Pub Date : 2019-08-20DOI: 10.1080/15376516.2019.1646367
Unzile Sur, P. Erkekoğlu, A. Buluş, N. Andıran, B. Kocer-Gumusel
Abstract In this study, we aimed to investigate whether bisphenol A (BPA) and di-(2-ethylhexyl) phthalate (DEHP) exposure have any association with Hashimoto’s thyroiditis (HT) and its biomarkers and to determine whether oxidative stress biomarkers and trace element levels showed any alterations in children with HT. We found that superoxide dismutase and glutathione peroxidase activities are lower in HT group from control (24% and 46%, respectively, p < 0.05). Zinc levels were significantly lower in HT group vs. control. In addition, the levels of mono-(2-ethylhexyl) phthalate (MEHP) which is the primary metabolite for DEHP, were markedly higher in HT group compared to control (p < 0.05). A negative correlation was observed between urinary BPA levels and fT4. In children with HT, oxidant/antioxidant balance is changed and these differences may be related by EDC exposure, the importance of which should be elucidated with further studies.
{"title":"Oxidative stress markers, trace elements, and endocrine disrupting chemicals in children with Hashimoto’s thyroiditis","authors":"Unzile Sur, P. Erkekoğlu, A. Buluş, N. Andıran, B. Kocer-Gumusel","doi":"10.1080/15376516.2019.1646367","DOIUrl":"https://doi.org/10.1080/15376516.2019.1646367","url":null,"abstract":"Abstract In this study, we aimed to investigate whether bisphenol A (BPA) and di-(2-ethylhexyl) phthalate (DEHP) exposure have any association with Hashimoto’s thyroiditis (HT) and its biomarkers and to determine whether oxidative stress biomarkers and trace element levels showed any alterations in children with HT. We found that superoxide dismutase and glutathione peroxidase activities are lower in HT group from control (24% and 46%, respectively, p < 0.05). Zinc levels were significantly lower in HT group vs. control. In addition, the levels of mono-(2-ethylhexyl) phthalate (MEHP) which is the primary metabolite for DEHP, were markedly higher in HT group compared to control (p < 0.05). A negative correlation was observed between urinary BPA levels and fT4. In children with HT, oxidant/antioxidant balance is changed and these differences may be related by EDC exposure, the importance of which should be elucidated with further studies.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"29 1","pages":"633 - 643"},"PeriodicalIF":3.2,"publicationDate":"2019-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15376516.2019.1646367","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48435075","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 : 2019-08-08DOI: 10.1080/15376516.2019.1646368
Mingtian Zhang, H. Park, S. Seo, Hye-Ryoung Seo, Hyuk Song
Abstract The reproductive toxicity of 4-octylphenol (4-OP) has been studied in animals such as mouse and fish. In humans, the exposure of sperm to 4-OP has been shown to decrease motility and viability. In this study, we performed an in vitro assessment of the toxic effects of 4-OP on mouse TM4 Sertoli cells and investigated the underlying molecular mechanisms. TM4 cells were treated with four concentrations (0, 10, 30, and 50 µM) of 4-OP at the following time points: 24, 48, and 72 h. Cell viability and apoptosis assays were conducted following 4-OP exposure. We found that 4-OP significantly decreased cell viability in a concentration- and time-dependent manner, and increased apoptosis. Quantitative PCR analysis showed that the mRNA expression levels of BCL2 Associated X, Apoptosis Regulator (Bax) and BCL2 Antagonist/Killer (Bak) increased while that of BCL2 Apoptosis Regulator (Bcl-2) decreased in 4-OP-exposed cells compared with that in the controls. Western blotting revealed that 4-OP induced caspase-3 activity and Bad phosphorylation in a concentration- and time-dependent manner. Additionally, cytochrome C protein did not colocalize with mitochondrial marker dye by 24 h. Cytochrome c protein expression increased in a time-dependent manner upon exposure to 50 µM 4-OP. These results suggest that 4-OP induces mitochondria-mediated apoptosis through regulation of Bcl-2 family proteins and caspase-3 activation in male Sertoli cells.
{"title":"Evaluation of toxicity of 4-octylphenol in TM4 Sertoli cells: an in vitro study","authors":"Mingtian Zhang, H. Park, S. Seo, Hye-Ryoung Seo, Hyuk Song","doi":"10.1080/15376516.2019.1646368","DOIUrl":"https://doi.org/10.1080/15376516.2019.1646368","url":null,"abstract":"Abstract The reproductive toxicity of 4-octylphenol (4-OP) has been studied in animals such as mouse and fish. In humans, the exposure of sperm to 4-OP has been shown to decrease motility and viability. In this study, we performed an in vitro assessment of the toxic effects of 4-OP on mouse TM4 Sertoli cells and investigated the underlying molecular mechanisms. TM4 cells were treated with four concentrations (0, 10, 30, and 50 µM) of 4-OP at the following time points: 24, 48, and 72 h. Cell viability and apoptosis assays were conducted following 4-OP exposure. We found that 4-OP significantly decreased cell viability in a concentration- and time-dependent manner, and increased apoptosis. Quantitative PCR analysis showed that the mRNA expression levels of BCL2 Associated X, Apoptosis Regulator (Bax) and BCL2 Antagonist/Killer (Bak) increased while that of BCL2 Apoptosis Regulator (Bcl-2) decreased in 4-OP-exposed cells compared with that in the controls. Western blotting revealed that 4-OP induced caspase-3 activity and Bad phosphorylation in a concentration- and time-dependent manner. Additionally, cytochrome C protein did not colocalize with mitochondrial marker dye by 24 h. Cytochrome c protein expression increased in a time-dependent manner upon exposure to 50 µM 4-OP. These results suggest that 4-OP induces mitochondria-mediated apoptosis through regulation of Bcl-2 family proteins and caspase-3 activation in male Sertoli cells.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"29 1","pages":"623 - 631"},"PeriodicalIF":3.2,"publicationDate":"2019-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15376516.2019.1646368","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44151490","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 : 2017-02-20DOI: 10.1080/15376516.2017.1288767
Deborah Navit de Carvalho Cavalcante, J. C. Spósito, B. Crispim, A. V. Nascimento, A. Grisolia
Abstract Nuclear abnormalities (micronuclei and meta-nuclear changes) have been used as biomarkers to identify cell damages. As children are more vulnerable to the adverse effects of pollution when compared to adults, assessing genetic damage caused by environmental influences is of great interest. As such, the objective was to determine metanuclear (karyolysis, pycnosis, karyorrhexis, binucleated cells, chromosome bridges and micronuclei) in cells from the oral mucosa of children associated with the school environment, gender, exposure to cigarette smoke and vehicular traffic. Analyses of nuclear abnormalities were performed in exfoliated buccal cells of children from two public schools located in Dourados – MS. The data were analyzed through Kruskal–Wallis test considering a significance level of 5% (p < .05). The results showed that children exposed to cigarette smoke presented higher levels of nuclear abnormalities than children who were not usually exposed to this type of mutagenic and genotoxic agent, suggesting that such contaminants are related to clastogenic and aneugenic effects on DNA. Moreover, female children had higher amounts of nuclear abnormalities when compared to male children. With regards to the school environment, the study results indicated statistical differences in of term chromosomal abnormalities for schools A and B. Thus, it was possible to determine that children exposed to cigarette smoke are susceptible to further genetic damage than unexposed children, and female children may be more susceptible to genotoxic and mutagenic agents. This study contributes to the current knowledge on the mutagenic characteristics of human cells, supporting the adoption of preventive Public Health measures.
{"title":"Genotoxic and mutagenic effects of passive smoking and urban air pollutants in buccal mucosa cells of children enrolled in public school","authors":"Deborah Navit de Carvalho Cavalcante, J. C. Spósito, B. Crispim, A. V. Nascimento, A. Grisolia","doi":"10.1080/15376516.2017.1288767","DOIUrl":"https://doi.org/10.1080/15376516.2017.1288767","url":null,"abstract":"Abstract Nuclear abnormalities (micronuclei and meta-nuclear changes) have been used as biomarkers to identify cell damages. As children are more vulnerable to the adverse effects of pollution when compared to adults, assessing genetic damage caused by environmental influences is of great interest. As such, the objective was to determine metanuclear (karyolysis, pycnosis, karyorrhexis, binucleated cells, chromosome bridges and micronuclei) in cells from the oral mucosa of children associated with the school environment, gender, exposure to cigarette smoke and vehicular traffic. Analyses of nuclear abnormalities were performed in exfoliated buccal cells of children from two public schools located in Dourados – MS. The data were analyzed through Kruskal–Wallis test considering a significance level of 5% (p < .05). The results showed that children exposed to cigarette smoke presented higher levels of nuclear abnormalities than children who were not usually exposed to this type of mutagenic and genotoxic agent, suggesting that such contaminants are related to clastogenic and aneugenic effects on DNA. Moreover, female children had higher amounts of nuclear abnormalities when compared to male children. With regards to the school environment, the study results indicated statistical differences in of term chromosomal abnormalities for schools A and B. Thus, it was possible to determine that children exposed to cigarette smoke are susceptible to further genetic damage than unexposed children, and female children may be more susceptible to genotoxic and mutagenic agents. This study contributes to the current knowledge on the mutagenic characteristics of human cells, supporting the adoption of preventive Public Health measures.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"27 1","pages":"346 - 351"},"PeriodicalIF":3.2,"publicationDate":"2017-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15376516.2017.1288767","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44604390","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 : 2017-02-20DOI: 10.1080/15376516.2017.1288768
G. Krishna, G. Gopalakrishnan, S. Goel
Abstract Neuroleptic drug molindone hydrochloride is a dopamine D2/D5 receptor antagonist and it is in late stage development for the treatment of impulsive aggression in children and adolescents who have attention deficient/hyperactivity disorder (ADHD). This new indication for this drug would expand the target population to include younger patients, and therefore, toxicity assessments in juvenile animals were undertaken in order to determine susceptibility differences, if any, between this age group and the adult rats. Adult rats were administered molindone by oral gavage for 13 weeks at dose levels of 0, 5, 20, or 60 mg/kg-bw/day. Juvenile rats were dosed for 8 weeks by oral gavage at dose levels of 0, 5, 25, 50, or 75 mg/kg-bw/day. Standard toxicological assessments were made using relevant study designs in consultation with FDA. Treatment-related elevation in serum cholesterol and triglycerides and decreases in glucose levels were observed in both the age groups. Organ weight changes included increases in liver, adrenal gland and seminal vesicles/prostate weights. Decreases in uterine weights were also observed in adult females exposed to the top two doses with sufficient exposure. In juveniles, sexual maturity parameters secondary to decreased body weights were observed, but, were reversed. In conclusion, the adverse effects noted in reproductive tissues of adults were attributed to hyperprolactinemia and these changes were not considered to be relevant to humans due to species differences in hormonal regulation of reproduction. On the whole, there were no remarkable differences in the toxicity profile of the drug between the two age groups.
{"title":"Toxicity assessment of molindone hydrochloride, a dopamine D2/D5 receptor antagonist in juvenile and adult rats","authors":"G. Krishna, G. Gopalakrishnan, S. Goel","doi":"10.1080/15376516.2017.1288768","DOIUrl":"https://doi.org/10.1080/15376516.2017.1288768","url":null,"abstract":"Abstract Neuroleptic drug molindone hydrochloride is a dopamine D2/D5 receptor antagonist and it is in late stage development for the treatment of impulsive aggression in children and adolescents who have attention deficient/hyperactivity disorder (ADHD). This new indication for this drug would expand the target population to include younger patients, and therefore, toxicity assessments in juvenile animals were undertaken in order to determine susceptibility differences, if any, between this age group and the adult rats. Adult rats were administered molindone by oral gavage for 13 weeks at dose levels of 0, 5, 20, or 60 mg/kg-bw/day. Juvenile rats were dosed for 8 weeks by oral gavage at dose levels of 0, 5, 25, 50, or 75 mg/kg-bw/day. Standard toxicological assessments were made using relevant study designs in consultation with FDA. Treatment-related elevation in serum cholesterol and triglycerides and decreases in glucose levels were observed in both the age groups. Organ weight changes included increases in liver, adrenal gland and seminal vesicles/prostate weights. Decreases in uterine weights were also observed in adult females exposed to the top two doses with sufficient exposure. In juveniles, sexual maturity parameters secondary to decreased body weights were observed, but, were reversed. In conclusion, the adverse effects noted in reproductive tissues of adults were attributed to hyperprolactinemia and these changes were not considered to be relevant to humans due to species differences in hormonal regulation of reproduction. On the whole, there were no remarkable differences in the toxicity profile of the drug between the two age groups.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"27 1","pages":"352 - 362"},"PeriodicalIF":3.2,"publicationDate":"2017-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15376516.2017.1288768","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49600043","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 : 2017-02-16DOI: 10.1080/15376516.2017.1285971
A. Prestes, M. D. dos Santos, A. Ecker, D. Zanini, M. Schetinger, D. B. Rosemberg, J. D. da Rocha, N. V. Barbosa
Abstract Methylglyoxal (MG) is a reactive dicarbonyl metabolite originated mainly from glucose degradation pathway that plays an important role in the pathogenesis of diabetes mellitus (DM). Reactions of MG with biological macromolecules (proteins, DNA and lipids) can induce cytotoxicity and apoptosis. Here, human erythrocytes, leukocytes and platelets were acutely exposed to MG at concentration ranging from 0.025 to 10 mM. Afterwards, hemolysis and osmotic fragility in erythrocytes, DNA damage and cell viability in leukocytes, and the activity of purinergic ecto-nucleotidases in platelets were evaluated. The levels of glycated products from leukocytes and free amino groups from erythrocytes and platelets were also measured. MG caused fragility of membrane, hemolysis and depletion of amino groups in erythrocytes. DNA damage, loss of cell viability and increased levels of glycated products were observed in leukocytes. In platelets, MG inhibited the activity of enzymes NTPDase, 5′-nucleotidase and adenosine deaminase (ADA) without affecting the levels of free amino groups. Our findings provide insights for understanding the mechanisms involved in MG acute toxicity towards distinct blood cells.
{"title":"Evaluation of methylglyoxal toxicity in human erythrocytes, leukocytes and platelets","authors":"A. Prestes, M. D. dos Santos, A. Ecker, D. Zanini, M. Schetinger, D. B. Rosemberg, J. D. da Rocha, N. V. Barbosa","doi":"10.1080/15376516.2017.1285971","DOIUrl":"https://doi.org/10.1080/15376516.2017.1285971","url":null,"abstract":"Abstract Methylglyoxal (MG) is a reactive dicarbonyl metabolite originated mainly from glucose degradation pathway that plays an important role in the pathogenesis of diabetes mellitus (DM). Reactions of MG with biological macromolecules (proteins, DNA and lipids) can induce cytotoxicity and apoptosis. Here, human erythrocytes, leukocytes and platelets were acutely exposed to MG at concentration ranging from 0.025 to 10 mM. Afterwards, hemolysis and osmotic fragility in erythrocytes, DNA damage and cell viability in leukocytes, and the activity of purinergic ecto-nucleotidases in platelets were evaluated. The levels of glycated products from leukocytes and free amino groups from erythrocytes and platelets were also measured. MG caused fragility of membrane, hemolysis and depletion of amino groups in erythrocytes. DNA damage, loss of cell viability and increased levels of glycated products were observed in leukocytes. In platelets, MG inhibited the activity of enzymes NTPDase, 5′-nucleotidase and adenosine deaminase (ADA) without affecting the levels of free amino groups. Our findings provide insights for understanding the mechanisms involved in MG acute toxicity towards distinct blood cells.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"27 1","pages":"307 - 317"},"PeriodicalIF":3.2,"publicationDate":"2017-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15376516.2017.1285971","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47848563","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 : 2017-02-15DOI: 10.1080/15376516.2016.1273428
Pathomwat Wongrattanakamon, V. Lee, P. Nimmanpipug, B. Sirithunyalug, S. Chansakaow, Supat Jiranusornkul
Abstract In this work, molecular docking, pharmacophore modeling and molecular dynamics (MD) simulation were rendered for the mouse P-glycoprotein (P-gp) (code: 4Q9H) and bioflavonoids; amorphigenin, chrysin, epigallocatechin, formononetin and rotenone including a positive control; verapamil to identify protein–ligand interaction features including binding affinities, interaction characteristics, hot-spot amino acid residues and complex stabilities. These flavonoids occupied the same binding site with high binding affinities and shared the same key residues for their binding interactions and the binding region of the flavonoids was revealed that overlapped the ATP binding region with hydrophobic and hydrophilic interactions suggesting a competitive inhibition mechanism of the compounds. Root mean square deviations (RMSDs) analysis of MD trajectories of the protein–ligand complexes and NBD2 residues, and ligands pointed out these residues were stable throughout the duration of MD simulations. Thus, the applied preliminary structure-based molecular modeling approach of interactions between NBD2 and flavonoids may be gainful to realize the intimate inhibition mechanism of P-gp at NBD2 level and on the basis of the obtained data, it can be concluded that these bioflavonoids have the potential to cause herb–drug interactions or be used as lead molecules for the inhibition of P-gp (as anti-multidrug resistance agents) via the NBD2 blocking mechanism in future.
{"title":"Insight into the molecular mechanism of P-glycoprotein mediated drug toxicity induced by bioflavonoids: an integrated computational approach","authors":"Pathomwat Wongrattanakamon, V. Lee, P. Nimmanpipug, B. Sirithunyalug, S. Chansakaow, Supat Jiranusornkul","doi":"10.1080/15376516.2016.1273428","DOIUrl":"https://doi.org/10.1080/15376516.2016.1273428","url":null,"abstract":"Abstract In this work, molecular docking, pharmacophore modeling and molecular dynamics (MD) simulation were rendered for the mouse P-glycoprotein (P-gp) (code: 4Q9H) and bioflavonoids; amorphigenin, chrysin, epigallocatechin, formononetin and rotenone including a positive control; verapamil to identify protein–ligand interaction features including binding affinities, interaction characteristics, hot-spot amino acid residues and complex stabilities. These flavonoids occupied the same binding site with high binding affinities and shared the same key residues for their binding interactions and the binding region of the flavonoids was revealed that overlapped the ATP binding region with hydrophobic and hydrophilic interactions suggesting a competitive inhibition mechanism of the compounds. Root mean square deviations (RMSDs) analysis of MD trajectories of the protein–ligand complexes and NBD2 residues, and ligands pointed out these residues were stable throughout the duration of MD simulations. Thus, the applied preliminary structure-based molecular modeling approach of interactions between NBD2 and flavonoids may be gainful to realize the intimate inhibition mechanism of P-gp at NBD2 level and on the basis of the obtained data, it can be concluded that these bioflavonoids have the potential to cause herb–drug interactions or be used as lead molecules for the inhibition of P-gp (as anti-multidrug resistance agents) via the NBD2 blocking mechanism in future.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"27 1","pages":"253 - 271"},"PeriodicalIF":3.2,"publicationDate":"2017-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15376516.2016.1273428","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43450869","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 : 2017-02-15DOI: 10.1080/15376516.2017.1285973
M. Elkhadragy, Ahmed E. Abdel Moneim
Abstract This study investigated the protective effect of Fragaria ananassa methanolic extract on cadmium chloride (CdCl2)-induced hepatotoxicity in rats. CdCl2 was intraperitoneally injected at a dose of 6.5 mg/kg of body weight for 5 d with or without methanol extract of Fragaria ananassa (250 mg/kg). The hepatic cadmium concentration, lipid peroxidation, nitric oxide, glutathione (GSH) content, and antioxidant enzyme activities, including superoxide dismutase, catalase (CAT), GSH peroxidase, and GSH reductase, were estimated. CdCl2 injection induced a significant elevation in cadmium concentration, lipid peroxidation, and nitric oxide and caused a significant depletion in GSH content compared to controls, along with a remarkable decrease in antioxidant enzymes. Oxidative stress induction and cadmium accumulation in the liver were successfully ameliorated by F. ananassa (strawberry) pre-administration. In addition, the pre-administration of strawberry decreased the elevated gene expression of the pro-apoptotic Bax gene as well as the protein expression of caspases-3 in the liver of CdCl2-injected rats. In addition, the reduced gene expression of anti-apoptotic Bcl-2 was increased. Our results show an increase in the expression of tumor necrosis factor α in the liver of rats treated with cadmium. In sum, our results suggested that F. ananassa successfully prevented deleterious effects on liver function by reinforcing the antioxidant defense system, inhibiting oxidative stress and reducing apoptosis.
{"title":"Protective effect of Fragaria ananassa methanolic extract on cadmium chloride (CdCl2)-induced hepatotoxicity in rats","authors":"M. Elkhadragy, Ahmed E. Abdel Moneim","doi":"10.1080/15376516.2017.1285973","DOIUrl":"https://doi.org/10.1080/15376516.2017.1285973","url":null,"abstract":"Abstract This study investigated the protective effect of Fragaria ananassa methanolic extract on cadmium chloride (CdCl2)-induced hepatotoxicity in rats. CdCl2 was intraperitoneally injected at a dose of 6.5 mg/kg of body weight for 5 d with or without methanol extract of Fragaria ananassa (250 mg/kg). The hepatic cadmium concentration, lipid peroxidation, nitric oxide, glutathione (GSH) content, and antioxidant enzyme activities, including superoxide dismutase, catalase (CAT), GSH peroxidase, and GSH reductase, were estimated. CdCl2 injection induced a significant elevation in cadmium concentration, lipid peroxidation, and nitric oxide and caused a significant depletion in GSH content compared to controls, along with a remarkable decrease in antioxidant enzymes. Oxidative stress induction and cadmium accumulation in the liver were successfully ameliorated by F. ananassa (strawberry) pre-administration. In addition, the pre-administration of strawberry decreased the elevated gene expression of the pro-apoptotic Bax gene as well as the protein expression of caspases-3 in the liver of CdCl2-injected rats. In addition, the reduced gene expression of anti-apoptotic Bcl-2 was increased. Our results show an increase in the expression of tumor necrosis factor α in the liver of rats treated with cadmium. In sum, our results suggested that F. ananassa successfully prevented deleterious effects on liver function by reinforcing the antioxidant defense system, inhibiting oxidative stress and reducing apoptosis.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"27 1","pages":"335 - 345"},"PeriodicalIF":3.2,"publicationDate":"2017-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15376516.2017.1285973","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45212697","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 : 2017-02-13DOI: 10.1080/15376516.2017.1285972
Xiaowen Jiang, Xinxin Feng, Hui Huang, Lin Liu, Lu Qiao, Binqing Zhang, Wenhui Yu
Abstract Rotenone has been used as a pesticide for many years, it is an environmental poison reported to cause neurological diseases. However, the effects of rotenone on the rat liver are unclear, as are the mechanisms of toxicity. In the present study, Sprague–Dawley (SD) rats were divided into five groups: control, dimethyl sulfoxide (DMSO), rotenone low-dose (1 mg/kg), rotenone mid-dose (2 mg/kg) and rotenone high-dose (4 mg/kg). The treatments were orally administered daily for 28 days, we assessed health status, mRNA expression levels of inflammatory factors, protein levels, nitric oxide (NO) content and histological changes. The results showed that body weight was significantly decreased in each rotenone group in a dose-dependent manner, compared with the control group. Rotenone significantly increased the mRNA levels of cyclooxygenase-2 (COX-2), nuclear factor kappaB (NF-κB), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF-α) in each rotenone group compared with the control group, except iNOS and TNF-α mRNA expression in the low-dose group. The protein levels of COX-2 were significantly higher in each rotenone group compared with the control group, NF-κB protein expression were significantly higher in the rotenone mid and high-dose groups, but not in the low-dose group, compared with the control group, similar changes were observed in NO content. Additionally, histological analysis revealed that the most severe tissue damage occurred in the high-dose group. These results indicated that rotenone has toxic effect in rat liver relating to inflammatory factors. Our findings provide insight into the mechanisms of rotenone hepatotoxicity.
{"title":"The effects of rotenone-induced toxicity via the NF-κB–iNOS pathway in rat liver","authors":"Xiaowen Jiang, Xinxin Feng, Hui Huang, Lin Liu, Lu Qiao, Binqing Zhang, Wenhui Yu","doi":"10.1080/15376516.2017.1285972","DOIUrl":"https://doi.org/10.1080/15376516.2017.1285972","url":null,"abstract":"Abstract Rotenone has been used as a pesticide for many years, it is an environmental poison reported to cause neurological diseases. However, the effects of rotenone on the rat liver are unclear, as are the mechanisms of toxicity. In the present study, Sprague–Dawley (SD) rats were divided into five groups: control, dimethyl sulfoxide (DMSO), rotenone low-dose (1 mg/kg), rotenone mid-dose (2 mg/kg) and rotenone high-dose (4 mg/kg). The treatments were orally administered daily for 28 days, we assessed health status, mRNA expression levels of inflammatory factors, protein levels, nitric oxide (NO) content and histological changes. The results showed that body weight was significantly decreased in each rotenone group in a dose-dependent manner, compared with the control group. Rotenone significantly increased the mRNA levels of cyclooxygenase-2 (COX-2), nuclear factor kappaB (NF-κB), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF-α) in each rotenone group compared with the control group, except iNOS and TNF-α mRNA expression in the low-dose group. The protein levels of COX-2 were significantly higher in each rotenone group compared with the control group, NF-κB protein expression were significantly higher in the rotenone mid and high-dose groups, but not in the low-dose group, compared with the control group, similar changes were observed in NO content. Additionally, histological analysis revealed that the most severe tissue damage occurred in the high-dose group. These results indicated that rotenone has toxic effect in rat liver relating to inflammatory factors. Our findings provide insight into the mechanisms of rotenone hepatotoxicity.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"27 1","pages":"318 - 325"},"PeriodicalIF":3.2,"publicationDate":"2017-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15376516.2017.1285972","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45402569","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 : 2017-02-12DOI: 10.1080/15376516.2016.1268229
S. M. Kumar, Madhumitha Haridoss, Kavitha Swaminathan, Ramesh Kumar Gopal, D. Clemens, A. Dey
Abstract Alcohol-mediated liver injury is associated with changes in the level of the major cellular antioxidant glutathione (GSH). It is interesting to investigate if the changes in intracellular GSH level through exogenous agents affect the intracellular cysteine content and the protein adduct formation indicative of oxidative insult in chronic alcohol treated liver cells. In VL-17A cells treated with 2 mM N-acetyl cysteine (NAC) or 0.1 mM ursodeoxycholic acid (UDCA) plus 100 mM ethanol, an increase in cysteine concentration which was accompanied by decreases in hydroxynonenal (HNE) and glutathionylated protein adducts were observed. Pretreatment of 100 mM ethanol treated VL-17A cells with 0.4 mM buthionine sulfoximine (BSO) or 1 mM diethyl maleate (DEM) had opposite effects. Thus, altered GSH level through exogenous agents may either potentiate or ameliorate chronic alcohol-mediated protein adduct formation and change the cysteine level in chronic alcohol treated VL-17A cells. The gene expression of non-treated and ethanol-treated hepatocytes in 2 microarray datasets was also compared to locate differentially expressed genes involved in cysteine metabolism. The study demonstrates that increased protein adducts formation and changes in cysteine concentration occur under chronic alcohol condition in liver cells which may increase alcohol-mediated oxidative injury.
酒精介导的肝损伤与主要细胞抗氧化剂谷胱甘肽(GSH)水平的变化有关。在慢性酒精处理的肝细胞中，通过外源性药物改变细胞内GSH水平是否会影响细胞内半胱氨酸含量和指示氧化损伤的蛋白质加合物形成，这是一个有趣的研究。在2 mM n -乙酰半胱氨酸(NAC)或0.1 mM熊去氧胆酸(UDCA)加100 mM乙醇处理的VL-17A细胞中，观察到半胱氨酸浓度增加，同时羟基壬烯醛(HNE)和谷胱甘肽化蛋白加合物减少。用0.4 mM丁硫氨酸亚砜(BSO)或1 mM马来酸二乙酯(DEM)对100 mM乙醇处理的VL-17A细胞进行预处理，效果相反。因此，外源性药物改变的谷胱甘肽水平可能增强或改善慢性酒精介导的蛋白质加合物形成，并改变慢性酒精处理的VL-17A细胞的半胱氨酸水平。还比较了2个微阵列数据集中未处理和乙醇处理的肝细胞的基因表达，以定位参与半胱氨酸代谢的差异表达基因。研究表明，在慢性酒精状态下，肝细胞中蛋白质加合物的形成增加和半胱氨酸浓度的变化可能会增加酒精介导的氧化损伤。
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