Biomedical subjects

Y Hashimoto

Publications and source records attributed to Y Hashimoto.

At least 631 records · Page 35Linked to original sources

PubMed1996

Effect of CYP2C polymorphisms on the pharmacokinetics of phenytoin in Japanese patients with epilepsy.

We examined the effect of CYP2C9/19 polymorphisms on the pharmacokinetics of phenytoin in 17 Japanese patients with epilepsy. The maximal elimination rate (Vmax) of phenytoin was slightly decreased (up to 14%) in patients with CYP2C19 mutations for the defective allele. The Vmax values in patients with a CYP2C9 mutation for the heterozygous Ile/Leu359 allele were 40% lower than those in patients with wild-type CYP2C9 for the homozygous Ile359 allele. These findings suggested that the genetic polymorphism of CYP2C isoenzymes plays an important role in the pharmacokinetic variability of phenytoin, and that the mutation in CYP2C9 proteins is a determinant of impaired metabolism of the drug.

Anticonvulsants↗

PubMed1996

The surface properties of chemically synthesized peptides analogous to human pulmonary surfactant protein SP-C.

A number of peptides with different lengths corresponding to various regions of human pulmonary surfactant protein SP-C were synthesized and their activity evaluated to improve in vitro surface activities and in situ lung pressure-volume characteristics of a ternary lipid mixture composed of dipalmitoylphosphatidylcholine, phosphatidylglycerol and palmitic acid (75:25:10, w/w). SP-C (1-35), a synthetic peptide with the entire length of human SP-C, and some other peptides with various lengths of its partial sequences were remarkably active. All of these peptides shared a common core sequence of (C)CPVHLKRLLIVVVVVVLIVVVIVGAL(L). Any deletion in this core sequence resulted in reduction of activity of the peptide. SP-C (5-31) and SP-C (6-32), the minimum peptides containing the core sequence, were combined with the ternary lipid mixture at the final peptide concentration of 2% (w/w) into synthetic surfactants which showed excellent properties comparable with those of Surfacten, a commercially available modified bovine lung surfactant. In a Langmuir-Wilhelmy surface balance, the synthetic surfactant containing SP-C (6-32) spread and adsorbed quickly to reach a surface tension of 30.8 mN/m at 30-s spreading time and 41.2 mN/m at 1-min adsorption time, respectively; the presence of SP-C (6-32) significantly prevented the decrease of surface activity of the ternary lipid mixture during dynamic compression-expansion cycles. Furthermore, tracheal instillation of the synthetic surfactant containing SP-C (6-32) at the dose of 50 mg of phospholipids/kg improved lung pressure-volume characteristics of immature rabbit neonates to a level similar to that of mature neonates at term.

Amino Acid Sequence↗

PubMed1996

Evaluation of differentiation-inducing activity of retinoids on human leukemia cell lines HL-60 and NB4.

Retinoids, including all-trans-retinoic acid (ATRA), its isomers, and fifty synthetic retinoids (retinobenzoic acids), were tested for differentiation-inducing activity on human leukemia cell lines HL-60 and NB4. Binding activity of typical retinoids to nuclear retinoic acid receptors (RARs) was also investigated. A good linear correlation between the ED50 values of differentiation-inducing activity towards HL-60 cells and those towards NB4 cells was found. Binding activities of retinoids to RAR alpha and RAR beta also correlated well to the differentiation-inducing activities.

Benzoates↗

PubMed1996

Characterization of poly-leucine substituted analogues of the human surfactant protein SP-C.

A series of novel amphipathic peptides constituted of an N-terminal hydrophilic portion (CPVHLKR, residues 6-12) of human pulmonary surfactant protein-C (SP-C) and a poly-leucine (poly-L) stretch of various chain lengths as the C-terminal hydrophobic tail were synthesized and evaluated relevant to their ability to improve the surface activity of a ternary lipid mixture composed of dipalmitoylphosphatidylcholine, egg-phosphatidylglycerol and palmitic acid (DPPC/E-PG/PA, 75:25:10, w/w) in a Langmuir-Wilhelmy surface balance. CPVHLKRL11, a human SP-C analogue bearing an 11-residue poly-L tail, and its related peptides with longer tails in the ternary lipid mixture, accelerated not only the surface spreading at the air-water interface but also exhibited significantly improved dynamic surface activity, compared to the ternary lipid mixture. Their surface activities were almost indiscernible from those of the synthetic human SP-C. When reconstituted into a ternary lipid mixture containing members of the homologous series of n-saturated diacylphosphatidylglycerol, the surface activities of the poly-L analogues were almost completely unaffected, whereas replica peptides carrying the hydrophobic portion of native SP-C were found to have distinct surface activities depending upon the acyl-chain lengths of phosphatidylglycerol. The poly-L stretch of a poly-L analogue could be replaced with poly-norleucine of the same chain length without a significant loss of surface activity. Substitution of the poly-L portion in the analogues with poly-valine or poly-isoleucine resulted in a considerable decrease in surface activity. The poly-L analogue in the DPPC/E-PG/PA mixture was demonstrated to act as an excellent surfactant comparable with Surfacten, a modified bovine surfactant preparation that was used for treatment for infant respiratory distress syndrome, based on evaluation of the lung pressure-volume characteristics using premature rabbit neonates.

Amino Acid Sequence↗

PubMed1996

Population pharmacokinetics of phenytoin in Japanese patients with epilepsy: analysis with a dose-dependent clearance model.

The population pharmacokinetic parameters of phenytoin were estimated using routine therapeutic drug monitoring data from 116 epileptic patients. The 531 serum concentration values at steady-state after repetitive oral administration were analyzed using a nonlinear mixed effects model (NONMEM) program designed for estimation of population pharmacokinetic parameters. A one-compartment model with dose-dependent clearance was used for the pharmacokinetic analysis of phenytoin. The volume of distribution (V) was estimated to be 1.231/kg in a typical 42-kg patient, assuming that the bioavailability of orally administered phenytoin is 100%. The maximal elimination rate (V(max)) and the Michaelis-Menten constant (K(m)) were 9.80 mg/d/kg and 9.19 micrograms/ml, respectively. The parameter of power function of weight to adjust V and V(max) was estimated to be 0.463. In addition, K(m) for phenytoin appeared to be 16% increased in patients receiving zonisamide concurrently. The population pharmacokinetic parameters of phenytoin will be useful for designing dosage regimens in epileptic patients.

Adolescent↗

PubMed1996

Location of two photoaffinity-labeled sites on the ligand-binding domain of retinoic acid receptor alpha.

Retinoic acid receptors (RARs) consist of six domain structures. The C-terminal region (D/E/F-domains) is involved in ligand binding, dimerization, and ligand-dependent transactivation. Structural information about RARs is required for understanding its complex function. A photoreactive retinoid denoted as ADAM-3, which was designed as the result of comparison of two fluorescent retinoids (DAM-3 and DAM-15), was synthesized and used for photoaffinity labeling of recombinant protein MBP-RAR alpha/E. The photoaffinity-labeled site was determined by an endoprotease combination method which utilizes four endoproteinases in a two-phase digestion procedure. Two major labeled fragments were detected in each digestion, and the results of two-phase digestion allowed identification of the labeled residues as being located within residues 492-510 and 585-594, which correspond to 288-306 and 381-390 in human RAR alpha, respectively.

Affinity Labels↗

PubMed1996

Phenylphthalimides with tumor necrosis factor alpha production-enhancing activity.

Phenylphthalimides (2-phenyl-1H-isoindole-1,3-diones) were prepared and their effects on tumor necrosis factor alpha (TNF-alpha) production by human leukemia cell line HL-60 stimulated with 12-O-tetradecanoylphorbol-13-acetate (TPA) were examined. An analysis of the structure-activity relationships of the phenylphthalimides indicated that potent enhancing activity on TPA-induced TNF-alpha production by HL-60 cells requires medium-sized substituent(s) at the ortho position(s) of the phenyl group; 2-(2,6-diisopropylphenyl)-1H-isoindole-1,3-dione (PP-33) increased the TNF-alpha production to more than 600% at the concentration of 1 x 10(-5) M. Introduction of a nitro group at the phthalimide moiety of PP-33 enhanced the activity; 2-(2,6-diisopropylphenyl)-4-nitro-1H-isoindole-1,3-dione (4NPP-33) and its 5-nitro isomer (5NPP-33) enhanced the TNF-alpha production to more than 800% and 700%, respectively, at the concentration of 1 x 10(-5) M. Introduction of fluorines into the phthalimide moiety of PP-33 greatly lowered the concentration of the compound necessary to elicit the TNF-alpha production-enhancing activity; 2-(2,6-diisopropylphenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3-dio ne (FPP-33) showed the activity at nanomolar concentration, with the optimum concentration of 1 x 10(-7) M.

HL-60 Cells↗

PubMed1996

Inducer-specific regulators of tumor necrosis factor alpha production.

Novel potent regulators of tumor necrosis factor alpha (TNF-alpha) production by a human promyelocytic leukemia cell line, HL-60, were prepared. All the compounds showed inducer-specific and bidirectional regulation of TNF-alpha production, i.e., they enhanced 12-O-tetradecanoylphorbol-13-acetate-induced TNF-alpha production, while they inhibited okadaic acid-induced one.

Carcinogens↗

PubMed1996

Novel aromatic urea derivatives with DNA-binding ability.

Several aromatic urea derivatives were designed and synthesized as DNA-targeting agents. N,N'-Dimethyl-N,N'-bis[(4-amidylphenyl)aminocarbonyl]-2,6-di aminopyridine (1) and 1,3-bis[5-(glycylamino)pyrid-2-yl]urea (3) showed remarkable DNA-binding abilities as determined by ultrafiltration assay using calf thymus DNA, their potencies being equal to and half that of netropsin, respectively. Compound 1 inhibited the proliferation of both L1210 cells and KB cells with similar IC50 values to netropsin.

Animals↗

PubMed1996

meso-DNAs with homopurine sequences: analysis of their interaction with natural DNAs.

Two homopurine sequences of meso-DNAs (DNAs having an alternating sequence of 2-deoxy-L-ribose and 2-deoxy-D-ribose in their sugar moieties), d(LADG)5 and d(LGDA)5, were prepared. Both d(LADG)5 and d(LGDA)5 interacted with the corresponding complementary natural DNAs, d(DCDT)5 and d(DTDC)5, respectively. In the interactions, pH-dependent duplex/triplex selectivity was observed, i.e., meso-d(Pu)10 formed a duplex at pH 7.5 and a triplex at pH 5.0 with the complementary D-d(Py)10. The meso-d(Pu)10/D-d(Py)10 complex showed a CD spectrum similar in shape to that of the natural complex, suggesting that meso/natural complexes form right-handed helices. At pH 7.5, ethidium bromide intercalated into both d(LADG)5/d(DCDT)5 and d(LGDA)5/d(DTDC)5 duplexes. A clear difference between d(LADG)5/d(DCDT)5 and d(LGDA)5/d(DTDC)5 was observed at pH 5.0. Addition of ethidium bromide did not affect the formed d(LADG)5/d(DCDT)5 triplex, and ethidium bromide did not intercalate into the triplex. On the other hand, d(LGDA)5 did not form a triplex with d(DTDC)5 in the presence of ethidium bromide even at pH 5.0, but it formed a duplex. Ethidium bromide intercalated into the duplex at pH 5.0.

Circular Dichroism↗

PubMed1996

[Retinoid antagonists].

Retinoids, retinoic acid and its bioisosters, regulate many biological functions such as cell differentiation, proliferation and embryonic development in vertebrates, through binding to and activating their specific nuclear receptors. There are two classes of nuclear receptors for retinoids, retinoic acid receptors (RAR alpha, beta, gamma) and retinoid X receptors (RXR alpha, beta, gamma). Several retinoid antagonists, which bind to but not activate RARs, have been reported. Among them, 4-(5H-7,8,9,10-tetrahydro-5,7,7,10,10-pentamethylbenzo[e]naphtho [2,3-b][1,4]diazepin-13-yl)benzoic acid (LE135, 20) is a RAR beta-selective retinoid antagonist. Structure-activity relationships of LE135 (20) showed that the naphthalenyl analogs [LE540 (21) and LE550 (22)] are more potent retinoid antagonists in HL-60 assay. Contrary to the antagonistic activity of LE135 (20), an isomer of LE135 (20), 4-[5H-2,3-(2,5-dimethyl-2,5-hexano)-5-methyldibenzo- [b,e][1,4]diazepin-11-yl)benzoic acid (HX600, 39) enhanced the activities of retinoids. Although the synergistic activity of HX600 (39) can be explained by the binding to RXRs and the further activation of RAR/RXR heterodimer activated by retinoid (RAR ligand), the significantly different biological character of HX600 (39) from the typical RXR-selective ligand suggested the possibility of the participation of other nuclear receptors or cofactors in the retinoid synergism.

Animals↗

PubMed1996

Conversion of a cyanhydrin compound into S-(-)-3-phenyllactic acid by enantioselective hydrolytic activity of Pseudomonas sp. BC-18.

A Pseudomonas strain, named BC-18, which can convert racemic phenylacetaldehyde-cyanhydrin (3-phenyllactonitrile) enantioselectively to S-(-)-3-phenyllactic acid (S-PLA), was isolated from soil. Although PLA produced with intact cells contained the S enantiomers of approximately 75% enantiomeric excess (% e.e.), repeated crystallization gave a higher purity (99.8% e.e.) of the S configuration product. Production of S-PLA was significantly increased when 2.0% (w/v) of calcium chloride were added to the reaction mixture for precipitation of S-PLA. Chemical mutagenesis yielded a mutant strain, named BC348-9, with 16 times higher activity (40 mU/OD630), compared with that of the parent strain (2.5 mU/OD630). When the mutant strain BC348-9 was used, approximately 18 g/OD630 was produced, which is 12 times higher than that of the parent strain. The final accumulation of PLA exceeded 6.0%, 1.2 times higher than that of the parent strain.

Calcium Chloride↗

PubMed1996

Hormonal regulation of T-cell subsets in the oviduct: an immunohistochemical study using sex-hormone-treated chicken.

The present immunohistochemical study deals with dynamic alteration of T-cell subsets in the oviduct sex-hormone-treated chickens. Monoclonal antibodies (CT3, CT4, and CT8) specific for the chicken homologues of CD3, CD4, and CD8 were used in estrogen- or progesterone-treated chickens. In control animals, no lymphocytes appeared throughout the oviduct until 4 weeks of age. When 7-day-old chickens were injected with either diethylstilbestrol (DES) or (DES) plus progesterone, T cells immunoreactive for CT3 first infiltrated the oviduct at 12 hr after the hormone treatment. Their frequency of occurrence rose from 48 to 96 hr. Subsequently, CT3+ cells in the magnum declined in number per area coincident with the proliferation of albuminous glands in the lamina propria, while in the vagina no decline of T cells was observed. The population of T-cell subsets in the lamina propria of both the magnum and vagina was significantly higher in the DES-treated chickens than in DES plus progesterone-treated chickens. Among T-cell subsets CT8+ cells were more numerous than CT4+ cells throughout the study, this relative frequency being shared by normal adults. Depopulation of lymphocytes from the thymus, spleen and cecal tonsil, their mobilization to the circulating blood, and subsequent dynamic infiltration into the oviduct suggested that the sex hormones induced the traffic of T cells from the lymphoid organs into the oviduct.

Animals↗

PubMed1996

An immunohistochemical analysis of T-cell subsets in the chicken bursa of Fabricius during postnatal stages of development.

T-cell subsets in the chicken bursa of Fabricius were analysed immunohistochemically during postnatal stages. Distinct types of T cells were present both in the surface epithelium and lamina propria of the bursa. TcR1+ and CT8+ cells were predominant in the surface epithelium, while TcR2+ and CT8+ cells were numerous in the lamina propria. These T-cell subsets peaked in frequency of occurrence at 5 weeks. They then decreased in number, and a few T cells remained in the bursa until 15 weeks of age. This result showed that the bursa of chickens is furnished with the distinct types of T-cell subsets at early postnatal stages of development to maintain its local immunity.

Aging↗

PubMed1996

The relationship between adherence and liver metastatic ability in murine mastocytoma cell line.

P815 murine mastocytoma cells were separated to plastic-adherent and -nonadherent cell populations by repetitive in vitro selections. Their abilities of experimental and spontaneous metastases were investigated in the syngeneic DBA/2 mice. While the plastic-adherent populations were found to be liver-metastatic, the plastic-nonadherent populations were liver-nonmetastatic. The inability of plastic-nonadherent P815 cells to metastasize to the liver did not mean that these cells were not tumorigeneic because they could metastasize to tissues and/or organs other than the liver. Hence it could be looked as inability for liver specific metastasis resulted from, or related to, the loss of plastic adhesiveness. By limiting dilution of plastic-adherent and -nonadherent P815 cells, two series of well comparable P815 clones were established: (1) plastic-adherent, liver-metastatic clone and (2) plastic-nonadherent, liver-nonmetastatic one. Since these two series of P815 clone are originated from a common parent line, they might be valuable in the study of the molecular mechanisms of liver specific metastasis and of the relations between liver metastasis and cell adhesiveness.

Animals↗

PubMed1996

Characterization of a new breast cancer-associated antigen and its relationship to MUC1 and TAG-72 antigens.

We have characterized a new tumor-associated antigen defined by monoclonal antibody (MAb) generated against HMA-1 breast cancer cell line. MAb AM-1 was selected based on its preferential reactivity to breast cancer cells versus to normal or benign epithelial cells by immunofluorescence and immunohistochemical assays of cultured, or fresh specimens. AM-1 demonstrated strong reactivity to breast cancer cell lines including HMA-1, YMB-1-E, YMB-1 and MDA-MB-231 in flow cytometry. In immunoprecipitation, AM-1 recognized high molecular weight components of 160-210 kDa and > 370 kDa. Reactivity with HMA-1 cells was diminished markedly when treated by heat, protease or periodate, suggesting that the antigenic epitope is composed with carbohydrates and peptides. Enzyme digestion of precipitated antigens demonstrated that the antigen contains O-linked and N-linked carbohydrates with neuraminic acid structures. Furthermore, binding inhibition and sandwich ELISA assays using MAbs reactive with known breast cancer-associated antigens and synthetic MUC1 core peptide (PDTRPAPGSTAPPAHGVTSAPDTR) demonstrated that the antigen is distinct from CEA, TAG-72 or MUC1, while the antigen conjoins with MUC1 and TAG-72 as a trimmer form in HMA-1 cells. These results suggest that AM-1 recognizes a novel glycoprotein which is abundant in breast cancer, and may be utilized in the management of breast cancer patients.

Adenocarcinoma↗

PubMed1996

Presence of atypical laminin on the surface of mouse Lewis lung carcinoma cells.

We investigated the expression and distribution of laminin in Lewis lung carcinoma LL2-Lu3 cells. The microscopic immunofluorescence study of the non-permeabilized cells and blotting assay after immunoprecipitation with anti-laminin antibodies of biotinylated cell surface proteins demonstrated that LL2-Lu3 cells retained laminin on their cell surfaces. This laminin was atypical in that it lacked A chain as revealed by the immunoblot analysis. The results of the reverse transcription polymerase chain reaction method indicated that LL2-Lu3 cells contained mRNA for B1 and B2 chains, but not A chain corresponding to those of typical laminin derived from murine Engelbreth-Holm-Swarm sarcoma. A precursor form of 67 kDa laminin receptor protein was also shown to exist on the surfaces of LL2-Lu3 cells. These findings suggest that the interaction between atypical laminin and the precursor form of the 67 kDa laminin receptor protein on the cell surfaces may function in regulating cell activities such as metastasis of LL2-Lu3 cells.

Animals↗

PubMed1996

Wear of polyethylene cups in total hip arthroplasty. A study of specimens retrieved post mortem.

The wear of polyethylene components of total hip replacements has previously been studied radiographically and by analysis of retrieved components. The extent of wear, however, has largely been determined from components retrieved at reoperation and has therefore been based on a subset of patients in whom the prosthesis is more likely to show excessive wear. The study of cups retrieved post mortem provides a better indication of the extent of wear of well functioning components. Twenty-six polyethylene liners were retrieved at autopsy from nineteen patients, after a mean of ninety-one months (range, thirty-three to 206 months) in situ. Each component had articulated with a thirty-two-millimeter-diameter femoral head. The components were evaluated visually for evidence of polyethylene wear such as pitting, scratching, and burnishing. Additionally; a shadowgraph technique was used to examine molds of the inner surface of the liner to determine the direction and extent of wear. The mean extent of linear wear of the retrieved liners was 0.45 millimeter (range, 0.17 to 1.07 millimeters), and the mean rate of wear was 0.07 millimeter (range, 0.02 to 0.18 millimeter) per year. The mean volumetric wear was 245.3 cubic millimeters (range, 13.0 to 779.1 cubic millimeters), and the mean rate of volumetric wear was 39.8 cubic millimeters (range, 1.0 to 131.3 cubic millimeters) per year. The mean rate of wear for the twenty-six liners was 45 to 69 per cent less than the rates reported in the literature for polyethylene liners retrieved at reoperation. Examination of the articulating surface did not reveal gross evidence of surface failure such as delamination or fatigue cracks. In general, the surfaces were merely burnished and scratched. The rates of wear of press-fit, metal-backed liners were significantly higher than those of all-polyethylene cemented components (p < 0.05). Additionally, statistical analysis revealed no correlation between wear and the patient's age, weight, or gender; the duration of implantation; or the thickness of the polyethylene. These results indicate that wear of the polyethylene of well functioning hip replacements is not as excessive as reported previously.

Acetabulum↗