Astrocytic Cebpd Regulates Pentraxin 3 Expression to Promote Fibrotic Scar Formation After Spinal Cord Injury

Wang, Shao-Ming; Hsu, Jung-Yu C; Ko, Chiung-Yuan; Wu, Hsiang‐En; Hsiao, Yu-Wei; Wang, Ju‐Ming

doi:10.1007/s12035-023-03207-z

Cited by 3 publications

(2 citation statements)

References 28 publications

(52 reference statements)

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“…After puri cation, the RNA was collected and reverse transcribed into DNA using an RT-qPCR kit [18]. The resulting cDNA was mixed with designed primers and enzymes in CFX96 Touch Real-Time PCR Detection System (BioRad), then we determined the CT values and calculated the relative expression of the target genes [19].…”

Section: Rna Extraction and Reverse Transcription-quantitative Polyme...mentioning

confidence: 99%

Fluvoxamine restores TFEB-mediated autophagy through Sigma-1R-controlled POM121 expression

Lin,

Wu,

Weng

et al. 2023

Preprint

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Expansion of the GGGGCC-RNA repeat is a known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two conditions that currently have no cure. Recent studies have shown that activation of the Sigma-1 receptor plays an important role in providing neuroprotection, particularly in ALS and Alzheimer’s disease. However, the mechanisms underlying Sigma-1R activation and its effect on (G4C2)n-RNA-induced cell death remain unclear. In this study, we demonstrated that fluvoxamine is a Sigma-1R agonist that can increase chaperone activity and rescue Pom121 intensity in (G4C2)31-RNA-expressing NSC34 cells, thereby stabilizing the protein expression of Pom121. Interestingly, fluvoxamine treatment increased Pom121 protein expression without affecting transcription. In C9orf72-ALS, the TFEB autophagy factor translocation decreased owing to nucleocytoplasmic transport defects. Our results showed that pretreatment of NSC34 cells with fluvoxamine promoted TFEB translocation into the nucleus and increased LC3-II expression compared to the overexpression of (G4C2)31-RNA alone. Collectively, fluvoxamine may act as a promising repurposed medicine for patients with C9orf72-ALS, as it stabilizes the nucleoporin Pom121 and promotes the translocation of TFEB in (G4C2)31-RNA-expressing NSC34 cells.

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Section: Rna Extraction and Reverse Transcription-quantitative Polyme...mentioning

confidence: 99%

Fluvoxamine restores TFEB-mediated autophagy through Sigma-1R-controlled POM121 expression

Lin,

Wu,

Weng

et al. 2023

Preprint

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show abstract

“…CCAAT/Enhancer-Binding Protein Delta (CEBPD) is an inflammatory transcription factor associated with the progression of neurological diseases, including neurodegenerative diseases and central nervous system injuries [3,[9][10][11]. Previous studies have shown that CEBPD contributes to neuroinflammation, gliosis, and oxidative stress in central nervous system diseases/injuries [3,9].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of MMP8 effectively alleviates manic-like behavior and reduces neuroinflammation by modulating astrocytic CEBPD

Wang,

Weng,

Hsu

et al. 2024

J Neuroinflammation

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There is an intrinsic relationship between psychiatric disorders and neuroinflammation, including bipolar disorder. Ouabain, an inhibitor of Na+/K+-ATPase, has been implicated in the mouse model with manic-like behavior. However, the molecular mechanisms linking neuroinflammation and manic-like behavior require further investigation. CCAAT/Enhancer-Binding Protein Delta (CEBPD) is an inflammatory transcription factor that contributes to neurological disease progression. In this study, we demonstrated that the expression of CEBPD in astrocytes was increased in ouabain-treated mice. Furthermore, we observed an increase in the expression and transcript levels of CEBPD in human primary astrocytes following ouabain treatment. Transcriptome analysis revealed high MMP8 expression in human primary astrocytes following CEBPD overexpression and ouabain treatment. We confirmed that MMP8 is a CEBPD-regulated gene that mediates ouabain-induced neuroinflammation. In our animal model, treatment of ouabain-injected mice with M8I (an inhibitor of MMP8) resulted in the inhibition of manic-like behavior compared to ouabain-injected mice that were not treated with M8I. Additionally, the reduction in the activation of astrocytes and microglia was observed, particularly in the hippocampal CA1 region. Excessive reactive oxygen species formation was observed in ouabain-injected mice, and treating these mice with M8I resulted in the reduction of oxidative stress, as indicated by nitrotyrosine staining. These findings suggest that MMP8 inhibitors may serve as therapeutic agents in mitigating manic symptoms in bipolar disorder.

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Fluvoxamine Exerts Sigma-1R to Rescue Autophagy via Pom121-Mediated Nucleocytoplasmic Transport of TFEB

Lin,

Wu,

Weng

et al. 2024

Mol Neurobiol

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Expansion of the GGGGCC-RNA repeat is a known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which currently have no cure. Recent studies have indicated the activation of Sigma-1 receptor plays an important role in providing neuroprotection, especially in ALS and Alzheimer’s disease. Nevertheless, the mechanisms underlying Sigma-1R activation and its effect on (G4C2)n-RNA-induced cell death remain unclear. In this study, we demonstrated that fluvoxamine is a Sigma-1R agonist that can increase chaperone activity and stabilize the protein expression of Pom121 in (G4C2)31-RNA-expressing NSC34 cells, leading to increased colocalization at the nuclear envelope. Interestingly, fluvoxamine treatment increased Pom121 protein expression without affecting transcription. In C9orf72-ALS, the nuclear translocation of TFEB autophagy factor decreased owing to nucleocytoplasmic transport defects. Our results showed that pretreatment of NSC34 cells with fluvoxamine promoted the shuttling of TFEB into the nucleus and elevated the expression of LC3-II compared to the overexpression of (G4C2)31-RNA alone. Additionally, even when used alone, fluvoxamine increases Pom121 expression and TFEB translocation. To summarize, fluvoxamine may act as a promising repurposed medicine for patients with C9orf72-ALS, as it stabilizes the nucleoporin Pom121 and promotes the translocation of TFEB in (G4C2)31-RNA-expressing NSC34 cells.

show abstract

Astrocytic Cebpd Regulates Pentraxin 3 Expression to Promote Fibrotic Scar Formation After Spinal Cord Injury

Cited by 3 publications

References 28 publications

Fluvoxamine restores TFEB-mediated autophagy through Sigma-1R-controlled POM121 expression

Fluvoxamine restores TFEB-mediated autophagy through Sigma-1R-controlled POM121 expression

Inhibition of MMP8 effectively alleviates manic-like behavior and reduces neuroinflammation by modulating astrocytic CEBPD

Fluvoxamine Exerts Sigma-1R to Rescue Autophagy via Pom121-Mediated Nucleocytoplasmic Transport of TFEB

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