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S Kusumoto

Publications and source records attributed to S Kusumoto.

At least 127 records · Page 7Linked to original sources
PubMed1989

IL-1 induction-capacity of defined lipopolysaccharide partial structures.

Natural and synthetic lipid A as well as natural and synthetic oligosaccharide partial structures of LPS were examined in dose-response experiments to define the minimal structure necessary for IL-1 induction and release in cultures of human mononuclear cells. Wild type LPS (S. abortus equi) and rough mutant LPS was active in minimal-doses of 1 to 100 pg/ml, whereas synthetic heptaacyl and hexaacyl lipid A (Salmonella minnesota and Escherichia coli lipid A, respectively) induced IL-1 in minimal-doses of 100 to 1,000 pg/ml and 10 to 1,000 pg/ml, respectively. Nanogram amounts (0.1 to 10 ng/ml) of synthetic monodephospho partial structures of E. coli lipid A were necessary for IL-1 induction. Synthetic pentaacyl partial structures induced IL-1 very weakly. Synthetic tetraacyl and bisacyl partial structures lacking non-hydroxylated fatty acids were not active. Compared to LPS million-fold higher doses of natural and synthetic 3-deoxy-D-manno-octulosonic acid containing core oligosaccharides were necessary for IL-1 induction. Dose-response investigations with LPS and natural or synthetic partial structures established the following hierarchy in IL-1 induction-capacity: LPS greater than lipid A much greater than lipid A partial structures greater than core oligosaccharides greater than oligoacyl lipid A. Lipid A was shown here to be the portion of LPS mainly responsible for induction of IL-1 activity. The high potency of lipid A in inducing IL-1 release and the failure of the precursor Ia of lipid A to induce IL-1 production and release was also observed measuring intracellular IL-1 activity after freeze-thawing the cells. Levels of IL-1 beta mRNA in extracts of mononuclear cells correlated with biologic activity. In co-incubation experiments, precursor Ia of lipid A produced dose-dependent inhibition of production and release of IL-1 activity induced by lipid A or LPS, but not by Staphylococcus epidermidis or PHA. Incubation of cells with precursor Ia for 1h, followed by a medium change and further incubation of stimulus without precursor Ia of lipid A also resulted in inhibition. We conclude that lipid A is the main portion of LPS responsible for induction of IL-1, and that specific activation- and/or binding-mechanisms are involved in stimulation of cells with LPS and/or lipid A.

Acinetobacter↗
PubMed1989

Comparative X-ray and Fourier-transform-infrared investigations of conformational properties of bacterial and synthetic lipid A of Escherichia coli and Salmonella minnesota as well as partial structures and analogues thereof.

By using the X-ray and infrared spectroscopic characteristics of various synthetic analogues and partial structures of lipid A in the dried state, a comparison of these compounds with their natural counterparts was undertaken. As judged by their X-ray diffraction and infrared spectroscopic features, the compounds tested could be divided into two main groups. The first group covered those samples synthesized in accordance with a previously assumed structure, while those synthesized in accordance with present knowledge on the lipid-A primary structure formed the second group. Members of the first group were characterized by a liquid-like, alpha-type arrangement of their fatty acyl chains in a non-lamellar supramolecular structure, while all members of the second group formed bilayered phases with a much more ordered, beta-type conformation of their fatty acyl chains. Synthetic Escherichia coli-type lipid A (compound 506), proved to be essentially identical to its natural counterpart with respect to those conformational properties accessible by our methods. The synthetic hepta-acyl species of Salmonella minnesota lipid A (compound 516) revealed an unexpected conformational behaviour, whereby a fatty-acyl-chain packing could be detected which was different from the hexagonal arrangement found for all other compounds of the second group.

Escherichia coli↗
PubMed1989

Enhancement of humoral immune responses against viral vaccines by a non-pyrogenic 6-O-acylmuramyldipeptide and synthetic low toxicity analogues of lipid A.

6-O-Acyl derivatives of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) and synthetic, low toxicity lipid-A analogues were examined for their ability to enhance the potency of current viral vaccines. 6-O-(2-Tetradecylhexadecanoyl)-MDP (B30-MDP) in non-irritative vehicles such as physiological saline, phosphate-buffered saline (PBS), squalene-PBS emulsion, Intralipid or liposomes, significantly stimulated the primary and secondary antibody production of guinea-pigs against influenza split or subunit vaccine and inactivated the hepatitis B virus surface (HBs) antigen. Mice seemed less responsive to the adjuvanticity of B30-MDP than guinea-pigs. Two low toxicity lipid A analogues, acylated beta(1-6)-D-glucosamine disaccharide bisphosphates (which do not have amide-bound or ester-bound 3-acyloxyacyl groups unlike fully toxic Escherichia coli-type lipid A), caused significantly enhanced antibody responses, primary or secondary, when administered to mice by incorporation into liposomes with inactivated HBs antigen.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1989

Induction of tumor necrosis factor-alpha release by lipopolysaccharide and defined lipopolysaccharide partial structures.

We have investigated the release of tumor necrosis factor-alpha (TNF-alpha) by human mononuclear cells (MNC) and isolated human monocytes/macrophages stimulated with S- and R-form lipopolysaccharide (LPS), natural lipid A, and natural and synthetic partial structures thereof. We found that LPS of Salmonella minnesota (S. min.) Rb2, which represents a partial structure of wildtype LPS of Salmonella abortus equi (S.a.e.) lacking the O-chain and parts of the outer core region, was the most active inducer of all substances tested, even more active than the wildtype LPS. Lipid A also induced the production of TNF-alpha by monocytes/macrophages but was less active than wildtype LPS. The natural Escherichia coli (E. coli) type hexaacyl lipid A (compound 506) was more active than the natural S. min. type heptaacyl lipid A (compound 516). The 1- and 4'-monodephospho partial structures (compounds 505 and 504) of E. coli lipid A were less active and represented the smallest structures tested that were able to induce TNF-alpha release by monocytes/macrophages. Synthetic tetraacyl lipid A precursor Ia of E. coli lipid A, lacking non-hydroxylated fatty acids (compound 406), and the monosaccharide precursor lipid X did not induce the release of TNF-alpha in MNC or isolated monocytes/macrophages. This might indicate that the ability of a lipid A structure to induce the release of TNF-alpha is closely connected with the conditions to be at least hexaacylated and/or to contain hydroxylated fatty acids. These results demonstrate a structure-dependent hierarchy of LPS and natural or synthetic partial structures in their capacity of inducing TNF-alpha release by monocytes/macrophages.

Humans↗
PubMed1989

Endotoxic properties of chemically synthesized lipid A analogs. Studies on six inflammatory reactions in vivo, and one reaction in vitro.

Biological activities of two groups of synthesized lipid A analogs, the counterpart of biosynthetic precursor, Lehmann's Ia type, 406, and E. coli lipid A type, 506, as well as their non-phosphorylated, and mono-phosphorylated analogs were investigated. The activities employed included four bone marrow cell reactions in mice, mice skin reaction, leukocytes migration in rabbits' cornea, and hemagglutination. Compound 406 and 506 elicited bone marrow reactions in mice and hemagglutination of mouse RBC, although 406 failed to elicit hemorrhage and necrosis also in mice skin. Compound 406 did not elicit corneal reaction in rabbits. The results suggest that for elicitation of this reaction and mice skin reaction, acyloxyacyl structure is required. Cytotoxicity and thromboplastin production of four bone marrow reactions had been reported by us to be endotoxic reactions, since these had not been elicited by peptidoglycan of Lactobacillus and Staphylococcus (1981) and 300 series synthesized analogs (1984) which did not have endotoxic structures. From these results, it seems that these two marrow reactions and hemagglutination require, as does the limulus test, the lipid A part structure as is present in 406.

Animals↗
PubMed1989

Somnogenic activities of synthetic lipid A.

Bacterial infections and various immune response modifiers, including endotoxin and its lipid A moiety, alter sleep duration. The purpose of this study is to amplify our understanding of lipid A structure-somnogenic-pyrogenic activity relationships. Four synthetic disaccharide analogs of lipid A (LA-15-PP, LA-15-PH, LA-16-PH, and LA-18-PP) and a biosynthetic monosaccharide analog of lipid A (lipid X) were tested in rabbits for their effects on slow-wave sleep, rapid-eye-movement sleep, electroencephalographic slow-wave (0.5- to 4.0-Hz) amplitudes, and brain-colonic temperatures. Substances were injected intravenously and intracerebroventricularly. Compound LA-15-PP was the most potent; it significantly increased slow-wave sleep, delta electroencephalographic amplitudes, and brain-colonic temperatures while reducing rapid-eye-movement sleep. Compound LA-15-PH (monophosphoryl analog of LA-15-PP) induced effects similar to those of LA-15-PP, although the responses were weaker. Compound LA-18-PP induced increases in slow-wave sleep and delta amplitudes only after high doses, whereas compound LA-16-PH was devoid of these activities at the doses tested. Intracerebroventricular, but not intravenous, injections of lipid X induced small but significant increases in both slow-wave sleep and rapid-eye-movement sleep without affecting delta amplitudes or brain-colonic temperatures. These data suggest that the somnogenic actions of these lipid A analogs depend on the acylation or phosphorylation pattern and backbone structures of the molecules. Their soporific activities parallel their relative behaviors in other biological assays.

Animals↗
PubMed1989

Oxidation of methionine residues of recombinant human interleukin 2 in aqueous solutions.

When recombinant human interleukin 2 (rIL-2) was stored for a long period in aqueous solutions, its methionine residues were spontaneously oxidized to the corresponding methionine sulfoxides. To clarify the oxidation process, rIL-2 was treated with hydrogen peroxide, and three oxidation products were separated by reversed-phase high-performance liquid chromatography. By means of amino acid analyses after cyanogen bromide cleavage of these products, we found that Met104, Met23, and Met39 were consecutively oxidized in this order; Met46 was not oxidized easily. The substances generated by extended storage of rIL-2 in aqueous solutions were identified by comparison of their peptide maps with those of the chemically oxidized products. The protein-chemical properties of these products, except for the modifications of the methionine residues, were similar to those of intact rIL-2; their biological activities were almost the same.

Humans↗
PubMed1989

[Radiotherapy in bone metastases--with special reference to its effect on relieving pain].

Between December 1986 and January 1978, 68 patients with bone metastases were analyzed to evaluate the effect of radiation for the relief of pain. The 68 patients, who had a total of 97 lesions, complained of pain caused by their bone metastasis. The good, fair, and poor responses were found to be 18%, 60%, and 22%, respectively. With reference to the primary neoplasms, the effective response rate was 73% in lung cancer, 100% in breast cancer, 75% in gastric cancer, 100% in hepatic cancer, 100% in bladder cancer, 25% in epipharyngeal cancer, and 70% in the other neoplasms. Depending on the cell types of the lung cancer, the effective response rate was 80% for small cell carcinomas, 72% for adenocarcinomas and 40% for squamous cell carcinomas. Our results suggest that radiotherapy for bone metastases is to be recommended, since the effective response rate was 78% for the relief of pain.

Adenocarcinoma↗
PubMed1989

Interleukin 1 and tumor necrosis factor: studies on the induction by lipopolysaccharide partial structures.

Minimal concentration ranges of lipopolysaccharides, natural and synthetic lipid As, and partial structures were established for the induction of release of IL-1 and TNF from human MNC. LPS was more potent than lipid A. Partial structures of lipid A lacking nonhydroxylated fatty acids were inactive, but in combination with LPS or lipid A exhibited time-dependent synergistic or antagonistic effects.

Glycolipids↗
PubMed1988

Intracellular serine-protease zymogen, factor C, from horseshoe crab hemocytes. Its activation by synthetic lipid A analogues and acidic phospholipids.

An intracellular clotting factor, factor C, found in the horseshoe crab hemocytes is a lipopolysaccharide-sensitive serine-protease zymogen, which participates in the initiation of the hemolymph clotting system [T. Nakamura et al. (1986) Eur. J. Biochem. 154, 511-521]. The subsequent study of this zymogen, using various synthetic lipid A analogues, revealed that the zymogen factor C is rapidly activated by acylated (beta 1-6)-D-glucosamine disaccharide bisphosphate (synthetic Escherichia coli-type lipid A), and the corresponding 4'-monophosphate analogues. However, the corresponding non-phosphorylated lipid A did not activate factor C, indicating that a phosphate ester group linked with the (beta 1-6)-D-glucosamine disaccharide backbone is required for the zymogen activation. During these studies we also found that the zymogen factor C is significantly activated by acidic phospholipids, such as phosphatidylinositol, phosphatidylglycerol and cardiolipin, but not at all by neutral phospholipids. The rate of this activation, however, was affected markedly by ionic strength in the reaction mixture, although such an effect was not observed in the lipid-A-mediated activation of factor C. A variety of negatively charged surfaces, such as sulfatide, dextran sulfate and ellagic acid, which are known as typical initiators for activation of the mammalian intrinsic clotting system, did not show any effect on the zymogen factor C activation. These results suggest that lipid A is the most effective trigger to initiate the activation of the horseshoe crab hemolymph clotting system.

Animals↗
PubMed1988

Structural requirements of lipid A species in activation of clotting enzymes from the horseshoe crab, and the human complement cascade.

The structure/activity relationship of lipid A, a bioactive center of endotoxic lipopolysaccharides, in the activation of the clotting enzyme cascade of a horseshoe crab amoebocyte lysate (Limulus activity) and the complement system in human serum, was examined using synthetic lipids A and related compounds. Regarding Limulus activity, a newly developed colorimetric method, which utilizes a mixture of recombined clotting factors and a chromogenic substance, was much more sensitive for detecting changes in the chemical structure of test compounds than the conventional gelation method using the amoebocyte whole lysate. (beta 1-6)-D-Glucosamine disaccharide bisphosphates, which had neither 3-hydroxyacyl nor 3-acyloxyacyl groups, and acylglucosamine phosphates, which in structure correspond or are analogous to the non-reducing or reducing moieties of lipids A and biosynthetic disaccharide lipid A precursors showed only negligible activity in the colorimetric tests, but they exhibited a distinct though much weaker gelation activity than the parent disaccharide molecules. The assay results obtained by the colorimetric Limulus test correlate better with the pyrogenicity of the test synthetic compounds than those given by the gelation method, although the dependence of pyrogenicity on chemical structure is greater. The presence of 3-hydroxyacyl groups on the bisphosphorylated (beta 1-6)-D-glucosamine disaccharide backbone is the prerequisite for effective activation of the clotting enzyme cascade of horseshoe crab amoebocyte lysate, while the presence of an adequate number (one or two) of 3-acyloxyacyl groups on the disaccharide bisphosphate backbone is needed for full pyrogenicity. Complement activation, on the other hand, showed structural requirements quite different from those for the colorimetric Limulus activity and the pyrogenicity. The disaccharide compounds that had only non-hydroxylated acyl groups, acylated glucosamine phosphates that had the structure of the non-reducing portion of lipids A and biosynthetic disaccharide precursors, which were scarcely active in the colorimetric Limulus test, caused complement activation comparable to or sometimes stronger than that of the parent disaccharide molecules. Acylglucosamine phosphates, corresponding in structure to the reducing moiety of disaccharide compounds, however, showed little activity.

Animals↗
PubMed1988

Age factor relevant to the development of radiation pneumonitis in radiotherapy of lung cancer.

The significance of age factor for the development of radiation pneumonitis is evaluated in 62 patients with lung cancer between 1977 and 1985. The younger group consists of those less than 70 years old and the elderly group of those 70 years old or more. Radiation doses ranged from 1.5 to 2 Gy, 3 to 5 times per week, therefore the delivered doses were converted to nominal single doses (rets dose). Severe radiation pneumonitis was more often observed in the elderly than in the younger regardless of radiation field size and chemotherapy (n.s.). The onset of radiation pneumonitis occurred earlier in a field size of 90 sq cm or more than in that of less than 90 sq cm in both age groups; there was no significant difference between the two age groups in each field size. The pneumonitis was more frequently noted with increasing rets dose in both age groups (n.s.) regardless of field size and chemotherapy. It is concluded that there is no significant difference in the development of radiation pneumonitis between the younger group and the elderly group, but the pneumonitis is inclined to be more severe in the latter.

Adult↗
PubMed1988

Structural requirements of endotoxic lipopolysaccharides and bacterial cell walls in induction of interleukin-1.

A variety of compounds, synthetic, semisynthetic or bacterial, which corresponds to structural components of endotoxic lipopolysaccharides (LPS) and bacterial cell wall peptidoglycans were studied for their activity to enhance interleukin-1 (IL-1) production of murine peritoneal macrophages and the ability to activate the complement cascade in fresh adult human serum. Not only bacterial LPS and cell walls or peptidoglycans but also their structural components with appropriate size and structure induced IL-1 production by macrophages and activated the human complement cascade, which may lead to the IL-1 production by monocytes/macrophages.

Animals↗
PubMed1988

[A case of malignant lymphoma, an anemone cell tumor of the leg, arising from osteomyelitis].

An 80-year-old man, complaining of multiple fungating growth on his right leg, was hospitalized. A review of his previous history revealed that he had undergone three operations because of repeating osteomyelitis. A clinical examination showed that a tumor was localized on the right leg. Light microscopy revealed that tumor was composed of diffuse large round cell proliferations. Malignant lymphoma was suspected, but was difficult to distinguish in the undifferentiated carcinoma. Electron microscopically, extensive cytoplasmic processes resembling microvilli from the circumferential surface membrane were observed, but desmosomes, tonofilaments, secretory products or basal lamina were not seen. Immunohistochemically, IgG was demonstrated on the tumor cells. These findings led us to diagnoses an anemone cell tumor, originating from a malignant lymphoma and arising from osteomyelitis.

Aged↗