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Ageratina adenophora induces mice hepatotoxicity via ROS-NLRP3-mediated pyroptosis.

ABSTRACT: Increasing evidences have demonstrated that Ageratina adenophora (A. adenophora) can cause hepatotoxicity of animals. Liver is an important site in immune regulation and inflammatory responses. However, the information about hepatotoxicity induced by A. adenophora in relation to inflammation is still finite. To investigate the underlying mechanism, we conducted animal experiments with different dosage of A. adenophora. Mice were randomly divided into 4 groups and administrated with 0%, 10%, 20% and 30% levels of A. adenophora pallet diet in control, group A, B and C, respectively. The results showed that A. adenophora caused hepatotoxicity as revealed by increasing alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase. Then, the reactive oxygen species (ROS) levels were shown to be elicited by A. adenophora through flow cytometry assay in a dose-dependent manner. Furthermore, pyroptosis was activated by A. adenophora, which was characterized by increasing protein and mRNA levels of caspase-1, gasdermin D and interleukin-1?. Notably, ROS down-stream factors, including nod-like receptor inflammasome protein 3 and nuclear factor-?B, were also activated by A. adenophora. These data demonstrated that A. adenophora caused liver inflammatory injury and induced hepatocyte pyroptosis by activating NLRP3 inflammasome, which was triggered by elevating ROS production levels. This research might provide new insights into the mechanism of hepatotoxicity induced by A. adenophora.

SUBMITTER: Sun W

PROVIDER: S-EPMC6207671 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Ageratina adenophora induces mice hepatotoxicity via ROS-NLRP3-mediated pyroptosis.

Sun Wei W Zeng Chaorong C Liu Shanshan S Fu Jie J Hu Liwen L Shi Zhen Z Yue Dong D Ren Zhihua Z Zhong Zhijun Z Zuo Zhicai Z Cao Suizhong S Peng Guangneng G Deng Junliang J Hu Yanchun Y

Scientific reports 20181030 1

Increasing evidences have demonstrated that Ageratina adenophora (A. adenophora) can cause hepatotoxicity of animals. Liver is an important site in immune regulation and inflammatory responses. However, the information about hepatotoxicity induced by A. adenophora in relation to inflammation is still finite. To investigate the underlying mechanism, we conducted animal experiments with different dosage of A. adenophora. Mice were randomly divided into 4 groups and administrated with 0%, 10%, 20% ...[more]

PMID: 30375483

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Project description:Trillium tschonoskii Maxim (TTM), a traditional Chinese medicine, has been demonstrated to have a potent anti-tumor effect. Recently, polyphyllin VI (PPVI), a main saponin isolated from TTM, was reported by us to significantly suppress the proliferation of non-small cell lung cancer (NSCLC) via the induction of apoptosis and autophagy in vitro and in vivo. In this study, we further found that the NLRP3 inflammasome was activated in PPVI administrated A549-bearing athymic nude mice. As is known to us, pyroptosis is an inflammatory form of caspase-1-dependent programmed cell death that plays an important role in cancer. By using A549 and H1299 cells, the in vitro effect and action mechanism by which PPVI induces activation of the NLRP3 inflammasome in NSCLC were investigated. The anti-proliferative effect of PPVI in A549 and H1299 cells was firstly measured and validated by MTT assay. The activation of the NLRP3 inflammasome was detected by using Hoechst33324/PI staining, flow cytometry analysis and real-time live cell imaging methods. We found that PPVI significantly increased the percentage of cells with PI signal in A549 and H1299, and the dynamic change in cell morphology and the process of cell death of A549 cells indicated that PPVI induced an apoptosis-to-pyroptosis switch, and, ultimately, lytic cell death. In addition, belnacasan (VX-765), an inhibitor of caspase-1, could remarkably decrease the pyroptotic cell death of PPVI-treated A549 and H1299 cells. Moreover, by detecting the expression of NLRP3, ASC, caspase-1, IL-1?, IL-18 and GSDMD in A549 and h1299 cells using Western blotting, immunofluorescence imaging and flow cytometric analysis, measuring the caspase-1 activity using colorimetric assay, and quantifying the cytokines level of IL-1? and IL-18 using ELISA, the NLRP3 inflammasome was found to be activated in a dose manner, while VX-765 and necrosulfonamide (NSA), an inhibitor of GSDMD, could inhibit PPVI-induced activation of the NLRP3 inflammasome. Furthermore, the mechanism study found that PPVI could activate the NF-?B signaling pathway via increasing reactive oxygen species (ROS) levels in A549 and H1299 cells, and N-acetyl-L-cysteine (NAC), a scavenger of ROS, remarkably inhibited the cell death, and the activation of NF-?B and the NLRP3 inflammasome in PPVI-treated A549 and H1299 cells. Taken together, these data suggested that PPVI-induced, caspase-1-mediated pyroptosis via the induction of the ROS/NF-?B/NLRP3/GSDMD signal axis in NSCLC, which further clarified the mechanism of PPVI in the inhibition of NSCLC, and thereby provided a possibility for PPVI to serve as a novel therapeutic agent for NSCLC in the future.

Dataset Information

Ageratina adenophora induces mice hepatotoxicity via ROS-NLRP3-mediated pyroptosis.

Publications

Ageratina adenophora induces mice hepatotoxicity via ROS-NLRP3-mediated pyroptosis.

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