BMC Pharmacology & Toxicology最新文献

Background: Sulforaphane, a natural antioxidant rich in cruciferous vegetables, has emerged as a promising dietary supplement for autism spectrum disorder (ASD). However, its therapeutic efficacy remains controversial, and the pharmacological mechanisms are not fully elucidated.

Methods: Eligible randomized controlled trials were retrieved from PubMed, Web of Science, Embase, and Cochrane Library databases. Review Manager 5.4 was used for meta-analysis and bias risk assessment. Network pharmacology, Mendelian randomization, GEO data analyses, molecular docking, and molecular dynamics simulation were employed to explore the mechanisms of sulforaphane in ASD.

Results: Six trials involving 333 participants were included in the meta-analysis. Pooled results demonstrated that both 4-5 weeks and 8-10 weeks of sulforaphane supplementation significantly decreased the scores on the Social Responsiveness Scale compared to placebo controls. No significant difference was observed in the incidence of adverse events. Network pharmacology identified 10 core targets of sulforaphane in ASD, including AKT1, EGFR, HSP90AA1, SRC, CASP3, STAT1, MAPK1, MMP9, MAPK8, and JAK2. These targets were implicated in the PI3K-Akt signaling pathway, MAPK signaling pathway, Chemokine signaling pathway, Chemical carcinogenesis - reactive oxygen species, TNF signaling pathway, Th17 cell differentiation, mTOR signaling pathway, and IL-17 signaling pathway. Mendelian randomization further revealed an inverse association between STAT1 levels and ASD risk. GEO transcriptomic data provided independent validation for the network pharmacology predictions. The binding energies between sulforaphane and the top 10 core targets are all ≤ -4.0 kcal/mol. Molecular dynamics simulations further validated the stable interaction between MMP-9 and sulforaphane.

Conclusion: Sulforaphane may serve as an efficacious and safe adjunctive therapy for ASD, mediated by its anti-oxidant and anti-inflammatory effects along with the modulation of autophagy.

Prospero registration number: CRD42025635045.

Background: The misfunction of the protein 16SrRNA methyltransferase can result in Urinary tract infections (UTI), Gastrointestinal (GI) infections, sepsis, pneumonia, and wound infections; various tactics are used to lessen the fatal consequences. It confers resistance to aminoglycoside medications, which complicates the treatment of infections caused by these bacteria. Innovative methods are desperately needed to stop these diseases from spreading because there are no reliable medical therapies available.

Objectives: Herein, we aim to evaluate Doxycycline's Role in AI-Driven Drug Design and identification of effective inhibitors targeting the 16S rRNA methyltransferase gene. Additionally, to investigate the toxicological profiles of designed drug through AI approach for advancement in medical sciences.

Methodology: Methodology involves, selection of three effective de novo medicinal compounds that target the 16SrRNA methyltransferase protein for designing an AI driven drug. Multiple in silico tools were used for designing AI based drug includes: Expasy for protein annotation, ProtParam to calculate physiochemical parameters, SWISS-MODEL to estimate the 3D structure, and UniProt to generate the 16SrRNA methyltransferase protein sequence. An adequate foundation for the development and validation of AI-designed phytochemical medicines for infections is provided by quality assessment, binding site prediction, drug design with WADDAICA, toxicity screening, ADMET evaluation, and docking analysis with CB-dock.

Results: Comprehensive pharmacokinetic and toxicology analyses confirm that the AI-designed doxycycline exhibits a non-toxic character, with particularly high absorption through the blood-brain barrier. Furthermore, the AI-designed doxycycline docked complex demonstrates a strong docking affinity with the 16S rRNA methyltransferase protein, showing a binding energy of approximately - 7.6 kcal/mol, suggesting significant therapeutic potential.

Conclusion: Even though the in silico studies show efficacy and safety, still there is need of in vivo trials to investigate the hidden medical aspects. By addressing existing constraints, presenting a non-invasive approach to infections, and providing viable substitutes for traditional surgical procedures, this work considerably expands the knowledge about newer methods and also helps to understand deep insights of dug design mechanism for treatment.

Background: Although cisplatin is an effective chemotherapy, a major downside is its toxicity, including cerebellar neurotoxicity, which is mediated by the induction of inflammation and oxidative stress. On the other hand, daflon, a micronized purified flavonoid fraction, suppresses inflammation and oxidative stress. However, the effect of daflon on cisplatin-induced cerebellar neurotoxicity has not been documented.

Aim: The present study evaluated the effect of daflon in cisplatin-induced cerebellar toxicity. In addition, the role of TLR4/NF-kB signaling was explored.

Materials and methods: Twenty male Wistar rats were acclimatized for 2 weeks and then randomized into 4 equal groups: control, daflon-treated, cisplatin-treated, and cisplatin+daflon-treated.

Results: Daflon significantly improved cisplatin-induced distortions in cerebellar histology, evidenced by increased thickness in the molecular and intergranular layers, increased Purkinje cells, and reduced pyknotic neurons. Also, daflon attenuated cisplatin-induced rise in malondialdehyde and cisplatin-driven decline in glutathione, superoxide dismutase, and catalase activities. Furthermore, daflon ameliorated cisplatin-induced rise in myeloperoxidase activity and tumour-necrosis factor α, interleukin-1β 1β, and interleukin-6 levels. Additionally, daflon suppressed cisplatin-induced upregulation of toll-like receptor-4, nuclear factor-kappa B, cyclo-oxygenase-2, prostaglandin E2, and caspase-3 activity in the cerebellar tissue.

Conclusion: In conclusion, daflon confers neuroprotection against cisplatin-induced cerebellar neurotoxicity through the suppression of TLR4/NF-kB-mediated oxidative-inflammatory and apoptotic injury.

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.