MicroRNA-125b mimic inhibits ischemia reperfusion-induced neuroinflammation and aberrant p53 apoptotic signalling activation through targeting TP53INP1

Li, Xiaoqian; Q, Yu; Tan, Wen-Fei; Zhang, Zaili; Ma, Hong

doi:10.1016/j.bbi.2018.09.002

Cited by 35 publications

(64 citation statements)

References 39 publications

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“…miRs are widely expressed in the CNS and able to negatively regulate target genes by either degradation or posttranscriptional repression [5,6,28]. In our previous studies, we identified hundreds of aberrant miRs in injured spinal cords by microarray analysis [5,6,29]. Intrathecal pretreatment with synthetic miR mimic resulted in significant improvement in neurological deficits by recovering the altered miR expression [5,6,29].…”

Section: Introductionmentioning

confidence: 91%

“…Usually, reperfusion cannot prevent ischemia-induced neurological impairment (known as primary insults); on the contrary, reperfusion will further aggravate neurological function (known as secondary insults) during the initial period [3]. Apart from the high incidence of sensory deficits, IR injury is reported as a major cause of permanent motor dysfunction due to wide neuronal death after recovery of blood flow [4][5][6]. Due to the limited proliferation capacity of adult neurons, exploring the underlying mechanisms to prevent neuronal death is of particular importance [7].…”

Section: Introductionmentioning

confidence: 99%

“…Due to the limited proliferation capacity of adult neurons, exploring the underlying mechanisms to prevent neuronal death is of particular importance [7]. Various types of death have been found in neurons, including apoptosis, necroptosis, and ferroptosis [5,7,8]. We previously identified which types of cell death are involved in a specific type of spinal cord IR injury and found that blocking the process of apoptosis was effective in preserving hindlimb motor function in rodent models [5,9].…”

Section: Introductionmentioning

confidence: 99%

“…Various types of death have been found in neurons, including apoptosis, necroptosis, and ferroptosis [5,7,8]. We previously identified which types of cell death are involved in a specific type of spinal cord IR injury and found that blocking the process of apoptosis was effective in preserving hindlimb motor function in rodent models [5,9]. Recently, some studies have shown that disturbed ionic homeostasis, such as ischemic or mechanical injury-induced excessive intracellular calcium ion concentration ([Ca 2+ ]) in neurons, could eventually trigger neuronal apoptosis by influencing vital biological functions and metabolism [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

“…MicroRNAs (miRs) are a group of small, endogenous, noncoding RNAs [28]. miRs are widely expressed in the CNS and able to negatively regulate target genes by either degradation or posttranscriptional repression [5,6,28]. In our previous studies, we identified hundreds of aberrant miRs in injured spinal cords by microarray analysis [5,6,29].…”

Section: Introductionmentioning

confidence: 99%

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Roles of the miR-137-3p/CAPN-2 gene pair in ischemia-reperfusion-induced neuronal apoptosis through modulation of p35 cleavage and subsequent caspase-8 overactivation

Zhang

et al. 2019

Preprint

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Background: Neuron survival after ischemia-reperfusion (IR) injury is the primary determinant of motor function prognosis. MicroRNA (miR)-based gene therapy has gained attention. Our previous work explored the mechanisms by which miR-137-3p modulates neuronal apoptosis in both in vivo and in vitro IR models.Methods: IR-induced motor dysfunction and spinal calpain (CAPN) subtype expression and subcellular distribution were detected within 12 h post IR. Dysregulated miRs, including miR-137-3p, were identified by miR microarray analysis and confirmed by PCR. Luciferase assay confirmed that CAPN-2 is a corresponding target of miR-137-3p, and their modulation of motor function was evaluated by intrathecal infection with synthetic miRs. CAPN-2 activity was measured by the intracellular Ca2+ concentration and mean fluorescence intensity in vitro. Neuronal apoptosis was detected by flow cytometry and lactate dehydrogenase (LDH) release. The activities of p35, p25, Cdk5 and caspase-8 were evaluated by ELISA and Western blotting after transfection with specific inhibitors and miRs.Results: The IR-induced motor dysfunction time course was closely associated with CAPN-2 protein upregulation, which was mainly distributed in neurons. The miR-137-3p/CAPN-2 gene pair was confirmed by luciferase assay. miR-137-3p mimic significantly improved IR-induced motor dysfunction and decreased CAPN-2 expression, even in combination with recombinant rat calpain-2 (rr-CALP2) injection, whereas miR-137-3p inhibitor reversed these effects. Similar changes were observed in the intracellular Ca2+ concentration and CAPN-2 expression and activity when cells were exposed to OGD/R and transfected with synthetic miRs in vitro. Moreover, double fluorescence revealed that CAPN-2, p35, p25 and caspase-8 were all identically distributed in neurons. The decrease in CAPN-2 expression and activity was accompanied by the opposite changes in p35 activity and protein expression in cells transfected with miR-137-3p mimic, roscovitine (a Cdk5 inhibitor) or Z-IETD-FMK (a caspase-8 inhibitor). Correspondingly, more surviving neurons were observed with the abovementioned treatments, indicated by a decrease in apoptotic cell percentage, LDH release and p25, Cdk5, caspase-8 and caspase-3 protein expression.Conclusions: The miR-137-3p/CAPN-2 gene pair functions to modulate neuronal apoptosis during IR injury, possibly through CAPN-2 inhibition leading to p35 cleavage and inhibition of subsequent p25/Cdk5 and caspase-8 overactivation.

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Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Roles of the miR-137-3p/CAPN-2 gene pair in ischemia-reperfusion-induced neuronal apoptosis through modulation of p35 cleavage and subsequent caspase-8 overactivation

Zhang

et al. 2019

Preprint

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Targeting p53 for neuroinflammation: New therapeutic strategies in ischemic stroke

Gao

Liu

et al. 2023

J of Neuroscience Research

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Ischemic stroke (IS) is characterized by high incidence, high recurrence, and high mortality and places a heavy burden on society and families. The pathological mechanisms of IS are complex, among which secondary neurological impairment mediated by neuroinflammation is considered to be the main factor in cerebral ischemic injury.At present, there is still a lack of specific therapies to treat neuroinflammation. The tumor suppressor protein p53 has long been regarded as a key substance in the regulation of the cell cycle and apoptosis in the past. Recently, studies have found that p53 also plays an important role in neuroinflammatory diseases, such as IS. Therefore, p53 may be a crucial target for the regulation of the neuroinflammatory response. Here, we provide a comprehensive review of the potential of targeting p53 in the treatment of neuroinflammation after IS. We describe the function of p53, the major immune cells involved in neuroinflammation, and the role of p53 in inflammatory responses mediated by these cells. Finally, we summarize the therapeutic strategies of targeting p53 in regulating the neuroinflammatory response after IS to provide new directions and ideas for the treatment of ischemic brain injury.

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MircoRNA-29a in Astrocyte-derived Extracellular Vesicles Suppresses Brain Ischemia Reperfusion Injury via TP53INP1 and the NF-κB/NLRP3 Axis

Liu

et al. 2021

Cell Mol Neurobiol

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MicroRNA-125b mimic inhibits ischemia reperfusion-induced neuroinflammation and aberrant p53 apoptotic signalling activation through targeting TP53INP1

Cited by 35 publications

References 39 publications

Roles of the miR-137-3p/CAPN-2 gene pair in ischemia-reperfusion-induced neuronal apoptosis through modulation of p35 cleavage and subsequent caspase-8 overactivation

Roles of the miR-137-3p/CAPN-2 gene pair in ischemia-reperfusion-induced neuronal apoptosis through modulation of p35 cleavage and subsequent caspase-8 overactivation

Targeting p53 for neuroinflammation: New therapeutic strategies in ischemic stroke

MircoRNA-29a in Astrocyte-derived Extracellular Vesicles Suppresses Brain Ischemia Reperfusion Injury via TP53INP1 and the NF-κB/NLRP3 Axis

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