[A histologic study of atherosclerosis of the internal mammary artery used for coronary artery bypass surgery].
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Biomedical subjects
Publications and source records attributed to S Taniguchi.
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Angiotensin II-induced hypertension chemotherapy using cis-diamminedichloroplatinum (II) (DDP) or carboquone (CQ), and a modification of the therapy through combination with a cardiotonic, such as aminophylline (AP) and trans-pi-oxocamphor (pi OC), were compared with regard to therapeutic efficacy on an established mouse mammary carcinoma grown s.c. in syngeneic mice. The hypertension chemotherapy proved to be more effective than conventional administration with the anticancer drug alone. On the other hand, a remarkable improvement in antitumor effect without any increase in the general toxicity was more apparent in the modified hypertension chemotherapy than in angiotensin II hypertension chemotherapy. The combination therapy using DDP, AP or pi OC, but not AT-II, did not produce any increase in antitumor effect as compared to conventional administration with anticancer drug alone. The cytotoxicity of DDP against cultured HeLa cells was not enhanced by co-administration with AT-II, AP and/or pi OC. Thus, the increase in the therapeutic efficacy obtained by the modified hypertension chemotherapy may be attributable to the specific augmentation in delivery of the anticancer drug to the tumor tissue, but not to any specific enhancement in the cytotoxicity of the anticancer drug against to the tumor cells.
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The properties of Ca2+-dependent incorporation of [3H]serine, [3H]ethanolamine and [3H]choline into the corresponding phospholipids mediated by base-exchange enzymes in rabbit platelet membranes were studied in the presence or absence of the calmodulin antagonists chlorpromazine, trifluoperazine and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), all of which markedly activate three base-exchange reactions. The base-exchange activities were dependent on Ca2+ both in the presence and absence of the drugs. Other metal ions tested did not stimulate the base-exchange reactions, even in the presence of the drugs. Apparent Km values for serine, ethanolamine and choline were not affected significantly by the concentration of Ca2+, with or without the drugs. [3H]Serine incorporation into phospholipid was competitively inhibited by ethanolamine and choline, [3H]choline incorporation was competitively inhibited by serine and ethanolamine, whereas [3H]ethanolamine incorporation was competitively inhibited by serine and noncompetitively by choline. These competitive and noncompetitive relations between each base were also not affected by the drugs. The amount of 45Ca2+ binding to platelet membranes was decreased by the drugs dose dependently. A weaker calmodulin antagonist, N-(6-aminohexyl)-1-naphthalenesulfonamide (W-5), only slightly stimulated the base-exchange reactions, but did clearly inhibit 45Ca2+ binding to the membranes, in the same manner as that of the other calmodulin antagonists used. The concentration of chlorpromazine, trifluoperazine, W-7 and W-5, required to produce half-maximal inhibition of Ca2+ binding, was approximately 30 microM. These results suggest that the calmodulin antagonists used activate the base-exchange reactions only in the presence of Ca2+ without changing the affinity of each free base to base-exchange enzymes. The activation of the base-exchange reactions was not due to the increase in free Ca2+ caused by the drug-induced inhibition of Ca2+ binding to platelet membranes.
The biosynthesis of phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (PS) by base-exchange reactions, and of PC and PE by the CDP pathways, was assessed in the membrane phospholipids of human leukocytes (neutrophils, lymphocytes, T lymphocytes, non-T lymphocytes, and monocytes). Of the three base-exchange activities, ethanolamine exchange was the highest and choline exchange the lowest in each leukocyte membrane. In the CDP pathways, ethanolaminephosphotransferase (EPT) and cholinephosphotransferase (CPT) had comparable activities. Among subpopulations of leukocytes, T lymphocytes showed the highest levels of each enzyme activity, and neutrophils showed the least. In contrast to the enzymes of the CDP pathways, each base-exchange activity was directly proportional to the Ca2+ concentration, but markedly inhibited by Mg2+. Despite this Ca2+ dependence, the base-exchange activities were increased in a dose-dependent manner by calmodulin antagonists and, except for ethanolamine exchange, inhibited by the addition of calmodulin; EPT and CPT activities were only slightly inhibited by calmodulin antagonists and were unaffected by calmodulin. PE formation in both neutrophil and lymphocyte base-exchange reactions was enhanced in a dose-dependent manner by the presence of low concentrations of bioactive stimulants (zymosan, 0.05-0.2 mg/ml; Con A, 0.5-2 micrograms/ml), while EPT and CPT activities were not increased by these cell stimulants. Taken together, our data suggest that base-exchange activity, the biological significance of which has been hitherto unclear, may be related to cell activation; in contrast, the CDP pathways appear primarily to involve the constitutive biosynthesis of phospholipids. Our data further suggest that ethanolamine required for base-exchange reactions is a precursor of PE, N-transmethylation of which can serve as a source of cell activation, leading to production of arachidonic through PC by mediation of phospholipase A2 activity.
The polypeptides of mouse B16 melanoma lines of defined metastatic potential have been analyzed by two-dimensional electrophoresis. Parent B16 melanoma and two independently isolated B16-F1 lines, which are low metastatic, exhibited a new polypeptide, Ax (pI 5.2; Mr = 43,000), comprising approximately 30% of the total actin, in addition to normal beta- and gamma-actin. The Ax is present in the Triton-insoluble fraction (cytoskeleton and nuclear matrix) as well as in the Triton-soluble fraction at a constant ratio of about 0.5 to beta- plus gamma-actin. The Ax polypeptide has been identified as a variant form of actin by immunostaining with anti-actin antibody and by a comparison of its tryptic patterns with those produced by beta- and gamma-actin polypeptides; the Ax is also identified as a component of microfilaments. On the other hand, the Ax polypeptide disappears or its expression is very low in high metastatic lines, two independently isolated B16-F10s and B16-BL6. By in vitro translation, we have identified the mRNA species that code for Ax in B16-F1, but not in B16-F10.
The effect of an immunosuppressive drug, cyclosporin A, and dexamethasone was assessed on the enzymatic reactions of membrane phospholipid in normal human lymphocytes and neutrophils. Incubation for 20 min with cyclosporin A markedly suppressed, in a dose dependent manner, phospholipase A2 activity and the release of prostaglandin E2 in lymphocytes, and slightly those in neutrophils, while no inhibition of phosphatidylethanolamine (PE)-N methyltransferase activity was observed. Choline phosphotransferase (CPT) activity was not inhibited by the drug, either. These inhibitory effects on enzyme activities of membrane phospholipid are similar to those of dexamethasone, although different incubation time of the drug was required to induce inhibitory effects. These findings suggest that cyclosporin A acts upon early membrane events in the activation of cells involved in inflammatory reactions; they further suggest that suppression of immune response by cyclosporin A is at least partly due to inhibition of phospholipase A2 in the plasma membrane of inflammatory cells. This inhibition reduces the production of cell membrane lyso-phosphatidylcholine (PC) and arachidonic acid from PC, which is produced by transmethylation of PE and cytidine diphosphate (CDP) choline pathway of which the last reaction to PC is mediated by CPT.
Histamine-N-methyltransferase, a major histamine-degrading enzyme in the skin, was purified from guinea pig skin about 150-fold. The enzymological characteristics including pH optimum, Km values for substrates, and molecular weight were almost consistent with those reported in the brain. Regulatory mechanism of the enzyme activity by biogenic amines was investigated using the purified specimen. Serotonin, tryptamine, and 5-methoxytryptamine intensely inhibited the activity while tryptophan, melatonin, N-acetylserotonin, tryptophol, and 5-hydroxyindole acetic acid had no significant effects. Dopamine, tyramine, 3-methyltyramine, and phenylethylamine also inhibited the activity while no particular effects were obtained by adrenaline, noradrenaline, tyrosine, and DOPA. Spermidine and cadaverine caused significant but weaker inhibition. These amines acted competitively with respect to histamine, although varying manners were observed with respect to S-adenosyl-L-methionine. From these results, it was concluded that the enzyme activity was inhibited by such compounds in which a certain chemical structure, CH2-CH2-NH2 group neighboring the hydrophobic group, was contained. A possible mechanism of inhibition by the amines is postulated, and possible roles of such compounds in the inflammation by impairing the histamine metabolism is discussed.
Histamine metabolism, i.e., concentration of histamine and activities of histamine-degrading enzymes, histamine-N-methyltransferase (HMT), and diamine oxidase (DAO), were examined in the Arthus reaction induced in guinea pig skin. The specific activity of HMT was 44.12 +/- 3.80 pmole/min/mg protein and was about 15 times greater than that of DAO in control specimens. However, HMT activity decreased time dependently to 35% of the control at 3 hr and to 10% 48 hr after the initiation of the reaction. DAO activity increased to 150% till 1 hr followed by a linear decrease to 35% at 6 hr and to 10% at 48 hr. Histamine concentration showed a prominent linear decrease to 15% of the control at 2 hr followed by an increase to about 85% at 6 hr. This biphasic change seemed to be well explained by the dynamic changes in the activities of histamine-degrading enzymes. Such decrease in enzyme activities were not observed in other experimentally induced inflammations including dinitrochlorobenzene allergic and croton oil dermatitis. The addition of tissue extract from the Arthus reaction sites resulted in about 30% inhibition in both of two enzyme activities, suggesting the presence of some inhibitory factor(s) in the reaction sites.
The activities of three enzymes catalyzing the production or degradation of phosphatidylcholine, a major structural phospholipid of cell membranes, were assessed in hepatocyte membrane microsomal preparation from patients with various types of liver disease. Choline phosphotransferase activity of preparation from patients with chronic aggressive, chronic active, chronic persistent, alcoholic hepatitis and cirrhosis accompanied by marked necrosis and relatively slight fibrosis was markedly decreased, compared with normal liver; the activity from patients with fatty liver and chronic inactive hepatitis was slightly decreased. Specimens from patients with acute transient hepatitis were not significantly different from normal. Methyltransferase and phospholipase A2 activities tended to parallel that of choline phosphotransferase, although the degree of changes was generally less marked. Our studies indicate that enzyme activities that are critical for hepatic cell membrane integrity and activity are attenuated in liver specimens from patients with disease in which there is marked hepatic cell necrosis.
The effects of Ca2+ on ethanolaminephosphotransferase [EC 2.7.8.1] and cholinephosphotransferase [EC 2.7.8.2] activities in rabbit platelet membranes were studied using endogenous diglyceride and CDP-[3H]ethanolamine or CDP-[14C]choline as substrates. Both transferases required Mn2+, Co2+, or Mg2+ as a metal cofactor and the optimal concentrations of the metals for both activities were about 5, 10, and 5 mM, respectively. When 5 mM Mg2+ was used as a cofactor, both transferase activities were inhibited by a low concentration of Ca2+ (half maximal inhibition at approx. 15 microM). In the presence of 5 mM Mn2+, however, approx. 5 mM Ca2+ was required to produce half maximal inhibition. The Ca2+-induced inhibition was reversible and the rate of the inhibition was not affected either by the concentrations of the CDP-compound or by exogenously added diacylglycerol. The relationship between Ca2+ and both Mg2+ and Mn2+ on the transferase activities was competitive. 45Ca2+ binding (and/or uptake) to the platelet membranes was inhibited by Mn2+, Mg2+, and Co2+, in a concentration-dependent manner. However, the inhibitory effects of the three metal ions on the total Ca2+ binding (and/or uptake) did not correlate with the activation of both transferase activities by the three metal ions in the presence of Ca2+. These results suggest that both transferase activities are regulated by low concentrations of Ca2+ in the presence of optimal concentrations of Mg2+, and that the inhibition is mediated directly by Ca2+, which interacts with a specific metal cofactor binding site(s) of the transferases.
Effects of the calmodulin antagonists chlorpromazine, trifluoperazine, and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide on phospholipid metabolism were examined in rabbit platelets using [3H]serine, [3H]ethanolamine, [3H]choline, and [3H]glycerol. All these drugs markedly stimulated the incorporation of [3H]serine into phosphatidylserine. On the other hand, these drugs had only a slight effect on the rate of incorporation of [3H]ethanolamine and [3H]choline into the corresponding phospholipid. When [3H]glycerol was used as a precursor of the phospholipids, 3H-labeled phospholipids were mainly composed of phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol. Although the phosphorus content of phosphatidylserine was about 40% of that of phosphatidylcholine in rabbit platelets, the amount of phosphatidylserine labeled with [3H]glycerol was less than 2% of that of the labeled phosphatidylcholine, and calmodulin antagonists slightly stimulated the incorporation of [3H]glycerol into phosphatidylserine. Treatment with calmodulin antagonists caused a marked decrease in the content of endogenous free serine with concomitant increase in the contents of endogenous free ethanolamine and choline. On the other hand, the contents of other free amino acids, including essential and non-essential amino acids, were unchanged. These results suggest that the calmodulin antagonists we used did not affect de novo synthesis of phosphatidylserine, but did stimulate the serine phospholipid base-exchange reaction in rabbit platelets.
Two cases of penis tuberculides are described. Although this disease once used to be comparatively common in Japan, the number of people affected by the disease has recently decreased as the prevalence of tuberculosis has fallen. However, we can still find a few cases in the Japanese literature every year. Outside Japan, we can hardly find reports of this disease, except for a few cases reported under the title of 'Papulonecrotic tuberculides on the penis' from Northern European countries. In addition to reporting 2 cases, we summarize clinical features of this disease. Racial predisposition or endemic factors may be related to the tuberculides in such a special site.
The changes in the cytosol glucocorticoid receptor (GR) content during a long-term administration of a glucocorticoid were studied to examine the mechanism of the development of steroid hormone resistance. Dexamethasone (Dex) (0.2 microgram/ml and 2.0 micrograms/ml) was given to adrenalectomized rats, and the GR content was determined using the exchange assay 1, 10, 20 and 50 days after the start of administration. The activity of tyrosine aminotransferase (TAT) in the cytosol was also assayed as a measure of the biological responsiveness of these animals to the administered glucocorticoid. The dissociation constant (Kd) was elevated and the Bmaxs of the GR in the cytosol were decreased by the lower concentration of Dex. The Bmaxs decreased to 30% of the untreated controls within 24 h and this lower level was maintained as long as the hormone treatment continued. On the other hand, the cytosol obtained from animals treated with 2.0 micrograms/ml of Dex for 20-24 days did not show any measurable amount of binding to 3H-Dex. The activity of TAT was elevated 24 h after the administration of Dex but decreased gradually and steadily with time during the experimental period. To examine the biological potency of remaining GR in the liver cytosol, 2.0 micrograms/ml Dex was again administered after a long-term treatment. This treatment eliminated the remaining GR completely and induced TAT at almost the same rate as observed in the untreated control animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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Angiotensin II-induced hypertension chemotherapy proved to be more effective than conventional chemotherapy using cis-diamminedichloroplatinum (II) (DDP), when applied to an established mouse mammary carcinoma. In an attempt to improve the effectiveness, a cardiotonic such as aminophylline or trans-pi-oxocamphor was added to a solution containing angiotensin II and DDP. A remarkable improvement in therapeutic efficacy was apparent as compared to angiotensin II hypertension chemotherapy. A possible synergism between angiotensin II and the cardiotonic may result in selective delivery of the antitumor drug to the tumor tissue.