斑马鱼模型筛选揭示高效天然霉菌毒素解毒剂——缓解玉米赤霉烯酮诱导的毒性

张鸿运, 姜维丹, 吴培, 刘杨, 任红梅, 金小婉, 周小秋, 冯琳

工程（英文） ›› 2024, Vol. 42 ›› Issue (11) : 196-212.

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工程（英文） ›› 2024, Vol. 42 ›› Issue (11) : 196-212. DOI: 10.1016/j.eng.2024.03.016
研究论文
Article

斑马鱼模型筛选揭示高效天然霉菌毒素解毒剂——缓解玉米赤霉烯酮诱导的毒性

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Revealing High-Efficiency Natural Mycotoxin Antidotes in Zebrafish Model Screening Against Zearalenone-Induced Toxicity

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摘要

玉米赤霉烯酮（ZEA）是一种霉菌毒素，对全球人类和动物的健康构成了严重的危害。天然产物（NPs）由于其多样化的生物活性而被认为可以缓解ZEA的不利影响。然而，目前的挑战在于缺乏一种有效的策略来系统地筛选和鉴定能够有效缓解ZEA诱导毒性的NPs。本研究构建了一种基于表型的筛选策略，用于筛选NPs文库，并发现更有效的化合物来减轻或抵消ZEA在动物体内暴露后的不良后果。利用这一策略，初步鉴定了96种NPs，并基于胚胎表型和运动活性，使用评分系统和TCMacro方法评估了两种有效的候选化合物——秦皮素和羟基酪醇的效价和功效。此外，本研究进行了转录组和蛋白质-蛋白质相互作用（PPI）网络分析，提取了两组mRNA标签，以查询连接图谱数据库（CMap）并预测NPs。预测的NPs显示出了能逆转与ZEA毒性相关的基因表达谱的潜力。因此，使用斑马鱼模型进一步筛选这些化合物，结果表明牛奶树碱、瑞香素和核黄素在斑马鱼中表现出良好的体内功效。值得注意的是，在整个研究过程中，秦皮素一直表现出较好的效果。生物学途径分析和功能验证表明，极低剂量的秦皮素完全逆转了ZEA的毒性作用。这是通过修复受损细胞凋亡、改变细胞周期通路和防止衰老诱导来实现的，具有良好的应用潜力。总的来说，本研究证明了这种整合策略可以成功地应用于开发潜在的解毒剂。

Abstract

Zearalenone (ZEA), a mycotoxin, poses a significant global hazard to human and animal health. Natural products (NPs) have shown promise for mitigating the adverse effects of ZEA owing to their diverse functional activities. However, the current challenge lies in the absence of an efficient strategy for systematic screening and identification of NPs that can effectively protect against ZEA-induced toxicity. This study describes a phenotype-based screening strategy for screening NP libraries and discovering more effective compounds to mitigate or counteract the adverse consequences of ZEA exposure in animals. Using this strategy, we initially identified 96 NPs and evaluated the potency and efficacy of two effective candidate compounds, fraxetin, and hydroxytyrosol, based on embryonic phenotype and locomotor activity using a scoring system and the TCMacro method. Furthermore, we performed transcriptome and protein−protein interaction (PPI) network analyses to extract two mRNA signatures to query the Connectivity Map (CMap) database and predict NPs. The predicted NPs showed the potential to reverse the gene expression profiles associated with ZEA toxicity. Consequently, we further screened these compounds using our model, which indicated that hispidin, daphnetin, and riboflavin exhibit promising in vivo efficacy in zebrafish. Notably, throughout the process, fraxetin consistently stood out as the most promising NP. Biological pathway analysis and functional verification revealed that fraxetin completely reversed the toxic effects of ZEA at very low doses. This was achieved by repairing damaged cell apoptosis, modifying the cell cycle pathway, and preventing senescence induction, indicating good application potential. Overall, we demonstrated that this integration strategy can be successfully applied to effectively discover potential antidotes.

关键词

玉米赤霉烯酮 / 天然产物 / 表型筛选 / 转录组分析 / 秦皮素

Keywords

Zearalenone / Natural products / Phenotype-based screening / Transcriptome analysis / Fraxetin

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张鸿运, 姜维丹, 吴培. 斑马鱼模型筛选揭示高效天然霉菌毒素解毒剂——缓解玉米赤霉烯酮诱导的毒性. Engineering. 2024, 42(11): 196-212 https://doi.org/10.1016/j.eng.2024.03.016

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