BMC Pharmacology & Toxicology最新文献

{"title":"Assessment of the efficiency of new regenerative gel and spray in experimental model systems.","authors":"Natalia Bezdieniezhnykh, Oleksandra Lykhova, Maryna Borshchevska, Andriy Goy, Kyrylo Saulenko, Tamara Kozak, Dmytro Kukurudza, Yevgen Kruglov, Genadiy Borshchevskiy, Liubov Buchynska","doi":"10.1186/s40360-026-01132-0","DOIUrl":"10.1186/s40360-026-01132-0","url":null,"abstract":"<p><p>INTRODUCTION: The problem of wound healing and the availability of effective and safe agents with regenerative properties is critically important today. The aim of the study was to develop an algorithm for evaluating products with regenerative potential using a set of in vitro and in vivo experimental models. METHODS: In vitro research included methods of working with cell culture. Studies were conducted using cell lines: HaCat, MAEС, 3T3-A31. In vivo research was conducted on Wistar rats with simulation of the pathological condition of a cut wound and the application of experimental samples and the following assessment of a set of indicators. RESULTS: As a result of using a comprehensive approach to assess the effectiveness of agents with regenerative activity, it was shown that the spray and gel samples, the main component of which is collagen, with decamethoxine, particles of silver sulfadiazine, hyaluronic acid, and additionally a set of amino acids in a spray, were shown to cause a statistically significant increase in the number of live cells at certain concentrations in vitro and increase the speed of restoration of the damaged monolayer of endothelial cells. According to the results of the speed of healing of the skin in the area of ​​the simulated cut wound, a statistically significant increase in the speed of healing from 10 to 19% with the use of the spray and from 5 to 18% with the use of the gel in comparison with the animals of the control group (р≤0.05 and p ≤ 0.01). The evaluation of the results of the morphological analysis showed that with repeated application of the spray or gel, a significant reduction in the area of ​​the wound is observed already on the 8th day with faster healing compared to the control. Already from the 8th day, inflammatory changes and the area of ​​necrotic in the experimental groups significantly decreased. CONCLUSION: A wound healing assessment model was developed and tested, which is convenient for monitoring the wound healing process and evaluating treatment outcomes. The efficacy and potential role in accelerating wound healing of new gel and spray products for external use was shown. CLINICAL TRIAL NUMBER: Not applicable.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13202844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147688106","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 silico and in vitro insights into the wound-healing potential of syringic acid: protective and regenerative effects on human fibroblasts.","authors":"Ufuk Okkay, İlkin Kazimov, Irmak Ferah Okkay, Azizeh Shadidizaji, Mehmet Ali Yoruk, Murat Ozdemir, Fatih Burak Yildiz, Fatma Yesilyurt, Mustafa Ozkaraca, Ahmet Hacimuftuoglu","doi":"10.1186/s40360-026-01138-8","DOIUrl":"10.1186/s40360-026-01138-8","url":null,"abstract":"<p><p>This study aimed to investigate the wound-healing potential of syringic acid (SA) through integrated in silico and in vitro approaches using human dermal fibroblasts (HDFs). Network pharmacology analysis identified myeloperoxidase (MPO), a key enzyme involved in oxidative stress and inflammation, as a primary target of SA. Computational predictions also indicated favorable pharmacokinetic and ADMET properties. In vitro experiments were conducted using SA at concentrations of 50–400 µM. Cell viability was assessed by MTT and LDH assays, while antioxidant and inflammatory responses were evaluated by measuring SOD, CAT, MDA, TNF-α, IL-1β, TGF-β, iNOS, and hydroxyproline levels. SA treatment significantly enhanced fibroblast viability and exhibited strong antioxidant effects, as demonstrated by increased SOD and CAT activities and reduced MDA levels. Additionally, SA suppressed pro-inflammatory mediators (TNF-α, IL-1β, and iNOS) while upregulating TGF-β expression. Importantly, SA promoted collagen synthesis, evidenced by increased hydroxyproline content. Among the tested doses, 100–200 µM showed the most pronounced effects. Overall, these findings demonstrate that SA facilitates wound healing by improving cellular viability, reducing oxidative stress and inflammation, and enhancing collagen production. This study highlights SA as a promising multi-target therapeutic candidate for wound repair, although further in vivo and safety studies are required to support its clinical application.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13104482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147688084","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":"Effects of MDMA treatment and cessation on sexual behaviour and testicular functions in male sprague-dawley rats.","authors":"O O Obembe, E T George, R A Mustapha, R E Akhigbe","doi":"10.1186/s40360-026-01131-1","DOIUrl":"10.1186/s40360-026-01131-1","url":null,"abstract":"<p><p>BACKGROUND: 3,4-Methylenedioxymethamphetamine (MDMA) is a psychostimulant known for its social and empathogenic effects. However, its long-term impact on sexual performance and reproductive functions remain controversial. OBJECTIVE: In this study, the effects of chronic MDMA exposure and subsequent withdrawal on sexual behaviour, reproductive hormones, sperm parameters, oxidative stress, systemic inflammation and testicular histology in male rats were investigated. METHODS: Fifteen male rats were divided into three groups (n = 5 rats/group): control (distilled water-treated), MDMA-treated (100 mg/kg orally for 30 days), and MDMA-withdrawal (100 mg/kg of MDMA for 30 days followed by 30-day drug-free recovery). Sexual behaviour was assessed every ten days for 60 days. Epididymal sperm suspension analysis, serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, markers of oxidative stress and inflammation interleukins 1beta, 6, and 10 (IL-1β, IL-6, IL-10), tumor necrosis factor-alpha (TNF-α) in serum and testes, and histological evaluations of testes were performed. RESULTS: MDMA significantly enhanced sexual behavioural parameters (mount, intromission, and ejaculation frequencies) during exposure, but these declined with drug withdrawal. Sperm count and motility decreased following MDMA treatment, with partial recovery after withdrawal. Oxidative stress marker (malondialdehyde, MDA) and proinflammatory cytokines (IL-1β, IL-6, TNF-α) were significantly increased while antioxidant enzymes [superoxide dismutase (SOD), catalase, total thiol] were significantly decreased both in the serum and testes. MDMA also suppressed LH, FSH, and testosterone levels, while histological analysis showed reduced spermatid populations, which improved post-cessation. CONCLUSION: MDMA elicits prosexual effects that was accompanied by low epididymal sperm quality, oxidative stress, inflammation, and hormonal suppression during exposure. Nonetheless, partial recovery occurred following MDMA cessation, suggesting potential long-term reproductive risks. </p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13202832/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147661969","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":"Protective mechanism of sevoflurane preconditioning on myocardial ischemia-reperfusion injury by regulating RMRP/miR-206 axis.","authors":"Shuang Wu, Yuan Lu, Hao Chen, Shuai Wang, Yanyan Jiang, Dalong Wang, Quan Lin, Ke Liu, Shuai Zhang, Ying Cheng, Xiao Tian, Wenhan Ma","doi":"10.1186/s40360-026-01129-9","DOIUrl":"10.1186/s40360-026-01129-9","url":null,"abstract":"<p><p>OBJECTIVE: Myocardial ischemia-reperfusion injury (MIRI) is a major contributor to global disease mortality. This study aims to investigate the protective mechanism of the RMRP/miR-206 axis in MIRI following sevoflurane (Sev) preconditioning. METHODS: In this study, a hypoxia/reoxygenation (H/R) model was constructed by H9c2 cells. The optimal concentration of Sev was selected by assessing cell viability with a CCK-8 assay. After Sev preconditioning, flow cytometry was employed to detect cell apoptosis. The content of LDH was measured with a lactate dehydrogenase (LDH) assay kit. The SOD activity was examined by an SOD assay kit, and the levels of IL-6 and IL-10 were determined by enzyme-linked immunosorbent assay (ELISA). RT-qPCR was utilized to detect the RMRP and miR-206 expression. The luciferase reporter assay and RIP assay were employed to demonstrate the interaction between RMRP and miR-206. RESULTS: In this study, 2.0% was chosen as the optimal Sev concentration for subsequent experiments. After Sev preconditioning, cell viability increased, apoptosis decreased, LDH levels were reduced, SOD activity was enhanced, IL-6 was downregulated, and IL-10 was upregulated. Meanwhile, RMRP levels decreased significantly after Sev preconditioning. Overexpression of RMRP inhibited the protective effect of Sev preconditioning on H/R-induced cells. Further analysis revealed that RMRP targeted miR-206. While miR-206 increased after Sev preconditioning, RMRP transfection suppressed miR-206 expression. Overexpression of miR-206 rescued H/R-induced cell damage caused by RMRP upregulation. CONCLUSION: Sev preconditioning protects cells from MIRI by regulating the RMRP/miR-206 axis. CLINICAL TRIAL NUMBER: Not applicable. </p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13195936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147662096","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":"Lycopene attenuates DEHP-induced oxidative stress, mitochondrial dysfunction, and apoptosis in human granulosa cells via SIRT1-dependent mechanisms.","authors":"Juan Ma, Xiupeng Xu, Ben Yuan","doi":"10.1186/s40360-026-01116-0","DOIUrl":"10.1186/s40360-026-01116-0","url":null,"abstract":"<p><p>Di(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer and endocrine disruptor that can impair ovarian function by provoking oxidative stress, mitochondrial injury, and apoptosis in granulosa cells. Lycopene is a diet-derived carotenoid with antioxidant and mitochondria-protective activities. This study investigated whether lycopene protects human granulosa-like KGN and COV434 cells against DEHP-induced damage and whether SIRT1 mediates these effects. Cells were exposed to DEHP (50–800 µM) for 24–72 h to define concentration- and time-dependent cytotoxicity, followed by co-treatment with lycopene (1–3 µM). Cell viability was assessed using CCK-8, and apoptosis was evaluated by caspase-3/-7 activity. Intracellular reactive oxygen species (ROS) were quantified using DCFH-DA fluorescence. Mitochondrial function was assessed by JC-1 staining for mitochondrial membrane potential and by qPCR determination of mitochondrial DNA (mtDNA) copy number. Antioxidant defense and lipid peroxidation were evaluated by measuring superoxide dismutase (SOD) and catalase (CAT) activities and malondialdehyde (MDA) levels. SIRT1 expression was examined at the transcript and protein levels, and siRNA-mediated SIRT1 knockdown was used to test mechanistic dependence. DEHP significantly reduced cell viability and increased caspase-3/-7 activity in both cell lines, accompanied by ROS accumulation, loss of mitochondrial membrane potential, reduced mtDNA copy number, decreased SOD/CAT activities, and elevated MDA. Lycopene markedly mitigated these effects, restoring redox balance, antioxidant capacity, and mitochondrial integrity while suppressing apoptotic signaling. DEHP downregulated SIRT1, whereas lycopene restored SIRT1 expression, and SIRT1 silencing partially weakened lycopene-mediated cytoprotection. Collectively, these findings identify a SIRT1-dependent protective action of lycopene against DEHP-induced granulosa cell oxidative and mitochondrial injury, supporting lycopene as a potential strategy to mitigate phthalate-associated ovarian toxicity.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13192163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147653665","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":"Coenzyme Q10 protects against atorvastatin-induced hepatotoxicity via attenuation of oxidative stress and functional modulation of CYP3A1.","authors":"Mohammed A Abdel-Rasol, Mohamed S Anwar, Hoda A Taha, Wael M El-Sayed, Kholoud AbdelRaouf","doi":"10.1186/s40360-026-01125-z","DOIUrl":"10.1186/s40360-026-01125-z","url":null,"abstract":"<p><strong>Background: </strong>Atorvastatin (ATO) is a widely prescribed lipid-lowering drug, but its use can be limited by hepatotoxicity, potentially linked to metabolism-related mechanisms. The cellular pathways connecting ATO metabolism to oxidative imbalance and apoptotic alterations remain incompletely defined. This study examined the roles of oxidative stress, mitochondrial-associated apoptosis, and the pregnane X receptor (PXR)-CYP3A4 axis in ATO-induced hepatic changes, and evaluated whether coenzyme Q10 (CoQ10) could modulate these effects depending on administration timing.</p><p><strong>Methods: </strong>Forty male albino rats were randomly assigned to four groups (n = 10). Group I received vehicle (5% DMSO + olive oil), Group II received atorvastatin (ATO, 80 mg/kg), Group III received ATO (80 mg/kg) plus CoQ10 (10 mg/kg), and Group IV received ATO for 21 days followed by CoQ10 for 21 days. All treatments were administered orally once daily. Hepatic outcomes were assessed using biochemical markers, histopathology, and Bcl-2 immunohistochemistry. Microsomal CYP3A1 (rat ortholog of human CYP3A4) catalytic activity was determined using a testosterone 6β-hydroxylation assay. Molecular docking evaluated interactions of ATO, its lactone metabolite, and CoQ10 with CYP3A4 and PXR.</p><p><strong>Results: </strong>ATO induced oxidative imbalance, evidenced by increased lipid peroxidation and nitric oxide alongside depleted antioxidant defenses, accompanied by liver structural alterations and reduced Bcl-2 expression. ATO significantly reduced hepatic microsomal CYP3A1 activity to ~ 29% of vehicle control (~ 71% decrease). CoQ10 co-administration markedly attenuated these effects, restoring redox homeostasis and increasing Bcl-2 expression, while co-treatment restored CYP3A1 activity (~ 90% of vehicle control). Post-treatment with CoQ10 partially restored CYP3A1 activity (~ 60% of vehicle control). Docking analysis indicated favorable binding of ATO and its lactone to CYP3A4 and PXR, supporting metabolism-linked bioactivation, while CoQ10 exhibited lower affinity, suggesting indirect modulation.</p><p><strong>Conclusion: </strong>ATO-induced hepatic injury is associated with oxidative stress and mitochondrial-related apoptotic processes linked to metabolism-dependent mechanisms. Functional impairment of CYP3A1 activity accompanied ATO-induced oxidative damage, whereas CoQ10 preserved enzymatic activity, consistent with hepatocellular protection. Early CoQ10 intervention provided superior protection, highlighting the importance of timing in mitigating metabolism-related hepatic damage. These findings provide mechanistic insight into statin-induced hepatotoxicity and support further investigation of CoQ10 as a complementary strategy to enhance statin safety.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13067394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147643899","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":"Therapeutic effects of cold plasma-activated water on MCF7 breast cancer tumors in a mouse model.","authors":"Ghada Abd El-Reda, Manal A M Mahmoud, Fatma Abo Zakaib Ali, Fatma M Abdel-Maksoud, Asmaa M Zahran, F M El-Hossary","doi":"10.1186/s40360-026-01127-x","DOIUrl":"10.1186/s40360-026-01127-x","url":null,"abstract":"<p><p>BACKGROUND: Breast cancer is the most common cancer affecting women, and plasma-activated water (PAW) is emerging as a potential therapeutic approach. While early results are encouraging, additional research is necessary to assess its long-term effects and identify the most effective methods of application. Therefore, this study aimed to investigate the effects of PAW on an MCF7 breast cancer mouse model. METHODS: A total of eighteen BALB/c mice were divided into three groups (n = 6/group): one negative control group and two tumor groups injected with MCF7 cells. After 91 days of MCF7 injection, the tumor groups received either distilled water (DW) or PAW (for 3 min) twice weekly via oral gavage for 28 days. RESULTS: The results revealed that the conductivity, H2O2, and NO2- values were significantly higher for PAW than for DW, while pH was lower (P < 0.001). Hematological analysis showed an increase in neutrophil counts, neutrophil %, eosinophil %, and neutrophil/lymphocyte ratio in MCF7 and PAW groups. Conversely, there were reductions in red blood cells (RBC), platelets (PLT), hemoglobin (HGB), and hematocrit (HCT) percentages, while mean corpuscular hemoglobin concentration (MCHC) increased. Both the control and PAW groups had higher total antioxidants and levels of α-L-fucosidase, while MCF7 had elevated arginase levels. The CD44⁺/CD24⁻ and CD44⁺/CD24⁺ cell populations were highest in the MCF7 group and reduced in the PAW group. The percentage of parent cells in late apoptosis was significantly higher in the PAW group than in the MCF7 and DW groups. Histopathology analysis revealed carcinoma features in the MCF7 group, while PAW reduced these effects. Immunostaining showed increased ER-α and Caspase-3 expression in the MCF7 group, with PAW moderating expression levels. CONCLUSIONS: Overall, these findings suggest that PAW may offer promising therapeutic applications in managing oxidative stress and hindering cancer cell progression. </p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13067694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147626882","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":"Thyroid hormone changes after tumor necrosis factor inhibitor therapy in euthyroid patients with rheumatic diseases.","authors":"Bayram Kizilkaya, Filiz Mercantepe, Jelena Vekic, Osman Cure, Aleksandra Klisic","doi":"10.1186/s40360-026-01130-2","DOIUrl":"10.1186/s40360-026-01130-2","url":null,"abstract":"<p><p>BACKGROUND/AIM: Tumor necrosis factor-alpha (TNF-α) plays a central role in chronic inflammatory diseases. Anti-TNF agents are widely used in rheumatological conditions; however, their association with thyroid hormone parameters in patients without pre-existing thyroid disease remains incompletely understood. This study aimed to evaluate changes in thyroid hormone profiles during anti-TNF therapy in euthyroid patients with rheumatic diseases. METHODS: In this retrospective study, 98 patients diagnosed with rheumatoid arthritis, ankylosing spondylitis, or Behçet’s disease without known thyroid disease were evaluated. Thyroid function tests, including thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), and free thyroxine (fT4), anti-thyroid peroxidase (anti-TPO) antibodies, inflammatory markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), and metabolic parameters were assessed at baseline and after 3 and 6 months of anti-TNF therapy. RESULTS: Anti-TNF therapy was associated with significant reductions in inflammatory markers (CRP and ESR, p < 0.01). A modest decrease in fasting glucose levels and an increase in high-density lipoprotein cholesterol (HDL-C) were observed during follow-up (p = 0.024 and p = 0.044, respectively). TSH and fT4 levels remained stable over time, whereas a gradual increase in fT3 levels was observed (p < 0.01). No significant changes were detected in anti-TPO antibody levels. CONCLUSIONS: Among euthyroid patients with rheumatic diseases, predominantly rheumatoid arthritis and ankylosing spondylitis, anti-TNF therapy was associated with stable thyroid function parameters. The observed increase in fT3 levels may reflect reduced inflammatory burden rather than direct thyroidal effects. These findings support the thyroid safety of anti-TNF agents while highlighting potential links between inflammation control and peripheral thyroid hormone conversion. </p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13188237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147618483","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":"iRGD-functionalized PLGA nanocomplex co-loaded with paclitaxel and Trametes robiniophila Murr for targeted inhibition of chemoresistant and metastatic signaling gene PDCD4 in colon cancer.","authors":"Li Li, Ying Liu, Xiao Wei, Rui Li, Wang Shuan, Mei Yan, Qun Zhang","doi":"10.1186/s40360-026-01126-y","DOIUrl":"10.1186/s40360-026-01126-y","url":null,"abstract":"<p><strong>Background: </strong>Metastasis and chemoresistance remain key challenges in colon tumor management. Integrating transcriptomic screening with molecular modeling may reveal actionable therapeutic targets for rational nanocomplex design.</p><p><strong>Methods: </strong>Transcriptomic datasets GSE44076 (n = 98) and GSE253699 (n = 6) were analyzed using limma (adjusted p < 0.05, |log₂FC| > 1). Differentially expressed genes were intersected with curated metastasis and chemoresistance panels which resulted in 18 overlapping targets. Hub genes were identified via STRING and Cytoscape-BiNGO, and prognostic analysis using KMplotter highlighted PDCD4 and CCND1 as favorable markers. A PTX-TP@PLGA-iRGD nanocomplex was designed by co-encapsulating paclitaxel and Trametes robiniophila Murr-derived metabolites within a PLGA matrix functionalized with iRGD. Nanocomplexes were characterized by dynamic light scattering, zeta potential, and HPLC for size, stability, and drug encapsulation. Functional validation included docking, 50 ns MD simulations, in vitro cytotoxicity uptake, and target engagement assays.</p><p><strong>Results: </strong>PDCD4 and CCND1 emerged as convergence nodes, with PDCD4 showing stage-wise downregulation (p = 0.014) and positive correlation with immune infiltration. The nanocomplex exhibited a uniform particle size (~ 165 nm, PDI 0.12), and encapsulation efficiency > 75%. In vitro, PTX-TP@PLGA-iRGD demonstrated superior cytotoxicity (IC₅₀ ≈ 4.5 nM in HCT116; 6.5 nM in HT-29) compared to PTX-TP@PLGA and free PTX. Cellular uptake increased ~ 2.8-2.9× with iRGD modification, confirming receptor-mediated endocytosis. Clonogenic assays showed the lowest surviving fraction (~ 22-28%), and PDCD4 expression was upregulated (~ 2.2-fold HCT116; ~1.9-fold HT-29) following treatment. Docking revealed strong PDCD4-ligand affinities (- 6.0 to - 9.6 kcal/mol), and MD trajectories were stable (RMSD 4-6.5 Å; Rg 25-26.5 Å).</p><p><strong>Conclusion: </strong>The study identifies PDCD4 as a key therapeutic target and demonstrates that the PTX-TP@PLGA-iRGD nanocomplex enhances drug potency, selectivity and molecular engagement. This study offers a promising strategy to overcome metastasis and chemoresistance in colon cancer.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13173983/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147615920","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":"Computational-experimental repurposing reveals synergistic sorafenib/hydroxychloroquine response in KRAS-mutant breast cancer.","authors":"Mohammad M Abdelwahab, Mahmoud Soliman, Amr Nassrallah","doi":"10.1186/s40360-026-01122-2","DOIUrl":"10.1186/s40360-026-01122-2","url":null,"abstract":"<p><p>BACKGROUND: KRAS mutations are approximately 25% of human cancers, with particularly high incidence in breast and lung cancers, by constitutively triggering MAPK/ERK and PI3K/AKT pathways that advance proliferation, survival, and autophagy-mediated resistance. Targeting these pathways with kinase inhibitors upregulates autophagy, thereby diminishing therapeutic efficacy. Thus, combining kinase inhibitors with autophagy inhibitors offers a rational strategy to enhance antitumor benefits in KRAS-mutant malignancies. FDA-approved Sorafenib (multi-kinase inhibitor targeting Raf) and Hydroxychloroquine (autophagy inhibitor) show promise for repurposing, as Sorafenib induces autophagy leading to resistance, warranting combination testing in KRAS-mutant models. This study integrates computational modeling and in vitro assays to evaluate their synergistic potential in MDA-MB-231 breast and A549 lung cancer cells. METHODS: Raf-Sorafenib stability was evaluated using RMSD, RMSF, Rg, hydrogen bonds, contact frequency, and MM/GBSA for binding free energy in molecular dynamics simulations (100 ns, GROMACS with CHARMM36 force field). MTT assays were used for cytotoxicity on MDA-MB-231, A549, and normal gingival fibroblasts (48 h treatment); Chou-Talalay Combination Index and Dose Reduction Index were used for synergy; Annexin V/PI flow cytometry was performed for apoptosis; PI staining was used for cell cycle; and ANOVA/Tukey’s test (GraphPad Prism, p < 0.05) was conducted for statistics. RESULTS: Sorafenib bound Raf stably (RMSD ~ 0.25 nm protein/0.15 nm ligand, G_bind − 49.90 ± 2.69 kcal/mol), with persistent interactions (3–4 H-bonds, key residues VAL471, LEU513). IC50 values: Sorafenib 9.4 µM (MDA-MB-231), 12 µM (A549), 23.1 µM (fibroblasts); HQ 23.6/62.4/86.2 µM; SN:2HQ ratio showed synergy in MDA-MB-231 (CI = 0.32, DRI 9.36 Sorafenib/4.68 HQ at Fa = 0.5) but antagonism in A549 (CI > 1). Combination enhanced late apoptosis/necrosis (49.41%) in MDA-MB-231 with minimal normal cell cycle disruption. CONCLUSIONS: Sorafenib-HQ combination offers potent, context-specific synergy for KRAS-mutant breast cancer via Raf inhibition and autophagy blockade, enabling dose reductions and apoptosis enhancement. Tumor-type dependence (synergy vs. antagonism) highlights need for patient stratification; findings support repurposing with limited normal cell impact. </p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13064214/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147608095","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}