BMC Pharmacology & Toxicology最新文献

Background: Fibrosarcoma is an aggressive soft tissue malignancy with limited therapeutic options, highlighting the need for novel treatment strategies. Nafamostat mesylate, a clinically approved serine protease inhibitor, has demonstrated anticancer effects in various tumor types, yet its impact on fibrosarcoma remains unexplored. This study aimed to investigate the cytotoxic, antimigratory, pro-apoptotic, and anti-invasive effects of nafamostat mesylate in human HT1080 fibrosarcoma cells.

Methods: HT1080 cells were treated with varying concentrations of nafamostat mesylate. Cell viability was assessed by MTT assay, migration by wound healing assay, and cell cycle distribution by flow cytometry. Apoptosis induction was evaluated using Annexin V binding assay, multicaspase activity, and mitochondrial membrane potential analysis. Additionally, mRNA expression levels of matrix metalloproteinases (MMPs), MMP-2 and MMP-9, were quantified by qRT-PCR.

Results: Nafamostat mesylate reduced HT1080 cell viability in a dose- and time-dependent manner and induced G2/M cell cycle arrest, indicating disruption of mitotic progression. Migration assays demonstrated suppression of cell motility. Apoptosis was confirmed through increased Annexin V positivity, elevated caspase activity, and mitochondrial depolarization, supporting caspase-dependent, mitochondria-mediated cell death. Furthermore, nafamostat mesylate treatment significantly downregulated MMP-2 and MMP-9 mRNA expression, suggesting inhibition of key enzymes responsible for extracellular matrix (ECM) degradation, invasion and metastasis.

Conclusions: This study provides the first evidence that nafamostat mesylate exerts multifaceted anticancer effects in HT1080 fibrosarcoma cells, targeting proliferation, migration, apoptosis, and invasion. These findings support the potential repurposing of nafamostat mesylate as a therapeutic agent for fibrosarcoma and warrant further preclinical investigations to evaluate its translational applicability.

Objective: Methicillin-resistant Staphylococcus aureus (MRSA) infections among children are escalating annually. Vancomycin serves as the frontline therapeutic agent against MRSA infections. However, determining the therapeutic window that maximizes efficacy while minimizing the risk of toxicity for vancomycin in pediatric patients remains a challenge. This study aimed to explore a therapeutic window for vancomycin in pediatric patients.

Methods: This retrospective study collected data from hospitalized children aged 1 month to 18 years, who underwent routine therapeutic drug monitoring for vancomycin. We analyzed the distribution patterns of vancomycin concentrations in these patients. Factors influencing clinical outcomes and adverse reaction (nephrotoxicity) were investigated. ROC analysis was used to establish the therapeutic window for vancomycin in pediatric patients.

Results: A comprehensive dataset encompassing 183 pediatric patients with 330 samples was analyzed. The mean trough concentration (C_min) of vancomycin was 7.6 ± 5.5 mg/L. 74.3% of patients exhibited concentrations below the conventionally recommended therapeutic window of 10-20 mg/L. Patients responding positively to treatment exhibited significantly higher C_min values (8.4 ± 5.7 mg/L) compared to those with treatment failure (5.9 ± 4.4 mg/L, P = 0.006). Similarly, patients who developed nephrotoxicity had significantly elevated C_min levels (17.8 ± 5.3 mg/L) compared to those without nephrotoxicity (6.4 ± 3.9 mg/L, P < 0.001). Both univariate and multivariate logistic regressions revealed that the C_min of vancomycin was the predictor of both clinical outcomes and nephrotoxicity. Furthermore, receiver operating characteristic curve analysis pinpointed that C_min of vancomycin with 5.9 mg/L (AUC = 0.643) and 14.8 mg/L (AUC = 0.960) associated with clinical effectiveness and safety, respectively. When the therapeutic exposure targets established for adults are used as a reference, a substantial proportion of pediatric patients are found to have subtherapeutic vancomycin levels.

Conclusion: Based on our findings, we suggest a potential therapeutic window of 5.9-14.8 mg/L for vancomycin in pediatric patients, which may help optimize treatment efficacy and reduce toxicity. Further prospective studies are warranted to validate this range.

Background: Pyriproxyfen (PYR) is a pyridine-based broad-spectrum insect growth regulator and pesticide which works as an analogue of juvenile hormone. Its exposure to aquatic animals and crops is linked with various hazardous effects on biological functions. We aimed to find the possible reprotoxic effects of pyriproxyfen in adult female Sprague-Dawley rats through histological and biochemical approaches.

Methods: Adult female rats were assigned to four groups and were administered 0 mg/kg (Control), 62 mg/kg b.w, 124 mg/kg b.w, and 186 mg/kg b.w., of PYR dissolved in distilled water for 28 consecutive days. Body mass index, blood glucose levels, total protein concentration, lipid profile, ovarian histology and reproductive hormonal profiles were determined.

Results: There were no significant changes in body weight due to PYR exposure; however, slight alterations in ovarian and uterine weights were noted in the treatment groups. The 186 mg/kg b.w. treatment significantly affected estrous cyclicity. Furthermore, a non-significant increase in total protein levels and a significant (p < 0.05) rise in triglyceride and total cholesterol levels were recorded. However, a significant decline in high-density lipids was recorded in the high-dose treatment group (186 mg/kg bw) as compared to the control. A notable reduction in plasma concentration of estradiol, progesterone, and cortisol levels was recorded between the control and all the treated groups. Ovarian histomorphological analysis showed distorted basal membranes, increased empty spaces, tissue decompaction, degenerate follicles, and disassembled epithelium in the high-dose treated group (186 mg/kg b.w).

Conclusion: Oral administration of PYR in adult female rats leads to altered organ weights, disturbed normal estrous cycle, increased triglycerides and total cholesterol, reduced high-density lipids concentrations, and damaged ovarian architecture, affecting biochemical and reproductive function in female rats.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the interplay of genetic and environmental factors, and currently, there there is a lack of effective diagnostic or therapeutic strategies available. This study aims to identify circulating biomarkers for ALS and investigate their interactions with environmental toxins.

Methods: This research utilizes plasma proteomic genome-wide association study (GWAS) data and whole blood transcriptomic data from ALS patients to screen for potential circulating biomarkers through Mendelian randomization (MR). Subsequently, functional enrichment analysis and immune infiltration analysis were performed. An integrated machine learning approach will be used to construct a diagnostic model, with hub genes selected based on SHAP values. The model's performance will be validated using receiver operating characteristic (ROC) curves, nomogram, and decision curve analysis (DCA). Finally, reverse network toxicology will be used to explore the interaction mechanisms between hub genes and environmental toxins.

Results: Based on a MR analysis of plasma proteomics, we identified 68 plasma proteins significantly associated with the risk of ALS. By integrating differentially expressed genes (DEGs) from whole blood transcriptomics (1,116 DEGs), we selected four potential circulating biomarkers: FCRL3, HTATIP2, RNASE6, and SF3B4. Functional enrichment analysis indicated that the pathogenesis of ALS is closely related to autophagy, apoptosis, the endoplasmic reticulum unfolded protein response, and the NF-κB signaling pathway. Immune infiltration analysis revealed a disruption of the immune microenvironment mediated by T cells/myeloid cells in ALS patients. Validation through 113 machine learning algorithms showed that the random forest model exhibited the best diagnostic performance (AUC = 0.786), while SHAP analysis confirmed the contribution ranking of hub biomarkers: RNASE6 > FCRL3 > HTATIP2 > SF3B4. Further validation of their diagnostic value was performed using ROC curves, nomograms, and DCA. Environmental toxins analysis revealed that substances such as benzo(a)pyrene exhibit significant neurotoxicity, and molecular docking confirmed that they can interfere with the function of hub biomarkers through strong binding (∆G < -5 kcal·mol⁻¹), suggesting potential environmental pathogenic mechanisms in ALS.

Conclusions: This study not only highlights the value of FCRL3, HTATIP2, RNASE6, and SF3B4 as potential diagnostic biomarkers and therapeutic targets for ALS but also provides new evidence for the involvement of environmental toxins, particularly benzo(a)pyrene, in the pathogenesis of ALS through gene-environment interactions.