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Biomedical subjects

Koichi Sato

Publications and source records attributed to Koichi Sato.

At least 37 records · Page 2Linked to original sources
PubMed2005

Genistein, a phytoestrogen, attenuates monocrotaline-induced pulmonary hypertension.

BACKGROUND: Pulmonary hypertension is characterized by high pulmonary blood pressure, vascular remodeling, and right ventricular hypertrophy. Although recent studies suggest that an imbalance between endothelial mediators on pulmonary vasculature may contribute to the development of pulmonary hypertension, the pathogenesis is not fully understood and the treatment of pulmonary hypertension is still unresolved. OBJECTIVE: The purpose of this study was to investigate whether genistein, a phytoestrogen derived from soybean, would prevent the development of monocrotaline (MCT)-induced pulmonary hypertension in rats. Hemodynamic parameters of catheterized rats and morphological feature of lungs were evaluated among MCT-treated rats receiving or not receiving genistein. Furthermore, examination of expression in endothelial nitric oxide synthase and endothelin-1 peptide level was performed. METHODS: Daily supplementation with either genistein (0.2 mg/kg) or vehicle was started 2 days prior to a single-dose injection of MCT (60 mg/kg). On day 28, rats underwent catheterization, and right ventricular hypertrophy and morphological features were assessed. Furthermore, endothelial nitric oxide synthase and endothelin-1 were examined by Western blot analysis and radioimmunoassay, respectively, in homogenated lungs. RESULTS: In rats that received daily supplementation of genistein, mean pulmonary arterial pressure was significantly reduced, whereas mean systemic arterial pressure and heart rate were unaltered compared with MCT control rats on day 28 after MCT injection. Right ventricular hypertrophy, medial wall thickness of pulmonary arteries corresponding to the terminal bronchioles, and the degree of neo-muscularization of more distal arteries were less severe in genistein-treated rats. Genistein supplementation improved MCT-induced downregulation of expression of endothelial nitric oxide synthase in the lungs. However, endothelin-1 peptide levels did not differ among all groups of lungs. CONCLUSIONS: We conclude that daily supplementation of genistein potently attenuates MCT-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular remodeling in rats. The underlying mechanism responsible for this effect may be partly related to the restoration of a decreased expression of endothelial nitric oxide synthase.

Animals↗
PubMed2005

Sphingosine 1-phosphate receptors mediate stimulatory and inhibitory signalings for expression of adhesion molecules in endothelial cells.

Sphingosine 1-phosphate (S1P) stimulates expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in human umbilical vein endothelial cells. S1P-induced actions were associated with nuclear factor kappa-B activation and inhibited by pertussis toxin as well as by antisense oligonucleotides specific to S1P receptors, especially, S1P(3). S1P also stimulated endothelial nitric oxide synthase (eNOS) and its activation was markedly inhibited by the antisense oligonucleotide for the S1P(1) receptor rather than that for the S1P(3) receptor. The dose-response curve of S1P to stimulate adhesion molecule expression was shifted to the left in the presence of the phosphatidylinositol 3-kinase inhibitor wortmannin and the NOS inhibitor Nomega-nitro-l-arginine methyl ester. NO donor S-nitroso-N-acetylpenicillamine inhibited S1P-induced adhesion molecule expression. Moreover, tumor necrosis factor-alpha-induced adhesion molecule expression was markedly inhibited by S1P in a manner sensitive to inhibitors for PI3-K and NOS. These results suggest that S1P receptors are coupled to both stimulatory and inhibitory pathways for adhesion molecule expression. The stimulatory pathway involves nuclear factor kappa-B and inhibitory one does phosphatidylinositol 3-kinase and NOS.

Cells, Cultured↗
PubMed2005

Prostaglandin I(2) production and cAMP accumulation in response to acidic extracellular pH through OGR1 in human aortic smooth muscle cells.

Ovarian cancer G-protein-coupled receptor 1 (OGR1) and GPR4 have recently been identified as proton-sensing or extracellular pH-responsive G-protein-coupled receptors stimulating inositol phosphate production and cAMP accumulation, respectively. In the present study, we found that OGR1 and GPR4 mRNAs were expressed in human aortic smooth muscle cells (AoSMCs). Acidic extracellular pH induced inositol phosphate production, a transient increase in intracellular Ca(2+) concentration ([Ca(2+)](i)), and cAMP accumulation in these cells. When small interfering RNAs (siRNAs) targeted for OGR1 and GPR4 were transfected to the cells, the acid-induced inositol phosphate production and [Ca(2+)](i) increase were markedly inhibited by the OGR1 siRNA but not by the GPR4 siRNA. Unexpectedly, the acid-induced cAMP accumulation was also largely inhibited by OGR1 siRNA but only slightly by GPR4 siRNA. Acidic extracellular pH also stimulated prostaglandin I2 (PGI(2)) production, which was again inhibited by OGR1 siRNA. The specific inhibitors for extracellular signal-regulated kinase kinase and cyclooxygenase attenuated the acid-induced PGI(2) production and cAMP accumulation without changes in the inositol phosphate production. A specific inhibitor of phospholipase C also inhibited the acid-induced cAMP accumulation. In conclusion, OGR1 is a major receptor involved in the extracellular acid-induced stimulation of PGI(2) production and cAMP accumulation in AoSMCs. The cAMP accumulation may occur through OGR1-mediated stimulation of the phospholipase C/cyclooxygenase/PGI(2) pathway.

Aorta↗
PubMed2005

Dexamethasone prevents impairment of endothelium-dependent relaxation in arteries cultured with fetal bovine serum.

In the present study, we assessed the effects of dexamethasone on fetal bovine serum-induced dysfunction of mesenteric endothelial cells using an organ culture procedure. In rabbit mesenteric arteries cultured in the presence of 10% fetal bovine serum for 7 days, the endothelium-dependent, nitric oxide (NO)-mediated relaxations caused by substance P and ionomycin were decreased as compared to those in non-treated arteries. Dexamethasone (3 microM) inhibited the proliferative stimuli-induced endothelial dysfunction without affecting the contractility or NO susceptibility of smooth muscle cells. Cross-sectioned hematoxylin-eosin staining and whole-mount CD31 staining indicated that chronic proliferative stimulation induced detachment of endothelial cells from the tunica intima in some regions, and also caused thickening of the arterial wall and shortening of the internal diameter. Endothelial NO synthesis (eNOS) mRNA expression was also decreased by the treatment with fetal bovine serum. The dexamethasone treatment did not inhibit the smooth muscle hypertrophy, but it inhibited the peeling of endothelial cells and recovered the eNOS mRNA expression. These results suggest that DEX ameliorate the impairments of arterial relaxation induced by proliferative stimuli and that these beneficial effects may be mediated by maintaining the adhesion of endothelial cells to the vascular wall and/or by recovering eNOS mRNA expression.

Animals↗
PubMed2005

Effect of nifedipine on C-reactive protein levels in the coronary sinus and on coronary blood flow in response to acetylcholine in patients with stable angina pectoris having percutaneous coronary intervention.

The effects of nifedipine on inflammation and endothelial function in the coronary circulation were studied in patients who had angina pectoris (n = 17). Long-term treatment with nifedipine (nifedipine CR, 20 mg/day for 4 months) decreased levels of C-reactive protein in the coronary sinus (from 0.35 +/- 0.09 mg/dl to 0.07 +/- 0.01 mg/dl, mean +/- SEM, p <0.05) and enhanced acetylcholine-induced increases in coronary blood flow. Thus, nifedipine is effective in decreasing inflammation and incresing endothelial function in the coronary circulation.

Acetylcholine↗
PubMed2005

Study on action mode of sphingosine 1-phosphate in rat hepatocytes.

Sphingosine-1-phosphate (S1P) acts on a set of G protein-coupled receptors in the plasma membrane and also as a second messenger in certain cell types. There are two possible pathways to mobilize intracellular Ca(2+) concentration by S1P. One is through phospholipase C, and the other is through intracellular Ca(2+) channels operated by S1P. The Mn(2+) quenching method was applied to elucidate the action mode of S1P-induced Ca(2+) mobilization in rat hepatocytes. In permeabilized hepatocytes, inositol trisphosphate induced Mn(2+) quenching, and it was blocked by heparin. However, S1P did not induce Mn(2+) quenching. Results suggest that S1P did not mobilize Ca(2+) through intracellular Ca(2+) channels.

Animals↗
PubMed2005

Effects of atorvastatin on inflammation and oxidative stress.

Treatment with inhibitors of 3-hydroxyl-3-methylglutaryl coenzyme A reductase (statins) reduces the incidence of cardiovascular events, but it is unclear whether the beneficial effects are mediated solely by their lipid-lowering properties. We therefore investigated whether atorvastatin reduces inflammation and oxidative stress independently of its lipid-lowering effects. The subjects comprised 71 hyperlipidemic patients (64+/-9 years old, mean+/-SD) who were not receiving medical treatment. Serum lipid and C-reactive protein (CRP) levels, and urine 8-isoprostane level (an index of oxidative stress) were measured before and after 4 weeks of treatment with atorvastatin at 10 mg/day. In 38 patients, these biochemical variables and carotid intima-media thickness (IMT) were also measured after 6 months of treatment with atorvastatin. Atorvastatin markedly reduced CRP (from 0.69+/-0.36 to 0.42+/-0.20 and 0.35+/-0.19 mg/l, median+/-median absolute deviation, P<0.0001), 8-isoprostane (from 225+/-99 to 178+/-75 and 179+/-60 ng/g creatinine, P<0.05), and low density-lipoprotein cholesterol (LDLC; from 165+/-21 to 106+/-18 and 112+/-17 mg/dl, P<0.0001) after 4 weeks and 6 months of treatment, respectively. However, the reductions in CRP and 8-isoprostane were not correlated with those of LDLC. After 6 months of treatment, IMT was significantly decreased compared with the baseline value (from 0.94+/-0.26 to 0.90+/-0.20 mm, P<0.05), but this was not correlated with the reduction in LDLC. These results suggest that atorvastatin has beneficial effects on inflammation, oxidative stress, and the lipid profile in patients with hyperlipidemia. The extra-lipid effects are not attributable to the lipid-lowering effect of the statin, suggesting that the pleiotropic effects of atorvastatin are independent of its effects on the lipid profile.

Atorvastatin↗
PubMed2005

Arterial air embolism during percutaneous pulmonary marking under computed tomography guidance.

Percutaneous pulmonary marking under computed tomography (CT) guidance is often used to identify the location of small nodules prior to pulmonary wedge resection by video assisted thoracoscopic surgery. Although pneumothorax and pulmonary hemorrhage are known complications that accompany this method, arterial air embolism is an extremely rare and occasionally fatal complication. We report a case of arterial air embolism during percutaneous pulmonary marking under CT guidance. Percutaneous pulmonary marking was performed in the prone position in a 59-year-old male with a right lung nodule. The chest CT performed immediately after this procedure revealed an air-fluid level in the heart. The skin of the patient's back appeared cyanotic and neurological dysfunction was noted in his left thigh, although his vital signs were stable. Four hours later, the air in the heart and aorta disappeared, as observed by a chest CT. The patient underwent pulmonary resection 12 days later.

Embolism, Air↗
PubMed2005

High-density lipoprotein inhibits migration of vascular smooth muscle cells through its sphingosine 1-phosphate component.

High-density lipoprotein (HDL) is a well-established anti-risk factor against atherosclerosis, but the mechanism of its anti-atherogenic actions is not fully understood. Here, we examined the role of the HDL-associated sphingosine 1-phosphate (S1P), a lysolipid mediator, in the lipoprotein-induced actions in rat vascular smooth muscle cells (VSMCs). Both HDL and S1P inhibited platelet-derived growth factor-induced migration of VSMCs. The inhibitory effect was associated with an inhibition of cell spreading and these responses were reversed by a desensitization of VSMCs with S1P. HDL and S1P also inhibited migration of Chinese hamster ovary cells and this effect was enhanced by overexpressing S1P2 receptor. Finally, we showed that, even though S1P promoted DNA synthesis, HDL and S1P did not increase cell number of VSMCs. These findings suggest a novel mechanism for anti-atherogenic actions of HDL through its S1P component.

Animals↗
PubMed2005

Proton-sensing and lysolipid-sensitive G-protein-coupled receptors: a novel type of multi-functional receptors.

OGR1, GPR4, G2A, and TDAG8 share 40% to 50% homology with each other and seem to form a family of GPCRs. They have been described as receptors for lipid molecules such as sphingosylphosphorylcholine, lysophosphatidylcholine, and psychosine. Recent studies, however, have revealed that these receptors also sense extracellular protons or pH through histidine residues of receptors and stimulate a variety of intracellular signaling pathways through several species of hetero-trimeric G-proteins, including G(s), G(i), G(q), and G(12/13). Thus, this family of GPCR seems to recognize both lipid molecules and protons as ligands. Although our knowledge of proton-sensing and lysolipid-sensitive GPCRs is preliminary, the receptor levels and ligand levels especially protons are both sensitively modulated in response to a variety of microenvironmental changes. These results suggest a multiple role of proton-sensing GPCRs in a variety of physiological and pathophysiological states.

Amino Acid Sequence↗
PubMed2005

Adenocarcinoma of the thymus: mucinous subtype.

Primary thymic adenocarcinoma, mucinous subtype, is extremely rare with only one case reported to date. We describe herein a case of thymic mucinous adenocarcinoma. A 59-year-old man was identified to have an anterior mediastinal tumor and was diagnosed as mucinous adenocarcinoma. Clinical and radiographic examinations disclosed no evidence of tumor elsewhere. The patient received radiotherapy, but the general condition deteriorated and died 11 months after tumor detection. Thoracic autopsy revealed an anterior mediastinal tumor measuring greater than 10 cm, uncapsulated, and white. The tumor had clear margins and was clearly isolated from the lung. Histologically, the tumor demonstrated papillary, acinar, and cribriform structure and produced abundant extracellular mucin. Immunohistochemically, most tumor cells were positive for cytokeratin 7, were partially positive for CD5, and were negative for TTF-1, Sp-A, CDX-2, MUC2, napsin A, and cytokeratin 20. Collectively, the diagnosis of the tumor was primary mucinous adenocarcinoma of the thymus. We propose that the mucinous subtype should be recognized as one of the histopathological entities of thymic adenocarcinoma.

Adenocarcinoma, Mucinous↗
PubMed2005

Estimation of plasma IC50 of donepezil hydrochloride for brain acetylcholinesterase inhibition in monkey using N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A) and PET.

Donepezil hydrochloride is a potent and selective inhibitor for brain acetylcholinesterase (AChE) and is currently used worldwide for the treatment of Alzheimer's disease. Until now, there is no in vivo study on the relation between the plasma concentration and the brain AChE inhibition. The purpose of this study was to estimate in vivo plasma IC(50) of donepezil in living monkeys by measuring plasma donepezil concentration (LC/MS/MS) and brain AChE activity with positron emission tomography (PET) and N-[(11)C]methylpiperidin-4-yl acetate, which is an acetylcholine analog recently developed by us for quantifying in vivo brain AChE activity. PET scans with donepezil at two doses, 100 microg/kg (donepezil-1; N=5) or 250 microg/kg (donepezil-2; N=5), were performed using the same monkeys at 4-week intervals. Before each PET scan, baseline PET scans (N=10 in total) were performed without donepezil. The plasma donepezil concentrations 14 min after intravenous injection were proportional to the doses, 17.2+/-2.9 ng/ml (donepezil-1) and 44.0+/-5.0 ng/ml (donepezil-2), and the mean AChE inhibitions in four neocortical regions as evaluated by PET were also dose-dependent, 27% (donepezil-1) and 53% (donepezil-2). In IC(50) estimation, measured plasma donepezil concentrations were corrected for the change during PET scan. The IC(50) values (estimate+/-SE) were 42+/-9.0 (ng/ml; donepezil-1), 34+/-3.2 (donepezil-2), and 37+/-4.1 (combined data). The present method may be useful for in vivo evaluation of other AChE inhibitors and novel drugs.

Acetylcholinesterase↗
PubMed2005

Identification of autotaxin as a neurite retraction-inducing factor of PC12 cells in cerebrospinal fluid and its possible sources.

Abstract Cerebrospinal fluid (CSF) induced neurite retraction of differentiated PC12 cells; the action was observed in 15 min (a rapid response) and the activity further increased until 6 h (a long-acting response) during exposure of CSF to the cells. The CSF action was sensitive to monoglyceride lipase and diminished by homologous desensitization with lysophosphatidic acid (LPA) and by pretreatment with an LPA receptor antagonist Ki16425. Although fresh CSF contains LPA to some extent, the LPA content in the medium was increased during culture of PC12 cells with CSF. The rapid response was mimicked by exogenous LPA, and a long-acting response was duplicated by a recombinant autotaxin, lysophospholipase D (lyso-PLD). Although the lyso-PLD substrate lysophosphatidylcholine (LPC) was not detected in CSF, lyso-PLD activity and an approximately 120-kDa autotaxin protein were detected in CSF. On the other hand, LPC but not lyso-PLD activity was detected in the conditioned medium of a PC12 cell culture without CSF. Among neural cells examined, leptomeningeal cells expressed the highest lyso-PLD activity and autotaxin protein. These results suggest that leptomeningeal cells may work as one of the sources for autotaxin, which may play a critical role in LPA production and thereby regulate axonal and neurite morphological change.

Animals↗
PubMed2005

[Inter-laboratory study for validation of a Japanese official analytical method for determination of patulin in apple juice].

To validate a modified version of AOAC official method of analysis 995.10 as an official standard in Japan for determination of patulin in apple juice, an inter-laboratory study was performed in 11 laboratories using a non-contaminated sample, 2 naturally contaminated samples and 2 spiked samples of apple juice. For naturally contaminated apple juices, the relative standard deviations for repeatability and reproducibility were 3.2, 7.1% and 10.0, 21.7%, respectively. HORRAT values were 0.4, 0.9. The average recovery of patulin from spiked sample was 83.7%. The limit of quantification was calculated as 10 microg/kg. From these results, the method was thought to be suitable as an official standard for determination of patulin in apple juice in Japan.

Chromatography, High Pressure Liquid↗
PubMed2005

[Clinical evaluation of meningeal carcinomatosis associated with primary lung cancer].

We evaluated diagnosis and treatment of four cases of meningeal carcinomatosis associated with primary lung cancer: case 1; small cell carcinoma (64 years old), case 2; small cell carcinoma (50 years old), case 3; adenocarcinoma (53 years old), and case 4; adenocarcinoma (55 years old). Determination of tumor markers in cerebrospinal fluid (CSF) together with the MRI findings that Gd-DTPA-enhanced T1-weighted image showing high intensity signal along the spinal cord was clinically useful in the diagnosis of meningeal carcinomatosis. Two of four patients received intrathecal chemotherapy and/or CSF drainage through Ommaya-Reservoir, resulting in dramatic improvement of various symptoms such as motor weakness and vesicorectal disorder. Intrathecal chemotherapy and placement of an Ommaya-Reservoir for CSF drainage should be considered to provide better Quality of Life (QOL) when patient can tolerate it.

Adenocarcinoma↗
PubMed2005

[An elderly case of sarcoidosis with multiple pulmonary cysts].

We report an elderly case of sarcoidosis with multiple pulmonary cysts. An 80-year-old woman was admitted to our hospital for detailed examinations of multiple cysts in both lungs. Chest radiography and chest CT revealed multiple cystic lesions with thin walls which were clearly separated from normal lung. A transbronchial lung biopsy revealed epitheloid cell granuloma, indicating sarcoidosis. Although elderly cases of sarcoidosis with multiple pulmonary cysts are very rare, sarcoidosis should be considered in the differential diagnosis.

Aged↗
PubMed2004

Sphingosine 1-phosphate receptors mediate the lipid-induced cAMP accumulation through cyclooxygenase-2/prostaglandin I2 pathway in human coronary artery smooth muscle cells.

Sphingosine 1-phosphate (S1P) has been shown to exert a variety of biological responses through extracellular specific receptors or intracellular mechanisms. In the present study, we characterized a signaling pathway of S1P-induced cAMP accumulation in human coronary artery smooth muscle cells (CASMCs). S1P induced biphasic cAMP accumulation composed of a short-term and transient response (a peak at 2.5 min) and a late and sustained response ( approximately 4-6 h). The late phase of cAMP accumulation was parallel to the increment of cyclooxygenase-2 protein expression and was inhibited by N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS398), a cyclooxygenase-2-specific inhibitor. We were surprised to find that the cyclooxygenase-2 inhibitor also inhibited short-term cAMP accumulation even when cyclooxygenase-2 protein expression was not yet increased. More interestingly, the short-term cAMP accumulation was also completely inhibited by pertussis toxin, an inhibitor of G(i/o) proteins. JTE-013, a specific antagonist for S1P(2) receptors, inhibited the S1P-induced cAMP accumulation. Furthermore, small interfering RNAs targeted for S1P(2) receptors significantly inhibited the S1P-induced cAMP accumulation. The cAMP response was also inhibited by specific inhibitors for phospholipase C, extracellular signal-regulated kinase pathways, and cytosolic phospholipase A(2). S1P actually activated these enzyme activities and stimulated prostaglandin I(2) (PGI(2)) synthesis. Finally, exogenously applied arachidonic acid and PGI(2) induced cAMP accumulation to a similar extent as S1P. In conclusion, S1P induced cAMP accumulation through S1P receptors, including S1P(2) receptor and G(i/o) protein-mediated stimulation of intracellular signaling pathways involving cyclooxygenase-2-dependent PGI(2) synthesis.

Cells, Cultured↗