Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China.
Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; Department of Pharmaceutical Sciences, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
Ecotoxicol Environ Saf. 2023 Nov 15;267:115664. doi: 10.1016/j.ecoenv.2023.115664. Epub 2023 Nov 8.
Ageratina adenophora (A. adenophora), one of the prominent invasive plants in the Asian continent has shown toxicity in animals. However, studies examining the gene expression and metabolic profiles of animals that ingest A. adenophora have not yet been reported in the literature. Therefore, considering the wide distribution of A. adenophora, it is necessary to elucidate the toxic mechanisms of A. adenophora via multiomics approach. In this study, we identified and evaluated the toxic mechanisms of action associated with bioactive compounds in A. adenophora by using network toxicology studies combined with metabolomics and transcriptomics and found that 2-deoxo-2-(acetyloxy)- 9-oxoageraphorone, 10Hβ-9-oxo-agerophorone, 10Hα-9-oxo-agerophorone, nerolidol, 9-oxo-10,11-dehydro-agerophorone were the main active toxic compounds in A. adenophora. In addition, using metabolomics approach we identified differential metabolites such as L-pyroglutamic acid, 1-methylhistidine, prostaglandin F2alpha and hydrocortisone from A. adenophora and these metabolites were involved in amino acid metabolism, lipid metabolism and signal conducting media regulation. Based on network toxicological analysis, we observed that, A. adenophora can affect the Ras signaling, Phospholipase D signaling and MAPK signaling pathways by regulating EGFR, PDGFRB, KIT and other targets. From the results of this study we concluded that A. adenophora induces liver inflammatory damage by activating the EGFR expression and Ras/Raf/MEK/ERK signaling pathways as well as affect nutrients metabolism and neuron conduction.
紫茎泽兰（A. adenophora）是亚洲大陆主要的入侵植物之一，已被证明对动物具有毒性。然而，目前尚未有文献报道研究动物摄入紫茎泽兰后的基因表达和代谢谱。因此，考虑到紫茎泽兰的广泛分布，有必要通过多组学方法阐明其毒性机制。在这项研究中，我们通过网络毒理学研究结合代谢组学和转录组学，鉴定和评估了与紫茎泽兰生物活性化合物相关的毒性作用机制，并发现 2-脱氧-2-（乙酰氧基）-9-氧代泽兰酮、10Hβ-9-氧代泽兰酮、10Hα-9-氧代泽兰酮、橙花叔醇、9-氧代-10,11-脱氢泽兰酮是紫茎泽兰中的主要活性有毒化合物。此外，通过代谢组学方法，我们从紫茎泽兰中鉴定出了差异代谢物，如 L-焦谷氨酸、1-甲基组氨酸、前列腺素 F2α和氢化可的松，这些代谢物参与了氨基酸代谢、脂质代谢和信号传导介质的调节。基于网络毒理学分析，我们观察到紫茎泽兰通过调节 EGFR、PDGFRB、KIT 等靶点，影响 Ras 信号、磷脂酶 D 信号和 MAPK 信号通路。本研究结果表明，紫茎泽兰通过激活 EGFR 表达和 Ras/Raf/MEK/ERK 信号通路，影响营养物质代谢和神经元传导，导致肝脏炎症损伤。
