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Biomedical subjects

Y Yazaki

Publications and source records attributed to Y Yazaki.

At least 181 records · Page 10Linked to original sources
PubMed1999

Serial serum thrombopoietin levels in a pregnant woman with essential thrombocythaemia.

Thrombopoietin (TPO) is a ligand for c-mpl, which regulates the differentiation and maturation of megakaryocytes. Essential thrombocythaemia (ET) is a clonal myeloproliferative disorder. It has been reported that the platelet count declines during pregnancy in ET patients. We examined serial changes in the serum TPO level during the course of pregnancy in a patient with ET. The serum TPO level showed significant negative correlation with the platelet count. Although it mimicked the normal feed back system, the TPO levels were consistently higher than the normal upper limit. Accumulation of these data will be helpful in revealing the pathogenesis of ET and the decline in the platelet count during pregnancy.

Adult↗
PubMed1999

Insulin action on heart and skeletal muscle FDG uptake in patients with hypertriglyceridemia.

UNLABELLED: Abnormal heart and skeletal muscle 18F-fluorodeoxyglucose (FDG) uptake in patients with insulin resistance has been demonstrated. Although the existence of whole-body insulin resistance has been reported in hypertriglyceridemics, its specific role in heart and skeletal muscle FDG uptake in hypertriglyceridemics has not been clarified. METHODS: We compared heart and skeletal muscle FDG uptake using PET and the whole-body glucose disposal rate (GDR) during insulin clamping in 17 hypertriglyceridemics and 12 age-matched control subjects to increase our knowledge of whole-body insulin resistance and its relationship to heart and skeletal muscle FDG uptake in hypertriglyceridemics. RESULTS: GDR was significantly reduced in hypertriglyceridemics compared with control subjects (4.50 +/- 1.37 mg/min/kg versus 10.0 +/- 2.97 mg/min/kg, P = 0.00001), as were the skeletal muscle FDG Ki = (k1 x k3)/(k2 + k3) (SFKi: 0.007 +/- 0.003 mL/min/g versus 0.018 +/- 0.01 mL/min/g, P = 0.0001) and skeletal muscle FDG uptake ([SMFU] 0.725 +/- 0.282 mg/min/100 g versus 1.86 +/- 1.06 mg/min/100 g, P = 0.00023). However, myocardial FDG Ki (MFKi) tended to be reduced in hypertriglyceridemics compared with that in control subjects (0.062 +/- 0.017 mL/min/g versus 0.068 +/- 0.015 mL/min/g), but the difference was statistically insignificant (P = 0.3532). Moreover, myocardial FDG uptake (MFU) in hypertriglyceridemics (6.47 +/- 1.72 mg/min/100 g) tended to be reduced compared with that in control subjects (6.97 +/- 1.73 mg/min/100 g), but the difference was statistically insignificant (P = 0.4485). GDR was significantly correlated with SFKi (r = 0.69, P = 0.0022), SMFU (r = 0.612, P = 0.009), MFKi (r = 0.57, P = 0.0174) and MFU (r = 0.505, P = 0.0385) in hypertriglyceridemics. CONCLUSION: Both heart and skeletal muscle glucose utilization were related to insulin resistance in hypertriglyceridemics. However, the less severe reduction in MFU (compared with SMFU) suggests that myocardium may have a mechanism to oppose insulin resistance in hypertriglyceridemics.

Case-Control Studies↗
PubMed1999

[Estimation of pulmonary hypertension in lung and valvular heart diseases by perfusion lung scintigraphy].

To estimate pulmonary hypertension, we measured postural differences in pulmonary blood flow for the lateral decubitus positions on perfusion lung scintigrams with Tc-99 m macro-aggregated albumin, applying the method devised by Tanaka et al (Eur J Nucl Med 17: 320-326, 1990). Utilizing a scintillation camera coupled to a minicomputer system, changes in the distribution of pulmonary blood flow caused by gravitational effects, namely, changes in the total count ratios for the right lung versus the left lung in the right and left lateral decubitus positions (R/L), were obtained for 44 patients with lung disease, 95 patients with valvular heart disease, and 23 normal subjects. Mean standard deviation in the R/L ratios was 3.09 +/- 1.28 for the normal subjects, 1.97 +/- 0.89 for the patients with lung disease, and 1.59 +/- 0.59 for the patients with valvular heart disease. The R/L ratios correlated with mean pulmonary arterial pressure and cardio-thoracic ratios in the lung disease and valvular heart disease groups, with pulmonary arteriolar resistance in the former, and with pulmonary capillary wedge pressure in the latter. Defining pulmonary hypertension (> 20 mmHg) as an R/L ratio of less than 1.81, which is the mean-1 standard deviation for normal subjects, the sensitivity and the specificity of the R/L ratio for the diagnosis of pulmonary hypertension were 62.9% and 76.2%, respectively, for the lung disease patients, and 80.3% and 61.8%, respectively, for the valvular heart disease patients. This method seems to be useful for the pathophysiologic evaluation of pulmonary perfusion in cases of lung disease and valvular heart disease.

Adult↗
PubMed1999

Molecular characterization of the genomic breakpoints in a case of t(3;21)(q26;q22).

The t(3;21)(q26;q22) is a recurring chromosomal abnormality in blastic crisis of chronic myelogenous leukemia (CML) and in therapy-related myelodysplastic syndrome and acute leukemia. In order to clarify the genetic recombination mechanism underlying the t(3;21), we molecularly cloned the breakpoints and determined their nucleotide sequence in a case of CML in blastic crisis with t(3;21). Near the breakpoint on chromosome 21, three homopyrimidine (CT)-rich sequences were found. We also identified a sequence homologous to the topoisomerase II binding and cleavage consensus sequence surrounding the breakpoint on chromosome 3, and two topoisomerase II binding and cleavage consensus sequences near the breakpoint on chromosome 21. In addition, around the breakpoint on chromosome 21, four chi-like sequences, potential consensus signals for activating recombination, were found. There were no Alu sequences or antigen receptor gene-like heptamer/nonamer signal sequences within the breakpoints on chromosomes 3 and 21. The breakpoints were found adjacent to the topoisomerase II binding and cleavage consensus sequence or the homopyrimidine-rich sequence. Furthermore, the chi-like sequences and the homopyrimidine-rich sequence were detected on chromosome 21 but not on chromosome 3. Genes Chromosomes Cancer 26:92-96, 1999.

Amino Acid Sequence↗
PubMed1999

Overexpressed lipoprotein lipase protects against atherosclerosis in apolipoprotein E knockout mice.

Lipoprotein lipase (LPL) is known to play a crucial role in lipoprotein metabolism by hydrolyzing triglycerides; however its role in atherogenesis has yet to be determined. We have previously shown that low density lipoprotein receptor knockout mice overexpressing LPL are resistant to diet-induced atherosclerosis due to the suppression of remnant lipoproteins. Plasma lipoproteins and atherosclerosis of apolipoprotein (apo) E knockout mice which overexpress the human LPL transgene (LPL/APOEKO) were compared with those of control apoE knockout mice (APOEKO). On a normal chow diet, LPL/APOEKO mice showed marked suppression of the plasma triglyceride levels compared with APOEKO mice (54 vs. 182 mg/dl), but no significant changes in plasma cholesterol and apoB levels. Non-high density lipoproteins (HDL) from LPL/APOEKO mice had lower triglyceride content, a smaller size, and a more positive charge compared with those from APOEKO mice. Cholesterol, apoA-I, and apoA-IV were increased in HDL. Although both groups developed hypercholesterolemia to a comparable degree in response to an atherogenic diet, the LPL/APOEKO mice developed 2-fold smaller fatty streak lesions in the aortic sinus compared to the APOEKO mice. In conclusion, overproduction of LPL is protective against atherosclerosis even in the absence of apoE.

Animals↗
PubMed1999

Endothelin and neural crest development.

A series of gene targeting research have revealed novel roles of endothelins (ETs), peptides with potent vasoconstrictive and proliferative activities, in neural crest development in mammals. The phenotype of mice lacking the ET-1/ET-A receptor-mediated signalling affects cranial/cardiac neural crest-derived structures including the branchial arches and great vessels, and is highly similar to a set of the phenotypes of the avian neural crest ablation model. In contrast, mice lacking the ET-3/ET-B receptor-mediated signalling have defects in enteric neurons and melanocytes derived from trunk/vagal neural crest, resulting in megacolon and coat color spotting. Thus, both distinct pathways of the ET system seem to participate in the normal development of different neural crest lineages. Moreover, mutations in the human ET-3 and ET-B receptor genes have been identified in patients with Hirschsprung disease. As for the mechanisms involving the ET system in neural crest development, HANDs and Goosecoid, transcriptional factors essential for embryogenesis, have been suggested as key molecules downstream to the ET-mediated signalling in cranial/cardiac neural crest.

Animals↗
PubMed1998

Hypotension and reduced nitric oxide-elicited vasorelaxation in transgenic mice overexpressing endothelial nitric oxide synthase.

Nitric oxide (NO), constitutively produced by endothelial nitric oxide synthase (eNOS), plays a major role in the regulation of blood pressure and vascular tone. We generated transgenic mice overexpressing bovine eNOS in the vascular wall using murine preproendothelin-1 promoter. In transgenic lineages with three to eight transgene copies, bovine eNOS-specific mRNA, protein expression in the particulate fractions, and calcium-dependent NOS activity were confirmed by RNase protection assay, immunoblotting, and L-arginine/citrulline conversion. Immunohistochemical studies revealed that eNOS protein was predominantly localized in the endothelial cells of aorta, heart, and lung. Blood pressure was significantly lower in eNOS-overexpressing mice than in control littermates. In the transgenic aorta, basal NO release (estimated by Nomega-nitro-L-arginine-induced facilitation of the contraction by prostaglandin F2alpha) and basal cGMP levels (measured by enzyme immunoassay) were significantly increased. In contrast, relaxations of transgenic aorta in response to acetylcholine and sodium nitroprusside were significantly attenuated, and the reduced vascular reactivity was associated with reduced response of cGMP elevation to these agents as compared with control aortas. Thus, our novel mouse model of chronic eNOS overexpression demonstrates that, in addition to the essential role of eNOS in blood pressure regulation, tonic NO release by eNOS in the endothelium induces the reduced vascular reactivity to NO-mediated vasodilators, providing several insights into the pathogenesis of nitrate tolerance.

Animals↗
PubMed1998

The t(3;21) fusion product, AML1/Evi-1, interacts with Smad3 and blocks transforming growth factor-beta-mediated growth inhibition of myeloid cells.

The t(3;21)(q26;q22) chromosomal translocation associated with blastic crisis of chronic myelogenous leukemia results in the formation of the AML1/Evi-1 chimeric protein, which is thought to play a causative role in leukemic transformation of hematopoietic cells. Here we show that AML1/Evi-1 represses growth-inhibitory signaling by transforming growth factor-beta (TGF-beta) in 32Dcl3 myeloid cells. The activity of AML1/Evi-1 to repress TGF-beta signaling depends on the two separate regions of the Evi-1 portion, one of which is the first zinc finger domain. AML1/Evi-1 interacts with Smad3, an intracellular mediator of TGF-beta signaling, through the first zinc finger domain, and represses the Smad3 activity, as Evi-1 does. We also show that suppression of endogenous Evi-1 in leukemic cells carrying inv(3) restores TGF-beta responsiveness. Taken together, AML1/Evi-1 acts as an inhibitor of TGF-beta signaling by interfering with Smad3 through the Evi-1 portion, and both AML1/Evi-1 and Evi-1 repress TGF-beta-mediated growth suppression in hematopoietic cells. Thus, AML1/Evi-1 may contribute to leukemogenesis by specifically blocking growth-inhibitory signaling of TGF-beta in the t(3;21) leukemia.

Animals↗
PubMed1998

TLE, the human homolog of groucho, interacts with AML1 and acts as a repressor of AML1-induced transactivation.

The AML1 gene encodes DNA-binding proteins that contain the Runt domain and is found at the breakpoints of some translocations associated with leukemias. It has been reported that AML1 plays pivotal roles in myeloid differentiation, probably through the transcriptional regulation of various hematopoietic genes. Here we demonstrate the physical and the functional interaction between AML1 and TLE1 (transducin-like Enhancer of split) human homolog of Groucho that is known to be a corepressor of Hairy-related proteins. TLE1 binds to AML1 through the Runt domain and the C terminus of AML1 that includes the VWRPY motif. The interaction is mainly mediated by the SP domain of TLE1. Moreover, TLE1 inhibits AML1-induced transactivation of the target promoters through the C terminus of AML1. These results suggest that TLE1 acts as a repressor of AML1 and provide important insights into the mechanism of the negative regulation of the AML1 functions in hematopoiesis and leukemogenesis.

Animals↗
PubMed1998

A novel type of vascular endothelial growth factor, VEGF-E (NZ-7 VEGF), preferentially utilizes KDR/Flk-1 receptor and carries a potent mitotic activity without heparin-binding domain.

Vascular endothelial growth factor (VEGF) mediates endothelial cell proliferation, angiogenesis, and vascular permeability via the endothelial cell receptors, KDR/Flk-1 and Flt-1. Recently, a gene encoding a polypeptide with about 25% amino acid identity to mammalian VEGF was identified in the genome of Orf virus (OV), a parapoxvirus that affects sheep and goats and occasionally, humans, to generate lesions with angiogenesis. In this study, we examined the biological activities and receptor of OV-derived NZ-7 VEGF (VEGF-E). VEGF-E was found to be a dimer of about 20 kDa with no basic domain nor affinity for heparin column, similar to VEGF121 subtype. VEGF121 has 10-100-fold less endothelial cell mitotic activity than VEGF165 due to lack of a heparin-binding basic region. Interestingly, however, VEGF-E showed almost equal levels of mitotic activity on primary endothelial cells and vascular permeability activity as VEGF165. Furthermore, VEGF-E bound KDR/Flk-1 (VEGFR-2) and induced its autophosphorylation to almost the same extent as VEGF165, but did not bind Flt-1 (VEGFR-1) nor induce autophosphorylation of Flt-1. These results indicate that VEGF-E is a novel type of endothelial growth factor, utilizing only one of the VEGF receptors, and carrying a potent mitogenic activity without affinity to heparin.

Animals↗
PubMed1998

Different subcellular distribution and regulation of expression of insulin receptor substrate (IRS)-3 from those of IRS-1 and IRS-2.

Adipocytes contain three major substrate proteins of the insulin receptor, termed IRS-1, IRS-2, and IRS-3. We demonstrated that IRS-1 and IRS-2 are located mainly in the low density microsome (LDM) fraction and are tyrosine phosphorylated in response to insulin stimulation, leading to phosphatidylinositol (PI) 3-kinase activation. In contrast, IRS-3 is located mainly in the plasma membrane (PM) fraction and contributes to PI 3-kinase activation in the PM fraction. The different cellular localizations of IRS proteins may account for the mechanism of insulin resistance induced by a high fat diet, considering that PI 3-kinase activation in the LDM fraction is reportedly essential for the translocation of GLUT4 in adipocytes. High fat feeding in rats increased both protein and mRNA levels of IRS-3 but decreased those of IRS-1 and IRS-2 in epididymal adipocytes. As a result, selective impairment of insulin-induced PI 3-kinase activation was observed in the LDM fraction, whereas PI 3-kinase activation was conserved in the PM fraction. This is the first report showing that different IRS proteins function in different subcellular compartments, which may contribute to determining the insulin sensitivity in adipocytes.

Adipocytes↗
PubMed1998

Renal sympathetic nerve activity in mice: comparison between mice and rats and between normal and endothelin-1 deficient mice.

Recently generated knockout mice with disrupted genes encoding endothelin (ET)-1 showed an elevation of arterial blood pressure (AP) and supplied an evidence for intrinsic ET-1 as one of the physiological regulators of systemic AP. Little is yet known, however, why deficiency of ET-1, which was originally found as a potent vasoconstrictor, led to higher AP in these mice. To address this apparent paradox, we first developed a method to measure renal sympathetic nerve activity (RSNA) in mice using rats as reference and successively compared it between normal and ET-1 deficient mice. RSNA was successfully recorded in urethane-anesthetized and artificially ventilated mice by a slight modification of the method used for rats. At basal condition, mean AP (MAP) and RSNA in ET-1 deficient mice (105+/-2 mmHg and 9.71+/-1.49 muVs, n=20) were significantly higher than those in wild-type mice (96+/-2 mmHg and 5. 07+/-0.70 muVs, n=25). Basal heart rate (HR) and baroreflex-control of HR was not significantly different between the two. On the other hand, resting RSNA, RSNA range, and maximum RSNA were significantly greater in ET-1 deficient mice, and thus MAP-RSNA relationship was upwards reset. Hypoxia-induced increase in RSNA was not different between ET-1 deficient (73.4+/-9.4%) and wild-type mice (91.2+/-12.0%), while hypercapnia-induced one was significantly attenuated in ET-1 deficient mice (18.8+/-3.6 vs. 39.1+/-5.2% at 10% CO2). These results indicate that endogenous ET-1 participates in the central chemoreception of CO2 and reflex control of the RSNA. Baroreceptor resetting and normally preserved hypoxia-induced chemoreflex may explain a part of the elevation of AP in ET-1 deficient mice.

Animals↗