Epigenetic Mechanisms Underlying Adult Post Stroke Neurogenesis

Liu, Xianshuang; Fan, Baoyan; Chopp, Michael; Zhang, Zhenggang

doi:10.3390/ijms21176179

Cited by 14 publications

(17 citation statements)

References 138 publications

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“…Meanwhile, our results in vivo also suggested that HDAC1 repression is correlated to the reduction of mNSS, edema formation, and cerebral infarction volume. Nevertheless, downstream regulatory mechanisms of miRNAs are currently a widely studied mechanism ( Chen et al, 2020 ; Liu J. et al, 2020 ), and epigenetic mechanisms such as DNA methylation and histone modification are also known to mediate miRNAs, which in turn have a regulatory role on epigenetics ( Chen et al, 2018 ; Liu X. et al, 2020 ; Zhao et al, 2020 ). It remains to be established whether miR-410 can regulate other epigenetic markers in an HIBD model.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Vesicle-Derived microRNA-410 From Mesenchymal Stem Cells Protects Against Neonatal Hypoxia-Ischemia Brain Damage Through an HDAC1-Dependent EGR2/Bcl2 Axis

Han

Yang

Hao

et al. 2021

Front. Cell Dev. Biol.

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Hypoxia-ischemia brain damage (HIBD) is a neurological disorder occring in neonates, which is exacerbated by neuronal apoptosis. Mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) have been proposed as a promising strategy for treating or preventing ischemia-related diseases. However, their mechanisms in HIBD remain unclear. Thus, we aimed to address the role of EV-derived microRNA (miR)-410 in HIBD. Neonatal HIBD mouse model was constructed using HI insult, from which neurons were isolated, followed by exposure to oxygen glucose deprivation (OGD). EVs were isolated from human umbilical cord (hUC)-derived MSCs. In silico analyses, dual-luciferase reporter gene and chromatin immunoprecipitation assays were adopted to determine relationships among miR-410, histone deacetylase 1 (HDAC1), early growth response protein 2 (EGR2), and B cell lymphoma/leukemia 2 (Bcl2). The functional roles of EV-derived miR-410 were determined using loss- and gain-of functions experiments, and by evaluating neuronal viability, cell-cycle distribution and neuronal apoptosis in vitro as well as modified neurological severity score (mNSS), edema formation, and cerebral infarction volume in vivo. hUC-MSCs-derived EVs protected against HIBD in vivo and inhibited the OGD-induced neuronal apoptosis in vitro. miR-410 was successfully delivered to neurons by hUC-MSCs-EVs and negatively targeted HDAC1, which inversely mediated the expression of EGR2/Bcl2. Upregulation of EV-derived miR-410 promoted the viability but inhibited apoptosis of neurons, which was reversed by HDAC1 overexpression. EV-derived miR-410 elevation reduced mNSS, edema formation, and cerebral infarction volume by increasing EGR2/Bcl2 expression through downregulating HDAC1 expression in vivo. In summary, EV-derived miR-410 impeded neuronal apoptosis by elevating the expression of EGR2/Bcl2 via HDAC1 downregulation, thereby providing a potential strategy for treating or preventing HIBD.

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Section: Discussionmentioning

confidence: 99%

Extracellular Vesicle-Derived microRNA-410 From Mesenchymal Stem Cells Protects Against Neonatal Hypoxia-Ischemia Brain Damage Through an HDAC1-Dependent EGR2/Bcl2 Axis

Han

Yang

Hao

et al. 2021

Front. Cell Dev. Biol.

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“…Accumulated studies had shown epigenetic modifications played significant roles in the molecular and cellular mechanisms for brain ischemic stroke ( Miao et al., 2015 ; Liu et al., 2020 ). During the past several years, the NLRP3 inflammasome is a vital regulator for cytokine secretions during ischemia/reperfusion injury.…”

Section: Discussionmentioning

confidence: 99%

LncRNA TUG1 Demethylated by TET2 Promotes NLRP3 Expression, Contributes to Cerebral Ischemia/Reperfusion Inflammatory Injury

et al. 2021

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LncRNA TUG1 has not yet been reported in cerebral ischemia/reperfusion (I/R) injury. Methylcytosine dioxygenase TET2 is involved in ischemic damage. This study aimed to investigate the effects of TUG1 demethylated by TET2 on I/R-induced inflammatory response and identified its possible mechanisms.We found that TUG1 expression was significantly upregulated in oxygen-glucose deprivation and reoxygenation (OGD/R)-induced SH-SY5Y and SK-N-SH cells. Using the middle cerebral artery occlusion (MCAO) mice, we observed a similar effect. We also found that I/R injury could downregulate miR-200a-3p and upregulate NLRP3 and TET2. The knockdown of TUG1 could alleviate OGD/R-induced inflammatory response through upregulating miR-200a-3p and downregulating NLRP3 and other pro-inflammatory molecules. miR-200a-3p inhibition can partially reverse the effects of TUG1 silencing. Further experiments confirmed that TUG1 sponged miR-200a-3p to diminish miR-200a-3p and promote NLRP3 dependent inflammatory responses. Mechanically, knockdown of TET2 induced low levels of TUG1 and high levels of miR-200a-3p in both SK-N-SH and SH-SY5Y cells. IL-18, IL-1β, NLRP3, Caspase-1, and GSDMD-N were highly downregulated in OGD/R-induced SK-N-SH and SH-SY5Y cells after TET2 knockdown. TUG1 overexpression could reverse this effect. All the data indicated that TET2 could demethylate TUG1 and contribute to the inflammatory response. In additional experiments using the MCAO mice model, we confirmed knockdown of TET2 attenuated I/R-induced inflammatory response and brain injuries via decreasing TUG1 and increasing miR-200a-3p to inhibit NLRP3 expression. The demethylation of TUG1 by TET2 might aggravate I/R-induced inflammatory injury via modulating NLRP3 by miR-200a-3p. Our data confirmed that TET2 contributed to I/R-induced inflammatory response via the demethylation of TUG1 and regulated TUG1/miR-200a-3p/NLRP3 pathway.

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“…118 Research has identified epigenetic changes as both cause and consequence of cerebral ischemia and stroke. 119,120 Therefore it is conceivable that ischemia could lead to altered expression of neurosteroidogenic enzymes and neuroactive steroids.…”

Section: Neuroendocrine Microbiotic and Epigenetic Changes Associated...mentioning

confidence: 99%

From organ injury to disability: a proposed model for 5-alpha reductase inhibitor syndrome

Montaigne¹

2022

Preprint

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Persistent dysfunctions emerging from use and discontinuation of 5-alpha reductase inhibitors (PD-5ARI) may be explained as the aftermath of a pathological recovery from microvasculopathy or ischemia in multiple systems. Focusing on persistent sexual dysfunction, the most common class of symptoms: 5ARIs’ inhibition of angiogenesis leads to stress on penile microvasculature, depriving the tissue of blood supply and oxygen. These hypoxic conditions lead to tissue injury and atrophy, triggering a pathological recovery that further alters penile tissue, including smooth muscle loss, fibrosis, damage to vascular architecture and impairment of neural pathways supporting arousal and erectile function. This damaging cascade may result in severe and lasting sexual dysfunction. Persistent neuropsychiatric, cognitive, sensory and sleep dysfunctions emerging from 5ARI treatment may similarly be explained as pathological responses to microvasculopathy or ischemia in supporting structures, particularly those in the limbic system. Systemic spread is proposed to arise from a vicious cycle of tissue injury, oxidative stress and proinflammatory activity which spreads via the vascular network, leading to systemic endothelial dysfunction. The latter may in turn set off a damaging cascade in other organs and tissues. Risks of developing PD-5ARI may arise from 5ARI-mediated disruptions of vascular tone, angiogenesis and neoangiogenesis. Pharmacovigilance data, animal studies and human studies provide converging evidence for the proposed etiopathology. It is, moreover, consistent with variable presentation and severity of PD-5ARI symptoms; irreversibility of symptoms; typically normal results of clinical lab tests; and resistance to treatment.

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Epigenetic Mechanisms Underlying Adult Post Stroke Neurogenesis

Cited by 14 publications

References 138 publications

Extracellular Vesicle-Derived microRNA-410 From Mesenchymal Stem Cells Protects Against Neonatal Hypoxia-Ischemia Brain Damage Through an HDAC1-Dependent EGR2/Bcl2 Axis

Extracellular Vesicle-Derived microRNA-410 From Mesenchymal Stem Cells Protects Against Neonatal Hypoxia-Ischemia Brain Damage Through an HDAC1-Dependent EGR2/Bcl2 Axis

LncRNA TUG1 Demethylated by TET2 Promotes NLRP3 Expression, Contributes to Cerebral Ischemia/Reperfusion Inflammatory Injury

From organ injury to disability: a proposed model for 5-alpha reductase inhibitor syndrome

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