Biomedical subjects

H Sakagami

Publications and source records attributed to H Sakagami.

At least 289 records · Page 16Linked to original sources

PubMedDate not supplied

Quantumchemical structure of carcinogenic benz[c]acridines.

Resonance energies, circuit resonance energies and bond currents of benz[c]acridines were calculated by Aihara's IRE theory. Consequently, it was shown that these compounds had very stable aromatic characters with positive resonance energies and that the resonance energies per pi-electron values for the compounds with lack of the double bond corresponding to the K-region from parent skeleton were more stable than those of their parent compounds. Carcinogenic activity of the compounds was related to the charge at QK, QN and QL and high electron density on HOMO orbital.

Acridines↗

PubMedDate not supplied

Induction of DNA fragmentation in human myelogenous leukemic cell lines by sodium 5,6-benzylidene-L-ascorbate and its related compounds.

High-performance liquid chromatography revealed that sodium 5,6-benzylidene-L-ascorbate (SBA), dissolved in distilled water, was gradually decomposed into ascorbic acid and benzaldehyde. Among these three compounds, ascorbic acid showed the most potent cytotoxic activity. The cytotoxic activity of each compound was significantly reduced during degradation in culture medium. Agarose gel electrophoresis and fluorometric determination of DNA revealed that ascorbic acid, as well as SBA, induced DNA fragmentation into nucleosomal oligomers in human myelogenous leukemic cell lines, but not in freshly isolated human peripheral blood cells. The results suggest that antitumor activity of SBA might be at least in part mediated by the action of ascorbic acid, a degradation product of SBA.

Animals↗

PubMedDate not supplied

Effect of benzo[a]phenothiazines on natural killer cell activity of human peripheral blood mononuclear cells.

Four benzo[a]phenothiazines were investigated for their effects on antibody-dependent cellular cytotoxicity (ADCC) and natural killer (NK) cell and blast transformation of human peripheral blood mononuclear cells (PBM). Benzo[a]phenothiazines dose-dependently suppressed the nitrogen-stimulated T cell proliferation. The suppressive effect of non differentiation-inducing benzo[a]phenothiazines was higher than that of differentiation-inducing benzo[a]phenothiazines. The stimulation effect of differentiation-inducing compounds on the NK activity was reduced by removal of monocytes from the PBM. The results suggest the direct activation of monocytes (Mo) by differentiation-inducing benzo[a]phenothiazines.

Antibody-Dependent Cell Cytotoxicity↗

PubMedDate not supplied

Stimulation by PSK of interleukin-1 production by human peripheral blood mononuclear cells.

PSK (Krestin), a protein-bound polysaccharide extracted from Coriolus versicolor, stimulated the production of interleukin-1 (IL-1) by human peripheral blood mononuclear cells more efficiently than the production of tumor necrosis factor (TNF). More IL-1 alpha was accumulated in the cells than in the medium fraction, whereas IL-1 beta was distributed evenly into both fractions. PSK stimulated the production of adherent mononuclear cells, in which significantly higher amounts of IL-1 alpha/IL-1 beta were accumulated per cell than in nonadherent cells. Although IL-1 alpha mRNA synthesis (assessed by Reverse Transcriptase-Polymerase Chain Reaction) was slightly enhanced, IL-1 beta mRNA synthesis was not significantly changed by PSK treatment. This suggests that PSK might increase the efficiency of IL-1 mRNA translation or the posttranslational processing of IL-1 protein. Despite potent cytokine-inducing activity, lipopolysaccharide (LPS) did not significantly stimulate the production of adherent cells. These data suggest that PSK and LPS might stimulate mononuclear cells by different mechanisms.

Base Sequence↗

PubMedDate not supplied

Stimulation of iodination and cytokine production by dehydrogenation polymers of phenylpropenoids.

Dehydrogenation polymers of phenylpropenoids (so-called 'synthetic lignins') stimulated the iodination (incorporation of radioactive iodine into an acid-insoluble fraction) of human peripheral blood monocytes and polymorphonuclear cells (PMN). The stimulation activity of the polymers strongly depended on the amount of hydrogen peroxide used during sample preparation, and on the temperature during iodination assay. These polymers also stimulated the production of interleukin-1 and tumor necrosis factor by peripheral blood mononuclear cells. On the other hand, neither iodination nor cytokine production was significantly affected by the phenylpropenoid monomers. Although the polymers stimulated the iodination of human leukemic cell lines (HL-60, ML-1), they did not induce cytokine production in these cells. The results suggest that stimulation of iodination and cytokine production by dehydrogenation polymers of phenylpropenoids might be regulated differently.

Animals↗

PubMedDate not supplied

Diverse biological activities displayed by phenothiazines, benzo[a]phenothiazines and benz[c]acridins (review).

This review summarizes our experiments which are investigating the relationship between the structure and activity of mainly phenothiazines, benzo[a]phenothiazines and benz[c]acridines. Phenothiazines had potent antiplasmid and antibacterial activities, but induced weak antimicrobial activity in vivo. Their antiplasmid activity seemed to be enhanced by Cl- or CF3- substitution at the 2C position of phenothiazines and modified by the side-chain length and hydrophobicity. Benzo[a]phenothiazines did not show any significant antiplasmid or antibacterial activity, but stimulated the differentiation of human myelogenous leukemic cell lines and natural killing activity of human peripheral blood mononuclear cells in vitro, and induced antimicrobial activity in vivo. Circuit current energy (CRE), circuit current (CC), bond current (BC), diatropic and paratropic properties of benzo[a]phenothiazines might be correlated with their biological activity. Benz[a]acridine showed both in vitro and in vivo antimicrobial activities, and carcinogenic activity for skin tumor. The carcinogenic benz[c]acridines showed out-of-phase in the L-region and their energy was accumulated in the K-region of the molecular orbitals. The results suggest the involvement of different molecular orbitals for the expression of various biological activities by phenothiazines, benzo[a]phenothiazines and benz[c]acridines.

Acridines↗

PubMedDate not supplied

Effect of sodium benzylideneascorbate on chemically-induced tumors in rats.

Intravenous administration of sodium benzylideneascorbate (SBA) dose-dependently induced degeneration (vacuolar and eosinophilic degeneration and cell shrinkage and nuclear condensation, which are characteristic of apoptotic cell death) of 3'-methyl-4-dimethylaminoazobenzene-induced rat hepatocellular carcinoma. SBA did not significantly induce lymphocyte infiltration and fibrosis in the liver, nor damage the gross morphology of kidney and spleen cells. SBA failed to stimulate the production of tumor necrosis factor and interleukin-1 beta in both in vitro and in vivo systems. These results may suggest a direct antitumor action of SBA via induction of apoptosis in the tumor. However, SBA did not significantly affect the doubling time, or the extent of invasion and differentiation of dimethylhydrazine-induced colon carcinoma in rats. These data suggest that the conditions of SBA administration should be re-established for each tumor sample to produce maximum antitumor activity.

Animals↗

PubMedDate not supplied

Antiplasmid and carcinogenic molecular orbitals of benz[c]acridine and related compounds.

Effect of K- and L- molecular orbital regions on expression of antiplasmid and carcinogenic activity was studied with various benz[c]acridine derivatives, tricyclic compounds (acridine orange, phenothiazines) and dibenzoazepine (imipramine). Antiplasmid compounds showed the out-of-phase of molecular orbital in the L-region. On the other hand, mutagenic and carcinogenic compounds showed the out-of-phase in the L-region, and their energy was accumulated in the K-region of the molecular orbitals. The present study suggests that the molecular orbitals responsible for the expression of antiplasmid and carcinogenic effects might be basically different.

Acridines↗

PubMedDate not supplied

Immunomodulation activity of phenothiazines, benzo[a]phenothiazines and benz[c]acridines.

Some non-differentiation-induction benzo[a]phenothiazines and mutagenic benz[c]acridines more potently inhibited the mitogen-induced blast transformation of human-peripheral blood lymphocytes than differentiation-induction and non-mutagenic counterparts and phenothiazines. Differential absorption spectrophotometry revealed tight complex formation between these drugs and bacterial endotoxin or mitogens. All of these compounds only slightly affected antibody dependent cellular cytotoxicity and natural killer cell activity, but significantly inhibited the endotoxin-or heat-killed Staphylococcus aureus induced tumor necrosis factor production by human mononuclear cells. Pretreatment of mice with these drugs protected them from lethal E. coli infection. Quantumchemical analysis suggests a correlation between the biological activity of these compounds and some molecular orbital parameters such as the charge at C7, and the ratio of polar/total surface areas.

Acridines↗

PubMedDate not supplied

Induction of DNA fragmentation by tannin- and lignin-related substances.

A variety of tannin and lignin-related compounds were compared for their ability to induce nucleosome-sized DNA fragmentation (a biochemical hallmark of apoptosis), using agarose gel electrophoresis and a fluorescence activated cell sorter. Monomeric, dimeric, trimeric and tetrameric hydrolysable tannins induced nucleosome-sized DNA fragmentation in HL-60 cells, more potently than condensed tannins. The highest activity was detected in gallic acid, a component unit of tannins. Natural lignified materials, except for caffeic acid and its dehydrogenation polymer, showed much weaker activity. Protein-bound polysaccharide (PSK) was inactive. Gallic acid induced DNA fragmentation in four human myelogenous leukaemic cell lines, but not in human T-cell leukaemia and erythroleukaemia cell lines. Ca2+ depletion from the culture medium slightly, but significantly, reduced the apoptosis-inducing activity of gallic acid, but did not significantly affect that of tannic acid or caffeic acid. After treatment with gallic acid, intracellular Ca2+ concentration was significantly elevated. The apoptosis-inducing activity of polyphenols may further emphasize their medicinal efficacy.

Apoptosis↗

PubMedDate not supplied

Induction of DNA fragmentation in human myelogenous leukaemic cell lines by phenothiazine-related compounds.

A series of phenothiazine, benzo[a]phenothiazine and benz[c]acridine derivatives were compared for their ability to induce nucleosome-sized DNA fragmentation (a biochemical hallmark of apoptosis), using agarose gel electrophoresis and a fluorescence activated cell sorter. Significant DNA fragmentation-inducing activity was detected in 12H-benzo[a]phenothiazine, 5-oxo-5H-benzo[a]phenothiazine and 9-methyl-12H-benzo[a]phenothiazine, which induced the monocytic differentiation of human myelogenous leukaemic cell lines. On the other hand, an other three benzo[a]phenothiazines, six 10-[n-(phthalimido)alkyl]-2-substituted-10H-phenothiazines, six 1-(2-chloroethyl)-3-(2-substituted-10H-phenothiazin-10-yl)alkyl-1- ureas, and twelve benz[c]acridines showed little or no DNA fragmentation-inducing activity. Active benzo[a]phenothiazines induced DNA fragmentation in four human myelogenous leukaemic cell lines (HL-60, ML-1, U-937, THP-1), but not in human T-cell leukaemic MOLT-4 and erythroleukaemic K-562 cell lines, which were also resistant to other apoptosis-inducing agents. Ca2+-depletion from the culture medium did not significantly affect their DNA fragmentation-inducing activity. The differentiation and apoptosis-inducing activity of benzo[a]phenothiazines have an important role for their medicinal efficacy.

Acridines↗

PubMedDate not supplied

Chromatin structure and endonuclease sensitivity in human leukemic cell lines.

The relationship between chromatin structure and endonuclease sensitivity was investigated. The cells used in this study were a) human myelogenous leukemic cell lines (HL-60, ML-I, U-937, THP-I) (Group I), which produced internucleosomal DNA cleavage, and b) human T-cell leukemia (MOLT-4), erythroleukemia (K562), glioblastoma (T98G, U87MG) and glioma (KG-1-C) cell lines (Group II), which produced no internucleosomal DNA cleavage, upon treatment with various apoptosis-inducing agents. When the nuclei, isolated from these cells were digested with micrococcal nuclease, chromatin DNA was cleaved into oligonucleosomal units. Although sensitivity to micrococcal nuclease considerably differed from cell to cell, Group I cells were generally more sensitive to micrococcal nuclease digestion than Group II cells. Similar sensitivity to DNase I was observed in both groups of cells. Acid-urea polyacrylamide gel electrophoresis of histone fractions from control and apoptosing HL-60 cells (induced either by hydrogen peroxide or UV irradiation) revealed no significant change in the relative composition of five major histones, indicating the absence of selective degradation of histone HI, but rather the nonspecific degradation of many nuclear proteins. These data suggest a difference in a chromatin structure between Group I and II cells, which might result in the selective production of internucleosomal DNA cleavage only in Group I cells.

Apoptosis↗

PubMedDate not supplied

The interaction between two antioxidants, sodium ascorbate and gallic acid: radical intensity and apoptosis induction.

ESR spectroscopy revealed that both the radical intensity and degradation rate of sodium ascorbate were increased with increasing pH. Gallic acid significantly reduced the radical intensity of sodium ascorbate, which in turn reduced the radical intensity of gallic acid. Sodium ascorbate inhibited the apoptosis-inducing activity of gallic acid, and gallic acid inhibited the intracellular incorporation of ascorbic acid. These data suggest that interaction between sodium ascorbate and gallic acid might modify their biological activity.

Antioxidants↗

PubMedDate not supplied

Effect of the type of serum in the medium on sodium ascorbate-induced cytotoxicity.

Sodium ascorbate induced cytotoxicity against human glioblastoma T98G cells in RPMI1640 medium supplemented with fetal bovine serum or human serum samples was studied. Several human serum samples significantly reduced the cytotoxic activity of sodium ascorbate, regardless of sex, age or the disease of the serum donor with or without heat-inactivation of the serum. ESR spectroscopy revealed that this serum effect was not simply due to the alteration of the ascorbyl radical intensity, produced from sodium ascorbate. The present study suggests that the apoptosis-inducing activity of sodium ascorbate might be significantly affected by human serum.

Adult↗

PubMedDate not supplied

Ca2+ mobilization during cell death induction by sodium 5, 6-benzylidene-L-ascorbate.

The cytotoxic activity of sodium 5,6-benzylidene-L-ascorbate (SBA) against human KG-1-C glioma and T98G glioblastoma cell lines was augmented by pretreatment of the cells with L-buthionine-[S, R]-sulfoximine (BSO), which reduced the intracellular glutathione concentrations. SBA produced shrunken cells and large DNA fragments, without the induction of nuclear and internucleosomal DNA fragmentation. The rapid elevation of intracellular free Ca2+ concentration observed after SBA treatment was further augmented by BSO pretreatment. A confocal experiment with Fluo-3 fluorescence revealed that SBA markedly elevated the free Ca2+ concentration in the nuclear region, but did not significantly affect that in the cytoplasmic region. The present study suggests that the nuclear accumulation of Ca2+ is an important initial step for cell death induction by SBA.

Antineoplastic Agents↗

PubMedDate not supplied

Relationship between ascorbyl radical intensity and apoptosis-inducing activity.

Ascorbic acid and its related compounds were compared for their ascorbyl radical intensity and apoptosis-inducing activity. Sodium L-ascorbate, L-ascorbic acid, D-isoascorbic acid, sodium 6-beta-O-galactosyl-L-ascorbate and sodium 5,6-benzylidene-L-ascorbate, at the concentration of 1-10 mM, induced apoptotic cell death characterized by cell shrinkage, nuclear fragmentation and internucleosomal DNA cleavage in human promyelocytic leukemic HL-60 cells. On the other hand, L-ascorbic acid-2-phosphate magnesium salt and L-ascorbic acid 2-sulfate did not induce any of these apoptosis-associated characteristics. ESR measurements revealed that all the active compounds were progressively degraded, producing the ascorbyl radical (g = 2.0064, hfc = 0.17 mT) in culture medium, whereas the inactive compounds were stable and did not produce the ascorbyl radical. Cytotoxicity began to appear when the radical intensity exceeded a certain threshold level. In the presence of N-acetyl-L-cysteine, both ascorbyl radical intensity and apoptosis-inducing activity were significantly reduced. These data suggest the possible involvement of the ascorbyl radical in apoptosis induction by ascorbic acid-related compounds. Exposure of HL-60 cells to ascorbic acid or its active derivatives resulted in the rapid elevation of intracellular Ca2+ concentration, which might serve as the initial signal leading to the cell death pathway.

Antineoplastic Agents↗

PubMedDate not supplied

Stimulation of two step degradation of sodium ascorbate by lignins.

Alkali-lignin stimulated the degradation of sodium ascorbate in phosphate-buffered saline, fetal bovine serum and culture medium, but not in distilled water. ESR spectroscopy revealed that alkali-lignin stimulated ascorbyl radical production even in distilled water. Similar stimulation activity was found in several other plant extracts, commercial and natural lignified materials. These data suggest that the lignin-stimulated degradation process of ascorbate might be separated into two processes, the first being the ascorbyl radical production process and the second the degradation process.

Animals↗

PubMedDate not supplied

Ascorbyl radical scavenging activity of polyphenols.

A variety of tannin and lignin-related compounds were compared for their ability to modify the ascorbyl radical intensity of sodium ascorbate. Hot-water extracts prepared from green tea, black tea and pine cone (Pinus parviflora Sieb. et Zucc.), and various wines potently scavenged ascorbyl radical intensity. Low molecular weight tannins and phenylpropenoid monomers showed the greatest scavenging activity, whereas the dehydrogenation polymers of phenylpropenoids were much less active. On the other hand, natural lignified materials, protein-bound polysaccharide (PSK) and positively-charged glucans enhanced the ascorbyl radical intensity. Lignin sulfonate stimulated the sodium ascorbate-induced cytotoxicity in human promyelocytic leukemic HL-60 cells. These data suggest that the ascorbyl radical scavenging activity of polyphenols depends on molecular weight, the functional group and the presence of polysaccharides in the molecule.

Ascorbic Acid↗