Abstract Flurochloridone (FLC) is a widely used herbicide in developing countries. Although the testes are a target organ for FLC in rats, the adverse effects of FLC on testes have not been fully elucidated. To clarify them, we performed RNA-seq analysis using the testes of FLC-treated rats from our previous subchronic toxicity tests. Unilateral testes of three male rats from solvent control groupand three FLC-treated groups (3 mg/kg, 31.25 mg/kg and 125 mg/kg) were used for RNA extraction. A poly A selection protocol coupled with an Illumina TruSeq RNA-Seq library protocol was used to construct RNA-Seq libraries. Principal component analysis (PCA), differentially expressed gene (DEG) analysis, and hierarchical clustering analysis (HCA) were conducted using R. Gene Ontology (GO) term enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to understand the biological characteristics of the DEGs using the Database for Annotation, Visualization and Integrated Discovery (DAVID). The results indicated that many up-regulated DEGs were enriched in pathways associated with testicular injury, such as mitogen-activated protein kinase (MAPK) signaling, lysosome and focal adhesion. Many down-regulated DEGs were enriched in pathways associated with testicular reproduction function, such as sexual reproduction, spermatogenesis and germ cell development. Moreover, we confirmed the oral no-observed-adverse-effect level (NOAEL) of 3 mg/kg in subchronic toxicity test, because the overall testicular gene expression in 3 mg/kg FLC-treated group was similar to that of the solvent control group. In 31.25 mg/kg and 125 mg/kg groups, DEGs revealed that testicular injury was related to oxidative stress.
摘要氟氯酮是一种在发展中国家广泛使用的除草剂。尽管睾丸是大鼠FLC的靶器官，但FLC对睾丸的不良影响尚未完全阐明。为了阐明它们，我们使用先前亚慢性毒性试验中FLC处理的大鼠睾丸进行了RNA-seq分析。溶剂对照组和三个FLC处理组的三只雄性大鼠的单侧睾丸（3 mg/kg，31.25 mg/kg和125 mg/kg）用于RNA提取。使用poly A选择方案与Illumina TruSeq RNA-Seq文库方案偶联来构建RNA-Seq文库。使用R.gene Ontology（GO）术语富集分析和Kyoto Encyclopedia of Genes and Genomes（KEGG）通路富集分析进行主成分分析（PCA）、差异表达基因（DEG）分析和层次聚类分析（HCA），可视化和集成发现（DAVID）。结果表明，许多上调的DEG在与睾丸损伤相关的途径中富集，如丝裂原活化蛋白激酶（MAPK）信号传导、溶酶体和局灶性粘附。许多下调的DEG在与睾丸生殖功能相关的途径中富集，如性生殖、精子发生和生殖细胞发育。此外，我们确认口服无不良反应水平（NOAEL）为 mg/kg的亚慢性毒性试验，因为3 mg/kg FLC处理组与溶剂对照组相似。31.25 mg/kg和125 mg/kg组，DEG显示睾丸损伤与氧化应激有关。
{"title":"RNA-seq analysis of testes from flurochloridone-treated rats","authors":"Su Zhou, Rui Li, Wanwan Hou, Yue Wang, Suhui Zhang, Ying Yu, Lei Zhang, Hongyan Zhu, Zhichao Zhang, Jing Fang, X. Chang, Yubin Zhang, Luqing Liu, Liming Tang, Zhijun Zhou","doi":"10.1080/15376516.2019.1701593","DOIUrl":"https://doi.org/10.1080/15376516.2019.1701593","url":null,"abstract":"Abstract Flurochloridone (FLC) is a widely used herbicide in developing countries. Although the testes are a target organ for FLC in rats, the adverse effects of FLC on testes have not been fully elucidated. To clarify them, we performed RNA-seq analysis using the testes of FLC-treated rats from our previous subchronic toxicity tests. Unilateral testes of three male rats from solvent control groupand three FLC-treated groups (3 mg/kg, 31.25 mg/kg and 125 mg/kg) were used for RNA extraction. A poly A selection protocol coupled with an Illumina TruSeq RNA-Seq library protocol was used to construct RNA-Seq libraries. Principal component analysis (PCA), differentially expressed gene (DEG) analysis, and hierarchical clustering analysis (HCA) were conducted using R. Gene Ontology (GO) term enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to understand the biological characteristics of the DEGs using the Database for Annotation, Visualization and Integrated Discovery (DAVID). The results indicated that many up-regulated DEGs were enriched in pathways associated with testicular injury, such as mitogen-activated protein kinase (MAPK) signaling, lysosome and focal adhesion. Many down-regulated DEGs were enriched in pathways associated with testicular reproduction function, such as sexual reproduction, spermatogenesis and germ cell development. Moreover, we confirmed the oral no-observed-adverse-effect level (NOAEL) of 3 mg/kg in subchronic toxicity test, because the overall testicular gene expression in 3 mg/kg FLC-treated group was similar to that of the solvent control group. In 31.25 mg/kg and 125 mg/kg groups, DEGs revealed that testicular injury was related to oxidative stress.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"30 1","pages":"219 - 227"},"PeriodicalIF":3.2,"publicationDate":"2019-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15376516.2019.1701593","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44633185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-12-05DOI: 10.1080/15376516.2019.1701596
E. Cortés-Gutiérrez, J. García-Salas, M. Dávila-Rodríguez, J. P. Ceyca-Contreras, Michel Cortez-Reyes, J. Fernández, J. Gosálvez
Abstract The monitoring of environmental genotoxicity requires the selection of model organisms as ‘sentinels’ as well as the development of sensitive and reliable tests for the assessment of DNA damage. The aims of this study were to quantify genomic DNA strand breakage in the erythrocytes of Columba livia induced by thermal stress using the modified chromatin dispersion test and to validate the results by alkaline comet assay and DNA breakage detection–fluorescence in situ hybridization (DBD-FISH). The chromatin dispersion test allowed for clear visualization of erythrocyte cells with DNA damage and of cells with no DNA damage. DNA damage increased significantly with increase in temperature. Additionally, we observed nuclear abnormalities associated with apoptosis, such as karyorrhexis (nuclear disintegration) and karyolysis (nuclear dissolution). These results were validated by alkaline comet assay and DBD-FISH. In conclusion, this procedure is a reliable, precise, and inexpensive morphological bioassay for routine quantitative analysis of DNA breakage in pigeon erythrocytes induced by thermal stress. This method could also be useful as a practical screening tool for genotoxicity testing in environmental care.
{"title":"Detection of DNA damage in pigeon erythrocytes using a chromatin dispersion assay","authors":"E. Cortés-Gutiérrez, J. García-Salas, M. Dávila-Rodríguez, J. P. Ceyca-Contreras, Michel Cortez-Reyes, J. Fernández, J. Gosálvez","doi":"10.1080/15376516.2019.1701596","DOIUrl":"https://doi.org/10.1080/15376516.2019.1701596","url":null,"abstract":"Abstract The monitoring of environmental genotoxicity requires the selection of model organisms as ‘sentinels’ as well as the development of sensitive and reliable tests for the assessment of DNA damage. The aims of this study were to quantify genomic DNA strand breakage in the erythrocytes of Columba livia induced by thermal stress using the modified chromatin dispersion test and to validate the results by alkaline comet assay and DNA breakage detection–fluorescence in situ hybridization (DBD-FISH). The chromatin dispersion test allowed for clear visualization of erythrocyte cells with DNA damage and of cells with no DNA damage. DNA damage increased significantly with increase in temperature. Additionally, we observed nuclear abnormalities associated with apoptosis, such as karyorrhexis (nuclear disintegration) and karyolysis (nuclear dissolution). These results were validated by alkaline comet assay and DBD-FISH. In conclusion, this procedure is a reliable, precise, and inexpensive morphological bioassay for routine quantitative analysis of DNA breakage in pigeon erythrocytes induced by thermal stress. This method could also be useful as a practical screening tool for genotoxicity testing in environmental care.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"30 1","pages":"228 - 235"},"PeriodicalIF":3.2,"publicationDate":"2019-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15376516.2019.1701596","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43789051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-11-28DOI: 10.1080/15376516.2019.1695991
S. Galal, Heba H. Mansour, Abeer A. Elkhoely
Abstract Diallyl sulfide (DAS) is a garlic-derived organosulfur compound. The current study was planned to evaluate the protecting effects of DAS against cyclophosphamide (CP)-induced nephropathic encephalopathy. DAS (100 mg/kg) was orally administered for 4 days, 60 min after the last dose, rats were injected with CP (150 mg/kg). DAS treatment before CP significantly decreased serum urea, creatinine, sodium, potassium, calcium, blood urea nitrogen (BUN), C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-1β (IL-1ß) and tumor necrosis factor-alpha (TNF-α) compared with CP-treated rats. DAS treatment decreased malondialdehyde (MDA) and increased superoxide dismutase (SOD) and reduced glutathione (GSH) levels in the renal tissues and significantly attenuated the elevated neurotransmitters N-methyl-D-aspartate/adenosine triphosphate (NMDA), γ-aminobutyric acid (GABA) levels and remarkably restored neuronal nitric oxide (NO) level and nitric oxide synthase (nNOS) activity in the brain compared to CP-treated rats. DAS for 4 consecutive days before CP showed moderate positive immunohistochemically expression of the glial fibrillary acidic protein (GFAP) in the brain and kidney tissues comparable to CP-treated rats. DAS afforded renal and neuroprotection against CP-induced nephropathic encephalopathy due to its capacity to ameliorates the afore-mentioned biochemical parameters which were supported by histopathological and immunohistochemically examination.
{"title":"Diallyl sulfide alleviates cyclophosphamide-induced nephropathic encephalopathy in rats","authors":"S. Galal, Heba H. Mansour, Abeer A. Elkhoely","doi":"10.1080/15376516.2019.1695991","DOIUrl":"https://doi.org/10.1080/15376516.2019.1695991","url":null,"abstract":"Abstract Diallyl sulfide (DAS) is a garlic-derived organosulfur compound. The current study was planned to evaluate the protecting effects of DAS against cyclophosphamide (CP)-induced nephropathic encephalopathy. DAS (100 mg/kg) was orally administered for 4 days, 60 min after the last dose, rats were injected with CP (150 mg/kg). DAS treatment before CP significantly decreased serum urea, creatinine, sodium, potassium, calcium, blood urea nitrogen (BUN), C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-1β (IL-1ß) and tumor necrosis factor-alpha (TNF-α) compared with CP-treated rats. DAS treatment decreased malondialdehyde (MDA) and increased superoxide dismutase (SOD) and reduced glutathione (GSH) levels in the renal tissues and significantly attenuated the elevated neurotransmitters N-methyl-D-aspartate/adenosine triphosphate (NMDA), γ-aminobutyric acid (GABA) levels and remarkably restored neuronal nitric oxide (NO) level and nitric oxide synthase (nNOS) activity in the brain compared to CP-treated rats. DAS for 4 consecutive days before CP showed moderate positive immunohistochemically expression of the glial fibrillary acidic protein (GFAP) in the brain and kidney tissues comparable to CP-treated rats. DAS afforded renal and neuroprotection against CP-induced nephropathic encephalopathy due to its capacity to ameliorates the afore-mentioned biochemical parameters which were supported by histopathological and immunohistochemically examination.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"30 1","pages":"208 - 218"},"PeriodicalIF":3.2,"publicationDate":"2019-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15376516.2019.1695991","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49656508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-11-20DOI: 10.1080/15376516.2019.1687629
Ibraheem M. Attafi, S. Bakheet, H. Korashy
Abstract Lead (Pb) is recognized as the first heavy metal of the top six toxic air pollutants threatening human health and the second hazardous substance. Pb exposure is associated with lung impairment and high incidences of lung cancer. Nuclear factor kappa B (NF-κB) and aryl hydrocarbon receptor (AhR) signaling pathways are known to be expressed and play an important role in the lung. However, the link between Pb lung toxicity and NF-κB and/or AhR pathways remains unclear. This study was established to explore the role of NF-κB and AhR modulation in Pb-induced lung toxicity in human lung cancer A549 cells. In the current study, treatment of A549 cells with Pb significantly induced cell apoptosis as evidenced by increasing a) the percentage of cells underwent apoptosis determined by flow cytometry and b) p53 mRNA level. Pb treatment induced oxidative stress by a) increasing the formation of reactive oxygen species and b) decreasing GSTA1 mRNA levels. The toxic effects of Pb on the lung was associated with significant increases in NF-κB and AhR levels which was accompanied with increases in downstream targets genes, iNOS and CYP1A1, respectively. Inhibition of NF-κB or AhR either chemically using resveratrol or genetically using small interfering RNA (siRNA) significantly rescued A549 cells from Pb-mediated lung toxicity. The results clearly indicate that Pb-mediated lung toxicities are NF-κB and AhR-dependent mechanism.
{"title":"The role of NF-κB and AhR transcription factors in lead-induced lung toxicity in human lung cancer A549 cells","authors":"Ibraheem M. Attafi, S. Bakheet, H. Korashy","doi":"10.1080/15376516.2019.1687629","DOIUrl":"https://doi.org/10.1080/15376516.2019.1687629","url":null,"abstract":"Abstract Lead (Pb) is recognized as the first heavy metal of the top six toxic air pollutants threatening human health and the second hazardous substance. Pb exposure is associated with lung impairment and high incidences of lung cancer. Nuclear factor kappa B (NF-κB) and aryl hydrocarbon receptor (AhR) signaling pathways are known to be expressed and play an important role in the lung. However, the link between Pb lung toxicity and NF-κB and/or AhR pathways remains unclear. This study was established to explore the role of NF-κB and AhR modulation in Pb-induced lung toxicity in human lung cancer A549 cells. In the current study, treatment of A549 cells with Pb significantly induced cell apoptosis as evidenced by increasing a) the percentage of cells underwent apoptosis determined by flow cytometry and b) p53 mRNA level. Pb treatment induced oxidative stress by a) increasing the formation of reactive oxygen species and b) decreasing GSTA1 mRNA levels. The toxic effects of Pb on the lung was associated with significant increases in NF-κB and AhR levels which was accompanied with increases in downstream targets genes, iNOS and CYP1A1, respectively. Inhibition of NF-κB or AhR either chemically using resveratrol or genetically using small interfering RNA (siRNA) significantly rescued A549 cells from Pb-mediated lung toxicity. The results clearly indicate that Pb-mediated lung toxicities are NF-κB and AhR-dependent mechanism.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"30 1","pages":"197 - 207"},"PeriodicalIF":3.2,"publicationDate":"2019-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15376516.2019.1687629","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46667062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-11-18DOI: 10.1080/15376516.2019.1695303
Y. Yordanov
Abstract Phase-contrast micrographs are often used for confirmation of proliferation and viability assays. However, they are usually only a qualitative tool and fail to exclude with certainty the presence of assay interference by test substances. The complexity of image analysis workflows hinders life scientists from routinely utilizing micrograph data. Here, we present an open-source software-based, combined ilastik segmentation/ImageJ measurement of area (ISIMA) approach for cell monolayer segmentation and confluence percentage measurement of phase-contrast micrographs of Hep G2 cells. The aim of this study is to test whether the proposed approach is suitable for quantitative confirmation of proliferation data, acquired by the 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Our results show that ISIMA is user-friendly and provides reproducible data, which strongly correlates to the results of the MTT assay. In conclusion, ISIMA is an affordable, simple, and fast approach for confluence quantification by researchers without image analysis background.
{"title":"Hep G2 cell culture confluence measurement in phase-contrast micrographs – a user-friendly, open-source software-based approach","authors":"Y. Yordanov","doi":"10.1080/15376516.2019.1695303","DOIUrl":"https://doi.org/10.1080/15376516.2019.1695303","url":null,"abstract":"Abstract Phase-contrast micrographs are often used for confirmation of proliferation and viability assays. However, they are usually only a qualitative tool and fail to exclude with certainty the presence of assay interference by test substances. The complexity of image analysis workflows hinders life scientists from routinely utilizing micrograph data. Here, we present an open-source software-based, combined ilastik segmentation/ImageJ measurement of area (ISIMA) approach for cell monolayer segmentation and confluence percentage measurement of phase-contrast micrographs of Hep G2 cells. The aim of this study is to test whether the proposed approach is suitable for quantitative confirmation of proliferation data, acquired by the 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Our results show that ISIMA is user-friendly and provides reproducible data, which strongly correlates to the results of the MTT assay. In conclusion, ISIMA is an affordable, simple, and fast approach for confluence quantification by researchers without image analysis background.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"30 1","pages":"146 - 152"},"PeriodicalIF":3.2,"publicationDate":"2019-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15376516.2019.1695303","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41777967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-11-18DOI: 10.1080/15376516.2019.1686795
I. Ide, Eri Nagao, Sakura Kajiyama, Natsumi Mizoguchi
Abstract Predicting drug-induced liver injury is important in early stage drug discovery; however, an accurate prediction with existing hepatotoxicity evaluation tools is difficult. Conventional monolayer (2D) cultures have short viabilities and are therefore inappropriate for performing long-term toxicity tests. Conventionally used 200-μm spheroids also have toxicity detection limits. The goal of this study was to develop a humanized liver tissue capable of evaluating long-term toxicity with high sensitivity. Spheroids consisting of co-cultured cryopreserved primary human hepatocytes and human hepatic stellate cells were developed using a 3D bio-printer. The “3D bio-printed liver tissue”, of ∼1 mm, was then used for long-term viability assessments (over 25 days) based on ATP, albumin, and urea levels. Hepatotoxicity evaluation was performed by analyzing the expression of genes involved in drug metabolism and transport over a 2-week drug exposure period. The 3D bio-printed liver tissue showed improved viability and enhanced gene expression of enzymes related to drug metabolism and transport, as compared to the controls. Additionally, the 3D bio-printed liver tissue demonstrated a high sensitivity for hepatotoxicity evaluation when combined with pathological evaluation and measurements for ATP production, and secretion of albumin and urea. In conclusion, the 3D bio-printed liver tissue was able to detect the toxicity of compounds that was, otherwise, undetected by 2D culture and conventionally used spheroids. These findings demonstrate a 3D bio-printed liver tissue with increased accuracy of hepatotoxicity prediction in the early stages of drug discovery, as compared to currently available methods.
{"title":"A novel evaluation method for determining drug-induced hepatotoxicity using 3D bio-printed human liver tissue","authors":"I. Ide, Eri Nagao, Sakura Kajiyama, Natsumi Mizoguchi","doi":"10.1080/15376516.2019.1686795","DOIUrl":"https://doi.org/10.1080/15376516.2019.1686795","url":null,"abstract":"Abstract Predicting drug-induced liver injury is important in early stage drug discovery; however, an accurate prediction with existing hepatotoxicity evaluation tools is difficult. Conventional monolayer (2D) cultures have short viabilities and are therefore inappropriate for performing long-term toxicity tests. Conventionally used 200-μm spheroids also have toxicity detection limits. The goal of this study was to develop a humanized liver tissue capable of evaluating long-term toxicity with high sensitivity. Spheroids consisting of co-cultured cryopreserved primary human hepatocytes and human hepatic stellate cells were developed using a 3D bio-printer. The “3D bio-printed liver tissue”, of ∼1 mm, was then used for long-term viability assessments (over 25 days) based on ATP, albumin, and urea levels. Hepatotoxicity evaluation was performed by analyzing the expression of genes involved in drug metabolism and transport over a 2-week drug exposure period. The 3D bio-printed liver tissue showed improved viability and enhanced gene expression of enzymes related to drug metabolism and transport, as compared to the controls. Additionally, the 3D bio-printed liver tissue demonstrated a high sensitivity for hepatotoxicity evaluation when combined with pathological evaluation and measurements for ATP production, and secretion of albumin and urea. In conclusion, the 3D bio-printed liver tissue was able to detect the toxicity of compounds that was, otherwise, undetected by 2D culture and conventionally used spheroids. These findings demonstrate a 3D bio-printed liver tissue with increased accuracy of hepatotoxicity prediction in the early stages of drug discovery, as compared to currently available methods.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"30 1","pages":"189 - 196"},"PeriodicalIF":3.2,"publicationDate":"2019-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15376516.2019.1686795","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47031835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-11-01Epub Date: 2019-08-14DOI: 10.1080/15376516.2019.1646371
Weijia Han, Mei Ding, Shuang Liu, Yu Chen, Zhongping Duan
Background: Application of hepatoprotectants, such as drugs or cytokines, can reduce drug-induced hepatotoxicity (DIH). Due to species-specific differences and abnormal cell polarity and drug-metabolizing enzymes (DMEs), in vivo animal models and in vitro 2D plastic dishes are not good DIH models. The aim of this study was to evaluate whether 3D re-cellularized liver is a sensitive, accurate and efficient DIH model for evaluation of hepatoprotectants. Methods: 2D plastic dishes and 3D decellular liver scaffolds were perfused with HepG2 cells or augmenter of liver regeneration (ALR)-HepG2 cells. These two cell lines were exposed to 4 μM troglitazone (TRO) or 20 μM diclofenac sodium (DIC) on day 8. DME-related genes were analyzed by quantitative reverse transcription polymerase chain reaction; morphological images were revealed by immunohistochemistry, scanning electron microscopy, transmission electron microscopy, and hematoxylin and eosin staining. Results: DME activity and cell polarity were retained and lower doses of TRO and DIC led to DIH in 3D re-cellularized liver. This DIH model reflected the protective effects and mechanism of ALR, which is one of the hepatoprotectants. ALR reduced mitochondrial damage, decreased transaminase level, and alleviated inflammation in TRO-DIH and DIC-DIH. Our re-cellularized liver lobe also showed the effect of ALR in suppressing expression of DMEs. Conclusions: Drug-induced 3D re-cellularized tissue engineering is a sensitive, accurate, and efficient DIH model for evaluation of hepatoprotectants.
{"title":"Evaluation of 3D re-cellularized tissue engineering: a drug-induced hepatotoxicity model for hepatoprotectant research.","authors":"Weijia Han, Mei Ding, Shuang Liu, Yu Chen, Zhongping Duan","doi":"10.1080/15376516.2019.1646371","DOIUrl":"10.1080/15376516.2019.1646371","url":null,"abstract":"<p><p><b>Background:</b> Application of hepatoprotectants, such as drugs or cytokines, can reduce drug-induced hepatotoxicity (DIH). Due to species-specific differences and abnormal cell polarity and drug-metabolizing enzymes (DMEs), <i>in vivo</i> animal models and <i>in vitro</i> 2D plastic dishes are not good DIH models. The aim of this study was to evaluate whether 3D re-cellularized liver is a sensitive, accurate and efficient DIH model for evaluation of hepatoprotectants. <b>Methods:</b> 2D plastic dishes and 3D decellular liver scaffolds were perfused with HepG2 cells or augmenter of liver regeneration (ALR)-HepG2 cells. These two cell lines were exposed to 4 μM troglitazone (TRO) or 20 μM diclofenac sodium (DIC) on day 8. DME-related genes were analyzed by quantitative reverse transcription polymerase chain reaction; morphological images were revealed by immunohistochemistry, scanning electron microscopy, transmission electron microscopy, and hematoxylin and eosin staining. <b>Results:</b> DME activity and cell polarity were retained and lower doses of TRO and DIC led to DIH in 3D re-cellularized liver. This DIH model reflected the protective effects and mechanism of ALR, which is one of the hepatoprotectants. ALR reduced mitochondrial damage, decreased transaminase level, and alleviated inflammation in TRO-DIH and DIC-DIH. Our re-cellularized liver lobe also showed the effect of ALR in suppressing expression of DMEs. <b>Conclusions:</b> Drug-induced 3D re-cellularized tissue engineering is a sensitive, accurate, and efficient DIH model for evaluation of hepatoprotectants.</p>","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"29 1","pages":"654-664"},"PeriodicalIF":3.2,"publicationDate":"2019-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15376516.2019.1646371","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42726756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-10-02DOI: 10.1080/15376516.2019.1669250
D. Jett, Judith Laney
{"title":"Civilian research on chemical medical countermeasures","authors":"D. Jett, Judith Laney","doi":"10.1080/15376516.2019.1669250","DOIUrl":"https://doi.org/10.1080/15376516.2019.1669250","url":null,"abstract":"","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"31 1","pages":"242 - 243"},"PeriodicalIF":3.2,"publicationDate":"2019-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15376516.2019.1669250","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49542053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-10-01DOI: 10.1080/15376516.2019.1669244
S. Achanta, S. Jordt
Abstract Chlorine gas is one of the highly produced chemicals in the USA and around the world. Chlorine gas has several uses in water purification, sanitation, and industrial applications; however, it is a toxic inhalation hazard agent. Inhalation of chlorine gas, based on the concentration and duration of the exposure, causes a spectrum of symptoms, including but not limited to lacrimation, rhinorrhea, bronchospasm, cough, dyspnea, acute lung injury, death, and survivors develop signs of pulmonary fibrosis and reactive airway disease. Despite the use of chlorine gas as a chemical warfare agent since World War I and its known potential as an industrial hazard, there is no specific antidote. The resurgence of the use of chlorine gas as a chemical warfare agent in recent years has brought speculation of its use as weapons of mass destruction. Therefore, developing antidotes for chlorine gas-induced lung injuries remains the need of the hour. While some of the pre-clinical studies have made substantial progress in the understanding of chlorine gas-induced pulmonary pathophysiology and identifying potential medical countermeasure(s), yet none of the drug candidates are approved by the U.S. Food and Drug Administration (FDA). In this review, we summarized pathophysiology of chlorine gas-induced pulmonary injuries, pre-clinical animal models, development of a pipeline of potential medical countermeasures under FDA animal rule, and future directions for the development of antidotes for chlorine gas-induced lung injuries.
{"title":"Toxic effects of chlorine gas and potential treatments: a literature review","authors":"S. Achanta, S. Jordt","doi":"10.1080/15376516.2019.1669244","DOIUrl":"https://doi.org/10.1080/15376516.2019.1669244","url":null,"abstract":"Abstract Chlorine gas is one of the highly produced chemicals in the USA and around the world. Chlorine gas has several uses in water purification, sanitation, and industrial applications; however, it is a toxic inhalation hazard agent. Inhalation of chlorine gas, based on the concentration and duration of the exposure, causes a spectrum of symptoms, including but not limited to lacrimation, rhinorrhea, bronchospasm, cough, dyspnea, acute lung injury, death, and survivors develop signs of pulmonary fibrosis and reactive airway disease. Despite the use of chlorine gas as a chemical warfare agent since World War I and its known potential as an industrial hazard, there is no specific antidote. The resurgence of the use of chlorine gas as a chemical warfare agent in recent years has brought speculation of its use as weapons of mass destruction. Therefore, developing antidotes for chlorine gas-induced lung injuries remains the need of the hour. While some of the pre-clinical studies have made substantial progress in the understanding of chlorine gas-induced pulmonary pathophysiology and identifying potential medical countermeasure(s), yet none of the drug candidates are approved by the U.S. Food and Drug Administration (FDA). In this review, we summarized pathophysiology of chlorine gas-induced pulmonary injuries, pre-clinical animal models, development of a pipeline of potential medical countermeasures under FDA animal rule, and future directions for the development of antidotes for chlorine gas-induced lung injuries.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"31 1","pages":"244 - 256"},"PeriodicalIF":3.2,"publicationDate":"2019-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15376516.2019.1669244","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41689883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-09-03DOI: 10.1080/15376516.2019.1646372
Sapna Khowal, S. Wajid
Abstract Smoking is a pernicious practice prevalent worldwide. It involves breathing of burnt-tobacco fumes/smoke which comprises of numerous chemical entities posing deleterious aftermaths in the oral cavity. Tobacco fumes carry carcinogens and damaging chemicals like nitrosamines, polycyclic aromatic hydrocarbons, aldehydes, nicotine, phenols, carbon monoxides, radioactive elements, heavy metal ions. Oral cavity (mouth or buccal cavity), forming initial contacts with tobacco smokables, plays an essential role in the digestive system, facial determinations and speech. Smoking is a significant risk factor for oral cavity cancers. Nearly 50% of deaths from oral cavity cancer (oral cancer) attribute to smoking. This review intends to focus on the smoking mediated molecular modulations that are associated with the genesis of oral cancers.
{"title":"Role of Smoking-Mediated molecular events in the genesis of oral cancers","authors":"Sapna Khowal, S. Wajid","doi":"10.1080/15376516.2019.1646372","DOIUrl":"https://doi.org/10.1080/15376516.2019.1646372","url":null,"abstract":"Abstract Smoking is a pernicious practice prevalent worldwide. It involves breathing of burnt-tobacco fumes/smoke which comprises of numerous chemical entities posing deleterious aftermaths in the oral cavity. Tobacco fumes carry carcinogens and damaging chemicals like nitrosamines, polycyclic aromatic hydrocarbons, aldehydes, nicotine, phenols, carbon monoxides, radioactive elements, heavy metal ions. Oral cavity (mouth or buccal cavity), forming initial contacts with tobacco smokables, plays an essential role in the digestive system, facial determinations and speech. Smoking is a significant risk factor for oral cavity cancers. Nearly 50% of deaths from oral cavity cancer (oral cancer) attribute to smoking. This review intends to focus on the smoking mediated molecular modulations that are associated with the genesis of oral cancers.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"29 1","pages":"665 - 685"},"PeriodicalIF":3.2,"publicationDate":"2019-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15376516.2019.1646372","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43042757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：