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.

中文翻译：

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在斑马鱼模型筛选中揭示针对玉米赤霉烯酮诱导毒性的高效天然霉菌毒素解毒剂


玉米赤霉烯酮 （ZEA） 是一种霉菌毒素，对人类和动物健康构成重大的全球危害。天然产物 （NPs） 由于其多种功能活性，已显示出减轻 ZEA 不利影响的前景。然而，目前的挑战在于缺乏一种有效的策略来系统筛选和鉴定 NPs，可以有效防止 ZEA 诱导的毒性。本研究描述了一种基于表型的筛选策略，用于筛选 NP 文库并发现更有效的化合物来减轻或抵消动物 ZEA 暴露的不良后果。使用这种策略，我们最初确定了 96 个 NPs，并使用评分系统和 TCMacro 方法根据胚胎表型和运动活动评估了两种有效的候选化合物 fraxetin 和羟基酪醇的效力和功效。此外，我们进行了转录组和蛋白质-蛋白质相互作用 （PPI） 网络分析，以提取两个 mRNA 特征以查询连接图 （CMap） 数据库并预测 NPs。预测的 NPs 显示出逆转与 ZEA 毒性相关的基因表达谱的潜力。因此，我们使用我们的模型进一步筛选了这些化合物，这表明 hispidin、daphnetin 和 riboflavin 在斑马鱼中表现出有希望的体内疗效。值得注意的是，在整个过程中，fraxetin 始终脱颖而出，成为最有前途的 NP。生物途径分析和功能验证表明，fraxetin 在极低剂量下完全逆转了 ZEA 的毒性作用。这是通过修复受损细胞凋亡、改变细胞周期途径和防止衰老诱导来实现的，显示出良好的应用潜力。 总体而言，我们证明了这种整合策略可以成功应用于有效发现潜在的解毒剂。