Abstract
Many phytochemicals exert activities as agonists of peroxisome proliferator-activated receptor gamma (PPARγ). This study aims to investigate whether phytochemicals are agonists of the PPARγ/RXRα pathway and modulate the target gene OCTN2. In this study, a luciferase reporter gene system was used to screen novel OCTN2 activators from 39 phytochemicals. Kaempferol, curcumin, and puerarin were found to show the significant PPRE-mediated luciferase activities (>150%) at 20 μM and showed a dose-dependent manner. Phytochemicals also elevated the mRNA and protein expression of OCTN2 in a dose-dependent fashion in colorectal cancer SW480 cells. These induction effects were gradually inhibited by PPARγ antagonist GW9662 in the luciferase reporter gene system and in SW480 cells. Moreover, the results of cell viability assay imply that three phytochemicals probably induce OCTN2 expression leading to the enhanced uptake of its substrate, oxaliplatin, thereby making cells more sensitive to oxaliplatin. The molecular docking study showed the possible binding sites of phytochemicals in PPARγ protein, and all of the docked phytochemicals fitted the same active pocket in PPARγ as troglitazone. All three phytochemicals exhibited hydrogen bonds between their polar moieties and the amino acid residues. Thus, we identified three phytochemicals as PPARγ ligands, which potentiated the expression and activity of OCTN2.
Highlights
Phytochemicals are derived from plants and play an essential role in long-term health and offer chemical scaffolds for discovering novel drugs against a wide range of therapeutic targets (Ernst, 2003)
In cells transiently transfected with pGL4.23-Organic anion/cation transporter 2 (OCTN2)/peroxisomePhytochemicals Mediates OCTN2 proliferator responsive element (PPRE) and PPARγ/RXRα, the luciferase activity increased 3.9fold (p < 0.05) and 11-fold (p < 0.05), respectively, which was stimulated by troglitazone compared to cells transfected with pGL4.23 without transfection of PPARγ/RXRα (Figure 1B)
To detect whether endogenous PPARγ interferes with luciferase activity, only pGL4.23-OCTN2/PPRE was transfected in COS-7 cells with or without exposure to troglitazone
Summary
Phytochemicals are derived from plants and play an essential role in long-term health and offer chemical scaffolds for discovering novel drugs against a wide range of therapeutic targets (Ernst, 2003). Many phytochemicals govern the expression of drug-metabolizing enzymes and drug transporters through activating several nuclear receptors (NRs) and binding to the responsive elements within those genes. Ligand-activated PPARγ acts as a transcription factor and assembles into a heterodimer complex with retinoid X receptor alpha (RXRα) or retinoic acid receptor alpha (RARα), binding to the peroxisome. Phytochemicals Mediates OCTN2 proliferator responsive element (PPRE) within the promoter of target genes. Trans-activation could regulate adipocyte proliferation and differentiation (CCAAT/enhancer binding protein alpha, signal transducer and activator of transcription 1), lipid metabolism (GABA receptor modulator, lipoprotein lipase), glucose homeostasis (glucose transporter type 4, c-Cbl-associated protein, insulin receptor substrates 1 and 2) as well as insulin sensitization (tumor necrosis factor-α, leptin, adiponectin; Ricote et al, 1998; Evans et al, 2004; Zoete et al, 2007). The development of novel and effective PPARγ agonists from naturally occurring compounds with an improved safety profile and fewer side effects is of great interest
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