Regulatory mechanism of the SNHG3/miR-302a-3p/E2F1 feedback loop in nerve repair post cerebral ischemic stroke

Objective: Cerebral ischemic stroke (CIS) remains a primary cause of death worldwide. The current knowledge has identified the implication of microRNAs (miRNAs) in the pathophysiology of CIS. This study investigated the mechanism of miR-302a-3p in nerve repair post-CIS. Methods: A middle cerebral artery occlusion (MCAO) model was established in mice to simulate CIS. miR-302a-3p expression in brain tissues of MCAO mice was up-regulated by injecting agomiR-302a-3p. The neurological deficit of MCAO mice was evaluated through neurological function score, forelimb placing test, and balance beam walking test. Neuronal damage was measured using Nissl staining. The concentrations of nerve injury-related factors (S100B and GFAP) and the contents of neuroinflammatory factors (TNF-α and IL-1β) in serum were examined using ELISA kits. miR-302a-3p, E2F1, and long non-coding RNA (lncRNA) SNHG3 expressions in brain tissues of MCAO mice were determined using RT-qPCR and Western blot. The binding relationships between miR-302a-3p and E2F1 and E2F1 and SNHG3 were validated using dual-luciferase and ChIP assays, respectively. Results: miR-302a-3p expression was reduced in brain tissues of MCAO mice. miR-302a-3p overexpression increased the number of neurons, decreased the concentrations of S100B and GFAP, reduced the contents of TNF-α and IL-1β, promoted nerve repair, and alleviated CIS-induced brain injury. miR-302a-3p targeted E2F1 expression, and E2F1 activated SNHG3 transcription. E2F1 overexpression or SNHG3 overexpression reversed the effect of miR-302a-3p overexpression on nerve repair in MCAO mice. Conclusion: miR-302a-3p overexpression repressed SNHG3 transcription by targeting E2F1 expression, thereby promoting nerve repair and alleviating CIS.

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LncRNA WT1-AS Attenuates hypoxia/ischemia Induced Neuronal Injury in Cerebral Ischemic Stroke via miR-186-5p/XIAP Axis

10.21203/rs.3.rs-818657/v1 ◽

2021 ◽

Author(s):

Jianquan You ◽

Fei Qian ◽

Yu Huang ◽

Yingxuan Guo ◽

Yaqian Lv ◽

...

Keyword(s):

Ischemic Stroke ◽

Cell Viability ◽

Cell Apoptosis ◽

Neuronal Damage ◽

Luciferase Reporter ◽

Occurrence Rate ◽

Pcr Analysis ◽

Gene Assay ◽

Cerebral Ischemic Stroke ◽

Cerebral Ischemic

Abstract BackgroundCerebral ischemic stroke was a nervous system disease with high occurrence rate and mortality rate. This study aimed to investigate the role and mechanism of lncRNA WT1-AS in cerebral ischemic stroke. Materials and methodsStarbase and dual luciferase reporter gene assay were used to analyze the target relationship between lncRNA WT1-AS and miR-186-5p. qRT-PCR analysis was used to detect lncRNA WT1-AS and miR-186-5p expression. OGD-induced SH-SY5Y cells injury model was conducted, and cell viability and cell apoptosis were determined by MTT and flow cytometer assay. Caspase3 ability was determined using Caspase3 activity detection kit. ResultsmiR-186-5p was a target of lncRNA-WT1-AS. lncRNA WT1-AS was down-regulated and miR-186-5p was up-regulated in blood samples of patients with ischemic stroke and in OGD-induced SH-SY5Y cells. We found that WT1-AS-plasmid promoted OGD-induced cell viability, reduced cell apoptosis and decreased caspase3 ability, and these changes were reversed by miR-186-5p mimic. Subsequently, our results proved that XIAP was a target of miR-186-5p. Similarly, miR-186-5p inhibitor reduced OGD-induced neuronal damage by up-regulating XIAP expression. ConclusionlncRNA-WT1-AS/miR-186-5p/XIAP might be a new target for cerebral ischemic stroke treatment.

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A Stepwise-Targeting Strategy For The Treatment of Cerebral Ischemic Stroke

10.21203/rs.3.rs-797270/v1 ◽

2021 ◽

Author(s):

Jing-Bo Hu ◽

Xueying Tan ◽

Dongwei Wang ◽

Hongze Liang ◽

Jiejun Peng ◽

...

Keyword(s):

Oxidative Stress ◽

Ischemic Stroke ◽

Targeted Delivery ◽

Infarct Volume ◽

Stress Injury ◽

Therapeutic Outcomes ◽

Cerebral Ischemic Stroke ◽

Cerebral Ischemic ◽

In Cis ◽

Brain Tissues

Abstract Background: Effective amelioration of neuronal damages in the case of cerebral ischemic stroke (CIS) is essential for the protection of brain tissues and their functional recovery. However, most drugs can not penetrate the blood-brain barrier (BBB), resulting in the poor therapeutic outcomes. Results: In this study, the derivatization and dual targeted delivery technologies were used to actively transport antioxidant melatonin (MLT) into the mitochondria of oxidative stress-damaged cells in brain tissues. A mitochondrial targeting molecule triphenylphosphine (TPP) was conjugated to melatonin (TPP-MLT) to increase the distribution of melatonin in intracellular mitochondria with the push of mitochondrial transmembrane potential. Then, TPP-MLT was encapsulated in dual targeted micelles mediated by TGN peptide (TGNYKALHPHNG) with high affinity for BBB and SHp peptide (CLEVSRKNG) for the glutamate receptor of oxidative stress-damaged neural cells.TGN/SHp/TPP-MLT micelles could effectively scavenge the overproduced ROS to protect neuronal cells from oxidative stress injury during CIS occurrence, as reflected by the improved infarct volume and neurological deficit in CIS model animals.Conclusions: These promising results showed this stepwise-targeting drug-loaded micelles potentially represent a significant advancement in the precise treatment of CIS.

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A stepwise-targeting strategy for the treatment of cerebral ischemic stroke

Journal of Nanobiotechnology ◽

10.1186/s12951-021-01118-6 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Jingbo Hu ◽

Xueying Tan ◽

Dongwei Wang ◽

Yixuan Li ◽

Hongze Liang ◽

...

Keyword(s):

Oxidative Stress ◽

Ischemic Stroke ◽

Targeted Delivery ◽

Infarct Volume ◽

Stress Injury ◽

Therapeutic Outcomes ◽

Cerebral Ischemic Stroke ◽

Cerebral Ischemic ◽

In Cis ◽

Brain Tissues

Abstract Background Effective amelioration of neuronal damages in the case of cerebral ischemic stroke (CIS) is essential for the protection of brain tissues and their functional recovery. However, most drugs can not penetrate the blood–brain barrier (BBB), resulting in the poor therapeutic outcomes. Results In this study, the derivatization and dual targeted delivery technologies were used to actively transport antioxidant melatonin (MLT) into the mitochondria of oxidative stress-damaged cells in brain tissues. A mitochondrial targeting molecule triphenylphosphine (TPP) was conjugated to melatonin (TPP-MLT) to increase the distribution of melatonin in intracellular mitochondria with the push of mitochondrial transmembrane potential. Then, TPP-MLT was encapsulated in dual targeted micelles mediated by TGN peptide (TGNYKALHPHNG) with high affinity for BBB and SHp peptide (CLEVSRKNG) for the glutamate receptor of oxidative stress-damaged neural cells.TGN/SHp/TPP-MLT micelles could effectively scavenge the overproduced ROS to protect neuronal cells from oxidative stress injury during CIS occurrence, as reflected by the improved infarct volume and neurological deficit in CIS model animals. Conclusions These promising results showed this stepwise-targeting drug-loaded micelles potentially represent a significant advancement in the precise treatment of CIS. Graphical Abstract

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Cerebral ischemic stroke cellular fate and therapeutic opportunities

Frontiers in Bioscience ◽

10.2741/4727 ◽

2019 ◽

Vol 24 (3) ◽

pp. 435-450 ◽

Cited By ~ 14

Author(s):

Mrinal Kanti Ghosh

Keyword(s):

Ischemic Stroke ◽

Cerebral Ischemic Stroke ◽

Cerebral Ischemic ◽

Cellular Fate

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Irisin Ameliorates Hypoxia/Reoxygenation-Induced Inflammation and Apoptosis in PC12 Cells by Inhibiting TLR4/MYD88 Signaling Pathway

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.17:329-336 ◽

2019 ◽

Vol 17 (3) ◽

pp. 329-336

Author(s):

Wang Jinli ◽

Xu Fenfen ◽

Zheng Yuan ◽

Cheng Xu ◽

Zhang Piaopiao ◽

...

Keyword(s):

Ischemic Stroke ◽

Signaling Pathway ◽

Pc12 Cells ◽

Major Complication ◽

Lactic Dehydrogenase ◽

Dependent Manner ◽

Cerebral Ischemic Stroke ◽

Cerebral Ischemic ◽

Myd88 Signaling ◽

Hypoxia Reoxygenation

Cardiovascular disease including cerebral ischemic stroke is the major complication that increases the morbidity and mortality in patients with diabetes mellitus as much as four times. It has been well established that irisin, with its ability to regulate glucose and lipid homeostasis as well as anti-inflammatory and anti-apoptotic properties, has been widely examined for its therapeutic potentials in managing metabolic disorders. However, the mechanism of irisin in the regulation of cerebral ischemic stroke remains unclear. Using PC12 cells as a model, we have shown that hypoxia/reoxygenation inhibits cell viability and increases lactic dehydrogenase. Irisin, in a dose-dependent manner, reversed these changes. The increase in inflammatory mediators (IL-1β, IL-6, and TNF-α) by hypoxia/reoxygenation was reversed by irisin. Furthermore, the cell apoptosis promoted by hypoxia/reoxygenation was also inhibited by irisin. Irisin suppressed TLR4/MyD88 signaling pathway leading to amelioration of inflammation and apoptosis in PC12 cells. Thus, inhibition of TLR4/MyD88 signaling pathway via irisin could be an important mechanism in the regulation of hypoxia/reoxygenation-induced inflammation and apoptosis in PC12 cells.

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