Role of miR-181 Family Members in Stroke: Insights into Mechanisms and Therapeutic Potential
Abstract
:1. Introduction
2. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Benjamin, E.J.; Muntner, P.; Alonso, A.; Bittencourt, M.S.; Callaway, C.W.; Carson, A.P.; Chamberlain, A.M.; Chang, A.R.; Cheng, S.; Das, S.R.; et al. Heart Disease and Stroke Statistics-2019 Update: A Report From the American Heart Association. Circulation 2019, 139, e56–e528. [Google Scholar] [PubMed]
- Feigin, V.L.; Roth, G.A.; Naghavi, M.; Parmar, P.; Krishnamurthi, R.; Chugh, S.; Mensah, G.A.; Norrving, B.; Shiue, I.; Ng, M.; et al. Global burden of stroke and risk factors in 188 countries, during 1990-2013: A systematic analysis for the Global Burden of Disease Study 2013. Lancet Neurol. 2016, 15, 913–924. [Google Scholar] [CrossRef] [PubMed]
- Grefkes, C.; Fink, G.R. Recovery from stroke: Current concepts and future perspectives. Neurol. Res. Pract. 2020, 2, 17. [Google Scholar] [CrossRef] [PubMed]
- Turner, D.A.; Yang, W. Phase-specific manipulation of neuronal activity: A promising stroke therapy approach. Neural Regen. Res. 2021, 16, 1425–1426. [Google Scholar] [CrossRef]
- Salaudeen, M.A.; Bello, N.; Danraka, R.N.; Ammani, M.L. Understanding the Pathophysiology of Ischemic Stroke: The Basis of Current Therapies and Opportunity for New Ones. Biomolecules 2024, 14, 305. [Google Scholar] [CrossRef]
- Bulygin, K.V.; Beeraka, N.M.; Saitgareeva, A.R.; Nikolenko, V.N.; Gareev, I.; Beylerli, O.; Akhmadeeva, L.R.; Mikhaleva, L.M.; Solis, L.F.T.; Herrera, A.S.; et al. Can miRNAs Be Considered as Diagnostic and Therapeutic Molecules in Ischemic Stroke Pathogenesis?—Current Status. Int. J. Mol. Sci. 2020, 21, 6728. [Google Scholar] [CrossRef]
- Cepparulo, P.; Cuomo, O.; Vinciguerra, A.; Torelli, M.; Annunziato, L.; Pignataro, G. Hemorrhagic Stroke Induces a Time-Dependent Upregulation of miR-150-5p and miR-181b-5p in the Bloodstream. Front. Neurol. 2021, 12, 736474. [Google Scholar] [CrossRef]
- Braicu, C.; Catana, C.; Calin, G.A.; Berindan-Neagoe, I. NCRNA combined therapy as future treatment option for cancer. Curr. Pharm. Des. 2014, 20, 6565–6574. [Google Scholar] [CrossRef]
- Strmsek, Z.; Kunej, T. MicroRNA Silencing by DNA Methylation in Human Cancer: A Literature Analysis. Non-Coding RNA 2015, 1, 44. [Google Scholar] [CrossRef]
- Calin, G.A.; Croce, C.M. Genomics of chronic lymphocytic leukemia microRNAs as new players with clinical significance. Semin. Oncol. 2006, 33, 167–173. [Google Scholar] [CrossRef]
- Redis, R.S.; Berindan-Neagoe, I.; Pop, V.I.; Calin, G.A. Non-coding RNAs as theranostics in human cancers. J. Cell Biochem. 2012, 113, 1451–1459. [Google Scholar] [CrossRef] [PubMed]
- Pan, J.-Y.; Sun, C.-C.; Bi, Z.-Y.; Chen, Z.-L.; Li, S.-J.; Li, Q.-Q.; Wang, Y.-X.; Bi, Y.-Y.; Li, D.-J. miR-206/133b Cluster: A Weapon against Lung Cancer? Mol. Ther. Nucleic Acids 2017, 8, 442–449. [Google Scholar] [CrossRef] [PubMed]
- Volinia, S.; Calin, G.A.; Liu, C.G.; Ambs, S.; Cimmino, A.; Petrocca, F.; Visone, R.; Iorio, M.; Roldo, C.; Ferracin, M.; et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc. Natl. Acad. Sci. USA 2006, 103, 2257–2261. [Google Scholar] [CrossRef] [PubMed]
- Cipolla, G.; de Oliveira, J.; Salviano-Silva, A.; Lobo-Alves, S.; Lemos, D.; Oliveira, L.; Jucoski, T.S.; Mathias, C.; Pedroso, G.A.; Zambalde, E.P.; et al. Long Non-Coding RNAs in Multifactorial Diseases: Another Layer of Complexity. Non-Coding RNA 2018, 4, 13. [Google Scholar] [CrossRef] [PubMed]
- Braicu, C.; Cojocneanu-Petric, R.; Chira, S.; Truta, A.; Floares, A.; Achimas-Cadariu, P.; Berindan-Neagoe, I.; Petrut, B. Clinical and pathological implications of miRNA in bladder cancer. Int. J. Nanomed. 2015, 10, 791–800. [Google Scholar] [CrossRef]
- Catana, C.S.; Calin, G.A.; Berindan-Neagoe, I. Inflamma-miRs in Aging and Breast Cancer: Are They Reliable Players? Front. Med. 2015, 2, 85. [Google Scholar] [CrossRef]
- Irimie, A.I.; Braicu, C.; Sonea, L.; Zimta, A.A.; Cojocneanu-Petric, R.; Tonchev, K.; Mehterov, N.; Diudea, D.; Buduru, S.; Berindan-Neagoe, I. A Looking-Glass of Non-coding RNAs in oral cancer. Int. J. Mol. Sci. 2017, 18, 2620. [Google Scholar] [CrossRef]
- Catana, C.S.; Pichler, M.; Giannelli, G.; Mader, R.M.; Berindan-Neagoe, I. Non-coding RNAs, the Trojan horse in two-way communication between tumor and stroma in colorectal and hepatocellular carcinoma. Oncotarget 2017, 8, 29519–29534. [Google Scholar] [CrossRef]
- Berindan-Neagoe, I.; Monroig Pdel, C.; Pasculli, B.; Calin, G.A. MicroRNAome genome: A treasure for cancer diagnosis and therapy. CA A Cancer J. Clin. 2014, 64, 311–336. [Google Scholar] [CrossRef]
- Braicu, C.; Calin, G.A.; Berindan-Neagoe, I. MicroRNAs and cancer therapy—From bystanders to major players. Curr. Med. Chem. 2013, 20, 3561–3573. [Google Scholar] [CrossRef]
- Eastlack, S.C.; Alahari, S.K. MicroRNA and Breast Cancer: Understanding Pathogenesis, Improving Management. Non-Coding RNA 2015, 1, 17–43. [Google Scholar] [CrossRef] [PubMed]
- Munker, R.; Calin, G.A. MicroRNA profiling in cancer. Clin. Sci. (Lond. Engl. 1979) 2011, 121, 141–158. [Google Scholar] [CrossRef] [PubMed]
- Pop-Bica, C.; Pintea, S.; Cojocneanu-Petric, R.; Del Sal, G.; Piazza, S.; Wu, Z.H.; Alencar, A.J.; Lossos, I.S.; Berindan-Neagoe, I.; Calin, G.A. MiR-181 family-specific behavior in different cancers: A meta-analysis view. Cancer Metastasis Rev. 2018, 37, 17–32. [Google Scholar] [CrossRef] [PubMed]
- Gulei, D.; Petrut, B.; Tigu, A.B.; Onaciu, A.; Fischer-Fodor, E.; Atanasov, A.G.; Ionescu, C.; Berindan-Neagoe, I. Exosomes at a glance—Common nominators for cancer hallmarks and novel diagnosis tools. Crit. Rev. Biochem. Mol. Biol. 2018, 53, 564–577. [Google Scholar] [CrossRef]
- Bell-Hensley, A.; Das, S.; McAlinden, A. The miR-181 family: Wide-ranging pathophysiological effects on cell fate and function. J. Cell Physiol. 2023, 238, 698–713. [Google Scholar] [CrossRef]
- Indrieri, A.; Carrella, S.; Carotenuto, P.; Banfi, S.; Franco, B. The Pervasive Role of the miR-181 Family in Development, Neurodegeneration, and Cancer. Int. J. Mol. Sci. 2020, 21, 2092. [Google Scholar] [CrossRef]
- Lv, B.; He, S.; Li, P.; Jiang, S.; Li, D.; Lin, J.; Feinberg, M.W. MicroRNA-181 in cardiovascular disease: Emerging biomarkers and therapeutic targets. FASEB J. 2024, 38, e23635. [Google Scholar] [CrossRef]
- An, T.H.; He, Q.W.; Xia, Y.P.; Chen, S.C.; Baral, S.; Mao, L.; Jin, H.-J.; Li, Y.-N.; Wang, M.-D.; Chen, J.-G.; et al. MiR-181b Antagonizes Atherosclerotic Plaque Vulnerability Through Modulating Macrophage Polarization by Directly Targeting Notch1. Mol. Neurobiol. 2016, 54, 6329–6341. [Google Scholar] [CrossRef]
- Sun, X.; Sit, A.; Feinberg, M.W. Role of miR-181 family in regulating vascular inflammation and immunity. Trends Cardiovasc. Med. 2014, 24, 105–112. [Google Scholar] [CrossRef]
- Braicu, C.; Gulei, D.; Cojocneanu, R.; Raduly, L.; Jurj, A.; Knutsen, E.; Calin, G.A.; Berindan-Neagoe, I. miR-181a/b therapy in lung cancer: Reality or myth? Mol. Oncol. 2019, 13, 9–25. [Google Scholar] [CrossRef]
- Braicu, C.; Gulei, D.; Raduly, L.; Harangus, A.; Rusu, A.; Berindan-Neagoe, I. Altered expression of miR-181 affects cell fate and targets drug resistance-related mechanisms. Mol. Asp. Med. 2019, 70, 90–105. [Google Scholar] [CrossRef] [PubMed]
- Rezaei, T.; Amini, M.; Hashemi, Z.S.; Mansoori, B.; Rezaei, S.; Karami, H.; Mosafer, J.; Mokhtarzadeh, A.; Baradaran, B. microRNA-181 serves as a dual-role regulator in the development of human cancers. Free Radic. Biol. Med. 2020, 152, 432–454. [Google Scholar] [CrossRef] [PubMed]
- Han, X.; Zheng, Z.; Wang, C.; Wang, L. Association between MEG3/miR-181b polymorphisms and risk of ischemic stroke. Lipids Health Dis. 2018, 17, 292. [Google Scholar] [CrossRef]
- Antony, M.; Scranton, V.; Srivastava, P.; Verma, R. Micro RNA 181c-5p: A promising target for post-stroke recovery in socially isolated mice. Neurosci. Lett. 2020, 715, 134610. [Google Scholar] [CrossRef]
- Edwardson, M.A.; Shivapurkar, N.; Li, J.; Khan, M.; Smith, J.; Giannetti, M.L.; Fan, R.; Dromerick, A.W. Expansion of plasma MicroRNAs over the first month following human stroke. J. Cereb. Blood Flow. Metab. 2023, 43, 2130–2143. [Google Scholar] [CrossRef]
- Bellaousov, S.; Reuter, J.S.; Seetin, M.G.; Mathews, D.H. RNAstructure: Web servers for RNA secondary structure prediction and analysis. Nucleic Acids Res. 2013, 41, W471–W474. [Google Scholar] [CrossRef]
- Li, S.; Zhu, P.; Wang, Y.; Huang, S.; Wu, Z.; He, J.; Hu, X.; Wang, Y.; Yuan, Y.; Zhao, B.; et al. miR-181a targets PTEN to mediate the neuronal injury caused by oxygen-glucose deprivation and reoxygenation. Metab. Brain Dis. 2023, 38, 2077–2091. [Google Scholar] [CrossRef]
- Anatomica LMTTHY-yWY-sAbtpaelotfm-asoisJA. Available online: https://jpxb.bjmu.edu.cn/EN/10.16098/j.issn.0529-1356-2022.04.010 (accessed on 29 December 2024).
- Ma, Q.; Zhao, H.; Tao, Z.; Wang, R.; Liu, P.; Han, Z.; Ma, S.; Luo, Y.; Jia, J. MicroRNA-181c Exacerbates Brain Injury in Acute Ischemic Stroke. Aging Dis. 2016, 7, 705–714. [Google Scholar] [CrossRef]
- Song, X.; Xue, Y.; Cai, H. Down-Regulation of miR-181a-5p Prevents Cerebral Ischemic Injury by Upregulating En2 and Activating Wnt/β-catenin Pathway. J. Stroke Cerebrovasc. Dis. 2021, 30, 105485. [Google Scholar] [CrossRef]
- Shu, J.; Yang, L.; Wei, W.; Zhang, L. Identification of programmed cell death-related gene signature and associated regulatory axis in cerebral ischemia/reperfusion injury. Front. Genet. 2022, 13, 934154. [Google Scholar] [CrossRef]
- Ouyang, Y.B.; Lu, Y.; Yue, S.; Xu, L.J.; Xiong, X.X.; White, R.E.; Sun, X.; Giffard, R.G. miR-181 regulates GRP78 and influences outcome from cerebral ischemia in vitro and in vivo. Neurobiol. Dis. 2012, 45, 555–563. [Google Scholar] [CrossRef] [PubMed]
- Li, S.; Chen, S.; Wang, Y.; Hu, X.; Wang, Y.; Wu, Z.; Huang, S.; He, J.; Deng, F.; Zhao, B.; et al. Direct targeting of DOCK4 by miRNA-181d in oxygen-glucose deprivation/reoxygenation-mediated neuronal injury. Lipids Health Dis. 2023, 22, 34. [Google Scholar] [CrossRef] [PubMed]
- Yang, X.; Yan, S.; Wang, P.; Wang, G. Identification of Hub Genes in the Pathogenesis of Ischemic Stroke Based on Bioinformatics Analysis. J. Korean Neurosurg. Soc. 2022, 65, 697–709. [Google Scholar] [CrossRef] [PubMed]
- Hutchison, E.R.; Kawamoto, E.M.; Taub, D.D.; Lal, A.; Abdelmohsen, K.; Zhang, Y.; Wood, W.H., III; Lehrmann, E.; Camandola, S.; Becker, K.G.; et al. Involvement of miR-181 in Neuroinflammatory Responses of Astrocytes. Glia 2013, 61, 1018–1028. [Google Scholar] [CrossRef]
- Xue, L.X.; Shu, L.Y.; Wang, H.M.; Lu, K.L.; Huang, L.G.; Xiang, J.Y.; Geng, Z.; Zhao, Y.-W.; Chen, H. miR-181b promotes angiogenesis and neurological function recovery after ischemic stroke. Neural Regen. Res. 2023, 18, 1983–1989. [Google Scholar]
- Zhang, L.; Li, Y.J.; Wu, X.Y.; Hong, Z.; Wei, W.S. MicroRNA-181c negatively regulates the inflammatory response in oxygen-glucose-deprived microglia by targeting Toll-like receptor 4. J. Neurochem. 2015, 132, 713–723. [Google Scholar] [CrossRef]
- Cao, D.-W.; Liu, M.-M.; Duan, R.; Tao, Y.-F.; Zhou, J.-S.; Fang, W.-R.; Zhu, J.-R.; Niu, L.; Sun, J.-G. The lncRNA Malat1 functions as a ceRNA to contribute to berberine-mediated inhibition of HMGB1 by sponging miR-181c-5p in poststroke inflammation. Acta Pharmacol. Sin. 2020, 41, 22–33. [Google Scholar] [CrossRef]
- Xie, W.; Li, M.; Xu, N.; Lv, Q.; Huang, N.; He, J.; Zhang, Y. MiR-181a regulates inflammation responses in monocytes and macrophages. PLoS ONE 2013, 8, e58639. [Google Scholar] [CrossRef]
- Zhang, L.; Dong, L.-Y.; Li, Y.-J.; Hong, Z.; Wei, W.-S. The microRNA miR-181c controls microglia-mediated neuronal apoptosis by suppressing tumor necrosis factor. J. Neuroinflamm. 2012, 9, 211. [Google Scholar] [CrossRef]
- Walsh, K.B.; Zimmerman, K.D.; Zhang, X.; Demel, S.L.; Luo, Y.; Langefeld, C.D.; Wohleb, E.; Schulert, G.; Woo, D.; Adeoye, O. miR-181a Mediates Inflammatory Gene Expression After Intracerebral Hemorrhage: An Integrated Analysis of miRNA-seq and mRNA-seq in a Swine ICH Model. J. Mol. Neurosci. 2021, 71, 1802–1814. [Google Scholar] [CrossRef]
- Zhuo, Y.; Chen, W.; Li, W.; Huang, Y.; Duan, D.; Ge, L.; He, J.; Liu, J.; Hu, Z.; Lu, M. Ischemic-hypoxic preconditioning enhances the mitochondrial function recovery of transplanted olfactory mucosa mesenchymal stem cells via miR-181a signaling in ischemic stroke. Aging 2021, 13, 11234–11256. [Google Scholar] [CrossRef]
- Moon, J.M.; Xu, L.; Giffard, R.G. Inhibition of microRNA-181 reduces forebrain ischemia-induced neuronal loss. J. Cereb. Blood Flow. Metab. 2013, 33, 1976–1982. [Google Scholar] [CrossRef] [PubMed]
- Yang, Y.; Cai, Y.; Zhang, Y.; Liu, J.; Xu, Z. Exosomes Secreted by Adipose-Derived Stem Cells Contribute to Angiogenesis of Brain Microvascular Endothelial Cells Following Oxygen-Glucose Deprivation In Vitro Through MicroRNA-181b/TRPM7 Axis. J. Mol. Neurosci. 2018, 65, 74–83. [Google Scholar] [CrossRef] [PubMed]
- Xu, G.; Song, X.; Wang, X.; Xue, R.; Yan, X.; Qin, L.; Chang, X.; Gao, J.; Chen, Z.; Song, G. Combined miR-181a-5p and Ag Nanoparticles are Effective Against Oral Cancer in a Mouse Model. Int. J. Nanomed. 2024, 19, 9227–9253. [Google Scholar] [CrossRef] [PubMed]
- Xu, L.J.; Ouyang, Y.B.; Xiong, X.; Stary, C.M.; Giffard, R.G. Post-stroke treatment with miR-181 antagomir reduces injury and improves long-term behavioral recovery in mice after focal cerebral ischemia. Exp. Neurol. 2015, 264, 1–7. [Google Scholar] [CrossRef] [PubMed]
- Griffiths, B.B.; Ouyang, Y.-B.; Xu, L.; Sun, X.; Giffard, R.G.; Stary, C.M. Postinjury Inhibition of miR-181a Promotes Restoration of Hippocampal CA1 Neurons After Transient Forebrain Ischemia in Rats. eneuro 2019, 6, ENEURO.0002-19.2019. [Google Scholar] [CrossRef]
- Deng, B.; Bai, F.; Zhou, H.; Zhou, D.; Ma, Z.; Xiong, L.; Wang, Q. Electroacupuncture enhances rehabilitation through miR-181b targeting PirB after ischemic stroke. Sci. Rep. 2016, 6, 38997. [Google Scholar] [CrossRef]
- Kim, M.; Lee, Y.; Lee, M. Hypoxia-specific anti-RAGE exosomes for nose-to-brain delivery of anti-miR-181a oligonucleotide in an ischemic stroke model. Nanoscale 2021, 13, 14166–14178. [Google Scholar] [CrossRef]
- Zhang, X.; Liu, Z.; Shu, Q.; Yuan, S.; Xing, Z.; Song, J. LncRNA SNHG6 functions as a ceRNA to regulate neuronal cell apoptosis by modulating miR-181c-5p/BIM signalling in ischaemic stroke. J. Cell Mol. Med. 2019, 23, 6120–6130. [Google Scholar] [CrossRef]
SNP Locus | Polymorphism | Relevant Findings of the Study and Correlation with Expression Level or Other Relevant Clinical Data | Reference |
---|---|---|---|
miR-181a | rs322931 | Variant related to a higher risk of IS | [37] |
miR-181b | rs322931 | MEG3/miR-181b polymorphisms for risk stratification | [33] |
miR-181c | rs16927589, rs77418916, rs8108402 | Association between the polymorphism and expression level of the family miR-181s | [38] |
Transcript Member | Biological Specimens | Evaluation Methos | Findings | Ref. |
---|---|---|---|---|
↑ miR-181a-3p ↑ miR-181a-5p | IS samples at 48h, 5, 15, and 30 days post-IS (n = 55) versus healthy control plasma | Profiling study (miRNA microarray) Validation cohort qRT-PCR: IS at 48h respectively, 15-days post-IS (n = 55) to healthy control samples (n = 48) | ↑ miR-181a part of a biomarker signature; involved in apoptosis, synapse regulation and neuronal protection. | [35] |
↑ miR-181a-5p | IS (n = 81) and healthy controls (n = 42) plasma samples; MCAO models; OGD/R-induced N2a cells MACAO model versus sham group; OGD/R-induced N2a cells versus control N2a cells | qRT-PCR | correlated to the pathological of IS | [40] |
↓ miR-181a-5p ↓ miR-181a-3p ↓ miR-181c-5p ↓ miR-181c-3p ↓ miR-181d-5p | IS versus healthy control lymphocytes | Profiling study (miRNA microarray) | part of altered miRNA signature specific for IS | [39] |
↓ miR-181c-5p ↓ miR-181d-5p | IS (n = 10) and healthy controls (n = 7) plasma | qRT-PCR | miR-181c correlated with clinical parameters of IS (lymphocyte percentage, neutrophil number) | [39] |
In Vitro and/or In Vivo Methods | Therapeutic Approaches/Delivery System | Fold Change | Observation Related to Therapeutic Role of Modulation of This Transcript | Ref. |
---|---|---|---|---|
Astrocyte | ||||
N2a cells Astrocytes, Male Sprague–Dawley rats | 10 pmol of miR-181a mimic and 20 pmol of inhibitor; cationic lipid DOTAP 1:3 infused stereotactically just outside the left hippocampus (from bregma −3.8 mm, M-L 2.0 mm, deep 2.5 mm) at 1 μL/minute, maximal total volume 16 μL via a burr hole | ↑ miR-181a | miR-181a is upregulated in the infarct core and downregulated in the penumbra after focal ischemia. Inhibition of miR-181 reduces forebrain ischemia-induced neuronal loss and activated cell death mechansims by caspases 3 and 7 activation | [53] |
Mouse primary astrocyte cultures C57BL/6J mice or TNFR1/TNFR2 double knockout (DKO) | miR-181c and miR-181b hairpin inhibitors/Lipofectamine | ↑ miR-181b/c/d | regulate cell proliferation and neuroinflammation; affect cytokine production cell death and inflammation responses genes; direct targets MeCP2 and XIAP | [45] |
Neurons | ||||
N2a cells, primary mouse neuronal culture | miR-181a mimics and inhibitors Lipofectamine 2000 | N/A | Inhibition of miR-181a reduces forebrain ischemia-induced neuronal loss, affects apoptosis via BCL2 and GLT-1 | [59] |
Primary hippocampal microglial and hippocampal neuronal rat cells | miR-181a mimics and inhibitors Lipofectamine 2000 | N/A | microglia-mediated neuronal apoptosis by targeting TNF-α | [50] |
Microglia | ||||
BV-2 microglial cell line and primary cultured rat microglial cells | miR-181c mimics/inhibitors and negative control/Lipofectamine 2000 | miR-181c regulates TLR4 expression; miR-181c inhibits NF-κB activation and the downstream production of proinflammatory mediators | [47] | |
BV-2 microglial cells and HEK-293T cells | Lenti-miR-181a-5p inhibitor, Lenti-NC, sham, miR-181a and NC inhibitor Lipofectamine 2000 | rescues HMGB1 inhibition induced by Malat1 downregulation | [48] | |
BV2 microglial cells and Neuro-2a cells | Lipopolysaccharide (LPS)/hydrogen peroxide (H2O2); miR-181c mimic/inhibitor (50 nM/L), Lipofectamine RNAiMAX | ↓ miR-181a/c/d | MiR-181c agomir inhibits proliferation and induces apoptosis of BV2 microglial cells upon oxidative stress and inflammation, accelerates apoptosis of neuronal cells co-cultured with microglial cells | [39] |
Cerebral ischemia | ||||
OGD/R N2a cell culture model and MCAO in vivo model | miR-181a inhibitor si NC, Lipofectamine 2000 | ↑ miR-181a | Down-regulation of miR-181a-5p prevents cerebral ischemic injury by upregulating En2 and activating the Wnt/β-catenin pathway | [40] |
OGD/R N2a cell culture model and MCAO in vivo model | miR-181b antagomir and negative control/intracerebroventricular infusion (5 pmol/ll, at a rate of 1 ll/hr) | ↓ miR-181b in Response to Ischemic Exposure | Downregulation of miR-181b Reduces OGD Induced N2A Cell Injury; miR-181b Regulates HSPA5 and UCHL1 Protein Levels Through Binding to 30 -UTR mRNAs region | [45] |
Neuro2A and HEK293T cells; MCAO in vivo model | AMO181a-chol loaded onto RBP-Exo | neuroprotective effects in the ischemic brain | [59] | |
OGD/R N2a cell culture model; MCAO in vivo model | siRNA SNHG6, mR-181c mimic/inhibitor and negative control, Lipofectamine 2000 | N/A | SNHG6 directly binds to miR-181c-5p and negatively regulates its expression; miR-181c-5p targets the 3′UTR of BIM and negatively regulates the expression of BIM; ceRNA- SNHG6-miR-181c-BIM and promote cell apoptosis | [60] |
SH-SY5Y cell in OGD/R condition and MCAO in vivo model | miR-181a inhibitor Lipofectamine 2000 | ↑miR-181a in the MCAO model versus sham | PTEN overexpression reduced cell apoptosis and oxidative stress induced by miR-181a upregulation under an OGD/R condition | [37] |
OGD/R N2a cell culture model; Transient MCAO model in rats | miR-181a inhibitor si NC, Lipofectamine 2000 | ↑miR-181d | miR-181d regulates cerebral ischemia/reperfusion injury by negatively targeting DOCK4 under OGD/R | [43] |
BMVECs and MCAO in vivo model | miR-181b-5p mimic si inhibitor | - | regulate angiogenesis and neurological function via PTEN/Akt; miR-181b-5p agomir promotes neurological function recovery and reduces infarct volume in MCAO rats | [46] |
MCAO or intracerebroventricular (ICV) | Lenti-miR-181c-5p, miR-181c-5p inhibitor Lenti-NC or NC | Malat1/miR-181c-5p/HMGB1 axis a key pathway in stroke | [48] | |
Hemorrhagic stroke | ||||
Plasma MACAO-collagenase-induced hemorrhagic stroke | miR-181a-5p | ↑ miR-181a | time-dependent upregulation of miR-150-5p and miR-181b-5p in the plasma | [7] |
Ischemic-hypoxic preconditioned olfactory mucosa-derived mesenchymal stem cells (IhOM-MSCs) and MSCs and SH-SY5Y neurons in a co-culture system and MCAO in vivo model | miR-181a mimic and inhibitor | N/A | IhOM-MSCs mediated the upregulation of the downstream target genes GRP78 and Bcl-2 by miR-181a to protect mitochondrial function and inhibit apoptosis and pyroptosis of neurons in the ischemia/reperfusion injury model. | [52] |
Mice Intracerebroventricular Infusion (ICV) and Intravenous Injection (IV) of 181a Antagomir | miRNA-181a antagomir (3 pmol/gram in 2 μL final volume) and a negative control: mismatched (MM)-for miR-181a antagomir mixed with the cationic lipid DOTAP (4 μL) | ↑ miR-181a in stroke | Post-stroke treatment with miR-181a antagomir reduces infarction size, reduces long-term neurobehavioral deficits and inflammation; targets BCL2 and XIAP; both administration routes are effective. | [56] |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Braicu, C.; Mureșanu, F.D.; Isachesku, E.; Bornstein, N.; Filipović, S.R.; Strilciuc, S.; Pana, A. Role of miR-181 Family Members in Stroke: Insights into Mechanisms and Therapeutic Potential. Int. J. Mol. Sci. 2025, 26, 440. https://doi.org/10.3390/ijms26020440
Braicu C, Mureșanu FD, Isachesku E, Bornstein N, Filipović SR, Strilciuc S, Pana A. Role of miR-181 Family Members in Stroke: Insights into Mechanisms and Therapeutic Potential. International Journal of Molecular Sciences. 2025; 26(2):440. https://doi.org/10.3390/ijms26020440
Chicago/Turabian StyleBraicu, Cornelia, Fior Dafin Mureșanu, Ekaterina Isachesku, Natan Bornstein, Saša R. Filipović, Stefan Strilciuc, and Adrian Pana. 2025. "Role of miR-181 Family Members in Stroke: Insights into Mechanisms and Therapeutic Potential" International Journal of Molecular Sciences 26, no. 2: 440. https://doi.org/10.3390/ijms26020440
APA StyleBraicu, C., Mureșanu, F. D., Isachesku, E., Bornstein, N., Filipović, S. R., Strilciuc, S., & Pana, A. (2025). Role of miR-181 Family Members in Stroke: Insights into Mechanisms and Therapeutic Potential. International Journal of Molecular Sciences, 26(2), 440. https://doi.org/10.3390/ijms26020440