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Biomedical subjects

D Fukushima

Publications and source records attributed to D Fukushima.

At least 19 recordsLinked to original sources
PubMed2006

Continuous low-dose human atrial natriuretic peptide promotes diuresis in oliguric patients after living donor liver transplantation.

Human atrial natriuretic peptide (ANP) is beneficial for the prophylaxis of acute renal failure (ARF) after liver transplantation (OLT). We evaluated renal function in OLT patients with or without ARF, describing cases unresponsive to loop diuretics successfully treated with continuous low-dose ANP infusion without hemodialysis. Twenty-seven consecutive adult-to-adult living donor liver transplantations (LDLTs) were performed in 26 patients. One case was excluded due to the need for continuous hemodialysis (HD) during the operation. Of the 26 cases, 6 (23%, group 2) developed ARF in the first 30 days after LDLT; the other 20 were ARF-free (group 1). The median follow-up was 24 months. No patient required either continuous or intermittent HD. Only one patient died due to multiple liver abscesses. Mean preoperative serum creatinine (sCr) value and intraoperative blood loss in group 2 were significantly higher than those in group 1. Three cases in group 2 failed to improve on high-dose loop diuretics with low-dose dopamine, exhibiting fluid overload. The remaining three cases in group 2 responded to conventional diuretic treatments. Continuous low-dose ANP was started 2, 4, or 5 days after LDLT, and urine output significantly increased after ANP administration. The serum creatinine values were 1.1, 1.2, and 1.1 at 1 month and 1.0, 0.9, and 0.6 mg/dL at 6 months after LDLT. Massive blood loss during the operation caused ARF, but did not affect renal function after LDLT. Continuous low-dose ANP improved renal function and diuresis for oliguric ARF patients, preventing the need for HD or continuous venovenous hemodialysis.

Adult↗
PubMed2001

Novel low molecular weight spirodiketopiperazine derivatives potently inhibit R5 HIV-1 infection through their antagonistic effects on CCR5.

Novel low molecular weight spirodiketopiperazine derivatives which potently inhibit R5 human immunodeficiency virus type 1 (HIV-1) infection through their antagonistic effects on CCR5 were identified. One such compound E913 (M(r) 484) specifically blocked the binding of macrophage inflammatory protein-1alpha (MIP-1alpha) to CCR5 (IC(50) 0.002 microm) and MIP-1alpha-elicited cellular Ca(2+) mobilization (IC(50) approximately 0.02 microm). E913 potently inhibited the replication of laboratory and primary R5 HIV-1 strains as well as various multidrug-resistant monocyte/macrophage tropic (R5) HIV-1 at IC(50) values of 0.03 to 0.06 microm. E913 was inactive against T cell tropic (X4) HIV-1; however, when combined with a CXCR4 antagonist AMD-3100, E913 potently and synergistically inhibited the replication of dualtropic HIV-1 and a 50:50 mixture of R5 and X4 HIV-1. Antagonism in anti-HIV-1 activity was not seen when E913 was combined with the reverse transcriptase inhibitor zidovudine or protease inhibitors. E913 proved to compete with the binding of antibodies to CCR5 which recognize the C-terminal half of the second extracellular loop (ECL2B) of CCR5. E913 and its analogs are acid-resistant and orally bioavailable in rodents. These data warrant that spirodiketopiperazine derivatives be further developed as potential therapeutics for HIV-1 infection.

Animals↗
PubMed1997

Degradation of decorin by matrix metalloproteinases: identification of the cleavage sites, kinetic analyses and transforming growth factor-beta1 release.

Decorin (DCN) is a ubiquitous proteoglycan comprised of a core protein attached to a single dermatan/chondroitin sulphate glycosaminoglycan chain. It may play a role in regulation of collagen fibrillogenesis and function as a reservoir of transforming growth factor beta (TGF-beta) in the extracellular milieu. We have examined the susceptibility of DCN to five different matrix metalloproteinases (MMPs): MMP-1 (tissue collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin 1), MMP-7 (matrilysin) and MMP-9 (gelatinase B). MMP-2 and MMP-3 digest DCN into seven major fragments in a similar pattern. The N-terminal sequence of the two fragments generated by MMP-2 and MMP-3 is Leu211-Lys-Gly-Leu-Asn, but that of the others is Asp1-Glu-Ala-Ser-Gly. MMP-7 cleaves DCN into three major fragments which have the N-termini Asp1-Glu-Ala-Ser-Gly, Glu2-Ala-Ser-Gly-Ile and Leu244-His-Leu-Asp-Asn. Activities of MMP-1 and MMP-9 against DCN are negligible. The values of Km for the MMPs capable of degrading DCN are very similar (10-12 microM), but the kcat/Km value for MMP-7 (30.5 microM-1.h-1) is 4.5-fold higher than those for MMP-2 and MMP-3. Incubation of a DCN-TGF-beta1 complex with MMP-2, -3 or -7 results in release of TGF-beta1 from the complex. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues.

Amino Acid Sequence↗
PubMed1997

A case of desmoplastic ameloblastoma of the maxilla.

A case of desmoplastic ameloblastoma of the maxilla is presented. The tumor showed characteristic radiographical and histological features. Radiographically, the tumor showed a mixed radiolucent-radiopaque lesion occupying the left maxillary sinus with undefined borders in the alveolar process. Histopathologically, the tumor was characterized by abundant, densely collagenous stroma with small nests and strands of odontogenic epithelium and bone tissues. Findings during operation suggested that the tumor arising in the alveolar process had grown upwards and almost displaced the left maxillary sinus. Complete resection is recommended for this variant because of the possibility of tumor infiltration into the surrounding bone marrow spaces.

Aged↗
PubMed1993

Localization of transforming growth factor beta binding site in betaglycan. Comparison with small extracellular matrix proteoglycans.

The most abundant binding molecule for transforming growth factor beta (TGF-beta) on many cell types is betaglycan, a transmembrane proteoglycan. To localize the binding site for TGF-beta in betaglycan, parts of the betaglycan extracellular portion were expressed as recombinant fusion proteins in bacteria and tested for their ability to compete for the binding of TGF-beta 1 to Hep G2 cells. One fragment encompassing 226 residues near the transmembrane domain (amino acids 543-769) (López-Casillas, F., Cheifetz, S., Doody, J., Andres, J. L., Lane, W. S., and Massagué, J. (1991) Cell 67, 785-795) was active, whereas fusion proteins representing the other parts of the betaglycan ectodomain were inactive. Affinity measurements revealed two classes of binding sites (Kd = 3.9 nM and Kd = 145 nM) for the active fusion protein. The binding of the betaglycan fusion protein to immobilized TGF-beta 1 was inhibited by fusion proteins representing the core proteins of the small interstitial proteoglycans decorin, biglycan and fibromodulin, each also known to bind TGF-beta. The effective concentrations of TGF-beta for binding to these other proteoglycans were similar to those required for binding to betaglycan, indicating similar affinities for the binding of proteoglycans and betaglycan. Affinity cross-linking showed that, at low concentrations, the betaglycan fragment enhanced the binding of TGF-beta to the type II receptor and to endogenous betaglycan but had no effect on the binding to type I receptor. At high concentrations, the TGF-beta binding fragment inhibited the binding of TGF-beta to all these receptors. The fragment enhanced the activity of TGF-beta in mink lung cell bioassay at all active concentrations. The results indicate that betaglycan and the decorin type proteoglycans all bind to the same or closely spaced sites in TGF-beta and compete with one another for the binding. In addition, betaglycan may cooperate with the type II receptor on TGF-beta binding.

Animals↗
PubMed1993

Activation of the secretory pathway leads to a decrease in the intracellular amyloidogenic fragments generated from the amyloid protein precursor.

The activation of the secretory pathway for the amyloid protein precursor (APP) by phorbol 12-myristate 13-acetate in human glioblastoma A-172 cells leads to a decrease in intracellular beta-amyloidogenic fragments derived from APP. The result suggests that a metabolic switch of APP from the endosomal/lysosomal pathway to a secretion route occurs after PMA treatment.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1993

A 60-kD protein mediates the binding of transforming growth factor-beta to cell surface and extracellular matrix proteoglycans.

The biological activity of many cytokines is regulated by binding proteins present at the cell surface, in extracellular matrices or in soluble phase. We describe here a TGF-beta binding protein that is both an extracellular matrix and a cell surface protein. When intact extracellular matrices of HEP-G2 cells were affinity cross-linked with 125I-TGF-beta 1, two major binding components were seen: a 250-kD, proteoglycan-like molecule, presumed to be betaglycan, and a 60-kD protein. The 60-kD TGF-beta-binding protein was also present at the cell surface. It could be released from the cell surface by treating cells with high salt, heparin, chondroitin sulfate, heparitinase, or chondroitinase, indicating that it is bound to heparan sulfate and chondroitin sulfate proteoglycans. The 60-kD protein bound TGF-beta 1 with an apparent dissociation constant of 1.6 nM, and there were 30,000 binding sites per cell at the cell surface. In addition to the HEP-G2 cells and another hepatoma cell line, the 60-kD protein was also found in a human colon carcinoma (HT-29) cell line but not in rat kidney (NRK-49F) or human fibroblast (HUT-12) cell lines. The 60-kD protein could be extracted from cells containing it and transferred to the surface of previously negative cells. The 60-kD protein may serve to regulate the binding of TGF-beta to its signal transducing receptors by targeting TGF-beta to appropriate locations in the microenvironment of cells.

Carrier Proteins↗
PubMed1987

Interleukin 4 (IgG1 induction factor): a multifunctional lymphokine acting also on T cells.

A cDNA encoding the murine interleukin 4 (IL4) (IgG1 induction factor/B cell-stimulating factor no. 1) was recently cloned (Noma et al., Nature 1986.319: 640; Lee et al., Proc. Natl. Acad. Sci. USA 1986. 83: 2061). In this report we tested recombinant IL 4 in various T cell assays. It was found that IL 4 activated the murine T cell line CTLL to increased DNA synthesis but not to growth. It also activated normal concanavalin A (Con A)-stimulated T cells both to increased DNA synthesis and to growth. These T cell growth factor-like activities were not inhibitable by anti-IL 2 receptor antibodies. Evidence is given that both Lyt-2+ and L3T4+ T cells responded to IL 4. Finally, IL 4 acted synergistically with phytohemagglutinin or Con A on normal T lymphocytes as well as on thymocytes. These data, as well as those of others, imply that lymphokines have a broader range of activity than previously anticipated.

Animals↗
PubMed1985

Nucleotide sequence of cloned cDNA for human pancreatic kallikrein.

Cloned cDNA sequences for human pancreatic kallikrein have been isolated and determined by molecular cloning and sequence analysis. The identity between human pancreatic and urinary kallikreins is indicated by the complete coincidence between the amino acid sequence deduced from the cloned cDNA sequence and that reported partially for urinary kallikrein. The active enzyme form of the human pancreatic kallikrein consists of 238 amino acids and is preceded by a signal peptide and a profragment of 24 amino acids. A sequence comparison of this with other mammalian kallikreins indicates that key amino acid residues required for both serine protease activity and kallikrein-like cleavage specificity are retained in the human sequence, and residues corresponding to some external loops of the kallikrein diverge from other kallikreins. Analyses by RNA blot hybridization, primer extension, and S1 nuclease mapping indicate that the pancreatic kallikrein mRNA is also expressed in the kidney and sublingual gland, suggesting the active synthesis of urinary kallikrein in these tissues. Furthermore, the tissue-specific regulation of the expression of the members of the human kallikrein gene family has been discussed.

Amino Acid Sequence↗
PubMed1985

Structural organization of the human kininogen gene and a model for its evolution.

The entire human kininogen gene has been isolated as a set of overlapping genomic DNA fragments, and the 11 exons encompassing approximately 27 kilobase pairs have been mapped by restriction enzyme analysis and nucleotide sequence determination. The nine 5'-terminal exons encode the 5'-untranslated region and the protein-coding region for the signal peptide and the heavy chain, which are common for high molecular weight (HMW) and low molecular weight (LMW) prekininogen mRNAs. Exon 10 consists of the common sequence for bradykinin and the immediately following unique sequence for HMW prekininogen mRNA. Exon 11 is then located following a 90-nucleotide sequence downstream from exon 10 and precisely specifies the sequence unique to LMW prekininogen mRNA. This, together with the hybridization analysis of total human cellular DNA, leads us to conclude that human HMW and LMW prekininogen mRNAs are produced from a single gene as a consequence of alternative RNA processing events. The structural analysis of the kininogen gene also shows that each of the nine 5'-terminal exons discretely specifies the nine protein domains observed in the amino-terminal portion of the kininogens. Furthermore, these nine genetic domains can be characterized by a thrice repeated pattern of three genetic segments, and two sets of these three domains, encompassing exons 3-5 and exons 6-8, are most closely related to each other. Therefore, we have proposed two successive duplication mechanisms as a model for the generation of the structure of the kininogen gene.

Base Sequence↗
PubMed1982

An NADP-linked 15-hydroxyprostaglandin dehydrogenase specific for prostaglandin D2 from swine brain.

NADP-linked prostaglandin D2 dehydrogenase was purified from swine brain to apparent homogeneity, as judged by polyacrylamide gel electrophoresis and ultracentrifugation. Using the purified enzyme free of the 15-ketoprostaglandin delta 13-reductase activity, the reaction product was identified as 15-ketoprostaglandin D2 by mass spectrometry and spectrophotometry. The purified enzyme was a monomeric protein of a molecular weight of 29,000 +/- 1,000. It had a relative abundance of hydrophobic amino acids such as leucine, alanine, and valine. The optimal pH of the enzyme reaction was 9.5. The purified enzyme exhibited high substrate specificity for prostaglandin D2 and strict specificity for NADP. The Vmax and the Km values for prostaglandin D2 and NADP were 22.0 nmol/min/mg of protein at 24 degrees C and 52 microM and 0.4 microM, respectively. The Vmax and the Km values for various types of prostaglandins for 8.6 nmol/min/mg of protein at 24 degrees C and 250 microM for D1; 8.0 and 350 for E2; 3.4 and 400 for F2 alpha; and 9.6 and 540 for I2. Prostaglandin A2, B2, and E1 could not serve as substrate. Although other NADP-linked 15-hydroxyprostaglandin dehydrogenases were reported to contain the NADPH-linked prostaglandin E 9-ketoreductase activity, this enzyme was free of the reductase activity. These results indicate that this dehydrogenase is responsible for the specific inactivation of prostaglandin D2 in the brain.

Amino Acids↗
PubMed1982

Sex difference in the influence of obesity on the 24 hr mean plasma concentration of cortisol.

The 24 hr mean plasma cortisol concentration was measured in 65 healthy women ranging from 21% below to 218% above desirable weight and in 47 healthy men ranging from 5% below to 330% above desirable weight. In the women, there was a clear-cut inverse linear correlation between the plasma cortisol concentration and the percent deviation from desirable weight (y = 7.5 -- 0.3 x; r = -0.49; p less than 0.001); the relation of free to total cortisol concentration was weight-invariant; the MCR of cortisol in the most obese women was much higher than that of nonobese women (340 +/- 76 versus 211 +/- 31 liters/gm urinary creatinine; p less than 0.01). In the men, the plasma cortisol level and MCR were weight-invariant. To account for the finding in women of a linear correlation of the decrement in plasma cortisol level with the percent deviation from desirable weight (which in turn is nearly perfectly correlated with the total body fat content), we postulate that a given weight of adipose tissue in women takes up a constant amount of cortisol; this in turn suggests that their adipose tissue contains a saturable binding system such as corticosteroid receptor. By the same logic, the weight-invariance of plasma cortisol and MCR in men suggests the absence of significant amounts of corticosteroid receptor in their adipose tissue. The finding that the increased cortisol MCR of obese women results in decreased plasma cortisol levels rather than an increase in cortisol production (the latter, corrected for muscle mass, is normal in obesity: Strain et al, Metabolism 29:980, 1980) suggests a defect in their cortisol ACTH feedback system. Such a defect, presumably hypothalamic, is not unexpected in the light of reports of defective hypothalamic control of prolactin and growth hormone secretion in obesity.

Body Weight↗
PubMed1981

Binding of amphiphilic peptides to phospholipid/cholesterol unilamellar vesicles: a model for protein--cholesterol interaction.

In earlier studies, we prepared a docosapeptide, 1, designed with minimum homology as an amphiphilic alpha-helical model of apolipoprotein A-I (apo A-I) and described its lipid-binding characteristics, surface properties, and enzyme-activating ability. Although the affinity of 1 for egg lecithin unilamellar vesicles was comparable with that for the binding of apo A-I, the affinity of 1 for mixed lecithin/cholesterol (4:1 mol/mol) vesicles was less than that of apo A-I. It appeared possible that the 3-hydroxyl group of cholesterol may have a deleterious interaction with the hydrophobic portion of the amphiphilic helix of 1 that is inserted into the vesicles. Examination of the amphiphilic alpha-helical segments of apo A-I suggested that the preferential interaction of apo A-I with the mixed vesicles might be due to the presence of polar arginine residues in the otherwise hydrophobic regions of two of the helices. Therefore, we synthesized a model docosapeptide, 2, corresponding to the sequence of 1 but containing arginine rather than leucine at position 10 in the hydrophobic region of the alpha helix to assess the role of the alcohol function of cholesterol in protein--cholesterol interactions. The results of studies on the binding of 2 to unilamellar vesicles containing lecithin only, lecithin/cholesterol, lecithin/cholesterol hemisuccinate, or lecithin/cholesterol methyl ether were consistent with the postulate that the major role of cholesterol in the binding of proteins to phospholipid surfaces is the creation of free space between the phospholipid head groups that can accommodate the amphiphilic peptide chains at the interface.

Amino Acid Sequence↗
PubMed1980

Chain length-function correlation of amphiphilic peptides. Synthesis and surface properties of a tetratetracontapeptide segment of apolipoprotein A-I.

The segment corresponding to residues 121 to 164 of human plasma apolipoprotein A-I (apo-A-I) has been synthesized by the Merrifield solid phase method. The peptide binds to unilamellar phospholipid vesicles and to phospholipid-cholesterol mixed vesicles. The surface affinity of the peptide measured in this way indicated that the mechanism of binding is the same as that of apo A-I (144-165) and apo A-I itself. The peptide appears to be a globular monomer in a aqueous solution, with 17% alpha helix content. The peptide bound to vesicles activates lecithin:cholesterol acyltransferase: compared to apo A-I, the peptide is about 30% as efficient in the activation of cholesterol esterification and of phospholipid hydrolysis when the surface is saturated by the activator. For a variety of amphiphilic peptides and for apo A-I, the lecithin: cholesterol acyltransferase-activating ability correlates well with their alpha helix contents in 50% trifluoroethanol.

Amino Acid Sequence↗