Metabolite of esculetin plays an important role in cytotoxic effects induced by chloroquine on porcine immature Sertoli cells

IF 2.6 3区医学 Q3 TOXICOLOGY Toxicology in Vitro Pub Date : 2024-09-13 DOI:10.1016/j.tiv.2024.105941

Fang Wang, Han Zhao, Qiao Mou, Zhi-Qiang Du, Cai-Xia Yang

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Abstract

Chloroquine (CQ) is widely used in the therapy against malarial, tumor and recently the COVID-19 pandemic, as a lysosomotropic agent to inhibit the endolysosomal trafficking in the autophagy pathway. We previously reported that CQ (20 μM, 36 h) could reprogram transcriptome, and impair multiple signaling pathways vital to porcine immature Sertoli cells (iSCs). However, whether CQ treatment could affect the metabolomic compositions of porcine iSCs remains unclear. Here, we showed that CQ (20 μM, 36 h) treatment of porcine iSCs induced significant changes of 63 metabolites (11 up and 52 down) by the metabolomics method, which were involved in different metabolic pathways. Caffeic acid and esculetin, the top two up-regulated metabolites, were validated by ELISA. The combined analysis of metabolomics and transcriptome showed caffeic acid and esculetin to be highly correlated with multiple differentially expressed genes (DEGs), including Ndrg1, S100a8, Sqstm1, S100a12, S100a9, Ill1, Lif, Ntn4 and Peg10. Furthermore, esculetin treatment (53 nM, 36 h) significantly decreased the viability and proliferation, suppressed the mitochondrial function, whereas promoted the apoptosis of porcine iSCs, similar to those by CQ treatment (20 μM, 36 h). Collectively, our results showed that CQ treatment induces metabolic changes, and its effect on porcine iSCs could be partially mediated by esculetin.

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在氯喹对猪未成熟 Sertoli 细胞诱导的细胞毒性作用中，鱼藤酮的代谢物发挥了重要作用

氯喹（CQ）作为一种溶酶体促进剂，可抑制自噬途径中的溶酶体内转运，被广泛用于治疗疟疾、肿瘤以及最近的 COVID-19 大流行病。我们以前曾报道过，CQ（20 μM，36 小时）可以重编转录组，并损害对猪未成熟的Sertoli细胞（iSCs）至关重要的多种信号通路。然而，CQ处理是否会影响猪iSCs的代谢组组成仍不清楚。在这里，我们用代谢组学方法研究发现，CQ（20 μM，36 h）处理猪iSCs会诱导63种代谢物发生显著变化（11种增加，52种减少），这些代谢物涉及不同的代谢途径。通过酶联免疫吸附试验（ELISA）验证了咖啡酸和鱼腥草素这两种上调幅度最大的代谢物。代谢组学和转录组的联合分析表明，咖啡酸和鱼藤素与多个差异表达基因（DEGs）高度相关，包括Ndrg1、S100a8、Sqstm1、S100a12、S100a9、Ill1、Lif、Ntn4和Peg10。此外，esculetin 处理（53 nM，36 h）显著降低猪iSCs的活力和增殖，抑制线粒体功能，同时促进凋亡，与CQ处理（20 μM，36 h）的结果相似。总之，我们的研究结果表明，CQ 处理会诱导代谢变化，而其对猪 iSCs 的影响可能部分是由 esculetin 介导的。

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来源期刊

Toxicology in Vitro 医学-毒理学

CiteScore

6.50

自引率

3.10%

发文量

181

审稿时长

65 days

期刊介绍： Toxicology in Vitro publishes original research papers and reviews on the application and use of in vitro systems for assessing or predicting the toxic effects of chemicals and elucidating their mechanisms of action. These in vitro techniques include utilizing cell or tissue cultures, isolated cells, tissue slices, subcellular fractions, transgenic cell cultures, and cells from transgenic organisms, as well as in silico modelling. The Journal will focus on investigations that involve the development and validation of new in vitro methods, e.g. for prediction of toxic effects based on traditional and in silico modelling; on the use of methods in high-throughput toxicology and pharmacology; elucidation of mechanisms of toxic action; the application of genomics, transcriptomics and proteomics in toxicology, as well as on comparative studies that characterise the relationship between in vitro and in vivo findings. The Journal strongly encourages the submission of manuscripts that focus on the development of in vitro methods, their practical applications and regulatory use (e.g. in the areas of food components cosmetics, pharmaceuticals, pesticides, and industrial chemicals). Toxicology in Vitro discourages papers that record reporting on toxicological effects from materials, such as plant extracts or herbal medicines, that have not been chemically characterized.