The lncRNA Malat1 functions as a ceRNA to contribute to berberine-mediated inhibition of HMGB1 by sponging miR-181c-5p in poststroke inflammation

Article metrics

  • 189 Accesses


Long non-coding RNAs (lncRNAs) have been identified as essential mediators in neurological dysfunction. Our previous study shows that berberine (BBR) hampers the nuclear-to-cytosolic translocation of high-mobility group box 1 (HMGB1) in the process of poststroke inflammation. In this study, we explored the role of lncRNA metastasis‐associated lung adenocarcinoma transcript 1 (Malat1) in the process of BBR-induced inhibition of HMGB1 in ischemic brain. Before the 60-min MCAO surgery, the mice were pretreated with BBR (50 mg· kg−1 per day, ig) for 14 days or ICV injected with specific lentiviral vector or shRNA. We showed that MCAO caused marked increase in the expression Malat1 and HMGB1 in the ipsilateral cortex, which was significantly attenuated by pretreatment with BBR. Knockdown of Malat1 attenuated the inflammatory injury after brain ischemia, whereas overexpression of Malat1 exacerbated ischemic brain inflammation. Overexpression of Malat1 also reversed BBR-induced reduction of HMGB1 and proinflammatory cytokines. The above results suggested a potential correlation between Malat1 and stroke inflammation. Based on informatics analysis we predicted that HMGB1 was a direct downstream target of miR-181c-5p, whereas Malat1 acted as a competitive endogenous RNA (ceRNA) for miR-181c-5p targeted the 3′-UTR of HMGB1 to promote inflammation after ischemic stroke. Knockdown of Malat1 significantly decreased HMGB1 level, which could be abrogated by transfection with miR-181c-5p inhibitors. Taken together, our results demonstrate for the first time that Malat1/miR-181c-5p/HMGB1 axis may be a key pathway of BBR-induced antiinflammation effects in stroke, and they may provide a novel avenue for targeted therapy.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8


  1. 1.

    Pandian JD, Gall SL, Kate MP, Silva GS, Akinyemi RO, Ovbiagele BI, et al. Prevention of stroke: a global perspective. Lancet. 2018;392:1269–78.

  2. 2.

    Della-Morte D, Guadagni F, Palmirotta R, Testa G, Caso V, Paciaroni M, et al. Genetics of ischemic stroke, stroke-related risk factors, stroke precursors and treatments. Pharmacogenomics. 2012;13:595–613.

  3. 3.

    Zhang ZG, Chopp M. Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic. Lancet Neurol. 2009;8:491–500.

  4. 4.

    Li D, Wang C, Yao Y, Chen L, Liu G, Zhang R, et al. mTORC1 pathway disruption ameliorates brain inflammation following stroke via a shift in microglia phenotype from M1 type to M2 type. FASEB J. 2016;30:3388–99.

  5. 5.

    Brennan-Minnella AM, Won SJ, Swanson RA. NADPH oxidase-2: linking glucose, acidosis, and excitotoxicity in stroke. Antioxid Redox Signal. 2015;22:161–74.

  6. 6.

    Anrather J, Iadecola C. Inflammation and stroke: an overview. Neurotherapeutics. 2016;13:661–70.

  7. 7.

    Guo JM, Liu AJ, Su DF. Genetics of stroke. Acta Pharmacol Sin. 2010;31:1055–64.

  8. 8.

    Zampa F, Hartzell AL, Zolboot N, Lippi G. Non-coding RNAs: the gatekeepers of neural network activity. Curr Opin Neurobiol. 2019;57:54–61.

  9. 9.

    Chandran R, Mehta SL, Vemuganti R. Non-coding RNAs and neuroprotection after acute CNS injuries. Neurochem Int. 2017;111:12–22.

  10. 10.

    Ng SY, Lin L, Soh BS, Stanton LW. Long noncoding RNAs in development and disease of the central nervous system. Trends Genet. 2013;29:461–8.

  11. 11.

    Aprea J, Calegari F. Long non-coding RNAs in corticogenesis: deciphering the non-coding code of the brain. EMBO J. 2015;34:2865–84.

  12. 12.

    Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409:860–921.

  13. 13.

    Indolfi C, Iaconetti C, Gareri C, Polimeni A, Rosa SD. Non-coding RNAs in vascular remodeling and restenosis. Vasc Pharmacol. 2019;114:49–63.

  14. 14.

    Sun Y, Ma L. New insights into long non-coding RNA MALAT1 in cancer and metastasis. Cancers. 2019;11:E216.

  15. 15.

    Zhang T, Wang H, Li Q, Fu J, Huang J, Zhao Y. MALAT1 activates the p53 signaling pathway by regulating MDM2 to promote ischemic stroke. Cell Physiol Biochem. 2018;50:2216–28.

  16. 16.

    Zhou HJ, Wang LQ, Wang DB, Yu JB, Zhu Y, Xu QS, et al. Long noncoding RNA MALAT1 contributes to inflammatory response of microglia following spinal cord injury via the modulation of a miR-199b/IKKbeta/NF-kappaB signaling pathway. Am J Physiol Cell Physiol. 2018;315:C52–C61.

  17. 17.

    Dong N, Xu B, Shi H. Long noncoding RNA MALAT1 acts as a competing endogenous RNA to regulate Amadori-glycated albumin-induced MCP-1 expression in retinal microglia by a microRNA-124-dependent mechanism. Inflamm Res. 2018;67:913–25.

  18. 18.

    Chaudhry SR, Hafez A, Rezai Jahromi B, Kinfe TM, Lamprecht A, Niemela M, et al. Role of damage associated molecular pattern molecules (DAMPs) in aneurysmal subarachnoid hemorrhage (aSAH). Int J Mol Sci. 2018;19:E2035.

  19. 19.

    Gulke E, Gelderblom M, Magnus T. Danger signals in stroke and their role on microglia activation after ischemia. Ther Adv Neurol Disord. 2018;11:1–14.

  20. 20.

    Richard SA, Sackey M, Su Z, Xu H. Pivotal neuroinflammatory and therapeutic role of high mobility group box 1 in ischemic stroke. Biosci Rep. 2017;37:1–28.

  21. 21.

    Zhu JR, Lu HD, Guo C, Fang WR, Zhao HD, Zhou JS, et al. Berberine attenuates ischemia–reperfusion injury through inhibiting HMGB1 release and NF-κB nuclear translocation. Acta Pharmacol Sin. 2018;39:1706–15.

  22. 22.

    Chen CZ, Li L, Lodish HF, Bartel DP. MicroRNAs modulate hematopoietic lineage differentiation. Science. 2004;303:83–86.

  23. 23.

    Ma Q, Zhao H, Tao Z, Wang R, Liu P, Han Z, et al. MicroRNA-181c exacerbates brain injury in acute ischemic stroke. Aging Dis. 2016;7:705–14.

  24. 24.

    Zhang L, Li YJ, Wu XY, Hong Z, Wei WS. MicroRNA‐181c negatively regulates the inflammatory response in oxygen‐glucose‐deprived microglia by targeting Toll‐like receptor 4. J Neurochem. 2015;132:713–23.

  25. 25.

    Guo D, Ma J, Yan L, Li T, Li Z, Han X, et al. Down-regulation of Lncrna MALAT1 attenuates neuronal cell death through suppressing beclin1-dependent autophagy by regulating Mir-30a in cerebral ischemic stroke. Cell Physiol Biochem. 2017;43:182–94.

  26. 26.

    Yong HYF, Rawji KS, Ghorbani S, Xue M, Yong VW. The benefits of neuroinflammation for the repair of the injured central nervous system. Cell Mol Immunol. 2019;16:540–6.

  27. 27.

    Lambertsen KL, Finsen B, Clausen BH. Post-stroke inflammation-target or tool for therapy? Acta Neuropathol. 2019;137:693–714.

  28. 28.

    Chamorro Á, Dirnagl U, Urra X, Planas AM. Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. Lancet Neurol. 2016;15:869–81.

  29. 29.

    Tsukagawa T, Katsumata R, Fujita M, Yasui K, Akhoon C, Ono K, et al. Elevated serum high-mobility group box-1 protein level is associated with poor functional outcome in ischemic stroke. J Stroke Cereb Dis. 2017;26:2404–11.

  30. 30.

    Yang X, Zi XH. LncRNA SNHG1 alleviates OGD induced injury in BMEC via miR-338/HIF-1alpha axis. Brain Res. 2019;1714:174–81.

  31. 31.

    Miao SY, Miao SM, Cui RT, Yu AL, Miao ZJ. SETD5-AS1 stimulates neuron death in stroke via promoting PTEN expression. Eur Rev Med Pharm Sci. 2018;22:6035–41.

  32. 32.

    Wang Y, Li G, Zhao L, Lv J. Long noncoding RNA HOTTIP alleviates oxygen-glucose deprivation-induced neuronal injury via modulating miR-143/hexokinase 2 pathway. J Cell Biochem. 2018;119:10107–17.

  33. 33.

    Zhang X, Hamblin MH, Yin KJ. The long noncoding RNA Malat1: its physiological and pathophysiological functions. RNA Biol. 2017;14:1705–14.

  34. 34.

    Wang LQ, Zhou HJ. LncRNA MALAT1 promotes high glucose-induced inflammatory response of microglial cells via provoking MyD88/IRAK1/TRAF6 signaling. Sci Rep. 2018;8:8346.

  35. 35.

    Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP. A ceRNA hypothesis: the rosetta stone of a hidden RNA language? Cell. 2011;146:353–8.

  36. 36.

    Chen F, Zhang L, Wang E, Zhang C, Li X. LncRNA GAS5 regulates ischemic stroke as a competing endogenous RNA for miR-137 to regulate the Notch1 signaling pathway. Biochem Biophys Res Commun. 2018;496:184–90.

  37. 37.

    Yan H, Rao J, Yuan J, Gao L, Huang W, Zhao L, et al. Long non-coding RNA MEG3 functions as a competing endogenous RNA to regulate ischemic neuronal death by targeting miR-21/PDCD4 signaling pathway. Cell Death Dis. 2017;8:3211.

  38. 38.

    Zhang L, Luo X, Chen F, Yuan W, Xiao X, Zhang X, et al. LncRNA SNHG1 regulates cerebrovascular pathologies as a competing endogenous RNA through HIF-1alpha/VEGF signaling in ischemic stroke. J Cell Biochem. 2018;119:5460–72.

  39. 39.

    Hutchison ER, Kawamoto EM, Taub DD, Lal A, Abdelmohsen K, Zhang Y, et al. Evidence for miR-181 involvement in neuroinflammatory responses of astrocytes. Glia. 2013;61:1018–28.

  40. 40.

    Li X, Liu L, Yang J, Yu Y, Chai J, Wang L, et al. Exosome derived from human umbilical cord mesenchymal stem cell mediates MiR-181c attenuating burn-induced excessive inflammation. EBioMedicine. 2016;8:72–82.

Download references


This work was supported by the National Natural Science Foundation of China (grant No. 81773987), the Program of Nanjing Health and Family Planning Commission (YKK188107) and the Hospital Pharmaceutical Research Program of Nanjing Pharmaceutical Commission (2017YX001).

Author information

JRZ and JGS conceived and designed the study. DWC, MML and RD performed the experiments. MML, RD and LN analyzed the data. DWC and WRF wrote the paper. JRZ, LN and JGS reviewed and edited the manuscript. All authors read and approved the manuscript.

Correspondence to Jun-rong Zhu or Li Niu or Jian-guo Sun.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

These authors are co-first authors: Ding-wen Cao, Man-man Liu, Rui Duan

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark


  • Malat1
  • miR-181c-5p
  • HMGB1
  • stroke
  • inflammation
  • berberine