Toxicity of triptolide and the molecular mechanisms involved

Chen, Xi; Peng, Shaojun; Wu, Zhengping; Zhou, Qingping; Zhou, Jie

doi:10.1016/j.biopha.2017.04.003

Cited by 195 publications

(118 citation statements)

References 90 publications

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“…However, its increasing use has led to more adverse reaction events, including drug‐induced liver disease, renal insufficiency, digestive system bleeding and myelosuppression, which have been observed successively. Among these, liver injury is a most common adverse event and has caused serious concerns (Li et al, ; Mei, Li, Wu, Hu, & Yang, ; Xi, Peng, Wu, Zhou, & Zhou, ).…”

Section: Introductionmentioning

confidence: 99%

High‐content analysis boosts identification of the initial cause of triptolide‐induced hepatotoxicity

Zheng¹,

Wang

Wei³

et al. 2019

J of Applied Toxicology

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Triptolide (TP) has been widely used in China for more than 40 years as an immunosuppressive agent. Recently, serious concerns have been raised over TP-induced liver injury, though the real hepatotoxic mechanism is still unclear, particularly in terms of the initial cause. To our knowledge, this study is the first to screen systematically the mechanism of TP-induced toxicity through a global cytotoxicity profile high-content analysis using three independent cytotoxic assay panels with multiple endpoints of cytotoxicity, including cell loss, mitochondrial membrane potential, nuclear membrane permeability, manganese superoxide dismutase, phosphorylated gamma-H2AX, light chain 3B, lysosome, reactive oxygen species and glutathione. We assessed nine parameters and four stress response pathway models by labeling nuclear factor erythroid 2-related factor 2, activating transcription factor 6, hypoxia inducible factor 1α and nuclear factor κB and found that all testing parameters except glutathione and manganese superoxide dismutase showed concentration-and time-dependent changes, as well as increased cell loss after TP treatment. Considering that RNA polymerase II is the molecular target of TP, we quantified transcription from inducible genes, bromodeoxyuridine incorporation, and expression from transiently transfected green fluorescence protein plasmids in HepG2 cells. The results show that inhibition of global transcription by TP took place at earlier times and at lower concentrations than those observed for cell death.Therefore, global transcriptional suppression and the cell dysfunction it drives play a central role in TP-induced hepatotoxicity. This provides valuable information for the safe use of TP in the clinic. KEYWORDShigh-content analysis, liver injury, RNAPII, TP-induced hepatotoxicity, triptolide

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Section: Introductionmentioning

confidence: 99%

High‐content analysis boosts identification of the initial cause of triptolide‐induced hepatotoxicity

Zheng¹,

Wang

Wei³

et al. 2019

J of Applied Toxicology

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“…However, due to the reported risk of toxic action on such organs as the liver, kidney, spleen, gastrointestinal tract or heart [27], application of TWH raises the question on the safety of its use in CD treatment. As toxicity was related to medication course, combined intervention, and drug dosage, the importance of follow-up animal experiments should be emphasized.…”

Section: Discussionmentioning

confidence: 99%

A network pharmacology study on the Tripteryguim wilfordii Hook for treatment of Crohn’s disease

Zhang

Huang

Zhao

et al. 2020

BMC Complement Med Ther

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Background: To explore the mechanism of action of Tripterygium wilfordii Hook (TWH) in the treatment of Crohn's disease (CD) by network pharmacology. Methods: Traditional Chinese Medicine Systems Pharmacology database and analysis platform (TCMSP) was used to obtain the active constituents and targets of TWH. "Crohn's disease" was used as a search term to search for related targets of CD from GeneCards database and OMIM database, thereby obtaining the targets of TWH against CD. The Cytoscape 3.7.1 software was used to construct a Chinese medicine compound-target network and STRING database to construct a protein-protein interaction network (PPI). The DAVID 6.8 online tool was used to perform gene ontology (GO) and kyoto encyclopedia of genes and genome (KEGG) pathway enrichment analysis of overlapping targets. Results: The database results showed that there were 30 active ingredients (14 key active ingredients) in TWH and 36 targets were screened out for CD treatment. Network analysis indicated that main targets of main active components of TWH were target genes such as VEGFA, MAPK8 and CASP3, which are involved in the regulation of cancer pathway, TNF signal pathway, hepatitis B pathway, apoptosis pathway, NF-kappa B signal pathway and so forth. Conclusions: TWH can play a multi-target and multi-channel synergistic treatment of CD by anti-angiogenesis, antiapoptosis, anti-inflammation and immune regulation.

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“…Recently, TPL was reported to have a potent anti-depressive function by its in uences on hippocampal neuroin ammation in a rat model of depression comorbidity of chronic pain [2]. However, clinical reports showed that TPL exposure resulted in the injury of some organs, including liver, kidney, heart, testes, and ovary in humans [9][10][11]. Severe hepatotoxicity was also shown after TPL exposure in animals [9,12,13].…”

Section: Introductionmentioning

confidence: 99%

Intravenous administration of triptonide attenuates CFA-induced pain hypersensitivity through inhibiting AKT signaling pathway in mice

Ling

Ding

Gao

et al. 2020

Preprint

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Background: Triptonide (TPN) is a major component of Tripterygium wilfordii Hook.f., and reportedly has anti-inflammatory and neuroprotective effects. Recent studies have demonstrated that the phosphatidylinositol 3-kinase (PI3K)/AKT pathway plays an important role in the pathogenesis of inflammatory pain. Here we investigated the anti-nociceptive effect of systemic treatment with TPN on mouse models of chronic inflammatory pain and explored possible mechanisms. Results: Unilateral hind paw injection of complete Freund’s adjuvant (CFA) induced paw edema and persistent pain hypersensitivity. Intravenous treatment with TPN attenuated CFA-induced paw edema, mechanical allodynia, and thermal hyperalgesia. Western blotting and immunofluorescence results showed that CFA induced AKT activation in the dorsal root ganglion (DRG) neurons, which was inhibited by TPN treatment. Furthermore, TPN treatment inhibited mRNA increase of proinflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin 1 beta (IL-1β), and Interleukin 6 (IL-6)] induced by CFA. Finally, pretreatment with AKT inhibitor, AKT inhibitor Ⅳ, attenuated CFA-induced mechanical allodynia and thermal hyperalgesia, and decreased the mRNA expression of pro-inflammatory cytokines. Conclusions: These data indicate that TPN attenuates CFA-induced pain potentially via inhibiting AKT-mediated pro-inflammatory cytokines production in DRG. TPN may be used for the treatment of chronic inflammatory pain.

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Toxicity of triptolide and the molecular mechanisms involved

Cited by 195 publications

References 90 publications

High‐content analysis boosts identification of the initial cause of triptolide‐induced hepatotoxicity

High‐content analysis boosts identification of the initial cause of triptolide‐induced hepatotoxicity

A network pharmacology study on the Tripteryguim wilfordii Hook for treatment of Crohn’s disease

Intravenous administration of triptonide attenuates CFA-induced pain hypersensitivity through inhibiting AKT signaling pathway in mice

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