Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Key Laboratory of Diabetes Immunology, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Central South University, Changsha, Hunan, China.
J Diabetes Investig. 2020 Jan;11(1):101-109. doi: 10.1111/jdi.13074. Epub 2019 Jun 25.
AIMS/INTRODUCTION: Metformin, a widely prescribed antidiabetic agent, has been shown to exhibit anti-inflammatory effects in obese and type 2 diabetes patients, but the mechanism is not well elucidated. Microribonucleic acids (miRNAs) are a group of small non-coding ribonucleic acids that participate in many biological and pathological processes. The aim of the present study was to investigate whether Dicer, a key miRNA biogenesis enzyme, and miRNAs in macrophages are implicated in the anti-inflammatory effects of metformin.
Enzyme-linked immunosorbent assay and reverse transcription quantitative polymerase chain reaction were carried out to verify the anti-inflammatory effects of metformin. miRNA microarray was applied to detect the expression profile of miRNA. Western-blotting, enzyme-linked immunosorbent assay and reverse transcription quantitative polymerase chain reaction were used to examine the role Dicer and miRNAs play in the anti-inflammatory effects of metformin.
In parallel with the suppression of interleukin-6 and tumor necrosis factor-α production in resting and lipopolysaccharide-stimulated macrophages, metformin could induce an increase in Dicer and most miRNAs. When Dicer was knocked down, the anti-inflammatory effects of metformin were significantly attenuated. Additionally, the upregulation of miRNA (miR)-34a-5p and miR-125b-5p by metformin were also blunted in Dicer knockdown macrophages. Furthermore, inhibition of miR-34a-5p and miR-125b-5p could impair the suppressive action of metformin on pro-inflammatory factors production, whereas overexpression of the two miRNAs mimicked the anti-inflammatory effects of metformin.
Metformin might show anti-inflammatory effects in macrophages through the induction of Dicer and the subsequent upregulation of miR-34a-5p and miR-125b-5p.
目的/引言：二甲双胍是一种广泛应用于治疗 2 型糖尿病的抗糖尿病药物，已被证明在肥胖和 2 型糖尿病患者中具有抗炎作用，但作用机制尚不清楚。微小 RNA（miRNA）是一组参与多种生物学和病理过程的小非编码 RNA。本研究旨在探讨关键 miRNA 生物发生酶 Dicer 及巨噬细胞中的 miRNA 是否参与二甲双胍的抗炎作用。
采用酶联免疫吸附试验和逆转录定量聚合酶链反应验证二甲双胍的抗炎作用。采用 miRNA 微阵列检测 miRNA 的表达谱。采用 Western-blotting、酶联免疫吸附试验和逆转录定量聚合酶链反应检测 Dicer 和 miRNA 在二甲双胍抗炎作用中的作用。
与静止和脂多糖刺激的巨噬细胞中白细胞介素-6 和肿瘤坏死因子-α产生的抑制作用平行，二甲双胍可诱导 Dicer 和大多数 miRNA 的增加。当 Dicer 被敲低时，二甲双胍的抗炎作用明显减弱。此外，miR-34a-5p 和 miR-125b-5p 的上调也被 Dicer 敲低的巨噬细胞削弱。此外，抑制 miR-34a-5p 和 miR-125b-5p 可损害二甲双胍对促炎因子产生的抑制作用，而过表达这两种 miRNA 可模拟二甲双胍的抗炎作用。
二甲双胍可能通过诱导 Dicer 及其随后上调 miR-34a-5p 和 miR-125b-5p 在巨噬细胞中发挥抗炎作用。
