Polyacetylenes from Notopterygium incisum–New Selective Partial Agonists of Peroxisome Proliferator-Activated Receptor-Gamma
Open Access
- 22 April 2013
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 8 (4), e61755
- https://doi.org/10.1371/journal.pone.0061755
Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of glucose and lipid metabolism and therefore an important pharmacological target to combat metabolic diseases. Since the currently used full PPARγ agonists display serious side effects, identification of novel ligands, particularly partial agonists, is highly relevant. Searching for new active compounds, we investigated extracts of the underground parts of Notopterygium incisum, a medicinal plant used in traditional Chinese medicine, and observed significant PPARγ activation using a PPARγ-driven luciferase reporter model. Activity-guided fractionation of the dichloromethane extract led to the isolation of six polyacetylenes, which displayed properties of selective partial PPARγ agonists in the luciferase reporter model. Since PPARγ activation by this class of compounds has so far not been reported, we have chosen the prototypical polyacetylene falcarindiol for further investigation. The effect of falcarindiol (10 µM) in the luciferase reporter model was blocked upon co-treatment with the PPARγ antagonist T0070907 (1 µM). Falcarindiol bound to the purified human PPARγ receptor with a Ki of 3.07 µM. In silico docking studies suggested a binding mode within the ligand binding site, where hydrogen bonds to Cys285 and Glu295 are predicted to be formed in addition to extensive hydrophobic interactions. Furthermore, falcarindiol further induced 3T3-L1 preadipocyte differentiation and enhanced the insulin-induced glucose uptake in differentiated 3T3-L1 adipocytes confirming effectiveness in cell models with endogenous PPARγ expression. In conclusion, we identified falcarindiol-type polyacetylenes as a novel class of natural partial PPARγ agonists, having potential to be further explored as pharmaceutical leads or dietary supplements.This publication has 84 references indexed in Scilit:
- TMS-evoked changes in brain-state dynamics quantified by using EEG dataFrontiers in Human Neuroscience, 2013
- The role of peroxisome proliferator-activated receptors in carcinogenesis and chemopreventionNature Reviews Cancer, 2012
- N-Acetylfarnesylcysteine Is a Novel Class of Peroxisome Proliferator-activated Receptor γ Ligand with Partial and Full Agonist Activity in Vitro and in VivoOnline Journal of Public Health Informatics, 2011
- Rhythmic TMS Causes Local Entrainment of Natural Oscillatory SignaturesCurrent Biology, 2011
- The nuclear receptor PPARγ individually responds to serotonin- and fatty acid-metabolitesThe EMBO Journal, 2010
- Computer-Aided Discovery, Validation, and Mechanistic Characterization of Novel Neolignan Activators of Peroxisome Proliferator-Activated Receptor γMolecular Pharmacology, 2010
- Methodology for Combined TMS and EEGBrain Topography, 2009
- PPARs and molecular mechanisms of transrepressionBiochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2007
- A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye bindingAnalytical Biochemistry, 1976
- Relationship between the inhibition constant (KI) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reactionBiochemical Pharmacology, 1973