Current medicinal chemistry最新文献

Introduction: Centrosome Amplification (CA) is a state where malignant cells contain excessive centrosomes due to cell cycle dysregulation. Altered CA has been observed in Glioblastoma (GBM). This study developed a CA-related gene model to assess the Tumor Immune Microenvironment (TIME) and prognostic outcomes for patients with GBM.

Methods: TCGA-GBM and mRNAseq_325 cohorts were obtained from the Chinese Glioma Genome Atlas (CGGA) database. CA-relevant gene modules and feature genes were identified via WGCNA analysis. Key genes were selected to develop a risk model, followed by validation of the model's performance. We further compared the gene mutation landscape, TIME characteristics, drug sensitivity, and enriched pathways between high- and low-risk patient groups.

Results: The brown module, which showed the highest correlation with CA, was selected to identify CA-related key genes to develop a Riskscore model. The model can accurately categorize patients into high- and low-risk groups and predict their clinical outcomes with precision. Notably, high-risk GBM patients exhibited higher StromalScore and dendritic score, and the Riskscore was positively correlated with fibroblast infiltration. Moreover, patients with different risk levels displayed distinct enriched pathways and gene mutation landscapes. Further, the high-risk group showed an evidently higher CAF score, and the differential relation between drug sensitivity and the Riskscore was detected.

Discussion: Though CA was altered in GBM, its prognostic utility remained to be explored. The current study addressed this gap by developing a 6-gene risk model capable of predicting the prognosis and TIME of GBM patients.

Conclusion: A CA-related model was constructed to assess the prognosis and TIME of GBM patients, contributing to the management of GBM in clinical practice.

Introduction: This study investigates the therapeutic effects of Osthole and elucidates its mechanisms in oral squamous cell carcinoma (OSCC).

Materials and methods: Differential expression analysis was performed, followed by nomogram construction, gene set enrichment analysis, and immune infiltration analysis. Molecular docking was conducted to evaluate binding interactions, and single-cell analysis was performed.

Results: PTGS2 was identified as a key candidate capable of binding with Osthole. Immune infiltration analysis revealed elevated levels of activated inflammatory cells in OSCC. Single-cell analysis further showed high PTGS2 expression in macrophages and mast cells.

Discussion: This study demonstrates PTGS2's involvement in OSCC, highlighting its potential as both a biomarker and a therapeutic target.

Conclusion: Osthole can modulate OSCC by targeting PTGS2, providing a theoretical basis for OSCC management.

Introduction: Osteosarcoma is a highly aggressive cancer with a notably low five-year survival rate. Although aspirin has demonstrated potential in inhibiting the malignant progression of osteosarcoma, the underlying mechanisms remain unclear.

Methods: In this study, RNA sequencing (RNA-seq) was employed to identify the downstream targets of aspirin in osteosarcoma cells. Then, we examined the expression and clinical significance of PDE4D using osteosarcoma patient samples, tissue microarrays, and data from the TARGET and GTEx databases. The effects of PDE4D on cell growth and mobility were assessed by CCK-8, colony formation, transwell, and wound-healing assays. To explore how aspirin influenced the NF-κB/p65/PDE4D axis, we performed qRT-PCR, Western blotting, luciferase reporter assays, etc. Additionally, mouse models with subcutaneous tumors were used to confirm the roles of aspirin and PDE4D.

Results: Our results showed that aspirin significantly impeded the proliferation, migration, and invasion of osteosarcoma cells by various functional assays. RNA-seq identified PDE4D as a key target modulated by aspirin treatment in osteosarcoma. Clinically, PDE4D was highly expressed in osteosarcoma cells and tissues, and higher levels of PDE4D were linked to poorer patient outcomes. Functionally, PDE4D served as an oncogene that promoted the malignant traits of osteosarcoma both in vitro and in vivo. Mechanistically, our findings revealed that NF-κB/p65 directly interacted with the core region of the PDE4D promoter, increasing its expression.

Discussion: The findings of this study reveal a novel mechanism whereby aspirin exerts its anti-tumor effects by inhibiting the NF-κB/p65/PDE4D axis, providing a mechanistic basis for its therapeutic potential. Further validation in different animal models of osteosarcoma is warranted.

Conclusion: Aspirin suppressed the malignant progression of osteosarcoma by targeting the NF-κB/p65/PDE4D axis, positioning PDE4D as a potential therapeutic target for aspirin- based treatment strategies.

Introduction: Radiotherapy remains a cornerstone of treatment for non-small cell lung cancer (NSCLC). Despite its critical role, the emergence of radiation resistance remains a significant hurdle, often leading to therapeutic failure and disease progression. This research aimed to investigate the expression of Pellino E3 ubiquitin protein ligase family member 3 (PELI3) in NSCLC and examine its involvement in modulating the tumor's response to radiation.

Materials and methods: To quantify PELI3 levels in NSCLC tissues, real-time PCR and Western blotting techniques were employed. The effects of silencing PELI3 on cancer cell proliferation were evaluated using CCK-8 and colony formation assays. Furthermore, an in vivo mouse xenograft model was used to corroborate the in vitro results.

Results: PELI3 expression was markedly elevated in NSCLC tumor samples relative to normal tissues and showed a strong association with clinical features, such as tumor volume, lymph node involvement, and radiotherapy responsiveness. Further analysis revealed that PELI3 promoted epithelial-to-mesenchymal transition (EMT) following radiation exposure. Suppressing PELI3 expression mitigated radiation-induced EMT in both cellular and animal models.

Discussion: Elevated PELI3 promotes radiation-induced EMT and radioresistance in NSCLC. Suppressing PELI3 reverses EMT features and enhances radiosensitivity in vitro and in vivo, highlighting PELI3 as a potential biomarker and therapeutic target to improve radiotherapy outcomes.

Conclusion: These findings suggest that PELI3 could serve as a valuable prognostic marker in NSCLC and may represent a promising target to improve tumor sensitivity to radiotherapy.

Introduction: To address critical knowledge gaps in understanding drug-specific risk profiles of breast cancer (BC), ultimately informing regulatory decision-making and clinical practice.

Methods: This study conducted a retrospective drug safety study based on the FDA's Adverse Event Reporting System (FAERS) database, examining BC drug treatment data from 2004 to 2024. The research involved data cleaning, standardization of drug names, and the application of statistical analysis methods such as the proportional imbalance method and the Reporting Odds Ratio (ROR) to assess potential associations between drugs and adverse events.

Results: Significant differences were determined in adverse reaction reports among different drugs in BC treatment. Specific drugs such as trastuzumab, lapatinib, and certain endocrine therapy medications accounted for a higher proportion of adverse event reports and exhibited higher ROR values. Additionally, the study identified that cardiotoxicity, osteoporosis, ovarian function impairment, and immune complications are adverse reactions requiring special attention in BC drug treatment.

Discussion: This comprehensive analysis of FAERS data highlights the significance in drug-induced adverse event reporting across BC therapies. This work promotes the advancement of patient safety by providing actionable evidence for therapeutic decision making in the oncology of BC. A limitation of this study is the lack of integration of potential mechanisms for adverse events in BC patients.

Conclusion: Targeted therapies of lapatinib, fulvestrant, and endocrine agents (letrozole or ribociclib) show disproportionately high AE reporting odds ratios, necessitating vigilant monitoring. HER2-positive BC treatments (trastuzumab) and TNBC agents (sonidegib) exhibit distinct risk profiles, advocating for personalized risk-benefit assessments for BC patients.

Introduction: Keloid is a chronic cutaneous fibrotic disorder caused by abnormal wound healing, and its pathogenesis is still unclear.

Methods: We conducted differential expression analysis and Weighted Gene Co-expression Network Analysis (WGCNA) based on the GSE90051 and GSE190626 datasets. Analysis of Gene Ontology (GO) and the Encyclopedia of Genes and Genomes (KEGG) explored the function and the pathways of key genes. STRING and Cytoscape were used to construct Protein-Protein Interaction (PPI) networks and identify hub genes. Support Vector Machine-Recursive Feature Elimination (SVM-RFE) was used to screen out the potential biomarkers. Mendelian Randomization (MR) identified biomarkers with causal effects on keloid. Single-cell transcriptomic analysis and intercellular communication analysis of GSE181316 deciphered the key intercellular signaling pathway in keloid.

Results: We first found 1028 key genes (differential expression analysis and WGCNA screening) and the pathways involved in these genes. We constructed the PPI network of these key genes and identified 15 hub genes and 28 diagnostic biomarkers for keloid among them. We further found that IGF1 was causally related to keloid, and IGF1 is a risk factor for keloid (IVW result, OR = 1.908, 95% CI = 1.017-3.580, p = 0.044). IGF1 was further found to be enriched in fibroblasts, epithelial cells, and stromal cells in keloid. Moreover, the IGF1-ITGA6+ITGB4 pathway plays an important role in the intercellular communication of fibroblasts, epithelial cells, and HSC CD34+ cells in keloid.

Discussion: In summary, we have found that IGF1 is a risk factor for keloid. The IGF1- ITGA6+ITGB4 pathway plays an important role in the formation process of keloid.

Conclusion: These results help us to gain a deeper understanding of the formation process of keloid and provide a theoretical basis for the clinical treatment of keloid patients in the future.

Introduction: Drug-resistant tuberculosis (TB) is a global health concern, necessitating novel therapeutics. Dihydrofolate reductase (DHFR) from Mycobacterium tuberculosis (Mtb-DHFR) is a promising target due to differences from human DHFR (h- DHFR), despite 26% structural similarity.

Materials and methods: Virtual screening of in-house and SPECS libraries identified Hit-02. Based on docking results, five derivatives (Ansh-01 to Ansh-05) were synthesized and confirmed via spectroscopic techniques. Compounds were evaluated against H37Rv strain using MABA and DHFR inhibition assays. ADMET profiles and sub-acute toxicity were also assessed.

Results: Ansh-04 showed potent activity by inhibiting Mtb-DHFR (IC50 = 99 μM) and h-DHFR (IC50 = 526 μM), yielding a selectivity index of 5.90, higher than Methotrexate. All synthesized compounds were found active against H37Rv strain in ranges (61-180 μM). Docking studies confirmed favorable binding to Mtb-DHFR. ADMET and toxicity data supported its drug-likeness and safety.

Discussion: The observed potency and selectivity of Ansh-04 highlight its potential as a lead molecule targeting Mtb-DHFR. Its superior selectivity index compared to Methotrexate reduces concerns of off-target effects on human DHFR. The SAR trends observed across the Ansh-series could guide future optimization for increased efficacy and bioavailability.

Conclusion: On the basis of cell-based and enzymatic results, we concluded that Ansh- 04 is a promising, selective Mtb-DHFR inhibitor with potential as an anti-TB lead candidate.

Introduction: Idiopathic pulmonary fibrosis (IPF) is associated with poor prognosis.

Methods: From related methylation, expression, and protein quantitative trait loci investigations (eQTL, mQTL, and pQTL), summary-level data were extracted. We obtained Genome-wide association study (GWAS) summary statistics of IPF from the Allen's study (discovery), the FinnGen study (finngen_R10_IPF) (replication), and the GWAS catalog study (replication). Summary-data based Mendelian randomization (SMR) and colocalization analysis were utilized to evaluate the relationships between gene molecular characteristics and IPF. Bioinformatics analysis was employed to validate the above results. Molecular docking and druggable targets exploration were utilized to examine the druggability of selected targets.

Results: After multi-omics SMR analysis and colocalization analysis, we identified six potential targets for IPF, namely RHPN1, USP28, ADAM15, FKBP5, MAD1L1, and FBXL16. By assessing relationships of the gene expression with IPF in lung tissues, specifically ADAM15 and FKBP5 were validated. Then, FKBP5 was further verified by employing bioinformatics analysis, which indicates FKBP5 may represent the most promising therapeutic target for IPF identified to date. Lastly, we identified 11 drugs that interact with FKBP5 and conducted molecular docking analyses of the top four candidate drugs with FKBP5, demonstrating favorable binding interactions.

Discussion: With the use of multi-omic analysis, we determined that RHPN1, USP28, ADAM15, FKBP5, MAD1L1, and FBXL16 were associated with IPF.

Conclusion: These findings provided evidence for the feasibility of developing therapeutic targets for IPF.

This article titled "Construction of a New Ferroptosis-related Prognosis Model for Survival Prediction in Colorectal Cancer", published in Volume 32, Issue 20, 2025 of Current Medicinal Chemistry (10.2174/0109298673296767240116215814). This article has been retracted at the request of the corresponding author due to an unresolved authorship dispute. In the interest of maintaining the integrity of the scientific record, the article has been retracted. The publisher apologizes to the readers for any inconvenience caused. The Bentham Editorial Policy on Retraction can be found at https://benthamscience.com/editorial-policies-main.php. BENTHAM SCIENCE DISCLAIMER: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure, or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication, the authors agree that the publishers have the legal right to take appropriate action against the authors if plagiarism or fabricated information is discovered. By submitting a manuscript, the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.