St. John’s Wort alleviates dextran sodium sulfate‐induced colitis through pregnane X receptor‐dependent NFκB antagonism

Abstract

St. John's wort (SJW), from traditional herbs, activates the pregnane X receptor (PXR), a potential drug target for treating inflammatory bowel disease (IBD).However, how SJW alleviates dextran sodium sulfate (DSS)-induced experimental IBD by activating PXR is unknown. To test this, PXR-humanized, wild-type (WT) and Pxr-null mice, primary intestinal organoids cultures, and the luciferase reporter gene assays were employed. In vivo, a diet supplemented with SJW was found to activate intestinal PXR both in WT and PXR-humanized mice, but not in Pxr-null mice. SJW prevented DSS-induced IBD in PXR-humanized and WT mice, but not in Pxr-null mice. In vitro, hyperforin, a major component of SJW, activated PXR and suppressed tumor necrosis factor (TNF)α-induced nuclear factor (NF) κB translocation in primary intestinal organoids from PXR-humanized mice, but not Pxr-null mice. Luciferase reporter gene assays showed that hyperforin dose-dependently alleviated TNFα-induced NFκB transactivation by activating human PXR in Caco2 cells. Furthermore, SJW therapeutically attenuated DSS-induced IBD in PXR-humanized mice. These data indicate the therapeutic potential of SJW in alleviating DSS-induced IBD in vivo, and TNFα-induced NFκB activation in vitro, dependent on PXR activation, which may have clinical implications for using SJW as a herbal drug anti-IBD treatment.

Hyperforin Elicits Cytostatic/Cytotoxic Activity in Human Melanoma Cell Lines, Inhibiting Pro-Survival NF-κB, STAT3, AP1 Transcription Factors and the Expression of Functional Proteins Involved in Mitochondrial and Cytosolic Metabolism

“…We and other authors have previously reported that HPF and SJW extract had the ability to hinder NF-κB activation [ 33 , 34 , 56 , 69 , 70 ]. Many data demonstrate that NF-κB can be a specific target for counteracting melanoma progression [ 58 ].…”

Salvia miltiorrhiza Bunge (Danshen) and Bioactive Compound Tanshinone IIA Alleviates Cisplatin-Induced Acute Kidney Injury Through Regulating PXR/NF-κB Signaling

“…Although substantial PXR-activating xenobiotics have been reported to exert immunosuppressive effects ( Wallace et al, 2010 ; Kittayaruksakul et al, 2013 ; Zhang J. et al, 2015 ; Rosette et al, 2019 ), the human PXR agonist rifampin is not an ideal choice for anti-inflammation treatment due to its adverse effects. The herbal PXR activators such as St. John’s Wort and Schisandra sphenanthera (Wuweizi) have been used for a long time which may serve as a beneficial alternative medicine for inflammatory diseases ( Mu et al, 2006 ; Yan et al, 2021 ). TanIIA is a bioactive compound derived from the root of Salvia miltiorrhiza and has been demonstrated as a PXR activator in various diseases ( Yu et al, 2009 ; Zhang et al, 2015a ; Zhang et al, 2015b ; Zhu et al, 2017 ; Liu et al, 2020 ).…”

The Function of Xenobiotic Receptors in Metabolic Diseases

“…Metabolic diseases are often accompanied by systemic inflammations. It is also widely recognized that chronic inflammation plays a critical role in the initiation and progression of metabolic diseases (Baker et al, 2011) St. John's wort, a PXR agonist, can activate PXR and further inhibit tumor necrosis factor (TNF) α-induced NF-κB translocation and activation (Yan T. et al, 2021). Intestinal PXR activation exerts a protective effect in the context of inflammatory bowel disease (IBD), and this is partially due to the attenuation of NF-κB signaling that leads to lower expression of cytokines (Cheng J. et al, 2012).…”