Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027960 (mole)
 21,279 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Platelet alpha-granules contain a factor that stimulates the proliferation of arterial smooth muscle cells and may play a role in atherogenesis. We have studied the role of arachidonic acid in mediating the release of the platelet-derived growth factor (PDGF) from human platelets. PDGF was assayed by stimulating of [(3)H]thymidine incorporation into DNA of mouse 3T3 cells. Platelet aggregation and the release of platelet factor 4,beta-thromboglobulin, and serotonin were also studied. A biphasic response pattern was observed when gel-filtered platelets were incubated with arachidonate over the concentration range 0.01-0.4 mM. At low arachidonate levels (approximately 0.025-0.1 mM), specific concentration-dependent aggregation and release of PDGF and of the other components were observed. This effect was not seen with any of five other fatty acids tested and was suppressed by indomethacin (25 muM). At higher arachidonate concentrations (approximately 0.15-0.35 mM), a concentration-dependent turn-off of both aggregation and release occurred. At these concentrations the platelets remained functional, and no release of lactate dehydrogenase was observed. A similar biphasic pattern of arachidonate-induced aggregation and release was observed with platelet-rich plasma, over a similar range of arachidonate to albumin mole ratios. These studies demonstrate that PDGF and other alpha-granule constituents can be released from platelets specifically by arachidonate via an indomethacin-sensitive pathway, most probably involving the platelet cyclooxygenase and conversion of arachidonate to prostaglandin metabolities. The mechanisms responsible for the turn-off of the specific arachidonate-mediated responses at higher arachidonate concentrations remain to be defined.
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PMID:Release of platelet-derived growth factor from human platelets by arachidonic acid. 29 Oct 68

The influence of the two antibiotics tetracycline hydrochloride (T) and penicillin G sodium (P) on PGI2 synthesis by the male rat thoracic aorta and day-20 pregnant rat myometrium was investigated in vitro using a rat platelet antiaggregatory bioassay method. Pretreatment of the tissues for 30 min at 37 degrees C with T (21-168 microM) or P (28-224 microM) significantly inhibited PGI2 synthesis in absence or presence of exogenous arachidonic acid (AA) (16.6 microM), (P less than 0.01, n = 5-6). Furthermore, pretreatment of rats with the two drugs (T 11 and P 175 mu mole kg-1 for 30 min) significantly antagonised AA (4 n mole kg-1)-induced hypotension in urethane-anaesthetised rats. They also (T 0.5-4 and P 1-6 microM) antagonised AA-induced aggregation in rabbit citrated platelet-rich plasma. T failed to affect ADP-induced aggregation to any significant level whereas P (3-6 microM) reduced ADP-induced aggregation. The drugs seemed to interfere with the action of the PG endoperoxide synthase (or PG cyclooxygenase) enzyme resulting in decreased formation of PGG2 and PGH2. Such an effect may have resulted from the induced formation of toxic [OH-] radicals and/or inhibition of O2 uptake by the tissues under the influence of the drugs. The demonstrated inherent property of these two antibiotics to inhibit the synthesis of the potent vasodilator, platelet antiaggregatory, anticonvulsant and inhibitor of gastric acid secretion--PGI2, may partly contribute towards better understanding of the biochemical mechanisms that underlie some of the previously known but poorly understood actions of these antibiotics. Furthermore, since good evidence exists for the involvement of excessive uterine prostaglandin synthesis in dysmenorrhoea and premature deliveries, it is suggested that the potential benefits of T or P in these two disorders be investigated.
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PMID:Influence of chemotherapeutic agents on prostacyclin synthesis. II. Effects of tetracycline and penicillin G on prostacyclin synthesis by the rat thoracic aorta and myometrial tissues. 194 60

Dose-response curves to leukotrienes B4 (LTB4), D4 (LTD4), PAF-acether and histamine applied as single or cumulative doses are studied on guinea-pig lung parenchymal strips (GPLP). A mole to mole comparison shows that PAF-acether is the most potent agonist, when GPLP contracts maximally to histamine. GPLP possesses specific receptors to histamine, LTD4 and PAF-acether which can be blocked by selective receptors antagonists: mepyramine as antihistaminic, FPL 55712 as anti-SRS-A substance, BN 52021 and kadsurenone as anti-PAF-receptor antagonists; meanwhile, a part of their action is mediated through the release of arachidonate metabolites. Histamine, LTB4, LTD4 and PAF-acether-induced contractions are all dependent on cyclooxygenase. Thromboxane A2 (TXA2) could be one of the cyclooxygenase products involved. A part of contractile effects of LTB4 and LTD4, but not of histamine, is liked to the generation of lipoxygenase metabolites as their contractions are partially inhibited by NDGA and ETYA. Contraction-induced by PAF-acether is reduced in presence of NDGA but not by FPL 55712, which indicates that lipoxygenase products other than peptidoleukotrienes are involved in the PAF-response.
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PMID:Comparative effects of drugs on leukotrienes-, PAF-acether- and histamine- induced contractions of guinea-pig lung parenchymal strips. 302 12

Arachidonic acid is metabolized to prostaglandins and thromboxane via the cyclooxygenase pathway and to leukotrienes B4, C4, D4, and E4 via the lipooxygenase pathway. A possible role played by leukotrienes in cardiogenic shock resulting from anaphylaxis prompted us to investigate the action of these compounds on coronary vessels and myocardial contractility. In this study leukotriene B4 (LTB4) and C4 (LTC4) were injected directly into the left circumflex (LCx) coronary artery of nine anesthetized Suffolk sheep. LTB4 had no effect on coronary artery blood flow or myocardial contractility, but 3 X 10(-9) mole induced profound transient circulating neutropenia, reflecting the potent chemotactic and chemokinetic properties of this compound. Injecting as little as 1.6 X 10(-11) mole of LTC4 caused a 14.5 +/- 4.3% (mean +/- SE) reduction of LCx coronary artery flow while 1.6 X 10(-10) mole caused a 26.5 +/- 3.7% decrease of LCx coronary artery flow and an 18.1 +/- 3.2% decrease in systolic shortening of the myocardial region supplied by the LCx coronary artery. Since the decrease in systolic shortening was far greater than that expected on the basis of the reduction in coronary artery flow, we postulate that LTC4 has a direct negative inotropic effect. FPL 55712, a receptor antagonist of leukotrienes C4, D4, and E4, blocked the vasoconstriction induced by LTC4 but only partially blocked the negative inotropic effects of LTC4. LTC4 is a potent vasoconstrictor and negative inotropic agent and may play an important role in anaphylactic shock.
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PMID:Effects of leukotrienes B4 and C4 on coronary circulation and myocardial contractility. 630 44

Leukotriene D4 (2 c 10(-9) mole), injected into the left circumflex coronary artery of anesthetized sheep, produced profound coronary vasoconstriction and impaired regional ventricular wall motion. This cardiac effect was neither inhibited by prior treatment of the sheep with a cyclooxygenase inhibitor nor associated with thromboxane B2 release into the coronary sinus. Intravenous FPL 55712 completely abolished the coronary vasoconstriction of leukotriene D4, but a significant reduction of regional wall shortening persisted.
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PMID:Leukotriene D4: a potent coronary artery vasoconstrictor associated with impaired ventricular contraction. 680 65

LY315920 is a potent, selective inhibitor of recombinant human, group IIA, nonpancreatic secretory PLA2 (sPLA2). In a chromogenic isolated enzyme assay, LY315920 inhibited sPLA2 activity with an IC50 of 9 +/- 1 nM or 7.3 x 10(-6) mole fraction, which approached the stiochiometric limit of this assay. The true potency of LY315920 was defined using a deoxycholate/phosphatidylcholine assay with a mole fraction of 1.5 x 10(-6). LY315920 was 40-fold less active against human, group IB, pancreatic sPLA2 and was inactive against cytosolic PLA2 and the constitutive and inducible forms of cyclooxygenase. Human sPLA2-induced release of thromboxane A2 (TXA2) from isolated guinea pig lung bronchoalveolar lavage cells was inhibited by LY315920 with an IC50 of 0.79 microM. The release of TXA2 from these cells by N-formyl-methionyl-leucyl-phenylalanine or arachidonic acid was not inhibited. The i.v. administration of LY315920, 5 min before harvesting the bronchoalveolar lavage cells, resulted in the inhibition of sPLA2-induced production of TXA2 with an ED50 of 16.1 mg/kg. Challenge of guinea pig lung pleural strips with sPLA2 produced contractile responses that were suppressed in a concentration-dependent manner by LY315920 with an apparent KB of 83 +/- 14 nM. Contractile responses induced by arachidonic acid were not altered. Intravenous or oral administration of LY315920 to transgenic mice expressing the human sPLA2 protein inhibited serum sPLA2 activity in a dose-related manner over a 4-h time course. LY315920 is a potent and selective sPLA2 inhibitor and represents a new class of anti-inflammatory agent designated SPI. This agent is currently undergoing clinical evaluation and should help to define the role of sPLA2 in various inflammatory disease states.
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PMID:Pharmacology of LY315920/S-5920, [[3-(aminooxoacetyl)-2-ethyl-1- (phenylmethyl)-1H-indol-4-yl]oxy] acetate, a potent and selective secretory phospholipase A2 inhibitor: A new class of anti-inflammatory drugs, SPI. 1002 49

The goal of this study was to examine arachidonic acid (AA) metabolism by murine bone marrow-derived mast cells (BMMC) during apoptosis induced by cytokine depletion. BMMC deprived of cytokines for 12-48 h displayed apoptotic characteristics. During apoptosis, levels of AA, but not other unsaturated fatty acids, correlated with the percentage of apoptotic cells. A decrease in both cytosolic phospholipase A(2) expression and activity indicated that cytosolic phospholipase A(2) did not account for AA mobilization during apoptosis. Free AA accumulation is also unlikely to be due to decreases in 5-lipoxygenase and/or cyclooxygenase activities, since BMMC undergoing apoptosis produced similar amounts of leukotriene B(4) and significantly greater amounts of PGD(2) than control cells. Arachidonoyl-CoA synthetase and CoA-dependent transferase activities responsible for incorporating AA into phospholipids were not altered during apoptosis. However, there was an increase in arachidonate in phosphatidylcholine (PC) and neutral lipids concomitant with a 40.7 +/- 8.1% decrease in arachidonate content in phosphatidylethanolamine (PE), suggesting a diminished capacity of mast cells to remodel arachidonate from PC to PE pools. Further evidence of a decrease in AA remodeling was shown by a significant decrease in microsomal CoA-independent transacylase activity. Levels of lyso-PC and lyso-PE were not altered in cells undergoing apoptosis, suggesting that the accumulation of lysophospholipids did not account for the decrease in CoA-independent transacylase activity or the induction of apoptosis. Together, these data suggest that the mole quantities of free AA closely correlated with apoptosis and that the accumulation of AA in BMMC during apoptosis was mediated by a decreased capacity of these cells to remodel AA from PC to PE.
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PMID:A decrease in remodeling accounts for the accumulation of arachidonic acid in murine mast cells undergoing apoptosis. 1102 38

Potent and selective inhibitors for phospholipases A2 (PLA2) are useful for studying their intracellular functions. PLA2 enzymes liberate arachidonic acid from phospholipids activating eicosanoid pathways that involve cyclooxygenase (COX) and lipoxygenase (LOX) leading to inflammation. Anti-inflammatory drugs target COX and LOX; thus, PLA2 can also be targeted to diminish inflammation at an earlier stage in the process. This paper describes the employment of enzymatic assays, hydrogen/deuterium exchange mass spectrometry (DXMS) and computational chemistry to develop PLA2 inhibitors. Beta-thioether trifluoromethylketones (TFKs) were screened against human GVIA calcium-independent, GIVA cytosolic and GV secreted PLA2s. These compounds exhibited inhibition toward Group VIA calcium-independent PLA2 (GVIA iPLA2), with the most potent and selective inhibitor 3 (OTFP) obtaining an XI(50) of 0.0002 mole fraction (IC50 of 110nM). DXMS binding experiments in the presence of OTFP revealed the peptide regions of GVIA iPLA2 that interact with the inhibitor. Molecular docking and dynamics simulations in the presence of a membrane were guided by the DXMS data in order to identify the binding mode of OTFP. Clustering analysis showed the binding mode of OTFP that occupied 70% of the binding modes occurring during the simulation. The resulted 3D complex was used for docking studies and a structure-activity relationship (SAR) was established. This paper describes a novel multidisciplinary approach in which a 3D complex of GVIA iPLA2 with an inhibitor is reported and validated by experimental data. The SAR showed that the sulfur atom is vital for the potency of beta-thioether analogues, while the hydrophobic chain is important for selectivity. This work constitutes the foundation for further design, synthesis and inhibition studies in order to develop new beta-thioether analogues that are potent and selective for GVIA iPLA2 exclusively.
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PMID:Computer-aided drug design guided by hydrogen/deuterium exchange mass spectrometry: A powerful combination for the development of potent and selective inhibitors of Group VIA calcium-independent phospholipase A2. 2732 Jun 59