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Biomedical subjects

Y Maeda

Publications and source records attributed to Y Maeda.

At least 253 records · Page 14Linked to original sources
PubMed1999

GPI1 stabilizes an enzyme essential in the first step of glycosylphosphatidylinositol biosynthesis.

Attachment of glycosylphosphatidylinositol (GPI) is essential for the surface expression of many proteins. Biosynthesis of glycosylphosphatidylinositol is initiated by the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol. In mammalian cells, this reaction is mediated by a complex of PIG-A, PIG-H, PIG-C, and GPI1. This complexity may be relevant for regulation and for usage of a particular phosphatidylinositol. However, the functions of the respective components have been unclear. Here we cloned the mouse GPI1 gene and disrupted it in F9 embryonal carcinoma cells. Disruption of the GPI1 gene caused a severe but not complete defect in the generation of glycosylphosphatidylinositol-anchored proteins, indicating some residual biosynthetic activity. A complex of PIG-A, PIG-H, and PIG-C decreased to a nearly undetectable level, whereas a complex of PIG-A and PIG-H was easily detected. A lack of GPI1 also caused partial decreases of PIG-C and PIG-H. Therefore, GPI1 stabilizes the enzyme by tying up PIG-C with a complex of PIG-A and PIG-H.

Animals↗
PubMed1999

Cyclin D1/PRAD1/BCL-1 alternative transcript [B] protein product in B-lymphoid malignancies with t(11;14)(q13;q32) translocation.

The cyclin-D1/PRAD1 oncogene, a key regulator of the G1-phase progression of the cell cycle, has been identified as the long-sought BCL-1 oncogene in B-cell malignancies with t(11;14)(q13;q32) translocation. A novel alternative spliced cyclin-D1 transcript, called transcript[b], has been identified. The level of the variant transcript[b] was lower than that of the originally reported cyclin-D1 transcript, called transcript[a], in several human non-lymphoid cancer cell lines but the endogenous cellular expression of transcript[b] products has not yet been determined. Northern-blot analysis and reverse-transcription-polymerase-chain-reaction (RT-PCR) analysis revealed that transcript[b] mRNA is well expressed in B-lymphoid cell lines with t(11;14)(q13;q32) translocation and at much lower or undetectable levels in other cells. Western-blot analysis using a human cyclin-D1-specific monoclonal antibody, which can recognize and distinguish the products of transcripts [a] and [b], strongly suggested that the transcript [b] protein is indeed expressed in these B-cell lines. The present study provides identification of the endogenous cellular expression of the cyclin-D1-transcript[b] protein and strongly suggests that this alternative form of cyclin D1 may play a significant role in the molecular pathogenesis of B-lymphoid malignancies with t(11;14)(q13;q32) translocation.

Alternative Splicing↗
PubMed1999

Mammalian PIG-L and its yeast homologue Gpi12p are N-acetylglucosaminylphosphatidylinositol de-N-acetylases essential in glycosylphosphatidylinositol biosynthesis.

Glycosylphosphatidylinositol (GPI) is used as a membrane anchor by many eukaryotic cell-surface proteins. The second step of GPI biosynthesis is de-N-acetylation of N-acetylglucosaminylphosphatidylinositol (GlcNAc-PI). We have previously cloned the rat PIG-L gene by expression cloning that complemented a mutant Chinese hamster ovary cell line defective in this step. Here we show that recombinant rat PIG-L protein purified from Escherichia coli as a complex with GroEL has GlcNAc-PI de-N-acetylase activity in vitro. The activity was not enhanced by GTP, which is known to enhance the de-N-acetylase activity of mammalian cell microsomes. As with other de-N-acetylases that act on the GlcNAc moiety, metal ions, in particular Mn2+ and Ni2+, enhanced the enzyme activity of PIG-L. The Saccharomyces cerevisiae YMR281W open reading frame encodes a protein (termed Gpi12p) with 24% amino acid identity with rat PIG-L. On transfection into mammalian PIG-L-deficient cells, this gene, GPI12, restored the cell-surface expression of GPI-anchored proteins and GlcNAc-PI de-N-acetylase activity. The disruption of the gene caused lethality in S. cerevisiae. These results indicate that GlcNAc-PI de-N-acetylase is conserved between mammals and yeasts and that the de-N-acetylation step is also indispensable in yeasts.

Amidohydrolases↗
PubMed1999

Effects of a specific endothelin-converting enzyme inhibitor on cardiac, renal, and neurohumoral functions in congestive heart failure: comparison of effects with those of endothelin A receptor antagonism.

BACKGROUND--Endothelin (ET)-1 is generated from big ET-1 by endothelin-converting enzyme (ECE). Plasma big ET-1 and ET-1 levels are strongly related to survival in patents with congestive heart failure (CHF). Because selective enzymatic processing of ET-1 formation appears to be an important therapeutic target for CHF, we investigated the acute effects of a specific ECE inhibitor on cardiorenal and endocrine functions in CHF compared with those of a selective ETA receptor antagonist. METHODS AND RESULTS--CHF was induced in beagle dogs by rapid right ventricular pacing (270 bpm, 14 days). Two incremental doses of a specific ECE inhibitor, FR901533, or a selective ETA receptor antagonist, FR139317 (1 and 3 mg/kg, n=8, respectively), were injected into dogs with CHF. FR901533 and FR139317 decreased mean arterial pressure and pulmonary capillary wedge pressure associated with reduction in systemic and pulmonary vascular resistance. These agents increased cardiac output but did not affect left ventricular fractional shortening. FR139317 exerted a greater depressor effect on mean arterial pressure than FR901533 (P<0.05). These agents decreased plasma atrial natriuretic peptide levels, but only FR901533 decreased plasma renin activity, angiotensin II, and aldosterone levels. Neither agent changed the plasma norepinephrine level despite the fall in blood pressure. These drugs increased the urinary water and sodium excretion rate associated with increases in the glomerular filtration rate and renal plasma flow, and the incremental magnitude induced by FR139317 was larger than that by FR901533 (P<0.05). CONCLUSIONS--An ETA receptor antagonist appeared to induce greater vasodilative effects on systemic and renal vasculature in CHF than an ECE inhibitor. However, the ECE inhibitor reduced the secretion of neurohumoral factors that are activated in proportion to the severity of CHF. Our acute complementary data may support the importance of the role of ECE in CHF and provide a rationale foundation for investigating the usefulness of long-term treatment with ECE inhibitors in CHF.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Transient expression of a mitochondrial gene cluster including rps4 is essential for the phase-shift of Dictyostelium cells from growth to differentiation.

Using synchronized Dictyostelium discoideum Ax-2 cells and the differential display method, a mitochondrial gene cluster (referred to as differentiation-associated gene 3; dia3) was isolated as one of the genes expressed specifically during the transition of Ax-2 cells from growth to differentiation. The dia3 gene encodes for a mitochondrial protein cluster (NADH dehydrogenase (NAD) subunit 11, 5, ribosomal protein S4 (RPS4), RPS2, and NAD4L). Northern blot analysis using nonsynchronized Ax-2 cells has shown that the dia3 RNA of about 8 kb is scarcely expressed during the vegetative growth phase, and the maximal expression was attained at 2 h after starvation. To analyze the gene function of dia3, we tried inactivation of rps4 by means of homologous recombination and obtained several transformed clones showing mitochondrial DNA heteroplasmy. The transformed cells grew normally in nutrient medium, but their development after starvation was greatly impaired, thus resulting in the failure of many cells to differentiate. In this connection, the cAMP receptor 1 (car1) expression, which is one of the earliest markers of differentiation, was found to be markedly reduced in the rps4-inactivated cells.

Animals↗
PubMed1999

Functional B-cell response in intrahepatic lymphoid follicles in chronic hepatitis C.

Intrahepatic lymphoid follicle (ILF) formation is one of the most characteristic and commonly observed histological features in patients with chronic hepatitis C. However, little is known regarding whether follicles in the liver belong to functional lymphoid tissues, where B cells are activated, differentiated, and proliferated, or if the lymphocytes are merely infiltrated after recruitment from the secondary lymphoid organs. To ascertain this possibility, we examined the expression of markers for B-cell activation, differentiation, and proliferation in ILFs in patients with chronic hepatitis C using surgically resected specimens, and compared them with specimens of perihepatic lymph nodes by an immunohistochemical technique. Germinal center (GC) formation in the ILFs was frequently found in HCV-positive cases. The distribution of immunoglobulin M (IgM)-, IgD-, and IgG-positive cells and the expression patterns of Ki-67, CD23, or bcl-2 and bcl-6 gene products in the follicles with GC formation in the liver of patients with chronic hepatitis C were similar to those of lymph nodes, indicating that B cells are activated, proliferated, and differentiated in the ILFs with GC formation in patients with chronic hepatitis C. Oligoclonal expansion of B cells in the livers with ILFs was confirmed by an analysis of immunoglobulin heavy chain (IgH) gene rearrangement determined by polymerase chain reaction (PCR). These data strongly suggest that ILFs with GC formation, which are frequently found in patients with chronic hepatitis C, may functionally be the same as those found in lymph nodes with respect to B-cell expansion and maturation.

Adult↗
PubMed1999

A predominant increase of arterial beta-hydroxybutyrate concentration during partial hepatectomies in patients with impaired indocyanine green clearance test.

BACKGROUND: It has been reported that a concentration ratio of two ketone bodies, [acetoacetate]/[beta-hydroxybutyrate], reflects the redox state in the liver mitochondria, but there are few reports which examined each ketone body concentration during hepatectomy. Materials and Methods. (1) Ketone body levels in the radial artery and the hepatic vein were measured simultaneously during hepatectomies in 12 patients. (2) Arterial ketone body levels were measured during hepatectomies (at three points) in 73 patients. RESULTS: (1) Both ketone body levels in the radial artery well reflected those in the hepatic vein (P < 0.001). (2) There was no change in the arterial acetoacetate level. The level of beta-hydroxybutyrate increased significantly from 30.4 to 76.5 micromol/L (P < 0.005) only in the group of 25 patients with seriously impaired indocyanine green clearance test. CONCLUSIONS: Ketosis during hepatectomy was caused by increased beta-hydroxybutyrate, and this phenomenon was observed only in patients with seriously impaired liver function.

3-Hydroxybutyric Acid↗
PubMed1999

A novel therapeutic trial of homogentisic aciduria in a murine model of alkaptonuria.

Alkaptonuria is a rare autosomal recessive disorder characterized by homogentisic aciduria, ochronosis, and arthritis. Although a deficiency of homogentisic acid 1,2-dioxygenase has recently been confirmed at the molecular level, no effective treatment regimen has yet been developed for this disorder. In the present study, 2(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), a potent inhibitor of p-hydroxyphenylpyruvate dioxygenase (which catalyzes the formation of homogentisic acid from p-hydroxyphenylpyruvic acid) was adopted as a possible therapeutic agent for alkaptonuria. NTBC dose-dependently reduced the urinary output of homogentisic acid in a murine model of alkaptonuria that had been created with ethylnitrosourea. These findings suggest that NTBC may be the first potent pharmacotherapeutic agent for alkaptonuria.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1999

1H-NMR and circular dichroism spectroscopic studies on changes in secondary structures of the sodium channel inactivation gate peptides as caused by the pentapeptide KIFMK.

The pentapeptide KIFMK, which contains three clustered hydrophobic amino acid residues of isoleucine, phenylalanine, and methionine (IFM) in the sodium channel inactivation gate on the cytoplasmic linker between domains III and IV (III-IV linker), is known to restore fast inactivation to the mutant sodium channels having a defective inactivation gate or to accelerate the inactivation of the wild-type sodium channels. To investigate the docking site of KIFMK and to clarify the mechanisms for restoring the fast inactivation, we have studied the interactions between KIFMK and the fragment peptide in the III-IV linker GGQDIFMTEEQK (MP-1A; G1484-K1495 in rat brain IIA) by one- and two-dimensional (1)H-NMR and circular dichroism (CD) spectroscopies. KIFMK was found to increase the helical content of MP-1A in 80% trifluoroethanol (TFE) solution by approximately 11%. A pentapeptide, KIFMT, which can restore inactivation but less effectively than KIFMK, also increased the helical content of MP-1A, but to a lesser extent ( approximately 6%) than did KIFMK. In contrast, KDIFMTK, which is ineffective in restoring inactivation, decreased the helical content ( approximately -4%). Furthermore, we studied the interactions between KIFMK and modified peptides from MP-1A, that is, MP-1NA (D1487N), MP-1QEA (E1492Q), or MP-1EQA (E1493Q). The KIFMK was found to increase the helical content of MP-1EQA to an extent nearly identical to that of MP-1A, whereas it was found to decrease those of MP-1NA and MP-1QEA. These findings mean that KIFMK, by allowing each of the Lys residues to interact with D1487 and E1492, respectively, stabilized the helical structure of the III-IV linker around the IFM residues. This helix-stabilizing effect of KIFMK on the III-IV linker may restore and/or accelerate fast inactivation to the sodium channels having a defective inactivation gate or to wild-type sodium channels.

Amino Acid Sequence↗
PubMed1999

Brain receptor binding characteristics and pharmacokinetics of JTP-2942, a novel thyrotropin-releasing hormone (TRH) analogue.

JTP-2942 competed with [3H]-Me-TRH for the binding sites in rat brain in vitro, and its inhibitory effect was approximately 17 times less potent than TRH, as shown by Ki values of 673 and 39.7 nM, respectively. Both JTP-2942 and TRH significantly increased apparent dissociation constant (Kd values) for brain [3H]-Me-TRH binding. Intravenous injection of JTP-2942 (0.3-3 mg/kg) and TRH (3 and 10 mg/kg) produced a significant reduction of [3H]-Me-TRH binding sites (Bmax values) in rat brain. Although the decrease by TRH was maximal 10 min after the injection and declined rapidly with time, the decrease by JTP-2942 (1 and 3 mg/kg) tended to be maximal at 30 min later and it lasted until 120 min. The intravenous injection of JTP-2942 was at least 3 times more potent than that of TRH in decreasing Bmax values for brain [3H]-Me-TRH binding. Plasma concentration of JTP-2942 (0.3-3 mg/kg) after intravenous injection in rats rose with the increase of dose, and it peaked immediately after the injection, thereafter decreasing with t1/2 of 19.3-29.9 min. It is concluded that JTP-2942, compared to TRH, may exert fairly potent and sustained occupation of brain TRH receptors under in vivo condition. Thus, JTP-2942 could be clinically useful for the treatment of CNS disorders.

Animals↗
PubMed1999

Hepatocyte growth inhibitory factor derived from HTLV-I(+) T-cell line is identical to IL-6.

We previously reported that the culture supernatant of the human T-cell leukemia virus (HTLV-I) infected-T-cell line--ATL-2--included factor(s), which had an inhibitory effect on epidermal growth factor (EGF)-stimulated proliferation of primary cultured rat hepatocytes. After crude purification, we arbitrarily named it hepatocyte growth inhibitory factor (HGI). In this study, we further purified HGI and determined its amino acid sequence. For purification, we used 4-steps column chromatography and SDS-PAGE. The purified proteins consisted of two bands of 20 and 27 kDa in SDS-PAGE analysis. Protein extracted from each band had an inhibitory effect on rat hepatocyte growth. Amino acid analysis of the purified 20 kDa band revealed that the 34 amino acids were identical to those of IL-6. The inhibitory effect of the factor was neutralized by an anti IL-6 neutralizing antibody. Using Western blot analysis of HGI, an anti IL-6 antibody recognized both 20 and 27 kDa bands. Consequently HGI was determined to be identical to IL-6, which occurred in higher levels in the sera of adult T-cell leukemia (ATL) patients.

Aged↗
PubMed1999

Utilization of a model lung system to assess the effects of an inspiratory impedance threshold valve on the relationship between active decompression and intra-thoracic pressure.

Use of an inspiratory impedance valve has recently been shown to increase the efficacy of standard and active compression-decompression cardiopulmonary resuscitation. We evaluated the effects of a prototypic impedance valve on the relationship between the active decompression and intra-thoracic pressure using a mechanical model lung system. Intermittent impedance to inspiratory flow of respiratory gases during the decompression phase of active compression-decompression cardiopulmonary resuscitation significantly decreased the intra-thoracic pressure, while the pressure was almost zero cm H2O during the cardiopulmonary resuscitation cycle when the impedance threshold valve was not functioning. Thus, this mechanical model will help in evaluating the valve as well as in optimizing its function by simulating various forms of lung disease.

Cardiopulmonary Resuscitation↗
PubMed1999

Coronary artery disease and endothelial nitric oxide synthase and angiotensin-converting enzyme gene polymorphisms.

Nitric oxide (NO) inhibits platelet aggregation, proliferation of vascular smooth muscle cells, and leukocyte adhesion to endothelial cells. Thus, genetic variation in or near NO synthase may be involved in the pathogenesis of coronary artery disease (CAD). We investigated the association between CAD and endothelial constitutive NO synthase (ecNOS) and angiotensin-converting enzyme (ACE) gene polymorphisms by polymerase chain reaction analysis. These genotypes were examined in consecutive patients with CAD (n = 40) and control subjects (n = 34). The frequency of ecNOS genotypes in the CAD group (4a/a + 4a/b: 48%; 4bb: 52%) did not differ from that in the control group (4a/a + 4a/b: 29%; 4bb: 71%). The allele frequencies of ecNOS4a and ecNOS4b also did not differ between the two groups. On the other hand, the frequency of the ACE DD genotype in the CAD group (DD: 45%; ID: 35%; II: 20%) was significantly higher than that in the control group (DD: 21%; ID: 35%; II: 44%). The frequency of the D allele in patients with CAD (0.63) was also significantly higher than in controls (0.38). Combined analysis showed that the frequency of the ecNOS genotypes in ACE DD genotype subjects (4a/a + 4a/b: 39%; 4b/b: 61%) in the CAD group was not significantly different from that in the control group (4a/a + 4a/b: 29%; 4b/b: 71%). The ACE genotype might be a predictor of CAD, while the ecNOS genotype appeared to confer no appreciable increase in the risk of CAD.

Case-Control Studies↗
PubMed1999

Apolipoprotein E polymorphism and plasma lipid levels in Native Mongolian sheep.

Apolipoprotein E (apoE) phenotypes were determined in 199 unrelated native sheep (Khalkhas line) of Central Mongolia, using a polyacrylamide gel isoelectric focusing-immunoblotting technique, and the plasma lipid levels in different phenotypes were assayed enzymatically. Twenty-eight phenotypes were identified in this sheep. In addition to all the previously detected seven apoE variants composing the phenotypes, four new variants were discovered, which were called E8, E9, E10, and E11. From the population data, these were found to be genetically controlled by four codominant alleles, designated APOE8, APOE9, APOE10, and APOE11, based on the same mode of inheritance as in the seven variants. These alleles were detected at a low frequency, in the range of 0.005 to 0.0126. The Khalkhas sheep differed most significantly from the Baruwal and Lampuchhre sheep of Nepal and the Vietnamese sheep with respect to the allele frequencies found in some Asian local sheep previously examined. Type 1/1 and/or 2/7 sheep had significantly higher plasma levels of total cholesterol and low-density lipoprotein cholesterol than type 7/7 sheep (P < 0.05 and/or P < 0.02).

Animals↗
PubMed1999

Hematopoietic progenitor cells from allogeneic bone marrow transplant donors circulate in the very early post-transplant period.

Despite the therapeutic efficacy of allogeneic bone marrow transplantation (allo-BMT), circulating hematopoietic progenitor cells after bone marrow transplantation have not been well characterized. In the present study, we focused on these 'post-transplant circulating progenitor cells (PTCPC)' which may be on their way to bone marrow. We analyzed the number of myeloid progenitor cells (CFU-GM) per 10 ml of peripheral blood (PB) on days 0 (just before transplantation), 1 (8-15 h after the completion of transplantation), 2, 3, 5, 7, 10, 14, 17, 21, 28 and 35 after allo-BMT in five transplant patients using a standard methylcellulose assay. In addition, high proliferative potential colony-forming cells (HPP-CFC) of the harvested donor bone marrow (BM) and day 1 PB of recipients were assayed in five patients. The origin of HPP-CFC from day 1 PB was analyzed by polymerase chain reaction of a DNA region containing a variable number of tandem repeats. The replating potential of these HPP-CFC was evaluated by a secondary colony assay. The proportion of CD38negative cells among CD34+ cells in the harvested BM and day 1 PB was evaluated by two-color flow cytometric analysis. The number of CFU-GM on day 1 ranged from 6 to 73/10 ml PB, and became undetectable on day 5. The reappearance of PTCPC was observed on day 14, along with hematopoietic recovery. The proportion of HPP-CFC among myeloid colonies from day 1 PB was significantly higher than that from harvested BM (44.3+/-10.4% vs 11.3+/-2.1%, respectively, n=5, P=0.0030). These HPP-CFC from day 1 PB were confirmed to be of donor origin. More than 90% of these HPP-CFC had replating potential. Two-color flow cytometric analysis revealed that the proportion of CD34+CD38negative cells was significantly higher in day 1 PB than in the harvested BM (61.0+/-16.5% vs 9.3+/-3.5%, respectively, n=7, P=0.0002). These observations suggest that both primitive and committed transplanted myeloid progenitor cells may circulate in the very early period following allo-BMT.

ADP-ribosyl Cyclase↗
PubMed1999

Molecular remission in adult T cell leukemia after autologous CD34+ peripheral blood stem cell transplantation.

This report describes a patient with acute-type adult T cell leukemia/lymphoma (ATLL) successfully treated by autologous CD34+ peripheral blood stem cell transplantation after fractionated total body irradiation and high-dose cytarabine and cyclophosphamide. A newly established inverse polymerase chain reaction method was used to demonstrate the disappearance of ATLL clonal cells. The patient achieved a sustained molecular remission after transplantation, but died from opportunistic infection 4 months after transplantation. Thus, autologous CD34+ peripheral blood stem cell transplantation is promising for this type of malignancy. However, a prudent clinical attitude toward immunological fragility after transplantation is needed for better outcome.

Antigens, CD34↗