Xenobiotica最新文献_第2页

Arctigenin-induced erythrocyte membrane remodelling is mediated through calcium influx, metabolic collapse, and casein kinase 1α. 牛蒡子素诱导的红细胞膜重构是通过钙内流、代谢衰竭和酪蛋白激酶1α介导的。

IF 1.3 4区医学

Xenobiotica Pub Date : 2025-06-04 DOI: 10.1080/00498254.2025.2513324

Mohammad A Alfhili, Rahaf F Alothaimeen, Jawaher Alsughayyir

{"title":"Arctigenin-induced erythrocyte membrane remodelling is mediated through calcium influx, metabolic collapse, and casein kinase 1α.","authors":"Mohammad A Alfhili, Rahaf F Alothaimeen, Jawaher Alsughayyir","doi":"10.1080/00498254.2025.2513324","DOIUrl":"10.1080/00498254.2025.2513324","url":null,"abstract":"Conclusive evidence suggests that arctigenin (AGN) holds great promise in anticancer therapy but a common and poorly understood complication of chemotherapy is anaemia which is precipitated by eryptosis and haemolysis. This study examines the cytotoxicity of AGN in RBCs.Eryptosis markers including intracellular calcium, phosphatidylserine (PS) externalisation, and cell shrinkage were detected by flow cytometry using Fluo4/AM, annexin-V-FITC, and forward light scatter, respectively. Membrane blebbing was examined using electron microscopy, and photometric and potentiometric methods were used to assay haemolytic markers including haemoglobin, potassium, AST, and LDH.AGN significantly increased Fluo4- and annexin-V-positive cells and decreased forward light scatter which was associated with membrane blebs. While PS externalisation and cell shrinkage were inhibited by extracellular calcium exclusion, suppression of haemolysis required both calcium exclusion and restriction of potassium efflux. Moreover, sucrose and mannitol rescued the cells from haemolysis while exacerbating PS externalisation, which was rather significantly blunted by guanosine and CK1α inhibitor D4476.AGN promotes calcium-dependent eryptosis through energy depletion and CK1α activation, and exhibits a potent haemolytic activity through dysregulated ion trafficking and osmotic stress. These findings underscore the hematological toxicity of AGN and identify potential inhibitors which inform future animal studies and clinical trials.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"1-11"},"PeriodicalIF":1.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genetic polymorphisms of ABCC2 and CBR3 can influence the efficacy and toxicity of doxorubicin therapy in Egyptian patients with non-Hodgkin lymphoma. ABCC2和CBR3基因多态性可影响阿霉素治疗埃及非霍奇金淋巴瘤患者的疗效和毒性。

IF 1.3 4区医学

Xenobiotica Pub Date : 2025-05-29 DOI: 10.1080/00498254.2025.2508814

Hagar A Elmekawy, Khaled Abdelkawy, Galal Magdy, Emad Sadaka, Gamal El-Azab, Ahmed Ali, Noha El-Khodary, Fawzy Elbarbry

{"title":"Genetic polymorphisms of ABCC2 and CBR3 can influence the efficacy and toxicity of doxorubicin therapy in Egyptian patients with non-Hodgkin lymphoma.","authors":"Hagar A Elmekawy, Khaled Abdelkawy, Galal Magdy, Emad Sadaka, Gamal El-Azab, Ahmed Ali, Noha El-Khodary, Fawzy Elbarbry","doi":"10.1080/00498254.2025.2508814","DOIUrl":"10.1080/00498254.2025.2508814","url":null,"abstract":"This study investigated the impact of single nucleotide polymorphisms (SNPs) in genes involved in doxorubicin (DOX) transport and metabolism on clinical outcomes and toxicity in Egyptian patients with non-Hodgkin lymphoma.Ninety-two patients received at least six DOX treatment cycles. SNP genotyping was performed using real-time PCR with high-resolution melting analysis. Laboratory tests were conducted at baseline, during, and after treatment.The AA genotype of ABCC2 (rs8187710) showed the strongest association with elevated DOX plasma levels and a significantly increased risk of acute cardiotoxicity (OR 26.9; 95% CI: 1.47-492; p = 0.026). The GA genotype was linked to a lower complete response rate and increased risks of leukopoenia (OR 2.66; 95% CI: 1.07-6.61; p = 0.034) and lymphocytopenia (OR 10; 95% CI: 3.57-27.9; p < 0.0001), with intermediate peak DOX levels. For CBR3 (rs8133052), the GA genotype was significantly associated with a higher risk of anaemia (OR 3.5; 95% CI: 1.05-11.7; p = 0.042), acute cardiotoxicity (OR 4.4; 95% CI: 1.86-11.5; p = 0.002), cardiac-related symptoms, and higher peak plasma DOX levels, along with reduced complete response.Polymorphisms in ABCC2 and CBR3 genes may contribute to individual variability in DOX-related toxicity and treatment response.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"1-11"},"PeriodicalIF":1.3,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144120981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Machine learning-driven bioavailability prediction in early-stage drug development: a KNIME-based computational workflow for digital health applications. 早期药物开发中机器学习驱动的生物利用度预测：用于数字健康应用的基于knime的计算工作流。

IF 1.3 4区医学

Xenobiotica Pub Date : 2025-05-28 DOI: 10.1080/00498254.2025.2508804

Majdi Hammami, Walid Yeddes, Hamza Gadhoumi, Raghda Yazidi, Moufida Saidani Tounsi, Kamel Msaada

{"title":"Machine learning-driven bioavailability prediction in early-stage drug development: a KNIME-based computational workflow for digital health applications.","authors":"Majdi Hammami, Walid Yeddes, Hamza Gadhoumi, Raghda Yazidi, Moufida Saidani Tounsi, Kamel Msaada","doi":"10.1080/00498254.2025.2508804","DOIUrl":"10.1080/00498254.2025.2508804","url":null,"abstract":"Bioavailability prediction remains a significant challenge in early-stage drug development, where conventional experimental approaches are time-consuming and resource-intensive. This study explores the application of machine learning techniques to enhance the efficiency of bioavailability prediction. By leveraging computational workflows within the KNIME Analytics Platform, we aim to automate bioavailability assessment and reduce dependence on costly in vitro and in vivo studies.A dataset comprising 475 drug-like compounds characterised by key molecular descriptors was analysed using multiple machine learning models, including Random Forest, Gradient Boosting, Decision Trees, k-Nearest Neighbours, and neural networks. Model performance was assessed through 5-fold cross-validation, with ensemble models outperforming linear and neural network-based approaches. Random Forest demonstrated the highest predictive performance (R2 = 0.87, RMSE = 0.08). Feature importance analysis identified topological polar surface area and solubility as the most influential factors in bioavailability prediction.The findings underscore the potential of integrating open-source tools and machine learning methodologies in pharmaceutical research, improving workflow efficiency while adhering to FAIR (Findable, Accessible, Interoperable, and Reusable) data principles. This approach facilitates rapid and cost-effective bioavailability assessment, supporting AI-driven predictive modelling and digital health applications in drug development.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"1-10"},"PeriodicalIF":1.3,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144112216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Meeting report: DMDG peptide and oligonucleotide ADME workshop 2024. 会议报告：DMDG肽和寡核苷酸ADME研讨会2024。

IF 1.3 4区医学

Xenobiotica Pub Date : 2025-05-28 DOI: 10.1080/00498254.2025.2506702

Inga Bjørnsdottir, Ralf Lotz, Bo Lindmark, Steve Hood, Jesper Kammersgaard Christensen

引用次数: 0

Nano-pharmacokinetics and pharmacodynamics of green-synthesized ZnO nanoparticles: a pathway to safer therapeutic applications. 绿色合成ZnO纳米颗粒的纳米药代动力学和药效学：通往更安全治疗应用的途径。

IF 1.3 4区医学

Xenobiotica Pub Date : 2025-05-21 DOI: 10.1080/00498254.2025.2505062

Aishwarya Jain, Kiran Bhise

引用次数: 0

From lab-to-clinic with model informed formulation development: a case study of hydroxyzine SR tablets. 从实验室到临床与模型知情处方开发：羟嗪SR片的案例研究。

IF 1.3 4区医学

Xenobiotica Pub Date : 2025-05-21 DOI: 10.1080/00498254.2025.2497045

Aditya Murthy, Shubham Jamdade, Manoj Gundeti, Maddukuri Harika, Rahul Chiliveri, Sangmesh Chaudhari, Veena Kambam, Sohel Khan, Anup Choudhury, Tausif Ahmed

{"title":"From lab-to-clinic with model informed formulation development: a case study of hydroxyzine SR tablets.","authors":"Aditya Murthy, Shubham Jamdade, Manoj Gundeti, Maddukuri Harika, Rahul Chiliveri, Sangmesh Chaudhari, Veena Kambam, Sohel Khan, Anup Choudhury, Tausif Ahmed","doi":"10.1080/00498254.2025.2497045","DOIUrl":"10.1080/00498254.2025.2497045","url":null,"abstract":"Model Informed Formulation Development (MIFD) uses physiologically based pharmacokinetic (PBPK) modelling and other in silico tools to facilitate new product development. These tools help set target profiles, predict in vivo formulation performance, guide iterative development, define dissolution parameters, and convince the regulatory agencies about a drug's safety and efficacy.This study involves development of a sustained release formulation for Hydroxyzine, an anti-histamine with sedation as a significant side effect. The aim was to design a formulation that releases the drug slowly, reducing the peak plasma concentration without losing on the effectiveness. A preliminary absorption model was developed using immediate release formulation data, and various hypothetical dissolution profiles were evaluated in this model. The new drug product, manufactured using MatrixealTM technology, underwent preliminary bioequivalence (BE) studies in healthy volunteers. These results were used to refine the model and further modify the formulation, whose performance was predicted via virtual BE studies. Confirmatory BE studies with 70 volunteers under fasting state validated the new formulation. The model also established clinically relevant dissolution specifications and assessed the food effect on the drug product.This work showcases the application of PBPK modelling in developing new modified release drug product of Hydroxyzine.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"1-10"},"PeriodicalIF":1.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144044770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Feature-based molecular networking updates the in vitro metabolic characterisation of fenbendazole across species. 基于特征的分子网络更新了芬苯达唑跨物种的体外代谢特征。

IF 1.3 4区医学

Xenobiotica Pub Date : 2025-03-01 Epub Date: 2025-05-04 DOI: 10.1080/00498254.2025.2497047

Young-Heun Jung, Dong-Cheol Lee, Bo-Hyun Choi, Junyoung O Park, Ju-Hyun Kim

{"title":"Feature-based molecular networking updates the in vitro metabolic characterisation of fenbendazole across species.","authors":"Young-Heun Jung, Dong-Cheol Lee, Bo-Hyun Choi, Junyoung O Park, Ju-Hyun Kim","doi":"10.1080/00498254.2025.2497047","DOIUrl":"10.1080/00498254.2025.2497047","url":null,"abstract":"Feature-based molecular networking (FBMN), an advanced metabolomics tool leveraging MS/MS spectral similarity, was applied to update metabolite characterisation of fenbendazole (FBZ), a veterinary antiparasitic agent with emerging anticancer potential in humans. Despite its therapeutic promise, FBZ's human metabolic pathways remain poorly understood.In this study, FBMN was utilised for the comprehensive in vitro profiling of FBZ metabolites across species, employing high-resolution liquid chromatography-mass spectrometry (LC-HRMS) with data-dependant MS2 acquisition.Nine metabolites, including two novel sulphate-conjugated forms (M2 sulphate and M7 sulphate), were identified and structurally characterised through integrated FBMN analysis. Oxidative metabolites (M1-M4) were found to be more abundant in rat liver microsomes, whereas monkey hepatocytes exhibited higher levels of most metabolites. Notably, hydrolysed FBZ (M5) dominated human samples, accounting for the largest proportion in both liver microsomes and hepatocytes, suggesting species-specific enzymatic activity.The application of FBMN provided an enhanced, systematic approach for metabolite identification and inter-species comparison, revealing critical metabolic differences that support FBZ biotransformation. These findings offer novel insights into FBZ's metabolic pathways, supporting its safety and efficacy assessment for potential human therapeutic applications.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"167-175"},"PeriodicalIF":1.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144050519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Regulatory effect of atorvastatin combined with berberine on PI3K/AKT/FoxO1 signaling pathway in rats with hyperlipidaemia. 阿托伐他汀联合小檗碱对高脂血症大鼠PI3K/Akt/ fox01信号通路的调控作用

IF 1.3 4区医学

Xenobiotica Pub Date : 2025-03-01 Epub Date: 2025-05-12 DOI: 10.1080/00498254.2025.2503359

Chao Yu, Weihong Yin, Jiao Li, Fan Wu, Siwen Wang, Zhaoyang Han, Haoliang Chen, Xueying Yan, Mingyu Cui

{"title":"Regulatory effect of atorvastatin combined with berberine on PI3K/AKT/FoxO1 signaling pathway in rats with hyperlipidaemia.","authors":"Chao Yu, Weihong Yin, Jiao Li, Fan Wu, Siwen Wang, Zhaoyang Han, Haoliang Chen, Xueying Yan, Mingyu Cui","doi":"10.1080/00498254.2025.2503359","DOIUrl":"10.1080/00498254.2025.2503359","url":null,"abstract":"Atorvastatin Calcium (AC) is the first line lipid-lowering drug in clinical. Nowadays, the combination of AC and BBR is often used to treat hyperlipidaemia in clinical. In order to determine the mechanism, we investigate the regulatory of atorvastatin combined with berberine on PI3K/Akt/FoxO1 signalling pathway in rats with hyperlipidaemia.The hyperlipidaemia rat model was constructed. Meanwhile, lipid-lowering and liver protective effects were determined by oil red O and H&E method. The expression of PI3K, Akt and FoxO1 was examined by IHC, WB and RT-pCR. The level of CK and LDH in serum was examined by ELISA.The results showed that the expression of PI3K, AKT increased and FoxO1 decreased in MC group compared with NC group (p < 0.01). The expression of PI3K, AKT decreased and FoxO1 increased compared with MC group (p < 0.05). The expression of FoxO1 in combination group is lower than AC group. The levels of CK and LDH in AC group increased compared with NC group (p < 0.01), but decreased significantly in AC+BBR group compared with AC group (p < 0.01).The combination of AC and BBR could regulate the lipid level by mediating PI3K/Akt/FoxO1, which is providing new references for the treatment of hyperlipidaemia.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"256-263"},"PeriodicalIF":1.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144050899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exploring ethanol's toxicity in the oral submucosa: chronic exposure versus abstinence in C57BL/6 mice. 探索乙醇在口腔黏膜下的毒性：C57BL/6小鼠的慢性暴露与戒断。

IF 1.3 4区医学

Xenobiotica Pub Date : 2025-03-01 Epub Date: 2025-05-25 DOI: 10.1080/00498254.2025.2505066

Devaraj Ezhilarasan, Karthik Shree Harini, Karthick Munusamy

{"title":"Exploring ethanol's toxicity in the oral submucosa: chronic exposure versus abstinence in C57BL/6 mice.","authors":"Devaraj Ezhilarasan, Karthik Shree Harini, Karthick Munusamy","doi":"10.1080/00498254.2025.2505066","DOIUrl":"10.1080/00498254.2025.2505066","url":null,"abstract":"Alcohol consumption is a recognised risk factor for the development of precancerous lesions in the oral cavity. This study investigates the effects of chronic ethanol exposure on inflammation and fibrosis in mice.Eighteen C57BL/6 mice were divided into three groups: Group I received only drinking water, while Groups II and III were exposed to 25% ethanol ad libitum for 14 weeks. Group II mice were sacrificed at the end of the 14th week, whereas Group III underwent a 4-week abstinence period before sacrifice. Gene expression related to inflammation and fibrosis, along with histopathological changes in submucosal tissue, was analysed.Chronic ethanol exposure significantly upregulated MAPK signalling markers, as well as inflammatory and fibrotic markers, in submucosal tissue. In Group III, inflammatory markers such as NF-κB, p65, NLRP3, and caspase-1 partially returned to normal levels after abstinence, whereas fibrotic markers, particularly MMP-9, remained elevated. Histopathological analysis of oral submucosa revealed epithelial atrophy and extracellular matrix accumulation in ethanol-exposed mice.These findings suggest that 14 weeks of ethanol exposure induces persistent epithelial damage, inflammation, and fibrosis in the oral submucosa, with incomplete reversal after 4 weeks of abstinence. This underscores the lasting impact of alcohol on oral tissue, even after cessation.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"209-216"},"PeriodicalIF":1.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144080806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Prediction of the neurotoxic mechanisms of the pesticide phorate using network toxicology, molecular docking, and molecular dynamics simulation. 应用网络毒理学、分子对接、分子动力学模拟等方法预测农药膦的神经毒性机制。

IF 1.3 4区医学

Xenobiotica Pub Date : 2025-03-01 Epub Date: 2025-05-05 DOI: 10.1080/00498254.2025.2498010

Jiahui Xu, Yinghao Xiao, Jixin Li, Zhongyi Liu, Lili Zhang, Wei Xu

{"title":"Prediction of the neurotoxic mechanisms of the pesticide phorate using network toxicology, molecular docking, and molecular dynamics simulation.","authors":"Jiahui Xu, Yinghao Xiao, Jixin Li, Zhongyi Liu, Lili Zhang, Wei Xu","doi":"10.1080/00498254.2025.2498010","DOIUrl":"10.1080/00498254.2025.2498010","url":null,"abstract":"Phorate is an organophosphate pesticide that may cause neurotoxicity, although the exact mechanisms remain unclear.This study aimed to elucidate the mechanisms of neurotoxicity caused by phorate overexposure using network toxicology, molecular docking, and molecular dynamics simulation.We identified 104 potential targets and 20 core targets associated with phorate-induced neurotoxicity. Key targets, including MMP9, CASP1, and KEAP1, may be involved in neuroactive ligand-receptor interaction signalling, as well as the cAMP and calcium signalling pathways. Furthermore, molecular dynamics simulations were conducted on the KEAP1 and CASP1 protein-ligand complexes, which demonstrated the highest binding stabilities in molecular docking analysis. The binding free energies were calculated to be -27.08 and -22.80 kcal/mol for KEAP1 and CASP1, respectively, indicating that both complexes are thermodynamically stable.The methodology used in this study facilitates the identification and assessment of previously unexplored agrochemical toxicity pathways and molecular mechanisms. These findings suggest a novel approach to controlling pesticide residues and screening drugs.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"217-229"},"PeriodicalIF":1.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143988985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0