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Circulating miRNAs expression as potential biomarkers of mild traumatic brain injury

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Abstract

TBI is the main cause of death and disability in individuals aged 1–45 in Western countries. One of the main challenges of TBI at present is the lack of specific diagnostic biomarkers, especially for mild TBI (mTBI), which remains currently difficult to value in clinical practice. In this context MiRNAs may be important mediators of the profound molecular and cellular changes that occur after TBI in both the short and the long term. Recently, plasma miRNAs profiling in human TBI, have revealed dynamic temporal regulation of miRNA expression within the cortex. Aim of this study was to select a specific miRNAs panel for mTBI, by focusing the research on the prognostic meaning of miRNAs in the hours following the trauma, in order to be able to use this MIRNAs as potential biomarkers useful for monitoring the follow up of mild TBI. Serum levels of 17 miRNAs were measured by RT-quantitative polymerase chain reaction (qPCR) in 20 patients with mTBI at three different time-points (0 h, 24 h, 48 h) and in 10 controls. For 15 miRNAs we found a significant differences in the comparison among the three time points: for each of these miRNAs the values were greater at baseline and progressively reduced at 24 h and 48 h. These data allow us to consider the miRNAs included in panel as sensitive and specific biomarkers for mTBI, useful in monitoring the post-trauma period.

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References

  1. Vella MA, Crandall ML, Patel MB (2017) Acute management of traumatic brain injury. Surg Clin North Am 97:1015–1030. https://doi.org/10.1016/j.suc.2017.06.003

    Article  PubMed  PubMed Central  Google Scholar 

  2. Langlois JA, Rutland-Brown W, Wald MM (2006) The epidemiology and impact of traumatic brain injury: a brief overview. J Head Trauma Rehabil 21:375–378. https://doi.org/10.1097/00001199-200609000-00001

    Article  PubMed  Google Scholar 

  3. Stocchetti N, Maas AI (2014) Traumatic intracranial hypertension. N Engl J Med 371:972. https://doi.org/10.1056/NEJMra1208708

    Article  CAS  PubMed  Google Scholar 

  4. Werner C, Engelhard K (2007) Pathophysiology of traumatic brain injury. Br J Anaesth 99:4–9. https://doi.org/10.1093/bja/aem131

    Article  CAS  PubMed  Google Scholar 

  5. Ganau M, Prisco L (2013) Comment on "neuromonitoring in traumatic brain injury". Minerva Anestesiol 79:310–311

    CAS  PubMed  Google Scholar 

  6. Di Pietro V, Ragusa M, Davies D et al (2017) MicroRNAs as novel biomarkers for the diagnosis and prognosis of mild and severe traumatic brain injury. J Neurotrauma 34:1948–1956. https://doi.org/10.1089/neu.2016.4857

    Article  PubMed  Google Scholar 

  7. Thelin E, Al Nimer F, Frostell A, Zetterberg H, Blennow K, Nyström H, Svensson M, Bellander BM, Piehl F, Nelson DW (2019) A serum protein biomarker panel improves outcome prediction in human traumatic brain injury. J Neurotrauma 36(20):2850–2862. https://doi.org/10.1089/neu.2019.6375

    Article  PubMed  PubMed Central  Google Scholar 

  8. Posti JP, Takala RSK, Lagerstedt L, Dickens AM, Hossain I, Mohammadian M, Ala-Seppälä H, Frantzén J, van Gils M, Hutchinson PJ, Katila AJ, Maanpää HR, Menon DK, Newcombe VF, Tallus J, Hrusovsky K, Wilson DH, Gill J, Sanchez JC, Tenovuo O, Zetterberg H, Blennow K (2019) Correlation of blood biomarkers and biomarker panels with traumatic findings on computed tomography after traumatic brain Injury. J Neurotrauma 36(14):2178–2189. https://doi.org/10.1089/neu.2018.6254

    Article  PubMed  Google Scholar 

  9. Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659. https://doi.org/10.1038/ncb1596

    Article  CAS  Google Scholar 

  10. Friedman R, Farh KK, Burge CB, Bartel DP (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19:92–105. https://doi.org/10.1101/gr.082701.108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lim LP, Lau NC, Garrett-Engele P et al (2005) Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433:769–773. https://doi.org/10.1038/nature03315

    Article  CAS  PubMed  Google Scholar 

  12. Baek D, Villén J, Shin C, Camargo FD, Gygi SP, Bartel DP (2008) The impact of microRNAs on protein output. Nature 455:64–71. https://doi.org/10.1038/nature07242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Watson CN, Belli A, Di Pietro V (2019) Small Non-coding RNAs: New Class of Biomarkers and Potential Therapeutic Targets in Neurodegenerative Disease. Front Genet 10:364. https://doi.org/10.3389/fgene.2019.00364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Keller A, Rounge T, Backes C et al (2017) Sources to variability in circulating human miRNA signatures. RNA Biol 14:1791–1798. https://doi.org/10.1080/15476286.2017.1367888

    Article  PubMed  PubMed Central  Google Scholar 

  15. Jung HJ, Su Y (2014) Circulating miRNAs in ageing and ageing-related diseases. J Genet Genomics 41:465–472. https://doi.org/10.1016/j.jgg.2014.07.003

    Article  PubMed  PubMed Central  Google Scholar 

  16. Lei P, Li Y, Chen X, Yang S, Zhang J (2009) Microarray based analysis of microRNA expression in rat cerebral cortex after traumatic brain injury. Brain Res 1284:191–201. https://doi.org/10.1016/j.brainres.2009.05.074

    Article  CAS  PubMed  Google Scholar 

  17. Orrison WW, Hanson EH, Alamo T et al (2009) Traumatic brain injury: a review and high-field MRI findings in 100 unarmed combatants using a literature based checklist approach. J Neurotrauma 26:689–701. https://doi.org/10.1089/neu.2008.0636

    Article  PubMed  Google Scholar 

  18. Redell JB, Liu Y, Dash PK (2009) Traumatic brain injury alters expression of hippocampal microRNAs: potential regulators of multiple pathophysiological processes. J Neurosci Res 87:1435–1448. https://doi.org/10.1002/jnr.21945

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bartels CL, Tsongalis GJ (2009) MicroRNAs: novel biomarkers for human cancer. Clin Chem 55:623–631. https://doi.org/10.1373/clinchem.2008.112805

    Article  CAS  PubMed  Google Scholar 

  20. Vemuganti R (2010) The microRNAs and stroke: no need to be coded to be counted. Transl Stroke Res 1:158–160. https://doi.org/10.1007/s12975-010-0030-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ye Y, Perez-Polo JR, Qian J et al (2011) The role of microRNA in modulating myocardial ischemia-reperfusion injury. Physiol Genom 43:534–542. https://doi.org/10.1152/physiolgenomics.00130.2010

    Article  CAS  Google Scholar 

  22. Bhomia M, Balakathiresan NS, Wang KK, Papa L, Maheshwari RK (2016) A panel of serum MiRNA biomarkers for the diagnosis of severe to mild traumatic brain injury in humans. Sci Rep 6:28148. https://doi.org/10.1038/srep28148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kawata K, Liu CY, Merkel SF, Ramirez SH, Tierney RT, Langford D (2016) Blood biomarkers for brain injury: What are we measuring? Neurosci Biobehav Rev 68:460–473. https://doi.org/10.1016/j.neubiorev.2016.05.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gerlach CV, Vaidya VS (2017) MicroRNAs in injury and repair. Arch Toxicol 91:2781–2797. https://doi.org/10.1007/s00204-017-1974-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Siddeek B, Inoubli L, Lakhdari N et al (2014) MicroRNAs as potential biomarkers in diseases and toxicology. Mutat Res Genet Toxicol Environ Mutagen 764–765:46–57. https://doi.org/10.1016/j.mrgentox.2014.01.010

    Article  CAS  PubMed  Google Scholar 

  26. Backes C, Meese E, Keller A (2016) Specific miRNA disease biomarkers in blood, serum and plasma: challenges and prospects. Mol Diagn Ther 20:509–518. https://doi.org/10.1007/s40291-016-0221-4

    Article  CAS  PubMed  Google Scholar 

  27. Pan YB, Sun ZL, Feng DF (2017) The role of microRNA in traumatic brain injury. Neuroscience 367:189–199. https://doi.org/10.1016/j.neuroscience.2017.10.046

    Article  CAS  PubMed  Google Scholar 

  28. Martinez B, Peplow PV (2017) MicroRNAs as diagnostic markers and therapeutic targets for traumatic brain injury. Neural Regen Res. https://doi.org/10.4103/1673-5374.219025

    Article  PubMed  PubMed Central  Google Scholar 

  29. Guerriero RM, Giza CC, Rotenberg A (2015) Glutamate and GABA imbalance following traumatic brain injury. Curr Neurol Neurosci Rep 15:27. https://doi.org/10.1007/s11910-015-0545-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhan LY, Lei SQ, Zhang BH et al (2018) Overexpression of miR-381 relieves neuropathic pain development via targeting HMGB1 and CXCR4. Biomed Pharmacother 107:818–823. https://doi.org/10.1016/j.biopha.2018.08.053

    Article  CAS  PubMed  Google Scholar 

  31. Shrestha A, Mukhametshina RT, Taghizadeh S et al (2017) MicroRNA-142 is a multifaceted regulator in organogenesis, homeostasis, and disease. Dev Dyn 246:285–290. https://doi.org/10.1002/dvdy.24477

    Article  CAS  PubMed  Google Scholar 

  32. Li Y, Lu J, Bao X, Wang X, Wu J, Li X, Hong W (2016) MiR-499-5p protects cardiomyocytes against ischaemic injury via anti-apoptosis by targeting PDCD4. Oncotarget 14:35607–35617. https://doi.org/10.18632/oncotarget.9597

    Article  Google Scholar 

  33. Zhang X, Zhang C, Wang N, Li Y, Zhang D, Li Q (2018) MicroRNA-486 alleviates hypoxia-induced damage in H9c2 cells by targeting NDRG2 to inactivate JNK/C-Jun and NF-κB signaling pathways. Cell Physiol Biochem 48:2483–2492. https://doi.org/10.1159/000492686

    Article  CAS  PubMed  Google Scholar 

  34. Wang W, Guo Z, Yang S, Wang H, Ding W (2018) Upregulation of miR-199 attenuates TNF-α-induced Human nucleus pulposus cell apoptosis by downregulating MAP3K5. Biochem Biophys Res Commun 505:917–924. https://doi.org/10.1016/j.bbrc.2018.09.194

    Article  CAS  PubMed  Google Scholar 

  35. Lyskjær I, Rasmussen MH, Andersen CL (2016) Putting a brake on stress signaling: miR-625-3p as a biomarker for choice of therapy in colorectal cancer. Epigenomics 8:1449–1452. https://doi.org/10.2217/epi-2016-0128

    Article  CAS  PubMed  Google Scholar 

  36. Yang G, Liu Z, Wang L et al (2018) MicroRNA-195 protection against focal cerebral ischemia by targeting CX3CR1. J Neurosurg 1:1–10. https://doi.org/10.3171/2018.5.JNS173061

    Article  Google Scholar 

  37. Vetere G, Barbato C, Pezzola S et al (2014) Selective inhibition of miR-92 in hippocampal neurons alters contextual fear memory. Hippocampus 24:1458–1465. https://doi.org/10.1002/hipo.22326

    Article  CAS  PubMed  Google Scholar 

  38. Wang Z (2013) miRNA in the regulation of ion channel/transporter expression. Compr Physiol 3:599–653. https://doi.org/10.1002/cphy.c110002

    Article  PubMed  Google Scholar 

  39. Hu HJ, Song M (2017) Disrupted ionic homeostasis in ischemic stroke and new therapeutic targets. J Stroke Cerebrovasc Dis 26:2706–2719. https://doi.org/10.1016/j.jstrokecerebrovasdis.2017.09.011

    Article  PubMed  Google Scholar 

  40. Tan PH, Pao YY, Cheng JK, Hung KC (2013) MicroRNA-based therapy in pain medicine: current progress and future prospects. Acta Anaesthesiol Taiwan 51:171–176. https://doi.org/10.1016/j.aat.2013.11.001

    Article  PubMed  Google Scholar 

  41. Wang WX, Sullivan PG, Springer JE (2017) Mitochondria and microRNA crosstalk in traumatic brain injury. Prog Neuropsychopharmacol Biol Psychiatry 73:104–108. https://doi.org/10.1016/j.pnpbp.2016.02.011

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Human Pathology of Adulthood and Childhood ‘G. Barresi’, University of Messina, Messina, Italy

    Francesca Polito, Fausto Famà, Giovanni Raffa, Alfredo Conti, Sacco Daniele, Marcello Passalacqua, Salvatore Cardali, Flavio F. Angileri & Antonino Germanò

  2. Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy

    Rosaria Oteri, Gianluca Vita, Vincenzo Macaione, Rosa Maria Di Giorgio & M’Hammed Aguennouz

  3. Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Unit of Neurosurgery, University of Messina, Messina, Italy

    Maria Gioffrè

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  1. Francesca Polito
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Contributions

Conceptualization, MA and AG; methodology, MA; statistical analysis, FP, RO; formal analysis, FP and RO; investigation, RO, FP, and MA; resources, AC, FFA, SC, GR, DS, MP; data curation, GR, DS, MP, and MA; writing—original draft preparation, FF, MA, and FP; writing—review and editing, FF, MA and FP; supervision, RMDG, MG, AG and MA.

Corresponding author

Correspondence to M’Hammed Aguennouz.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the Local Bioethical Committee at the University Hospital “G. Martino” of Messina and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained for all individual participants included in the study.

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Polito, F., Famà, F., Oteri, R. et al. Circulating miRNAs expression as potential biomarkers of mild traumatic brain injury. Mol Biol Rep 47, 2941–2949 (2020). https://doi.org/10.1007/s11033-020-05386-7

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