p53-Mediated oligodendrocyte apoptosis initiates demyelination after compressed spinal cord injury by enhancing ER-mitochondria interaction and E2F1 expression

Ma, Lan; Yu, Hong-Jin; Gan, Shengwei; Gong, Rui; Mou, Ke‐Jie; Xue, Jun; Sun, Shanquan

doi:10.1016/j.neulet.2017.02.038

Cited by 30 publications

(27 citation statements)

References 23 publications

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“…The pathophysiology of SCI includes myelin loss, axonal degradation, oxidative stress, inflammatory response, activation of various cytokines, cell death, etc. 4 – 7 Previous research has demonstrated that oligodendroglia apoptosis has been observed after SCI and has led to the occurrence of chronic demyelination. 8 Furthermore, microglia, widely located throughout the central nervous system (CNS), have also contributed to the mechanism of SCI.…”

Section: Introductionmentioning

confidence: 99%

The microglial activation profile and associated factors after experimental spinal cord injury in rats

Zhou¹,

Li²,

Zhu³

et al. 2018

NDT

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BackgroundSpinal cord injury (SCI) has imposed a great impact on the quality of life of patients due to its relatively young age of onset. The pathophysiology of SCI has been proven to be complicated. Microglia plays an important role in neuroinflammation and second injuries after SCI. Different environment and other factors may determine the microglial activation profile and what role they play. However, neither accurate time-course profiles of microglial activation nor influence factors have been demonstrated in varied SCI models.MethodsA rat compressive SCI model was used. Microglial activation profile and contents of inflammatory factors including IL-1β, IL-6 and TNF-α were detected. Myelination status as well as levels of iron and glutamate concentration, adenosine triphosphate (ATP) and potassium are also assessed.ResultsOur results showed that the activated microglia participating in immune-mediated responses peaked at day 7 post SCI and gradually decreased during the following 3 weeks. Contrarily, myelination and oligodendroglia showed an opposite trend, indicating that microglia may be a key factor partly through inflammatory reaction. Iron and glutamate concentration were found to be the highest at day 7 after SCI while both ATP and potassium reached a low valley at the same time.ConclusionThese findings showed a microglial activation profile and the alterations of associated factors after experiment SCI model. Moreover, our data suggest that high iron and glutamate concentration may be released by damaged oligodendroglia and contribute to the activation of microglial after SCI.

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Section: Introductionmentioning

confidence: 99%

The microglial activation profile and associated factors after experimental spinal cord injury in rats

Zhou¹,

Li²,

Zhu³

et al. 2018

NDT

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“…mTOR is a signaling molecule downstream of Akt leading to control and coordination of neural and muscle regrowth after SCI (Chen N.-N. et al, 2016 ; Zhou et al, 2016 ; Bai et al, 2017 ). Notwithstanding its role in malignancy, the tumor suppressor protein p53 is important for nerve cell differentiation and axonal growth regrowth (Eom et al, 2015 ; Ma et al, 2017 ). Interestingly, under stress, activation of p53 can lead to shortening of neurites and decrease of neuronal activity (Guo et al, 2014 ; Eom et al, 2015 ; Ma et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

“…Notwithstanding its role in malignancy, the tumor suppressor protein p53 is important for nerve cell differentiation and axonal growth regrowth (Eom et al, 2015 ; Ma et al, 2017 ). Interestingly, under stress, activation of p53 can lead to shortening of neurites and decrease of neuronal activity (Guo et al, 2014 ; Eom et al, 2015 ; Ma et al, 2017 ). Another important factor in regeneration after trauma is myelin basic protein (MBP) which is an important contributor to formation and maintenance of myelin sheaths and thereby enhances functional recovery after injury.…”

Section: Introductionmentioning

confidence: 99%

Electroacupuncture Restores Locomotor Functions After Mouse Spinal Cord Injury in Correlation With Reduction of PTEN and p53 Expression

Wei

Zhao

Schachner

2018

Front. Mol. Neurosci.

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Background: We previously showed that electroacupuncture (EA) at Jiaji points promotes expression of adhesion molecule L1 in spinal cord tissue after mouse spinal cord injury (SCI) and contributes to recovery of neural functions.Objective: We investigated the effects of EA on downstream signaling molecules of L1 and molecules relevant to apoptosis with the aim to understand the underlying molecular mechanisms.Methods: Female C57BL/6 mice were divided into a sham group, injury group, injury+acupuncture (AP) group and injury+EA group. We investigated the changes in cognate L1-triggered signaling molecules after SCI by immunofluorescence staining and immunoblot analysis.Results: Protein levels of phosphatase and tensin homolog (PTEN) and p53 were decreased by EA at different time points after injury, whereas the levels of phosphorylated mammalian target of rapamycin (pmTOR), p-Akt and phosphorylated extracellular signal-regulatedkinase (p-Erk) were increased. Also, levels of myelin basic protein (MBP) were increased by EA. AP alone showed less pronounced changes in expression of the investigated molecules, when compared to EA.Conclusion: We propose that EA contributes to neuroprotection by inhibiting PTEN and p53 expression and by increasing the levels of pmTOR/Akt/Erk and of MBP after SCI. These observations allow novel insights into the beneficial effects of EA via L1-triggered signaling molecules after injury.

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“…In addition, our results revealed that rafoxanide also promoted apoptosis in skin cancer cells. While the mechanisms are not known, it is possible that rafoxanide may induce apoptosis via the E2F-p53-Bax/caspase 3 signaling pathway (49)(50)(51). In the next phase of the study, the mechanisms of rafoxanide-induced apoptosis in skin cancer will be identified by microarray and other methods.…”

Section: Discussionmentioning

confidence: 99%

Discovery of rafoxanide as a dual CDK4/6 inhibitor for the treatment of skin cancer

Shi¹,

Shi

et al. 2018

Oncol Rep

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Since cyclin‑dependent kinases 4/6 (CDK4/6) play pivotal roles in cell cycle regulation and are overexpressed in human skin cancers, CDK4/6 inhibitors are potentially effective drugs for skin cancer. In the present study, we present a mixed computational and experimental study attempting to repurpose approved small‑molecule drugs as dual CDK4/6 inhibitors for skin cancer treatment. We performed structure‑based virtual screening using the docking software idock, targeting an ensemble of CDK4/6 structures. We identified and selected nine compounds with significant predicted scores, and evaluated their cytotoxic effects in vitro in A375 and A431 human skin cancer cell lines. Rafoxanide was found to exhibit the highest cytotoxic effects (IC50: 1.09 µM for A375 and 1.31 µM for A431 cells). Consistent with the expected properties of CDK4/6 inhibitors, rafoxanide significantly increased the G1 phase population. Notably, we revealed that rafoxanide specifically decreased the expression of CDK4/6, cyclin D, retinoblastoma protein (Rb) and the phosphorylation of CDK4/6 and Rb. Furthermore, the anticancer effect of rafoxanide was demonstrated in vivo in BALB/C nude mice subcutaneously xenografted with human skin cancer A375 cells. Rafoxanide (40 mg/kg, i.p.) exhibited significant antitumor activity, comparable to that of oxaliplatin (5 mg/kg, i.p.). The combined administration of rafoxanide and oxaliplatin produced a synergistic therapeutic effect. To the best of our knowledge, the present study is the first to indicate that rafoxanide inhibits CDK4/6 activity and is a potential candidate drug for the treatment of human skin cancer.

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p53-Mediated oligodendrocyte apoptosis initiates demyelination after compressed spinal cord injury by enhancing ER-mitochondria interaction and E2F1 expression

Cited by 30 publications

References 23 publications

The microglial activation profile and associated factors after experimental spinal cord injury in rats

The microglial activation profile and associated factors after experimental spinal cord injury in rats

Electroacupuncture Restores Locomotor Functions After Mouse Spinal Cord Injury in Correlation With Reduction of PTEN and p53 Expression

Discovery of rafoxanide as a dual CDK4/6 inhibitor for the treatment of skin cancer

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