Hereditas最新文献

Objectives: Circular RNAs play crucial regulatory roles in the progression of human diseases. This study aimed to investigate the functional mechanism of circRNA-14,052 in breast cancer progression.

Methods: The biological functions of circRNA-14,052 were assessed using CCK-8, wound healing, flow cytometry assays. The ceRNA regulatory network of circRNA-14,052-miR-214-3p- IKBKB was validated by luciferase reporter assay.

Results: The levels of circRNA-14,052 were notably elevated, but the levels of miR-214-3p were markedly reduced in breast cancer tissues compared to adjacent non-cancerous tissues. Downregulation of circRNA-14,052 or overexpression of miR-214-3p reduced MCF-7 cell proliferation and triggered cell apoptosis. Mechanically, circRNA-14,052 could elevate IKBKB levels via competitively sponging miR-214-3p. Notably, miR-214-3p inhibition reversed the growth-suppressive effects of circRNA-14,052 silencing. Additionally, circRNA-14,052 knockdown notably reduced IKBKB, IL-6, JAK2 and STAT3 levels in MCF-7 cells; whereas these changes were reversed by miR-214-3p deficiency. Furthermore, deficiency of circRNA-14,052 reduced xenograft tumor growth in vivo through targeting miR-214-3p/IKBKB/IL-6/JAK2/STAT3 axis.

Conclusion: Collectively, our results showed that circRNA-14,052 promotes breast cancer progression via the miR-214-3p/IKBKB axis. Targeting this molecular axis may represent a promising therapeutic strategy for breast cancer treatment.

Background: Ferroptosis is involved in the pathogenesis of Lupus nephritis (LN), but its mechanism of action in LN remains unknown. This study aims to explore the effect of the ferroptositic-related gene neutrophil cytosolic factor 2 (NCF2) on LN and its potential downstream mechanism.

Method: Differentially expressed genes (DEGs) between LN tissues and control tissues were screened out using "limma" R package. Weighted gene co-expression network analysis (WGCNA) was used to identify the key modules related to inflammation in LN based on DEGs. The genes associated with ferroptosis were obtained from the FerrDb database. Support vector machine recursive feature elimination (SVM-RFE) was used to screen candidate key genes. The expression and the diagnostic ability of candidate key genes was evaluated using an external validation set. Immune infiltration analysis was performed using CIBERSORT. Gene set enrichment analysis was used to reveal the molecular mechanisms of key genes. A cell model of LN was constructed using lipopolysaccharide (LPS) -induced human renal cortical proximal tubule epithelial cells HK-2 to explore the potential functions and mechanisms of the key gene NCF2 in LN.

Result: Nine ferroptosis-related genes in LN were obtained after cross-analysis, and six candidate genes were screened out using machine learning approach. Among them, NCF2 was identified as a key gene related to ferroptosis in LN. The expression of NCF2 was positively correlated with the infiltration levels of pro-inflammatory cells such as monocytes and M1 macrophages, and negatively correlated with those of anti-inflammatory cells such as regulatory T cells (Tregs). NCF2-related DEGs were significantly enriched in the peroxisome proliferator-activated receptor (PPAR) signaling pathway. In vitro experiments demonstrated that knocking down NCF2 significantly inhibited LPS-induced suppression of viability, apoptosis, inflammatory response and ferroptosis of HK-2 cells. NCF2 knockdown also inhibited ferroptosis by activating the PPARα pathway.

Conclusion: NCF2 is a key regulatory factor of LN. Its knockdown inhibits ferroptosis by activating the PPARα signaling, thereby alleviating inflammatory injury of renal tubular epithelial cells. Targeting NCF2 may provide a new strategy for the treatment of LN.

Clear cell renal cell carcinoma (ccRCC) is a highly heterogeneous tumor that lacks reliable biological markers for diagnosis and prognostic monitoring. Currently, the differentially expressed genes between paired adjacent normal tissues and ccRCC tumor tissues at single-cell resolution remained to be further discovered. To address this challenge, we performed an integrative analysis of multiple single-cell databases containing paired ccRCC samples. Using the "CopyKAT" algorithm, we accurately identified ccRCC tumor cells. Subsequently, various pseudotime algorithms were employed to identify malignant cells with tumor stem cell-like properties and high plasticity. This cell subgroup exhibited high expression of malignant features, including hypoxia, epithelial-mesenchymal transition (EMT), and proliferation/invasion phenotypes. We then performed differential analysis to identify genes highly expressed in this subgroup and constructed a reliable clinical diagnostic model for ccRCC using multiple machine learning algorithms. Furthermore, we identified AXL as a key gene with significant oncogenic activity, where high expression of AXL correlated with poor patient prognosis. Immune infiltration and spatial transcriptomics analyses further revealed that AXL promotes tumor progression interaction with M2 macrophages. Taken together, our analysis establishes a reliable 13-gene panel diagnostic model and AXL gene as reliable biological markers for ccRCC, providing valuable targets and a theoretical foundation for the development of precision-targeted therapies for ccRCC.

Background: The progression of esophageal cancer (EC) has been associated with aberrant activation of oncogenes and suppression of tumor suppressor genes. The EZR gene encodes ezrin, which is highly activated and upregulated in cancer cells, contributing to their invasive potential. This study aimed to elucidate the role of ezrin in EC progression, with a specific focus on the PI3K-AKT signaling pathway.

Method: Expression of the EZR gene was silenced in ECA109 cells to assess changes in the phosphorylation levels of multiple kinases Bioinformatics analyses were conducted to identify ezrin-associated signaling pathways. In vitro functional assays were performed to investigate the effects of EZR silencing on cell proliferation, apoptosis, migration, and invasion.

Results: Cells with EZR knockdown demonstrated markedly decreased phosphorylation of AKT1/2/3 (S473), EGFR (Y1086), PLC-γ1 (Y783), Src (Y419), STAT5a/b (Y694/Y699), Yes (Y426), and β-Catenin, relative to control cells. These findings indicate that the PI3K-AKT signaling pathway is a critical downstream mediator of ezrin activity. The inhibition of AKT phosphorylation resulting from EZR knockdown was reversed upon treatment with an AKT pathway activator, confirming the involvement of this signaling axis. Functionally, EZR silencing significantly reduced EC cell proliferation, migration, and invasion, and increased apoptosis. These effects were attenuated, in part, by concurrent activation of the AKT pathway. Collectively, the data suggest that ezrin modulates key oncogenic processes in EC through the PI3K-AKT signaling pathway.

Conclusion: Ezrin contributes to the progression of EC through modulation of the PI3K-AKT signaling cascade, influencing cellular proliferation, apoptosis, migration, and invasion.

Osteoporosis, a prevalent skeletal disorder characterized by decreased bone mineral density and increased fracture risk, continues to be a major global health concern. Traditional treatments for osteoporosis have limited efficacy and safety profiles, highlighting the need for novel therapeutic targets. This study integrates multi-omics data, including RNA-seq, expression quantitative trait loci (eQTL), and protein quantitative trait loci (pQTL) data, through Mendelian randomization (MR) to identify potential drug targets for osteoporosis. By leveraging bidirectional two-sample MR analysis, we identified CPXM1 (Carboxypeptidase X, M14 family member 1) as a novel gene that is causally linked to osteoporosis risk. Through transcriptomic and proteomic validation, we demonstrate that CPXM1 was upregulated in aged bone tissues and osteoporotic conditions in both human and murine models. Gene set enrichment analysis (GSEA) revealed significant dysregulation of bone homeostasis pathways, including increased extracellular matrix degradation and suppression of osteoblast differentiation in aged mice. Furthermore, phenome-wide association studies (PheWAS) confirmed minimal off-target effects of CPXM1, reinforcing its potential as a therapeutic target. Finally, computational drug repurposing predicted several promising drug candidates, including Doxorubicin, 5-Fluorouracil, and 2-Methylcholine, which may target CPXM1 pathways for osteoporosis treatment. These findings highlight CPXM1 as a potential biomarker and therapeutic target, offering new avenues for osteoporosis therapy.

Background: Patients with severe acute pancreatitis (SAP) often experience systemic inflammatory responses and microcirculatory disturbances, for which existing treatments have limited intervention effects.

Objectives: It aimed to investigate the impact of early blood purification on serum inflammatory mediators, hemorheological parameters, and clinical prognosis in patients with SAP.

Methods: 120 patients with SAP were randomly grouped: observation group (OG) (routine treatment + early continuous veno-venous hemodiafiltration) and control group (CG) (routine treatment). The time to clinical symptom improvement, hemorheological parameters [whole blood viscosity (WBV), plasma viscosity (PV), hematocrit, and platelet adhesion rate], and inflammatory mediators were compared. Multivariate logistic regression analysis (MLRA) was used to identify prognostic factors.

Results: The OG had markedly shorter times to symptom relief for fever, abdominal pain, and abdominal distension (all P < 0.001) and a higher cure rate (P = 0.012); The levels of C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), as well as WBV and PV, were more markedly improved (all P < 0.01). Multivariate analysis suggested that peak CRP (OR = 1.01, P < 0.001) and peak TNF-α (OR = 1.02, P = 0.003) maintained independent predictive value, and all hemorheological parameters were confirmed as independent prognostic factors.

Conclusion: Early blood purification can effectively improve the inflammatory response and hemodynamics in patients with SAP, with its efficacy influenced by multiple factors, including disease severity, intensity of inflammatory response, and hemorheological status.

Clinical trial number: Not applicable.

Context: Hyperuricemia (HUA) is a known factor contributing to testicular spermatogenic dysfunction. Shenling Baizhu San (SLBZS), a traditional Chinese medicine compound, has demonstrated efficacy in reducing uric acid levels. However, its specific impact on testicular spermatogenic function in mice with HUA remains unclear.

Objective: To investigate the impact and mechanism of SLBZS on testicular spermatogenic function in HUA mice.

Materials and methods: A hyperuricemia-induced spermatogenic dysfunction model was created by administering intraperitoneal injections of potassium oxonate (600 mg/kg/d) for seven days. Following model establishment, 48 Balb/c mice were randomly divided into six groups: control, model, low-dose SLBZS (5.04 g/kg/d), medium-dose SLBZS (10.07 g/kg/d), high-dose SLBZS (20.14 g/kg/d), and febuxostat (10 mg/kg/d). All groups, except the control, underwent model induction, followed by specific interventions. Subsequent analyses included serum uric acid levels, testicular and epididymal indices, histopathological assessments, sperm quality, oxidative stress and inflammation markers, and the expression of proteins related to apoptosis and inflammation signaling pathways.

Results: SLBZS markedly enhanced sperm quality, testicular and epididymal indices, and serum uric acid levels in mice, while ameliorating histopathological lesions in testicular tissue. Additionally, SLBZS significantly reduced oxidative stress, serum inflammation markers, and testicular cell apoptosis, with the high-dose group showing superior effects compared to the febuxostat group. Further investigation revealed that SLBZS inhibited the expression and phosphorylation of proteins in the MAPK/NF-κB pathway and suppressed the expression of proteins in the NLRP3 inflammasome pathway.

Discussion and conclusions: SLBZS potentially modulates the MAPK/NF-κB and NLRP3 inflammasome signaling pathways, thereby suppressing inflammatory responses and enhancing spermatogenesis in the testes of HUA mice.

Purpose: HOXB13 has been shown to act as a tumor promoter in various malignancies; however, its role in nasopharyngeal carcinoma (NPC) remains unexplored. This study aimed to investigate the function of HOXB13 in NPC and elucidate its underlying mechanism to identify novel targets for NPC diagnosis and therapy.

Methods: HOXB13 expression in NPC was examined through bioinformatic analyses of the TCGA and GEO databases, and the findings were validated using molecular biology techniques. After the transfection of NPC cell lines with siRNA targeting HOXB13 (si-HOXB13), the effects of HOXB13 knockdown on cell proliferation, migration, invasion, and stemness were evaluated. Expression levels of Wnt/β-catenin/SOX2 pathway-related proteins were assessed. In vivo, NPC cells transfected with sh-HOXB13 were injected into nude mice, after which tumor volume and mass were measured, and lung metastases were analyzed using hematoxylin and eosin (H&E) staining.

Results: HOXB13 knockdown significantly reduced NPC cell viability, suppressed clonogenicity and invasiveness, increased scratch width in wound healing assays, and decreased sphere formation and the proportion of CD133⁺ cells. Additionally, si-HOXB13 significantly downregulated the protein expression of β-catenin, c-Myc, and SOX2. In vivo, the sh-HOXB13 group exhibited reduced tumor mass, volume and lung metastatic nodules compared to the sh-NC group.

Conclusion: This study demonstrates that HOXB13 facilitates the malignant progression of NPC by regulating the Wnt/β-catenin/SOX2 signaling pathway, suggesting HOXB13 as a potential therapeutic and diagnostic target for NPC, thereby offering a new strategy to improve patient prognosis.

Background: Adult pneumonia is an infectious lung disease caused by bacteria, viruses, or other microorganisms and exhibits some degree of contagion. Tenuigenin, a bioactive compound derived from Polygala tenuifolia, possesses broad pharmacological effects, but its role in adult pneumonia remains incompletely understood.

Methods: Bioinformatics and database analysis were employed to screen and analyze the Tenuigenin target genes relevant to adult pneumonia. Cell functions were assessed using cell counting kit-8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU) staining, transwell, tube formation, Fluo-4 calcium assay, and transepithelial electrical resistance (TER) assays. Protein levels were measured by western blot. Network pharmacology and molecular docking were employed to screen core target genes and verify binding interactions.

Results: Tenuigenin targets in adult pneumonia were enriched in the pathways related to vascular permeability and calcium signaling. Tenuigenin mitigated lipopolysaccharide (LPS)-induced impairment of human pulmonary microvascular endothelial cell (HPMEC) viability, proliferation, migration, and angiogenesis, while attenuating LPS-induced increases in apoptosis, calcium ion, and reactive oxygen species (ROS) levels. Besides, Tenuigenin also attenuated the TER decrease and permeability increase caused by LPS exposure in HPMECs. Network pharmacology and molecular docking identified steroid receptor coactivator (SRC) as a core target of Tenuigenin, demonstrating binding to specific SRC amino acid residues. Tenuigenin also reduced LPS-induced increase in phosphor-SRC (p-SRC) expression. Crucially, after inhibition of SRC kinase activity, Tenuigenin no longer exerted significant protective effects against LPS-induced HPMEC injury and dysfunction.

Conclusion: Tenuigenin alleviates LPS-induced injury and dysfunction of HPMECs by targeting the SRC pathway, providing a target for managing adult pneumonia.