Potential Dissociative Glucocorticoid Receptor Activity for Protopanaxadiol and Protopanaxatriol.

Aikaterini Karra,Anna-Maria Psarra,Maria Konstantinou,Foteini Kalousi,Maria Tzortziou,Constantine Garagounis,Ioannis Tsialtas,Joseph Hayes

doi:10.3390/ijms20010094

Abstract

Glucocorticoids are steroid hormones that regulate inflammation, growth, metabolism, and apoptosis via their cognate receptor, the glucocorticoid receptor (GR). GR, acting mainly as a transcription factor, activates or represses the expression of a large number of target genes, among them, many genes of anti-inflammatory and pro-inflammatory molecules, respectively. Transrepression activity of glucocorticoids also accounts for their anti-inflammatory activity, rendering them the most widely prescribed drug in medicine. However, chronic and high-dose use of glucocorticoids is accompanied with many undesirable side effects, attributed predominantly to GR transactivation activity. Thus, there is a high need for selective GR agonist, capable of dissociating transrepression from transactivation activity. Protopanaxadiol and protopanaxatriol are triterpenoids that share structural and functional similarities with glucocorticoids. The molecular mechanism of their actions is unclear. In this study applying induced-fit docking analysis, luciferase assay, immunofluorescence, and Western blot analysis, we showed that protopanaxadiol and more effectively protopanaxatriol are capable of binding to GR to activate its nuclear translocation, and to suppress the nuclear factor-kappa beta activity in GR-positive HeLa and HEK293 cells, but not in GR-low level COS-7 cells. Interestingly, no transactivation activity was observed, whereas suppression of the dexamethasone-induced transactivation of GR and induction of apoptosis in HeLa and HepG2 cells were observed. Thus, our results indicate that protopanaxadiol and protopanaxatriol could be considered as potent and selective GR agonist.

Highlights

Glucocorticoids (GCs) are steroid hormones which exert their actions via binding to their cognate receptors, the glucocorticoid receptors (GRs)
IF−D5s5c7o.7re −5−5156.70.8 a Top-rankPePdDpobse based on IFDScore which had−a1li4g.a9n3d heavy atom RMSD just 0o.v6e1r0laÅppciPonmgPpTthaecrepdrewdiitchteditscocrmypstlaelxloaggraaipnhstic1cMo2nZf−o1rbm5y.a2mt3iaotnch(iPnDgBthceodrees:id1uMe 2bZa)c.kTbhoeneRaMto−Sm5D6s0wo.fa8sheclaiclceuslaHte5danbdy
The efficacy of binding is lower to that of the synthetic glucocorticoid DEX, and more importantly, experimental data, resulting from a comparative time-resolved fluorescence resonance energy transfer competitive ligand binding assay, showed that the number of glycosylated groups in ginsenosides is PPD- and PPT- type ginsenosides are capable of binding to GR [42,43,44,45,46]

Summary

Introduction

Glucocorticoids (GCs) are steroid hormones which exert their actions via binding to their cognate receptors, the glucocorticoid receptors (GRs). Glucocorticoid receptors belong to the large superfamily of nuclear receptors that act mainly as transcription factors [1]. GCs control many cellular functions such as metabolism, growth, development, immune and stress response, apoptosis, and glucose homeostasis [2]. The glucocorticoid receptor alpha (GR) is the most prominent transcriptionally active isoform of GRs. GR is predominantly localized in the cytoplasm. GR is translocated into the nucleus where it positively or negatively regulates the transcription of a plethora of GR target genes, either by direct binding to specific hormone response elements of the nuclear DNA, or by interaction with other transcription factors and regulation of their target genes expression

Methods

Results

Conclusion