<?xml version="1.0" encoding="UTF-8"?><xml><records><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Ali, Tomader</style></author><author><style face="normal" font="default" size="100%">Kokotos, George</style></author><author><style face="normal" font="default" size="100%">Magrioti, Victoria</style></author><author><style face="normal" font="default" size="100%">Bone, Robert N.</style></author><author><style face="normal" font="default" size="100%">Mobley, James A.</style></author><author><style face="normal" font="default" size="100%">Hancock, William</style></author><author><style face="normal" font="default" size="100%">Ramanadham, Sasanka</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Characterization of FKGK18 as Inhibitor of Group VIA Ca&lt;sup&gt;2+&lt;/sup&gt;-Independent Phospholipase A&lt;sub&gt;2&lt;/sub&gt;: Candidate Drug for Preventing Beta-Cell Apoptosis and Diabetes</style></title><secondary-title><style face="normal" font="default" size="100%">PLoS ONE</style></secondary-title></titles><dates><year><style  face="normal" font="default" size="100%">2013</style></year></dates><number><style face="normal" font="default" size="100%">8</style></number><publisher><style face="normal" font="default" size="100%">Public Library of Science</style></publisher><volume><style face="normal" font="default" size="100%">8</style></volume><pages><style face="normal" font="default" size="100%">e71748</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;span&gt;Ongoing studies suggest an important role for iPLA&lt;/span&gt;&lt;sub&gt;&lt;span&gt;2&lt;/span&gt;&lt;/sub&gt;&lt;span&gt;β in a multitude of biological processes and it has been implicated in neurodegenerative, skeletal and vascular smooth muscle disorders, bone formation, and cardiac arrhythmias. Thus, identifying an iPLA&lt;/span&gt;&lt;sub&gt;&lt;span&gt;2&lt;/span&gt;&lt;/sub&gt;&lt;span&gt;β inhibitor that can be reliably and safely used&amp;nbsp;&lt;/span&gt;&lt;em&gt;in vivo&lt;/em&gt;&lt;span&gt;&amp;nbsp;is warranted. Currently, the mechanism-based inhibitor bromoenol lactone (BEL) is the most widely used to discern the role of iPLA&lt;/span&gt;&lt;sub&gt;&lt;span&gt;2&lt;/span&gt;&lt;/sub&gt;&lt;span&gt;β in biological processes. While BEL is recognized as a more potent inhibitor of iPLA&lt;/span&gt;&lt;sub&gt;&lt;span&gt;2&lt;/span&gt;&lt;/sub&gt;&lt;span&gt;&amp;nbsp;than of cPLA&lt;/span&gt;&lt;sub&gt;&lt;span&gt;2&lt;/span&gt;&lt;/sub&gt;&lt;span&gt;&amp;nbsp;or sPLA&lt;/span&gt;&lt;sub&gt;&lt;span&gt;2&lt;/span&gt;&lt;/sub&gt;&lt;span&gt;, leading to its designation as a “specific” inhibitor of iPLA&lt;/span&gt;&lt;sub&gt;&lt;span&gt;2&lt;/span&gt;&lt;/sub&gt;&lt;span&gt;, it has been shown to also inhibit non-PLA&lt;/span&gt;&lt;sub&gt;&lt;span&gt;2&lt;/span&gt;&lt;/sub&gt;&lt;span&gt;&amp;nbsp;enzymes. A potential complication of its use is that while the&amp;nbsp;&lt;/span&gt;&lt;em&gt;S&lt;/em&gt;&lt;span&gt;&amp;nbsp;and&amp;nbsp;&lt;/span&gt;&lt;em&gt;R&amp;nbsp;&lt;/em&gt;&lt;span&gt;enantiomers of BEL exhibit preference for cytosol-associated iPLA&lt;/span&gt;&lt;sub&gt;&lt;span&gt;2&lt;/span&gt;&lt;/sub&gt;&lt;span&gt;β and membrane-associated iPLA&lt;/span&gt;&lt;sub&gt;&lt;span&gt;2&lt;/span&gt;&lt;/sub&gt;&lt;span&gt;γ, respectively, the selectivity is only 10-fold for both. In addition, BEL is unstable in solution, promotes irreversible inhibition, and may be cytotoxic, making BEL not amenable for&amp;nbsp;&lt;/span&gt;&lt;em&gt;in vivo&lt;/em&gt;&lt;span&gt;&amp;nbsp;use. Recently, a fluoroketone (FK)-based compound (FKGK18) was described as a potent inhibitor of iPLA&lt;/span&gt;&lt;sub&gt;&lt;span&gt;2&lt;/span&gt;&lt;/sub&gt;&lt;span&gt;β. Here we characterized its inhibitory profile in beta-cells and find that FKGK18: (a) inhibits iPLA&lt;/span&gt;&lt;sub&gt;&lt;span&gt;2&lt;/span&gt;&lt;/sub&gt;&lt;span&gt;β with a greater potency (100-fold) than iPLA&lt;/span&gt;&lt;sub&gt;&lt;span&gt;2&lt;/span&gt;&lt;/sub&gt;&lt;span&gt;γ, (b) inhibition of iPLA&lt;/span&gt;&lt;sub&gt;&lt;span&gt;2&lt;/span&gt;&lt;/sub&gt;&lt;span&gt;β is reversible, (c) is an ineffective inhibitor of α-chymotrypsin, and (d) inhibits previously described outcomes of iPLA&lt;/span&gt;&lt;sub&gt;&lt;span&gt;2&lt;/span&gt;&lt;/sub&gt;&lt;span&gt;β activation including (i) glucose-stimulated insulin secretion, (ii) arachidonic acid hydrolysis; as reflected by PGE&lt;sub&gt;2&lt;/sub&gt; release from human islets, (iii) ER stress-induced neutral sphingomyelinase 2 expression, and (iv) ER stress-induced beta-cell apoptosis. These findings suggest that FKGK18 is similar to BEL in its ability to inhibit iPLA&lt;/span&gt;&lt;sub&gt;&lt;span&gt;2&lt;/span&gt;&lt;/sub&gt;&lt;span&gt;β. Because, in contrast to BEL, it is reversible and not a non-specific inhibitor of proteases, it is suggested that FKGK18 is more ideal for&amp;nbsp;&lt;/span&gt;&lt;em&gt;ex vivo&lt;/em&gt;&lt;span&gt;&amp;nbsp;and&amp;nbsp;&lt;/span&gt;&lt;em&gt;in vivo&lt;/em&gt;&lt;span&gt;&amp;nbsp;assessments of iPLA&lt;/span&gt;&lt;sub&gt;&lt;span&gt;2&lt;/span&gt;&lt;/sub&gt;&lt;span&gt;β role in biological functions.&lt;/span&gt;</style></abstract></record></records></xml>