Pub Date : 2024-12-10DOI: 10.1016/j.toxlet.2024.12.005
Xiaoyu Yu, Hanbing Gao, Jie Zhang, Qiaojun Fang, Wenjie Kang, Haiqiong Shang, Xiangyu Lou, Ming Guan
The present study was designed to investigate the role and mechanism of the Apoptosis repressor with caspase recruitment domain (ARC) in protecting the neomycin-induced hair cell damage. HEI-OC1 cells and basilar membrane culture were applied to determine the effect of ARC. Plasmid transfection was used to regulate the ARC or Ras expression. We have found the ARC overexpression in HEI-OC1 cells can increase the cell viability and decrease cell apoptosis after neomycin injury. The cleaved caspase 3 was reduced in ARC overexpression group after neomycin treatment. The p-CREB expression was increased in ARC overexpression group, while the p-c-Jun expression was decreased after neomycin incubation. In HEI-OC1 cells and basilar membranes, JNK and Ras inhibitions both can reduce ARC expression, and Ras overexpression can increase the ARC expression. This study indicates that ARC can protect the hair cells from neomycin-induced apoptosis through Ras/JNK signaling pathway. Our findings provide new insights in preventing cochlear HC death after drug-induced ototoxicity.
{"title":"ARC protects cochlear hair cells from neomycin-induced ototoxicity via the Ras/JNK signaling pathway.","authors":"Xiaoyu Yu, Hanbing Gao, Jie Zhang, Qiaojun Fang, Wenjie Kang, Haiqiong Shang, Xiangyu Lou, Ming Guan","doi":"10.1016/j.toxlet.2024.12.005","DOIUrl":"10.1016/j.toxlet.2024.12.005","url":null,"abstract":"<p><p>The present study was designed to investigate the role and mechanism of the Apoptosis repressor with caspase recruitment domain (ARC) in protecting the neomycin-induced hair cell damage. HEI-OC1 cells and basilar membrane culture were applied to determine the effect of ARC. Plasmid transfection was used to regulate the ARC or Ras expression. We have found the ARC overexpression in HEI-OC1 cells can increase the cell viability and decrease cell apoptosis after neomycin injury. The cleaved caspase 3 was reduced in ARC overexpression group after neomycin treatment. The p-CREB expression was increased in ARC overexpression group, while the p-c-Jun expression was decreased after neomycin incubation. In HEI-OC1 cells and basilar membranes, JNK and Ras inhibitions both can reduce ARC expression, and Ras overexpression can increase the ARC expression. This study indicates that ARC can protect the hair cells from neomycin-induced apoptosis through Ras/JNK signaling pathway. Our findings provide new insights in preventing cochlear HC death after drug-induced ototoxicity.</p>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":" ","pages":"111-119"},"PeriodicalIF":2.9,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819332","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 : 2024-11-28DOI: 10.1016/j.toxlet.2024.11.010
Ege Arzuk , Güliz Armağan
Sunitinib, a multi-targeted tyrosine kinase inhibitor, is prescribed for the treatment of metastatic gastrointestinal stromal tumors, advanced metastatic renal cell carcinoma, and pancreatic neuroendocrine tumors. Hepatotoxicity and nephrotoxicity are significant adverse effects of sunitinib administration; however, there is limited information regarding the molecular mechanisms of these adverse effects. The aim of the present study was to elucidate the role of endoplasmic reticulum stress in hepatotoxicity and nephrotoxicity induced by sunitinib. In addition to endoplasmic reticulum stress, oxidative stress and mitochondrial membrane potential were evaluated to investigate the molecular mechanism more comprehensively. Findings revealed that sunitinib exposure significantly increased the reactive oxygen species levels and decreased the Nrf2 gene expression and GSH/GSSG ratio, suggesting oxidative stress induction in normal hepatocyte (AML12) and normal kidney (HK-2) cell lines. Endoplasmic reticulum stress markers, including ATF4, CHOP, IRE1α, XBP1s and ATF6 mRNA expressions, were upregulated in AML12 cells. Furthermore, enhanced intracellular calcium levels also indicate endoplasmic reticulum stress in hepatocytes. In contrast, sunitinib exposure did not alter endoplasmic reticulum-related gene expression levels and intracellular calcium levels in HK-2 cells. In terms of mitochondrial membrane potential and caspase-3 activity, sunitinib induced mitochondrial membrane damage and increased caspase-3 activation not only in AML12 cells but also in HK-2 cells. The research findings indicate that sunitinib may induce cytotoxic effects in hepatocytes through mechanisms involving oxidative stress, endoplasmic reticulum stress, and mitochondrial damage. However, in the kidney, the toxicity mechanism is different from that of liver, and the endoplasmic reticulum stress does not seem to be involved in this mechanism.
{"title":"In vitro assessment of the role of endoplasmic reticulum stress in sunitinib-induced liver and kidney toxicity","authors":"Ege Arzuk , Güliz Armağan","doi":"10.1016/j.toxlet.2024.11.010","DOIUrl":"10.1016/j.toxlet.2024.11.010","url":null,"abstract":"<div><div>Sunitinib, a multi-targeted tyrosine kinase inhibitor, is prescribed for the treatment of metastatic gastrointestinal stromal tumors, advanced metastatic renal cell carcinoma, and pancreatic neuroendocrine tumors. Hepatotoxicity and nephrotoxicity are significant adverse effects of sunitinib administration; however, there is limited information regarding the molecular mechanisms of these adverse effects. The aim of the present study was to elucidate the role of endoplasmic reticulum stress in hepatotoxicity and nephrotoxicity induced by sunitinib. In addition to endoplasmic reticulum stress, oxidative stress and mitochondrial membrane potential were evaluated to investigate the molecular mechanism more comprehensively. Findings revealed that sunitinib exposure significantly increased the reactive oxygen species levels and decreased the Nrf2 gene expression and GSH/GSSG ratio, suggesting oxidative stress induction in normal hepatocyte (AML12) and normal kidney (HK-2) cell lines. Endoplasmic reticulum stress markers, including ATF4, CHOP, IRE1α, XBP1s and ATF6 mRNA expressions, were upregulated in AML12 cells. Furthermore, enhanced intracellular calcium levels also indicate endoplasmic reticulum stress in hepatocytes. In contrast, sunitinib exposure did not alter endoplasmic reticulum-related gene expression levels and intracellular calcium levels in HK-2 cells. In terms of mitochondrial membrane potential and caspase-3 activity, sunitinib induced mitochondrial membrane damage and increased caspase-3 activation not only in AML12 cells but also in HK-2 cells. The research findings indicate that sunitinib may induce cytotoxic effects in hepatocytes through mechanisms involving oxidative stress, endoplasmic reticulum stress, and mitochondrial damage. However, in the kidney, the toxicity mechanism is different from that of liver, and the endoplasmic reticulum stress does not seem to be involved in this mechanism.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"403 ","pages":"Pages 9-16"},"PeriodicalIF":2.9,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142744124","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 : 2024-11-26DOI: 10.1016/j.toxlet.2024.11.006
Jennifer L. Fisher , Kris Yamada , Andrew J. Keebaugh , Kelly T. Williams , Carrie L. German , Adam M. Hott , Narender Singh , Rebecca A. Clewell
Quantitative Structure-Activity Relationship (QSAR) models can be used to predict the risk of novel and emergent chemicals causing adverse health outcomes, avoidance of which is crucial for military operations. While QSAR modeling approaches have been proposed for military and industry risk assessment, the applicability of peer-reviewed tissue-specific QSAR models in military and industrial contexts remain largely unexplored, particularly with respect to specific organ toxicity. We investigated the applicability domain (AD) of acute and sub-chronic tissue-specific QSAR models to evaluate the coverage of military- and industrial-relevant chemicals. Our analysis reveals that military-relevant compounds occupy a similar chemical space as industrial compounds. However, published models for acute target organ toxicity had minimal coverage of the military and industrial chemicals. The published Collaborative Acute Toxicity Modeling Suite (CATMoS) acute oral toxicity model was the notable exception, as it covers a broad range of military and industrial chemicals. Our study underscores the urgent need for development of novel tissue-specific QSAR models, or modification of existing models, to improve chemical risk prediction in both industrial and military applications.
{"title":"Evaluating applicability domain of acute toxicity QSAR models for military and industrial chemical risk assessment","authors":"Jennifer L. Fisher , Kris Yamada , Andrew J. Keebaugh , Kelly T. Williams , Carrie L. German , Adam M. Hott , Narender Singh , Rebecca A. Clewell","doi":"10.1016/j.toxlet.2024.11.006","DOIUrl":"10.1016/j.toxlet.2024.11.006","url":null,"abstract":"<div><div>Quantitative Structure-Activity Relationship (QSAR) models can be used to predict the risk of novel and emergent chemicals causing adverse health outcomes, avoidance of which is crucial for military operations. While QSAR modeling approaches have been proposed for military and industry risk assessment, the applicability of peer-reviewed tissue-specific QSAR models in military and industrial contexts remain largely unexplored, particularly with respect to specific organ toxicity. We investigated the applicability domain (AD) of acute and sub-chronic tissue-specific QSAR models to evaluate the coverage of military- and industrial-relevant chemicals. Our analysis reveals that military-relevant compounds occupy a similar chemical space as industrial compounds. However, published models for acute target organ toxicity had minimal coverage of the military and industrial chemicals. The published Collaborative Acute Toxicity Modeling Suite (CATMoS) acute oral toxicity model was the notable exception, as it covers a broad range of military and industrial chemicals. Our study underscores the urgent need for development of novel tissue-specific QSAR models, or modification of existing models, to improve chemical risk prediction in both industrial and military applications.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"403 ","pages":"Pages 1-8"},"PeriodicalIF":2.9,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740792","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 : 2024-11-22DOI: 10.1016/j.toxlet.2024.11.005
Xiaomeng Zha , Man Fang , Wen Zhong , Liang Chen , Hui Feng , Min Zhang , Hui Wang , Yuanzhen Zhang
Prednisone, a synthetic glucocorticoid, is commonly used to treat autoimmune diseases in pregnant women. However, some studies suggest that the use of prednisone during pregnancy may lead to adverse pregnancy outcomes. In this study, we established PPE mouse models at different doses (0.25, 0.5, 1.0 mg/kg·d) and different stages (whole pregnancy, early pregnancy and middle-late pregnancy) and determined outcomes on the placenta and fetus. The results of our study indicated that at the highest dose of 1 mg/kg PPE using a GD 0–18 dosing regime, PPE caused placental morphological changes measured as a decrease in placental weight relative to controls and a decrease in the placenta junctional zone (JZ)/labyrinth zone (LZ) ratio. No changes were observed on the fetuses for number of live, stillborn, and absorbed fetuses between the experimental groups and the control group. In the placentas at some doses, there were decreases in cell proliferation markers measured at the RNA and protein level by Western blot and increased apoptosis. Measures of gene expression at the mRNA level showed altered nutrients (including glucose, amino acid, and cholesterol) transport gene expressions with the most significant change associated with the male placentas at high-dose and whole pregnancy PPE group. It was further found that PPE led to the inhibition of the insulin-like growth factor 2 (IGF2)/insulin-like growth factor 1 receptor (IGF1R) signaling pathway, which was well correlated with the indicators of cell proliferation, syncytialization and nutrient (glucose and amino acid) transport indices. In conclusion, PPE can alter placental morphology and nutrient transport function, with differences in effect related to dose, stage and gender. Differential gene expressions measured for genes of the IGF2/IGF1R signaling pathway suggested this pathway may be involved in the effects seen with PPE. This study provides a theoretical and experimental basis for enhancing the understanding of the effects of prednisone use on placenta during human pregnancy but does not currently raise concerns for human use as effects were not seen on the fetuses and while the effects on cell proliferation are informative they were inconsistent and the differential effects on female and male placentas unexplained suggesting that further work is required to elucidate if these findings have relevance for human use of PPE during pregnancy.
泼尼松是一种人工合成的糖皮质激素，常用于治疗孕妇的自身免疫性疾病。然而，一些研究表明，孕期使用泼尼松可能会导致不良妊娠结局。在本研究中，我们建立了不同剂量（0.25、0.5、1.0mg/kg-d）和不同阶段（整个妊娠期、妊娠早期和妊娠中晚期）的 PPE 小鼠模型，并测定了其对胎盘和胎儿的影响。研究结果表明，在 GD 0-18 剂量制度下，最高剂量为 1mg/kg PPE 时，PPE 会引起胎盘形态学变化，表现为胎盘重量相对于对照组的减少，以及胎盘连接区（JZ）/迷宫区（LZ）比率的降低。实验组和对照组的胎儿在活胎、死胎和吸收胎的数量上没有变化。在某些剂量的胎盘中，通过 Western 印迹法测定的 RNA 和蛋白质水平的细胞增殖标志物减少，细胞凋亡增加。mRNA 水平的基因表达测量显示，营养物质（包括葡萄糖、氨基酸和胆固醇）转运基因表达发生了改变，其中与高剂量和整个孕期 PPE 组男性胎盘相关的变化最为显著。研究进一步发现，PPE 导致胰岛素样生长因子 2（IGF2）/胰岛素样生长因子 1 受体（IGF1R）信号通路受到抑制，这与细胞增殖、合胞化和营养物质（葡萄糖和氨基酸）转运指数等指标密切相关。总之，PPE 可改变胎盘形态和营养运输功能，其影响差异与剂量、阶段和性别有关。IGF2/IGF1R信号通路基因的差异表达表明，该通路可能与PPE的影响有关。这项研究为进一步了解人类妊娠期间使用泼尼松对胎盘的影响提供了理论和实验基础，但目前并未引起对人类使用泼尼松的关注，因为没有发现对胎儿的影响，尽管对细胞增殖的影响具有参考价值，但这些影响并不一致，而且对女性和男性胎盘的不同影响也没有得到解释。
{"title":"Dose-, stage- and sex- difference of prenatal prednisone exposure on placental morphological and functional development","authors":"Xiaomeng Zha , Man Fang , Wen Zhong , Liang Chen , Hui Feng , Min Zhang , Hui Wang , Yuanzhen Zhang","doi":"10.1016/j.toxlet.2024.11.005","DOIUrl":"10.1016/j.toxlet.2024.11.005","url":null,"abstract":"<div><div>Prednisone, a synthetic glucocorticoid, is commonly used to treat autoimmune diseases in pregnant women. However, some studies suggest that the use of prednisone during pregnancy may lead to adverse pregnancy outcomes. In this study, we established PPE mouse models at different doses (0.25, 0.5, 1.0 mg/kg·d) and different stages (whole pregnancy, early pregnancy and middle-late pregnancy) and determined outcomes on the placenta and fetus. The results of our study indicated that at the highest dose of 1 mg/kg PPE using a GD 0–18 dosing regime, PPE caused placental morphological changes measured as a decrease in placental weight relative to controls and a decrease in the placenta junctional zone (JZ)/labyrinth zone (LZ) ratio. No changes were observed on the fetuses for number of live, stillborn, and absorbed fetuses between the experimental groups and the control group. In the placentas at some doses, there were decreases in cell proliferation markers measured at the RNA and protein level by Western blot and increased apoptosis. Measures of gene expression at the mRNA level showed altered nutrients (including glucose, amino acid, and cholesterol) transport gene expressions with the most significant change associated with the male placentas at high-dose and whole pregnancy PPE group. It was further found that PPE led to the inhibition of the insulin-like growth factor 2 (IGF2)/insulin-like growth factor 1 receptor (IGF1R) signaling pathway, which was well correlated with the indicators of cell proliferation, syncytialization and nutrient (glucose and amino acid) transport indices. In conclusion, PPE can alter placental morphology and nutrient transport function, with differences in effect related to dose, stage and gender. Differential gene expressions measured for genes of the IGF2/IGF1R signaling pathway suggested this pathway may be involved in the effects seen with PPE. This study provides a theoretical and experimental basis for enhancing the understanding of the effects of prednisone use on placenta during human pregnancy but does not currently raise concerns for human use as effects were not seen on the fetuses and while the effects on cell proliferation are informative they were inconsistent and the differential effects on female and male placentas unexplained suggesting that further work is required to elucidate if these findings have relevance for human use of PPE during pregnancy.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"402 ","pages":"Pages 68-80"},"PeriodicalIF":2.9,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695844","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 : 2024-11-22DOI: 10.1016/j.toxlet.2024.11.004
Wolfgang Dekant
Polyolefin pipes used in drinking water distribution systems require a number of functional additives to ensure stability and durability. Some of these additives and/or their degradation products may migrate from the pipes into the drinking water. Previously, a number of branched chain alkylphenol degradants have been identified in drinking water; these were termed “Arvin substances” and numbered Arvin 1–10. As potential genotoxicity is a human health safety concern, the genotoxicity of Arvin substances is reviewed based on comprehensive in vitro and in vivo data available. Results obtained from genotoxicity studies addressing mutagenicity and clastogenicity are available for nine of the ten Arvin substances. These nine Arvin substances were consistently negative in bacterial mutagenicity studies. Divergent results were obtained in clastogenicity assays with some positive responses induced by the branched chain alkylphenols Arvin 1, 2, and 4, often accompanied by significant cytotoxicity. However, Arvin 1, 2, and 4 did not induce micronuclei or genotoxicity in vivo during follow-up testing. The other Arvin compounds did not show genotoxic activity in vitro. In conclusion, regarding human health risk characterization, the Arvin compounds are not considered genotoxic agents based on the available data.
{"title":"Review of the genotoxicity of “Arvin compounds”, drinking water contaminants formed by the degradation of antoxidants in polyolefin pipes","authors":"Wolfgang Dekant","doi":"10.1016/j.toxlet.2024.11.004","DOIUrl":"10.1016/j.toxlet.2024.11.004","url":null,"abstract":"<div><div>Polyolefin pipes used in drinking water distribution systems require a number of functional additives to ensure stability and durability. Some of these additives and/or their degradation products may migrate from the pipes into the drinking water. Previously, a number of branched chain alkylphenol degradants have been identified in drinking water; these were termed “Arvin substances” and numbered Arvin 1–10. As potential genotoxicity is a human health safety concern, the genotoxicity of Arvin substances is reviewed based on comprehensive <em>in vitro</em> and <em>in vivo</em> data available. Results obtained from genotoxicity studies addressing mutagenicity and clastogenicity are available for nine of the ten Arvin substances. These nine Arvin substances were consistently negative in bacterial mutagenicity studies. Divergent results were obtained in clastogenicity assays with some positive responses induced by the branched chain alkylphenols Arvin 1, 2, and 4, often accompanied by significant cytotoxicity. However, Arvin 1, 2, and 4 did not induce micronuclei or genotoxicity <em>in vivo</em> during follow-up testing. The other Arvin compounds did not show genotoxic activity <em>in vitro</em>. In conclusion, regarding human health risk characterization, the Arvin compounds are not considered genotoxic agents based on the available data.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"402 ","pages":"Pages 81-90"},"PeriodicalIF":2.9,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142711133","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}
Pub Date : 2024-11-14DOI: 10.1016/j.toxlet.2024.11.003
Langqun Chen , Siyu Cheng , Jiahui Ying , Qi Zhang , Chen Wang , Huimin Wu , Ying Wang , Hong Zhang , Jiahe Wang , Jing Ye , Liang Zhang
Aristolochic acid I (AAI) is strongly nephrotoxic and can cause "Aristolochic acid nephropathy (AAN)". Aristolochic acid nephropathy is characterized by extensive renal interstitial fibrosis. However, the exact mechanism by which it occurs has not been fully elucidated. lt has been reported that indoleamine 2,3-dioxygenase-1 (IDO1) promotes renal fibrosis in renal disorders, but it is unclear how IDO1 functions in AAI-induced kidney fibrosis. In this work, we systematically examined the role of IDO1 in AAI-induced renal tubulointerstitial fibrosis. The results showed that AAI induced upregulation of IDO1 expression in renal tubular epithelial cells and mouse kidney. Inhibition of IDO1 expression reduced the levels of fibrosis-associated markers α-SMA, COL-I and FN and ameliorated renal tubular epithelial cell fibrosis. It also improved renal function, reduced collagen deposition, and ameliorated interstitial fibrosis in mice. Moreover, we discovered that inhibition of IDO1 decreased the expression of the apoptotic protein BAX, raised the expression of BCL-2 protein, and reduced apoptosis. The above studies suggest that IDO1 is a target of action in renal tubulointerstitial fibrosis caused by AAI, and inhibition of IDO1 may be a viable approach for the therapy of AAI-induced renal tubulointerstitial fibrosis.
{"title":"Aristolochic acid I promotes renal tubulointerstitial fibrosis by up-regulating expression of indoleamine 2,3-dioxygenase-1 (IDO1)","authors":"Langqun Chen , Siyu Cheng , Jiahui Ying , Qi Zhang , Chen Wang , Huimin Wu , Ying Wang , Hong Zhang , Jiahe Wang , Jing Ye , Liang Zhang","doi":"10.1016/j.toxlet.2024.11.003","DOIUrl":"10.1016/j.toxlet.2024.11.003","url":null,"abstract":"<div><div>Aristolochic acid I (AAI) is strongly nephrotoxic and can cause \"Aristolochic acid nephropathy (AAN)\". Aristolochic acid nephropathy is characterized by extensive renal interstitial fibrosis. However, the exact mechanism by which it occurs has not been fully elucidated. lt has been reported that indoleamine 2,3-dioxygenase-1 (IDO1) promotes renal fibrosis in renal disorders, but it is unclear how IDO1 functions in AAI-induced kidney fibrosis. In this work, we systematically examined the role of IDO1 in AAI-induced renal tubulointerstitial fibrosis. The results showed that AAI induced upregulation of IDO1 expression in renal tubular epithelial cells and mouse kidney. Inhibition of IDO1 expression reduced the levels of fibrosis-associated markers α-SMA, COL-I and FN and ameliorated renal tubular epithelial cell fibrosis. It also improved renal function, reduced collagen deposition, and ameliorated interstitial fibrosis in mice. Moreover, we discovered that inhibition of IDO1 decreased the expression of the apoptotic protein BAX, raised the expression of BCL-2 protein, and reduced apoptosis. The above studies suggest that IDO1 is a target of action in renal tubulointerstitial fibrosis caused by AAI, and inhibition of IDO1 may be a viable approach for the therapy of AAI-induced renal tubulointerstitial fibrosis.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"402 ","pages":"Pages 44-55"},"PeriodicalIF":2.9,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639973","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}
Fine particulate matter (PM2.5) induces a range of diseases, including skin disorders, through inflammatory responses. In this study, we investigated the novel mechanisms by which PM2.5 causes skin inflammation in human keratinocytes HaCaT. We observed increased protein expression of cyclooxygenase-2 (COX-2) and the production of prostaglandin E2 (PGE2) in PM2.5-treated HaCaT cells. To identify the pathways promoting the expression of these inflammatory proteins, we conducted a phospho-kinase antibody array and confirmed that the phosphorylation levels of JNK and p38 were increased by PM2.5-treated HaCaT cells. Further investigation of the phosphorylation levels of mitogen-activated protein kinases (MAPKs) and upstream signals revealed that PM2.5 activated the MKK4/7-JNK-c-Jun and MKK3/6-p38-p70S6K signaling pathways, while the phosphorylation level of ERK1/2 remained unchanged. HaCaT cells treated with PM2.5 phosphorylated Mixed-lineage kinase 3 (MLK3), an upstream regulator of p38 and JNK. Furthermore, inhibition of ROS production by N-Acetylcysteine (NAC) treatment inhibited MLK3 phosphorylation. Taken together, ROS production induced by PM2.5 activated the MLK3 signaling pathway and induced skin inflammation.
{"title":"Activation of mixed lineage kinase 3 by fine particulate matter induces skin inflammation in human keratinocytes","authors":"Jamyeong Koo , Woo-Jin Sim , Wonchul Lim , Tae-Gyu Lim","doi":"10.1016/j.toxlet.2024.11.002","DOIUrl":"10.1016/j.toxlet.2024.11.002","url":null,"abstract":"<div><div>Fine particulate matter (PM<sub>2.5</sub>) induces a range of diseases, including skin disorders, through inflammatory responses. In this study, we investigated the novel mechanisms by which PM<sub>2.5</sub> causes skin inflammation in human keratinocytes HaCaT. We observed increased protein expression of cyclooxygenase-2 (COX-2) and the production of prostaglandin E2 (PGE2) in PM<sub>2.5</sub>-treated HaCaT cells. To identify the pathways promoting the expression of these inflammatory proteins, we conducted a phospho-kinase antibody array and confirmed that the phosphorylation levels of JNK and p38 were increased by PM<sub>2.5</sub>-treated HaCaT cells. Further investigation of the phosphorylation levels of mitogen-activated protein kinases (MAPKs) and upstream signals revealed that PM<sub>2.5</sub> activated the MKK4/7-JNK-c-Jun and MKK3/6-p38-p70<sup>S6K</sup> signaling pathways, while the phosphorylation level of ERK1/2 remained unchanged. HaCaT cells treated with PM<sub>2.5</sub> phosphorylated Mixed-lineage kinase 3 (MLK3), an upstream regulator of p38 and JNK. Furthermore, inhibition of ROS production by N-Acetylcysteine (NAC) treatment inhibited MLK3 phosphorylation. Taken together, ROS production induced by PM<sub>2.5</sub> activated the MLK3 signaling pathway and induced skin inflammation.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"402 ","pages":"Pages 38-43"},"PeriodicalIF":2.9,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639970","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 : 2024-11-14DOI: 10.1016/j.toxlet.2024.11.001
Wanting Fu , Mingxue Liu , Yu Wang , Huimin Yang , Aoqi Ye , Jianhong Wu , Yang Li , Zejun Yu , Yinsheng Qiu , Lingyun Xu
Nano-titanium dioxide (Nano-TiO2) is extensively utilized across various industries and has the capacity to penetrate human tissues through multiple biological barriers. The HaCaT cell line, as one of human immortalized keratinocytes, is usually used as a model for studying skin drug toxicology. The objective was to assess the toxic effects of nano-TiO2 on HaCaT cells and to trigger pyroptosis. We used MTT method to evaluate the effects of three nano-TiO2 particle sizes (15 nm, 30 nm and 80 nm) on cell viability at different concentrations. Subsequently, we used LDH, Hoechst 33342 and propidium iodide (PI) double staining, scanning electron microscopy (SEM), Western blotting (WB) and real-time quantitative polymerase chain reaction (RT-qPCR) to evaluate the effects of different particle sizes on cells at the same concentration. Our findings indicated that HaCaT cell viability diminished with increasing nano-TiO2 concentrations. Moreover, nano-TiO2 increased LDH level in cellular supernatant. Fluorescence double staining, SEM, WB and RT-qPCR showed that nano-TiO2 induced cell membrane damage by activating pyroptosis pathway of NLRP3/caspase-1/GSDMD. These results suggest that nano-TiO2 toxicity in HaCaT cells is influenced by both dose and particle size, and is associated with the induction of pyroptosis. Frequent and large exposures to nano- TiO2 in daily life may cause serious health hazards.
{"title":"Nano titanium dioxide induces HaCaT cell pyroptosis via regulating the NLRP3/caspase-1/GSDMD pathway","authors":"Wanting Fu , Mingxue Liu , Yu Wang , Huimin Yang , Aoqi Ye , Jianhong Wu , Yang Li , Zejun Yu , Yinsheng Qiu , Lingyun Xu","doi":"10.1016/j.toxlet.2024.11.001","DOIUrl":"10.1016/j.toxlet.2024.11.001","url":null,"abstract":"<div><div>Nano-titanium dioxide (Nano-TiO<sub>2</sub>) is extensively utilized across various industries and has the capacity to penetrate human tissues through multiple biological barriers. The HaCaT cell line, as one of human immortalized keratinocytes, is usually used as a model for studying skin drug toxicology. The objective was to assess the toxic effects of nano-TiO<sub>2</sub> on HaCaT cells and to trigger pyroptosis. We used MTT method to evaluate the effects of three nano-TiO<sub>2</sub> particle sizes (15 nm, 30 nm and 80 nm) on cell viability at different concentrations. Subsequently, we used LDH, Hoechst 33342 and propidium iodide (PI) double staining, scanning electron microscopy (SEM), Western blotting (WB) and real-time quantitative polymerase chain reaction (RT-qPCR) to evaluate the effects of different particle sizes on cells at the same concentration. Our findings indicated that HaCaT cell viability diminished with increasing nano-TiO<sub>2</sub> concentrations. Moreover, nano-TiO<sub>2</sub> increased LDH level in cellular supernatant. Fluorescence double staining, SEM, WB and RT-qPCR showed that nano-TiO<sub>2</sub> induced cell membrane damage by activating pyroptosis pathway of NLRP3/caspase-1/GSDMD. These results suggest that nano-TiO<sub>2</sub> toxicity in HaCaT cells is influenced by both dose and particle size, and is associated with the induction of pyroptosis. Frequent and large exposures to nano- TiO<sub>2</sub> in daily life may cause serious health hazards.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"402 ","pages":"Pages 27-37"},"PeriodicalIF":2.9,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639966","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 : 2024-11-13DOI: 10.1016/j.toxlet.2024.10.009
Matthew Jeffers , Hemalatha Kanniyappan , Kai Yuan Cheng , Saundarya Prithweeraj , Govindaraj Perumal , Mark Barba , Yang Lin , Mathew T. Mathew
In patients with total hip replacements (THRs), wear products in the form of nanoparticles and ions are released, especially around implant failure. In this study, we use N2a cells, a neuroblastoma cell line, to evaluate the effects of different flow rates on neuronal toxicity amidst exposure to CoCrMo particles. We hypothesized that increasing flow rates would increase N2a cell viability and decrease N2a cell-degradation products (DPs) toxicity. We conducted four 24-hour experiments, each with four flow rate conditions, 0, 50, 100, and 200 μL/min, based on the physiological shear stress of the vessels in the human body, to evaluate cell viability, cell morphology, and cell-DPs interaction. Steps included microfluidic channel preparation, N2a cell culturing, CoCrMo particle acquisition, microfluidic system assembly, and dynamic flow neurotoxicity evaluation, which included video microscopy, AlamarBlue, live/dead imaging, DAPI, and ROS assay. The results suggest that fewer neurotoxic reactions and greater viability at higher flow rates supported our hypothesis, although the full range of viable flow rates is yet to be studied. While cell-particle interaction is complex and dynamic, flow rate did modulate toxicity, viability, morphology, and growth environment. The microfluidic system should continue to be developed to study toxicology aspects of implants by simulating in vivo conditions more accurately.
{"title":"Toxicity risk from hip implant CoCrMo particles: The impact of dynamic flow rate on neuronal cells in microfluidic systems","authors":"Matthew Jeffers , Hemalatha Kanniyappan , Kai Yuan Cheng , Saundarya Prithweeraj , Govindaraj Perumal , Mark Barba , Yang Lin , Mathew T. Mathew","doi":"10.1016/j.toxlet.2024.10.009","DOIUrl":"10.1016/j.toxlet.2024.10.009","url":null,"abstract":"<div><div>In patients with total hip replacements (THRs), wear products in the form of nanoparticles and ions are released, especially around implant failure. In this study, we use N2a cells, a neuroblastoma cell line, to evaluate the effects of different flow rates on neuronal toxicity amidst exposure to CoCrMo particles. We hypothesized that increasing flow rates would increase N2a cell viability and decrease N2a cell-degradation products (DPs) toxicity. We conducted four 24-hour experiments, each with four flow rate conditions, 0, 50, 100, and 200 μL/min, based on the physiological shear stress of the vessels in the human body, to evaluate cell viability, cell morphology, and cell-DPs interaction. Steps included microfluidic channel preparation, N2a cell culturing, CoCrMo particle acquisition, microfluidic system assembly, and dynamic flow neurotoxicity evaluation, which included video microscopy, AlamarBlue, live/dead imaging, DAPI, and ROS assay. The results suggest that fewer neurotoxic reactions and greater viability at higher flow rates supported our hypothesis, although the full range of viable flow rates is yet to be studied. While cell-particle interaction is complex and dynamic, flow rate did modulate toxicity, viability, morphology, and growth environment. The microfluidic system should continue to be developed to study toxicology aspects of implants by simulating <em>in vivo</em> conditions more accurately.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"402 ","pages":"Pages 56-67"},"PeriodicalIF":2.9,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142628822","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 : 2024-10-25DOI: 10.1016/j.toxlet.2024.10.008
Gokul Sudhakaran , Karthikeyan Ramamurthy , V.N. Dhaareshwar , Rajakrishnan Rajagopal , Ahmed Alfarhan , Jesu Arockiaraj
Burning incense sticks is a traditional practice in many cultures, especially in Southeast Asia. While it is often regarded as sacred and beneficial, modern incense sticks contain various chemicals that can pose health risks. A GCMS analysis of the ICS revealed potential compounds. Network toxicology revealed that ICS contains compounds violating Lipinski's rule of five, leading to potential neurotoxic effects. Key pathways affected include neuroactive ligand-receptor interaction and calcium signaling, associated with neurodegenerative diseases like Parkinson's and Alzheimer's. Significant genes involved are STAT3, BCL2, and MTOR, emphasizing the chemical hazards of ICS exposure. We investigated the toxicity of ICS using zebrafish (Danio rerio) embryos as a mode. ICS exposure resulted in a dose-dependent increase in toxicity. High concentrations (7 and 14 µg/ml) led to immediate mortality, while lower concentrations (0.1, 0.3, 0.5, and 1 µg/ml) caused developmental defects such as yolk sac edema, skeletal malformations, and pericardial edema. Mortality rates increased with higher concentrations, confirming dose-dependent ICS exposure caused hypoactive locomotion, with reduced distance traveled and velocity toxicity. Higher concentrations of ICS led to increased ROS levels and cellular damage, as evidenced by enhanced staining levels. A dose-dependent increase in lipid peroxidation (DPPP assay) and lipid accumulation (Nile red assay) was observed. Higher ICS concentrations led to significant oxidative damage to lipids and increased lipid deposition. Enzymatic assays showed that ICS exposure significantly decreased the activities of antioxidant enzymes SOD and CAT, indicating impaired antioxidant defense, while increasing LDH activity, signaling tissue damage and cytotoxicity. Gene expression analysis revealed downregulation of SOD1 and CAT genes, upregulation of inflammatory genes TNF-α and IL-1β, and increased expression of the apoptotic gene p53 with decreased expression of Bcl-2 and BDNF. These findings highlight ICS's potential to cause oxidative stress, inflammation, apoptosis, and neurodevelopmental impairments.
{"title":"Neurotoxic and developmental effects of scented incense stick smoke: Network toxicology and zebrafish model study","authors":"Gokul Sudhakaran , Karthikeyan Ramamurthy , V.N. Dhaareshwar , Rajakrishnan Rajagopal , Ahmed Alfarhan , Jesu Arockiaraj","doi":"10.1016/j.toxlet.2024.10.008","DOIUrl":"10.1016/j.toxlet.2024.10.008","url":null,"abstract":"<div><div>Burning incense sticks is a traditional practice in many cultures, especially in Southeast Asia. While it is often regarded as sacred and beneficial, modern incense sticks contain various chemicals that can pose health risks. A GCMS analysis of the ICS revealed potential compounds. Network toxicology revealed that ICS contains compounds violating Lipinski's rule of five, leading to potential neurotoxic effects. Key pathways affected include neuroactive ligand-receptor interaction and calcium signaling, associated with neurodegenerative diseases like Parkinson's and Alzheimer's. Significant genes involved are STAT3, BCL2, and MTOR, emphasizing the chemical hazards of ICS exposure. We investigated the toxicity of ICS using zebrafish (<em>Danio rerio</em>) embryos as a mode. ICS exposure resulted in a dose-dependent increase in toxicity. High concentrations (7 and 14 µg/ml) led to immediate mortality, while lower concentrations (0.1, 0.3, 0.5, and 1 µg/ml) caused developmental defects such as yolk sac edema, skeletal malformations, and pericardial edema. Mortality rates increased with higher concentrations, confirming dose-dependent ICS exposure caused hypoactive locomotion, with reduced distance traveled and velocity toxicity. Higher concentrations of ICS led to increased ROS levels and cellular damage, as evidenced by enhanced staining levels. A dose-dependent increase in lipid peroxidation (DPPP assay) and lipid accumulation (Nile red assay) was observed. Higher ICS concentrations led to significant oxidative damage to lipids and increased lipid deposition. Enzymatic assays showed that ICS exposure significantly decreased the activities of antioxidant enzymes SOD and CAT, indicating impaired antioxidant defense, while increasing LDH activity, signaling tissue damage and cytotoxicity. Gene expression analysis revealed downregulation of SOD1 and CAT genes, upregulation of inflammatory genes TNF-α and IL-1β, and increased expression of the apoptotic gene p53 with decreased expression of Bcl-2 and BDNF. These findings highlight ICS's potential to cause oxidative stress, inflammation, apoptosis, and neurodevelopmental impairments.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"402 ","pages":"Pages 15-26"},"PeriodicalIF":2.9,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142508700","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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