Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
PLoS One. 2024 Jul 23;19(7):e0307598. doi: 10.1371/journal.pone.0307598. eCollection 2024.
Metformin is a biguanide currently used in the treatment of diabetes mellitus type 2. Besides its anti-glycemic effects, metformin has been reported to induce different cellular pleiotropic effects, depending on concentration and time of treatment. Here we report one administration of metformin (0.5 mM) has radioprotective effects in vitro on BJ human fibroblasts, increasing DNA damage repair and increasing SOD1 expression in the nucleus. Importantly, metformin (200 mg/kg) pre-administration for only 3 days in wild type 129/sv mice, decreases the formation of micronuclei in bone marrow cells and DNA damage in colon and lung tissues compared to control irradiated mice at sub-lethal and lethal doses, increasing the overall survival fraction by 37% after 10Gy total body irradiation. We next pre-treated with metformin and then exposed 129/sv mice, to a galactic cosmic rays simulation (GCRsim), at the NASA Space Radiation Laboratory (NSRL). We found metformin pre-treatment decreases the presence of bone marrow micronuclei and DNA damage in colon and lung tissues and an increase of 8-oxoguanine DNA glycosylase-1 (OGG1) expression. Our data highlight a radioprotective effect of metformin through an indirect modulation of the gene expression involved in the cellular detoxification rather than its effects on mitochondria.
二甲双胍是一种目前用于治疗 2 型糖尿病的双胍类药物。除了其降血糖作用外，二甲双胍还被报道具有不同的细胞多效性作用，这取决于治疗的浓度和时间。在这里，我们报告了一次给药（0.5mM）对 BJ 人成纤维细胞的体外放射保护作用，增加了 DNA 损伤修复，并增加了核内 SOD1 的表达。重要的是，在野生型 129/sv 小鼠中，仅预先给予二甲双胍（200mg/kg）3 天，就可以减少骨髓细胞微核的形成和结肠和肺组织的 DNA 损伤，与亚致死和致死剂量照射的对照小鼠相比，总全身照射 10Gy 后的总存活率提高了 37%。接下来，我们用二甲双胍预处理，然后将 129/sv 小鼠暴露于美国宇航局空间辐射实验室（NSRL）的银河宇宙射线模拟（GCRsim）中。我们发现二甲双胍预处理可减少骨髓微核的形成和结肠和肺组织的 DNA 损伤，并增加 8-氧鸟嘌呤 DNA 糖基化酶-1（OGG1）的表达。我们的数据突出了二甲双胍的放射保护作用，这是通过间接调节参与细胞解毒的基因表达，而不是其对线粒体的作用。
