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Biomedical subjects

I Azuma

Publications and source records attributed to I Azuma.

At least 55 records · Page 3Linked to original sources
PubMed1990

Activation by synthetic lipid A subunit analogues (GLA compounds) of tumoricidal properties in human blood monocytes.

The authors have determined that synthetic lipid A subunit analogues (GLA compounds), as well as E. coli type lipopolysaccharide (LPS) and synthetic lipid A (compound 506), are able to stimulate human monocytes to become cytotoxic against tumour target cells in vitro. GLA-60, a synthetic lipid A subunit analogue of low toxicity, was found to be more active for the induction of tumoricidal monocytes than GLA-59, and similar to that of LPS. GLA-60 could induce not only the secretion of cytotoxic factor into the culture supernatant but also expression of the membrane-associated form of cytotoxic factor in human monocytes. Supernatant-mediated cytotoxicity was completely inhibited by the addition of monoclonal anti-human TNF antibody. These results indicate that a synthetic lipid A subunit analogue, GLA-60, would be a useful activator of tumoricidal monocytes in spite of its low toxicity.

Adjuvants, Immunologic↗
PubMed1990

Prophylactic activity of dihydroheptaprenol, a synthetic polyprenol derivative, against Sendai virus infection in mice.

The effect of a chemically synthesized polyprenol derivative, dihydroheptaprenol (DHP), on the non-specific resistance of mice to Sendai virus infection was investigated. The mice that received 200 micrograms of DHP intranasally twice, at 3 days and 1 day before the infection, showed a significant protection against Sendai virus infection. Treatment of mice twice even with as much as 2000 micrograms of DHP through the subcutaneous route, however, had no protective effect against infection. Excess interferon and tumour necrosis factor production in intranasally DHP-treated mice was seen 1 day after the infection when compared with Sendai virus alone controls or with DHP alone controls. Variance analysis of these findings indicates a prophylactic activity of DHP in pulmonary viral infections.

Administration, Intranasal↗
PubMed1990

Staphylococcal enterotoxin A induced interferon (IFN)-gamma production in spleen cells from BCG-immunized mice: the IFN production is dependent on leukotriene C4 but not dependent on interleukin 2.

In our previous paper, we showed that IFN was induced in sera by injection of staphylococcal enterotoxin A (SEA) in Bacillus Calmette-Guérin (BCG) immunized C57BL/6 (B6) mice. In analyzing the phenomenon in vitro, we showed that SEA induced IFN-gamma in the supernatant of the spleen cell culture from BCG immunized B6 mice and that leukotriene C4 (LTC4) from BCG activated macrophages in the spleen was involved in the IFN production from Ly 1+ T cells. On the other hand, interleukin-2 (IL-2) has reported to play an important role in the regulation of synthesis of IFN-gamma by T cells. In the present study, we examined whether IL-2 is involved in SEA-induced IFN production. The result showed that the SEA-induced IFN-gamma production was observed in spite of suppression of SEA-induced IL-2 production in spleen cells from BCG-immunized B6 mice. On the contrary, the depressed IFN production was observed in spite of high SEA-induced IL-2 production in spleen cells from their control mice. On the other hand, LTC4 production was 8 times higher in spleen cells from BCG-immunized B6 mice, high producer of SEA-induced IFN, than in that from BCG-immunized C3H mice, the low producer. We also observed that the IFN and the LTC4 production of spleen cells from BCG-immunized B6 mice was suppressed in the presence of caffeic acid and nordihydroguaiaretic acid, non-specific lipoxygenase inhibitors, and that LTC4 augmented the IFN production of normal B6 mouse spleen cells in the presence of 2-mercaptoethanol. Therefore, involvement of LTC4 rather than of IL-2 was supported in our experimental system.

Animals↗
PubMed1990

Inherited hyperactivation of L-arginine synthesis in gamma + B lymphocytes of systemic autoimmune MRL mice.

The hyperactivation of B lymphocytes of MRL mice, which are an animal model for human systemic lupus erythematosus (SLE), is characterized as the preferential propagation of gamma + B lymphocytes and IgG overproduction followed by aging. Little is known about the molecular mechanisms, although the involvement of cytokines has been extensively investigated. Here we now show that gamma-committed B lymphocytes selectively exhibit a highly elevated L-citrulline metabolism while mu or alpha-committed B lymphocytes show a normal level in autoimmune MRL mice. L-Arginine proportionally supports the lymphocyte proliferation and antibody production in a concentration-dependent fashion (approximately 100 microM). However, normal murine lymphocytes show an extremely low activity of citrulline metabolism, which converts L-citrulline to L-arginine. Thus, these results suggest that the overexpression of elevated citrulline metabolism is associated with gamma chain expression, and this elevation may enable gamma-committed B lymphocytes to preferentially propagate and overproduce IgG compared with mu or alpha-committed B lymphocytes.

Animals↗
PubMed1990

Inhibition of tumor cell arrest in lungs by antimetastatic chitin heparinoid.

We have investigated the effect of sulfated chitin derivatives on the intravascular events in the metastatic cascade. 6-O-Sulfated carboxymethyl chitin (SCM-chitin III), as well as heparin, significantly inhibited the arrest of B16-BL6 cells in lungs after co-injection with radiolabeled tumor cells, but carboxymethylated chitin (CM-chitin) had no effect. Heparin showed a potent inhibitory effect on tumor cell-elicited platelet aggregation and on blood coagulation, which can subsequently enhance the survival, arrest and invasiveness of tumor cells, whereas SCM-chitin III showed much weaker properties. In contrast, SCM-chitin III was found to inhibit the adhesion of tumor cells to subendothelial matrix, while heparin did not. SCM-chitin III was still active in inhibiting experimental lung metastasis even in mice which had been pretreated with anti-asialo GM1 serum or carrageenan to eliminate NK cells or macrophages. Thus, these results suggest that SCM-chitin-mediated inhibition of tumor metastases is distinct from that by heparin and may be due to interference with tumor cell arrest in the capillaries and consequently to the inhibition of tumor cell adhesion to subendothelial matrix.

Animals↗
PubMed1990

In vitro activation of bovine macrophage and peripheral blood mononuclear cells by Nocardia rubra cell wall skeleton (N-CWS).

Nocardia rubra cell wall skeleton (N-CWS) was used for immunotherapy to bovine leukemia virus (BLV)-positive cattle with enlarged subcutaneous lymphatic nodules. Electron microscopical observations showed the infiltration of macrophage and T cells around N-CWS treated lesions. Antitumor effect induced by N-CWS was examined in vitro. The maximum cytolytic activity of macrophage was observed, when the cells were incubated with 10 micrograms/ml of N-CWS. Chemiluminescence response of peripheral blood mononuclear cells (PBMC) using N-CWS as stimulant was observed with a high level of activity for a long period, 5 hr. Mitogenic effect of N-CWS to PBMC was observed in the presence of macrophages but not without macrophages. Furthermore, interleukin 2 activity was recognized in supernatant of PBMC cultured with N-CWS. Maximum cytotoxic T lymphocyte response was induced when PBMC were cultured with 0.1 micrograms/ml of N-CWS.

Animals↗
PubMed1990

Cloning and nucleotide sequence of the gene encoding arginine deiminase of Mycoplasma arginini.

The existence of a mycoplasmal arginine deiminase which catalyzes the conversion of L-arginine to L-citrulline has been postulated. Here we show the partial amino acid sequence of arginine deiminase of Mycoplasma arginini and the complete nucleotide sequence of the arginine deiminase gene of M. arginini. The open reading frame deduced from this sequence consists of 1,230 bp encoding 410 amino acids. The mature form of this enzyme contains 409 amino acids after the deletion of the first methionine. In this open reading frame, TGA nonsense codons are used as tryptophan codons; this usage was verified by determination of the amino acid sequence. The molecular weight of the enzyme calculated from the deduced amino acid sequence is 46,372. Recently, the nucleotide sequence of the arginine deiminase gene of M. arginini was reported by Kondo et al. (K. Kondo, H. Sone, H. Yoshida, T. Toida, K. Kanatani, Y.-M. Hong N. Nishino, and J. Tanaka, Mol. Gen. Genet. 221:81-86, 1990). However, their sequence differed from ours in several places and especially at the C terminus.

Amino Acid Sequence↗
PubMed1990

Identification and purification of arginine deiminase that originated from Mycoplasma arginini.

A lymphocyte blastogenesis inhibitory factor, (LBIF), was purified from the culture supernatant of human histiocytic lymphoma U937 by fast protein liquid chromatography. In this study, we demonstrated, first, that LBIF originated from a mycoplasma, Mycoplasma arginini, infecting U937 cells, and second, that LBIF bore the arginine deiminase activity. The implication of in vivo immunosuppression induced by arginine-utilizing mycoplasma species is discussed.

Animals↗
PubMed1990

6-O-carboxymethyl-chitin (CM-chitin) as a drug carrier.

Gel was prepared from 6-O-carboxymethyl-chitin (CM-chitin) by the addition of iron(III) chloride under mild conditions without any organic solvent. The optimal conditions for the gel formation were 15 to 30 mM iron(III) chloride and 0.5 to 0.8 degree of substitution in CM-chitin. The amounts of bovine serum albumin (BSA) and the anticancer drug doxorubicin (DOX) incorporated into CM-chitin gels were more than 80% and 30%, respectively under the conditions described above. The release of BSA or DOX from the gels was observed to be increased by lysozyme digestion in a time-dependent manner. This result indicates that CM-chitin might prove useful as a carrier gel for the sustained release of drugs and cytokines, including vaccines.

Animals↗
PubMed1990

Effect of chitin heparinoids on the activation of peritoneal macrophages and on the production of monokines in mice.

Sulfonated derivatives of chitin which showed anticoagulant activity (chitin heparinoids) were studied with regard to the activation of mouse peritoneal macrophages and the production of monokines. In comparison with 70% deacetylated chitin (DAC-70), which was the most adjuvant-active derivative of chitin, all chitin heparinoids were less effective for the augmentation of cytolytic activity of peritoneal macrophages. The number of macrophages was hardly increased or decreased by intraperitoneal injection of chitin heparinoids, and the activity of circulating colony-stimulating factor was not changed by their treatment. Only N-sulfonated DAC-70 stimulated the production of interleukin-1 by thioglycolate-induced peritoneal macrophages in vitro. However, its effect was weaker than that of DAC-70. Chitin heparinoids showed no or weak mitogenic activity on normal mouse spleen cells.

Adjuvants, Immunologic↗
PubMed1989

Synthesis and immunoadjuvant activity of 2,2'-O-[2,2'-diacetamido-2,3,2',3'-tetradeoxy-6,6'-di-O-(2-tetradecyl- hexadecanoyl)-alpha,alpha'-trehalose-3,3'-diyl]bis(N-D-lactoyl-L-alanyl -D-isoglutamine).

The disaccharide of 6-O-(2-tetradecylhexadecanoyl)muramoyl dipeptide coupled through an alpha-(1----1)-alpha linkage, named in the title, and an analog bearing a single peptide moiety, have been synthesized from 2,2'-diazido-2,2'-dideoxy-alpha,alpha'-trehalose. The immunoadjuvant activities of the products were examined.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1989

Inhibition of the metastasis of murine malignant melanoma by synthetic polymeric peptides containing core sequences of cell-adhesive molecules.

We investigated that the antimetastatic and antiadhesive activities of peptides based on Arg-Gly-Asp adhesive signal in fibronectin could be augmented by their polymerization. Poly(Arg-Gly-Asp), which consists of a repetitive sequence of Arg-Gly-Asp, inhibited lung metastases in C57BL/6 mice more effectively than Arg-Gly-Asp tripeptide was able to do, when coinjected or separately injected with B16-BL6 cells. The adhesion of tumor cells to fibronectin was specifically inhibited by adding poly(Arg-Gly-Asp) but not unrelated peptides. In contrast, poly(Arg, Gly, Asp), in which three amino acids are randomly arranged, showed neither inhibition of lung metastases nor any adhesive ability to attach to tumor cells. The inhibitory effect of polymeric peptides containing the Arg-Gly-Asp sequence on lung metastases decreased according to the decreasing repeat units of the Arg-Gly-Asp core sequence. Polymeric peptides with Arg-Gly-Asp entrapped within the liposome membranes also caused a remarkable reduction of metastatic colonies. In a spontaneous metastasis model, multiple i.v. administrations of poly(Arg-Gly-Asp) after tumor inoculation caused the significant reduction of metastatic colonies in the lung but did not affect the growth (size) of primary tumor. We found that the polymerization (multivalency) of the Arg-Gly-Asp core sequence was able to augment the inhibition of tumor lung metastases in experimental and spontaneous metastasis models as well as the cell-adhesive property more effectively than a monovalent unit of Arg-Gly-Asp peptide.

Amino Acid Sequence↗
PubMed1989

A cytokine, lymphocyte blastogenesis inhibitory factor (LBIF), arrests mitogen-stimulated T lymphocytes at early G1 phase with no influence on interleukin 2 production and interleukin 2 receptor light chain expression.

The function of a human cytokine, lymphocyte blastogenesis inhibitory factor (LBIF), was characterized. To this end, LBIF was purified from crude supernatant of U-937 cells, a human macrophage-like cell line, by using fast protein liquid chromatography (FPLC). We demonstrated here that (a) the LBIF preparation completely inhibited phytohemagglutinin (PHA)-stimulated T cell proliferation; (b) however, in PHA-stimulated T lymphocytes LBIF inhibited neither interleukin (IL)2 production nor the expression of IL2 receptor (IL2R) light chain (CD25) which play a critical role for T cell proliferation; (c) LBIF arrested PHA-stimulated T lymphocytes at the G1 phase of cell cycle and inhibited entry into S phase, thus inhibiting lymphocyte proliferation. Wright-Giemsa's staining of the cells showed that PHA/LBIF-stimulated cells were arrested in early G1. In agreement with this result, LBIF strongly inhibited PHA-induced RNA synthesis. Further, LBIF inhibited the induction of the transferrin receptor which is normally expressed at the late G1 phase of the cell cycle. The inhibitory activity of LBIF was reversible. Thus, this study elucidated that LBIF arrests PHA-stimulated T lymphocytes at a point between the stages of IL2 production or IL2R light chain expression (in early G1) and transferrin receptor expression (in late G1). Taken together, these results suggest that there might be a control system of T cell proliferation distinct from the previously reported mechanisms, such as the inhibition of IL2 production or the inhibition of IL2R light chain (CD25) expression, and that LBIF might be an important molecule in the regulation of normal lymphocyte proliferation.

Biological Factors↗
PubMed1989

Induction of an endogenous tumor necrosis factor in mice by murine recombinant interferon-gamma combined with a lipid A subunit analog (GLA-60) of low toxicity.

We have investigated the endogenous production of a serum cytotoxic factor when recombinant interferon-gamma (rIFN-gamma) is combined with synthetic lipid A subunit analogs of low toxicity (GLA compounds). The cytotoxic activity of the serum was measured by the crystal violet staining method with L929 cells as a target. Intravenous administration of rIFN-gamma followed by intravenous administration of lipopolysaccharide induced the endogenous production of a cytotoxic factor in the serum. The priming effect of rIFN-gamma appeared immediately and persisted for approximately 20 h after the injection. Administration of lipopolysaccharide as a trigger enhanced the production of the cytotoxic factor in the serum maximally 2 h after the injection. The cytotoxic activity in the serum was completely inhibited by anti-(mouse tumor necrosis factor) (TNF) antibody. A synthetic lipid A subunit analog (GLA-60), which is much less toxic in its endotoxin activities than lipopolysaccharide or synthetic lipid A (compound 506), induced the endogenous production of serum TNF in rIFN-gamma-primed mice. GLA-60 entrapped within liposomes induced the production of serum TNF in rIFN-gamma-primed mice more effectively than GLA-60 solubilized in phosphate-buffered saline. Intravenous or intranasal administrations of rIFN-gamma followed by intranasal administration of GLA-60 produced TNF in the lung washing fluid but not in the serum, indicating that TNF production can be induced locally rather than systemically by the alteration of the administration route of the primer and trigger. These results indicate that GLA-60, a lipid A subunit analog of low toxicity, is a beneficial triggering agent in the production of endogenous TNF, as well as having other immunopharmacological properties, and may provide a basis for cancer (metastases) treatment as a result of its ability to induce endogenous TNF.

Animals↗
PubMed1989

Antimetastatic effect of endogenous tumor necrosis factor induced by the treatment of recombinant interferon gamma followed by an analogue (GLA-60) to synthetic lipid A subunit.

We have investigated the effect of endogenous production of tumor necrosis factor (TNF) induced by the combination of recombinant interferon gamma (rIFN gamma) as a primer followed by GLA-60 as a trigger (rIFN gamma/GLA-60) on murine lung metastases caused by B16-BL6 melanoma. In order to examine the therapeutic effect of endogenous TNF on tumor metastasis, the ability of multiple administrations of rIFN gamma/GLA-60 to induce TNF production was also tested. The multiple administrations of rIFN gamma/GLA-60 at intervals of 2 days were effective for the induction of endogenous TNF in mice but continuous multiple administrations of them for 2-4 days were not. In tumor-bearing mice, the production of endogenous TNF by rIFN gamma/GLA-60 was less than that of normal mice, but treatment 3 days after the surgical excision of primary tumors showed the endogenous TNF production to be similar to that in normal mice. In the experimental lung metastasis model, intravenous administration of rIFN gamma followed by intravenous or intranasal administration of GLA-60 showed potent inhibition of lung metastases of B16-BL6 melanoma, whereas the reverse sequence of administration (GLA-60/rIFN gamma) or administration of a mixture of rIFN gamma and GLA-60, which cannot induce the production of TNF, caused no inhibition of lung metastases. These results indicated that the regression of tumor metastases by rIFN gamma/GLA-60 was mediated by the production of endogenous TNF in addition to the direct effects of both immunostimulants. Furthermore, the administration of rIFN gamma and GLA-60 significantly inhibited the tumor metastases in spontaneous lung metastasis model. These results may provide a promising approach for the treatment of cancer metastasis as a result of its ability to induce endogenous TNF.

Adjuvants, Immunologic↗
PubMed1989

Effect of topical prostaglandin D2 on the aqueous humor dynamics in rabbits.

Effects of topically applied prostaglandin (PG) D2 on the aqueous outflow facility, uveoscleral flow, and aqueous flow rate were studied in rabbits to reveal its intraocular pressure (IOP)-reducing mechanism. The outflow facility after PGD2 application (50 micrograms) as measured by 2-min tonography was 0.19 microliters/min/mm Hg and did not differ from that before the application (0.22) or from that of the control contralateral eye (0.21). Direct measurement of the uveoscleral flow by perfusion of the anterior chamber for 30 min with fluorescein isothiocyanate-labeled dextran solution showed the flow rate to be about 0.15 microliters/min in indomethacin-treated (10 mg/kg, i.p.) rabbits. In these animals, PGD2 (50 micrograms) was ineffective in changing the flow rate, while PGF2 alpha (50 micrograms) significantly increased the flow by about 35%. Indirect assessment of the effects of PGs on this flow system was made using the uveoscleral flow-antagonizing ability of topical pilocarpine (1.5 mg). IOP reduction by PGD2 (50 micrograms) was only slightly inhibited by pilocarpine, while that by PGF2 alpha (10 micrograms) was markedly reduced. Aqueous flow rate measured fluorophotometrically was about 3.5 microliters/min in normal eyes. After PGD2 (50 micrograms) the flow rate was significantly reduced to 3.0 microliters/min. The magnitude of this reduction was estimated to be enough to account for the IOP reduction after application of 50 micrograms of PGD2. These results indicate that IOP reduction caused by topical PGD2 application is due mostly to the inhibition of aqueous flow rate.

Administration, Topical↗
PubMed1989

Biological activities of synthetic polypeptides containing a repetitive core sequence (Arg-Gly-Asp) of cell adhesion molecules.

A unique polypeptide containing the repeated structure of core sequence from cell adhesion molecules, poly(Arg-Gly-Asp), was successfully prepared by the polymerization procedure with diphenylphosphoryl azide. This polypeptide dramatically inhibited the aggregation of platelets induced by adenosine diphosphate (ADP) or malignant melanoma cells.

Adenosine Diphosphate↗