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Biomedical subjects

T Saeki

Publications and source records attributed to T Saeki.

At least 127 records · Page 7Linked to original sources
PubMed1994

[An analysis of autopsy cases with cancer of unknown primary site].

A retrospective review of autopsy cases with cancer of clinically unknown primary site seen at Shikoku Cancer Center Hospital from 1959 to 1992 was performed. Fifty three cases (3.1%) were registered as having cancer of unknown primary site among 1690 consecutive autopsy cases with malignancies except for leukemias and brain tumors. Major discrepancies on the primary site between the clinical diagnoses and the autopsy reports were present in 30 cases (1.8%). Twelve cases (0.7%) with malignancy of peritoneum or retroperitoneum primary were found that were clinically regarded as peritonitis carcinomatosa. Latent cancer, in which a new primary cancer was subsequently identified at autopsy, was recognized in 190 cases (11.2%). The mean age in latent cancer group was significantly higher than in control group, but patients with cancer of unknown primary site tended to be somewhat younger. A high male: female ratio was found in latent cancer group, whereas it was reverse in cases with clinically undetermined primary cancer. Survival overall was poor, with a median survival of 5 months. As diagnostic techniques (such as sonography, computerized tomography scanning and nuclear scans) have been improved, cases with cancer of unknown primary site have tended to decrease, but the percentage of cases presenting latent cancer has remained relatively stable over the years. Precise autopsy examination revealed that the primary sites of clinically undetermined cancers were ovary, pancreas, stomach, gallbladder and peritoneum in order of decreasing frequency. The metastatic pattern and histologic types were not different from that in the control group.

Aged↗
PubMed1994

[Prognosis of interstitial pneumonitis (IP) in polymyositis (PM)/dermatomyositis (DM)].

IP, the major complication of PM/DM, is closely related to the life of these patients. In this study the course and prognosis of IP associated with PM/DM were investigated. Thirty IP patients with PM/DM were divided into 4 groups according to the course of IP. Clinical manifestations, laboratory data, chest radiographs and treatment were examined retrospectively. Eleven cases improved (Group I), 11 cases were exacerbated (Group E), 3 cases were unchanged (Group U), 2 cases died due to rapid progression of IP (Group D) and 3 cases dropped out. Both Group D patients were middle aged female DM patients without CPK elevation. All cases were treated with corticosteroids. The clinical manifestations, laboratory data, chest radiographs and initial dose of corticosteroid were not markedly different between Group I and E. The total dose of corticosteroids during the first 3 months tended to be higher in Group I than in Group E. Unlike idiopathic interstitial pneumonitis, the decrease in lung volume on chest radiographs improved after the treatment in 5 cases. We conclude that IP associated with PM/DM should be treated initially with high doses of corticosteroids.

Adult↗
PubMed1993

Cyclic GMP phosphodiesterase inhibitors. 1. The discovery of a novel potent inhibitor, 4-((3,4-(methylenedioxy)benzyl)amino)-6,7,8-trimethoxyquinazoline.

A newly synthesized compound, 4-((3,4-(methylenedioxy)benzyl)amino)-6,7,8-trimethoxyquinazoline (6), had a potent (IC50 = 0.36 microM) inhibitory action on cyclic GMP phosphodiesterase (cGMP-PDE) isolated from porcine aorta; its inhibitory activities toward other PDE isozymes were at least 10-fold weaker. In addition, 6 relaxed porcine coronary arteries precontracted with PGF2 alpha (EC50 = 1.96 +/- 0.58 microM). At the concentration of 30 microM, 6 caused elevation of the intracellular cGMP level in porcine coronary arteries without any change in cAMP level. Various other 4-substituted 6,7,8-trimethoxyquinazolines were also synthesized and evaluated for cGMP-PDE inhibitory activity. From their structure-activity relationships, we concluded that the 4-((3,4-(methylenedioxy)benzyl)-amino) group is essential for potent inhibition of cGMP-PDE.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1993

Isolation of cyclic nucleotide phosphodiesterase isozymes from pig aorta.

Five phosphodiesterase isozymes were separated from the supernatant of pig aortic smooth muscle homogenates, using DEAE-Toyopearl 650S chromatography in the presence of 0.1 mM Ca2+ followed by re-chromatography in the absence of Ca2+ and affinity chromatography on immobilized rolipram or cGMP. Type I (calmodulin-dependent family) preferentially hydrolysed cGMP and its activity was stimulated by calmodulin. Type II (cGMP-stimulated family), which had not yet been identified in aortic smooth muscle, hydrolysed both cGMP and cAMP. Its cAMP hydrolysis was stimulated by 10 microM cGMP. Type III (cGMP-inhibited family) and IV (cAMP-specific family) preferentially hydrolysed cAMP. The cAMP hydrolytic activity of Type III was inhibited by cGMP, but that of Type IV was not. Type V (cGMP-specific family) preferentially hydrolysed cGMP and its activity did not depend on calmodulin. The inhibition of all five phosphodiesterase isozymes by various phosphodiesterase inhibitors was investigated, and the potency and selectivity of each phosphodiesterase inhibitor discussed.

Animals↗
PubMed1993

P-glycoprotein-mediated transcellular transport of MDR-reversing agents.

Understanding of the interactions between P-glycoprotein and multidrug resistance (MDR) reversing agents is important in designing more effective MDR modulators. We examined transcellular transport of several MDR modulators by using a drug-sensitive epithelial cell line, LLC-PK1, and its transformant cell line, LLC-GA5-COL300, which expresses human P-glycoprotein on the apical surface. Basal-to-apical transports of azidopine and diltiazem across the LLC-GA5-COL300 monolayer were increased and apical-to-basal transports were decreased compared to those across the LLC-PK1 monolayer, indicating that P-glycoprotein transports azidopine and diltiazem. Movements of nitrendipine and staurosporine across the epithelial monolayer were not affected by P-glycoprotein. These results suggests that some MDR modulators exert their inhibitory effect not only by blocking the initial binding of anticancer drugs but throughout the course of the transport process.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Structure-activity relationship of N-[2-(dimethylamino)-6-[3-(5-methyl-4-phenyl-1H-imidazol-1-yl)propoxy] phenyl]-N'-pentylurea and analogues. Novel potent inhibitors of acyl-CoA:cholesterol O-acyltransferase with antiatherosclerotic activity.

We have discovered N-butyl-N'-[2-(dimethylamino)-6-[3-(4-phenyl-1H- imidazol-1-yl)propoxy]phenyl]urea (4), a novel, potent, and systemically bioavailable inhibitor of ACAT (acylCoA:cholesterol O-acyltransferase). The structure-activity relationships (SARs) of this lead compound 4 were investigated by systematic modification of four regions in the molecule. The compounds prepared in this study were tested for in vitro inhibitory activity toward both aortic and intestinal ACATs, and selected compounds were further tested for in vivo hypocholesterolemic activity. The studies not only resulted in the discovery of N-[2-(dimethylamino)-6-[3-(5-methyl-4-phenyl-1H-imidazol-1-yl) propoxy]phenyl]-N'-pentylurea (24), with potent activity and moderate plasma level after oral administration, but also revealed the SAR in each modified region. Four compounds (4, 13, 14, 24) were further selected for testing of in vivo antiatherosclerotic activity; 4, 13, and 24 reduced atherosclerotic plaque development to 38-45% of the control value in terms of area, while 14 did not have a significant antiatherosclerotic effect.

Animals↗
PubMed1993

Structure-activity relationship of a series of phenylureas linked to 4-phenylimidazole. Novel potent inhibitors of acyl-CoA:cholesterol O-acyltransferase with antiatherosclerotic activity. 2.

In our continuing search to find systemically bioavailable ACAT (acyl-CoA:cholesterol O-acyltransferase) inhibitors with more potent antiatherosclerotic effect than N-[2-(dimethylamino)-6-[3-(5-methyl-4-phenyl-1H-imidazol-1-yl)propoxy] phenyl]-N'-pentylurea (3), a series of phenylureas linked to 4-phenylimidazole were synthesized and evaluated for in vitro inhibitory activity toward both aortic and intestinal ACATs, and for in vivo hypocholesterolemic activity. The structure-activity relationships (SARs) were studied by strategic modification of five regions in the molecule of 3, i.e., by introducing functional groups or exchanging carbon atoms for heteroatoms. The SAR studies allowed us to select optimum substituents in the five regions, as follows. (1) Dimethylamino was convertible into nitro, methyl, ethyl, propyl, isopropyl, and chloro. On the basis of preliminary pharmacokinetic studies, the methyl group in the ortho-position of the phenylurea was selected. (2) Butyl, pentyl, isopentyl, and neopentyl were better substituents in the urea moiety. (3) Propoxy was the optimal moiety in the bridging portion. (4) Proton, methyl, ethyl, isopropyl, hydroxymethyl, and chloro were better substituents at the 5-position of the imidazole moiety. (5) An unsubstituted phenyl ring was selected as the phenyl group of phenylimidazole. The subsequent comparison studies of compounds containing various combinations of the optimum substituents in each region resulted in the selection of two compounds (67, 68) for further pharmacological and toxicological testing. These compounds were orally bioavailable, and possessed potent in vitro aortic ACAT inhibitory activity (IC50 = 0.16 and 0.012 microM, respectively) and in vivo cholesterol lowering effect (46% and 52% at 1 mg/kg po, respectively). In particular, 68 was 10-fold more potent in the in vitro aortic ACAT assay and 5-fold more potent with respect to hypocholesterolemic activity in vivo than 3.

Animals↗
PubMed1993

A novel ligand, [125I]BQ-3020, reveals the localization of endothelin ETB receptors.

The precise localization of an endothelin (ET) receptor subtype, the ETB receptor, in porcine lung was elucidated by in vitro microautoradiography using a novel ETB-selective radioligand, [125I]BQ-3020 ([125I-Tyr]-N-acetyl-Leu-Met-Asp-Lys-Glu-Ala-Val-Tyr-Phe-Ala-His-Leu-Asp -Ile-Ile-Trp). Of the labeled native ET isopeptides, [125I]ET-3 is selective for ETB receptors. However, [125I]ET-3 was not suitable for autoradiography due to its high degree of non-specific binding. On the other hand, [125I]BQ-3020 showed extremely low non-specific binding on autoradiography. The distribution of [125I]BQ-3020 binding in porcine lung was clearly different from that of [125I]ET-1, which showed more widespread binding than [125I]BQ-3020 due to a high affinity to both ETA and ETB receptors. [125I]BQ-3020 was found to bind to parenchyma, parasympathetic ganglia, pulmonary and submucosal plexuses, but bound only slightly to circular smooth muscle layers and the epithelium of airway tracts. Although [125I]ET-1 bound to the smooth muscle layer of all blood vessels, the binding of [125I]BQ-3020 differed among blood vessels. [125I]BQ-3020 binding in blood vessels paralleled acetylcholinesterase activity, suggesting that ETB receptors in blood vessels are located on parasympathetic nerves. Thus, the radioligand [125I]BQ-3020 is very useful for studying the precise localization of ETB receptors.

Acetylcholinesterase↗
PubMed1993

Release of protein 4.1-rich vesicles from diamide-treated erythrocytes under hydrostatic pressure.

The effect of cross-linking of membrane proteins on vesiculation under high pressure (2.0 kbar) of human erythrocytes was examined. To get the large molecular weight aggregates characterized by cross-linking of cytoskeletal proteins with integral ones, the erythrocytes were pretreated with diamide under pressure (1.0 kbar) where no vesiculation occurs. Vesicles released at 2.0 kbar from such erythrocytes contained protein 4.1 as major membrane protein. Upon reduction of cross-linking by dithiothreitol prior to vesiculation, the released vesicles contained membrane proteins similar to intact cells. On the other hand, in the erythrocyte pretreated with diamide at atmospheric pressure, no such large molecular weight aggregate was observed and the membrane protein composition of the vesicles released from the cells at 2.0 kbar was also similar to that of intact cells. These results suggest that the membrane protein composition of released vesicles is much affected by the properties of cross-linking of membrane proteins in erythrocytes.

Cytoskeletal Proteins↗
PubMed1993

Human P-glycoprotein transports cyclosporin A and FK506.

Cyclosporin A, a cyclic undecapeptide, and FK506 are efficient immunosuppressive agents. They also attract attention as effective P-glycoprotein modulators that inhibit P-glycoprotein from binding to anticancer drugs and overcome multidrug resistance. Cyclosporin A itself interacts with a common binding site of P-glycoprotein to which Vinca alkaloids and verapamil bind. We were interested to determine whether cyclosporin A and FK506 are substrates for P-glycoprotein to transport, and we studied their transcellular transport. In LLC-PK1 cells, derived from porcine kidney proximal tubule and forming a highly polarized epithelium, cyclosporin A was transported in a saturable manner. LLC-GA5-COL300, a transformant cell line derived by transfecting LLC-PK1 with human MDR1 cDNA isolated from normal adrenal gland, expresses P-glycoprotein specifically on the apical surface and shows a typical multidrug-resistant phenotype. LLC-GA5-COL300 cells showed increased transport of cyclosporin A from the basal to the apical side. Kinetic analysis showed that this transport was a typical saturable transport with the calculated apparent Michaelis constant (Kappm) and the maximum flux (Vmax) as 8.4 microM and 2.4 nmol/mg protein/h, respectively. LLC-GA5-COL300 also showed increased transport of FK506 from the basal to the apical side. These results indicate that P-glycoprotein transports the immunosuppressive agents cyclosporin A and FK506.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Expression of transforming growth factor alpha antisense mRNA inhibits the estrogen-induced production of TGF alpha and estrogen-induced proliferation of estrogen-responsive human breast cancer cells.

To ascertain if 17 beta-estradiol (E2)-induced proliferation could be attenuated by blocking the expression of endogenous transforming growth factor alpha (TGF alpha), estrogen receptor (ER)-positive, estrogen-responsive MCF-7 or ZR-75-1 cells and ER-negative, estrogen-nonresponsive MDA-MB-468 or HS-578T cells were infected with a recombinant amphotropic, replication-defective retroviral expression vector containing a 435 base pair (bp) Apa1-Eco R1 coding fragment of the human TGF alpha cDNA oriented in the 3' to 5' direction and under the transcriptional control of an internal heavy metal-inducible mouse metallothionein (MT-1) promoter and containing the neomycin (neo) resistance gene. E2-stimulated expression of endogenous TGF alpha mRNA was inhibited by 4-5-fold, and the production of TGF alpha protein was inhibited by 50-80% when M-1 mass-infected MCF-7 or MZ-1 mass-infected ZR-75-1 cells were treated with 0.75-1 microM CdCl2, whereas in comparably treated parental MCF-7 or ZR-75-1 cells there was no significant effect upon these parameters. E2-stimulated anchorage-dependent growth (ADG) and anchorage-independent growth (AIG) of the M-1 or MZ-1 cells was inhibited by 60-90% following CdCl2 treatment. In contrast, neither the ADG nor AIG of the parental noninfected MCF-7 or ZR-75-1 cells that were maintained in the absence or presence of E2 was affected by comparable concentrations of CdCl2. The ADG and AIG of TGF alpha antisense MD-1 mass-infected MDA-MB-468 cells that express high levels of endogenous TGF alpha mRNA were also inhibited by 1 microM CdCl2, whereas the ADG and AIG of MH-1 mass-infected HS-578T cells, a TGF alpha-negative cell line, were unaffected by CdCl2 treatment. These results suggest that TGF alpha may be one important autocrine intermediary in regulating estrogen-induced cell proliferation.

Breast Neoplasms↗
PubMed1993

The expression and biological activity of IL-2 receptor on a human pancreas cancer cell line.

To ascertain whether the tumor cells can regulate the host immune systems through the production of the cytokines or their receptors, we examined the expressions of tumor necrosis factor alpha (TNF alpha), tumor necrosis factor beta (TNF beta), interleukin 2 (IL-2) and interleukin 2 receptor alpha chain (IL-2R alpha) on the human cancer cell lines by Northern blot analysis. We used K562 (leukemia cell line), MCF-7 (breast cancer cell line), LS180, HT29 (colon cancer cell lines), SH101 (gastric cancer cell line) and PH101 (pancreas cancer cell line). Expressions of TNF alpha, TNF beta and IL-2 mRNA were not detected in any of the tumor cell lines. However, 1.4 and 3.5 kilobases of the IL-2R alpha mRNA were expressed in the PH101 cells, but not in the other five cell lines. Furthermore, IL-2R alpha was detected on the cell surface of the PH101 cells by the flow-cytometric analysis with an anti-IL-2R alpha monoclonal antibody. Interestingly, the soluble IL-2R alpha (sIL-2R alpha) was found in the conditioned media obtained from the PH101 cell culture with a sandwich enzyme immunoassay. Moreover, the sIL-2R alpha secreted from the PH101 cells blocked the IL-2 dependent lymphocyte proliferation. These results indicate that the expression of IL-2R alpha on PH101 might suppress the IL-2 induced lymphocyte proliferation.

Cell Division↗
PubMed1993

Nephrotoxic serum nephritis in nude rats: the roles of host immune reactions in the accelerated type.

By immunization with rabbit immunoglobulins and the injection of a subnephritogenic dose of rabbit nephrotoxic serum (NTS), accelerated-type nephrotoxic serum nephritis (NTN) was induced in heterozygous (rnu/+) rats but not in athymic nude (rnu/rnu) rats. By transferring rat antibody against rabbit immunoglobulins, marked proteinuria was induced also in nude rats (202.0 +/- 98.4 mg/day on day 3) as in rnu/+ rats (122.6 +/- 35.3 mg/day on day 3). No marked differences in histological findings could be found between both groups. The most marked increase in the number of intraglomerular infiltrating cells was observed in heterozygous rats indicating that the presence of thymus-derived cells leads to the accumulation of more cells in glomeruli. We conclude that humoral immunity alone is enough to accelerate the pathogenic mechanism which induces glomerular injury with heavy proteinuria in this model.

Animals↗
PubMed1993

Inhibitory effects of a novel antiplatelet agent, E5510, on collagen-induced platelet-derived growth factor release and aggregation of human platelets in vitro.

E5510, 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoic acid, is a new anti-platelet-aggregation agent under development. We examined the inhibitory efficacy of E5510 on PDGF-release from washed human platelets. E5510 concentration-dependently inhibited collagen-induced PDGF release from human platelets. PDGF release was reduced to below the detection limit (0.47 ng/ml) by preincubation of platelets with 0.04 microM or higher concentrations of E5510. Total growth factor release from platelets was also measured by a bioassay with cultured smooth muscle cells. E5510 almost completely abolished the mitogenic effect of collagen-induced platelet releasates at concentrations of 0.04 microM or higher. Our data suggest that the release of PDGF and other growth factors was inhibited by E5510 at the same concentration that inhibited platelet aggregation.

Animals↗
PubMed1993

[Clinicopathological evaluation and treatment of bucillamine induced membranous nephropathy].

We discussed clinicopathological evaluation and treatment of bucillamine induced renal destruction. Thirteen cases of rheumatoid arthritis were investigated in whom proteinuria had developed while being treated with bucillamine. The dose of bucillamine ranged from 100 to 300 mg/day, and many of them were treated with a dose of 200-300 mg/day. The total dose was in the range of 9-57 g. Proteinuria had developed within 3 months after perceiving the efficacy of bucillamine in many of the cases. The details of renal histology revealed that membranous nephropathy was noted in all of the 13 cases and that mesangial proliferative gromerulonephritis was noted in eight cases (61.5%), thin basement membrane was noted in four cases (30.8%) and in one case (7.7%) amyloidosis were identified in parallel. After suspending further administration of bucillamine, the proteinuria was gradually reduced without any specific treatment or without increase in the dose of corticosteroid, and was eliminated in all cases within 10 months. There were some cases in whom proteinuria was eliminated within a short period of time by the administration of corticosteroid in a moderate dose (prednisolone 30 mg/day). It is necessary to initiate the administration of bucillamine from a small dose such as 100 mg/day and pay attention to onset of any side effect. It was also seemed necessary to confirm the renal histology by renal biopsy as far as feasible because a large variety of pathological findings are developed in the kidney of these cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

Human P-glycoprotein transports cortisol, aldosterone, and dexamethasone, but not progesterone.

We expressed human MDR1 cDNA isolated from the human adrenal gland in porcine LLC-PK1 cells. A highly polarized epithelium formed by LLC-GA5-COL300 cells that expressed human P-glycoprotein specifically on the apical surface showed a multidrug-resistant phenotype and had 8.3-, 3.4-, and 6.5-fold higher net basal to apical transport of 3H-labeled cortisol, aldosterone, and dexamethasone, respectively, compared with host cells. But progesterone was not transported, although it inhibited azidopine photoaffinity labeling of human P-glycoprotein and increased the sensitivity of multidrug-resistant cells to vinblastine. An excess of progesterone inhibited the transepithelial transport of cortisol by P-glycoprotein. These results suggest that cortisol and aldosterone are physiological substrates for P-glycoprotein in the human adrenal cortex and that substances that efficiently bind to P-glycoprotein are not necessarily transported by P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Suppressive effects of the endothelin receptor (ETA) antagonist BQ-123 on ET-1-induced reduction of lipoprotein lipase activity in 3T3-L1 adipocytes.

Endothelin (ET)-1 reduced heparin-releasable lipoprotein lipase (LPL) activity in 3T3-L1 adipocytes in a concentration-dependent manner. However, a selective ETB receptor agonist, [Ala1,3,11,15]ET-1, did not act like ET-1. The ET-1-induced decrease in LPL activity was suppressed by a selective ETA receptor antagonist, BQ-123: the concentration-response curve for the ET-1 reduction of LPL activity was shifted to the right in the presence of BQ-123 in a concentration-dependent manner. This antagonistic effect of BQ-123 clarifies that the ETA receptor is responsible for the ET-1-induced reduction of LPL activity in 3T3-L1 adipocytes, which suggests that there is therapeutic potential for ETA antagonists in LPL-related lipoprotein disorders.

3T3 Cells↗