Chemical Research in Toxicology最新文献

{"title":"Elevating Research and Careers in the Development of Safer Drugs through Artificial Intelligence.","authors":"Alaa Marwan-Abu-Taha","doi":"10.1021/acs.chemrestox.4c00423","DOIUrl":"10.1021/acs.chemrestox.4c00423","url":null,"abstract":"<p><p>The session \"Elevating Research and Careers in the Development of Safer Drugs through Artificial Intelligence,\" held at the American Chemical Society meeting, showcased innovative methodologies that AI brings to drug development, from predictive modeling to personalized medicine.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"365-368"},"PeriodicalIF":3.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Promising Resveratrol Analogue Suppresses CSCs in Non-Small-Cell Lung Cancer via Inhibition of the ErbB2 Signaling Pathway.","authors":"Tanapon Soonthonsrima, Ismail Dwi Putra, Preeyaphan Phookphan, Zin Zin Ei, Masashi Yokoya, Pithi Chanvorachote","doi":"10.1021/acs.chemrestox.4c00436","DOIUrl":"10.1021/acs.chemrestox.4c00436","url":null,"abstract":"<p><p>The ErbB2 signaling pathway plays a crucial role in cancer stem cells (CSCs), governing cancer aggressiveness and proliferation. Targeting ErbB2 holds promise for advancing cancer therapeutics. Resveratrol (RES) and its derivatives have been noted for their ability to target proteins that are involved in CSCs. In this investigation, we synthesize novel derivatives of RES, aim at elucidating structure-activity relationships (SARs) that could enhance the anticancer properties of the RES analogues, and explore their capacities to suppress CSCs. YI-12, an O-benzyl-substituted 1,3-diphenylpropane, demonstrated the most potent anticancer activity against lung cancer cells (A549 and H460), showing high potential inhibiting cancer colony formation. Interestingly, not only does YI-12 suppress CSCs-related proteins, indicated by decreased expression of CSC-enhancing molecules such as CD133-, OCT4-, and CSC-related protein β-catenin, but it also induces apoptosis in CSC-rich spheroids after treatment. Additionally, molecular docking and bioinformatic analysis suggest ErbB2 as a potential target of the compound with a strong binding affinity (-6.709 kcal/mol) compared to the reference compound TAK-285 (-5.563 kcal/mol). YI-12's capability to bind and inhibit ErbB2 leads to the suppression of PI3K and AKT. In conclusion, we highlight the novel resveratrol derivative YI-12 for its ability to inhibit CSCs through the ErbB2 signaling pathway. This compound represents a promising structure that should be further developed for potential use in anticancer therapy.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"415-432"},"PeriodicalIF":3.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11921031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497540","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":"Consensus Modeling for Predicting Chemical Binding to Transthyretin as the Winning Solution of the Tox24 Challenge.","authors":"Dmitriy M Makarov, Alexander A Ksenofontov, Yury A Budkov","doi":"10.1021/acs.chemrestox.4c00421","DOIUrl":"10.1021/acs.chemrestox.4c00421","url":null,"abstract":"<p><p>The utilization of predictive methodologies for the assessment of toxicological properties represents an alternative approach that facilitates the identification of safe compounds while concurrently reducing the financial costs associated with the process. The objective of the Tox24 Challenge was to assess the progress in computational methods for predicting the activity of chemical binding to transthyretin (TTR). In order to fulfill the requirements of this task, the data set, measured by the Environmental Protection Agency, consisted of 1512 chemical substances of diverse nature. This paper describes the model that won the Tox24 Challenge and the steps taken for its further improvement. The Transformer convolutional neural network (CNN) model achieved the best performance as a standalone solution. Meanwhile, a multitask model built on a graph CNN, trained using 11 additional acute systemic toxicity data sets with increased weighting on the TTR binding activity, showed comparable results on the blind test set. The winning solution was a consensus model consisting of two catBoost models with OEstate and Mold2 descriptor sets, as well as two transformer-based models. The improvement of this solution involved adding a fifth model based on multitask learning using the graph CNN method, which led to a reduction in RMSE on the blind test set to 20.3%. The winning model was developed using the OCHEM web platform and is available online at https://ochem.eu/article/162082.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"392-399"},"PeriodicalIF":3.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic Activation of Stiripentol Correlates with Cytotoxicity.","authors":"Ziying Jiang, Yang Wang, Guode Zhao, Xinyu Luo, Yan Shen, Weiwei Li, Ying Peng, Jiang Zheng","doi":"10.1021/acs.chemrestox.4c00209","DOIUrl":"10.1021/acs.chemrestox.4c00209","url":null,"abstract":"<p><p>Stiripentol (SRP) is an antiepileptic agent utilized in managing seizures related to Dravet syndrome. Long-term safety studies have highlighted significant adverse effects in patients including drowsiness, reduced appetite, ataxia, and elevated levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The present study aimed at identifying the reactive metabolite of SRP and defining the potential correlation between its cytotoxicity and metabolic activation. Rat liver microsome incubation of SRP fortified with GSH as a trapping agent produced an <i>α</i>,β-unsaturated ketone metabolite (M1) and a related GSH conjugate (M2). Moreover, both the phase I metabolite and the GSH conjugate were detected in the bile of SRP-treated rats, indicating that both in vivo and in vitro metabolic activation of SRP took place. Notably, SRP exhibited significant cytotoxicity toward rat primary hepatocytes. Pretreatment with ketoconazole, a selective CYP3A enzyme inhibitor, mitigated the susceptibility of hepatocytes to SRP-induced cytotoxicity. These findings suggest that SRP may undergo metabolism to the α,β-unsaturated ketone metabolite, potentially contributing to the cytotoxic effects associated with SRP.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"369-379"},"PeriodicalIF":3.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nicotine Dosimetry in Evaluating Electronic Cigarettes Compared to Cigarette Smoking: Implications for Tobacco Regulatory Science.","authors":"Neal L Benowitz, Hao-Yuan Yang, Peyton Jacob, Gideon St Helen","doi":"10.1021/acs.chemrestox.4c00462","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00462","url":null,"abstract":"<p><p>The delivery and systemic absorption of nicotine are important for assessing the potential safety and efficacy of novel inhaled nicotine delivery devices. We describe an experimental approach for examining systemic nicotine intake, looking at individual variability, comparing JUUL electronic cigarettes and cigarette smoking, and comparing standardized puffing and ad libitum use. Fourteen cigarette smokers who were infrequent e-cigarette users vaped JUUL or smoked cigarettes, both in a standardized session (ten 3.5 s puffs over 5 min) and in a 4 h ad libitum use session. Plasma nicotine concentrations were measured, and using sex and body weight-based population nicotine clearance predictions, systemic nicotine dose was estimated in each session. The pharmacokinetically (PK)-estimated nicotine dose in the standardized session averaged 0.55 mg (range 0.16-0.82) for JUUL and 1.15 mg (range 0.35-4.56) for cigarette smoking. The PK-estimated dose with ad libitum use averaged 4.1 mg (range 0.4-9.5) for JUUL and 5.0 mg (range 1.5-15) for smoking (average 3.4 cigarettes). Within individual correlations, comparing PK-estimated dose for JUUL use with standardized vs ad libitum session was weak (<i>r</i> = 0.45, NS) but was much stronger for cigarette smoking (<i>r</i> = 0.82, <i>p</i> < 0.001). Data from ad libitum use predicted that consumption of the liquid contained in a JUUL pod would correspond to smoking 15 cigarettes, which is similar to that observed in real world studies. We conclude that standardized vaping sessions do not predict usual nicotine self-administration behavior with ad libitum use. With ad libitum use, nicotine intake is much more similar to vaping and smoking and provides a much better predictor of product delivery in the real world. This approach is recommended for screening of novel inhaled nicotine devices and to aid FDA regulatory decision making.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vitamin E Acetate Causes Softening of Pulmonary Surfactant Membrane Models.","authors":"Mitchell DiPasquale, Maksymilian Dziura, Omotayo Gbadamosi, Stuart R Castillo, Ambreen Fahim, Justin Roberto, Jeffrey Atkinson, Natalie Boccalon, Mario Campana, Sai Venkatesh Pingali, P Charukeshi Chandrasekera, Piotr A Zolnierczuk, Michihiro Nagao, Elizabeth G Kelley, Drew Marquardt","doi":"10.1021/acs.chemrestox.4c00425","DOIUrl":"10.1021/acs.chemrestox.4c00425","url":null,"abstract":"<p><p>The popularity of electronic cigarettes and vaping products has launched the outbreak of a condition affecting the respiratory system of users, known as electronic-cigarette/vaping-associated lung injury (EVALI). The build-up of vitamin E acetate (VEA), a diluent of some illicit vaping oils, in the bronchoalveolar lavage of patients with EVALI provided circumstantial evidence as a target for investigation. In this work, we provide a fundamental characterization of the interaction of VEA with lung cells and pulmonary surfactant (PS) models to explore the mechanisms by which vaping-related lung injuries may be present. We first confirm the localization and uptake of VEA in pulmonary epithelial cells. Further, as PS is vitally responsible for the biophysical functions of the lungs, we explore the effect of added VEA on three increasingly complex models of PS: dipalmitoylphosphatidylcholine (DPPC), a lipid-only synthetic PS, and the biologically derived extract Curosurf. Using high-resolution techniques of small-angle X-ray scattering, small-angle neutron scattering, neutron spin-echo spectroscopy, and neutron reflectometry, we compare the molecular-scale behaviors of these membranes to the bulk viscoelastic properties of surfactant monolayer films as studied by Langmuir monolayer techniques. While VEA does not obviously alter the structure or organization of PS membranes, a consistent softening of membrane systems─regardless of compositional complexity─provides a biophysical explanation for the respiratory distress associated with EVALI and yields a new perspective on the behavior of the PS system.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"400-414"},"PeriodicalIF":3.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unprecedented Alkylation of the Catalytic Histidine in the Aging of Cholinesterases after Inhibition by Organophosphorus Pesticides.","authors":"Kevin A Miller, Yiran He, Stacey K Allen, Craig A McElroy, Christopher S Callam, Christopher M Hadad","doi":"10.1021/acs.chemrestox.5c00031","DOIUrl":"10.1021/acs.chemrestox.5c00031","url":null,"abstract":"<p><p>Organophosphorus (OP) compounds pose a serious risk to human health by covalently modifying acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Currently approved oxime therapeutics can reactivate OP-inhibited AChE and BChE, despite significant limitations. The OP-inhibited enzymes undergo a secondary <i>O</i>-dealkylation event, known as aging, for which no currently approved therapeutics are effective as treatments. Many decades of research have studied the aging mechanism in AChE and BChE. It has previously been accepted that aging occurs via a spontaneous <i>O</i>-dealkylation event, by loss of a carbocation or by water hydrolysis of the OP-adducted serine residue. Here, we present a novel mechanism of aging in which the catalytic histidine acts as a nucleophile to induce aging and, as a result, becomes alkylated after exposure to methyl paraoxon (MP) and other pesticides. Using bottom-up proteomics, we identify that upon aging of MP-inhibited AChE and BChE, a methyl transfer occurs from the phosphylated serine residue to the catalytic histidine residue. The extent of histidine methylation is pH-dependent as less methylation is observed at lower pH, while increased methylation is observed at higher pH. At near physiological pH (7.5), the ratio of <i>N</i>-MeHis/His is 3:1 for AChE and 1.3:1 for BChE after 24 h. When other OP compounds were also tested for histidine modification, ethyl paraoxon was shown to result in ethylation of the catalytic histidine; however, when the alkoxy group was branched in the case of an isopropoxy group present in diisopropyl fluorophosphate, no alkylation of histidine was observed. Recent advances in the development of quinone methide precursors show promise in the recovery of OP-aged AChE. In this work, we discuss the importance of this novel aging mechanism and its impact on the recoverability of OP-aged AChE or BChE as it appears that the histidine modification limits the overall recovery of active AChE.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"503-518"},"PeriodicalIF":3.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"(Q)SAR Approaches to Predict the Extent of Nitrosation in Pharmaceutical Compounds.","authors":"Krystle Reiss, Roustem Saiakhov, Suman Chakravarti","doi":"10.1021/acs.chemrestox.4c00435","DOIUrl":"10.1021/acs.chemrestox.4c00435","url":null,"abstract":"<p><p>Since their discovery as impurities in numerous pharmaceuticals beginning in 2018, there has been a strong push to predict and prevent the formation of mutagenic nitrosamines. Several experimental methods, particularly the Nitrosation Assay Procedure, have been developed to predict a molecule's susceptibility to nitrosation. Here, we have compiled the results of hundreds of these experiments from the literature to construct two structure-activity relationship models: a statistical model and an expert rule-based model. The statistical model has been built with graph neural networks and was trained on a dataset of 207 nitrogen-containing molecules. This model makes a binary call for each nitrogen center, predicting if it is likely to be nitrosated or not. Conversely, the rule-based model labels each possible nitrosamine product as one of four categories, ranging from \"unlikely\" to \"very likely\". It makes this determination based on 15 rules, which cover 12 deactivating (inhibit nitrosation) and 3 activating (favor nitrosation) features that have been drawn from the literature. Both models perform remarkably well, with accuracies of ∼80%. The rule-based model is generally biased toward favoring nitrosation while the statistical model is more likely to classify an amine as un-nitrosatable due to the makeup of the dataset. Using the models together can balance these biases and further improve the reliability of both.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"433-447"},"PeriodicalIF":3.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11921035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522062","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":"Novel Organophosphate Ester Tris(2,4-di-<i>tert</i>-butylphenyl)phosphate Alters Lipid Metabolism: Insights from Lipidomic Analysis and mRNA Expression.","authors":"Pingping Kang, Qianyu Chen, Jia Wu, Qi Zhang, Doug Crump, Guanyong Su","doi":"10.1021/acs.chemrestox.4c00460","DOIUrl":"10.1021/acs.chemrestox.4c00460","url":null,"abstract":"<p><p>Tris(2,4-di-<i>tert</i>-butylphenyl)phosphate (TDTBPP), a novel organophosphate ester (OPE), has been extensively detected in various environmental and biological samples; however, its potential biological effects remain unexplored. In this study, we investigated biotransformation characteristics, alteration of lipid metabolism, and mRNA expression in primary mouse hepatocytes (PMHs) following exposure to TDTBPP. After 36-h exposure in PMHs, TDTBPP exhibited a high stability potential with no statistically significant degradation trend. Subsequently, we analyzed the disruption of lipid homeostasis in PMHs following exposure to 0-4.5 μM TDTBPP. Lipidomic analysis indicated that TDTBPP disrupted lipid homeostasis in PMHs, and several lipid classes were dysregulated, in particular, glycerolipids and glycerophospholipids. Additionally, three lipids were proposed as potential lipid biomarkers of TDTBPP exposure, including triglycerides (TGs) and phosphatidylcholines (PCs). These observations were further supported by transcriptional changes, with significant alteration observed in genes associated with lipid uptake, de novo lipogenesis, β-oxidation of fatty acids, glycerolipid metabolism, and lipid export. Overall, these findings highlight the detrimental effects of TDTBPP on lipid homeostasis, providing important insights for health risk assessments of this abundant OPE in the environment.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"448-457"},"PeriodicalIF":3.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perfluorobutanesulfonate Induces Hypothalamic-Pituitary-Gonadal Axis Disruption and Gonadal Dysplasia of <i>Lithobates catesbeianus</i> Tadpoles.","authors":"Yilin Shu, Liyuan Zhang, Jun He, Lizhu Tang, Yuting Wu, Pei Hong, Hailong Wu, Lianguo Chen","doi":"10.1021/acs.chemrestox.4c00498","DOIUrl":"10.1021/acs.chemrestox.4c00498","url":null,"abstract":"<p><p>It is uncertain whether exposure to environmental concentrations of perfluorobutanesulfonate (PFBS) disrupts the reproductive endocrine system in amphibian tadpoles. In this study, tadpoles (<i>Lithobates catesbeianus</i>) in G26 stage were treated with different levels of PFBS (0, 1, 3, and 10 μg/L) for 60 days to investigate whether and how PFBS affects the reproductive endocrine system and gonadal development in tadpoles. Tadpole testes exhibited structural damage to germ cells and significantly fewer spermatogonia following PFBS exposure, but the sex ratio remained unaffected. Further, PFBS exposure downregulated transcripts of genes associated with ovarian (<i>figla</i> and <i>nobox</i>) and testicular (<i>sox9</i> and <i>dmrt1</i>) development in tadpoles. Encoding gonadotropin hormone genes were transcriptionally upregulated in the pituitary, and serum gonadotropins (FSH and LH) were elevated. Genes related to testosterone synthesis were transcriptionally upregulated, and serum testosterone concentrations were raised. The transcription of the <i>cyp19a1</i> gene, which is involved in the synthesis of estradiol (E2), was downregulated, leading to decreased levels of serum E2. Furthermore, the transcript level of the vitellogenin gene was downregulated in the liver. Thus, PFBS exposure appears to disrupt the hypothalamic-pituitary-gonadal-liver axis in tadpoles, subsequently impacting gonadal development. The findings of this study indicate that environmental concentrations of PFBS threaten the reproductive endocrine system in amphibians for the first time. This provides important insights for further investigation into the risk that PFBS poses to the stability of the amphibian population.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"478-487"},"PeriodicalIF":3.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}