Ye Chenhao, Fu Yuedong, Zhou Xijie, Zhou Feiya, Zhu Xuwei, Chen Yiheng
Department of Hand and Microsurgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
Front Endocrinol (Lausanne). 2024 Feb 23;15:1309917. doi: 10.3389/fendo.2024.1309917. eCollection 2024.
The mechanism of Nicotinamide Adenine Dinucleotide (NAD+) metabolism-related genes (NMRGs) in diabetic peripheral neuropathy (DPN) is unclear. This study aimed to find new NMRGs biomarkers in DPN.
DPN related datasets GSE95849 and GSE185011 were acquired from the Gene Expression Omnibus (GEO) database. 51 NMRGs were collected from a previous article. To explore NMRGs expression in DPN and control samples, differential expression analysis was completed in GSE95849 to obtain differentially expressed genes (DEGs), and the intersection of DEGs and NMRGs was regarded as DE-NMRGs. Next, a protein-protein interaction (PPI) network based on DE-NMRGs was constructed and biomarkers were screened by eight algorithms. Additionally, Gene Set Enrichment Analysis (GSEA) enrichment analysis was completed, biomarker-based column line graphs were constructed, lncRNA-miRNA-mRNA and competing endogenouse (ce) RNA networks were constructed, and drug prediction was completed. Finally, biomarkers expression validation was completed in GSE95849 and GSE185011.
5217 DEGs were obtained from GSE95849 and 21 overlapping genes of DEGs and NMRGs were DE-NMRGs. Functional enrichment analysis revealed that DE-NMRGs were associated with glycosyl compound metabolic process. The PPI network contained 93 protein-interaction pairs and 21 nodes, with strong interactions between NMNAT1 and NAMPT, NADK and NMNAT3, ENPP3 and NUDT12 as biomarkers based on 8 algorithms. Expression validation suggested that ENPP3 and NUDT12 were upregulated in DPN samples (P < 0.05). Moreover, an alignment diagram with good diagnostic efficacy based on ENPP3 and NUDT12 were identified was constructed. GSEA suggested that ENPP3 was enriched in Toll like receptor (TLR) pathway, NUDT12 was enriched in maturity onset diabetes of the young and insulin pathway. Furthermore, 18 potential miRNAs and 36 Transcription factors (TFs) were predicted and the miRNA-mRNA-TF networks were constructed, suggesting that ENPP3 might regulate hsa-miR-34a-5p by affecting MYNN. The ceRNA network suggested that XLOC_013024 might regulate hsa-let-7b-5p by affecting NUDT12. 15 drugs were predicted, with 8 drugs affecting NUDT12 such as resveratrol, and 13 drugs affecting ENPP3 such as troglitazone.
ENPP3 and NUDT12 might play key roles in DPN, which provides reference for further research on DPN.
烟酰胺腺嘌呤二核苷酸（NAD+）代谢相关基因（NMRGs）在糖尿病周围神经病变（DPN）中的机制尚不清楚。本研究旨在寻找DPN中新的NMRGs生物标志物。
从基因表达综合数据库（GEO）获取DPN相关数据集GSE95849和GSE185011。从之前的一篇文章中收集了51个NMRGs。为了探究NMRGs在DPN和对照样本中的表达，在GSE95849中完成差异表达分析以获得差异表达基因（DEGs），并将DEGs与NMRGs的交集视为DE-NMRGs。接下来，基于DE-NMRGs构建蛋白质-蛋白质相互作用（PPI）网络，并通过八种算法筛选生物标志物。此外，完成基因集富集分析（GSEA）富集分析，构建基于生物标志物的柱状线图，构建lncRNA-miRNA-mRNA和竞争性内源性（ce）RNA网络，并完成药物预测。最后，在GSE95849和GSE185011中完成生物标志物表达验证。
从GSE95849中获得5217个DEGs，DEGs与NMRGs的21个重叠基因即为DE-NMRGs。功能富集分析表明，DE-NMRGs与糖基化合物代谢过程相关。PPI网络包含93个蛋白质相互作用对和21个节点，基于8种算法，NMNAT1与NAMPT、NADK与NMNAT3、ENPP3与NUDT12之间存在强相互作用，可作为生物标志物。表达验证表明，ENPP3和NUDT12在DPN样本中上调（P < 0.05）。此外，构建了基于ENPP3和NUDT12的具有良好诊断效能的比对图。GSEA表明，ENPP3在Toll样受体（TLR）通路中富集，NUDT12在青少年成熟型糖尿病和胰岛素通路中富集。此外，预测了18个潜在的miRNA和36个转录因子（TFs），并构建了miRNA-mRNA-TF网络，表明ENPP3可能通过影响MYNN来调节hsa-miR-34a-5p。ceRNA网络表明，XLOC_013024可能通过影响NUDT12来调节hsa-let-7b-5p。预测了15种药物，其中8种药物如白藜芦醇影响NUDT12，13种药物如曲格列酮影响ENPP3。
ENPP3和NUDT12可能在DPN中起关键作用，为DPN的进一步研究提供参考。
