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Effect of VX‑765 on the transcriptome profile of mice spinal cords with acute injury
Jing Chen1, Yu-Qing Chen1, Sai-Nan Wang1
1Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China.
Abstract:
Previous studies have shown that caspase-1 plays an important role in the acute inflammatory response of spinal cord injury (SCI). VX‑765, a novel and irreversible caspase‑1 inhibitor, has been reported to effectively intervene in inflammation. However, the effect of VX‑765 on genome‑wide transcription in acutely injured spinal cords remains unknown. Therefore, in the present study, RNA‑sequencing (RNA‑Seq) was used to analyze the effect of VX‑765 on the local expression of gene transcription 8 h following injury. The differentially expressed genes (DEGs) underwent enrichment analysis of functions and pathways by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, respectively. Parallel analysis of western blot confirmed that VX‑765 can effectively inhibit the expression and activation of caspase‑1. RNA‑Seq showed that VX‑765 treatment resulted in 1,137 upregulated and 1,762 downregulated DEGs. These downregulated DEGs and their associated signaling pathways, such as focal adhesion, cytokine‑cytokine receptor interaction, leukocyte transendothelial migration, extracellular matrix‑receptor interaction, phosphatidylinositol 3‑kinase‑protein kinase B, Rap1 and hypoxia inducible factor‑1 signaling pathway, are mainly associated with inflammatory response, local hypoxia, macrophage differentiation, adhesion migration and apoptosis of local cells. This suggests that the application of VX‑765 in the acute phase can improve the local microenvironment of SCI by inhibiting caspase‑1. However, whether VX‑765 can be used as a therapeutic drug for SCI requires further exploration. The sequence data have been deposited into the Sequence Read Archive (https://www.ncbi.nlm.nih.gov/sra/PRJNA548970).
Insights
VX-765, a caspase-1 inhibitor, impacts gene expression after spinal cord injury (SCI). It downregulates inflammatory and cell migration pathways, suggesting potential therapeutic benefits for the acute phase of SCI.
Area of Science:
- Neuroscience
- Molecular Biology
- Inflammation Research
Background:
- Spinal cord injury (SCI) involves acute inflammatory responses.
- Caspase-1 is a key mediator in SCI inflammation.
- The impact of caspase-1 inhibition on gene transcription in SCI is not well understood.
Purpose of the Study:
- To investigate the genome-wide transcriptional effects of VX-765, a caspase-1 inhibitor, in acutely injured spinal cords.
- To identify differentially expressed genes (DEGs) and associated pathways affected by VX-765 treatment 8 hours post-injury.
Main Methods:
- RNA-sequencing (RNA-Seq) was employed to analyze gene expression profiles.
- Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed for functional and pathway enrichment.
- Western blot was used to confirm caspase-1 inhibition.
Main Results:
- VX-765 effectively inhibited caspase-1 expression and activation.
- RNA-Seq identified 1,137 upregulated and 1,762 downregulated DEGs.
- Downregulated DEGs were linked to pathways involved in inflammation, cell migration, hypoxia, and apoptosis, including focal adhesion and PI3K-Akt signaling.
Conclusions:
- VX-765 treatment in the acute phase of SCI modulates gene transcription, potentially improving the local microenvironment by inhibiting caspase-1.
- Further research is needed to determine the therapeutic potential of VX-765 for SCI treatment.
