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Tao Chen - One of the best experts on this subject based on the ideXlab platform.
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Short Communication Mutagenicity of Comfrey (Symphytum Officinale) in rat liver
2013Co-Authors: N Mei, Robert H. Heflich, L Guo, Tao ChenAbstract:Comfrey is a rat liver toxin and carcinogen that has been used as a vegetable and herbal remedy by humans. In order to evaluate the mechanisms underlying its carcinogenicity, we examined the mutagenicity of Comfrey in the transgenic Big Blue rat model. Our results indicate that Comfrey is mutagenic in rat liver and the types of mutations induced by Comfrey suggest that its tumorigenicity results from the genotoxicity of pyrrolizidine alkaloids in the plant
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MicroRNAs and their predicted target messenger RNAs are deregulated by exposure to a carcinogenic dose of Comfrey in rat liver.
Environmental and molecular mutagenesis, 2011Co-Authors: James C. Fuscoe, Tao ChenAbstract:MicroRNAs (MiRNAs) are small noncoding RNAs that function as regulators of gene expression to control cell growth and differentiation. In this study, we analyzed miRNA and mRNA expression in the livers of rats treated with a carcinogenic dose of Comfrey (Symphytum officinale) for 12 weeks. Groups of six rats were fed a normal diet or a diet containing 8% Comfrey root. The animals were sacrificed 1 day after the last treatment and the livers were isolated for miRNA expression analysis using LC Sciences miRNA microarrays and for mRNA expression analysis using Affymetrix rat genome microarrays. MiRNA expression levels were significantly changed by Comfrey treatment. The treated samples were separated clearly from the control samples in both principal component analysis (PCA) and hierarchical clustering analysis (HCA). Quantitative measurements of seven miRNAs using TaqMan real-time PCR were consistent with the microarray results in terms of fold-change and the direction of the change in expression. Forty-five miRNAs (P < 0.01) and 1,921 mRNAs (q = 0) were significantly changed by Comfrey treatment. Using a target prediction algorithm, 434 differentially expressed genes (DEGs) were predicted to be targeted by the differentially expressed miRNAs (DEMs). The DEM-targeted DEGs were more likely to be involved in carcinogenesis than the DEGs that were not targeted by the DEMs. The nontargeted DEGs were enriched in noncancer-related biological processes. Our data suggest that Comfrey may exert its carcinogenic effects by disturbing miRNA expression resulting in altered mRNA levels of the DEM-targeted genes that are functionally associated with carcinogenesis. Environ. Mol. Mutagen., 2011. © Published 2011 Wiley-Liss, Inc.
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Comparison of gene expression profiles altered by Comfrey and riddelliine in rat liver-0
2011Co-Authors: Lei Guo, Nan Mei, James Fuscoe, Stacey Dial, Tao ChenAbstract:Copyright information:Taken from "Comparison of gene expression profiles altered by Comfrey and riddelliine in rat liver"http://www.biomedcentral.com/1471-2105/8/S7/S22BMC Bioinformatics 2007;8(Suppl 7):S22-S22.Published online 1 Nov 2007PMCID:PMC2099491.hese values were hierarchically clustered using Euclidean distance metric and average linkage. Each column represents the results from an individual animal. CTR, control; CFY, Comfrey treatment; RDL, riddelliine treatment
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Comparison of gene expression profiles altered by Comfrey and riddelliine in rat liver-6
2011Co-Authors: Lei Guo, Nan Mei, James Fuscoe, Stacey Dial, Tao ChenAbstract:Copyright information:Taken from "Comparison of gene expression profiles altered by Comfrey and riddelliine in rat liver"http://www.biomedcentral.com/1471-2105/8/S7/S22BMC Bioinformatics 2007;8(Suppl 7):S22-S22.Published online 1 Nov 2007PMCID:PMC2099491.hese values were hierarchically clustered using Euclidean distance metric and average linkage. Each column represents the results from an individual animal. CTR, control; CFY, Comfrey treatment; RDL, riddelliine treatment
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Metabolism, genotoxicity, and carcinogenicity of Comfrey.
Journal of toxicology and environmental health. Part B Critical reviews, 2010Co-Authors: Nan Mei, Lei Guo, James C. Fuscoe, Yang Luan, Tao ChenAbstract:Comfrey has been consumed by humans as a vegetable and a tea and used as an herbal medicine for more than 2000 years. Comfrey, however, produces hepatotoxicity in livestock and humans and carcinogenicity in experimental animals. Comfrey contains as many as 14 pyrrolizidine alkaloids (PA), including 7-acetylintermedine, 7-acetyllycopsamine, echimidine, intermedine, lasiocarpine, lycopsamine, myoscorpine, symlandine, symphytine, and symviridine. The mechanisms underlying Comfrey-induced genotoxicity and carcinogenicity are still not fully understood. The available evidence suggests that the active metabolites of PA in Comfrey interact with DNA in liver endothelial cells and hepatocytes, resulting in DNA damage, mutation induction, and cancer development. Genotoxicities attributed to Comfrey and riddelliine (a representative genotoxic PA and a proven rodent mutagen and carcinogen) are discussed in this review. Both of these compounds induced similar profiles of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts and similar mutation spectra. Further, the two agents share common mechanisms of drug metabolism and carcinogenesis. Overall, Comfrey is mutagenic in liver, and PA contained in Comfrey appear to be responsible for Comfrey-induced toxicity and tumor induction.
James C. Fuscoe - One of the best experts on this subject based on the ideXlab platform.
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MicroRNAs and their predicted target messenger RNAs are deregulated by exposure to a carcinogenic dose of Comfrey in rat liver.
Environmental and molecular mutagenesis, 2011Co-Authors: James C. Fuscoe, Tao ChenAbstract:MicroRNAs (MiRNAs) are small noncoding RNAs that function as regulators of gene expression to control cell growth and differentiation. In this study, we analyzed miRNA and mRNA expression in the livers of rats treated with a carcinogenic dose of Comfrey (Symphytum officinale) for 12 weeks. Groups of six rats were fed a normal diet or a diet containing 8% Comfrey root. The animals were sacrificed 1 day after the last treatment and the livers were isolated for miRNA expression analysis using LC Sciences miRNA microarrays and for mRNA expression analysis using Affymetrix rat genome microarrays. MiRNA expression levels were significantly changed by Comfrey treatment. The treated samples were separated clearly from the control samples in both principal component analysis (PCA) and hierarchical clustering analysis (HCA). Quantitative measurements of seven miRNAs using TaqMan real-time PCR were consistent with the microarray results in terms of fold-change and the direction of the change in expression. Forty-five miRNAs (P < 0.01) and 1,921 mRNAs (q = 0) were significantly changed by Comfrey treatment. Using a target prediction algorithm, 434 differentially expressed genes (DEGs) were predicted to be targeted by the differentially expressed miRNAs (DEMs). The DEM-targeted DEGs were more likely to be involved in carcinogenesis than the DEGs that were not targeted by the DEMs. The nontargeted DEGs were enriched in noncancer-related biological processes. Our data suggest that Comfrey may exert its carcinogenic effects by disturbing miRNA expression resulting in altered mRNA levels of the DEM-targeted genes that are functionally associated with carcinogenesis. Environ. Mol. Mutagen., 2011. © Published 2011 Wiley-Liss, Inc.
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Metabolism, genotoxicity, and carcinogenicity of Comfrey.
Journal of toxicology and environmental health. Part B Critical reviews, 2010Co-Authors: Nan Mei, Lei Guo, James C. Fuscoe, Yang Luan, Tao ChenAbstract:Comfrey has been consumed by humans as a vegetable and a tea and used as an herbal medicine for more than 2000 years. Comfrey, however, produces hepatotoxicity in livestock and humans and carcinogenicity in experimental animals. Comfrey contains as many as 14 pyrrolizidine alkaloids (PA), including 7-acetylintermedine, 7-acetyllycopsamine, echimidine, intermedine, lasiocarpine, lycopsamine, myoscorpine, symlandine, symphytine, and symviridine. The mechanisms underlying Comfrey-induced genotoxicity and carcinogenicity are still not fully understood. The available evidence suggests that the active metabolites of PA in Comfrey interact with DNA in liver endothelial cells and hepatocytes, resulting in DNA damage, mutation induction, and cancer development. Genotoxicities attributed to Comfrey and riddelliine (a representative genotoxic PA and a proven rodent mutagen and carcinogen) are discussed in this review. Both of these compounds induced similar profiles of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts and similar mutation spectra. Further, the two agents share common mechanisms of drug metabolism and carcinogenesis. Overall, Comfrey is mutagenic in liver, and PA contained in Comfrey appear to be responsible for Comfrey-induced toxicity and tumor induction.
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Analysis of gene expression changes in relation to toxicity and tumorigenesis in the livers of Big Blue transgenic rats fed Comfrey (Symphytum officinale).
BMC Bioinformatics, 2006Co-Authors: Lu Zhang, James C. Fuscoe, Leming Shi, Yongming Andrew Sun, Chris Fung, Carrie L Moland, Stacey L Dial, Tao ChenAbstract:Background Comfrey is consumed by humans as a vegetable and a tea, and has been used as an herbal medicine for more than 2000 years. Comfrey, however, is hepatotoxic in livestock and humans and carcinogenic in experimental animals. Our previous study suggested that Comfrey induces liver tumors by a genotoxic mechanism and that the pyrrolizidine alkaloids in the plant are responsible for mutation induction and tumor initiation in rat liver.
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Analysis of gene expression changes in relation to toxicity and tumorigenesis in the livers of Big Blue transgenic rats fed Comfrey (Symphytum officinale).
BMC bioinformatics, 2006Co-Authors: Lu Zhang, James C. Fuscoe, Leming Shi, Yongming Andrew Sun, Chris Fung, Carrie L Moland, Stacey L Dial, Tao ChenAbstract:Comfrey is consumed by humans as a vegetable and a tea, and has been used as an herbal medicine for more than 2000 years. Comfrey, however, is hepatotoxic in livestock and humans and carcinogenic in experimental animals. Our previous study suggested that Comfrey induces liver tumors by a genotoxic mechanism and that the pyrrolizidine alkaloids in the plant are responsible for mutation induction and tumor initiation in rat liver. In this study, we identified Comfrey-induced gene expression profile in the livers of rats. Groups of 6 male transgenic Big Blue rats were fed a basal diet and a diet containing 8% Comfrey roots, a dose that resulted in liver tumors in a previous carcinogenicity bioassay. The animals were treated for 12 weeks and sacrificed one day after the final treatment. We used a rat microarray containing 26,857 genes to perform genome-wide gene expression studies. Dietary Comfrey resulted in marked changes in liver gene expression, as well as in significant decreases in the body weight and increases in liver mutant frequency. When a two-fold cutoff value and a P-value less than 0.01 were selected, 2,726 genes were identified as differentially expressed in Comfrey-fed rats compared to control animals. Among these genes, there were 1,617 genes associated by Ingenuity Pathway Analysis with particular functions, and the differentially expressed genes in Comfrey-fed rat livers were involved in metabolism, injury of endothelial cells, and liver injury and abnormalities, including liver fibrosis and cancer development. The gene expression profile provides us a better understanding of underlying mechanisms for Comfrey-induced hepatic toxicity. Integration of gene expression changes with known pathological changes can be used to formulate a mechanistic scheme for Comfrey-induced liver toxicity and tumorigenesis.
Stacey L Dial - One of the best experts on this subject based on the ideXlab platform.
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Comparison of gene expression profiles altered by Comfrey and riddelliine in rat liver.
BMC bioinformatics, 2007Co-Authors: Stacey L Dial, James Fuscoe, Tao ChenAbstract:Comfrey (Symphytum officinale) is a perennial plant and has been consumed by humans as a vegetable, a tea and an herbal medicine for more than 2000 years. It, however, is hepatotoxic and carcinogenic in experimental animals and hepatotoxic in humans. Pyrrolizidine alkaloids (PAs) exist in many plants and many of them cause liver toxicity and/or cancer in humans and experimental animals. In our previous study, we found that the mutagenicity of Comfrey was associated with the PAs contained in the plant. Therefore, we suggest that carcinogenicity of Comfrey result from those PAs. To confirm our hypothesis, we compared the expression of genes and processes of biological functions that were altered by Comfrey (mixture of the plant with PAs) and riddelliine (a prototype of carcinogenic PA) in rat liver for carcinogenesis in this study. Groups of 6 Big Blue Fisher 344 rats were treated with riddelliine at 1 mg/kg body weight by gavage five times a week for 12 weeks or fed a diet containing 8% Comfrey root for 12 weeks. Animals were sacrificed one day after the last treatment and the livers were isolated for gene expression analysis. The gene expressions were investigated using Applied Biosystems Rat Whole Genome Survey Microarrays and the biological functions were analyzed with Ingenuity Analysis Pathway software. Although there were large differences between the significant genes and between the biological processes that were altered by Comfrey and riddelliine, there were a number of common genes and function processes that were related to carcinogenesis. There was a strong correlation between the two treatments for fold-change alterations in expression of drug metabolizing and cancer-related genes. Our results suggest that the carcinogenesis-related gene expression patterns resulting from the treatments of Comfrey and riddelliine are very similar, and PAs contained in Comfrey are the main active components responsible for carcinogenicity of the plant.
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Analysis of gene expression changes in relation to toxicity and tumorigenesis in the livers of Big Blue transgenic rats fed Comfrey (Symphytum officinale).
BMC Bioinformatics, 2006Co-Authors: Lu Zhang, James C. Fuscoe, Leming Shi, Yongming Andrew Sun, Chris Fung, Carrie L Moland, Stacey L Dial, Tao ChenAbstract:Background Comfrey is consumed by humans as a vegetable and a tea, and has been used as an herbal medicine for more than 2000 years. Comfrey, however, is hepatotoxic in livestock and humans and carcinogenic in experimental animals. Our previous study suggested that Comfrey induces liver tumors by a genotoxic mechanism and that the pyrrolizidine alkaloids in the plant are responsible for mutation induction and tumor initiation in rat liver.
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Analysis of gene expression changes in relation to toxicity and tumorigenesis in the livers of Big Blue transgenic rats fed Comfrey (Symphytum officinale).
BMC bioinformatics, 2006Co-Authors: Lu Zhang, James C. Fuscoe, Leming Shi, Yongming Andrew Sun, Chris Fung, Carrie L Moland, Stacey L Dial, Tao ChenAbstract:Comfrey is consumed by humans as a vegetable and a tea, and has been used as an herbal medicine for more than 2000 years. Comfrey, however, is hepatotoxic in livestock and humans and carcinogenic in experimental animals. Our previous study suggested that Comfrey induces liver tumors by a genotoxic mechanism and that the pyrrolizidine alkaloids in the plant are responsible for mutation induction and tumor initiation in rat liver. In this study, we identified Comfrey-induced gene expression profile in the livers of rats. Groups of 6 male transgenic Big Blue rats were fed a basal diet and a diet containing 8% Comfrey roots, a dose that resulted in liver tumors in a previous carcinogenicity bioassay. The animals were treated for 12 weeks and sacrificed one day after the final treatment. We used a rat microarray containing 26,857 genes to perform genome-wide gene expression studies. Dietary Comfrey resulted in marked changes in liver gene expression, as well as in significant decreases in the body weight and increases in liver mutant frequency. When a two-fold cutoff value and a P-value less than 0.01 were selected, 2,726 genes were identified as differentially expressed in Comfrey-fed rats compared to control animals. Among these genes, there were 1,617 genes associated by Ingenuity Pathway Analysis with particular functions, and the differentially expressed genes in Comfrey-fed rat livers were involved in metabolism, injury of endothelial cells, and liver injury and abnormalities, including liver fibrosis and cancer development. The gene expression profile provides us a better understanding of underlying mechanisms for Comfrey-induced hepatic toxicity. Integration of gene expression changes with known pathological changes can be used to formulate a mechanistic scheme for Comfrey-induced liver toxicity and tumorigenesis.
Lu Zhang - One of the best experts on this subject based on the ideXlab platform.
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Analysis of gene expression changes in relation to toxicity and tumorigenesis in the livers of Big Blue transgenic rats fed Comfrey (Symphytum officinale).
BMC Bioinformatics, 2006Co-Authors: Lu Zhang, James C. Fuscoe, Leming Shi, Yongming Andrew Sun, Chris Fung, Carrie L Moland, Stacey L Dial, Tao ChenAbstract:Background Comfrey is consumed by humans as a vegetable and a tea, and has been used as an herbal medicine for more than 2000 years. Comfrey, however, is hepatotoxic in livestock and humans and carcinogenic in experimental animals. Our previous study suggested that Comfrey induces liver tumors by a genotoxic mechanism and that the pyrrolizidine alkaloids in the plant are responsible for mutation induction and tumor initiation in rat liver.
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Analysis of gene expression changes in relation to toxicity and tumorigenesis in the livers of Big Blue transgenic rats fed Comfrey (Symphytum officinale).
BMC bioinformatics, 2006Co-Authors: Lu Zhang, James C. Fuscoe, Leming Shi, Yongming Andrew Sun, Chris Fung, Carrie L Moland, Stacey L Dial, Tao ChenAbstract:Comfrey is consumed by humans as a vegetable and a tea, and has been used as an herbal medicine for more than 2000 years. Comfrey, however, is hepatotoxic in livestock and humans and carcinogenic in experimental animals. Our previous study suggested that Comfrey induces liver tumors by a genotoxic mechanism and that the pyrrolizidine alkaloids in the plant are responsible for mutation induction and tumor initiation in rat liver. In this study, we identified Comfrey-induced gene expression profile in the livers of rats. Groups of 6 male transgenic Big Blue rats were fed a basal diet and a diet containing 8% Comfrey roots, a dose that resulted in liver tumors in a previous carcinogenicity bioassay. The animals were treated for 12 weeks and sacrificed one day after the final treatment. We used a rat microarray containing 26,857 genes to perform genome-wide gene expression studies. Dietary Comfrey resulted in marked changes in liver gene expression, as well as in significant decreases in the body weight and increases in liver mutant frequency. When a two-fold cutoff value and a P-value less than 0.01 were selected, 2,726 genes were identified as differentially expressed in Comfrey-fed rats compared to control animals. Among these genes, there were 1,617 genes associated by Ingenuity Pathway Analysis with particular functions, and the differentially expressed genes in Comfrey-fed rat livers were involved in metabolism, injury of endothelial cells, and liver injury and abnormalities, including liver fibrosis and cancer development. The gene expression profile provides us a better understanding of underlying mechanisms for Comfrey-induced hepatic toxicity. Integration of gene expression changes with known pathological changes can be used to formulate a mechanistic scheme for Comfrey-induced liver toxicity and tumorigenesis.
Jeffery O Hall - One of the best experts on this subject based on the ideXlab platform.
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the comparative toxicity of a reduced crude Comfrey symphytum officinale alkaloid extract and the pure Comfrey derived pyrrolizidine alkaloids lycopsamine and intermedine in chicks gallus gallus domesticus
Journal of Applied Toxicology, 2016Co-Authors: Ammon W Brown, Bryan L Stegelmeier, Steven M Colegate, Dale R Gardner, K E Panter, Edward L Knoppel, Jeffery O HallAbstract:Comfrey (Symphytum officinale), a commonly used herb, contains dehydropyrrolizidine alkaloids that, as a group of bioactive metabolites, are potentially hepatotoxic, pneumotoxic, genotoxic and carcinogenic. Consequently, regulatory agencies and international health organizations have recommended Comfrey be used for external use only. However, in many locations Comfrey continues to be ingested as a tisane or as a leafy vegetable. The objective of this work was to compare the toxicity of a crude, reduced Comfrey alkaloid extract to purified lycopsamine and intermedine that are major constituents of S. officinale. Male, California White chicks were orally exposed to daily doses of 0.04, 0.13, 0.26, 0.52 and 1.04 mmol lycopsamine, intermedine or reduced Comfrey extract per kg bodyweight (BW) for 10 days. After another 7 days chicks were euthanized. Based on clinical signs of poisoning, serum biochemistry, and histopathological analysis the reduced Comfrey extract was more toxic than lycopsamine and intermedine. This work suggests a greater than additive effect of the individual alkaloids and/or a more potent toxicity of the acetylated derivatives in the reduced Comfrey extract. It also suggests that safety recommendations based on purified compounds may underestimate the potential toxicity of Comfrey. Published 2015. This article has been contributed to by US Government employees and their work is in the public domain in the USA.
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the comparative toxicity of a reduced crude Comfrey symphytum officinale alkaloid extract and the pure Comfrey derived pyrrolizidine alkaloids lycopsamine and intermedine in chicks gallus gallus domesticus
Journal of Applied Toxicology, 2016Co-Authors: Ammon W Brown, Bryan L Stegelmeier, Steven M Colegate, Dale R Gardner, K E Panter, Edward L Knoppel, Jeffery O HallAbstract:Comfrey (Symphytum officinale), a commonly used herb, contains dehydropyrrolizidine alkaloids that, as a group of bioactive metabolites, are potentially hepatotoxic, pneumotoxic, genotoxic and carcinogenic. Consequently, regulatory agencies and international health organizations have recommended Comfrey be used for external use only. However, in many locations Comfrey continues to be ingested as a tisane or as a leafy vegetable. The objective of this work was to compare the toxicity of a crude, reduced Comfrey alkaloid extract to purified lycopsamine and intermedine that are major constituents of S. officinale. Male, California White chicks were orally exposed to daily doses of 0.04, 0.13, 0.26, 0.52 and 1.04 mmol lycopsamine, intermedine or reduced Comfrey extract per kg bodyweight (BW) for 10 days. After another 7 days chicks were euthanized. Based on clinical signs of poisoning, serum biochemistry, and histopathological analysis the reduced Comfrey extract was more toxic than lycopsamine and intermedine. This work suggests a greater than additive effect of the individual alkaloids and/or a more potent toxicity of the acetylated derivatives in the reduced Comfrey extract. It also suggests that safety recommendations based on purified compounds may underestimate the potential toxicity of Comfrey.