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Intermedine (Im) and lycopsamine (La) are two monoesters of PAs that frequently coexist in the PA-containing plants (e.g., comfrey and tea). The present study aimed to explore the combined hepatotoxicity and toxicity mechanism of the Im and La mixture. In vitro, the combined cytotoxicity of the Im and La mixture on human hepatocytes (HepD) was examined by CCK-8, colony formation, wound healing, and Annexin V\/PI staining assays. The combination of Im and La inhibited the ability of HepD cells to proliferate, colonize, and migrate and induced hepatocytes apoptosis in a dose-dependent manner. In addition to significantly causing a burst of intracellular reactive oxygen species (ROS), mitochondrial apoptosis, and endoplasmic reticulum (ER) stress, the Im and La mixture can also cause an increase in intracellular Ca2+, triggering the PERK\/eIF2\u03b1\/ATF4\/CHOP apoptosis pathway. This study provided the first direct evidence that the combined PAs induced hepatotoxicity through ER-mediated apoptosis. These results supplemented the basic toxicity data for the combined PAs and provided a new perspective for the risk assessment of combined PA toxicity.<\/jats:p>","DOI":"10.3390\/toxins14090633","type":"journal-article","created":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T22:37:28Z","timestamp":1663108648000},"page":"633","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Combined Hepatotoxicity and Toxicity Mechanism of Intermedine and Lycopsamine"],"prefix":"10.3390","volume":"14","author":[{"given":"Ziqi","family":"Wang","sequence":"first","affiliation":[{"name":"Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China"},{"name":"College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Qiao","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinqin","family":"Zheng","sequence":"additional","affiliation":[{"name":"Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China"},{"name":"Key Laboratory of Tea Quality and Safety & Risk Assessment, Ministry of Agriculture, Hangzhou 310008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haolei","family":"Han","sequence":"additional","affiliation":[{"name":"Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China"},{"name":"Key Laboratory of Tea Quality and Safety & Risk Assessment, Ministry of Agriculture, Hangzhou 310008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuguang","family":"Li","sequence":"additional","affiliation":[{"name":"College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9292-3563","authenticated-orcid":false,"given":"Xiangchun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China"},{"name":"Key Laboratory of Tea Quality and Safety & Risk Assessment, Ministry of Agriculture, Hangzhou 310008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongping","family":"Chen","sequence":"additional","affiliation":[{"name":"Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China"},{"name":"Key Laboratory of Tea Quality and Safety & Risk Assessment, Ministry of Agriculture, Hangzhou 310008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kwon, Y., Koo, Y., and Jeong, Y. 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