Effect of VX-765 on the transcriptome profile of mice spinal cords with acute injury
Effect of VX-765 on the transcriptome profile of mice spinal cords with acute injury
复制标题
VX-765对急性脊髓损伤小鼠转录组谱的影响
DOI：
10.3892/mmr.2020.11129
复制
发表时间：
2020-07-01
影响因子：
3.4
通讯作者：
Lu, He-Zuo
中科院分区：
文献类型：
--
作者：
Chen, Jing;Chen, Yu-Qing;Lu, He-Zuo
以往的研究表明，caspase-1在脊髓损伤（SCI）的急性炎症反应中起重要作用。VX-765是一种新型的不可逆的caspase-1抑制剂，据报道可有效干预炎症。然而，VX-765对急性损伤脊髓全基因组转录的影响仍然未知。因此，在本研究中，RNA测序（RNA-Seq）用于分析VX-765对损伤后8 h基因转录局部表达的影响。差异表达基因（DEG）分别通过基因本体论和京都基因百科全书和基因组分析进行功能和途径的富集分析。Western blot平行分析证实VX-765能有效抑制caspase-1的表达和活化。RNA-Seq显示VX-765处理导致1，137个DEG上调和1，762个DEG下调。这些下调的DEG及其相关信号通路，如粘着斑、白细胞-细胞因子受体相互作用、白细胞跨内皮迁移、细胞外基质-受体相互作用、磷脂酰肌醇3-激酶-蛋白激酶B、Rap 1和缺氧诱导因子-1信号通路，主要与炎症反应、局部缺氧、巨噬细胞分化、粘附迁移和局部细胞凋亡有关。提示急性期应用VX-765可通过抑制caspase-1改善SCI局部微环境。但VX-765能否作为SCI的治疗药物还需进一步探索。序列数据已存入Sequence Read Archive（https：//www.ncbi.nlm.nih.gov/sra/PRJNA548970）。
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).