Hadley J. Hartwell , Bingzhen Shang , Christelle Douillet , Audrey G. Bousquet , Tianyi Liu , Fei Zou , Folami Ideraabdullah , Miroslav Stýblo , Rebecca C. Fry
{"title":"Heritable dysregulation of DNA methylation may underlie the diabetogenic effects of paternal preconception exposure to inorganic arsenic in C57BL/6J mice","authors":"Hadley J. Hartwell , Bingzhen Shang , Christelle Douillet , Audrey G. Bousquet , Tianyi Liu , Fei Zou , Folami Ideraabdullah , Miroslav Stýblo , Rebecca C. Fry","doi":"10.1016/j.taap.2025.117242","DOIUrl":"10.1016/j.taap.2025.117242","url":null,"abstract":"<div><div>Chronic exposure to inorganic arsenic (iAs) has been linked with the development of diabetes mellitus (DM). We recently showed that parental exposure to iAs (200 ppb) prior to mating was associated with diabetic phenotypes in offspring and altered gene expression in parents and offspring. The goal of the present study was to determine if DNA methylation underlies the differential gene expression in the livers of offspring. DNA methylation was assessed in paternal (G0) sperm and livers of their offspring (G1) using a genome wide DNA methylation array. We found that iAs exposure significantly altered CpG methylation (<em>p</em> < 0.05) in 54.3 %, 49.4 %, and 63.7 % of the differentially expressed genes in G0 sperm, G1 female livers, and G1 male livers, respectively. Importantly, a subset of differentially methylated CpG sites were shared across generations. Sensitivity analyses (FDR < 0.1) of imprinted and DM-associated genes revealed differential methylation of 74 imprinted genes and 100 DM-associated genes in the livers of G1 males. These male-specific results are intriguing given the prior findings of diabetic phenotypes found exclusively in male offspring from parents exposed to iAs. In summary, these data demonstrate that heritable changes in DNA methylation through the paternal germline may underlie the diabetogenic effects of preconception iAs exposure.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"496 ","pages":"Article 117242"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143081141","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}
Jianping Luo , Mingyuan He , Changzhu Liang , Xiaoxia Huang , Yingqi Zhu , Donghong Hu , Junyu Yan , Mingjue Li , Hairuo Lin , Wangjun Liao , Jianping Bin , Ziyun Guan , Cankun Zheng , Yulin Liao
{"title":"Canagliflozin reverses doxorubicin-induced cardiotoxicity via restoration of autophagic homeostasis","authors":"Jianping Luo , Mingyuan He , Changzhu Liang , Xiaoxia Huang , Yingqi Zhu , Donghong Hu , Junyu Yan , Mingjue Li , Hairuo Lin , Wangjun Liao , Jianping Bin , Ziyun Guan , Cankun Zheng , Yulin Liao","doi":"10.1016/j.taap.2024.117183","DOIUrl":"10.1016/j.taap.2024.117183","url":null,"abstract":"<div><div>Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been reported as successful for preventing doxorubicin (DOX) -induced cardiotoxicity (DIC), but the underlying mechanisms are elusive. This study aimed to determine whether canagliflozin, an SGLT2i, protects against DIC by regulation of autophagic flux in cardiomyocytes through a mechanism independent of SGLT2. The differentially expressed autophagy-related genes (ARGs) in DIC were analyzed. Neonatal rat cardiomyocytes (NRCMs), H9C2 rat cardiomyocytes or C57BL/6 mice were treated with canagliflozin or vehicle. The effects on cellular apoptosis and autophagy were investigated using qRT-PCR, western blotting and immunofluorescence. Additionally, cardiac function, myocardial fibrosis, and apoptosis of cardiomyocytes were also assessed in mice. The potential molecular targets of canagliflozin were identified through molecular docking analysis. A total of 26 differentially expressed ARGs were identified. Canagliflozin significantly activated autophagic flux and inhibited apoptosis of cardiomyocytes in both DOX-treated H9C2 rat cardiomyocytes and NRCMs. In a murine model of DIC, canagliflozin improved cardiac dysfunction by suppressing cardiac remodeling, fibrosis, and apoptosis. Moreover, canagliflozin promoted autophagy by enhancing SIRT1 levels and inhibiting the PI3K/Akt/mTOR signaling pathway. Immunofluorescence assays revealed that canagliflozin promoted the translocation of LC3 from the nucleus to the cytoplasm. Molecular docking analysis confirmed that canagliflozin has high affinity for targets associated with DIC. These findings suggest that canagliflozin protects cardiomyocytes from DOX-induced cell death by activating SIRT1, inhibiting the PI3K/Akt/mTOR pathway, and enhancing autophagic flux.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117183"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142781128","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}
Heba A. Bahriz, Rania R. Abdelaziz, Dalia H. El-Kashef
{"title":"Desloratadine mitigates hepatocellular carcinoma in rats: Possible contribution of TLR4/MYD88/NF-κB pathway","authors":"Heba A. Bahriz, Rania R. Abdelaziz, Dalia H. El-Kashef","doi":"10.1016/j.taap.2024.117202","DOIUrl":"10.1016/j.taap.2024.117202","url":null,"abstract":"<div><div>Chemotherapeutic medication-induced systemic toxicity makes cancer treatment less effective. Thus, the need for drug repurposing, which aids in the development of safe and efficient cancer therapies, is urgent. The primary goal of this research was to assess desloratadine hepatoprotective abilities and its capacity to attenuate TLR4/MyD88/NF-κB inflammatory pathway in hepatocellular carcinoma (HCC) induced by thioacetamide (TAA). Male Sprague Dawely rats received TAA injections (200 mg/kg, i.p., 2 times/week) for 16 weeks. To confirm the development of HCC, liver function biomarkers and histopathological analysis were evaluated. Desloratadine (5 mg/kg, p.o.) was administered to rats in 2 treatment groups; HCC + DES 1 group received desloratadine with TAA for 1 month from week 13–16, HCC + DES 2 group received desloratadine with TAA for 2 months from week 9–16. Chronic TAA administration resulted in considerable overexpression of the profibrogenic cytokine TGF-β and elevation in protein expression of NF-κB besides levels of TLR4, MyD88, TRAF6, TAK1 and IL-1β. Desloratadine administration showed a significant improvement in liver function tests, as well as an increase in tissue antioxidant enzymes and an improvement in the liver's histopathological features. Collectively, desloratadine through modulating TLR4/MyD88/TRAF6/TAK1/NF-κB and acting as an antioxidant, is a promising treatment for HCC induced by TAA.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117202"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822628","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}
Antonio Ferreira de Melo Junior , Leonardo Escouto , António B. Pimpão , Pollyana Peixoto , Girlandia Brasil , Silas Nascimento Ronchi , Sofia Azeredo Pereira , Nazaré Souza Bissoli
{"title":"Anabolic-androgen steroids: A possible independent risk factor to Cardiovascular, Kidney and Metabolic Syndrome","authors":"Antonio Ferreira de Melo Junior , Leonardo Escouto , António B. Pimpão , Pollyana Peixoto , Girlandia Brasil , Silas Nascimento Ronchi , Sofia Azeredo Pereira , Nazaré Souza Bissoli","doi":"10.1016/j.taap.2025.117238","DOIUrl":"10.1016/j.taap.2025.117238","url":null,"abstract":"<div><div>Millions of individuals make illicit use of anabolic-androgenic steroids (AAS), remaining a public health issue. It often leads to detrimental effects, including cardiovascular and renal diseases, besides hormonal and metabolic imbalances. The objective of this review is to emphasize the contribution of oxidative stress and inflammation to these effects and connect the findings of experimental animal studies with the alterations found in clinical contexts, in AAS users. The study's results showed that AAS promotes a redox disruption and a pro-inflammatory state on organs that are involved in important physiologic processes. These drugs increase inflammatory high-sensitivity C-reactive protein (hs-CRP) and cytokines that contribute to the progression of atherosclerosis, cardiovascular disease risk or endpoints, including stroke, myocardial infarction and death. In the kidney, the AAS increase proteinuria and structural damage. Studies have linked AAS abuse with high BP, low HDL-C levels, high triglyceride levels and impaired fasting blood glucose that characterize Metabolic syndrome. Overall, the studies indicate that oxidative stress, apoptosis, and AAS-mediated inflammation play a significant role in tissue damage, regardless of the dose and duration of exposure, and we point it as a putative independent risk factor to Cardiovascular, Kidney and Metabolic syndrome.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117238"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143041902","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}
Luping Qiu, Steven W. Kumpf, Elias M. Oziolor, Mark Sheehan, James E. Finley, David M. Rubitski, Jessie Qian, Mark M. Gosink , Anna K. Kopec, Thomas A. Lanz, Andrew D. Burdick
{"title":"In vitro NIH3T3 mouse embryonic fibroblast cell model does not predict AAV2 or AAVdj-mediated cell transformation","authors":"Luping Qiu, Steven W. Kumpf, Elias M. Oziolor, Mark Sheehan, James E. Finley, David M. Rubitski, Jessie Qian, Mark M. Gosink , Anna K. Kopec, Thomas A. Lanz, Andrew D. Burdick","doi":"10.1016/j.taap.2025.117229","DOIUrl":"10.1016/j.taap.2025.117229","url":null,"abstract":"<div><div>One of the potential risk factors of recombinant adeno-associated virus (rAAV)-based gene therapy is insertional mutagenesis, which has been associated with the development of hepatocellular carcinoma (HCC) in rAAV-treated neonatal mice. The objective of this study was to investigate if well-established <em>in vitro</em> cell transformation assays (CTA) in mouse cell lines can detect AAV2 or AAVdj-mediated cell transformation. Since AAV integration at the <em>Rian</em> locus in neonatal mice has been implicated in AAV-mediated HCC, an rAAV vector specifically targeting the mouse <em>Rian</em> locus and an additional rAAV vector previously shown to cause HCC in neonatal mice were both tested for the induction of cell transformation in NIH3T3 cells. To increase the frequency of AAV DNA integration at the <em>Rian</em> locus in the genome of NIH3T3 cells, double-strand breaks in <em>Rian</em> locus of NIH3T3 cells were created by CRISPR-Cas9 to increase the homologous crossover between viral DNA and the cell genome. When transduced cells were assayed in CTA, the transformation frequency observed in AAV-transduced NIH3T3 cells was not significantly different from that of untreated vehicle cells. The finding that rAAV is unable to transform the NIH3T3 <em>in vitro</em> indicates that either the transformation rate is less than the spontaneous rate of NIH3T3 cellular transformation, or <em>in vitro</em> CTA are not predictive of rAAV-induced HCC in mice.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117229"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984881","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":"Cadmium alters the cellular metabolome of human ovarian granulosa cells","authors":"Jun Zhang , Guofeng Xu , Shuang Liu , Meng Yang","doi":"10.1016/j.taap.2024.117187","DOIUrl":"10.1016/j.taap.2024.117187","url":null,"abstract":"<div><div>Cadmium (Cd) is a toxic heavy metal that has been extensively implicated in disordered folliculogenesis, but the mechanisms underlying the ovarian toxicity of Cd remain to be explored fully. Granulosa cells are key players in ovarian follicular development and are the primary cells affected by Cd exposure-induced damage and dysfunction. In this study, we investigated how various levels of exposure of Cd (3 and 10 μM) to human granulosa cells (KGN cells) impacted the metabolism of the KGN cells utilizing a non-targeted metabolomics methodology. In vitro cell experiments revealed that Cd exposure dose-dependently diminished the viability of KGN cells. Metabolomics analysis revealed the presence of 296 (182 elevated and 114 reduced) and 397 (244 elevated and 153 reduced) differentially expressed metabolites after exposure to 3 and 10 μM, respectively. Cd exposure was found to significantly enrich nucleotide metabolism, sphingolipid metabolism, and ABC transporters in both groups. Although amino acid metabolic pathways exhibited significant enrichment across all groups, only glutathione, cysteine, and methionine metabolism were notably enriched in KGN cells exposed to 3 μM Cd, while glutathione and tryptophan metabolism were significantly enriched in the 10 μM Cd exposure cohort. The outcomes of this study provide mechanistic clues for elucidating Cd’s cytotoxic impact on granulosa cells, and deepen our understanding of the ovarian toxicity of Cd.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117187"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142786863","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}
Lei Shan, Pengzhan Guo, Mumeike Wen, Yue Sun, Fei Gao, Kai Zhang, Ning Zhang, Baoshan Yang
{"title":"Knockdown of regulator of Calcineurin 2 promotes transcription factor EB-mediated lipophagy to prevent non-alcoholic fatty liver disease","authors":"Lei Shan, Pengzhan Guo, Mumeike Wen, Yue Sun, Fei Gao, Kai Zhang, Ning Zhang, Baoshan Yang","doi":"10.1016/j.taap.2024.117210","DOIUrl":"10.1016/j.taap.2024.117210","url":null,"abstract":"<div><div>Non-alcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease. The present work aimed to explore the function of regulator of Calcineurin 2 (RCAN2) in NAFLD and its related mechanisms. Mice were fed with high-fat diet (HFD) to construct NAFLD model. Adeno-associated virus injection was performed to interference with RCAN2 in mice. RCAN2 knockdown meliorated HFD-induced NAFLD and impaired glucose metabolism. Abnormal lipid metabolism and inflammation in HFD-fed mice were relieved when RCAN2 was downregulated. Besides, hepatocyte Huh-7 cells, treated with free fatty acids (oleic acid and palmitic acid), were used as NAFLD models in vitro. We found that knockdown of RCAN2 inhibited the accumulation of lipid droplets and inflammation induced by free fatty acids. RCAN2 interference increased the activity of calcineurin (CaN), which enhanced the nuclear translocation of Transcription factor EB (TFEB). Autophagosome and lysosome biogenesis was augmented, and autophagy-dependent lipid degradation (lipophagy) was promoted. Collectively, we demonstrate that RCAN2 insufficiency protects against NAFLD by promoting TFEB-mediated lipophagy.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117210"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877926","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}
Zhexuan Li , Juan Nie , Runyu Zhou , Hui Huang , Xuemei Li , Li Wang , Lin Lv , Sichong Ren , Ming Zhao
{"title":"Thiostrepton suppresses colorectal cancer progression through reactive oxygen species related endoplasmic reticulum stress","authors":"Zhexuan Li , Juan Nie , Runyu Zhou , Hui Huang , Xuemei Li , Li Wang , Lin Lv , Sichong Ren , Ming Zhao","doi":"10.1016/j.taap.2024.117221","DOIUrl":"10.1016/j.taap.2024.117221","url":null,"abstract":"<div><div>Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Due to the poor therapeutic efficacy of CRC treatments and poor prognosis of the disease, effective treatment strategies are urgently needed. As long-term proteotoxic stress is a major cause of cell death, agents that induce proteotoxic stress offer a promising strategy for cancer intervention. Thiostrepton is a natural antibiotic derived from the <em>Streptomyces</em> genus. In the present study, we found that thiostrepton triggered apoptosis, reduced the migration of CRC cells, and inhibited xenograft tumour growth <em>in vivo</em>. Mechanistically, thiostrepton reduced proteasome activity; induced the aggregation of ubiquitinated proteins; caused endoplasmic reticulum (ER) stress, which was characterized by increased protein levels of GRP78, ATF4, P-eIF2α, and CHOP and cytosolic calcium release; and ultimately resulted in cell death. Thiostrepton-related changes in cell survival and cell migration, as well as mechanistical processes, were almost completely reversed by treatment with the antioxidant <em>N</em>-acetylcysteine (NAC), suggesting that the mechanism is dependent on reactive oxygen species (ROS). These results demonstrated that thiostrepton induced apoptosis and inhibited migration through ROS-induced ER stress and proteotoxic stress in colorectal cancer.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117221"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902857","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}
Robin A. Faber , Victor M. Baart , Mark W. Bordo , Taryn L. March , Adrianus R.P.M. Valentijn , Stefan Harmsen , Martin Pool , Jacobus Burggraaf , John V. Frangioni , Alexander L. Vahrmeijer
{"title":"Cardiac inotropy and cardiac calcium sensitization of PanLN800(-Forte), a cationic heptamethine indocyanine fluorescent contrast agent for intraoperative pan lymph node imaging","authors":"Robin A. Faber , Victor M. Baart , Mark W. Bordo , Taryn L. March , Adrianus R.P.M. Valentijn , Stefan Harmsen , Martin Pool , Jacobus Burggraaf , John V. Frangioni , Alexander L. Vahrmeijer","doi":"10.1016/j.taap.2024.117222","DOIUrl":"10.1016/j.taap.2024.117222","url":null,"abstract":"<div><h3>Introduction</h3><div>Accurate staging of malignancies often requires comprehensive evaluation of lymph nodes. However, finding these lymph nodes during oncological surgery is a daunting and time-consuming task, which increases the risk of missed lymph nodes and complications. Near-infrared (NIR) fluorescence imaging with the experimental fluorescent contrast agent PanLN800(-Forte) could provide real-time identification of lymph nodes and may solve this longstanding problem. In the current study we performed the preclinical toxicology evaluation of PanLN800(-Forte) towards its clinical translation for intraoperative pan lymph node imaging in thoracic surgery.</div></div><div><h3>Methods</h3><div>A single extended dose toxicology study was conducted to determine the safety and potential toxicity of PanLN800(-Forte) after administration of a single intravenous dose to Wistar Han rats. The study included a control group and two treatment groups (5.0 mg/kg and 15.0 mg/kg PanLN800(-Forte)), each consisting of 10 male and 10 female rats. Experimental endpoints included moribundity/mortality, clinical signs, body weights, body weight gains, clinical pathology, toxicity, and gross necropsy observations.</div></div><div><h3>Results</h3><div>Unexpected acute mortality was observed after administration of 5.0 mg/kg PanLN800(-Forte) to rats. No clear cause of sudden death was found after gross necropsy and pathology observations. To understand the mechanism of toxicity of PanLN800(-Forte), several additional tests were performed. By elimination, acute cardiac toxicity appears to be the cause of acute mortality in rats, in which PanLN800(-Forte) was found to be a potent inotrope acting as a cardiac calcium sensitizer.</div></div><div><h3>Conclusion</h3><div>PanLN800(-Forte) is not a viable fluorescent contrast agent for lymph node imaging in surgery because of cardiac calcium sensitization but may be a novel treatment for heart failure.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117222"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915645","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}
Jing Huang , Kaifeng He , Xin Guo , Jiaxuan Wang , Han Hu , Xuhui Zhang , Na Guo , Yiwen Wang , Wenlong Huang , Rongsheng Huang , Tingting Liu , Xi Jiang , Deizhi Zhang , Qianyong Li , Zhengkai Wei
{"title":"T-2 toxin triggers immunotoxic effects in goats by inducing ferroptosis and neutrophil extracellular traps","authors":"Jing Huang , Kaifeng He , Xin Guo , Jiaxuan Wang , Han Hu , Xuhui Zhang , Na Guo , Yiwen Wang , Wenlong Huang , Rongsheng Huang , Tingting Liu , Xi Jiang , Deizhi Zhang , Qianyong Li , Zhengkai Wei","doi":"10.1016/j.taap.2025.117232","DOIUrl":"10.1016/j.taap.2025.117232","url":null,"abstract":"<div><div>T-2 toxin, a prevalent mycotoxin, represents a notable global public health risk. Neutrophil extracellular traps (NETs) and ferroptosis are involved in a variety of pathophysiological processes and are implicated in goat immunity. However, the impact of T-2 toxin on NETs release, ferroptosis, and their interplay have not been previously documented. In this study, neutrophils were stimulated with T-2 toxin for 4 h. The structure and mechanism of NETs were analyzed using immunofluorescence and Pico Green staining. The expressions of glutathione peroxidase 4 (GPX4) and ferritin (FT) was quantified by qRT-PCR and western blotting. The levels of ROS and lipid ROS were assessed using DCFH-DA and C11 BODIPY 581/591 probes, and cellular mitochondria Fe<sup>2+</sup> were detected by using Mito-FerroGreen probe. Inhibitors were utilized to explore the interaction between these two processes. The results confirmed that the T-2 toxin stimulated the NETs production, characterized by a structure co-modified by citrullinated histones (citH3), neutrophil elastase (NE) and DNA. Notably, significant inhibition of NETs production by T-2 toxin was observed with the NOX inhibitor DPI (<em>P</em> < 0.001), the ERK inhibitor U0126 (P < 0.001), the TLR2 inhibitor C29 (P < 0.001), and the TLR4 inhibitor TLR4-IN-C34 (P < 0.001). T-2 toxin triggered ferroptosis in neutrophils by suppressing GPX4 and FT expression, elevating ROS and lipid ROS, and augmenting the concentration of mitochondrial Fe<sup>2+</sup>. The ferroptosis inhibitor Fer-1 could rescue this induction; however, Fer-1 was unable to inhibit NETs which is induced by T-2 toxin. Conversely, T-2 toxin effectively triggered the downregulation of GPX4, which was counteracted by DPI, U0126, C29, and C34. This research elucidates the immunotoxic mechanisms of T-2 toxin in goat neutrophils and offers a novel perspective on preventing and treating T-2 toxin.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117232"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012088","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}