Hereditas最新文献

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.

Background: Epithelial-mesenchymal transition (EMT) of tubular epithelial cells are one of the major pathological changes of diabetic nephropathy (DN). Cluster of differentiation 248 (CD248) has been reported to be associated with fibrosis after kidney injury. The aim of this study was to investigate the mechanism of CD248 in DN and its targeted compounds.

Materials and methods: Virtual screening, molecular docking and Cellular thermal shift assays were used to explore potential small molecule compounds targeting CD248. In vitro DN model was established by treating human proximal renal tubular epithelial cell line HK-2 with high glucose (HG), and db/db mice were used as the animal model. siRNA transfection was used to knockdown CD248 in HK-2 cells, and HK-2 cells and the animals were treated with veratramine (VER) or neobavaisoflavone (NBIF). qPCR was used to detect the mRNA expression of CD248, tumor necrosis factor-α (TNF-α), interleukin (IL)-6 (IL-6), and IL-1β. Western blot was used to assess protein expression level of CD248, EMT-associated proteins, fibrosis markers, and TGF-β1/Smads pathway-associated proteins. CCK-8 assay and flow cytometry were used to detect cell viability and apoptosis, respectively. Histopathological and various biochemical indicators were used to assess renal injury in animals.

Results: CD248 was significantly up-regulated in HG-induced HK-2 cells. CD248 knockdown inhibited HG-induced cell proliferation inhibition, apoptosis and inflammatory response. HG stimulation significantly reduced the protein expression level of E-cadherin in HK-2 cells, and increased the expression levels of vimentin, α-smooth muscle actin (α-SMA), collagen I, collagen IV, fibronectin, TGF-β1, p-Smad2, p-Smad3, and Smad4, while CD248 knockdown reversed these effects. In addition, VER and neobavaisoflavone were found to bind with CD248, and they inhibited HG-induced apoptosis, inflammation, EMT and extracellular matrix synthesis in HK-2 cells, and ameliorate the renal injury of db/db mice. VER and NBIF also inhibited HG-induced activation of TGF-β1/Smads axis.

Conclusion: CD248 participates in HG-induced EMT of renal tubular epithelial cells and renal fibrosis by regulating TGF-β1/Smads pathway, and VER and NBIF are two potential natural drugs which targets it to ameliorate DN.

Background & objective: MicroRNAs (miRNAs) offer advantages in stability and therapeutic specificity. This study investigated the diagnostic and therapeutic potential of miR-143-5p in sepsis (SP) and SP-associated cardiac dysfunction (CD). ‌Methods. Quantitative Real-Time polymerase chain reaction (qRT-PCR) quantified serum and cellular miR-143-5p levels. Receiver operator characteristic (ROC) curve evaluated miR-143-5p's diagnostic efficacy. Pearson correlation analysis assessed the association between miR-143-5p and SP. Univariate logistic regression identified CD risk factors, with multivariate logistic analysis including significant variables from univariate analysis. Lipopolysaccharide (LPS)-induced macrophage (THP-1) and cardiomyocyte (AC16) models elucidated miR-143-5p mechanisms in SP, with bioinformatics predicting the potential pathways. ‌Results. MiR-143-5p downregulation demonstrated diagnostic value for SP (AUC: 0.897) and SP-CD (AUC: 0.812). MiR-143-5p expression correlated (P < 0.0001) with white blood cell count (WBC, r = -0.680), C-reactive protein (CRP, r = -0.563), procalcitonin (PCT, r = - 0.693), left ventricular ejection fraction (LVEF, r = 0.640), cardiac troponin I (cTnI, r = -0.599), Acute Physiology And Chronic Health Evaluation II (APACHE II, r = -0.695), and Sequential Organ Failure Assessment (SOFA, P < 0.05) scores. MiR-143-5p served as a risk factor for CD in SP (OR: 0.100). MiR-143-5p overexpression reduced M1 polarization and pro-inflammatory cytokines in LPS-treated THP-1. In AC16 cardiomyocytes, it enhanced viability, suppressed apoptosis, and attenuated inflammation. Bioinformatics analysis indicated miR-143-5p was involved in p53 and MAPK signal pathways regulation. ‌Conclusions. MiR-143-5p downregulation showed diagnostic potential for SP and SP with CD, correlating with disease severity and CD risk. Mechanistically, miR-143-5p overexpression mitigated macrophage and cardiomyocyte injury.

Background: Diabetic kidney disease (DKD) is a serious microvascular complication of type 2 diabetes mellitus (T2DM). miR-127-3p is dysregulated in T2DM, but the specific molecular mechanism remains unclear. We aim to probe the diagnostic value of miR-127-3p and its molecular mechanism in T2DM and DKD.

Methods: This study comprised 218 individuals, including 78 patients with T2DM, 72 patients with DKD and 68 healthy controls. All participants underwent fasting peripheral blood collection. In vitro, we simulated a hyperglycemic environment by treating human mesangial cells (HMC) with high-concentration glucose (HG). Subsequently, RT-qPCR was used to detect the levels of miR-127-3p in serum and HMC. Cell viability and inflammatory cytokine (TNF-α, IL-1β and IL-6) levels were assessed using the CCK-8 assay and ELISA, respectively. The dual-luciferase reporter assay validated the target relationship between miR-127-3p and ACO2.

Results: By comparing baseline clinical characteristics, we identified significant differences among the three groups in high density lipoprotein cholesterol (HDL-C), triglycerides (TG), fasting blood glucose (FBG), glycated hemoglobin A1c (HbA1c), blood urea nitrogen (BUN), estimated glomerular filtration rate (eGFR) and albuminuria. Additionally, miR-127-3p was elevated in T2DM and DKD patients. It could distinguish healthy individuals from T2DM or T2DM from DKD. In HG-induced HMC, miR-127-3p inhibitor elevated the cell viability and the levels of SOD while suppressing the levels of MDA. These effects were abolished by ACO2 silencing. Furthermore, downregulated miR-127-3p reduced the levels of TNF-α, IL-1β and IL-6. sh-ACO2 alleviated the inhibitory effects of miR-127-3p.

Conclusions: Upregulated miR-127-3p was involved in the progression of T2DM and DKD. In HG-induced HMC, down-regulated miR-127-3p improved cell viability and suppressed oxidative stress and inflammatory responses by negatively regulating ACO2.