Identification and validation of NAD+ metabolism-related biomarkers in patients with diabetic peripheral neuropathy.

Background: 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. Methods: 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. Results: 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. Conclusion: ENPP3 and NUDT12 might play key roles in DPN, which provides reference for further research on DPN.

The bone mesenchymal stem cell-derived exosomal miR-146a-5p promotes diabetic wound healing in mice via macrophage M1/M2 polarization.

A diabetic wound is a refractory disease that afflicts patients globally. MicroRNA-146a-5p (miR-146a-5p) is reported to represent a potential therapeutic target for diabetic wounds. However, microRNA easily degrades in the wound microenvironment. This study extracted bone marrow mesenchymal stem cell (BMSC)-derived exosomes (EXO). Electroporation technology was used to load miR-146a-5p into EXO (labeled as EXO-miR-146a). The endothelial cells (human umbilical vein endothelial cells [HUVECs]) and macrophages were cocultured in transwell chambers in the presence of high glucose. Cell proliferation, migration, and angiogenesis were measured with cell counting kit 8, scratch, and tube forming assays, respectively. Flow cytometry was introduced to validate the biomarker of macrophages and BMSCs. The expression level of macrophage polarization-related proteins and tumor necrosis factor receptor-associated factor 6 (TRAF6) was assessed with western blotting analysis. The full-thickness skin wound model was developed to verify the in vitro results. EXO-miR-146a promoted the proliferation, migration, and angiogenesis of HUVECs in the hyperglycemic state by suppressing the TRAF6 expression in vitro. Additionally, EXO-miR-146a treatment facilitated M2 but inhibited M1 macrophage polarization. Furthermore, EXO-miR-146a enhances reepithelialization, angiogenesis, and M2 macrophage polarization, thereby accelerating diabetic wound healing in vivo. The EXO-miR-146a facilitated M2 macrophage polarization, proliferation, migration, and angiogenesis of HUVECs through TRAF6, thereby ameliorating intractable diabetic wound healing. These results established the basis for using EXO to deliver drugs and revealed mediators for diabetic wound treatment.

T1-weighted images-based radiomics for structural lesions evaluation in patients with suspected axial spondyloarthritis.

PURPOSE: The aim of this study was to investigate the feasibility of radiomics based on T1-weighted images (T1WI) for assessing sacroiliac joint (SIJ) structural lesions in patients with suspected axial spondyloarthritis (axSpA). MATERIALS AND METHODS: A total of 266 patients with clinical suspicion of axSpA between December 2016 and January 2022 were enrolled. Structural lesions were assessed on low-dose CT (ldCT) and MRI, respectively. Radiomic features, extracted from SIJ T1WI, were included to generate the radiomics model. The performance of the radiomics model was evaluated using receiver operating characteristic (ROC) curve. Furthermore, point-biserial correlation analysis was used to interpret the associations between the radiomic feature and structural lesions. RESULTS: Using ldCT as the reference standard, the radiomics model showed favorable performance for detecting positive global structural lesions in the training cohort (AUC, 0.82 [95% CI: 0.76, 0.88]) and validation cohort (AUC, 0.82 [95% CI: 0.72, 0.91]. Experienced MRI raters yielded predictive AUCs of 0.73 (95% CI: 0.67, 0.79), and 0.74 (95% CI: 0.66, 0.83) in the training and validation cohort, respectively. The seven radiomic features included in the radiomics model showed significant correlation with different kinds of structural lesions (P all < 0.05). Among them, Wavelet.LHL_firstorder_90Percentile showed the strongest association with fat lesion (r = 0.48, P < 0.05). CONCLUSION: The radiomics analysis with T1WI could effectively detect SIJ structural lesions and achieved expert-level performance. Each radiomic feature was correlated with different structural lesions significantly, which might inform radiomic-based applications for axSpA intelligent diagnosis.

Can radiomics replace the SPARCC scoring system in evaluating bone marrow edema of sacroiliac joints in patients with axial spondyloarthritis?

OBJECTIVES: To develop an objective and efficient method based on radiomics to evaluate bone marrow edema (BMO) of sacroiliac joints (SIJs) by magnetic resonance imaging (MRI) in patients with axial spondyloarthritis (axSpA) and to compare with the Spondyloarthritis Research Consortium of Canada (SPARCC) scoring system. METHODS: From September 2013 to March 2022, patients with axSpA who underwent 3.0T SIJ-MRI were included and were randomly divided into training and validation cohorts at a ratio of 7:3. The optimal radiomics features selected from the SIJ-MRI in the training cohort were included to generate the radiomics model. The performance of the model was evaluated by ROC analysis and decision curve analysis (DCA). Rad scores were calculated using the radiomics model. The responsiveness was compared for Rad scores and SPARCC scores. We also assessed the correlation between the Rad score and SPARCC score. RESULTS: A total of 558 patients were finally included. The radiomics model showed favorable discrimination of a SPARCC score <2 or ≥2 both in the training (AUC, 0.90; 95% CI: 0.87-0.93) and validation cohorts (AUC, 0.90; 95% CI, 0.86-0.95). DCA confirmed that the model was clinically useful. Rad score showed higher responsiveness to treatment-related change than SPARCC score. Furthermore, a significant correlation was noted between the Rad score and SPARCC score when scoring the status of BMO (rs=0.80, P < 0.001), and a strong correlation was noted when scoring the change in BMO (r=0.70, P < 0.001). CONCLUSION: The study proposed a radiomics model to accurately quantify the BMO of SIJs in patients with axSpA, providing an alternative to the SPARCC scoring system. Key Points • The Rad score is an index with high validity for the objective and quantitative evaluation of bone marrow edema (BMO) of the sacroiliac joints in axial spondyloarthritis. • The Rad score is a promising tool to monitor the change of BMO upon treatment.