Biomedical subjects

T Saeki

Publications and source records attributed to T Saeki.

At least 109 records · Page 6Linked to original sources

PubMed1995

[Outcome of patients with chronic systemic lupus erythematosus].

We analyzed data on 69 Japanese patients who had been affected with systemic lupus erythematosus (SLE) for more than 10 years to clarify the clinical and social features of the chronic phase of this disease. There were 3 men and 66 women. Mean age at disease onset was 24.3 years, and the mean duration of disease was 17.4 years. In these patients, the mean number of relapses was 1.5, and the mean duration of the relapse was 4.7 years. These patients were receiving prednisolone at a mean dosage of 9.2 mg/day. While only 4 patients were thought to be in the active disease stage at the time of evaluation, hypercholesterolemia was present in 33.3% (20 patients out of 60) and 64. 3% (27 patients out of 42) showed a decrease in bone mineral content by DEXA method. Ten patients out of 69 patients (14.5%) had aseptic necrosis of the head of the femur (ANF). ANF was related to the relapse and the administration of immunosuppressant in the initial therapy. Seventeen female patients had gotten married after the onset of SLE and 14 patients became pregnant and gave birth. Of the 9 deaths that occurred, only 3 cases were thought to be due to SLE. Two patients died suddenly, and there was 1 case of acute heart failure. Mean age at death was 39.8 years old. However, data suggest that many patients in the chronic phase of SLE may have a reasonably high quality of life, despite the disease.

Adolescent↗

PubMed1995

[A case of acute lupus pneumonitis].

Forty-five-year-old woman with systemic lupus erythematosus who had treated with sulindac had exacerbation of her rash and arthralgia. On her admission for treatment, chest X-ray showed bilateral pathy infiltrates in lower lung fields. We performed a transbronchial lung biopsy. Immunohistopathologic studies showed granular deposits of IgM and C 3 in the subendothelial area of pulmonary arteriolae. She was treated with prednisolone (1.0 mg/kg/day) and deoxyspergualin. Chest X-ray showed improvement and her serum IgG, anti-DNA antibodies and complement diminished quickly. We suggest that these immunopathologic observations may be important in the pathogenesis of the lung injury in systemic lupus erythematosus.

Acute Disease↗

PubMed1995

A selective type V phosphodiesterase inhibitor, E4021, dilates porcine large coronary artery.

We investigated the inhibitory effects of a newly synthesized compound, sodium 1-[6-chloro-4-(3,4-methylenedioxybenzyl)-aminoquinazolin-2-y l]piperidine-4- carboxylate sesquihydrate (E4021), on five phosphodiesterase (PDE) isozymes isolated from porcine aortic smooth muscle. E4021 specifically inhibited type V phosphodiesterase (cyclic guanosine monophosphate [cGMP]-specific PDE) in a competitive manner. A comparison of the inhibitory profiles of zaprinast and E4021 indicated that E4021 is 100 times more potent and selective as a type V PDE inhibitor. E4021 caused a significant and sustained increase in the cGMP level in endothelium-denuded porcine coronary artery, but it had no effect on the cAMP level. This compound had a relaxant effect in porcine coronary artery precontracted by prostaglandin F2 alpha in the absence of endothelial cells and relaxed it more markedly in the presence of endothelial cells. E4021 had a synergistic effect with nitroglycerin in both the increase in cGMP level and the relaxant effect in isolated porcine coronary artery. E4021 caused a dose-dependent dilation of the large epicardial coronary artery, with a reduction in mean pulmonary arterial pressure, in conscious pigs instrumented chronically with a pair of piezoelectric crystals. These results suggest that the highly selective and potent inhibitor of type V phosphodiesterase E4021 causes relaxation of the large coronary artery via an increase in the cGMP level.

Animals↗

PubMed1995

Association of epidermal growth factor-related peptides and type I receptor tyrosine kinase receptors with prognosis of human colorectal carcinomas.

The frequency of expression and localization of cripto-1 (CR-1), amphiregulin (AR), transforming growth factor alpha (TGF alpha), epidermal growth factor receptor (EGFR) and erbB-2 were examined by immunohistochemistry in 45 carcinomas and adjacent non-involved normal colon mucosa. Thirty (66.7%), 24 (53.3%), 23 (51.1%), 23 (51.1%) and 13 (28.9%) of the 45 carcinomas showed positive staining for CR-1, AR, TGF alpha, EGFR and erbB-2, respectively, whereas 7 (15.5%), 17 (37.7%), 15 (33.3%), 20 (44.4%) and 0 (0%) of the corresponding non-involved normal mucosa specimens were reactive. Among 13 carcinomas with lymph node involvement, 10 (76.9%), 8 (61.5%), 10 (76.9%), 8 (61.5%) and 7 (53.8%) exhibited positive staining for CR-1, AR, TGF-alpha, EGFR and erbB-2, respectively. There was a statistically significant association between the frequency of either TGF alpha (P < 0.05) or erbB-2 (P < 0.05) expression and lymph node metastasis. In addition, a significantly higher frequency of positive staining for TGF alpha was observed in Dukes' grade C carcinomas (P < 0.05). Finally, significant trends for coexpression of EGFR and either TGF alpha (P < 0.01) or AR (P < 0.05) were detected in carcinomas. These data suggest that AR and TGF alpha may play an important role in the development of colorectal carcinomas through an autocrine mechanism involving EGFR, and demonstrate that TGF alpha and erbB-2 may be more reliable indicators of metastasis or prognosis than CR-1, AR or EGFR in human colon cancers.

Adenocarcinoma↗

PubMed1995

Synthesis and properties of 5-fluorouracil oligonucleotides.

Oligonucleotides of 5-fluoro-2'-deoxyuridine (FUdR) 1 and 5-fluorouridine (FUR) 2 have been prepared by the standard phosphoramidite method. Homo oligomers (24 mer) of 1, 2 and hetero oligomers of those will be described.

Antimetabolites, Antineoplastic↗

PubMed1994

Block of Na+ channel by moricizine hydrochloride in isolated feline ventricular myocytes.

The effect of moricizine hydrochloride, a potent class I antiarrhythmic agent, on Na+ current (INa) of single feline ventricular myocytes were studied using whole cell patch clamp techniques. Moricizine inhibited INa in a concentration-dependent manner without altering the current-voltage relationship for INa. INa inhibition was expressed by the Hill equation with a Hill coefficient of 1.3 and dissociation constant of 105 microM in the resting state (holding potential = -140 mV). Moricizine 30 microM shifted the steady state inactivation curve for INa toward more negative potentials by 7.3 +/- 2.4 mV without causing significant changes in the slope factor. Recovery of INa from inactivation was retarded (time constant = 8 s) at a holding potential of -140 mV in the presence of 30 microM moricizine. When the start of INa block was studied in experiments using a double pulse protocol, moricizine reduced INa by only 4% after a 4-ms prepulse, but strongly inhibited it after prepulses longer than 200 ms. Intracellular application of 100 microM moricizine did not produce significant resting or use-dependent INa block. These results suggest that (1) moricizine blocks INa by binding to the Na+ channel with a 1:1 stoichiometry, (2) the drug has a higher affinity to the inactivated state than to the activated and resting states of the Na+ channel, (3) recovery kinetics of moricizine from Na+ channel inactivation, or drug dissociation observed during the transition from inactivated to resting state was relatively slow, (4) the drug binding site appeared to be located on the external side of the membrane.

Animals↗

PubMed1994

Cyclic GMP phosphodiesterase inhibitors. 2. Requirement of 6-substitution of quinazoline derivatives for potent and selective inhibitory activity.

We synthesized various 4-[[3,4-(methylenedioxy)benzyl]amino]quinazolines substituted at the 5- to 8-positions and evaluated their inhibitory activities toward cyclic GMP phosphodiesterase (cGMP-PDE) from porcine aorta. Monosubstitution at the 6-position was essential for the inhibitory activity, and the preferred substituents were compact and hydrophobic: methoxy (3b, IC50 = 0.23 microM), methyl (3c, 0.10 microM), chloro (3d, 0.019 microM), thiomethyl (3f, 0.031 microM), and cyano (3p, 0.090 microM) groups. Compounds 3b-d,f,p lacked inhibitory activity toward other PDE isozymes (all IC50 values > 100 microM), and their relaxing activities in porcine coronary arteries were well correlated with the inhibitory activities toward cGMP-PDE (r = 0.88, p < 0.05). One of these compounds, 3b, elevated the intracellular cGMP level in isolated porcine coronary arteries without causing any change in the cAMP level. We consider that this series of compounds dilates coronary arteries via potent and specific inhibition of cGMP-PDE.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed1994

Biochemical and pharmacological profile of a potent and selective endothelin B-receptor antagonist, BQ-788.

We describe the characteristics of a potent and selective endothelin (ET) B-receptor antagonist, BQ-788 [N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D -1- methoxycarbonyltryptophanyl-D-norleucine]. In vitro, this compound potently and competitively inhibits 125I-labeled endothelin 1 (ET-1) binding to ETB receptors on human Girardi heart cells (IC50, 1.2 nM) but only poorly inhibits the binding to ETA receptors on human neuroblastoma cell line SK-N-MC cells (IC50, 1300 nM). In isolated rabbit pulmonary arteries, BQ-788 shows no agonist activity up to 10 microM and competitively antagonizes the vasoconstriction induced by an ETB-selective agonist, BQ-3020 (pA2, 8.4). In rat, an ETA-selective antagonist, BQ-123 (1 mg/kg, i.v.), does not affect transient depressor response to ET-1 (0.3 nmol/kg, i.v.) but potently inhibits following sustained pressor response; vice versa, BQ-788 (1 mg/kg, i.v.) abolishes the depressor response, resulting in a rapid onset of apparently enhanced pressor response. Thus, being a potent and selective ETB receptor antagonist, BQ-788 may be considered as a powerful tool for investigating the role of ET in physiological and pathological processes.

Amino Acid Sequence↗

PubMed1994

Amphiregulin as an autocrine growth factor for c-Ha-ras- and c-erbB-2-transformed human mammary epithelial cells.

Amphiregulin (AR), a member of the epidermal growth factor (EGF) family, was found to be as potent as EGF in stimulating the anchorage-dependent growth (ADG) of immortalized, nontransformed human mammary epithelial MCF-10A cells. MCF-10A cells transformed by either an activated human c-Ha-ras protooncogene (MCF-10A ras) or by overexpression of a nonactivated rat c-neu gene (MCF-10A neu) exhibited a 35% reduction in the response to AR in ADG when compared to MCF-10A cells, but AR was still as potent as EGF in these transformants. Exogenous AR exhibited only 15-20% of the activity of EGF in stimulating the anchorage-independent growth, a response that is normally dependent upon exogenous EGF, of the oncogene-transformed MCF-10A cells. MCF-10A cells express low levels of a 1.4-kb AR mRNA transcript, while MCF-10A ras and MCF-10A neu cells display a 15- to 30-fold increase in the levels of AR mRNA and endogenous AR protein as determined by Western blot analysis. Exogenous EGF was found to induced both the AR mRNA and protein in the MCF-10A parental and transformed cells. A 20-mer phosphorothioate antisense deoxyoligonucleotide complementary to the 5' sequence of AR mRNA was able to significantly reduce the levels of endogenous AR protein and to inhibit the EGF-stimulated ADG and anchorage-independent growth of MCF-10A ras and MCF-10A neu cells. These data suggest that AR may function as an EGF-dependent autocrine growth factor in mammary epithelial cells that have been transformed by either a point-mutated c-Ha-ras or c-neu.

Amphiregulin↗

PubMed1994

Disseminated Mycobacterium avium-intracellulare infection in a patient with myelodysplastic syndrome (refractory anemia).

A 31-year-old woman presented with fever and arthralgia. Despite treatment with antimicrobials and corticosteroids, her symptoms persisted. A diagnosis of myelodysplastic syndrome (MDS)-refractory anemia (RA) was made by pancytopenia, dysplasia, and trisomy 8. Cultures of bone marrow, blood, and gastric juice showed Mycobacterium avium-intracellulare (MAI). She was treated with antimycobacterial drugs and recombinant human G-CSF/M-CSF and showed an initial response, but spike fever recurred and pancytopenia progressed. Hepatosplenomegaly and marked retroperitoneal lymphadenopathy were revealed, indicating further dissemination of MAI. Treatment with recombinant human GM-CSF and very-low-dose cytosine arabinoside, was started but was not effective. This case showed significant reduction in peripheral blood T-lymphocytes, especially the CD4+ population, and low immunoglobulin levels. Immunodeficiency state associated with long-term steroid therapy and MDS seemed to contribute to the development of the disseminated infection with MAI.

AIDS-Related Opportunistic Infections↗

PubMed1994

Effects of membrane lipid peroxidation by tert butyl hydroperoxide on the sodium current in isolated feline ventricular myocytes.

Membrane lipid peroxidation is known to play a pivotal role in the genesis of coronary reperfusion arrhythmias in both experimental and clinical settings. To elucidate the electrophysiological mechanisms underlying these arrhythmias, the effects of tert butyl hydroperoxide (TBH) on the Na+ current (INa) in isolated feline ventricular myocytes were studied using whole-cell patch clamp techniques under 100% O2 bubbling. This agent at 20 mM inhibited INa from 2.2 +/- 1.3 to 1.7 +/- 1.0 nA (P < 0.01, n = 7) without changing time courses of INa inactivation. Twenty millimoles TBH shifted the steady-state inactivation curve for INa from -77.4 +/- 1.7 to -81.3 +/- 1.8 mV when measured at INa half inhibition voltage (P < 0.01, n = 7), but did not affect the slope factor. The kinetics of INa recovery from inactivation remained unchanged. These findings suggest that lipid peroxidation in the membrane by TBH reduces INa conductance and voltage-dependent INa availability, most likely as a result of structural damage to the Na+ channels.

Animals↗

PubMed1994

Effect of the acyl-CoA:cholesterol acyltransferase inhibitor, E5324, on experimental atherosclerosis in rabbits.

E5324, n-butyl-N'-[2-[3-(5-ethyl-4-phenyl-1H-imidazol-1-yl)propoxy]-6- methylphenyl]urea, a novel and orally absorbable acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, was evaluated for its antiatherosclerotic and antihyperlipidemic effects in cholesterol-fed hypercholesterolemic rabbits. When administered concurrently with a high-cholesterol (0.5% cholesterol) diet for 12 weeks, E5324 (0.0025%, 0.005% and 0.01% in diet) lowered plasma total cholesterol levels dose-dependently (by about 55%-87% at the end of the experiment compared with the control) and also reduced atherosclerotic plaque formation (about 90% reduction at the highest dose; P < 0.01). In pre-established hypercholesterolemic rabbits, which had been pre-fed a high-cholesterol diet for 8 weeks, E5324 administered in the same diet at a dose of 0.005%, 0.01% or 0.02% for 4 weeks significantly reduced plasma cholesterol levels dose-dependently. Cholesterol content and ACAT activity in the aortic arch were also decreased (by about 72% and 58% at the highest dose, respectively) compared with the control. Another ACAT inhibitor, CI-976, had a similar action, but cholestyramine and probucol (2% and 1% in diet, respectively) lacked anti-atherosclerotic activity in this model. Furthermore, when pre-established hypercholesterolemic rabbits were fed normal rabbit chow diet with or without 0.02% E5324 for 4 weeks, changes in plasma cholesterol levels were similar in both E5324-treated and control groups. On the other hand, E5324 significantly reduced cholesterol content and ACAT activity in the aortic arch (by about 52% and 50%, respectively) compared with the control group. These results indicate that E5324 not only has hypocholesterolemic activity, but also may have a direct effect on the arterial wall in experimental atherosclerosis.

Anilides↗

PubMed1994

Expression of transforming growth factor alpha, amphiregulin and cripto-1 in human breast carcinomas.

The expression of three epidermal growth factor (EGF)-related peptides, transforming growth factor alpha (TGF-alpha), amphiregulin (AR) and cripto-1 (CR-1), was examined by immunocytochemistry (ICC) in 68 primary infiltrating ductal (IDCs) and infiltrating lobular breast carcinomas (ILCs), and in 23 adjacent non-involved human mammary tissue samples. Within the 68 IDC and ILC specimens, 54 (79%) expressed immunoreactive TGF-alpha, 52 (77%) expressed AR and 56 (82%) expressed CR-1. Cytoplasmic staining was observed with all of the antibodies, and this staining could be eliminated by preabsorption of the antibodies with the appropriate peptide immunogen. Cytoplasmic staining with all of the antibodies was confined to the carcinoma cells, since no specific immunoreactivity could be detected in the surrounding stromal or endothelial cells. In addition to cytoplasmic reactivity, the AR antibody also exhibited nuclear staining in a number of the carcinoma specimens. No significant correlations were found between the percentage of carcinoma cells that were positive for TGF-alpha, AR or CR-1 and oestrogen receptor status, axillary lymph node involvement, histological grade, tumour size, proliferative index, loss of heterozygosity on chromosome 17p or overall patient survival. However, a highly significant inverse correlation was observed between the average percentage of carcinoma cells that expressed AR in individual tumours and the presence of a point-mutated p53 gene. Likewise, a significantly higher percentage of tumour cells in the ILC group expressed AR as compared with the average percentage of tumour cells that expressed AR in the IDC group. Of the 23 adjacent, non-involved breast tissue samples, CR-1 could be detected by ICC in only three (13%), while TGF-alpha was found in six (26%) and AR in ten (43%) of the non-involved breast tissues. These data demonstrate that breast carcinomas express multiple EGF-related peptides and show that the differential expression of CR-1 in malignant breast epithelial cells may serve as a potential tumour marker for breast cancer.

Amphiregulin↗

PubMed1994

Human P-glycoprotein as a multi-drug transporter analyzed by using transepithelial transport system.

To analyze the mechanism of drug transport, mechanism of inhibitors, and physiological substrates of human P-glycoprotein, we established a transepithelial transport system by introducing MDR1 cDNA into LLC-PK1, a pig kidney epithelial cell line. P-glycoprotein functions as a steroid transporter as well as a drug transporter as physiological functions. P-glycoprotein also transports MDR modulators such as cyclosporin A, FK506, and calcium channel blockers.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1994

Endothelin ETB receptors couple to two distinct signaling pathways in porcine kidney epithelial LLC-PK1 cells.

We characterized the endothelin (ET) receptor subtypes responsible for signal transduction in cultured porcine kidney epithelial LLC-PK1 cells. Both ET-1 (IC50, 43 pM) and ET-3 (IC50, 46 pM) inhibited the binding of [125I]ET-1 to LLC-PK1 cells to a similar extent. The binding affinity of LLC-PK1 cells was about 10,000 times higher for the ETB antagonist BQ-788 [N-cis-2,6-dimethyl-piperidinocarbonyl-L-tau-metylleucyl-D-+ ++Nin- methoxycarbonyltryptophanyl-D-norleucine] (IC50, 1.3 nM) than for the ETA antagonist BQ-123 [cyclo-(D-Trp-D-Asp-Pro-D-Val-Leu)] (IC50, 14 microM). ET-1 enhanced cyclic GMP (cGMP) production, but reduced vasopressin- and forskolin-stimulated cyclic AMP (cAMP) production. Both effects of ET-1 were antagonized by BQ-788, but not by BQ-123. The cAMP decrease, but not the cGMP increase, in response to ET-1 was inhibited by pertussis toxin, suggesting that the former response is mediated by pertussis toxin-sensitive Gi, whereas the latter is mediated by a pertussis toxin-insensitive G-protein. Therefore, the ETB receptors in LLC-PK1 cells couple to the two types of signal transduction cascades to reduce cAMP production and stimulate cGMP production via distinct G-proteins. ET-1 and probably also ET-3 may play a role in the regulation of renal epithelial transport by decreasing cAMP and increasing cGMP.

Amino Acid Sequence↗

PubMed1994

[A clinicopathological study of renal hemodynamics in patients with systemic lupus erythematosus].

We evaluated the clinical value of the glomerular filtration rate (GFR) and renal plasma flow (RPF) in patients with systemic lupus erythematosus (SLE). All of the patients fulfilled the criteria for SLE of the American Rheumatism Association and were divided into two groups by the criteria for disease activity. GFR and RPF were simultaneously measured by the standard clearance technique using sodium thiosulfate and sodium paraaminohippurate, respectively. Ninety-six clinically active patients and 60 inactive patients underwent one clearance study. In 36 other patients, repeated clearance studies were undertaken on two occasions during the period from the active to inactive phase. The mean RPF was 590.3 +/- 213.7 ml/min in 132 active patients and 485.7 +/- 184.0 ml/min in 96 patients without disease activity (p < 0.01), whereas the mean GFR was comparable between the two groups. In active SLE, the mean GFR in 76 patients with proteinuria was 76.0 +/- 38.2 ml/min as compared with 104.8 +/- 34.3 ml/min in 56 patients without proteinuria (p < 0.01); however, there was no significant difference in the mean RPF between the two groups. A fall in GFR was frequently observed in patients with class IV lupus nephritis. In contrast, there was no significant difference in the mean RPF between class IV patients and the patients in the other classes. As a result, a marked decrease in the filtration fraction (FF) was frequently observed in class IV lupus nephritis, irrespective of the use of diuretics or antihypertensive agents. Semiquantitative histological analyses revealed that mesangial proliferative changes were more responsible than glomerular sclerotic changes for these hemodynamic features.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1994

[A clinical study of renal hemodynamics in patients with lupus nephritis].

This study was designed to evaluate the clinical significance of glomerular filtration rate (GFR) and renal plasma flow (RPF) in 122 patients with lupus nephritis. All patients had definite clinical evidence of active lupus nephritis, including urinary and immunological abnormalities. The average RPF was 634.5 +/- 171.4 ml/min in systemic lupus erythematosus patients and 537.4 +/- 141.9 ml/min in 37 age-and sex-matched patients with primary glomerular disease (PGD) (p < 0.01). A fall in GFR, accompanied by massive proteinuria and hypocomplementemia, was observed frequently in patients with class IV lupus nephritis (diffuse proliferative GN). In contrast, RPF did not change in most patients except in some with increased RPF. No correlation was noticed between RPF and proteinuria or immunological abnormalities. As a result, a marked fall in filtration fraction (FF) was observed frequently in class IV lupus nephritis, and was correlated significantly with urinary and immunological abnormalities. Follow-up data during treatment in the active to inactive phases (average 7.8 months) were available for 39 patients. The average GFR increased significantly from 56.9 +/- 31.4 ml/min in the pre-treatment stage to 74.5 +/- 26.9 ml/min in the post-treatment stage, accompanied by an improvement in proteinuria and hypocomplementemia. On the other hand, RPF decreased significantly from 521.3 +/- 217.1 to 437.6 +/- 156.2 ml/min, so that FF increased significantly as the renal and immunological parameters normalized. Additionally, the renal function was evaluated in 11 patients during the exacerbation of lupus nephritis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1994

[Our surgical indication for breast-conserving therapy for breast cancer--special reference to extensive intraductal component and mammographic calcifications].

To ascertain accurate indications for breast-conserving therapy, we clinicopathologically examined 597 primary breast cancers. From July 1989 to October 1993, 118 of 597 (19.8%) patients were treated with lumpectomy plus breast radiation therapy. Among 118 of these primary breast cancers, 79 tumors were histologically further investigated with deep cut sections. In 20 of 79 (25.3%) breast cancers, microscopic tumor involvement was observed at resection margins. Most of them showed an extensive intraductal component (EIC). In order to predict EIC, intraductal lesions were histologically examined and classified either as comedo type or non-comedo (e.g., papillary type, cribriform type and solid type). Among 118 primary breast cancer tissues derived from lumpectomy, 66 breast tissues were histologically classified as comedo type. Sixty of 66 (90.9%) of these comedo types showed specific microcalcifications by light microscopic examination. These irregular shaped and relatively large granulated microcalcifications were localized in intraductal lesions with central necrotic ducts. With retrospective mammographic findings, these histological calcifications of comedo type reflected specific mammographic calcifications with columnar and specular formation. These evidences suggested that detection of mammographic calcifications in comedo type breast cancers may be helpful to predict EIC, and this prediction can possibly increase the accuracy of the indication for breast-conserving therapy.

Adult↗