Pub Date : 2025-02-01DOI: 10.1016/j.taap.2024.117216
Yifan Zhao , Chuanxuan Wang , Jun Du , Wei Wang , Jiaojiao Wu , Ting Liu , Peng Xue , Yingzi Ju , Xinyu Hong , Jianheng Zheng , Weidong Qu , Yubin Zhang
Cadmium (Cd) is a highly toxic metal in human body, and therefore understanding the immunotoxicity of Cd is significant for public health. The aim of this study was to investigate the role of hematopoietic stem cells (HSC) in regulating the immunotoxicity of Cd. After exposure to 10 ppm Cd via drinking water for up to 9 months, C57BL/6 mice had a suppressed adaptive immune system at day 135 but had an enhanced adaptive immune system at day 270 during Cd exposure. The biphasic impacts of Cd on the adaptive immune system were correlated to the mitochondrial (MT) activation of HSC. Mechanistically, a direct action of Cd activated the non-canonical Wnt signaling to increase MT activation in HSC in the bone marrow (BM) at day 90, thus resulting in an impaired adaptive immune system in mice at day 135 during Cd exposure; conversely, Cd reduced the production of thrombopoietin (TPO) by osteoblasts in the BM to suppress MT activation in HSC at day 180, which in turn caused an enhanced adaptive immune system in mice at day 270 during Cd exposure. Thus, Cd biphasically impacts the adaptive immune system via regulating MT activation of HSC, providing a novel angle for understanding the immunotoxicology of metals.
{"title":"Cadmium biphasically impacts the adaptive immune system via regulating mitochondrial activation of hematopoietic stem cells in mice","authors":"Yifan Zhao , Chuanxuan Wang , Jun Du , Wei Wang , Jiaojiao Wu , Ting Liu , Peng Xue , Yingzi Ju , Xinyu Hong , Jianheng Zheng , Weidong Qu , Yubin Zhang","doi":"10.1016/j.taap.2024.117216","DOIUrl":"10.1016/j.taap.2024.117216","url":null,"abstract":"<div><div>Cadmium (Cd) is a highly toxic metal in human body, and therefore understanding the immunotoxicity of Cd is significant for public health. The aim of this study was to investigate the role of hematopoietic stem cells (HSC) in regulating the immunotoxicity of Cd. After exposure to 10 ppm Cd via drinking water for up to 9 months, C57BL/6 mice had a suppressed adaptive immune system at day 135 but had an enhanced adaptive immune system at day 270 during Cd exposure. The biphasic impacts of Cd on the adaptive immune system were correlated to the mitochondrial (MT) activation of HSC. Mechanistically, a direct action of Cd activated the non-canonical Wnt signaling to increase MT activation in HSC in the bone marrow (BM) at day 90, thus resulting in an impaired adaptive immune system in mice at day 135 during Cd exposure; conversely, Cd reduced the production of thrombopoietin (TPO) by osteoblasts in the BM to suppress MT activation in HSC at day 180, which in turn caused an enhanced adaptive immune system in mice at day 270 during Cd exposure. Thus, Cd biphasically impacts the adaptive immune system via regulating MT activation of HSC, providing a novel angle for understanding the immunotoxicology of metals.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117216"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142898156","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}
Pub Date : 2025-02-01DOI: 10.1016/j.taap.2025.117235
Oğuz Kaan Tombul , Arife Dilşad Akdağ , Pınar Buket Thomas , Nur Kaluç
The widespread use of polyethylene terephthalate (PET) in food and beverage packaging raises concerns about its potential health effects, particularly when PET-derived nanoplastics (PET-NPs) are released into the environment. This study investigates the reproductive toxicity of PET-NPs in male mice. Mice were exposed to PET-NPs at doses of 0.1 mg/day and 0.5 mg/day for 28 days, and the testes index, sperm count, sperm morphology, Reactive Oxygen Species (ROS) production, DNA integrity, histopathology, and spermatogenesis were evaluated. PET-NP exposure resulted in a significant decrease in sperm concentration and an increase in abnormal spermatozoa—particularly blunt-headed sperm and sperm with neck and tail anomalies— and elevated ROS levels in testicular tissue in a dose-dependent manner (p < 0.05). Additionally, PET-NPs induced DNA strand breaks, as demonstrated by the COMET assay (p < 0.05). Histopathological analysis revealed disorganization of the germinal epithelium, vacuolization, reduced sperm density, and increased interstitial spaces, accompanied by a significant decline in spermatogenic activity, as assessed by Johnsen scoring. These findings strongly suggest that the observed adverse effects on male reproductive health, including sperm abnormalities, DNA damage, and impaired spermatogenesis, are primarily driven by ROS-induced oxidative stress. The observed changes provide clear evidence of the adverse effects of subchronic exposure to PET nanoplastics on male reproductive health, highlighting the inherent risks associated with nanoplastic exposure and offering crucial insights for public health awareness and regulatory considerations.
{"title":"Assessing the impact of sub-chronic polyethylene terephthalate nanoplastic exposure on male reproductive health in mice","authors":"Oğuz Kaan Tombul , Arife Dilşad Akdağ , Pınar Buket Thomas , Nur Kaluç","doi":"10.1016/j.taap.2025.117235","DOIUrl":"10.1016/j.taap.2025.117235","url":null,"abstract":"<div><div>The widespread use of polyethylene terephthalate (PET) in food and beverage packaging raises concerns about its potential health effects, particularly when PET-derived nanoplastics (PET-NPs) are released into the environment. This study investigates the reproductive toxicity of PET-NPs in male mice. Mice were exposed to PET-NPs at doses of 0.1 mg/day and 0.5 mg/day for 28 days, and the testes index, sperm count, sperm morphology, Reactive Oxygen Species (ROS) production, DNA integrity, histopathology, and spermatogenesis were evaluated. PET-NP exposure resulted in a significant decrease in sperm concentration and an increase in abnormal spermatozoa—particularly blunt-headed sperm and sperm with neck and tail anomalies— and elevated ROS levels in testicular tissue in a dose-dependent manner (<em>p</em> < 0.05). Additionally, PET-NPs induced DNA strand breaks, as demonstrated by the COMET assay (p < 0.05). Histopathological analysis revealed disorganization of the germinal epithelium, vacuolization, reduced sperm density, and increased interstitial spaces, accompanied by a significant decline in spermatogenic activity, as assessed by Johnsen scoring. These findings strongly suggest that the observed adverse effects on male reproductive health, including sperm abnormalities, DNA damage, and impaired spermatogenesis, are primarily driven by ROS-induced oxidative stress. The observed changes provide clear evidence of the adverse effects of subchronic exposure to PET nanoplastics on male reproductive health, highlighting the inherent risks associated with nanoplastic exposure and offering crucial insights for public health awareness and regulatory considerations.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117235"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012042","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}
Pub Date : 2025-02-01DOI: 10.1016/j.taap.2024.117220
Hyun Kil Shin , Se-Myo Park , Mi-Sun Choi , Jung-Hwa Oh , Sang Kyum Kim , Seokjoo Yoon , Hae-Ryung Park , Hyoung-Yun Han
New approach methods (NAMs) are required to predict human toxicity effectively, particularly due to limitations in conducting in vivo studies. While NAMs have been established for various industries, such as cosmetics, pesticides, and drugs, their applications in natural products (NPs) are lacking. NPs' complexity (multiple ingredients and structural differences from synthetic compounds) complicates NAM development. In this study, we devised NAMs for NPs using (quantitative) structure-toxicity relationship (Q)STR models and in vitro assays.
Validation involved testing each method with single compounds isolated from NPs. A linear regression model was developed for (Q)STR prediction (R2 on test set: 0.52), with an applicability domain analysis demonstrating its reliability across NPs. This model was applied to predict the LD50 range of species, aiding in the development of herbal medicine and dietary supplements. In vitro screening employed three reporter cell lines (AP-1, P53, and Nrf2), with Tox scores derived by integrating in silico and in vitro data.
Nimbolide exhibited the highest Tox score, with experimental studies corroborating the accuracy and reliability of the predictions made via Tox score analysis. The findings of the study align well with the purpose, as the suggested NAMs, utilizing (Q)STR models and in vitro assays, provide a Tox score to efficiently prioritize NPs for herbal medicine and dietary supplements.
{"title":"Enhancing toxicity prediction for natural products in herbal medicine and dietary supplements: Integrating (Q)STR models and in vitro assays","authors":"Hyun Kil Shin , Se-Myo Park , Mi-Sun Choi , Jung-Hwa Oh , Sang Kyum Kim , Seokjoo Yoon , Hae-Ryung Park , Hyoung-Yun Han","doi":"10.1016/j.taap.2024.117220","DOIUrl":"10.1016/j.taap.2024.117220","url":null,"abstract":"<div><div>New approach methods (NAMs) are required to predict human toxicity effectively, particularly due to limitations in conducting <em>in vivo</em> studies. While NAMs have been established for various industries, such as cosmetics, pesticides, and drugs, their applications in natural products (NPs) are lacking. NPs' complexity (multiple ingredients and structural differences from synthetic compounds) complicates NAM development. In this study, we devised NAMs for NPs using (quantitative) structure-toxicity relationship (Q)STR models and <em>in vitro</em> assays.</div><div>Validation involved testing each method with single compounds isolated from NPs. A linear regression model was developed for (Q)STR prediction (R<sup>2</sup> on test set: 0.52), with an applicability domain analysis demonstrating its reliability across NPs. This model was applied to predict the LD<sub>50</sub> range of species, aiding in the development of herbal medicine and dietary supplements. <em>In vitro</em> screening employed three reporter cell lines (AP-1, P53, and Nrf2), with Tox scores derived by integrating <em>in silico</em> and <em>in vitro</em> data.</div><div>Nimbolide exhibited the highest Tox score, with experimental studies corroborating the accuracy and reliability of the predictions made <em>via</em> Tox score analysis. The findings of the study align well with the purpose, as the suggested NAMs, utilizing (Q)STR models and <em>in vitro</em> assays, provide a Tox score to efficiently prioritize NPs for herbal medicine and dietary supplements.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117220"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896785","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}
Pub Date : 2025-02-01DOI: 10.1016/j.taap.2024.117199
Qiong Duan , Zhenting Cui , Mingxiao Wang , Ruochen Li , Feng Han , Jianxin Ma
Breast cancer (BC) is a critical threat to women's lives. Radiotherapy (RT) is a pivotal treatment modality for BC, but the failure of RT due to radioresistance is still not well facilitated. Ginkgetin (GK) has a potent anti-tumor activity intimately associated with ferroptosis. This study applied in vitro and in vivo experimental models to ascertain the GK mechanism of action on BC radioresistance. The outcomes reported that GK could inhibit BC cell growth and increase apoptosis. In addition, when BC cells generated radioresistance, GK promoted ferroptosis of radioresistant BC cells by mitigating NRF2 expression, suppressing HO-1 and NQO1 expression, increasing the intracellular content of reactive oxygen species (ROS) and ferrous ions, accelerating the glutathione (GSH) depletion, and decreasing GPX4 expression. Notably, GK can damage intracellular mitochondria and cause a substantial increase in ferrous ions in BC cells. Therefore, GK shows immense potential for enhancing breast cancer radiotherapy sensitivity, which may provide pivotal evidence for subsequent RT sensitization.
{"title":"Ginkgetin enhances breast cancer radiotherapy sensitization by suppressing NRF2-HO-1 axis activity","authors":"Qiong Duan , Zhenting Cui , Mingxiao Wang , Ruochen Li , Feng Han , Jianxin Ma","doi":"10.1016/j.taap.2024.117199","DOIUrl":"10.1016/j.taap.2024.117199","url":null,"abstract":"<div><div>Breast cancer (BC) is a critical threat to women's lives. Radiotherapy (RT) is a pivotal treatment modality for BC, but the failure of RT due to radioresistance is still not well facilitated. Ginkgetin (GK) has a potent anti-tumor activity intimately associated with ferroptosis. This study applied in vitro and in vivo experimental models to ascertain the GK mechanism of action on BC radioresistance. The outcomes reported that GK could inhibit BC cell growth and increase apoptosis. In addition, when BC cells generated radioresistance, GK promoted ferroptosis of radioresistant BC cells by mitigating NRF2 expression, suppressing HO-1 and NQO1 expression, increasing the intracellular content of reactive oxygen species (ROS) and ferrous ions, accelerating the glutathione (GSH) depletion, and decreasing GPX4 expression. Notably, GK can damage intracellular mitochondria and cause a substantial increase in ferrous ions in BC cells. Therefore, GK shows immense potential for enhancing breast cancer radiotherapy sensitivity, which may provide pivotal evidence for subsequent RT sensitization.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117199"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142802161","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}
Pub Date : 2025-02-01DOI: 10.1016/j.taap.2024.117201
Jiahao Liu , Liya Fang , Chao Gong , Jiawei Li , Yuanyuan Liu , Pei Zeng , Yanping Fan , Yao Liu , Jin Guo , Luchuan Wang , Yue Li
Cenobamate (CNB) is a novel anti-seizure medication with significant efficacy in treating epilepsy. However, in clinical trials, the most common adverse reactions observed in patients are central nervous system (CNS) symptoms. In animal studies, administration of CNB during pregnancy or lactation has been associated with adverse effects on neurodevelopment in offspring. To optimize the clinical use of CNB, we investigated the neurotoxicity of different concentrations of CNB (10, 20, 40, 80, and 160 μM) on zebrafish embryos. Following exposure, zebrafish embryos exhibited abnormal phenotypes such as shortened body length, impaired yolk sac absorption, and decreased heart rate. Behavioral experiments showed that CNB caused abnormal movements such as decreased spontaneous tail curling frequency, shortened total movement distance, and reduced average movement speed. We also found that CNB leads to increased acetylcholinesterase (AChE) activity levels in zebrafish embryos, along with differential expression of neurodevelopment-related genes such as nestin, gfap, synapsin IIa, and gap43. In summary, our research findings indicated that CNB may induce developmental and neurotoxic effects in zebrafish embryos by altering neurotransmitter systems and the expression of neurodevelopmental genes, thereby influencing behavior. This study will provide information for the clinical use of CNB, aiming to benefit more epilepsy patients through its appropriate administration.
{"title":"Neurotoxicity study of cenobamate-induced zebrafish early developmental stages","authors":"Jiahao Liu , Liya Fang , Chao Gong , Jiawei Li , Yuanyuan Liu , Pei Zeng , Yanping Fan , Yao Liu , Jin Guo , Luchuan Wang , Yue Li","doi":"10.1016/j.taap.2024.117201","DOIUrl":"10.1016/j.taap.2024.117201","url":null,"abstract":"<div><div>Cenobamate (CNB) is a novel anti-seizure medication with significant efficacy in treating epilepsy. However, in clinical trials, the most common adverse reactions observed in patients are central nervous system (CNS) symptoms. In animal studies, administration of CNB during pregnancy or lactation has been associated with adverse effects on neurodevelopment in offspring. To optimize the clinical use of CNB, we investigated the neurotoxicity of different concentrations of CNB (10, 20, 40, 80, and 160 μM) on zebrafish embryos. Following exposure, zebrafish embryos exhibited abnormal phenotypes such as shortened body length, impaired yolk sac absorption, and decreased heart rate. Behavioral experiments showed that CNB caused abnormal movements such as decreased spontaneous tail curling frequency, shortened total movement distance, and reduced average movement speed. We also found that CNB leads to increased acetylcholinesterase (AChE) activity levels in zebrafish embryos, along with differential expression of neurodevelopment-related genes such as nestin, gfap, synapsin IIa, and gap43. In summary, our research findings indicated that CNB may induce developmental and neurotoxic effects in zebrafish embryos by altering neurotransmitter systems and the expression of neurodevelopmental genes, thereby influencing behavior. This study will provide information for the clinical use of CNB, aiming to benefit more epilepsy patients through its appropriate administration.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117201"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819329","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}
Pub Date : 2025-02-01DOI: 10.1016/j.taap.2024.117173
Madison Miller , Christelle Douillet , Peter H. Cable , Sergey A. Krupenko , Bingzhen Shang , Hadley J. Hartwell , Fei Zou , Beverly H. Koller , Rebecca C. Fry , Fernando Pardo-Manuel de Villena , Miroslav Stýblo
Arsenic (+3 oxidation state) methyltransferase (AS3MT) catalyzes the S-adenosylmethionine (SAM)-dependent methylation of inorganic arsenic (iAs), yielding monomethyl‑arsenic (MAs) and dimethyl‑arsenic (DMAs) metabolites. The formation of DMAs in this pathway is considered a key mechanism for iAs detoxification. Availability of SAM for iAs methylation depends in part on dietary intake of folate. Results of population studies suggest that supplementation with folate stimulates iAs methylation, increasing DMAs and decreasing iAs and MAs proportions in urine and/or blood. The goal of the present study was to determine if folate intake affects methylation and clearance of iAs in a recently established mouse strain that expresses human AS3MT and exhibits a human-like pattern of iAs metabolism. The humanized male and female mice were fed folate-deficient (FD) or folate-supplemented (FS) diet for 6 weeks, followed by exposure to 0 ppb or 400 ppb iAs in drinking water for 5 weeks, while on the same types of diet. The concentrations and proportions of iAs, MAs and DMAs were determined in urine, liver, kidneys, and spleen. The diet-, sex- and dose-related differences were assessed by t-test or a non-parametric test; Bonferroni test was used to correct for multiple comparisons. In general, proportions of DMAs were greater and proportions of iAs were smaller in urine and tissues of FS mice as compared to FD mice. However, folate supplementation also increased MAs proportions. Notably, the folate intake had no effect on the concentrations of total arsenic either in the urine or the tissues. These results suggest that, similar to humans, folate supplementation stimulates iAs methylation in the humanized mice. However, the stimulation of iAs methylation is not associated with clearance of arsenic from tissues, possibly due to an inefficient conversion of MAs to DMAs.
{"title":"Metabolism of inorganic arsenic in mice carrying the human AS3MT gene and fed folate deficient or folate supplemented diet","authors":"Madison Miller , Christelle Douillet , Peter H. Cable , Sergey A. Krupenko , Bingzhen Shang , Hadley J. Hartwell , Fei Zou , Beverly H. Koller , Rebecca C. Fry , Fernando Pardo-Manuel de Villena , Miroslav Stýblo","doi":"10.1016/j.taap.2024.117173","DOIUrl":"10.1016/j.taap.2024.117173","url":null,"abstract":"<div><div>Arsenic (+3 oxidation state) methyltransferase (AS3MT) catalyzes the S-adenosylmethionine (SAM)-dependent methylation of inorganic arsenic (iAs), yielding monomethyl‑arsenic (MAs) and dimethyl‑arsenic (DMAs) metabolites. The formation of DMAs in this pathway is considered a key mechanism for iAs detoxification. Availability of SAM for iAs methylation depends in part on dietary intake of folate. Results of population studies suggest that supplementation with folate stimulates iAs methylation, increasing DMAs and decreasing iAs and MAs proportions in urine and/or blood. The goal of the present study was to determine if folate intake affects methylation and clearance of iAs in a recently established mouse strain that expresses human AS3MT and exhibits a human-like pattern of iAs metabolism. The humanized male and female mice were fed folate-deficient (FD) or folate-supplemented (FS) diet for 6 weeks, followed by exposure to 0 ppb or 400 ppb iAs in drinking water for 5 weeks, while on the same types of diet. The concentrations and proportions of iAs, MAs and DMAs were determined in urine, liver, kidneys, and spleen. The diet-, sex- and dose-related differences were assessed by <em>t</em>-test or a non-parametric test; Bonferroni test was used to correct for multiple comparisons. In general, proportions of DMAs were greater and proportions of iAs were smaller in urine and tissues of FS mice as compared to FD mice. However, folate supplementation also increased MAs proportions. Notably, the folate intake had no effect on the concentrations of total arsenic either in the urine or the tissues. These results suggest that, similar to humans, folate supplementation stimulates iAs methylation in the humanized mice. However, the stimulation of iAs methylation is not associated with clearance of arsenic from tissues, possibly due to an inefficient conversion of MAs to DMAs.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117173"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740731","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}
Pub Date : 2025-02-01DOI: 10.1016/j.taap.2024.117184
Chien-Hung Lin , Wen-Sheng Liu , Chuan Wan , Hsin-Hui Wang
Increasing evidence links exposure to fine particulate matter (PM2.5) with an elevated risk of kidney disease. In this study, we investigated the effect of PM2.5 exposure on human proximal tubular epithelial (HK−2) cells and found that it elevated ferroptotic stress markers, including increased iron, reactive oxygen species (ROS), and malondialdehyde (MDA), along with reducing glutathione (GSH) levels. PM2.5 promotes the epithelial-to-mesenchymal transition (EMT) in these cells, which is associated with the loss of epithelial morphology, lowered expression of E-cadherin, and elevated expression of α-smooth muscle actin (α-SMA). Notably, a reduction in PM2.5-induced EMT characteristics was observed using either a ferroptosis-specific inhibitor (Fer-1) or a mitochondrial ROS scavenger (Mito-Tempo). Moreover, Fer-1 effectively counteracted ferroptotic stress and restored glutathione peroxidase 4 (GPX4) expression in PM2.5-exposed cells, which may explain its efficacy in inhibiting EMT induced by PM2.5. In contrast, GPX4 knockdown exacerbated EMT features in PM2.5-treated cells. Further studies showed that GPX4 overexpression alleviated EMT markers in mouse tubular cells following PM2.5 exposure, indicating the role of GPX4 in reducing ferroptotic stress and may prevent tubular injury caused by PM2.5 exposure. Our study highlights that PM2.5 may induce GPX4-regulated ferroptotic stress in tubular cells, potentially triggering the EMT process and contributing to kidney injury.
{"title":"Induction of GPX4-regulated ferroptotic stress promotes epithelial-to-mesenchymal transition in renal tubule cells induced by PM2.5","authors":"Chien-Hung Lin , Wen-Sheng Liu , Chuan Wan , Hsin-Hui Wang","doi":"10.1016/j.taap.2024.117184","DOIUrl":"10.1016/j.taap.2024.117184","url":null,"abstract":"<div><div>Increasing evidence links exposure to fine particulate matter (PM2.5) with an elevated risk of kidney disease. In this study, we investigated the effect of PM2.5 exposure on human proximal tubular epithelial (HK−2) cells and found that it elevated ferroptotic stress markers, including increased iron, reactive oxygen species (ROS), and malondialdehyde (MDA), along with reducing glutathione (GSH) levels. PM2.5 promotes the epithelial-to-mesenchymal transition (EMT) in these cells, which is associated with the loss of epithelial morphology, lowered expression of E-cadherin, and elevated expression of α-smooth muscle actin (α-SMA). Notably, a reduction in PM2.5-induced EMT characteristics was observed using either a ferroptosis-specific inhibitor (Fer-1) or a mitochondrial ROS scavenger (Mito-Tempo). Moreover, Fer-1 effectively counteracted ferroptotic stress and restored glutathione peroxidase 4 (GPX4) expression in PM2.5-exposed cells, which may explain its efficacy in inhibiting EMT induced by PM2.5. In contrast, GPX4 knockdown exacerbated EMT features in PM2.5-treated cells. Further studies showed that GPX4 overexpression alleviated EMT markers in mouse tubular cells following PM2.5 exposure, indicating the role of GPX4 in reducing ferroptotic stress and may prevent tubular injury caused by PM2.5 exposure. Our study highlights that PM2.5 may induce GPX4-regulated ferroptotic stress in tubular cells, potentially triggering the EMT process and contributing to kidney injury.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117184"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780770","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}
Osteosarcoma (OS) is a highly fatal malignant tumor with a high metastatic rate and poor prognosis. Matrix metalloproteinase-13 (MMP13) is involved in OS metastasis. Its increased expression is closely related to distant metastasis and poor prognosis. The trifluoromethyl quinazoline compound KZL-201 was designed and synthesized, and its inhibitory effect on the progression of OS cells was investigated. The aim of this study was to investigate the underlying mechanism of action of KZL-201 in OS using a combination of bioinformatics analysis, molecular biology, cytology, and zoology. The in vitro experiments showed that KZL-201 inhibited OS cell proliferation, invasion, and migration; KZL-201 induced apoptosis and arrested the cell cycle at the G2/M phase. The results of molecular docking, the cellular thermal shift assay, and gene silencing experiments showed that KZL-201 had a strong affinity for MMP13. KZL-201 inhibited the progression of 143B cells by regulating the TGF-β1/Smad2/3 pathway. Thus, MMP13 is an important target gene of KZL-201 in inhibiting 143B cell progression. The in vivo experiments showed that KZL-201 inhibited the growth of OS tissues and the expression of MMP13 in OS tissues. In summary, KZL-201 targeted MMP13 and inhibited its expression, consequently suppressing the progression of OS by regulating the TGF-β1/Smad2/3 pathway.
{"title":"MMP13 as an effective target of an active trifluoromethyl quinazoline compound against osteosarcoma","authors":"Chang-hua Zhou , Ting Zhang , Jia Yu , Gang Yu , Sha Cheng , Hui Wu , Bi-xue Xu , Heng Luo , Xiao-bin Tian","doi":"10.1016/j.taap.2024.117204","DOIUrl":"10.1016/j.taap.2024.117204","url":null,"abstract":"<div><div>Osteosarcoma (OS) is a highly fatal malignant tumor with a high metastatic rate and poor prognosis. Matrix metalloproteinase-13 (MMP13) is involved in OS metastasis. Its increased expression is closely related to distant metastasis and poor prognosis. The trifluoromethyl quinazoline compound KZL-201 was designed and synthesized, and its inhibitory effect on the progression of OS cells was investigated. The aim of this study was to investigate the underlying mechanism of action of KZL-201 in OS using a combination of bioinformatics analysis, molecular biology, cytology, and zoology. The <em>in vitro</em> experiments showed that KZL-201 inhibited OS cell proliferation, invasion, and migration; KZL-201 induced apoptosis and arrested the cell cycle at the G2/M phase. The results of molecular docking, the cellular thermal shift assay, and gene silencing experiments showed that KZL-201 had a strong affinity for MMP13. KZL-201 inhibited the progression of 143B cells by regulating the TGF-β1/Smad2/3 pathway. Thus, MMP13 is an important target gene of KZL-201 in inhibiting 143B cell progression. The <em>in vivo</em> experiments showed that KZL-201 inhibited the growth of OS tissues and the expression of MMP13 in OS tissues. In summary, KZL-201 targeted MMP13 and inhibited its expression, consequently suppressing the progression of OS by regulating the TGF-β1/Smad2/3 pathway.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117204"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824502","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}
Pub Date : 2025-02-01DOI: 10.1016/j.taap.2025.117228
Minju Park , Wenwen Zhuang , Junsu Jeong , Hye Ryung Kim , YeEun Jang , Mi Seon Seo , Jin Ryeol An , Hongzoo Park , Eun-Taek Han , Jin-Hee Han , Wanjoo Chun , Won Sun Park
This study explored the vasodilatory mechanisms of the sodium-glucose cotransporter-2 inhibitor remogliflozin using femoral arteries of rabbits. Remogliflozin dilated femoral arterial rings pre-contracted with phenylephrine in a concentration-dependent manner. Pretreatment with the Ca2+-sensitive K+ channel inhibitor (paxilline), the ATP-sensitive K+ channel inhibitor (glibenclamide), or the inwardly rectifying K+ channel inhibitor (Ba2+) did not alter the vasodilatory effect. However, vasodilation was significantly reduced by pretreatment with the voltage-dependent K+ (Kv) channel inhibitor (4-AP) and with the Kv1.5 subtype inhibitor (DPO-1) but not with Kv2.1 or Kv7 subtype inhibitor. Neither endothelium removal nor the inhibition of nitric oxide production altered the vasodilatory effect of remogliflozin. However, pretreatment with the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitors thapsigargin and cyclopiazonic acid effectively reduced the remogliflozin effect, as did pretreatment with cGMP/PKG-related but not cAMP/PKA-related signaling pathway inhibitors. These results indicate that remogliflozin-mediated dilation of the femoral artery occurs via the activation of Kv channels, mainly the Kv1.5 subtype, SERCA pump, and cGMP/PKG-related signaling pathways.
{"title":"The SGLT2 inhibitor remogliflozin induces vasodilation in the femoral artery of rabbits via activation of a Kv channel, the SERCA pump, and the cGMP signaling pathway","authors":"Minju Park , Wenwen Zhuang , Junsu Jeong , Hye Ryung Kim , YeEun Jang , Mi Seon Seo , Jin Ryeol An , Hongzoo Park , Eun-Taek Han , Jin-Hee Han , Wanjoo Chun , Won Sun Park","doi":"10.1016/j.taap.2025.117228","DOIUrl":"10.1016/j.taap.2025.117228","url":null,"abstract":"<div><div>This study explored the vasodilatory mechanisms of the sodium-glucose cotransporter-2 inhibitor remogliflozin using femoral arteries of rabbits. Remogliflozin dilated femoral arterial rings pre-contracted with phenylephrine in a concentration-dependent manner. Pretreatment with the Ca<sup>2+</sup>-sensitive K<sup>+</sup> channel inhibitor (paxilline), the ATP-sensitive K<sup>+</sup> channel inhibitor (glibenclamide), or the inwardly rectifying K<sup>+</sup> channel inhibitor (Ba<sup>2+</sup>) did not alter the vasodilatory effect. However, vasodilation was significantly reduced by pretreatment with the voltage-dependent K<sup>+</sup> (Kv) channel inhibitor (4-AP) and with the Kv1.5 subtype inhibitor (DPO-1) but not with Kv2.1 or Kv7 subtype inhibitor. Neither endothelium removal nor the inhibition of nitric oxide production altered the vasodilatory effect of remogliflozin. However, pretreatment with the sarcoplasmic/endoplasmic reticulum Ca<sup>2+</sup>-ATPase (SERCA) pump inhibitors thapsigargin and cyclopiazonic acid effectively reduced the remogliflozin effect, as did pretreatment with cGMP/PKG-related but not cAMP/PKA-related signaling pathway inhibitors. These results indicate that remogliflozin-mediated dilation of the femoral artery occurs <em>via</em> the activation of Kv channels, mainly the Kv1.5 subtype, SERCA pump, and cGMP/PKG-related signaling pathways.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117228"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142955676","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}
Pub Date : 2025-02-01DOI: 10.1016/j.taap.2024.117190
James A. Campbell , Catherine E. Petersen
Kidney stones resulting from ingestion of melamine-tainted food products were originally detected in dogs and cats in 2004 and 2007. Nephroliths were removed at necropsy from dogs that had died from acute kidney injury in Asia in 2004. Samples of these were submitted to our laboratories for analysis. The presence of a mixed s-triazine matrix comprising melamine, cyanuric acid, and ammelide, but no detectable ammeline was found in the canine stone samples we analyzed. The unusual and unique green coloration of these stones was attributed to the presence of biliverdin. The techniques developed in the canine study were applied to the analysis of human kidney stones. In 2008, high levels of melamine were detected in some infant formula and other liquid and powdered milk products originating from China. Human kidney stones, resulting from this type of contamination, were obtained from children, and analyzed using mass spectral techniques. The results indicated the presence of melamine, ammeline, uric acid, but no ammelide. No green color was observed, thereby eliminating biliverdin. Careful monitoring of food additives is warranted to prevent future problems in both animals and humans.
{"title":"Analysis of children's kidney stones and comparison to canine kidney stones: Both resulting from ingesting adulterated food products","authors":"James A. Campbell , Catherine E. Petersen","doi":"10.1016/j.taap.2024.117190","DOIUrl":"10.1016/j.taap.2024.117190","url":null,"abstract":"<div><div>Kidney stones resulting from ingestion of melamine-tainted food products were originally detected in dogs and cats in 2004 and 2007. Nephroliths were removed at necropsy from dogs that had died from acute kidney injury in Asia in 2004. Samples of these were submitted to our laboratories for analysis. The presence of a mixed <em>s</em>-triazine matrix comprising melamine, cyanuric acid, and ammelide, but no detectable ammeline was found in the canine stone samples we analyzed. The unusual and unique green coloration of these stones was attributed to the presence of biliverdin. The techniques developed in the canine study were applied to the analysis of human kidney stones. In 2008, high levels of melamine were detected in some infant formula and other liquid and powdered milk products originating from China. Human kidney stones, resulting from this type of contamination, were obtained from children, and analyzed using mass spectral techniques. The results indicated the presence of melamine, ammeline, uric acid, but no ammelide. No green color was observed, thereby eliminating biliverdin. Careful monitoring of food additives is warranted to prevent future problems in both animals and humans.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117190"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142795135","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}
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