Artemisinin protects against dextran sulfate-sodium-induced inflammatory bowel disease, which is associated with activation of the pregnane X receptor

Hu, Donghua; Wang, Yuguang; Chen, Zhiwu; You, Qing; Zhang, Xianxie; Zhou, Tao; Xiao, Yong; Liang, Qi; H, Tan; Xiao, Cheng-Rong; Tang, Xiao‐Qing; Zhang, Boli; Gao, Yue

doi:10.1016/j.ejphar.2014.04.050

Cited by 29 publications

(19 citation statements)

References 35 publications

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“…Additionally, dysregulation of PXR/Nrf2 activity in the intestine is thought to contribute to colitis pathophysiology (Khor et al, 2006;Yang et al, 2017). In the present study of DSS-induced colitis rats, PXR and Nrf2 expression were decreased in the colon, in accordance with previous studies (Hu et al, 2014;Yang et al, 2017); however, in the berberine-treated group, only the decrease in Nrf2 expression was reversed by berberine, with no effect observed on PXR expression ( Fig. 4).…”

Section: Discussionsupporting

confidence: 91%

Berberine Upregulates P-Glycoprotein in Human Caco-2 Cells and in an Experimental Model of Colitis in the Rat via Activation of Nrf2-Dependent Mechanisms

Jing

Safarpour

Zhang

et al. 2018

J Pharmacol Exp Ther

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Downregulation of P-glycoprotein (P-gp) is implicated in the pathophysiology of inflammatory bowel disease (IBD). Berberine, a principal isoquinoline alkaloid extracted from species, has been reported to exhibit therapeutic potential in IBD. In this study, we used a dextran sulfate sodium (DSS)-induced colitis rat model to evaluate the effect of berberine on P-gp and explore its mechanism of action. Berberine treatment improved DSS-induced colitis symptoms, attenuated inflammatory markers (myeloperoxidase, tumor necrosis factor-, and interleukin-1 and -6), and enhanced P-gp expression in a dose-dependent manner. Although colonic expression of the P-gp-related nuclear receptor pregnane X receptor and transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) were downregulated in the colitis model, gene and protein expression analysis revealed that berberine treatment reversed only the downregulation of Nrf2. In vitro studies using Caco-2 cells showed that the multidrug resistance 1 () gene and P-gp protein were upregulated by berberine in a dose- and time-dependent manner. Significant upregulation of the gene by berberine was abrogated by Nrf2 silencing, indicating that the Nrf2-mediated pathway was responsible for this activation. Luciferase assays showed a dose-dependent increase in Nrf2 reporter gene activity after berberine treatment in Caco-2 cells, with a significant 2-fold elevation at 2.5M berberine, suggesting that berberine is a strong Nrf2 activator. These results indicate the possible involvement of Nrf2-mediated upregulation of P-gp in the therapeutic effect of berberine on colitis and highlight the potential of P-gp and/or Nrf2 as new therapeutic targets for IBD.

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Section: Discussionsupporting

confidence: 91%

Berberine Upregulates P-Glycoprotein in Human Caco-2 Cells and in an Experimental Model of Colitis in the Rat via Activation of Nrf2-Dependent Mechanisms

Jing

Safarpour

Zhang

et al. 2018

J Pharmacol Exp Ther

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“…The first type takes advantage of a bulky substituent in the compound to physically push the AF‐2 helix away from the active state, creating an unfavorable position for coactivator recruitment . Antagonists of the second type reside in the ligand‐binding site, but they fail to provide sufficient stabilization of the AF‐2 helix in the active form, in part because of poor contact between the ligand and key residues . This passive mode of an action precludes the agonist from residing in the ligand pocket, and it may also increase the compactness of the apo NR by providing a network of interactions, thus acting as a “glue” to hold the different sections of the LBD in a condensed structure for corepressor recruitment.…”

Section: Current Status Of Pxr Antagonist Development Challenges Anmentioning

confidence: 99%

“…Several PXR agonists have been investigated as potential IBD therapeutics, including solomonsterol A, artemisinin, chrysin, isorhamnetin, and hydroxyflavone and its structurally related analogs . The tissue distribution of PXR agonists appears to be important: rifampicin failed to provide protection against IBD, possibly because it concentrates significantly in the liver, where it can lower the plasma level of anti‐inflammatory unsaturated fatty acids .…”

Section: Introductionmentioning

confidence: 99%

Strategies for developing pregnane X receptor antagonists: Implications from metabolism to cancer

Chai

Wright

Chen

2019

Medicinal Research Reviews

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Pregnane X receptor (PXR) is a ligand-activated nuclear receptor (NR) that was originally identified as a master regulator of xenobiotic detoxification. It regulates the expression of drug-metabolizing enzymes and transporters to control the degradation and excretion of endobiotics and xenobiotics, including therapeutic agents. The metabolism and disposition of drugs might compromise their efficacy and possibly cause drug toxicity and/or drug resistance. Because many drugs can promiscuously bind and activate PXR, PXR antagonists might have therapeutic value in preventing and overcoming drug-induced PXR-mediated drug toxicity and drug resistance. Furthermore, PXR is now known to have broader cellular functions, including the regulation of cell proliferation, and glucose and lipid metabolism. Thus, PXR might be involved in human diseases such as cancer and metabolic diseases. The importance of PXR antagonists is discussed in the context of the role of PXR in xenobiotic sensing and other disease-related pathways. This review focuses on the development of PXRantagonists, which has been hampered by the promiscuity of PXR ligand binding. However, substantial progress has been made in recent years, suggesting that it is feasible to develop selective PXR antagonists. We discuss the current status, challenges, and strategies in developing selective PXR antagonists. The strategies are based on the molecular mechanisms of antagonism in related NRs that can be applied to the design of PXR antagonists, primarily driven by structural information.The nuclear receptor (NR) pregnane X receptor (PXR, NR1I2) plays a prominent role in the detoxification system that humans and other organisms utilize to eliminate endobiotics such as steroid hormones, bile acids, and glucose and xenobiotics such as therapeutic agents. Upon the binding of a ligand, PXR transcriptionally upregulates the expression of drug-metabolizing enzymes and transporters, leading to the metabolism and, ultimately, clearance of endobiotics and xenobiotics. These chemicals undergo biotransformation and disposition through a series of processes comprising oxidation and conjugation reactions (involving cytochrome P450 enzymes [CYPs], such as CYP3A4, UDP-glucuronosyltransferases, and glutathione-S-transferases, sulfotransferases) and active efflux (involving the transporter proteins multidrug resistance proteins and multidrug resistance-associated proteins). [1][2][3][4] PXR and the detoxification system represent a double-edged sword: Although detoxification serves as a beneficial protection mechanism against toxic compounds, it also compromises therapeutic outcomes by decreasing drug efficacy and possibly inducing drug toxicity and resistance. Therefore, a balance between PXR transcriptional activation and repression is needed, not only to maintain appropriate physiologic levels of endogenous chemicals but also to achieve optimal therapeutic efficacy with fewer drug-induced toxicities. Because of its important role in regulating drug efficacy and drug toxicity, as wel...

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“…Solomonsterol A, isolated from the marine sponge Theonella swinhoei , is a potent PXR agonist and effectively protects humanized PXR mice from developing the clinical signs and symptoms of colitis through PXR-dependent inhibition of NF-κB activation [30]. Artemisinin, a natural compound used to treat malaria, was identified as a potential PXR agonist [31], and a recent report indicated that this drug can prevent and reduce IBD development in a mouse model of DSS-induced IBD by a mechanism associated with the transcriptional activation of PXR [32]. Chrysin, a flavonoid compound that can be extracted from many plants, can activate hPXR and mPXR in reporter gene assays and upregulate xenobiotic detoxification genes in the colon but not in the liver.…”

Section: Pxrmentioning

confidence: 99%

Small-molecule modulators of PXR and CAR

Chai

Cherian

Wang

et al. 2016

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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Two nuclear receptors, the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), participate in the xenobiotic detoxification system by regulating the expression of drug-metabolizing enzymes and transporters in order to degrade and excrete foreign chemicals or endogenous metabolites. This review aims to expand the perceived relevance of PXR and CAR beyond their established role as master xenosensors to disease-oriented areas, emphasizing their modulation by small molecules. Structural studies of these receptors have provided much-needed insight into the nature of their binding promiscuity and the important elements that lead to ligand binding. Reports of species- and isoform-selective activation highlight the need for further scrutiny when extrapolating from animal data to humans, as animal models are at the forefront of early drug discovery.

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Artemisinin protects against dextran sulfate-sodium-induced inflammatory bowel disease, which is associated with activation of the pregnane X receptor

Cited by 29 publications

References 35 publications

Berberine Upregulates P-Glycoprotein in Human Caco-2 Cells and in an Experimental Model of Colitis in the Rat via Activation of Nrf2-Dependent Mechanisms

Berberine Upregulates P-Glycoprotein in Human Caco-2 Cells and in an Experimental Model of Colitis in the Rat via Activation of Nrf2-Dependent Mechanisms

Strategies for developing pregnane X receptor antagonists: Implications from metabolism to cancer

Small-molecule modulators of PXR and CAR

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