-MC cells as well as in rat pheochromocytoma PC12 cells, suggesting that FGF8 acts as a neurotrophic factor. FGF8 also supported neuronal survival and differentiation in cultured human neural progenitor cells. In a cell growth assay, treatment with 50 ng/ml FGF8 on human cultured neuroblastoma SK-N-MC and IMR32 cells attenuated the growth of both. In accordance with these in vitro findings, the immunohistochemical analysis on human neurological diseases showed that FGF8 expression is evident in differentiating histological types of neuroblastoma and ganglioneuroblastoma, and that the levels of FGF8 immunoreactivity in the substantia nigra from Parkinson's disease are significantly lower than those in age-matched controls. Taken together, the present findings strongly suggest that FGF8 acts as a more generalized neurotrophic factor than previously reported.

Animals↗
PubMed2001

Synthesis and biological activity of novel macrocyclic antifungals. modification of the tyrosine moiety of the lipopeptidolactone FR901469.

A series of tyrosine-modified derivatives of the macrocyclic lipopeptidolactone FR901469 have been prepared and evaluated for in vitro and in vivo antifungal activity and for hemolytic activity towards red blood cells. Compound 14 displayed significantly reduced hemolytic potential at 1mg/mL and a comparable protective effect to FR901469 in a mouse candidiasis model.

Animals↗
PubMed2001

Regulation of erythrocyte ghost membrane mechanical stability by chlorpromazine.

Chlorpromazine (CPZ), a widely used tranquilizer, is known to induce stomatocytic shape changes in human erythrocytes. However, the effect of CPZ on membrane mechanical properties of erythrocyte membranes has not been documented. In the present study we show that CPZ induces a dose-dependent increase in mechanical stability of erythrocyte ghost membrane. Furthermore, we document that spectrin specifically binds to CPZ intercalated into inside-out vesicles depleted of all peripheral proteins. These findings imply that CPZ-induced mechanical stabilization of the erythrocyte ghost membranes may be mediated by direct binding of spectrin to the bilayer. Membrane active drugs that partition into lipid bilayer can thus induce cytoskeletal protein interactions with the membrane and modulate membrane material properties.

Binding Sites↗
PubMed2001

Peripheral PAR-2 triggers thermal hyperalgesia and nociceptive responses in rats.

Protease-activated receptor-2 (PAR-2), a member of the G protein-coupled, seven trans-membrane domain receptor family, is activated by trypsin/tryptase and present in various tissues including the primary sensory neurons, playing a role in development of neurogenic inflammation. The present study examined if activation of peripheral PAR-2 could modulate nociception in the rat. Expression of mRNA for PAR-2 was confirmed in the L4-6 dorsal root ganglia, but not spinal cord. The PAR-2-activating peptide SLIGRL-NH2 administered by the intraplantar (i.pl.) route, produced thermal, but not mechanical, hyperalgesia in the rat, although the PAR-2-inactive control peptide LSIGRL-NH2 had no effect. Not only the PAR-2-activating but also inactive peptides elicited nociceptive behavior (licking/biting) in the intact rats, whereas only the former peptide produced such behavior in the rats that had received repeated administration of compound 48/80 for mast cell depletion. These data provide novel evidence that activation of peripheral PAR-2 is pro-nociceptive, producing thermal hyperalgesia and also triggering pain sensation, by itself, independently of mast cell degranulation.

Animals↗
PubMed2001

Regional characteristics of sulfur and lead isotope ratios in the atmosphere at several Chinese urban sites.

Sulfur and lead isotope ratios in the atmosphere were measured at several selected sites (Harbin, Changchun, Dalian, Waliguan, Shanghai, Nanjing, Guiyang) in China and Tsukuba (Japan), to reveal regional sources characteristics over Eastern Asia. Average S isotope ratios for SO2 and sulfate in the atmosphere in China were close to those of the coals used in each region, indicating a considerable contribution of coal combustion to the sulfur compounds in the atmosphere. Most northern cities had around 5% sulfur isotope ratio, while Guiyang, a southwestern city in China, showed a considerably lower sulfur isotope ratio (about -3%) because of the unusually light sulfur isotope ratio of coals in this region. These were considerably different from the value (-1.4%) for Tsukuba (Japan). Lead isotope ratios also suggested that coal combustion considerably contributed to atmospheric lead in some cases in China. At the same time, influences by the emission of Chinese lead ores were also observed in northern cities. Seasonal variations of both sulfur and lead isotope ratios indicated the existence of a certain amount of industrial sources other than coal combustion. In addition, fractionation effect between SO2 and sulfate showed a seasonal tendency (high in winter (0-6%) and low in summer (-1-3%)), suggesting the oxidation pathway of SO2 changed seasonally.

Air Pollution↗
PubMed2001

Coumarin and chromen-4-one analogues as tautomerase inhibitors of macrophage migration inhibitory factor: discovery and X-ray crystallography.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine released from T-cells and macrophages. Although a detailed understanding of the biological functions of MIF has not yet been clarified, it is known that MIF catalyzes the tautomerization of a nonphysiological molecule, D-dopachrome. Using a structure-based computer-assisted search of two databases of commercially available compounds, we have found 14 novel tautomerase inhibitors of MIF whose K(i) values are in the range of 0.038-7.4 microM. We also have determined the crystal structure of MIF complexed with the hit compound 1. It showed that the hit compound is located in the active site of MIF containing the N-terminal proline which plays an important role in the tautomerase reaction and forms several hydrogen bonds and undergoes hydrophobic interactions. A crystallographic study also revealed that there is a hydrophobic surface which consists of Pro-33, Tyr-36, Trp-108, and Phe-113 at the rim of the active site of MIF, and molecular modeling studies indicated that several more potent hit compounds have the aromatic rings which can interact with this hydrophobic surface. To our knowledge, our compounds are the most potent tautomerase inhibitors of MIF. One of these small, drug-like molecules has been cocrystallized with MIF and binds to the active site for tautomerase activity. Molecular modeling also suggests that the other hit compounds can bind in a similar fashion.

Binding Sites↗
PubMed2001

Asymmetric activation of chiral alkoxyzinc catalysts by chiral nitrogen activators for dialkylzinc addition to aldehydes: super high-throughput screening of combinatorial libraries of chiral ligands and activators by HPLC-CD/UV and HPLC-OR/RIU systems.

Asymmetric catalysts, prepared by chiral ligand exchange or chiral modification, can evolve further into highly activated catalysts through engineering with chiral activators. Two new methodologies for "super high-throughput screening" (SHTS) of chiral ligands and activators have been developed as a combination of HPLC-CD/UV (CD/ UV = circular dichroism/ultraviolet spectroscopy) or -OR/RIU (OR/RIU = optical rotation/refractive index unit) with a combinatorial chemistry (CC) factory. With these techniques, the % ee of the product is determined within minutes without separation of the enantiomeric products by using a nonchiral stationary phase. Therefore, those SHTS techniques combined with our 'asymmetric activation' concept can provide a powerful strategy for finding the best activated chiral catalyst.

Journal Article↗
PubMed2001

Analysis of the microheterogeneity of the IgA1 hinge glycopeptide having multiple O-linked oligosaccharides by capillary electrophoresis.

It was found that the self-aggregation of IgA1 was closely connected with the glycoform of a mucin-type sugar chain on its hinge portion. In this report, normal human serum IgA1 was separated into two subfractions by a jacalin column. The elution condition, 25 mM galactose, used here was similar to that reported for the glycoprotein with a single mucin-type sugar chain per molecule. The IgA1 eluted under this condition was substantially the monomeric form. In contrast, the remaining IgA1 eluted from the column with 0. 8 M galactose was substantially the aggregated form. An analytical method for the microheterogeneity of the IgA1 hinge glycopeptide (HGP33) was developed to determine the difference between these IgA1 fractions by capillary electrophoresis (CE). Native HGP33 from both IgA1 fractions was separated into peaks 1-11, depending on their glycoforms. Because the sialic acid-rich component migrated slowly on CE, the 25 mM fraction was abundant in the sialic acid-rich components (peaks 7-11), but the 0.8 M fraction was abundant in the sialic acid-poor components (peaks 1-4). Comparison of the number of sugar chains per hinge peptide indicated that the 25 mM fraction was relatively well glycosylated. Thus, application of CE analysis to the HGP33 indicated that the monomeric IgA1 was composed of a relatively complete molecule with respect to the glycoform rather than the aggregated IgA1.

Chromatography, Affinity↗
PubMed2001

Molecular genetic, biochemical, and clinical studies in three families with cardiac Fabry's disease.

The variant form of Fabry's disease, called cardiac Fabry's disease, which has left ventricular hypertrophy as its main clinical manifestation is not uncommon. Because there has been no pedigree analysis in families with cardiac Fabry's disease, we performed gene analyses, enzyme assays, and cardiac evaluations in 3 distinct families with cardiac Fabry's disease. Gene analyses were performed in all 18 members of 3 families including 3 male probands. Five hemizygotes and 6 heterozygotes were identified. Plasma alpha-galactosidase A activity was measured in all 18 family members. Echocardiography and electrocardiography were performed in the 5 hemizygotes and in 5 of the 6 heterozygotes. The proband and 3 heterozygotes from a pedigree with a mutation in exon 6 of the alpha-galactosidase A sequence leading to a Met296Ile substitution showed a decrease in alpha-galactosidase A activity. In a separate pedigree, a proband and his hemizygous brother, with a mutation in exon 2 leading to a Glu66Gln substitution, had a decrease in alpha-galactosidase A activity, whereas 3 heterozygotes had normal values. In the third pedigree, a decrease in alpha-galactosidase A activity was observed in 2 hemizygotes who have a mutation in exon 1 leading to an Ala2OPro substitution. Although all 5 hemizygotes exhibited left ventricular hypertrophy on echocardiography, all 5 heterozygotes lacked this finding. Because plasma alpha-galactosidase A activity was normal in some heterozygotes with cardiac Fabry's disease, gene analysis is essential for an accurate diagnosis. Patients with cardiac Fabry's disease thus show an x-linked form of hypertrophic cardiomyopathy.

Adolescent↗
PubMed2001

Necessity of thromboxane A2 for initiation of platelet-mediated contact sensitivity: dual activation of platelets and vascular endothelial cells.

To investigate the crucial role of platelet-derived thromboxane A(2) (TXA(2)) in initiating Ag-specific contact sensitivity (CS), a platelet-dependent CS model using genetically mast cell-deficient W/W(v) mice, was provided. In vivo treatment with BAYu3405, a TXA(2) receptor antagonist, markedly suppressed CS responses in a dose-dependent manner. This inhibitory effect occurred when BAYu3405 was administered before an early initiating phase, suggesting that TXA(2) may be a potent initiator of platelet-mediated CS responses. When platelets were pretreated with BAYu3405 in vitro, platelet aggregation as well as serotonin release, which is able to induce the early phase response allowing local recruitment of CS effector T cells due to direct activation of vascular endothelial cells, was inhibited. The addition of U46619, a TXA(2) agonist, or a mixture of platelets and thrombin-enhanced expression of both ICAM-1 and VCAM-1 on isolated mouse aortic endothelial cells, which was completely abolished by pretreatment with BAYu3405. Furthermore, intradermal injection of U46619 into the ear of platelet-depleted mice led to CS responses with marked expression of ICAM-1 and VCAM-1 on the vascular endothelium. These findings suggest that TXA(2) generated from platelets activated with Ag may mediate initiation of CS responses through inducing serotonin release from platelets and the subsequent aggregation and up-regulated expression of ICAM-1 and VCAM-1 on vascular endothelial cells.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2001

Brain magnetic resonance imaging in 23 patients with mucopolysaccharidoses and the effect of bone marrow transplantation.

A longitudinal study of cranial magnetic resonance imaging (MRI) was carried out in 23 patients with mucopolysaccharidoses (MPS); 1 each of types IH, VI, and VII; 2 of type IS; 10 of type II; and 4 each of types IIIB and IVA. Six types of distinct abnormalities were 1) cribriform changes or spotty changes in the corpus callosum, basal ganglia, and white matter; 2) high-intensity signal in the white matter on T2-weighted image; 3) ventriculomegaly; 4) diffuse cerebral cortical atrophy; 5) spinal cord compression; and 6) megacisterna magna. The cribriform changes that corresponded to dilated perivascular spaces were found in the patients with MPS IS, II, and VI. The patchy and diffuse intensity changes were found in the patient with MPS II and IIIB, respectively. MPS IH and the severe type of MPS II showed marked ventriculomegaly. Marked cerebral atrophy was observed in all MPS IIIB patients and in the severe type of MPS II patients. Spinal cord compression was a feature usually observed in MPS IH, IVA, VI, and VII. Megacisterna magna was frequent in the patients with MPS II (6/10). In two of five patients, the therapeutic effect of bone marrow transplantation (BMT) was remarkable. Both the cribriform changes and the intensity change of the white matter in a MPS VI patient disappeared eight years after the BMT. Slight improvement of cribriform change was noted in one patient with MPS II three years after the BMT. MRS was not sufficient to estimate the accumulation of glycosaminoglycans but was useful for evaluating neuronal damages.

Adolescent↗