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  1. Article ; Online: Butyrate and docosahexaenoic acid interact in alterations of specific lipid classes in differentiating colon cancer cells.

    Tylichová, Zuzana / Slavík, Josef / Ciganek, Miroslav / Ovesná, Petra / Krčmář, Pavel / Straková, Nicol / Machala, Miroslav / Kozubík, Alois / Hofmanová, Jiřina / Vondráček, Jan

    Journal of cellular biochemistry

    2018  Volume 119, Issue 6, Page(s) 4664–4679

    Abstract: Docosahexaenoic acid (DHA) and sodium butyrate (NaBt) exhibit a number of interactive effects on colon cancer cell growth, differentiation, or apoptosis; however, the molecular mechanisms responsible for these interactions and their impact on cellular ... ...

    Abstract Docosahexaenoic acid (DHA) and sodium butyrate (NaBt) exhibit a number of interactive effects on colon cancer cell growth, differentiation, or apoptosis; however, the molecular mechanisms responsible for these interactions and their impact on cellular lipidome are still not fully clear. Here, we show that both dietary agents together induce dynamic alterations of lipid metabolism, specific cellular lipid classes, and fatty acid composition. In HT-29 cell line, a model of differentiating colon carcinoma cells, NaBt supported incorporation of free DHA into non-polar lipids and their accumulation in cytoplasmic lipid droplets. DHA itself was not incorporated into sphingolipids; however, it significantly altered representation of individual ceramide (Cer) classes, in particular in combination with NaBt (DHA/NaBt). We observed altered expression of enzymes involved in Cer metabolism in cells treated with NaBt or DHA/NaBt, and exogenous Cer 16:0 was found to promote induction of apoptosis in differentiating HT-29 cells. NaBt, together with DHA, increased n-3 fatty acid synthesis and attenuated metabolism of monounsaturated fatty acids. Finally, DHA and/or NaBt altered expression of proteins involved in synthesis of fatty acids, including elongase 5, stearoyl CoA desaturase 1, or fatty acid synthase, with NaBt increasing expression of caveolin-1 and CD36 transporter, which may further promote DHA incorporation and its impact on cellular lipidome. In conclusion, our results indicate that interactions of DHA and NaBt exert complex changes in cellular lipidome, which may contribute to the alterations of colon cancer cell differentiation/apoptotic responses. The present data extend our knowledge about the nature of interactive effects of dietary fatty acids.
    MeSH term(s) Apoptosis/drug effects ; Butyrates/pharmacology ; Cell Differentiation/drug effects ; Colonic Neoplasms/metabolism ; Colonic Neoplasms/pathology ; Docosahexaenoic Acids/pharmacology ; HCT116 Cells ; Humans ; Lipid Metabolism/drug effects ; Membrane Lipids/classification ; Membrane Lipids/metabolism
    Chemical Substances Butyrates ; Membrane Lipids ; Docosahexaenoic Acids (25167-62-8)
    Language English
    Publishing date 2018-02-27
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 392402-6
    ISSN 1097-4644 ; 0730-2312
    ISSN (online) 1097-4644
    ISSN 0730-2312
    DOI 10.1002/jcb.26641
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1114: Show issues Location:
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  2. Article: Relative effective potencies of dioxin-like compounds in rodent and human lung cell models

    Strapáčová, Simona / Brenerová, Petra / Krčmář, Pavel / Andersson, Patrik / van Ede, Karin I / van Duursen, Majorie B.M / van den Berg, Martin / Vondráček, Jan / Machala, Miroslav

    Toxicology. 2018 July 01, v. 404-405

    2018  

    Abstract: Toxicity of dioxin-like compounds (DLCs), such as polychlorinated dibenzo-p-dioxins, dibenzofurans and biphenyls, is largely mediated via aryl hydrocarbon receptor (AhR) activation. AhR-mediated gene expression can be tissue-specific; however, the ... ...

    Abstract Toxicity of dioxin-like compounds (DLCs), such as polychlorinated dibenzo-p-dioxins, dibenzofurans and biphenyls, is largely mediated via aryl hydrocarbon receptor (AhR) activation. AhR-mediated gene expression can be tissue-specific; however, the inducibility of AhR in the lungs, a major target of DLCs, remains poorly characterized. In this study, we developed relative effective potencies (REPs) for a series of DLCs in both rodent (MLE-12, RLE-6TN) and human (A549, BEAS-2B) lung and bronchial epithelial cell models, using expression of both canonical (CYP1A1, CYP1B1) and less well characterized (TIPARP, AHRR, ALDH3A1) AhR target genes. The use of rat, murine and human cell lines allowed us to determine both species-specific differences in sensitivity of responses to DLCs in lung cellular models and deviations from established WHO toxic equivalency factor values (TEF) values. Finally, expression of selected AhR target genes was determined in vivo, using lung tissues of female rats exposed to a single oral dose of DLCs and compared with the obtained in vitro data. All cell models were highly sensitive to DLCs, with murine MLE-12 cells being the most sensitive and human A549 cells being the least sensitive. Interestingly, we observed that four AhR target genes were more sensitive than CYP1A1 in lung cell models (CYP1B1, AHRR, TIPARP and/or ALDH3A1). We found some deviations, with strikingly low REPs for polychlorinated biphenyls PCBs 105, 167, 169 and 189 in rat RLE-6TN cells-derived REPs for a series of 20 DLCs evaluated in this study, as compared with WHO TEF values. For other DLCs, including PCBs 126, 118 and 156, REPs were generally in good accordance with WHO TEF values. This conclusion was supported by in vivo data obtained in rat lung tissue. However, we found that human lung REPs for 2,3,4,7,8-pentachlorodibenzofuran and PCB 126 were much lower than the respective rat lung REPs. Furthermore, PCBs 118 and 156 were almost inactive in these human cells. Our observations may have consequences for risk assessment. Given the differences observed between rat and human data sets, development of human-specific REP/TEFs, and the use of CYP1B1, AHRR, TIPARP and/or ALDH3A1 mRNA inducibility as sensitive endpoints, are recommended for assessment of relative effective potencies of DLCs.
    Keywords World Health Organization ; data collection ; dibenzofuran ; epithelial cells ; females ; gene expression ; human cell lines ; humans ; lungs ; messenger RNA ; mice ; models ; oral administration ; polychlorinated biphenyls ; polychlorinated dibenzodioxins ; rats ; risk assessment ; toxicity
    Language English
    Dates of publication 2018-0701
    Size p. 33-41.
    Publishing place Elsevier B.V.
    Document type Article
    ZDB-ID 184557-3
    ISSN 1879-3185 ; 0300-483X
    ISSN (online) 1879-3185
    ISSN 0300-483X
    DOI 10.1016/j.tox.2018.05.004
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    In stock of ZB MED Cologne/Königswinter

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  3. Article: Quantitative detection of species-specific DNA in feedstuffs and fish meals.

    Krcmar, Pavel / Rencova, Eva

    Journal of food protection

    2005  Volume 68, Issue 6, Page(s) 1217–1221

    Abstract: A sensitive and rapid method for the quantitative detection of bovine-, ovine-, swine-, and chicken-specific mitochondrial DNA sequences based on real-time PCR has been developed. The specificity of the primers and probes for real-time PCR has been ... ...

    Abstract A sensitive and rapid method for the quantitative detection of bovine-, ovine-, swine-, and chicken-specific mitochondrial DNA sequences based on real-time PCR has been developed. The specificity of the primers and probes for real-time PCR has been tested using DNA samples of other vertebrate species that may also be present in rendered products. The quantitative detection was performed with dual-labeled probes (TaqMan) using absolute quantification with external standards of single species meat-and-bone meals. This method facilitates the detection of 0.01% of the target species-derived material in concentrate feed mixtures and fish meals.
    MeSH term(s) Animal Feed/analysis ; Animals ; Cattle/genetics ; Chickens/genetics ; DNA, Mitochondrial/analysis ; Fish Products/analysis ; Polymerase Chain Reaction/methods ; Prion Diseases/prevention & control ; Ruminants ; Sensitivity and Specificity ; Sheep/genetics ; Species Specificity ; Swine/genetics
    Chemical Substances DNA, Mitochondrial
    Language English
    Publishing date 2005-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 243284-5
    ISSN 1944-9097 ; 0362-028X
    ISSN (online) 1944-9097
    ISSN 0362-028X
    DOI 10.4315/0362-028x-68.6.1217
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Z 2631: Show issues

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  4. Article: Identification of species-specific DNA in feedstuffs.

    Krcmar, Pavel / Rencova, Eva

    Journal of agricultural and food chemistry

    2003  Volume 51, Issue 26, Page(s) 7655–7658

    Abstract: Due to the menace of transmission of spongiform encephalopathies, feed components intended for ruminant nutrition must be checked for the presence of ruminant-derived materials. A sensitive method for the identification of bovine- and ovine- and also ... ...

    Abstract Due to the menace of transmission of spongiform encephalopathies, feed components intended for ruminant nutrition must be checked for the presence of ruminant-derived materials. A sensitive method for the identification of bovine- and ovine- and also swine- and chicken-specific mitochondrial DNA sequences based on Polymerase Chain Reaction (PCR) has been developed. The specificity of the primers for PCR has been tested using samples of DNA of other vertebrate species, which may also be present in rendering plant products intended for feed manufacture. The method allows the detection in concentrate mixtures of 0.01% of the target species derived material. The identity of a sample containing 0.1% of bovine, ovine, swine, and chicken meat-and-bone meal has further been confirmed by sequencing.
    MeSH term(s) Animal Feed/analysis ; Animals ; Bone and Bones ; Cattle/genetics ; Chickens/genetics ; DNA, Mitochondrial/analysis ; Meat ; Polymerase Chain Reaction ; Prion Diseases/prevention & control ; Ruminants ; Sensitivity and Specificity ; Sheep/genetics ; Swine/genetics
    Chemical Substances DNA, Mitochondrial
    Language English
    Publishing date 2003-12-17
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 241619-0
    ISSN 1520-5118 ; 0021-8561
    ISSN (online) 1520-5118
    ISSN 0021-8561
    DOI 10.1021/jf034167y
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1172: Show issues Location:
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  5. Article ; Online: Relative effective potencies of dioxin-like compounds in rodent and human lung cell models.

    Strapáčová, Simona / Brenerová, Petra / Krčmář, Pavel / Andersson, Patrik / van Ede, Karin I / van Duursen, Majorie B M / van den Berg, Martin / Vondráček, Jan / Machala, Miroslav

    Toxicology

    2018  Volume 404-405, Page(s) 33–41

    Abstract: Toxicity of dioxin-like compounds (DLCs), such as polychlorinated dibenzo-p-dioxins, dibenzofurans and biphenyls, is largely mediated via aryl hydrocarbon receptor (AhR) activation. AhR-mediated gene expression can be tissue-specific; however, the ... ...

    Abstract Toxicity of dioxin-like compounds (DLCs), such as polychlorinated dibenzo-p-dioxins, dibenzofurans and biphenyls, is largely mediated via aryl hydrocarbon receptor (AhR) activation. AhR-mediated gene expression can be tissue-specific; however, the inducibility of AhR in the lungs, a major target of DLCs, remains poorly characterized. In this study, we developed relative effective potencies (REPs) for a series of DLCs in both rodent (MLE-12, RLE-6TN) and human (A549, BEAS-2B) lung and bronchial epithelial cell models, using expression of both canonical (CYP1A1, CYP1B1) and less well characterized (TIPARP, AHRR, ALDH3A1) AhR target genes. The use of rat, murine and human cell lines allowed us to determine both species-specific differences in sensitivity of responses to DLCs in lung cellular models and deviations from established WHO toxic equivalency factor values (TEF) values. Finally, expression of selected AhR target genes was determined in vivo, using lung tissues of female rats exposed to a single oral dose of DLCs and compared with the obtained in vitro data. All cell models were highly sensitive to DLCs, with murine MLE-12 cells being the most sensitive and human A549 cells being the least sensitive. Interestingly, we observed that four AhR target genes were more sensitive than CYP1A1 in lung cell models (CYP1B1, AHRR, TIPARP and/or ALDH3A1). We found some deviations, with strikingly low REPs for polychlorinated biphenyls PCBs 105, 167, 169 and 189 in rat RLE-6TN cells-derived REPs for a series of 20 DLCs evaluated in this study, as compared with WHO TEF values. For other DLCs, including PCBs 126, 118 and 156, REPs were generally in good accordance with WHO TEF values. This conclusion was supported by in vivo data obtained in rat lung tissue. However, we found that human lung REPs for 2,3,4,7,8-pentachlorodibenzofuran and PCB 126 were much lower than the respective rat lung REPs. Furthermore, PCBs 118 and 156 were almost inactive in these human cells. Our observations may have consequences for risk assessment. Given the differences observed between rat and human data sets, development of human-specific REP/TEFs, and the use of CYP1B1, AHRR, TIPARP and/or ALDH3A1 mRNA inducibility as sensitive endpoints, are recommended for assessment of relative effective potencies of DLCs.
    MeSH term(s) A549 Cells ; Animals ; Dioxins/toxicity ; Dose-Response Relationship, Drug ; Female ; Humans ; Lung/drug effects ; Lung/metabolism ; Lung/pathology ; Mice ; Rats ; Rats, Sprague-Dawley ; Rodentia ; Species Specificity ; Toxicity Tests, Acute/methods
    Chemical Substances Dioxins
    Language English
    Publishing date 2018-05-05
    Publishing country Ireland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 184557-3
    ISSN 1879-3185 ; 0300-483X
    ISSN (online) 1879-3185
    ISSN 0300-483X
    DOI 10.1016/j.tox.2018.05.004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Benzo[a]pyrene and tumor necrosis factor-α coordinately increase genotoxic damage and the production of proinflammatory mediators in alveolar epithelial type II cells

    Umannová, Lenka / Machala, Miroslav / Topinka, Jan / Schmuczerová, Jana / Krčmář, Pavel / Neča, Jiří / Šujanová, Klára / Kozubík, Alois / Vondráček, Jan

    Toxicology letters. 2011 Oct. 10, v. 206, no. 2

    2011  

    Abstract: Alveolar type II epithelial (AEII) cells regulate lung inflammatory response and, simultaneously, they are a target of environmental carcinogenic factors. We employed an in vitro model of rat AEII cells, the RLE-6TN cell line, in order to analyze the ... ...

    Abstract Alveolar type II epithelial (AEII) cells regulate lung inflammatory response and, simultaneously, they are a target of environmental carcinogenic factors. We employed an in vitro model of rat AEII cells, the RLE-6TN cell line, in order to analyze the interactive effects of tumor necrosis factor-α (TNF-α), a cytokine which plays a key role in the initiation of inflammatory responses in the lung, and benzo[a]pyrene (BaP), a highly carcinogenic polycyclic aromatic hydrocarbon. TNF-α strongly augmented the formation of stable BaP diol epoxide-DNA adducts in AEII cells, which was associated with enhanced p53-Ser15 phosphorylation and decreased cell survival. The increased genotoxicity of BaP was associated with altered expression of cytochrome P450 (CYP) enzymes involved in its bioactivation, a simultaneous suppression of CYP1A1 and enhancement of CYP1B1 expression. Importantly, BaP and TNF-α acted synergistically to upregulate key inflammatory regulators in AEII cells, including the expression of inducible NO synthase and cyclooxygenase-2 (COX-2), and enhanced prostaglandin E2 production and expression of proinflammatory cytokines, such as TNF-α, interleukin-1β and interleukin-6. We observed that BaP and TNF-α together strongly activated p38 kinase, a principal regulator of inflammatory response. SB202190, a specific p38 inhibitor, prevented induction of both COX-2 and proinflammatory cytokines, thus confirming that p38 activity was crucial for the observed inflammatory reaction. Taken together, our data demonstrated, for the first time, that a proinflammatory cytokine and an environmental PAH may interact to potentiate both DNA damage and the inflammatory response in AEII cells, which may occur through coordinated upregulation of p38 activity.
    Keywords DNA damage ; animal models ; benzo(a)pyrene ; carcinogenicity ; carcinogens ; cell viability ; cytochrome P-450 ; genotoxicity ; inflammation ; interleukin-1beta ; interleukin-6 ; necrosis ; nitric oxide synthase ; phosphorylation ; polycyclic aromatic hydrocarbons ; prostaglandin synthase ; prostaglandins ; tumor necrosis factor-alpha
    Language English
    Dates of publication 2011-1010
    Size p. 121-129.
    Publishing place Elsevier Ireland Ltd
    Document type Article
    ZDB-ID 433788-8
    ISSN 1879-3169 ; 0378-4274
    ISSN (online) 1879-3169
    ISSN 0378-4274
    DOI 10.1016/j.toxlet.2011.06.029
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1367: Show issues Location:
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  7. Article ; Online: AhR-mediated changes in global gene expression in rat liver progenitor cells.

    Faust, Dagmar / Vondráček, Jan / Krčmář, Pavel / Smerdová, Lenka / Procházková, Jiřina / Hrubá, Eva / Hulinková, Petra / Kaina, Bernd / Dietrich, Cornelia / Machala, Miroslav

    Archives of toxicology

    2013  Volume 87, Issue 4, Page(s) 681–698

    Abstract: Although the tumor-promoting effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), coplanar polychlorinated biphenyls (PCBs), and related compounds in liver tissue are primarily attributed to the activation of the aryl hydrocarbon receptor (AhR), the ... ...

    Abstract Although the tumor-promoting effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), coplanar polychlorinated biphenyls (PCBs), and related compounds in liver tissue are primarily attributed to the activation of the aryl hydrocarbon receptor (AhR), the underlying molecular mechanisms are still unclear. Liver progenitor (oval) cells have been suggested to constitute a potential target for hepatocarcinogenic chemicals. To better understand AhR-driven pathways, we analyzed the transcriptional program in response to coplanar PCB 126 in contact-inhibited rat liver progenitor WB-F344 cells using high-density microarrays. After 6-h treatment, we identified 145 significantly deregulated genes considered to be direct AhR-dependent target genes. The number of differentially regulated genes increased to 658 and 968 genes after 24 and 72 h, respectively. Gene ontology analysis revealed that these genes were primarily involved in drug and lipid metabolism, cell cycle and growth control, cancer developmental processes, cell-cell communication, and adhesion. Interestingly, the Wnt and TGF-β signaling pathways, both being involved in developmental and tumorigenic processes, belonged to the most affected pathways. AhR- and ARNT-dependent regulation of selected target genes of interest was then confirmed using TCDD as a model AhR agonist, together with pharmacological inhibition of the AhR and by RNA-interference techniques. We demonstrated AhR-dependent regulation of emerging and novel AhR target genes, such as Fst, Areg, Hbegf, Ctgf, Btg2, and Foxq1. Among them, the transcription factor Foxq1, recently suggested to contribute to tumor promotion and/or progression, was found to be regulated at both mRNA and protein levels by AhR/ARNT activation.
    MeSH term(s) Animals ; Cell Line ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; Estrogen Antagonists/toxicity ; Gene Expression Regulation/drug effects ; Gene Expression Regulation/genetics ; Gene Knockdown Techniques ; Liver/drug effects ; Liver/metabolism ; Liver/pathology ; Oligonucleotide Array Sequence Analysis ; Polychlorinated Biphenyls/toxicity ; Rats ; Receptors, Aryl Hydrocarbon/genetics ; Receptors, Aryl Hydrocarbon/metabolism ; Stem Cells/drug effects ; Stem Cells/metabolism ; Stem Cells/pathology
    Chemical Substances Estrogen Antagonists ; Receptors, Aryl Hydrocarbon ; Polychlorinated Biphenyls (DFC2HB4I0K) ; 3,4,5,3',4'-pentachlorobiphenyl (TSH69IA9XF)
    Language English
    Publishing date 2013-04
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 124992-7
    ISSN 1432-0738 ; 0340-5761
    ISSN (online) 1432-0738
    ISSN 0340-5761
    DOI 10.1007/s00204-012-0979-z
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    Uf I Zs.90: Show issues Location:
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  8. Article ; Online: The 2,2',4,4',5,5'-hexachlorobiphenyl-enhanced degradation of connexin 43 involves both proteasomal and lysosomal activities.

    Simecková, Pavlína / Vondrácek, Jan / Andrysík, Zdenek / Zatloukalová, Jirina / Krcmár, Pavel / Kozubík, Alois / Machala, Miroslav

    Toxicological sciences : an official journal of the Society of Toxicology

    2009  Volume 107, Issue 1, Page(s) 9–18

    Abstract: One of the toxic effects of non-dioxin-like polychlorinated biphenyls (NDL-PCBs) is the acute inhibition of gap junctional intercellular communication (GJIC), an event possibly associated with tumor promotion. The model NDL-PCB-2,2',4,4',5,5'- ... ...

    Abstract One of the toxic effects of non-dioxin-like polychlorinated biphenyls (NDL-PCBs) is the acute inhibition of gap junctional intercellular communication (GJIC), an event possibly associated with tumor promotion. The model NDL-PCB-2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153)-induces a sustained GJIC inhibition in rat liver epithelial WB-F344 cells. As this effect might be related to deregulation of connexin 43 (Cx43) synthesis, trafficking, or degradation, we investigated the impact of PCB 153 on these events. Although PCB 153 had no effect on Cx43 mRNA levels, it induced a gradual loss of Cx43 protein and significantly decreased the amount of gap junction plaques in plasma membrane. PCB 153 contributed to extracellular signal-regulated kinases 1 and 2 (ERK1/2)-dependent accumulation of hyperphosphorylated Cx43-P3 form, thus indicating that ERK1/2 activation by PCB 153 might contribute to its effects on Cx43 internalization or degradation. Inhibition of either proteasomes or lysosomes with their specific inhibitors largely restored total Cx43 protein levels, thus suggesting that both proteasomes and lysosomes may participate in the PCB 153-enhanced Cx43 internalization and degradation. However, neither the proteasomal nor the lysosomal inhibitors restored normal GJIC or number/size of gap junction plaques. Finally, PCB 153 also interfered with restoration of gap junction plaques following the inhibition of Cx43 transport to plasma membrane. Taken together, multiple modes of action seem to contribute to downregulation of Cx43 in PCB 153-treated rat liver epithelial cells. The enhanced degradation of Cx43, together with persistent inhibition of GJIC, might contribute to tumor-promoting effects of NDL-PCBs.
    MeSH term(s) Analysis of Variance ; Animals ; Cell Communication/drug effects ; Cell Line ; Cell Membrane/drug effects ; Connexin 43/genetics ; Connexin 43/metabolism ; Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Gap Junctions/drug effects ; Gap Junctions/metabolism ; Leupeptins/pharmacology ; Liver/metabolism ; Lysosomes/drug effects ; Lysosomes/metabolism ; Metabolic Networks and Pathways/drug effects ; Polychlorinated Biphenyls/pharmacology ; Proteasome Endopeptidase Complex/drug effects ; Proteasome Endopeptidase Complex/metabolism ; Proteasome Inhibitors ; Rats
    Chemical Substances Connexin 43 ; Leupeptins ; Proteasome Inhibitors ; Polychlorinated Biphenyls (DFC2HB4I0K) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; leupeptin (J97339NR3V) ; 2,4,5,2',4',5'-hexachlorobiphenyl (ZRU0C9E32O)
    Language English
    Publishing date 2009-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1420885-4
    ISSN 1096-0929 ; 1096-6080
    ISSN (online) 1096-0929
    ISSN 1096-6080
    DOI 10.1093/toxsci/kfn202
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  9. Article ; Online: Benzo[a]pyrene and tumor necrosis factor-α coordinately increase genotoxic damage and the production of proinflammatory mediators in alveolar epithelial type II cells.

    Umannová, Lenka / Machala, Miroslav / Topinka, Jan / Schmuczerová, Jana / Krčmář, Pavel / Neča, Jiří / Šujanová, Klára / Kozubík, Alois / Vondráček, Jan

    Toxicology letters

    2011  Volume 206, Issue 2, Page(s) 121–129

    Abstract: Alveolar type II epithelial (AEII) cells regulate lung inflammatory response and, simultaneously, they are a target of environmental carcinogenic factors. We employed an in vitro model of rat AEII cells, the RLE-6TN cell line, in order to analyze the ... ...

    Abstract Alveolar type II epithelial (AEII) cells regulate lung inflammatory response and, simultaneously, they are a target of environmental carcinogenic factors. We employed an in vitro model of rat AEII cells, the RLE-6TN cell line, in order to analyze the interactive effects of tumor necrosis factor-α (TNF-α), a cytokine which plays a key role in the initiation of inflammatory responses in the lung, and benzo[a]pyrene (BaP), a highly carcinogenic polycyclic aromatic hydrocarbon. TNF-α strongly augmented the formation of stable BaP diol epoxide-DNA adducts in AEII cells, which was associated with enhanced p53-Ser15 phosphorylation and decreased cell survival. The increased genotoxicity of BaP was associated with altered expression of cytochrome P450 (CYP) enzymes involved in its bioactivation, a simultaneous suppression of CYP1A1 and enhancement of CYP1B1 expression. Importantly, BaP and TNF-α acted synergistically to upregulate key inflammatory regulators in AEII cells, including the expression of inducible NO synthase and cyclooxygenase-2 (COX-2), and enhanced prostaglandin E2 production and expression of proinflammatory cytokines, such as TNF-α, interleukin-1β and interleukin-6. We observed that BaP and TNF-α together strongly activated p38 kinase, a principal regulator of inflammatory response. SB202190, a specific p38 inhibitor, prevented induction of both COX-2 and proinflammatory cytokines, thus confirming that p38 activity was crucial for the observed inflammatory reaction. Taken together, our data demonstrated, for the first time, that a proinflammatory cytokine and an environmental PAH may interact to potentiate both DNA damage and the inflammatory response in AEII cells, which may occur through coordinated upregulation of p38 activity.
    MeSH term(s) Alveolar Epithelial Cells/drug effects ; Alveolar Epithelial Cells/immunology ; Alveolar Epithelial Cells/metabolism ; Animals ; Apoptosis/drug effects ; Aryl Hydrocarbon Hydroxylases/genetics ; Aryl Hydrocarbon Hydroxylases/metabolism ; Benzo(a)pyrene/metabolism ; Benzo(a)pyrene/toxicity ; Carcinogens, Environmental/toxicity ; Cell Line ; Cell Proliferation/drug effects ; Cytochrome P-450 CYP1A1/genetics ; Cytochrome P-450 CYP1A1/metabolism ; Cytochrome P-450 CYP1B1 ; DNA Adducts/metabolism ; Enzyme Activation/drug effects ; Gene Expression Regulation/drug effects ; Inflammation Mediators/metabolism ; Mutagens/toxicity ; Phosphorylation/drug effects ; Protein Kinase Inhibitors/pharmacology ; Protein Processing, Post-Translational/drug effects ; RNA, Messenger/metabolism ; Rats ; Tumor Necrosis Factor-alpha/metabolism ; Tumor Suppressor Protein p53/metabolism ; p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors ; p38 Mitogen-Activated Protein Kinases/metabolism
    Chemical Substances Carcinogens, Environmental ; DNA Adducts ; Inflammation Mediators ; Mutagens ; Protein Kinase Inhibitors ; RNA, Messenger ; Tumor Necrosis Factor-alpha ; Tumor Suppressor Protein p53 ; Benzo(a)pyrene (3417WMA06D) ; Aryl Hydrocarbon Hydroxylases (EC 1.14.14.1) ; Cyp1b1 protein, rat (EC 1.14.14.1) ; Cytochrome P-450 CYP1A1 (EC 1.14.14.1) ; Cytochrome P-450 CYP1B1 (EC 1.14.14.1) ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24)
    Language English
    Publishing date 2011-10-10
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 433788-8
    ISSN 1879-3169 ; 0378-4274
    ISSN (online) 1879-3169
    ISSN 0378-4274
    DOI 10.1016/j.toxlet.2011.06.029
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  10. Article: beta-Naphthoflavone and 3'-methoxy-4'-nitroflavone exert ambiguous effects on Ah receptor-dependent cell proliferation and gene expression in rat liver 'stem-like' cells.

    Zatloukalová, Jirina / Svihálková-Sindlerová, Lenka / Kozubík, Alois / Krcmár, Pavel / Machala, Miroslav / Vondrácek, Jan

    Biochemical pharmacology

    2007  Volume 73, Issue 10, Page(s) 1622–1634

    Abstract: Both natural and synthetic flavonoids are known to interact with the aryl hydrocarbon receptor (AhR); however, their agonist/antagonist properties in vitro have been so far studied mostly in the context of cytochrome P450 1A1 gene (Cyp1a1) regulation. We ...

    Abstract Both natural and synthetic flavonoids are known to interact with the aryl hydrocarbon receptor (AhR); however, their agonist/antagonist properties in vitro have been so far studied mostly in the context of cytochrome P450 1A1 gene (Cyp1a1) regulation. We investigated effects of two synthetic flavones known either as AhR agonist (beta-naphthoflavone; BNF) or antagonist (3'-methoxy-4'-nitroflavone; 3M4NF), using an in vitro model of liver 'stem-like' cells, on expression of various AhR target genes and AhR-dependent cell proliferation. We found that the presumed antagonist 3M4NF induces a partial nuclear translocation and activation of AhR. Although inhibiting the 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced Cyp1a1 expression, 3M4NF alone induced a minor increase of CYP1A1 mRNA and protein. However, 3M4NF did not induce AhR binding to synthetic dioxin response elements (DRE). In contrast to Cyp1a1, 3M4NF induced a marked expression of other AhR-regulated genes, such as Cyp1b1 and Nqo1, as well as transcriptional repression of Cdh13 gene, confirming that its effects may be promoter-context specific. Like BNF, 3M4NF induced AhR-dependent cell proliferation of contact-inhibited rat liver 'stem-like' WB-F344 cells, associated with a marked upregulation of Cyclin A, as well as the downregulation of proteins involved in formation of cell-cell contacts. Based on these experimental findings, we conclude that partial agonists/antagonists of AhR can increase cell proliferation rate and AhR-dependent genes expression in both cell type- and gene-specific manner. The specificity of effects of flavones on diverse AhR targets should be taken into account, when studying AhR signaling using presumed AhR antagonists.
    MeSH term(s) Animals ; Cadherins/genetics ; Cadherins/metabolism ; Cell Proliferation/drug effects ; Cells, Cultured ; Cytochrome P-450 CYP1A1/genetics ; Cytochrome P-450 CYP1A1/metabolism ; Flavonoids/pharmacology ; Gene Expression/drug effects ; Gene Expression/physiology ; Hepatocytes/drug effects ; Hepatocytes/physiology ; Liver/cytology ; NAD(P)H Dehydrogenase (Quinone)/genetics ; NAD(P)H Dehydrogenase (Quinone)/metabolism ; Rats ; Rats, Inbred F344 ; Receptors, Aryl Hydrocarbon/genetics ; Receptors, Aryl Hydrocarbon/metabolism ; beta-Naphthoflavone/pharmacology
    Chemical Substances 3'-methoxy-4'-nitroflavone ; Cadherins ; Flavonoids ; H-cadherin ; Receptors, Aryl Hydrocarbon ; beta-Naphthoflavone (6051-87-2) ; Cytochrome P-450 CYP1A1 (EC 1.14.14.1) ; NAD(P)H Dehydrogenase (Quinone) (EC 1.6.5.2) ; NQO1 protein, rat (EC 1.6.5.2)
    Language English
    Publishing date 2007-05-15
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 208787-x
    ISSN 1873-2968 ; 0006-2952
    ISSN (online) 1873-2968
    ISSN 0006-2952
    DOI 10.1016/j.bcp.2007.01.032
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