Hereditas最新文献

Background: The incidence of diabetic peripheral neuropathy (DPN) is increasing every year for type 2 diabetes mellitus (T2DM) patients, and diabetic polyneuropathy is a common type.

Objective: To quantify and analyze the factors associated with diabetic polyneuropathy using the virtual tissue imaging quantification (VTIQ) technique.

Method: 182 patients with T2DM, 137 patients with diabetic polyneuropathy, and 198 healthy volunteers were included in this retrospective cross-sectional diagnostic study. Sciatic neuropathy was evaluated through Doppler ultrasound examination with a VTIQ quantitative analysis system to acquire elastic modulus, cross-sectional area (CSA) and shear wave velocity (SWV). Nerve conduction velocity (NCV) was also evaluated via neurophysiological examination. Logistic regression was used to analyze odds ratios (OR) related diabetic polyneuropathy. The diagnostic accuracy of the VTIQ technique-acquired index on diabetic polyneuropathy was analyzed using the receiver operating characteristic (ROC) curve.

Results: VTIQ technique-acquired indexes all differed significantly among three study groups, among which Elastic modulus and CSA were independently related to diabetic polyneuropathy risk according to the logistic regression analysis. NCV was also an independent risk factor for diabetic polyneuropathy. ROC analysis revealed that Elastic modulus, CSA and NCV can distinguish diabetic polyneuropathy patients from T2DM cases with the AUC of 0.797, 0.654 and 0.775 respectively. But their combination achieved the highest diagnostic value (AUC = 0.883). CSA and SWV of the sciatic nerve are positively correlated with visual analog scale (VAS) scores.

Conclusion: VTIQ technology contributes to the diagnosis of diabetic polyneuropathy, it can improve the diagnostic value of neurophysiological examination on sciatic neuropathy for T2DM patients.

Background: Lung cancer ranks among the most prevalent malignancies globally, with non-small cell lung cancer (NSCLC) constituting the predominant subtype. Currently, there are limitations in the treatment options and prognostic evaluation for NSCLC. Hsa_circ_0071271, a non-coding RNA, has an unclear expression and mechanism in NSCLC treatment. In this study, the impacts of hsa_circ_0071271 on NSCLC progression/prognosis and the possible mechanism of its inhibitory role in NSCLC progression through miR-23a-5p were investigated.

Methods: This investigation employed RT-qPCR to initially determine the expression levels of hsa_circ_0071271 in NSCLC tissues and cell lines. To evaluate the clinical significance of hsa_circ_0071271, ROC curve analysis, Kaplan-Meier survival analysis, and Cox regression were conducted. The impact of hsa_circ_0071271 knockdown on NSCLC cell lines A549 and CALU3 was examined through CCK-8 assays, flow cytometry, and transwell assays, corresponding to cell proliferation, apoptosis, and migration/invasion. The dual-luciferase reporter assay was used to examine the relationships between miR-23a-5p and hsa_circ_0071271, as well as between PTEN and miR-23a-5p. Pearson correlation analysis was conducted to assess the correlation between PTEN and miR-23a-5p. Subsequent experiments with CCK-8, flow cytometry, and transwell assays were carried out to explore how hsa_circ_0071271 regulates miR-23a-5p/PTEN and thereby affects NSCLC cell proliferation, apoptosis, migration, and invasion.

Results: Hsa_circ_0071271 was expressed highly in NSCLC tissues and multiple cell lines. Hsa_circ_0071271 effectively distinguishes tumor tissues from normal ones and is associated with patient survival rates. Knocking down hsa_circ_0071271 inhibits NSCLC cell proliferation and migration/invasion while promoting apoptosis. The study also revealed an interaction between hsa_circ_0071271 and miR-23a-5p, as well as between PTEN and miR-23a-5p, with their expression levels showing a significant negative correlation. Further experiments indicated that hsa_circ_0071271 regulates miR-23a-5p/PTEN to suppress NSCLC cell proliferation, migration, and invasion and promote apoptosis.

Conclusions: Regulating miR-23a-5p/PTEN by hsa_circ_0071271 knockdown has been found to inhibit NSCLC cell proliferation, migration and invasion, as well as promote apoptosis.

Background: Sepsis is a life-threatening systemic inflammatory response triggered by infection. The rapid progression of the disease necessitates early diagnosis and precise intervention, making the identification of reliable biomarkers and therapeutic targets crucial for improving clinical outcomes and reducing sepsis-related mortality.

Aim: Exploring miR-142-5p as a novel diagnostic biomarker for sepsis and its therapeutic potential via targeting CXCL8.

Methods: The expression levels of inflammatory factors (IL-6, TNF-α, IL-1β) and miR-142-5p in the serum of patients with sepsis and healthy controls were detected by ELISA and qPCR methods respectively. The diagnostic potential of miR-142-5p was evaluated using Pearson correlation, ROC curve, and logistic regression analyses. Bioinformatic prediction and dual-luciferase assays identified CXCL8 as a target, while LPS-induced models and cell transfection experiments investigated miR-142-5p's therapeutic effects through CXCL8 regulation.

Results: Sepsis patients exhibited significantly decreased miR-142-5p expression, inversely correlating with inflammatory markers (IL-6, TNF-α, IL-1β). ROC analysis showed excellent diagnostic value (AUC = 0.917). Pearson correlations indicated significant clinical associations, while logistic regression identified miR-142-5p as an independent protective factor (HR = 0.498, 95% CI:0.282-0.882, P = 0.017). LPS models confirmed miR-142-5p's anti-inflammatory effects through cytokine suppression, with knockdown showing opposite effects. Mechanistically, dual-luciferase and transfection assays verified CXCL8 as a direct target mediating these effects.

Conclusion: miR-142-5p may alleviate sepsis by targeting CXCL8-mediated inflammation, suggesting its potential as a diagnostic biomarker and therapeutic target.

Background: We aim to employ single-cell RNA (scRNA) sequencing technology to investigate potential regulatory mechanism of Danggui Buxue Tang (DBT) in wound healing for its utilization in post-anal fistula surgery recovery.

Methods: Fistula-like wound model in mice was established and administered DBT to assess its effects. Mice were divided into control and DBT groups and collected samples on the first day and 7th day after model establishment. The DBT was prepared from Astragalus membranaceus and Angelica sinensis. ScRNA sequencing was performed on each group.

Results: Our results showed that DBT treatment obviously reduced wound area in mice with anal fistula through activation of OPN/PI3K/Akt/eNOS signaling. Furthermore, the results of scRNA sequencing showed that all cells were clustered into 7 types, and the macrophages were categorized into 13 distinct clusters. In the early stages of wound formation, M1-like macrophages (M1C1) abundant in both groups at day1. However, by day 7 post-injury, the DBT-treated group exhibited a reduction in the infiltration of M1-like macrophages (M1C1) compared to the model group. Conversely, the proportion of M2-like macrophages (M2C3) showed a marked increase in the DBT group at day 7, while decreasing in the model group. Pseudo-time trajectory analysis confirmed that DBT treatment modulates macrophage polarization, potentially enhancing the wound healing process by promoting a transition from pro-inflammatory to anti-inflammatory macrophage populations.

Conclusion: DBT has the potential to accelerate wound healing after anal fistula by promoting M2 macrophage polarization, likely through activation of the PI3K/Akt signaling pathway.

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.