Beneficial Effects of Resveratrol-Mediated Inhibition of the mTOR Pathway in Spinal Cord Injury

Zhou, Jingying; Huo, Xue; Botchway, Benson O. A.; Xu, Luyao; Meng, Xiaofang; Zhang, Songou; Liu, Xuehong

doi:10.1155/2018/7513748

Cited by 22 publications

(16 citation statements)

References 88 publications

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“…mTOR pathway was inactivated in tissues and cells after Mettl14 knockdown. Resveratrol-mediated inhibition of mTOR pathway may be beneficial for neural recovery after SCI [27].…”

Section: Discussionmentioning

confidence: 99%

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Mettl14-mediated m6A modification modulates neuron apoptosis during the repair of spinal cord injury by regulating the transformation from pri‐mir‐375 to miR-375

Wang

Yuan²,

Dang

et al. 2021

Cell Biosci

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Background Spinal cord injury (SCI) is a disabling disorder, resulting in neurological impairments. This study investigated the mechanism of methyltransferase-like 14 (Mettl14) on apoptosis of spinal cord neurons during SCI repair by mediating pri-microRNA (miR) dependent N6-methyladenosine (m6A) methylation. Methods The m6A content in total RNA and Mettl14 levels in spinal cord tissues of SCI rats were detected. Mettl14 expression was intervened in SCI rats to examine motor function, neuron apoptosis, and recovery of neurites. The cell model of SCI was established and intervened with Mettl14. miR-375, related to SCI and positively related to Mettl14, was screened out. The expression of miR-375 and pri-miR-375 after Mettl14 intervention was detected. The expression of pri-miR-375 combined with DiGeorge critical region 8 (DGCR8) and that modified by m6A was detected. Furthermore, the possible downstream gene and pathway of miR-375 were analysed. SCI cell model with Mettl14 intervention was combined with Ras-related dexamethasone-induced 1 (RASD1)/miR-375 intervention to observe the apoptosis. Results Mettl14 level and m6A content in spinal cord tissue were significantly increased. After Mettl14 knockdown, the injured motor function was restored and neuron apoptosis was reduced. In vitro, Mettl14 silencing reduced the apoptosis of SCI cells; miR-375 was reduced and pri-miR-375 was increased; miR-375 targeted RASD1. Silencing Mettl14 inactivated the mTOR pathway. The apoptosis in cells treated with silencing Mettl14 + RASD1/miR-375 was inhibited. Conclusions Mettl14-mediated m6A modification inhibited RASD1 and induced the apoptosis of spinal cord neurons in SCI by promoting the transformation of pri-miR-375 to mature miR-375.

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“…mTOR pathway was inactivated in tissues and cells after Mettl14 knockdown. Resveratrol-mediated inhibition of mTOR pathway may be beneficial for neural recovery after SCI [27].…”

Section: Discussionmentioning

confidence: 99%

“…6b, c). In addition, RASD1 can negatively regulate the Akt/mTOR pathway [26], and inhibition of mTOR pathway has a positive effect on neuronal repair after SCI [27]. Thereafter, we measured mTOR levels in spinal cord tissues and cells.…”

Section: Mir-375 Targeted Rasd1 To Activate the Mtor Pathwaymentioning

confidence: 99%

Mettl14-mediated m6A modification modulates neuron apoptosis during the repair of spinal cord injury by regulating the transformation from pri‐mir‐375 to miR-375

Wang

Yuan²,

Dang

et al. 2021

Cell Biosci

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“…An apparent decrease in phosphorylation of AKT and GSK transducers upon VEEV infection was observed in this study, and the expressional changes of the AKT pathway have also been demonstrated to be correlated with the severity of a specific disease [ 54 ]. For example, oxidatively damaged neural tissues were ameliorated by resveratrol via enhancing AKT phosphorylation [ 55 ].…”

Section: Discussionmentioning

confidence: 67%

Resveratrol Inhibits Venezuelan Equine Encephalitis Virus Infection by Interfering with the AKT/GSK Pathway

Lehman

Kehn-Hall

Aggarwal

et al. 2021

Plants

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The host proteins Protein Kinase B (AKT) and glycogen synthase kinase-3 (GSK-3) are associated with multiple neurodegenerative disorders. They are also important for the replication of Venezuelan equine encephalitis virus (VEEV), thereby making the AKT/GSK-3 pathway an attractive target for developing anti-VEEV therapeutics. Resveratrol, a natural phytochemical, has been shown to substantially inhibit the AKT pathway. Therefore, we attempted to explore whether it exerts any antiviral activity against VEEV. In this study, we utilized green fluorescent protein (GFP)- and luciferase-encoding recombinant VEEV to determine the cytotoxicity and antiviral efficacy via luciferase reporter assays, flow cytometry, and immunofluorescent assays. Our results indicate that resveratrol treatment is capable of inhibiting VEEV replication, resulting in increased viability of Vero and U87MG cells as well as reduced virion production and viral RNA contents within host cells for at least 48 h with a single treatment. Furthermore, the suppression of apoptotic signaling adaptors, caspase-3, caspase-7, and annexin V may also be implicated in resveratrol-mediated antiviral activity. We found that decreased phosphorylation of the AKT/GSK-3 pathway, mediated by resveratrol, can be triggered during the early stages of VEEV infection, suggesting that resveratrol disrupts the viral replication cycle and consequently promotes cell survival. Finally, molecular docking and dynamics simulation studies revealed that resveratrol can directly bind to VEEV glycoproteins, which may interfere with virus attachment and entry. In conclusion, our results suggest that resveratrol exerts inhibitory activity against VEEV infection and upon further modification could be a useful compound to study in neuroprotective research and veterinary sciences.

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“…In general, in astrocytes, a hyperactive mTOR is a negative regulator for recovery following SCI [41]. Restravol is an example of an mTOR inhibiting drug that has been successful in restoring nerve function following SCI [42]. However, in spinal cord hemisection, mTOR activation efficiently promotes regrowth and regeneration of the corticospinal tract [5] (Figure 3c).…”

Section: The Cell-specific Mtor Signaling Roles In Mammalian Spinal Cmentioning

confidence: 99%

mTOR Signaling at the Crossroad between Metazoan Regeneration and Human Diseases

Lund-Ricard

Morales

Boutet

2020

IJMS

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A major challenge in medical research resides in controlling the molecular processes of tissue regeneration, as organ and structure damage are central to several human diseases. A survey of the literature reveals that mTOR (mechanistic/mammalian target of rapamycin) is involved in a wide range of regeneration mechanisms in the animal kingdom. More particularly, cellular processes such as growth, proliferation, and differentiation are controlled by mTOR. In addition, autophagy, stem cell maintenance or the newly described intermediate quiescence state, Galert, imply upstream monitoring by the mTOR pathway. In this review, we report the role of mTOR signaling in reparative regenerations in different tissues and body parts (e.g., axon, skeletal muscle, liver, epithelia, appendages, kidney, and whole-body), and highlight how the mTOR kinase can be viewed as a therapeutic target to boost organ repair. Studies in this area have focused on modulating the mTOR pathway in various animal models to elucidate its contribution to regeneration. The diversity of metazoan species used to identify the implication of this pathway might then serve applied medicine (in better understanding what is required for efficient treatments in human diseases) but also evolutionary biology. Indeed, species-specific differences in mTOR modulation can contain the keys to appreciate why certain regeneration processes have been lost or conserved in the animal kingdom.

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Beneficial Effects of Resveratrol-Mediated Inhibition of the mTOR Pathway in Spinal Cord Injury

Cited by 22 publications

References 88 publications

Mettl14-mediated m6A modification modulates neuron apoptosis during the repair of spinal cord injury by regulating the transformation from pri‐mir‐375 to miR-375

Mettl14-mediated m6A modification modulates neuron apoptosis during the repair of spinal cord injury by regulating the transformation from pri‐mir‐375 to miR-375

Resveratrol Inhibits Venezuelan Equine Encephalitis Virus Infection by Interfering with the AKT/GSK Pathway

mTOR Signaling at the Crossroad between Metazoan Regeneration and Human Diseases

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