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Biomedical subjects

I Azuma

Publications and source records attributed to I Azuma.

At least 37 records · Page 2Linked to original sources
PubMed1999

Terminal diols as efficient substrates for transglycosylational activity of NAD glycohydrolase.

Linear terminal alkane-diols have been shown to function as more efficient substrates of the transglycosylational activity of NAD+ glycohydrolase (NADase) than the corresponding respective 1-alkanols. A series of eight alkane-diols from ethane-1,2- to nonane-1,9-diols underwent an O-ADP-ribosylation in the incubation reaction with NAD/NADase to provide the corresponding ribosylated products. The structural properties of these products were characterized by 1H NMR and MS spectrometries. No substantial double ADP-ribosylation of the two hydroxy functions was observed which was initially expected in the diols of higher carbon number.

Alcohols↗
PubMed1999

[Effect of the consumption of ethanol on the microcirculation of the human optic nerve head in the acute phase].

PURPOSE: The effect of the consumption of ethanol on the circulation of the optic nerve head (ONH) in the human eye in the acute phase and its mechanism were studied. METHODS: Eleven volunteers drank a bottle of beer (633 ml) with or without ethanol (29.5 g). Normalized blur (NB), a quantitative index of blood flow velocity, was measured in the temporal site of the ONH. NB, blood pressure (BP) and pulse rate (PR) were measured before, immediately after, and every 15 minutes for 90 minutes after consumption. Intraocular pressure (IOP) and plasma ethanol concentration were measured before, and 30 and 90 minutes after consumption. Genotyping of the aldehyde dehydrogenase (ALDH) 2 gene was also performed. RESULTS: NB in the ONH increased significantly from 15 to 45 minutes after consumption of ethanol and the maximum increase was 14% at 15 minutes. IOP was lowered at 90 minutes after consumption, but it was not significant. Mean BP was lowered significantly after 60 minutes. PR and ocular perfusion pressure did not change. A significant correlation was found between plasma ethanol concentration at 30 minutes and maximum NB. NB in the ALDH 2-deficient group was significantly larger from 15 to 45 minutes after consumption than in the proficient group. CONCLUSION: It appeared that the consumption of ethanol can increase the blood flow in the human ONH in the acute phase through decreased resistance in blood vessels induced by acetaldehyde, a metabolite of ethanol.

Adult↗
PubMed1998

Desmopressin-induced dog ciliary artery relaxation.

In isolated dog posterior ciliary arteries contracted with prostaglandin F2alpha, desmopressin (10(-10) to 10(-8) M), a vasopressin V2 receptor agonist, produced a concentration-related relaxation, which was reversed to a contraction by removal of the endothelium. Desmopressin was approximately 1/100 as potent as arginine vasopressin. Treatment with NG-nitro-L-arginine, a nitric oxide (NO) synthase inhibitor, reversed the desmopressin-induced relaxation to a contraction and the addition of L-arginine restored the relaxation. SR49059 ((2S)1-[(2 R3S)-(5-chloro-3-(2-chlorophenyl)-1-(3,4-methoxybenzene-s ulfony)-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl]-pyrrolidine-2-car boxamide), a selective vasopressin V1 receptor antagonist, suppressed the relaxation. In endothelium-denuded arteries, desmopressin-induced contractions were also inhibited by SR49059. It is concluded that desmopressin, although much less potent than vasopressin, relaxes ciliary arteries via a mediation of NO synthesized from L-arginine in the endothelium. Vasopressin V1-receptor Subtypes appear to be involved in the desmopressin-induced relaxation and contraction.

Animals↗
PubMed1998

Bovine lactoferrin and Lactoferricin inhibit tumor metastasis in mice.

The effect of a bovine milk protein, lactoferrin (bLf), and a pepsin-generated peptide of bLf, lactoferricin (Lfcin-B), on inhibition of tumor metastasis produced by highly metastatic murine tumor cells, B16-BL6 melanoma and L5178Y-ML25 lymphoma cells, was examined in experimental and spontaneous metastasis models using syngeneic mice. The subcutaneous (s.c.) administration of bovine apo-lactoferrin (apo-bLf) and Lfcin-B 1 day after tumor inoculation significantly inhibited liver and spleen metastasis of L5178Y-ML25 cells and lung metastasis of B16-BL6 cells, whereas human apo-lactoferrin (apo-hLf) and bovine holo-lactoferrin (holo-Lf) at the dose of 1 mg/mouse did not. Furthermore, both apo-bLf and Lfcin-B, but not apo-hLf and holo-bLf, inhibited the number of tumor-induced blood vessels and suppressed tumor growth on day 8 after tumor inoculations in an in vivo model. However, in a long-term analysis of tumor growth for up to 21 days after tumor inoculation, single administration of apo-bLf significantly suppressed the growth of B16-BL6 cells throughout the examination period, but Lfcin-B showed inhibitory activity only during the early period (8 days). In spontaneous metastasis model, multiple administration of both apo-bLf and Lfcin-B significantly inhibited lung metastasis of B16-BL6 cells, however it was only apo-bLf that exhibited the inhibitory effect of tumor growth at the time of primary tumor amputation (on day 21) after tumor inoculation. The results suggest that apo-bLf and Lfcin-B inhibit tumor metastasis through different mechanisms, and that the inhibitory activity of bLf on tumor metastasis may be related to the property of iron (Fe3+)-saturation.

Animals↗
PubMed1998

Characterization of neutralizing monoclonal antibody escape mutants of Hantaan virus 76118.

Neutralizing monoclonal antibody (MAb) escape mutants of Hantaan virus were generated using MAbs to envelope protein G1 (16D2) and G2 (11E10). The mutant viruses (mu16D2 and mu11E10), lacked reactivity only to the selecting MAb, or a MAb belonging to the same antigenic site. Both mutants had a single amino acid (a.a.) substitution. The a.a. substitution, found in mu16D2, was different from that found in another mutant selected with the same MAb (16D2). Although MAb 11E10 immunoprecipitated G2 protein, a deduced a.a. substitution was located in the G1 region. These results suggest that antigenic sites defined by neutralizing MAbs are composed of discontinuous epitopes over the G1 and G2 proteins. Mutant 11E10 showed a significant decrease in virulence in suckling mice. A virulence revertant of mu11E10, selected through passages in suckling mice brain, showed exactly the same deduced a.a. sequence as mu11E10 and still was not neutralized by MAb 11E10. Since mutant 16D2 was virulent for suckling mice, neutralization related epitopes found with MAbs 11E10 and 16D2 were independent of pathogenicity in BALB/c mice.

Amino Acid Substitution↗
PubMed1998

Mannan decelerates the clearance of human red blood cells in SCID mouse.

Mannans and its related compounds decelerated human (Hu) red blood cell (RBC)-clearance in severe combined immunodeficiency (SCID) mice by inhibiting erythro-phagocytosis of macrophages. Chimeric SCID mice for Hu-RBC which are generated by repeated transfusions with mature Hu-RBCs are described recently as a model for Plasmodium falciparum infection, though the Hu-RBC clearance in the mice at present is very rapid and the parasitemia in the mice is only erratic. Here, we aimed to study the method to decelerate Hu-RBC clearance in SCID mice, to establish a suitable mouse model for malaria parasites. Yeast and Candida mannans as well as lactoferrin, a glycoprotein containing both oligomannoside- and N-acetyllactosamine-type glycans, decelerated Hu-RBC clearance, but instead other saccharides such as carboxymethyl chitin, N-acetylglucosamine, and D-glucose did not. Yeast mannan and lactoferrin interfered significantly with in vitro Hu-RBC-phagocytosis which was also inhibited by mannopentaose and mannotoriose. D-mannose exhibited a moderate inhibitory activity. N-acetyl-D-glucosamine, however, showed only a slight inhibitory activity, but D-glucose had no inhibitory activity on Hu-RBC phagocytosis. These results may postulate that Hu-RBC clearance in SCID mouse might be mediated by receptor-ligand binding by a macrophage lectin like receptor with mannose specificity.

Acetylglucosamine↗
PubMed1998

Enhancing activity of mycobacterial cell-derived adjuvants on immunogenicity of recombinant human hepatitis B virus vaccine.

In a previous study, we demonstrated that a lipophilic derivative of muramyl dipeptide [MDP-Lys(L18)] augmented antibody response to recombinant human hepatitis B surface antigen (rhHBsAg) when it was co-immunized with rhHBsAg solubilized in PBS. Here, we examined adjuvant activity of two bacterial cell-derived adjuvants such as Bacillus Calmette-Guérin cell wall skeleton (BCG-CWS) and trehalose-6,6'-dimycolate (TDM), to enhance immunogenicity of rhHBsAg, comparing their activity with that of MDP-Lys(L18). In an animal model where mice were immunized subcutaneously (s.c.) with rhHBsAg (25 micrograms/mouse) admixed with 100 micrograms/mouse of BCG-CWS (Vac/BCG-CWS) or 50 micrograms/mouse of TDM (Vac/TDM) in o/w emulsion formulation, both mice immunized with Vac/BCG-CWS and Vac/TDM showed higher antibody titres to HB antigen than those of mice immunized with the recombinant vaccine alone. The activity of BCG-CWS and TDM to enhance antibody induction seemed to be almost the same with that of MDP-Lys(L18). Furthermore, the enhanced antibody response raised by these adjuvants was shown to be due to high titres of HB antigen-specific IgG1. In addition, the activity of these three adjuvants to enhance antibody response was shown to be higher than that of the present clinical vaccine, aluminium hydroxide-attached rhHBsAg (rhHBsAg-alum). In an analysis of delayed-type hypersensitivity (DTH) reaction where mice were immunized with rhHBsAg admixed with or without each adjuvant in o/w emulsion and followed by intrafootpad (i.f.) injection of rhHBsAg 4 weeks after immunization, mice immunized with Vac/BCG-CWS and Vac/TDM as well as Vac/MDP-Lys(L18) showed a significant increment of swelling reaction. These results suggest that BCG-CWS, TDM and MDP-Lys(L18) are potential adjuvants to enhance the immunogenicity of rhHBsAg to induce humoral and cellular responses.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1998

A new pseudo-peptide of Arg-Gly-Asp (RGD) with inhibitory effect on tumor metastasis and enzymatic degradation of extracellular matrix.

A series of pseudo-peptide analogs of the Arg-Gly-Asp (RGD) sequence of fibronectin have been synthesized, and their anti-metastatic effects in mice and inhibitory effects on tumor cell invasion in vitro have been examined. The partially modified retro pseudo-peptide of RGD, Rrev-COCH2CO-D (FC-63), was more effective in inhibiting tumor metastasis than the original RGDS peptide. Replacement of the malonyl moiety of FC-63 with a carboxyethylene linkage (Rrev-COCH2CH2-D, FC-303 ) achieved more potent inhibition of lung metastasis of melanoma cells than FC-63. Among the analogs, FC-336, a p-xylylendiamine derivative having two FC-303 moieties, showed the most potent inhibitory effect on experimental lung metastasis produced by i.v. co-injection with B16-BL6 melanoma or colon 26 M3.1 cells in a dose-dependent manner. Multiple administrations of FC-336 after tumor inoculation also showed efficient therapeutic potency against spontaneous lung metastasis of B16-BL6 melanoma in mice. Furthermore, FC-336 effectively inhibited the invasion, migration and adhesion of tumor cells in vitro, but its inhibitory effects were not more than those of RGDS peptide. Zymography analysis revealed that FC-336 inhibited the degradation of gelatin substrate by matrix metalloproteinases (MMPs) produced by tumor cells, while the RGDS peptide did not affect the enzymatic degradation. These findings indicate that the pseudo-peptides of the RGD sequence, possessing the inhibitory property of the degradation by MMPs differently from original RGD-containing peptides, may be advantageous and useful in preventing tumor metastasis.

Animals↗
PubMed1998

Vaccination with B7-1+ tumor and anti-adhesion therapy with RGD pseudo-peptide (FC-336) efficiently induce anti-metastatic effect.

We have previously shown that expression of costimulatory ligand B7-1 on MHC class I+ tumor cells (B16-BL6 melanoma) resulted in marked reduction of lung metastasis caused by i.v. injection into immunocompetent syngeneic mice and led to induction of immunity to the challenge by the parental B7-1 negative tumor. Here we investigated the effectiveness of irradiated B7-1 transfected tumor cells as a vaccine on established tumor metastasis and whether or not expression of B7-1 molecule on tumor cells in combination with administration of anti-adhesion peptide FC-336 can augment the antimetastatic efficacy. Immunization with X-irradiated B7-1 transfectants after i.v. injection of B7-1- parental B16-BL6 cells was effective in inhibiting lung metastasis. We also found that vaccination with irradiated B7-1 transfectants after excision of primary tumor on day 21 resulted in significant inhibition of spontaneous lung metastasis by intrafootpad injection of viable parental B16-BL6 melanoma, as compared with the untreated control. However, immunizing twice with mock transfectants did not affect inhibition of spontaneous lung metastasis of wild-type tumors. On the other hand, multiple administration of a pseudo-peptide of RGD sequence (FC-336) after tumor inoculation inhibited spontaneous lung metastasis through the interference of tumor invasion, migration and adhesion. Combined treatment of B7-1 transfected tumor vaccine and anti-adhesive therapy with FC-336 led to the augmentation of the antimetastatic effect in both experimental and spontaneous metastasis models, as compared with either treatment alone. B7-1- and FC-336-mediated inhibition of tumor metastasis may be mediated by different mechanisms at various steps of metastasis, based on the regulation (promotion or inhibition) of tumor interaction with host cells and components.

Animals↗
PubMed1998

[Biochemical and immunological properties of the fractions of tubercle bacilli].

In 1954, Dr. Yuichi Yamamura and his coassociates, National Sanatorium Toneyama Hospital, has reported the formation of experimental tuberculous cavity in rabbits. This work was a milestone of the researches in the field of cellular immunology. In 1960, I have started my scientific carrier in Kyushu University Medical School as the post-graduate student under the guidance of Prof. Yamamura. Since then, I have worked on the field of biochemical and immunological properties of tubercle bacilli. The arabinose mycolate, polysaccharides, cell-wall skeleton (CWS) and trehalose dimycolate (TDM) were purified from tubercle bacilli and their Chemical structures and biological activities were investigated in detail in our laboratory. In 1971, we have reported that adjuvant active principle of tubercle bacilli was a CWS fraction, and the details of chemical structure and adjuvantity of mycobacterial CWS were investigated in our research group. The application of BCG-CWS to cancer immunotherapy was also studied. In 1974, Prof. E. Lederer and his coworkers, University of Paris, have reported that N-acetyl muramyl-L-alanyl-D-isoglutamine (MDP) was the minimum adjuvant-active structure of bacterial cell wall. We have synthesized several hundreds of MDP derivatives and selected, MDP-Lys(L18), romurtide, as the candidate of cytokine inducer for the clinical application. Romurtide is applied in cancer patients for the recovery of the number and functions of monocytes, neutrophils and platelets. These results suggest that the tubercle bacilli, especially, CWS and related synthetic MDP derivatives, are effective for the potentiation of host resistance against infectious diseases and cancer.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1998

[The effect of continuous and intravenous application of carteolol chloride on tissue blood flow in the rabbit optic nerve head].

The effect of systemic application of carteolol, which induces almost the same plasma carteolol level as obtained by a long-term instillation on rabbit eyes, on the tissue blood flow in the optic nerve head (ONH) was investigated in rabbits. The plasma carteolol levels in 27 rabbits which received 3-week instillation, intravenous injection (10, 20, 30 micrograms/kg), or continuous intravenous injection (2.5, 5, 20, 40, 80 micrograms/kg/hr) were measured by gas chromatography-negative-ion chemical ionization mass spectrometry. The plasma level with 3-week instillation was determined as 5.55 ng/ml and a continuous intravenous injection (5 micrograms/kg/hr) caused nearly the same plasma level. The intravenous injection of this dose significantly increased the ONH blood flow which was determined by the hydrogen clearance method, compared with controls from 30 minutes to 2 hours after the injection (n = 10). The vascular resistance in ONH was thought to be reduced because mean blood pressure and intraocular pressure (n = 6) were not significantly changed. The results suggest that the plasma carteolol level in rabbits after a long-term instillation can increase ONH blood flow due to a decreased vascular resistance.

Adrenergic beta-Antagonists↗
PubMed1997

Apoptosis in human leukemic cells induced by lactoferricin, a bovine milk protein-derived peptide: involvement of reactive oxygen species.

We examined the activity of bovine lactoferricin (Lfcin-B), a peptide derived from a bovine milk protein lactoferrin (LF-B), to induce apoptosis in THP-1 human monocytic leukemic cells. Treatment with Lfcin-B at up to 50 micrograms/ml induced cell death in THP-1 cells in dose- and time-dependent manner, showing apparent morphological changes, hypodiploid forms of genomic DNA and apoptotic DNA fragmentation, whereas LF-B was inactive even at a high dose (500 micrograms/ml). The apoptosis-inducing effect of Lfcin-B increased with reduction of serum concentration, but was inhibited by addition of Zn2+, a inhibitor of Ca2+/Mg(2+)-dependent endonucleases in a dose-dependent manner. Furthermore, Lfcin-B-induced apoptosis in THP-1 cells was completely abolished by addition of antioxidants such as N-acetyl-L-cysteine (NAC) and glutathione (GSH), but not by various cytokines and mitogen which can activate monocytic cells. In addition, THP-1 cells treated with Lfcin-B, but not LF-B, showed high levels of intracellular reactive oxygen species (ROS) from the early period (20 min) of Lfcin-B treatment. And the production of ROS by Lfcin-B was dependent upon the dose of Lfcin-B added. These results suggested that Lfcin-B, a LF-B-derived peptide, but not LF-B itself, is able to induce apoptosis in THP-1 human monocytic tumor cells, and that its apoptosis-inducing activity is related to the pathway mediated by production of the intracellular ROS and activation of Ca2+/Mg(2+)-dependent endonucleases.

Acetylcysteine↗
PubMed1997

Domain-specific phosphorylation of vimentin and glial fibrillary acidic protein by PKN.

PKN is a serine/threonine protein kinase with a catalytic domain homologous to the protein kinase C family and unique N-terminal leucine zipper-like sequences. Using analyses with the yeast two-hybrid system and in vitro binding assay, we found that the regulatory domain of PKN interacted with vimentin. We then examined whether PKN would phosphorylate vimentin in vitro. Vimentin proved to be an excellent substrate for PKN, and the phosphorylation of vimentin by PKN occurred in the head domain with the result of a nearly complete inhibition of its filament formation in vitro. Similar results were also obtained with another type III intermediate filament protein, glial fibrillary acidic protein (GFAP). These results raise the possibility that PKN may regulate filament structures of vimentin and GFAP by domain-specific phosphorylation.

Animals↗
PubMed1997

Clinical evaluation of UF-021 (Rescula; isopropyl unoprostone).

We have reviewed two Phase III clinical studies of isopropyl unoprostone conducted in Japan: a 12-week comparative study of 0.12% isopropyl unoprostone and 0.5% timolol, and a 52-week administration of two concentrations of isopropyl unoprostone in ocular hypertensive and primary open-angle glaucoma patients. These studies showed a similar ocular hypotensive effect of 0.12% isopropyl unoprostone to 0.5% timolol and a sustained ocular hypotensive effect of the drug for up to one year. Adverse reactions of isopropyl unoprostone were minor and similar to those of timolol. No pigmentary changes of the irides were noticed. In view of these results, isopropyl unoprostone seems to be a useful antiglaucoma medication.

Administration, Topical↗
PubMed1997

Protective effect of mucosal administration of recombinant human macrophage colony-stimulating factor (rhM-CSF) on mucosal infection of Sendai virus in mice.

We investigated the protection confered by the mucosal administration of recombinant human macrophage colony-stimulating factor (rhM-CSF) against mucosal infection of Sendai virus in mice. In an experimental infection model using Sendai virus, an intranasal (i.n.) administration of rhM-CSF (20 micrograms per mouse) 2 days before injection induced significant protection against a lethal infection of this virus. Also, its antiviral activity was dependent upon the dose of rhM-CSF. However, a subcutaneous (s.c.) administration of rhM-CSF with an effective dose (20 micrograms per mouse) i.n. did not confer protection. In a time course analysis of virus growth in the lungs, mice given rhM-CSF. i.n. significantly inhibited the early period of infection, compared with the untreated mice. Moreover, the level of interferon-gamma (IFN-gamma) in lung wash fluids from the rhM-CSF-treated mice was higher than that of the untreated mice. These results suggested that the mucosal (i.n.), but not the systemic (s.c.) administration of rhM-CSF augments host resistance against mucosal infection with Sendai virus, and that its prophylactic activity is related to growth inhibition of the virus and enhanced IFN-gamma secretion in the lungs.

Animals↗
PubMed1997

Romurtide, a synthetic muramyl dipeptide derivative, promotes megakaryocytopoiesis through stimulation of cytokine production in nonhuman primates with myelosuppression.

The response of megakaryocytes and cytokines to the administration of romurtide, a synthetic muramyl dipeptide derivative, was investigated in monkeys with myelosuppression by carboplatin-treatment. Romurtide increased the number of megakaryocytes and promoted the shift of megakaryocytes towards high ploidy class indicative of the promotion of the proliferation and maturation of megakaryocytes. The serum levels of interleukin-6, stem cell factor, and erythropoietin elevated significantly before the enhanced response of megakaryocytes induced by romurtide was observed. Romurtide also enhanced production of colony-stimulating factors (CSFs), such as granulocyte-CSF, macrophage-CSF, and granulocyte-macrophage CSF by monkey mononuclear cells. The stimulating effect of romurtide on the production of those cytokines and CSFs is likely to be responsible for the subsequent promotion of the proliferation and maturation of marrow megakaryocytes.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1997

Bovine lactoferrin and lactoferricin, a peptide derived from bovine lactoferrin, inhibit tumor metastasis in mice.

We investigated the effect of a bovine milk protein, lactoferrin (LF-B), and a pepsin-generated peptide of LF-B, lactoferricin (Lfcin-B), on inhibition of tumor metastasis produced by highly metastatic murine tumor cells, B16-BL6 melanoma and L5178Y-ML25 lymphoma cells, using experimental and spontaneous metastasis models in syngeneic mice. The subcutaneous (s.c.) administration of bovine apo-lactoferrin (apo-LF-B, 1 mg/mouse) and Lfcin-B (0.5 mg/mouse) 1 day after tumor inoculation significantly inhibited liver and lung metastasis of L5178Y-ML25 cells. However, human apolactoferrin (apo-LF-H) and bovine holo-lactoferrin (holo-LF-B) at the dose of 1 mg/mouse failed to inhibit tumor metastasis of L5178Y-ML25 cells. Similarly, the s.c. administration of apo-LF-B as well as Lfcin-B, but not apo-LF-H and holo-LF-B, 1 day after tumor inoculation resulted in significant inhibition of lung metastasis of B16-BL6 cells in an experimental metastasis model. Furthermore, in in vivo analysis for tumor-induced angiogenesis, both apo-LF-B and Lfcin-B inhibited the number of tumor-induced blood vessels and suppressed tumor growth on day 8 after tumor inoculation. However, in a long-term analysis of tumor growth for up to 21 days after tumor inoculation, single administration of apo-LF-B significantly suppressed the growth of B16-BL6 cells throughout the examination period, whereas Lfcin-B showed inhibitory activity only during the early period (8 days). In spontaneous metastasis of B16-BL6 melanoma cells, multiple administration of both apo-LF-B and Lfcin-B into tumor-bearing mice significantly inhibited lung metastasis produced by B16-BL6 cells, though only apo-LF-B exhibited an inhibitory effect on tumor growth at the time of primary tumor amputation (on day 21) after tumor inoculation. These results suggest that apo-LF-B and Lfcin-B inhibit tumor metastasis through different mechanisms, and that the inhibitory activity of LF-B on tumor metastasis may be related to iron (Fe3+)-saturation.

Animals↗