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Effect of VX?765 on the transcriptome profile of mice spinal cords with acute injury.

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).

SUBMITTER: Chen J

PROVIDER: S-EPMC7248530 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Effect of VX‑765 on the transcriptome profile of mice spinal cords with acute injury.

Chen Jing J Chen Yu-Qing YQ Wang Sai-Nan SN Duan Fei-Xiang FX Shi Yu-Jiao YJ Ding Shu-Qin SQ Hu Jian-Guo JG Lü He-Zuo HZ

Molecular medicine reports 20200505 1

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 ...[more]

PMID: 32377730

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Project description:BackgroundRecent studies have found that probenecid has neuroprotective and reparative effects on central nervous system injuries. However, its effect on genome-wide transcription in acute spinal cord injury (SCI) remains unknown. In the present study, RNA sequencing (RNA-Seq) is used to analyze the effect of probenecid on the local expression of gene transcription 8 h after spinal injury.MethodsAn Infinite Horizon impactor was used to perform contusive SCI in mice. The SCI model was made by using a rod (1.3 mm diameter) with a force of 50 Kdynes. Sham-operated mice only received a laminectomy without contusive injury. The injured mice were randomly assigned into either the control (SCI_C) or probenecid injection (SCI_P) group. In the latter group, the probenecid drug was intraperitoneally injected (0.5 mg/kg) immediately following injury. Eight hours after the injury or laminectomy, the spinal cords were removed from the mice in both groups. The total RNAs were extracted and purified for library preparation and transcriptome sequencing. Differential gene expressions (DEGs) of the three groups-sham, SCI_C and SCI_P-were analyzed using a DESeq software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of DEGs were performed using a GOseq R package and KOBAS software. Real-time quantitative reverse-transcriptase polymerase chain reaction was used to validate RNA-Seq results.ResultsRNA-Seq showed that, compared to the SCI_C group, the number of DEGs was 641 in the SCI_P group (286 upregulated and 355 downregulated). According to GO analysis, DEGs were most enriched in extracellular matrix (ECM), collagen trimer, protein bounding and sequence specific DNA binding. KEGG analysis showed that the most enriched pathways included: cell adhesion molecules, Leukocyte transendothelial migration, ECM-receptor interactions, PI3K-Akt signaling pathways, hematopoietic cell lineages, focal adhesions, the Rap1 signaling pathway, etc. The sequence data have been deposited into the Sequence Read Archive (https://www.ncbi.nlm.nih.gov/sra/PRJNA554464).

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Effect of VX?765 on the transcriptome profile of mice spinal cords with acute injury.

Publications

Effect of VX‑765 on the transcriptome profile of mice spinal cords with acute injury.

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