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N Moriya

Publications and source records attributed to N Moriya.

At least 19 recordsLinked to original sources
PubMed2000

In vitro organogenesis of pancreas in Xenopus laevis dorsal lips treated with retinoic acid.

Dorsal lips of Xenopus laevis may differentiate into pancreas after treatment with retinoic acid in vitro. The dorsal lip region is fated to be dorsal mesoderm and anterior endoderm. Dorsal lip cells isolated from stage 10 early gastrula differentiate into tissues such as notochord, muscle and pharynx. However, in the present study, dorsal lips treated with 10(-4) M retinoic acid for 3 h differentiated into pancreas-like structures accompanied by notochord and thick endodermal epithelium. Sections of the explants showed that some cells gathered and formed an acinus-like structure as observed under microscopes. In addition to the morphological changes, expressions of the pancreas-specific molecular markers, XIHbox8 and insulin, were induced in retinoic acid-treated dorsal lip explants. Therefore, it is suggested that retinoic acid may induce the dorsal lip cells to differentiate into a functional pancreas. However, continuous treatment with retinoic acid did not induce pancreas differentiation at any concentration. Dorsal lips treated with retinoic acid within 5 h after isolation differentiated into pancreas-like cells, while those treated after 15 h or more did not. The present study provided a suitable test system for analyzing pancreas differentiation in early vertebrate development.

Animals↗
PubMed2000

In vitro pancreas formation from Xenopus ectoderm treated with activin and retinoic acid.

In the present study, isolated presumptive ectoderm from Xenopus blastula was treated with activin and retinoic acid to induce differentiation into pancreas. The presumptive ectoderm region of the blastula consists of undifferentiated cells and is fated to become epidermis and neural tissue in normal development. When the region is isolated and cultured in vitro, it develops into atypical epidermis. Isolated presumptive ectoderm was treated with activin and retinoic acid. The ectoderm frequently differentiated into pancreas-like structures accompanied by an intestinal epithelium-like structure. Sections of the explants viewed using light and electron microscopy showed some cells clustered and forming an acinus-like structure, including secretory granules. The pancreas-specific molecular markers insulin and XIHbox8 were also expressed in the treated explants. The pancreatic hormones, insulin and glucagon, were detected in the explants using immunohistochemistry. Therefore, sequential treatment with activin and retinoic acid can induce presumptive ectoderm to differentiate into a morphological and functional pancreas in vitro. When ectoderm was immediately treated with retinoic acid after treatment with activin, well-differentiated pronephric tubules were seen in a few of the differentiated pancreases. Treatment with retinoic acid 3-5 h after activin treatment induced frequent pancreatic differentiation. When the time lag was longer than 15h, the explants developed into axial mesoderm and pharynx. The present study provides an effective system for analyzing pancreas differentiation in vertebrate development.

Activins↗
PubMed1997

Effects of TAK-029, a novel GPIIb/IIIa antagonist, on arterial thrombosis in guinea pigs, dogs and monkeys.

The antithrombotic and bleeding time (BT) prolonging effects of TAK-029, a novel GPIIb/IIIa antagonist, were examined in three arterial thrombosis models. In guinea pigs, TAK-029 at 30 micrograms/kg (i.v.) inhibited ADP-induced ex vivo platelet aggregation completely and prolonged BT to 4.5 times the control value 5 min after administration, and it prevented thrombotic occlusion in 2 out of 5 animals in a photochemically-induced basilar thrombosis model. TAK-029 at 100 micrograms/kg (i.v.) prolonged BT more than 9 times 5 min after administration, and it prevented thrombus formation for over 60 min. In dogs, TAK-029 at 30 micrograms/kg (i.v.) inhibited ADP-induced ex vivo platelet aggregation by 87% 5 min after administration, and it prevented thrombotic occlusion in injured and stenosed coronary arteries for 22 min without prolonging the BT. TAK-029 at 100 micrograms/ kg (i.v.) inhibited platelet aggregation completely and prolonged BT 3.6 times 5 min after administration, and it prevented thrombus formation for over 45 min. In monkeys, TAK-029 at 10 micrograms/kg (i.v.) inhibited ADP-induced ex vivo platelet aggregation by 84% and prolonged BT 4.6 times 5 min after the administration, and it prevented thrombotic occlusion in injured and stenosed carotid arteries for 24 min. TAK-029 at 30 micrograms/kg (i.v.) completely inhibited platelet aggregation and thrombus formation for over 60 min, and it prolonged BT more than 7.3 times 60 min after administration. In conclusion, TAK-029 exerted potent antithrombotic effects with BT prolongation in three different arterial thrombosis models. TAK-029 may be effective for the treatment of various arterial thrombotic diseases.

Animals↗
PubMed1997

Epidermal T cells: their functional role and disease relevance for dermatologists.

T cells found within the epidermis in inflammatory dermatoses are generally accepted as making a major contribution to epidermal damage. On the other hand, those T cells residing in the murine epidermis are supposed to play an important role in protecting the epidermis from potentially dangerous immune reactions. Overwhelming evidence has accumulated that dendritic epidermal T cells (DETC) expressing monomorphic TCR gammadelta are responsible for the protection of epidermal structures against skin tumor, bacterial infection, and autoimmune attack. In animals congenitally lacking these gammadelta+ DETC, the epidermis is populated with bone marrow-derived TCR alphabeta+, CD8+ DETC. Although it remains unclear whether this subset of DETC could home to the epidermis to substitute for the physiologic function of gammadelta+ DETC or whether they would be pathologically relevant to epidermal injury, it should be noted that this subset represents the major fraction of T cells present in normal human epidermis and the most abundant in the lesional epidermis of fixed drug eruption (FDE). Because they are shown to kill target cells including keratinocytes upon stimulation and utilize a very limited range of TCR V alpha and Vbeta gene families, localized epidermal injury in FDE lesions would be mediated by activation of these epidermal T cells with autoaggressive potential. Epidermal T cells are thus likely to form several T-cell populations with different immunologic functions that are triggered by different modes of stimulation. Immune homeostasis in the epidermis would rely on a delicate balance between at least two types of epidermal T cells: autoaggressive T cells and protective T cells.

Animals↗
PubMed1997

Novel amino acid metabolite produced by Streptomyces sp.: I. Taxonomy, isolation, and structural elucidation.

A strain of streptomycete isolated from a soil sample was found to produce a novel amino acid metabolite. The compound was purified from the culture fluid by chromatography, using cation exchange resin, a synthetic adsorbent, and finally by preparative HPLC with a reverse-phase column. The structure of the compound was established as N(delta)-(5-methyl-4-oxo-2-imidazolin-2-yl)-L-ornithine on the basis of an analysis of the spectral data and chemical degradation. This was confirmed by comparing the NMR spectrum of the metabolite with that of the compound synthesized by treating methylglyoxal and N(alpha)-acetyl-L-arginine. The substance did not show any antimicrobial activity against bacteria, fungi and yeasts by the agar plate method, but exhibited a weak preventive effect on cucumber mildew disease in a pot test.

Absorption↗
PubMed1996

Adult thymus contains dendritic epidermal T cell precursors that home to the epidermis in irradiated, but not in normal, mice.

It was generally assumed that Vgamma5+ fetal thymocytes are the only cells capable of homing to the epidermis. However, we have recently demonstrated that reconstitution of thymectomized irradiated mice with T-cell-depleted bone marrow (BM) cells results in the appearance of donor-type CD8+, TCR-alphabeta+ dendritic epidermal T cells (DETC) phenotypically distinct from their normal gammadelta+ counterparts. In the present study, we found that the epidermis of lethally irradiated, BM-reconstituted (XBM) mice was also repopulated by DETC of host origin as well as donor BM-derived DETC and that the host-derived DETC were rarely detected in the epidermis of athymic BM chimeras (ATXBM). This result indicates that the host-derived DETC are originated from intrathymic radioresistant cells that may share migratory capacities with the fetal thymocytes. We demonstrated that transfer of radioresistant intrathymic precursor cells into ATXBM mice resulted in the appearance of donor-type CD8+, TCR-alphabeta+ DETC. Contrary to our initial expectation, however, transferred normal adult thymocytes also gave rise to donor-type DETC with frequency similar to radioresistant thymocyte-derived DETC. These thymocyte-derived DETC were phenotypically similar to those derived from BM cells but differed in some respects. Tissue tropism by the CD8+ subset was observed only for the epidermis, but not for other lymphoid organs, such as lymph nodes. The epidermis of normal mice, unlike that of irradiated mice, was refractory to the appearance of the thymus-derived DETC. These results suggest that prior irradiation of the host may confer a susceptibility of the epidermis to repopulation of DETC precursors, which are otherwise incapable of migrating into the epidermis. This provides an explanation for why CD8+, TCR-alphabeta+ DETC of adult thymus or BM origin are rarely detected in the normal epidermis, but abundantly observed in the irradiated mice.

Aging↗
PubMed1996

Resistance to cutaneous graft-vs.-host disease is not induced in T cell receptor delta gene-mutant mice.

The function of murine dendritic epidermal cells (dEC) remains largely speculative, probably because of the lack of a suitable in vivo model, although previous studies suggest that gamma/delta+ dEC may have originally evolved to serve as a self-protection mechanism(s). Our previous study demonstrated that the epidermis of mice that had spontaneously recovered from cutaneous graft-vs-host disease (GVHD) induced by local injection of CD4+ autoreactive T cells contained unexpectedly large numbers of dEC and became resistant to subsequent attempts to induce GVHD in a site-restricted manner, suggesting that the resistance is mediated by dEC. However, because alpha/beta+ dEC as well as gamma/delta+ dEC were greatly increased in number in the epidermis, it was unclear whether gamma/delta+ dEC are indeed responsible for this protection. The availability of this murine model and mice selectively lacking gamma/delta T cells as a result of disruption of the T cell receptor C delta gene segment allowed us to investigate the role of gamma/delta+ dEC. In the epidermis of gamma/delta T cell-deficient mice (delta-/-), a congenital lack of gamma/delta+ dEC was substituted for by alpha/beta+ dEC of either a CD4-8+ or a CD4-8- phenotype. After intradermal injection of the autoreactive T cells, delta-/- mice developed significantly enhanced delayed-type hypersensitivity responses and cutaneous GVHD, which persisted longer than in heterozygous littermate controls (delta+/-). Surprisingly, resistance to the cutaneous GVHD was not induced in the epidermis of delta-/- mice after spontaneous recovery from the GVHD, whereas the "susceptible" epidermis of delta-/+ mice contained large numbers of alpha/beta dEC comparable to those in "resistant" epidermis of delta+/- mice. Injection of day 16 fetal thymocytes from wild-type mice into delta-/- mice resulted in the appearance of donor-type gamma/delta+ dEC in the epidermis, and reconstitution with gamma/delta+ dEC restored the protective immune response of the epidermis against the GVHD to nearly normal levels. These results indicate that gamma/delta+ dEC are responsible for the site-restricted protection against cutaneous GVHD.

Animals↗
PubMed1996

DNA breaking activity and mutagenicity of soy sauce: characterization of the active components and identification of 4-hydroxy-5-methyl-3(2H)-furanone.

Soy sauce is a seasoning consumed widely in Southeast Asia. When supercoiled DNA was incubated with soy sauce at pH7.4 and 37 degrees C, extensive breaking of DNA single-strands was caused. It was found that the breaking activity was due to multiple components with different molecular weight and polarity. One of the components with the breaking activity was purified successively by extraction with ethyl acetate, thin-layer chromatography and high performance liquid chromatography, and identified as 4-hydroxy-5-methyl-3(2H)-furanone (HMF), one of the fragrant components in soy sauce. Formation of this component was found due to Maillard reaction of pentoses/amino acids. HMF was readily degraded into the compound with an endiol-ketol structure and reducing activity. Using 5,5-dimethyl-1-pyrroline N-oxide (DMPO) in an electron spin resonance-spin trapping technique, generation of hydroxyl radical in an aqueous solution of HMF was confirmed. While DNA breaking by soy sauce was little inhibited by the scavengers of active oxygen radicals, the breaking by HMF was effectively inhibited by superoxide dismutase, catalase, hydroxyl radical scavengers, spin-trapping agents, thiol compounds and metal chelating agents. Hence, DNA breaking activity of HMF was found due to generation of active oxygen radicals. HMF was found mutagenic to Salmonella bacteria without metabolic activation, probably due to generation of active oxygen radicals.

DNA↗
PubMed1996

T cell receptor (TCR) repertoire and function of human epidermal T cells: restricted TCR V alpha-V beta genes are utilized by T cells residing in the lesional epidermis in fixed drug eruption.

Human epidermis contains a phenotypically heterogeneous population of T cells. No information however, is available regarding the TCR repertoire of these T cells and their relevant physiologic and pathologic functions in vivo. To this end, T cells were prepared from the lesional epidermis in two patients with fixed drug eruption (FDE) and their phenotype, function and TCR repertoire were examined in parallel. Both epidermal T cells, termed FDE-1 and -2 cells, respectively, expressed alpha beta TCR, but displayed some phenotypic heterogeneity. These T cells were induced to display cytolytic activity by ligation of the CD3/TCR-alpha beta complex. Comparative analyses of TCR V alpha and V beta expression in the epidermal T cells and the paired peripheral blood lymphocytes (PBL) by quantitative polymerase chain reaction (PCR) demonstrated that the epidermal T cells, but not the paired PBL, utilized a very limited range of V alpha and V beta genes. These results indicate that some expansion or preferential migration of epidermal T cells that recognize a restricted set of antigens expressed within the epidermis could occur in situ following ingestion of the causative drug. The persistence of these epidermal T cells in FDE lesions suggests their pathologic role in a drug-induced flare.

Base Sequence↗
PubMed1996

Formation of the mutagenic/carcinogenic imidazoquinoxaline-type heterocyclic amines through the unstable free radical Maillard intermediates and its inhibition by phenolic antioxidants.

Generation of the imidazoquinoxaline-type heterocyclic amines in the heated model system composed of glucose/glycine/creatinine in aqueous diethylene glycol was effectively prevented by phenolic antioxidants, butylated hydroxyanisole (BHA), propyl gallate (PG), sesamol, esculetin and epigallocatechin gallate (EGCG) in a dose-dependent manner. Generation of the mutagens in heated-and-dried bonito meat was effectively prevented on pretreatment with EGCG or green tea extract. Electron spin resonance (ESR) studies showed that the heated model mixture of glucose/glycine generated the unstable pyrazine cation radical, and its formation was inhibited by BHA, sesamol and EGCG. ESR-spin trapping studies using 5,5-dimethyl-1-pyrroline N-oxide (DMPO) and N-tert-butyl-alpha-phenylnitrone (PBN) showed that the heated model mixture of glucose/glycine or glucose/glycine/creatinine generated unstable carbon-centred radical(s), and their formation was effectively inhibited by BHA, sesamol and EGCG. It is likely that the unstable free radical Maillard intermediates played an important role in the formation of the imidazoquinoxaline-type heterocyclic amines, and the phenolic antioxidants effectively scavenged the radical species to prevent the mutagen formation.

Anticarcinogenic Agents↗
PubMed1996

Antithrombotic effects of TAK-029, a novel GPIIb/IIIa antagonist, in guinea pigs: comparative studies with ticlopidine, clopidogrel, aspirin, prostaglandin E1 and argatroban.

The antithrombotic and bleeding time (BT)-prolonging effects of TAK-029, a novel glycoprotein IIb/IIIa antagonist, were characterized and compared with those of conventional antithrombotic agents in guinea pigs. TAK-029 potently inhibited the binding of fibrinogen and von Willebrand factor to purified human GPIIb/IIIa with IC50 values of 0.67 +/- 0.03 and 0.33 +/- 0.04 nM; it also inhibited human platelet aggregation induced by various aggregating agents with IC50 values of 29 to 38 nM. The in vitro antiplatelet effect of TAK-029 was potent in humans, guinea pigs and monkeys. When TAK-029 was given p.o. to guinea pigs, severe prolonging of BT (>1800 sec) was not observed with plasma concentrations of TAK-029 that inhibited ex vivo platelet aggregation by < 100%. The p.o. administration of TAK-029, ticlopidine and clopidogrel prolonged BT to the same extent, in parallel with their inhibition of ex vivo platelet aggregation. TAK-029 inhibited ex vivo platelet adhesion and thrombus formation in an arteriovenous shunt model more strongly than ticlopidine, clopidogrel and aspirin at doses causing similar prolongations of BT. In a balloon catheter-induced carotid thrombosis model, i.v. administration of TAK-029 significantly inhibited thrombus formation without prolonging BT. At doses that caused an incomplete antithrombotic effect, PGE1-alpha-cyclodextrin and argatroban produced hypotension and prolongation of BT, respectively. TAK-029 may be effective in patients suffering from arterial thrombotic diseases, which are refractory to these conventional antithrombotic agents.

Alprostadil↗
PubMed1995

GAPO syndrome: report on the first case in Japan.

We studied a 3.5-year-old Japanese boy with growth retardation, alopecia, pseudoanodontia, and bilateral papilledema. He was born of nonconsanguineous parents, but his paternal grandparents were related. From his characteristic physical manifestations, we diagnosed him as the first known case of GAPO syndrome in Japan and perhaps in the Mongoloid race. Our case had prominent dilatation of scalp veins and an audible intracranial bruit. Cranial angiography documented a narrowing of the sigmoid sinuses, with no flow to either jugular vein. We discuss here the relationships between optic atrophy and intracranial vascular changes in this syndrome.

Abnormalities, Multiple↗
PubMed1995

A new constitutively activating point mutation in the luteinizing hormone/choriogonadotropin receptor gene in cases of male-limited precocious puberty.

A single point mutation that encodes an aspartic acid (Asp578) to glycine substitution in the LH/CG receptor (LH/CGR) gene, D578G, was recently found in American patients with familial male-limited precocious puberty and in a Japanese patient with a sporadic form of the disorder. Transfection of the mutant, compared to the wild-type, LH/CGR complementary DNA into COS-7 cells results in higher basal cAMP production, but a normal agonist-induced response; the mutation is, therefore, proposed to constitutively activate Leydig cells and elevate serum testosterone, despite low levels of gonadotropin. In the current study we examined two additional Japanese patients with male-limited precocious puberty without a family history of the disease. We describe a heterozygous cytosine (C) to thymine (T) transition at nucleotide 1715 in both; the mutation encodes an alanine to valine substitution in codon 572 of transmembrane helix 6, A572V. Transfected into COS-7 cells, the A572V mutant exhibited the same constitutively high basal cAMP levels and normal agonist-induced cAMP response as the D578G mutant. We conclude that the constitutively higher cAMP levels caused by the A572V mutation led to Leydig cell activation and male-limited precocious puberty, as in the previously described D578G mutation. As the mother of one of the two patients had the same heterozygous mutation, this patient represents the first recognized case of inherited male-limited precocious puberty in the Japanese population. The previously described D578G mutant did not increase basal or agonist-induced inositol phosphate production in transfected COS-7 cells, or the number of LH/CGRs or their affinity for LH/CG. In contrast, transfection of the A572V mutation in COS-7 cells exhibited significantly higher inositol phosphate levels basally and at 10(-11) mol/L hCG, but significantly lower inositol phosphate levels at 10(-7) mol/L hCG. These data suggest that the A572V mutation of the LH/CGR may have effects on the guanine nucleotide binding protein which activates phospholipase C (Gq) coupling and phospholipase-C activation in addition to its effects on Gs coupling and activation of adenylyl cyclase. A572V-transfected cells also exhibited a higher affinity, despite an apparent decrease in the number of binding sites, for [125I]hCG, compared to transfectants with the wild-type LH/CGR. We hypothesize that these differences between the A572V and D578G mutations reflect a greater impact of the A572V mutation on receptor conformation.

Base Sequence↗
PubMed1994

Clinical study of biological response modifiers as maintenance therapy for hepatocellular carcinoma.

We conducted a randomized, controlled trial comparing 5-fluorouracil (5-FU) with or without biological response modifiers (BRMs) as a maintenance therapy for hepatocellular carcinoma (HCC) after treatment with percutaneous ethanol injection (PEI), transcatheter arterial embolization (TAE) or arterial infusion of antitumor agents (AI). A total of 58 cases of HCC were classified into 4 groups as follows: group I, PSK with 5-FU (n = 15); group II, lentinan with 5-FU (n = 15); group III, OK-432 with 5-FU (n = 12); and group IV, 5-FU alone as the control (n = 16). The mean survival time, mortality rate, time to progression, and T4/T8 ratio of lymphocytes in the peripheral blood were compared among the four groups. There was no significant difference in the background factors among the groups. In group I, the T4/T8 ratio of lymphocytes was reduced after the therapy. No significant difference was found among the groups in terms of the mean survival time, mortality rate, or time to progression. PEI for initial therapy was superior to the other therapies in terms of the mean survival time and mortality rate. These results suggest that the addition of BRM to maintenance therapy with 5-FU exerts no prognostic benefit on HCC patients treated with PEI, TAE, or AI.

Aged↗
PubMed1994

Isolation and characterization of Streptoverticillium anticoagulant (SAC), a novel protein inhibitor of blood coagulation produced by Streptoverticillium cinnamoneum subsp. cinnamoneum.

Three Streptoverticillium anticoagulants, SAC I, II, and III, which strongly inhibit human intrinsic blood coagulation, were each isolated in a homogeneous form from a culture fluid of Streptoverticillium cinnamoneum subsp. cinnamoneum IFO 12852. SAC I, II, and III are simple proteins with molecular weights of around 12,000, and with isoelectric points of 9.7, 9.7, and 9.9, respectively. Their amino acid compositions are similar and each SAC possesses two disulfide bonds. The COOH-terminal residue of each of these proteins is phenylalanine. Together with the similarity of their protein chemical properties, the results of NH2-terminal amino acid sequence analysis of these SAC proteins strongly suggested that the deletion of Ser-Leu and Ser-Leu-Tyr from the NH2-terminus of SAC I (Ser-Leu-Tyr-Ala-Pro-...) results in the generation of SAC II and III, respectively. The amount of each SAC necessary to double the partial thromboplastin time was around 5 micrograms/ml. SAC I inhibited activated human factor XII and human plasma kallikrein. It also inhibited, but to a lesser extent, activated factor X. The inhibition constants (Ki) of SAC I toward activated factor XII and plasma kallikrein were 5.3 x 10(-8) and 7.2 x 10(-9) M, respectively. The SACs also inhibited some microbial serine proteases such as subtilisin Carlsberg and, to a lesser extent, mammalian serine proteases including bovine trypsin and alpha-chymotrypsin. Of these three inhibitors, only SAC I inhibited metalloproteases such as thermolysin in addition to these serine proteases.

Amino Acid Sequence↗
PubMed1994

Drug-induced expression of intercellular adhesion molecule-1 on lesional keratinocytes in fixed drug eruption.

The mechanism(s) and the factor(s) that contribute to preferential localization of fixed drug eruption (FDE) lesions to certain skin sites remain speculative. Previous studies suggested that populations of T cells residing in the lesional epidermis may be involved in selective destruction of the epidermis in FDE. In this study, to define the earliest cellular and molecular events with potential relevance to activation of the epidermal T cells, expression of adhesion molecules on keratinocytes (KC) and vascular endothelium was examined sequentially in the lesional skin of FDE patients after challenge with the causative drug. Rapid and intense intercellular adhesion molecule-1 (ICAM-1) expression was induced on the vascular endothelium and KC as early as 1.5 hours after challenge, at which time E-selectin and vascular cell adhesion molecule-1 (VCAM-1) were not up-regulated. In vitro studies using skin organ culture showed that the lesional KC and endothelium responded more rapidly and intensely to express ICAM-1 to tumor necrosis factor-alpha or interferon-gamma compared with those in the nonlesional skin. Surprisingly, such selective induction of KC ICAM-1 restricted to the lesional skin was also observed after exposure to the causative drug alone in skin organ culture. Pretreatment of the lesional skin with anti-tumor necrosis factor completely abrogated in vitro induction of KC ICAM-1 expression by the drug. Drug-induced, TNF-alpha-dependent KC ICAM-1 expression in the lesional skin suggests that induction of ICAM-1 expression by the lesional KC after ingestion of the drug would probably provide a localized initiating stimulus for activation of the disease-associated epidermal T cells.

Adolescent↗