BMC Pharmacology & Toxicology最新文献

{"title":"Population pharmacokinetics of tacrolimus and CYP3A5-driven variability: implications for model-informed dose individualization in pediatric renal transplant recipients.","authors":"Lesly Yanira Xajil-Ramos, Jesús Alonso Gándara-Mireles, Mariela Guerra-García, Rodrigo José Vargas Rosales, Andrea Mariela Ruano Toledo, Dulce Sofia Ocaña-Garrido, Ismael Lares-Asseff, Oscar Cóbar, Sindy Méndez Soveranis, Leslie Patrón-Romero, Horacio Almanza-Reyes, Randall Lou-Meda","doi":"10.1186/s40360-026-01157-5","DOIUrl":"10.1186/s40360-026-01157-5","url":null,"abstract":"<p><strong>Background: </strong>Population pharmacokinetics and pharmacogenomics are essential tools for understanding interindividual variability in tacrolimus exposure in pediatric transplant recipients. Identifying clinical and genetic factors associated with tacrolimus disposition may support individualized dosing strategies. This study aimed to develop a population pharmacokinetic (PopPK) model of tacrolimus in pediatric renal transplant patients and evaluate the impact of CYP3A5 genotype and relevant clinical covariates on pharmacokinetic parameters.</p><p><strong>Methods: </strong>A total of 165 tacrolimus whole-blood concentrations from 51 pediatric patients receiving immunosuppressive therapy were analyzed at ≥ 6 months following renal transplantation. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling implemented in Monolix^®, assessing associations between pharmacokinetic parameters and clinical, biochemical, and genetic covariates to explain interindividual variability.</p><p><strong>Results: </strong>A two-compartment model with first-order absorption adequately described tacrolimus pharmacokinetics in the study population. Estimated population parameters were: Ka = 2.1282 h⁻¹, CL = 0.01633 L/h/1.44 m², V1 = 0.09417 L/1.44 m², V2 = 0.9558 L/1.44 m², and Q = 0.0514 L/h/1.44 m². CYP3A5 genotype was significantly associated with clearance, and estimated glomerular filtration rate (eGFR) influenced both clearance and central volume of distribution. Age was positively associated with the absorption rate constant.</p><p><strong>Conclusions: </strong>The developed PopPK model provided and adequate characterization of tacrolimus pharmacokinetics in pediatric renal transplant recipients. CYP3A5 genotype, eGFR, and age were identified as relevant covariates associated with interindividual pharmacokinetic variability. These findings provide a basis for future evaluation of model-informed individualized dosing strategies in this population.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13501838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148248842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of ACEIs/ARBs treatment with clinical outcomes in acute kidney injury: a multicenter retrospective cohort analysis.","authors":"Hai Wang, Ji Zhao, Jun-Hua Lv, Zheng-Hai Bai, Hong-Hong Pei","doi":"10.1186/s40360-026-01166-4","DOIUrl":"10.1186/s40360-026-01166-4","url":null,"abstract":"<p><strong>Background: </strong>ACEIs/ARBs (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers) constituted the cornerstone of therapy for various cardiovascular and renal disorders. The appropriate management of ACEIs/ARBs in the acute kidney injury (AKI) remained controversial.</p><p><strong>Methods: </strong>In this multicenter study involving 1,285 AKI patients, we investigated the associations of ACEIs/ARBs discontinuation (n = 436), persistence (n = 657), and initiation (n = 192) with 14-day AKI progression and mortality. Multivariate logistic regression analysis and subgroup analyses were conducted to evaluate the associations between ACEI/ARB utilization patterns and clinical outcomes.</p><p><strong>Results: </strong>The persistence usage of ACEIs/ARBs was independently associated with lower odds of 14-day AKI progression compared to discontinuation (adjusted OR 0.44, 95% CI 0.29-0.67, P < 0.001) Regarding 14-day mortality, the persistence usage of ACEIs/ARBs exhibited an inverse correlation in the unadjusted model (OR 0.30, 95% CI 0.13-0.71, P = 0.006), but the association was attenuated after full adjustment model (OR 0.39, 95% CI 0.13-1.20, P = 0.101). No statistically significant differences in the risk of 14-day AKI progression or mortality were observed between the initiation and discontinuation cohorts across all models.</p><p><strong>Conclusions: </strong>In this retrospective cohort, the persistence of ACEI/ARB at the onset of AKI was associated with lower odds of 14-day progression, but not mortality. For the 14-day mortality, due to limited events, wide-ranging confidence intervals, and post-adjustment attenuation, these statistical instabilities need highly conservative interpretation and prospective validation.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13491579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148248914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin and cerium oxide nanoparticles additively mitigate capecitabine-induced hepatotoxicity via targeting oxidative stress, apoptosis, and ERK signaling.","authors":"Khalid M Mohany, Heba M Elkady, Nashwa Hamad, Sahar E M El-Deek","doi":"10.1186/s40360-026-01150-y","DOIUrl":"10.1186/s40360-026-01150-y","url":null,"abstract":"<p><strong>Background: </strong>Capecitabine (CAP), a chemotherapy prodrug, is associated with a significant dose-limiting hepatotoxicity. This study evaluated the protective efficacy of melatonin (MEL) and cerium oxide nanoparticles (CeO₂ NPs) against CAP-induced toxicity.</p><p><strong>Methods: </strong>Fifty male Wistar rats were divided into five groups: control, CAP-only (500 mg/kg/week), CAP + MEL (10 mg/kg/day), CAP + CeO₂ NPs (30 mg/kg/day), and a combination therapy group (CAP + MEL + CeO₂ NPs). After a six-week treatment period, assessments included alanine and aspartate transaminases (ALT, AST); hepatic oxidative stress markers [glutathione peroxidase-1 (GPx-1), superoxide dismutase (SOD), and malondialdehyde (MDA)]; apoptotic markers [B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (BAX) mRNA, cleaved caspase-3 (c-caspase-3), and protein 53 (p53)]; pro-survival signaling [extracellular signal-regulated kinase (ERK1/2)]; and histopathological evaluation of liver tissue.</p><p><strong>Results: </strong>CAP administration induced significant liver damage, characterized by elevated ALT and AST, depletion of GPx-1 and SOD, increased MDA, and activation of the mitochondrial apoptotic pathway, indicated by an elevated BAX/Bcl-2 ratio and increased levels of p53 and c-caspase-3. This was accompanied by suppression of ERK1/2 signaling and severe histopathological alterations. Both MEL and CeO₂ NPs, significantly attenuated these deleterious effects. The combination therapy demonstrated a comparatively superior effect, resulting in a near-complete normalization of all measured parameters, including oxidative stress, apoptosis, ERK1/2 activity, and liver histoarchitecture.</p><p><strong>Conclusion: </strong>Melatonin and CeO₂ NPs provide hepatoprotection via distinct yet complementary mechanisms. Their combined administration presents a superior strategy to mitigate CAP-induced liver injury by concurrently counteracting oxidative stress, inhibiting apoptosis, and enhancing pro-survival signaling.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13262367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148223090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanotechnology-based detoxification of profenofos using red blood cell membrane-coated polymeric nanoparticles.","authors":"Sidra Altaf, Faqir Muhammad, Rao Zahid Abbas, Mostafa A Abdel-Maksoud, Salman Alrokayan, Ahmed Othman Alsabih","doi":"10.1186/s40360-026-01152-w","DOIUrl":"10.1186/s40360-026-01152-w","url":null,"abstract":"<p><strong>Background: </strong>Organophosphate (OP) poisoning poses a critical global health challenge due to the absence of specific antidotes. Profenofos (PRF), an organophosphate pesticide, is associated with severe toxicity and high risk of mortality. In this study, a novel biomimetic nanoformulation was synthesized and evaluated for its detoxification effectiveness and safety against profenofos.</p><p><strong>Methods: </strong>The nanoformulation consisted of red blood cell (RBC) membrane-coated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (RBC-PLGA NPs). RBC membranes were used to cloak PLGA nanoparticles, and the formulation was characterized using a zeta sizer, transmission electron microscopy, and Fourier transform infrared spectroscopy. In vitro assays were performed to evaluate the adsorption of profenofos, while in vivo studies were conducted to assess survival rate, erythrocyte acetylcholinesterase (AChE) activity, and hepatotoxic and renal toxicity markers in a rabbit model.</p><p><strong>Results: </strong>RBC-PLGA NPs effectively adsorbed profenofos, with removal efficiencies reaching up to 89.92% at a concentration of 4 mg/mL. In vivo experiments showed a significant increase in survival rates following treatment with RBC-PLGA NPs. Moreover, acetylcholinesterase (AChE) activity in erythrocytes was restored by the fourth day post-treatment, and no substantial hepatotoxicity or renal toxicity was observed.</p><p><strong>Conclusions: </strong>This study demonstrates that RBC membrane-coated PLGA nanoparticles effectively detoxify profenofos, significantly enhancing survival rate and restoring acetylcholinesterase activity without inducing notable toxicity. This work highlights a biomimetic nanoplatform that mimics erythrocyte functionality for toxin detoxification, offering a potential approach for the management of organophosphate poisoning.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13479988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148216038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical effects of lamotrigine combined with duloxetine in the treatment of bipolar depression.","authors":"Xiaokang Wang, Shanshan Li, Yuxian Chen, Gengrui Xu, Lin Jiang, Jiaoyu Rao","doi":"10.1186/s40360-026-01164-6","DOIUrl":"10.1186/s40360-026-01164-6","url":null,"abstract":"<p><strong>Objective: </strong>This study aims to assess the therapeutic efficacy and safety profile of lamotrigine-duloxetine (LTG + DUL) combination therapy in the treatment of bipolar depression (BD), with a focus on understanding cortisol-mediated adverse drug reactions.</p><p><strong>Methods: </strong>In this retrospective cohort study, 104 adults with BD initiating lamotrigine (LTG) therapy between January 2023 and December 2024 were stratified into monotherapy (LTG, n=56) and combination therapy (LTG + duloxetine [DUL], n=48) groups through clinician-driven treatment algorithms. A multidimensional assessment protocol was implemented over 16 weeks. Systematically clinical effect and safty were assessed by including Hamilton Depression Rating Scale (HAMD), Montreal Cognitive Assessment (MoCA), neurochemical dynamics serum 5-hydroxytryptamine (5-HT) and cortisol (CS), safety endpoints (LTG - related adverse reactions).</p><p><strong>Results: </strong>After 8 weeks of treatment, the group receiving LTG + DUL exhibited significantly greater improvement in depressive symptoms compared to the LTG monotherapy group. At the 12-week mark, the LTG + DUL group demonstrated increased serum 5-HT levels and decreased CS levels relative to the LTG group (P < 0.05). By 16 weeks, the LTG + DUL group achieved higher scores on the MoCA than the LTG group (P < 0.05). Additionally, by the 16-week point, the incidence of lamotrigine-related adverse reactions was significantly higher in the LTG + DUL group compared to the LTG group (P < 0.05), potentially linked to the reduction in serum cortisol levels.</p><p><strong>Conclusion: </strong>The combination therapy of LTG + DUL exhibits statistically superior efficacy over LTG monotherapy in treating BD. However, the cortisol-lowering effect of the combination therapy may increase the risk of mild cutaneous adverse reactions associated with LTG. These findings underscore the importance of monitoring cortisol levels in patients undergoing combination therapy, thereby contributing to pharmacovigilance strategies in precision psychiatry.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13678966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148216051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and application of a simple LC-MS/MS method for therapeutic drug monitoring to guide colistin dosing in critically Ill patients.","authors":"Yueyuan Wang, Yani Gu, Kai Fan, Chen Feng, XinYun Zhang, Aiming Shi, Yunli Yu","doi":"10.1186/s40360-026-01162-8","DOIUrl":"10.1186/s40360-026-01162-8","url":null,"abstract":"<p><strong>Objectives: </strong>This study aims to develop a simple, rapid, and cost-effective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determining the concentration of colistin in human serum, including its two active components, colistin A and colistin B, to support routine therapeutic drug monitoring (TDM).</p><p><strong>Methods: </strong>Protein precipitation was performed using pure acetonitrile, with polymyxin B1 as the internal standard (IS). Chromatographic separation was achieved using a Phenomenex KINETEX XB-C18 column (2.6 μm, 3 × 50 mm) with a gradient elution system consisting of 0.1% formic acid (FA) in water and pure acetonitrile as the mobile phase. Detection was carried out using an electrospray ionization (ESI) source in positive ion mode with multiple reaction monitoring (MRM). After applying the validated method to critically ill patients for approximately one year, we used the receiver operating characteristic (ROC) curve to identify the preliminary cut-off value of colistin trough concentration for predicting acute kidney injury (AKI).</p><p><strong>Results: </strong>The total runtime for chromatographic separation and mass spectrometric detection was 5 min. Excellent linearity was achieved over the concentration range of 0.27-8.69 µg/mL for colistin A and 0.08-2.56 µg/mL for colistin B, with R² greater than 0.99 for both analytes. The method demonstrated acceptable matrix effects and recovery rates. In addition‌, the ROC curve analysis of colistin TDM in critically ill patients determined a preliminary cut-off value for AKI at a trough concentration of 2.22 µg/mL.</p><p><strong>Conclusion: </strong>The validated method enables simultaneous and precise quantification of the two active substances, with a simple procedure and minimal analytical cost. The utility of TDM in critically ill patients is paramount for individualizing dosing regimens to optimize outcomes and safety. Specifically, the correlation between trough concentration and AKI risk highlights the importance for clinicians to monitor renal function during colistin treatment to prevent drug-induced AKI.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13479573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148209615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tranexamic acid inhibits mitochondrial DNA release and reduces inflammatory response in an in vitro model of OGD/R-induced Caco-2 cell injury.","authors":"Ziyue Wang, Liman Huo, Hong Liu, Shuwei Shi, Rui Feng","doi":"10.1186/s40360-026-01160-w","DOIUrl":"10.1186/s40360-026-01160-w","url":null,"abstract":"<p><strong>Background: </strong>Ischemia-reperfusion (I/R) injury of the intestine remains a challenging clinical issue, and there is currently no definitive treatment protocol. Tranexamic acid (TXA), an antifibrinolytic drug used in bleeding patients, has been shown in previous studies to protect the intestinal epithelial barrier, but the specific mechanism remains unclear. This study aimed to explore the molecular mechanisms by which TXA protects the intestinal barrier after intestinal I/R.</p><p><strong>Methods: </strong>The cell viability assay was assessed to verify the cytotoxicity of TXA toward Caco-2 cells. A Caco-2 cell oxygen-glucose deprivation-reperfusion (OGD/R) model was established. The transepithelial electrical resistance (TEER) of Caco-2 cell monolayers and FITC-dextran permeability assays were performed to assess the intestinal barrier function. The JC-1 fluorescent probe was used for assessment of mitochondrial membrane potential. Quantitative PCR (qPCR) was used to quantify mitochondrial DNA (mtDNA) released by Caco-2 cells, and enzyme-linked immunosorbent assay (ELISA) was employed to assess inflammatory factors.</p><p><strong>Results: </strong>TXA reversed OGD/R-induced decreases in TEER and increases in FITC-dextran permeability in Caco-2 cell monolayers. Microscopy images of the Caco-2 monolayer also support these results. Additionally, TXA enhanced mitochondrial membrane potential, suppressed mtDNA release and alleviated inflammatory responses.</p><p><strong>Conclusions: </strong>TXA protects the intestinal barrier after intestinal I/R by enhancing mitochondrial membrane potential, inhibiting mtDNA release and reducing inflammation, suggesting its potential as a therapeutic agent for intestinal I/R injury.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13326343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148194281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intravenous diazepam application in a departmental convulsive status epilepticus protocol with CYP2C19 polymorphisms: a pediatric prospective cohort study.","authors":"Muazzez Seker Gezici, Caner Turan, Durdugul Ayyildiz Emecen, Seda Kanmaz, Esra Isik, Ali Yurtseven, Tahir Atik, Sanem Keskin Yilmaz, Hasan Tekgul, Eylem Ulas Saz","doi":"10.1186/s40360-026-01159-3","DOIUrl":"10.1186/s40360-026-01159-3","url":null,"abstract":"<p><strong>Background: </strong>Individual variability of therapeutic response and adverse effects of diazepam is frequently observed in pediatric cohorts. It might be related to the genetic polymorphisms in cytochrome P450 2C19 (CYP2C19), a principal enzyme mediating diazepam metabolism.</p><p><strong>Objectives: </strong>To investigate the association between CYP2C19*2 (c.681G > A), CYP2C19*3 (c.636G > A), and CYP2C19*17 (-806 C > T) polymorphisms and clinical outcomes-specifically treatment efficacy and respiratory adverse effects-following intravenous diazepam administration in children with seizures.</p><p><strong>Methods: </strong>This prospective, single-center cohort study enrolled 100 pediatric patients (0-18 years) treated with IV diazepam for febrile/afebrile seizures. Genetic analysis was performed using next-generation sequencing. Clinical endpoints included seizure control following one or two diazepam doses and the incidence of respiratory complications. Statistical analyses assessed associations between CYP2C19 genotypes and seizure control outcomes.</p><p><strong>Results: </strong>The median age was 4.5 years (IQR: 2.4-8.5); 61% were male. Overall, seizure cessation was achieved in 76% with the first dose of IV diazepam and in 79% cumulatively. Respiratory side effects were observed in 15% of patients, with 9% requiring positive pressure ventilation. The CYP2C19*2 and CYP2C19*17 alleles were identified in 19% and 49% of participants, respectively. However, the CYP2C19*3 variant was absent. Notably, the presence of the CYP2C19*17 CT/TT genotype-particularly in combination with the CYP2C19*2 GG genotype-was significantly associated with both diazepam treatment failure (p = 0.038) and increased risk of respiratory adverse effects (p = 0.005).</p><p><strong>Conclusion: </strong>This study is the first to delineate the clinical relevance of CYP2C19 polymorphisms in a Turkish pediatric population treated with diazepam. The findings underscore the potential utility of pharmacogenetic profiling to predict therapeutic response and enhance the safety of benzodiazepine use in pediatric seizure management.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13471298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148175288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In-vitro pharmacological and cytotoxic evaluation of genipin-crosslinked human serum albumin nanoparticles loaded with methyltestosterone in MCF-7 breast cancer cells.","authors":"Elena Ganji, Maryam Heydari, Aref Arminfar, Midiya Mirzaei","doi":"10.1186/s40360-026-01158-4","DOIUrl":"10.1186/s40360-026-01158-4","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer remains one of the leading causes of cancer-related mortality among women worldwide. Although methyltestosterone (MT) has demonstrated therapeutic potential in hormone-responsive breast cancer, its clinical application may be limited by poor aqueous solubility and non-specific distribution. Albumin-based nanocarriers may enhance drug stability and intracellular availability. This study aimed to develop genipin-crosslinked human serum albumin (HSA) nanoparticles loaded with MT and to evaluate their physicochemical properties, release behavior, and in-vitro pharmacological and cytotoxic effects in MCF-7 breast cancer cells.</p><p><strong>Methods: </strong>MT-loaded HSA nanoparticles were prepared using the desolvation method followed by genipin crosslinking. Particle size, polydispersity index (PDI), and zeta potential were determined by dynamic light scattering (DLS), while morphology and crystallinity were evaluated using SEM and XRD analysis. Drug loading (DL) and encapsulation efficiency (EE) were quantified spectrophotometrically. In-vitro release was assessed under different pH conditions (5.5, 6.8, and 7.4). Cytotoxicity and pharmacological activity were evaluated in MCF-7 cells using MTT, LDH, and TUNEL assays. Statistical analysis was performed using one-way ANOVA (p < 0.05).</p><p><strong>Results: </strong>The formulated MT-HSA nanoparticles exhibited a mean diameter of 83 nm (PDI 0.25) and a zeta potential of - 16.3 mV, indicating uniform nanoscale distribution and moderate colloidal stability. Encapsulation efficiency and drug loading were 77% and 11%, respectively. Sustained and pH-dependent drug release was observed over 100 h, with higher release under acidic conditions (83% at pH 5.5). MT-HSA nanoparticles significantly reduced MCF-7 cell viability compared with free MT (p < 0.05), accompanied by increased LDH release and higher apoptotic index in TUNEL assays. Unloaded HSA nanoparticles showed negligible cytotoxicity. The formulation remained physically stable for two months at 4 °C.</p><p><strong>Conclusions: </strong>Genipin-crosslinked MT-HSA nanoparticles demonstrated improved in-vitro pharmacological efficacy, enhanced cytotoxic and pro-apoptotic activity compared with free methyltestosterone, and favorable carrier biocompatibility. These findings support albumin-based nanoencapsulation as a promising strategy for optimizing steroid-based therapy in hormone-responsive breast cancer, although further in-vivo studies are required to confirm translational potential.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13470952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148175308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acridine-derived small molecule associates with VEGF and is linked to reduced CAM vascularization: a combined in silico and CAM study.","authors":"Sayantani Karmakar, Shuvojit Moulik, Semanti Ghosh, Gunjan Uttam, Ashwag Alsharidah, Ranjay Kumar Choudhary, Moattar Raza Rizvi","doi":"10.1186/s40360-026-01148-6","DOIUrl":"10.1186/s40360-026-01148-6","url":null,"abstract":"<p><strong>Background: </strong>Acridine derivatives exhibit diverse biological activities, yet their potential to modulate angiogenesis remains underexplored. This study evaluated 9-phenyl acridine (ACPH) as a small-molecule ligand capable of engaging vascular endothelial growth factor (VEGF) and altering conformational features relevant to receptor recognition, with the working hypothesis that ACPH may modulate VEGF structural dynamics in regions involved in VEGF-VEGFR interaction rather than directly inhibiting receptor binding.</p><p><strong>Methods: </strong>Structure-based binding was assessed using AutoDock, PatchDock, and GOLD, with VEGF as the molecular target. Complex stability and conformational effects were examined by 50-ns molecular dynamics simulations, including RMSD, residue-level flexibility, compactness, solvent exposure, and interaction energetics. Functional activity was evaluated using the chick embryo chorioallantoic membrane (CAM) assay at 0.04 nM, 0.4 nM, and 0.8 nM, with ImageJ-based quantification of vascular features over 24-48 h.</p><p><strong>Results: </strong>Docking consistently positioned ACPH within a VEGF pocket, with predicted contacts involving Phe36, Ile46, Phe47, and Lys48 (chain A) and Cys60, Cys61, Asn62, Asp63, Glu64, and Glu67 (chain B). Across simulations, ACPH association was associated with reduced conformational variability of VEGF, particularly in regions relevant to protein-protein interaction, supported by an estimated ligand-protein interaction energy of approximately - 26.77 kcal/mol derived from trajectory-based and interpreted qualitatively rather than as a rigorous thermodynamic binding free energy. In ovo, ACPH exposure was associated with a dose-dependent reduction in CAM vascularization, with observable effects at 0.4 nM and more pronounced effects at 0.8 nM; however, this represents a phenotypic observation and does not establish VEGF-specific inhibition or a defined anti-angiogenic mechanism. Prolonged exposure at 0.8 nM was also associated with reduced embryo viability, indicating that non-specific toxicity may contribute at the highest dose.</p><p><strong>Conclusions: </strong>Docking and MD simulations consistently positioned ACPH within a transient VEGF cavity and were associated with reduced conformational drift and residue-level fluctuations. In the CAM model, ACPH exposure was associated with dose-dependent vascular reduction, with reduced embryo viability at 0.8 nM suggesting possible non-specific toxicity; these findings warrant receptor-facing validation and cytotoxicity-controlled endothelial assays.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13263954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148154890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}