Toxicology and applied pharmacology最新文献

{"title":"Aminooxyacetic acid up-regulates the Cry1 and Bmal1 clock gene in a sirtuin 1 dependent manner. In vitro study","authors":"Maria Romerowicz-Misielak ,&nbsp;Katarzyna Kozioł ,&nbsp;Sławomir Nowak ,&nbsp;Renata Wojnarowska-Nowak ,&nbsp;Klaudia Łuc","doi":"10.1016/j.taap.2025.117338","DOIUrl":"10.1016/j.taap.2025.117338","url":null,"abstract":"<div><div>The regulation of the cyclic oscillation of the components of the circadian clock is complex in itself. Numerous clock interactions with processes and molecules present in cells further complicate this mechanism. Recently, the anti-aging protein Silencing Information Regulator Two family member, SIRT1, has been linked with the molecular circadian clock. In this study, we investigated the <em>in vitro</em> effect of aminooxyacetic acid on SIRT1 expression in relation to circadian dynamics of <em>Cry1</em> and <em>Bma11</em> expressions in serum shocked NIH-3 T3 and HaCaT cells. The study was carried out in the context of the inhibitory activity of aminooxyacetic acid against cystathionine-<em>β</em>-synthase and cystathionine-<em>γ</em>-lyase. We have shown that aminooxyacetic acid effectively inhibits SIRT1 transcription and synthesis, which, given the pleiotropic effects of sirtuin 1 on numerous metabolic pathways, may have other implications. We also found that AOAA contributes to up-regulation of the expression of the <em>Cry1</em> and <em>Bmal1</em> genes in cells. This effect does not appear to be related to inhibition of the activity of cystathionine-<em>β</em>-synthase and cystathionine-<em>γ</em>-lyase. At the same time, this does not deny the role of hydrogen sulphide, a product of the activity of these enzymes, in the regulation of the circadian clock.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117338"},"PeriodicalIF":3.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143817719","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":"Estimation of species- and sex-specific PFAS pharmacokinetics in mice, rats, and non-human primates using a Bayesian hierarchical methodology","authors":"Todd J. Zurlinden ,&nbsp;Michael W. Dzierlenga ,&nbsp;Dustin F. Kapraun ,&nbsp;Caroline Ring ,&nbsp;Amanda S. Bernstein ,&nbsp;Paul M. Schlosser ,&nbsp;Viktor Morozov","doi":"10.1016/j.taap.2025.117336","DOIUrl":"10.1016/j.taap.2025.117336","url":null,"abstract":"<div><div>The carbon chain length, degree of fluorination, and functional group of <em>per</em>- and polyfluoroalkyl substances (PFAS) influences the bioaccumulation and half-lives of these substances in humans and laboratory animals. Pharmacokinetic (PK) studies using laboratory animals characterize the absorption, distribution, metabolism, and excretion (ADME) of a PFAS and can provide the underlying data for inter-species extrapolation to inform human pharmacokinetics. However, variations in ADME arise due to differences in protein binding and renal and hepatobiliary clearance mechanisms. In particular, sex- and species-specific differences in active transporter abundance and PFAS binding affinity challenge body weight-based extrapolation assumptions from animal models to human PK parameters. Because these protein-dependent changes in ADME do not always scale with species body weight, classic allometric scaling assumptions can fail to account for species-specific transporter-mediated clearance. In addition, study-dependent differences in pharmacokinetic modeling approaches and parameterization techniques can result in large differences among the PK parameters reported in the literature. To better quantify PFAS pharmacokinetics and characterize the underlying uncertainty, we implemented a Bayesian inference hierarchical model to estimate PFAS PK parameters for multiple species (mice, rats, and non-human primates) using numerous single-dose animal studies. Through an alternative parameterization of the one- and two-compartment models, this method improved parameter identifiability and allowed for the use of prior information on PFAS absorption rate, clearance, and volume of distribution. Using reported time-course concentration data, we estimated sex-specific clearance, volume of distribution, and half-life across mice, rats, and non-human primates using a consistent modeling methodology for eight PFAS: PFHxA, PFHxS, PFNA, PFDA, PFBS, PFBA, PFOA, and PFOS. The resulting comparison to available human data demonstrated that standard volume of distribution body-mass scaling (BW¹) for PFAS generally agrees with reported human values while standard assumptions for allometric scaling of clearance (BW^3/4) are not appropriate for most of the PFAS investigated in this study. In addition, we demonstrated that there may be considerable differences in clearance for PFAS in some species when comparing across different sexes and routes of exposure.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117336"},"PeriodicalIF":3.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826461","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":"Honokiol attenuates oxidative stress and vascular calcification via the upregulation of heme oxygenase-1 in chronic kidney disease","authors":"Xuemin Xian ,&nbsp;Xin Zhao ,&nbsp;Xingchen Zhou ,&nbsp;Hanfang Liu ,&nbsp;Changxi Li ,&nbsp;Xinquan Wu ,&nbsp;Yuhang Chen ,&nbsp;Keyue Ye ,&nbsp;Hongwei Yang ,&nbsp;Mingxi Li ,&nbsp;Jianyun Yan ,&nbsp;Xiuli Zhang","doi":"10.1016/j.taap.2025.117318","DOIUrl":"10.1016/j.taap.2025.117318","url":null,"abstract":"<div><div>Vascular calcification (VC) is a common complication of chronic kidney disease (CKD), with oxidative stress identified as a key contributor to VC progression. Honokiol (HKL), a biphenolic compound derived from plants, has been found to be effective in treating various models of cardiovascular disease through the mitigation of oxidative stress. However, its effects on VC remain unexplored. To elucidate the effects of HKL on VC, a CKD rat model, a vitamin D₃-overload-induced mouse model of vascular calcification, and a high-phosphate-induced human vascular smooth muscle cell (VSMC) calcification model were established. Calcification levels were assessed using alizarin red staining, calcium quantification, and western blotting of osteogenic markers. Oxidative stress was assessed by measuring reactive oxygen species. Furthermore, transcriptome sequencing was employed to identify molecules and pathways affected by HKL. HKL was found to significantly reduce calcification in both in vivo and in vitro models. It also mitigated oxidative stress induced by high phosphate in human VSMCs. Mechanistically, HKL upregulated heme oxygenase-1 (HMOX-1), thereby inhibiting oxidative stress and reducing calcification. Pharmacological inhibition of HMOX-1 counteracted the protective effect of HKL against vascular calcification. In summary, the findings suggest that HKL ameliorates VC by upregulating HMOX-1 and decreasing oxidative stress.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117318"},"PeriodicalIF":3.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804280","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":"CB-5083 and luteolin synergistically induce the apoptosis of bladder cancer cells via multiple mechanisms","authors":"Shuben Sun ,&nbsp;Ping Liu ,&nbsp;Guohai Xie ,&nbsp;Junhua Zheng","doi":"10.1016/j.taap.2025.117333","DOIUrl":"10.1016/j.taap.2025.117333","url":null,"abstract":"<div><h3>Purpose</h3><div>Bladder cancer (BC) is a common urological malignancy for which effective treatments are lacking. In recent years, valosin-containing protein (VCP) has emerged as a potential target for the treatment of cancers. CB-5083 is a VCP inhibitor that has been evaluated in phase I clinical trials. However, drug resistance and severe side effects hamper the application of CB-5083. Mounting evidence suggests that combined treatment is a useful strategy to improve anticancer efficiency with lower toxicity. The aim of this study was to evaluate the combined effects of CB-5083 and luteolin (Lut), a natural flavonoid, on BC cells.</div></div><div><h3>Methods</h3><div>Cellular viability was measured via MTT assays. The cell cycle distribution, degree of cell death and mitochondrial membrane potential were assayed via flow cytometry. mRNA levels were assayed via qRT–PCR. Protein levels were measured via western blotting. RNA interference was applied to knockdown genes. Xenograft experiments were conducted to evaluate the toxicity in vivo.</div></div><div><h3>Results</h3><div>Cotreatment with CB-5083 and luteolin synergistically reduced the viability of BC cells. In addition, cotreatment with CB-5083 and Lut synergistically induced cell cycle arrest at the G1 phase and apoptosis in BC cells. Mechanistically, CB-5083/Lut cooperatively reduced the expression of Bcl-xl and Mcl-1 in BC cells. Moreover, CB-5083 and Lut synergistically induced endoplasmic reticulum (ER) stress in BC cells. The genetic or pharmacological inhibition of ER stress markedly reduced the degree of apoptosis induced by CB-5083, Lut or their combination in BC cells. In addition, combined treatment with CB-5083 and Lut synergistically repressed the growth of BC cells in vivo.</div></div><div><h3>Conclusion</h3><div>Our data suggest that combined treatment with CB-5083 and Lut might be applied to treat BC.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117333"},"PeriodicalIF":3.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804251","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":"Ran drives pancreatic cancer metastasis by activating the osteopontin-PI3K/AKT-androgen receptor signaling cascade","authors":"Lin Deng ,&nbsp;Jingyi Ren ,&nbsp;Dong Liu,&nbsp;Hong Li,&nbsp;Guang Yang,&nbsp;Kairui Wang,&nbsp;Yang Song,&nbsp;Haichuan Su","doi":"10.1016/j.taap.2025.117328","DOIUrl":"10.1016/j.taap.2025.117328","url":null,"abstract":"<div><div>The small GTPase Ran has emerged as a key player in cancer metastasis. Our previous studies demonstrated that Ran drives pancreatic cancer metastasis by modulating androgen receptor (AR) expression. However, the detailed mechanisms by which Ran regulates AR expression remain unclear. This study aimed to elucidate the regulatory mechanisms through which Ran influences AR expression in the context of pancreatic cancer metastasis. We observed elevated levels of Ran, osteopontin (OPN), and AR in metastatic lymph node tissues, with OPN positively correlated with either Ran or AR expression. Ran silencing led to decreased levels of OPN and AR, whereas Ran upregulation increased their expression. Notably, OPN overexpression restored AR levels in Ran-silenced cells, whereas OPN knockdown diminished the inductive effect of Ran on AR expression. Additionally, OPN knockdown decreased AR expression and was associated with reduced activation of the PI3K/AKT signaling pathway. Functional assays revealed that silencing OPN significantly impaired the mobility and invasion of pancreatic cancer cells and restricted hepatic metastasis. Conversely, OPN overexpression restored the impaired metastasis caused by Ran knockdown. Furthermore, inhibiting PI3K/AKT signaling abolished the promoting effects of either Ran or OPN on pancreatic cancer metastasis. Importantly, re-expressing AR reversed the inhibitory effects of Ran or OPN silencing on the mobility and invasion of pancreatic cancer cells. In summary, Ran induces AR expression through the regulation of the OPN-PI3K/AKT signaling cascade. The Ran-OPN-PI3K/AKT-AR signaling pathway is crucial for driving pancreatic cancer metastasis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117328"},"PeriodicalIF":3.3,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788953","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":"Protective effect of hydrogen-rich water on spermatogenesis in high-fat diet obese rats","authors":"Mohammad Hossein Rigi ,&nbsp;Seyyedeh Zahra Asghari ,&nbsp;Elaheh Eshtad ,&nbsp;Seyedeh Elnaz Nazari ,&nbsp;Akram Aminian ,&nbsp;Khatereh Kharazmi ,&nbsp;Fereshteh Asgharzadeh ,&nbsp;Amir Avan ,&nbsp;Seyed Mahdi Hassanian ,&nbsp;Tyler W. LeBaron ,&nbsp;Majid Khazaei","doi":"10.1016/j.taap.2025.117334","DOIUrl":"10.1016/j.taap.2025.117334","url":null,"abstract":"<div><div>Obesity can impair spermatogenesis by various mechanisms such as decreased sperm concentration and increased oxidative DNA damage. Hydrogen-rich water (HRW) possesses therapeutic antioxidant properties that may help offer protection to sperm. This study aimed to investigate the therapeutic potential of HRW on spermatogenesis dysfunction in rats with high-fat diet (HFD)-induced obesity. In this experiment, thirty male Wistar Albino rats were divided into three groups. 1) Control group: fed a normal diet, 2) Obese group: fed a HFD (45 % fat), and 3) HFD + HRW group: fed a high-fat diet and received HRW. HRW (1.5 mM) was administered orally every day. After 16 weeks, blood and tissue samples (testis and epididymis) were collected for biochemical and histopathological analysis. Serum LH, FSH and testosterone and oxidative and antioxidative markers, malondialdehyde (MDA), superoxide dismutase (SOD), and total thiol groups were measured in testis and epididymal tissues. The results showed that the HFD significantly increased food intake, body weight, and lee index, all of which were reduced in the HRW-treated obese group. Testis weight, sperm count, Serum LH and histological evaluation of testis including Sertoli and spermatogonia cell counts were significantly lower in the obese group but improved with HRW treatment. Additionally, HRW treatment increased the luminal diameter of seminiferous tubules, epididymal epithelia height, tissue SOD, and total thiol levels, while reducing MDA level in the testis. This study showed that administration of HRW can improve spermatogenesis in obese animals by reducing oxidative stress and ameliorating histological changes in the testis and epididymis, suggesting its potential benefits in combating high-fat diet-induced reproductive dysfunction.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117334"},"PeriodicalIF":3.3,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143785859","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":"Jaceosidin overcomes osimertinib resistance in lung cancer by inducing G2/M cycle arrest through targeting DDB1","authors":"Zhijie Chen ,&nbsp;Zhuoying Yang ,&nbsp;Yingying Liu,&nbsp;Zehao Zhou,&nbsp;Biying Men,&nbsp;Liang Yun,&nbsp;Jianjun Jiang,&nbsp;Haotian Ge,&nbsp;Meijuan Dian,&nbsp;Yujing He,&nbsp;Ruihao Zhang,&nbsp;Kaican Cai,&nbsp;Xuguang Rao,&nbsp;Shuan Rao","doi":"10.1016/j.taap.2025.117327","DOIUrl":"10.1016/j.taap.2025.117327","url":null,"abstract":"<div><h3>Background</h3><div>Osimertinib is a third-generation Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) widely used to treat advanced non-small cell lung cancer with EGFR mutations. However, resistance to osimertinib frequently develops, limiting its long-term effectiveness.</div></div><div><h3>Purpose</h3><div>This study aimed to establish a lung cancer TKI-resistant model and identify Traditional Chinese Medicine (TCM) components that could reverse TKI resistance, enhancing lung cancer sensitivity to targeted therapies, while exploring the underlying molecular mechanisms.</div></div><div><h3>Materials and methods</h3><div>Osimertinib-resistant cell lines and organoids were developed using a dose-escalation approach. A screen of 302 traditional Chinese medicine monomers revealed compounds that increased sensitivity to osimertinib. RNA sequencing and limited proteolysis coupled with small molecule mapping were employed to investigate the molecular mechanisms by which jaceosidin reverses resistance. The efficacy of the jaceosidin and osimertinib combination was confirmed in cell lines, organoids, and a mouse model.</div></div><div><h3>Results</h3><div>The osimertinib-resistant lung cancer model was successfully established, and 12 compounds were identified that enhanced the sensitivity of resistant cells to osimertinib. Among these, Jaceosidin, a flavonoid compound derived from <em>Eupatorium lindleyanum</em> DC., was confirmed to notably increase osimertinib sensitivity. Mechanistic studies, including limited proteolysis and RNA interference analysis, demonstrated that Jaceosidin directly interacts with Damage Specific DNA Binding Protein 1 (DDB1), promoting its protein expression and downregulating CDK1/Cyclin B1 levels. This interaction induced G2/M cell cycle arrest, thereby sensitizing lung cancer cells to osimertinib. Furthermore, both in vitro and in vivo experiments confirmed that the combination of Jaceosidin and osimertinib significantly inhibited tumor growth in osimertinib-resistant models.</div></div><div><h3>Conclusion</h3><div>These findings offer new insights into the role of DDB1 in overcoming osimertinib resistance and suggest that combining jaceosidin with osimertinib may serve as a promising therapeutic strategy to enhance the efficacy of EGFR-TKIs treatment in resistant Non-small Cell Lung Cancer (NSCLC).</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117327"},"PeriodicalIF":3.3,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788807","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":"Pulmonary effects of waterpipe generated smoke in adult diabetic rats","authors":"Rima Kamel ,&nbsp;Sibelle Kassouf ,&nbsp;Selim M. Nasser ,&nbsp;Amale Mcheik ,&nbsp;Nathalie Hayeck ,&nbsp;Elias Abi-Ramia ,&nbsp;Hanan ElKazzaz ,&nbsp;Christian Khalil ,&nbsp;Aniella Abi-Gerges","doi":"10.1016/j.taap.2025.117319","DOIUrl":"10.1016/j.taap.2025.117319","url":null,"abstract":"<div><div>Waterpipe smoking (WPS) is associated with pulmonary inflammation and DNA damage. Tobacco use among diabetic patients adds substantial clinical and public health burden. This study aims to investigate the combined pulmonary effects of diabetes and smoking. To achieve this goal, type 1 diabetes (T1D) was induced in adult male rats by Streptozotocin (65 mg/kg) injection. Rats were then exposed either to fresh air or WPS for one hour daily over five weeks (five days/week). Lung remodeling was evaluated by histology. Changes affecting inflammation, oxidative stress, apoptosis and survival pathways were characterized by real-time quantitative PCR and Western blot. Our findings showed that T1D was associated with pulmonary remodeling characterized by increases in lung weight/BW ratio, exacerbated by WPS, and elevated alveolar count. Both T1D and WPS exposure led to an accumulation of alveolar foamy macrophages and decreased alveolar septal thickness. Upregulation in the transcript levels of pro-inflammatory cytokine, TNF-α and anti-inflammatory marker, IL-10, were reported in diabetic lungs irrespective of WPS exposure. Moreover, diabetic lungs also displayed significant changes in the expression of mitochondrial complexes III and IV and antioxidant enzyme, SOD2, irrespective of the exposure condition. We also noted significant downregulation in the expression of caspases 3 and 9, p-P53/P53 ratio and JNK protein in diabetic lungs compared to control irrespective of the exposure condition. Lastly, diabetes and WPS exposure triggered significant decreases in EGFR expression. In conclusion, we show for the first time pulmonary remodeling and damages caused by the combined effects of T1D and smoking. Our findings highlight the pressing need for future better management of waterpipe consumption among patients with diabetes.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117319"},"PeriodicalIF":3.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143785858","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":"Application of cytochrome P450 enzyme assays to predict p53 inducers and AChE inhibitors that require metabolic activation","authors":"Deborah K. Ngan ,&nbsp;Srilatha Sakamuru ,&nbsp;Jinghua Zhao ,&nbsp;Menghang Xia ,&nbsp;Stephen S. Ferguson ,&nbsp;David M. Reif ,&nbsp;Anton Simeonov ,&nbsp;Ruili Huang","doi":"10.1016/j.taap.2025.117315","DOIUrl":"10.1016/j.taap.2025.117315","url":null,"abstract":"<div><div>Metabolically active compounds can cause toxicity which would otherwise be undetected using traditional <em>in vitro</em> assays with limited proficiency for xenobiotic metabolism. Introduction of liver microsomes to assay systems enables enhanced identification of compounds that require biotransformation to induce toxicity. Previously, metabolically active compounds from the Tox21 10 K compound library were identified using assays probing two targets, p53 and acetylcholinesterase (AChE), in the presence and absence of human or rat liver microsomes, due to the established roles of cytochrome P450 (CYP) enzymes in human drug metabolism. To further explore the role of metabolic activation, the activities of the identified metabolically active compounds were evaluated against five CYP enzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. CYP bioactivities were found to be highly predictive (&gt;80 % accuracy) of compounds that required metabolic activation in these assays. Chemical features significantly enriched in metabolically active compounds, as well as chemical features that were specific for each of the five CYPs, were identified. Product use exposures of the metabolically active compounds were examined in this study, with “pesticides” appearing to be the largest category that may produce harmful metabolites. Additionally, the compound interactions with different CYPs were assessed and frequencies for both classes of compounds, drugs and environmental chemicals, were found to be proportionally similar across the five CYP isoforms.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117315"},"PeriodicalIF":3.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781221","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":"Association of arsenic exposure with PDGF-BB in vitro and in a South Texas population exposed through drinking water","authors":"Alexandra E. Svetlik ,&nbsp;Nishat Tasnim Hasan ,&nbsp;Nusrat Fahmida Trisha ,&nbsp;Daniel W. White ,&nbsp;Raj Satkunasivam ,&nbsp;Natalie M. Johnson ,&nbsp;Taehyun Roh","doi":"10.1016/j.taap.2025.117316","DOIUrl":"10.1016/j.taap.2025.117316","url":null,"abstract":"<div><div>Exposure to arsenic (As) from drinking water is a global public health concern, as As is a recognized carcinogen. Groundwater in South Texas, particularly in areas with Gulf Coast aquifers, contains high levels of As. Private wells are neither regulated nor regularly monitored, leaving residents vulnerable to arsenic exposure. This study aimed to investigate potential biomarkers of health effects for long-term, low-level As exposure among private well users in South Texas and to cross-validate findings using an in vitro model. Among 74 private well users, the association between urinary As levels and urinary LDH and 16 cytokine levels was assessed. After adjusting for covariates, linear regression analysis showed weak but significant associations between urinary total inorganic As levels and LDH (β = 0.37, <em>p</em> &lt; 0.01, R² = 0.23) and PDGF-BB (β = 0.22, <em>p</em> = 0.02, R² = 0.17). However, no significant associations were found with other cytokines. To compare findings from the population study, SV-HUC-1 uroepithelial cells were exposed to 0.1 or 0.5 μM NaAsO₂ subchronically for 5 weeks, corresponding to total arsenic levels of 7.5 and 37.5 μg/L in drinking water. As exposure was not cytotoxic at either dose, as indicated by lactate dehydrogenase (LDH) activity. However, platelet-derived growth factor (PDGF)-BB protein levels showed a statistically significant increase at a lower concentration of 0.1 μM. These findings suggest that PDGF-BB may serve as a potential biomarker for low-level As exposure, but further studies are required for confirmation.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117316"},"PeriodicalIF":3.3,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143746735","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}