Avermectin, a widely used deworming drug, poses a significant threat to fisheries. Silybin is recognized for its antioxidant and anti-inflammatory properties. The kidney, being crucial for fish survival, plays a vital role in maintaining ion balance, nitrogen metabolism, and hormone regulation. While residual avermectin in water could pose a risk to carp (Cyprinus carpio), it remains unclear whether silybin can alleviate the renal tissue toxicity induced by avermectin in this species. In current study, we developed a model of long-term exposure of carp to avermectin to investigate the potential protective effect of silybin against avermectin-induced nephrotoxicity. The results indicated that avermectin induced renal inflammation, oxidative stress, ferroptosis, and autophagy in carp. Silybin suppressed the mRNA transcript levels of pro-inflammatory factors, increased catalase (CAT) activity, reduced glutathione (GSH) activity, diminished reactive oxygen species (ROS) accumulation in renal tissues, and promoted the activation of the Nrf2-Keap1 signaling pathway. Furthermore, the transcript levels of ferroptosis-associated proteins, including gpx4 and slc7a11, were significantly reduced, while those of cox2, ftl, and ncoa4 were elevated. The transcript levels of autophagy-related genes, including p62 and atg5, were also regulated. Network pharmacological analysis revealed that silybin inhibited ROS accumulation and mitigated avermectin-induced renal inflammation, oxidative stress, ferroptosis, and autophagy in carp through the involvement of PPAR-γ. Silybin exerted its anti-inflammatory effect through the NF-κB pathway and antioxidant effect through the Nrf2-Keap1 pathway, induced renal cell iron efflux through the SLC7A11/GSH/GPX4, and suppressed autophagy initiation via the PI3K/AKT pathway. This study provides evidence of the protective effect of silybin against avermectin-induced nephrotoxicity in carp, highlighting its potential as a therapeutic agent to alleviate the adverse effects of avermectin exposure in fish.

中文翻译：

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水飞蓟宾通过调节 PPAR γ参与的炎症、氧化应激、铁死亡和自噬来防止阿维菌素诱导的鲤鱼 （Cyprinus carpio） 肾毒性


阿维菌素是一种广泛使用的驱虫药，对渔业构成重大威胁。水飞蓟宾因其抗氧化和抗炎特性而得到认可。肾脏对鱼类的生存至关重要，在维持离子平衡、氮代谢和激素调节方面起着至关重要的作用。虽然水中残留的阿维菌素可能对鲤鱼 （Cyprinus carpio） 构成风险，但目前尚不清楚水飞蓟宾是否能减轻阿维菌素对该物种诱导的肾组织毒性。在目前的研究中，我们开发了一个鲤鱼长期暴露于阿维菌素的模型，以研究水飞蓟宾对阿维菌素诱导的肾毒性的潜在保护作用。结果表明，阿维菌素诱导鲤鱼肾脏炎症、氧化应激、铁死亡和自噬。水飞蓟宾抑制促炎因子的 mRNA 转录水平，增加过氧化氢酶 （CAT） 活性，降低谷胱甘肽 （GSH） 活性，减少活性氧 （ROS） 在肾组织中的积累，并促进 Nrf2-Keap1 信号通路的激活。此外，铁死亡相关蛋白（包括 gpx4 和 slc7a11）的转录水平显著降低，而 cox2 、 ftl 和 ncoa4 的转录水平升高。自噬相关基因（包括 p62 和 atg5）的转录水平也受到调节。网络药理分析显示，水飞蓟宾通过参与 PPAR-γ 抑制 ROS 积累并减轻阿维菌素诱导的鲤鱼肾脏炎症、氧化应激、铁死亡和自噬。 水飞蓟宾通过 NF-κB 通路发挥抗炎作用，通过 Nrf2-Keap1 通路发挥抗氧化作用，通过 SLC7A11/GSH/GPX4 诱导肾细胞铁外流，通过 PI3K/AKT 通路抑制自噬启动。这项研究提供了水飞蓟宾对阿维菌素诱导的鲤鱼肾毒性的保护作用的证据，突出了其作为治疗剂的潜力，以减轻鱼类阿维菌素暴露的不利影响。