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UBC Theses and Dissertations

Evaluation of ginsenosides in transactivation and transrepression of human glucocorticoid receptor alpha Hu, Catherine


Ginsenosides are pharmacologically active compounds in ginseng, a medicinal herb that is highly valued and widely consumed. They are reported to have diverse effects, including neuromodulation, anticancer, and immunomodulation. Glucocorticoid receptor (GR) is a nuclear receptor involved in transcriptional regulation of genes in numerous important physiological processes, such as stress-related homeostasis, gluconeogenesis, bone remodeling, and anti-inflammation. Previous research suggested ginsenosides as agonists of rodent GRα. Studies on human GRα (hGRα) mainly focused on a single ginsenoside and its effect on either hGRα-mediated transactivation or transrepression. However, only a few ginsenosides (compound K, Rh1, Rh2, Re, Rg1) were examined and it is not known whether ginsenosides activate hGRα in an analog-selective manner. In this study, seven protopanaxadiol (PPD)-type ginsenosides (Rb1, Rb2, Rc, Rd, compound K, Rh2, PPD) and five protopanaxatriol (PPT)-type ginsenosides (Re, Rf, Rg1, Rh1, PPT) were investigated to determine whether they act as functional ligands of hGRα for both its transactivation and transrepression activity. In vitro time resolved-fluorescence resonance energy transfer (TR-FRET) competitive ligand-binding assay revealed that ginsenosides can weakly bind to the ligand-binding domain of hGRα. Among the selected ginsenosides, monoglycosylated PPD-type ginsenosides compound K and Rh2 exhibited strongest binding to the receptor. Dual-luciferase reporter gene assays employing firefly luciferase reporter vectors carrying either glucocorticoid response element or NF-κB response element were conducted in human colon adenocarcinoma cells (LS180). None of the ginsenosides increased or attenuated hGRα-mediated transactivation or transrepression activity. Furthermore, hGRα target gene (hTAT and hCBG) expression was studied in human hepatocellular carcinoma cells (HepG2) and quantified by real-time PCR. The data indicated that ginsenoside Rh2 did not influence hGRα target gene expression. In summary, among all PPD-type ginsenosides (Rb1, Rb2, Rc, Rd, compound K, Rh2, PPD) and PPT-type ginsenosides (Re, Rf, Rg1, Rh1, PPT) tested, monoglycosylated PPD-type ginsenosides compound K and Rh2 exhibited stronger binding to hGRα-LBD, while others could only bind weakly. Nevertheless, none of the ginsenosides could modulate hGRα activity or affect target gene expression. Therefore, these ginsenosides are not functional ligands of hGRα in LS180 and HepG2 cells.

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