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Biomedical subjects

N Fukuda

Publications and source records attributed to N Fukuda.

At least 55 records · Page 3Linked to original sources
PubMed2001

[Simultaneous occurrence of Basedow's disease and autoimmune hemolytic anemia].

A 43-year-old man with a 7-year history of low antinuclear factor titer developed Basedow's disease and autoimmune hemolytic anemia (AIHA) simultaneously. Such simultaneous occurrence of these autoimmune disorders has been reported only rarely. Administration of methimazole for Basedow's disease and prednisolone for AIHA was effective for ameliorating both conditions. The patient had the HLA DR2, DRB1 1501 and DPB1 0501 alleles, suggesting a genetic predisposition for these diseases.

Adult↗
PubMed2001

[Regulation of Ca2+ sensitivity of contractile elements in cardiac muscle].

Contraction of cardiac muscle is regulated by changes in the concentration of intracellular Ca(2+) . An increase in the Ca(2+) concentration results in enhanced contractility of cardiac muscle. It is also known that cardiac contractility is influenced by changes in Ca(2+) sensitivity of contractile elements. Recent studies at the molecular level have revealed the complexity of the regulation of Ca(2+) sensitivity of contractile elements.

English Abstract↗
PubMed2000

Ribozyme to human TGF-beta1 mRNA inhibits the proliferation of human vascular smooth muscle cells.

Transforming growth factor-beta (TGF-beta) has been reported to be involved in the pathogenesis of cardiovascular proliferative diseases such as hypertensive vascular disease, atherosclerosis, and arterial restenosis after angioplasty. We designed a 38-base DNA-RNA chimeric hammerhead ribozyme to cleave human TGF-beta1 mRNA as a gene therapy for human arterial proliferative diseases. In the presence of MgCl(2), synthetic ribozyme to human TGF-beta1 mRNA cleaved the synthetic target RNA into two RNA fragments of predicted size. A control mismatch ribozyme, with one different base in the catalytic loop region, was inactive. DNA-RNA chimeric ribozyme (0. 01-1.0 microM) significantly inhibited angiotensin II (Ang II)-stimulated DNA synthesis in a dose-dependent manner in human vascular smooth muscle cells (VSMC). The mismatch ribozyme did not affect Ang II-stimulated DNA synthesis in the cells. DNA-RNA chimeric ribozyme (1.0 microM) inhibited the proliferation of human VSMC in the presence of Ang II. DNA-RNA chimeric ribozyme (1.0 microM) significantly inhibited Ang II-stimulated TGF-beta1 mRNA and protein expression in human VSMC. These results indicate that the designed DNA-RNA chimeric hammerhead ribozyme targeted to human TGF-beta1 mRNA can effectively and potentially inhibit growth of human VSMC by cleaving the TGF-beta1 mRNA. This finding suggests that this ribozyme will be useful in the gene therapy of arterial proliferative diseases.

Base Sequence↗
PubMed2000

Total synthesis of the antitumor antibiotic (+/-)-fredericamycin A by a linear approach.

A linear approach to the total synthesis of racemic fredericamycin A (1) through the oxidative intramolecular [4 + 2] cycloaddition of a (phenylthio)acetylene-cobalt complex is described, which is applicable for the asymmetric total synthesis of naturally occuring 1. The highlight of this work is the aromatic Pummerer-type reaction with 1-ethoxyvinyl chloroacetate, which effects the introduction of the oxygen functional group to the internal B-ring of the highly functionalized, congested polyaromatic ABC-ring moiety.

Antibiotics, Antineoplastic↗
PubMed2000

Dual control of the brainstem on the spindle oscillation in humans.

In human subjects, the excitability change of the brainstem was investigated over the course of the spindle oscillation. The investigation was carried out by a sequential analysis of brainstem auditory evoked potentials (BAEPs) with reference to one sequence of spindle oscillation. The method was based on the characteristics of BAEPs, i.e. far-field evoked potential. The brainstem revealed two types of excitability change: one in the lower ventral brainstem (wave-III components), and the other in the upper dorsal brainstem (wave-V components). The excitability in the dorsal brainstem showed an oscillation with one cycle period of about 1.5 s, whereas in the ventral brainstem, the excitability showed a long-range biphasic (decaying-growing) fluctuation. Both excitability changes in the brainstem preceded the spindle oscillation, and the phase was reversed during the emerging period of spindle oscillation. The results suggest a primary triggering mechanism of the brainstem for the spindle oscillation, which is independent of preceding cortical drives (K-complexes) upon the thalamus. The difference of the excitability change between the spindle oscillation and the paroxysmal discharge (spike-and-wave complex) was also discussed.

Adult↗
PubMed2000

Role of aquaporins in alveolar fluid clearance in neonatal and adult lung, and in oedema formation following acute lung injury: studies in transgenic aquaporin null mice.

Aquaporin (AQP) water channels provide a major pathway for osmotically driven water movement across epithelial and microvascular barriers in the lung. We used mice deficient in each of the three principal lung aquaporins, AQP1, AQP4 and AQP5, to test the hypothesis that aquaporins are important in neonatal lung fluid balance, adult lung fluid clearance and formation of lung oedema after acute lung injury. Wet-to-dry weight ratios (W/D) in lungs from wild-type mice decreased from 7.9 to 5.7 over the first hour after spontaneous delivery. AQP deletion did not significantly affect W/D at 45 min after birth. Alveolar fluid clearance was measured in living ventilated mice in which 0.5 ml saline containing radiolabelled albumin was instilled into the airspaces. Fluid clearance was 17.4 % in 15 min and inhibited >90 % by amiloride, but clearance was not affected by AQP deletion. W/D was measured in established models of acute lung injury - acid aspiration and thiourea administration. Two hours after intratracheal administration of HCl, W/D increased from 3.7 to 7.5 but was not affected by AQP deletion. Three hours after intraperitoneal infusion of thiourea, W/D increased to 5.5 and marked pleural effusions appeared, but there were no differences in wild-type and AQP knockout mice. Hyperoxic subacute lung injury was induced by 95 % oxygen. Neither mean survival (143 h) nor W/D at 65 h (5.1) were significantly affected by AQP deletion. Despite their role in osmotically driven lung water transport, aquaporins are not required for the physiological clearance of lung water in the neonatal or adult lung, or for the accumulation of extravascular lung water in the injured lung.

Acids↗
PubMed2000

Effect of troponin I phosphorylation by protein kinase A on length-dependence of tension activation in skinned cardiac muscle fibers.

We examined the effect of troponin I (TnI) phosphorylation by cAMP-dependent protein kinase (PKA) on the length-dependent tension activation in skinned rat cardiac trabeculae. Increasing sarcomere length shifted the pCa (-log[Ca2+])-tension relation to the left. Treatment with PKA decreased the Ca2+ sensitivity of the myofilament and also decreased the length-dependent shift of the pCa-tension relation. Replacement of endogenous TnI with phosphorylated TnI directly demonstrated that TnI phosphorylation is responsible for the decreased length-dependence. When MgATP concentration was lowered in the absence of Ca2+, tension was elicited through rigorous cross-bridge-induced thin filament activation. Increasing sarcomere length shifted the pMgATP (-log[MgATP])-tension relation to the right, and either TnI phosphorylation or partial extraction of troponin C (TnC) abolished this length-dependent shift. We conclude that TnI phosphorylation by PKA attenuates the length-dependence of tension activation in cardiac muscle by decreasing the cross-bridge-dependent thin filament activation through a reduction of the interaction between TnI and TnC.

Adenosine Triphosphate↗
PubMed2000

Effect of methylene methylimino linkage of antisense oligonucleotide to the platelet-derived growth factor A-chain on growth of vascular smooth muscle cells from spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR)-derived vascular smooth muscle cells show exaggerated growth and increased expression of platelet-derived growth factor (PDGF) A-chain mRNA. We examined the effect of methylene methylimino linkage of antisense oligodeoxynucleotide, a novel modification of antisense oligodeoxynucleotide designed to increase nuclease resistance, to PDGF A-chain on the exaggerated growth of vascular smooth muscle cells from SHR. Methylene methylimino-linked oligodeoxynucleotide provided complete resistance against S1 nuclease. Methylene methylimino linkage of antisense oligodeoxynucleotide to PDGF A-chain resulted in a rapid inhibition of basal DNA synthesis of vascular smooth muscle cells from SHR. This inhibition was much greater than that produced by phosphorothioate linkage of antisense oligodeoxynucleotide to PDGF A-chain. The methylene methylimino linkage of antisense oligodeoxynucleotide to PDGF A-chain may prove useful in the treatment of arterial proliferative diseases including hypertension.

Alkenes↗
PubMed2000

Carbon dioxide permeability of aquaporin-1 measured in erythrocytes and lung of aquaporin-1 null mice and in reconstituted proteoliposomes.

Measurements of CO(2) permeability in oocytes and liposomes containing water channel aquaporin-1 (AQP1) have suggested that AQP1 is able to transport both water and CO(2). We studied the physiological consequences of CO(2) transport by AQP1 by comparing CO(2) permeabilities in erythrocytes and intact lung of wild-type and AQP1 null mice. Erythrocytes from wild-type mice strongly expressed AQP1 protein and had 7-fold greater osmotic water permeability than did erythrocytes from null mice. CO(2) permeability was measured from the rate of intracellular acidification in response to addition of CO(2)/HCO(3)(-) in a stopped-flow fluorometer using 2',7'-bis-(2-carboxyethyl)-5-(and -6)-carboxyfluorescein (BCECF) as a cytoplasmic pH indicator. In erythrocytes from wild-type mice, acidification was rapid (t((1)/(2)), 7.3 +/- 0.4 ms, S.E., n = 11 mice) and blocked by acetazolamide and increasing external pH (to decrease CO(2)/HCO(3)(-) ratio). Apparent CO(2) permeability (P(CO(2))) was not different in erythrocytes from wild-type (0.012 +/- 0.0008 cm/s) versus null (0.011 +/- 0.001 cm/s) mice. Lung CO(2) transport was measured in anesthetized, ventilated mice subjected to a decrease in inspired CO(2) content from 5% to 0%, producing an average decrease in arterial blood pCO(2) from 77 +/- 4 to 39 +/- 3 mm Hg (14 mice) with a t((1)/(2)) of 1.4 min. The pCO(2) values and kinetics of decreasing pCO(2) were not different in wild-type versus null mice. Because AQP1 deletion did not affect CO(2) transport in erythrocytes and lung, we re-examined CO(2) permeability in AQP1-reconstituted liposomes containing carbonic anhydrase (CA) and a fluorescent pH indicator. Whereas osmotic water permeability in AQP1-reconstituted liposomes was >100-fold greater than that in control liposomes, apparent P(CO(2)) (approximately 10(-3) cm/s) did not differ. Measurements using different CA concentrations and HgCl(2) indicated that liposome P(CO(2)) is unstirred layer-limited and that HgCl(2) slows acidification because of inhibition of CA rather than AQP1. These results provide direct evidence against physiologically significant AQP1-mediated CO(2) transport and establish an upper limit to the CO(2) permeability through single AQP1 water channels.

Animals↗
PubMed2000

Effects of MgADP on length dependence of tension generation in skinned rat cardiac muscle.

The effect of MgADP on the sarcomere length (SL) dependence of tension generation was investigated using skinned rat ventricular trabeculae. Increasing SL from 1.9 to 2.3 microm decreased the muscle width by approximately 11% and shifted the midpoint of the pCa-tension relationship (pCa(50)) leftward by about 0.2 pCa units. MgADP (0.1, 1, and 5 mmol/L) augmented maximal and submaximal Ca(2+)-activated tension and concomitantly diminished the SL-dependent shift of pCa(50) in a concentration-dependent manner. In contrast, pimobendan, a Ca(2+) sensitizer, which promotes Ca(2+) binding to troponin C (TnC), exhibited no effect on the SL-dependent shift of pCa(50), suggesting that TnC does not participate in the modulation of SL-dependent tension generation by MgADP. At a SL of 1. 9 microm, osmotic compression, produced by 5% wt/vol dextran (molecular weight approximately 464 000), reduced the muscle width by approximately 13% and shifted pCa(50) leftward to a similar degree as that observed when increasing SL to 2.3 microm. This favors the idea that a decrease in the interfilament lattice spacing is the primary mechanism for SL-dependent tension generation. MgADP (5 mmol/L) markedly attenuated the dextran-induced shift of pCa(50), and the degree of attenuation was similar to that observed in a study of varying SL. The actomyosin-ADP complex (AM.ADP) induced by exogenous MgADP has been reported to cooperatively promote myosin attachment to the thin filament. We hereby conclude that the increase in the number of force-generating crossbridges on a decrease in the lattice spacing is masked by the cooperative effect of AM.ADP, resulting in depressed SL-dependent tension generation.

Adenosine Diphosphate↗
PubMed2000

Role of circulating vascular endothelial growth factor and hepatocyte growth factor in patients with coronary artery disease.

Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) are thought to stimulate endothelial cell proliferation and induce angiogenesis in vivo. However. the precise mechanism responsible for VEGF and HGF release in patients with coronary artery disease is still unknown. We studied serum concentrations of VEGF and HGF in 20 patients with acute myocardial infarction (AMI), 20 patients with stable angina pectoris (AP) who had reversible perfusion defects on stress myocardial scintigraphy, and 16 patients with old myocardial infarction (OMI) who had no reversible defects on stress myocardial scintigraphy. The control group consisted of 20 patients with atypical chest pain who had angiographically normal coronary arteries. Serum VEGF and HGF concentrations were measured by enzyme-linked immunosorbent assay. Both the serum VEGF and HGF concentrations in the early stage of myocardial infarction in the patients with AMI were higher than those in the patients with AP and with OMI, and control patients. The VEGF concentration in the patients with AP was higher than in the patients with OMI, whereas the HGF concentration did not differ in the patients with AP and OMI. The VEGF concentration in AMI patients who had had preinfarction angina on admission was higher than that of patients who had had no preinfarction angina, whereas the HGF concentration did not differ between the two groups of patients. These results suggest that the serum VEGF concentration may reflect myocardial ischemia to a greater degree than the serum HGF concentration.

Aged↗
PubMed2000

DNA-RNA chimeric hammerhead ribozyme to transforming growth factor-beta(1) mRNA inhibits the exaggerated growth of vascular smooth muscle cells from spontaneously hypertensive rats.

OBJECTIVE: The purpose of this study was to develop DNA-RNA chimeric hammerhead ribozyme against transforming growth factor-beta(1) (TGF-beta(1)) mRNA as a gene therapy agent for arterial proliferative diseases. METHODS: A 38-base hammerhead ribozyme against rat TGF-beta(1) mRNA, to produce cleavage at the GUC sequence at nucleotide 825 according to the secondary structure of rat TGF-beta(1) mRNA was designed. To enhance its stability, we synthesized a DNA-RNA chimeric ribozyme with two phosphorothioate linkages at the 3'-terminal. We also synthesized a mismatch ribozyme with single base change in the catalytic loop region as a control. These ribozymes were delivered into rat vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats by lipofectin-mediated transfection, and their biological effects were investigated. RESULTS: According to in vitro cleavage studies, the synthetic ribozyme can cleave the synthetic substrate RNA into two RNA fragments. Chimeric ribozyme significantly inhibited DNA synthesis in VSMC from SHR but not in cells from WKY rats. Mismatch ribozyme showed only a little effect on growth of VSMC from SHR. Chimeric ribozyme significantly inhibited proliferation of VSMC from SHR; in contrast, the proliferation of VSMC from WKY rats was significantly increased by this chimeric ribozyme. Mismatch ribozyme did not affect proliferation of VSMC from either rat strain. Chimeric hammerhead ribozyme to rat TGF-beta(1) dose-dependently inhibited TGF-beta(1) mRNA expression detected by reverse transcription and polymerase chain reaction analysis in VSMC from both rat strains. Chimeric hammerhead ribozyme to rat TGF-beta(1) also dose-dependently inhibited TGF-beta(1) protein production detected by Western blot analysis. CONCLUSIONS: The present results demonstrated that our designed DNA-RNA chimeric hammerhead ribozyme to TGF-beta(1) mRNA might be a useful gene therapy agent for hypertensive vascular diseases.

Analysis of Variance↗
PubMed2000

Alveolar epithelial barrier. Role in lung fluid balance in clinical lung injury.

Several studies have established that transport of sodium from the air spaces to the lung interstitium is a primary mechanism driving alveolar fluid clearance, although further work is needed to determine the role of chloride in vectorial fluid transport across the alveolar epithelium. Although there are significant differences among species in the basal rates of sodium and fluid transport, the basic mechanism seems to depend on sodium uptake by channels on the apical membrane of alveolar type II cells, followed by extrusion of sodium on the basolateral surface by Na,K-ATPase. This process can be upregulated by several catecholamine-dependent and independent mechanisms. The identification of water channels expressed in lung, together with the high water permeabilities, suggest a potential role for channel-mediated water movement between the air space and capillary compartments, although definitive evidence will depend on the results of transgenic mouse knock-out studies. The application of this new knowledge regarding salt and water transport in alveolar epithelium in relation to pathologic conditions has been successful in clinically relevant experimental studies, as well as in a few clinical studies. The studies of exogenous and endogenous catecholamine regulation of alveolar fluid clearance are a good example of how new insights into the basic mechanisms of alveolar sodium and fluid transport can be translated to clinically relevant experimental studies. Exogenous catecholamines can increase the rate of alveolar fluid clearance in several species, including the human lung, and it is also apparent that release of endogenous catecholamines can upregulate alveolar fluid clearance in animals with septic or hypovolemic shock. It is possible that therapy with beta-adrenergic agonists might be useful to accelerate the resolution of alveolar edema in some patients. In some patients, the extent of injury to the alveolar epithelial barrier may be too severe for beta-adrenergic agonists to enhance the resolution of alveolar edema, although some experimental studies indicate that alveolar fluid clearance can be augmented in the presence of moderately severe lung injury. A longer-term upregulation of alveolar epithelial fluid transport might be achieved by strategies that accelerate the proliferation of alveolar type II cells repopulating the injured epithelium in clinical lung injury. More clinical research is needed to evaluate the strategies that can upregulate alveolar epithelial fluid transport with both short-term therapy (i.e., beta-agonists) and more sustained, longer-term effects of epithelial mitogens such as keratinocyte growth factor. These approaches may be useful in reducing mortality in the acute respiratory distress syndrome.

Animals↗
PubMed2000

Effects of Momordica charantia powder on serum glucose levels and various lipid parameters in rats fed with cholesterol-free and cholesterol-enriched diets.

The effects of dietary bitter melon (Momordica charantia) freeze-dried powder on serum glucose level and lipid parameters of the serum and liver were studied in rats fed diets supplemented with and without cholesterol. Rats were fed the diets for 14 days containing bitter melon freeze-dried powder at the level of 0.5, 1 and 3% without an added dietary cholesterol (experiment I) and those containing bitter melon at the level of 1% with or without 0.5% cholesterol and 0.15% bile acid (experiment II). No adverse effect of dietary bitter melon powder on growth parameters and relative liver weight were noted. Dietary bitter melon resulted in a consistent decrease in serum glucose levels in rats fed cholesterol-free diets, but not in those fed cholesterol-enriched diets, although no dose-response was noted. Addition of cholesterol to the diets as compared to those without added cholesterol caused hypercholesterolemia and fatty liver. Bitter melon had little effect on serum lipid parameters, except for high density lipoprotein (HDL)-cholesterol; HDL-cholesterol levels tended to decrease by dietary cholesterol, while they were consistently elevated by dietary bitter melon both in the presence and absence of dietary cholesterol, indicating an antiatherogenic activity of bitter melon. In addition, bitter melon exhibited a marked reduction in the hepatic total cholesterol and triglyceride levels both in the presence and absence of dietary cholesterol; the reduction of triglyceride levels in the absence of dietary cholesterol was in a dose-dependent manner. These results suggest that bitter melon can be used as a health food.

Animals↗
PubMed2000

Angiotensin II regulates the cell cycle of vascular smooth muscle cells from SHR.

We have demonstrated that spontaneously hypertensive rats (SHR)-derived vascular smooth muscle cells (VSMC) show the exaggerated growth and produce angiotensin II (Ang II). In the current study, we investigated the role of endogenous Ang II in the regulation of the cell cycle in VSMC from SHR. Levels of Ang II in conditioned medium from SHR-derived VSMC cultured without serum were significantly higher than levels in conditioned medium from Wistar-Kyoto (WKY) rat-derived VSMC. Basal DNA synthesis was higher in quiescent VSMC from SHR than that in cells from WKY rats. An Ang II type 1 receptor antagonist, CV11974, significantly inhibited the elevation in DNA synthesis in quiescent VSMC from SHR but did not affect it in cells from WKY rats. Cellular DNA content analysis by flow cytometry revealed that the proportion of cells in S phase was higher, whereas the proportion of cells in G1+G0 phase was lower in VSMC from SHR than those in cells from WKY rats. CV11974 significantly decreased the proportion of cells in S phase and correspondingly increased the proportion of cells in G1+G0 phase in VSMC from SHR, but it did not affect the proportion in cells from WKY rats. Cyclin-dependent kinase 2 (CDK2) activity, which is known to induce the progression from G1 to S phase, was higher in VSMC from SHR than in cells from WKY rats. Expression of CDK2 inhibitor p27(kip1) mRNA was markedly higher in VSMC from SHR than in cells from WKY rats. CV11974 decreased expression of p27(kip1) mRNA in VSMC from SHR, whereas CV11974 increased it in cells from WKY rats. These findings indicate that enhanced production of endogenous Ang II regulates the cell cycle especially in the progression from G1 to S phase, and increases CDK2 activity, which is independent of p27(kip1) in VSMC from SHR.

Angiotensin II↗
PubMed2000

Angiotensin II upregulates transforming growth factor-beta type I receptor on rat vascular smooth muscle cells.

Angiotensin II (Ang II) and transforming growth factor-beta (TGF-beta) modulate cell growth and metabolism. Our objective was to evaluate the effect of Ang II on the characteristics and expression of TGF-beta receptors on vascular smooth muscle cells (VSMC) from Wistar-Kyoto rats. The addition of TGF-beta1 elicited a biphasic response on DNA synthesis in cultured VSMC in the absence of Ang II, but TGF-beta1 did not stimulate DNA synthesis in the presence of Ang II. TGF-beta binding data showed that Ang II increased the specific binding of 125I-TGF-beta1 by enhancing the expression of lower affinity receptors and increasing the number of binding sites. Ang II alone did not stimulate DNA synthesis in these cultures. However, Ang II significantly stimulated DNA synthesis after the inhibition of endogenous TGF-beta with a neutralizing antibody. The DNA synthesis stimulated by phorbol ester milisterol (PMA) was not affected by the TGF-beta neutralizing antibody. Affinity labeling data revealed receptor-ligand complexes of 280, 85, and 70 kDa, corresponding to TGF-beta type III, II, and I receptors, respectively. Incubation of VSMC with Ang II but not with PMA markedly increased the expression of the TGF-beta type I receptor. Reverse transcription and polymerase chain reaction data also indicated that Ang II, but not PMA, significantly increased the expression of TGF-beta type I receptor mRNA. Results suggest that Ang II increases the binding of TGF-beta with upregulation of TGF-beta type I receptor via a C-kinase-independent pathway. The enhanced expression of the TGF-beta type I receptor may counteract Ang II-promoted growth of VSMC.

Activin Receptors, Type I↗