Ginsenosides Regulate PXR/NF-κB Signaling and Attenuate Dextran Sulfate Sodium–Induced Colitis

Abstract

Pregnane X receptor (PXR) activation exhibits anti-inflammatory effects via repressing nuclear factor-kB (NF-kB); however, its overactivation may disrupt homeostasis of various enzymes and transporters. Here we found that ginsenosides restore PXR/NFkB signaling in inflamed conditions without disrupting PXR function in normal conditions. The effects and mechanisms of ginsenosides in regulating PXR/NF-kB signals were determined both in vitro and in vivo. Ginsenosides significantly inhibited NFkB activation and restored the expression of PXR target genes in tumor necrosis factor-a-stimulated LS174T cells. Despite not being PXR agonists, ginsenosides repressed NF-kB activation in a PXR-dependent manner. Ginsenosides significantly increased the physical association between PXR and the NF-kB p65 subunit and thereby decreased the nuclear translocation of p65. Ginsenoside Rb1 and compound K (CK) were major bioactive compounds in the regulating PXR/NF-kB signaling. Consistently, ginsenosides significantly attenuated dextran sulfate sodium-induced experimental colitis, which was associated with restored PXR/NF-kB signaling. This study indicates that ginsenosides may elicit antiinflammatory effects via targeting PXR/NF-kB interaction without disrupting PXR function in healthy conditions. Ginsenoside Rb1 and CK may serve as leading compounds in the discovery of new drugs that target PXR/NF-kB interaction in therapy for inflammatory bowel disease.

β-Sitosterol and stigmasterol ameliorate dextran sulfate sodium-induced colitis in mice fed a high fat Western-style diet

“…Excessive production of COX-2 is usually observed in uncontrolled inflammation 26, 27 . In our study, COX-2 was found to be upregulated in colon tissues by DSS.…”

Cellular stress response mechanisms as therapeutic targets of ginsenosides

“…Nuclear translocation, NF‐κB phosphorylation, and DNA binding are three important events in the final stage of NF‐κB pathway activation and have been shown to be inhibited by ginsenosides under various conditions. Nuclear translocation of NF‐κB p65 can be blocked by Rg1, 20( S )‐protopanaxatriol, Rh1, Rh2, Rb1, CK, Rg3, PF11, Rf, Rd, and Rb3 . The phosphorylation of NF‐κB p65 was found to be inhibited by Rg1, Rg3, and Ro .…”

“…Activated NF‐κB eventually binds to κB elements in the promoter region of target genes and initiates the transcriptional process of numerous genes . Recent investigations have demonstrated that the NF‐κB pathway is suppressed by a large number of ginsenosides, including Rg1, Rh2, Rb1, Compound K (CK), Rg3, Rb3, Rd, Pseudoginsenoside‐F11 (PF11), Re, Rh1, Rf, 20( S )‐protopanaxatriol, and Ro (Fig. ).…”

“…The pregnane X receptor (PXR) is a ligand‐activated transcription factor that is readily stimulated by various different xenobiotics . It has been reported that PXR and NF‐κB were reciprocally suppressed .…”

“…Ginsenosides with Rb1 and CK as major bioactive compounds were shown to restore the expression of PXR target genes in TNF‐ α ‐stimulated LS174T cells and inhibit NF‐κB activation in a PXR‐dependent manner. Importantly, ginsenosides enhanced the physical association between PXR and NF‐κB p65 and subsequently suppressed NF‐κB activation …”