Naunyn-Schmiedeberg's archives of pharmacology最新文献

Triple-negative breast cancer (TNBC) demonstrates elevated death rates in its advanced stage. Bortezomib (BTZ) and Noscapine (NCP) have potential as antitumor agents in various cancers, including TNBC. In this investigation, we present a way to enhance the therapeutic outcomes in TNBC by utilizing BTZ and NCP, employing poly(D,L-Lactide-coglycolide, PLGA). BTZ and NCP, which exhibit lower water solubility, were co-encapsulated in PLGA nanoparticles (BN-PLGA) and stabilized with 0.5% PVA, resulting in a low PDI and greater homogeneity. Several spectroscopic techniques were used to analyze BTZ- and NCP-loaded PLGA (BN-PLGA NPs). The in vitro release of these drugs from BN-PLGA NPs was examined at physiological and acidic pH to evaluate the drug release process. The effectiveness of BN-PLGA NPs against TNBC (MDA-MB-231) was assessed. In vitro drug release at pH 7.4 and 5.0 showed that BTZ and NCP encapsulated in PLGA NPs containing 0.5% PVA were sustained, unlike the free drugs, which showed a relatively rapid release. BN-PLGA NPs containing 0.5% PVA were spherical, with a mean diameter of 223 nm, and exhibited high encapsulation efficiency (BTZ ∼ 83%, NCP ∼ 78%) and enhanced cytotoxicity relative to BTZ monotherapy in vitro. The BN-PLGA NPs showed better MICs against P. aeruginosa, S. epidermidis, and S. aureus than the pure drug. The findings indicate that combining NCP and BTZ via PLGA NPs could be a viable approach for TNBC treatment, potentially paving the way for extensive in vivo investigations to assess the safety and efficacy of these innovative nanoformulations using TNBC animal models.

A novel synthetic bromophenol (BP), inspired by marine-derived natural bromophenols, was evaluated for its antitumor activity and for the enhancement of its in vitro performance through liposomal encapsulation (LipoBP). Etoposide was used as a reference in characterization, release, and loading studies. PEGylated liposomes were employed to improve BP's solubility, bioavailability, and therapeutic potential. The cytotoxicity, apoptosis, and gene expression effects of free BP and LipoBP were assessed in A549 (lung) and MCF-7 (breast) cancer cell lines. WST-8 assays showed that encapsulation significantly increased BP's cytotoxic activity, particularly in A549 cells, while flow cytometry and Annexin V-FITC/PI analyses indicated more pronounced apoptotic induction by LipoBP compared with free BP. qRT-PCR analyses revealed upregulation of proapoptotic genes (BAX, CASP6, CASP3 and CASP9) and downregulation of antiapoptotic/survival genes (BCL-XL, IQSEC2) in both cell lines, indicating activation of intrinsic apoptotic pathways. Plain liposomes exhibited minimal cytotoxicity, confirming their biocompatibility. Liposomal bromophenol, which we have introduced to the literature for the first time, is expected to be a promising nanocarrier system that could be effective in cancer treatment by improving the therapeutic index of new drug candidates such as marine bromophenols.

Coumarins are known to provide promising scaffolds for the development of new anticancer drugs, yet their multitarget biological profiles remain insufficiently explored. This study presents a comprehensive evaluation of four newly synthesized 4-substituted 7-hydroxycoumarin derivatives C1-C4, highlighting their combined antiproliferative, enzyme-inhibitory, and pharmacokinetic properties. The compounds were tested for their cytotoxic effects on A549 lung carcinoma cells and CCD-18Co fibroblasts, inhibition of topoisomerase I (Topo I), and binding interactions with human serum albumin (HSA). Derivatives C1, C2, and C4 showed selective suppression of A549 metabolic activity and proliferation, while exhibiting minimal toxicity toward non-cancerous fibroblasts. All compounds inhibited Topo I to varying degrees, with C1 displaying the highest potency, indicating that specific hydroxyl group arrangements are crucial for enzyme inhibition. Fluorescence spectroscopy and molecular docking revealed moderate to high HSA affinity (10⁴-10⁶ M^-1) and predominantly single-site binding, supporting their favorable plasma transport potential. Thermodynamic analysis showed distinct interaction patterns: C1 and C2 formed complexes stabilized primarily by hydrogen bonds and van der Waals forces, whereas C3 and C4 interacted mainly through hydrophobic forces. Competitive displacement assays identified Sudlow site I as the principal binding region, although molecular docking studies also suggested the possible involvement of site III. Overall, this work introduces a novel series of coumarin derivatives with a clearly defined multitarget anticancer profile which combines selective cytotoxicity, effective Topo I inhibition, and strong pharmacokinetic characteristics, thereby underscoring the potential of these derivatives as lead structures for further anticancer drug development.

The functionality of cellular models to provide relevant and functional information has been demonstrated. Several stimuli can result in intracellular changes that can be tracked through omics sciences, such as metabolomics, a valuable tool for characterizing and quantifying metabolic changes associated. RAW 264.7 macrophage cell line is a polarizable immune cell, making it a classic cellular model for the analysis of inflammatory processes, diverse stimuli provide an overview of the cell-stimulus interaction. Although the procedures for conducting a metabolomic study, from the collection of treated cells to the obtention of the data generated, have not yet become widespread, most research using this cell line indicates that there are common metabolites, and their variation in the metabolic pathways could be fundamental for performance and function of the immune cell. Thus, in this review, we describe the application of RAW 264.7 macrophages as a metabolomic model, highlighting the sample collection processes, commonly used analytical methods, software for data analysis, multivariate analysis used for the characterization of metabolites and how these changes can help to understand inflammatory processes.

Antibiotic-related arrhythmias represent a major clinical challenge, characterized by risk patterns that remain not fully elucidated. This study employed the FP-growth algorithm to uncover associations between antibiotic classes and specific arrhythmias, and to identify key high-risk patient profiles. We included 246 cases of antibiotic-related arrhythmia from Center for Adverse Drug Reaction Monitoring of Chongqing (2013-2023). In the FP-growth association algorithm, we took antibiotic categories, age, gender, and time to arrhythmia onset as the antecedents, and the types of arrhythmias as the consequents. The minimum thresholds were set at a support of ≥ 1.0%, a confidence of ≥ 50.0%, and a lift of > 1.8. Sinus tachycardia (36.18%), premature contractions (25.20%), and QT prolongation (16.26%) were the predominant arrhythmias. Key associations included antituberculosis drugs and quinolones with QT prolongation (lift 3.514-6.150 and 3.075-4.100, respectively), and macrolides with premature beats (lift 2.645-2.976). Crucially, onset timing differed: QT prolongation occurred mainly after 5 days of anti-tuberculosis therapy or with prolonged quinolone use, whereas premature contractions and sinus tachycardia predominantly emerged during drug infusion. Moreover, females were more prone to QT prolongation induced by anti-tuberculosis drugs and premature contractions associated with macrolides, whereas males exhibited a stronger link to quinolones. Furthermore, the association with sinus tachycardia was more pronounced in children than in adults. In conclusion, The FP-growth algorithm effectively uncovered complex antibiotic-arrhythmia risk patterns. While controlling for other susceptible factors (including underlying disease, concomitant medication, and electrolyte disorders), these findings highlight distinct patterns of association that may inform more targeted monitoring during antibiotic therapy, particularly regarding the timing and type of arrhythmic events.

Ramucirumab, a VEGFR-2-targeting monoclonal antibody, has been widely adopted in the treatment of various solid tumors. However, its safety profile in routine clinical practice remains incompletely understood. To address this, we examined adverse event reports associated with ramucirumab collected in the FAERS database between 2014 and 2024. Following careful deduplication, 3,435 reports were analyzed, identifying 139 Preferred Terms with significant signals across four disproportionality methods. In addition to well-established toxicities such as gastrointestinal perforation, hemorrhage, hypertension, and proteinuria, several previously underrecognized events were detected, including heart failure, chylothorax, and pseudocirrhosis. Gastrointestinal perforation events were particularly frequent and often occurred within the first three months of therapy. Temporal analyses indicated that the early treatment period is critical for the onset of severe adverse events. While the FAERS data cannot confirm causality, these findings underscore the importance of vigilant monitoring, especially during the initial phase of treatment, and highlight areas for further clinical and mechanistic investigation into the safety risks of ramucirumab.

Peripheral metabolic disorders, which drive brain insulin resistance, increase the risk of cognitive impairment, a key contributor to Alzheimer's disease. Conditioned media derived from human mesenchymal stem cells (CM-hMSCs) have shown potential for modulating neurological pathways. Male and female offspring exposed to maternal and post-weaning high-fat diet (HFD) were treated with CM-hMSCs. Spatial memory and anxiety-like behaviors were assessed along with hippocampal markers of glucose metabolism, inflammation, and Alzheimer's disease-related pathways. In male offspring, CM-hMSCs partially improved molecular pathways involved in brain glucose metabolism, as indicated by increased hippocampal mRNA expression of Glut1, Glut4, and IDE, and elevated BDNF levels. CM-hMSC treatment also modulated the inflammatory profile, with increased IL-10 and reduced IL-1β in the hippocampus. However, CM-hMSCs did not produce significant improvements in behavioral outcomes. CM-hMSCs exert early, region-specific molecular effects on hippocampal glucose metabolism and inflammatory responses in HFD-exposed male offspring.

Lung cancer (LC) represents a pivotal cause of human mortality. Ginkgetin (GK), a bioactive flavonoid derived from Ginkgo biloba leaves, exhibits anti-tumor properties. Our objective was to integrate network pharmacology with cellular experiments to elucidate the potential targets and molecular mechanisms of GK in non-small cell lung cancer (NSCLC) therapy. We systematically extracted data from multiple databases to identify potential therapeutic targets and pathways for GK against NSCLC. Then, cellular experiments were conducted to verify GK's inhibitory effect on A549 and LLC cells. Network pharmacology identified 52 potential targets, 5 key proteins, and 113 signaling pathways. Molecular docking results showed that core proteins and GK can bind tightly. The MD simulation revealed that EGFR exhibits strong binding to GK. Differential gene expression analysis demonstrated elevated levels of proteins such as HSP90AA1 in NSCLC. Cellular experimental methods reported that GK suppresses A549 and LLC cell proliferation and metastasis. Our findings suggest that GK may exert its anti-NSCLC effect through the HSP90-AKT signaling pathway, providing a foundation for further study.

Inflammatory bowel disease (IBD) is a major chronic inflammatory disorder whose pathogenesis involves impaired mucosal barrier function, dysbiosis, immune dysregulation, and oxidative stress. The JAK-STAT signalling axis plays a pivotal role in driving inflammatory cytokine response in IBD. Consequently, natural antioxidant and anti-inflammatory compounds have emerged as promising therapeutic candidates. This study aimed to elucidate the molecular mechanisms underlying the anti-IBD potential of sesamol through an integrative computational and experimental approach. Potential sesamol-associated targets were identified using network pharmacology and protein-protein interaction analyses. Gene Ontology and KEGG pathway enrichment were conducted to identify key biological processes and signalling pathways. Molecular docking, molecular dynamics simulations, and MM-GBSA binding free energy calculations were performed by Schrödinger V14.1.38 to evaluate interactions with Janus kinases. Therapeutic relevance was validated using dextran sulphate sodium (DSS)-induced murine colitis model. Sixty-three overlapping therapeutic targets were identified, with JAK1 and JAK2 emerging as central signalling nodes. Sesamol exhibited strong binding affinity toward both kinases, forming a more stable and sustained complex with JAK1, as evidenced by lower RMSD and RMSF values and favourable MM-GBSA energies compared with JAK2. In vivo, JAK1 expression was significantly elevated in inflamed colonic tissue and was markedly normalised following sesamol treatment, corroborating computational predictions. Sesamol exerts protective effects in IBD by modulating the JAK-STAT signalling pathway, reducing intestinal inflammation, and promoting mucosal restoration. These findings highlight sesamol as a promising multi-target natural candidate for restoring immune homeostasis and intestinal barrier integrity in IBD.

Benzo[a]pyrene (BaP), a ubiquitous environmental carcinogen predominantly found in tobacco smoke and air pollution, plays a pivotal role in head and neck squamous cell carcinoma (HNSC) pathogenesis. However, the molecular networks governing BaP-induced toxicity and programmed cell death (PCD) mechanisms in HNSC remain poorly characterized, limiting the development of targeted therapeutic interventions. We systematically analyzed PCD patterns in HNSC using the GSE30784 dataset and identified BaP toxicity targets through comprehensive database mining. Machine learning algorithms, including RF and SVM, were employed to identify core toxic targets. Target validation was performed using the TCGA-HNSC cohort, followed by the construction of a prognostic nomogram. Mechanistic insights were obtained through spatial transcriptomics, single-cell RNA sequencing (scRNA-seq), gene set enrichment analysis (GSEA), molecular docking, and molecular dynamics simulations to elucidate BaP-protein interactions. We identified ten distinct PCD modes significantly dysregulated in HNSC compared to normal tissues. Among 260 putative BaP targets, 24 demonstrated significant associations with PCD pathways in HNSC. Machine learning analysis revealed SERPINE1, TNFRSF10B, and STK3 as core mediators of BaP toxicity, with SERPINE1 emerging as the predominant driver of BaP-induced cellular dysfunction. The integrated nomogram achieved robust performance in cancer risk stratification. Spatial transcriptomic analysis demonstrated preferential enrichment of these targets in malignant epithelial cells, while scRNA-seq revealed cell type-specific expression patterns. GSEA identified enrichment in apoptotic signaling, TGF-β pathway activation, and DNA damage response mechanisms. Molecular docking studies revealed high-affinity binding interactions, with molecular dynamics simulations confirming stable BaP-protein complexes. This integrative multi-omics analysis elucidates the complex molecular architecture underlying BaP-induced toxicity in HNSC, establishing SERPINE1 and STK3 as promising prognostic biomarkers and potential therapeutic targets. Our findings provide mechanistic insights into environmental carcinogen-mediated HNSC pathogenesis and offer a rational framework for developing precision medicine approaches targeting BaP-associated malignancies.