Background. Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis, affects approximately one-quarter of the global population and is considered one of the most lethal infectious diseases worldwide. The prevention of latent tuberculosis infection (LTBI) from progressing into active tuberculosis (ATB) is crucial for controlling and eradicating TB. Unfortunately, currently available biomarkers have limited effectiveness in identifying subpopulations that are at risk of developing ATB. Hence, it is imperative to develop advanced molecular tools for TB risk stratification. Methods. The TB datasets were downloaded from the GEO database. Three machine learning models, namely LASSO, RF, and SVM-RFE, were used to identify the key characteristic genes related to inflammation during the progression of LTBI to ATB. The expression and diagnostic accuracy of these characteristic genes were subsequently verified. These genes were then used to develop diagnostic nomograms. In addition, single-cell expression clustering analysis, immune cell expression clustering analysis, GSVA analysis, immune cell correlation, and immune checkpoint correlation of characteristic genes were conducted. Furthermore, the upstream shared miRNA was predicted, and a miRNA–genes network was constructed. Candidate drugs were also analyzed and predicted. Results. In comparison to LTBI, a total of 96 upregulated and 26 downregulated genes related to the inflammatory response were identified in ATB. These characteristic genes have demonstrated excellent diagnostic performance and significant correlation with many immune cells and immune sites. The results of the miRNA–genes network analysis suggested a potential role of hsa-miR-3163 in the molecular mechanism of LTBI progressing into ATB. Moreover, retinoic acid may offer a potential avenue for the prevention of LTBI progression to ATB and for the treatment of ATB. Conclusion. Our research has identified key inflammatory response-related genes that are characteristic of LTBI progression to ATB and hsa-miR-3163 as a significant node in the molecular mechanism of this progression. Our analyses have demonstrated the excellent diagnostic performance of these characteristic genes and their significant correlation with many immune cells and immune checkpoints. The CD274 immune checkpoint presents a promising target for the prevention and treatment of ATB. Furthermore, our findings suggest that retinoic acid may have a role in preventing LTBI from progressing to ATB and in treating ATB. This study provides a new perspective for differential diagnosis of LTBI and ATB and may uncover potential inflammatory immune mechanisms, biomarkers, therapeutic targets, and effective drugs in the progression of LTBI into ATB.
The statins are a class of HMG CoA-reductase inhibitors used clinically for their ability to reduce serum cholesterol levels via inhibition of the prenylation pathway. However, not all of their clinical benefits, including both vascular barrier protection and reduced superoxide generation, can be attributed to their lipid-lowering properties. One potential mechanism of these effects is via inhibition of geranylgeranylation, a covalent modification that allows translocation to the cell membrane and activation of the small GTPases Rho and Rac, mediators of cytoskeletal rearrangement. While statins inhibit Rho, we previously reported the paradoxical activation of Rac (Rac-GTP) in endothelial cell (EC) after prolonged treatment with simvastatin (5 µM, 16 hours). In this study, upon membrane fractionation and subsequent Western blotting, we report a 37% reduction in Rac translocation to the EC membrane by simvastatin (5 µM, 16 hours) relative to untreated control cells, consistent with the inhibition of geranylgeranylation and evidence of a separate mechanism of simvastatinmediated Rac activation. In addition, as Rac is required for activation of the NADPH oxidase complex and subsequent superoxide anion generation, we examined the effect of simvastatin on the peripheral translocation of P47 phox , an NADPH oxidase component. Simvastatin affected a 47% reduction in P47 phox at the EC membrane relative to control cells. Finally, we measured transendothelial electrical resistance and quantified the effects of simvastatin pretreatment on sphingosine 1-phosphate-induced barrier enhancement, an event dependent on Rac. S1P-induced (1 µM) EC barrier function was increased by simvastatin (5 µM, 16 hours) 70% at peak effect relative to S1P-treated control cells. These data are consistent with a functional role for Rac in simvastatin-mediated EC barrier protection and further define the mechanism by which simvastatin is able to directly modulate EC.
Although rare, the distribution of the 5-hydroxymethylcytosine (hmC) modification in mammalian DNA is tissue-and gene-specific, yet distinct from its transcriptionally-repressive methylcytosine (mC) precursor, suggesting unique signaling potential. To examine this possibility, we fractionated mammalian brain extracts to discover binding partners specific for oxidized states of mC. We demonstrate that one such factor, WDR76, is a highly hmC-specific binding protein that modulates gene expression within chromosomal regions enriched in hmC where it binds. We demonstrate direct transcriptional activation of several target genes in mouse embryonic stem cells as a function of hmC levels and contingent upon WDR76. In human cell lines and mouse models, WDR76 recruitment by hmC is critical for the initiation and maintenance of MLLrearranged leukemias. Beyond its canonical role as an intermediate in mC remediation, we show that hmC can be an epigenetic mark whose recognition drives leukemogenesis, portending analogous signaling pathways for other rare DNA modifications.
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