Mature neurons dynamically restrict apoptosis <i>via</i> redundant premitochondrial brakes

Annis, Ryan P.; Swahari, Vijay; Nakamura, Ayumi; Xie, Alison Xiaoqiao; Hammond, Scott M.; Deshmukh, Mohanish

doi:10.1111/febs.13944

Cited by 19 publications

(17 citation statements)

References 42 publications

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“…105 On the other hand, regarding other miRNAs here identified, such as miR-221-3p, miR-222-3p, miR-24-3p, and miR-28-5p, limited or conflicting data about their function and implication in neuronal processes have been reported. [106][107][108][109] Besides neurotrophin signaling, interestingly, the pathway-based analysis revealed that these miRNAs act on pathways known to be altered in ischemic conditions and involved in neuroprotection, such as TNF, Hippo, and PI3K. [110][111][112] Among the miRNAs targets here identified, supposed to be downregulated in our model, we highlighted several genes involved in apoptosis and inflammation processes.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective effects of human amniotic fluid stem cells-derived secretome in an ischemia/reperfusion model

Castelli

Antonucci

Tessitore

et al. 2020

Stem Cells Translational Medicine

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Stem cells offer the basis for the promotion of robust new therapeutic approaches for a variety of human disorders. There are still many limitations to be overcome before clinical therapeutic application, including a better understanding of the mechanism by which stem cell therapies may lead to enhanced recovery. In vitro investigations are necessary to dissect the mechanisms involved and to support the potential development in stem cell-based therapies. In spite of growing interest in human amniotic fluid stem cells, not much is known about the characteristics of their secretome and regarding the potential neuroprotective mechanism in different pathologies, including stroke. To get more insight on amniotic fluid cells therapeutic potential, signal transduction pathways activated by human amniotic fluid stem cells (hAFSCs)derived secretome in a stroke in vitro model (ischemia/reperfusion [I/R] model) were investigated by Western blot. Moreover, miRNA expression in the exosomal fraction of the conditioned medium was analyzed. hAFSCs-derived secretome was able to activate prosurvival and anti-apoptotic pathways. MicroRNA analysis in the exosomal component revealed a panel of 16 overexpressed miRNAs involved in the regulation of coherent signaling pathways. In particular, the pathways of relevance in ischemia/reperfusion, such as neurotrophin signaling, and those related to neuroprotection and neuronal cell death, were analyzed. The results obtained strongly point toward the neuroprotective effects of the hAFSCs-conditioned medium in the in vitro stroke model here analyzed. This can be achieved by the modulation and activation of pro-survival processes, at least in part, due to the activity of secreted miRNAs.

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Section: Discussionmentioning

confidence: 99%

Neuroprotective effects of human amniotic fluid stem cells-derived secretome in an ischemia/reperfusion model

Castelli

Antonucci

Tessitore

et al. 2020

Stem Cells Translational Medicine

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“…It has been demonstrated that the downregulation of miR-29 contributed to neuronal cell death in focal ischemia by enhancing the expression of Bcl-2-like protein 2, an anti-apoptotic member of the BCL-2 protein family ( 31 ). By contrast, upregulation of miR-29 protected neurons from apoptosis during neuronal maturation ( 32 ), a well as during forebrain ( 24 ) and focal ischemia ( 26 ). Therefore, the expression and function of miR-29b in cerebral ischemia injury remains unknown.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-29b alleviates oxygen and glucose deprivation/reperfusion-induced injury via inhibition of the p53‑dependent apoptosis pathway in N2a neuroblastoma cells

et al. 2017

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Cerebral ischemic injury causes severe brain damage and remains one of the leading causes of morbidity and mortality worldwide. Members of the microRNA-29 (miR-29) family are involved in regulating the process of ischemia and may be developed as biomarkers to diagnose and treat cerebral ischemia. The role of miR-29b in cerebral ischemia injury remains poorly understood. The purpose of the present study was to investigate whether miR-29b overexpression suppressed cerebral ischemic injury and to explore its underlying mechanism of action. The results demonstrated that levels of miR-29b in N2a neuroblastoma cells decreased following oxygen and glucose deprivation/reperfusion (OGD/R) treatment. Transfection with miR-29b mimics significantly increased cell viability, decreased lactate dehydrogenase (LDH) leakage, inhibited apoptosis by decreasing morphological changes occurring in the nuclei and reduced caspase-3 activity in OGD/R-treated N2a cells. Conversely, miR-29b inhibitors enhanced OGD/R-induced cytotoxicity and apoptosis. In addition, the miR-29b mimics blocked the increase in Bax and p53 expression and decreased Bcl-2 expression in OGD/R-treated N2a cells, whereas miR-29b inhibitors exacerbated the changes in the expression of these apoptosis-associated proteins caused by OGD/R. p53 knockdown using p53 small interfering RNA decreased cell viability and increased LDH leakage, reversing the improvements that the miR-29b mimics induced in damaged cells. Taken together, the results of the present study demonstrated that miR-29b attenuates ischemic injury by negatively regulating the p53-dependent apoptosis pathway and may therefore be a novel potential therapeutic target for treating ischemic stroke.

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“…However, miR-29b is also significantly up-regulated in neural cells under an OGD/R environment and in patients with cerebral I/R injury ( 10 , 15 ). Activated miR-29b has also been reported to promote neural cell apoptosis targeting BH3 protein during neuronal maturation ( 16 ). Supporting previous studies, our results indicate that miR-29 binds the 3′UTR of MCL-1, an important Bcl-2 family protein.…”

Section: Discussionmentioning

confidence: 99%

miR‑29b affects neurocyte apoptosis by targeting MCL‑1 during cerebral ischemia/reperfusion injury

Huang

Lu²,

Jiang

et al. 2018

Exp Ther Med

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The present study aimed to determine whether an miRNA (miR)-29b inhibitor protected against cerebral ischemia/reperfusion (I/R) injury in vitro and to investigate the underlying mechanisms. As a model for induced cerebral IR injury, N2a cells were exposed to an oxygen-glucose deprivation/reoxygenation (OGD/R) environment. Using this model, it was demonstrated that miR-29b was significantly upregulated compared with cells in a normal environment. The interactions between miR-29b and myeloid cell leukemia sequence (MCL)-1 were then investigated using dual-luciferase assays, revealing a strong regulation of MCL-1 through the 3′untranslated region. Using the OGD/R model, the present study additionally examined the effects of miR-29b and miR-29b inhibitor on cell viability and apoptosis using Cell Counting kit 8 and flow cytometry assays, respectively. miR-29b transfection led to increased N2a cell apoptosis and reduced cell viability under an OGD/R environment. However, this effect was reversed by the miR-29b inhibitor. Finally, the effects of miR-29b on the expression of several Wnt-associating proteins were examined. It was observed that B cell lymphoma-2 was inhibited by miR-29b, as was MCL-1, whereas caspase-3 expression was promoted. The miR-29b inhibitor demonstrated the opposite effect. Overall, miR-29b promoted neurocyte apoptosis by targeting MCL-1 during cerebral I/R injury. The results of the present study suggest a potential novel therapeutic target for the treatment of ischemic stroke.

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Mature neurons dynamically restrict apoptosis via redundant premitochondrial brakes

Cited by 19 publications

References 42 publications

Neuroprotective effects of human amniotic fluid stem cells-derived secretome in an ischemia/reperfusion model

Neuroprotective effects of human amniotic fluid stem cells-derived secretome in an ischemia/reperfusion model

MicroRNA-29b alleviates oxygen and glucose deprivation/reperfusion-induced injury via inhibition of the p53‑dependent apoptosis pathway in N2a neuroblastoma cells

miR‑29b affects neurocyte apoptosis by targeting MCL‑1 during cerebral ischemia/reperfusion injury

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