Danazol therapy in hypoplasminogenemia.
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Danazol↗
Biomedical subjects
Y Kishi
Publications and source records attributed to Y Kishi.
Structural basis of protein kinase C activation by diacylglycerols and tumor promoters.
Protein kinase C is a ubiquitous and important regulatory enzyme. The enzyme is physiologically activated in a temporary manner by (S)-diacylglycerols (DAGs), which are themselves generated by the phospholipase C mediated hydrolysis of polyphosphoinositides. The (S)-DAGs specifically bind to the regulatory domain of PKC and cause the activation of the PKC toward substrate. Minor modifications in the DAG result in inactive molecules. On the other hand, the structurally diverse, polycyclic tumor promoters also specifically activate PKC by binding to the same effector site as do the DAGs. The object of this paper is to present a discrete structural model that accounts for the activation of PKC by both the tumor promoters and the DAGs. The unique model presented is based on experimentation rather than on computer-driven hypotheses which, experience has shown, generally produce incorrect structural models when applied to PKC. The model described here begins with a structural analysis of the tumor-promoting debromoaplysiatoxins (DATs). DAT is an ideal starting molecule, because it is conformationally rigid with a known relative and absolute configuration, and it is synthetically manipulable. The pharmacophore of DAT was experimentally determined, and this pharmacophore serves as a template for further analyses. This template is used to predict the active conformer of the acylic DAGs; this conformer is then used to reveal the pharmacophore of various families of tumor promoters. The overall model presented is consistent with published structure-activity studies on the tumor promoters and makes testable predictions that have proven to be correct thus far.
Animals↗
Enhanced flow velocity increase through the left ventricular inflow tract of patients with isolated aortic regurgitation.
Twenty-five patients with chronic aortic regurgitation (AR), and 12 control subjects were studied using Doppler echocardiography to investigate the effects of AR on transmitral flow. Peak early filling velocities at the levels of the mitral valve tips (E1) and annulus (E2) were measured, and the transmitral flow restriction index (delta E = (E1-E2)/E2) was obtained. Patients with AR were classified into 2 groups according to the ratio of the cross-sectional area of the regurgitant jet to that of the left ventricular outflow tract. Group I had the ratio less than 0.20, and group II had greater than or equal to 0.20. E2 in group II was lower than in control subjects, whereas E1 was not significantly different in any groups. delta E in group II was higher than in group I or in control subjects (p less than 0.05 and 0.01, respectively). delta E showed a significant correlation with the cross-sectional area ratio in all patients with AR (r = 0.70, p less than 0.01) and in group II (r = 0.82; p less than 0.01). Our data suggest that AR restricts early transmitral filling, and that delta E may indicate the increased driving pressure caused by flow restriction and is a useful hemodynamic index of AR.
Adult↗
Alteration of adenine nucleotide metabolism in coronary smooth muscle cells by activated platelets.
Cultured porcine coronary smooth muscle cells were preloaded with [3H]adenine and the inside and outside radioactive metabolites of the cells were analyzed following exposure to activated platelets. Incubation of the cells with human platelets activated by collagen enhanced intracellular conversion of ATP to ADP and caused dose- and time-dependent increase in radioisotopic release, mainly adenosine. Isolation of cyclic AMP revealed decreased cyclic AMP levels in the treated cells, both intra- and extracellularly. Of the substances released by the activated platelets, thromboxane A2 and serotonin enhanced radioisotopic release. The modulation of adenine metabolism by the activated platelets was preceded by increase in accumulation of inositol phosphates in the cells and was prevented by Iloprost (1 microM), a prostacyclin analog, cilostamide (10 microM), a cyclic AMP-specific phosphodiesterase inhibitor, or dibutyryl cyclic AMP (1 mM). Nifedipine showed only minor preventive effect. The agents which elevate cyclic AMP accumulation also attenuated phosphoinositide hydrolysis, whereas nifedipine had no effect. These results suggest that activated platelets may stimulate adenine metabolism in coronary smooth muscle cells, presumably due to activation of phosphoinositide turnover resulting in increased intracellular calcium. Enhanced adenosine release from the cells exposed to activated platelets may be a compensatory mechanism to prevent further platelet aggregation and contraction of coronary smooth muscle.
Adenine↗
Vasospastic angina in Crow-Fukase syndrome.
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Adult↗
Inhibition of platelet aggregation by prostacyclin is attenuated after exercise in patients with angina pectoris.
We tested whether alteration of platelet sensitivity to prostacyclin (PGI2) is involved in the activation of platelets induced by exercise in patients with stable angina. Twenty patients and 20 control subjects underwent treadmill testing. Blood samples were obtained before and immediately after exercise for plasma thromboxane B2 (TXB2) and 6-keto-PGF1 alpha (6kP) assays and platelet aggregation studies. Dose-response curves for platelet aggregation to collagen were obtained in the presence and absence of 1 nmol/L PGI2 to quantify the antiaggregation effects of PGI2. At rest, platelet aggregation by collagen was enhanced in the patients. However, platelets were more sensitive to exogenous PGI2, apparently associated with lower plasma 6kP levels in the patients. After exercise, plasma TXB2 levels increased in the patients but not in the control subjects. Plasma 6kP levels remained unchanged and platelet sensitivity to PGI2 decreased in the patients whereas these values increased in the control subjects. The exercise-induced changes in platelet sensitivity to PGI2 correlated with those of platelet adenylate cyclase activity in response to 1 nmol/L PGI2 (r = 0.787, p less than 0.01). Thus impaired sensitivity of platelets to PGI2, in addition to the reduced response of prostanoid secretion, might be relevant to the platelet activation associated with exercise in patients with stable angina.
6-Ketoprostaglandin F1 alpha↗
HLA-DP antigen and Takayasu arteritis.
Sixty-four patients with Takayasu arteritis and 317 healthy individuals in the Japanese population were examined for HLA-A, -B and -C alleles by serological typing and for HLA-DR, DQ and DP alleles by DNA typing using PCR/SSOP analysis. The frequencies of HLA-Bw52, DRB1*1502, DRB5*0102, DQA1*0103, DQB1*0601 and DPB1*0901 alleles were significantly increased and the frequencies of HLA-Bw54, DRB1*0405, DRB4*0101, DQA1*0301, DQB1*0401 alleles were significantly decreased. Strong linkage disequilibria among the increased alleles and among the decreased alleles were evident in the Japanese population. Therefore, the combination or haplotype of HLA-Bw52-DRB1*1502-DRB5*0102-DQA1*0103-DQB1*0601 -DPA1*02-DPB1*0901 may confer susceptibility to Takayasu arteritis while another combination or haplotype of HLA-Bw54-DRB1*0405-DRB4*0101-DQA1*0301-DQB1++ +*0401 may confer resistance to the disease. Because this is the first evidence for the association between an HLA-DP allele and Takayasu arteritis, we examined the nucleotide sequences of the DPB1*0901 allele from a patient and her healthy relatives and found no difference. The disease is therefore not caused by a mutated DPB1 gene.
Alleles↗
Clinical studies of phosphodiesterase inhibitors for cardiovascular disease.
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Adult↗
Phosphodiesterases in vascular endothelial cells.
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1-Methyl-3-isobutylxanthine↗
Vascularization after pulpotomy.
The vascular changes of the pulpal vessels in experimentally induced pulpotomy in dog tooth were investigated using microcorrosive resin casts technique and scanning electron microscopic examination. The pulpal tissues of the permanent mandibular molars were amputated and then dressed with calcium hydrate. At one to eight weeks after pulpotomy, the experimental teeth were prepared for resin casts of pulpal vessels with hard tissues. One week after pulpotomy, a concave region, which was supposed to be due to the compression by the calcium hydrate, was found in the newly formed pulpal vascular network. Around the concave region was a flat, dense capillary network. In eight weeks, the thick dentin bridge was formed in close proximity to the amputated pulpal surface. The vascular network just beneath the dentin bridge changed into similar features in the three layers of the normal pulpal vascular architecture, which are (i) terminal capillary network (TCN), (ii) capillary network (CN), and (iii) venular network (VN) and which distributed in the superficial layer of the pulpal vessels.
Animals↗
[Probucol inhibits tobacco smoke-induced decrease in plasma anti-elastase activity and ferroxidase activity in rats].
Elastolytic enzymes and active oxygen species derived from leukocytes and alveolar macrophages during exposure to tobacco smoke, together with active oxygen species directly derived from tobacco smoke, are thought to play a crucial role in the pathogenesis of pulmonary emphysema by inactivating alpha 1 protease inhibitor (alpha 1 PI), a novel anti-elastase. We studied the inhibitory effect of probucol, an oral hypocholesterolemic agent, on tobacco smoke-induced decrease in plasma anti-elastase activity (EIA) and ferroxidase activity (FA) in conscious venous catheter instrumented rats. Rats exposed to the smoke of 5 cigarettes (nicotine 11 mg, tar 115 mg) in a plastic chamber showed a prompt increase in plasma COHb to 17.9 +/- 2.7%, and a prompt decrease in plasma EIA by -17.9% (p less than 0.05) and FA by -14.8% (p less than 0.01), which lasted for 6 hours after exposure. Rats administered probucol (1% probucol in food) for 3 days showed normal cholesterol plasma levels, and rats administered probucol for 4 weeks showed hypocholesterolemic plasma levels. EIA and FA were not depressed after smoking, and lipid peroxide product (TBA reactive substance) in lung tissue (p less than 0.05) and serum (p less than 0.1) showed a smaller increase in association with a smaller decrease in the ratio of lung tissue GSH/GSSG (p less than 0.01) compared with control rats. These results indicate that probucol, via its antioxidant action rather than its cholesterol lowering effect, has a protective effect on lung exposed to tobacco smoke in terms of protease-antiprotease balance and oxidant-antioxidant balance.
Animals↗
[A case of pulmonary tuberculosis associated with severe respiratory failure, DIC and intractable bilateral pneumothoraces].
We had a sixty-five year old male patient who suddenly complained of dyspnea and fever with pulmonary tuberculosis, severe respiratory failure, disseminated intravascular coagulation (DIC) and intractable bilateral pneumothoraces. From the first hospital day severe hypoxemia which did not respond to conventional oxygen therapy developed with a diffuse ill-defined reticulo-nodular shadow in the plain chest x-ray film. On the 2nd hospital day mechanical ventilation with 2cmH2O PEEP was introduced. Antituberculous agents as well as corticosteroids were started suspecting acute interstitial pneumonia with pulmonary tuberculosis and adult respiratory distress syndrome (ARDS). Medication was followed by the treatment of Gabexate mesilate and heparin against DIC on laboratory data. Though clinical findings and pulmonary infiltrate on chest x-ray film transiently improved, right pneumothorax occurred suddenly on the 6th day followed with left pneumothorax on the 36th day. Tube drainage of both pleural spaces and repeated instillation of thrombin-rich oxycel cotton via bronchofiberscope failed to stop air leakage. He ultimately expired on 49th hospital day. At postmortem lung had multiple bilateral bulla several of which ruptured to the pleural site and caseating necrotic area containing bacilli positively stained with Ziehl-Nielsen stain in the bilateral upper lobe. No typical caseating necrotic lesion, however, was found in the other lung tissue. Therefore, it seemed to show a chronic phase of diffuse alveolar damage (DAD).
Aged↗
[Leukotoxin, 9,10-epoxy-12-octadecenoate, causes vasodilation in isolated pulmonary artery rings preconstricted with endothelin 1].
Leukotoxin, a cytochrome P450-dependent metabolite of linoleate synthesized by neutrophils, caused dose dependent vasodilation (10(15)-5 x 10(-4) M) of isolated rat pulmonary arterial rings preconstricted with endothelin 1 (10(-8) M), although similar doses of linoleate had no effect. The relaxing effect of leukotoxin was largely ablated by mechanical denudation of the endothelium and by treatment with L-NMMA (1 mM) and methylene blue (5 x 10(-6) M), but not indomethacin (10(-5) M). Endothelium-independent relaxation of leukotoxin was not inhibited by pretreatment with nicardipine (10(-6) M) in both pulmonary arterial rings and aortic rings. In A7r5 cultured rat aortic smooth muscle cells, leukotoxin markedly inhibited Ca2+ uptake in the basal nonstimulated state, and in the stimulated state with endothelin 1. We conclude that leukotoxin causes vascular tone-dependent vasodilation via augmentation of EDRF production, and causes decrease of intracellular calcium concentration that is not related to the dihydropyridine-sensitive calcium channel, which may be a mechanism of the endothelium-independent relaxation caused by leukotoxin.
Animals↗
[Inhibitory effects of alpha 1 protease inhibitor on the production of IL-1 and TNF alpha by alveolar macrophages in patients with lung cancer].
In the present study, we investigated the effect of alpha 1 protease inhibitor (alpha 1PI) on the production of interleukin-1 alpha (IL-1 alpha, ELISA), IL-1 beta (ELISA), and tumor necrosis factor alpha (TNF alpha, ELISA) by alveolar macrophages (AM) recruited by bronchoalveolar lavage (BAL) from patients with lung cancer and benign pulmonary diseases. Levels of BALF alpha 1PI were significantly increased in patients with lung cancer compared with benign pulmonary diseases. When BALF AM were cultured and stimulated by LPS (20 micrograms/ml) for 48 hours, production of IL-1 alpha and IL-1 beta was less marked in patients with lung production showed a similar tendency, but the difference between patients with lung cancer and benign pulmonary diseases was not significant. Addition of alpha 1PI to the LPS-stimulated AM culture system inhibited production of these cytokines dose-dependently. Thus, the local increase of alpha 1PI in lung cancer may act as a humoral inhibitor against the production of IL-1 and TNF by AM.
Adult↗
The pharmacophore of debromoaplysiatoxin responsible for protein kinase C activation.
Protein kinase C is physiologically activated by 1,2-diacyl-sn-glycerol in the S configuration. The enzyme is also powerfully activated by structurally diverse tumor promotors. A model has been developed that demonstrates how the various tumor promotors and diacylglycerols can all be accommodated by the same binding site of the kinase. One prediction of this model concerns the structural nature of the pharmacophore in the tumor promotor debromoaplysiatoxin. This prediction is realized by synthesizing the analogs with the deduced pharmacophore and demonstrating that they are potent activators of protein kinase C. These findings provide strong experimental support for our structural model of protein kinase C activation.
Animals↗
Gonyauline: a novel endogenous substance shortening the period of the circadian clock of a unicellular alga.
The circadian clock in the unicellular alga Gonyaulax polyedra is accelerated by a substance in extracts from the cells themselves. The extracts have been fractionated using the circadian rhythm of bioluminescence as bioassay. The active substance, termed gonyauline, has been isolated and characterized as a novel low molecular weight cyclopropanecarboxylic acid (S-methyl-cis-2-(methylthio) cyclopropanecarboxylic acid). Synthetic gonyauline has a similar shortening effect on the period of the circadian clock.
Animals↗
Palytoxin induces an increase in the cation conductance of red cells.
Palytoxin (PTX), isolated from the marine soft coral Palythoa tuberculosa, increases the cation conductance of human red cell membranes. In the presence of 10(-10) M PTX and 10(-5) M DIDS, the membrane potential approximates the equilibrium potential for Na+ or K+ rather than Cl-. Even in the absence of DIDS, the Na+ and K+ conductances were greater than the Cl- conductance. The selectivity of the PTX-induced cation conductance is K+ greater than Rb+ greater than Cs+ greater than Na+ greater than Li+ much greater than choline+ greater than TEA+ much greater than Mg2+. Measurements of K+ efflux revealed two apparent sites for activation by PTX, one with a Kal of 0.05 nM and a maximum flux, nu max1, of 1.4 mol/liter of cells per h and another with a Ka2 of 98 nM and a nu max2 of 24 mol/liter of cells per h. These effects of PTX are completely blocked by external ouabain (300 microM) and prevented by internal vanadate (100 microM). When the PTX channels are open, the Na,K pumps do not catalyze ATP hydrolysis. Upon thorough washout of cells exposed to about five molecules of PTX/pump, the Na,K pump of these cells operates normally. Blockage of the positively charged NH2 terminus of PTX with a p-bromobenzoyl group reduces the potency of the compound to induce Na and K fluxes by at least a factor of 100, and to compete with the binding of [3H]ouabain by at least a factor of 10. These data are consistent with the conclusion that PTX binds reversibly to the Na,K pumps in the red cell membrane and opens a (10-pS) channel equally permeable to Na and K at or near each pump site.
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
Noninfectious doughnut-shaped human immunodeficiency virus type 1 can induce syncytia mediated by fusion of the particles with CD4-positive cells.
A defective doughnut-shaped human immunodeficiency virus type 1 (HIV-1)-producing cell clone (designated as L-2) was isolated from persistently HIV-1-infected MT-4 cells. The syncytium-forming capacity of the cell and virus particle fractions was examined in human CD4-positive T cells. Several cell lines producing infectious HIV-1 particles, such as persistently HIV-1-infected MOLT-4 (MOLT-4/HIV-1) cells, were used as controls. Syncytia were formed within 20 h by the cell fraction of both L-2 and MOLT-4/HIV-1 and the virus particle fraction of L-2, but not MOLT-4/HIV-1. These formations were not affected by 3'-azido-3'-deoxythymidine (ZDV). In contrast, similar syncytium formation was first observed 2 days after the incubation of the virus particle fraction of MOLT-4/LAV-1 and this syncytium formation mediated by the cell fractions of MOLT-4/HIV-1 and L-2 or the virus particle fraction of L-2 differently.
Antibodies, Monoclonal↗