Circulating MicroRNAs as Potential Noninvasive Biomarkers of Spontaneous Intracerebral Hemorrhage

Gareev, Ilgiz; Yang, Guang; Sun, Jinxian; Beylerli, Ozal; Chen, Xin; Zhang, Daming; Zhao, Boxian; Zhang, Ruotian; Sun, Zhenying; Yang, Quan; Li, Lili; Павлов, В. Н.; Safin, Shamil M.; Zhao, Shen

doi:10.1016/j.wneu.2019.09.016

Cited by 25 publications

(20 citation statements)

References 37 publications

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“…Rapidly accumulating evidences have indicated that miRNAs are crucial regulators in ICH. 13,14 Exosomal miRNAs expression varies widely in different cell types and pathological states, and miRmodified Exos may alter its function. MiR-146a-5p is highly conserved among humans, mice, and rats.…”

Section: Introductionmentioning

confidence: 99%

<p>Exosomes Derived from MicroRNA-146a-5p-Enriched Bone Marrow Mesenchymal Stem Cells Alleviate Intracerebral Hemorrhage by Inhibiting Neuronal Apoptosis and Microglial M1 Polarization</p>

Duan

Wang

Cao

et al. 2020

DDDT

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Introduction: Intracerebral hemorrhage (ICH) is a devastating type of stroke with high mortality, and the effective therapies for ICH remain to be explored. Exosomes (Exos) have been found to play important roles in cell communication by transferring molecules, including microRNAs (miRNAs/ miRs). MiRNAs are critical regulators of genes involved in many various biological processes and have been demonstrated to aggravate or alleviate brain damages induced by ICH. The aim of the present study was to investigate the effect of Exos derived from miR-146a-5p-enriched bone marrow mesenchymal stem cells (BMSCs-miR-146a-5p-Exos) on experimental ICH. Methods: ICH was induced in adult male Sprague-Dawley rats by an intrastriatal injection of collagenase type IV. At 24 h after surgery, Exos were administrated. For detecting apoptotic cells, TUNEL staining was performed using an in situ Cell Death Detection Kit. Fluoro-Jade B staining was performed to detect degenerating neurons. Immunofluorescence assay was performed to detect the expression of myeloperoxidase (MPO) and OX-42. The binding of miR-146a-5p and its target genes was confirmed by luciferase reporter assay. Results: At 24 h after surgery, BMSCs-miR-146a-5p-Exos administration significantly improved neurological function, reduced apoptotic and degenerative neurons, and inhibited inflammatory response. Furthermore, miR-146a-5p-enriched Exos obviously inhibited the M1 polarization of microglia after ICH in rats, accompanied by the reduced expression of pro-inflammatory mediators releasing by M1 microglia including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and monocyte chemoattractant protein-1 (MCP-1). Finally, we observed that miR-146a-5p directly targeted interleukin-1 receptor-associated kinase1 (IRAK1) and nuclear factor of activated T cells 5 (NFAT5), which contributed to the inflammation response and the polarization of M1 microglia/macrophages. Conclusion: We demonstrated that miR-146a-5p-riched BMSCs-Exos could offer neuroprotection and functional improvements after ICH through reducing neuronal apoptosis, and inflammation associated with the inhibition of microglial M1 polarization by downregulating the expression of IRAK1 and NFAT5.

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Section: Introductionmentioning

confidence: 99%

<p>Exosomes Derived from MicroRNA-146a-5p-Enriched Bone Marrow Mesenchymal Stem Cells Alleviate Intracerebral Hemorrhage by Inhibiting Neuronal Apoptosis and Microglial M1 Polarization</p>

Duan

Wang

Cao

et al. 2020

DDDT

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“…miRNAs, a group of small non-coding RNA molecules consisting of 20–22 nucleotides, can regulate target genes by binding with the 3′-UTRs of mRNAs [ 17 ]. Various reports have confirmed that miRNAs act as a vital regulator in the pathology of ICH [ 18 – 21 ]. The expression of plasma circulating miR-181b was reported to be decreased in patients with ICH compared with that in the control group [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

lncRNA MEG3 Downregulation Relieves Intracerebral Hemorrhage by Inhibiting Oxidative Stress and Inflammation in an miR-181b-Dependent Manner

2021

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Background This study was designed to illustrate the effects and latent mechanism of lncRNA maternally expressed gene 3 (MEG3) on intracerebral hemorrhage (ICH)-induced brain injury. Material/Methods An ICH rat model was generated to determine the role of lncRNA MEG3 in ICH. The interaction between lncRNA MEG3 and microRNA (miR)-181b were confirmed by Starbase and dual-luciferase reporter assay. One hour (h) or 3 days after ICH stimulation, rat neurological injury was evaluated by modified Neurological Severity Score (mNSS). Brain water content and cell apoptosis were assessed using brain edema assessment and flow cytometry (FCM), respectively. Caspase3 activity was also determined. Enzyme-linked immunosorbent assay (ELISA) was applied to evaluate the levels of pro-inflammatory cytokines. Moreover, the representative biomarkers of oxidative stress were evidenced using detection kits. Results The lncRNA MEG3 level in ICH rat brain tissues was higher than that in the sham group. miR-181b was a direct target of lncRNA MEG3 and it was downregulated in brain tissues of ICH rats. Notably, we found that neurobehavioral scores, brain water content, and neuronal apoptosis were decreased and caspase3 activity was reduced in MEG3-shRNA-treated ICH rats, while we observed the opposite result in ICH+MEG3-shRNA+miR-181b inhibitor rats. Further analyses revealed that MEG3-shRNA inhibited inflammatory cytokines release and reduced oxidative stress. All these results were reversed by miR-181b inhibitor. In addition, MEG3-shRNA activated the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway, which was reversed by miR-181b inhibitor. Conclusions MEG3-shRNA restrained oxidative stress and inflammation following ICH in an miR-181b-dependent manner.

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“…U6 was used as an endogenous control miRNA that is stably expressed in exosomes. qRT-PCR was performed as described earlier ( Gareev et al, 2019 ). The relative expression of miR-2276-5p was calculated using the equation 2 –ΔCt , in which ΔCt = Ct miR-2276-5p-Ct U6.…”

Section: Methodsmentioning

confidence: 99%

Exosomal miR-2276-5p in Plasma Is a Potential Diagnostic and Prognostic Biomarker in Glioma

Sun

Gareev

et al. 2021

Front. Cell Dev. Biol.

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IntroductionExosomal microRNAs (miRNAs) play an essential role in near and distant intercellular communication and are potential diagnostic and prognostic biomarkers for various cancers. This study focused on evaluation of exosomal miR-2276-5p in plasma as a diagnostic and prognostic biomarker for glioma.MethodsPlasma exosomes from 124 patients with glioma and 36 non-tumor controls were collected and subjected to quantitative real-time polymerase chain reaction (qRT-PCR) analysis for the exosomal miR-2276-5p expression. Bioinformatic analyses were performed to identify a gene target, and CGGA and TCGA databases were checked for evaluation of prognostic relevance.ResultsThe exosomal miR-2276-5p in glioma patients had a significantly decreased expression, compared with non-glioma patients (p < 0.01). Receiver operating characteristics (ROC) curve analyses were observed to regulate the diagnostic sensitivity and specificity of miR-2276-5p in glioma; the area under the curve (AUC) for miR-2276-5p was 0.8107. The lower expression of exosomal miR-2276-5p in patients with glioma correlated with poorer survival rates. RAB13 was identified as the target of miR-2276-5p which was high in glioma patients, especially those with higher tumor grades and correlated with poor survival.ConclusionThe circulating exosomal miR-2276-5p is significantly reduced in the plasma of glioma patients, and thus, it could be a potential biomarker for patients with glioma for diagnostic and/or prognostic purposes.

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Circulating MicroRNAs as Potential Noninvasive Biomarkers of Spontaneous Intracerebral Hemorrhage

Cited by 25 publications

References 37 publications

<p>Exosomes Derived from MicroRNA-146a-5p-Enriched Bone Marrow Mesenchymal Stem Cells Alleviate Intracerebral Hemorrhage by Inhibiting Neuronal Apoptosis and Microglial M1 Polarization</p>

<p>Exosomes Derived from MicroRNA-146a-5p-Enriched Bone Marrow Mesenchymal Stem Cells Alleviate Intracerebral Hemorrhage by Inhibiting Neuronal Apoptosis and Microglial M1 Polarization</p>

lncRNA MEG3 Downregulation Relieves Intracerebral Hemorrhage by Inhibiting Oxidative Stress and Inflammation in an miR-181b-Dependent Manner

Exosomal miR-2276-5p in Plasma Is a Potential Diagnostic and Prognostic Biomarker in Glioma

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