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At least 1,117 records · Page 62Linked to original sources
PubMed1985

Characterization of extracellular phospholipase A2 in rheumatoid synovial fluid.

Phospholipase A2 (PLA2) activity has now been identified in rheumatoid synovial fluids. This PLA2 is a calcium-requiring protein of MW 11,000 with a neutral pH optimum. Its activity was inhibited by high concentrations of Mg2+, and by the active site-directed histidine reagent p-bromophenacyl bromide. Ionic and nonionic detergents, or the sulfhydryl reagent dithiothreitol caused loss of enzyme activity. Synovial fluid PLA2 did not interact with sulphated mucopolysaccharides such as heparin or chondroitin sulphate. Release and sequestration of PLA2 in the joint space may contribute to the characteristic rheumatoid inflammatory changes.

Acetophenones↗
PubMed1991

Enzymatic dispersion of mast cells from human sinus mucosa: characterization of histamine release and its comparison with chopped fragments of the tissue.

Functional characteristics of mast cells in chopped fragments from sinus mucosa, which was dissected from patients with chronic sinusitis, were compared with those from dispersed cells prepared by enzymatic treatment. The results obtained in this study were the following. (1) Both chopped fragments and dispersed cells released histamine in a dose-dependent manner when incubated with anti-IgE. However, higher histamine release was always observed in dispersed cells. (2) Although no differences in the ability to reduce histamine release with salbutamol or forskolin could be observed between chopped fragments and dispersed cells, staurosporin and p-bromophenacyl bromide were more active on dispersed mast cells than chopped fragments. (3) Passive sensitization of dispersed cells with an allergic serum containing IgE to mite could be achieved only after elution of IgE on the cells with lactic acid.

Acetophenones↗
PubMed1991

Detection and characterization of extracellular phospholipase A2 in pleural effusion of patients with tuberculosis.

Extracellular phospholipase A2 activity has been identified in pleural fluid of patients with tuberculosis. This enzyme is a calcium requiring protein and has a pH optimum of 10.0. The enzyme was inhibited by the active site-directed histidine reagent, rho-bromophenacyl bromide. Ionic and non-ionic detergents, or the sulfhydryl reagent dithiothreitol, caused loss of enzyme activity. When substrate specificity was tested using 2-[1-14C]linoleoyl phospholipids as substrates, phosphatidyl-ethanolamine was the best substrate, followed by phosphatidylserine and phosphatidylcholine. This phospholipase A2 showed high affinity for heparin, and was recognized by a monoclonal antibody raised against phospholipase A2 from human synovial fluid. These findings suggest that an extracellular phospholipase A2, which may belong to the 14K group II phospholipase A2 family, exists in the pleural fluid of patients with tuberculosis.

Acetophenones↗
PubMed1984

Role of arachidonate lipoxygenase and cyclooxygenase products in insulin and glucagon secretion from rat pancreatic islets.

Rat pancreatic islets incubated in nutrient medium were used to study the role of endogenous arachidonic acid metabolism in pancreatic hormone secretion. Both glucose and fetal calf serum stimulated radioimmunoassayable PGE2 production and insulin secretion from islets. These effects were abolished by the phospholipase inhibitor p-bromophenacyl bromide or by concurrent inhibition of cyclooxygenase and lipoxygenase by flurbiprofen plus nordihydroguaiaretic acid (NDGA), respectively. Bromophenacyl bromide also inhibited glucagon secretion. When used alone, flurbiprofen caused a significant enhancement of glucose-induced insulin secretion that was attributed to reactive stimulation of lipoxygenase-product formation rather than to selective cyclooxygenase inhibition. NDGA given alone in the presence of stimulatory concentrations of glucose suppressed the normal eight-fold rise in insulin secretion, but caused a marked enhancement in glucagon secretion that could be overcome by simultaneous inclusion of flurbiprofen. We concluded that: (1) Increased metabolism of arachidonic acid in pancreatic islets amplifies the secretion of insulin and glucagon. (2) The lipoxygenase as well as the cyclooxygenase pathways of arachidonate metabolism participate in the amplification of insulin secretion. (3) The observations made in this study are inconclusive with respect to the involvement of the lipoxygenase and cyclooxygenase pathways in glucagon secretion; an inhibitory role for lipoxygenase pathway products is suggested.

Acetophenones↗
PubMed1991

Pro-oxidative interactions of dithranol with human phagocytes promote oxidative damage to DNA of bystander leucocytes.

Dithranol at therapeutic concentrations (5-40 micrograms ml-1) induced strand breaks in human leucocyte DNA in vitro in a dose-related manner. Leucocytes from individuals with chronic granulomatous disease (CGD) incurred substantially less DNA strand breaks than did normal leucocytes during exposure to dithranol indicating that activated phagocytes are involved. H-7, 4-beta-bromophenacyl bromide (BPB) and staurosporine, all inhibitors of protein kinase C, decreased both dithranol-mediated activation of the phagocyte respiratory burst and induction of DNA strand breaks. Similar effects were observed with the hydrogen peroxide scavenger catalase. These results suggest that dithranol induces DNA strand breaks, mainly as a result of pro-oxidative interactions with phagocytes.

Acetophenones↗
PubMed1986

Respiratory-phase-related coding of olfactory information in the olfactory bulb of awake freely-breathing rabbits.

The "across-neuron pattern" theory of olfactory information coding states that odorants are represented by spatial patterns of activity produced across-neurons in the olfactory bulbs. The present study analyzes the different response patterns encoding olfactory information in both the inspiratory and expiratory phases of the respiratory cycles of awake freely-breathing rabbits. We recorded the single-unit responses of 31 neurons to 5 different odorants, 3 of which were repeatedly delivered 5 times each. These responses were characterized by the change in their mean firing activity during the inspiratory and expiratory phases of the respiratory cycles respectively. Their processing using principal component analyses revealed that both the inspiration- and the expiration-related across-neuron profiles of responses contained information appropriate to the specification of each odorant. It was therefore concluded that there was a dynamic representation of odorants in the olfactory bulb of awake freely-breathing animals. This alternate representation of odorants by two profiles and its physiological significance are discussed.

Acetophenones↗
PubMed1995

Maternal ingestion of ortho-aminoacetophenone during gestation affects intake by offspring.

Ingested flavor chemicals cross the placental barrier and occur in the fetal blood and amniotic fluid. This occurrence is detectable by the fetus, and can influence post parturition feeding. In the present experiment, pregnant mice were offered either 0.1% ortho-aminoacetophenone emulsions (OAP) or water throughout gestation. OAP is normally avoided by mice, apparently on the basis of chemosensory characteristics. Subsequently, offspring were offered 0.5%, 0.25%, or 0.1% OAP in one-bottle tests at 26 or 88 days of age. Offspring of mothers given OAP drank greater amounts of OAP than did offspring of mothers given water. Enhanced acceptance of OAP was not detected in mice exposed to 0.1% OAP as adults for a duration similar to that given during gestation. We conclude that fetal experiences with OAP lowered sensitivity and/or raised tolerance for the compound.

Acetophenones↗
PubMed1993

Na+/H+ exchange and PLA2 activity act interdependently to mediate the rapid effects of 1 alpha, 25-dihydroxyvitamin D3.

1 alpha, 25-Dihydroxyvitamin D3 (1 alpha, 25-(OH)2D3) has been shown to rapidly increase cytosolic calcium in freshly isolated and cultured rat hepatocytes. The rise in cytosolic calcium is dependent on phospholipase A2 (PLA2) activation and cell alkalinization through the Na+/H+ antiport system. To further characterize the rapid effects of 1 alpha, 25-(OH)2D3, cultured hepatocytes were treated with inhibitors of PLA2 and the Na+/H+ antiport system. 1 alpha, 25-(OH)2D3 treatment caused a 31-66% increase in [32P]lysophosphatidylinositol (LPI) and a 0.04 increase in pH within 5 minutes. Inhibition of the Na+/H+ antiport system with amiloride or removal of extracellular sodium abolished the 1 alpha, 25-(OH)2D3 rise in LPI. Inhibition of PLA2 with bromophenacylbromide also blocked the 1 alpha, 25-(OH)2D3-induced rise in [32P]LPI and cytosolic alkalinization in response to 1 alpha, 25-(OH)2D3. The data indicate that 1 alpha, 25-(OH)2D3 rapidly increases the activity of PLA2 and the Na+/H+ antiport system. The production of LPI is dependent on PLA2 activation and cell alkalinization through the Na+/H+ antiport system. It appears that the two events are interdependent in hepatocytes.

Acetophenones↗
PubMed1986

Hepatic peroxisomal changes induced by a tetrazole-substituted alkoxyacetophenone in rats and comparison with other species.

Previous work in this laboratory indicated that compound LY171883, a tetrazole-substituted alkoxyacetophenone with leukotriene D4 antagonist activity, caused dose-related hepatomegaly in rodents without other histological evidence of liver toxicity. In the present studies, administration of LY171883 at dietary concentrations of 0.25 or 0.50% to rats for 2 weeks increased peroxisomal beta-oxidation, catalase activity, and peroxisome volume fraction in the liver. The effects were dose-related and corresponded with increases in liver weight. Dietary concentrations of 0.05 and 0.1% LY171883 did not significantly alter peroxisome morphology, enzyme activity, or liver weight. Serum triglycerides were lowered equivalently by all four dietary concentrations of LY171883, indicating that the hypotriglyceridemia was dissociated from induction of peroxisomal beta-oxidation. The hepatic effects in rats reversed within 16 days after discontinuing treatment with LY171883. Liver weight and peroxisomal enzyme activities were increased in mice by LY171883 in a manner comparable to that observed in rats, whereas hamsters were less responsive. In guinea pigs there was a minor increase in beta-oxidation at a toxic dose of LY171883, but no change in catalase or liver weight. Neither hepatomegaly nor induction of peroxisomal enzymes occurred in beagle dogs or rhesus monkeys given LY171883. Since the hepatic effects of LY171883 in rats are not observed in higher species at a significant multiple of the anticipated clinical dose, it is unlikely that such effects will occur in humans.

Acetophenones↗
PubMed1990

Effect of ciprofibrate, bezafibrate, and LY171883 on peroxisomal beta-oxidation in cultured rat, dog, and rhesus monkey hepatocytes.

Cultured rat hepatocytes have been used extensively to study the mechanisms of chemically induced peroxisome proliferation. Hepatocytes from nonrodent species have been used on a limited scale to study interspecies differences in the response. Because of their importance in pharmaceutical safety assessment, we have developed a model to study the response of beagle dog and rhesus monkey hepatocytes to peroxisome proliferators. Treatment of the hepatocytes with peroxisome proliferators was begun after 20 hr in culture and continued for 72 hr. Untreated rat, dog, and monkey hepatocytes retained 62, 42, and 43% of their initial (20 hr) peroxisomal beta-oxidation activity throughout 92 hr of culture. Ciprofibrate, bezafibrate, and LY171883 caused a dose-related increase in beta-oxidation in rat hepatocytes to a maximum of 10-, 8-, and 5-fold, respectively. In dog and monkey hepatocytes the increases in beta-oxidation were less than 2-fold. Peroxisome morphology in dog and monkey hepatocytes appeared to be unchanged by the drugs. Morphometric analysis in monkey hepatocytes showed no increase in peroxisome volume fraction in response to the chemicals. Treatment of dog and monkey hepatocytes with dexamethasone and glucagon during the final 24 hr in culture caused a 4- to 6-fold increase in tyrosine aminotransferase activity. This induction is characteristic of the in vivo response. The small increase in beta-oxidation reflects the relative insensitivity of the dog and monkey liver to peroxisome proliferators in vivo rather than a loss of sensitivity during culture. Cultured hepatocytes from beagle dog and rhesus monkey may provide a model for studying the mechanisms underlying the interspecies differences. Such information would help clarify the relevance of rodent data in human risk assessment.

Acetophenones↗
PubMed1990

Changes in hepatic lipid metabolism associated with lipid accumulation and its reversal in rats given the peroxisome proliferator LY171883.

Dietary administration of 0.05, 0.1, and 0.3% LY171883 to rats for 1 day caused a dose-related increase in hepatic triglycerides. When added to rat liver mitochondria in vitro, LY171883 caused competitive inhibition of carnitine palmitoyltransferase 1 (CPT-1), the rate-limiting enzyme for mitochondrial fatty acid oxidation. This effect appears to be involved in the lipid accumulation. The hepatic triglycerides in rats given 0.1% LY171883 increased progressively through 3 months of treatment. In contrast, hepatic triglycerides in high-dose rats returned to control levels by Day 3 and remained there throughout the study. The regression of the lipid corresponded with increases in hepatic peroxisomal beta-oxidation, mitochondrial beta-oxidation, and CPT-1 activity of up to 13-, 7-, and 3.2-fold, respectively. The 0.1% dose increased these parameters modestly compared to those of high-dose rats (2-, 3-, and 1.6-fold, respectively). Addition of LY171883 to mitochondria from rats given dietary treatment for 2 weeks inhibited CPT-I by the same percentage as in control mitochondria. In mid-dose rats, the induction of CPT-I was largely negated by LY171883 in vitro. Even with the inhibition, CPT-I activity in mitochondria from high-dose rats remained 2-fold higher than that in untreated controls. The data suggest that the induction of CPT-I in high-dose rats was sufficient to overcome the inhibitory action of LY171883. The increased oxidative capacity in peroxisomes and mitochondria led to the regression of the lipid in high-dose rats. The more modest increases in fatty acid oxidation in rats given 0.1% LY171883 were not sufficient to reverse the lipid accumulation.

Acetophenones↗
PubMed1982

Accessibility of the active site of crotoxin B in the crotoxin complex.

Basic phospholipases A and the crotoxin complex isolated from Crotalus durissus terrificus venom exhibited similar initial reaction rates, time course and degree of hydrolysis of synthetic short chain lecithins in the monomeric state. Although monomeric lecithins seem to promote dissociation of crotoxin up to a certain extent, this cannot explain the high activity observed with the complex. The crotoxin complex is able to bind the non-hydrolyzable analog D-diheptanoyllecithin, as demonstrated by equilibrium gel-filtration, with a dissociation constant of 0.12 mM. This value is similar to the dissociation constant of the crotoxin B-D-diheptanoyllecithin complex (about 0.13 mM), estimated from the protection against enzyme inactivation by p-bromophenacyl bromide, which further supports the free accessibility of the substrate to the enzyme active site in the crotoxin complex. The lack of enzyme inactivation when crotoxin is treated with p-bromophenacyl bromide may be interpreted in terms of the specific requirements of the reagent to react with the enzyme rather than protection of the active site. Crotoxin B inhibition by complex formation with crotoxin A, which is not apparent on monomeric substrates, seems not to involve the active site of the enzyme.

Acetophenones↗
PubMed1982

Presynaptic toxicity of the histidine-modified, phospholipase A2-inactive, beta-bungarotoxin, crotoxin and notexin.

Beta-Bungarotoxin, crotoxin and notexin were treated extensively with p-bromophenacyl bromide in order to modify the histidine group of the active site and to greatly decrease the phospholipase A2(PLA) catalytic activity. They were studied for their residual presynaptic effects on the mouse isolated phrenic nerve-diaphragm and chick biventer cervicis muscle preparations. The modified toxins still had 1.7-5.2% PLA activity, which was inhibited by Sr2+, as is the enzyme activity of the native toxins. The neuromuscular blocking activity of these modified toxins, which was reduced 30-60 fold in the mouse diaphragm, was due to a presynaptic effect, as judged from the unchanged amplitude of m.e.p.p.s in the blocked preparations. In contrast to the native toxins, however, the presynaptic effect of modified beta-bungarotoxin and notexin was neither antagonized by Sr2+ nor accelerated by increasing the rate of nerve stimulation, indicating that the presynaptic effects of the modified beta-bungarotoxin and notexin are not likely to be due to their PLA enzyme activity. The modified toxins retained a much greater fraction of their early presynaptic effects in comparison to their enzymatic and neuromuscular blocking activities, although the time-course of the early effects was delayed. The results indicate that the modified neurotoxins per se have their own presynaptic effects, which are unrelated to the PLA enzyme activities.

Acetophenones↗
PubMed1985

Isolation and properties of two phospholipases A2 from the venom of an Australian elapid snake (Pseudechis australis).

Two phospholipases A2 (Pa-11 and Pa-13) were purified from the venom of an Australian elapid snake (subfamily Acanthophiinae) Pseudechis australis (king brown snake) by chromatography on CM-cellulose CM-52 followed by gel filtration on a Sephadex G-75 column. The apparent molecular weights of the two phospholipases A2 (Pa-11 and Pa-13) were 14,000 and 13,500, respectively, by gel filtration analysis on a Sephadex G-75 column. Each enzyme molecule consists of a single polypeptide chain of 118 amino acid residues. The isoelectric points of Pa-11 and Pa-13 were 10.5 and 10.0, respectively. The optimum pH values of Pa-11 and Pa-13 for hydrolysis of egg-yolk phosphatidylcholine were 7.8 and 7.5, respectively. Pa-11 was lethal to mice (LD50 0.23 micrograms/g body weight), whereas Pa-13 showed no lethal activity at a dose level of 7.4 micrograms/g mouse. Each enzyme was inactivated by reaction with p-bromophenacylbromide on the sole histidine residue (Pa-11) or on one of the two histidine residues (Pa-13). Oxidation of the tryptophan residues in Pa-11 and Pa-13 with N-bromosuccinimide led to a decrease in the phospholipase A activity. A complete loss of both enzymic and lethal activities of Pa-11 was observed upon oxidation of one of the two tryptophan residues of the molecule.

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