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10.1111/bph.13746 http://scihub22266oqcxt.onion/10.1111/bph.13746 C5406298!5406298 !28198010     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=28198010 &cmd=llinks): Failed to open stream: HTTP request failed! 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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 ): 1090-1103 PMID28198010 show 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. |Animals [MESH] |Cells, Cultured [MESH] |Cytokines/metabolism [MESH] |Dose-Response Relationship, Drug [MESH] |Female [MESH] |Inflammation/*drug therapy/metabolism [MESH] |Ketones/chemistry/*pharmacology [MESH] |Lipopolysaccharides/*antagonists & inhibitors/pharmacology [MESH] |Lymphocyte Antigen 96/antagonists & inhibitors/metabolism [MESH] |Magnesium/*metabolism [MESH] |Male [MESH] |Microglia/drug effects/metabolism [MESH] |Molecular Structure [MESH] |Rats [MESH] |Rats, Sprague-Dawley [MESH] |Signal Transduction/drug effects [MESH] |Structure-Activity Relationship [MESH]Phenolic 1,3-diketones attenuate lipopolysaccharide-induced inflammato(epmc).pdf DeepDyve Pubget Overpricing