Metformin Shows Anti-inflammatory Effects in Murine Macrophages Through Dicer/microribonucleic Acid-34a-5p and Microribonucleic Acid-125b-5p

Overview

Journal J Diabetes Investig

Specialty Endocrinology

Date 2019 May 19

PMID 31102492

Citations 18

Authors

Xi Luo

Rong Hu

Ying Zheng

Shiping Liu

Zhiguang Zhou

Affiliations

Soon will be listed here.

Abstract

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.

Materials And Methods: 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.

Results: 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.

Conclusions: 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.

Citing Articles

Neutrophil-modulated Dicer expression in macrophages influences inflammation resolution.

Wang Z, Li W, Li J, Jin T, Chen H, Liang F Cell Mol Life Sci. 2025; 82(1):114.

PMID: 40074991 PMC: 11904050. DOI: 10.1007/s00018-025-05644-6.

Restoring autophagic function: a case for type 2 diabetes mellitus drug repurposing in Parkinson's disease.

Greco M, Munir A, Musaro D, Coppola C, Maffia M Front Neurosci. 2023; 17:1244022.

PMID: 38027497 PMC: 10654753. DOI: 10.3389/fnins.2023.1244022.

Small Extracellular Vesicles Secreted by iPSC-Derived MSCs Ameliorate Pulmonary Inflammation and Lung Injury Induced by Sepsis through Delivery of miR-125b-5p.

Peng W, Yang Y, Chen J, Xu Z, Lou Y, Li Q J Immunol Res. 2023; 2023:8987049.

PMID: 37425491 PMC: 10329558. DOI: 10.1155/2023/8987049.

The development and benefits of metformin in various diseases.

Dong Y, Qi Y, Jiang H, Mi T, Zhang Y, Peng C Front Med. 2023; 17(3):388-431.

PMID: 37402952 DOI: 10.1007/s11684-023-0998-6.

Metformin inhibits ovarian granular cell pyroptosis through the miR-670-3p/NOX2/ROS pathway.

Zhou L, Zou H, Hao J, Huang Y, Zhang J, Xu X Aging (Albany NY). 2023; 15(10):4429-4443.

PMID: 37244286 PMC: 10258021. DOI: 10.18632/aging.204745.

References

Blandino G, Valerio M, Cioce M, Mori F, Casadei L, Pulito C . Metformin elicits anticancer effects through the sequential modulation of DICER and c-MYC. Nat Commun. 2012; 3:865. DOI: 10.1038/ncomms1859. View

Demolli S, Doebele C, Doddaballapur A, Lang V, Fisslthaler B, Chavakis E . MicroRNA-30 mediates anti-inflammatory effects of shear stress and KLF2 via repression of angiopoietin 2. J Mol Cell Cardiol. 2015; 88:111-9. DOI: 10.1016/j.yjmcc.2015.10.009. View

Kim V . MicroRNA biogenesis: coordinated cropping and dicing. Nat Rev Mol Cell Biol. 2005; 6(5):376-85. DOI: 10.1038/nrm1644. View

Johnson A, Olefsky J . The origins and drivers of insulin resistance. Cell. 2013; 152(4):673-84. DOI: 10.1016/j.cell.2013.01.041. View

Wang F, Xu J, Liu H, Liu Z, Xia F . Metformin induces apoptosis by microRNA-26a-mediated downregulation of myeloid cell leukaemia-1 in human oral cancer cells. Mol Med Rep. 2016; 13(6):4671-6. DOI: 10.3892/mmr.2016.5143. View

Olefsky J, Glass C . Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010; 72:219-46. DOI: 10.1146/annurev-physiol-021909-135846. View

Palaga T, Buranaruk C, Rengpipat S, Fauq A, Golde T, Kaufmann S . Notch signaling is activated by TLR stimulation and regulates macrophage functions. Eur J Immunol. 2007; 38(1):174-83. DOI: 10.1002/eji.200636999. View

Hattori Y, Suzuki K, Hattori S, Kasai K . Metformin inhibits cytokine-induced nuclear factor kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells. Hypertension. 2006; 47(6):1183-8. DOI: 10.1161/01.HYP.0000221429.94591.72. View

Wunderlich C, Hovelmeyer N, Wunderlich F . Mechanisms of chronic JAK-STAT3-SOCS3 signaling in obesity. JAKSTAT. 2013; 2(2):e23878. PMC: 3710326. DOI: 10.4161/jkst.23878. View

10.

Ying W, Cheruku P, Bazer F, Safe S, Zhou B . Investigation of macrophage polarization using bone marrow derived macrophages. J Vis Exp. 2013; (76). PMC: 3728835. DOI: 10.3791/50323. View

11.

Noren Hooten N, Martin-Montalvo A, Dluzen D, Zhang Y, Bernier M, Zonderman A . Metformin-mediated increase in DICER1 regulates microRNA expression and cellular senescence. Aging Cell. 2016; 15(3):572-81. PMC: 4854919. DOI: 10.1111/acel.12469. View

12.

Self-Fordham J, Naqvi A, Uttamani J, Kulkarni V, Nares S . MicroRNA: Dynamic Regulators of Macrophage Polarization and Plasticity. Front Immunol. 2017; 8:1062. PMC: 5583156. DOI: 10.3389/fimmu.2017.01062. View

13.

Yang Q, Zhang D, Li Y, Li Y, Li Y . Paclitaxel alleviated liver injury of septic mice by alleviating inflammatory response via microRNA-27a/TAB3/NF-κB signaling pathway. Biomed Pharmacother. 2017; 97:1424-1433. DOI: 10.1016/j.biopha.2017.11.003. View

14.

Slabakova E, Culig Z, Remsik J, Soucek K . Alternative mechanisms of miR-34a regulation in cancer. Cell Death Dis. 2017; 8(10):e3100. PMC: 5682661. DOI: 10.1038/cddis.2017.495. View

15.

Zhu Z, Fang Z, Hu X, Zhou S . MicroRNAs and mesenchymal stem cells: hope for pulmonary hypertension. Rev Bras Cir Cardiovasc. 2015; 30(3):380-5. PMC: 4541786. DOI: 10.5935/1678-9741.20150033. View

16.

Banerjee S, Cui H, Xie N, Tan Z, Yang S, Icyuz M . miR-125a-5p regulates differential activation of macrophages and inflammation. J Biol Chem. 2013; 288(49):35428-36. PMC: 3853290. DOI: 10.1074/jbc.M112.426866. View

17.

Zhang H, Liu L, Hu J, Song L . MicroRNA Regulatory Network Revealing the Mechanism of Inflammation in Atrial Fibrillation. Med Sci Monit. 2015; 21:3505-13. PMC: 4651320. DOI: 10.12659/msm.895982. View

18.

Lee S, Lee J, Kim J, Kim S, You G, Moon J . Metformin sensitizes insulin signaling through AMPK-mediated PTEN down-regulation in preadipocyte 3T3-L1 cells. J Cell Biochem. 2011; 112(5):1259-67. DOI: 10.1002/jcb.23000. View

19.

Andrews M, Soto N, Arredondo M . [Effect of metformin on the expression of tumor necrosis factor-α, Toll like receptors 2/4 and C reactive protein in obese type-2 diabetic patients]. Rev Med Chil. 2013; 140(11):1377-82. DOI: 10.4067/S0034-98872012001100001. View

20.

Jiang P, Liu R, Zheng Y, Liu X, Chang L, Xiong S . MiR-34a inhibits lipopolysaccharide-induced inflammatory response through targeting Notch1 in murine macrophages. Exp Cell Res. 2012; 318(10):1175-84. DOI: 10.1016/j.yexcr.2012.03.018. View