Current medicinal chemistry最新文献

Introduction: Telomeres have become extensively studied in renal cell carcinoma (RCC), and this study aims to identify relevant diagnostic biomarkers in the predominant RCC subtype, clear cell RCC (ccRCC).

Materials and methods: This study retrieved telomere-related genes from the TelNet database and integrated data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) to calculate telomere enrichment scores using single-sample gene set enrichment analysis (ssGSEA). Weighted gene co-expression network analysis (WGCNA) and differential expression analysis were then applied to identify candidate genes, which were further refined through protein-protein interaction (PPI) network construction and two machine learning methods: least absolute shrinkage and selection operator (LASSO) regression and support vector machine-recursive feature elimination (SVM-RFE). The associations between the identified feature genes and immune cell infiltration were subsequently evaluated using CIBERSORT and ESTIMATE. Furthermore, single-cell analysis was employed to determine the highly expressed genes in different cell clusters. Finally, using a ccRCC cell line, quantitative real-time PCR, wound healing, and Transwell assays were performed to validate the expression and potential biological functions of the selected key genes.

Results: A higher telomere score was observed in ccRCC. The common genes from the DEGs and the gene modules were mainly enriched in cell division- and senescence-related pathways. Moreover, six genes (ASPM, CENPF, CEP55, MELK, BUB1, and EXO1) were identified as feature genes with satisfactory diagnostic efficacy and high expression in ccRCC; they were positively correlated with most immune cells and highly expressed in T cells. Notably, CEP55 knockdown suppressed the migration and invasion of ccRCC cells.

Discussion: Our present study, based on the data from the public databases, unraveled 6 genes with diagnostic efficacy in ccRCC, which may aid the development of a relevant future diagnostic method in ccRCC.

Conclusion: This study identified six telomere-related genes with high expression and strong diagnostic value in ccRCC, highlighting their association with immune infiltration and potential as diagnostic and therapeutic targets.

Background: Head and neck squamous cell carcinoma (HNSCC) has a poor prognosis and a high fatality rate. To predict the prognosis of HNSCC, this study developed a prognostic model based on nitrogen metabolism (NM)-related genes.

Methods: This study utilized transcriptomic data and clinical information from HNSCC obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to identify differentially expressed NM-related genes. Subsequently, an NMrelated prognostic risk model was established by integrating univariate Cox regression, LASSO regression, and multivariate Cox regression. Its predictive value was validated using Kaplan-Meier and ROC curves. Further analysis using GSVA and CIBERSORT examined the relationship between the risk model and the tumor microenvironment immune status, while also evaluating chemotherapy drug sensitivity across different risk groups. Finally, protein-protein interaction (PPI) networks and key gene screening were employed, and the functional validation of the core genes was conducted through in vitro experiments.

Results: We identified 10 key NM-related genes (GLS, ASNS, EXT2, HPRT1, SLC7A5, SMS, B3GNT8, GATM, NAGK, and SULT1B1) to construct a prognostic risk model. The GSVA analysis revealed that the low-risk group was enriched in immune-related pathways, while the high-risk group favored metabolic pathways. Additionally, the low-risk group exhibited higher levels of immune cell infiltration. We discovered that gefitinib, belinostat, erlotinib, and phenformin were more effective against cancer cells with lower risk scores. The PPI network screening identified key hub genes, including LORICRIN. Experimental validation demonstrated that LORICRIN overexpression significantly suppressed migration and invasion in HNSCC cells, suggesting its potential tumor- suppressive role in carcinogenesis and progression.

Discussion: This study emphasizes the links between NM signatures, immune regulation, and signaling pathways, underscoring their potential in the HNSCC mechanism research.

Conclusion: Our study established a NM-related gene signature closely linked to immune microenvironment and drug sensitivity, highlighting potential biomarkers and therapeutic targets for prognosis and personalized therapy in HNSCC.

Background: Acute respiratory distress syndrome (ARDS) is a life-threatening condition associated with high mortality and morbidity. However, targeted therapies that effectively improve patient outcomes remain limited. Exosomes play pivotal roles in intercellular communication and epigenetic regulation.

Objective: This study aimed to identify exosome-related differentially expressed genes (EXORDEGs) in whole blood associated with ARDS and to explore their potential mechanistic roles in the disease.

Methods: Two gene expression datasets (GSE32707 and GSE66890) were retrieved from the Gene Expression Omnibus for comprehensive bioinformatics analysis. Analytical approaches included Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, protein-protein interaction network construction using the STRING database, and immune infiltration profiling via single-sample gene set enrichment analysis in relation to hub genes.

Results: We identified 21 EXORDEGs, primarily enriched in biological processes such as endothelial cell development and apoptosis. Four hub genes-PI3, EEF1A1, ANAPC1, and PSMD2-were robustly associated with ARDS, with PSMD2 showing the most pronounced differential expression. Immune infiltration analysis revealed significant disparities in nine immune cell populations between ARDS and control samples.

Discussion: The results of this comprehensive bioinformatics analysis identified four EXORDEGs-PI3, EEF1A1, ANAPC1, and PSMD2-with important roles in acute respiratory distress syndrome.

Conclusion: This study first systematically identified EXORDEGs in ARDS, discovering four hub genes and their associations with immune cells. The hub genes may be implicated in endothelial injury, inflammation, and immune dysregulation. These findings provide novel insights into ARDS pathogenesis and highlight potential therapeutic targets for further investigation. Given the disease heterogeneity, our findings primarily reflect common molecular characteristics, while the specific features of different etiological subtypes require further investigation.

Introduction: Non-Small Cell Lung Cancer (NSCLC) treatment is often challenged by drug resistance. The antihypertensive drug telmisartan has shown anti-tumor potential, but its underlying mechanism remains unclear. Ferroptosis, a newly identified form of cell death, may serve as a promising therapeutic target. The objective is to investigate whether telmisartan inhibits NSCLC by inducing ferroptosis and to elucidate its underlying mechanism.

Methods: in vitro cell assays and in vivo mouse models were used, along with molecular biology techniques, to evaluate the effects of telmisartan on NSCLC and its mechanism of action.

Results: Telmisartan significantly suppressed NSCLC cell proliferation and tumor growth. Mechanistic studies revealed that telmisartan induced ferroptosis by inhibiting the nuclear translocation of Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) and downregulating Glutathione Peroxidase 4 (GPX4) expression. The anti-tumor effect of telmisartan was reversed by ferroptosis inhibitors.

Discussion: Telmisartan can inhibit the proliferation of NSCLC cells in vitro and in vivo and induce cell ferroptosis. Telmisartan can also inhibit the nuclear translocation of NRF2, thereby affecting the expression of GPX4.

Conclusion: Telmisartan inhibited NSCLC by inducing ferroptosis via the NRF2/GPX4 axis, offering a new therapeutic strategy and potential clinical application for NSCLC treatment.

Background: Observational studies have suggested associations between circulating metabolites and breast cancer (BC) risk, but the direction and causality of these relationships remain unclear due to confounding and reverse causation. Therefore, we aimed to evaluate the potential causal effects of 1,400 circulating metabolites on BC subtypes using Mendelian randomization (MR) based on GWAS data from European-ancestry populations.

Methods: Two-sample and reverse MR analyses were performed to explore potential causal links between metabolites and BC from the FinnGen and Breast Cancer Association Consortium (BCAC) cohorts. The inverse-variance weighted (IVW) approach served as the main analytical method to evaluate these associations. To further ensure the robustness and credibility of the MR findings, sensitivity analyses were conducted, incorporating leave-one-out procedures, the Cochran's Q test, and the MR-Egger intercept test.

Results: Following correction using the False Discovery Rate (FDR) method at a significance level of 0.10, we identified 5alpha-pregnan-3beta,20alpha-diol monosulfate levels (p = 6.7714*10-5, PFDR = 0.0798) and Myristoleate (14:1n5) levels (p =0.0002, PFDR = 0.0798) were associated with an increased risk of ER+ BC. Conversely, the Caffeine to paraxanthine ratio (p =0.0001, PFDR = 0.0798) was associated with a reduced risk. In the reverse MR analysis, interactions were observed between Eicosanedioate (C20-DC) levels, Piperine levels, Caffeine to theobromine ratio, Indolepropionate levels, 1-oleoyl- GPC (18:1) levels, and Oleoylcarnitine levels with BC. Notably, the p-values of intercept terms in MR-Egger regression all exceeded 0.05, suggesting an absence of potential horizontal pleiotropy.

Discussion: These findings suggested that hormone-related, lipid-related, and diet- derived metabolites might play subtype-specific roles in breast cancer development. The identified metabolites provided mechanistic insights and highlighted potential biological pathways that warrant further functional validation. They may also serve as preliminary biomarkers for future metabolomic and translational research.

Conclusion: Our MR study identified several metabolites that may be causally associated with BC risk. These findings offer potential candidates for further mechanistic investigation and highlight the importance of subtype-specific approaches in metabolomics research.

Introduction: Lung cancer remains a major global health burden with high mortality rates and limited therapeutic options. Natural flavonoids, particularly those derived from Cassia species, have shown immunomodulatory and anticancer potential. This study investigates the therapeutic promise of selected Cassia-derived flavonoids targeting key lung cancer-associated proteins: Prostaglandin-endoperoxide synthase 2 (PTGS2), Mast/stem cell growth factor receptor (KIT), and Xanthine dehydrogenase (XDH).

Methodology: Eight flavonoids were selected based on literature and database-reported bioactivity. Target prediction was performed using SwissTargetPrediction and STITCH, followed by pathway enrichment via STRING and KEGG databases. Molecular docking was conducted using AutoDock Vina against PTGS2 (PDB: 5IKQ), KIT (1N5X), and XDH (4U0I). Top-ranked complexes underwent 100 ns molecular dynamics (MD) simulations with GROMACS to assess binding stability, RMSD, and conformational behavior. Drug-likeness, ADME, and toxicity profiles were evaluated using SwissADME and ProTox-II. Standard drugs (Trametinib, Nivolumab, Erlotinib) were used for comparison.

Results: Epicatechin and Hispidulin showed the strongest binding affinities with PTGS2 (-9.04 kcal/mol) and XDH (-8.22 kcal/mol), respectively, with stable RMSD profiles. Chrysoeriol demonstrated the highest binding to KIT (-8.68 kcal/mol), outperforming Nivolumab (-6.03 kcal/mol). All selected flavonoids displayed acceptable pharmacokinetic profiles and low predicted toxicity. MD simulations confirmed the dynamic stability of key complexes.

Conclusion: Cassia-derived flavonoids represent promising multi-target candidates for lung cancer therapy, particularly through modulation of PTGS2, KIT, and XDH. Their favorable interaction profiles and safety predictions warrant further experimental and in vivo validation.

Tigecycline (TIG) is a broad-spectrum antibiotic of the tetracycline class that evades the resistance mechanisms common to first- and second-generation tetracyclines and is effective against Gram-negative and Gram-positive bacteria, as well as intracellular bacteria. TIG is indicated for the treatment of intra-abdominal, skin, and soft tissue infections in adults, as well as community-acquired bacterial pneumonia. The clinical performance of the TIG has been the subject of discussion since its introduction due to variable safety and efficacy outcomes. Concerns have arisen regarding its association with increased mortality when used in ventilator-associated pneumonia. In addition, resistance to TIG has been reported, driven by various mechanisms such as expulsion by efflux via chromosomal pumps, target site modifications, mutations in tet genes, and enzymatic inactivation. The latter, particularly due to the emergence of multiple TetX monooxygenase variants, is of growing concern. The rise of resistance to last-line antibiotics like TIG presents a significant public health challenge, given the limited therapeutic alternatives available. Therefore, this review analyzes the safety and efficacy reports of TIG, third-generation tetracyclines, documented clinical cases of resistance, and the underlying mechanisms contributing to resistance. Keywords: Tigecycline, multidrug resistance, efflux pumps, Tet(X).

Introduction: The global incidence of colon cancer is rising, highlighting the need for complementary therapeutic approaches using natural products such as citral. A self-nano-emulsifying drug delivery system incorporated with citral (CIT-SNEDDS) was formulated, and prior studies have demonstrated its potent antiproliferative effects on colon cancer cell lines.

Materials and methods: The apoptosis-inducing ability of CIT-SNEDDS treatment on SW620 cells was evaluated using Acridine Orange/Propidium Iodide (AO/PI) assay, Annexin V-FITC assay, and cell cycle analysis by flow cytometry. Scratch assay and migration, and invasion assays were performed to assess its anti-metastatic effects.

Results: The cytotoxicity assay results showed that SNEDDS with citral (CIT-SNEDDS) significantly reduced cell viability in a dose-dependent manner compared to free citral and SNEDDS without citral. Acridine orange/propidium iodide staining and Annexin V assay results confirmed apoptosis in CIT-SNEDDS-treated cells. Cell cycle analysis indicated that CIT-SNEDDS induced arrest at the S and G2/M phases, which may contribute to apoptosis initiation. The scratch and trans-well assays demonstrated a reduction in SW620 cell migration and invasion capabilities following CIT-SNEDDS treatment, suggesting a potent anti-metastatic effect.

Discussion: The ability of CIT-SNEDDS to induce apoptosis, disrupt the cell cycle, and inhibit cellular migration in cancer cells aligns with the goals of targeted cancer therapies, which aim to selectively eradicate cancer cells while minimizing effects on healthy tissue.

Conclusion: These findings highlight the therapeutic potential of CIT-SNEDDS for enhancing the efficacy of citral as an anti-tumor and antimetastatic agent for colorectal cancer, warranting further in vivo and preclinical studies to optimize its application.

Introduction: Prostate cancer is the fourth most commonly diagnosed cancer worldwide and the eighth leading cause of cancer-related mortality, primarily affecting elderly males. Conventional therapeutic approaches, while effective in some cases, often come with substantial side effects, posing particular challenges for older patients. As a result, the exploration of natural compounds from traditional Chinese medicine (TCM) as potential anticancer agents has gained increasing attention. Sesamin, a dietary lignan found in sesame seeds and frequently used in TCM, has shown promise in preliminary studies for its antioxidant, anti-inflammatory, and potential anticancer properties. However, its specific effects and underlying mechanisms against prostate cancer cells remain inadequately characterized.

Materials and methods: This study investigated the anticancer effects of sesamin on human prostate cancer DU145 cells. Cell viability was evaluated using MTT assays. Apoptosis induction and cell cycle distribution were assessed by flow cytometry. Protein expression levels of PPAR-γ, p21, and p53 were measured using Western blotting. Additionally, in silico molecular docking was performed using the LibDock algorithm to evaluate sesamin's binding affinity with the target proteins PPAR-γ and p21.

Results: Sesamin treatment significantly reduced the viability of DU145 cells in a dose-dependent manner. Flow cytometry revealed increased apoptosis and cell cycle arrest at the G1 phase. Western blot analysis showed upregulated expression of PPAR-γ and p21, while p53 expression remained largely unchanged. Molecular docking analysis demonstrated strong binding affinity of sesamin to PPAR-γ (LibDock score: 125.03) and p21 (LibDock score: 105.45), supporting its involvement in a p53-independent apoptotic mechanism.

Discussion: The study demonstrates that sesamin exerts significant anticancer effects on prostate cancer DU145 cells by inhibiting cell viability, inducing apoptosis, and causing G1 phase cell cycle arrest. The upregulation of PPAR-γ and p21, coupled with unchanged p53 expression, suggests that sesamin may activate a p53-independent pathway, a valuable feature in treating prostate cancers with defective p53 signaling. Molecular docking results corroborate these findings, indicating direct interactions between sesamin and its molecular targets.

Conclusion: Sesamin exhibits promising antiproliferative and pro-apoptotic activities against DU145 prostate cancer cells. Its potential to act as a G1-phase-specific chemotherapeutic agent via a p53-independent mechanism warrants further investigation and development as a natural candidate for prostate cancer therapy.

Introduction: This study investigates the prognostic value of Epidermal Growth Factor (EGF) family genes in Cervical Cancer (CC) and experimentally validates the role of AREG in the progression of CC.

Methods: Transcriptome and clinical data of CC were obtained from the TCGA database. We constructed a prognostic model using LASSO Cox regression analysis based on candidate EGF family genes. Multiple bioinformatics approaches were employed to analyze functional pathways and immune characteristics. The biological function of Amphiregulin (AREG) was validated through in vitro experiments, including colony formation, CCK8 proliferation assay, wound healing assay, transwell assay, macrophage polarization analysis using the co-culture system, and in vivo subcutaneous tumor formation in nude mice. Combination therapy with anti-AREG and anti-PD-L1 antibodies was evaluated in a murine C57BL/6 model.

Results: We identified 116 EGF family-related genes associated with CC progression and established a prognostic model. High-risk and low-risk groups showed distinct functional enrichment patterns and immune characteristics. AREG emerged as a key prognostic factor, with significantly elevated expression in CC cells. Knockdown of AREG suppressed CC cell proliferation, migration, and invasion, potentially through modulating Epithelial-Mesenchymal Transition (EMT). AREG promoted M2 macrophage polarization, fostering an immunosuppressive tumor microenvironment. Anti-AREG antibody treatment demonstrated antitumor effects in vitro and in vivo, synergizing with anti- PD-L1 therapy to significantly inhibit tumor growth and reverse EMT.

Discussion: Our findings establish the first EGF family-based prognostic model for CC and reveal AREG's dual role in promoting EMT and reshaping the immune microenvironment. The observed synergy between AREG inhibition and PD-L1 blockade provides mechanistic insights for overcoming immunotherapy resistance. Limitations include retrospective data analysis and a lack of multi-omics validation.

Conclusion: Our study establishes a robust EGF family gene-based prognostic model for CC patients and identifies AREG as a promising therapeutic target. These findings provide new insights for CC prognosis assessment and treatment strategies.