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Biomedical subjects

Y Yazaki

Publications and source records attributed to Y Yazaki.

At least 235 records · Page 13Linked to original sources
PubMed1998

Role of JTT-501, a new insulin sensitiser, in restoring impaired GLUT4 translocation in adipocytes of rats fed a high fat diet.

JTT-501 is an insulin-sensitising compound with an isoxazolidinedione rather than a thiazolidionedione structure. Sprague-Dawley rats fed a high fat diet for 2 weeks were used as an animal model of insulin resistance, and JTT-501 was administered for the final week of the diet. An euglycaemic glucose clamp study showed that the glucose infusion rate (GIR) required to maintain euglycaemia was 57% lower in rats fed a high fat diet than in control rats, and that JTT-501 treatment restored the reduction in GIR produced by the high fat diet. To explain the mechanisms underlying the effects of a high fat diet and JTT-501 treatment, epididymal fat pads were excised and used in the analysis of insulin action. The high fat diet caused: (1) a 58% decrease in insulin receptor substrate-1 (IRS-1) content with a 58% decrease in IRS-1 tyrosine phosphorylation; (2) reductions of 56% and 73% respectively in insulin-induced maximal PI 3-kinase activation in anti-phosphotyrosine and anti-IRS-1 antibody immunoprecipitates; (3) a 46% reduction in the glucose transporter protein, GLUT4 content and, consequently, (4) severely impaired insulin-induced GLUT4 translocation to the plasma membrane and glucose uptake in adipocytes. JTT-501 treatment restored appreciably the protein content and tyrosine phosphorylation level of IRS-1. Insulin-stimulated PI 3-kinase activation was also restored in anti-phosphotyrosine and anti-IRS-1 antibody immunoprecipitates. As reflected by these improvements in insulin signalling, JTT-501 treatment improved considerably insulin-induced GLUT4 translocation to the plasma membrane as well as insulin-induced glucose uptake. However, JTT-501 had no effect on the decrease in GLUT4 content produced by the high fat diet. These observations suggest that JTT-501 enhances insulin signalling and may be effective in reducing insulin resistance.

Adipocytes↗
PubMed1998

Ultrastructural and immunohistochemical analysis of biopsy-proven chronic active mycocarditis with numerous clusters of lymphocytes.

A 60-year-old women was admitted to our hospital with deteriorating congestive heart failure. Although the diagnosis of active myocarditis was confirmed by right ventricular endomyocardial biopsy, this patient died of refractory heart failure during corticosteroid treatment. Numerous lymphocytic clusters were observed microscopically in the heart at autopsy. Most of the infiltrating cells in the clusters were positive for CD 8, HAM 56 or MHC class 2 antigen; few cells were positive for CD 56. Expression of perforin was found in some of the infiltrating cells. Electron microscopic examination revealed small lymphocytes adhering to the surface of injured cardiac myocytes. Close contact of these lymphocytes to macrophages was shown in the clusters. ICAM-1 and MHC class 1 antigens were strongly expressed in the cardiac tissue. These results indicate that cytotoxic T lymphocyte-mediated cytotoxicity had continued to operate during immunosuppressive therapy. Corticosteroids may not be suitable for the treatment of chronic active myocarditis when persistent expression of ICAM-1 is observed.

Antibodies↗
PubMed1998

Genomic organization and mutational analysis of HERG, a gene responsible for familial long QT syndrome.

Familial long QT syndrome (LQTS) is characterized by prolonged ventricular repolarization. Clinical symptoms include recurrent syncopal attacks, and sudden death may occur as a result of ventricular tachyarrhythmias. Three genes responsible for this syndrome (KVLQT1, HERG, and SCN5A) have been identified so far, and mutations have been reported on the basis of partially characterized genomic organization. To optimize the search for HERG mutations, we have determined the genomic structure of HERG and investigated mutations in LQTS families. Human genomic clones containing the HERG gene were isolated from a human genomic library by using reverse-transcribed polymerase chain reaction (RT-PCR) products from this gene as probes. We determined exon/intron boundaries and flanking intronic sequences by using primers synthesized on the basis of the HERG cDNA sequence available in the DNA database. HERG was shown to consist of 15 exons spanning approximately 19 kb on chromosome 7q35. Subsequently, we synthesized oligonucleotide primers to cover the entire coding region and searched for mutations in 36 Japanese LQTS families. When genomic DNA from each proband was examined by the PCR/single-strand conformation polymorphism technique followed by direct DNA sequencing, five novel mutations were detected. Each mutation was present in affected relatives of the respective proband. This work should increase the efficiency of screening mutations associated with HERG.

Amino Acid Sequence↗
PubMed1998

Genomic organization and mutational analysis of KVLQT1, a gene responsible for familial long QT syndrome.

To elucidate the role of the KVLQT1 gene in the pathogenesis of long QT syndrome (LQTS), we have established a screening system for detecting KVLQT1 mutations by the polymerase chain reaction-single strand conformation polymorphism technique (PCR-SSCP). We first determined exon/intron boundaries and flanking intronic sequences, and found that the KVLQT1 gene consists of 17 coding exons. Subsequently, we synthesized oligonucleotide primers to cover the coding region and the flanking intronic sequences, and searched for mutations in 31 Japanese LQTS families. When genomic DNA from each proband was examined by PCR-SSCP followed by direct DNA sequencing, mutations were detected in five families; two independent families carried the same mutation and three of the four were novel. Each mutation was present in affected relatives of the respective proband. This work will enable us to search more thoroughly for LQTS mutations associated with KVLQT1, and eventually will help us in finding genotype/phenotype relationships.

DNA Mutational Analysis↗
PubMed1998

Signalling pathways for cardiac hypertrophy.

Mechanical stretch is an initial factor for cardiac hypertrophy in response to haemodynamic overload (high blood pressure). Stretch of cardiomyocytes activates second messengers such as phosphatidylinositol, protein kinase C, Raf-1 kinase and extracellular signal-regulated protein kinases (ERKs), which are involved in increased protein synthesis. The cardiac renin-angiotensin system is linked to the formation of pressure-overload hypertrophy. Angiotensin II increases the growth of cardiomyocytes by an autocrine mechanism. Angiotensin II-evoked signal transduction pathways differ among cell types. In cardiac fibroblasts, angiotensin II activates ERKs through a pathway including the Gbetagamma subunit of Gi protein, Src family tyrosine kinases, Shc, Grb2 and Ras, whereas Gq and protein kinase C are important in cardiac myocytes. In addition, mechanical stretch enhances the endothelin-1 release from the cardiomyocytes. Further, the Na+ -H+ exchanger mediates mechanical stretch-induced Raf-1 kinase and ERK activation followed by increased protein synthesis in cardiomyocytes. Not only mechanical stress, but also neurohumoral factors induce cardiac hypertrophy. The activation of protein kinase cascades by norepinephrine is induced by protein kinase A through beta-adrenoceptors as well as by protein kinase C through alpha-adrenoceptors.

Angiotensin II↗
PubMed1998

Cardiovascular anomaly, impaired actin bundling and resistance to Src-induced transformation in mice lacking p130Cas.

p130Cas (Cas), the protein encoded by the Crkas gene (also known as Cas), is an adaptor molecule with a unique structure that contains a Src homology (SH)-3 domain followed by multiple YXXP motifs and a proline-rich region. Cas was originally cloned as a highly tyrosine-phosphorylated protein in cells transformed by v-Src (refs 2,3) or v-Crk (ref. 4) and has subsequently been implicated in a variety of biological processes including cell adhesion, cell migration, growth factor stimulation, cytokine receptor engagement and bacterial infection. To determine its role in vivo, we generated mice lacking Cas. Cas-deficient embryos died in utero showing marked systemic congestion and growth retardation. Histologically, the heart was poorly developed and blood vessels were prominently dilated. Electron microscopic analysis of the heart revealed disorganization of myofibrils and disruption of Z-disks. In addition, actin stress fiber formation was severely impaired in Cas-deficient primary fibroblasts. Moreover, expression of activated Src in Cas-deficient primary fibroblasts did not induce a fully transformed phenotype, possibly owing to insufficient accumulation of actin cytoskeleton in podosomes. These findings have defined Cas function in cardiovascular development, actin filament assembly and Src-induced transformation.

Actin Cytoskeleton↗
PubMed1998

B cell lymphoma-associated hemophagocytic syndrome after PBSCT.

Hemophagocytic syndrome (HPS) associated with T cell lymphoma is well known, but an association with B cell lymphoma is rare. We report a patient who developed subcutaneous non-Hodgkin's lymphoma (NHL) of B cell origin. Autologous peripheral blood stem cell transplantation (PBSCT) was undertaken in her second complete remission (CR), but HPS appeared 5 months after transplantation. The patient deteriorated rapidly and died of metabolic acidosis. Necropsy revealed that she had relapsed B cell NHL involving liver, spleen and bone marrow. B cell NHL after PBSCT, associated with HPS as an initial sign, is rare. We report this case and review the literature.

Adult↗
PubMed1998

Phimosis as a manifestation of chronic graft-versus-host disease after allogeneic bone marrow transplantation.

Chronic GVHD is one of the major complications of BMT, involving a variety of organs, but rarely involving the genitourinary system. We report a patient who simultaneously developed extensive chronic GVHD and phimosis after BMT. From the clinical course and pathological findings, chronic GVHD was considered to be responsible for the phimosis. Despite intensive immunosuppressive therapy, the phimosis persisted. Phimosis is a rare complication after BMT, which may often remain neglected. Possibility of this complication should be considered in patients with chronic GVHD.

Adult↗
PubMed1998

Increased soluble Fas-ligand in sera of bone marrow transplant recipients with acute graft-versus-host disease.

Acute graft-versus-host disease (aGVHD) is a major complication following allogeneic bone marrow transplantation (BMT). Recently, accumulating evidence indicates that the Fas/Fas ligand (FasL) system is implicated in the pathogenesis of aGVHD in murine models. We determined the serum levels of soluble FasL (sFasL) in BMT recipients using an enzyme-linked immunosorbent assay. The serum sFasL was suppressed during the period of myelosuppression following the preparative regimen and subsequently increased with hematopoietic reconstitution after BMT. In patients with aGVHD, the serum sFasL level was significantly higher than in those without aGVHD. In the mixed lymphocyte reaction assay, sFasL in the supernatants was increased with a significant correlation to the level of 3H-thymidine uptake. Our findings suggest that the Fas/FasL system is activated by allogeneic stimulation and may have close correlation to the development of aGVHD in human BMT.

Adolescent↗
PubMed1998

Time course analysis of semi-quantitative PCR and antigenaemia assay for prevention of cytomegalovirus disease after bone marrow transplantation.

Cytomegalovirus (CMV) disease is a serious complication after bone marrow transplantation (BMT). Recently, semi-quantitative polymerase chain reaction (SQ-PCR) analysis for CMV-DNA has been developed. We compared the time course of SQ-PCR and that of antigenaemia assay after BMT. Our findings suggested that SQ-PCR is more sensitive than antigenaemia assay in the detection of CMV infection and that quantitation of CMV-DNA could discriminate patients with positive PCR but without the risk for CMV disease. We considered that SQ-PCR could be a useful guide for starting pre-emptive therapy against CMV disease.

Adolescent↗
PubMed1998

Elevated B-type natriuretic peptide levels after anthracycline administration.

BACKGROUND: Cardiotoxicity leading to congestive heart failure is a complication of the anthracyclines. Biochemical methods to diagnose and monitor cardiac function after anthracycline administration would be most useful. We examined the diagnostic role of B-type natriuretic peptide (BNP), a potent biochemical marker of left ventricular dysfunction, in patients administered anthracyclines. METHODS: Twenty-seven consecutive patients receiving anthracyclines were investigated by serial measurements of BNP levels and other cardiac neurohormones (A-type natriuretic peptide, renin, aldosterone, angiotensin II, norepinephrine, and epinephrine) and myocardial markers (creatine kinase-MB and myosin light chain). Echocardiography was done to assess systolic (ejection fraction) and diastolic (mitral inflow A/E ratio) functions. RESULTS: Of the examined cardiac biochemical markers, BNP levels alone showed marked elevations to abnormal levels after anthracycline administration. Most patients showed transient increases (peak at 3 to 7 days). Patients with persistent elevations showed a poor prognosis. A/E ratio also correlated with increases in BNP levels in selected patients, which may suggest that raised BNP levels are reflective of induced diastolic dysfunction. CONCLUSIONS: Our studies suggest the possible use of BNP levels to assess the cardiac state after anthracycline administration. BNP levels most likely reflect cardiac tolerance to the cardiotoxic agent. Serial BNP profiles also suggest persistent elevations to be associated with potentially decompensatory states in contrast to tolerable transient increases. Diagnosis of degree of cardiac tolerance by response to drug administration may be analogous to use of stress testing (exercise) to help define underlying left ventricular dysfunction.

Adult↗
PubMed1998

Isolation and initial characterization of GBF, a novel DNA-binding zinc finger protein that binds to the GC-rich binding sites of the HIV-1 promoter.

Human immunodeficiency virus (HIV) and its clinical syndrome, acquired immune deficiency syndrome (AIDS), are one of the world's most prominent health problems. To understand the mechanisms underlying HIV transcription and thereby its propagation, we have focused on the molecular interactions at the GC-rich binding sites of the HIV-1 core promoter, a region important for HIV-1 transcription. Previous biochemical studies have shown that Sp1, a zinc finger transcription factor initially isolated as a cellular factor binding that binds to the SV40 early promoter GC-rich sequence, binds to the HIV-1 GC-rich binding sites due to sequence similarities. However, the HIV-1 GC-rich binding sites are considerably different from the Sp1 consensus binding sequence, and recent genetic studies have shown the lack of regulation by Sp1 in numerous genes thought to be regulated by that factor in the past. We reasoned that other factors may bind to the HIV-1 GC-rich binding sites. Using the native HIV-1 GC-rich binding sequence as the bait, genetic screening for interacting factors was performed by the yeast one-hybrid method. A cDNA encoding a novel zinc finger protein named GBF, GC-rich sites binding factor, was isolated from a human peripheral blood leukocyte library. Primary structure analysis of GBF revealed a C2H2 Krüppel-type zinc finger at its C-terminus, and putative acidic and proline-rich domains at its N-terminus. We also show that GBF belongs to a subgroup of Krüppel-type zinc fingers distinct from Sp1. By directly addressing interactions at the HIV-1 GC-rich binding sites, our present study sheds new light on molecular interactions at the HIV-1 promoter.

Amino Acid Sequence↗
PubMed1998

Upregulation of endothelin-1 and adrenomedullin gene expression in the mouse endotoxin shock model.

Septic shock is a life-threatening disorder caused by lipopolysaccharide (LPS) and other bacterial products. Accumulating evidence indicates a role for vasoactive substances and cytokines in this disease process. In this study we examined the effect of LPS on the gene expression of endothelin-1 (ET-1) and adrenomedullin (AM), two major vasoactive peptides predominantly produced by vascular endothelial cells, to investigate their role in the pathophysiology of septic shock. LPS induced ET-1 and AM gene expression in the heart, lung, kidney, liver, and aorta within 6 h. In the liver, whereas basal ET-1 and AM mRNA were hardly detectable, ET-1 and AM gene expression and peptide production were markedly increased by LPS. This LPS-induced upregulation of ET-1 and AM expression is greatly potentiated by D-galactosamine (D-GalN), although D-GalN alone could not induce ET-1 and AM gene expression. These results, together with the previous findings that liver injury induced by LPS and D-GalN is mainly mediated by tumor necrosis factor-alpha (TNF-alpha), suggest that the LPS-cytokine pathway may cause upregulation of ET-1 and AM production, leading to dysregulation of systemic and regional vascular tone.

Adrenomedullin↗
PubMed1998

Systemic and renal response to salt loading in endothelin-1 knockout mice.

Endothelin-1 (ET-1) knockout mice demonstrate elevated blood pressure, which may be associated with disturbance in central cardiorespiratory regulation. In this study we examined responses to salt loading in ET-1 knockout mice to investigate whether ET-1 is involved in the pathophysiology of salt-sensitive hypertension. Male Edn1+/- heterozygous mice and their wild-type littermates were fed either a high NaCl (8%) or a normal (0.2%) diet for 4 weeks. Systemic blood pressure and tissue ET-1 levels were measured as well as several parameters relating to sodium handling and volume homeostasis. On normal diet, renal ET-1 levels of Edn1+/- mice were about 50% of those of wild-type mice. A high-salt diet caused a significant decrease in renal ET-1 levels by about 50% in both groups. Urine volume, urinary sodium excretion, and FENa in mice on the 8% NaCl diet were significantly higher than those in mice on the 0.2% NaCl diet, whereas there were no differences in circulating plasma volume, serum electrocytes, and creatinine clearance. These responses were similar in Edn1+/- and wild-type mice. Although systemic blood pressure was significantly higher in Edn1+/- mice than in the wild-type, the effect of salt loading on blood pressure was not significant in either Edn1+/- or wild-type mice. We conclude that changes in ET-1 production within a physiologic range do not affect salt sensitivity, although renal ET-1 content is decreased by salt loading.

Animals↗
PubMed1998

Frameshift mutations of the hMSH6 gene in human leukemia cell lines.

Defects in DNA mismatch repair mechanisms, including frameshift mutations of the hMSH6 and hMSH3 genes at their (C)8 and (A)8 tracks, respectively, have been shown to be associated with human malignancies. To clarify the possible involvement of these mutations in hematopoietic malignancies, we screened a total of forty-four human leukemia and lymphoma cell lines for mutations in the hMSH6 and hMSH3 genes, as well as in other genes required for DNA replication or repair, by polymerase chain reaction single-strand conformation polymorphism analysis and sequencing analysis. Frameshift mutations at the (C)8 track of the hMSH6 gene were detected in two cell lines established from lymphoid leukemias. These two cell lines had no wild-type alleles, and both of them showed microsatellite instability. This is the first report that describes mutations and inactivation of the hMSH6 gene in hematological malignancies, suggesting that defects of the hMSH6 gene may be associated with development of hematological malignancies.

Base Sequence↗