Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study the possible dual effects of adenosine as substrate and adenosine receptor agonist in rat granulosa cells, cumulus-oocyte complexes, luteal cells and ovarian membranes are discussed. Adenosine is an indispensable compound in cell energy metabolism, as precursor to cofactors, second messenger and nucleic acids. Adenosine is also an agonist to adenosine receptors. The adenosine receptor can either inhibit (A1) or stimulate (A2) adenylate cyclase. Alternatively, in some cells adenosine receptor activation is linked to other cellular events like inhibition of Ca2+ fluxes. Adenosine is taken up by isolated preovulatory granulosa and luteal cells from pregnant mare serum gonadotropin-treated immature rats, but follicle stimulating hormone (FSH) decreases the uptake by granulosa cells. Adenosine, but not the non-metabolizable adenosine analogs 5'-(N-ethyl)carboxamide-adenosine (NECA), 2-chloro-adenosine (2-Clado), N6-(R-phenyl-isopropyl)-adenosine (R-PLA) and N6-(S-phenyl-isopropyl)-adenosine (S-PLA), increase granulosa cell ATP levels. FSH and luteinizing hormone (LH) decrease granulosa cell ATP levels in the presence or absence of adenosine. It has previously been shown that FSH and LH decrease oxygen consumption by cumulus-oocyte complexes and increase their lactate production. These effects have been suggested to be due to a competition of cofactors (e.g. ADP) common to glycolysis and the respiratory chain. The fact that adenosine reverse the gonadotropin-induced effects on oxygen consumption and lactate production support this theory. Adenosine and its analogs increase cAMP accumulation in luteal and granulosa cells only in the presence of gonadotropins, and this effect is antagonized by the adenosine receptor antagonist 8-phenyl-theophylline (8-PHT). Furthermore, adenylate cyclase is stimulated by adenosine analogs in membranes from non-luteinized and luteinized ovarian membranes and in luteal cell homogenates. The effect of NECA is antagonized by 8-PHT. In the membranes, the rank order of potency was NECA greater than 2-Clado greater than R-PLA greater than S-PLA, suggesting adenosine A2 receptors. In summary, it is suggested that adenosine can act both as a substrate to intracellular metabolism and as an adenosine A2 receptor agonist in granulosa and luteal cells. A paracrine short loop positive feedback model is proposed where extracellular adenosine, derived from a gonadotropin-induced extracellular increase in cAMP and a decrease in cellular ATP, enhances gonadotropin stimulation in granulosa and luteal cells.
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PMID:Adenosine as substrate and receptor agonist in the ovary. 255

Defibrotide is a polydeoxyribonucleotide that possesses profibrinolytic and cytoprotective activities. These properties have been associated with its capacity to induce the release of prostacyclin and tissue plasminogen activator (t-PA) from endothelial cells. In the present study, the bolus administration of defibrotide in humans was able to induce (100-800 mg) a dose-dependent decrease in plasminogen activator inhibitor (PAI) (from 19.4 +/- 7.11 to 7.20 +/- 6.41 AU/mL) and an increase in t-PA (from 3.70 +/- 0.96 to 4.50 +/- 1.20 IU/mL) and in the stable prostacyclin derivative 6-keto-PGF1 alpha (from 18.83 +/- 3.83 to 26.75 +/- 8.48 pg/0.1 mL) in the venous blood. In a second part of the study, defibrotide has been shown to inhibit dose-dependently (10-100 microns) neutrophil activation in vitro: it decreased lysosomal enzyme release and superoxide anion and chemiluminescence production induced by the oligopeptide fMLP and the ionophores A23187 and ionomycin. The increase in extracellular calcium concentration from 0.5 to 2 mm antagonized the inhibitory effect of the drug. Defibrotide was able to reduce the cytosolic free calcium increase induced by specific stimuli by blunting calcium entry. Such an inhibitory activity of defibrotide was antagonized by theophylline, an adenosine receptor antagonist. The study confirms some pharmacological activities of defibrotide (release of t-PA and prostacyclin in vivo), and it also suggests that the compound blocks Ca2+ entry into the cells, possibly by interfering with the adenosine receptors.
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PMID:Modulation of venous endothelial activity and transcellular calcium transport by defibrotide: the adenosine hypothesis. 880 23

We investigated what adenosine receptor type exists and the signaling pathways on the contraction of circular muscle cells isolated by enzymatic digestion from the cat esophagus. Adenosine or the selective A1 receptor agonist R-PIA causes a concentration-dependent contraction. After pretreatment with A1 receptor antagonist, DPCPX, adenosine-mediated contraction was abolished. Adenosine-induced contraction was significantly increased when A1 receptors were preserved by pretreatment with DPCPX followed by inactivation of all unprotected receptors with N-ethylmaleimide. Adenosine- or R-PIA-induced contraction was significantly augmented in the preserved cells and the increase was abolished in the presence of the A1 receptor antagonist DPCPX. PTX abolished contraction induced by adenosine or R-PIA, implying that contraction activated by A1 receptor was coupled to a pertussis toxin (PTX)-sensitive G(i) protein. After permeabilization, contraction was inhibited by G(i2), but not by G(i1) and G(i3), antibodies. These data suggest that adenosine-induced contraction of esophagus depends on PTX-sensitive G(i2.) Adenosine- or R-PIA-induced contraction of esophageal smooth muscle cells was not affected by the phospholipase D (PLD) inhibitor rho-chloromercuribenzoic acid (rhoCMB), phospholipase A(2) (PLA(2)) inhibitor DEDA or PKC antagonist chelerythrine, but was significantly abolished by phospholipase C (PLC) inhibitor, neomycin. PLC-beta3 antibody inhibited R-PIA-induced contraction. R-PIA-induced contraction of esophageal muscle cells was inhibited by IP(3) receptor antagonist heparin, which suggests that the contraction of esophageal smooth muscle cells is dependent on phosphatidylinositol-specific phospholipase (PI-PLC) and IP(3). In conclusion, adenosine- and R-PIA-induced contraction in cat esophageal smooth muscle cell was mediated by A1 receptor. A1 receptor is coupled to PTX-sensitive G protein G(i2), which results in the activation of PI-PLC-beta3. PI hydrolysis by PI-PLC forms IP(3), which binds to IP(3) receptor on endoplasmic reticulum, resulting in the release of intracellular Ca(2+).
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PMID:Signal transduction mechanism via adenosine A1 receptor in the cat esophageal smooth muscle cells. 1185 44

We used the patch-clamp technique to examine the effect of adenosine on epithelial sodium channel (ENaC) activity in rat cortical collecting duct (CCD). Application of adenosine inhibits ENaC activity, and the effect of adenosine was mimicked by cyclohexyladenosine (CHA), an A(1) adenosine-receptor agonist that reduced channel activity from 1.32 to 0.64. The inhibitory effect of CHA on ENaC was mimicked by cyclopentyladenosine (CPA), which reduced channel activity from 1.1 to 0.55. In contrast, application of CGS-21680, an A(2a) adenosine-receptor agonist, had no effect on ENaC and increased channel activity from 0.96 to 1.22. This suggests that the inhibitory effect of adenosine analogs resulted from stimulation of the A(1) adenosine receptor. Inhibition of PLC with U-73122 failed to abolish the effect of CHA on ENaC. In contrast, the inhibitory effect of CHA on ENaC was absent in the presence of the PLA(2) inhibitor arachidonyl trifluoromethyl ketone (AACOCF(3)). This suggests a role of arachidonic acid (AA) in mediating the effect of adenosine on ENaC. To determine the metabolic pathway of AA responsible for the effect of adenosine, we examined the effect of CHA in the presence of indomethacin or N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH). Inhibition of cytochrome P-450 (CYP) epoxygenase with MS-PPOH blocked the effect of CHA on ENaC. In contrast, CHA reduced ENaC activity in the presence of indomethacin. This suggests that CYP epoxygenase-dependent metabolites of AA mediate the effect of adenosine. Because 11,12-epoxyeicosatrienoic acid (11,12-EET) inhibits ENaC activity in the CCD (Wei Y, Lin DH, Kemp R, Yaddanapudi GSS, Nasjletti A, Falck JR, and Wang WH. J Gen Physiol 124: 719-727, 2004), we examined the role of 11,12-EET in mediating the effect of adenosine on ENaC. Addition of 11,12-EET inhibited ENaC channels in the CCD in which adenosine-induced inhibition was blocked by AACOCF3. We conclude that adenosine inhibits ENaC activity by stimulation of the A(1) adenosine receptor in the CCD and that the effect of adenosine is mediated by 11,12-EET.
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PMID:Adenosine inhibits ENaC via cytochrome P-450 epoxygenase-dependent metabolites of arachidonic acid. 1623 12

Short biologic half-lives limit the therapeutic utility of many small molecules. One approach to extending the half-life of pharmacologically active small molecules is conjugation to less degradable nanoparticles; here we report the synthesis and activity of six targeted polymeric (PEG-b-PLA) nanoparticles for use as adenosine receptor agonists. Using click chemistry, PLA-b-PEG400-N3 and PLA-b-PEG2000 block copolymers were bound to adenosine at the 3',4'-OH, 5'-OH, and 6-NH2 positions with an acetylene group. Activity of the conjugates as adenosine receptor ligands was tested by their capacity to stimulate cAMP increases in RAW264.7 murine macrophage cells. Only adenosine-conjugated nanoparticles (A-3',4'-OH-TPN2), in which PEG2000 was bound to adenosine on the 3',4' hydroxyl groups, stimulated cAMP increases and these increases were blocked by selective antagonists of both adenosine A2A and A2B receptors, consistent with ligation of these receptors. Adenosine nanoparticles were tested in vivo in a rat model of post-traumatic osteoarthritis; intra-articular injection of adenosine nanoparticles prevented the development of osteoarthritis in this model. These studies suggest that attachment of adenosine to biodegradable nanoparticles provides a novel approach to achieving prolonged therapeutic effects.
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PMID:Adenosine-Functionalized Biodegradable PLA-b-PEG Nanoparticles Ameliorate Osteoarthritis in Rats. 3109 64