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Biomedical subjects

S Goto

Publications and source records attributed to S Goto.

At least 37 records · Page 2Linked to original sources
PubMed2004

Understanding the mechanism and prevention of arterial occlusive thrombus formation by anti-platelet agents.

For many years, platelet aggregation, which is mediated exclusively by the binding of fibrinogen to activated glycoprotein (GP) IIb/IIIa, has been used for the screening of antiplatelet agents. However, clinical experience with anti-GP IIb/IIIa agents, which can completely inhibit platelet aggregation, has shown that these drugs are not the most ideal agents for the prevention of atherothrombosis. Recently, many investigators have reported that platelets play a major role in thrombus formation at sites exposed to blood flow, and also that there is a crucial difference between the mechanism of platelet thrombus formation under blood flow conditions in vivo and that of platelet aggregation occurring in conventional aggregometry. Indeed, multiple receptor-ligand interactions, including von Willebrand factor (VWF) binding with platelet GP Ibalpha and GP IIb/IIIa, collagen binding with collagen receptors, as well as stimulation of platelet receptors, such as adenosine 5'-diphosphate (ADP) receptors, appear to be involved in the process of in vivo arterial thrombus formation. Moreover, not only platelets, but also the coagulation cascade activated by the procoagulant activity expressed on the surface of activated platelets, are believed to play a crucial role in the formation of occlusive thrombi. These findings suggest that drugs which block events upstream of the final common pathway for platelet aggregation might be better antiplatelet agents than those that merely inhibit platelet aggregation. We may then expect new antiplatelet agents on the horizon that exert their actions against both thrombus formation under blood flow conditions and against the procoagulant activity appearing on the surface of activated platelets.

Animals↗
PubMed2003

Analysis of estrogenic activity of foodstuffs and cigarette smoke condensates using a yeast estrogen screening method.

Hormone mimics present in our environment are of concern because such agents could potentially reduce fertility and increase sexual dysfunction in wildlife and increase the risk of breast and reproductive organ cancers in man. Therefore, monitoring of the levels of estrogenic compounds in environmental materials is essential in order to prevent their exposure to man and to discover potential harmful effects on human health. In the present study, we analyzed estrogenic activity in 23 foodstuffs and cigarette smoke condensate samples extracted with an organic solvent, using the yeast estrogen screening (YES) system. Three soybean-related foodstuffs (soy sauce, tofu, miso), beer, coffee and cigarette smoke condensates showed clear estrogenic activity in the YES system. HPLC fractionations followed by the YES of these YES-positive samples revealed the presence of many estrogenic compounds in cigarette smoke condensates, whereas the other samples exerted estrogenic activities in only one or two fractions. Genistein was able to be isolated as the major active principle in soy sauce, tofu and miso, its concentration in these three foodstuffs ranging from 0.1 to 394 microg/g or ml. 8-Prenylnaringenin was also isolated from beer extracts as a major compound with estrogenic activity present at 0.22-4.0 ng/ml. Estrogenic activity of 8-prenylnaringenin with YES was 10-times as high as that of genistein, although it was 100-times less than that of 17beta-estradiol. Based on our results in vitro, 10 mg miso and 10 ml beer can be calculated to have similar estrogenic activity to 1 pmole 17beta-estradiol. It is very important that the effects of genistein and 8-prenylnaringenin on human health are elucidated.

Chromatography, High Pressure Liquid↗
PubMed2003

Peroxisome proliferator-activated receptor gamma C161T polymorphisms and survival of Japanese patients with immunoglobulin A nephropathy.

Peroxisome proliferator-activated receptor gamma (PPAR gamma) plays an important role in lipid metabolism, insulin sensitivity, atherogenesis, and immune regulation. A genetic polymorphism (C161T) at exon 6 of PPAR gamma gene (PPARG) was reported to be associated with the onset of coronary artery disease. However, there has been no report of an association with renal disease. Genomic DNAs were isolated from 225 Japanese patients with histologically confirmed immunoglobulin A nephropathy (IgAN). The PPARG C161T genotype was determined by polymerase chain reaction-restriction fragment length polymorphism. The association of the polymorphism with renal prognosis in IgAN patients was analyzed using the Kaplan-Meier method and Cox proportional hazard regression model. The PPARG polymorphism was not associated with the renal survival rate. However, when patients were stratified into those either with or without hypertension at the time of diagnosis, the renal survival of the CT/TT genotypes was significantly better in those without hypertension than those with the CC genotype. We report that the PPARG C161T polymorphism is associated with the survival of IgAN patients without hypertension. The T allele of the polymorphism might have a protective effect on the progression of IgAN.

Adult↗
PubMed2003

Involvement of FGF-2 in the action of Emdogain on normal human osteoblastic activity.

OBJECTIVE: The present study was designed to evaluate the pharmacological characteristics of Emdogain (EMD) on cell growth and cell activity in human osteoblasts. METHODS: Cell proliferation as well as several gene and protein expressions were examined using reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) procedures in human osteoblastic cells (SaM-1) treated with EMD (30 microg ml(-1)). RESULTS: Treatment of osteoblasts with EMD significantly stimulated cell proliferation and fibroblast growth factor (FGF)-2 expression but decreased alkaline phosphatase expression. In addition, increases in cyclooxygenase (COX)-2 expression and decreases in matrix metalloproteinases (MMP)-1 expression were observed in osteoblasts treated with EMD. The effects of EMD on FGF-2 and MMP-1 expressions were not observed in osteoblasts treated with NS-398, an inhibitor of COX-2. The decrease in MMP-1 mRNA by EMD was prevented by treatment with antisense oligodeoxynucleotide (AS-ODN) for FGF-2. CONCLUSION: Emdogain showing both stimulation of cell proliferation and inhibition of cell differentiation has been shown to increase FGF-2 expression in the mediation of prostaglandin E2 and to decrease MMP-1 mRNA expression through the activation of FGF-2. FGF-2 may underlie in the action of EMD on osteoblasts during periodontal regeneration.

Adult↗
PubMed2003

Different effects of various anti-GPIIb-IIIa agents on shear-induced platelet activation and expression of procoagulant activity.

Inhibitors of the platelet glycoprotein (GP)IIb-IIIa receptor (integrin alphaIIbbeta3) reduce acute thrombotic events in patients with coronary artery disease. To characterize the mechanism of action of these drugs, we evaluated the effects of different GPIIb-IIIa antagonists on shear-induced platelet aggregation, activation, and the expression of procoagulant activity. Samples of platelet-rich plasma from 16 volunteers were exposed to the shear rate of 10 800 s-1 for 6 min in an optically modified cone-plate viscometer. Abciximab, tirofiban and eptifibatide inhibited aggregation to a similar extent (mean +/- SD: 74.1 +/- 8.5%, 69.5 +/- 13.6%, 65.6 +/- 17.0%, respectively), but only abciximab inhibited significantly microparticle release associated with shear-induced platelet activation (64.4 +/- 13.6%, P = 2.2 x 10-7; tirofiban = 20.0 +/- 23.4%; eptifibatide = 23.9 +/- 17.4%). P-selectin platelet surface translocation was also strongly inhibited by abciximab, weakly by eptifibatide, but not by tirofiban. The addition of anti-alphavbeta3 to tirofiban enhanced the inhibiting effects on shear-induced P-selectin translocation and microparticle release. Shearing of platelet-rich plasma shortened the re-calcification clotting time after addition of kaolin from 106.9 +/- 14.3 to 94.2 +/- 10.7 s (mean +/- SD; P = 0.0013). This effect, which is mediated by the appearance of procoagulant phospholipids on the surface of sheared platelets and microparticles, was prevented by abciximab and by the combination of tirofiban and anti-alphavbeta3, but not by tirofiban alone or eptifibatide. The ability to inhibit shear-induced platelet activation, as evidenced by microparticle release and P-selectin surface translocation as well as the expression of procoagulant activity, differentiates the effects of anti-GPIIb-IIIa agents, which may explain the distinct antithrombotic efficacy of the agents.

Abciximab↗
PubMed2003

Development of hungry bone syndrome after rapid lowering of PTH with intravenous maxacalcitol therapy in a patient with non-uremic secondary hyperparathyroidism.

A 41 year-old woman complained of general bone pain and polyuria. She did not have Albright hereditary osteodystrophy. Laboratory examination revealed hypokalemia, hypocalcemia, and an elevation of serum intact PTH concentration. The patient was polyuric and relatively hypercalciuric, though her glomerular filtration rate (GFR) was normal. Neither urinary Pi nor cAMP excretion was remarkably promoted by an exogenous PTH load. An iliac bone biopsy revealed osteopenia, active osteoclastic bone resorption, fibrous transformation in bone marrow tissue, and severely disturbed calcification. Although the oral administration of alfacalcidol showed no effects, 3 weeks of intermittent intravenous injection of maxacalcitol therapy decreased the serum intact PTH concentration from 597 pg/ml to 40 pg/ml, and the bone pain was greatly relieved. However, plasma Ca concentration also decreased and symptoms of tetany appeared. Pseudohypoparathyroidism type Ib was the most likely diagnosis in this patient. In conclusion, maxacalcitol therapy satisfactorily suppressed parathyroid function in a patient with secondary hyperparathyroidism without uremia. Appropriate Ca supplementation was required to perform it safely.

Adult↗
PubMed2002

Activation of ribosomal S6 kinase (RSK) during porcine oocyte maturation.

The normal kinetics of ribosomal S6 kinase (RSK) during the meiotic maturation of porcine oocytes were examined. The phosphorylation states of RSK and extracellular signal-regulated kinase (ERK), major mitogen-activated protein (MAP) kinases in maturating porcine oocytes, were detected by Western blotting analysis. The S6 protein kinase activity was assayed using a specific substrate peptide which contained the major phosphorylation sites of S6 kinase. Full phosphorylation of RSK was correlated with ERK phosphorylation and was observed before germinal vesicle breakdown. S6 kinase activity was low in both freshly isolated and 20 h cultured oocytes. S6 kinase activity was significantly elevated in matured oocytes to a level about 6 times higher than that in freshly isolated oocytes. Furthermore, full phosphorylation of RSK was inhibited when oocytes were treated with U0126, a specific MAP kinase kinase inhibitor, in dose-dependent manner, indicating that RSK is one of the substrates of MAP kinase. These results suggest that the activation of RSK is involved in the regulation of meiotic maturation of porcine oocytes.

Animals↗
PubMed2002

Changes of the elastic fibre network of the rabbit temporomandibular joint following discectomy.

Elastic fibres are thought to be very important for the function of various organs including the temporomandibular joint (TMJ). The current study was designed to examine changes in the elastic fibres of the TMJ following discectomy. The TMJs of six rabbits were surgically exposed, and the disc removed with a scalpel. Three untreated and three sham-operated rabbits were used as controls. Complete TMJs were removed in three rabbits 1 month and in three rabbits 3 months after discectomy and processed for histochemical demonstration of elastic fibres. In the TMJ 1 month after discectomy, osteoarthritic changes and a significant increase in the numbers of elastic fibres were observed in the condyle and articular eminence. In the TMJs 3 months after discectomy, they tended to revert to the levels in the condyle and articular eminence of the control TMJs. Our results show that after experimental discectomy, elastic fibres very often appear initially in the condyle and articular eminence, but they are destined to disappear later. This information may improve our understanding of the consequences of removal of the disc in clinical practice.

Animals↗
PubMed2002

Mutation induction in human cells after low dose X ray exposure.

Mutations induced after low dose ionising radiation exposure have been intensively analysed not only for radiation risk estimation but also for basic understanding of cellular responses. Human lymphoblastoid TK6-20C cells were irradiated with 100 mGy of X rays and mutation at the heterozygous thymidine kinase (TK) locus was selected by trifluorothymidine (TFT) resistance. Although the mutation frequency at the TK locus increased from 5.6 x 10(-6) to 7.4 x 10(-6), this increase was not statistically significant. However, molecular analysis of TK mutants exhibiting loss of heterozygocity (LOH) demonstrated a clear effect of such low dose IR exposure. Exposure to 100 mGy X ray increased the fraction of hemizygous-LOH from 10% to 42%. In previous experiments, a similar tendency in the increase of hemizygous-LOH was also observed in TK6 cells after exposure to a 2 Gy dose of X rays. This type of LOH can be considered as a result of end-joining repair of DNA double strand breaks.

Cell Line↗
PubMed2002

Cellular responses to low dose heavy-ion exposure in human cells.

The human lymphoblastoid cell line TK6 was used to study the cellular responses after low-dose (100, 200, 500 mGy) or high-dose (3 Gy) of X rays, C (22 keV.micron-1) and Fe (1000 keV.micron-1) ion exposures. p53 protein induction in individual cells was determined by indirect immunofluorescence staining. Cell-cycle progression after heavy-ion exposure was determined by using a laser scanning cytometer. A characteristic pattern of cell-cycle progression was observed with 3 Gy exposure of Fe ions but not with 100 mGy. Similarly such a pattern with 100 mGy C ion exposure did not match that with 3 Gy. The proportion of p53-induced cells is proportional to the probability of cell being hit by a primary heavy ion. The observed low-dose effect can be reflected in the probability of a hit, although detailed nature about their energy deposition must be considered for more precise estimation of such an effect. New detection methodology must be developed for identification of heavy-ion specific cellular responses.

Cell Cycle↗
PubMed2001

Characterization of genes encoding multi-domain proteins in the genome of the filamentous nitrogen-fixing Cyanobacterium anabaena sp. strain PCC 7120.

Computational analysis of gene structures in the genome of Anabaena sp. PCC 7120 revealed the presence of a large number of genes encoding proteins with multiple functional domains. This was most evident in the genes for signal transduction pathway and the related systems. Comparison of the putative amino acid sequences of the gene products with those in the Pfam database indicated that and PAS domains which may be involved in signal recognition were extremely abundant in Anabaena: 87 GAF domains in 62 ORFs and 140 PAS domains in 59 ORFs. As for the two-component signal transduction system, 73, 53, and 77 genes for simple sensory His kinases, hybrid His kinases and simple response regulators, respectively, many of which contained additional domains of diverse functions, were presumptively assigned. A total of 52 ORFs encoding putative Hanks-type Ser/Thr protein kinases with various domains such as WD-repeat, GAF and His kinase domains, as well as genes for presumptive protein phosphatases, were also identified. In addition, genes for putative transcription factors and for proteins in the cAMP signal transduction system harbored complex gene structures with multiple domains.

Bacterial Proteins↗
PubMed2001

Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors: a report from the Children's Cancer Group.

BACKGROUND: The International Neuroblastoma Pathology Classification (International Classification), which was established in 1999, is significant prognostically and is relevant biologically for the evaluation and analysis of patients with neuroblastic tumors (NTs). MYCN amplification is a known molecular marker for aggressive progression of NTs. These have been used together as important prognostic factors to define risk groups for patient stratification and protocol assignment. METHODS: A total of 628 NTs (535 neuroblastomas [NBs]); 21 ganglioneuroblastoma, intermixed [GNBi]; 9 ganglioneuromas [GN]; and 63 ganglioneuroblastoma, nodular [GNBn]) from the Children's Cancer Group studies were evaluated histologically (favorable histology [FH] tumors vs. unfavorable histology [UH] tumors) according to the International Classification and were tested molecularly for MYCN status (amplified vs. nonamplified). Four tumor subsets (FH-nonamplified, FH-amplified, UH-nonamplified, and UH-amplified) were defined by histopathology and MYCN status, and their prognostic effects were analyzed. Detailed analysis between morphologic indicators (grade of neuroblastic differentiation and mitosis-karyorrhexis index [MKI]) and MYCN status was done by using tumors in the NB category. RESULTS: There were 339 FH-nonamplified tumors (5-year event free survival [EFS], 92.1%); 8 FH-amplified tumors (EFS, 37.5%); 172 UH-nonamplified tumors (EFS, 40.9%); and 109 UH-amplified tumors (EFS, 15.0%). The prognostic effects on patients with tumors in the four subsets were independent from the factors of patient age and disease stage (P < 0.0001). MYCN amplification was seen almost exclusively in tumors of the NB category, and no patients with tumors in either the GNBi category or in the GN category and only two patients with tumors in the GNBn category had amplified MYCN. Among the patients with tumors in the NB category, patients with FH-nonamplified tumors (309 patients) had an excellent prognosis, and patients with UH-amplified tumors (107 patients) had the poorest clinical outcome in any age group. The prognosis for children with UH-nonamplified tumors (111 patients) was poor when they were diagnosed at age > 1.5 years. It was also noted that patients with UH-amplified tumors (median age, 2.14 years) were diagnosed at a significantly younger age compared with the patients with UH-nonamplified tumors (median age, 3.55 years). Histologically, MYCN-amplified tumors lacked neuroblastic differentiation regardless of the age of patients. MYCN amplification also was linked generally to increased mitotic and karyorrhectic activities. However, MKI classes in patients with MYCN-amplified tumors varied significantly, depending on the age at diagnosis, and younger patients had higher MKI classes. CONCLUSIONS: The combination of histopathologic evaluation and MYCN status distinguishes four clinical and biologic tumor subsets in patients with NTs. MYCN amplification seems to be the powerful driving force for preventing cellular differentiation regardless of patient age and for increasing mitotic and karyorrhectic activities in an age dependent manner.

Adolescent↗