microRNA‐125b and its downstream Smurf1/KLF2/ATF2 axis as important promoters on neurological function recovery in rats with spinal cord injury

Zhao, Kunchi; Li, Ran; Ruan, Qing; Meng, Chunyang; Yin, Fei; Zhu, Qingsan

doi:10.1111/jcmm.16283

Cited by 7 publications

(5 citation statements)

References 27 publications

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“…Disrupting Smurf1 expression ameliorated LPS‐evoked neuroinflammation and neuronal necroptosis in PC12 cells 32 . Besides that, Zhao's team showed that Smurf1 attenuated miR‐125b‐meidated neurological recovery after SCI by promoting KLF2 degradation 33 . All these data indicated the neurotoxic action of Smurf1 in SCI.…”

Section: Discussionmentioning

confidence: 90%

“… 32 Besides that, Zhao's team showed that Smurf1 attenuated miR‐125b‐meidated neurological recovery after SCI by promoting KLF2 degradation. 33 All these data indicated the neurotoxic action of Smurf1 in SCI. In the present study, we found that LPS decreased miR‐340‐5p expression, but elevated Smurf1 expression in PC12 cells.…”

Section: Discussionmentioning

confidence: 90%

“…32 Besides that, Zhao's team showed that Smurf1 attenuated miR-125b-meidated neurological recovery after SCI by promoting KLF2 degradation. 33 All these data indicated the neurotoxic action of Smurf1 in SCI.…”

Section: Discussionmentioning

confidence: 90%

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CircSmox knockdown alleviates PC12 cell apoptosis and inflammation in spinal cord injury by miR‐340‐5p/Smurf1 axis

Han

Mou

Jing

et al. 2023

Immunity Inflam & Disease

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Background Spinal cord injury (SCI) is a traumatic central nervous system disorder that leads to irreversible neurological dysfunction. Emerging evidence has shown that differentially expressed circular RNAs (circRNAs) after SCI is closely associated with the pathophysiological process. Herein, the potential function of circRNA spermine oxidase (circSmox) in functional recovery after SCI was investigated. Methods Differentiated PC12 cells stimulated with lipopolysaccharide (LPS) were employed as an in vitro model for neurotoxicity research. Levels of genes and proteins were detected by quantitative real‐time PCR and Western blot analysis. Cell viability and apoptosis were determined by CCK‐8 assay and flow cytometry. Western blot analysis was used to detect the protein level of apoptosis‐related markers. The levels of interleukin (IL)‐1β, IL‐6, IL‐8, and tumor necrosis factor (TNF)‐α. Dual‐luciferase reporter, RIP, and pull‐down assays were used to confirm the target relationship between miR‐340‐5p and circSmox or Smurf1 (SMAD Specific E3 Ubiquitin Protein Ligase 1). Results LPS elevated the levels of circSmox and Smurf1, but decreased the levels of miR‐340‐5p in PC12 cells in a dose‐dependent manner. Functionally, circSmox silencing alleviated LPS‐induced apoptosis and inflammation in PC12 cells in vitro. Mechanistically, circSmox directly sponged miR‐340‐5p, which targeted Smurf1. Rescue experiments showed that miR‐340‐5p inhibition attenuated the neuroprotective effect of circSmox siRNA in PC12 cells. Moreover, miR‐340‐5p suppressed LPS‐triggered neurotoxicity in PC12 cells, which was reversed by Smurf1 overexpression. Conclusion CircSmox enhances LPS‐induced apoptosis and inflammation via miR‐340‐5p/Smurf1 axis, providing an exciting view of the potential involvement of circSmox in SCI pathogenesis.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 90%

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CircSmox knockdown alleviates PC12 cell apoptosis and inflammation in spinal cord injury by miR‐340‐5p/Smurf1 axis

Han

Mou

Jing

et al. 2023

Immunity Inflam & Disease

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“…Xie et al 107 have reported that SMURF1 targets and promotes the ubiquitination of KLF2, which is essential for ubiquitin‐proteasome‐induced KLF2 degradation. Building on this finding, Zhao et al 108 have shown that SMURF1 is also involved in neurological function recovery after SCI in rats. Significant inhibition of microRNA‐125b and KLF2, as well as upregulation of SMURF1 and ATF2, were observed in SCI rats.…”

Section: Nervous Systemmentioning

confidence: 93%

The role ofSMURFsin non‐cancerous diseases

et al. 2023

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The ubiquitin‐proteasome system is a crucial mechanism for regulating protein levels in cells, with substrate‐specific E3 ubiquitin ligases serving as an integral component of this system. Among these ligases are SMAD‐specific E3 ubiquitin‐protein ligase 1 (SMURF1) and SMAD‐specific E3 ubiquitin‐protein ligase 2 (SMURF2), which belong to the neural precursor cell‐expressed developmentally downregulated 4 (NEDD4) subfamily of Homologous to E6‐AP COOH terminus (HECT)‐type E3 ligases. As E3 ligases, SMURFs have critical functions in regulating the stability of multiple proteins, thereby maintaining physiological processes such as cell migration, proliferation, and apoptosis. The occurrence of many diseases is attributed to abnormal cell physiology and an imbalance in cell homeostasis. It is noteworthy that SMURFs play pivotal roles in disease progression, with the regulatory functions being complex and either facilitative or inhibitory. In this review, we elucidate the mechanisms by which SMURF1 and SMURF2 can regulate disease progression in non‐cancerous diseases. These significant findings offer potential novel therapeutic targets for various diseases and new avenues for research on SMURF proteins.

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“…Recent works have revealed that KLF2 overexpression protects against ischemic stroke and alleviates BBB dysfunction by regulating the expression of OCC (occludin, a member of TJ proteins) in endothelial cells 15 . Recently, Zhao and colleagues demonstrated that KLF2 enhanced neurological function recovery in rat SCI model, following treatment with miR-125b 16 . Nevertheless, the exact cellular mechanisms of KLF2 in regulating BSCB function after SCI have never been explored.…”

Section: Introductionmentioning

confidence: 99%

Kruppel-like factor 2 contributes to blood-spinal cord barrier integrity and functional recovery from spinal cord injury by augmenting autophagic flux

He¹,

Du²,

Xu³

et al. 2023

Theranostics

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Background: Increasing evidence suggests that acute traumatic spinal cord injury (SCI)-induced defects in autophagy and autophagy-lysosomal pathway (ALP) may contribute to endothelial barrier disruption following injury. Recently, Kruppel-like factor 2 (KLF2) was reported as a key molecular switch on regulating autophagy. Whether KLF2 coordinates endothelial endothelial ALP in SCI is not known. Methods: Genetic manipulations of KLF2 were performed in bEnd.3 cells and SCI model. Western blot, qRT-PCR, immunofluorescence staining and Lyso-Tracker Red staining, Evans blue dye extravasation, behavioral assessment via Basso mouse scale (BMS), electrophysiology and footprint analysis were performed. Results: In SCI, autophagy flux disruption in endothelial cells contributes to TJ proteins degradation, leading to blood-spinal cord barrier (BSCB) impairment. Furthermore, the KLF2 level was decreased in SCI, overexpression of which alleviated TJ proteins loss and BSCB damage, which improve motor function recovery in SCI mice, while knockdown of KLF2 displayed the opposite effects. At the molecular level, KLF2 overexpression alleviated the TJ proteins degradation and the endothelial permeability by tuning the ALP dysfunction caused by SCI and oxygen glucose deprivation (OGD). Conclusions: Endothelial KLF2 as one of the key contributors to SCI-mediated ALP dysfunction and BSCB disruption. KLF2 could be a promising pharmacological target for the management and treatment of SCI.

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microRNA‐125b and its downstream Smurf1/KLF2/ATF2 axis as important promoters on neurological function recovery in rats with spinal cord injury

Cited by 7 publications

References 27 publications

CircSmox knockdown alleviates PC12 cell apoptosis and inflammation in spinal cord injury by miR‐340‐5p/Smurf1 axis

CircSmox knockdown alleviates PC12 cell apoptosis and inflammation in spinal cord injury by miR‐340‐5p/Smurf1 axis

The role ofSMURFsin non‐cancerous diseases

Kruppel-like factor 2 contributes to blood-spinal cord barrier integrity and functional recovery from spinal cord injury by augmenting autophagic flux

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