Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 1.727
Index Copernicus  – 152.95 pts
MNiSW – 40 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

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Advances in Clinical and Experimental Medicine

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doi: 10.17219/acem/131217

Publication type: original article

Language: English

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Investigation of the role of miR-221 in diabetic peripheral neuropathy and related molecular mechanisms

Xiaole Wu1,2,A,B,C,D,E,F, Xiaoyu Wang3,B,C,E,F, Yiyu Yin4,B,C,E,F, Lei Zhu5,B,C,E,F, Fengchao Zhang2,B,C,E,F, Jianping Yang1,C,E,F

1 Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou, China

2 Department of Anesthesiology, Xuzhou Children’s Hospital, Xuzhou Medical University, China

3 Department of Thoracic Surgery, Xuzhou Children’s Hospital, Xuzhou Medical University, China

4 Department of General Surgery, Xuzhou Children’s Hospital, Xuzhou Medical University, China

5 Intensive Care Unit, Xuzhou Children’s Hospital, Xuzhou Medical University, China


Background. Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes, but the molecular mechanisms of DPN are still unclear.
Objectives. To investigate the role of miR-221 in DPN and the related molecular mechanisms.
Material and Methods. Streptozotocin (STZ) was used to establish an in vivo DPN model. An in vitro DPN model was established using high glucose-induced SH-SY5Y cells. The pain condition of rats was measured by evaluating the 50% paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). Serum exosomes were extracted and identified. Expression of miR-221 in serum exosomes and serum SOCS3 expression were determined using reverse-transcription quantitative polymerase chain reaction (RT-qPCR). Western blotting was used to measure the protein levels of SOCS3, bradykinin (BK) and prostaglandin E2 (PEG2). The dual luciferase reporter assay was performed to confirm SOCS3 3’-UTR as a target of miR-221. The serum or cell supernatant levels of PEG2, BK, interleukin (IL)-6, IL-1β, and tumor necrosis factor alpha (TNF-α) were measured using enzyme-linked immunosorbent assay (ELISA).
Results. Induction of the lenti-miR-221 inhibitor significantly decreased the expression of miR-221 in DPN rats. Both 50% PWT and PWL values were markedly decreased in DPN rats. When miR-221 was inhibited, the 50% PWT and PWL values were both significantly increased. Knockdown of miR-221 significantly increased the expression of SOCS3 and decreased the expression of NF-κB. Furthermore, knockdown of miR-221 remarkably decreased the expression of PEG2, BK, IL-6, IL-1β, and TNF-α in both STZ-treated DPN rats and high glucose-induced SH-SY5Y cells, which was reversed by inhibition of SOCS3. The dual luciferase reporter assay showed that miR-221 directly targeted and negatively regulated SOCS3.
Conclusion. Inhibition of miR-221 can reduce pain and decrease expression of inflammatory factors through targeting SOCS3 in DPN.

Key words

exosomes, miR-221, SOCS3, diabetic peripheral neuralgia

References (30)

  1. Nathan CVS, Paul J, Abraham MM, Sasirekha M. Efficacy of low level laser therapy over conventional therapy on diabetic peripheral neuro­pathy: A pilot study. Call for Editorial Board Members. 2019;12(3):226.
  2. Pop-Busui R, Boulton AJM, Feldman EL, et al. Diabetic neuropathy: A position statement by the American Diabetes Association. Diabetes Care. 2017;40(1):136–154. doi:10.2337/dc16-2042
  3. Singh R, Kishore L, Kaur N. Diabetic peripheral neuropathy: Current perspective and future directions. Pharmacol Res. 2014;80:21–35. doi:10.1016/j.phrs.2013.12.005
  4. Juster-Switlyk K, Smith AG. Updates in diabetic peripheral neuropathy. F1000Research. 2016;5:F1000 Faculty Rev-738. doi:10.12688/f1000research.7898.1
  5. Tesfaye S, Selvarajah D. Advances in the epidemiology, pathogenesis and management of diabetic peripheral neuropathy. Diabetes Metabol Res Rev. 2012;28:8–14. doi:10.1002/dmrr.2239
  6. Dixit S, Maiya A, Shastry BA. Effect of moderate-intensity aerobic exercise on glycosylated haemoglobin among elderly patients with type 2 diabetes & peripheral neuropathy. Indian J Med Res. 2017;145(1):129–132. doi:10.4103/ijmr.IJMR_699_14
  7. Teodoro JS, Nunes S, Rolo AP, Reis F, Palmeira CM. Therapeutic options targeting oxidative stress, mitochondrial dysfunction and inflammation to hinder the progression of vascular complications of diabetes. Front Physiol. 2019;9:1857. doi:10.3389/fphys.2018.01857
  8. Sifuentes-Franco S, Pacheco-Moisés FP, Rodríguez-Carrizalez AD, Miranda-Díaz AG. The role of oxidative stress, mitochondrial function, and autophagy in diabetic polyneuropathy. J Diabetes Res. 2017;2017:1673081. doi:10.1155/2017/1673081
  9. Kozomara A, Birgaoanu M, Griffiths-Jones S. miRBase: From micro­RNA sequences to function. Nucleic Acids Res. 2019;47(D1):D155–D62. doi:10.1093/nar/gky1141
  10. Oh SE, Park HJ, He L, Skibiel C, Junn E, Mouradian MM. The Parkinson’s disease gene product DJ-1 modulates miR-221 to promote neuronal survival against oxidative stress. Redox Biol. 2018;19:62–73. doi:10.1016/j.redox.2018.07.021
  11. Fornari F, Pollutri D, Patrizi C, et al. In hepatocellular carcinoma miR-221 modulates sorafenib resistance through inhibition of caspase-3-mediated apoptosis. Clin Cancer Res. 2017;23(14):3953–3965. doi:10.1158/1078-0432.CCR-16-1464
  12. Lightell DJ, Moss SC, Woods TC. Upregulation of miR-221 and miR-222 in response to increased extracellular signal-regulated kinases 1/2 activity exacerbates neointimal hyperplasia in diabetes mellitus. Atherosclerosis. 2018;269:71–78. doi:10.1016/j.atherosclerosis.2017.12.016
  13. Qian LB, Jiang SZ, Tang XQ, et al. Exacerbation of diabetic cardiac hypertrophy in OVE26 mice by angiotensin II is associated with JNK/c-Jun/miR-221-mediated autophagy inhibition. Oncotarget. 2017;8(63):106661–106671. doi:10.18632/oncotarget.21302
  14. Xiaoxu G, Bojin X, Wenwei X, Lili X, Shan H. Long noncoding RNA GAS5 inhibits cell proliferation and fibrosis in diabetic nephropathy by sponging miR-221 and modulating SIRT1 expression. Aging. 2019;11(20):8745–8759. doi:10.18632/aging.102249
  15. Liu HN, Li X, Wu N, et al. Serum microRNA-221 as a biomarker for diabetic retinopathy in patients associated with type 2 diabetes. Int J Ophthalmol. 2018;11(12):1889–1894. doi:10.18240/ijo.2018.12.02
  16. Fan L, Shan A, Su Y, et al. MiR-221/222 inhibit insulin production of pancreatic β-cells in mice. Endocrinology. 2019;161(1):bqz027. doi:10.1210/endocr/bqz027
  17. Zhao D, Zhuang N, Ding Y, Kang Y, Shi L. MiR-221 activates the NF-κB pathway by targeting A20. Biochem Biophys Res Commun. 2016;472(1): 11–18. doi:10.1016/j.bbrc.2015.11.009
  18. Wang T, Jiang L, Wei X, et al. Inhibition of miR-221 alleviates LPS-induced acute lung injury via inactivation of SOCS1/NF-κB signaling pathway. Cell Cycle. 2019;18(16):1893–1907. doi:10.1080/15384101.2019.1632136
  19. Xia L, Zhang Y, Dong T. Inhibition of microRNA-221 alleviates neuropathic pain through targeting suppressor of cytokine signaling 1. J Mol Neurosci. 2016;59(3):411–420. doi:10.1007/s12031-016-0748-1
  20. Babon JJ, Varghese LN, Nicola NA. Inhibition of IL-6 family cytokines by SOCS3. Semin Immunol. 2014;26(1):13–19. doi:10.1016/j.smim.2013.12.004
  21. Gao A, Van DTE. Role of suppressors of cytokine signaling 3 in bone inflammatory responses. Front Immunol. 2013;4:506. doi:10.3389/fimmu.2013.00506
  22. Yan C, Ward PA, Wang X, Gao H. Myeloid depletion of SOCS3 enhances LPS-induced acute lung injury through CCAAT/enhancer binding protein δ pathway. FASEB J. 2013;27(8):2967–2976. doi:10.1096/fj.12-225797
  23. Yuan K, Lei Y, Chen HN, et al. HBV-induced ROS accumulation promotes hepatocarcinogenesis through Snail-mediated epigenetic silencing of SOCS3. Cell Death Differ. 2016;23(4):616–627. doi:10.1038/cdd.2015.129
  24. Yan Z, Yang W, Parkitny L, et al. Deficiency of SOCS3 leads to brain-targeted experimental autoimmune encephalomyelitis via enhanced neutrophil activation and ROS production. JCI Insight. 2019;4(9):e126520. doi:10.1172/jci.insight.126520
  25. Zhu SH, Liu BQ, Hao MJ, et al. Paeoniflorin suppressed high glucose-induced retinal microglia MMP-9 expression and inflammatory response via inhibition of TLR4/NF-κB pathway through upregulation of SOCS3 in diabetic retinopathy. Inflammation. 2017;40(5):1475–1486. doi:10.1007/s10753-017-0571-z
  26. Duan WN, Xia ZY, Min L, Qian S, Yan L. Protective effects of SOCS3 overexpression in high glucose induced lung epithelial cell injury through the JAK2/STAT3 pathway. Mol Med Rep. 2017;16(3):2668–2874. doi:10.3892/mmr.2017.6941
  27. Wu R, Liu X, Yin J, Wu H, Wang F. IL-6 receptor blockade ameliorates diabetic nephropathy via inhibiting inflammasome in mice. Metabolism. 2018;83:18–24. doi:10.1016/j.metabol.2018.01.002
  28. Kneitz B, Krebs M, Kalogirou C, et al. Survival in patients with high-risk prostate cancer is predicted by miR-221, which regulates proliferation, apoptosis, and invasion of prostate cancer cells by inhibiting IRF2 and SOCS3. Cancer Res. 2014;74(9):2591–2603. doi:10.1158/0008-5472.CAN-13-1606
  29. Liu B, Wu S, Ma J, et al. lncRNA GAS5 reverses EMT and tumor stem cell-mediated gemcitabine resistance and metastasis by targeting miR-221/SOCS3 in pancreatic cancer. Mol Ther Nucleic Acids. 2018;13:472–482. doi:10.1016/j.omtn.2018.09.026
  30. Navarro A, Pairet S, Alvarez-Larrán A, et al. MiR-203 and miR-221 regulate SOCS1 and SOCS3 in essential thrombocythemia. Blood Cancer J. 2016;6(3):e406. doi:10.1038/bcj.2016.10