Studies on the synthesis and anti-inflammatory activity of 2,6-di-tert-butylphenols with a heterocyclic group at the 4-position. II.
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Biomedical subjects
Publications and source records attributed to H Homma.
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Diffuse panbronchiolitis (DPB) is a disease with chronic inflammation exclusively located in the region of respiratory bronchioles. The pathologic features of the disease are characterized by thickening of the wall of the respiratory bronchiole with infiltration of lymphocytes, plasma cells and histiocytes, and extension of the inflammatory changes toward peribronchiolar tissues. In the advanced stage, secondary ectasia of proximal bronchioli may occur. These changes appear as diffusely disseminated small nodular shadows throughout both lungs on the chest roentgenogram. Obstructive respiratory functional impairment, occasional symptoms of wheezing, and also cough and sputum resemble the feature of emphysema, bronchial asthma, or chronic bronchitis, respectively. In the advanced stage, large amounts of purulent sputum and dilatation of proximal terminal conducting bronchioli resemble bronchiectasis. However, diffuse panbronchiolitis belongs to a distinctly different category from these diseases, and should be distinguished from them, because it may often show rapid progression with fatal outcome. The disease is dominant in males and the onset is unrelated to age. More than 1,000 cases of probable diffuse panbronchiolitis and 82 histologically-confirmed cases have been collected in Japan.
Metabolism of platelet-activating factor (PAF) in rabbit plasma or in rabbit platelets was studied. [C3H3]-Labeled PAF was degraded into lysoPAF and choline in plasma. An agonist of PAF, NT071 was not degraded in the plasma. Albumin protects the degradation of PAF in plasma deprived of albumin but not the degradation of lysoPAF. These findings indicate that PAF may be metabolized in plasma by acetylhydrolase and then by lysophospholipase D. PAF was converted to phosphatidylcholine (PC) in washed rabbit platelets. The radioactivities in PC was recovered in the fraction of lysoPC after mild alkaline treatment, suggesting that the product is 1-alkyl-2-acyl-glycerophosphocholine. The binding of PAF and lysoPAF to rabbit platelets, rabbit erythrocytes and liposomal membranes were next examined. The binding of PAF to various membranes was inhibited by albumin. Albumin also suppressed the activation of platelets by PAF. A monomeric form of PAF, which is free from albumin, may react with target cell membrane and also be degraded by catabolic enzymes. The binding of lysoPAF to platelets, erythrocytes and liposomes was more effectively inhibited by albumin than that of PAF. The affinity of PAF to lipid bilayers may be higher than that of lysoPAF.
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The echoflowscan findings of 121 patients with acute cerebro-vascular diseases were compared with the angiographic features. The results of the degree of carotid stenosis correlated well in 86%. In 14% the ultrasonic findings were false. To be more effective in non-invasive carotid evaluation, a selected battery of tests is required.
When 2-acyl lysophosphatidylethanolamine, 2-acyl lysophosphatidylglycerol, and 2-acyl lysophosphatidylcholine were incubated with the envelope fraction of Escherichia coli in the presence of Mg2+ ion, they were acylated to the corresponding diacylphospholipids. The inner and outer membrane fractions both had acylation activity. 2-Acyl lysophosphatidylethanolamine was shown to be acylated at the 1-position by an endogenous acyl donor present in the envelope fraction. Under the conditions used, acylation was specific for 2-acyl lysophosphatidylethanolamine, and the 1-acyl isomer was not appreciably acylated. The acylation was resistant to N-ethylmaleimide and p-chloromercuribenzoate, but was inhibited by Cu2+ and Hg2+ ions. Ca2+ and Mg2+ ions stimulated the activity about 1.5-fold, but EDTA was not inhibitory. The activity had a broad pH optimum between 6 and 8. On boiling the envelope fraction, about 55% of the activity was lost rapidly, while the remainder was lost gradually. The endogenous acyl donor present in the envelope fraction was shown to be membrane phospholipids. The acylation was not observed with free fatty acids prepared by alkaline hydrolysis of the phospholipids. Studies with purified phospholipids showed that the major phospholipids of E. coli (phosphatidylethanolamine, phosphatidylglycerol, and cardiolipin) and phosphatidic acid acted as acyl donors. Thus, transacylation between diacylphospholipids and 2-acyl lysophospholipids catalyzed by E. coli envelopes was demonstrated.
When 2-[14C]acyl lysophosphatidylethanolamine was incubated with the envelope fraction of E. coli in the presence of Mg2+ ion, phosphatidylethanolamine, acylphosphatidylglycerol and free fatty acid were produced. When 2-[14C]acyl lysophosphatidylglycerol was examined similarly, six phospholipids as well as free fatty acid were produced. These were dilysocardiolipin, lysocardiolipin, phosphatidylglycerol, cardiolipin, bis(monoacylglycero)phosphate and acylphosphatidylglycerol; they were identified by thin layer chromatography, acetolysis and mild alkaline hydrolysis. Studies with an E. coli mutant which is deficient in cardiolipin synthase showed that dilysocardioilipin, lysocardiolipin and cardiolipin were synthesized by cardiolipin synthase. Bis(monoacylglycero)phosphate as well as acylphosphatidylglycerol was produced by acylphosphatidylglycerol synthase. While phosphatidylglycerol and cardiolipin were produced predominantly from 2-acyl lysophosphatidylglycerol, almost the same amounts of dilysocardiolipin, lysocardiolipin and bis(monoacylglycero)phosphate were produced from the 1-acyl and 2-acyl isomers. Metabolites of 2-[14C]acyl lysophosphatidic acid were also examined. Phosphatidic acid, acylphosphatidylglycerol, free fatty acid and monoglyceride were produced, together with a small amount of diglyceride.
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The incorporation of 2-acyl lysophospholipids into Escherichia coli, and their metabolism were studied. 2-[14C]Acyl lysophosphatidylethanolamine could penetrate into E. coli cells and was mainly incorporated into phosphatidylethanolamine. 2-Acyl lysophosphatidylethanolamine was partially degraded, but some of it was incorporated into membrane phospholipids by acylation. 2-Acyl lysophosphatidylcholine also entered cells and was acylated to phosphatidylcholine. The acylation of 2-acyl lysophospholipid by the envelope fraction was also studied. Fatty acids were incorporated into 2-acyl lysophospholipids by the envelope fraction in the presence of ATP and Mg2+, and the incorporation was stimulated by acyl carrier protein, but not by coenzyme A. No acylation was observed with acyl coenzyme A as acyl donor. The acylation activities of the inner and outer membranes were examined. Pathways for degradation and modification of membrane phospholipids in E. coli are proposed.
Chemiluminescence response upon phagocytosis was found to be enhanced in circulating blood monocytes derived from patients with active sarcoidosis, suggesting that these monocytes are activated and easily generate reactive species of oxygen including singlet oxygen. Such enhancement was observed even when patients were receiving high doses of corticosteroids but not when the sarcoidosis was chronic or the patients had recovered. Chemiluminescence measurements may thus be a useful aid for confirming diagnosis and assessing the effects of treatment of the disease.
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