Activation of the farnesoid X receptor attenuates triptolide-induced liver toxicity

Jin, Jing; Sun, Xiaozhe; Zhao, Zhongxiang; Wang, Wenwen; Qiu, Yudong; Fu, Xinlu; Huang, Min; Huang, Zhiying

doi:10.1016/j.phymed.2015.06.007

Cited by 41 publications

(23 citation statements)

References 24 publications

(31 reference statements)

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“…9,82,83 Chinese herb-extracted triptolide-induced liver injury may also be alleviated by FXR agonists. 84 Furthermore, it has been noted that FXR agonists not only affect bile acid transporters and metabolism but also delay hepatic fibrogenesis and modulate immunity. 85 It has been reported that over 80 compounds have been identified as potential FXR ligands with varied degrees of affinity.…”

Section: Fxr Agonists For Treating Cholestatic Diseasesmentioning

confidence: 99%

“…To date, FXR agonists have been used in treating PBC, primary sclerosing cholangitis (PSC), alcoholic disease and NAFLD, and in preventing gallstone formation . Chinese herb‐extracted triptolide‐induced liver injury may also be alleviated by FXR agonists . Furthermore, it has been noted that FXR agonists not only affect bile acid transporters and metabolism but also delay hepatic fibrogenesis and modulate immunity …”

Section: Introductionmentioning

confidence: 99%

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Role of farnesoid X receptor in cholestasis

Yuan

2016

J of Digest Diseases

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The nuclear receptor farnesoid X receptor (FXR) plays an important role in physiological bile acid synthesis, secretion and transport. Defects of FXR regulation in these processes can cause cholestasis and subsequent pathological changes. FXR regulates the synthesis and uptake of bile acid via enzymes. It also increases bile acid solubility and elimination by promoting conjugation reactions and exports pump expression in cholestasis. The changes in bile acid transporters are involved in cholestasis, which can result from the mutations of transporter genes or acquired dysfunction of transport systems, such as inflammation-induced intrahepatic cholestasis. The modulation function of FXR in extrahepatic cholestasis is not identical to that in intrahepatic cholestasis, but the discrepancy may be reduced over time. In extrahepatic cholestasis, increasing biliary pressure can induce bile duct proliferation and bile infarcts, but the absence of FXR may ameliorate them. This review provides an update on the function of FXR in the regulation of bile acid metabolism, its role in the pathophysiological process of cholestasis and the therapeutic use of FXR agonists.

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Section: Fxr Agonists For Treating Cholestatic Diseasesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of farnesoid X receptor in cholestasis

Yuan

2016

J of Digest Diseases

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“…16 However, when used in the treatment of RA in clinical trials, TP exhibits some disadvantages, such as low solubility in water and various side effects. 17,18 It can damage the liver, spleen, circulating blood, kidney, genital systems, and bone marrow. [19][20][21][22] Delivery systems are innovative ways for administering to alleviate the disadvantages of the drug.…”

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confidence: 99%

Fabrication of novel vesicles of triptolide for antirheumatoid activity with reduced toxicity in vitro and in vivo

Zhang

Wang

et al. 2016

IJN

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Triptolide (TP) displays a strong immunosuppression function in immune-mediated diseases, especially in the treatment of rheumatoid arthritis. However, in addition to its medical and health-related functions, TP also exhibits diverse pharmacological side effects, for instance, liver and kidney toxicity and myelosuppression. In order to reduce the side effects, a nano drug carrier system (γ-PGA- l -PAE-TP [PPT]), in which TP was loaded by a poly-γ-glutamic acid-grafted l -phenylalanine ethylester copolymer, was developed. PPT was characterized by photon scattering correlation spectroscopy and transmission electron microscopy, which demonstrated that the average diameter of the drug carrier system is 98±15 nm, the polydispersity index is 0.18, the zeta potential is −35 mV, and the TP encapsulation efficiency is 48.6% with a controlled release manner. The methylthiazolyldiphenyl-tetrazolium bromide assay and flow cytometry revealed that PPT could decrease toxicity and apoptosis induced by free TP on RAW264.7 cells, respectively. The detection of reactive oxygen species showed that PPT could decrease the cellular reactive oxygen species induced by TP. Compared with the free TP-treated group, PPT improved the survival rate of the mice ( P <0.01) and had no side effects or toxic effects on the thymus index ( P >0.05) and spleen index ( P >0.05). The blood biochemical indexes revealed that PPT did not cause much damage to the kidney (blood urea nitrogen and creatinine), liver (serum alanine aminotransferase and aspartate aminotransferase), or blood cells ( P >0.05). Meanwhile, hematoxylin and eosin staining and terminal-deoxynucleotidyl transferase dUTP nick-end labeling staining indicated that PPT reduced the damage of free TP on the liver, kidney, and spleen. Our results demonstrated that PPT reduced free TP toxicity in vitro and in vivo and that it is a promising fundamental drug delivery system for rheumatoid arthritis treatment.

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“…Many efforts have been done to detoxify the toxicity of TP. Studies reported that Farnesoid X receptor (FXR) and Nrf2 pathway played a significant role in protecting against TP‐induced toxicity (Jin et al, ; Li et al, ; Li et al, ). Some compounds including quercetin, isoliquiritigenin and GA were discovered to provide protection against TP‐induced toxicity through its antioxidant properties (Hu et al, ; Cao et al, ).…”

Section: Discussionmentioning

confidence: 99%

Glycyrrhetinic Acid Accelerates the Clearance of Triptolide through P‐gp In Vitro

Yan

Cao

et al. 2017

Phytotherapy Research

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Triptolide (TP) is an active ingredient isolated from Tripterygium wilfordii Hook. f. (TWHF), which is a traditional herbal medicine widely used for the treatment of rheumatoid arthritis and autoimmune disease in the clinic. However, its adverse reactions of hepatotoxicity and nephrotoxicity have been frequently reported which limited its clinical application. The aim of this study was to investigate the mechanism of glycyrrhetinic acid (GA) effecting on the elimination of TP in HK-2 cells and the role of the efflux transporters of P-gp and multidrug resistance-associated proteins (MRPs) in this process. An ultra performance liquid chromatography-electrospray ionization-mass spectrometry (UPLC-ESI-MS) analytical method was established to determine the intracellular concentration of TP. In order to study the role of efflux transporters of P-gp and MRPs in GA impacting on the accumulation of TP, the inhibitors of efflux transporters (P-gp: verapamil; MRPs: MK571) were used in this study. The results showed that GA could enhance the elimination of TP and reduce the TP accumulation in HK-2 cells. Verapamil and MK571 could increase the intracellular concentration of TP; in addition, GA co-incubation with verapamil significantly increased the TP cellular concentration compared with the control group. In conclusion, GA could reduce the accumulation of TP in HK-2 cells, which was related to P-gp. This is probably one of the mechanisms that TP combined with GA to detoxify its toxicity. Copyright © 2017 John Wiley & Sons, Ltd.

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Activation of the farnesoid X receptor attenuates triptolide-induced liver toxicity

Cited by 41 publications

References 24 publications

Role of farnesoid X receptor in cholestasis

Role of farnesoid X receptor in cholestasis

Fabrication of novel vesicles of triptolide for antirheumatoid activity with reduced toxicity in vitro and in vivo

Glycyrrhetinic Acid Accelerates the Clearance of Triptolide through P‐gp In Vitro

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