Metabolic characteristics of evodiamine were associated with its hepatotoxicity via PPAR/PI3K/AKT/NF-кB/tight junction pathway-mediated apoptosis in zebrafish.

Autor: Fan Q; Beijing University of Chinese Medicine, Beijing 100102,China; Beijing Key laboratory for Quality Evaluation of Chinese Materia Medica, Beijing 100102, China., Liang R; National Institutes for Food and Drug Control, Beijing 100050, China., Chen M; Beijing University of Chinese Medicine, Beijing 100102,China; Beijing Key laboratory for Quality Evaluation of Chinese Materia Medica, Beijing 100102, China., Li Z; Beijing University of Chinese Medicine, Beijing 100102,China; Beijing Key laboratory for Quality Evaluation of Chinese Materia Medica, Beijing 100102, China., Tao X; Beijing University of Chinese Medicine, Beijing 100102,China; Beijing Key laboratory for Quality Evaluation of Chinese Materia Medica, Beijing 100102, China., Ren H; Beijing University of Chinese Medicine, Beijing 100102,China; Beijing Key laboratory for Quality Evaluation of Chinese Materia Medica, Beijing 100102, China., Sheng Y; Beijing University of Chinese Medicine, Beijing 100102,China., Li J; Beijing University of Chinese Medicine, Beijing 100102,China; Beijing Key laboratory for Quality Evaluation of Chinese Materia Medica, Beijing 100102, China., Lin R; Beijing University of Chinese Medicine, Beijing 100102,China; Beijing Key laboratory for Quality Evaluation of Chinese Materia Medica, Beijing 100102, China. Electronic address: linrch307@sina.com., Zhao C; Beijing University of Chinese Medicine, Beijing 100102,China; Beijing Key laboratory for Quality Evaluation of Chinese Materia Medica, Beijing 100102, China. Electronic address: 1014256537@qq.com., She G; Beijing University of Chinese Medicine, Beijing 100102,China. Electronic address: shegaimei@126.com.
Jazyk: angličtina
Zdroj: Ecotoxicology and environmental safety [Ecotoxicol Environ Saf] 2024 Jul 01; Vol. 279, pp. 116448. Date of Electronic Publication: 2024 May 15.
DOI: 10.1016/j.ecoenv.2024.116448
Abstrakt: Evodiae Fructus (EF), an herbal medicine, possesses remarkable anti-inflammatory and analgesic properties. It exhibits insecticidal activity as a potent insecticide candidate. However, the toxic characteristics of EF and the underlying mechanisms have not been comprehensively elucidated comprehensively. Thus, we comprehensively explored the toxic components of EF and established the relationship between the therapeutic and toxic effects of EF, encouraging its therapeutic use. We found that evodiamine (EVO), one of the main ingredients of EF, can truly reflect its analgesic properties. In phenotype observation trials, low doses of EVO (< 35 ng/mL) exhibited distinct analgesic activity without any adverse effects in zebrafish. However, EVO dose-dependently led to gross morphological abnormalities in the liver, followed by pericardial edema, and increased myocardial concentrations. Furthermore, the toxic effects of EVO decreased after processing in liver microsomes but increased after administering CYP450 inhibitors in zebrafish, highlighting the prominent effect of CYP450s in EVO-mediated hepatotoxicity. EVO significantly changed the expression of genes enriched in multiple pathways and biological processes, including lipid metabolism, inflammatory response, tight junction damage, and cell apoptosis. Importantly, the PPAR/PI3K/AKT/NF-кB/tight junction-mediated apoptosis pathway was confirmed as a critical functional signaling pathway inducing EVO-mediated hepatotoxicity. This study provided a typical example of the overall systematic evaluation of traditional Chinese medicine (TCM) and its active ingredients with significant therapeutic effects and simultaneous toxicities, especially metabolic toxicities.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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