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Biomedical subjects

F Takaku

Publications and source records attributed to F Takaku.

At least 289 records · Page 16Linked to original sources
PubMed1989

Production of platelet-derived endothelial cell growth factor by normal and transformed human cells in culture.

Platelet-derived endothelial cell growth factor (PD-ECGF) is a 45-kDa endothelial cell mitogen which has angiogenic properties in vivo. We report here that human foreskin fibroblasts, a human squamous cell carcinoma cell line, and 2 out of the 3 human thyroid carcinoma cell lines investigated produce PD-ECGF, whereas 21 other cell lines examined do not. The positive cell lines contained a 1.8-kilobase PD-ECGF mRNA, and a 45-kDa protein could be demonstrated in lysates of the cell lines by immunoblotting and immunoprecipitation using a specific antiserum against PD-ECGF. Furthermore, the cell lysates contained mitogenic activity for endothelial cells that was neutralized by the PD-ECGF antiserum. PD-ECGF was found to be secreted only slowly from the producer cells, consistent with the previous finding that the primary translation product lacks a signal sequence. The restricted expression and intracellular sequestration of PD-ECGF imply a strictly controlled function in endothelial cell proliferation and angiogenesis. Aberrant production of PD-ECGF may play a role in tumor angiogenesis.

Animals↗
PubMed1989

Increased clearance of plasma cholesterol after injection of apolipoprotein E into Watanabe heritable hyperlipidemic rabbits.

Apolipoprotein E (apoE) is known to play an important role in lipoprotein metabolism. We have studied the effect of apoE on the metabolism of plasma cholesterol by injecting apoE intravenously into rabbits deficient in low density lipoprotein receptors [Watanabe heritable hyperlipidemic (WHHL) rabbits]. Approximately 30 mg of apoE was injected per rabbit; a total of five WHHL rabbits were used. One hour later, plasma cholesterol levels fell 8.3% (from 488 +/- 192 to 446 +/- 174 mg/dl). After 3 hr, cholesterol levels had fallen by 19% (to 392 +/- 152 mg/dl). The reduced levels were maintained for at least 8 hr after injection of apoE. Cholesterol in very low density lipoproteins (VLDLs) and intermediate density lipoproteins fell rapidly during the first 2 hr after injection, followed by a reduction in the low density lipoprotein cholesterol level. Changes in apolipoprotein B levels in each lipoprotein fraction were very similar to those of cholesterol. Plasma apoE levels 3 min after injection were elevated 3-fold to 22.8 +/- 6.3 mg/dl and returned to initial levels 8 hr after injection. The rate of removal of intravenously injected 125I-labeled VLDL that had been incubated with apoE was 3-fold higher than that of unmodified VLDL. From these results, we conclude that the injected apoE is incorporated into VLDLs and that VLDL particles carrying more apoE are removed from the blood more rapidly, resulting in reduced formation of low density lipoprotein and lowered cholesterol levels.

Animals↗
PubMed1989

Identification and characterization of receptors for granulocyte colony-stimulating factor on human placenta and trophoblastic cells.

Since radioiodination of human granulocyte colony-stimulating factor (G-CSF) is difficult, we synthesized a mutein of human G-CSF that retains full biological activity and receptor-binding capacity for at least 2 weeks after radioiodination. Receptors for human G-CSF were characterized in the plasma membrane fraction from the human term placenta (human placental membranes) and trophoblastic cells by using the 125I-labeled mutein of human G-CSF (KW-2228). The specific binding of 125I-labeled KW-2228 to placental membranes was pH-dependent, with maximal specific binding at pH 7.8; it increased linearly with protein to 3.7 mg of protein per ml and was both time- and temperature-dependent, with maximal binding at 4 degrees C after a 24-hr incubation. When we examined the ability of hematopoietic growth factors to inhibit 125I-labeled KW-2228 binding, we found that KW-2228 and intact human G-CSF inhibited 125I-labeled KW-2228 binding, whereas erythropoietin or granulocyte-macrophage colony-stimulating factor did not. Scatchard analysis revealed a single receptor type with a Bmax of 210 fmol/mg of protein and a Kd of 480 pM. The human G-CSF receptors on human placental membranes were shown to consist of two molecular species of 150 kDa and 120 kDa that could be specifically cross-linked to 125I-labeled KW-2228. Human trophoblastic cells, T3M-3, also possessed a single receptor for G-CSF with a Bmax of 533 receptors per cell and a Kd of 390 pM. Thus we have identified the receptor for human G-CSF on human placental membranes and trophoblastic cells, and the presence of this receptor in these membranes suggests that human G-CSF plays some role in the feto-placental unit during human development.

Binding, Competitive↗
PubMed1989

Flat reversion by okadaic acid of raf and ret-II transformants.

Okadaic acid is a non-phorbol 12-myristate 13-acetate (PMA)-type tumor promoter on mouse skin and known to be a potent inhibitor of serine/threonine protein phosphatases. Contrary to expectation from its tumor-promoting activity, okadaic acid was shown to have a potential to revert the phenotypes of cells transformed by raf and ret-II to that of normal cells. Two to 3 days after addition of 8 ng of okadaic acid per ml to the culture medium, raf and ret-II transformants changed to flat cells and gained contact inhibition. The amount of fibronectin, which was decreased in malignant transformed cells, was increased in the flat revertants. Moreover, okadaic acid caused a dose-dependent loss of ability to grow in soft agar. The morphology of the cells reverted to malignant phenotype within 1 week after removal of okadaic acid. The levels of mRNA and protein of activated c-raf in flat revertants were similar to those in parental transformed cells. The level of mRNA of ret-II was also not changed by flat reversion. No induction of flat reversion was observed with okadaic acid tetramethyl ether, an inactive compound, or a phorbol ester, PMA. As okadaic acid is a potent inhibitor of protein phosphatases 1 and 2A, the possibility that these phosphatases are involved in signal transduction from the raf and ret-II oncogenes is suggested.

Animals↗
PubMed1989

Single base substitution between human intestinal and hepatic apolipoprotein B mRNA detected by ribonuclease cleavage analysis.

The molecular mechanism of human intestinal apolipoprotein (apo) B-48 synthesis has been elucidated by a combination of sequencing of cloned complementary DNAs and RNase cleavage analysis of RNA heteroduplex. All intestinal cDNA clones contained a single C to T base substitution in the codon CAA encoding Gln2153 in apoB-100 cDNA, resulting in a translational stop. One of the our intestinal apoB cDNA clones was polyadenylated 106 bases downstream from the stop codon, possibly producing a 7-kb apoB message in the intestine. RNase cleavage analysis of the RNA heteroduplex between hepatic or intestinal RNA and apoB cDNA-directed anti-sense RNA showed that this single C to U substitution may occur in most of intestinal apoB mRNA. These results suggested that human apoB-48 is mostly produced by apoB mRNA with an in-frame stop codon in the intestine.

Apolipoproteins B↗
PubMed1989

Purification of human lung angiotensin-converting enzyme by high-performance liquid chromatography: properties and N-terminal amino acid sequence.

Angiotensin-converting enzyme from the human lung was purified to apparent homogeneity, using high-performance liquid chromatography following trypsin treatment of the detergent-extract. A 1,750-fold purification was achieved with a 26% yield. The specific activity of the enzyme was 105 units per mg protein with the substrate hippuryl-L-histidyl-L-leucine (HHL) at 37 degrees C, and the Km value for HHL was 1.9 mM. The molecular weight was estimated to be 170,000 by sodium dodecyl sulfate gel electrophoresis, and the isoelectric point was about 4.8, by chromatofocusing. The N-terminal amino acid sequence was (NH2)-X-X-Pro-Gly-Leu-Glu-Pro-Gly-X-Phe-Ser-Ala-Arg-Glu-Ala-Gly-Ala. This is highly homologous to the corresponding sequences of the enzymes from bovine and rabbit lung and from pig, bovine, and mouse kidney, but significantly different from that of the human kidney enzyme.

Amino Acid Sequence↗
PubMed1989

The possible role of endothelin-1 in the pathogenesis of coronary vasospasm.

We investigated the in vivo vasoconstrictor effects of endothelin-1 (ET-1) on canine coronary arteries and the regulation of ET-1 gene expression with special reference to the pathogenesis of coronary vasospasm. ET-1, administered into the coronary arteries of anesthetized dogs, produced a profound and long-lasting reduction in coronary blood flow with myocardial ischemia. Coronary angiography revealed delayed filling of the distal branches and, in some cases, total occlusion in the epicardial portions of coronary arteries. The coronary vasoconstriction induced by ET-1 subsided after intracoronary administration of nitroglycerin. Pretreatment with the Ca2+-channel antagonist, nitrendipine, suppressed ET-1-induced vasoconstriction. In cultured porcine aortic endothelial cells, ET-1 gene expression was induced by agents related to thrombus formation, such as thrombin and transforming growth factor beta (TGF beta). These findings suggest that ET-1, produced by vascular endothelial cells, may contribute to the regulation of coronary circulation and the pathogenesis of coronary vasospasm with respect to intimal injury and subsequent thrombus formation.

Angiocardiography↗
PubMed1989

Hematologic and cytogenetic findings in myelodysplastic syndromes treated with recombinant human granulocyte colony-stimulating factor.

We administered recombinant human granulocyte colony-stimulating factor (rhG-CSF) to four patients with myelodysplastic syndrome (MDS) and three patients with non-MDS (two malignant lymphoma and one lung cancer) as a part of a phase II trial and analyzed the effects of rhG-CSF on the neoplastic cells of MDS by performing sequential chromosome analyses on the bone marrow cells. A greater than 3-fold increase in neutrophil count was observed in the MDS patients after rhG-CSF infusions, whereas the number of blasts in the bone marrow did not increase and none of them progressed into the leukemic phase. After rhG-CSF treatment, the bone marrow cells obtained from patients without MDS did not show any particular chromosome abnormalities such as chromosomal breakage. On the contrary, two of the four MDS patients with acquired chromosome abnormalities showed a change in the frequency of marrow cells with clonal abnormalities after rhG-CSF treatment; the proportion of metaphase cells with additional numerical chromosome abnormalities decreased in these two MDS patients. After discontinuation of the treatment, the constitution of marrow cells with chromosome changes reverted to that before treatment. The remaining two MDS patients did not show any particular chromosome changes after the rhG-CSF treatment, indicating that rhG-CSF may not promote the characteristics of dyshematopoiesis in MDS, and act on cells derived from an MDS clone.

Adult↗
PubMed1989

Binding properties and proliferative effects of human recombinant granulocyte-macrophage colony-stimulating factor in primary leukemia and lymphoma.

Binding of radiolabeled human granulocyte-macrophage colony-stimulating factor (GM-CSF) was studied with blast cells from eight patients with acute myeloblastic leukemia (AML), and neoplastic lymphoid cells from one patient with acute lymphoblastic leukemia (ALL), two patients with chronic lymphocytic leukemia (CLL) and one patient with undiagnosed B cell neoplasia. In all AML cases studied, Scatchard graphs of the direct binding data were curvilinear, and were best fitted by curves derived from a two-binding-site model; one site with high affinity (Kd1 = 12-71 pM; 174-602 sites/cell) and the other with low affinity (Kd2 = 0.5-2.7 nM; 1137-6020 sites/cell). A cross-linking study on blast cells from one AML patient demonstrated specific bands which were similar to those reported for peripheral blood neutrophils. Furthermore, blast colony assays for the same preparations showed remarkable proliferative response to GM-CSF in the concentration range from 0.3 nM to 7.0 nM (ED50 greater than 0.7 nM). This concentration range is approximately one order of magnitude higher than that which is effective for colony formation from normal bone marrow progenitors (ED50 in equilibrium 0.1 nM). No significant correlation could be observed between the responsiveness of blast progenitors to GM-CSF, and the numbers or affinities of GM-CSF binding sites demonstrated on blast cells. In studies with neoplastic lymphoid cells from four patients, 125I-GM-CSF also specifically bound in two cases, while response to GM-CSF was not observed in these cases. These results indicate that the expression of GM-CSF receptor is not restricted to the GM-CSF-responsive AML blast cells, but can be observed in other AML blast cells and even in neoplastic lymphoid cells.

Binding Sites↗
PubMed1989

Combined effects of differentiation-inducing factor and other cytokines on induction of differentiation of mouse myeloid leukemic cells.

Mouse myeloid leukemic M1 cells are induced to differentiate into macrophage-like cells by differentiation-inducing factors (D-factors) and granulocyte colony-stimulating factor. We examined the effects of recombinant human tumor necrosis factor (rTNF), lymphotoxin (rLT) and interleukin 1 (rIL-1) on the induction of differentiation of M1 cells, compared with the effects of D-factor purified from the conditioned medium of mouse Ehrlich ascites tumor cells and recombinant human granulocyte colony-stimulating factor (rG-CSF). rIL-1 induced phagocytic activity, a typical marker of cell differentiation, in at most 30% of M1 cells at concentrations ranging from 10(-10) M to 10(-7) M. The differentiation-inducing activity of rIL-1 was similar to that of rG-CSF and less than that of D-factor. rTNF induced phagocytic activity in 14% of M1 cells only at a high concentration (10(-7) M). rLT did not induce differentiation of the cells even at 10(-7) M. rTNF stimulated induction of differentiation of M1 cells by D-factor, rG-CSF or rIL-1 by two or three fold. The combination of any two of the cytokines D-factor, rG-CSF and rIL-1 induced differentiation of M1 cells more efficiently than any of these cytokines alone. Moreover, the combination of three cytokines rG-CSF, rIL-1 and rTNF, all of which are known to be produced by macrophages, was more effective than the combination of any two of these cytokines in induction of differentiation of M1 cells.

Animals↗
PubMed1989

Effects of 12-O-tetradecanoyl phorbol-13-acetate (TPA) on rat thymocytes.

The short-term incubation of rat thymocytes with 12-O-tetradecanoylphorbol-13-acetate (TPA) resulted in a significant increase in sialyltransferase (S-T) activity and a decrease in terminal deoxyribonucleotidyl transferase (TdT) activity. The ratio of peanut agglutinin (PNA)-positive cells and of TdT-positive cells in TPA-treated cells also decreased. However, TPA had no significant effects on the viability, morphology, DNA synthesis, and DNA polymerase alpha activity of the cells. More marked changes were observed by incubating a non-T, non-B human lymphoid leukaemia cell line with TPA. Similar findings were also noted in TPA-treated mouse thymocytes. These changes may represent an aspect of TPA-induced differentiation of murine thymocytes.

Animals↗
PubMed1989

Treatment of multiple myeloma with carboquone-prednisolone.

18 previously untreated patients with multiple myeloma were entered in a clinical study of a combination chemotherapy, carboquone (CQ) and prednisolone (P) (CQ-P). Response was observed in 44% of patients treated with CQ-P judged by the criteria for response to chemotherapy. The median survival time was 33 months. Serious toxic reactions seldom occurred. The results suggest that the combination of CQ-P has efficacy in the treatment of multiple myeloma and could have a role among primary chemotherapeutic regimens for the disease. Further clinical trials should be conducted to establish a new drug combination in which CQ is included.

Aged↗
PubMed1989

Behenoyl cytosine arabinoside, aclacinomycin A, 6-mercaptopurine, and prednisolone combination therapy for acute non-lymphocytic leukaemia in adults.

38 consecutive, previously untreated adult patients with acute non-lymphocytic leukaemia (ANLL) were treated with BHAC-AMP (N4-behenoyl-1-beta-D-arabinofuranosyl-cytosine, aclacinomycin A, 6-mercaptopurine, and prednisolone) therapy between March 1980 and February 1985. 25 patients (65.8%) achieved complete remission (CR). Median CR duration and median survival of patients who achieved CR were 14, and 24 months, respectively. The Kaplan-Meier analysis revealed a probability for remaining in CR of 18.0% at 5 years. Analysis of failure cases revealed that most of them were due to resistant disease. Major toxicities were infection, diarrhoea, liver dysfunction, nausea and vomiting but these were acceptable. The results indicate that BHAC-AMP therapy is comparable to the regimen with daunorubicin and cytosine arabinoside and a further clinical trial is necessary for previously untreated adult patients with ANNL.

Aclarubicin↗
PubMed1989

Effects of smoking on the synthesis of leukotriene B4 by rat alveolar macrophages.

Leukotriene B4 (LTB4) is a potent chemotactic factor for polymorphonuclear leukocytes. It was reported recently that pulmonary macrophages from some mammalian species synthesize and release LTB4. Laviolette et al. reported the decrease of LTB4 synthesis in smokers' alveolar macrophages (AM). In this paper, we report the chronic effects of passive smoking on the production of LTB4 by rat AM. Some rats inhaled tobacco smoke and some inhaled smoke which did not contain nicotine. LTB4 production from AM from these rats was compared. In the tobacco-smoking group (n = 12), LTB4 production was 8.0 +/- 2.4 ng/10(6) cells. This value was significantly lower than in the nonsmoking (NS) group (n = 12; 16.5 +/- 4.5 ng/10(6) cells; p less than 0.01) and in the non-nicotinized cigarette smoking (NNCS) group (n = 8; 18.5 +/- 3.5 ng/10(6) cells; p less than 0.01). There were no significant differences between the NS and the NNCS group. These data may suggest that chronic inhalation of nicotine in tobacco smoke decreases LTB4 production activity of rat AM. The precise mechanism of decreased synthesis of LTB4 is not clear but it may have some immunological effects on the lung.

Animals↗
PubMed1989

Treatment of pure red cell aplasia that is resistant to conventional immunosuppressive therapy with intermittent administration of methotrexate.

Two patients with pure red cell aplasia were treated with intermittent administration of methotrexate. One who was refractory to conventional immunosuppressive therapy showed a favorable response to methotrexate within 2 weeks of treatment and entered complete remission. The other also showed an increase in reticulocytes within 3 weeks of methotrexate treatment. Although continuous administration of methotrexate was abandoned in the second case because of its hepatotoxicity, our results suggest that methotrexate may be effective in patients with pure red cell aplasia refractory to conventional immunosuppressive therapy.

Drug Resistance↗
PubMed1989

Quantification of myocardial infarct size after coronary reperfusion by serum cardiac myosin light chain II in conscious dogs.

The effects of early coronary artery reperfusion on the relation between the extent of myocardial infarction and serum levels of cardiac myosin light chain II or plasma creatine kinase levels were evaluated in the conscious dog. Hydraulic occluders were placed on the left anterior descending arteries of 38 dogs. Seven to 10 days later, myocardial infarction was produced. Coronary reperfusion was performed 3 hours (group A1, n = 13) and 6 hours (group A2, n = 12) after the occlusion. In the other 13 dogs, coronary occlusion was sustained throughout the course of the experiment (group B). Seven days after the occlusion, the heart was cut from the apex to the base into 4-mm slices, and infarct size was determined macroscopically. Rapid appearance and early peaking of creatine kinase were observed in group A. Cumulative release of creatine kinase significantly correlated with infarct size in group A (infarct size ranged from 0.1 to 20.1 g, r = 0.90) and group B (from 0.6 to 26.8 g, r = 0.91). However, since creatine kinase release in group A was greater in comparison with that from infarcts of the same size in group B, the slope of the regression line for group A was significantly steeper (p less than 0.05). Cardiac myosin light chain II appeared as early as creatine kinase did and continued to be elevated for 7 days. A very close relation was observed between infarct size and total cardiac myosin light chain II release (r = 0.87 for group A, and r = 0.88 for group B) or peak level of light chain II (r = 0.85 for group A, and r = 0.81 for group B). In addition, the slopes of the regression lines for infarct size and both peak and total release of light chain II did not differ between group A and group B. On histological examination, viable myocardium was frequently observed in the epicardium of the ischemic area in group A1; therefore, infarct size was greater in group B than in group A1 (p less than 0.05). Also, myocardial creatine kinase content in the epicardium of the center of the ischemic area in group A1 was greater than that in group B. Cardiac myosin light chain II release in group A1 was less than that in group B, whereas no difference was found in plasma creatine kinase release among groups A1, A2, and B.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗