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10.1111/bph.13746 http://scihub22266oqcxt.onion/10.1111/bph.13746 C5406298!5406298!28198010     free     free     free Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       Br+J+Pharmacol 2017 ; 174 (10): 1090-103 Nephropedia Template TP {{tp|p=28198010|t=2017. Phenolic 1,3?diketones attenuate lipopolysaccharide?induced inflammatory response by an alternative magnesium?mediated mechanism |pdf=|usr=}}{{28198010}} gab.com Text Phenolic 1,3 diketones attenuate lipopolysaccharide induced inflammatory response by an alternative magnesium mediated mechanism JO: Br J Pharmacol http://www.kidney.de/pget.php?&tw=1&pmid=28198010 #FOAvip Background and Purpose: Toll?like receptor 4 (TLR4) plays a key role in the induction of inflammatory responses both in peripheral organs and the CNS. Curcumin exerts anti?inflammatory functions by interfering with LPS?induced dimerization of TLR4?myeloid differentiation protein?2 (MD?2) complex and suppressing pro?inflammatory mediator release. However, the inhibitory mechanism of curcumin remains to be defined. Experimental Approach: Binding of bis?demethoxycurcumin (GG6) and its cyclized pyrazole analogue (GG9), lacking the 1,3?dicarbonyl function, to TLR4?MD?2 was determined using molecular docking simulations. The effects of these compounds on cytokine release and NF??B activation were examined by ELISA and fluorescence staining in LPS?stimulated primary microglia. Interference with TLR4 dimerization was assessed by immunoprecipitation in Ba/F3 cells. Key Results: Both curcumin analogues bound to the hydrophobic region of the MD?2 pocket. However, only curcumin and GG6, both possessing the 1,3?diketone moiety, inhibited LPS?induced TLR4 dimerization, activation of NF??B and secretion of pro?inflammatory cytokines in primary microglia. Consistent with the ability of 1,3?diketones to coordinate divalent metal ions, LPS stimulation in a low magnesium environment decreased pro?inflammatory cytokine release and NF??B p65 nuclear translocation in microglia and decreased TLR4?MD?2 dimerization in Ba/F3 cells. Curcumin and GG6 also significantly reduced cytokine output in contrast to the pyrazole analogue GG9. Conclusions and Implications: These results indicate that phenolic 1,3?diketones, with a structural motif able to coordinate magnesium ions, can modulate LPS?mediated TLR4?MD?2 signalling. Taken together, these studies identify a previously uncharacterized mechanism involving magnesium, underlying the inflammatory responses to LPS. Twit Text FOAVip Phenolic 1,3 diketones attenuate lipopolysaccharide induced inflammatory response by an alternative magnesium mediated mechanism ????Br J Pharmacol http://www.kidney.de/pget.php?&tw=1&pmid=28198010 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=28198010 #FOAvip English Wikipedia <ref>{{Cite pmid|28198010}}</ref> Phenolic 1,3?diketones attenuate lipopolysaccharide?induced inflammatory response by an alternative magnesium?mediated mechanism #MMPMID28198010 Zusso M; Mercanti G; Belluti F; Di Martino RMC; Pagetta A; Marinelli C; Brun P; Ragazzi E; Lo R; Stifani S; Giusti P; Moro S Br J Pharmacol 2017[May]; 174 (10): 1090-103 PMID28198010show ga Background and Purpose: Toll?like receptor 4 (TLR4) plays a key role in the induction of inflammatory responses both in peripheral organs and the CNS. Curcumin exerts anti?inflammatory functions by interfering with LPS?induced dimerization of TLR4?myeloid differentiation protein?2 (MD?2) complex and suppressing pro?inflammatory mediator release. However, the inhibitory mechanism of curcumin remains to be defined. Experimental Approach: Binding of bis?demethoxycurcumin (GG6) and its cyclized pyrazole analogue (GG9), lacking the 1,3?dicarbonyl function, to TLR4?MD?2 was determined using molecular docking simulations. The effects of these compounds on cytokine release and NF??B activation were examined by ELISA and fluorescence staining in LPS?stimulated primary microglia. Interference with TLR4 dimerization was assessed by immunoprecipitation in Ba/F3 cells. Key Results: Both curcumin analogues bound to the hydrophobic region of the MD?2 pocket. However, only curcumin and GG6, both possessing the 1,3?diketone moiety, inhibited LPS?induced TLR4 dimerization, activation of NF??B and secretion of pro?inflammatory cytokines in primary microglia. Consistent with the ability of 1,3?diketones to coordinate divalent metal ions, LPS stimulation in a low magnesium environment decreased pro?inflammatory cytokine release and NF??B p65 nuclear translocation in microglia and decreased TLR4?MD?2 dimerization in Ba/F3 cells. Curcumin and GG6 also significantly reduced cytokine output in contrast to the pyrazole analogue GG9. Conclusions and Implications: These results indicate that phenolic 1,3?diketones, with a structural motif able to coordinate magnesium ions, can modulate LPS?mediated TLR4?MD?2 signalling. Taken together, these studies identify a previously uncharacterized mechanism involving magnesium, underlying the inflammatory responses to LPS. äPhenolic 1,3?diketones attenuate lipopolysaccharide?induced inflammato(epmc).pdf DeepDyve Pubget Overpricing