Hereditas最新文献

Background: The role of cholesterol metabolism in IgA nephropathy (IgAN) remains poorly understood.

Methods: We applied a multi-omics integrative framework to systematically identify key regulatory genes. This approach combined genome-wide association study (GWAS), summary-data-based mendelian randomization (SMR), conventional MR, Bayesian colocalization, single-cell RNA sequencing (scRNA-seq), bulk transcriptome validation, molecular docking, and molecular dynamics simulations.

Results: ACOX2 was identified as a protective hub gene. Genetic analyses revealed an inverse association between ACOX2 expression and IgAN risk (OR = 0.917, 95% CI: 0.879-0.957; PPH4 = 90.75%). scRNA-seq demonstrated the downregulation of ACOX2 in proximal tubular cells, which was further confirmed in external datasets. Molecular docking and molecular dynamics simulation suggested flavin adenine dinucleotide (FAD) as a potential therapeutic ligand targeting ACOX2.

Conclusion: This study uncovers a cholesterol metabolism-related regulatory axis in IgAN, establishes ACOX2 as a protective biomarker, and highlights a therapeutically actionable pathway; it provides mechanistic insights and translational opportunities for biomarker development and drug discovery.

Hepatic ischemia-reperfusion (I/R) injury is an unavoidable process in liver surgeries like transplantation and hepatectomy, and it greatly impairs postoperative liver function. Recent studies have shown that anesthetic agents, such as remifentanil, offer liver protection. However, the exact mechanisms of remifentanil's protective effects remain unclear. In this study, a rat hepatic I/R injury model and a hepatocyte BRL-3 A hypoxia/reoxygenation (H/R) model were successfully established, and remifentanil preconditioning (RPC) was administered. Liver function enzyme activities were measured using biochemical assays, and the extent of liver damage was assessed via HE staining as well as TUNEL staining. The survival rate and apoptosis rate of BRL-3 A cells were determined by CCK-8 assay and flow cytometry, respectively. Levels of proinflammatory cytokines were quantified using ELISA. qRT-PCR and Western blotting analysis were employed to evaluate the expression of α7 nicotinic acetylcholine receptor (α7nAChR) and the phosphorylation of NF-κB. Loss-of- function experiments of α7nAChR were conducted to further elucidate the underlying molecular mechanism by which remifentanil protects the liver against I/R injury. The findings demonstrated that RPC markedly mitigated liver dysfunction, decreased hepatic cell necrosis and apoptosis, and suppressed the inflammation in rats subjected to I/R. Furthermore, RPC provided protection for BRL-3 A cells against H/R-induced injury and inflammation. Notably, RPC upregulated α7nAChR expression in I/R liver tissue and H/R-exposed BRL-3 A cells while concurrently inhibiting NF-κB phosphorylation. However, the protective effects of RPC on hepatic I/R injury and H/R-induced BRL-3 A cells injury were abrogated by the administration of an α7nAChR antagonist or α7nAChR knockdown. Taken together, these data reveal a novel mechanism of remifentanil's hepatoprotective effect, which is that remifentanil alleviates hepatic I/R injury by upregulating α7nACh to inhibit inflammation mediated by NF-κB activation.

Background: The microRNA expression profile in the bodily fluids of individuals with acute pancreatitis (AP) undergoes considerable alterations; nevertheless, the precise mechanism requires more elucidation.

Methods: A dataset of 2083 human blood microRNAs (miRNAs) was obtained from the miRNA expression quantitative loci data. The genome-wide association study data for AP was obtained from the FinnGen Consortium. The causal association between miRNA and susceptibility to AP was evaluated using the Mendelian randomization (MR) method. Receiver operating characteristic (ROC) curve analyses were implemented to assess the miRNA's clinical usefulness. The GSE188819 and GSE249349 datasets were analyzed to determine changes in cell subset amounts and differentially expressed genes during the advancement and regression of AP mice. We assessed the inhibitory impact of miR-27b-3p and miR-193a-5p overexpression on AR42J cell and RAW 264.7 cell inflammation using western blot.

Results: Following a thorough process of genetic variation selection, MR analysis, and sensitivity analysis, we identified 66 miRNAs with suggestive causality to AP susceptibility. We conducted ROC curve analysis on 66 variables, identifying 6 miRNAs that have the potential to diagnose AP. Six and twelve cell subsets were identified from the GSE249349 and GSE188819 datasets, respectively. In the inflammatory advancement stage, the percentage of acinar cells in the AP group decreased relative to the control group samples. In the inflammatory regression phase, the percentage of monocytes in the AP (96 h) group decreased relative to the AP (12 h) group. In vitro, experiments have found that the overexpression of miR-27b-3p and miR-193a-5p in RAW 264.7 cells AR42J cells significantly inhibited the protein expression of p-P65.

Conclusion: Our research identified novel miRNAs associated with the pathogenesis of AP. In vitro experiments have confirmed that miR-27b-3p and miR-193a-5p can inhibit the inflammatory response in RAW 264.7 cells and AR42J cells.

Background: Ubiquitination-related genes (UbRGs) play critical roles in tumor biology. However, their functions in multiple myeloma (MM) remain insufficiently explored.

Methods: Transcriptomic data from public databases were integrated to identify UbRGs in MM through WGCNA, differential expression, and protein-protein interaction (PPI) analyses. Functional roles were examined by GO, KEGG, and GSEA, while immune infiltration and drug sensitivity were evaluated using CIBERSORT, ESTIMATE, and OncoPredict. UbRG expression was validated in clinical samples and cell lines by qRT-PCR and western blot, and functional effects of UbRG knockdown in MM cells were examined using CCK-8, Transwell, EdU, and TUNEL assays.

Results: Ring Finger Protein 25 (RNF25) is a ubiquitination-related gene closely associated with MM, exhibiting consistent overexpression across multiple independent datasets. Elevated RNF25 expression is significantly correlated with poorer overall survival and serves as an independent adverse prognostic factor. Functional enrichment analysis revealed that RNF25 may regulate key pathways such as ATP-dependent chromatin remodeling, cell cycle progression, and ubiquitin-mediated proteolysis. Immune analysis further indicated that high RNF25 expression is associated with reduced immune and stromal scores, increased plasma cell infiltration, and elevated T cell co-inhibition activity. RNF25 was highly expressed in tumor tissues from clinical samples, and its knockdown significantly reduced the viability, proliferation, and migration of U266 cells, while promoting apoptosis.

Conclusions: RNF25 may serve as a potential prognostic biomarker for MM and holds promise as a candidate therapeutic target.

Background: Breast cancer is a leading cause of cancer-related mortality among women worldwide. Identifying reliable molecular biomarkers and therapeutic targets is crucial for improving early diagnosis and treatment strategies. This study aimed to identify and functionally validate key hub genes involved in breast cancer progression using an integrated bioinformatics and experimental approach.

Methodology: Three microarray datasets (GSE42568, GSE29431, and GSE21422) were retrieved from the GEO database to identify differentially expressed genes (DEGs). DEGs common across datasets were subjected to PPI network analysis using STRING and Cytoscape, and hub genes were identified via CytoHubba. The expression of hub genes was validated using RT-qPCR in six breast cancer and five normal epithelial cell lines. Methylation status, survival correlation, immune associations, and drug sensitivity were assessed via GSCA, cBioPortal, OncoDB, and TISIDB. Functional assays, including cell proliferation, colony formation, and wound healing assays were performed following gene overexpression in MCF-7 and T47D cells.

Results: Four hub genes (PPARG, LEP, CD36, and PLIN1) were consistently downregulated in breast cancer and showed higher promoter methylation. Their expression correlated with tumor progression, poor survival, immune infiltration, and drug sensitivity. Functional validation demonstrated that overexpression of each gene reduced proliferation, colony formation, and migration in vitro. Additionally, these genes exhibited subtype-specific immune interactions and drug response profiles, with PPARG emerging as a particularly strong therapeutic biomarker.

Conclusion: This study identified and experimentally validated four hub genes as potential biomarkers and therapeutic targets in breast cancer. Their expression is regulated by methylation and contributes to tumor progression and immune modulation, highlighting their clinical utility in precision oncology.