Effects of ischemic postconditioning and long non-coding RNAs in ischemic stroke

Figures & data

Table 1. Common mechanisms of cerebral injury in ischemic stroke.

Effect on the brain	Related factors	Mechanisms related to cerebral injury	References
Neuroinflammation	1. Pro-inflammatory cytokines: IL-6, IL-8, IL-1β, COX-2, TNF-α; Anti-inflammatory factors: IL-4 and IL-10 2. MAPK, NLRP inflammasome 3. MiRNA, caspase-3 4. ACSL4, rhFGF21, NF-κB, PPAR-γ	1.Regulation of pro-inflammatory and anti-inflammatory cytokines in the ischemic brain. 2. Activation of the MAPK signaling pathway contributes to activation of the NLRP1 and NLRP3 inflammasome proteins in neurons and brain tissues. 3. Circulating miRNA-3552 interacts with caspase-3 to participate in neuroinflammatory responses. 4. ACSL4 and rhFGF21 modulate microglia/macrophage-mediated neuroinflammation via the NF-κB and PPAR-γ signaling pathways.	1. [5–8,15,16] 2. [9,10] 3. [20] 4. [25]
Neuronal apoptosis	Caspase family, TNF-α, TNF-R, Bcl-2 family, CREB, Hes1, FoxP2, p38 MAPK signaling pathway	Regulation of neuronal cell apoptosis in the ischemic brain.	[18–20]
Steady-state balance of Ca^2+	NMDA receptor	Activation of NMDA receptors may result in Ca^2+ influx in neurons and activation of Ca^2+-dependent protease-induced cell death pathways, resulting in neuronal apoptosis after cerebral ischemia.	[21–23]
Oxidative stress	1. ROS 2. Glutathione peroxidase	1. Oxidative stress induced by ROS overproduction is associated with ischemia-reperfusion injury, neuronal apoptosis, inflammatory signaling pathway activation, and blood-brain barrier damage in ischemic stroke. 2. Neuronal glutathione reduction is the result of oxidative stress in the brain caused by ischemia-reperfusion.	[26–29,139]
Autophagy	1. Beclin-1 2. Malat1 3. MEG3	1. Beclin-1 induces autophagy and regulates the survival or death of ischemic neurons. 2. Downregulation of Malat1 inhibits Beclin1-dependent autophagy in ischemic stroke. 3. MEG3 is upregulated and interacts with p53 to mediate neuron autophagy in ischemic stroke.	1. [20] 2. [30] 3. [31]
Energy metabolism disorders	1. NADPH 2. PGC-1α 3. AMPK	1. NADPH diaphorease expression is upregulated in hippocampal astrocytes after ischemic stroke. 2. PGC-1α increases mitochondrial fatty acid oxidation gene expression in ischemic brain tissue. 3. AMPK resists cerebral ischemic injury by activating catabolic pathways and inactivating ATP-consuming processes.	1. [33] 2. [35] 3. [36]
Excessive intracellular free radicals and NO	1. Superoxide dismutase 2. Nitric oxide synthase	1. Superoxide dismutase protects the brain by removing excessive free radicals from cells. 2. Increases in nitric oxide synthase expression and NO production by reactive astrocytes may play a role in delayed neuronal death after ischemic damage.	1. [37] 2. [11]
Excitatory amino acid toxicity	1. Glutamate levels, glutamate transporters (glt-1), gap junction proteins (Cx43), Na^+-K^+-ATPase activity 2. NMDA receptors 3. NO, oxygen free radicals	1. The expression levels of glutamate, glt-1, Cx43, and AMPARs and Na^+-K^+-ATPase activity are related to excitotoxicity and anti-excitotoxicity in ischemic stroke. 2. NMDA receptor antagonists can inhibit the release of excitatory amino acids during ischemic stroke. 3. The neurotoxicity of NO is mainly caused by its reaction with oxygen free radicals.	1. [39,40] 2. [41,42] 3. [43]
Blood-brain barrier damage	1. Aquaporin-4 2. Mitochondrial proteins 3. A Na^+ channel blocker and an antioxidant: AM-36 4. MMP-2/MMP-9	1. Downregulation of aquaporin-4 can increase the integrity of the blood-brain barrier and improve cerebral blood flow after transient MCAO. 2. Nitrite may increase cerebral blood flow via its effect on nitrosylation of mitochondrial proteins. 3. AM-36 exhibits a neuroprotective effect by modulating neutrophil accumulation in the ischemic brain. 4. Activation of MMP-2 or MMP-9 contributes to the breakdown of the blood-brain barrier in ischemic stroke. High serum MMP-9 levels are related to an increased risk of death and disability in acute ischemic stroke.	1. [45] 2. [46] 3. [47,48] 4. [49–51]
Formation of glial scars	Cytokines from neurons and neuroglial cells, such as vimentin, nestin, IL-1β, monocyte chemotactic protein-1, and glial fibrillary acidic protein	Cytokines contribute to the development of reactive gliosis and the formation of glial scars.	[14,52]

IL: interleukin, COX: cyclooxygenase, TNF: tumor necrosis factor, MAPK: mitogen-activated protein kinase, NLRP: nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing protein, miRNA: microRNA, ACSL: acyl-CoA synthetase long chain, NF-κB: nuclear factor kappa B, PPAR: peroxisome proliferator-activated receptor, NMDA: N-methyl-D-aspartate, ROS: reactive oxygen species, CREB: cAMP-response element binding protein. Malat1: metastasis-associated lung adenocarcinoma transcript 1, MEG3: maternal expression gene 3, NADPH: nicotinamide adenine dinucleotide phosphate, PGC: peroxisome proliferator-activated receptor-gamma coactivator, AMPK: adenosine 5’-monophosphate-activated protein kinase, NO: nitric oxide, MMP: matrix metalloproteinase, MCAO: middle cerebral artery occlusion.

Table 2. The neuroprotective mechanisms of IPostC in ischemic stroke.

Effect on brain	Neuroprotective mechanism	References
Exosomes	Exosomes can alleviate the excitotoxicity of glutamate and reduce the cerebral infarction volume, cerebral edema, and NMDA receptor expression in the ischemic brain.	[74–76]
Limitation of inflammation and delayed cell death	IPostC can stimulate protective factors to alleviate inflammation and delayed cell death.	[55–57,80,81]
Attenuation of reperfusion injury	IPostC can reduce ischemia-reperfusion injury by regulating a variety of endogenous neuroprotective mechanisms, including reducing ROS production, alleviating inflammation, activating autophagy, endoplasmic reticulum stress, and neuronal apoptosis, and improving the cerebral blood supply.	[58,59,81,82]
Regulation of autophagy	Autophagy eliminates or activates the neuroprotective effects mediated by IPostC, including regulation of the inflammatory reaction, ROS production, endoplasmic reticulum stress, neuronal apoptosis, and phosphorylation of the MAPK, PKC, Notch, and PI3K/Akt pathways.	[58–63]
Anti-edema effects	IPostC effectively reduces brain edema after reperfusion by inhibiting AQP4 expression.	[69,73,83]
Enhancement of collateral microvascular circulation	RIPostC can enhance collateral microvascular circulation.	[84–86]
Nitric oxide synthase	1. The neuronal isoform of nitric oxide synthase participates in the neuroprotective effect of RIPostC. 2. RIPostC protects the brain against cerebral ischemia-reperfusion injury by upregulating eNOS through the PI3K/Akt pathway.	1. [87,88] 2. [85]
Alleviation of blood brain barrier disruption	RIPostC can effectively improve blood-brain barrier permeability by activating matrix metalloproteinase-9 and inhibiting claudin-5.	[80,89]
Inhibition of ROS production and excessive intracellular Ca^2+ accumulation	RIPostC can reduce ROS levels and neutrophil activation through the MyD88-TRAF6-MAPK pathway.	[78,79]

IPostC: ischemic postconditioning, NMDA: N-methyl-D-aspartate, ROS: reactive oxygen species, MAPK: mitogen-activated protein kinase, PKC: protein kinase C, PI3K: phosphoinositide 3-kinase, AQP4: aquaporin-4, RIPostC: remote ischemic postconditioning, eNOS: endothelial nitric oxide synthase.

Table 3. LncRNAs associated with ischemic stroke.

LncRNA	Mechanisms in ischemic stroke	References
ANRIL	Regulation of the expression level of the antisense ANRIL lncRNA and promotion of angiogenesis and inflammation through the NF-κB and VEGF signaling pathways.	[101–103]
C2dat1	Activation of C2dat1 lncRNA can increase calcium/calmodulin dependent protein kinase II delta expression and then activate the NF-κB signaling pathway to inhibit the inflammatory response.	[91,104]
H19	The circulating expression level of lncRNA H19 is significantly upregulated in the plasma of stroke patients, OGD/R SH-SY5Y cells, and MCAO/R rat brains.	[106–109]
Malat1	Silencing Malat1 results in increased expression of pro-inflammatory cytokines, and upregulation of Malat1 lncRNA can alleviate ischemic cerebrovascular and brain parenchymal damage. Malat1 lncRNA affects AQP4 expression by competitively binding miR-145 to promote cerebral ischemia-reperfusion injury.	[110] [111]
MEG3	The expression of MEG3 lncRNA is significantly increased in MCAO mouse brain tissue. Inhibition of MEG3 reduces the cerebral infarction volume and degree of cerebral edema. MEG3 lncRNA accelerates the ischemic stroke process by inhibiting miRNA 424–5p to regulate MAPK pathway activation.	[20] [112]
SNHG12	SNHG12 lncRNA targets miR-199a to reduce cell death and inflammation or targets miR-150 to de-repress its target gene, VEGF, in OGD-injured mouse BMECs. SNHG12 lncRNA is upregulated in mouse neuronal cells during ischemia. SNHG12 lncRNA is upregulated at 24 hours of reperfusion in the post-stroke adult mouse cortex.	[114–117]
FosDT	Inhibition of FosDT lncRNA promotes post-stroke neuroprotection via abrogation of REST-mediated gene silencing. FosDT lncRNA is associated with decreased induction of inflammatory genes, decreased apoptosis, mitochondrial dysfunction, and oxidative stress in the ischemic brain.	[86,87] [120]
NEAT1	NEAT1 lncRNA upregulates HOXA1 to alleviate cell apoptosis and promotes cell viability in neonatal mice with hypoxic-ischemic brain damage. NEAT1 knockout can significantly reduce brain injury by inhibiting microglial activation and release of pro-inflammatory cytokines.	[121] [122]
HOTAIR	Silencing of HOTAIR lncRNA improves the recovery of neurological function after ischemic stroke via the miR-148a-3p/KLF6 axis. HOTAIR lncRNA mediates OGD/R-induced cell injury and angiogenesis in an EZH2-dependent manner.	[123,124]
ENSG00000226482 ENSG00000260539	The ENSG00000226482 and ENSG00000260539 lncRNAs are associated with the PPAR signaling pathway and cell adhesion molecules.	[125]
MIAT	Ischemic stroke patients with higher MIAT lncRNA expression levels have a relatively poor prognosis.	[136]
UCA1	A high UCA1 lncRNA expression level is associated with worse accumulated recurrence and survival in ischemic stroke patients.	[138]

IPostC: ischemic postconditioning, lncRNA: long non-coding RNA, ANRIL: antisense non-coding RNA in the INK4 locus, NF-κB: nuclear factor kappa B, VEGF: vascular endothelial growth factor, C2dat1: calcium/calmodulin dependent protein kinase II delta associated transcript 1, OGD/R: oxygen-glucose deprivation/reoxygenation, MCAO: middle cerebral artery occlusion, Malat1: metastasis-associated lung adenocarcinoma transcript 1, AQP4: aquaporin-4, MEG3: maternal expression gene 3, miR: microRNA, MAPK: mitogen-activated protein kinase, SNHG12: small nucleolar RNA host gene 12, FosDT: Fos downstream transcript, NEAT1: nuclear-enriched abundant transcript1, HOXA1: homeoboxA1, HOTAIR: Hox transcript antisense intergenic RNA, EZH2: enhancer of zeste homolog 2, PPAR: peroxisome proliferator-activated receptor, MIAT: myocardial infarction-associated transcript, UCA1: urothelial carcinoma-associated 1, BMECs: brain microvascular endothelial cells.

Maida CD, Norrito RL, Daidone M, et al. Neuroinflammatory Mechanisms in Ischemic Stroke: focus on Cardioembolic Stroke, Background, and Therapeutic Approaches. Int J Mol Sci. 2020;21(18):6454.

 PubMed Web of Science ®Google Scholar

Cui Y, Zhang Y, Zhao X, et al. ACSL4 exacerbates ischemic stroke by promoting ferroptosis-induced brain injury and neuroinflammation. Brain Behav Immun. 2021;93:312–321.

 PubMed Web of Science ®Google Scholar

Liu X, Zhang CS, Lu C, et al. A conserved motif in JNK/p38-specific MAPK phosphatases as a determinant for JNK1 recognition and inactivation. Nat Commun. 2016;7:10879.

 PubMed Web of Science ®Google Scholar

Fann DY-W, Lim Y-A, Cheng Y-L, et al. Evidence that NF-κB and MAPK Signaling Promotes NLRP Inflammasome Activation in Neurons Following Ischemic Stroke. Mol Neurobiol. 2018;55(2):1082–1096.

 PubMed Web of Science ®Google Scholar

Yan H, Yuan J, Gao L, et al. Long noncoding RNA MEG3 activation of p53 mediates ischemic neuronal death in stroke. Neuroscience. 2016;337:191–199.

 PubMed Web of Science ®Google Scholar

Chen H, Yoshioka H, Kim GS, et al. Oxidative stress in ischemic brain damage: mechanisms of cell death and potential molecular targets for neuroprotection. Antioxid Redox Signal. 2011;14(8):1505–1517.

 PubMed Web of Science ®Google Scholar

Won SJ, Kim JE, Cittolin-Santos GF, et al. Assessment at the single-cell level identifies neuronal glutathione depletion as both a cause and effect of ischemia-reperfusion oxidative stress. J Neurosci. 2015;35(18):7143–7152.

 PubMed Web of Science ®Google Scholar

Su J, Zhang T, Wang K, et al. Autophagy activation contributes to the neuroprotection of remote ischemic perconditioning against focal cerebral ischemia in rats. Neurochem Res. 2014;39(11):2068–2077.

 PubMed Web of Science ®Google Scholar

Fan YY, Hu WW, Nan F, et al. Postconditioning-induced neuroprotection, mechanisms and applications in cerebral ischemia. Neurochem Int. 2017;107:43–56.

 PubMed Web of Science ®Google Scholar

Su XT, Wang L, Ma SM, et al. Mechanisms of Acupuncture in the Regulation of Oxidative Stress in Treating Ischemic Stroke. Oxid Med Cell Longev. 2020;2020:7875396.

 PubMed Web of Science ®Google Scholar

Ham PB 3rd, Raju R. Mitochondrial function in hypoxic ischemic injury and influence of aging. Prog Neurobiol. 2017;157:92–116.

 PubMed Web of Science ®Google Scholar

Jiang S, Li T, Ji T, et al. AMPK: potential Therapeutic Target for Ischemic Stroke. Theranostics. 2018;8(16):4535–4551.

 PubMed Web of Science ®Google Scholar

Si Z, Liu J, Hu K, et al. Effects of thrombolysis within 6 hours on acute cerebral infarction in an improved rat embolic middle cerebral artery occlusion model for ischaemic stroke. J Cell Mol Med. 2019;23(4):2468–2474.

 PubMed Web of Science ®Google Scholar

Pluta R, Januszewski S, Czuczwar SJ. Neuroinflammation in Post-Ischemic Neurodegeneration of the Brain: friend, Foe, or Both? Int J Mol Sci. 2021;22(9):4405 .

 PubMed Web of Science ®Google Scholar

Bonova P, Burda J, Danielisova V, et al. Delayed post-conditioning reduces post-ischemic glutamate level and improves protein synthesis in brain. Neurochem Int. 2013;62(6):854–860.

 PubMed Web of Science ®Google Scholar

You J, Feng L, Xin M, et al. Cerebral Ischemic Postconditioning Plays a Neuroprotective Role through Regulation of Central and Peripheral Glutamate. Biomed Res Int. 2018;2018:6316059.

 PubMed Web of Science ®Google Scholar

Graham SH, Chen J, Sharp FR, et al. Limiting ischemic injury by inhibition of excitatory amino acid release. J Cereb Blood Flow and Metab. 1993;13(1):88–97.

 PubMed Web of Science ®Google Scholar

Liu Y, Chu S, Hu Y, et al. Exogenous Adenosine Antagonizes Excitatory Amino Acid Toxicity in Primary Astrocytes. Cell Mol Neurobiol. 2021;41(4):687–704.

 PubMed Web of Science ®Google Scholar

Wang Y, Lu S, Chen Y, et al. Smoothened is a therapeutic target for reducing glutamate toxicity in ischemic stroke. Sci Transl Med. 2021;13(610):eaba3444.

 PubMed Web of Science ®Google Scholar

Patabendige A, Singh A, Jenkins S, et al. Astrocyte Activation in Neurovascular Damage and Repair Following Ischaemic Stroke. Int J Mol Sci. 2021;22(8):4280.

 PubMed Web of Science ®Google Scholar

Hess DC, Khan MB, Kamat P, et al. Conditioning medicine for ischemic and hemorrhagic stroke. Conditioning med. 2021;4(3): 124–129.

 PubMedGoogle Scholar

Weston RM, Jarrott B, Ishizuka Y, et al. AM-36 modulates the neutrophil inflammatory response and reduces breakdown of the blood brain barrier after endothelin-1 induced focal brain ischaemia. Br J Pharmacol. 2006;149(6):712–723.

 PubMed Web of Science ®Google Scholar

Ruhnau J, Schulze J, Dressel A, et al. Neuroinflammation, and Poststroke Infection: the Multifaceted Role of Neutrophils in Stroke. J Immunol Res. 2017;2017:5140679.

 PubMed Web of Science ®Google Scholar

Radenovic L, Nenadic M, Ułamek-Kozioł M, et al. Heterogeneity in brain distribution of activated microglia and astrocytes in a rat ischemic model of Alzheimer’s disease after 2 years of survival. Aging (Albany NY). 2020;12(12):12251–12267.

 PubMedGoogle Scholar

Wang H, Song G, Chuang H, et al. Portrait of glial scar in neurological diseases. Int J Immunopathol Pharmacol. 2018;31:2058738418801406.

 Web of Science ®Google Scholar

Li J, Hu XS, Zhou FF, et al. Limb remote ischemic postconditioning protects integrity of the blood-brain barrier after stroke. Neural Regen Res. 2018;13(9):1585–1593.

 PubMed Web of Science ®Google Scholar

Doeppner TR, Kaltwasser B, Kuckelkorn U, et al. Systemic Proteasome Inhibition Induces Sustained Post-stroke Neurological Recovery and Neuroprotection via Mechanisms Involving Reversal of Peripheral Immunosuppression and Preservation of Blood-Brain-Barrier Integrity. Mol Neurobiol. 2016;53(9):6332–6341.

 PubMed Web of Science ®Google Scholar

Zhao H, Ren C, Chen X, et al. From rapid to delayed and remote postconditioning: the evolving concept of ischemic postconditioning in brain ischemia. Curr Drug Targets. 2012;13(2):173–187.

 PubMed Web of Science ®Google Scholar

Zhou M, Xia ZY, Lei SQ, et al. Role of mitophagy regulated by Parkin/DJ-1 in remote ischemic postconditioning-induced mitigation of focal cerebral ischemia-reperfusion. Eur Rev Med Pharmacol Sci. 2015;19(24):4866–4871.

 PubMed Web of Science ®Google Scholar

Landman TRJ, Schoon Y, Warlé MC, et al. Remote Ischemic Conditioning as an Additional Treatment for Acute Ischemic Stroke. Stroke. 2019;50(7):1934–1939.

 PubMed Web of Science ®Google Scholar

Han D, Sun M, He PP, et al. Ischemic Postconditioning Alleviates Brain Edema After Focal Cerebral Ischemia Reperfusion in Rats Through Down-Regulation of Aquaporin-4. J Mol Neurosci. 2015;56(3):722–729.

 PubMed Web of Science ®Google Scholar

Li CY, Ma W, Liu KP, et al. Different ischemic duration and frequency of ischemic postconditioning affect neuroprotection in focal ischemic stroke. J Neurosci Methods. 2020;346:108921.

 PubMed Web of Science ®Google Scholar

Doeppner TR, Zechmeister B, Kaltwasser B, et al. Very Delayed Remote Ischemic Post-conditioning Induces Sustained Neurological Recovery by Mechanisms Involving Enhanced Angioneurogenesis and Peripheral Immunosuppression Reversal. Front Cell Neurosci. 2018;12:383.

 PubMed Web of Science ®Google Scholar

Pignataro G, Esposito E, Sirabella R, et al. nNOS and p-ERK involvement in the neuroprotection exerted by remote postconditioning in rats subjected to transient middle cerebral artery occlusion. Neurobiol Dis. 2013;54:105–114.

 PubMed Web of Science ®Google Scholar

Gulati P, Singh N, Muthuraman A. Pharmacologic evidence for role of endothelial nitric oxide synthase in neuroprotective mechanism of ischemic postconditioning in mice. J Surg Res. 2014;188(1):349–360.

 PubMed Web of Science ®Google Scholar

Torres-Querol C, Quintana-Luque M, Arque G, et al. Preclinical evidence of remote ischemic conditioning in ischemic stroke, a metanalysis update. Sci Rep. 2021;11(1):23706.

 PubMed Web of Science ®Google Scholar

Yang F, Zhang X, Sun Y, et al. Ischemic postconditioning decreases cerebral edema and brain blood barrier disruption caused by relief of carotid stenosis in a rat model of cerebral hypoperfusion. PloS one. 2013;8(2):e57869.

 PubMed Web of Science ®Google Scholar

Chen G, Zhang J, Sheng M, et al. Serum of limb remote ischemic postconditioning inhibits fMLP-triggered activation and reactive oxygen species releasing of rat neutrophils. Redox Rep. 2021;26(1):176–183.

 PubMed Web of Science ®Google Scholar

Sengul D, Sengul I. Connection of reactive oxygen species as an essential factor for the mechanism of phenomena; ischemic preconditioning and postconditioning: come to age or ripening. North Clin Istanb. 2021;8(6):644–649.

 PubMed Web of Science ®Google Scholar

Xu Q, Deng F, Xing Z, et al. Long non-coding RNA C2dat1 regulates CaMKIIδ expression to promote neuronal survival through the NF-κB signaling pathway following cerebral ischemia. Cell Death Dis. 2016;7(3):e2173.

 PubMed Web of Science ®Google Scholar

Ye J, Das S, Roy A, et al. Ischemic Injury-Induced CaMKIIδ and CaMKIIγ Confer Neuroprotection Through the NF-κB Signaling Pathway. Mol Neurobiol. 2019;56(3):2123–2136.

 PubMed Web of Science ®Google Scholar

Zhang X, Tang X, Liu K, et al. Long Noncoding RNA Malat1 Regulates Cerebrovascular Pathologies in Ischemic Stroke. J Neurosci. 2017;37(7):1797–1806.

 PubMed Web of Science ®Google Scholar

Wang H, Zheng X, Jin J, et al. LncRNA MALAT1 silencing protects against cerebral ischemia-reperfusion injury through miR-145 to regulate AQP4. J Biomed Sci. 2020;27(1):40.

 PubMed Web of Science ®Google Scholar

Xiang Y, Zhang Y, Xia Y, et al. LncRNA MEG3 targeting miR-424-5p via MAPK signaling pathway mediates neuronal apoptosis in ischemic stroke. Aging (Albany NY). 2020;12(4):3156–3174.

 PubMedGoogle Scholar

Kitagawa K, Saitoh M, Ishizuka K, et al. Remote Limb Ischemic Conditioning during Cerebral Ischemia Reduces Infarct Size through Enhanced Collateral Circulation in Murine Focal Cerebral Ischemia. J Stroke Cerebrovasc Dis. 2018;27(4):831–838.

 PubMed Web of Science ®Google Scholar

Mehta SL, Chokkalla AK, Kim T, et al. Long Noncoding RNA Fos Downstream Transcript Is Developmentally Dispensable but Vital for Shaping the Poststroke Functional Outcome. Stroke. 2021;52(7):2381–2392.

 PubMed Web of Science ®Google Scholar

Zhao J, He L, Yin L. lncRNA NEAT1 Binds to MiR-339-5p to Increase HOXA1 and Alleviate Ischemic Brain Damage in Neonatal Mice. Mol Ther Nucleic Acids. 2020;20:117–127.

 PubMedGoogle Scholar

Jin F, Ou W, Wei B, et al. Transcriptome-Wide Analysis to Identify the Inflammatory Role of lncRNA Neat1 in Experimental Ischemic Stroke. J Inflamm Res. 2021;14:2667–2680.

 PubMed Web of Science ®Google Scholar

Huang Y, Wang Y, Liu X, et al. Silencing lncRNA HOTAIR improves the recovery of neurological function in ischemic stroke via the miR-148a-3p/KLF6 axis. Brain Res Bull. 2021;176:43–53.

 PubMed Web of Science ®Google Scholar

Wang Y, Mao J, Li X, et al. lncRNA HOTAIR mediates OGD/R-induced cell injury and angiogenesis in a EZH2-dependent manner. Exp Ther Med. 2022;23(1):99.

 PubMed Web of Science ®Google Scholar

Fu J, Yu Q, Xiao J, et al. Long noncoding RNA as a biomarker for the prognosis of ischemic stroke: a protocol for meta-analysis and bioinformatics analysis. Medicine (Baltimore). 2021;100(17):e25596.

 PubMed Web of Science ®Google Scholar

Zhu M, Li N, Luo P, et al. Peripheral Blood Leukocyte Expression of lncRNA MIAT and Its Diagnostic and Prognostic Value in Ischemic Stroke. J Stroke Cerebrovasc Dis. 2018;27(2):326–337.

 PubMed Web of Science ®Google Scholar

Ren B, Song Z, Chen L, et al. Long non-coding RNA UCA1 correlates with elevated disease severity, Th17 cell proportion, inflammatory cytokines, and worse prognosis in acute ischemic stroke patients. J Clin Lab Anal. 2021;35(3):e23697.

 PubMed Web of Science ®Google Scholar