N-acylphosphatidylethanolamine-hydrolysing phospholipase D lacks the ability to transphosphatidylate

AbstractThe N-acylphosphatidylethanolamine-hydrolysing phospholipase D (NAPE-PLD) generates N-acylethanolamines, including N-arachidonoyl-ethanolamine (anandamide), that may be neuroprotective and analgesic. The properties of NAPE-PLD from rat heart and brain microsomes are investigated and compared to those of other PLDs. NAPE-PLD is inhibited by the fatty acid aminohydrolase inhibitor MAFP in high concentrations (≥100 μM) while PMSF in high concentrations (10 mM) tends to stabilise NAPE-PLD activity. Oleate inhibits NAPE-PLD but the enzyme is not affected by PIP2, α-synuclein or mastoparan. Furthermore, it is for the first time reported that NAPE-PLD is not capable of catalysing a transphosphatidylation reaction like most other known PLDs

Dietary non-esterified oleic Acid decreases the jejunal levels of anorectic N-acylethanolamines

BACKGROUND AND AIMS: Oleoylethanolamide and several other N-acylethanolamines (NAEs), e.g. linoleoylethanolamide and palmitoylethanolamide, have anorectic properties in rats, and prolonged intake of a high-fat diet decreases the levels of the anorectic NAEs in jejunum. Jejunal anorectic NAEs are thought to add to the control of food intake via activation of PPARalpha and the vagus nerve. The fat-induced decrease may explain part of the hyperphagic effect of high-fat diets. In the present study, we investigated 1) whether the reduced levels of anorectic NAEs were reversible in rats, 2) whether mice respond to dietary fat (olive oil) by reducing levels of anorectic NAEs, and 3) whether dietary non-esterified oleic acid also can decrease levels of anorectic NAEs in mice. We are searching for the fat sensor in the intestine, which mediates the decreased levels of anorectic NAEs. METHODS: Male rats and mice were fed diets high (45 energy% fat) in either triacylglycerol or free fatty acids for 7-14 days, and jejunal NAE and N-acylphosphatidylethanolamine (NAPE) levels were determined by liquid-chromatography mass spectrometry. RESULTS: In rats, reduced levels of anorectic NAEs could be reversed after 3 days from changing the diet from high-fat to chow. Corresponding NAPE levels tended to show the same changes. In mice, jejunal levels of anorectic NAEs were also reduced when fed a high-fat diet. In addition, we found that non-esterified oleic acid were also able to reduce levels of anorectic NAEs in mice. CONCLUSIONS: These results suggest that the down-regulation of the jejunal level of anorectic NAEs by dietary fat is not restricted to rats, and that the fatty acid component oleic acid, in dietary olive oil may be sufficient to mediate this regulation. Thus, a fatty acid sensor may mediate this effect of dietary fat

The antiparasitic compound Licochalcon A is a potent echinocytogenic agent that modifies erythrocyte membrane in the concentration region where the antiplasmodial activity is observed

The well-known antiparasitic compound licochalcone A is a potent membrane-active agent that transforms normal erythrocytes into echinocytes in parallel with the inhibition of growth of Plasmodium falciparum cultures, the in vitro antiplasmodial effect apparently being an indirect effect on the host cell. In vitro experiments with synchronous cultures demonstrate that inhibition of invasion is the principal mechanism of growth inhibition. The erythrocyte membrane-modifying effect was also transiently observed in vivo in mice after intravenous administration

Spatio-temporal trends in stock mixing of eastern and western Baltic cod in the Arkona Basin and the implications for recruitment

In the Baltic Sea, two genetically distinct cod populations occur, the eastern and the western Baltic cod. Since 2006, cod abundance has increased substantially in the Arkona Basin (SD 24), the potential mixing area between the two stocks management areas, presumably due to spill-over from the eastern stock. In this study, the spatio-temporal dynamics of stock mixing were analysed using shape analysis of archived otoliths. Further, the impact of eastern cod immigration on recruitment in the western Baltic Sea was investigated using hydrographic drift modelling. The percentage of eastern Baltic cod in the Arkona Basin increased from ca. 30% before 2005 to >80% in recent years. Geographic patterns in stock mixing with a pronounced east–west trend suggest that immigration occurs north of Bornholm, but propagates throughout the Arkona Basin. The immigration cannot be attributed to spawning migration, as no seasonal trend in stock mixing was observed. Based on environmental threshold levels for egg survival and time-series of hydrography data, the habitat suitable for successful spawning of eastern cod was estimated to range between 20 and 50% of the maximum possible habitat size, limited by primarily low salinity. Best conditions occurred irregularly in May–end June, interspersed with years where successful spawning was virtually impossible. Using a coupled hydrodynamic modelling and particle-tracking approach, the drift and survival of drifters representing eastern cod eggs was estimated. On average, 19% of the drifters in the Arkona Basin survive to the end of the yolk-sac stage, with mortality primarily after bottom contact due to low salinity. The general drift direction of the surviving larvae was towards the east. Therefore, it is the immigration of eastern cod, rather than larval transport, that contributes to cod recruitment in the western Baltic Sea

Biased signaling of lipids and allosteric actions of synthetic molecules for GPR119

AbstractGPR119 is a Gαs-coupled lipid-sensor in the gut, where it mediates release of incretin hormones from the enteroendocrine cells and in pancreatic α-cells, where it releases insulin. Naturally occurring lipids such as monoacylglycerols (MAGs) and N-acylethanolamines (NAEs), like oleoylethanolamide (OEA), activate GPR119, and multiple synthetic ligands have been described. Here, we extend the GPR119 signaling profile to Gαq and Gαi in addition to β-arrestin recruitment and the downstream transcription factors CRE (cAMP response element), SRE (serum response element) and NFAT (nuclear factor of activated T cells). The endogenous OEA and the synthetic AR231453 were full agonists in all pathways except for NFAT, where no ligand-modulation was observed. The potency of AR231453 varied <16-fold (EC50 from 6 to 95nM) across the different signaling pathways, whereas that of OEA varied >175-fold (from 85nM to 15μM) indicating a biased signaling for OEA. The degree of constitutive activity was 1–10%, 10–30% and 30–70% of OEA-induced Emax in Gαi, Gαq and Gαs-driven pathways, respectively. This coincided with the lowest and highest OEA potency observed in Gαi and Gαs-driven pathways, respectively. Incubation for 2h with the 2-MAG-lipase inhibitor JZL84 doubled the constitutive activity, indicating that endogenous lipids contribute to the apparent constitutive activity. Finally, besides being an agonist, AR231453 acted as a positive allosteric modulator of OEA and increased its potency by 54-fold at 100nM AR231453. Our studies uncovering broad and biased signaling, masked constitutive activity by endogenous MAGs, and ago-allosteric properties of synthetic ligands may explain why many GPR119 drug-discovery programs have failed so far