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It is suspected that microbial infections take part in the pathogenesis of diabetes mellitus type 1 (T1DM). Glucose-induced insulin secretion is accompanied by the release of free arachidonic acid (AA) mainly by cytosolic- and calcium independent phospholipases A2 (cPLA2 and iPLA2). Insulinoma cell line (INS-1E) was infected with E. coli isolated from the blood culture of a patient with sepsis. Invasion assay, Scanning Electron Microscopy and Transmission Electron Microscopy demonstrated the capacity of E. coli to enter cells, which was reduced by PLA2 inhibitors. Glucose-induced insulin secretion was significantly increased after acute infection (8h) but significantly decreased after chronic infection (72h). PLA2 activities, cPLA2, iPLA2, phospho-cPLA2, and COX-2 expressions were increased after acute and, even more, after chronic E. coli infection. The silencing of the two isoforms of PLA2s, with specific cPLA2- or iPLA2-siRNAs, reduced insulin secretion after acute infection and determined a rise in insulin release after chronic infection. Prostaglandins E2 (PGE2) production was significantly elevated in INS-1E after long-term E. coli infection and the restored insulin secretion in presence of L798106, a specific EP3 antagonist, and NS-398, a COX-2 inhibitor, and the reduction of insulin secretion in presence of sulprostone, a specific EP3 agonist, revealed their involvement in the effects triggered by bacterial infection. The results obtained demonstrated that cPLA2 and iPLA2 play a key role in insulin secretion process after E. coli infection. The high concentration of AA released is transformed into PGE2, which could be responsible for the reduced insulin secretion.
Increased activity of secretory phospholipases A2 (sPLA2) type-II was previously observed in ileum of Crohn's disease (CD). Our aims were to explore the involvement of calcium-independent (i)PLA2β in the release of sPLA2s from the human mast cell (MC) line (HMC-1) and investigate expressions of cytosolic (c)PLA2α, iPLA2β, sPLA2-IIA and sPLA2-V in MCs of CD ileum. The release of sPLA2 was investigated in HMC-1 by immunocytochemistry and ELISA. The expression intensities of PLA2s in mucosal MCs, and the proportion of PLA2-positive MCs, were investigated in normal ileum and in ileum from patients with CD by immunohistochemistry. The calcium ionophore-stimulated release of sPLA2-IIA and sPLA2-V from HMC-1 was reduced by the iPLA2-inhibitor bromoenol lactone. All four PLA2s were detectable in mucosal MCs, both in normal ileum and in CD, but the proportion of iPLA2β-containing mucosal MCs and the expression intensity of sPLA2-IIA was increased in CD. Results indicate that iPLA2β is involved in the secretion of sPLA2s from HMC-1, and suggest that iPLA2β-mediated release of sPLA2 from intestinal MCs may contribute to CD pathophysiology. Ex vivo studies on isolated mucosal mast cells are however needed to clarify the precise role of MC PLA2s in the inflammatory processes of CD.
The present study was carried out, using inhibitors to secretory phospholipase A2 (sPLA2, 12-epi-scalaradial), cytosolic phospholipase A2 (cPLA2, AACOCF3), or calcium-independent phospholipase A2 (iPLA2, bromoenol lactone), to compare possible contributions of central nervous PLA2 isoforms to the development of allodynia after facial carrageenan injection in mice. C57BL/6J (B6) mice showed increased responses to facial stimulation using a von Frey hair (1 g force), at 8 h, 1 day, and 3 days after facial carrageenan injection. On the other hand, BALB/c mice did not show increased responses at any of the time points. In both B6 and BALB/c mice, intracerebroventricular injection of inhibitors to each of the three PLA2 isoforms significantly reduced responses to von Frey hair stimulation at 8 h and 1 day after facial carrageenan injection, but at 3 days after injection, only the sPLA2 inhibitor had an effect. Since BALB/c mice did not show increased responses after facial carrageenan injection, the reduction in responses actually indicates that there is loss of normal sensitivity to von Frey hair stimulation after intracerebroventricular injection of each of these inhibitors, in this strain of mice. The effects of PLA2 inhibitors are unlikely to be due simply to inhibition of arachidonic acid generation, since intracerebroventricular injection of arachidonic acid also had an anti-nociceptive effect. The above results support an important role of central nervous PLA2s in neurotransmission and pain transmission.
Phospholipase A2 (PLA2) enzymes are involved in various inflammatory pathological conditions including arthritis, cardiovascular and autoimmune diseases. The regulation of their catalytic activity is of high importance and a great effort has been devoted in developing synthetic inhibitors. We summarize the most important small-molecule synthetic PLA2 inhibitors developed to target each one of the four major types of human PLA2 (cytosolic cPLA2, calcium-independent iPLA2, secreted sPLA2, and lipoprotein-associated LpPLA2). We discuss recent applications of inhibitors to understand the role of each PLA2 type and their therapeutic potential. Potent and selective PLA2 inhibitors have been developed. Although some of them have been evaluated in clinical trials, none reached the market yet. Apart from their importance as potential medicinal agents, PLA2 inhibitors are excellent tools to unveil the role that each PLA2 type plays in cells and in vivo. Modern medicinal chemistry approaches are expected to generate improved PLA2 inhibitors as new agents to treat inflammatory diseases.
Assaying lipolytic enzymes is extremely challenging because they act on water-insoluble lipid substrates, which are normally components of micelles, vesicles, and cellular membranes. We extended a new lipidomics-based liquid chromatographic-mass spectrometric assay for phospholipases A2 to perform inhibition analysis using a variety of commercially available synthetic and natural phospholipids as substrates. Potent and selective inhibitors of three recombinant human enzymes, including cytosolic, calcium-independent, and secreted phospholipases A2 were used to establish and validate this assay. This is a novel use of dose-response curves with a mixture of phospholipid substrates, not previously feasible using traditional radioactive assays. The new application of lipidomics to developing assays for lipolytic enzymes revolutionizes in vitro testing for the discovery of potent and selective inhibitors using mixtures of membranelike substrates.
The abilities of docosahexaenoic acid (DHA) and exercise to counteract cognitive decay after traumatic brain injury (TBI) is getting increasing recognition; however, the possibility that these actions can be complementary remains just as an intriguing possibility. Here we have examined the likelihood that the combination of diet and exercise has the added potential to facilitate functional recovery following TBI. Rats received mild fluid percussion injury (mFPI) or sham injury and then were maintained on a diet high in DHA (1.2% DHA) with or without voluntary exercise for 12days. We found that FPI reduced DHA content in the brain, which was accompanied by increased levels of lipid peroxidation assessed using 4-hydroxy-2-hexenal (4-HHE). FPI reduced the enzymes acyl-CoA oxidase 1 (Acox1) and 17β-hydroxysteroid dehydrogenase type 4 (17β-HSD4), and the calcium-independent phospholipases A2 (iPLA2), which are involved in metabolism of membrane phospholipids. FPI reduced levels of syntaxin-3 (STX-3), involved in the action of membrane DHA on synaptic membrane expansion, and also reduced brain-derived neurotrophic factor (BDNF) signaling through its tyrosine kinase B (TrkB) receptor. These effects of FPI were optimally counteracted by the combination of DHA and exercise. Our results support the possibility that the complementary action of exercise is exerted on restoring membrane homeostasis after TBI, which is necessary for supporting synaptic plasticity and cognition. It is our contention that strategies that take advantage of the combined applications of diet and exercise may have additional effects to the injured brain.
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