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二甲双胍可减轻免疫细胞中的 ROS FOXO3 激活。

Metformin Attenuates ROS FOXO3 Activation in Immune Cells.

机构信息

Institute of Medical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität (FU) Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health (BIH), Berlin, Germany.

Science Center, Carl-Thiem-Klinikum Cottbus, Cottbus, Germany.

出版信息

Front Immunol. 2021 Apr 19;12:581799. doi: 10.3389/fimmu.2021.581799. eCollection 2021.

DOI:10.3389/fimmu.2021.581799
PMID:33953705
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8089390/
Abstract

Forkhead box O 3 (FOXO3) is a transcription factor involved in cell metabolism, inflammation and longevity. Here, we investigated if metformin can activate FOXO3 in human immune cells and affects the subsequent level of reactive oxygen/nitrogen species (ROS/RNS) in immune cells. AMP-activated protein kinase (AMPK) and FOXO3 activation were investigated by immunoblot or flow cytometry (FC) analysis, respectively. FOXO3 target gene expression was quantified by real-time PCR. ROS/RNS measurement using dichlorodihydrofluorescein diacetate (DCFH-DA) dye was investigated by FC. The role of the FOXO3 single nucleotide polymorphisms (SNPs) , and on ROS/RNS production was studied using allelic discrimination PCR. Metformin induced activation of AMPK (pT172) and FOXO3 (pS413). ROS/RNS level was reduced in immune cells after metformin stimulation accompanied by induction of the FOXO3 targets mitochondrial superoxide dismutase and cytochrome c. Studies in Foxo3 deficient ( ) mouse splenocytes confirmed that metformin mediates its effects Foxo3 as it attenuates ROS/RNS in myeloid cells of wildtype (WT) but not of mice. Our results suggest that FOXO3 can be activated by metformin leading to reduced ROS/RNS level in immune cells. This may add to the beneficial clinical effects of metformin observed in large cohort studies on longevity, cardiovascular and cancer risk.

摘要

叉头框蛋白 O3（FOXO3）是一种参与细胞代谢、炎症和长寿的转录因子。在这里，我们研究了二甲双胍是否可以激活人免疫细胞中的 FOXO3，并影响免疫细胞中随后的活性氧/氮物种（ROS/RNS）水平。通过免疫印迹或流式细胞术（FC）分析分别研究 AMP 激活的蛋白激酶（AMPK）和 FOXO3 的激活。通过实时 PCR 定量测定 FOXO3 靶基因的表达。通过 FC 研究使用二氯二氢荧光素二乙酸酯（DCFH-DA）染料的 ROS/RNS 测量。使用等位基因鉴别 PCR 研究 FOXO3 单核苷酸多态性（SNP） 和 对 ROS/RNS 产生的作用。二甲双胍诱导 AMPK（pT172）和 FOXO3（pS413）的激活。ROS/RNS 水平在免疫细胞中经二甲双胍刺激后降低，同时诱导 FOXO3 靶基因线粒体超氧化物歧化酶和细胞色素 c 的表达。Foxo3 缺陷（ ）小鼠脾细胞的研究证实，二甲双胍通过介导其作用于 Foxo3 来发挥作用，因为它可以减轻野生型（WT）而不是 小鼠中髓样细胞中的 ROS/RNS。我们的结果表明，二甲双胍可以激活 FOXO3，从而降低免疫细胞中的 ROS/RNS 水平。这可能会增加二甲双胍在大型队列研究中观察到的对长寿、心血管和癌症风险的有益临床效果。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36fa/8089390/0bf8ec43a4b1/fimmu-12-581799-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36fa/8089390/1fd850e9d044/fimmu-12-581799-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36fa/8089390/4867242628de/fimmu-12-581799-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36fa/8089390/bcf757716afb/fimmu-12-581799-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36fa/8089390/0947df975864/fimmu-12-581799-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36fa/8089390/347f6866f5e9/fimmu-12-581799-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36fa/8089390/0bf8ec43a4b1/fimmu-12-581799-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36fa/8089390/1fd850e9d044/fimmu-12-581799-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36fa/8089390/4867242628de/fimmu-12-581799-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36fa/8089390/bcf757716afb/fimmu-12-581799-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36fa/8089390/0947df975864/fimmu-12-581799-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36fa/8089390/347f6866f5e9/fimmu-12-581799-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36fa/8089390/0bf8ec43a4b1/fimmu-12-581799-g006.jpg

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