Phytochemicals Mediate the Expression and Activity of OCTN2 as Activators of the PPARγ/RXRα Pathway.
Phytochemicals Mediate the Expression and Activity of OCTN2 as Activators of the PPARγ/RXRα Pathway.
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植物化学物质作为 PPAR γ/RXR α 通路激活剂介导 OCTN2 的表达和活性
DOI：
10.3389/fphar.2016.00189
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发表时间：
2016
影响因子：
5.6
通讯作者：
Qu Q
中科院分区：
文献类型：
--
作者：
Luo J;Qu J;Yang R;Ge MX;Mei Y;Zhou BT;Qu Q
许多植物化学物质作为过氧化物酶体增殖物激活受体γ（PPARγ）的激动剂发挥活性。本研究旨在探讨植物化学物质是否是PPARγ/RXRα通路的激动剂并调节靶基因OCTN 2。在这项研究中，荧光素酶报告基因系统被用来筛选新的OCTN 2激活剂从39种植物化学物质。发现山奈酚、姜黄素和葛根素在20 μM时显示出显著的PPRE介导的荧光素酶活性（>150%），并且显示出剂量依赖性方式。植物化学物质还以剂量依赖性方式在结肠直肠癌SW 480细胞中升高OCTN 2的mRNA和蛋白表达。在荧光素酶报告基因系统和SW 480细胞中，这种诱导作用被PPARγ拮抗剂GW 9662逐渐抑制。此外，细胞活力测定的结果表明，三种植物化学物质可能诱导OCTN 2表达，导致其底物奥沙利铂的摄取增强，从而使细胞对奥沙利铂更敏感。分子对接研究表明，植物化学物质与PPARγ蛋白可能存在结合位点，所有对接的植物化学物质与曲格列酮均位于PPARγ的活性口袋中。所有三种植物化学物质的极性部分和氨基酸残基之间表现出氢键。因此，我们鉴定了三种植物化学物质作为PPARγ配体，其增强了OCTN 2的表达和活性。
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.