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伊维菌素通过 AMPK/mTOR 信号通路诱导 RAW264.7 细胞的细胞毒性和自噬。

Cytotoxicity and Autophagy Induced by Ivermectin via AMPK/mTOR Signaling Pathway in RAW264.7 Cells.

机构信息

Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.

Department of Imaging, Weifang Hospital of Traditional Chinese Medicine, Shandong 261041, China.

出版信息

Molecules. 2023 Feb 27;28(5):2201. doi: 10.3390/molecules28052201.

DOI:10.3390/molecules28052201
PMID:36903447
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10005495/
Abstract

The widespread and excessive use of ivermectin (IVM) will not only cause serious environmental pollution, but will also affect metabolism of humans and other mammals that are exposed. IVM has the characteristics of being widely distributed and slowly metabolized, which will cause potential toxicity to the body. We focused on the metabolic pathway and mechanism of toxicity of IVM on RAW264.7 cells. Colony formation and LDH detection assay showed that IVM significantly inhibited the proliferation of and induced cytotoxicity in RAW264.7 cells. Intracellular biochemical analysis using Western blotting assay showed that LC3-B and Beclin-1 were upregulated and p62 was down-regulated. The combination of confocal fluorescence, calcein-AM/CoCl, and fluorescence probe results showed that IVM could induce the opening of the mitochondrial membrane permeability transition pore, reduce mitochondrial content, and increase lysosome content. In addition, we focused on induction of IVM in the autophagy signal pathway. The Western blotting results showed that IVM increased expression of p-AMPK and decreased p-mTOR and p-S6K expression in protein levels, indicating that IVM activated the AMPK/mTOR signaling pathway. Therefore, IVM may inhibit cell proliferation by inducing cell cycle arrest and autophagy.

摘要

伊维菌素（IVM）的广泛和过度使用不仅会造成严重的环境污染，还会影响暴露在其中的人类和其他哺乳动物的新陈代谢。IVM 具有分布广泛和代谢缓慢的特点，这会对身体造成潜在的毒性。我们专注于 IVM 对 RAW264.7 细胞的代谢途径和毒性机制。集落形成和 LDH 检测试验表明，IVM 显著抑制 RAW264.7 细胞的增殖并诱导其细胞毒性。使用 Western blot 试验进行的细胞内生化分析表明，LC3-B 和 Beclin-1 上调，p62 下调。共聚焦荧光、钙黄绿素-AM/CoCl 和荧光探针结果的组合表明，IVM 可诱导线粒体膜通透性转换孔的开放，减少线粒体含量，增加溶酶体含量。此外，我们还专注于 IVM 对自噬信号通路的诱导。Western blot 结果表明，IVM 在蛋白水平上增加了 p-AMPK 的表达，降低了 p-mTOR 和 p-S6K 的表达，表明 IVM 激活了 AMPK/mTOR 信号通路。因此，IVM 可能通过诱导细胞周期停滞和自噬来抑制细胞增殖。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/137a/10005495/efe262e1096e/molecules-28-02201-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/137a/10005495/8adea897e8cd/molecules-28-02201-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/137a/10005495/2c20463b0790/molecules-28-02201-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/137a/10005495/83fbf7a937fa/molecules-28-02201-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/137a/10005495/35330b7afd6c/molecules-28-02201-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/137a/10005495/5858d19d08e6/molecules-28-02201-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/137a/10005495/efe262e1096e/molecules-28-02201-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/137a/10005495/8adea897e8cd/molecules-28-02201-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/137a/10005495/2c20463b0790/molecules-28-02201-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/137a/10005495/83fbf7a937fa/molecules-28-02201-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/137a/10005495/35330b7afd6c/molecules-28-02201-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/137a/10005495/5858d19d08e6/molecules-28-02201-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/137a/10005495/efe262e1096e/molecules-28-02201-g006.jpg

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