Hereditas最新文献

Background: Carboplatin resistance represents a critical therapeutic challenge in non-small cell lung cancer (NSCLC) treatment. Although KHSRP has been implicated in lung cancer progression, its molecular mechanisms and impacts on chemotherapy sensitivity remain elusive. Notably, KHSRP has the capacity to activate the transcription of HMGB1, an oncogene known to influence chemotherapy sensitivity. However, it remains to be determined whether KHSRP affects chemotherapy response in NSCLC via HMGB1.

Methods: KHSRP expression in NSCLC cells was analyzed using qRT-PCR. Cell proliferation, apoptosis, and migration were evaluated using colony formation, flow cytometry and wound healing assays. A luciferase reporter assay was conducted to assess whether KHSRP transcriptionally regulates HMGB1. Additionally, A549 cell xenografts were established in nude mice to investigate the tumor growth-promoting effects of KHSRP in vivo.

Results: KHSRP expression was notably elevated in NSCLC cells. Overexpression of KHSRP remarkably promoted A549 cell proliferation, migration, and epithelial-mesenchymal transition (EMT); while KHSRP knockdown exhibited the opposite effects. Mechanically, KHSRP notably promoted the transcription of HMGB1 and upregulated its expression in A549 cells. Importantly, deficiency of KHSRP remarkably enhanced the suppressive effects of carboplatin on A549 cell proliferation, migration, EMT and HMGB1 expression. Meanwhile, in vivo experiments demonstrated that downregulation of KHSRP potentiated the inhibitory effect of carboplatin on tumor growth in tumor-bearing nude mice.

Conclusion: These findings demonstrate that silencing of KHSRP enhances the drug sensitivity of carboplatin in NSCLC, potentially mediated through the inhibition of HMGB1. Targeting KHSRP may represent a promising therapeutic strategy to improve chemotherapy efficacy in NSCLC.

Objective: Cisplatin (DDP) is the major chemotherapeutic drug used to treat gastric cancer (GC). However, DDP-associated side effects and resistance chemoresistance have limited its clinical application. Psoralidin (PSO) is the main extract of Psoralea corylifolia and has antitumor effects. The present study is designed to investigate the antitumor functions and mechanisms of PSO and DDP in GC.

Methods: GC cells (HGC-27 and MKN-45 cells) were treated with PSO (2.5 to 120 µM) and/or DDP. A CCK-8 assay, colony formation assay, and EdU staining were used to test cell proliferation. Cell migration and invasion were tested via a transwell assay. An in vivo assay in nude mice was carried out to analyze the influence of PSO and DDP on tumor growth. H&E staining was conducted to test the histopathological changes of organs and tumor tissues. Ferroptosis-associated indicators, including GSH, MDA, Fe²⁺ levels, were examined. Western blotting was conducted to determine the profiles of ACSL4, GPX4, AIFM2, and SLC7A11.

Results: PSO impeded GC cell proliferation, migration, invasion, and growth in vivo. PSO exhibited no significant toxic effects on organs and mitigated DDP-mediated liver and kidney injuries. The combination of PSO and DDP exhibited enhanced inhibitory functions. PSO and DDP can significantly promote GC cell ferroptosis. Moreover, PSO promoted ACSL4 expression and suppressed GPX4, AIFM2, and SLC7A11.

Conclusion: The combination of PSO and DDP has synergistic antitumor effects on GC cells by inducing ACSL4-mediated ferroptosis. PSO may serve as a nontoxic adjuvant to enhance DDP's efficacy and reduce side effects in GC.

Background: Protein disulfide isomerase family A member 4 (PDIA4), a member of the protein disulfide isomerase family, has been associated with the progression of cancer. Nevertheless, its specific function in oral squamous cell carcinoma (OSCC) is not yet well understood.

Methods: To assess the prognostic significance and functional profile of the PDIA4, survival analysis and GSEA were conducted. Additionally, we examined the differences in immune infiltration and immunotherapy response between groups with low and high expression levels of PDIA4. Subsequently, RT-qPCR and western blot assays were employed to verify PDIA4 expression in OSCC tissues. The functional implications of PDIA4 in OSCC cells were also investigated.

Results: Analysis of the TCGA-OSCC dataset revealed a notable increase in PDIA4 expression in OSCC tissues, as verified by RT-qPCR and western blot analyses. Additionally, elevated PDIA4 levels were associated with poor prognosis in OSCC patients. GSEA results showed that the cellular senescence, FoxO and Hippo signaling pathways were remarkably inactivated in the high PDIA4 expression group. Moreover, a negative correlation was observed between PDIA4 levels and the infiltration of CD4, CD8 and natural killer T cells. Conversely, a positive correlation was observed between PDIA4 levels and M0 macrophage and regulatory T cell infiltration. Meanwhile, OSCC patients exhibiting elevated PDIA4 expression demonstrated elevated TIDE scores, implying a reduced responsiveness to immunotherapy in these individuals. Functionally, the suppression of PDIA4 significantly suppressed both proliferation and migration of OSCC cells, potentially through activating the FoxO1/p21^CIP1 pathway.

Conclusion: These findings suggest that PDIA4 may potentially serve as both a prognostic biomarker and a therapeutic target for OSCC patients.

Background: Endometriosis (EMs), a common gynecological disorder, involves complex molecular mechanisms. Metabolic reprogramming (MR) has been recognized as a hallmark of EMs, contributing to lesion survival and immune microenvironment remodeling. This study aimed to identify MR-associated hub genes and pathways associated with EMs through integrated multi-omics analyses.

Methods: EMs-related datasets were downloaded from the Gene Expression Omnibus database, including training sets (GSE51981 and GSE7305) and validation sets (GSE25628 and GSE141549). MR related genes were retrieved from the Genecards database. EMs-related differentially expressed genes (DEGs) were identified, and WGCNA was performed to identify module genes. Protein-protein interaction (PPI) networks were constructed. The expression of key genes was validated in an external dataset and clinical samples (immunohi0stochemistry). The CIBERSORT and ssGSEA tools were utilized to explore immune cell infiltration. In vitro experiments involving overexpression and RT-qPCR in Z12 cells were conducted to explore gene function on MR.

Results: A total 107 MR-associated candidate genes were identified. PPI network analysis identified top 10 hub genes. External validation confirmed significant downregulation of key genes in ectopic endometrium, with HNRNPR, SYNCRIP, HSP90B1, HSPA4, HSPA8, CCT2 and CCT5 demonstrating high diagnostic value (AUC > 0.8). Immune infiltration analysis revealed associations between key genes and CD8 + T cells, regulatory T cells, and mast cells. Immunohistochemistry confirmed reduced expression of CCT2, HSP90B1, and SYNCRIP in EMs lesions. In vitro validation confirmed that HSP90B1 overexpression upregulated GLUT1, LDH, and COX-2 expression in Z12 cells.

Conclusion: This study identified several MR-related genes, as potential diagnostic biomarkers and mechanistic contributors to EMs.

Objective: The aim of this study is to evaluate the therapeutic efficacy of Bushen Chushi Formula (BSCSF) in a rat model of knee osteoarthritis (KOA), with a focus on the modulation of ferroptosis-related signaling pathways and inflammatory responses, and to assess its effects on cartilage integrity and subchondral bone microstructure.

Methods: A total of 66 male Sprague-Dawley rats were randomly assigned to six groups: control, model, diclofenac sodium (DCF), and BSCSF high-dose (BSCSF-H), medium-dose (BSCSF-M), and low-dose (BSCSF-L) groups. KOA was induced via intra-articular injection of monosodium iodoacetate. Following induction, BSCSF or DCF was administered orally for 4 weeks. Therapeutic outcomes were assessed through Lequesne MG scores, body weight measurements, histopathological evaluation (hematoxylin and eosin, Safranin O-Fast Green staining), and micro-computed tomography of the subchondral bone. Expression levels of ferroptosis-associated proteins (SLC7A11, GPX4, p38 MAPK, MMP-13), glutathione (GSH), and iron accumulation (Fe²⁺), as well as inflammatory cytokines (IL-1β, TNF-α), were also measured.

Results: When compared to the model group, rats in the BSCSF-H and BSCSF-M groups exhibited significantly lower Lequesne MG scores, improved cartilage morphology, and enhanced subchondral bone microstructure, as indicated by increased bone volume fraction, trabecular thickness, trabecular number, and connectivity density along with decreased bone surface-to-volume ratio and trabecular separation. These groups also demonstrated increased expression of SLC7A11 and GPX4, elevated GSH levels, and reduced Fe²⁺ accumulation in cartilage, suggesting attenuation of ferroptosis. Inflammatory mediators, including IL-1β, TNF-α, MMP-13, and p38 MAPK, were significantly downregulated, indicating reduced inflammation and extracellular matrix degradation. The BSCSF-L group indicated modest improvements, primarily in inflammatory parameters and joint function.

Conclusion: BSCSF attenuated KOA progression in rats by inhibiting ferroptosis through the MAPK/SLC7A11/GPX4 signaling axis and suppressing inflammatory responses. The observed preservation of cartilage structure and enhancement of subchondral bone quality highlight its therapeutic potential in the management of KOA.

Background: Osteoarthritis (OA) is a common degenerative disorder characterized primarily by articular cartilage degradation and chronic inflammation. Although direct evidence elucidating the specific mechanisms underlying the coagulation-immune axis in OA remains limited, emerging studies have suggested a potential link.

Methods: Four microarray datasets were retrieved from the Gene Expression Omnibus (GEO) database. Then, differentially expressed genes (DEGs) (|log₂FC| ≥ 1, P < 0.05) were identified. Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on these DEGs. Molecular Signatures Database (MsigDB) coagulation genes were intersected with DEGs to identify coagulation-related DEGs. Then, hub genes were determined using multiple Machine learning (ML) algorithms, Least Absolute Shrinkage and Selection Operator (LASSO), Support Vector Machine-Recursive Feature Elimination (SVM-RFE), and Random Forest (RF). Diagnostic performance of these genes was evaluated via a nomogram and ROC analysis (AUC). Immune cell infiltration was assessed with CIBERSORT. The expression of hub genes was validated in vitro via real-time qPCR and Western blot (WB).

Results: Based on 103 samples across four datasets, 294 DEGs were identified. Gene set enrichment analyses (GSEA, GO, KEGG) revealed significant enrichment of these genes in immune- and coagulation-related pathways in OA. Intersecting MsigDB coagulation genes with DEGs yielded nine coagulation-associated DEGs. Based on four distinct ML algorithms, six hub genes were selected: Fibroblast activation protein (FAP), Cathepsin H (CTSH), matrix metalloproteinase 1 (MMP1), matrix metalloproteinase 9 (MMP9), Complement component 6 (C6), MAF Basic Leucine Zipper Transcription Factor F (MAFF). These hub genes demonstrated high diagnostic accuracy according to ROC analysis. Immune infiltration analysis showed significant differences between OA and normal samples. M0 macrophages, plasma cells, and γδ T cells were elevated in OA, while activated mast cells and resting memory CD4⁺ T cells were decreased. The qPCR and WB results corroborated the ML findings: in the interleukin-1β (IL-1β)-treated group, FAP, MMP1, MMP9, and CTSH were significantly upregulated, while MAFF and C6 were markedly downregulated.

Conclusions: This study, based on publicly available GEO datasets, identified six potential diagnostic biomarkers for OA: FAP, CTSH, MMP1, MMP9, C6, and MAFF. These findings highlight the potential involvement of coagulation-immune interactions in OA pathogenesis and offer novel insights into the molecular mechanisms and diagnostic strategies for the disease.

Background: Triple-negative breast cancer (TNBC), is characterized by its highly aggressive nature, with chemotherapy resistance and immune evasion contributing to poor outcomes. The role of major histocompatibility complex class I (MHCI) downregulation in TNBC progression remains incompletely understood.

Aim: The present research focused on elucidating the roles of miR-518c-5p/miR-4524a-3p in immune evasion and chemoresistance in TNBC, and evaluating their clinical significance.

Methods: Bioinformatics analysis predicted miRNAs targeting HLA-A/B/C, validated by dual-luciferase assays. Functional studies in TNBC cell lines (MDA-MB-231/468 and ADR-resistant sublines) included chromium release, proliferation, invasion, and apoptosis assays. Clinical relevance was assessed in 88 TNBC patients and 88 controls using RT-PCR and survival analysis.

Results: MiR-518c-5p/miR-4524a-3p directly targeted HLA-A, HLA-B, and HLA-C, downregulating MHCI expression and promoting immune evasion. Overexpression of miR-518c-5p/miR-4524a-3p enhanced TNBC cell proliferation, invasion, and chemoresistance to doxorubicin, while their inhibition reversed these effects. High expression of miR-518c-5p/miR-4524a-3p correlated with adverse clinical outcomes in TNBC patients, including shorter recurrence-free survival.

Conclusions: MiR-518c-5p/miR-4524a-3p contribute to TNBC progression by facilitating immune evasion and chemoresistance. Targeting miR-518c-5p/miR-4524a-3p may represent a promising therapeutic approach for improving TNBC treatment outcomes.

Objective: This study aimed to investigate the correlation between blood pressure and the levels of two renal function markers, cystatin C and microalbuminuria, with the goal of evaluating their correlation across varying blood pressure categories.

Methods: A cohort of 3,000 participants, comprising 1,500 individuals with a diagnosis of hypertension and 1,500 normotensive controls, was analyzed. Data on blood pressure, serum cystatin C, microalbuminuria, and other relevant clinical parameters were collected at admission. Correlations between these markers and blood pressure levels were analyzed using SPSS 26.0 statistical software.

Results: Levels of cystatin C and microalbuminuria were significantly higher in individuals with hypertension compared to the control group (P < 0.05). Furthermore, both biomarkers demonstrated a positive correlation with blood pressure (r = 0.140, P < 0.001). Multiple linear regression analysis revealed that the combined use of cystatin C and microalbuminuria provided a superior predictive value for blood pressure levels (P < 0.001). The combined predictive accuracy (R² = 0.114. R² = 0.112 after rectifying age, body mass index, and blood lipid levels) exceeded that of cystatin C (R² = 0.100) or microalbuminuria (R² = 0.113) when analyzed individually.

Conclusion: The biomarkers cystatin C and microalbuminuria are closely correlated with blood pressure levels. Their combined assessment offers an enhanced diagnostic approach for the early detection of renal complications in individuals with hypertension.