Medium Chain Fatty Acids Are Selective Peroxisome Proliferator Activated Receptor (PPAR) γ Activators and Pan-PPAR Partial Agonists

Thiazolidinediones (TZDs) act through peroxisome proliferator activated receptor (PPAR) γ to increase insulin sensitivity in type 2 diabetes (T2DM), but deleterious effects of these ligands mean that selective modulators with improved clinical profiles are needed. We obtained a crystal structure of PPARγ ligand binding domain (LBD) and found that the ligand binding pocket (LBP) is occupied by bacterial medium chain fatty acids (MCFAs). We verified that MCFAs (C8–C10) bind the PPARγ LBD in vitro and showed that they are low-potency partial agonists that display assay-specific actions relative to TZDs; they act as very weak partial agonists in transfections with PPARγ LBD, stronger partial agonists with full length PPARγ and exhibit full blockade of PPARγ phosphorylation by cyclin-dependent kinase 5 (cdk5), linked to reversal of adipose tissue insulin resistance. MCFAs that bind PPARγ also antagonize TZD-dependent adipogenesis in vitro. X-ray structure B-factor analysis and molecular dynamics (MD) simulations suggest that MCFAs weakly stabilize C-terminal activation helix (H) 12 relative to TZDs and this effect is highly dependent on chain length. By contrast, MCFAs preferentially stabilize the H2-H3/β-sheet region and the helix (H) 11-H12 loop relative to TZDs and we propose that MCFA assay-specific actions are linked to their unique binding mode and suggest that it may be possible to identify selective PPARγ modulators with useful clinical profiles among natural products

Modified Silica Nanoparticles with an Aminonaphthoquinone

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)The synthesis and characterization of silica nanoparticles (NPs) covalently modified with an aminonaphthoquinone are reported. The aminopropylsilicagelnaphthoquinone (APSGNQ) was obtained by nucleophilic substitution of 2-methoxy-1,4-naphthoquinone with aminopropylsilicalgel (APSG) NPs. Solid state C-13 and Si-29 nuclear magnetic resonance spectra confirmed that the naphthoquinone is covalently bonded to APSG. Due to the solubility of APSGNQ in common organic solvents, solution ultraviolet-visible spectroscopy was used to determine the amount of naphthoquinone on the NPs surface (0.56 mmol of incorporated naphthoquinone per gram of APSGNQ) by comparison with the spectrum of 2-aminobutyl-1,4-naphthoquinone (ABNQ). Elemental analysis indicated that about 8% of the surface propylamine remained unreacted in APSGNQ. These multifunctional silica NPs have potential in medical applications.225961U226Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Pronex-FAPERJ [E-26/171.512/2006