RESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) is widely recognized for its unfavorable prognosis. Increasing evidence has revealed that LGALS3 has an essential function in initiating and developing several malignancies in humans. Nevertheless, thorough analysis of the expression profile, clinical prognosis, pathway prediction, and immune infiltration of LGALS3 has not been fully explored in HCC. METHODS: In this study, an initial pan-cancer analysis was conducted to investigate the expression and prognosis of LGALS3. Following a comprehensive analysis, which included expression analysis and correlation analysis, noncoding RNAs that contribute to the overexpression of LGALS3 were subsequently identified. This identification was further validated using HCC clinical tissue samples. TIMER2 and GEPIA2 were employed to examine the correlation between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration in HCC. The R program was applied to analyze the expression distribution of immune score in in HCC patients with high and low LGALS3 expression. The expression profiles of immune checkpoints were also analyzed. Use R to perform GSVA analysis in order to explore potential signaling pathways. RESULTS: First, we conducted pan-cancer analysis for LGALS3 expression level through an in-depth analysis of public databases and found that HCC has a high LGALS3 gene and protein expression level, which were then verified in clinical HCC specimens. Meanwhile, high LGALS3 gene expression is related to malignant progression and poor prognosis of HCC. Univariate and multivariate analyses confirmed that LGALS3 could serve as an independent prognostic marker for HCC. Next, by combining comprehensive analysis and validation on HCC clinical tissue samples, we hypothesize that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC. KEGG and GO analyses highlighted that the LGALS3-related genes were involved in tumor immunity. Furthermore, we detected a significant positive association between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration. In addition, high LGALS3 expression groups had significantly higher immune cell scores and immune checkpoint expression levels. Finally, GSVA analysis was performed to predict potential signaling pathways linked to LGALS3 and HCP5 in immune evasion and metabolic reprogramming of HCC. CONCLUSIONS: Our findings indicated that the upregulation of LGALS3 via the HCP5/hsa-miR-27b-3p axis is associated with unfavorable prognosis and increased tumor immune infiltration in HCC.
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Based on our previous research, a 3D-QSAR model (q2=0.51, ONC=5, r2=0.982, F=271.887, SEE=0.052) was established to predict the inhibitory effects of triazole Schiff base compounds on Fusarium graminearum, and its predictive ability was also confirmed through the statistical parameters. According to the results of the model design, 30 compounds with superior bioactivity compared to the template molecule 4 were obtained. Seven of these compounds (DES2-6, DES9-10) with improved biological activity and readily available raw materials were successfully synthesized. Their structures were confirmed through HRMS, NMR, and single crystal X-ray diffraction analysis (DES-5). The bioactivity of the final products was investigated through an inâ vitro antifungal assay. There was little difference in the EC50 values between the experimental and predicted values of the model, demonstrating the reliability of the model. Especially, DES-3 (EC50=9.915â mg/L) and DES-5 (EC50=9.384â mg/L) exhibited better inhibitory effects on Fusarium graminearum compared to the standard drug (SD) triadimenol (EC50=10.820â mg/L). These compounds could serve as potential new fungicides for future research. The interaction between the final products and isocitrate lyase (ICL) was investigated through molecular docking. Compounds with R groups that have a higher electron-donating capacity were found to be biologically active.
Asunto(s)
Antifúngicos , Fusarium , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad Cuantitativa , Bases de Schiff , Triazoles , Bases de Schiff/química , Bases de Schiff/farmacología , Bases de Schiff/síntesis química , Triazoles/química , Triazoles/farmacología , Triazoles/síntesis química , Antifúngicos/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Fusarium/efectos de los fármacos , Estructura Molecular , Simulación del Acoplamiento MolecularRESUMEN
Background: Lung adenocarcinoma (LUAD) is the predominant pathological subtype of non-small cell lung cancer (NSCLC). The four primary forms of RNA adenosine modifications, N6-methyladenosine (m6A), N1-methyladenosine (m1A), alternative polyadenylation (APA) and adenosine-to-inosine (A-to-I) RNA editing, play a critical role in tumor progression. However, the clinical significance of RNA modification writer-related long non-coding RNAs (lncRNAs) in LUAD remains unclear. Methods: The Cancer Genome Atlas (TCGA) database was used to obtain transcriptomic and clinicopathological data. Univariate Cox regression analysis, consensus cluster analysis, and least absolute shrinkage and selection operator (LASSO) Cox regression were used to establish the molecular subtypes and prognostic signatures of LUAD based on the expression levels of lncRNAs. ESTIMATE, CIBERSORT, ssGSEA, and TIDE algorithms were used to investigate immune cell infiltration and immunotherapy. In addition, IC50 of chemotherapeutic agents were calculated for different risk subgroups using the "pRRophetic" R package. Finally, the expression of prognosis-associated lncRNAs in lung cancer tissues was verified using qPCR. Results: A prognostic risk signature containing seven lncRNAs associated with four types of RNA modification writers was established. The high-risk group had a poorer prognosis and higher clinicopathological grade. Most immune checkpoint genes and immune cell infiltration differed significantly between the two risk groups. The high-risk group had a higher tumor mutation burden (TMB), lower TIDE score, and was more sensitive to immunotherapy. Conclusion: We developed an RNA modification writer-related seven-lncRNA signature prognostic model that was associated with prognosis, tumor microenvironment, and response to immunotherapy in LUAD patients. Among them, LINC01352, AC024075.1, AC005070.3, AL133445.2, AC005856.1, and LINC00968 were downregulated in LUAD, whereas AC092168.2 was upregulated. This model may be a valuable tool for personalized LUAD therapies.