The role of inflammasome activation in Triptolide-induced acute liver toxicity

Yuan, Ziqiao; Hasnat, Muhammad; Liang, Peishi; Yuan, Zihang; Zhang, Haoran; Sun, Lixin; Zhang, Luyong; Jiang, Zhenzhou

doi:10.1016/j.intimp.2019.105754

Cited by 35 publications

(19 citation statements)

References 54 publications

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“…And caspase-1 inhibitor (Ac-Yvad-Cmk) pretreatment effectively decreased the recruitment of neutrophils and inhibited the production of massive pro-inflammatory factors (IL-1β, TNF-α, IL-6, and MCP1; Yuan et al, 2019). Those findings suggested that triptolide induced hepatotoxicity mainly through the proinflammatory effects mediated by NLRP3 inflammasome.…”

Section: Triptolide-induced Liver Injurymentioning

confidence: 87%

“…Mice treated with a single dose of triptolide (600 µg/kg) displayed liver injury with a time-dependent activation of NLRP3 inflammasome, accompanied by the increase of serum transaminases and elevation of neutrophils infiltration. The activation of TLR4-Myd88-NF-κB pathway and oxidative stress induced by triptolide might be responsible for the activation of NLRP3 inflammasome (Yuan et al, 2019).…”

Section: Triptolide-induced Liver Injurymentioning

confidence: 99%

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NLRP3 Inflammasome: A Promising Therapeutic Target for Drug-Induced Toxicity

Wei

Zhang

et al. 2021

Front. Cell Dev. Biol.

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Drug-induced toxicity, which impairs human organ function, is a serious problem during drug development that hinders the clinical use of many marketed drugs, and the underlying mechanisms are complicated. As a sensor of infections and external stimuli, nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays a key role in the pathological process of various diseases. In this review, we specifically focused on the role of NLRP3 inflammasome in drug-induced diverse organ toxicities, especially the hepatotoxicity, nephrotoxicity, and cardiotoxicity. NLRP3 inflammasome is involved in the initiation and deterioration of drug-induced toxicity through multiple signaling pathways. Therapeutic strategies via inhibiting NLRP3 inflammasome for drug-induced toxicity have made significant progress, especially in the protective effects of the phytochemicals. Growing evidence collected in this review indicates that NLRP3 is a promising therapeutic target for drug-induced toxicity.

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Section: Triptolide-induced Liver Injurymentioning

confidence: 87%

Section: Triptolide-induced Liver Injurymentioning

confidence: 99%

NLRP3 Inflammasome: A Promising Therapeutic Target for Drug-Induced Toxicity

Wei

Zhang

et al. 2021

Front. Cell Dev. Biol.

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“…In addition, Fu et al [88] indicated that triptolide administration induced liver injury accompanied by microcystic steatosis, hyperlactatemia and increased oxidative stress, resulting from the inhibition of mitochondrial respiratory chain and secondary β-oxidative damage. Furthermore, Yuan et al [89] suggested oxidative stress induced by triptolide might be related to the activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome, which can result in the release of cytokines and recruitment of the inflammatory cells, and further augment the liver damage. Besides, Wang et al [90] showed that 0.5 mg/kg of triptolide enhanced the expansion of Th17 cells and suppressed the production of Tregs in female C57BL/6 mice, which may represent a new pathogenesis of TPinduced liver injury.…”

Section: Hepatotoxicitymentioning

confidence: 99%

Therapeutic potential of triptolide in autoimmune diseases and strategies to reduce its toxicity

2021

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With the increasing epidemiology of autoimmune disease worldwide, there is an urgent need for effective drugs with low cost in clinical treatment. Triptolide, the most potent bioactive compound from traditional Chinese herb Tripterygium Wilfordii Hook F, possesses immunosuppression and anti-inflammatory activity. It is a potential drug for the treatment of various autoimmune diseases, but its clinical application is still restricted due to severe toxicity. In this review, the pharmacodynamic effects and pharmacological mechanisms of triptolide in autoimmune diseases are summarized. Triptolide exerts therapeutic effect by regulating the function of immune cells and the expression of cytokines through inflammatory signaling pathways, as well as maintaining redox balance and gut microbiota homeostasis. Meanwhile, the research progress on toxicity of triptolide to liver, kidney, reproductive system, heart, spleen, lung and gastrointestinal tract has been systematically reviewed. In vivo experiments on different animals and clinical trials demonstrate the dose- and time- dependent toxicity of triptolide through different administration routes. Furthermore, we focus on the strategies to reduce toxicity of triptolide, including chemical structural modification, novel drug delivery systems, and combination pharmacotherapy. This review aims to reveal the potential therapeutic prospect and limitations of triptolide in treating autoimmune diseases, thus providing guiding suggestions for further study and promoting its clinical translation.

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“…However, abnormal accumulation of neutrophils can lead to unexpected injury to host organs including DILI. Recently, more studies have defined that neutrophil activation commonly causes DILI, in which mitochondrial DNA originates from injured hepatocytes that could further activate neutrophils (You et al, 2006;Moles et al, 2014;Williams et al, 2014;Yuan et al, 2019). Liver injury increased expressions of chemokines, cytokines, and other immune molecules that could regulate neutrophil recruitment and activation, which cause cytotoxicity and hepatocyte death (Ramaiah and Jaeschke, 2007).…”

Section: Neutrophilsmentioning

confidence: 99%

The Immunological Mechanisms and Immune-Based Biomarkers of Drug-Induced Liver Injury

et al. 2021

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Drug-induced liver injury (DILI) has become one of the major challenges of drug safety all over the word. So far, about 1,100 commonly used drugs including the medications used regularly, herbal and/or dietary supplements, have been reported to induce liver injury. Moreover, DILI is the main cause of the interruption of new drugs development and drugs withdrawn from the pharmaceutical market. Acute DILI may evolve into chronic DILI or even worse, commonly lead to life-threatening acute liver failure in Western countries. It is generally considered to have a close relationship to genetic factors, environmental risk factors, and host immunity, through the drug itself or its metabolites, leading to a series of cellular events, such as haptenization and immune response activation. Despite many researches on DILI, the specific biomarkers about it are not applicable to clinical diagnosis, which still relies on the exclusion of other causes of liver disease in clinical practice as before. Additionally, circumstantial evidence has suggested that DILI is mediated by the immune system. Here, we review the underlying mechanisms of the immune response to DILI and provide guidance for the future development of biomarkers for the early detection, prediction, and diagnosis of DILI.

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The role of inflammasome activation in Triptolide-induced acute liver toxicity

Cited by 35 publications

References 54 publications

NLRP3 Inflammasome: A Promising Therapeutic Target for Drug-Induced Toxicity

NLRP3 Inflammasome: A Promising Therapeutic Target for Drug-Induced Toxicity

Therapeutic potential of triptolide in autoimmune diseases and strategies to reduce its toxicity

The Immunological Mechanisms and Immune-Based Biomarkers of Drug-Induced Liver Injury

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