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Biomedical subjects

H Maeda

Publications and source records attributed to H Maeda.

At least 829 records · Page 46Linked to original sources
PubMed1990

Degradation pathway of kinins in tumor ascites and inhibition by kininase inhibitors: analysis by HPLC.

We have recently found presence of a high concentration of a novel type of kinin, hydroxyprolyl3-bradykinin (Hyp3-BK) in human tumor ascites in addition to conventional bradykinin (BK). Because of their potential physiological activity, it is of interest to know how these bradykinins can be degraded in ascites. Degradation of two synthetic kinins, BK and Hyp3-BK, added to the ascitic fluid from patients with ovarian carcinoma and hepatoma, were analyzed by reversed phase HPLC. Both kinins were degraded into their desArg9-BK or -Hyp3-BK and desPhe8-Arg-9-BK or -Hyp3-BK products following incubation with the ascitic fluid. The rate of the degradation of BK and Hyp3-BK was the same. The formation of desArg9-BK was completely inhibited by kininase I inhibitor, while the formation of desPhe8-Arg9-BK was not completely inhibited by a kininase II inhibitor. The degradation of both kinins was inhibited completely by EDTA. The results indicate the presence of other metalloprotease(s) which cleaves kinins in the ascitic fluid, in addition to kininase I and kininase II. The carboxypeptidase A and carboxypeptidase B inhibitor, benzyl malic acid, failed to block degradation of both kinins. A rapid cleave of Phe-Arg into Phe and Arg was also found in the ascitic fluid. Thus, the major degradation products of kinins in the ascitic fluid were demonstrated to be either desArg9-BK or Hyp3-BK, desPhe8-Arg9-BK or -Hyp3-BK, phenylalanine and arginine. Lysyl-BK and lysylhydroxyprolyl3-BK were rapidly converted into BK and hydroxyprolyl3-BK by the ascitic fluid.

Amino Acid Sequence↗
PubMed1990

Positive indium-111 leukocyte imaging in post myocardial infarction syndrome.

The diagnosis of post myocardial infarction syndrome (PMIS) is sometimes difficult because of the absence of a specific test. We report a 68-year-old man with PMIS who had a persistent accumulation of indium-111 oxine labeled leukocytes in the infarcted myocardium for 1 month. The uptake of leukocytes preceded the appearance of the main symptoms and disappeared with the clinical improvement after the therapy with steroids. Leukocyte imaging has a potential as a useful tool for early diagnosis, evaluation of therapy and assessing the mechanism of PMIS.

Aged↗
PubMed1990

Depletion of macrophages expressing I-J antigen results in efficient generation of alloreactive cytotoxic T lymphocytes.

The role of suppressor macrophages (S-M phi) produced during generation of cytotoxic T lymphocytes (CTL) stimulated with allogeneic lymphocytes was investigated. Splenic CTL from C3H/He mice (H-2k) were generated by in vivo immunization and subsequent in vitro stimulation by splenic lymphocytes from C57B1/6 mice (H-2b) in mixed lymphocyte reaction (MLR). In addition to in vitro standard 51Cr release assay, the CTL activity was mainly measured in vivo using the Winn assay against EL-4 thymoma cells in B6C3F1 mice (H-2b/k). In mice injected with CTL plus EL-4 cells survival rate was 20% compared with no survival of mice treated with normal spleen cells plus EL-4 cells. The antitumor activity of the CTL was significantly increased when immunized mice were treated with a 5 mg/kg ip dose of indomethacin at the time of immunization (80% survival). Macrophages were depleted from spleen cells of immunized mice by plastic adherence or carbonyl-iron treatment, replaced with an equivalent number of M phi from normal mice, and then introduced into a 5-day MLR. When the antitumor activity of the cells isolated from this MLR was measured in the Winn assay, 90-100% survival in EL-4-bearing mice was observed. In contrast, none of the mice inoculated with EL-4 alone and 20% of the mice that received CTL obtained after alloimmunization followed by MLR in addition to EL-4 survived. These results of CTL activity were confirmed by in vitro cytotoxicity tests. When the M phi isolated from spleens of immunized mice were analyzed for I-Jk antigen expression, a 2.5-fold increase was detected, compared with splenic M phi obtained from normal C3H/He mice. In contrast, Ia and I-Ak antigen expression was equivalent in M phi isolated from normal or immunized C3H/He mice. When immune spleen cells were treated with anti-I-Jk antiserum followed by complement and then, subjected to the MLR, the antitumor activity of CTL was significantly enhanced (80% survival). However, treatment of these cells with anti-I-Ak antiserum and complement did not alter CTL activity. These data suggest that the increase of S-M phi expressing I-Jk+ antigen to be induced during alloimmunization results in suppression of allospecific CTL-generation in MLR.

Animals↗
PubMed1990

Plasma thrombomodulin concentration in diabetes mellitus.

Thrombomodulin is an endothelial cell membrane protein acting as a cofactor for the activation of plasma protein C. Recently, it was found that soluble forms of thrombomodulin exist in plasma. Although the physiological significance of circulating thrombomodulin is presently obscure, it may reflect injury of the endothelial cell. In the present study, we examined plasma thrombomodulin concentrations in 106 Type 2 (non-insulin-dependent) diabetic patients. Plasma thrombomodulin was determined by a sandwich ELISA employing monoclonal anti-thrombomodulin antibodies. The patients with proteinuria had higher plasma thrombomodulin concentrations (61.0 +/- 36.0 ng/ml) compared to the patients without proteinuria (33.6 +/- 9.5 ng/ml, P less than 0.001) and control subjects (32.8 +/- 6.5 ng/ml, P less than 0.001). Plasma thrombomodulin concentrations were positively correlated with the level of serum creatine, blood urea nitrogen, urinary albumin and urinary beta 2-microglobulin (P less than 0.001 for each), but not with fasting plasma glucose, hemoglobin A1c or fructosamine. Elevated plasma thrombomodulin was also observed in the patients with pre-proliferative (63.4 +/- 28.9 ng/ml) or proliferative retinopathy (57.4 +/- 34.7 ng/ml), but not in the patients with non-proliferative retinopathy (33.5 +/- 12.9 ng/ml) or those without retinopathy (32.4 +/- 8.9 ng/ml). Even in the 81 diabetic subjects without proteinuria as determined by a dip and read method, and whose serum creatinine was lower than 1.0 mg/dl, the plasma thrombomodulin concentration was significantly higher in the patients with pre-proliferative (41.5 +/- 4.4 ng/ml) and proliferative retinopathy (41.0 +/- 12.8 ng/ml) compared to the patients without retinopathy (32.2 +/- 8.8 ng/ml) and those with non-proliferative retinopathy (31.9 +/- 7.8 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Biomarkers↗
PubMed1990

Production of interleukin 1 from human monocytes stimulated by synthetic lipid A subunit analogues.

We have investigated 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 release IL-1 in vitro. Of monosaccharide-type GLA compounds, GLA-60 was found to be more active for the induction of IL-1 production than GLA-59 and GLA-27, and similar to that of LPS or compound 506. GLA-60 could induce not only the secretion of IL-1 into culture supernatant but also the expression of membrane-associated form of IL-1 in human monocytes. Furthermore, no detectable IL-2 activity was observed in the culture supernatant. These results show that synthetic lipid A analogues of low toxicity, in particular GLA-60, are active in inducing IL-1 production in human monocytes.

Cell Division↗
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

Reduced bone marrow toxicity of neocarzinostatin by conjugation with divinyl ether-maleic acid copolymer.

Neocarzinostatin (NCS) was conjugated with divinyl ether-maleic acid anhydride copolymer (pyran copolymer), and its therapeutic effect was compared with that of NCS. The conjugated NCS (pyran-NCS) with a molecular weight of about 23,000, exhibited in vitro cytotoxic activity against eight cell lines and bone marrow cells that was similar to the cytotoxic activity of NCS on a molar basis. Furthermore, both drugs had similar effects against a multidrug-resistant Chinese hamster ovary cell line (CHR C5) and its parent cell line (AUXB1) in vitro. However, pharmacological analysis showed that pyran-NCS had reduced accumulation in the spleen, and most important was three times less hematotoxic in vivo compared with NCS. Also, pyran-NCS had a 1.7-fold higher 50% lethal dose (LD50). Antitumor activity of pyran-NCS and NCS was tested against two different forms of Meth A tumor. In a solid tumor model, pyran-NCS and NCS suppressed tumor growth at three-fourths of the LD50 to 12.8 and 19.0% of the control tumor as evaluated on day 28, respectively (P less than 0.025). In an ascitic tumor model, the percentage increase in the median life span caused by pyran-NCS and NCS was more than 400 and 150% on day 60, respectively. Pyran-NCS is more effective than NCS because the reduced acute toxicity permits an increased drug dosage.

Animals↗
PubMed1990

A validation study on the reproducibility of transcranial Doppler velocimetry.

The transcranial Doppler method for the measurement of intracranial arterial blood flow velocity is a useful noninvasive technique with a number of applications. The present study validated the reproducibility of this method for repeated measurements of flow velocity in the middle cerebral and basilar arteries. Fifteen healthy volunteers were studied. Measurements were made twice by one examiner and once by another in a single day and again by the first examiner on another day. The reproducibility was evaluated by calculating the correlation coefficient (r) and the coefficient of variation (CV) of the difference between the values obtained from each pair of measurements. Although depending on the examiner, the time interval between the examinations and the vessels studied some differences were noted in the reproducibility, both the r (0.69-0.95) and CV (6.7%-19.5%) values in the whole study were good enough to warrant the applicability of this method for the repeated measurements of the intracranial arterial blood flow velocity in future studies.

Cerebral Arteries↗
PubMed1990

Free radical generation during brief period of cerebral ischemia may trigger delayed neuronal death.

We investigated the pathogenic role of free radical formation in ischemic neuronal death using radical scavenger, superoxide dismutase. Cerebral ischemia was produced in the gerbil by bilateral common carotid occlusion for 5 min, which consistently resulted in delayed neuronal death in the CA1 region of the hippocampus. The effects of free superoxide dismutase and a derivatized superoxide dismutase, pyran copolymer conjugated superoxide dismutase, on early ischemic damages, detected sensitively by the immunohistochemical reaction for microtubule associated protein 2, and a subsequent delayed neuronal death after restoration of blood flow were investigated. Preischemic treatment by pyran conjugated superoxide dismutase showed clear protective effects against both the neuronal damages detected by immunohistochemistry after 5 min ischemia and the delayed neuronal necrosis after one week of recovery, although no clear beneficial effects were observed when this drug was administered just before the recirculation or free superoxide dismutase was used. These results strongly suggest that free radical generation during brief period of ischemia plays a pivotal role in triggering the ischemic neuronal damages causing delayed neuronal death at the selectively vulnerable areas of the brain.

Animals↗
PubMed1990

Relationships in the structure-tissue distribution of basic drugs in the rabbit.

The relationship between the tissue-to-plasma partition coefficients (Kp) and drug lipophilicity was investigated using highly lipophilic drugs with apparent partition coefficients of 150 or above in an octanol-water system at pH 7.4. Ten clinically popular basic drugs with different dissociation coefficients (pKa) and lipophilicity were used. The Kp values were determined in nondisposing organs after the i.v. administration of individual drugs in rabbits. The free fraction in plasma and the blood-to-plasma concentration ratio were determined in vitro. Then the tissue-to-plasma ratios of nonionized and unbound drug concentrations (Kpfu) were calculated from Kpf (ratio of unbound drug). The true octanol-water partition coefficient of the nonionized drugs (P) was used to analyze the Kpf and Kpfu. In all tissues, log Kpfu was more highly correlated with log P than log Kpf.

Animals↗
PubMed1990

Enhanced intestinal absorption of a hydrophobic polymer-conjugated protein drug, smancs, in an oily formulation.

Intestinal absorption of neocarzinostatin (NCS) and smancs (copolystyrene maleic acid-conjugated NCS), in aqueous and oily formulations, was investigated after oral administration in mice. Blood concentrations of NCS and smancs were determined with a cytotoxicity assay employing the highly sensitive Epstein-Barr (EB) virus-transformed B-lymphoblastoid cell line, TK/B. Smancs was more efficiently absorbed from a medium-chain triglyceride solution (oily smancs) than from an aqueous solution in phosphate-buffered saline (PBS). The maximum blood concentration and the area under the concentration curve versus time course (AUC) of oily smancs were 9 and 11 times greater than those of the aqueous form of smancs, respectively. At 5 hr after administration of oily smancs, 0.044% of the total smancs dose was found in blood, whereas the parent compound NCS was not detectable at any time. When oily smancs was administered orally to sarcoma 180 tumor-bearing mice, a selective accumulation of smancs in tumor tissue was observed. These results indicated that a biologically active protein, which cannot be used orally, may be rendered orally active drug by conjugation with a hydrophobic polymer in combination with an oily formulation.

Administration, Oral↗
PubMed1990

Energetics of RNA cleavage: implications for the mechanism of action of ribozymes.

A new class of ribozymes produce 2',3'-cyclic phosphate upon self-catalyzed cleavage of RNA molecules, similar to those observed during enzymatic (RNase-catalyzed) as well as non-enzymatic hydrolyses of RNAs. This product suggests that the reaction intermediate/transition state is a pentacoordinated oxyphosphorane. In order to elucidate the energetics of these RNA cleaving reactions, the reaction coordinate has been simulated and a pentacoordinated intermediate has been characterized via ab initio molecular orbital calculations utilizing the dianionic hydrolysis-intermediate of methyl ethylene phosphate as a model compound. The calculated reaction coordinate indicates that the transition state for the P-O(2') bond cleavage is lower in energy than that for the P-O(5') bond cleavage under uncatalyzed conditions. Thus, the dianionic pentacoordinated phosphorus intermediate tends to revert back to the starting RNA by cleaving the P-O(2') bond rather than productively cleaving the P-O(5') bond. In order for ribozymes to effectively cleave RNA molecules, it is therefore mandatory to stabilize the leaving 5'-oxygen, e.g. by means of a divalent magnesium ion.

Catalysis↗
PubMed1990

Construction of a novel artificial-ribozyme-releasing plasmid.

A novel 'active-ribozyme-releasing system' was constructed, taking advantage of the consensus sequence of a new class of ribozyme. An active ribozyme sequence, targeted for the SFL1 gene (a yeast suppressor gene for flocculation) was fused just downstream of the T7 promoter. The 3' terminus of the first ribozyme was designed to be trimmed by the second ribozyme connected to the downstream of the first active ribozyme. In vitro experiments revealed that the active ribozyme targeted to SFL1 was successfully released by the action of the second ribozyme, subsequently cleaving the SFL1 mRNA at the predetermined site. Since the first active ribozyme with a defined 3'-terminus can be produced even when a circular DNA is used as a template, this kind of construct has a potential to release an 'active ribozyme' tailored to destroy a target gene (RNA) in vivo. Moreover, the second ribozyme in this construct can be utilized as a universal pseudo-terminator for generation of any RNA transcripts inserted in place of the cassette portion of the first ribozyme.

Base Sequence↗
PubMed1990

Griffonia simplicifolia agglutinin-2-binding glycoprotein as a novel carbohydrate antigen of human colonic carcinoma.

Griffonia simplicifolia agglutinin-2-binding glycoprotein (GBG) in human colonic carcinoma was examined immunochemically and histochemically, GBG was extracted from colonic carcinoma as a serum-type glycoprotein of 160 kilodaltons. GBG was not identical with carcinoembryonic antigen (CEA), since its molecular weight and localization in tissue sections were different from those of CEA. The non-reducing terminals of GBG probably carry N-acetylglucosamine, but not blood group determinants. Furthermore, GBG was released by phosphatidylinositol-specific phospholipase C from cell membrane. GBG was suggested to be anchored to the membrane via linkage to a glycosyl-phosphatidylinositol molecule. Among colonic carcinoma-associated antigens, serum-type glycoproteins having N-acetylglucosamine at non-reducing terminals have not previously been reported. GBG is a novel carbohydrate antigen of human colonic carcinoma.

Adult↗
PubMed1990

Restriction fragment length polymorphism of complement C4 in Japanese patients with rheumatoid arthritis and normal Japanese.

Restriction fragment length polymorphism (RFLP) of the two genes for complement C4A and C4B was studied in 56 Japanese patients with rheumatoid arthritis (RA) and 161 normal individuals. HindIII digestion revealed six common patterns, from which the segregation of three common RFLP-types were deduced; 32-15 kb, 32-25 kb, and 32-20-13-6.5 kb. The last type showed positive associations with C4B5 and HLA-DR4. In the RA patients, an increase of this type was found as well as a decrease of the 32-15 kb/32-25-15 kb heterozygotes.

Arthritis, Rheumatoid↗
PubMed1990

Inactivation of chemotactic activity of C5a by the serratial 56-kilodalton protease.

The effects of the 56-kilodalton protease (56K protease) from Serratia marcescens on complement-derived chemotactic activity were examined. Fresh human serum was incubated with zymosan to produce C5a. This activated serum was then incubated with various concentrations of 56K protease, and the chemotactic activity of mouse peritoneal exudate polymorphonuclear leukocytes (PMN) and macrophages was evaluated. A significant dose-dependent decrease of chemotactic activity was observed after protease treatment. Furthermore, treatment of human recombinant C5a with 56K protease at a dose of 1.0 microgram/ml resulted in a complete loss of chemotactic activity. When the living bacteria of the virulent strain, which produced about 10 times more protease than did the less virulent strain, were injected intraperitoneally into mice, the magnitude of infiltration of polymorphonuclear leukocytes into the peritoneal cavity was much lower than that caused by the less virulent strain. Because complement-dependent chemotactic activity is an initial response to bacterial infection, these results suggest indirect pathogenic functions of serratial proteases that suppress chemotactic activity.

Blood Bactericidal Activity↗