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Biomedical subjects

T Oki

Publications and source records attributed to T Oki.

At least 415 records · Page 23Linked to original sources

Ultrastructure of cartilage in heritable disorders of connective tissue.

Ultrastruct of cartilage were examined in Marfan syndrome, Menkes kinky hair syndrome, achondroplasia, asphyxiating thoracic dysplasia, mild diastrophic dysplasia and mucopolysaccharidoses I and III. Ruthenium red staining revealed decrease of proteoglycans in cases with Marfan syndrome and kinky hair syndrome, and increase in cases with osteochondrodysplasia and mucopolysaccharidosis III. This morphologic tendency coincided with the result obtained by biochemical analysis of glycosaminoglycan contents in cartilage matrix from cases with Marfan syndrome (decreased content) and asphyxiating thoracic dysplasia (increased content). It was postulated that proteoglycan content in cartilage matrix might be related to excessive or reduced skeletal growth in Marfan syndrome or osteochondrodysplasia.

Achondroplasia↗

Reduction of cinerulose in aclacinomycin-A by soluble and microsomal cinerulose reductases.

The in vitro metabolism of the antitumor anthracycline antibiotic, aclacinomycin-A, was studied using rat liver homogenate. In the presence of NADH or NADPH, aclacinomycin-A was converted to aclacinomycin-A analogs, MA144 M1 and MA144 N1, which were stereospecifically reduced at the keto group of the C-4''' position of L-cinerulose in aclacinomycin-A. Subcellular fractionation indicated that the production of MA144 M1, which was reduced to L-amicetose, was catalyzed by NADPH-dependent soluble cinerulose reductase I, and the production of MA144 N1, which was reduced to L-rhodinose, was catalyzed by NADPH-dependent soluble cinerulose reductase II and NADH-dependent microsomal cinerulose reductase. The properties of these three enzymes were studied. Soluble cinerulose reductase I which produces MA144 M1 showed a optimum pH at 6.3, Km values of 3.3 x 10(-4) M for aclacinomycin-A and 3.2 x 10(-5) M for NADPH. Soluble cinerulose reductase II which produces MA144 N1 showed a pH optimum at 6.3 and Km values of 2.0 x 10(-3) M for aclacinomycin-A and 4.0 x 10(-5) M for NADPH. All thesse reductases were sensitive to sulfhydryl reagents and were inhibited by vitamin K3. Microsomal cinerulose reductase showed sensitivity to diconmarol and ferrous ion. The main nondegradative pathways of aclacinomycin-A were discussed from these results.

Animals↗

Reduction of anthracycline glycoside by NADPH--cytochrome P-450 reductase.

The in vitro degradation of the new antitumor anthracycline antibiotic, aclacinomycin-A, was studied using rat liver homogenate. In the presence of NADH or NADPH, the glycosidic bond at C-7 position of aclacinomycin-A was reductively cleaved to produce 7-deoxyaklavinone and 7-deoxyaklavinone dimer, MA144 E1. Subcellular fractionation indicated that most of the enzyme activity was present in the microsomal fraction and required anaerobic condition and NADPH. The purified enzyme reduced the glycosidic metabolites, MA144 M1 and MA144 N1, as well as aclacinomycin-A. The optimum pH for the anthracycline glycoside reductase reaction using aclacinomycin-A as substrate was 7.4. The enzyme was sigmoidally saturated with aclacinomycin-A and showed the concentration of 1.2 x 10(-4) M required for half maximal activity, and Km value of 7.7 x 10(-5) M for NADPH. The degradative pathway of aclacinomycin-A and its glycosidic metabolites was discussed.

Anaerobiosis↗

Effect of guanosine 5'-diphosphate 3'-diphosphate and related nucleoside polyphosphates on induction of tryptophanase and beta-galactosidase in permeabilized cells of Escherichia coli.

Exogenous addition of guanosine and adenosine 5'-(mono, di and tri) phosphate 3'-diphosphates (pppGpp, ppGpp, pGpp, pppApp, ppApp and pApp) stimulated the synthesis of tryptophanase and beta-galactosidase in permeabilized cells of Escherichia coli. From the results obtained with ppGpp and pppApp, this effect appeared to be at a transcriptional level and depended greatly on the growth condition; the largest effect was observed in cells under shiftdown or grown on poor enrgy source. ppGpp and pppApp, unlike cyclic AMP, did not act to overcome the inhibition of enzyme induction by glucose, but in combination with cyclic AMP caused a synergistic stimulation effect. In the shiftdown cells, ppGpp and pppApp gave 30% or more stimulation effect on tryptophanase induction while cyclic AMP did not stimulate induction. There was therefore a pronounced difference between cyclic AMP and ppGpp or pppApp in stimulatory function.

Adenine Nucleotides↗

Inhibition of platelet aggregation by alpha-tocopherol and its nicotinate and acetate esters.

Two esters of vitamin E, dl-a-tocopheryl nicotinate and dl-a-tocopheryl acetate were found to be more inhibitors than tocopherol itself on platelet aggregation induced by arachidonic acid and collagen. The nicotinate was 1--5 times more potent than the acetate and 2--18 times more potent than the unesterified tocopherol in inhibiting collagen induced aggregation in human citratet platelet-rich plasma.

Arachidonic Acids↗

Antitumor activity of new anthracycline antibiotics, aclacinomycin-A and its analogs, and their toxicity.

New anthracycline antibiotics have been isolated from the culture of Streptomyces galilaeus MA144-M1. Among 14 anthracycline compounds, aclacinomycin-A showed the strongest activity in inhibiting leukemia L-1210 and had lower toxicity than others. Antitumor activity of aclacinomycin-A against leukemia L-1210 and P-388, solid sarcoma-180, and lymphosarcoma 6C3HED was examined in comparison with adriamycin and daunomycin. Aclacinomycin-A showed the same degree of activity against leukemia L-1210 and P-388, when administered intraperitoneally, as daunomycin and somewhat less than adriamycin. In oral administration, aclacinomycin-A also exhibited a significant activity on leukemia L-1210. The degree of inhibition of the growth of sarcoma-180 and 6C3HED lymphosarcoma transplanted subcutaneously by aclacinomycin-A was almost the same as that of adriamycin and daunomycin, although the optimal dose was about twice more than adriamycin. Acute cardiotoxicity of aclacinomycin-A by a test using hamsters was more than 10 times lower than that of adriamycin.

Aclarubicin↗

New anthracycline antibiotics.

A number of anthracycline antibiotics have been found in Streptomyces cultures. Among them, adriamycin and daunomycin have been studied most in detail, because these compounds have exhibited a strong antitumor activities 1, 2). However, their clinical usefuleness is limited by side effects, particularly by bone marrow suppression and cumulative dose-dependent cardiac toxicity. 3 approximately 5) By the collaboration with Prof. H. UMEZAWA and Dr. T. TAKEUCHI, Institute of Microbial Chemistry, for the studies to find out new anthracycline antibiotics that may have lower cardiac toxicity and the same degree of the antitumor activity, we found 32 new anthracycline compounds in Streptomyces cultures and aclacinomycin A is under the phase II clinical study. Anthracycline compounds can be classified depending on the structures of their aglycones as shown in Table 1. These compounds have a linear tetracyclic polyhydroxy anthracyclines, and can be grouped into seven groups. Biologically active anthracycline antibiotics have various sugar moieties at C-7 and/or C-10 position of the anthracyclinones. In 1951, H. BROCKMANN6) discovered rhodomycins A and B in the culture of a new species of Streptomyces purpurascens. Since then, he found numerous anthracycline compounds such as rhodomycin-, isorhodomycin- and pyrromycin-types in Streptomyces and elucidated their structures. All of these anthracyclines are red pigments. In 1964 and 1969 new group of orange-red anthracycline antibiotics: daunomycin10) and adriamycin11) was reported by DiMARCO and F. ARCAMONE. Moreover, aklavin12, 13) which has yellow aklavinone as aglycone and citromycinone aglycone14) which is also yellow have been isolated in the Streptomyces cultures. Aclacinomycin A15), which we found in Streptomyces galilaeus MA144-M1, has aklavinone aglycone and is becoming more interesting in its low cardiac toxicity.

Animals↗

Occurrence of pppApp-synthesizing activity in actinomycetes and isolation of purine nucleotide pyrophosphotransferase.

The occurrence of adenosine 5'-triphosphate-3'diphosphate-synthesizing activity was detected in five strains of actinomycetes; Streptomyces morookaensis, Streptomyces aspergilloides, Streptomyces hachijoensis, tactinomyces violascens and Streptoverticillium septatum, out of 825 strains of actinomycetes, bacteria, fungi and fungi imperficti. Purine nucleotide pyrophosphotransferase were extracellularly excreted associating with the cell growth, and were purified partially or to apparent homogeneiety from the culture filtrate. The enzymes are a monomeric protein with molecular weight of 18,000-26,000 and synthesize adenosine, guanosine and inosine 5'-phosphate (mono, di or tri)-3'-diphosphate such as pApp, ppA pp, pppApp, pGpp, ppGpp, pppGpp, and pppIpp by transferring a pyrophosphoryl group from the 5'-position of ATP, dATP and ppApp to the 3'-position of purine nucleotides in the presence of a divalent cation and in alkaline state.

Actinomycetales↗