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10.1186/s13075-015-0771-6 http://scihub22266oqcxt.onion/10.1186/s13075-015-0771-6 C4570588!4570588!26370839     free     free     free Deprecated: Implicit conversion from float 209.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 209.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 209.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 209.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 209.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 243.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 243.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 243.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       Arthritis+Res+Ther 2015 ; 17 (1): ä Nephropedia Template TP {{tp|p=26370839|t=2015. Apremilast, a novel phosphodiesterase 4 (PDE4) inhibitor, regulates inflammation through multiple cAMP downstream effectors |pdf=|usr=}}{{26370839}} gab.com Text Apremilast, a novel phosphodiesterase 4 (PDE4) inhibitor, regulates inflammation through multiple cAMP downstream effectors JO: Arthritis Res Ther http://www.kidney.de/pget.php?&tw=1&pmid=26370839 #FOAvip Introduction: This work was undertaken to delineate intracellular signaling pathways for the PDE4 inhibitor apremilast and to examine interactions between apremilast, methotrexate and adenosine A2A receptors (A2AR). Methods: After apremilast and LPS incubation, intracellular cAMP, TNF-?, IL-10, IL-6 and IL-1? were measured in the Raw264.7 monocytic murine cell line. PKA, Epac1/2 (signaling intermediates for cAMP) and A2AR knockdowns were performed by shRNA transfection and interactions with A2AR and A2BR, as well as with methotrexate were tested in vitro and in the murine air pouch model. Statistical differences were determined using one or two-way ANOVA or Student?s t test. The alpha nominal level was set at 0.05 in all cases. A P value of < 0.05 was considered significant. Results: In vitro, apremilast increased intracellular cAMP and inhibited TNF-? release (IC50=104nM) and the specific A2AR-agonist CGS21680 (1?M) increased apremilast potency (IC50=25nM). In this cell line, apremilast increased IL-10 production. PKA, Epac1 and Epac2 knockdowns prevented TNF-? inhibition and IL-10 stimulation by apremilast. In the murine air pouch model, both apremilast and MTX significantly inhibited leukocyte infiltration, while apremilast, but not MTX, significantly inhibited TNF-? release. The addition of MTX (1 mg/kg) to apremilast (5 mg/kg) yielded no more inhibition of leukocyte infiltration or TNF-? release than with apremilast alone. Conclusions: The immunoregulatory effects of apremilast appear to be mediated by cAMP through the downstream effectors PKA, Epac1, and Epac2. A2AR agonism potentiated TNF-? inhibition by apremilast, consistent with the cAMP-elevating effects of that receptor. Because the A2AR is also involved in the anti-inflammatory effects of MTX, the mechanism of action of both drugs involves cAMP-dependent pathways and is therefore partially overlapping in nature. Electronic supplementary material: The online version of this article (doi:10.1186/s13075-015-0771-6) contains supplementary material, which is available to authorized users. Twit Text FOAVip Apremilast, a novel phosphodiesterase 4 (PDE4) inhibitor, regulates inflammation through multiple cAMP downstream effectors ????Arthritis Res Ther http://www.kidney.de/pget.php?&tw=1&pmid=26370839 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=26370839 #FOAvip English Wikipedia <ref>{{Cite pmid|26370839}}</ref> Apremilast, a novel phosphodiesterase 4 (PDE4) inhibitor, regulates inflammation through multiple cAMP downstream effectors #MMPMID26370839 Perez-Aso M; Montesinos MC; Mediero A; Wilder T; Schafer PH; Cronstein B Arthritis Res Ther 2015[]; 17 (1): ä PMID26370839show ga Introduction: This work was undertaken to delineate intracellular signaling pathways for the PDE4 inhibitor apremilast and to examine interactions between apremilast, methotrexate and adenosine A2A receptors (A2AR). Methods: After apremilast and LPS incubation, intracellular cAMP, TNF-?, IL-10, IL-6 and IL-1? were measured in the Raw264.7 monocytic murine cell line. PKA, Epac1/2 (signaling intermediates for cAMP) and A2AR knockdowns were performed by shRNA transfection and interactions with A2AR and A2BR, as well as with methotrexate were tested in vitro and in the murine air pouch model. Statistical differences were determined using one or two-way ANOVA or Student?s t test. The alpha nominal level was set at 0.05 in all cases. A P value of < 0.05 was considered significant. Results: In vitro, apremilast increased intracellular cAMP and inhibited TNF-? release (IC50=104nM) and the specific A2AR-agonist CGS21680 (1?M) increased apremilast potency (IC50=25nM). In this cell line, apremilast increased IL-10 production. PKA, Epac1 and Epac2 knockdowns prevented TNF-? inhibition and IL-10 stimulation by apremilast. In the murine air pouch model, both apremilast and MTX significantly inhibited leukocyte infiltration, while apremilast, but not MTX, significantly inhibited TNF-? release. The addition of MTX (1 mg/kg) to apremilast (5 mg/kg) yielded no more inhibition of leukocyte infiltration or TNF-? release than with apremilast alone. Conclusions: The immunoregulatory effects of apremilast appear to be mediated by cAMP through the downstream effectors PKA, Epac1, and Epac2. A2AR agonism potentiated TNF-? inhibition by apremilast, consistent with the cAMP-elevating effects of that receptor. Because the A2AR is also involved in the anti-inflammatory effects of MTX, the mechanism of action of both drugs involves cAMP-dependent pathways and is therefore partially overlapping in nature. Electronic supplementary material: The online version of this article (doi:10.1186/s13075-015-0771-6) contains supplementary material, which is available to authorized users. äApremilast, a novel phosphodiesterase 4 (PDE4) inhibitor, regulates in(epmc).pdf DeepDyve Pubget Overpricing