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At least 1,045 records · Page 58Linked to original sources
PubMed1989

Mastoparan, a wasp venom, stimulates insulin release by pancreatic islets through pertussis toxin sensitive GTP-binding protein.

A wasp venom, mastoparan, rapidly stimulated insulin release by rat pancreatic islets in a dose-related manner. The amount of insulin released in response to 58 microM mastoparan far exceeded that induced by 27.8 mM glucose. Mastoparan stimulated insulin release to similar degrees at ambient glucose concentrations of 1.7 mM and 5.6 mM. The islets obtained from pertussis toxin-treated rats showed unequivocally less response to mastoparan. Pretreatment of islets with bromophenacyl bromide, a phospholipase A2 inhibitor, abolished their responsiveness to mastoparan. Pretreatment of islets with nifedipine, a Ca2+ channel blocker, was without effect. Mastoparan is a unique stimulator of insulin release by the pancreatic islets, which acts through GTP-binding protein(s) and phospholipase A2.

Acetophenones↗
PubMed1989

The role of phospholipase A2 in microsomal lipid peroxidation induced with t-butyl hydroperoxide.

The role of phospholipase A2 (PlA2) in lipid peroxidation induced with t-butyl hydroperoxide was examined in rat liver microsomes. Exposure of microsomes to t-butyl hydroperoxide was associated with activation of endogenous PlA2. When PlA2 was inhibited with chlorpromazine, mepacrine, or p-bromphenacyl bromide, the accumulation of thiobarbituric acid reactive substances (TBARS) was reduced in a dose dependent manner. In contrast, the accumulation of conjugated dienes was not affected by chlorpromazine, and was slightly increased by mepacrine. When endogenous PlA2 was activated with mellitin prior to induction of peroxidation, accumulation of both TBARS and dienes was reduced. Analogously, pretreatment with exogenous PlA2 reduced both dienes and TBARS. In contrast, addition of mellitin following the induction of peroxidation did not alter either TBARS or dienes.

Acetophenones↗
PubMed1982

Glutathione-dependent reductive dehalogenation of 2,2',4'-trichloroacetophenone to 2',4'-dichloroacetophenone.

alpha-Haloketones are highly reactive compounds, which are known to undergo enzymatic reduction to methyl ketones. The objective of this research was to characterize the enzymes involved in this reaction and to investigate the mechanism of the reaction. 2,2',4'-Trichloroacetophenone was reduced to 2',4'-dichloroacetophenone by glutathione-dependent cytosolic enzymes present in the liver, kidney, and brain. The actual substrate for the enzyme was S-(2,4-dichlorophenacyl)glutathione, which is formed by the nonenzymic reaction of 2,2',4'-trichloroacetophenone and glutathione. The reaction mechanism may involve an enzyme-catalyzed nucleophilic attack of glutathione on the sulfur atom of S-(2,4-dichlorophenacyl)glutathione to yield a carbanion and glutathione disulfide; protonation of the carbanion would yield 2',4'-dichloroacetophenone. Stoichiometry studies showed that the glutathione disulfide/2',4'-dichloroacetophenone ratio was 1.25 +/- 0.13.

Acetophenones↗
PubMed1983

Suppression by phospholipase A2 inhibitors of secretion of catecholamines from isolated adrenal medullary cells by suppression of cellular calcium uptake.

The involvement of phospholipase A2 in the secretion of catecholamines and cellular uptake of 45Ca2+ was investigated in isolated bovine adrenal medullary cells. In these cells, stimulation of cholinergic receptors by carbamylcholine causes the activation of receptor-linked Ca-channels and influx of Ca2+ is known to trigger the secretory process. Phospholipase A2 inhibitors, such as quinacrine, chloroquine, quinine and p-bromophenacyl bromide, all inhibited the secretion of catecholamines evoked by carbamylcholine in a dose-dependent manner. These phospholipase A2 inhibitors also inhibited the cellular uptake of 45Ca2+ evoked by carbamylcholine with similar dose-response curves to those for inhibition of catecholamine secretion. The inhibition by phospholipase A2 inhibitors was found to be distinct from inhibition by d-tubocurarine which competitively blocks acetylcholine receptors, and from inhibition by diltiazem which acts as a Ca-antagonist at Ca-channels. Phospholipase A2 inhibitors seem to suppress the secretion of catecholamines by interfering with the linkage between acetylcholine receptors and Ca-channels by the membrane effects including the inhibition of endogenous phospholipase A2 activity of the adrenal medullary cells.

Acetophenones↗
PubMed1983

Phospholipase A2 inhibitors. Differential inhibition of fatty acid acylation into kidney lipids by mepacrine and p-bromophenacyl bromide.

Mepacrine and p-bromophenacyl bromide, in addition to their inhibitory effect on lipolysis, are also potent inhibitors of fatty acid acylation into renal medullary lipids. Significant qualitative and quantitative differences in the inhibition by the two drugs were seen. p-Bromophenacyl bromide exerted a non-selective effect inhibiting the incorporation of saturated and unsaturated fatty acids into all phospholipid classes and triacylglycerols. In contrast, mepacrine selectively inhibited the incorporation of both saturated and unsaturated acids into phosphatidylcholine, phosphatidylethanolamine and triglycerides, and concurrently markedly enhanced their incorporation into phosphatidylinositol. Quantitative analysis of these mepacrine effects, together with the known inhibitory effects of this compound on phospholipase A2 and phosphatidylinositol-specific phospholipase C, suggests that mepacrine also inhibits phosphatidic acid phosphatase, thereby shunting the flux of phosphatidic acid away from diglyceride formation and into synthesis of phosphatidylinositol.

Acetophenones↗
PubMed1984

Inhibition by mepacrine and p-bromophenacylbromide of phosphoinositide hydrolysis, glucose oxidation, calcium uptake and insulin release in rat pancreatic islets.

Mepacrine and p-bromophenacylbromide were both found to impair 3H-inositol phosphate production in response to both nutrient and hormone-neurotransmitter stimuli in islets prelabelled with 3H-inositol. Both drugs also inhibited net 45Ca uptake in response to glucose or glibenclamide and considerably modified the patterns of 45Ca and 86Rb efflux from perifused islets under both basal and glucose-stimulated conditions. In addition, the oxidation of [U-14C] glucose in islets was impaired by either mepacrine or p-bromophenacylbromide. These inhibitory effects were found to be concentration-related for both mepacrine (0.01-1.0 mM) and p-bromophenacylbromide (0.03-0.3 mM) and were accompanied, in general, by a similar degree of inhibition of insulin secretion. These results suggest that both mepacrine and p-bromophenacylbromide can inhibit phospholipase C activity in intact islets, but also impair 45Ca and 86Rb fluxes and oxidation of nutrients. The diversity of these drugs' inhibitory actions makes them unsuitable tools for examining the role of specific cellular processes in the regulation of islet function.

Acetophenones↗
PubMed1986

Factors regulating prostaglandin E2 biosynthesis in renal cortical tubular cells.

Prostaglandin synthesis by isolated rat renal cortical tubular cells was studied in vitro with a superfusion system. The cells were introduced in Teflon chambers and intermittently stimulated. The PGE2 production was measured in the effluent. ANG II (10(-10)-10(-6)M) induced a dose-dependent increase in PGE2 synthesis. Saralasin antagonized the response to ANG II. Hyperosmolar mannitol or NaCl and Ca2+-ionophore A23187 also stimulated PGE2 synthesis. The PGE2 response to all stimuli was blocked in Ca2+-free media containing EGTA. The Ca2+-channel blocker nifedipine (10(-10)-10(-6)M) did not significantly inhibit the PGE2 response to ANG II, hyperosmolar mannitol or NaCl, and A23187, whereas the phospholipase-inhibitors p-bromophenacyl bromide (10(-4)M) and chloroquine (10(-4)M) inhibited the response. Thus, PGE2 synthesis in response to these stimuli in rat renal cortical tubular cell is a Ca2+-dependent process, acting via phospholipases by a mechanism which does not appear to involve voltage-dependent Ca2+-channels.

Acetophenones↗
PubMed1987

Carrageenan-stimulated release of arachidonic acid and of lactate dehydrogenase from rat pleural cells.

Cells isolated from the rat pleural cavity consist mainly of macrophages, mast cells, eosinophils, and lymphocytes. Isolated pleural cells labeled with [14C]arachidonic acid released appreciable amounts (approximately 12%) of radiolabel upon exposure to pharmacological concentrations of carrageenan (1-100 micrograms/ml). The release of radiolabel was decreased by an inhibitor of phospholipase A2 (p-bromophenacyl bromide) but not by an inhibitor of arachidonate cyclooxygenase (indomethacin). The released products were arachidonic acid and, to a much lesser extent, prostaglandin E2 and leukotriene C4. The release of radiolabel was associated with release of cytosolic lactate dehydrogenase over the same range of carrageenan concentrations. Time-course studies indicated that release of radiolabel preceded that of lactate dehydrogenase. Since p-bromophenacyl bromide blocked stimulated release of radiolabel but did not prevent release of lactate dehydrogenase, it is unlikely that increase in arachidonate causes carrageenan-induced cell damage. Nevertheless, the question of whether the activation of phospholipase A2 in the pleural cells, most probably the macrophages, was sufficient to initiate the carrageenan-induced inflammatory response requires further study. Cytotoxicity which was apparent with as little as 5 micrograms/ml of carrageenan, may have been a significant consequence of carrageenan action.

Acetophenones↗
PubMed1988

Apparent involvement of phospholipase A2, but not protein kinase C, in the pro-oxidative interactions of clofazimine with human phagocytes.

The anti-leprosy agent, clofazimine, at concentrations of 0.1-5 micrograms/ml caused a dose-related, stimulus-non-specific (N-formyl-methionyl-leucyl-phenylalanine, calcium ionophore, opsonised zymosan, arachidonic acid and phorbol myristate acetate) potentiation of superoxide generation by human neutrophils in vitro without affecting basal oxidative responses. The pro-oxidative interactions of clofazimine with neutrophils were eliminated by the phospholipase A2 inhibitor 4-p-bromophenacyl bromide but not by the protein kinase C (PKC) inhibitor H-7. In support of these observations clofazimine promoted the release of radiolabeled arachidonic acid from neutrophil membrane phospholipids but did not influence the activity of PKC in cytosolic extracts of neutrophils or of purified PKC from rat brain. Pro-oxidative interactions of clofazimine with human phagocytes may contribute to the intraphagocytic antimycobacterial activity of this agent.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1989

Relationship between ionophoric and haemolytic activities of perimycin A and vacidin A, two polyene macrolide antifungal antibiotics.

The ionophoric and hemolytic activities of two antifungal aromatic heptaenes: vacidin A and perimycin A, were studied on human red blood cells. Measurements of hemolysis, K+ influx and efflux, H+ movement and potential difference across the cell membrane, show that the hemolytic activity, being related to the K+ permeability induced by the polyene, is strongly dependent on the ability of this polyene to induce H+ movement. It was shown that: (1) both antibiotics have approximately the same efficiency in inducing K+ permeability, but a 100-fold difference in their hemolytic activity; (2) their hemolytic activity is related to their ability to induce H+ movement; (3) the protonophoric activity requires the existence of a free carboxyl group in the macrolide ring, as in vacidin A. The hemolytic activity is determined by the intrinsic efficiency of a K+/H+ exchange induced by this polyene. With perimycin A, which lacks the free carboxyl group, the hemolytic activity is dependent on the Cl- conductive flux which slows down the K+ flux.

Acetophenones↗
PubMed1991

Effect of the peroxisome proliferator LY171883 on triglyceride accumulation in rats fed a fat-free diet.

LY171883 is a leukotriene D4 antagonist that induces peroxisome proliferation in the rodent liver. Like many peroxisome-proliferating agents, it causes transient lipid accumulation and several other changes in hepatic lipid metabolism. The effect of LY171883 on lipid metabolism was studied further in rats maintained on a fat-free diet. Administration of a fat-free diet for 14 days caused a 5.6-fold increase in liver triglycerides associated with a 3.3-fold increase in fatty acid synthetase. Co-administration of 0.1% LY171883 increased liver triglycerides slightly, whereas 0.3% LY171883 prevented the accumulation of triglycerides. Furthermore, treatment with 0.3% LY171883 reversed the fatty liver in rats pretreated with the fat-free diet for 14 days. Fatty acid synthetase activity increased comparably in all treatment groups, indicating that 0.3% LY171883 did not prevent the lipogenic response to a fat-free diet. In rats treated with 0.3% LY171883, peroxisomal beta-oxidation increased 9.5-fold, mitochondrial beta-oxidation 4.8-fold, carnitine palmitoyltransferase I 1.9-fold, and plasma ketones 3-fold. In the 0.1% dose group the increases in these parameters were smaller. The data indicate that 0.3% LY171883 sufficiently increased mitochondrial and peroxisomal beta-oxidation such that fatty acids generated by lipogenesis were preferentially oxidized rather than esterified to triglycerides. In the 0.1% dose group oxidation was only mildly increased, and the excess fatty acids continued to be esterified.

Acetophenones↗