Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand activated transcription factor, belonging to the metazoan family of nuclear hormone receptors. Activation of PPARgamma increases the transcription of enzymes involved in primary metabolism, leading to lower blood levels of fatty acids and glucose. Hence, PPARgamma represents the major target for the glitazone type of drugs currently being used clinically for the treatment of type 2 diabetes. Furthermore, activators of PPARgamma show beneficial anti-inflammatory and anti-tumour effects. Utilizing a fusion receptor of the yeast Gal4-DNA binding domain joined to the hinge region and ligand binding domain of the human PPARgamma in combination with a Gal4-driven luciferase reporter gene, cotransfected into Cos7 cells, we tested sage and rosemary extracts prepared with 80 % aqueous ethanol for possible PPARgamma activation. This revealed that both extracts are capable of selectively activating Gal4-PPARgamma fusion receptor, in a concentration-dependent manner, with EC (50) values of 22.8 +/- 8.4 mg/L and 33.7 +/- 7.3 mg/L for rosemary and sage, respectively. Subsequent analysis of the characteristic constituents revealed the phenolic diterpene compounds carnosol, present in both herbs, and carnosic acid to be active principles of these extracts, showing EC (50) values of 41.2 +/- 5.9 microM and 19.6 +/- 2.0 microM, respectively. Thus it can be concluded that the glucose lowering effect reported recently for rosemary may be attributed to PPARgamma activation. Moreover, our observations may also explain the anti-inflammatory and antiproliferative effects of both compounds published previously.

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Previous results indicate that the polyphenol resveratrol inhibits cell growth of colon carcinoma cells via modulation of polyamine metabolic key enzymes. The aim of this work was to specify the underlying molecular mechanisms and to identify a possible role of transcription factor peroxisome proliferator-activated receptor ; (PPAR;). Cell growth was determined by bromodeoxyuridine incorporation and crystal violet staining. Protein levels were examined by Western blot analysis. Spermine/spermidine acetyltransferase (SSAT) activity was determined by a radiochemical assay. PPAR; ligand-dependent transcriptional activity was measured by a luciferase assay. A dominant-negative PPAR; mutant was transfected in Caco-2 cells to suppress PPAR;-mediated functions. Resveratrol inhibits cell growth of both Caco-2 and HCT-116 cells in a dose-and time-dependent manner (P < 0.001). In contrast to Caco-2-wild type cells (P < 0.05), resveratrol failed to increase SSAT activity in dominantnegative PPAR; cells. PPAR; involvement was further confirmed via ligand-dependent activation (P < 0.01) as well as by induction of cytokeratin 20 (P < 0.001) after resveratrol treatment. Coincubation with SB203580 abolished SSAT activation significantly in Caco-2 (P < 0.05) and HCT-116 (P < 0.01) cells. The involvement of p38 mitogen-activated protein kinase (MAPK) was further confirmed by a resveratrol-mediated phosphorylation of p38 protein in both cell lines. Resveratrol further increased the expression of PPAR; coactivator PGC-1A (P < 0.05) as well as SIRT1 (P < 0.01) in a dose-dependent manner after 24 hours of incubation. Based on our findings, p38 MAPK and transcription factor PPAR; can be considered as molecular targets of resveratrol in the regulation of cell proliferation and SSAT activity, respectively, in a cell culture model of colon cancer. (Cancer Res 2006; 66(14): 7348-54)

Peroxisome proliferator-activated receptors (PPAR) are nuclear receptors, playing a pivotal role in energy homeostasis. Activators of the PPARalpha subtype are in widespread use for the treatment of hyperlipidemia, while activators of the PPARgamma subtype are in clinical use for the treatment of type-2 diabetes. Since both of these diseases are frequently associated, the combined treatment with one drug simultaneously activating PPARalpha and PPARgamma seems worthwhile. Starting with pirinixic acid, which is a moderately active dual PPARalpha/gamma agonist, we improved potency at the human PPARalpha and PPARgamma by substituting the alpha-position with an aliphatic chain. The maximal effect was achieved at a chain length of four and six carbons, respectively, leading to an activity induction by a factor of 36 for PPARalpha and 18 for PPARgamma, respectively.

Advanced kernel‐based machine learning methods enable the identification of innovative bioactive compounds with minimal experimental effort. Comparative virtual screening revealed that nonlinear models of the underlying structure–activity relationship are necessary for successful compound picking. In a proof‐of‐concept study a novel truxillic acid derivative was found to selectively activate transcription factor PPARγ.

We report the combination of chemical cross-linking and high-resolution mass spectrometry for analyzing conformational changes in target proteins that are induced by drug binding. With this approach conformational changes in the peroxisome proliferator-activated receptor alpha (PPARalpha) upon binding of low-molecular weight compounds were readily detected, proving that the strategy provides a basis to efficiently characterize target protein-drug interactions.

Pirinixic acid is known for its peroxisome proliferator-activated receptor (PPAR) agonistic action. In a recent publication, we have shown that aliphatic alpha-substitution of pirinixic acid enhances both PPARalpha and PPARgamma agonism. The goal of this study was to evaluate, whether the PPAR agonism of pirinixic acid may be also maintained in quinoline-based derivatives. The present study revealed that the mere substitution of the dimethyl aniline moiety of pirinixic acid by quinoline leads to a total loss of PPARalpha/gamma agonism, whereas concomitant alpha-substitution with n-butyl or n-hexyl groups restores and even enforces PPAR activation, leading to potent dual PPARalpha/gamma agonists. In the following we report the synthesis of quinoline-based derivatives of pirinixic acid, which in a Gal4-based luciferase-reporter gene assay proved to be potent dual PPARalpha/gamma agonists. Molecular docking of compound 4 with FlexX suggests a binding mode resembling to that of tesaglitazar.

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