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Sample records for significantly induced cyp1a1

  1. Harman induces CYP1A1 enzyme through an aryl hydrocarbon receptor mechanism

    International Nuclear Information System (INIS)

    El Gendy, Mohamed A.M.; El-Kadi, Ayman O.S.

    2010-01-01

    Harman is a common compound in several foods, plants and beverages. Numerous studies have demonstrated its mutagenic, co-mutagenic and carcinogenic effects; however, the exact mechanism has not been fully identified. Aryl hydrocarbon receptor (AhR) is a transcription factor regulating the expression of the carcinogen-activating enzyme; cytochrome P450 1A1 (CYP1A1). In the present study, we examined the ability of harman to induce AhR-mediated signal transduction in human and rat hepatoma cells; HepG2 and H4IIE cells. Our results showed that harman significantly induced CYP1A1 mRNA in a time- and concentration-dependent manner. Similarly, harman significantly induced CYP1A1 at protein and activity levels in a concentration-dependent manner. Moreover, the AhR antagonist, resveratrol, inhibited the increase in CYP1A1 activity by harman. The RNA polymerase inhibitor, actinomycin D, completely abolished the CYP1A1 mRNA induction by harman, indicating a transcriptional activation. The role of AhR in CYP1A1 induction by harman was confirmed by using siRNA specific for human AhR. The ability of harman to induce CYP1A1 was strongly correlated with its ability to stimulate AhR-dependent luciferase activity and electrophoretic mobility shift assay. At post-transcriptional and post-translational levels, harman did not affect the stability of CYP1A1 at the mRNA and the protein levels, excluding other mechanisms participating in the obtained effects. We concluded that harman can directly induce CYP1A1 gene expression in an AhR-dependent manner and may represent a novel mechanism by which harman promotes mutagenicity, co-mutagenicity and carcinogenicity.

  2. Strong synergistic induction of CYP1A1 expression by andrographolide plus typical CYP1A inducers in mouse hepatocytes

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    Jaruchotikamol, Atika [Department of Toxicology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194 (Japan); Jarukamjorn, Kanokwan [Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002 (Thailand); Sirisangtrakul, Wanna [Department of Toxicology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194 (Japan); Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002 (Thailand); Sakuma, Tsutomu; Kawasaki, Yuki [Department of Toxicology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194 (Japan); Nemoto, Nobuo [Department of Toxicology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194 (Japan)

    2007-10-15

    The effects of andrographolide, the major diterpenoid constituent of Andrographis paniculata, on the expression of cytochrome P450 superfamily 1 members, including CYP1A1, CYP1A2, and CYP1B1, as well as on aryl hydrocarbon receptor (AhR) expression in primary cultures of mouse hepatocytes were investigated in comparison with the effects of typical CYP1A inducers, including benz[a]anthracene, {beta}-naphthoflavone, and 2,3,7,8-tetrachlorodibenzo-p-dioxin. Andrographolide significantly induced the expression of CYP1A1 and CYP1A2 mRNAs in a concentration-dependent manner, as did the typical CYP1A inducers, but did not induce that of CYP1B1 or AhR. Interestingly, andrographolide plus the typical CYP1A inducers synergistically induced CYP1A1 expression, and the synergism was blocked by an AhR antagonist, resveratrol. The CYP1A1 enzyme activity showed a similar pattern of induction. This is the first report that shows that andrographolide has a potency to induce CYP1A1 enzyme and indicates that andrographolide could be a very useful compound for investigating the regulatory mechanism of the CYP1A1 induction pathway. In addition, our findings suggest preparing advice for rational administration of A. paniculata, according to its ability to induce CYP1A1 expression.

  3. Strong synergistic induction of CYP1A1 expression by andrographolide plus typical CYP1A inducers in mouse hepatocytes

    International Nuclear Information System (INIS)

    Jaruchotikamol, Atika; Jarukamjorn, Kanokwan; Sirisangtrakul, Wanna; Sakuma, Tsutomu; Kawasaki, Yuki; Nemoto, Nobuo

    2007-01-01

    The effects of andrographolide, the major diterpenoid constituent of Andrographis paniculata, on the expression of cytochrome P450 superfamily 1 members, including CYP1A1, CYP1A2, and CYP1B1, as well as on aryl hydrocarbon receptor (AhR) expression in primary cultures of mouse hepatocytes were investigated in comparison with the effects of typical CYP1A inducers, including benz[a]anthracene, β-naphthoflavone, and 2,3,7,8-tetrachlorodibenzo-p-dioxin. Andrographolide significantly induced the expression of CYP1A1 and CYP1A2 mRNAs in a concentration-dependent manner, as did the typical CYP1A inducers, but did not induce that of CYP1B1 or AhR. Interestingly, andrographolide plus the typical CYP1A inducers synergistically induced CYP1A1 expression, and the synergism was blocked by an AhR antagonist, resveratrol. The CYP1A1 enzyme activity showed a similar pattern of induction. This is the first report that shows that andrographolide has a potency to induce CYP1A1 enzyme and indicates that andrographolide could be a very useful compound for investigating the regulatory mechanism of the CYP1A1 induction pathway. In addition, our findings suggest preparing advice for rational administration of A. paniculata, according to its ability to induce CYP1A1 expression

  4. Cyp1a1(-/-) male mice: protection against high-dose TCDD-induced lethality and wasting syndrome, and resistance to intrahepatocyte lipid accumulation and uroporphyria

    International Nuclear Information System (INIS)

    Uno, Shigeyuki; Dalton, Timothy P.; Sinclair, Peter R.; Gorman, Nadia; Wang, Bin; Smith, Andrew G.; Miller, Marian L.; Shertzer, Howard G.; Nebert, Daniel W.

    2004-01-01

    To study liver toxicity and uroporphyrin (URO) accumulation and urinary excretion, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent ligand for the aryl hydrocarbon receptor (AHR), is often used as the prototype. In this study, we asked the question how important is the role of CYP1A1 in causing TCDD toxicity. Using a single large intraperitoneal dose of TCDD (200 μg/kg) and following the response over an 8-week period, we found this dose: (a) was lethal in less than 4 weeks to Cyp1a1(+/+) males but not to Cyp1a1(-/-) males or to females of either genotype; (b) caused a wasting syndrome in Cyp1a1(+/+) but not Cyp1a1(-/-) mice; (c) resulted in thymic atrophy, regardless of gender or genotype; (d) decreased spleen size and caused leukocytopenia in males but not females of either genotype; (e) caused hepatocyte hypertrophy in Cyp1a1(+/+) more so than in Cyp1a1(-/-) mice; (f) increased intrahepatocyte lipids and total liver fat content in Cyp1a1(+/+) more than Cyp1a1(-/-) males and females; and (g) caused uroporphyria in Cyp1a1(+/+) males much more than Cyp1a1(+/+) females, or in Cyp1a1(-/-) mice. Contrary to Cyp1a2(-/-) knockout mice that exhibited 15 times less accumulation of TCDD in liver than Cyp1a1/1a2(+/+) wild-type mice, Cyp1a1(-/-) mice did not show this altered TCDD distribution - indicating that CYP1A2 but not CYP1A1 is the major hepatic TCDD-binding 'sink'. Our data demonstrate that CYP1A1 contributes to high-dose TCDD-induced toxicity, uroporphyria, and lethality

  5. Caffeic acid phenethyl ester inhibits 3-MC-induced CYP1A1 expression through induction of hypoxia-inducible factor-1α

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    Kim, Hyung Gyun [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of); Han, Eun Hee [Division of Life Science, Korea Basic Science Institute, Daejeon (Korea, Republic of); Im, Ji Hye; Lee, Eun Ji; Jin, Sun Woo [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of); Jeong, Hye Gwang, E-mail: hgjeong@cnu.ac.kr [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of)

    2015-09-25

    Caffeic acid phenethyl ester (CAPE), a natural component of propolis, is reported to have anticarcinogenic properties, although its precise chemopreventive mechanism remains unclear. In this study, we examined the effects of CAPE on 3-methylcholanthrene (3-MC)-induced CYP1A1 expression and activities. CAPE reduced the formation of the benzo[a]pyrene-DNA adduct. Moreover, CAPE inhibited 3-MC-induced CYP1A1 activity, mRNA expression, protein level, and promoter activity. CAPE treatment also decreased 3-MC-inducible xenobiotic-response element (XRE)-linked luciferase, aryl hydrocarbons receptor (AhR) transactivation and nuclear localization. CAPE induced hypoxia inducible factor-1α (HIF-1α) protein level and HIF-1α responsible element (HRE) transcriptional activity. CAPE-mediated HIF-1α reduced 3-MC-inducible CYP1A1 protein expression. Taken together, CAPE decreases 3-MC-mediated CYP1A1 expression, and this inhibitory response is associated with inhibition of AhR and HIF-1α induction. - Highlights: • CAPE reduced the formation of the benzo[a]pyrene-DNA adduct. • CAPE inhibited 3-MC-induced CYP1A1 expression. • CAPE induced HIF-1α induction. • CAPE-mediated HIF-1α reduced 3-MC-inducible CYP1A1 expression.

  6. Hypoxia perturbs aryl hydrocarbon receptor signaling and CYP1A1 expression induced by PCB 126 in human skin and liver-derived cell lines

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    Vorrink, Sabine U. [Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA (United States); Department of Radiation Oncology, The University of Iowa, Iowa City, IA (United States); Severson, Paul L. [Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ (United States); Kulak, Mikhail V. [Department of Surgery, The University of Iowa, Iowa City, IA (United States); Futscher, Bernard W. [Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ (United States); Domann, Frederick E., E-mail: frederick-domann@uiowa.edu [Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA (United States); Department of Radiation Oncology, The University of Iowa, Iowa City, IA (United States); Department of Surgery, The University of Iowa, Iowa City, IA (United States)

    2014-02-01

    The aryl hydrocarbon receptor (AhR) is an important mediator of toxic responses after exposure to xenobiotics including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dioxin-like polychlorinated biphenyls (PCBs). Activation of AhR responsive genes requires AhR dimerization with the aryl hydrocarbon receptor nuclear translocator (ARNT), a heterodimeric partner also shared by the hypoxia-inducible factor-1α (HIF-1α) protein. TCDD-stimulated AhR transcriptional activity can be influenced by hypoxia; however, it less well known whether hypoxia interferes with AhR transcriptional transactivation in the context of PCB-mediated AhR activation in human cells. Elucidation of this interaction is important in liver hepatocytes which extensively metabolize ingested PCBs and experience varying degrees of oxygen tension during normal physiologic function. This study was designed to assess the effect of hypoxia on AhR transcriptional responses after exposure to 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126). Exposure to 1% O{sub 2} prior to PCB 126 treatment significantly inhibited CYP1A1 mRNA and protein expression in human HepG2 and HaCaT cells. CYP1A1 transcriptional activation was significantly decreased upon PCB 126 stimulation under conditions of hypoxia. Additionally, hypoxia pre-treatment reduced PCB 126 induced AhR binding to CYP1 target gene promoters. Importantly, ARNT overexpression rescued cells from the inhibitory effect of hypoxia on XRE-luciferase reporter activity. Therefore, the mechanism of interference of the signaling crosstalk between the AhR and hypoxia pathways appears to be at least in part dependent on ARNT availability. Our results show that AhR activation and CYP1A1 expression induced by PCB 126 were significantly inhibited by hypoxia and hypoxia might therefore play an important role in PCB metabolism and toxicity. - Highlights: • Significant crosstalk exists between AhR and HIF-1α signaling. • Hypoxia perturbs PCB 126 induced AhR function and

  7. Sulforaphane inhibits CYP1A1 activity and promotes genotoxicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in vitro

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    Yang, Fangxing, E-mail: fxyang@zju.edu.cn [MOE Key Laboratory of Environmental Remediation and Ecosystem Health, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou, 310058 (China); Zhuang, Shulin [MOE Key Laboratory of Environmental Remediation and Ecosystem Health, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou, 310058 (China); Zhang, Chao; Dai, Heping [State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072 (China); Liu, Weiping, E-mail: wliu@zju.edu.cn [MOE Key Laboratory of Environmental Remediation and Ecosystem Health, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou, 310058 (China)

    2013-06-15

    Increasing environmental pollution by carcinogens such as some of persistent organic pollutants (POPs) has prompted growing interest in searching for chemopreventive compounds which are readily obtainable. Sulforaphane (SFN) is isolated from cruciferous vegetables and has the potentials to reduce carcinogenesis through various pathways. In this study, we studied the effects of SFN on CYP1A1 activity and genotoxicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The results showed that SFN inhibited TCDD-induced CYP1A1 activity in H4IIE cells by directly inhibiting CYP1A1 activity, probably through binding to aryl hydrocarbon receptor and/or CYP1A1 revealed by molecular docking. However, SFN promoted TCDD-induced DNA damage in yeast cells and reduced the viability of initiated yeast cells. Besides, it is surprising that SFN also failed to reduce genotoxicity induced by other genotoxic reagents which possess different mechanisms to lead to DNA damage. Currently, it is difficult to predict whether SFN has the potentials to reduce the risk of TCDD based on the conflicting observations in the study. Therefore, further studies should be urgent to reveal the function and mechanism of SFN in the stress of such POPs on human health. - Highlights: • Sulforaphane inhibited TCDD-induced CYP1A1 activity in H4IIE cells. • Sulforaphane may bind to aryl hydrocarbon receptor and/or CYP1A1. • Sulforaphane promoted TCDD-induced DNA damage in yeast cells. • Sulforaphane may promote DNA damage by DNA strand breaks or DNA alkylation.

  8. Vinclozolin, a widely used fungizide, enhanced BaP-induced micronucleus formation in human derived hepatoma cells by increasing CYP1A1 expression.

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    Wu, Xin-Jiang; Lu, Wen-qing; Roos, Peter H; Mersch-Sundermann, Volker

    2005-10-15

    Vinclozolin, a widely used fungicide, can be identified as a residue in numerous vegetable and fruit samples. To get insight in its genetic toxicity, we investigated the genotoxic effect of vinclozolin in the human derived hepatoma cell line HepG2 using the micronucleus (MN) assay. Additionally, to evaluate the co- or anti-mutagenic potency of vinclozolin, we treated HepG2 cells with different concentrations of vinclozolin for 24 h. Subsequently, the cells were exposed to benzo[a]pyrene (BaP) for 1h. Exposure of HepG2 cells to 50-400 microM vinclozolin alone did not cause any induction of micronuclei. However, a pronounced co-mutagenic effect was observed. MN frequencies caused by BaP increased by 30.6%, 52.8% and 65.3% after pretreatment of the cell cultures with 50, 100 and 200 microM vinclozolin, respectively. The highest concentration (400 microM) of vinclozolin tested caused cytotoxicity. Therefore, micronuclei were not considered for that concentration. To clarify the mechanism of cogenotoxicity, we assayed cytochrome P450 1A1 (CYP1A1), which plays a pivotal role in activation of BaP. Cells exposed to vinclozolin led to significant increase of CYP1A1 expression in Western blot. The result suggested that induction of CYP1A1 by vinclozolin account for its enhancing effect on genotoxicity caused by BaP.

  9. Retinoids repress Ah receptor CYP1A1 induction pathway through the SMRT corepressor

    International Nuclear Information System (INIS)

    Fallone, Frederique; Villard, Pierre-Henri; Seree, Eric; Rimet, Odile; Nguyen, Quock Binh; Bourgarel-Rey, Veronique; Fouchier, Francis; Barra, Yves; Durand, Alain; Lacarelle, Bruno

    2004-01-01

    CYP1A1 isoform is mainly regulated by the transcription factor AhR and to a lesser extent by the nuclear receptor RAR. The effect of a coexposure with 3MC, a AhR ligand, and RA, a RAR ligand, which are, respectively, strong and weak CYP1A1 inducers, is poorly known. We showed in Caco-2 cells that addition of RA significantly decreased 3MC-induced CYP1A1 expression by -55% for mRNA level and -30% for promoter and enzymatic activities. We further showed that RA decreased AhR protein level. Moreover, a physical interaction between AhR and the RAR-corepressor SMRT has been described in vitro. Using the corepressor inhibitor TSA, transfected-cells with SMRT cDNA, and coimmunoprecipitation experiments, we demonstrated that RA addition repressed AhR function through a marked AhR/SMRT physical interaction. This interaction explains the decrease of 3MC-induced CYP1A1 expression. This new mechanism involving the repression of AhR-induced CYP1A1 expression by retinoids allows better knowledge of the CYP1A1 regulation

  10. 2,3,7,8-Tetrachlorodibenzo-p-dioxin modulates estradiol-induced aldehydic DNA lesions in human breast cancer cells through alteration of CYP1A1 and CYP1B1 expression.

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    Chen, Shou-Tung; Chen, Dar-Ren; Fang, Ju-Pin; Lin, Po-Hsiung

    2015-05-01

    Many genes responsible for the bioactivation of endogenous estrogen to reactive quinonoid metabolites, including cytochrome P450 (CYP) 1A1, 1A2, and 1B1, are well-known target genes of the aryl hydrocarbon receptor agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The purpose of this research was to investigate the roles of TCDD-mediated altered gene expression in the induction of aldehydic DNA lesions (ADLs) by 17β-estradiol (E2) in human MDA-MB-231 and MCF-7 breast cancer cells. We demonstrated that increases in the number of oxidant-mediated ADLs, including abasic sites and aldehydic base/sugar lesions, were detected in MDA-MB-231 cells exposed to E2. The DNA-damaging effects of E2 in MDA-MB-231 cells were prevented by pretreatment of cells with TCDD. In contrast, we did not observe statistically significant increases in the number of ADLs in MCF-7 cells exposed to E2. However, with TCDD pretreatment, an approximately twofold increase in the number of ADLs was detected in MCF-7 cells exposed to E2. TCDD pretreatment induces disparity in the disposition of E2 to reactive quinonoid metabolites and the subsequent formation of oxidative DNA lesions through alteration of CYP1A1 and CYP1B1 expression in human breast cancer cells.

  11. Epigenetic Determinants of CYP1A1 Induction by the Aryl Hydrocarbon Receptor Agonist 3,3',4,4',5-Pentachlorobiphenyl (PCB 126

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    Sabine U. Vorrink

    2014-08-01

    Full Text Available Many enzymes involved in xenobiotic metabolism, including cytochrome P450 (CYP 1A1, are regulated by the aryl hydrocarbon receptor (AhR. 3,3',4,4',5-Penta chlorobiphenyl (PCB 126 is a potent ligand for AhR and can thus induce the expression of CYP1A1. Interestingly, we observed that human carcinoma cell lines derived from different types of epithelial cells displayed divergent degrees of CYP1A1 induction after exposure to PCB 126. Since epigenetic mechanisms are known to be involved in cell type-specific gene expression, we sought to assess the epigenetic determinants of CYP1A1 induction in these carcinoma cell lines. In contrast to HepG2 hepatocarcinoma cells, HeLa cervical carcinoma cells showed significantly lower levels of CYP1A1 mRNA expression following PCB 126 exposure. Our results show that the two cell lines maintained differences in the chromatin architecture along the CYP1A1 promoter region. Furthermore, treatment with the epigenetic modifiers, trichostatin A (TSA and 5-aza-2'-deoxycytidine (5-Aza-dC, significantly increased the expression of CYP1A1 after PCB 126 treatment in HeLa cells. However, we did not observe apparent differences in methylation levels or specific location of CpG DNA methylation between the two cell lines in the analyzed CYP1A1 promoter region. Taken together, our findings suggest that the differences in CYP1A1 expression between HepG2 and HeLa cells are due to differences in the chromatin architecture of the CYP1A1 promoter and thus establish a role of epigenetic regulation in cell-specific CYP1A1 expression.

  12. Passive smoking, Cyp1A1 gene polymorphism and dysmenorrhea

    Science.gov (United States)

    Liu, Hong; Yang, Fan; Li, Zhiping; Chen, Changzhong; Fang, Zhian; Wang, Lihua; Hu, Yonghua; Chen, Dafang

    2007-01-01

    Objective This study investigated whether the association between passive smoking exposure and dysmenorrhea is modified by two susceptibility genes, CYP1A1MspI and CYP1A1HincII. Methods This report includes 1645 (1124 no dysmenorrhea, 521 dysmenorrhea) nonsmoking and nondrinking newly wed female workers at Anqing, China between June 1997 and June 2000. Multiple logistic regression models were used to estimate the associations of passive smoking exposure and genetic susceptibility with dysmenorrhea, adjusting for perceived stress. Results When stratified by women genotype, the adjusted OR of dysmenorrhea was 1.6 (95%CI=1.3-2.1) for passive smoking group with Ile/Ile462 genotype, and 1.5 (95%CI=1.1-2.1) with C/C6235 genotype, compared to non passive smoking group, respectively. The data further showed that there was a significant combined effect between passive smoking and the CYP1A1 Msp1 C/C6235 and HincII Ile/Ile462 genotype (OR=2.6, 95%CI=1.3-5.2). Conclusion CYP1A1 MspI and HincII genotypes modified the association between passive smoking and dysmenorrhea. PMID:17566695

  13. Alteration in the Expression of Cytochrome P450s (CYP1A1, CYP2E1, and CYP3A11 in the Liver of Mouse Induced by Microcystin-LR

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    Bangjun Zhang

    2015-03-01

    Full Text Available Microcystins (MCs are cyclic heptapeptide toxins and can accumulate in the liver. Cytochrome P450s (CYPs play an important role in the biotransformation of endogenous substances and xenobiotics in animals. It is unclear if the CYPs are affected by MCs exposure. The objective of this study was to evaluate the effects of microcystin-LR (MCLR on cytochrome P450 isozymes (CYP1A1, CYP2E1, and CYP3A11 at mRNA level, protein content, and enzyme activity in the liver of mice the received daily, intraperitoneally, 2, 4, and 8 µg/kg body weight of MCLR for seven days. The result showed that MCLR significantly decreased ethoxyresorufin-O-deethylase (EROD (CYP1A1 and erythromycin N-demthylase (ERND (CYP3A11 activities and increased aniline hydroxylase (ANH activity (CYP2E1 in the liver of mice during the period of exposure. Our findings suggest that MCLR exposure may disrupt the function of CYPs in liver, which may be partly attributed to the toxicity of MCLR in mice.

  14. Association of CYP1A1 gene polymorphism with chronic kidney disease: a case control study.

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    Siddarth, Manushi; Datta, Sudip K; Ahmed, Rafat S; Banerjee, Basu D; Kalra, Om P; Tripathi, Ashok K

    2013-07-01

    CYP1A1 is an important xenobiotic metabolizing enzyme, present in liver and kidney. Expression of CYP1A1 enzyme increases manifold when kidney cells are exposed to nephrotoxins/chemicals leading to oxidative stress-induced cell damage. To study the association of CYP1A1 gene polymorphism in patients of chronic kidney disease with unknown etiology (CKDU), we recruited 334 CKDU patients and 334 age and sex matched healthy controls. CYP1A1*2A and *2C polymorphisms were studied by PCR-RFLP and allele specific-PCR respectively. Subjects carrying at least one mutant allele of CYP1A1*2A (TC, CC) and *2C (AG, GG) were shown to be associated with 1.4-2-fold increased risk of CKDU. Also, genotypic combinations of hetero-/homozygous mutants of CYP1A1*2A (TC, CC) with hetero-/homozygous mutant genotypes of CYP1A1*2C (AG, GG) i.e. TC/AG (pCKDU with an odd ratio ranging 1.8-3.3 times approximately. This study demonstrates association of CYP1A1 polymorphisms with CKDU. Copyright © 2013 Elsevier B.V. All rights reserved.

  15. Increased CYP1A1 expression in human exfoliated urothelial cells of cigarette smokers compared to non-smokers

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    Doerrenhaus, Angelika; Roos, Peter H. [Institute for Occupational Physiology at the University Dortmund, Dortmund (Germany); Mueller, Tina [Institute for Occupational Physiology at the University Dortmund, Dortmund (Germany); University Dortmund, Department of Statistics, Mathematical Statistics with Applications in Biometrics, Dortmund (Germany)

    2007-01-15

    Polycyclic aromatic hydrocarbons, arylamines and nitrosamines, constituents of cigarette smoke, are known inducers of bladder cancer. The biochemical response of the target tissue, the bladder urothelium, following inhalation of cigarette smoke has not been studied so far. We used exfoliated transitional urothelial cells from human urine samples to analyze effects of smoking on induction of the cytochrome P450 enzyme CYP1A1. Samples of 40 subjects, including male and female smokers and non-smokers, were examined. A prerequisite for the immunofluorescence microscopic analysis of the cells was the enrichment of the urothelial cell population. This was achieved by a new method which is based on magnetic cell sorting exploiting specific binding of immobilized Griffonia simplicifolia lectin to the surface of urothelial cells. Immunostaining of the final cell preparation with a monoclonal antibody to CYP1A1 showed that about 6% of the urothelial cells of non-smokers stained positive for CYP1A1. However, this fraction of positive cells was more than 44% of the urothelial cells in samples from cigarette smokers. In spite of the individual variation, the difference was statistically significant. There were no gender-related differences in the portion of CYP1A1 expressing urothelial cells of smokers and non-smokers. In essence, we show for the first time that human urothelial cells respond to cigarette smoking by induction of CYP1A1. The approach opens new fields of mechanistic and biomarker research with respect to the pathogenetic processes of cancer development in the human bladder. (orig.)

  16. Cytochrome P450 CYP1A1: wider roles in cancer progression and prevention

    International Nuclear Information System (INIS)

    Androutsopoulos, Vasilis P; Tsatsakis, Aristidis M; Spandidos, Demetrios A

    2009-01-01

    CYP1A1 is one of the main cytochrome P450 enzymes, examined extensively for its capacity to activate compounds with carcinogenic properties. Continuous exposure to inhalation chemicals and environmental carcinogens is thought to increase the level of CYP1A1 expression in extrahepatic tissues, through the aryl hydrocarbon receptor (AhR). Although the latter has long been recognized as a ligand-induced transcription factor, which is responsible for the xenobiotic activating pathway of several phase I and phase II metabolizing enzymes, recent evidence suggests that the AhR is involved in various cell signaling pathways critical to cell cycle regulation and normal homeostasis. Disregulation of these pathways is implicated in tumor progression. In addition, it is becoming increasingly evident that CYP1A1 plays an important role in the detoxication of environmental carcinogens, as well as in the metabolic activation of dietary compounds with cancer preventative activity. Ultimately the contribution of CYP1A1 to cancer progression or prevention may depend on the balance of procarcinogen activation/detoxication and dietary natural product extrahepatic metabolism

  17. Analysis of CYP1A1 and COMT polymorphisms in women with cervical cancer.

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    Kleine, J P; Camargo-Kosugi, C M; Carvalho, C V; Silva, F C; Silva, I D C G

    2015-12-29

    The aim of this case-control study was to obtain a comprehensive panel of genetic polymorphisms present only in genes (cytochrome P-450 1A1--CYP1A1 and catechol-O-methyl transferase--COMT) within the metabolic pathway of sex steroids and determine their possible associations with the presence or absence of cervical cancer. Genotypes of 222 women were analyzed: a) 81 with cancer of the cervix treated at the Cancer Hospital Alfredo Abram, between June 2012 and May 2013, with diagnosis confirmed surgically and/or through histomorphological examination; and b) 141 healthy women who assisted at the Endocrine Gynecology and Climacteric Ambulatory, Department of Gynecology, UNIFESP-EPM. These polymorphisms were detected by polymerase chain reaction amplification-restriction fragment length polymorphism analysis and visualized on 3% agarose gels stained with ethidium bromide. We found a significant association between the frequency of the CYP1A1 polymorphism and the development of cervical cancer. A statistical difference was observed between patient and control groups for CYP1A1 polymorphism genotype distributions (P 0.05) or between other risk variables analyzed. The CYP1A1 gene involved in the metabolic pathway of sex steroids might influence the emergence of pathological conditions such as cervical cancer in women who carry a mutated allele, and result in 1.80 and 13.46 times increased risk for women with heterozygous or homozygous mutated genotypes, respectively.

  18. CYP1A1 Genetic Polymorphisms in Ecuador, South America

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    César Paz-y-Miño

    2005-01-01

    Full Text Available A total of 108 individuals from the Ecuadorian population from rural and urban places were analyzed for two CYP1A1 gene polymorphisms. The frequency of the val allele at codon 462 was 0.50, while the frequency of the Msp I restriction site, m2 allele at the T6235C position was 0.70. These polymorphisms in Ecuador have higher frequencies if we compare with others around the world, with the exception of some South American population in Brazil and Chile.

  19. Genetic variation in the CYP1A1 gene is related to circulating PCB118 levels in a population-based sample

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    Lind, Lars [Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala (Sweden); Penell, Johanna [Department of Medical Sciences, Occupational and Environmental Medicine, Uppsala University, Uppsala (Sweden); Syvänen, Anne-Christine; Axelsson, Tomas [Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala (Sweden); Ingelsson, Erik [Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala (Sweden); Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford (United Kingdom); Morris, Andrew P.; Lindgren, Cecilia [Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford (United Kingdom); Salihovic, Samira; Bavel, Bert van [MTM Research Centre, School of Science and Technology, Örebro University, Örebro (Sweden); Lind, P. Monica, E-mail: monica.lind@medsci.uu.se [Department of Medical Sciences, Occupational and Environmental Medicine, Uppsala University, Uppsala (Sweden)

    2014-08-15

    Several of the polychlorinated biphenyls (PCBs), i.e. the dioxin-like PCBs, are known to induce the P450 enzymes CYP1A1, CYP1A2 and CYP1B1 by activating the aryl hydrocarbon receptor (Ah)-receptor. We evaluated if circulating levels of PCBs in a population sample were related to genetic variation in the genes encoding these CYPs. In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (1016 subjects all aged 70), 21 SNPs in the CYP1A1, CYP1A2 and CYP1B1 genes were genotyped. Sixteen PCB congeners were analysed by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/ HRMS). Of the investigated relationships between SNPs in the CYP1A1, CYP1A2 and CYP1B1 and six PCBs (congeners 118, 126, 156, 169, 170 and 206) that captures >80% of the variation of all PCBs measured, only the relationship between CYP1A1 rs2470893 was significantly related to PCB118 levels following strict adjustment for multiple testing (p=0.00011). However, there were several additional SNPs in the CYP1A2 and CYP1B1 that showed nominally significant associations with PCB118 levels (p-values in the 0.003–0.05 range). Further, several SNPs in the CYP1B1 gene were related to both PCB156 and PCB206 with p-values in the 0.005–0.05 range. Very few associations with p<0.05 were seen for PCB126, PCB169 or PCB170. Genetic variation in the CYP1A1 was related to circulating PCB118 levels in the general elderly population. Genetic variation in CYP1A2 and CYP1B1 might also be associated with other PCBs. - Highlights: • We studied the relationship between PCBs and the genetic variation in the CYP genes. • Cross sectional data from a cohort of elderly were analysed. • The PCB levels were evaluated versus 21 SNPs in three CYP genes. • PCB 118 was related to variation in the CYP1A1 gene.

  20. Cytochrome P450 1A1 (CYP1A1) protects against nonalcoholic fatty liver disease caused by Western diet containing benzo[a]pyrene in mice.

    Science.gov (United States)

    Uno, Shigeyuki; Nebert, Daniel W; Makishima, Makoto

    2018-03-01

    The Western diet contributes to nonalcoholic fatty liver disease (NAFLD) pathogenesis. Benzo[a]pyrene (BaP), a prototypical environmental pollutant produced by combustion processes, is present in charcoal-grilled meat. Cytochrome P450 1A1 (CYP1A1) metabolizes BaP, resulting in either detoxication or metabolic activation in a context-dependent manner. To elucidate a role of CYP1A1-BaP in NAFLD pathogenesis, we compared the effects of a Western diet, with or without oral BaP treatment, on the development of NAFLD in Cyp1a1(-/-) mice versus wild-type mice. A Western diet plus BaP induced lipid-droplet accumulation in liver of Cyp1a1(-/-) mice, but not wild-type mice. The hepatic steatosis observed in Cyp1a1(-/-) mice was associated with increased cholesterol, triglyceride and bile acid levels. Cyp1a1(-/-) mice fed Western diet plus BaP had changes in expression of genes involved in bile acid and lipid metabolism, and showed no increase in Cyp1a2 expression but did exhibit enhanced Cyp1b1 mRNA expression, as well as hepatic inflammation. Enhanced BaP metabolic activation, oxidative stress and inflammation may exacerbate metabolic dysfunction in liver of Cyp1a1(-/-) mice. Thus, Western diet plus BaP induces NAFLD and hepatic inflammation in Cyp1a1(-/-) mice in comparison to wild-type mice, indicating a protective role of CYP1A1 against NAFLD pathogenesis. Copyright © 2018 Elsevier Ltd. All rights reserved.

  1. CYP1A1, CYP3A5 and CYP3A7 polymorphisms and testicular cancer susceptibility.

    Science.gov (United States)

    Kristiansen, W; Haugen, T B; Witczak, O; Andersen, J M; Fosså, S D; Aschim, E L

    2011-02-01

    Testicular cancer (TC) incidence is increasing worldwide, but the aetiology remains largely unknown. An unbalanced level of oestrogens and androgens in utero is hypothesized to influence TC risk. Polymorphisms in genes encoding cytochrome P450 (CYP) enzymes involved in metabolism of reproductive hormones, such as CYP1A1, CYP3A5 and CYP3A7, may contribute to variability of an individual's susceptibility to TC. The aim of this case-control study was to investigate possible associations between different CYP genotypes and TC, as well as histological type of TC. The study comprised 652 TC cases and 199 controls of Norwegian Caucasian origin. Genotyping of the CYP1A1*2A (MspI), CYP1A1*2C (I462V), CYP1A1*4 (T461N), CYP3A5*3C (A6986G) and CYP3A7*2 (T409R) polymorphisms was performed using TaqMan allelic discrimination or sequencing. The CYP1A1*2A allele was associated with 44% reduced risk of TC with each polymorphic allele [odds ratio (OR) = 0.56, 95% confidence interval (CI) = 0.40-0.78, p(trend) = 0.001], whereas the CYP1A1*2C allele was associated with 56% reduced risk of TC with each polymorphic allele (OR = 0.44, 95% CI = 0.25-0.75, p(trend) = 0.003). The decreased risk per allele was significant for seminomas (OR = 0.46, 95% CI, 0.31-0.70, p(trend) < 0.001 and OR = 0.31, 95% CI = 0.14-0.66, p(trend) = 0.002, respectively), but only borderline significant for non-seminomas (OR = 0.65, 95% CI = 0.45-0.95, p(trend) = 0.027 and OR = 0.55, 95% CI = 0.30-1.01, p(trend) = 0.052, respectively). There were no statistically significant differences in the distribution of the CYP3A5*3C and CYP3A7*2 polymorphic alleles between TC cases and controls. This study suggests that polymorphisms in the CYP1A1 gene may contribute to variability of individual susceptibility to TC. © 2010 The Authors. International Journal of Andrology © 2010 European Academy of Andrology.

  2. CYP1A1 m1 and m2 polymorphisms: genetic susceptibility to lung cancer

    Directory of Open Access Journals (Sweden)

    Paula Mota

    2010-01-01

    Full Text Available Lung cancer is considered an environment-related disease that develops as a consequence of exposure to mutagenic agents, namely those present in tobacco. The CYP1A1 gene codifies the phase I enzyme aryl hydrocarbon hydroxilase (AHH belonging to the cytochrome P450 system that plays a major role in the bio-activation of tobacco procarcinogenes. Two CYP1A1 polymorphisms, m1 (T6235C transition and m2 (A4889G transition, are associated with greater enzymatic activity and have been described as genetic susceptibility factors for lung cancer.The aim of this study was to verify if this association holds true in blood samples of 175 lung cancer patients and 217 non-cancer patients from Portugal's midlands region. The samples were studied by restriction fragment length polymorphism (RFLP assay.The allelic frequencies of the mutant alleles were 0.12 for allele C and 1.14 for allele G in the control population. The results were not statistically different from those alleles in the patient population. There was also no statistically significant difference in genotype distribution in lung cancer patients and controls even when combining high risk genotypes. In our control sample, as in other populations of different ethnic origin, both polymorphisms also seem to be in linkage disequilibrium. We conclude that in this sample of the Portuguese population, CYP1A1 m1 and m2 polymorphisms are too rare to be of clinical relevance, and do not seem to be associated with susceptibility to lung cancer. Resumo: O cancro do pulmão é considerado uma doença relacionada com o meio ambiente, consequência da exposição a agentes mutagénicos, nomeadamente os presentes no fumo do tabaco. O gene CYP1A1 codifica a enzima aril hidrocarboneto hidroxilase (AHH, da fase I, do sistema multienzimático do citocromo P450, que desempenha uma função preponderante na bioactivação dos procarcinogénios do tabaco. Dois polimorfismos do CYP1A1, m1 (transi

  3. A novel CYP1A1 gene polymorphism and the risk of head and neck ...

    African Journals Online (AJOL)

    Several polymorphisms in the CYP1A1 locus have been identified and their genotypes appear to exhibit population frequencies that depend on ethnicity. In this study, we assessed the role of CYP1A1 genotype in 388 head and neck cancer patients in Pakistani population via a case-control study. Polymerase chain reaction ...

  4. Metformin suppresses CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating aryl hydrocarbon receptor expression

    Energy Technology Data Exchange (ETDEWEB)

    Do, Minh Truong; Kim, Hyung Gyun; Tran, Thi Thu Phuong; Khanal, Tilak; Choi, Jae Ho [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of); Chung, Young Chul [Department of Food Science and Culinary, International University of Korea, Jinju (Korea, Republic of); Jeong, Tae Cheon, E-mail: taecheon@ynu.ac.kr [College of Pharmacy, Yeungnam University, Gyeongsan (Korea, Republic of); Jeong, Hye Gwang, E-mail: hgjeong@cnu.ac.kr [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of)

    2014-10-01

    Induction of cytochrome P450 (CYP) 1A1 and CYP1B1 by environmental xenobiotic chemicals or endogenous ligands through the activation of the aryl hydrocarbon receptor (AhR) has been implicated in a variety of cellular processes related to cancer, such as transformation and tumorigenesis. Here, we investigated the effects of the anti-diabetes drug metformin on expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and inducible conditions. Our results indicated that metformin down-regulated the expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced conditions. Down-regulation of AhR expression was required for metformin-mediated decreases in CYP1A1 and CYP1B1 expression, and the metformin-mediated CYP1A1 and CYP1B1 reduction is irrelevant to estrogen receptor α (ERα) signaling. Furthermore, we found that metformin markedly down-regulated Sp1 protein levels in breast cancer cells. The use of genetic and pharmacological tools revealed that metformin-mediated down-regulation of AhR expression was mediated through the reduction of Sp1 protein. Metformin inhibited endogenous AhR ligand-induced CYP1A1 and CYP1B1 expression by suppressing tryptophan-2,3-dioxygenase (TDO) expression in MCF-7 cells. Finally, metformin inhibits TDO expression through a down-regulation of Sp1 and glucocorticoid receptor (GR) protein levels. Our findings demonstrate that metformin reduces CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating AhR signaling. Metformin would be able to act as a potential chemopreventive agent against CYP1A1 and CYP1B1-mediated carcinogenesis and development of cancer. - Graphical abstract: Schematic of the CYP1A1 and CYP1B1 gene regulation by metformin. - Highlights: • Metformin inhibits CYP1A1 and CYP1B1 expression. • Metformin down-regulates the AhR signaling. • Metformin reduces Sp1 protein expression. • Metformin suppresses TDO expression.

  5. Metformin suppresses CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating aryl hydrocarbon receptor expression

    International Nuclear Information System (INIS)

    Do, Minh Truong; Kim, Hyung Gyun; Tran, Thi Thu Phuong; Khanal, Tilak; Choi, Jae Ho; Chung, Young Chul; Jeong, Tae Cheon; Jeong, Hye Gwang

    2014-01-01

    Induction of cytochrome P450 (CYP) 1A1 and CYP1B1 by environmental xenobiotic chemicals or endogenous ligands through the activation of the aryl hydrocarbon receptor (AhR) has been implicated in a variety of cellular processes related to cancer, such as transformation and tumorigenesis. Here, we investigated the effects of the anti-diabetes drug metformin on expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and inducible conditions. Our results indicated that metformin down-regulated the expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced conditions. Down-regulation of AhR expression was required for metformin-mediated decreases in CYP1A1 and CYP1B1 expression, and the metformin-mediated CYP1A1 and CYP1B1 reduction is irrelevant to estrogen receptor α (ERα) signaling. Furthermore, we found that metformin markedly down-regulated Sp1 protein levels in breast cancer cells. The use of genetic and pharmacological tools revealed that metformin-mediated down-regulation of AhR expression was mediated through the reduction of Sp1 protein. Metformin inhibited endogenous AhR ligand-induced CYP1A1 and CYP1B1 expression by suppressing tryptophan-2,3-dioxygenase (TDO) expression in MCF-7 cells. Finally, metformin inhibits TDO expression through a down-regulation of Sp1 and glucocorticoid receptor (GR) protein levels. Our findings demonstrate that metformin reduces CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating AhR signaling. Metformin would be able to act as a potential chemopreventive agent against CYP1A1 and CYP1B1-mediated carcinogenesis and development of cancer. - Graphical abstract: Schematic of the CYP1A1 and CYP1B1 gene regulation by metformin. - Highlights: • Metformin inhibits CYP1A1 and CYP1B1 expression. • Metformin down-regulates the AhR signaling. • Metformin reduces Sp1 protein expression. • Metformin suppresses TDO expression

  6. CYP1A1 and CYP1B1 in human lymphocytes as biomarker of exposure: effect of dioxin exposure and polymorphisms

    Energy Technology Data Exchange (ETDEWEB)

    Duursen, M. van; Sanderson, T.; Berg, M. van den [Inst. for Risk Assessment Sciences, Utrecht (Netherlands)

    2004-09-15

    There are several known genetic polymorphisms of the CYP1A1 and CYP1B1 genes. A polymorphism in the 3'-untranslated region of the CYP1A1 gene (CYP1A1 MspI or CYP1A1 m1) is often studied in relation with breast or lung cancer, but little is known about the functional effect of this polymorphism. An amino acid substitution in codon 432 (Val to Leu) of the CYP1B1 gene is associated with a lower catalytic activity of the enzyme. However, the involvement of these polymorphisms on the inducibility of CYP1A1 and CYP1B1 gene expression is unclear. CYP1A1 and CYP1B1 mRNA expression levels can be determined in peripheral blood lymphocytes. This makes them potential candidates for use as biomarker of exposure to environmental compounds. Interindividual variations in mRNA expression patterns, catalytic activity and polymorphisms are very important factors when CYP1A1 and CYP1B1 expression patterns are used as biomarker of exposure, but little is known about it. Spencer et al. showed a concentration-dependent increase of CYP1B1 mRNA in lymphocytes upon exposure in vitro to 2,3,7,8-tetrachloro-p-dibenzodioxin (TCDD), the most potent dioxin. Yet, only a few studies describe the in vivo correlation between polymorphisms, mRNA expression level and exposure to environmental factors. In this study, we wanted to obtain a better insight in the CYP1A1 and CYP1B1 mRNA expression and enzyme activity in human lymphocytes. We determined the constitutive CYP1A1 and CYP1B1 mRNA expression in lymphocytes of ten healthy volunteers and the variability in sensitivity toward enzyme induction by TCDD. Further, the CYP1A1 m1 and CYP1B1 Val432Leu polymorphisms were determined.

  7. Epistatic Interaction of CYP1A1 and COMT Polymorphisms in Cervical Cancer

    Directory of Open Access Journals (Sweden)

    Andreia Matos

    2016-01-01

    Full Text Available There is a clear association between the excessive and cumulative exposure to estrogens and the development of cancer in hormone-sensitive tissues, such as the cervix. We studied the association of CYP1A1 M1 (rs4646903 and COMT (rs4680 polymorphisms in 130 cervical cancer cases (c-cancer and 179 controls. The CYP1A1 TT genotype was associated with a lower risk for c-cancer (OR = 0.39, p=0.002. The allele C of CYP1A1 was a risk for c-cancer (OR = 2.29, p=0.002. Women with COMT LL genotype had a higher risk of developing c-cancer (OR = 4.83, p<0.001. For the interaction of the CYP1A1&COMT, we observed that TC&HL genotypes had a greater risk for c-cancer (OR = 6.07, p=0.006 and TT&HL genotypes had a protection effect (OR = 0.24, p<0.001. The CYP1A1 TT and COMT LL genotypes had higher estradiol levels in c-cancer (p<0.001 and p=0.037, resp.. C-cancer is associated with less production of 2-methoxy-estradiol resultant of functional polymorphisms of CYP1A1 and COMT, separately. CYP1A1 and COMT work in a metabolic sequence and their interaction could lead to an alternative pathway of estrogen metabolism with production of 16-OH-estrone that is more proliferative.

  8. Camel Milk Modulates the Expression of Aryl Hydrocarbon Receptor-Regulated Genes, Cyp1a1, Nqo1, and Gsta1, in Murine hepatoma Hepa 1c1c7 Cells

    Directory of Open Access Journals (Sweden)

    Hesham M. Korashy

    2012-01-01

    Full Text Available There is a traditional belief in the Middle East that camel milk may aid in prevention and treatment of numerous cases of cancer yet, the exact mechanism was not investigated. Therefore, we examined the ability of camel milk to modulate the expression of a well-known cancer-activating gene, Cytochrome P450 1a1 (Cyp1a1, and cancer-protective genes, NAD(PH:quinone oxidoreductase 1 (Nqo1 and glutathione S-transferase a1 (Gsta1, in murine hepatoma Hepa 1c1c7 cell line. Our results showed that camel milk significantly inhibited the induction of Cyp1a1 gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, the most potent Cyp1a1 inducer and known carcinogenic chemical, at mRNA, protein, and activity levels in a concentration-dependent manner. In addition, camel milk significantly decreased the xenobiotic responsive element (XRE-dependent luciferase activity, suggesting a transcriptional mechanism is involved. Furthermore, this inhibitory effect of camel milk was associated with a proportional increase in heme oxygenase 1. On the other hand, camel milk significantly induced Nqo1 and Gsta1 mRNA expression level in a concentration-dependent fashion. The RNA synthesis inhibitor, actinomycin D, completely blocked the induction of Nqo1 mRNA by camel milk suggesting the requirement of de novo RNA synthesis through a transcriptional mechanism. In conclusion, camel milk modulates the expression of Cyp1a1, Nqo1, and Gsta1 at the transcriptional and posttranscriptional levels.

  9. Cardiac remodeling during and after renin-angiotensin system stimulation in Cyp1a1-Ren2 transgenic rats

    DEFF Research Database (Denmark)

    Heijnen, Bart Fj; Pelkmans, Leonie Pj; Danser, Ah Jan

    2013-01-01

    This study investigated renin-angiotensin system (RAS)-induced cardiac remodeling and its reversibility in the presence and absence of high blood pressure (BP) in Cyp1a1-Ren2 transgenic inducible hypertensive rats (IHR). In IHR (pro)renin levels and BP can be dose-dependently titrated by oral...... administration of indole-3-carbinol (I3C). Young (four-weeks old) and adult (30-weeks old) IHR were fed I3C for four weeks (leading to systolic BP >200 mmHg). RAS-stimulation was stopped and animals were followed-up for a consecutive period. Cardiac function and geometry was determined echocardiographically...

  10. Environmental exposure to polychlorinated biphenyls and placental CYP1A1 activity in Inuit women from northern Québec.

    OpenAIRE

    Pereg, Daria; Dewailly, Eric; Poirier, Guy G; Ayotte, Pierre

    2002-01-01

    Some polychlorinated biphenyl (PCB) congeners are CYP1A1 inducers, and induction of this enzyme in the placenta has been linked to adverse effects on fetal development. The objective of this study was to determine if the body burden of PCBs is related to placental CYP1A1 activity in Inuit women from Nunavik (northern Québec), a population highly exposed to organochlorines. Placenta and cord blood samples were obtained from 35 Inuit women and 30 women from a southern Québec community exposed t...

  11. Comparative in vitro effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and selected polynuclear aromatic hydrocarbons on cyp1a1 gene transcription in cells which contain or are deficient in the 4S binding protein

    International Nuclear Information System (INIS)

    Kamps, C.; Safe, S.

    1990-01-01

    Using [ 3 H]-benzo[a]pyrene as the radioligand, several cell culture lines have been screened for the presence (or absence) of the 4S binding protein. Murine Hepa 1c1c7 cells contained both the 4S binding protein and the 9S (Ah) receptor whereas only the 9S receptor was detected in rat hepatoma H-4-II E cells in culture. The effects of a series of polynuclear aromatic hydrocarbons (PAHs) which included benzo[e]pyrene, benzo[ghi]perylene and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and their interactive effects on CYP1A1 gene transcription was determined by Northern analysis in both cell lines. The results showed that the PAHs which exhibited high affinity for the 4S binding protein were inactive as inducers in both cell lines; TCDD was active in both cell lines and the interactive effects between the PAHs and TCDD did not significantly modulate TCDD-mediated CYP1A1 gene transcription. The results suggest that the 4S binding protein does not regulate CYP1A1 gene transcription

  12. TLR2 Controls Intestinal Carcinogen Detoxication by CYP1A1

    DEFF Research Database (Denmark)

    Do, Khoa; Fink, Lisbeth Nielsen; Jensen, Thomas Elbenhardt

    2012-01-01

    of ligands for TLR2 of bacterial origin seems to be crucial for detoxication of luminal carcinogens by CYP1A1 in the intestine. This unprecedented finding indicates a complex interplay between the immune system of the host and intestinal bacteria with detoxication mechanisms. This highlights the relevance...

  13. Induction of Cyp1a1 and Cyp1b1 and formation of DNA adducts in C57BL/6, Balb/c, and F1 mice following in utero exposure to 3-methylcholanthrene

    International Nuclear Information System (INIS)

    Xu Mian; Nelson, Garret B.; Moore, Joseph E.; McCoy, Thomas P.; Dai, Jian; Manderville, Richard A.; Ross, Jeffrey A.; Miller, Mark Steven

    2005-01-01

    Fetal mice are more sensitive to chemical carcinogens than are adults. Previous studies from our laboratory demonstrated differences in the mutational spectrum induced in the Ki-ras gene from lung tumors isolated from [D2 x B6D2F1]F2 mice and Balb/c mice treated in utero with 3-methylcholanthrene (MC). We thus determined if differences in metabolism, adduct formation, or adduct repair influence strain-specific responses to transplacental MC exposure in C57BL/6 (B6), Balb/c (BC), and reciprocal F1 crosses between these two strains of mice. The induction of Cyp1a1 and Cyp1b1 in fetal lung and liver tissue was determined by quantitative fluorescent real-time PCR. MC treatment caused maximal induction of Cyp1a1 and Cyp1b1 RNA 2-8 h after injection in both organs. RNA levels for both genes then declined in both fetal organs, but a small biphasic, secondary increase in Cyp1a1 was observed specifically in the fetal lung 24-48 h after MC exposure in all four strains. Cyp1a1 induction by MC at 4 h was 2-5 times greater in fetal liver (7000- to 16,000-fold) than fetal lung (2000- to 6000-fold). Cyp1b1 induction in both fetal lung and liver was similar and much lower than that observed for Cyp1a1, with induction ratios of 8- to 18-fold in fetal lung and 10- to 20-fold in fetal liver. The overall kinetics and patterns of induction were thus very similar across the four strains of mice. The only significant strain-specific effect appeared to be the relatively poor induction of Cyp1b1 in the parental strain of B6 mice, especially in fetal lung tissue. We also measured the levels of MC adducts and their disappearance from lung tissue by the P 32 post-labeling assay on gestation days 18 and 19 and postnatal days 1, 4, 11, and 18. Few differences were seen between the different strains of mice; the parental strain of B6 mice had nominally higher levels of DNA adducts 2 (gestation day 19) and 4 (postnatal day 1) days after injection, although this was not statistically significant

  14. The risk of developing cervical cancer in Mexican women is associated to CYP1A1 MspI polymorphism.

    Science.gov (United States)

    Juárez-Cedillo, Teresa; Vallejo, Maite; Fragoso, José Manuel; Hernández-Hernández, Dulce Maria; Rodríguez-Pérez, José Manuel; Sánchez-García, Sergio; del Carmen García-Peña, María; García-Carrancá, Alejandro; Mohar-Betancourt, Alejandro; Granados, Julio; Vargas-Alarcón, Gilberto

    2007-07-01

    The aim of the study was to evaluate the association of two CYP1A1 polymorphisms (Msp1 and exon 7) with cervical cancer in Mexican women considering their smoking habit. The polymorphisms were determined in 310 individuals (155 with cervical cancer and 155 healthy controls). Women with MspI T/C or C/C showed increased risk of developing cervical cancer (3.7- and 8.3-fold increase, respectively) compared to women with T/T genotype. When smoking habit was considered, the risk for non-smokers with T/C and C/C genotypes was similar (5.2 and 4.1, respectively), whereas smoking women with C/C genotype showed a 19.4-fold increase of cervical cancer. Number of child births, number of sexual partners and marital status were strong risk factors for developing cervical cancer in women with T/T genotype; however, in women with T/C genotype, only the number of child births and sexual partners had a significant influence. These results suggest an important role of the CYP1A1 MspI polymorphism in the risk of developing cervical cancer.

  15. CYP1A1 MspI Polymorphism and Cervical Carcinoma Risk in the Multi-Ethnic Population of Malaysia: a Case-Control Study.

    Science.gov (United States)

    Tan, Yee Hock; Sidik, Shiran Mohd; Syed Husain, Sharifah Noor Akmal; Lye, Munn Sann; Chong, Pei Pei

    2016-01-01

    Tobacco smoking is considered a risk factor for cervical cancer development due to the presence of tobacco based carcinogenic metabolites in cervical cells of female smokers. In this study, we investigated the role of the T3801C (MspI) polymorphism of CYP1A1, a gene encoding an enzyme necessary for the initiation of tobacco based carcinogen metabolism, on cervical cancer risk. The T to C substitution may alter CYP1A1 activities, potentially elevating cervical cancer risk. Since results of gene-disease association studies vary according to the study population, the multi-ethnic population of Malaysia provides an excellent representative cohort for identifying and comparing the cervical cancer risk among the 3 major ethnics in Southeast Asia in relation to CYP1A1 MspI polymorphism. A total of 195 Thin Prep Pap smear samples from HPV negative and cancer free females were randomly selected as controls while 106 formalin fixed paraffin embedded samples from females with invasive cervical cancer were randomly selected for the cases group. The polymorphisms were identified using restriction fragment length polymorphism (RFLP) PCR. We found no significant associations between CYP1A1 MspI polymorphism and cervical cancer in the general Malaysian female population. However, upon ethnic stratification, the variant C/C genotype was significantly associated with a 4.66-fold increase in cervical cancer risk in Malay females (95% CI= 1.21-17.9; p=0.03). No significant association was observed in the Chinese and Indian females. Additionally, there were no significant associations in the dominant model and allele frequency model analysis in both the general and ethnically stratified female population of Malaysia. Our findings suggest that the C/C genotype of CYP1A1 MspI polymorphism is associated with the development of cervical carcinoma in the Malay females of Malaysia.

  16. Polymorphisms in CYP1A1 and CYP3A5 Genes Contribute to the Variability in Granisetron Clearance and Exposure in Pregnant Women with Nausea and Vomiting.

    Science.gov (United States)

    Bustos, Martha L; Zhao, Yang; Chen, Huijun; Caritis, Steve N; Venkataramanan, Raman

    2016-12-01

    Nausea and vomiting affect up to 90% of pregnant women. Granisetron is a potent and highly selective serotonin receptor antagonist and is an effective antiemetic. Findings from a prior study in pregnant women demonstrated a large interindividual variability in granisetron exposure. Granisetron is primarily metabolized by the cytochrome P450 (CYP) enzymes CYP1A1 and CYP3A and is likely a substrate of the ABCB1 transporter. Single-nucleotide polymorphisms (SNPs) in CYP3A, CYP1A1, and ABCB1 can alter drug metabolism. This study evaluated the influence of polymorphisms in CYP3A4, CYP3A5, CYP1A1, and ABCB1 on the pharmacokinetic properties of granisetron in pregnant women. The study enrolled 16 pregnant women (gestational age of 12-19 wks). All patients had nausea and vomiting and were treated with granisetron 1 mg. Granisetron plasma concentrations were determined using liquid chromatography tandem-mass spectrometry. The patients' genotype was determined using TaqMan SNP Genotyping Assays. The Hardy-Weinberg equilibrium was assessed by comparing observed and expected genotype frequencies, using the exact test. Intravenous granisetron clearance was used as the dependent variable for analysis of associations. Of 16 patients, 25% were homozygous for the allele variant CYP3A5*3 and had a significantly lower granisetron clearance and increased area under the plasma concentration-versus-time curve (AUC) compared with nonhomozygous patients. Approximately one-third of patients (n=5) were carriers for the allele variant CYP1A1*2A and had a significantly higher granisetron clearance and decreased AUC. We did not find significant differences in the AUC or clearance for any SNPs in CYP3A4 and ABCB1 genes. Polymorphisms in CYP3A5 and CYP1A1 account for some of the variability in systemic clearance and exposure of granisetron in pregnant women. © 2016 Pharmacotherapy Publications, Inc.

  17. CYP1A1 and CYP1A2 expression: Comparing 'humanized' mouse lines and wild-type mice; comparing human and mouse hepatoma-derived cell lines

    International Nuclear Information System (INIS)

    Uno, Shigeyuki; Endo, Kaori; Ishida, Yuji; Tateno, Chise; Makishima, Makoto; Yoshizato, Katsutoshi; Nebert, Daniel W.

    2009-01-01

    Human and rodent cytochrome P450 (CYP) enzymes sometimes exhibit striking species-specific differences in substrate preference and rate of metabolism. Human risk assessment of CYP substrates might therefore best be evaluated in the intact mouse by replacing mouse Cyp genes with human CYP orthologs; however, how 'human-like' can human gene expression be expected in mouse tissues? Previously a bacterial-artificial-chromosome-transgenic mouse, carrying the human CYP1A1 C YP1A2 locus and lacking the mouse Cyp1a1 and Cyp1a2 orthologs, was shown to express robustly human dioxin-inducible CYP1A1 and basal versus inducible CYP1A2 (mRNAs, proteins, enzyme activities) in each of nine mouse tissues examined. Chimeric mice carrying humanized liver have also been generated, by transplanting human hepatocytes into a urokinase-type plasminogen activator(+/+) s evere-combined-immunodeficiency (uPA/SCID) line with most of its mouse hepatocytes ablated. Herein we compare basal and dioxin-induced CYP1A mRNA copy numbers, protein levels, and four enzymes (benzo[a]pyrene hydroxylase, ethoxyresorufin O-deethylase, acetanilide 4-hydroxylase, methoxyresorufin O-demethylase) in liver of these two humanized mouse lines versus wild-type mice; we also compare these same parameters in mouse Hepa-1c1c7 and human HepG2 hepatoma-derived established cell lines. Most strikingly, mouse liver CYP1A1-specific enzyme activities are between 38- and 170-fold higher than human CYP1A1-specific enzyme activities (per unit of mRNA), whereas mouse versus human CYP1A2 enzyme activities (per unit of mRNA) are within 2.5-fold of one another. Moreover, both the mouse and human hepatoma cell lines exhibit striking differences in CYP1A mRNA levels and enzyme activities. These findings are relevant to risk assessment involving human CYP1A1 and CYP1A2 substrates, when administered to mice as environmental toxicants or drugs.

  18. Association of Cytochrome CYP1A1 Gene Polymorphisms and Tobacco Smoking With the Risk of Breast Cancer in Women From Iraq

    Directory of Open Access Journals (Sweden)

    Hassan M. Naif

    2018-04-01

    Full Text Available BackgroundCYP1A1 gene polymorphisms and tobacco smoking are among several risk factors for various types of cancers, but their influence on breast cancer remains controversial. We analyzed the possible association of CYP1A1 gene polymorphisms and tobacco smoking-related breast cancer in women from Iraq.Materials and methodsIn this case–control study, gene polymorphism of CYP1A1 gene (CYP1A1m1, T6235C and CYP1A1m2, A4889G of 199 histologically verified breast cancer patients’ and 160 cancer-free control women’s specimens were performed by using PCR-based restriction fragment length polymorphism.ResultsThree genotype frequencies (TT, TC, and CC of CYP1A1m1T/C appeared in 16.1, 29.6, and 54.3% of women with breast cancer, respectively, compared with 41.2, 40, and 18.8% in the control group, respectively. CYP1A1m1 CC genotype and C allele were significantly associated with increased risks for breast cancer in patients (54.3 and 69%, respectively compared with controls (18.8 and 39%, respectively. While the three genotype frequencies (AA, AG, and GG of CYP1A1m2A/G were detected in 20.1, 31.2, and 48.7% in patients compared with 46.3, 40.6, and 13.1% in controls, respectively. The frequency of GG genotypes and G allele was significantly higher in patients (48.7 and 64%, respectively than in the controls (13.1 and 33%, respectively. Smoking women having either CC or GG genotypes showed a highly significant association with increased risk of breast cancer [odds ratio (OR = 1.607, 95% confidence interval (CI 0.91–1.64, p = 0.0001, and OR, 1.841, 95% CI, 0.88–1.67, p = 0.0001, respectively]. On the other hand, the T and A alleles of predominantly seen in healthy smoking women (83 and 85%, p = 0.0001, respectively.ConclusionThese findings indicated that both C and G alleles of CYP1A1m1 and m2 were significantly associated with elevated risk of breast cancer in Iraqi women, while the T and A alleles were predominantly seen in

  19. Genetic polymorphisms in CYP1A1, CYP1B1 and COMT genes in Greenlandic Inuit and Europeans.

    Science.gov (United States)

    Ghisari, Mandana; Long, Manhai; Bonefeld-Jørgensen, Eva C

    2013-01-01

    The Indigenous Arctic population is of Asian descent, and their genetic background is different from the Caucasian populations. Relatively little is known about the specific genetic polymorphisms in genes involved in the activation and detoxification mechanisms of environmental contaminants in Inuit and its relation to health risk. The Greenlandic Inuit are highly exposed to legacy persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs), and an elucidation of gene-environment interactions in relation to health risks is needed. The aim of this study was to determine and compare the genotype and allele frequencies of the cytochrome P450 CYP1A1 Ile462Val (rs1048943), CYP1B1 Leu432Val (rs1056836) and catechol-O-methyltransferase COMT Val158Met (rs4680) in Greenlandic Inuit (n=254) and Europeans (n=262) and explore the possible relation between the genotypes and serum levels of POPs. The genotype and allele frequency distributions of the three genetic polymorphisms differed significantly between the Inuit and Europeans. For Inuit, the genotype distribution was more similar to those reported for Asian populations. We observed a significant difference in serum polychlorinated biphenyl (CB-153) and the pesticide 1,1-dichloro-2,2-bis(p-chlorophenyl)-ethylene (p,p'-DDE) levels between Inuit and Europeans, and for Inuit also associations between the POP levels and genotypes for CYP1A1, CYP1B1 and COMT. Our data provide new information on gene polymorphisms in Greenlandic Inuit that might support evaluation of susceptibility to environmental contaminants and warrant further studies.

  20. CYP1A1 expression in breast milk cells of Japanese population

    Energy Technology Data Exchange (ETDEWEB)

    Yonemoto, Junzo; Shiizaki, Kazuhiro; Sone, Hideko; Morita, Masatosi [National Institute for Environmental Studies, Tsukuba (Japan); Uechi, Hiroto [Uechi Obstetrics and Gynecology Clinic, Utsunomiya (Japan); Masuzaki, Yuko; Koizumi, Atsuko; Matzumura, Toru [Metocean Environment Inc., Ohigawa (Japan)

    2004-09-15

    Dioxins are persistent, lipophilic compounds that are ubiquitous in the environment. Concern over the reproductive and developmental toxicity of dioxins has been growing since they have endocrine-disrupting properties and have adversely affected the health of offspring in experimental and epidemiological studies. Monitoring of maternal body burdens of dioxins and their biological responses to dioxin exposure is needed to estimate the potential health risk to their offspring. Breast milk has been used for monitoring dioxins in humans for decades. Breast milk has some advantages in exposure monitoring. Sampling is non-invasive, and dioxin levels are relatively high because of the high lipid content. It is assumed that mammary glands are exposed to a higher level of dioxins than other tissues since mammary glands synthesize and store milk fat. Breast milk contains leukocytes and exfoliated ductal epithelial cells. If these cells responded to dioxins and expressed CYP enzymes, a sensitive biomarker for dioxin exposure, they would be useful as biomarkers for dioxin exposure. In the present study, the expression of CYP enzymes in intact milk cells or cells cultured with TCDD was investigated. In addition, breast milk samples were collected from mothers within one week of childbearing, and the expression of CYP1A1 mRNA in milk cells was determined. The relationship between CYP1A1 mRNA expression in milk cells and dioxin levels in the cream layer of breast milk was analyzed.

  1. All-trans retinoic acid inhibits the recruitment of ARNT to DNA, resulting in the decrease of CYP1A1 mRNA expression in HepG2 cells

    International Nuclear Information System (INIS)

    Ohno, Marumi; Ikenaka, Yoshinori; Ishizuka, Mayumi

    2012-01-01

    Highlights: ► AHR and ARNT transcriptionally regulate genes related to metabolisms such as CYP1A1. ► We investigated the effect of retinoic acid (RA) on the function of AHR/ARNT. ► RA inhibited the recruitment of ARNT, not AHR, to the regulatory region of CYP1A1. ► It resulted in a reduction of constitutive expression of CYP1A1 to less than half. -- Abstract: Aryl hydrocarbon receptor (AHR) and AHR nuclear translocator (ARNT) are well-conserved transcription factors among species. However, there are a very limited number of reports on the physiological function of AHR, particularly on the regulation of AHR by endogenous compounds. We hence investigated the effects of all-trans retinoic acid (atRA) on cytochrome P450 (CYP) 1A1 gene transcription as a model of AHR-regulated transcription mechanisms in HepG2 cells, a human hepatoma cell line. Treatment with atRA significantly reduced transactivation and expression of CYP1A1 mRNA to less than half of its control value, and this inhibitory effect was mediated by RARα. The result of chromatin immunoprecipitation assay indicated that treatment with atRA at 1–100 nM drastically inhibited the recruitment of ARNT to DNA regions containing xenobiotic responsive elements. In conclusion, atRA at physiological concentrations could reduce AHR-mediated gene transcription via the inhibition of recruitment of ARNT to relevant DNA regions.

  2. Biodegradation of dioxins by recombinant Escherichia coli expressing rat CYP1A1 or its mutant

    Energy Technology Data Exchange (ETDEWEB)

    Shinkyo, Raku; Inouye, Kuniyo [Kyoto Univ. (Japan). Div. of Food Science and Biotechnology; Kamakura, Masaki; Ikushiro, Shin-ichi; Sakaki, Toshiyuki [Toyama Prefectural Univ. (Japan). Biotechnology Research Center

    2006-09-15

    Among polychlorinated dibenzo-p-dioxins (PCDDs), 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TetraCDD) is the most toxic one. Recently, we reported that rat CYP1A1 mutant, F240A, expressed in yeast showed metabolic activity toward 2,3,7,8-TetraCDD. In this study, we successfully expressed N-terminal truncated P450s ({delta}1A1 and {delta}F240A) in Escherichia coli cells. Kinetic analysis using membrane fractions prepared from the recombinant E. coli cells revealed that {delta}F240A has enzymatic properties similar to F240A expressed in yeast. The metabolism of PCDDs by recombinant E. coli cells expressing both {delta}F240A and human NADPH-P450 reductase was also examined. When 2,3,7-TriCDD was added to the E. coli cell culture at a final concentration of 10 {mu}M, approximately 90% of the 2,3,7-TriCDD was converted into multiple metabolites within 8 h. These results indicate the possible application of prokaryotic cells expressing {delta}F240A to the bioremediation of PCDD-contaminated soil. (orig.)

  3. CYP1A1 genetic polymorphism is a promising predictor to improve chemotherapy effects in patients with metastatic breast cancer treated with docetaxel plus thiotepa vs. docetaxel plus capecitabine.

    Science.gov (United States)

    Zhou, Xinna; Qiao, Guoliang; Wang, Xiaoli; Song, Qingkun; Morse, Michael A; Hobeika, Amy; Gwin, William R; Ren, Jun; Lyerly, H Kim

    2018-02-01

    A prospective study was performed to compare the outcome for metastatic breast cancer (MBC) patients treated with docetaxel plus thiotepa (DT) or docetaxel plus capecitabine (DC), and to explore the value of CYP1A1*2C polymorphisms in predicting clinical efficacy of these chemotherapies. MBC patients (n = 130) were randomized to treatment with DT (n = 65) or DC (n = 65). Response rate, disease control rate, progression-free and overall survival were monitored. Genotyping of CYP1A1*2C was performed in all patients. DT and DC produced similar overall disease control rates (76.9 vs 69.2%), median PFS (6.7 vs. 7.5 months) and OS (20.1 vs. 21.0 months) (P > 0.05 for all comparisons); however, DT exhibited a higher rate of control of localized liver metastases (78.6 vs 41.2%, P = 0.023). Among patients homozygous for wild-type CYP1A1*1 genotype (AA), DT treatment was associated with a significantly longer PFS (8.4 vs. 6.4 months, P = 0.019) and OS (33.4 vs. 15.8 months, P = 0.018). Conversely, among patients carrying the variant CYP1A1*2C genotype (AG/GG), DC treatment was associated with a significantly longer PFS (8.4 vs. 5.5 month, P = 0.005), and OS (28.5 vs. 19.6 months, P = 0.010). After adjusting for competing risk factors, CYP1A1*2C genotype was confirmed to be an independent predictor of PFS and OS for each chemotherapy combination. Overall, DT and DC result in similar clinical efficacy for MBC patients; however, efficacy for each therapy differs depending on CYP1A1*2C genotype.

  4. Antimutagenic properties of Mangifera indica L. stem bark extract and evaluation of its effects on hepatic CYP1A1.

    Science.gov (United States)

    Morffi, Janet; Rodeiro, Idania; Hernández, Sandra Luz; González, Leonora; Herrera, Jose; Espinosa-Aguirre, J Javier

    2012-09-01

    Mangifera indica stem bark extract (MSBE) is a Cuban natural product which has shown strong antioxidant properties. In this work, the antimutagenic effect of MSBE was tested against 10 well-known mutagens/carcinogens in the Ames test in the absence or presence of metabolic fraction (S9). The chemical mutagens tested included: cyclophosphamide, mitomycin C, bleomycin, cisplatin, dimethylnitrosamine (DMNA), benzo[a]pyrene (BP), 2-acetylaminofluorene (2-AAF), sodium azide, 1-nitropyrene (1-NP) and picrolonic acid. Protective effects of the extract were also evaluated by comparing the efficiency of S9 fraction obtained from rats treated during 28 days with oral doses of MSBE (50-500 mg/kg) with that obtained from rats treated with vehicle (control) to activate bleomycin and cyclophosphamide in the Ames test. MSBE concentrations between 50 and 500 μg/plate significantly reduced the mutagenicity mediated by all the chemicals tested with the exception of sodium azide. Higher mutagenicity was found when bleomycin and cyclophosphamide (CP) were activated by control S9 than by MSBE S9. In addition, inhibition of CYP1A1 microsomal activity was observed in the presence of MSBE (10-20 μg/ml). We can conclude that besides its potent antioxidant activity previously reported, MSBE may also exert a chemoprotective effect due to its capacity to inhibit CYP activity.

  5. Genetic polymorphisms in CYP1A1, GSTM1, GSTP1 and GSTT1 metabolic genes and risk of lung cancer in Asturias

    International Nuclear Information System (INIS)

    López-Cima, M Felicitas; Álvarez-Avellón, Sara M; Pascual, Teresa; Fernández-Somoano, Ana; Tardón, Adonina

    2012-01-01

    Metabolic genes have been associated with the function of metabolizing and detoxifying environmental carcinogens. Polymorphisms present in these genes could lead to changes in their metabolizing and detoxifying ability and thus may contribute to individual susceptibility to different types of cancer. We investigated if the individual and/or combined modifying effects of the CYP1A1 MspI T6235C, GSTM1 present/null, GSTT1 present/null and GSTP1 Ile105Val polymorphisms are related to the risk of developing lung cancer in relation to tobacco consumption and occupation in Asturias, Northern Spain. A hospital-based case–control study (CAPUA Study) was designed including 789 lung cancer patients and 789 control subjects matched in ethnicity, age, sex, and hospital. Genotypes were determined by PCR or PCR-RFLP. Individual and combination effects were analysed using an unconditional logistic regression adjusting for age, pack-years, family history of any cancer and occupation. No statistically significant main effects were observed for the carcinogen metabolism genes in relation to lung cancer risk. In addition, the analysis did not reveal any significant gene-gene, gene-tobacco smoking or gene-occupational exposure interactions relative to lung cancer susceptibility. Lastly, no significant gene-gene combination effects were observed. These results suggest that genetic polymorphisms in the CYP1A1, GSTM1, GSTT1 and GSTP1 metabolic genes were not significantly associated with lung cancer risk in the current study. The results of the analysis of gene-gene interactions of CYP1A1 MspI T6235C, GSTM1 present/null, GSTT1 present/null and GSTP1 Ile105Val polymorphisms in lung cancer risk indicate that these genes do not interact in lung cancer development

  6. Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM.

    Science.gov (United States)

    Amin, N; Byrne, E; Johnson, J; Chenevix-Trench, G; Walter, S; Nolte, I M; Vink, J M; Rawal, R; Mangino, M; Teumer, A; Keers, J C; Verwoert, G; Baumeister, S; Biffar, R; Petersmann, A; Dahmen, N; Doering, A; Isaacs, A; Broer, L; Wray, N R; Montgomery, G W; Levy, D; Psaty, B M; Gudnason, V; Chakravarti, A; Sulem, P; Gudbjartsson, D F; Kiemeney, L A; Thorsteinsdottir, U; Stefansson, K; van Rooij, F J A; Aulchenko, Y S; Hottenga, J J; Rivadeneira, F R; Hofman, A; Uitterlinden, A G; Hammond, C J; Shin, S-Y; Ikram, A; Witteman, J C M; Janssens, A C J W; Snieder, H; Tiemeier, H; Wolfenbuttel, B H R; Oostra, B A; Heath, A C; Wichmann, E; Spector, T D; Grabe, H J; Boomsma, D I; Martin, N G; van Duijn, C M

    2012-11-01

    Coffee consumption is a model for addictive behavior. We performed a meta-analysis of genome-wide association studies (GWASs) on coffee intake from 8 Caucasian cohorts (N=18 176) and sought replication of our top findings in a further 7929 individuals. We also performed a gene expression analysis treating different cell lines with caffeine. Genome-wide significant association was observed for two single-nucleotide polymorphisms (SNPs) in the 15q24 region. The two SNPs rs2470893 and rs2472297 (P-values=1.6 × 10(-11) and 2.7 × 10(-11)), which were also in strong linkage disequilibrium (r(2)=0.7) with each other, lie in the 23-kb long commonly shared 5' flanking region between CYP1A1 and CYP1A2 genes. CYP1A1 was found to be downregulated in lymphoblastoid cell lines treated with caffeine. CYP1A1 is known to metabolize polycyclic aromatic hydrocarbons, which are important constituents of coffee, whereas CYP1A2 is involved in the primary metabolism of caffeine. Significant evidence of association was also detected at rs382140 (P-value=3.9 × 10(-09)) near NRCAM-a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 (P-value=7.1 × 10(-09))-an SNP associated with blood pressure-in the 15q24 region near the gene ULK3, in the meta-analysis of discovery and replication cohorts. Our results from GWASs and expression analysis also strongly implicate CAB39L in coffee drinking. Pathway analysis of differentially expressed genes revealed significantly enriched ubiquitin proteasome (P-value=2.2 × 10(-05)) and Parkinson's disease pathways (P-value=3.6 × 10(-05)).

  7. CYP1A1 Ile462Val polymorphism contributes to lung cancer susceptibility among lung squamous carcinoma and smokers: a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Ya-Nan Ji

    Full Text Available Many studies have examined the association between the CYP1A1 Ile462Val gene polymorphisms and lung cancer risk in various populations, but their results have been inconsistent. To assess this relationship more precisely, a meta-analysis was performed. Ultimately, 43 case-control studies, comprising 19,228 subjects were included. A significantly elevated lung cancer risk was associated with 2 Ile462Val genotype variants (for Val/Val vs Ile/Ile: OR = 1.22, 95% CI = 1.08-1.40; for (Ile/Val +Val/Val vs Ile/Ile: OR = 1.15, 95% CI = 1.07-1.23 in overall population. In the stratified analysis, a significant association was found in Asians, Caucasians and lung SCC, not lung AC and lung SCLC. Additionally, a significant association was found in smoker population and not found in non-smoker populations. This meta-analysis suggests that the Ile462Val polymorphisms of CYP1A1 correlate with increased lung cancer susceptibility in Asian and Caucasian populations and there is an interaction with smoking status, but these associations vary in different histological types of lung caner.

  8. Evaluation of primary DNA damage, cytogenetic biomarkers and genetic polymorphisms for CYP1A1 and GSTM1 in road tunnel construction workers.

    Science.gov (United States)

    Villarini, M; Moretti, M; Fatigoni, C; Agea, E; Dominici, L; Mattioli, A; Volpi, R; Pasquini, R

    2008-01-01

    In tunnel construction workers, occupational exposure to dust (alpha-quartz and other particles from blasting), gases (nitrogen dioxide, NO(2)), diesel exhausts, and oil mist has been associated with lung function decline, induction of inflammatory reactions in the lungs with release of mediators that may influence blood coagulation, and increased risk of chronic obstructive pulmonary disease. The present molecular epidemiology study was designed to evaluate whether occupational exposure to indoor pollutants during road tunnel construction might result in genotoxic effects. A study group of 39 underground workers and a reference group of 34 unexposed subjects were examined. Primary and oxidative DNA damage, sister-chromatid exchanges (SCE), and micronuclei (MN) were measured in peripheral blood cells. The possible influences of polymorphisms in gene encoding for CYP1A1 and GSTM1 xenobiotic-metabolizing enzymes were also investigated. Exposure assessment was performed with detailed interviews and questionnaires. There were no significant differences in the level of primary and oxidative DNA damage and frequency of SCE between the tunnel workers and controls, whereas the frequency of MN showed a significant increase in exposed subjects compared to controls. No effects of CYP1A1 or GSTM1 variants were observed for the analyzed biomarkers. Since MN in peripheral blood lymphocytes are recognized as a predictive biomarker of cancer risk within a population of healthy subjects, the genotoxic risk of occupational exposure to various indoor environmental pollutants during road tunnel construction cannot be excluded by this biomonitoring study.

  9. Genetic variation in genes for the xenobiotic-metabolizing enzymes CYP1A1, EPHX1, GSTM1, GSTT1 and GSTP1 and susceptibility to colorectal cancer in Lynch syndrome

    Science.gov (United States)

    Pande, Mala; Amos, Christopher I.; Osterwisch, Daniel R.; Chen, Jinyun; Lynch, Patrick M.; Broaddus, Russell; Frazier, Marsha L.

    2011-01-01

    Individuals with Lynch syndrome are predisposed to cancer due to an inherited DNA mismatch repair gene mutation. However, there is significant variability observed in disease expression, likely due to the influence of other environmental, lifestyle, or genetic factors. Polymorphisms in genes encoding xenobiotic-metabolizing enzymes may modify cancer risk by influencing the metabolism and clearance of potential carcinogens from the body. In this retrospective analysis, we examined key candidate gene polymorphisms in CYP1A1, EPHX1, GSTT1, GSTM1, and GSTP1 as modifiers of age at onset of colorectal cancer among 257 individuals with Lynch syndrome. We found that subjects heterozygous for CYP1A1 I462V (c.1384A>G) developed colorectal cancer 4 years earlier than those with the homozygous wild-type genotype (median ages 39 and 43 years, respectively; log-rank test P = 0.018). Furthermore, being heterozygous for the CYP1A1 polymorphisms, I462V and Msp1 (g.6235T>C), was associated with an increased risk for developing colorectal cancer [adjusted hazard ratio for AG relative to AA = 1.78, 95% CI = 1.16–2.74, P = 0.008; and hazard ratio for TC relative to TT = 1.53, 95% CI = 1.06–2.22, P = 0.02]. Since homozygous variants for both CYP1A1 polymorphisms were rare, risk estimates were imprecise. None of the other gene polymorphisms examined were associated with an earlier onset age for colorectal cancer. Our results suggest that the I462V and Msp1 polymorphisms in CYP1A1 may be an additional susceptibility factor for disease expression in Lynch syndrome since they modify the age of colorectal cancer onset by up to 4 years. PMID:18768509

  10. All-trans retinoic acid inhibits the recruitment of ARNT to DNA, resulting in the decrease of CYP1A1 mRNA expression in HepG2 cells

    Energy Technology Data Exchange (ETDEWEB)

    Ohno, Marumi; Ikenaka, Yoshinori [Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, N18 W9, Kita-ku, Sapporo 060-0818 (Japan); Ishizuka, Mayumi, E-mail: ishizum@vetmed.hokudai.ac.jp [Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, N18 W9, Kita-ku, Sapporo 060-0818 (Japan)

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer AHR and ARNT transcriptionally regulate genes related to metabolisms such as CYP1A1. Black-Right-Pointing-Pointer We investigated the effect of retinoic acid (RA) on the function of AHR/ARNT. Black-Right-Pointing-Pointer RA inhibited the recruitment of ARNT, not AHR, to the regulatory region of CYP1A1. Black-Right-Pointing-Pointer It resulted in a reduction of constitutive expression of CYP1A1 to less than half. -- Abstract: Aryl hydrocarbon receptor (AHR) and AHR nuclear translocator (ARNT) are well-conserved transcription factors among species. However, there are a very limited number of reports on the physiological function of AHR, particularly on the regulation of AHR by endogenous compounds. We hence investigated the effects of all-trans retinoic acid (atRA) on cytochrome P450 (CYP) 1A1 gene transcription as a model of AHR-regulated transcription mechanisms in HepG2 cells, a human hepatoma cell line. Treatment with atRA significantly reduced transactivation and expression of CYP1A1 mRNA to less than half of its control value, and this inhibitory effect was mediated by RAR{alpha}. The result of chromatin immunoprecipitation assay indicated that treatment with atRA at 1-100 nM drastically inhibited the recruitment of ARNT to DNA regions containing xenobiotic responsive elements. In conclusion, atRA at physiological concentrations could reduce AHR-mediated gene transcription via the inhibition of recruitment of ARNT to relevant DNA regions.

  11. CYP1A1 induction and CYP3A4 inhibition by the fungicide imazalil in the human intestinal Caco-2 cells-comparison with other conazole pesticides.

    Science.gov (United States)

    Sergent, Thérèse; Dupont, Isabelle; Jassogne, Coralie; Ribonnet, Laurence; van der Heiden, Edwige; Scippo, Marie-Louise; Muller, Marc; McAlister, Dan; Pussemier, Luc; Larondelle, Yvan; Schneider, Yves-Jacques

    2009-02-10

    Imazalil (IMA) is a widely used imidazole-antifungal pesticide and, therefore, a food contaminant. This compound is also used as a drug (enilconazole). As intestine is the first site of exposure to ingested drugs and pollutants, we have investigated the effects of IMA, at realistic intestinal concentrations, on xenobiotic-metabolizing enzymes and efflux pumps by using Caco-2 cells, as a validated in vitro model of the human intestinal absorptive epithelium. For comparison, other conazole fungicides, i.e. ketoconazole, propiconazole and tebuconazole, were also studied. IMA induced cytochrome P450 (CYP) 1A1 activity to the same extent as benzo(a)pyrene (B(a)P) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in a dose- and time-dependent manner. Cell-free aryl hydrocarbon receptor (AhR) binding assay and reporter gene assay suggested that IMA is not an AhR-ligand, implying that IMA-mediated induction should involve an AhR-independent pathway. Moreover, IMA strongly inhibited the CYP3A4 activity in 1,25-vitamin D(3)-induced Caco-2 cells. The other fungicides had weak or nil effects on CYP activities. Study of the apical efflux pump activities revealed that ketoconazole inhibited both P-glycoprotein (Pgp) and multidrug resistance-associated protein 2 (MRP-2) or breast cancer resistance protein (BCRP), whereas IMA and other fungicides did not. Our results imply that coingestion of IMA-contaminated food and CYP3A4- or CYP1A1-metabolizable drugs or chemicals could lead to drug bioavailability modulation or toxicological interactions, with possible adverse effects for human health.

  12. Induction of CYP1A1, CYP1A2, and CYP1B1 mRNAs by nitropolycyclic aromatic hydrocarbons in various human tissue-derived cells: chemical-, cytochrome P450 isoform-, and cell-specific differences

    Energy Technology Data Exchange (ETDEWEB)

    Iwanari, M.; Nakajima, M.; Yokoi, T. [Div. of Drug Metabolism, Kanazawa Univ., Kanazawa (Japan); Kizu, R.; Hayakawa, K. [Lab. of Hygienic Chemistry, Kanazawa Univ., Kanazawa (Japan)

    2002-06-01

    Nitropolycyclic aromatic hydrocarbons (NPAHs) are found in diesel exhaust and ambient air. NPAHs as well as polycyclic aromatic hydrocarbons (PAHs) are known to have mutagenicity, carcinogenicity, and endocrine-disruptive effects. In the present study, the inducibility of the human cytochrome P450-1 (CYP1) family by NPAHs was compared with those produced by their parent PAHs and some reductive metabolites, amino-PAHs. Furthermore, to investigate the differences in the inducibility of the CYP1 family in human tissues, various human tissue-derived cell lines, namely HepG2 (hepatocellular carcinoma), ACHN (renal carcinoma), A549 (lung carcinoma), MCF-7 (breast carcinoma), LS-180 (colon carcinoma), HT-1197 (bladder carcinoma), HeLa (cervix of uterus adenocarcinoma), OMC-3 (ovarian carcinoma), and NEC14 (testis embryonal carcinoma), were treated with NPAHs, PAHs, or amino-PAHs. The mRNA levels of CYP1A1, CYP1A2, and CYP1B1 were determined with reverse transcription-polymerase chain reaction (RT-PCR). The cell lines were classified into two groups: CYP1 inducible cell lines, comprising HepG2, MCF-7, LS-180, and OMC-3 cells, and CYP1 non-inducible cell lines, comprising ACHN, A549, HT-1197, HeLa, and NEC14 cells. In inducible cell lines, the induction profile of chemical specificity was similar for CYP1A1, CYP1A2, and CYP1B1, although the extent of induction differed among the cell lines and for the CYP isoforms. Pyrene, 1-nitropyrene, 1-aminopyrene, 1,3-, 1,6-, and 1,8-dinitropyrenes slightly induced CYP1 mRNAs, but 1,3-dinitropyrene produced a 6-fold induction of CYP1A1 mRNA in MCF-7 cells. 2-Nitrofluoranthene and 3-nitrofluoranthene exhibited stronger inducibility than fluoranthene in the inducible cell lines. 6-Nitrochrysene induced CYP1 mRNAs to the same extent or more potently than chrysene. The induction potencies of 6-nitrobenzo[a]pyrene and 7-nitrobenz[a]anthracene were weaker than those of their parents benzo[a]pyrene and benz[a]anthracene, respectively. This

  13. CYP1A1 gene polymorphisms increase lung cancer risk in a high-incidence region of Spain: a case control study

    Directory of Open Access Journals (Sweden)

    San Jose Carmen

    2010-08-01

    Full Text Available Abstract Background A rural region in south-west Spain has one of the highest lung cancer incidence rates of the country, as revealed by a previous epidemiological 10-year follow-up study. The present work was undertaken to ascertain the role of CYP1A1 gene polymorphisms and their interaction with tobacco smoking in the development of the disease in this location. Methods One-hundred-and-three cases of lung cancer and 265 controls participated in the study. The participants were screened for the presence of four CYP1A1 polymorphisms, namely MspI, Ile462Val, T3205C, and Thr461Asn. Lung cancer risk was estimated as odds ratios (OR and 95% confidence intervals (CI using unconditional logistic regression models adjusting for age, sex, and smoking. Results The distribution of the variant CYP1A1 alleles was different from that described for other Caucasian populations, with CYP1A1*2A showing an uncommonly high frequency (p CYP1A1*2B allele (carrying MspI and Ile462Val mutations was strongly associated with high lung cancer risk (OR = 4.59, CI:1.4-12.6, p p p = 0.04. Moreover, the Thr461Asn polymorphism was found to be associated with SCLC in a Caucasian population for the first time to our knowledge (OR = 8.33, CI: 1.3-15.2, p = 0.04. Conclusion The results suggest that CYP1A1 polymorphisms contribute to increase lung cancer susceptibility in an area with an uncommon high incidence rate.

  14. Evaluation of toxic equivalency factors for induction of cytochromes P450 CYP1A1 and CYP1A2 enzyme activity by dioxin-like compounds

    International Nuclear Information System (INIS)

    Toyoshiba, Hiroyoshi; Walker, Nigel J.; Bailer, A. John; Portier, Christopher J.

    2004-01-01

    The toxic equivalency factor (TEF) method has been used to characterize the toxicity of human mixtures of dioxin-like compounds and is being considered for use with other classes of potentially toxic agents. TEFs are estimated by examining the relative potencies of the various congeners for a series of biological and toxicological effects. In this paper, we consider changes in activity for two enzymes, cytochrome P450 1A1 (CYP1A1)-associated 7-ethoxyresorufin-O-deethylase (EROD) and CYP1A2-associated acetanilide-4-hydroxylase (A4H) activity, resulting from exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3',4,4',5-pentachlorobiphenyl (PCB), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) or a mixture of these agents. The ratio of median effective dose (ED 50 ) is one way to estimate the relative potencies, especially for gene expression and protein endpoints. ED 50 's were estimated with a nonlinear regression model in which dose-related changes in mean responses are described by a Hill function. ED 50 's along with other model parameters were estimated by fitting this model to a given data set. Significant differences in estimated model parameters were tested by likelihood ratio methods. The estimated parameters indicated that congener-specific dose-response shapes were significantly different, that additivity failed for these congeners, and that the ratios of ED 50 's did not predict the response seen for the mixture. These results indicate that for some biological responses, the use of a single relative potency factor (RPF) is not appropriate for the comparison of the dose response behavior of different dioxin-like congeners

  15. Genetic polymorphisms of the CYP1A1, GSTM1, and GSTT1 enzymes and their influence on cardiovascular risk and lipid profile in people who live near a natural gas plant.

    Science.gov (United States)

    Pašalić, Daria; Marinković, Natalija

    2017-03-01

    The aim of this cross-sectional study was to see whether genetic polymorphisms of the enzymes CYP1A1, GSTM1, and GSTT1 are associated with higher risk of coronary artery disease (CAD) and whether they affect lipid profile in 252 subjects living near a natural gas plant, who are likely to be exposed to polycyclic aromatic hydrocarbons (PAHs). Fasting serum concentrations of biochemical parameters were determined with standard methods. Genetic polymorphisms of CYP 1A1 rs4646903, rs1048943, rs4986883, and rs1799814 were genotyped with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFPL), while GSTM1 and GSTT1 deletions were detected with multiplex PCR. Cardiovascular risk was assessed with Framingham risk score, and the subjects divided in two groups: >10% risk and ≤10% risk. The two groups did not differ in the genotype frequencies. MANCOVA analysis, which included lipid parameters, glucose, and BMI with sex, age, hypertension and smoking status as covariates, showed a significant difference between the GSTT1*0 and GSTT1*1 allele carriers (p=0.001). UNIANCOVA with same covariates showed that total cholesterol and triglyceride levels were significantly higher in GSTT1*1 allele carriers than in GSTT1*0 carriers (prisk of CAD, but that GSTT1 affects lipid profile.

  16. Changes in persistent contaminant concentration and CYP1A1 protein expression in biopsy samples from northern bottlenose whales, Hyperoodon ampullatus, following the onset of nearby oil and gas development

    Energy Technology Data Exchange (ETDEWEB)

    Hooker, Sascha K. [Department of Biology, Dalhousie University, Halifax, Nova Scotia B3H 4J1 (Canada); Sea Mammal Research Unit, University of St Andrews, FIFE KY16 8YG (United Kingdom)], E-mail: s.hooker@st-andrews.ac.uk; Metcalfe, Tracy L.; Metcalfe, Chris D. [Environmental and Resource Studies, Trent University, Peterborough, Ontario K9J 7B8 (Canada); Angell, Carolyn M.; Wilson, Joanna Y.; Moore, Michael J. [Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA 02543 (United States); Whitehead, Hal [Department of Biology, Dalhousie University, Halifax, Nova Scotia B3H 4J1 (Canada)

    2008-03-15

    A small population of endangered northern bottlenose whales (Hyperoodon ampullatus) inhabits 'The Gully' a Marine Protected Area on the Scotian Shelf, eastern Canada. Amid concerns regarding nearby oil and gas development, we took 36 skin and blubber biopsy samples in 1996-1997 (prior to major development) and 2002-2003 (five years after development began), and three samples from a population in the Davis Strait, Labrador in 2003. These were analysed for cytochrome P4501A1 (CYP1A1) protein expression (n = 36), and for persistent contaminants (n = 23). CYP1A1 showed generally low expression in whales from The Gully, but higher levels during 2003, potentially coincident with recorded oil spills, and higher levels in Davis Strait whales. A range of PCB congeners and organochlorine compounds were detected, with concentrations similar to other North Atlantic odontocetes. Concentrations were higher in whales from The Gully than from the Davis Strait, with significant increases in 4,4'-DDE and trans-nonachlor in 2002-2003 relative to 1996-1997. - Whale contaminants highlight concerns from oil and gas development near a marine protected area.

  17. Changes in persistent contaminant concentration and CYP1A1 protein expression in biopsy samples from northern bottlenose whales, Hyperoodon ampullatus, following the onset of nearby oil and gas development

    International Nuclear Information System (INIS)

    Hooker, Sascha K.; Metcalfe, Tracy L.; Metcalfe, Chris D.; Angell, Carolyn M.; Wilson, Joanna Y.; Moore, Michael J.; Whitehead, Hal

    2008-01-01

    A small population of endangered northern bottlenose whales (Hyperoodon ampullatus) inhabits 'The Gully' a Marine Protected Area on the Scotian Shelf, eastern Canada. Amid concerns regarding nearby oil and gas development, we took 36 skin and blubber biopsy samples in 1996-1997 (prior to major development) and 2002-2003 (five years after development began), and three samples from a population in the Davis Strait, Labrador in 2003. These were analysed for cytochrome P4501A1 (CYP1A1) protein expression (n = 36), and for persistent contaminants (n = 23). CYP1A1 showed generally low expression in whales from The Gully, but higher levels during 2003, potentially coincident with recorded oil spills, and higher levels in Davis Strait whales. A range of PCB congeners and organochlorine compounds were detected, with concentrations similar to other North Atlantic odontocetes. Concentrations were higher in whales from The Gully than from the Davis Strait, with significant increases in 4,4'-DDE and trans-nonachlor in 2002-2003 relative to 1996-1997. - Whale contaminants highlight concerns from oil and gas development near a marine protected area

  18. Co-expression of human cytochrome P4501A1 (CYP1A1) variants and human NADPH-cytochrome P450 reductase in the baculovirus/insect cell system.

    Science.gov (United States)

    Schwarz, D; Kisselev, P; Honeck, H; Cascorbi, I; Schunck, W H; Roots, I

    2001-06-01

    1. Three human cytochrome P4501A1 (CYP1A1) variants, wild-type (CYP1A1.1), CYP1A1.2 (1462V) and CYP1A1.4 (T461N), were co-expressed with human NADPH-P450 reductase (OR) in Spodoptera frugiperda (Sf9) insect cells by baculovirus co-infection to elaborate a suitable system for studying the role of CYPA1 polymorphism in the metabolism of exogenous and endogenous substrates. 2. A wide range of conditions was examined to optimize co-expression with regard to such parameters as relative multiplicity of infection (MOI), time of harvest, haem precursor supplementation and post-translational stabilization. tinder optimized conditions, almost identical expression levels and molar OR/CYP1A1 ratios (20:1) were attained for all CYP1A1 variants. 3. Microsomes isolated from co-infected cells demonstrated ethoxyresorufin deethlylase activities (nmol/min(-1) nmol(-1) CYP1A1) of 16.0 (CYP1A1.1), 20.5 (CYP1A1.2) and 22.5 (CYP1A1.4). Pentoxyresorufin was dealkylated approximately 10-20 times slower with all enzyme variants. 4. All three CYP1A1 variants were active in metabolizing the precarcinogen benzo[a]pyrene (B[a]P), with wild-type enzyme showing the highest activity, followed by CYP1A1.4 (60%) and CYP1A1.2 (40%). Each variant produced all major metabolites including B[a]P-7,8-dihydrodiol, the precursor of the ultimate carcinogenic species. 5. These studies demonstrate that the baculovirus-mediated co-expression-by-co-infection approach all CYP1A1 variants yields functionally active enzyme systems with similar molar OR/CYP1A1 ratios, thus providing suitable preconditions to examine the metabolism of and environmental chemicals by the different CY1A1 variants.

  19. Linked expression of Ah receptor, ARNT, CYP1A1, and CYP1B1 in rat mammary epithelia, in vitro, is each substantially elevated by specific extracellular matrix interactions that precede branching morphogenesis.

    Science.gov (United States)

    Larsen, Michele Campaigne; Brake, Paul B; Pollenz, Richard S; Jefcoate, Colin R

    2004-11-01

    Cytochrome P4501B1 (CYP1B1), the major constitutively expressed CYP in the rat mammary gland, is induced by Ah-receptor (AhR) ligands, while CYP1A1 is predominantly expressed only after induction. These CYPs contribute to carcinogenic activation of polycyclic aromatic hydrocarbons (PAHs). AhR, ARNT, and CYP1B1 were only weakly expressed, even after 2,3,7,8-tetrachlorodibenzo-p-dioxin induction, when rat mammary epithelial cells (RMEC) were cultured on plastic. RMEC cultured on the extracellular matrix (ECM), Matrigel, or on a floating gel of collagen I demonstrated branching morphogenesis and substantially increased basal CYP1B1 and induced CYP1A1 expression, in parallel with large increases in AhR and ARNT expression. Branching was more pronounced in the Wistar Kyoto than in the Wistar Furth rat strain. Although EGF enhanced branching, neither strain nor growth factor treatment substantially impacted CYP expression. Increased AhR and ARNT expression is observed within 24 h of dispersal on Matrigel, substantially prior to branch formation. Culture on thin layers of collagen I, collagen IV, and laminin, respectively, failed to reproduce the branching morphogenesis or increases in AhR, ARNT, or CYP expression. However, adherent, gelled collagen I recapitulated the increased protein expression, without supporting branching. This increased protein expression was closely paralleled by enhanced expression of beta-catenin and E-cadherin, components of cell-cell adhesion complexes. A synthetic peptide that selectively antagonizes integrin-ECM interactions reduced branch formation, without diminishing AhR, ARNT, and CYP expression. These data demonstrate that early ECM surface adhesion interactions mediate AhR and ARNT expression, which enhances CYP expression, independent of branching morphogenesis.

  20. Effect of Flavonoids on Glutathione Level, Lipid Peroxidation and Cytochrome P450 CYP1A1 Expression in Human Laryngeal Carcinoma Cell Lines

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    Lidija Vuković

    2007-01-01

    Full Text Available Flavonoids are phytochemicals exhibiting a wide range of biological activities, among which are antioxidant activity, the ability to modulate activity of several enzymes or cell receptors and possibility to interfere with essential biochemical pathways. Using human laryngeal carcinoma HEp2 cells and their drug-resistant CK2 subline, we examined the effect of five flavonoids, three structurally related flavons (quercetin, fisetin, and myricetin, one flavonol (luteolin and one glycosilated flavanone (naringin for: (i their ability to inhibit mitochondrial dehydrogenases as an indicator of cytotoxic effect, (ii their influence on glutathione level, (iii antioxidant/prooxidant effects and influence on cell membrane permeability, and (iv effect on expression of cytochrome CYP1A1. Cytotoxic action of the investigated flavonoids after 72 hours of treatment follows this order: luteolin>quercetin>fisetin>naringin>myricetin. Our results show that CK2 were more resistant to toxic concentrations of flavonoids as compared to parental cells. Quercetin increased the total GSH level in both cell lines. CK2 cells are less perceptible to lipid peroxidation and damage caused by free radicals. Quercetin showed prooxidant effect in both cell lines, luteolin only in HEp2 cells, whereas other tested flavonoids did not cause lipid peroxidation in the tested cell lines. These data suggest that the same compound, quercetin, can act as a prooxidant, but also, it may prevent damage in cells caused by free radicals, due to the induction of GSH, by forming less harmful complex. Quercetin treatment damaged cell membranes in both cell lines. Fisetin caused higher cell membrane permeability only in HEp2 cells. However, these two compounds did not enhance the damage caused by hydrogen peroxide. Quercetin, naringin, myricetin and fisetin increased the expression of CYP1A1 in both cell lines, while luteolin decreased basal level of CYP1A1 only in HEp2 cells. In conclusion, small

  1. ANTIBODIES TO BENZO[A]PYRENE AND POLYMORPHISMS OF CYP1A1*2A, CYP1A2*1F, GSTT1, AND GSTM1 GENES IN HEALTHY MEN AND LUNG CANCER PATIENTS

    Directory of Open Access Journals (Sweden)

    A. N. Glushkov

    2016-01-01

    Full Text Available Some genetic polymorphisms of CYP and GST enzymes metabolizing low-molecular weight xenobiotics may represent endogenous risk factors for carcinogenesis. However, possible relationships between the enzyme activities, amounts of carcinogen adducts and synthesis of anticarcinogen antibodies in humans (including cancer patients are still poorly studied. The purpose of this study was to identify possible associations between occurrence of antibodies against benzo[a]pyrene, and frequency of genetic polymorphisms of CYP1A1*2A, CYP1A2*1F, GSTT1, GSTM1 in healthy men and in lung cancer patients. Materials and methods. We have examined 203 men with non-small cell lung cancer and 267 apparently healthy donors without respiratory diseases. A non-competitive solid phase immunoassay of antibodies to benzo[a]pyrene was performed. Analysis of polymorphic loci within CYP1A1 (rs4646903, CYP1A2 (rs762551, GSTP1 (rs1695, rs1138272 was performed by means of real-time PCR using TaqMan technology. Null-alleles of GSTM1 (del, GSTT1 (del genes were detected by multiplex PCR with real-time fluorescent assay. Results. Among the lung cancer patients, the proportion of cases with a high level of IgG antibodies to benzo[a]pyrene in carriers of GSTT1+ and GSTM1+ in conjunction with the CYP1A2*1F C allele was significantly greater than in AA homozygotes CYP1A2*1F. The risk of lung cancer was increased to 5.5 in carriers of CYP1A2*1F C allele combined with GSTT1+ and GSTM1+ at high levels of IgG antibodies to benzo [a] pyrene. In healthy male donors, we have not found differences between the incidence of low and high levels of IgG anti-benzo[a]pyrene antibodies in the carriers of certain CYP1A1*2A, CYP1A2*1F, GSTT1 and GSTM1 genotypes. Conclusions. We have first reported a relationship between CYP1 and GST gene polymorphisms and specific immune response to chemical carcinogens in lung cancer patients. Immunoassays of IgG antibodies to benzo[a]pyrene combined with molecular

  2. CYP1A1, CYP1A2, SULT1A1 AND SULT1E1 ALLELIC POLYMORPHISM IN CASE OF GENITAL ENDOMETRIOSIS

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    Konstantin Sergeevich Kublinskiy

    2016-02-01

    Up-to-date molecular and genetic analyses reveal that women predisposed to genital endometriosis possess Allele G and Genotypes AG and GG of the polymorphic option A-4889G of the CYP1A1 gene and Allele A and Genotypes CA and AA of the polymorphic option C-734A of the CYP1A2 gene. The polymorphism of the promoter regions of the SULT1A1 (G-638A and SULT1E1 (C-174T genes is not associated with genital endometriosis in women.

  3. CYP1A1, CYP2E1 Y RIESGO A CÁNCER GÁSTRICO EN UNA POBLACIÓN COLOMBIANA DE ALTA INCIDENCIA

    Directory of Open Access Journals (Sweden)

    Eduardo Castaño

    2009-09-01

    Full Text Available El objetivo fue probar la hipótesis de que en casos y controles, de una población colombiana con alta incidencia de cáncer gástrico, muestran diferencias significativas entre las frecuencias de los polimorfismos genéticos CYP1A1-m2 y CYP2E1-c2; y a la vez, probar si hay diferencias entre el hábito del tabaquismo, el consumo de licor y el estrato socioeconómico; así como también sus posibles interacciones. Ochenta y siete pacientes afectados por cáncer gástrico e igual número de controles, del mismo grupo poblacional, genéticamente aislado, pertenecientes a la comunidad “paisa” del departamento de Caldas, fueron genotipíficados por medio de PCR-RFLPs para los polimorfismos CYP1A1-m2 y CYP2E1-c2. Además, se tuvo en cuenta las variables socioeconómicas y el estilo de vida, con respecto al tabaquismo y al consumo de alcohol. Los resultados encontrados sugieren que los portadores del polimorfismo CYP2E1-c2, asociado con mayor actividad metabólica, tienen mayor riesgo a desarrollar cáncer gástrico (OR=3.6, CI95% 1.6-8.1/p=0,002. En contraste, la frecuencia del polimorfismo CYP1A1*2A (MspI, también asociado con mayor actividad enzimática, mostró similar frecuencia entre los dos grupos. El tabaquismo y el estrato socioeconómico bajo, también mostraron diferencias significativas. En conclusión, se evidencia interacción significativa entre gen-ambiente, particularmente entre el tabaquismo y los alelos bioactiavantes CYP2E1- c2 y CYP1A1-m2, que pueden alterar la susceptibilidad a cáncer de estómago en esta región Andina del noroeste de Sur América.

  4. Areca nut components affect COX-2, cyclin B1/cdc25C and keratin expression, PGE2 production in keratinocyte is related to reactive oxygen species, CYP1A1, Src, EGFR and Ras signaling.

    Directory of Open Access Journals (Sweden)

    Mei-Chi Chang

    Full Text Available Chewing of betel quid (BQ increases the risk of oral cancer and oral submucous fibrosis (OSF, possibly by BQ-induced toxicity and induction of inflammatory response in oral mucosa.Primary gingival keratinocytes (GK cells were exposed to areca nut (AN components with/without inhibitors. Cytotoxicity was measured by 3-(4,5-dimethyl- thiazol- 2-yl-2,5-diphenyl-tetrazolium bromide (MTT assay. mRNA and protein expression was evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR and western blotting. PGE2/PGF2α production was measured by enzyme-linked immunosorbent assays.Areca nut extract (ANE stimulated PGE2/PGF2α production, and upregulated the expression of cyclooxygenase-2 (COX-2, cytochrome P450 1A1 (CYP1A1 and hemeoxygenase-1 (HO-1, but inhibited expression of keratin 5/14, cyclinB1 and cdc25C in GK cells. ANE also activated epidermal growth factor receptor (EGFR, Src and Ras signaling pathways. ANE-induced COX-2, keratin 5, keratin 14 and cdc25C expression as well as PGE2 production were differentially regulated by α-naphthoflavone (a CYP 1A1/1A2 inhibitor, PD153035 (EGFR inhibitor, pp2 (Src inhibitor, and manumycin A (a Ras inhibitor. ANE-induced PGE2 production was suppressed by piper betle leaf (PBL extract and hydroxychavicol (two major BQ components, dicoumarol (aQuinone Oxidoreductase--NQO1 inhibitor and curcumin. ANE-induced cytotoxicity was inhibited by catalase and enhanced by dicoumarol, suggesting that AN components may contribute to the pathogenesis of OSF and oral cancer via induction of aberrant differentiation, cytotoxicity, COX-2 expression, and PGE2/PGF2α production.CYP4501A1, reactive oxygen species (ROS, EGFR, Src and Ras signaling pathways could all play a role in ANE-induced pathogenesis of oral cancer. Addition of PBL into BQ and curcumin consumption could inhibit the ANE-induced inflammatory response.

  5. Role of genetic polymorphisms of CYP1A1, CYP3A5, CYP2C9, CYP2D6, and PON1 in the modulation of DNA damage in workers occupationally exposed to organophosphate pesticides

    International Nuclear Information System (INIS)

    Singh, Satyender; Kumar, Vivek; Vashisht, Kapil; Singh, Priyanka; Banerjee, Basu Dev; Rautela, Rajender Singh; Grover, Shyam Sunder; Rawat, Devendra Singh; Pasha, Syed Tazeen; Jain, Sudhir Kumar; Rai, Arvind

    2011-01-01

    Organophosphate pesticides (OPs) are primarily metabolized by several xenobiotic metabolizing enzymes (XMEs). Very few studies have explored genetic polymorphisms of XMEs and their association with DNA damage in pesticide-exposed workers. The present study was designed to determine the role of genetic polymorphisms of CYP1A1, CYP3A5, CYP2C9, CYP2D6, and PON1 in the modulation of DNA damage in workers occupationally exposed to OPs. We examined 284 subjects including 150 workers occupationally exposed to OPs and 134 normal healthy controls. The DNA damage was evaluated using the alkaline comet assay and genotyping was done using PCR–RFLP. The results revealed that the PONase activity toward paraoxonase and AChE activity was found significantly lowered in workers as compared to control subjects (p < 0.001). Workers showed significantly higher DNA damage compared to control subjects (14.37 ± 2.15 vs. 6.24 ± 1.37 tail% DNA, p < 0.001). Further, the workers with CYP2D6*3 PM and PON1 (QQ and MM) genotypes were found to have significantly higher DNA damage when compared to other genotypes (p < 0.05). In addition, significant increase in DNA damage was also observed in workers with concomitant presence of certain CYP2D6 and PON1 (Q192R and L55M) genotypes which need further extensive studies. In conclusion, the results indicate that the PON1 and CYP2D6 genotypes can modulate DNA damage elicited by some OPs possibly through gene-environment interactions. -- Highlights: ► Role of CYP1A1, CYP3A5, CYP2C, CYP2D6 and PON1 genotypes on DNA damage. ► Workers exposed to some OPs demonstrated increased DNA damage. ► CYP2D6 *3 PM and PON1 (Q192R and L55M) genotypes are associated with DNA damage. ► Concomitant presence of certain CYP2D6 and PON1 genotypes can increase DNA damage.

  6. Role of genetic polymorphisms of CYP1A1, CYP3A5, CYP2C9, CYP2D6, and PON1 in the modulation of DNA damage in workers occupationally exposed to organophosphate pesticides

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Satyender [Division of Biochemistry and Biotechnology, National Centre for Disease Control 22, Sham Nath Marg, Delhi-110054 (India); Kumar, Vivek [Environmental Biochemistry and Molecular Biology laboratory, Department of Biochemistry, University College of Medical Sciences and GTB Hospital, University of Delhi, Dilshad Garden, Delhi-110095 (India); Vashisht, Kapil; Singh, Priyanka [Division of Biochemistry and Biotechnology, National Centre for Disease Control 22, Sham Nath Marg, Delhi-110054 (India); Banerjee, Basu Dev, E-mail: banerjeebd@hotmail.com [Environmental Biochemistry and Molecular Biology laboratory, Department of Biochemistry, University College of Medical Sciences and GTB Hospital, University of Delhi, Dilshad Garden, Delhi-110095 (India); Rautela, Rajender Singh; Grover, Shyam Sunder; Rawat, Devendra Singh; Pasha, Syed Tazeen [Division of Biochemistry and Biotechnology, National Centre for Disease Control 22, Sham Nath Marg, Delhi-110054 (India); Jain, Sudhir Kumar [Centre for Epidemiology and Parasitic Diseases, National Centre for Disease Control 22, Sham Nath Marg, Delhi-110054 (India); Rai, Arvind [Division of Biochemistry and Biotechnology, National Centre for Disease Control 22, Sham Nath Marg, Delhi-110054 (India)

    2011-11-15

    Organophosphate pesticides (OPs) are primarily metabolized by several xenobiotic metabolizing enzymes (XMEs). Very few studies have explored genetic polymorphisms of XMEs and their association with DNA damage in pesticide-exposed workers. The present study was designed to determine the role of genetic polymorphisms of CYP1A1, CYP3A5, CYP2C9, CYP2D6, and PON1 in the modulation of DNA damage in workers occupationally exposed to OPs. We examined 284 subjects including 150 workers occupationally exposed to OPs and 134 normal healthy controls. The DNA damage was evaluated using the alkaline comet assay and genotyping was done using PCR-RFLP. The results revealed that the PONase activity toward paraoxonase and AChE activity was found significantly lowered in workers as compared to control subjects (p < 0.001). Workers showed significantly higher DNA damage compared to control subjects (14.37 {+-} 2.15 vs. 6.24 {+-} 1.37 tail% DNA, p < 0.001). Further, the workers with CYP2D6*3 PM and PON1 (QQ and MM) genotypes were found to have significantly higher DNA damage when compared to other genotypes (p < 0.05). In addition, significant increase in DNA damage was also observed in workers with concomitant presence of certain CYP2D6 and PON1 (Q192R and L55M) genotypes which need further extensive studies. In conclusion, the results indicate that the PON1 and CYP2D6 genotypes can modulate DNA damage elicited by some OPs possibly through gene-environment interactions. -- Highlights: Black-Right-Pointing-Pointer Role of CYP1A1, CYP3A5, CYP2C, CYP2D6 and PON1 genotypes on DNA damage. Black-Right-Pointing-Pointer Workers exposed to some OPs demonstrated increased DNA damage. Black-Right-Pointing-Pointer CYP2D6 *3 PM and PON1 (Q192R and L55M) genotypes are associated with DNA damage. Black-Right-Pointing-Pointer Concomitant presence of certain CYP2D6 and PON1 genotypes can increase DNA damage.

  7. Evaluation of CYP1A1 and CYP2B1/2 m-RNA induction in rat liver slices using the NanoString technology: a novel tool for drug discovery lead optimization.

    Science.gov (United States)

    Palamanda, Jairam R; Kumari, Pramila; Murgolo, Nicholas; Benbow, Larry; Lin, Xinjie; Nomeir, Amin A

    2009-08-01

    Cytochrome P450 (CYP) induction in rodents and humans is considered a liability for new chemical entities (NCEs) in drug discovery. In particular, CYP1A1 and CYP2B1/2 have been associated with the induction of liver tumors in oncogenicity studies during safety evaluation studies of potential drugs. In our laboratory, real time PCR (Taqman) has been used to quantify the induction of rat hepatic CYP1A1 and CYP2B1/2 in precision -cut rat liver slices. A novel technology that does not require m-RNA isolation or RT-PCR, (developed by NanoString Technologies) has been investigated to quantify CYP1A1 and CYP2B1/2 induction in rat liver slices. Seventeen commercially available compounds were evaluated using both Taqman and NanoString technologies. Precision-cut rat liver slices were incubated with individual compounds for 24 hr at 37 degrees C in a humidified CO(2) incubator and CYP1A1 and CYP2B1/2 m-RNA were quantified. The results from the NanoString technology were similar to those of the Taqman(R) with a high degree of correlation for both CYP isoforms (r(2)>0.85). Therefore, NanoString provides an additional new technology to evaluate the induction of CYP1A1 and 2B1/2, as well as potentially other enzymes or transporters in rat liver slices.

  8. Sequencing and characterization of mixed function monooxygenase genes CYP1A1 and CYP1A2 of Mink (Mustela vison) to facilitate study of dioxin-like compounds

    International Nuclear Information System (INIS)

    Zhang Xiaowei; Moore, Jeremy N.; Newsted, John L.; Hecker, Markus; Zwiernik, Matthew J.; Jones, Paul D.; Bursian, Steven J.

    2009-01-01

    As part of an ongoing effort to understand aryl hydrocarbon receptor (AhR) mediated toxicity in mink, cDNAs encoding for CYP1A1 and the CYP1A2 mixed function monooxygenases were cloned and characterized. In addition, the effects of selected dibenzofurans on the expression of these genes and the presence of their respective proteins (P4501A) were investigated, and then correlated with the catalytic activities of these proteins as measured by ethoxyresorufin O-deethylase (EROD) and methoxyresorufin O-deethylase (MROD) activities. The predicted protein sequences for CYP1A1 and CYP1A2 comprise 517 and 512 amino acid residues, respectively. The phylogenetic analysis of the mink CYP1As with protein sequences of other mammals revealed high sequence homology with sea otter, seals and the dog, with amino acid identities ranging from 89 to 95% for CYP1A1 and 81 to 93% for CYP1A2. Since exposure to both 2,3,7,8-Tetrachlorodibenzofuran (TCDF) and 2,3,4,7,8-Pentachlorodibenzofuran (PeCDF) resulted in dose-dependent increases of CYP1A1 mRNA, CYP1A2 mRNA and CYP1A protein levels an underlying AhR-mediated mechanism is suggested. The up-regulation of CYP1A mRNA in liver was more consistent to the sum adipose TEQ concentration than to the liver TEQ concentration in minks treated with TCDF or PeCDF. The result suggested that the hepatic-sequestered fraction of PeCDF was biologically inactive to the induction of CYP1A1 and CYP1A2

  9. Activation of thiazide-sensitive co-transport by angiotensin II in the cyp1a1-Ren2 hypertensive rat.

    Directory of Open Access Journals (Sweden)

    Ali Ashek

    Full Text Available Transgenic rats with inducible expression of the mouse Ren2 gene were used to elucidate mechanisms leading to the development of hypertension and renal injury. Ren2 transgene activation was induced by administration of a naturally occurring aryl hydrocarbon, indole-3-carbinol (100 mg/kg/day by gastric gavage. Blood pressure and renal parameters were recorded in both conscious and anesthetized (butabarbital sodium; 120 mg/kg IP rats at selected time-points during the development of hypertension. Hypertension was evident by the second day of treatment, being preceded by reduced renal sodium excretion due to activation of the thiazide-sensitive sodium-chloride co-transporter. Renal injury was evident after the first day of transgene induction, being initially limited to the pre-glomerular vasculature. Mircoalbuminuria and tubuloinsterstitial injury developed once hypertension was established. Chronic treatment with either hydrochlorothiazide or an AT1 receptor antagonist normalized sodium reabsorption, significantly blunted hypertension and prevented renal injury. Urinary aldosterone excretion was increased ≈ 20 fold, but chronic mineralocorticoid receptor antagonism with spironolactone neither restored natriuretic capacity nor prevented hypertension. Spironolactone nevertheless ameliorated vascular damage and prevented albuminuria. This study finds activation of sodium-chloride co-transport to be a key mechanism in angiotensin II-dependent hypertension. Furthermore, renal vascular injury in this setting reflects both barotrauma and pressure-independent pathways associated with direct detrimental effects of angiotensin II and aldosterone.

  10. Arecoline inhibits the 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced cytochrome P450 1A1 activation in human hepatoma cells

    International Nuclear Information System (INIS)

    Chang, Eddy Essen; Miao Zhifeng; Lee, W.-J.; Chao, H.-R.; Li, Lih-Ann; Wang, Y.-F.; Ko, Y.-C.; Tsai, F.-Y.; Yeh, S.C.; Tsou, T.-C.

    2007-01-01

    In the present study, we investigated the effect of arecoline, a major areca nut alkaloid, on the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced activation of cytochrome P4501A1 (CYP1A1) in a human hepatoma cell line Huh-7. We treated Huh-7 cells with 10 nM TCDD in the presence of different concentrations of arecoline (50-300 μM). Our results indicated that arecoline attenuated the TCDD-induced CYP1A1 enzyme activation with an inhibitory effect on cell proliferation. By using real-time RT-PCR, we demonstrated that arecoline inhibited the TCDD-induced activations of CYP1A1 and AhR repressor (AhRR) mRNA expression in a similar pattern. Our results revealed that arecoline inhibited AhR mRNA expression with no direct effect on CYP1A1 enzyme activity. Therefore, in our present study, the observed inhibitory effect of arecoline on CYP1A1 activation was not due to the up-regulation of AhRR or direct inhibitory effect on CYP1A1. Taken together, here we have demonstrated that arecoline attenuates the TCDD-induced CYP1A1 activation mainly via down-regulation of AhR expression in human hepatoma cells, suggesting the possible involvement of arecoline in the AhR-mediated metabolism of environmental toxicants in liver

  11. 7,12-Dimethylbenzanthracene induces apoptosis in RL95-2 human endometrial cancer cells: Ligand-selective activation of cytochrome P450 1B1

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Ji Young [Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan 602-714 (Korea, Republic of); Medical Research Science Center, Dong-A University, Busan 602-714 (Korea, Republic of); Lee, Seung Gee [Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan 602-714 (Korea, Republic of); Mitochondria Hub Regulation Center, Dong-A University, Busan 602-714 (Korea, Republic of); Chung, Jin-Yong [Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan 602-714 (Korea, Republic of); Medical Research Science Center, Dong-A University, Busan 602-714 (Korea, Republic of); Kim, Yoon-Jae [Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan 602-714 (Korea, Republic of); Mitochondria Hub Regulation Center, Dong-A University, Busan 602-714 (Korea, Republic of); Park, Ji-Eun [Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan 602-714 (Korea, Republic of); Medical Research Science Center, Dong-A University, Busan 602-714 (Korea, Republic of); Oh, Seunghoon [Department of Physiology, College of Medicine, Dankook University, Cheonan 330-714 (Korea, Republic of); Lee, Se Yong [Department of Obstetrics and Gynecology, Busan Medical Center, Busan 611-072 (Korea, Republic of); Choi, Hong Jo [Department of General Surgery, College of Medicine, Dong-A University, Busan 602-714 (Korea, Republic of); Yoo, Young Hyun, E-mail: yhyoo@dau.ac.kr [Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan 602-714 (Korea, Republic of); Mitochondria Hub Regulation Center, Dong-A University, Busan 602-714 (Korea, Republic of); Medical Research Science Center, Dong-A University, Busan 602-714 (Korea, Republic of); and others

    2012-04-15

    7,12-Dimethylbenzanthracene (DMBA), a polycyclic aromatic hydrocarbon, exhibits mutagenic, carcinogenic, immunosuppressive, and apoptogenic properties in various cell types. To achieve these functions effectively, DMBA is modified to its active form by cytochrome P450 1 (CYP1). Exposure to DMBA causes cytotoxicity-mediated apoptosis in bone marrow B cells and ovarian cells. Although uterine endometrium constitutively expresses CYP1A1 and CYP1B1, their apoptotic role after exposure to DMBA remains to be elucidated. Therefore, we chose RL95-2 endometrial cancer cells as a model system for studying DMBA-induced cytotoxicity and cell death and hypothesized that exposure to DMBA causes apoptosis in this cell type following CYP1A1 and/or CYP1B1 activation. We showed that DMBA-induced apoptosis in RL95-2 cells is associated with activation of caspases. In addition, mitochondrial changes, including decrease in mitochondrial potential and release of mitochondrial cytochrome c into the cytosol, support the hypothesis that a mitochondrial pathway is involved in DMBA-induced apoptosis. Exposure to DMBA upregulated the expression of AhR, Arnt, CYP1A1, and CYP1B1 significantly; this may be necessary for the conversion of DMBA to DMBA-3,4-diol-1,2-epoxide (DMBA-DE). Although both CYP1A1 and CYP1B1 were significantly upregulated by DMBA, only CYP1B1 exhibited activity. Moreover, knockdown of CYP1B1 abolished DMBA-induced apoptosis in RL95-2 cells. Our data show that RL95-2 cells are susceptible to apoptosis by exposure to DMBA and that CYP1B1 plays a pivotal role in DMBA-induced apoptosis in this system. -- Highlights: ► Cytotoxicity-mediated apoptogenic action of DMBA in human endometrial cancer cells. ► Mitochondrial pathway in DMBA-induced apoptosis of RL95-2 endometrial cancer cells. ► Requirement of ligand-selective activation of CYP1B1 in DMBA-induced apoptosis.

  12. Modulation of 17{beta}-estradiol-induced responses in fish by cytochrome P4501A1 inducing compounds

    Energy Technology Data Exchange (ETDEWEB)

    Anderson, M.J.; Hinton, D.E. [Univ. of California, Davis, CA (United States)

    1995-12-31

    Some compounds which induce cytochrome P4501A1 (CYP1A1) are antiestrogenic in mammalian bioassay, and this effect is linked to aryl hydrocarbon (Ah) receptor. Liver of fish synthesizes estrogen-inducible egg yolk precursor protein vitellogenin (Vg) which is critical for oocyte maturation and ovarian development. To determine if Ah receptor-linked endocrine modulation could occur in fish liver, primary cultures of juvenile rainbow trout (Oncorhynchus mykiss) liver cells were co-administered 17{beta}-estradiol and CYP1A1 inducing compounds. Vitellogenin and albumin, estimated by ELISA measurement of concentration in the media 48 hrs after treatment, formed the basis for the test. Cellular CYP1A1 protein content and catalytic activity was estimated by ELISA and ethoxyresorufin-O-deethylase (EROD) activity assays respectively. Equivalent viability (mitochondrial dehydrogenase activity) and secretary functional capacity (albumin synthesis) were estimated and correlated with other results. In descending order, 2,3,4,7,8 pentachlorodibenzofuran (10{sup {minus}12} to 10{sup {minus}8} M) > 2,3,7,8 tetrachlorodibenzo-p-dioxin {approx_equal} 2,3,7,8 tetrachlorodibenzofuran (10{sup {minus}11} to 10{sup {minus}8} M) > {beta}-naphthoflavone (10{sup {minus}7} to 10{sup {minus}6} M) inhibited Vg synthesis in 17{beta}-estradiol treated liver cells. Potency of inhibition directly related to strength as an inducer of CYP1A1 protein. At 10-8 M, PCB congeners 77, 126, and 156 did not inhibit Vg synthesis and induced no or only moderate CYP1A1 protein. At 10-8 M, PCB congener 114, a weak CYP1A1 inducer, potentiated Vg synthesis relative to cells treated with 17{beta}-estradiol alone. This study increases their understanding of the consequences of hepatic CYP1A1 induction, forewarns of reproductive impairment of sexually maturing fishes exposed to CYP1A1 inducing compounds and argues for further, more detailed in vivo investigation.

  13. Changes in cytochrome P450 gene expression and enzyme activity induced by xenobiotics in rabbits in vivo and in vitro

    Directory of Open Access Journals (Sweden)

    Orsolya Palócz

    2017-06-01

    Full Text Available As considerable inter-species differences exist in xenobiotic metabolism, developing new pharmaceutical therapies for use in different species is fraught with difficulties. For this reason, very few medicines have been registered for use in rabbits, despite their importance in inter alia meat and fur production. We have developed a rapid and sensitive screening system for drug safety in rabbits based on cytochrome P450 enzyme assays, specifically CYP1A1, CYP1A2 and CYP3A6, employing an adaptation of the luciferin-based clinical assay currently used in human drug screening. Short-term (4-h cultured rabbit primary hepatocytes were treated with a cytochrome inducer (phenobarbital and 2 inhibitors (alpha-naphthoflavone and ketoconazole. In parallel, and to provide verification, New Zealand white rabbits were dosed with 80 mg/kg phenobarbital or 40 mg/kg ketoconazole for 3 d. Ketoconazole significantly increased CYP3A6 gene expression and decreased CYP3A6 activity both in vitro and in vivo. CYP1A1 activity was decreased by ketoconazole in vitro and increased in vivo. This is the first report of the inducer effect of ketoconazole on rabbit cytochrome isoenzymes in vivo. Our data support the use of a luciferin-based assay in short-term primary hepatocytes as an appropriate tool for xenobiotic metabolism assays and short-term toxicity testing in rabbits.

  14. Transgenic overexpression of p23 induces spontaneous hydronephrosis in mice

    Science.gov (United States)

    Lee, Jaehoon; Kim, Hye Jin; Moon, Jung Ah; Sung, Young Hoon; Baek, In-Jeoung; Roh, Jae-il; Ha, Na Young; Kim, Seung-Yeon; Bahk, Young Yil; Lee, Jong Eun; Yoo, Tae Hyun; Lee, Han-Woong

    2011-01-01

    p23 is a cochaperone of heat shock protein 90 and also interacts functionally with numerous steroid receptors and kinases. However, the in vivo roles of p23 remain unclear. To explore its in vivo function, we generated the transgenic (TG) mice ubiquitously overexpressing p23. The p23 TG mice spontaneously developed kidney abnormalities closely resembling human hydronephrosis. Consistently, kidney functions deteriorate significantly in the p23 TG mice compared to their wild-type (WT) littermates. Furthermore, the expression of target genes for aryl hydrocarbon receptor (AhR), such as cytochrome P450, family 1, subfamily A, polypeptide 1 (Cyp1A1) and cytochrome P450, family 1, subfamily B, polypeptide 1 (Cyp1B1), were induced in the kidneys of the p23 TG mice. These results indicate that the overexpression of p23 contributes to the development of hydronephrosis through the upregulation of the AhR pathway in vivo. PMID:21323770

  15. Regulation of cytochrome P4501A1 expression by hyperoxia in human lung cell lines: Implications for hyperoxic lung injury

    International Nuclear Information System (INIS)

    Bhakta, Kushal Y.; Jiang, Weiwu; Couroucli, Xanthi I.; Fazili, Inayat S.; Muthiah, Kathirvel; Moorthy, Bhagavatula

    2008-01-01

    Supplemental oxygen, used to treat pulmonary insufficiency in newborns, contributes to the development of bronchopulmonary dysplasia (BPD). Cytochrome P4501A enzymes are induced by hyperoxia in animal models, but their role in human systems is unknown. Here we investigated the molecular mechanisms of induction of CYP1A1 by hyperoxia in human lung cell lines. Three human lung cell lines were exposed to hyperoxia (95% O2) for 0-72 h, and CYP1A1 activities, apoprotein contents, and mRNA levels were determined. Hyperoxia significantly induced CYP1A1 activity and protein contents (2-4 fold), and mRNA levels (30-40 fold) over control in each cell line. Transfection of a CYP1A1 promoter/luciferase reporter construct, followed by hyperoxia (4-72 h), showed marked (2-6 fold) induction of luciferase expression. EMSA and siRNA experiments strongly suggest that the Ah receptor (AHR) is involved in the hyperoxic induction of CYP1A1. MTT reduction assays showed attenuation of cell injury with the CYP1A1 inducer beta-naphthoflavone (BNF). Our results strongly suggest that hyperoxia transcriptionally activates CYP1A1 expression in human lung cell lines by AHR-dependent mechanisms, and that CYP1A1 induction is associated with decreased toxicity. This novel finding of induction of CYP1A1 in the absence of exogenous AHR ligands could lead to novel interventions in the treatment of BPD

  16. Treatment with pioglitazone induced significant, reversible mitral regurgitation.

    Science.gov (United States)

    Dorkhan, Mozhgan; Dencker, Magnus; Frid, Anders

    2008-04-30

    There has in recent years been great concern about possible cardiac side effects of thiazolidinediones (TZDs). We present a case-report of a 60 year-old male who developed significant mitral regurgitation during six months treatment with pioglitazone in parallel with laboratory indications of fluid retention. Echocardiography six months after discontinuation of medication showed regression of mitral regurgitation and the laboratory parameters were also normalized. It is noteworthy that six months treatment with pioglitazone could induce significant valve dysfunction, which was reversible, and this underlines the importance of carefully monitoring patients when placing them on treatment with TZDs.

  17. Treatment with pioglitazone induced significant, reversible mitral regurgitation

    Directory of Open Access Journals (Sweden)

    Frid Anders

    2008-04-01

    Full Text Available Abstract There has in recent years been great concern about possible cardiac side effects of thiazolidinediones (TZDs. We present a case-report of a 60 year-old male who developed significant mitral regurgitation during six months treatment with pioglitazone in parallel with laboratory indications of fluid retention. Echocardiography six months after discontinuation of medication showed regression of mitral regurgitation and the laboratory parameters were also normalized. It is noteworthy that six months treatment with pioglitazone could induce significant valve dysfunction, which was reversible, and this underlines the importance of carefully monitoring patients when placing them on treatment with TZDs.

  18. Benzo[a]pyrene-induced immunotoxicity in Japanese medaka (Oryzias latipes): relationship between lymphoid CYP1A activity and humoral immune suppression

    International Nuclear Information System (INIS)

    Carlson, E.A.; Li, Y.; Zelikoff, J.T.

    2004-01-01

    Exposure to the environmental contaminant benzo[a]pyrene (BaP) results in suppression of immune function in both mammalian and fish species. This laboratory has previously demonstrated that a single intraperitoneal (IP) injection of BaP reduced lymphocyte proliferation, phagocyte-mediated superoxide generation, and antibody-forming cell (AFC) numbers in Japanese medaka (Oryzias latipes). The objective of the current study was to determine the role of BaP metabolism in the observed immunosuppression. Results from rodent studies have suggested that BaP elicits its immunotoxic effects via upregulation of cytochrome P4501A1 (CYP1A1) and the subsequent production of immunosuppressive BaP metabolites. In this study, exposure of medaka to 200 μg BaP/g BW significantly induced CYP1A expression or activity within lymphoid tissue 48 h post-IP injection; induction was observed specifically within distinct subpopulations of kidney mononuclear cells. Concurrent injection of fish with BaP and the CYP1A1 inhibitors α-naphthoflavone (ANF) or dehydroepiandrosterone (DHEA) resulted in inhibition of renal EROD activity and amelioration of BaP-induced suppression of medaka AFC numbers. Results of this study suggest that (1) BaP-induced suppression of medaka humoral immunity relies upon the CYP1A-catalyzed production of immunotoxic BaP metabolites and (2) BaP metabolites may be created in situ, directly by specific cells within kidney lymphoid tissue. Thus, apparently, mechanisms involved in BaP-induced immunosuppression have been phylogenetically conserved from fish to mammals

  19. One arm exercise induces significant interarm diastolic blood pressure difference.

    Science.gov (United States)

    Hong, Dezhi; Wang, Jiwei; Su, Hai; Xu, Jingsong; Liu, Yanna; Peng, Qiang; Wang, Lijuan

    2011-06-01

    This study is designed to investigate the inducing effect of one arm exercise on interarm difference (IAD) in the blood pressure (BP). Fifty healthy young participants were included in the study. Three-minute exercises of the right arm elbow flexion and extension were performed. The bilateral brachial BP was simultaneously measured with two automatic BP measurement devices before (basic) and immediately 0, 5, 10, 15, 20, and 30 min after exercise. The absolute difference in the systolic BP (SBP) and diastolic BP (DBP) between the left and right BP of at least 10 mmHg was recognized as sIAD and dIAD. The baseline data of the SBP and DBP in left and right arms revealed no significant difference (SBP: 110 ± 10 vs. 111 ± 11 mmHg; DBP: 66 ± 8 vs. 66 ± 9 mmHg, both not significant). The prevalence of dIAD was 2% at the baseline. However, this prevalence increased to 80% at 0 min, as right arm exercise induced the right DBP decrease and left DBP increase, and then the prevalence decreased gradually within a 30-min recovery period. The prevalence of sIAD was zero at the baseline and the maximal prevalence was 8% during the 20-min postexercise period. One arm exercise can lead to a significant IAD in DBP. Any arm exercise should be avoided before BP measurement.

  20. Prenatal administration of the cytochrome P4501A inducer, Β-naphthoflavone (BNF), attenuates hyperoxic lung injury in newborn mice: Implications for bronchopulmonary dysplasia (BPD) in premature infants

    International Nuclear Information System (INIS)

    Couroucli, Xanthi I.; Liang Yanhong Wei; Jiang Weiwu; Wang Lihua; Barrios, Roberto; Yang Peiying; Moorthy, Bhagavatula

    2011-01-01

    Supplemental oxygen contributes to the development of bronchopulmonary dysplasia (BPD) in premature infants. In this investigation, we tested the hypothesis that prenatal treatment of pregnant mice (C57BL/6J) with the cytochrome P450 (CYP)1A1 inducer, ss-napthoflavone (BNF), will lead to attenuation of lung injury in newborns (delivered from these dams) exposed to hyperoxia by mechanisms entailing transplacental induction of hepatic and pulmonary CYP1A enzymes. Pregnant mice were administered the vehicle corn oil (CO) or BNF (40 mg/kg), i.p., once daily for 3 days on gestational days (17-19), and newborns delivered from the mothers were either maintained in room air or exposed to hyperoxia (> 95% O 2 ) for 1-5 days. After 3-5 days of hyperoxia, the lungs of CO-treated mice showed neutrophil infiltration, pulmonary edema, and perivascular inflammation. On the other hand, BNF-pretreated neonatal mice showed decreased susceptibility to hyperoxic lung injury. These mice displayed marked induction of ethoxyresorufin O-deethylase (EROD) (CYP1A1) and methoxyresorufin O-demethylase (MROD) (CYP1A2) activities, and levels of the corresponding apoproteins and mRNA levels until PND 3 in liver, while CYP1A1 expression alone was augmented in the lung. Prenatal BNF did not significantly alter gene expression of pulmonary NAD(P)H quinone reductase (NQO1). Hyperoxia for 24-72 h resulted in increased pulmonary levels of the F 2 -isoprostane 8-iso-PGF 2α , whose levels were decreased in mice prenatally exposed to BNF. In conclusion, our results suggest that prenatal BNF protects newborns against hyperoxic lung injury, presumably by detoxification of lipid hydroperoxides by CYP1A enzymes, a phenomenon that has implications for prevention of BPD in infants. - Highlights: → Supplemental oxygen is routinely administered to premature infants. → Hyperoxia causes lung injury in experimental animals. → Prenatal treatment of mice with beta-naphthoflavone attenuates oxygen injury

  1. A novel CYP1A1 gene polymorphism and the risk of head and neck ...

    African Journals Online (AJOL)

    Administrator

    2011-06-15

    Jun 15, 2011 ... 5274 Afr. J. Biotechnol. The principal enzymes ..... Amalio T, Paul I, Francine M, Tobias S, Thomas B (1993). Direct, automated .... Olshan A, Weissler M, Watson MA, Bell D (2000). GSTM1, GSTT1, ... Jr. JF, editors. Cancer ...

  2. Significance and nature of bystander responses induced by various agents.

    Science.gov (United States)

    Verma, Neha; Tiku, Ashu Bhan

    2017-07-01

    Bystander effects in a biological system are the responses shown by non-targeted neighbouring cells/tissues/organisms. These responses are triggered by factors released from targeted cells when exposed to a stress inducing agent. The biological response to stress inducing agents is complex, owing to the diversity of mechanisms and pathways activated in directly targeted and bystander cells. These responses are highly variable and can be either beneficial or hazardous depending on the cell lines tested, dose of agent used, experimental end points and time course selected. Recently non-targeted cells have even been reported to rescue the directly exposed cells by releasing protective signals that might be induced by non-targeted bystander responses. The nature of bystander signal/s is not yet clear. However, there are evidences suggesting involvement of ROS, RNS, protein factors and even DNA molecules leading to the activation of a number of signaling pathways. These can act independently or in a cascade, to induce events leading to changes in gene expression patterns that could elicit detrimental or beneficial effects. Many review articles on radiation induced bystander responses have been published. However, to the best of our knowledge, a comprehensive review on bystander responses induced by other genotoxic chemicals and stress inducing agents has not been published so far. Therefore, the aim of the present review is to give an overview of the literature on different aspects of bystander responses: agents that induce these responses, factors that can modulate bystander responses and the mechanisms involved. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. The inhibition effect of 2,3,7,8-tetrachlorinated dibenzo-p-dioxin-induced aryl hydrocarbon receptor activation in human hepatoma cells with the treatment of cadmium chloride

    International Nuclear Information System (INIS)

    Chao, How-Ran; Tsou, Tsui-Chun; Chen, Hung-Ta; Chang, Eddy Essen; Tsai, Feng-Yuan; Lin, Ding-Yan; Chen, Fu-An; Wang, Ya-Fen

    2009-01-01

    Polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs), considered as endocrine disruptors, tend to accumulate in fatty tissues. Dioxin-responsive element chemical activated luciferase gene expression assay (DRE-luciferase assay) has been recognized as a semi-quantitative method for screening dioxins for its fast and low-cost as compared with HRGC/HRMS. However, some problems with the bioassay, including specificity, detection variation resulted from different cleanup strategies, and uncertainty of false-negative or false-positive results, remain to be overcome. Cadmium is a prevalent environmental contaminant around the world. This study was aimed to examine the effects of cadmium on the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced activation of aryl hydrocarbon receptor (AhR)-mediated gene expression in human hepatoma cells (Huh7-DRE-Luc cells and Huh7 cells). Ethoxyresorufin-O-deethylase (EROD) and DRE-luciferase assay were employed to determine the enzyme activity of cytochrome P450 1A1 (CYP1A1) and activation of AhR, respectively. The results showed that Cd 2+ levels significantly inhibited the induction of TCDD-induced CYP1A1 and DRE luciferase activation in hepatoma cells. The 50% inhibited concentrations (IC 50 ) of CdCl 2 were 0.414 μM (95% confidence interval (C.I.): 0.230-0.602 μM) in Huh7-DRE-Luc cells and 23.2 μM (95% C.I.: 21.7-25.4 μM) in Huh7 cells. Accordingly, prevention of interference with non-dioxin-like compounds in a DRE-luciferase assay is of great importance in an extensive cleanup procedure.

  4. Significance of hair-dye base-induced sensory irritation.

    Science.gov (United States)

    Fujita, F; Azuma, T; Tajiri, M; Okamoto, H; Sano, M; Tominaga, M

    2010-06-01

    Oxidation hair-dyes, which are the principal hair-dyes, sometimes induce painful sensory irritation of the scalp caused by the combination of highly reactive substances, such as hydrogen peroxide and alkali agents. Although many cases of severe facial and scalp dermatitis have been reported following the use of hair-dyes, sensory irritation caused by contact of the hair-dye with the skin has not been reported clearly. In this study, we used a self-assessment questionnaire to measure the sensory irritation in various regions of the body caused by two model hair-dye bases that contained different amounts of alkali agents without dyes. Moreover, the occipital region was found as an alternative region of the scalp to test for sensory irritation of the hair-dye bases. We used this region to evaluate the relationship of sensitivity with skin properties, such as trans-epidermal water loss (TEWL), stratum corneum water content, sebum amount, surface temperature, current perception threshold (CPT), catalase activities in tape-stripped skin and sensory irritation score with the model hair-dye bases. The hair-dye sensitive group showed higher TEWL, a lower sebum amount, a lower surface temperature and higher catalase activity than the insensitive group, and was similar to that of damaged skin. These results suggest that sensory irritation caused by hair-dye could occur easily on the damaged dry scalp, as that caused by skin cosmetics reported previously.

  5. Activation of aryl hydrocarbon receptor reduces carbendazim-induced cell death

    International Nuclear Information System (INIS)

    Wei, Kuo-Liang; Chen, Fei-Yun; Lin, Chih-Yi; Gao, Guan-Lun; Kao, Wen-Ya; Yeh, Chi-Hui; Chen, Chang-Rong; Huang, Hao-Chun; Tsai, Wei-Ren; Jong, Koa-Jen; Li, Wan-Jung; Su, Jyan-Gwo Joseph

    2016-01-01

    Carbendazim inhibits microtubule assembly, thus blocking mitosis and inhibiting cancer cell proliferation. Accordingly, carbendazim is being explored as an anticancer drug. Data show that carbendazim increased mRNA and protein expressions and promoter activity of CYP1A1. In addition, carbendazim activated transcriptional activity of the aryl hydrocarbon response element, and induced nuclear translocation of the aryl hydrocarbon receptor (AhR), a sign the AhR is activated. Carbendazim-induced CYP1A1 expression was blocked by AhR antagonists, and was abolished in AhR signal-deficient cells. Results demonstrated that carbendazim activated the AhR, thereby stimulating CYP1A1 expression. In order to understand whether AhR-induced metabolic enzymes turn carbendazim into less-toxic metabolites, Hoechst 33342 staining to reveal carbendazim-induced nuclear changes and flow cytometry to reveal the subG 0 /G 1 population were applied to monitor carbendazim-induced cell apoptosis. Carbendazim induced less apoptosis in Hepa-1c1c7 cells than in AhR signal-deficient Hepa-1c1c7 mutant cells. Pretreatment with β-NF, an AhR agonist that highly induces CYP1A1 expression, decreased carbendazim-induced cell death. In addition, the lower the level of AhR was, the lower the vitality present in carbendazim-treated cells, including hepatoma cells and their derivatives with AhR RNA interference, also embryonic kidney cells, bladder carcinoma cells, and AhR signal-deficient Hepa-1c1c7 cells. In summary, carbendazim is an AhR agonist. The toxicity of carbendazim was lower in cells with the AhR signal. This report provides clues indicating that carbendazim is more potent at inducing cell death in tissues without than in those with the AhR signal, an important reference for applying carbendazim in cancer chemotherapy. - Highlights: • Carbendazim induced transcriptional activity of the aryl hydrocarbon response element. • Carbendazim induced nuclear translocation of the aryl hydrocarbon

  6. Activation of aryl hydrocarbon receptor reduces carbendazim-induced cell death

    Energy Technology Data Exchange (ETDEWEB)

    Wei, Kuo-Liang [Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan, ROC (China); College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan, ROC (China); Chen, Fei-Yun; Lin, Chih-Yi [Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan, ROC (China); Gao, Guan-Lun [Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan, ROC (China); Department of Biological Resources, National Chiayi University, Chiayi, 60004, Taiwan, ROC (China); Kao, Wen-Ya [Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan, ROC (China); Yeh, Chi-Hui [Department of Environmental Engineering, College of Engineering, Da-Yeh University, Dacun, Changhua 51591, Taiwan, ROC (China); Chen, Chang-Rong [Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan, ROC (China); Huang, Hao-Chun [Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan, ROC (China); Tsai, Wei-Ren [Division of Applied Toxicology, Taiwan Agricultural Chemicals and Toxic Substances Research Institute, Council of Agriculture, Executive Yuan, Taichung 41358, Taiwan, ROC (China); Jong, Koa-Jen [Department of Biological Resources, National Chiayi University, Chiayi, 60004, Taiwan, ROC (China); Li, Wan-Jung [Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan, ROC (China); Su, Jyan-Gwo Joseph, E-mail: jgjsu@mail.ncyu.edu.tw [Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan, ROC (China)

    2016-09-01

    Carbendazim inhibits microtubule assembly, thus blocking mitosis and inhibiting cancer cell proliferation. Accordingly, carbendazim is being explored as an anticancer drug. Data show that carbendazim increased mRNA and protein expressions and promoter activity of CYP1A1. In addition, carbendazim activated transcriptional activity of the aryl hydrocarbon response element, and induced nuclear translocation of the aryl hydrocarbon receptor (AhR), a sign the AhR is activated. Carbendazim-induced CYP1A1 expression was blocked by AhR antagonists, and was abolished in AhR signal-deficient cells. Results demonstrated that carbendazim activated the AhR, thereby stimulating CYP1A1 expression. In order to understand whether AhR-induced metabolic enzymes turn carbendazim into less-toxic metabolites, Hoechst 33342 staining to reveal carbendazim-induced nuclear changes and flow cytometry to reveal the subG{sub 0}/G{sub 1} population were applied to monitor carbendazim-induced cell apoptosis. Carbendazim induced less apoptosis in Hepa-1c1c7 cells than in AhR signal-deficient Hepa-1c1c7 mutant cells. Pretreatment with β-NF, an AhR agonist that highly induces CYP1A1 expression, decreased carbendazim-induced cell death. In addition, the lower the level of AhR was, the lower the vitality present in carbendazim-treated cells, including hepatoma cells and their derivatives with AhR RNA interference, also embryonic kidney cells, bladder carcinoma cells, and AhR signal-deficient Hepa-1c1c7 cells. In summary, carbendazim is an AhR agonist. The toxicity of carbendazim was lower in cells with the AhR signal. This report provides clues indicating that carbendazim is more potent at inducing cell death in tissues without than in those with the AhR signal, an important reference for applying carbendazim in cancer chemotherapy. - Highlights: • Carbendazim induced transcriptional activity of the aryl hydrocarbon response element. • Carbendazim induced nuclear translocation of the aryl

  7. Electronic cigarette aerosol induces significantly less cytotoxicity than tobacco smoke

    Science.gov (United States)

    Azzopardi, David; Patel, Kharishma; Jaunky, Tomasz; Santopietro, Simone; Camacho, Oscar M.; McAughey, John; Gaça, Marianna

    2016-01-01

    Abstract Electronic cigarettes (E-cigarettes) are a potential means of addressing the harm to public health caused by tobacco smoking by offering smokers a less harmful means of receiving nicotine. As e-cigarettes are a relatively new phenomenon, there are limited scientific data on the longer-term health effects of their use. This study describes a robust in vitro method for assessing the cytotoxic response of e-cigarette aerosols that can be effectively compared with conventional cigarette smoke. This was measured using the regulatory accepted Neutral Red Uptake assay modified for air–liquid interface (ALI) exposures. An exposure system, comprising a smoking machine, traditionally used for in vitro tobacco smoke exposure assessments, was adapted for use with e-cigarettes to expose human lung epithelial cells at the ALI. Dosimetric analysis methods using real-time quartz crystal microbalances for mass, and post-exposure chemical analysis for nicotine, were employed to detect/distinguish aerosol dilutions from a reference Kentucky 3R4F cigarette and two commercially available e-cigarettes (Vype eStick and ePen). ePen aerosol induced 97%, 94% and 70% less cytotoxicity than 3R4F cigarette smoke based on matched EC50 values at different dilutions (1:5 vs. 1:153 vol:vol), mass (52.1 vs. 3.1 μg/cm2) and nicotine (0.89 vs. 0.27 μg/cm2), respectively. Test doses where cigarette smoke and e-cigarette aerosol cytotoxicity were observed are comparable with calculated daily doses in consumers. Such experiments could form the basis of a larger package of work including chemical analyses, in vitro toxicology tests and clinical studies, to help assess the safety of current and next generation nicotine and tobacco products. PMID:27690199

  8. The environmental pollutant and carcinogen 3-nitrobenzanthrone induces cytochrome P450 1A1 and NAD(P)H:quinone oxidoreductase in rat lung and kidney, thereby enhancing its own genotoxicity

    International Nuclear Information System (INIS)

    Stiborova, Marie; Dracinska, Helena; Mizerovska, Jana; Frei, Eva; Schmeiser, Heinz H.; Hudecek, Jiri; Hodek, Petr; Phillips, David H.; Arlt, Volker M.

    2008-01-01

    3-Nitrobenzanthrone (3-NBA) is a carcinogen occurring in diesel exhaust and air pollution. Using the 32 P-postlabelling method, we found that 3-NBA and its human metabolite, 3-aminobenzanthrone (3-ABA), are activated to species forming DNA adducts by cytosols and/or microsomes isolated from rat lung, the target organ for 3-NBA carcinogenicity, and kidney. Each compound generated identical five DNA adducts. We have demonstrated the importance of pulmonary and renal NAD(P)H:quinone oxidoreductase (NQO1) to reduce 3-NBA to species that are further activated by N,O-acetyltransferases and sulfotransferases. Cytochrome P450 (CYP) 1A1 is the essential enzyme for oxidative activation of 3-ABA in microsomes of both organs, while cyclooxygenase plays a minor role. 3-NBA was also investigated for its ability to induce NQO1 and CYP1A1 in lungs and kidneys, and for the influence of such induction on DNA adduct formation by 3-NBA and 3-ABA. When cytosols from rats treated i.p. with 40 mg/kg bw of 3-NBA were incubated with 3-NBA, DNA adduct formation was up to 2.1-fold higher than in incubations with cytosols from control animals. This increase corresponded to an increase in protein level and enzymatic activity of NQO1. Incubations of 3-ABA with microsomes of 3-NBA-treated rats led to up to a fivefold increase in DNA adduct formation relative to controls. The stimulation of DNA adduct formation correlated with the potential of 3-NBA to induce protein expression and activity of CYP1A1. These results demonstrate that 3-NBA is capable to induce NQO1 and CYP1A1 in lungs and kidney of rats thereby enhancing its own genotoxic and carcinogenic potential

  9. Metformin inhibits 7,12-dimethylbenz[a]anthracene-induced breast carcinogenesis and adduct formation in human breast cells by inhibiting the cytochrome P4501A1/aryl hydrocarbon receptor signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Maayah, Zaid H. [Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451 (Saudi Arabia); Ghebeh, Hazem [Stem Cell & Tissue Re-Engineering, King Faisal Specialist Hospital and Research Center, Riyadh 11211 (Saudi Arabia); Alhaider, Abdulqader A. [Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451 (Saudi Arabia); Camel Biomedical Research Unit, College of Pharmacy and Medicine, King Saud University, Riyadh 11451 (Saudi Arabia); El-Kadi, Ayman O.S. [Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton (Canada); Soshilov, Anatoly A.; Denison, Michael S. [Department of Environmental Toxicology, University of California at Davis, Davis, CA 95616 (United States); Ansari, Mushtaq Ahmad [Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451 (Saudi Arabia); Korashy, Hesham M., E-mail: hkorashy@ksu.edu.sa [Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451 (Saudi Arabia)

    2015-04-15

    Recent studies have established that metformin (MET), an oral anti-diabetic drug, possesses antioxidant activity and is effective against different types of cancer in several carcinogen-induced animal models and cell lines. However, whether MET can protect against breast cancer has not been reported before. Therefore, the overall objectives of the present study are to elucidate the potential chemopreventive effect of MET in non-cancerous human breast MCF10A cells and explore the underlying mechanism involved, specifically the role of cytochrome P4501A1 (CYP1A1)/aryl hydrocarbon receptor (AhR) pathway. Transformation of the MCF10A cells into initiated breast cancer cells with DNA adduct formation was conducted using 7,12-dimethylbenz[a]anthracene (DMBA), an AhR ligand. The chemopreventive effect of MET against DMBA-induced breast carcinogenesis was evidenced by the capability of MET to restore the induction of the mRNA levels of basic excision repair genes, 8-oxoguanine DNA glycosylase (OGG1) and apurinic/apyrimidinic endonuclease1 (APE1), and the level of 8-hydroxy-2-deoxyguanosine (8-OHdG). Interestingly, the inhibition of DMBA-induced DNA adduct formation was associated with proportional decrease in CYP1A1 and in NAD(P)H:quinone oxidoreductase 1 (NQO1) gene expression. Mechanistically, the involvements of AhR and nuclear factor erythroid 2-related factor-2 (Nrf2) in the MET-mediated inhibition of DMBA-induced CYP1A1 and NQO1 gene expression were evidenced by the ability of MET to inhibit DMBA-induced xenobiotic responsive element and antioxidant responsive element luciferase reporter gene expression which suggests an AhR- and Nrf2-dependent transcriptional control. However, the inability of MET to bind to AhR suggests that MET is not an AhR ligand. In conclusion, the present work shows a strong evidence that MET inhibits the DMBA-mediated carcinogenicity and adduct formation by inhibiting the expression of CYP1A1 through an AhR ligand-independent mechanism

  10. Metformin inhibits 7,12-dimethylbenz[a]anthracene-induced breast carcinogenesis and adduct formation in human breast cells by inhibiting the cytochrome P4501A1/aryl hydrocarbon receptor signaling pathway

    International Nuclear Information System (INIS)

    Maayah, Zaid H.; Ghebeh, Hazem; Alhaider, Abdulqader A.; El-Kadi, Ayman O.S.; Soshilov, Anatoly A.; Denison, Michael S.; Ansari, Mushtaq Ahmad; Korashy, Hesham M.

    2015-01-01

    Recent studies have established that metformin (MET), an oral anti-diabetic drug, possesses antioxidant activity and is effective against different types of cancer in several carcinogen-induced animal models and cell lines. However, whether MET can protect against breast cancer has not been reported before. Therefore, the overall objectives of the present study are to elucidate the potential chemopreventive effect of MET in non-cancerous human breast MCF10A cells and explore the underlying mechanism involved, specifically the role of cytochrome P4501A1 (CYP1A1)/aryl hydrocarbon receptor (AhR) pathway. Transformation of the MCF10A cells into initiated breast cancer cells with DNA adduct formation was conducted using 7,12-dimethylbenz[a]anthracene (DMBA), an AhR ligand. The chemopreventive effect of MET against DMBA-induced breast carcinogenesis was evidenced by the capability of MET to restore the induction of the mRNA levels of basic excision repair genes, 8-oxoguanine DNA glycosylase (OGG1) and apurinic/apyrimidinic endonuclease1 (APE1), and the level of 8-hydroxy-2-deoxyguanosine (8-OHdG). Interestingly, the inhibition of DMBA-induced DNA adduct formation was associated with proportional decrease in CYP1A1 and in NAD(P)H:quinone oxidoreductase 1 (NQO1) gene expression. Mechanistically, the involvements of AhR and nuclear factor erythroid 2-related factor-2 (Nrf2) in the MET-mediated inhibition of DMBA-induced CYP1A1 and NQO1 gene expression were evidenced by the ability of MET to inhibit DMBA-induced xenobiotic responsive element and antioxidant responsive element luciferase reporter gene expression which suggests an AhR- and Nrf2-dependent transcriptional control. However, the inability of MET to bind to AhR suggests that MET is not an AhR ligand. In conclusion, the present work shows a strong evidence that MET inhibits the DMBA-mediated carcinogenicity and adduct formation by inhibiting the expression of CYP1A1 through an AhR ligand-independent mechanism

  11. Deleterious genetic variants in ciliopathy genes increase risk of ritodrine-induced cardiac and pulmonary side effects.

    Science.gov (United States)

    Seo, Heewon; Kwon, Eun Jin; You, Young-Ah; Park, Yoomi; Min, Byung Joo; Yoo, Kyunghun; Hwang, Han-Sung; Kim, Ju Han; Kim, Young Ju

    2018-01-24

    Ritodrine is a commonly used tocolytic to prevent preterm labour. However, it can cause unexpected serious adverse reactions, such as pulmonary oedema, pulmonary congestion, and tachycardia. It is unknown whether such adverse reactions are associated with pharmacogenomic variants in patients. Whole-exome sequencing of 13 subjects with serious ritodrine-induced cardiac and pulmonary side-effects was performed to identify causal genes and variants. The deleterious impact of nonsynonymous substitutions for all genes was computed and compared between cases (n = 13) and controls (n = 30). The significant genes were annotated with Gene Ontology (GO), and the associated disease terms were categorised into four functional classes for functional enrichment tests. To assess the impact of distributed rare variants in cases with side effects, we carried out rare variant association tests with a minor allele frequency ≤ 1% using the burden test, the sequence Kernel association test (SKAT), and optimised SKAT. We identified 28 genes that showed significantly lower gene-wise deleteriousness scores in cases than in controls. Three of the identified genes-CYP1A1, CYP8B1, and SERPINA7-are pharmacokinetic genes. The significantly identified genes were categorized into four functional classes: ion binding, ATP binding, Ca 2+ -related, and ciliopathies-related. These four classes were significantly enriched with ciliary genes according to SYSCILIA Gold Standard genes (P side effects may be associated with deleterious genetic variants in ciliary and pharmacokinetic genes.

  12. Pyrethroid insecticide lambda-cyhalothrin induces hepatic cytochrome P450 enzymes, oxidative stress and apoptosis in rats.

    Science.gov (United States)

    Martínez, María-Aránzazu; Ares, Irma; Rodríguez, José-Luis; Martínez, Marta; Roura-Martínez, David; Castellano, Victor; Lopez-Torres, Bernardo; Martínez-Larrañaga, María-Rosa; Anadón, Arturo

    2018-08-01

    This study aimed to examine in rats the effects of the Type II pyrethroid lambda-cyhalothrin on hepatic microsomal cytochrome P450 (CYP) isoform activities, oxidative stress markers, gene expression of proinflammatory, oxidative stress and apoptosis mediators, and CYP isoform gene expression and metabolism phase I enzyme PCR array analysis. Lambda-cyhalothrin, at oral doses of 1, 2, 4 and 8mg/kg bw for 6days, increased, in a dose-dependent manner, hepatic activities of ethoxyresorufin O-deethylase (CYP1A1), methoxyresorufin O-demethylase (CYP1A2), pentoxyresorufin O-depentylase (CYP2B1/2), testosterone 7α- (CYP2A1), 16β- (CYP2B1), and 6β-hydroxylase (CYP3A1/2), and lauric acid 11- and 12-hydroxylase (CYP4A1/2). Similarly, lambda-cyhalothrin (4 and 8mg/kg bw, for 6days), in a dose-dependent manner, increased significantly hepatic CYP1A1, 1A2, 2A1, 2B1, 2B2, 2E1, 3A1, 3A2 and 4A1 mRNA levels and IL-1β, NFκB, Nrf2, p53, caspase-3 and Bax gene expressions. PCR array analysis showed from 84 genes examined (P1.5), changes in mRNA levels in 18 genes: 13 up-regulated and 5 down-regulated. A greater fold change reversion than 3-fold was observed on the up-regulated ALDH1A1, CYP2B2, CYP2C80 and CYP2D4 genes. Ingenuity Pathway Analysis (IPA) groups the expressed genes into biological mechanisms that are mainly related to drug metabolism. In the top canonical pathways, Oxidative ethanol degradation III together with Fatty Acid α-oxidation may be significant pathways for lambda-cyhalothrin. Our results may provide further understanding of molecular aspects involved in lambda-cyhalothrin-induced liver injury. Copyright © 2018. Published by Elsevier B.V.

  13. Inulin significantly improves serum magnesium levels in proton pump inhibitor-induced hypomagnesaemia.

    Science.gov (United States)

    Hess, M W; de Baaij, J H F; Broekman, M; Bisseling, T M; Haarhuis, B; Tan, A; Te Morsche, R; Hoenderop, J G J; Bindels, R J M; Drenth, J P H

    2016-06-01

    Proton pump inhibitors (PPI) are among the most widely prescribed drugs to treat gastric acid-related disorders. PPI-induced hypomagnesaemia, a defect in intestinal absorption of Mg(2+) , can be a severe side effect of chronic PPI use. To restore serum Mg(2+) concentrations in PPI-induced hypomagnesaemia patients by dietary supplementation with inulin fibres. Eleven patients with PPI-induced hypomagnesaemia and 10 controls were treated with inulin (20 g/day). Each trial consisted of two cycles of 14-day inulin treatment followed by a washout period of 14 days. Patients continued to use their PPI. Serum Mg(2+) levels served as the primary endpoint. Inulin significantly enhanced serum Mg(2+) levels from 0.60 to 0.68 mmol/L in PPI-induced hypomagnesaemia patients, and from 0.84 to 0.93 mmol/L in controls. As a consequence 24 h urinary Mg(2+) excretion was significantly increased in patients with PPI-induced hypomagnesaemia (0.3-2.2 mmol/day). Symptoms related to hypomagnesaemia, including muscle cramps and paraesthesia, were reduced during intervention with inulin. Inulin increases serum Mg(2+) concentrations under PPI maintenance in patients with PPI-induced hypomagnesaemia. © 2016 John Wiley & Sons Ltd.

  14. Monocrotophos induces the expression and activity of xenobiotic metabolizing enzymes in pre-sensitized cultured human brain cells.

    Directory of Open Access Journals (Sweden)

    Vinay K Tripathi

    Full Text Available The expression and metabolic profile of cytochrome P450s (CYPs is largely missing in human brain due to non-availability of brain tissue. We attempted to address the issue by using human brain neuronal (SH-SY5Y and glial (U373-MG cells. The expression and activity of CYP1A1, 2B6 and 2E1 were carried out in the cells exposed to CYP inducers viz., 3-methylcholanthrene (3-MC, cyclophosphamide (CPA, ethanol and known neurotoxicant- monocrotophos (MCP, a widely used organophosphorous pesticide. Both the cells show significant induction in the expression and CYP-specific activity against classical inducers and MCP. The induction level of CYPs was comparatively lower in MCP exposed cells than cells exposed to classical inducers. Pre-exposure (12 h of cells to classical inducers significantly added the MCP induced CYPs expression and activity. The findings were concurrent with protein ligand docking studies, which show a significant modulatory capacity of MCP by strong interaction with CYP regulators-CAR, PXR and AHR. Similarly, the known CYP inducers- 3-MC, CPA and ethanol have also shown significantly high docking scores with all the three studied CYP regulators. The expression of CYPs in neuronal and glial cells has suggested their possible association with the endogenous physiology of the brain. The findings also suggest the xenobiotic metabolizing capabilities of these cells against MCP, if received a pre-sensitization to trigger the xenobiotic metabolizing machinery. MCP induced CYP-specific activity in neuronal cells could help in explaining its effect on neurotransmission, as these CYPs are known to involve in the synthesis/transport of the neurotransmitters. The induction of CYPs in glial cells is also of significance as these cells are thought to be involved in protecting the neurons from environmental insults and safeguard them from toxicity. The data provide better understanding of the metabolizing capability of the human brain cells against

  15. Aryl Hydrocarbon Receptor (AhR Modulates Cockroach Allergen-Induced Immune Responses through Active TGFβ1 Release

    Directory of Open Access Journals (Sweden)

    Yufeng Zhou

    2014-01-01

    Full Text Available Background. Aryl hydrocarbon receptor (AhR, a multifunctional regulator that senses and responds to environmental stimuli, plays a role in normal cell development and immune regulation. Recent evidence supports a significant link between environmental exposure and AhR in the development of allergic diseases. We sought to investigate whether AhR plays a role in mediating cockroach allergen-induced allergic immune responses. Methods. AhR expression in human lung fibroblasts from asthmatic and healthy individuals and in cockroach extract (CRE treated human lung fibroblasts (WI-38 was examined. The role of AhR in modulating CRE induced TGFβ1 production was investigated by using AhR agonist, TCDD, antagonist CH122319, and knockdown of AhR. The role of latent TGFβ1 binding protein-1 (LTBP1 in mediating TCDD induced active TGFβ1 release was also examined. Results. AhR expression was higher in airway fibroblasts from asthmatic subjects as compared to healthy controls. AhR in fibroblasts was activated by TCDD with an increased expression of cyp1a1 and cyp1b1. Increased AhR expression was observed in CRE-treated fibroblasts. Importantly, CRE induced TGFβ1 production in fibroblasts was significantly enhanced by TCDD but inhibited by CH122319. Reduced TGFβ1 production was further confirmed in fibroblasts with AhR knockdown. Moreover, AhR knockdown inhibited CRE induced fibroblast differentiation. Furthermore, TCDD induced active TGFβ1 release was significantly inhibited by LTBP1 knockdown. Conclusion. These results provide evidence for the role of AhR in modulating cockroach allergen-induced immune responses through controlling the active TGFβ1 release, suggesting a possible synergistic effect between exposure to allergens and environmental chemicals on the development of allergic diseases.

  16. Clinical significance of plasminogen activator inhibitor activity in patients with exercise-induced ischemia

    International Nuclear Information System (INIS)

    Sakata, K.; Kurata, C.; Taguchi, T.; Suzuki, S.; Kobayashi, A.; Yamazaki, N.; Rydzewski, A.; Takada, Y.; Takada, A.

    1990-01-01

    To assess the fibrinolytic system in patients with exercise-induced ischemia and its relation to ischemia and severity of coronary artery disease (CAD), 47 patients with CAD confirmed by results of coronary angiography underwent symptom-limited multistage exercise thallium-201 emission computed tomography. All patients with CAD had exercise-induced ischemia as assessed from thallium-201 images. Pre- and peak exercise blood samples from each patient and preexercise blood samples from control subjects were assayed for several fibrinolytic components and were also assayed for plasma adrenaline. The extent of ischemia was defined as delta visual uptake score (total visual uptake score in delayed images minus total visual uptake score in initial images) and the severity of CAD as the number of diseased vessels. In the basal condition, plasminogen activator inhibitor (PAI) activity was significantly higher in patients with exercise-induced ischemia as compared to control subjects (p less than 0.01), although there were no significant differences in other fibrinolytic variables between the two groups. Moreover, PAI activity in the basal condition displayed a significantly positive correlation with the extent of ischemia (r = 0.47, p less than 0.01). Patients with exercise-induced ischemia were divided into two groups (24 with single-vessel disease and 23 with multivessel disease). There were no significant differences in coronary risk factors, hemodynamics, or plasma adrenaline levels during exercise between single-vessel and multivessel disease except that delta visual uptake score was significantly higher in multivessel disease (p less than 0.01)

  17. High-fat diet induces significant metabolic disorders in a mouse model of polycystic ovary syndrome.

    Science.gov (United States)

    Lai, Hao; Jia, Xiao; Yu, Qiuxiao; Zhang, Chenglu; Qiao, Jie; Guan, Youfei; Kang, Jihong

    2014-11-01

    Polycystic ovary syndrome (PCOS) is the most common female endocrinopathy associated with both reproductive and metabolic disorders. Dehydroepiandrosterone (DHEA) is currently used to induce a PCOS mouse model. High-fat diet (HFD) has been shown to cause obesity and infertility in female mice. The possible effect of an HFD on the phenotype of DHEA-induced PCOS mice is unknown. The aim of the present study was to investigate both reproductive and metabolic features of DHEA-induced PCOS mice fed a normal chow or a 60% HFD. Prepubertal C57BL/6 mice (age 25 days) on the normal chow or an HFD were injected (s.c.) daily with the vehicle sesame oil or DHEA for 20 consecutive days. At the end of the experiment, both reproductive and metabolic characteristics were assessed. Our data show that an HFD did not affect the reproductive phenotype of DHEA-treated mice. The treatment of HFD, however, caused significant metabolic alterations in DHEA-treated mice, including obesity, glucose intolerance, dyslipidemia, and pronounced liver steatosis. These findings suggest that HFD induces distinct metabolic features in DHEA-induced PCOS mice. The combined DHEA and HFD treatment may thus serve as a means of studying the mechanisms involved in metabolic derangements of this syndrome, particularly in the high prevalence of hepatic steatosis in women with PCOS. © 2014 by the Society for the Study of Reproduction, Inc.

  18. Radiation-induced secretory protein, clusterin. Its inductive mechanism and biological significance

    International Nuclear Information System (INIS)

    Suzuki, Masatoshi; Boothman, D.A.

    2007-01-01

    This paper describes biochemistry of secretory clusterin (C), its radiation-inductive mechanism and biological significance. C is a glycoprotein found to be secreted from cells given various stresses like radiation and ultraviolet (UV)-ray, and participates to red cell clustering. Human C gene locates on the chromosome 8p21-p12, C has MW of 60 kDa, its precursor undergoes the degrading processing to α- and β-chains to form their heterodimer before glycosylation, and the C is finally secreted. So many other names have been given to C due to its numerous functions which have been discovered in other fields, such as apolipoprotein J. C is abundant in plasma, milk, urine, cerebrospinal fluid, semen, etc. Within 24 hr after X-ray irradiation, extracellular insulin-like growth factor-1 (IGF-1) level is elevated, and through its binding to the receptor, Src/MAPK signaling participates to C expression. Nuclear C, also induced by radiation, is a splicing variant of C and not secreted from cells. C is induced by radiation with as low dose as 2 cGy, which is different from induction of nuclear C. Secreted C is incorporated in cells by endocytosis and promotes the intracellular survival reaction through IGF-1 receptor/MAPK/Egr-1 pathway, whereas nuclear C induces cell apoptosis via unknown mechanism. Further studies are required for elucidation of the roles of secretory and nuclear C in cellular radiation responses. (R.T.)

  19. Escherichia coli DinB inhibits replication fork progression without significantly inducing the SOS response.

    Science.gov (United States)

    Mori, Tetsuya; Nakamura, Tatsuro; Okazaki, Naoto; Furukohri, Asako; Maki, Hisaji; Akiyama, Masahiro Tatsumi

    2012-01-01

    The SOS response is readily triggered by replication fork stalling caused by DNA damage or a dysfunctional replicative apparatus in Escherichia coli cells. E. coli dinB encodes DinB DNA polymerase and its expression is upregulated during the SOS response. DinB catalyzes translesion DNA synthesis in place of a replicative DNA polymerase III that is stalled at a DNA lesion. We showed previously that DNA replication was suppressed without exogenous DNA damage in cells overproducing DinB. In this report, we confirm that this was due to a dose-dependent inhibition of ongoing replication forks by DinB. Interestingly, the DinB-overproducing cells did not significantly induce the SOS response even though DNA replication was perturbed. RecA protein is activated by forming a nucleoprotein filament with single-stranded DNA, which leads to the onset of the SOS response. In the DinB-overproducing cells, RecA was not activated to induce the SOS response. However, the SOS response was observed after heat-inducible activation in strain recA441 (encoding a temperature-sensitive RecA) and after replication blockage in strain dnaE486 (encoding a temperature-sensitive catalytic subunit of the replicative DNA polymerase III) at a non-permissive temperature when DinB was overproduced in these cells. Furthermore, since catalytically inactive DinB could avoid the SOS response to a DinB-promoted fork block, it is unlikely that overproduced DinB takes control of primer extension and thus limits single-stranded DNA. These observations suggest that DinB possesses a feature that suppresses DNA replication but does not abolish the cell's capacity to induce the SOS response. We conclude that DinB impedes replication fork progression in a way that does not activate RecA, in contrast to obstructive DNA lesions and dysfunctional replication machinery.

  20. Radiation-induced DNA-protein cross-links: Mechanisms and biological significance.

    Science.gov (United States)

    Nakano, Toshiaki; Xu, Xu; Salem, Amir M H; Shoulkamy, Mahmoud I; Ide, Hiroshi

    2017-06-01

    Ionizing radiation produces various DNA lesions such as base damage, DNA single-strand breaks (SSBs), DNA double-strand breaks (DSBs), and DNA-protein cross-links (DPCs). Of these, the biological significance of DPCs remains elusive. In this article, we focus on radiation-induced DPCs and review the current understanding of their induction, properties, repair, and biological consequences. When cells are irradiated, the formation of base damage, SSBs, and DSBs are promoted in the presence of oxygen. Conversely, that of DPCs is promoted in the absence of oxygen, suggesting their importance in hypoxic cells, such as those present in tumors. DNA and protein radicals generated by hydroxyl radicals (i.e., indirect effect) are responsible for DPC formation. In addition, DPCs can also be formed from guanine radical cations generated by the direct effect. Actin, histones, and other proteins have been identified as cross-linked proteins. Also, covalent linkages between DNA and protein constituents such as thymine-lysine and guanine-lysine have been identified and their structures are proposed. In irradiated cells and tissues, DPCs are repaired in a biphasic manner, consisting of fast and slow components. The half-time for the fast component is 20min-2h and that for the slow component is 2-70h. Notably, radiation-induced DPCs are repaired more slowly than DSBs. Homologous recombination plays a pivotal role in the repair of radiation-induced DPCs as well as DSBs. Recently, a novel mechanism of DPC repair mediated by a DPC protease was reported, wherein the resulting DNA-peptide cross-links were bypassed by translesion synthesis. The replication and transcription of DPC-bearing reporter plasmids are inhibited in cells, suggesting that DPCs are potentially lethal lesions. However, whether DPCs are mutagenic and induce gross chromosomal alterations remains to be determined. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Clinical significance of stress-induced ST segment changes in patients with previous myocardial infarction

    International Nuclear Information System (INIS)

    Futagami, Yasuo; Hamada, Masayuki; Makino, Katsutoshi; Ichikawa, Takehiko; Konishi, Tokuji

    1984-01-01

    To explain the clinical significance of stress(st)-induced ST-segment (ST) changes postinfarction, 93 patients with previous myocardial infarction (MI) were performed st- 201 Tl myocardial single photon emission computed tomography (SPECT) and compared ST changes with SPECT, coronary arteriographic and left ventriculographic findings. 30 out of 93 cases (32%) had ST depression, 20 (21.5%) had ST elevation, 9 (10%) had both ST depression and elevation and remaining 34 (36.5 %) had no significant ST changes. In single vessel disease, ST depression were noted in 29% (12/42), while in multivessel disease, 53% (27/51). 35 out of 39 cases (90%) with ST depression had transient perfusion defect but no apparent relation was noted between location of ST depression on ECG and region of transient perfusion defect in SPECT. All of 28 cases with ST elevation were noted in anterior MI cases, and 26 out of these showed severe LV wall motion abnormality in contrast left ventriculography and broad anterior permanent defect in SPECT. Only 15 cases (54%) showed slight redistribution. Thus, we conclude that in patients with previous MI, st-induced ST depression seems to reflect myocardial ischemia and ST elevation possibly related abnormal LV wall motion. (author)

  2. Clinical significance of exercise induced ST segment depression after successful percutaneous transluminal coronary angioplasty

    International Nuclear Information System (INIS)

    Aoki, Toshikazu; Konishi, Tokuji; Futagami, Yasuo

    1989-01-01

    To evaluate the clinical significance of ST segment depression during repeated Treadmill exercise after successful PTCA, Thallium-201 SPECT was performed. The Thallium-201 SPECT was performed before, one week after and 3-6 months after PTCA. All thirty-five patients had one vessel disease and positive Thallium-201 exercise test. During follow-up period for 3-6 months, 11 of 35 patients had persistent ST segment depression. Restenosis of dilated coronary lesion was demonstrated in 6 of 11 patients. In another 3 of 35 patients, exercise induced ST segment depression was disappered during follow-up Treadmill exercise. In 14 patients with persistent or transient ST segment depression after PTCA, Thallium-201 SPECT demonstrated transient ischemia in 5 of 6 patients with restenosis. In other 8 patients without restenosis, SPECT images did not demonstrate myocardial ischemia and coronary arteriographic findings could not verify side branch stenosis or intimal dissection which might cause myocardial ischemia. The etiology of ST segment depression after successful PTCA in one vessel disease is not produced by exercise induced myocardial ischemia but still unknown mechanisms may be present. (author)

  3. Exercise-induced thallium-201 myocardial perfusion defects in angina pectoris without significant coronary artery stenosis

    International Nuclear Information System (INIS)

    Nakazato, Masayasu; Maruoka, Yuji; Sunagawa, Osahiko; Kinjo, Kunihiko; Tomori, Masayuki; Fukiyama, Koshiro

    1990-01-01

    We performed exercise thallium-201 myocardial scintigraphy in 32 patients with angina pectoris to study the incidence of perfusion defects, who had no significant organic stenosis on coronary angiography. None of them had myocardial infarction or cardiomyopathy. Thallium-201 myocardial scintigraphy and 12-lead ECG recording were performed during supine bicycle ergometer exercise. Perfusion defects in thallium-201 scintigrams in SPECT images were assessed during visual analysis by two observers. In the coronary angiograms obtained during intravenous infusion of nitroglycerin, the luminal diameter of 75% stenosis or less in the AHA classification was regarded as an insignificant organic stenosis. Myocardial perfusion defects in the thallium-201 scintigrams were detected in eight (25%) of the 32 patients. Six of these eight patients had variant angina documented during spontaneous attacks with ST elevations in standard 12-lead ECGs. Perfusion defects were demonstrated at the inferior or infero-posterior regions in six patients, one of whom had concomitant anteroseptal defect. The defects were not always accompanied by chest pain. All but one patient demonstrating inferior or inferoposterior defects showed ST depression in leads II, III and aV F on their ECGs, corresponding to inferior wall ischemia. The exception was a case with right bundle branch block. Thus, 25% of the patients with angina pectoris, who had no evidence of significant organic stenosis on their coronary angiograms, exhibited exercise-induced perfusion defects in their thallium-201 scintigrams. Coronary spasms might have caused myocardial ischemia in these patients. (author)

  4. Characteristics and significance of D-tagatose-induced liver enlargement in rats: An interpretative review.

    Science.gov (United States)

    Bär, A

    1999-04-01

    This review addresses the issue of asymptomatic liver enlargement in rats. It was necessitated by the observation of significantly increased liver weights in rats fed diets with 10 to 20% D-tagatose, a potential new bulk sweetener, for between 28 and 90 days. Increases of liver size without accompanying histopathological changes or impairment of organ function have been observed in rats in response to the ingestion of various xenobiotic compounds (including some food additives), changes of dietary composition (e.g. , high doses of fructose and sucrose), metabolic aberrations (e.g., diabetes), as well as normal pregnancy and lactation. The underlying mechanism(s) are not yet understood in detail but peroxisome proliferation, microsomal enzyme induction, increased storage of glycogen or lipids, and hyperfunction due to an excessive workload are well-established causes of hepatomegaly in rats. In D-tagatose- and fructose-fed rats, a treatment-related increase of hepatic glycogen storage was identified as a likely cause of the liver enlargement. Dietary levels of 5% and about 15-20% were determined as no-effect levels (NOEL) for D-tagatose- and fructose-induced liver enlargement, respectively. At doses above the NOEL, D-tagatose is about four times more efficient than fructose in inducing liver enlargement. On the other hand, the estimated intake of D-tagatose from its intended uses in food is about four times lower than the actual fructose intake. Consequently, a similar safety margin would apply for both sugars. Considering the similarity of the liver effects in rats of fructose, a safe food ingredient, and D-tagatose, the absence of histopathological changes in rats fed a diet with 20% D-tagatose for 90 days, and the absence of adverse long-term consequences of glycogen-induced liver enlargement in rats, it is concluded that the observed liver enlargement in D-tagatose-fed rats has no relevance for the assessment of human safety of this substance. Copyright 1999

  5. Somatic mutations in stilbene estrogen-induced Syrian hamster kidney tumors identified by DNA fingerprinting

    Directory of Open Access Journals (Sweden)

    Roy Deodutta

    2004-01-01

    Full Text Available Abstract Kidney tumors from stilbene estrogen (diethylstilbestrol-treated Syrian hamsters were screened for somatic genetic alterations by Random Amplified Polymorphic DNA-polymerase chain-reaction (RAPD-PCR fingerprinting. Fingerprints from tumor tissue were generated by single arbitrary primers and compared with fingerprints for normal tissue from the same animal, as well as normal and tumor tissues from different animals. Sixty one of the arbitrary primers amplified 365 loci that contain approximately 476 kbp of the hamster genome. Among these amplified DNA fragments, 44 loci exhibited either qualitative or quantitative differences between the tumor tissues and normal kidney tissues. RAPD-PCR loci showing decreased and increased intensities in tumor tissue DNA relative to control DNA indicate that loci have undergone allelic losses and gains, respectively, in the stilbene estrogen-induced tumor cell genome. The presence or absence of the amplified DNA fragments indicate homozygous insertions or deletions in the kidney tumor DNA compared to the age-matched normal kidney tissue DNA. Seven of 44 mutated loci also were present in the kidney tissues adjacent to tumors (free of macroscopic tumors. The presence of mutated loci in uninvolved (non-tumor surrounding tissue adjacent to tumors from stilbene estrogen-treated hamsters suggests that these mutations occurred in the early stages of carcinogenesis. The cloning and sequencing of RAPD amplified loci revealed that one mutated locus had significant sequence similarity with the hamster Cyp1A1 gene. The results show the ability of RAPD-PCR to detect and isolate, in a single step, DNA sequences representing genetic alterations in stilbene estrogen-induced cancer cells, including losses of heterozygosity, and homozygous deletion and insertion mutations. RAPD-PCR provides an alternative molecular approach for studying cancer cytogenetics in stilbene estrogen-induced tumors in humans and experimental

  6. Looking for the Self: Phenomenology, Neurophysiology and Philosophical Significance of Drug-induced Ego Dissolution

    Directory of Open Access Journals (Sweden)

    Raphaël Millière

    2017-05-01

    Full Text Available There is converging evidence that high doses of hallucinogenic drugs can produce significant alterations of self-experience, described as the dissolution of the sense of self and the loss of boundaries between self and world. This article discusses the relevance of this phenomenon, known as “drug-induced ego dissolution (DIED”, for cognitive neuroscience, psychology and philosophy of mind. Data from self-report questionnaires suggest that three neuropharmacological classes of drugs can induce ego dissolution: classical psychedelics, dissociative anesthetics and agonists of the kappa opioid receptor (KOR. While these substances act on different neurotransmitter receptors, they all produce strong subjective effects that can be compared to the symptoms of acute psychosis, including ego dissolution. It has been suggested that neuroimaging of DIED can indirectly shed light on the neural correlates of the self. While this line of inquiry is promising, its results must be interpreted with caution. First, neural correlates of ego dissolution might reveal the necessary neurophysiological conditions for the maintenance of the sense of self, but it is more doubtful that this method can reveal its minimally sufficient conditions. Second, it is necessary to define the relevant notion of self at play in the phenomenon of DIED. This article suggests that DIED consists in the disruption of subpersonal processes underlying the “minimal” or “embodied” self, i.e., the basic experience of being a self rooted in multimodal integration of self-related stimuli. This hypothesis is consistent with Bayesian models of phenomenal selfhood, according to which the subjective structure of conscious experience ultimately results from the optimization of predictions in perception and action. Finally, it is argued that DIED is also of particular interest for philosophy of mind. On the one hand, it challenges theories according to which consciousness always involves

  7. Looking for the Self: Phenomenology, Neurophysiology and Philosophical Significance of Drug-induced Ego Dissolution

    Science.gov (United States)

    Millière, Raphaël

    2017-01-01

    There is converging evidence that high doses of hallucinogenic drugs can produce significant alterations of self-experience, described as the dissolution of the sense of self and the loss of boundaries between self and world. This article discusses the relevance of this phenomenon, known as “drug-induced ego dissolution (DIED)”, for cognitive neuroscience, psychology and philosophy of mind. Data from self-report questionnaires suggest that three neuropharmacological classes of drugs can induce ego dissolution: classical psychedelics, dissociative anesthetics and agonists of the kappa opioid receptor (KOR). While these substances act on different neurotransmitter receptors, they all produce strong subjective effects that can be compared to the symptoms of acute psychosis, including ego dissolution. It has been suggested that neuroimaging of DIED can indirectly shed light on the neural correlates of the self. While this line of inquiry is promising, its results must be interpreted with caution. First, neural correlates of ego dissolution might reveal the necessary neurophysiological conditions for the maintenance of the sense of self, but it is more doubtful that this method can reveal its minimally sufficient conditions. Second, it is necessary to define the relevant notion of self at play in the phenomenon of DIED. This article suggests that DIED consists in the disruption of subpersonal processes underlying the “minimal” or “embodied” self, i.e., the basic experience of being a self rooted in multimodal integration of self-related stimuli. This hypothesis is consistent with Bayesian models of phenomenal selfhood, according to which the subjective structure of conscious experience ultimately results from the optimization of predictions in perception and action. Finally, it is argued that DIED is also of particular interest for philosophy of mind. On the one hand, it challenges theories according to which consciousness always involves self-awareness. On

  8. Polycyclic aromatic hydrocarbon-induced CYP1B1 activity is suppressed by perillyl alcohol in MCF-7 cells

    International Nuclear Information System (INIS)

    Chan, Nelson L.S.; Wang Huan; Wang Yun; Leung, H.Y.; Leung, Lai K.

    2006-01-01

    Perillyl alcohol (POH) is a dietary monoterpene with potential applications in chemoprevention and chemotherapy. Although clinical trials are under way, POH's physiological and pharmacological properties are still unclear. In the present study, the effect of POH on polycyclic aromatic hydrocarbon (PAH)-induced genotoxicity, and the related expression were examined in MCF-7 cells. Exposure to environmental toxicant increases the risk of cancer. Many of these compounds are pro-carcinogens and are biotransformed into their ultimate genotoxic structures by xenobiotic metabolizing enzymes. CYP1A1 and 1B1 are enzymes that catalyze the biotransformation of dimethylbenz[a]anthracene (DMBA). Our data revealed that 0.5 μM of POH was effective in blocking DMBA-DNA binding. Ethoxyresorufin-O-deethylase (EROD) assay indicated that the administration of POH inhibited the DMBA-induced enzyme activity in MCF-7 cells. Enzyme kinetic analysis revealed that POH inhibited CYP1B1 but not CYP1A1 activity. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay also demonstrated that the monoterpene reduced CYP1B1 mRNA abundance induced by DMBA. The present study illustrated that POH might inhibit and downregulate CYP1B1, which could protect against PAH-induced carcinogenesis

  9. Mixed martial arts induces significant fatigue and muscle damage up to 24 hours post-combat.

    Science.gov (United States)

    Ghoul, Nihel; Tabben, Montassar; Miarka, Bianca; Tourny, Claire; Chamari, Karim; Coquart, Jeremy

    2017-06-22

    This study investigates the physiological/physical responses to a simulated mixed martial arts (MMA) competition over 24 hr. Twelve fighters performed a simulated MMA competition, consisting of three 5-min MMA matches. Physiological/physical data were assessed before (Trest), directly after round 1 (Trd1), round 2 (Trd2) and round 3 (Trd3), and then 30-min (Trecovery30min) and/or 24-hr (Trecovery24h) post-competition. Heart rate (HR), rating of perceived exertion (RPE) and blood lactate concentration ([La]) were assessed at Trest, Trd1, Trd2 and Trd3. Biological data were collected at Trest, Trd3, Trecovery30min and Trecovery24h. Physical tests were performed at Trest, Trecovery30min and Trecovery24h. HR, RPE and [La] were high during competition. Leukocytes, hemoglobin, total protein and glycemia were increased at Trd3 compared with all other time points (p<0.05). Cortisol was increased at Trd3 compared with Trest and Trecovery24h (p<0.05). Testosterone was higher at Trd3 and Trecovery30min than Trest (p<0.001). Higher values of uric acid were noted during recovery periods (p<0.001). Lactate dehydrogenase was lower at Trest compared with Trd3, Trecovery30min and Trecovery24h (p<0.05). Countermovement jump was higher at Trest than Trecovery30min (p=0.020). Consequently, MMA is a high-intensity intermittent combat sport that induces significant fatigue and muscle damage, both of which are still present 24-hr post-competition.

  10. Clinicopathologic significance of fascin, extracellular matrix metalloproteinase inducer, and ezrin expressions in colorectal adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Eun-Joo Jung

    2011-01-01

    Full Text Available Background: The over expression of fascin, extracellular matrix metalloproteinase inducer (EMMPRIN, and ezrin proteins has been associated with poor prognosis in various carcinomas and sarcomas. However, very few studies have reported the relationship between the expression of fascin, EMMPRIN, and ezrin proteins and the clinico-pathologic parameters of colorectal carcinomas. Aims: The aim was to investigate the relationship between fascin, EMMPRIN, and ezrin proteins in colorectal adenocarcinomas and their correlation with clinico-pathologic parameters. Settings and Design: The expression of fascin, EMMPRIN, and ezrin proteins was studied in 210 colorectal adenocarcinoma patients through immunohistochemical staining. Materials and Methods: Immunohistochemical staining by the avidin-biotin peroxidase method was done. The scoring of each protein expression was done and divided into three groups (negative, low-, and high-expression groups. Statistical Analysis: A chi-square test, and Kendall′s tau-b correlation test were used for comparing. Survival analysis was performed using the Kaplan-Meier method with log-rank tests and the Cox proportional hazard model. Results: The percentages of the high-expression group of fascin, EMMPRIN, and ezrin proteins in colorectal adenocarcinomas were 24%, 73%, and 62%, respectively. Weak positive correlations were observed among these protein expressions. An increased expression of the fascin protein was significantly associated with advanced tumor depth and shorter survival times, and a high expression of fascin protein was an independent prognostic factor in univariate and multivariate survival analyses. EMMPRIN and ezrin protein expressions were not associated with the clinico-pathologic parameters. Conclusions: The high expression of fascin protein may be an unfavorable prognostic marker for individual colorectal cancer patients.

  11. Nicotine Significantly Improves Chronic Stress-Induced Impairments of Cognition and Synaptic Plasticity in Mice.

    Science.gov (United States)

    Shang, Xueliang; Shang, Yingchun; Fu, Jingxuan; Zhang, Tao

    2017-08-01

    The aim of this study was to examine if nicotine was able to improve cognition deficits in a mouse model of chronic mild stress. Twenty-four male C57BL/6 mice were divided into three groups: control, stress, and stress with nicotine treatment. The animal model was established by combining chronic unpredictable mild stress (CUMS) and isolated feeding. Mice were exposed to CUMS continued for 28 days, while nicotine (0.2 mg/kg) was also administrated for 28 days. Weight and sucrose consumption were measured during model establishing period. The anxiety and behavioral despair were analyzed using the forced swim test (FST) and open-field test (OFT). Spatial cognition was evaluated using Morris water maze (MWM) test. Following behavioral assessment, both long-term potentiation (LTP) and depotentiation (DEP) were recorded in the hippocampal dentate gyrus (DG) region. Both synaptic and Notch1 proteins were measured by Western. Nicotine increased stressed mouse's sucrose consumption. The MWM test showed that spatial learning and reversal learning in stressed animals were remarkably affected relative to controls, whereas nicotine partially rescued cognitive functions. Additionally, nicotine considerably alleviated the level of anxiety and the degree of behavioral despair in stressed mice. It effectively mitigated the depression-induced impairment of hippocampal synaptic plasticity, in which both the LTP and DEP were significantly inhibited in stressed mice. Moreover, nicotine enhanced the expression of synaptic and Notch1 proteins in stressed animals. The results suggest that nicotine ameliorates the depression-like symptoms and improves the hippocampal synaptic plasticity closely associated with activating transmembrane ion channel receptors and Notch signaling components. Graphical Abstract ᅟ.

  12. Space radiation-induced bystander effect: kinetics of biologic responses, mechanisms, and significance of secondary radiations

    International Nuclear Information System (INIS)

    Gonon, Geraldine

    2011-01-01

    more cells than expected based on the fraction of cells traversed through the nucleus by an iron or silicon ion. The effect was expressed as early as 15 min after exposure, peaked at 1 h and decreased by 24 h. A similar tendency occurred after exposure to a mean absorbed dose of 0.2 cGy of 3.7 MeV a particles, but not after 0.2 cGy of 290 MeV/u carbon ions.Analyses in dishes that incorporate a CR-39 solid state nuclear track detector bottom identified the cells irradiated with iron or silicon ions and further supported the participation of bystander cells in the stress response. Mechanistic studies indicated that gap junction intercellular communication, DNA repair, and oxidative metabolism participate in the propagation of the induced effects. We also considered the possible contribution of secondary particles produced along the primary particle tracks to the biological responses. Simulations with the FLUKA multi-particle transport code revealed that fragmentation products, other than electrons, in cells cultures exposed to HZE particles comprise ≤1 % of the absorbed dose. Further, the radial spread of dose due to secondary heavy ion fragments is confined to approximately 10-20 μm. Thus, the latter are unlikely to significantly contribute to the stressful effects in cells not targeted by primary HZE particles. (author)

  13. Persistent aryl hydrocarbon receptor inducers increase with altitude, and estrogen-like disrupters are low in soils of the Alps.

    Science.gov (United States)

    Levy, Walkiria; Henkelmann, Bernhard; Bernhöft, Silke; Bovee, Toine; Buegger, Franz; Jakobi, Gert; Kirchner, Manfred; Bassan, Rodolfo; Kräuchi, Norbert; Moche, Wolfgang; Offenthaler, Ivo; Simončič, Primoz; Weiss, Peter; Schramm, Karl-Werner

    2011-01-01

    Soil samples from remote Alpine areas were analyzed for polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans and polychlorinated biphenyls by high-resolution gas chromatography/high-resolution gas spectrometry. Additionally, the EROD micro-assay and a genetically modified yeast estrogen bioassay were carried out to determine persistent aryl hydrocarbon receptors (AhR) and estrogen receptors (ER) agonists, respectively. Regarding the AhR agonists, the toxicity equivalents of analytical and EROD determined values were compared, targeting both altitude of samples and their soil organic content. The ratio between bioassay derived equivalents and analytical determinations suggested no significant contribution of unknown AhR inducers in these sampling sites and some antagonism in soils with relatively high PCB loading. More CYP1A1 expression was induced at the highest sites or about 1400-1500 m a.s.l. along the altitude profiles. Surprisingly, no clear tendencies with the soil organic content were found for dioxin-like compounds. Mean values obtained in the present study were for ER agonists, 2: 0.37±0.12ng 17ß-estradiol EQ g-1 dry soil [corrected] and 6.1 ± 4.2 pg TCDD-EQ g⁻¹ dry soil for AhR agonists. Low bioassay responses with a higher relative amount of ER disrupters than AhR inducers were detected,indicating the higher abundance of estrogen-like than persistent dioxin-like compounds in these forested areas [corrected].

  14. The relevance of cytokines in the radiation-induced lung reaction. Experimental basis and clinical significance

    International Nuclear Information System (INIS)

    Ruebe, C.E.; Ruebe, C.; Rodemann, H.P.

    2004-01-01

    Methods: published data on radiation-induced cytokine expression from experimental and clinical studies are reviewed. Results and conclusion: the major pro-inflammatory cytokines in the radiation response of the lung include tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6). Transforming growth factor-β (TGF-β) appears to be of particular importance in the development of lung fibrosis. First approaches with radioprotective agents and gene therapy to modify radiation-induced cytokine expression have been investigated for prevention of late effects of irradiation lung damage in animal experiments. Preliminary data of clinical studies suggest that elevated plasma TGF-β-levels during radiotherapy may predict the development of symptomatic radiation pneumonitis. The biological impacts of endogenous radiation-induced cytokine production by tumor cells in respect of tumor behavior, potential damage to normal tissue, and clinical status of the host still need to be determined more precisely. (orig.)

  15. Significance of Shrinkage Induced Clamping Pressure in Fiber-Matrix Bonding in Cementitious Composite Materials

    DEFF Research Database (Denmark)

    Stang, Henrik

    1996-01-01

    used in high performance cementitious composite materials.Assuming a Coulomb type of friction on the fiber/matrix interface andusing typical values for the frictional coefficient it is shownthat the shrinkage induced clamping pressure could be one of the mostimportant factors determining the frictional...

  16. The significant role of plasmonic effects in femtosecond laser-induced grating fabrication on the nanoscale

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Min; Zhao, Fuli [State Key Laboratory of Optoelectronic Materials and Technologies, Sun Yat-sen University, Guangzhou, 510275 (China); Cheng, Ya; Xu, Zhizhan [State Key Laboratory of High Field Laser Physics, Shanghai Institute of Optics and Fine Mechanics, Chinese Academy of Sciences, P.O. Box 800-211, Shanghai, 201800 (China)

    2013-02-15

    Nowadays, plasmonics aiming at manipulating light beyond the diffraction limit has aroused great interest on account of the promise of nanoscale optical devices. Generally, the ability to break diffraction barrier is achieved via controlling surface plasmons (SPs) on artificial structures as products of human ingenuity. Here, nevertheless, it is demonstrated that in short-pulse laser ablation ultrafast active plasmonic structures spontaneously generate by virtue of plasmonic effects rather than human will. First, with the experimental results on ZnO, Si, and GaAs, explicit evidence is provided for the grating-splitting phenomenon that acts as a direct route for the formation of laser-induced deep-subwavelength gratings. The splitting mechanism can break through the diffraction limit and push laser-induced structures towards the nanoscale. Then, through comprehensive numerical studies based on the viewpoint of plasmonics, it can be confirmed that the grating-splitting phenomenon originates in the conversion of SP modes from the resonant to the nonresonant mode and further to the inphase or antiphase asymmetric mode. In short, plasmonic effects play an important role in ultrafast laser-induced grating splitting towards the nanoscale, which will provide new insights into the mechanisms of ultrafast laser-induced nanostructures. (copyright 2012 by WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

  17. The significant role of plasmonic effects in femtosecond laser-induced grating fabrication on the nanoscale

    International Nuclear Information System (INIS)

    Huang, Min; Zhao, Fuli; Cheng, Ya; Xu, Zhizhan

    2013-01-01

    Nowadays, plasmonics aiming at manipulating light beyond the diffraction limit has aroused great interest on account of the promise of nanoscale optical devices. Generally, the ability to break diffraction barrier is achieved via controlling surface plasmons (SPs) on artificial structures as products of human ingenuity. Here, nevertheless, it is demonstrated that in short-pulse laser ablation ultrafast active plasmonic structures spontaneously generate by virtue of plasmonic effects rather than human will. First, with the experimental results on ZnO, Si, and GaAs, explicit evidence is provided for the grating-splitting phenomenon that acts as a direct route for the formation of laser-induced deep-subwavelength gratings. The splitting mechanism can break through the diffraction limit and push laser-induced structures towards the nanoscale. Then, through comprehensive numerical studies based on the viewpoint of plasmonics, it can be confirmed that the grating-splitting phenomenon originates in the conversion of SP modes from the resonant to the nonresonant mode and further to the inphase or antiphase asymmetric mode. In short, plasmonic effects play an important role in ultrafast laser-induced grating splitting towards the nanoscale, which will provide new insights into the mechanisms of ultrafast laser-induced nanostructures. (copyright 2012 by WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

  18. Chemically induced aneuploidy in mammalian cells: mechanisms and biological significance in cancer

    Energy Technology Data Exchange (ETDEWEB)

    Oshimura, M.; Barrett, J.C.

    1986-01-01

    A literature review with over 200 references examines the growing body of evidence from human and animal cancer cytogenetics that aneuploidy is an important chromosome change in carcinogenesis. Evidence from in vitro cell transformation studies supports the idea that aneuploidy has a direct effect on the conversion of a normal cell to a preneoplastic or malignant cell. Induction of an aneuploid state in a preneoplastic or neoplastic cell could have any of the following four biological effects: a change in gene dosage, a change in gene balance, expression of a recessive mutation, or a change in genetic instability (which could secondarily lead to neoplasia). There are a number of possible mechanisms by which chemicals might induce aneuploidy, including effects on microtubules, damage to essential elements for chromosome function reduction in chromosome condensation or pairing, induction of chromosome interchanges, unresolved recombination structures, increased chromosome stickiness, damage to centrioles, impairment of chromosome alignment ionic alterations during mitosis, damage to the nuclear membrane, and a physical disruption of chromosome segregation. Therefore, a number of different targets exist for chemically induced aneuploidy.

  19. [Etiological analysis and significance of anterior knee pain induced by gluteal muscles contracture].

    Science.gov (United States)

    Zhao, Gang; Liu, Yu-jie; Wang, Jun-liang; Qi, Wei; Qu, Feng; Yuan, Bang-tuo; Wang, Jiang-tao; Shen, Xue-zhen; Liu, Yang; Zhu, Juan-li

    2014-12-01

    To explore causes of gluteal muscle contracture induced anterior knee pain and curative effect of arthroscopic release. From March 2002 to August 2013,36 patients with gluteal muscle contracture induced anterior knee pain were treated, including 15 males, 21 females, aged from 9 to 40 years old with an average (18.7±7.2) years old; the courses of diseases ranged from 4 to 30 years. The clinical manifestations involved limited to symmelia, positive Ober sign, buttocks touch contracture belts, knee and patella slide to lateral when doing squat activities. All patients were performed gluteal muscle contracture release under arthroscopic. Postoperative complications were observed, Kujala scoring before and after operation was used for compare curative effect. All patients were followed up with an average of 29 months. The incision were healed well, and no complications were occurred. Postoperative Kujala score were improved more than preoperative. Gluteal muscle contracture release could alleviate hypertension of lateral patella, and palys an important role in preventing patellofemoral arthritis.

  20. Impact of beta-naphthoflavone on genotoxicity of food-derived carcinogens.

    Science.gov (United States)

    Hodek, Petr; Krizkova, Jitka; Frei, Eva; Singh, Rajinder; Arlt, Volker M; Stiborova, Marie

    2011-01-01

    Benzo[a]pyrene (BaP) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are carcinogens, which frequently occur in the human diet. Their metabolic activation to reactive species binding to DNA is mediated by cytochromes P450 (CYPs) 1A1 and 1A2. Thus, levels and activities of these CYPs are crucial for initiation of BaP- and PhPI-mediated carcinogenesis. Here, the effect of CYP1A1/2 induction due to their prototype flavonoid inducer, β-naphthoflavone (BNF), on BaP- and PhPI-derived DNA adduct formation in rats was examined. Male rats pretreated with BNF were treated with a single dose of either carcinogen by oral gavage. Nuclease P1 version of 32P-postlabeling assay and online column-switching liquid chromatography-electrospray ionization-tandem mass spectrometry were used to detect and quantify covalent DNA adducts formed by BaP and PhIP in-vivo, respectively. Expression of CYP1A1/2 enzymes was examined by Western blot. Enzymatic activities of CYP1A1/2 were assessed using their marker substrates (ethoxyresorufin and methoxyresorufin). Treatment of rats with a single dose of BNF produced an increase in levels CYP1A1/2 and CYP1A1 proteins in liver and small intestine, respectively. An increase in CYP1A1 protein expression found in both organs correlated well with specific activities of these CYPs. The CYP1A1 expression levels and its specific activity in small intestine decreased along the length of the organ, being highest in its proximal part and lowest in its distal part. The BNF induction of CYP1A1/2 resulted in a significant increase in the formation of BaP- and PhIP-DNA adducts in liver and in the distal part of the small intestine, respectively. Thus, pretreatment of rats with BNF did not prevent the PhIP and BaP activation, but vice versa, enhanced their genotoxicity. The results of this study demonstrate that the administration of only a single dose of CYP-inducing flavonoid prior to the intake of food carcinogens may increase the risk of a tumor

  1. Sulforaphane-induced transcription of thioredoxin reductase in lens: possible significance against cataract formation

    Directory of Open Access Journals (Sweden)

    Varma SD

    2013-10-01

    Full Text Available Shambhu D Varma, Krish Chandrasekaran, Svitlana Kovtun Department of Ophthalmology and Visual Sciences, University of Maryland, Baltimore, MD, USA Purpose: Sulforaphane is a phytochemically derived organic isothiocyanate 1-isothiocyanato-4-methylsulfinyl-butane present naturally in crucifers, including broccoli and cauliflower. Biochemically, it has been reported to induce the transcription of several antioxidant enzymes. Since such enzymes have been implicated in preventing cataract formation triggered by the intraocular generation of oxy-radical species, the purpose of this investigation was to examine whether it could induce the formation of antioxidant enzymes in the eye lens. Thioredoxin reductase (TrxR was used as the target of such induction. Methods: Mice lenses were cultured for an overnight period of 17 hours in medium 199 fortified with 10% fetal calf serum. Incubation was conducted in the absence and presence of sulforaphane (5 µM. Subsequently, the lenses were homogenized in phosphate-buffered saline (PBS, followed by centrifugation. TrxR activity was determined in the supernatant by measuring the nicotinamide adenine dinucleotide phosphate (reduced (NADPH-dependent reduction of 5,5´-dithiobis-2-nitrobenzoic acid (DTNB. Non-specific reduction of DTNB was corrected for by conducting parallel determinations in the presence of aurothiomalate. The reduction of DTNB was followed spectrophotometrically at 410 nm. Results: The activity of TrxR in the lenses incubated with sulforaphane was found to be elevated to 18 times of that observed in lenses incubated without sulforaphane. It was also noticeably higher in the lenses incubated without sulforaphane than in the un-incubated fresh lenses. However, this increase was much lower than that observed for lenses incubated with sulforaphane. Conclusion: Sulforaphane has been found to enhance TrxR activity in the mouse lens in culture. In view of the protective effect of the antioxidant enzymes

  2. Significant modulation of the hepatic proteome induced by exposure to low temperature in Xenopus laevis

    Directory of Open Access Journals (Sweden)

    Kazumichi Nagasawa

    2013-08-01

    The African clawed frog, Xenopus laevis, is an ectothermic vertebrate that can survive at low environmental temperatures. To gain insight into the molecular events induced by low body temperature, liver proteins were evaluated at the standard laboratory rearing temperature (22°C, control and a low environmental temperature (5°C, cold exposure. Using nano-flow liquid chromatography coupled with tandem mass spectrometry, we identified 58 proteins that differed in abundance. A subsequent Gene Ontology analysis revealed that the tyrosine and phenylalanine catabolic processes were modulated by cold exposure, which resulted in decreases in hepatic tyrosine and phenylalanine, respectively. Similarly, levels of pyruvate kinase and enolase, which are involved in glycolysis and glycogen synthesis, were also decreased, whereas levels of glycogen phosphorylase, which participates in glycogenolysis, were increased. Therefore, we measured metabolites in the respective pathways and found that levels of hepatic glycogen and glucose were decreased. Although the liver was under oxidative stress because of iron accumulation caused by hepatic erythrocyte destruction, the hepatic NADPH/NADP ratio was not changed. Thus, glycogen is probably utilized mainly for NADPH supply rather than for energy or glucose production. In conclusion, X. laevis responds to low body temperature by modulating its hepatic proteome, which results in altered carbohydrate metabolism.

  3. Biological Significance of the Suppression of Oxidative Phosphorylation in Induced Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Cheng Zhang

    2017-11-01

    Full Text Available We discovered that induced pluripotent stem cell (iPSC clones generated from aged tissue donors (A-iPSCs fail to suppress oxidative phosphorylation. Compared to embryonic stem cells (ESCs and iPSCs generated from young donors (Y-iPSCs, A-iPSCs show poor expression of the pluripotent stem cell-specific glucose transporter 3 (GLUT3 and impaired glucose uptake, making them unable to support the high glucose demands of glycolysis. Persistent oxidative phosphorylation in A-iPSCs generates higher levels of reactive oxygen species (ROS, which leads to excessive elevation of glutathione (a ROS-scavenging metabolite and a blunted DNA damage response. These phenotypes were recapitulated in Y-iPSCs by inhibiting pyruvate dehydrogenase kinase (PDK or supplying citrate to activate oxidative phosphorylation. In addition, oxidative phosphorylation in A-iPSC clones depletes citrate, a nuclear source of acetyl group donors for histone acetylation; this consequently alters histone acetylation status. Expression of GLUT3 in A-iPSCs recovers the metabolic defect, DNA damage response, and histone acetylation status.

  4. Xenobiotic-induced apoptosis: significance and potential application as a general biomarker of response

    Science.gov (United States)

    Sweet, Leonard I.; Passino-Reader, Dora R.; Meier, Peter G.; Omann, Geneva M.

    1999-01-01

    The process of apoptosis, often coined programmed cell death, involves cell injury induced by a variety of stimuli including xenobiotics and is morphologically, biochemically, and physiologically distinct from necrosis. Apoptotic death is characterized by cellular changes such as cytoplasm shrinkage, chromatin condensation, and plasma membrane asymmetry. This form of cell suicide is appealing as a general biomarker of response in that it is expressed in multiple cell systems (e.g. immune, neuronal, hepatal, intestinal, dermal, reproductive), is conserved phylogenetically (e.g. fish, rodents, birds, sheep, amphibians, roundworms, plants, humans), is modulated by environmentally relevant levels of chemical contaminants, and indicates a state of stress of the organism. Further, apoptosis is useful as a biomarker as it serves as a molecular control point and hence may provide mechanistic information on xenobiotic stress. Studies reviewed here suggest that apoptosis is a sensitive and early indicator of acute and chronic chemical stress, loss of cellular function and structure, and organismal health. Examples are provided of the application of this methodology in studies of health of lake trout (Salvelinus namaycush) in the Laurentian Great Lakes.

  5. Character, distribution, and ecological significance of storm wave-induced scour in Rhode Island Sound, USA

    Science.gov (United States)

    McMullen, Katherine Y.; Poppe, Lawrence J.; Parker, Castle E.

    2015-01-01

    Multibeam bathymetry, collected during NOAA hydrographic surveys in 2008 and 2009, is coupled with USGS data from sampling and photographic stations to map the seabed morphology and composition of Rhode Island Sound along the US Atlantic coast, and to provide information on sediment transport and benthic habitats. Patchworks of scour depressions cover large areas on seaward-facing slopes and bathymetric highs in the sound. These depressions average 0.5-0.8 m deep and occur in water depths reaching as much as 42 m. They have relatively steep well-defined sides and coarser-grained floors, and vary strongly in shape, size, and configuration. Some individual scour depressions have apparently expanded to combine with adjacent depressions, forming larger eroded areas that commonly contain outliers of the original seafloor sediments. Where cobbles and scattered boulders are present on the depression floors, the muddy Holocene sands have been completely removed and the winnowed relict Pleistocene deposits exposed. Low tidal-current velocities and the lack of obstacle marks suggest that bidirectional tidal currents alone are not capable of forming these features. These depressions are formed and maintained under high-energy shelf conditions owing to repetitive cyclic loading imposed by high-amplitude, long-period, storm-driven waves that reduce the effective shear strength of the sediment, cause resuspension, and expose the suspended sediments to erosion by wind-driven and tidal currents. Because epifauna dominate on gravel floors of the depressions and infauna are prevalent in the finer-grained Holocene deposits, it is concluded that the resultant close juxtaposition of silty sand-, sand-, and gravel-dependent communities promotes regional faunal complexity. These findings expand on earlier interpretations, documenting how storm wave-induced scour produces sorted bedforms that control much of the benthic geologic and biologic diversity in Rhode Island Sound.

  6. A human intervention study with foods containing natural Ah-receptor agonists does not significantly show AhR-mediated effects as measured in blood cells and urine.

    Science.gov (United States)

    de Waard, Pim W J; Peijnenburg, Ad A C M; Baykus, Hakan; Aarts, Jac M M J G; Hoogenboom, Ron L A P; van Schooten, Frederik J; de Kok, Theo M C M

    2008-10-22

    Binding and activation of the aryl hydrocarbon receptor (AhR) is thought to be an essential step in the toxicity of the environmental pollutants dioxins and dioxin-like PCBs. However, also a number of natural compounds, referred to as NAhRAs (natural Ah-receptor agonists), which are present in, for example, fruits and vegetables, can bind and activate this receptor. To study their potential effects in humans, we first investigated the effect of the prototypical AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on gene expression in ex vivo exposed freshly isolated human lymphocytes, and compared the resulting gene expression profile with those caused by the well-known NAhRA indolo[3,2-b]carbazole (ICZ), originating from cruciferous vegetables, and by a hexane extract of NAhRA-containing grapefruit juice (GJE). Only ICZ induced a gene expression profile similar to TCDD in the lymphocytes, and both significantly up-regulated CYP1B1 and TIPARP (TCDD-inducible poly (ADP-ribose) polymerase) mRNA. Next, we performed a human intervention study with NAhRA-containing cruciferous vegetables and grapefruit juice. The expression of the prototypical AhR-responsive genes CYP1A1, CYP1B1 and NQO1 in whole blood cells and in freshly isolated lymphocytes was not significantly affected. Also enzyme activities of CYP1A2, CYP2A6, N-acetyltransferase 2 (NAT2) and xanthine oxidase (XO), as judged by caffeine metabolites in urine, were unaffected, except for a small down-regulation of NAT2 activity by grapefruit juice. Examination of blood plasma with DR CALUX showed a 12% increased AhR agonist activity 3 and 24 h after consumption of cruciferous vegetables, but did not show a significant effect of grapefruit juice consumption. We conclude that intake of NAhRAs from food may result in minor AhR-related effects measurable in human blood and urine.

  7. Dietary Selenium as a Modulator of PCB 126–Induced Hepatotoxicity in Male Sprague-Dawley Rats

    Science.gov (United States)

    Lai, Ian K.; Chai, Yingtao; Simmons, Donald; Watson, Walter H.; Tan, Rommel; Haschek, Wanda M.; Wang, Kai; Wang, Bingxuan; Ludewig, Gabriele; Robertson, Larry W.

    2011-01-01

    Homeostasis of selenium (Se), a critical antioxidant incorporated into amino acids and enzymes, is disrupted by exposure to aryl hydrocarbon receptor (AhR) agonists. Here we examined the importance of dietary Se in preventing the toxicity of the most toxic polychlorinated biphenyl congener, 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126), a potent AhR agonist. Male Sprague-Dawley rats were fed a modified AIN-93 diet with differing dietary Se levels (0.02, 0.2, and 2 ppm). Following 3 weeks of acclimatization, rats from each dietary group were given a single ip injection of corn oil (vehicle), 0.2, 1, or 5 μmol/kg body weight PCB 126, followed 2 weeks later by euthanasia. PCB exposure caused dose-dependent increases in liver weight and at the highest PCB 126 dose decreases in whole body weight gains. Hepatic cytochrome P-450 (CYP1A1) activity was significantly increased even at the lowest dose of PCB 126, indicating potent AhR activation. PCB exposure diminished hepatic Se levels in a dose-dependent manner, and this was accompanied by diminished Se-dependent glutathione peroxidase activity. Both these effects were partially mitigated by Se supplementation. Conversely, thioredoxin (Trx) reductase activity and Trx oxidation state, although significantly diminished in the lowest dietary Se groups, were not affected by PCB exposure. In addition, PCB 126–induced changes in hepatic copper, iron, manganese, and zinc were observed. These results demonstrate that supplemental dietary Se was not able to completely prevent the toxicity caused by PCB 126 but was able to increase moderately the levels of several key antioxidants, thereby maintaining them roughly at normal levels. PMID:21865291

  8. Significance of bacterial flora in abdominal irradiation-induced inhibition of lung metastases

    International Nuclear Information System (INIS)

    Matsumoto, T.; Ando, K.; Koike, S.

    1988-01-01

    We have previously reported that abdominal irradiation prior to i.v. injection of syngeneic tumor cells reduced metastases in lung. Our report described an investigation of the significance of intestinal organisms in the radiation effect. We found that eliminating intestinal organisms with antibiotics totally abolished the radiation effect. Monoassociation of germ-free mice revealed that the radiation effect was observable only for Enterobacter cloacae, never for Streptococcus faecium, Bifidobacterium adlesentis, or Escherichia coli. After abdominal irradiation of regular mice, E. cloacae multiplied in cecal contents, adhered to mucous membranes, invaded the cecal wall, and translocated to mesenteric lymph nodes. Intravenous administration of E. cloacae in place of abdominal irradiation inhibited metastases. E. cloacae-monoassociated mice developed fewer metastases than germ-free mice, and the reduction was further enhanced by abdominal irradiation. We concluded that abdominal irradiation caused the invasion of E. cloacae from the mucous membrane of the intestine and inhibited formation of lung metastases

  9. [The significance of free radicals and antioxidants due to the load induced by sport activity].

    Science.gov (United States)

    Holecek, V; Liska, J; Racek, J; Rokyta, R

    2004-01-01

    Sport performance is followed by a high production of free radicals. The main reasons are reperfusion after the previous imbalance between the increased need of the organism and the ability of blood supply by oxygen, increased production of ATP, decomposition of the cells particularly white blood cells, oxidation of the purin basis from DNA, stress, output of epinephrine release of free iron, increased temperature in the muscle and its inflammation, and the reception of free radicals from external environment. Peroxidation of lipids, proteins, DNA and other compounds follows the previous biochemical steps. Antioxidants are consumed by free radicals, antioxidative enzymes are released into blood plasma, intracellular calcium is increased, the production of nitric oxide rises, the levels of hydrogen peroxide and hypochlorous acid increase. These penetrate through the membranes and oxidatively damage the tissues. Training improves the ability of the organism to balance the increased load of free radicals. The damage can be lowered by the application of a mixture of antioxidants, the most important are vitamin C, A, E, glutathione, selenium, carnosine, eventually bioflavonoids and ginkgo biloba. The lack of antioxidants can significantly diminish the sport performance and therefore the supplementation with antioxidants is for top sportsmen but also for aged people advisable.

  10. Significant clinical improvement in radiation-induced lumbosacral poly-radiculopathy by a treatment combining pentoxifylline, tocopherol, and clodronate (Pentoclo)

    Energy Technology Data Exchange (ETDEWEB)

    Delanian, S. [Hop St Louis, Serv Oncol Radiotherapie, APHP, F-75010 Paris, (France); Lefaix, J.L. [CEA-LARIA, CIRIL-GANIL, Caen, (France); Maisonobe, T. [Hop La Pitie Salpetriere, Federat Neurophysiol Clin, APHP, Paris, (France)

    2008-07-01

    Radiation-induced (RI) peripheral neuropathy is a rare and severe delayed complication of radiotherapy that is spontaneously irreversible, with no standard of treatment. We previously developed a successful antioxidant treatment in RI fibrosis and necrosis. Two patients with progressive worsening RI lumbosacral poly-radiculopathy experienced over several years a significant clinical improvement in their neurological sensorimotor symptoms with long-term pentoxifylline-tocopherol-clodronate treatment, and good safety. (authors)

  11. Immunogenic Cell Death Induced by Ginsenoside Rg3: Significance in Dendritic Cell-based Anti-tumor Immunotherapy.

    Science.gov (United States)

    Son, Keum-Joo; Choi, Ki Ryung; Lee, Seog Jae; Lee, Hyunah

    2016-02-01

    Cancer is one of the leading causes of morbidity and mortality worldwide; therefore there is a need to discover new therapeutic modules with improved efficacy and safety. Immune-(cell) therapy is a promising therapeutic strategy for the treatment of intractable cancers. The effectiveness of certain chemotherapeutics in inducing immunogenic tumor cell death thus promoting cancer eradication has been reported. Ginsenoside Rg3 is a ginseng saponin that has antitumor and immunomodulatory activity. In this study, we treated tumor cells with Rg3 to verify the significance of inducing immunogenic tumor cell death in antitumor therapy, especially in DC-based immunotherapy. Rg3 killed the both immunogenic (B16F10 melanoma cells) and non-immunogenic (LLC: Lewis Lung Carcinoma cells) tumor cells by inducing apoptosis. Surface expression of immunogenic death markers including calreticulin and heat shock proteins and the transcription of relevant genes were increased in the Rg3-dying tumor. Increased calreticulin expression was directly related to the uptake of dying tumor cells by dendritic cells (DCs): the proportion of CRT(+) CD11c(+) cells was increased in the Rg3-treated group. Interestingly, tumor cells dying by immunogenic cell death secreted IFN-γ, an effector molecule for antitumor activity in T cells. Along with the Rg3-induced suppression of pro-angiogenic (TNF-α) and immunosuppressive cytokine (TGF-β) secretion, IFN-γ production from the Rg3-treated tumor cells may also indicate Rg3 as an effective anticancer immunotherapeutic strategy. The data clearly suggests that Rg3-induced immunogenic tumor cell death due its cytotoxic effect and its ability to induce DC function. This indicates that Rg3 may be an effective immunotherapeutic strategy.

  12. Interaction between CYP1A1 polymorphisms and exposure to environmental tobacco smoke in the modulation of lymphocyte bulky DNA adducts and chromosomal aberrations

    Czech Academy of Sciences Publication Activity Database

    Georgiadis, P.; Topinka, Jan; Vlachodimitropoulos, D.; Stoikidou, M.; Gioka, M.; Stephanou, G.; Autrup, H.; Demopoulos, N. A.; Katsouyanni, K.; Šrám, Radim; Kyrtopoulos, S. A.

    2005-01-01

    Roč. 26, č. 1 (2005), s. 93-101 ISSN 0143-3334 Institutional research plan: CEZ:AV0Z50390512 Keywords : DNA adducts * aberrant cells Subject RIV: DI - Air Pollution ; Quality Impact factor: 5.108, year: 2005

  13. CROSS-REACTIVITY OF MONOCLONAL ANTIBODIES AGAINST PEPTIDE 277-294 OF RAINBOW TROUT CYP1A1 WITH HEPATIC CYP1A AMONG FISH. (R823881)

    Science.gov (United States)

    AbstractExposure to a variety of xenobiotics, including polychlorinated biphenyls (PCBs) and polycyclic aromatic hydrocarbons (PAHs), results in the induction of CYP1A and related biological activity. Historically, antibodies against purified CYP1A have been raised...

  14. Characterization of the transgenic CA-AhR mouse - cell specific expression of the CA-AhR using CYP1A1 as a marker

    Energy Technology Data Exchange (ETDEWEB)

    Brunnberg, S.; Lindstam, M.; Andersson, P.; Hanberg, A. [Institute of Environmental Medicine, Stockholm (Sweden); Poellinger, L. [Department of Cell and Molecular Biology, Stockholm (Sweden)

    2004-09-15

    The risk assessments of dioxins and dioxin-like PCBs performed by WHO and EU lead to major concerns. The tolerable daily intake for humans has been assessed to be within the range of human exposures occurring in the general population today. Dioxins are known to adversely impair reproduction and affect development of reproductive organs, as well as the early development of the immune and the nervous systems. The Aryl hydrocarbon Receptor (AhR) mediates most toxic effects of dioxins, such as 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) and PCBs. In order to study the mechanisms of toxicity of ligands of the Ah receptor we have created a transgenic mouse model expressing a constitutively active Ah receptor (CA-AhR). The mutant Ah receptor is expressed and functionally active in most (or all) organs. Consequently, the CA-AhR mice show several of the well-known effects of dioxin exposure. Since the CA-AhR is continuously active at a relatively low level and from early development, this model resembles the human exposure scenario and is thus suitable for studies on mechanisms of action of Ah receptor ligands.

  15. Epoxyeicosatrienoic acid analog attenuates the development of malignant hypertension, but does not reverse it once established: a study in Cyp1a1-Ren-2 transgenic rats

    Czech Academy of Sciences Publication Activity Database

    Jíchová, Š.; Kopkan, L.; Husková, Z.; Doleželová, Š.; Neckář, Jan; Kujal, P.; Vernerová, Z.; Kramer, H. J.; Sadowski, J.; Kompanowska; Jezierska, E.; Reddy, N. R.; Falck, J. R.; Imig, J. D.; Červenka, L.

    2016-01-01

    Roč. 34, č. 10 (2016), s. 2008-2025 ISSN 0263-6352 R&D Projects: GA ČR(CZ) GA15-07544S Institutional support: RVO:67985823 Keywords : epoxyeicosatrienoic acid analog * malignant hypertension * renal blood flow autoregulation * renin-angiotensin system * sodium excretion Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 4.085, year: 2016

  16. Restoration of dioxin-induced damage to fetal steroidogenesis and gonadotropin formation by maternal co-treatment with α-lipoic acid.

    Directory of Open Access Journals (Sweden)

    Takayuki Koga

    Full Text Available 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, an endocrine disruptor, causes reproductive and developmental toxic effects in pups following maternal exposure in a number of animal models. Our previous studies have demonstrated that TCDD imprints sexual immaturity by suppressing the expression of fetal pituitary gonadotropins, the regulators of gonadal steroidogenesis. In the present study, we discovered that all TCDD-produced damage to fetal production of pituitary gonadotropins as well as testicular steroidogenesis can be repaired by co-treating pregnant rats with α-lipoic acid (LA, an obligate co-factor for intermediary metabolism including energy production. While LA also acts as an anti-oxidant, other anti-oxidants; i.e., ascorbic acid, butylated hydroxyanisole and edaravone, failed to exhibit any beneficial effects. Neither wasting syndrome nor CYP1A1 induction in the fetal brain caused through the activation of aryl hydrocarbon receptor (AhR could be attenuated by LA. These lines of evidence suggest that oxidative stress makes only a minor contribution to the TCDD-induced disorder of fetal steroidogenesis, and LA has a restorative effect by targeting on mechanism(s other than AhR activation. Following a metabolomic analysis, it was found that TCDD caused a more marked change in the hypothalamus, a pituitary regulator, than in the pituitary itself. Although the components of the tricarboxylic acid cycle and the ATP content of the fetal hypothalamus were significantly changed by TCDD, all these changes were again rectified by exogenous LA. We also provided evidence that the fetal hypothalamic content of endogenous LA is significantly reduced following maternal exposure to TCDD. Thus, the data obtained strongly suggest that TCDD reduces the expression of fetal pituitary gonadotropins to imprint sexual immaturity or disturb development by suppressing the level of LA, one of the key players serving energy production.

  17. HMGB1 and Histones Play a Significant Role in Inducing Systemic Inflammation and Multiple Organ Dysfunctions in Severe Acute Pancreatitis

    Directory of Open Access Journals (Sweden)

    Runkuan Yang

    2017-01-01

    Full Text Available Severe acute pancreatitis (SAP starts as a local inflammation of pancreatic tissue that induces the development of multiple extrapancreatic organs dysfunction; however, the underlying mechanisms are still not clear. Ischemia-reperfusion, circulating inflammatory cytokines, and possible bile cytokines significantly contribute to gut mucosal injury and intestinal bacterial translocation (BT during SAP. Circulating HMGB1 level is significantly increased in SAP patients and HMGB1 is an important factor that mediates (at least partly gut BT during SAP. Gut BT plays a critical role in triggering/inducing systemic inflammation/sepsis in critical illness, and profound systemic inflammatory response syndrome (SIRS can lead to multiple organ dysfunction syndrome (MODS during SAP, and systemic inflammation with multiorgan dysfunction is the cause of death in experimental SAP. Therefore, HMGB1 is an important factor that links gut BT and systemic inflammation. Furthermore, HMGB1 significantly contributes to multiple organ injuries. The SAP patients also have significantly increased circulating histones and cell-free DNAs levels, which can reflect the disease severity and contribute to multiple organ injuries in SAP. Hepatic Kupffer cells (KCs are the predominant source of circulating inflammatory cytokines in SAP, and new evidence indicates that hepatocyte is another important source of circulating HMGB1 in SAP; therefore, treating the liver injury is important in SAP.

  18. Bioactivation of the citrus flavonoid nobiletin by CYP1 enzymes in MCF7 breast adenocarcinoma cells.

    Science.gov (United States)

    Surichan, Somchaiya; Androutsopoulos, Vasilis P; Sifakis, Stavros; Koutala, Eleni; Tsatsakis, Aristidis; Arroo, Randolph R J; Boarder, Michael R

    2012-09-01

    Recent studies have demonstrated cytochrome P450 CYP1-mediated metabolism and CYP1-enzyme induction by naturally occurring flavonoids in cancer cell line models. The arising metabolites often exhibit higher activity than the parent compound. In the present study we investigated the CYP1-mediated metabolism of the citrus polymethoxyflavone nobiletin by recombinant CYP1 enzymes and MCF7 breast adenocarcinoma cells. Incubation of nobiletin in MCF7 cells produced one main metabolite (NM1) resulting from O-demethylation in either A or B rings of the flavone moiety. Among the three CYP1 isoforms, CYP1A1 exhibited the highest rate of metabolism of nobiletin in recombinant CYP microsomal enzymes. The intracellular CYP1-mediated bioconversion of the flavone was reduced in the presence of the CYP1A1 and CYP1B1-selective inhibitors α-napthoflavone and acacetin. In addition nobiletin induced CYP1 enzyme activity, CYP1A1 protein and CYP1B1 mRNA levels in MCF7 cells at a concentration dependent manner. MTT assays in MCF7 cells further revealed that nobiletin exhibited significantly lower IC50 (44 μM) compared to cells treated with nobiletin and CYP1A1 inhibitor (69 μM). FACS analysis demonstrated cell a cycle block at G1 phase that was attenuated in the presence of CYP1A1 inhibitor. Taken together the data suggests that the dietary flavonoid nobiletin induces its own metabolism and in turn enhances its cytostatic effect in MCF7 breast adenocarcinoma cells, via CYP1A1 and CYP1B1 upregulation. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. Significant Suppression of CT Radiation-Induced DNA Damage in Normal Human Cells by the PrC-210 Radioprotector.

    Science.gov (United States)

    Jermusek, Frank; Benedict, Chelsea; Dreischmeier, Emma; Brand, Michael; Uder, Michael; Jeffery, Justin J; Ranallo, Frank N; Fahl, William E

    2018-05-21

    While computed tomography (CT) is now commonly used and considered to be clinically valuable, significant DNA double-strand breaks (γ-H2AX foci) in white blood cells from adult and pediatric CT patients have been frequently reported. In this study to determine whether γ-H2AX foci and X-ray-induced naked DNA damage are suppressed by administration of the PrC-210 radioprotector, human blood samples were irradiated in a CT scanner at 50-150 mGy with or without PrC-210, and γ-H2AX foci were scored. X-ray-induced naked DNA damage was also studied, and the DNA protective efficacy of PrC-210 was compared against 12 other common "antioxidants." PrC-210 reduced CT radiation-induced γ-H2AX foci in white blood cells to near background ( P 95% DNA damage. A systemic PrC-210 dose known to confer 100% survival in irradiated mice had no discernible effect on micro-CT image signal-to-noise ratio and CT image integrity. PrC-210 suppressed DNA damage to background or near background in each of these assay systems, thus supporting its development as a radioprotector for humans in multiple radiation exposure settings.

  20. Endomembrane Ca2+-AtPases play a significant role in virus-induced adaptation to oxidative stress

    DEFF Research Database (Denmark)

    Shabala, Sergey; Bækgaard, Lone; Shabala, Lana

    2011-01-01

    Although the role of Ca2+ influx channels in oxidative stress signaling and cross-tolerance in plants is well established, little is known about the role of active Ca2+ efflux systems in this process. In our recent paper,17 we reported Potato Virus X (PVX)-induced acquired resistance to oxidative...... in adaptive responses to oxidative stress by removing excessive Ca2+ from the cytosol, and that their functional expression is significantly altered in PVX-inoculated plants. These findings highlight the crucial role of Ca2+ efflux systems in acquired tolerance to oxidative stress and open up prospects...... stress in Nicotiana benthamiana and showed the critical role of plasma membrane Ca2+/H+ exchangers in this process. The current study continues this research. Using biochemical and electrophysiological approaches, we reveal that both endomembrane P2A and P2B Ca2+-ATPases play significant roles...

  1. The microRNA effector RNA-induced silencing complex in hidradenitis suppurativa: a significant dysregulation within active inflammatory lesions.

    Science.gov (United States)

    Hessam, S; Sand, M; Skrygan, M; Bechara, Falk G

    2017-09-01

    Recently, we could show that the expression levels of the key regulators of the microRNA (miRNA) maturation and transport were dysregulated in inflamed hidradenitis suppurativa (HS) tissue (Heyam et al. in Wiley Interdiscip Rev RNA 6:271-289, 2015). The RNA-induced silencing complex (RISC) is the central element of the miRNA pathway and regulates miRNA formation and function. We investigated the expression of the RISC components, namely transactivation-responsive RNA-binding protein-1 (TRBP1), TRBP2, protein activator (PACT) of the interferon-induced protein kinase R, Argonaute RISC Catalytic Component-1 (AGO1) and Component-2 (AGO2), metadherin, and staphylococcal nuclease and Tudor domain-containing-1 (SND1) in inflamed HS tissue compared to healthy and psoriatic controls by real-time reverse transcription polymerase chain reaction. Expression levels of all investigated components were significantly lower in lesional HS skin (n = 18) compared to healthy controls (n = 10). TRBP1, PACT, AGO1, AGO2, and SND1 expression levels were significantly down-regulated in lesional HS skin compared to healthy-appearing perilesional skin (n = 7). TRBP2 and SND1 expression levels were significantly lower in healthy-appearing perilesional skin compared to healthy controls. In lesional HS skin, expression levels of PACT, AGO1, and AGO2 were significantly lower compared to psoriatic skin (n = 10). In summary, our data showed that all investigated components of RISC are dysregulated in the skin of HS patients, providing support for the hypothesis that miRNAs may have a pathological role in the inflammatory pathogenesis of HS.

  2. Prenatal exposure to TCDD triggers significant modulation of microRNA expression profile in the thymus that affects consequent gene expression.

    Directory of Open Access Journals (Sweden)

    Narendra P Singh

    Full Text Available MicroRNAs (miRs are a class of small RNAs that regulate gene expression. There are over 700 miRs encoded in the mouse genome and modulate most of the cellular pathways and functions by controlling gene expression. However, there is not much known about the pathophysiological role of miRs. TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin, an environmental contaminant is well known to induce severe toxicity (acute and chronic with long-term effects. Also, in utero exposure of fetus to TCDD has been shown to cause thymic atrophy and alterations in T cell differentiation. It is also relevant to understand "the fetal basis of adult disease" hypothesis, which proposes that prenatal exposure to certain forms of nutritional and environmental stress can cause increased susceptibility to clinical disorders later in life. In the current study, therefore, we investigated the effects of prenatal exposure to TCDD on miR profile in fetal thymocytes and searched for their possible role in causing thymic atrophy and alterations in the expression of apoptotic genes.miR arrays of fetal thymocytes post exposure to TCDD and vehicle were performed. Of the 608 mouse miRs screened, 78 miRs were altered more than 1.5 fold and 28 miRs were changed more than 2 fold in fetal thymocytes post-TCDD exposure when compared to vehicle controls. We validated the expression of several of the miRs using RT-PCR. Furthermore, several of the miRs that were downregulated contained highly complementary sequence to the 3'-UTR region of AhR, CYP1A1, Fas and FasL. Also, the Ingenuity Pathway Analysis software and database was used to analyze the 78 miRs that exhibited significant expression changes and revealed that as many as 15 pathways may be affected.These studies revealed that TCDD-mediated alterations in miR expression may be involved in the regulation of its toxicity including cancer, hepatic injury, apoptosis, and cellular development.

  3. Significance of dipyridamole-induced transient dilation of the left ventricle during thallium-201 scintigraphy in suspected coronary artery disease

    International Nuclear Information System (INIS)

    Chouraqui, P.; Rodrigues, E.A.; Berman, D.S.; Maddahi, J.

    1990-01-01

    The occurrence and significance of transient dilation of the left ventricle during dipyridamole stress-redistribution thallium-201 scintigraphy was studied in 73 patients who underwent both dipyridamole thallium-201 study and coronary angiography. Transient dilation ratio was calculated from planar anterior images by dividing the computer-derived left ventricular area on the initial image by that of the 4-hour image. In 11 patients with normal coronary arteriograms or less than 50% coronary stenosis, the transient dilation ratio was 0.98 +/- 0.046. An abnormal transient dilation ratio was defined as greater than or equal to 1.12, representing greater than or equal to 3 standard deviations above the mean normal value. When the 15 patients with an abnormal ratio were compared with the 58 with a normal ratio, the former group had a significantly higher frequency of 3 critical (greater than or equal to 90%) coronary stenoses (33 vs 5%), higher prevalence of collaterals (67 vs 24%), more extensive myocardial reversible defects by planar (71 vs 10%) or by single-photon emission computed tomography (87.5 vs 35%) imaging and a higher incidence of dipyridamole-induced anginal chest pain (53 vs 22%). No significant difference between the 2 groups was noted with respect to age, gender, prior myocardial infarction, single or double critical coronary stenosis, dipyridamole-induced ischemic electrocardiographic response and increased lung uptake. An abnormal transient dilation ratio of greater than or equal to 1.12 was a specific marker of multivessel (87%) or 3-vessel (85%) critical coronary artery disease

  4. Clinical significance of changes of plasma ET, NO, THcy and cystatin C levels in patients with pregnancy induced hypertension (PIH)

    International Nuclear Information System (INIS)

    Yu Qiuyue

    2009-01-01

    Objective: To investigate the relationship between development of illness and changes of plasma endothelin (ET) nitric oxide (NO), total homocysteine (THcy) and Cystatin C (Cyst C) levels in patients with pregnancy induced Hypertension. Methods: Plasma levels of ET, THcy (with RIA), NO (with chemical Greiss method) and Cyst C (with particle enhanced) immunoneph-elometric assay (PETIA) in 32 patients with PIH, 35 non-pregnant women and 35 normal pregnant women. Results: The plasma ET, NO levels were significantly higher in 35 normal pregnant women than those in the healthy non-pregnantwomen (all P 0.05). Plasma ET levels and THcy, Cyst C levels were mutually positivety correlated (r=0.6097, 0.7213, all P<0.01), while the plasma ET levels and NO levels were negatively correlated (r=0.5812, P<0.01). Conclusion: Determination of changes of plasma ET, NO, THcy and Cyst C levels in patients with Pregnancy induced Hypertension were helpful for disease mechanism elucidation and outcome prediction. (authors)

  5. Hypoxis hemerocallidea Significantly Reduced Hyperglycaemia and Hyperglycaemic-Induced Oxidative Stress in the Liver and Kidney Tissues of Streptozotocin-Induced Diabetic Male Wistar Rats

    Directory of Open Access Journals (Sweden)

    Oluwafemi O. Oguntibeju

    2016-01-01

    Full Text Available Background. Hypoxis hemerocallidea is a native plant that grows in the Southern African regions and is well known for its beneficial medicinal effects in the treatment of diabetes, cancer, and high blood pressure. Aim. This study evaluated the effects of Hypoxis hemerocallidea on oxidative stress biomarkers, hepatic injury, and other selected biomarkers in the liver and kidneys of healthy nondiabetic and streptozotocin- (STZ- induced diabetic male Wistar rats. Materials and Methods. Rats were injected intraperitoneally with 50 mg/kg of STZ to induce diabetes. The plant extract-Hypoxis hemerocallidea (200 mg/kg or 800 mg/kg aqueous solution was administered (daily orally for 6 weeks. Antioxidant activities were analysed using a Multiskan Spectrum plate reader while other serum biomarkers were measured using the RANDOX chemistry analyser. Results. Both dosages (200 mg/kg and 800 mg/kg of Hypoxis hemerocallidea significantly reduced the blood glucose levels in STZ-induced diabetic groups. Activities of liver enzymes were increased in the diabetic control and in the diabetic group treated with 800 mg/kg, whereas the 200 mg/kg dosage ameliorated hepatic injury. In the hepatic tissue, the oxygen radical absorbance capacity (ORAC, ferric reducing antioxidant power (FRAP, catalase, and total glutathione were reduced in the diabetic control group. However treatment with both doses improved the antioxidant status. The FRAP and the catalase activities in the kidney were elevated in the STZ-induced diabetic group treated with 800 mg/kg of the extract possibly due to compensatory responses. Conclusion. Hypoxis hemerocallidea demonstrated antihyperglycemic and antioxidant effects especially in the liver tissue.

  6. Omeprazole induces NAD(P)H quinone oxidoreductase 1 via aryl hydrocarbon receptor-independent mechanisms: Role of the transcription factor nuclear factor erythroid 2–related factor 2

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Shaojie; Patel, Ananddeep; Moorthy, Bhagavatula; Shivanna, Binoy, E-mail: shivanna@bcm.edu

    2015-11-13

    Activation of the aryl hydrocarbon receptor (AhR) transcriptionally induces phase I (cytochrome P450 (CYP) 1A1) and phase II (NAD(P)H quinone oxidoreductase 1 (NQO1) detoxifying enzymes. The effects of the classical and nonclassical AhR ligands on phase I and II enzymes are well studied in human hepatocytes. Additionally, we observed that the proton pump inhibitor, omeprazole (OM), transcriptionally induces CYP1A1 in the human adenocarcinoma cell line, H441 cells via AhR. Whether OM activates AhR and induces the phase II enzyme, NAD(P)H quinone oxidoreductase 1 (NQO1), in fetal primary human pulmonary microvascular endothelial cells (HPMEC) is unknown. Therefore, we tested the hypothesis that OM will induce NQO1 in HPMEC via the AhR. The concentrations of OM used in our experiments did not result in cytotoxicity. OM activated AhR as evident by increased CYP1A1 mRNA expression. However, contrary to our hypothesis, OM increased NQO1 mRNA and protein via an AhR-independent mechanism as AhR knockdown failed to abrogate OM-mediated increase in NQO1 expression. Interestingly, OM activated Nrf2 as evident by increased phosphoNrf2 (S40) expression in OM-treated compared to vehicle-treated cells. Furthermore, Nrf2 knockdown abrogated OM-mediated increase in NQO1 expression. In conclusion, we provide evidence that OM induces NQO1 via AhR-independent, but Nrf2-dependent mechanisms. - Highlights: • We investigated whether omeprazole induces NQO1 in human fetal lung cells. • Omeprazole induces the phase II enzyme, NQO1, in human fetal lung cells. • AhR deficiency fails to abrogate omeprazole-mediated induction of NQO1. • Omeprazole increases phosphoNrf2 (S40) protein expression in human fetal lung cells. • Nrf2 knockdown abrogates the induction of NQO1 by omeprazole in human lung cells.

  7. Menadione Suppresses Benzo(αpyrene-Induced Activation of Cytochromes P450 1A: Insights into a Possible Molecular Mechanism.

    Directory of Open Access Journals (Sweden)

    Yulia A Sidorova

    Full Text Available Oxidative reactions that are catalyzed by cytochromes P450 1A (CYP1A lead to formation of carcinogenic derivatives of arylamines and polycyclic aromatic hydrocarbons (PAHs, such as the widespread environmental pollutant benzo(αpyrene (BP. These compounds upregulate CYP1A at the transcriptional level via an arylhydrocarbon receptor (AhR-dependent signaling pathway. Because of the involvement of AhR-dependent genes in chemically induced carcinogenesis, suppression of this signaling pathway could prevent tumor formation and/or progression. Here we show that menadione (a water-soluble analog of vitamin K3 inhibits BP-induced expression and enzymatic activity of both CYP1A1 and CYP1A2 in vivo (in the rat liver and BP-induced activity of CYP1A1 in vitro. Coadministration of BP and menadione reduced DNA-binding activity of AhR and increased DNA-binding activity of transcription factors Oct-1 and CCAAT/enhancer binding protein (C/EBP, which are known to be involved in negative regulation of AhR-dependent genes, in vivo. Expression of another factor involved in downregulation of CYP1A-pAhR repressor (AhRR-was lower in the liver of the rats treated with BP and menadione, indicating that the inhibitory effect of menadione on CYP1A is not mediated by this protein. Furthermore, menadione was well tolerated by the animals: no signs of acute toxicity were detected by visual examination or by assessment of weight gain dynamics or liver function. Taken together, our results suggest that menadione can be used in further studies on animal models of chemically induced carcinogenesis because menadione may suppress tumor formation and possibly progression.

  8. Menadione Suppresses Benzo(α)pyrene-Induced Activation of Cytochromes P450 1A: Insights into a Possible Molecular Mechanism.

    Science.gov (United States)

    Sidorova, Yulia A; Perepechaeva, Maria L; Pivovarova, Elena N; Markel, Arkady L; Lyakhovich, Vyacheslav V; Grishanova, Alevtina Y

    2016-01-01

    Oxidative reactions that are catalyzed by cytochromes P450 1A (CYP1A) lead to formation of carcinogenic derivatives of arylamines and polycyclic aromatic hydrocarbons (PAHs), such as the widespread environmental pollutant benzo(α)pyrene (BP). These compounds upregulate CYP1A at the transcriptional level via an arylhydrocarbon receptor (AhR)-dependent signaling pathway. Because of the involvement of AhR-dependent genes in chemically induced carcinogenesis, suppression of this signaling pathway could prevent tumor formation and/or progression. Here we show that menadione (a water-soluble analog of vitamin K3) inhibits BP-induced expression and enzymatic activity of both CYP1A1 and CYP1A2 in vivo (in the rat liver) and BP-induced activity of CYP1A1 in vitro. Coadministration of BP and menadione reduced DNA-binding activity of AhR and increased DNA-binding activity of transcription factors Oct-1 and CCAAT/enhancer binding protein (C/EBP), which are known to be involved in negative regulation of AhR-dependent genes, in vivo. Expression of another factor involved in downregulation of CYP1A-pAhR repressor (AhRR)-was lower in the liver of the rats treated with BP and menadione, indicating that the inhibitory effect of menadione on CYP1A is not mediated by this protein. Furthermore, menadione was well tolerated by the animals: no signs of acute toxicity were detected by visual examination or by assessment of weight gain dynamics or liver function. Taken together, our results suggest that menadione can be used in further studies on animal models of chemically induced carcinogenesis because menadione may suppress tumor formation and possibly progression.

  9. Protective effect of tea polyphenols against paracetamol-induced hepatotoxicity in mice is significantly correlated with cytochrome P450 suppression.

    Science.gov (United States)

    Chen, Xia; Sun, Chang-Kai; Han, Guo-Zhu; Peng, Jin-Yong; Li, Ying; Liu, Yan-Xia; Lv, Yuan-Yuan; Liu, Ke-Xin; Zhou, Qin; Sun, Hui-Jun

    2009-04-21

    To investigate the hepatoprotective activity of tea polyphenols (TP) and its relation with cytochrome P450 (CYP450) expression in mice. Hepatic CYP450 and CYPb(5) levels were measured by UV-spectrophotometry in mice 2 d after intraperitoneal TP (25, 50 and 100 mg/kg per day). Then the mice were intragastricly pre-treated with TP (100, 200 and 400 mg/kg per day) for six days before paracetamol (1000 mg/kg) was given. Their acute mortality was compared with that of control mice. The mice were pre-treated with TP (100, 200, and 400 mg/kg per day) for five days before paracetamol (500 mg/kg) was given. Hepatic CYP2E1 and CYP1A2 protein and mRNA expression levels were evaluated by Western blotting, immunohistochemical staining and transcriptase-polymerase chain reaction. The hepatic CYP450 and CYPb(5) levels in mice of TP-treated groups (100, 200 and 400 mg/kg per day) were decreased in a dose-dependent manner compared with those in the negative control mice. TP significantly attenuated the paracetamol-induced hepatic injury and dramatically reduced the mortality of paracetamol-treated mice. Furthermore, TP reduced CYP2E1 and CYP1A2 expression at both protein and mRNA levels in a dose-dependent manner. TP possess potential hepatoprotective properties and can suppress CYP450 expression.

  10. High-intensity interval training (swimming) significantly improves the adverse metabolism and comorbidities in diet-induced obese mice.

    Science.gov (United States)

    Motta, Victor F; Aguila, Marcia B; Mandarim-DE-Lacerda, Carlos A

    2016-05-01

    Controlling obesity and other comorbidities in the population is a challenge in modern society. High-intensity interval training (HIIT) combines short periods of high-intensity exercise with long recovery periods or a low-intensity exercise. The aim was to assess the impact of HIIT in the context of diet-induced obesity in the animal model. C57BL/6 mice were fed one of the two diets: standard chow (lean group [LE]) or a high-fat diet (obese group [OB]). After twelve weeks, the animals were divided into non-trained groups (LE-NT and OB-NT) and trained groups (LE-T and OB-T), and began an exercise protocol. For biochemical analysis of inflammatory and lipid profile, we used a colorimetric enzymatic method and an automatic spectrophotometer. One-way ANOVA was used for statistical analysis of the experimental groups with Holm-Sidak post-hoc Test. Two-way ANOVA analyzed the interactions between diet and HIIT protocol. HIIT leads to significant reductions in body mass, blood glucose, glucose tolerance and hepatic lipid profile in T-groups compared to NT-groups. HIIT was able to reduce plasma levels of inflammatory cytokines. Additionally, HIIT improves the insulin immunodensity in the islets, reduces the adiposity and the hepatic steatosis in the T-groups. HIIT improves beta-oxidation and peroxisome proliferator-activated receptor (PPAR)-alpha and reduces lipogenesis and PPAR-gamma levels in the liver. In skeletal muscle, HIIT improves PPAR-alpha and glucose transporter-4 and reduces PPAR-gamma levels. HIIT leads to attenuate the adverse effects caused by a chronic ingestion of a high-fat diet.

  11. Expression of LIGHT/TNFSF14 Combined with Vaccination against Human Papillomavirus Type 16 E7 Induces Significant Tumor Regression

    Science.gov (United States)

    Kanodia, Shreya; Da Silva, Diane M.; Karamanukyan, Tigran; Bogaert, Lies; Fu, Yang-Xin; Kast, W. Martin

    2010-01-01

    LIGHT, a ligand for the lymphotoxin-beta receptor, establishes lymphoid-like tissues inside tumor sites and recruits naïve T-cells into the tumor. However, whether these infiltrating T-cells are specific for tumor antigens is not known. We hypothesized that therapy with LIGHT can expand functional tumor-specific CD8+ T-cells that can be boosted using HPV16E6E7-Venezuelan Equine Encephalitis Virus Replicon Particles (HPV16-VRP) and that this combined therapy can eradicate HPV16-induced tumors. Our data show that forced expression of LIGHT in tumors results in an increase in expression of interferon gamma (IFNg) and chemottractant cytokines such as IL-1a, MIG and MIP-2 within the tumor and that this tumor microenvironment correlates with an increase in frequency of tumor-infiltrating CD8+ T-cells. Forced expression of LIGHT also results in the expansion of functional T-cells that recognize multiple tumor-antigens, including HPV16 E7, and these T-cells prevent the outgrowth of tumors upon secondary challenge. Subsequent boosting of E7-specific T-cells by vaccination with HPV16-VRP significantly increases their frequency in both the periphery and the tumor, and leads to the eradication of large well-established tumors, for which either treatment alone is not successful. These data establish the safety of Ad-LIGHT as a therapeutic intervention in pre-clinical studies and suggest that patients with HPV16+ tumors may benefit from combined immunotherapy with LIGHT and antigen-specific vaccination. PMID:20460520

  12. Functional Analysis of Promoter Region from Eel Cytochrome P450 1A1 Gene in Transgenic Medaka.

    Science.gov (United States)

    Ogino; Itakura; Kato; Aoki; Sato

    1999-07-01

    : Transcription of the CYP1A1 genes in mammals and fish is stimulated by polyaromatic hydrocarbons. DNA sequencing analysis revealed that CYP1A1 gene in eel (Anguilla japonica) contains two kinds of putative cis-acting regulatory elements, XRE (xenobiotic-responsive element) and ERE (estrogen-responsive element). XRE is known as the enhancer that is responsible for the inducibility of the genes of CYP1A1 and some other drug-metabolizing enzymes. In the eel CYP1A1 gene, XRE motifs are distributed as follows: five times in the region from -2136 to -1125 bp, XRE(-6) to (-2); once in the proximal basal promoter region, XRE(-1); and once in the first intron, XRE(+1). The region between XRE(-2) and XRE(-1) contains three ERE motifs. To investigate the function of the cis-acting regulatory elements in the eel CYP1A1 gene, recombinant plasmids prepared with its 5' upstream sequence and the structural gene for luciferase were microinjected into fertilized eggs of medaka at the one-cell stage. Hatched fry were treated with 3-methylcholanthrene, and the transcription efficiency was assayed using competitive polymerase chain reaction analysis. Deletion of the region containing the five XREs, XRE(-6) to XRE(-2), and the point mutation of XRE(-1) reduced the inducible expressions by 75% and 56%, respectively, showing apparent dependency of the drug induction on the XREs. Constitutive expression, however, was not significantly affected by deletion or disruption of the XREs. When the region between XRE(-2) and XRE(-1) containing no XREs but three ERE motifs was internally deleted, the inducible expression and the constitutive expression were reduced by 88% and 75%, respectively. Replacement of this region with a partial fragment of eel CYP1A1 complementary DNA, with slight alteration of the distance between the five XREs and XRE(-1), reduced the inducible expression and the constitutive expression by 91% and 60%, respectively. These results strongly suggest that not only XRE but

  13. Memory accessibility and medical decision-making for significant others: The role of socially-shared retrieval induced forgetting

    Directory of Open Access Journals (Sweden)

    Dora M Coman

    2013-06-01

    Full Text Available Medical decisions will often entail a broad search for relevant information. No sources alone may offer a complete picture, and many may be selective in their presentation. This selectivity may induce forgetting for previously learned material, thereby adversely affecting medical decision-making. In the study phase of two experiments, participants learned information about a fictitious disease and advantages and disadvantages of four treatment options. In the subsequent practice phase, they read a pamphlet selectively presenting either relevant (Experiment 1 or irrelevant (Experiment 2 advantages or disadvantages. A final cued recall followed and, in Experiment 2, a decision as to the best treatment for a patient. Not only did reading the pamphlet induce forgetting for related and unmentioned information, the induced forgetting adversely affected decision-making. The research provides a cautionary note about the risks of searching through selectively presented information when making a medical decision.

  14. Functional significance of metastasis-inducing S100A4(Mts1) in tumor-stroma interplay

    DEFF Research Database (Denmark)

    Schmidt-Hansen, Birgitte; Klingelhöfer, Jörg; Grum-Schwensen, Birgitte

    2004-01-01

    Causal implication of S100A4 in inducing metastases was convincingly shown previously. However, the mechanisms that associate S100A4 with tumor progression are not well understood. S100A4 protein, as a typical member of the S100 family, exhibits dual, intracellular and extracellular, functions. T...

  15. Significance of aerophytotherapy in complex sanatorial-climatic treatment of patients with pneumoconiosis and dust-induced bronchitis

    Energy Technology Data Exchange (ETDEWEB)

    Ostapchuk, I.F.; Dubrovina, R.M.; Akimov, Yu.A.; Kalinina, T.F.; Protsko, G.V.; Kudzi, Eh.K.; Soboleva, O.S.

    1986-09-01

    Investigation is conducted to examine effectiveness of sanatorial-climatic treatment of patients with pneumoconiosis and dust-induced bronchitis while including aerophytotherapy. Patients with both lung diseases received sanatorial, gymnastic and climatic procedures. Experimental group also received aerophytotherapy - inhalation of ester oils of lavender, anise, mint, and salvia in form of spray corresponding to their molecular composition in air. Control group did not receive aerophytotherapy. Tables present results of experiment showing changes in parameters of external breathing in patients with pneumoconiosis and in patients with dust-induced bronchitis. Tables show greater improvement in characteristics of external breathing of patients treated with inclusion of aerophytotherapy and confirm effectiveness of combined sanatorial-climatic treatment with aerophytotherapy. Patients with chronic bronchitis also experienced reduction of bronchospasm and improvement in bronchial passability. Method does not require special equipment and is economical. 9 refs.

  16. Memory accessibility and medical decision-making for significant others: The role of socially-shared retrieval induced forgetting

    OpenAIRE

    Dora M Coman; Alin eComan; William eHirst

    2013-01-01

    Medical decisions will often entail a broad search for relevant information. No sources alone may offer a complete picture, and many may be selective in their presentation. This selectivity may induce forgetting for previously learned material, thereby adversely affecting medical decision-making. In the study phase of two experiments, participants learned information about a fictitious disease and advantages and disadvantages of four treatment options. In the subsequent practice phase, the...

  17. Significant efficiency enhancement in thin film solar cells using laser beam-induced graphene transparent conductive electrodes

    OpenAIRE

    Thekkekara, L. V.; Cai, Bouyan

    2018-01-01

    Thin film solar cells have been attractive for decades in advanced green technology platforms due to its possibilities to be integrated with buildings and on-chip applications. However, the bottleneck issues involved to consider the current solar cells as a major electricity source includes the lower efficiencies and cost-effectiveness. We numerically demonstrate the concept of the absorption enhancement in thin-film amorphous silicon solar cells using the laser beam-induced graphene material...

  18. Landolphia owariensis Attenuates Alcohol-induced Cerebellar Neurodegeneration: Significance of Neurofilament Protein Alteration in the Purkinje Cells

    Directory of Open Access Journals (Sweden)

    Oyinbo Charles A.

    2016-12-01

    Full Text Available Background: Alcohol-induced cerebellar neurodegeneration is a neuroadaptation that is associated with chronic alcohol abuse. Conventional drugs have been largely unsatisfactory in preventing neurodegeneration. Yet, multimodal neuro-protective therapeutic agents have been hypothesised to have high therapeutic potential for the treatment of CNS conditions; there is yet a dilemma of how this would be achieved. Contrarily, medicinal botanicals are naturally multimodal in their mechanism of action.

  19. Clinical significance of determination of the changes of plasma vasoactive substances ET, NO, CGRP levels in patients with pregnancy induced hypertension

    International Nuclear Information System (INIS)

    Zhang Danhui

    2006-01-01

    Objective: To investigate the clinical significance of changes of plasma ET, CGRP and NO levels in patients with pregnancy induced hypertension. Methods: Plasma levels of ET, CGRP (with RIA) and NO (with colorimetry) were measured in 36 patients with pregnancy induced hypertension 30 women with normal pregnancy and 32 controls. Results: Plasma levels of ET, CGRP and NO in normal pregnant women were not significantly different from those in controls (P>0.05) and plasma levels of ET, CGRP and NO in patients with mild pregnancy induced hypertension (n=12) were not significantly different flora those in normal pregnant women (P>0.05), However, plasma levels of ET in patients with moderate (n=14) and severe (n=10) pregnancy induced hypertension were significantly higher than those in normal pregant women, while levels of CGRP and NO were significantly lower (all P< 0.01). Conclusion: Detection of changes of plasma ET, CGRP and NO contents in patients with pregnancy induced hypertension provides a valuable laboratory basis for study of relationship between endothelial cell function and pathogenesis of hypertension. (authors)

  20. Mechanisms and significance of brain glucose signaling in energy balance, glucose homeostasis, and food-induced reward.

    Science.gov (United States)

    Devarakonda, Kavya; Mobbs, Charles V

    2016-12-15

    The concept that hypothalamic glucose signaling plays an important role in regulating energy balance, e.g., as instantiated in the so-called "glucostat" hypothesis, is one of the oldest in the field of metabolism. However the mechanisms by which neurons in the hypothalamus sense glucose, and the function of glucose signaling in the brain, has been difficult to establish. Nevertheless recent studies probing mechanisms of glucose signaling have also strongly supported a role for glucose signaling in regulating energy balance, glucose homeostasis, and food-induced reward. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  1. Clinical significance of exercise-induced left ventricular wall motion abnormality occurring at a low heart rate

    International Nuclear Information System (INIS)

    Kimchi, A.; Rozanski, A.; Fletcher, C.; Maddahi, J.; Swan, H.J.; Berman, D.S.

    1987-01-01

    We studied the relationship between the heart rate at the time of onset of exercise-induced wall motion abnormality and the severity of coronary artery disease in 89 patients who underwent exercise equilibrium radionuclide ventriculography as part of their evaluation for coronary artery disease. Segmental wall motion was scored with a five-point system (3 = normal; -1 = dyskinesis); a decrease of one score defined the onset of wall motion abnormality. The onset of wall motion abnormality at less than or equal to 70% of maximal predicted heart rate had 100% predictive accuracy for coronary artery disease and higher sensitivity than the onset of ischemic ST segment depression at similar heart rate during exercise: 36% (25 of 69 patients with coronary disease) vs 19% (13 of 69 patients), p = 0.01. Wall motion abnormality occurring at less than or equal to 70% of maximal predicted heart rate was present in 49% of patients (23 of 47) with critical stenosis (greater than or equal to 90% luminal diameter narrowing), and in only 5% of patients (2 of 42) without such severe stenosis, p less than 0.001. The sensitivity of exercise-induced wall motion abnormality occurring at a low heart rate for the presence of severe coronary artery disease was similar to that of a deterioration in wall motion by more than two scores during exercise (49% vs 53%) or an absolute decrease of greater than or equal to 5% in exercise left ventricular ejection fraction (49% vs 45%)

  2. A Significant Role of the Truncated Ghrelin Receptor GHS-R1b in Ghrelin-induced Signaling in Neurons.

    Science.gov (United States)

    Navarro, Gemma; Aguinaga, David; Angelats, Edgar; Medrano, Mireia; Moreno, Estefanía; Mallol, Josefa; Cortés, Antonio; Canela, Enric I; Casadó, Vicent; McCormick, Peter J; Lluís, Carme; Ferré, Sergi

    2016-06-17

    The truncated non-signaling ghrelin receptor growth hormone secretagogue R1b (GHS-R1b) has been suggested to simply exert a dominant negative role in the trafficking and signaling of the full and functional ghrelin receptor GHS-R1a. Here we reveal a more complex modulatory role of GHS-R1b. Differential co-expression of GHS-R1a and GHS-R1b, both in HEK-293T cells and in striatal and hippocampal neurons in culture, demonstrates that GHS-R1b acts as a dual modulator of GHS-R1a function: low relative GHS-R1b expression potentiates and high relative GHS-R1b expression inhibits GHS-R1a function by facilitating GHS-R1a trafficking to the plasma membrane and by exerting a negative allosteric effect on GHS-R1a signaling, respectively. We found a preferential Gi/o coupling of the GHS-R1a-GHS-R1b complex in HEK-293T cells and, unexpectedly, a preferential Gs/olf coupling in both striatal and hippocampal neurons in culture. A dopamine D1 receptor (D1R) antagonist blocked ghrelin-induced cAMP accumulation in striatal but not hippocampal neurons, indicating the involvement of D1R in the striatal GHS-R1a-Gs/olf coupling. Experiments in HEK-293T cells demonstrated that D1R co-expression promotes a switch in GHS-R1a-G protein coupling from Gi/o to Gs/olf, but only upon co-expression of GHS-R1b. Furthermore, resonance energy transfer experiments showed that D1R interacts with GHS-R1a, but only in the presence of GHS-R1b. Therefore, GHS-R1b not only determines the efficacy of ghrelin-induced GHS-R1a-mediated signaling but also determines the ability of GHS-R1a to form oligomeric complexes with other receptors, promoting profound qualitative changes in ghrelin-induced signaling. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. A Significant Role of the Truncated Ghrelin Receptor GHS-R1b in Ghrelin-induced Signaling in Neurons*

    Science.gov (United States)

    Navarro, Gemma; Aguinaga, David; Angelats, Edgar; Medrano, Mireia; Moreno, Estefanía; Mallol, Josefa; Cortés, Antonio; Canela, Enric I.; Casadó, Vicent; McCormick, Peter J.; Lluís, Carme; Ferré, Sergi

    2016-01-01

    The truncated non-signaling ghrelin receptor growth hormone secretagogue R1b (GHS-R1b) has been suggested to simply exert a dominant negative role in the trafficking and signaling of the full and functional ghrelin receptor GHS-R1a. Here we reveal a more complex modulatory role of GHS-R1b. Differential co-expression of GHS-R1a and GHS-R1b, both in HEK-293T cells and in striatal and hippocampal neurons in culture, demonstrates that GHS-R1b acts as a dual modulator of GHS-R1a function: low relative GHS-R1b expression potentiates and high relative GHS-R1b expression inhibits GHS-R1a function by facilitating GHS-R1a trafficking to the plasma membrane and by exerting a negative allosteric effect on GHS-R1a signaling, respectively. We found a preferential Gi/o coupling of the GHS-R1a-GHS-R1b complex in HEK-293T cells and, unexpectedly, a preferential Gs/olf coupling in both striatal and hippocampal neurons in culture. A dopamine D1 receptor (D1R) antagonist blocked ghrelin-induced cAMP accumulation in striatal but not hippocampal neurons, indicating the involvement of D1R in the striatal GHS-R1a-Gs/olf coupling. Experiments in HEK-293T cells demonstrated that D1R co-expression promotes a switch in GHS-R1a-G protein coupling from Gi/o to Gs/olf, but only upon co-expression of GHS-R1b. Furthermore, resonance energy transfer experiments showed that D1R interacts with GHS-R1a, but only in the presence of GHS-R1b. Therefore, GHS-R1b not only determines the efficacy of ghrelin-induced GHS-R1a-mediated signaling but also determines the ability of GHS-R1a to form oligomeric complexes with other receptors, promoting profound qualitative changes in ghrelin-induced signaling. PMID:27129257

  4. Significant Traumatic Intracranial Hemorrhage in the Setting of Massive Bee Venom-Induced Coagulopathy: A Case Report.

    Science.gov (United States)

    Stack, Kelsey; Pryor, Lindsey

    2016-09-01

    Bees and wasps of the Hymenoptera order are encountered on a daily basis throughout the world. Some encounters prove harmless, while others can have significant morbidity and mortality. Hymenoptera venom is thought to contain an enzyme that can cleave phospholipids and cause significant coagulation abnormalities. This toxin and others can lead to reactions ranging from local inflammation to anaphylaxis. We report a single case of a previously healthy man who presented to the emergency department with altered mental status and anaphylaxis after a massive honeybee envenomation that caused a fall from standing resulting in significant head injury. He was found to have significant coagulopathy and subdural bleeding that progressed to near brain herniation requiring emergent decompression. Trauma can easily occur to individuals escaping swarms of hymenoptera. Closer attention must be paid to potential bleeding sources in these patients and in patients with massive bee envenomation. Copyright © 2016 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.

  5. Significance of the Melanocortin 1 and Endothelin B Receptors in Melanocyte Homeostasis and Prevention of Sun-Induced Genotoxicity

    Directory of Open Access Journals (Sweden)

    Zalfa A. Abdel-Malek

    2016-08-01

    Full Text Available The membrane bound melanocortin 1 receptor (MC1R, and the endothelin B receptor (ENDBR are two G-protein coupled receptors that play important roles in constitutive regulation of melanocytes and their response to ultraviolet radiation (UVR, the main etiological factor for melanoma. The human MC1R is a Gs protein-coupled receptor, which is activated by its agonists α-melanocyte stimulating hormone (α-melanocortin; α-MSH and adrenocorticotropic hormone (ACTH. The ENDBR is a Gq coupled-receptor, which is activated by Endothelin (ET-3 during embryonic development, and ET-1 postnatally. Pigmentation and the DNA repair capacity are two major factors that determine the risk for melanoma. Activation of the MC1R by its agonists stimulates the synthesis of eumelanin, the dark brown photoprotective pigment. In vitro studies showed that α-MSH and ET-1 interact synergistically in the presence of basic fibroblast growth factor (bFGF to stimulate human melanocyte proliferation and melanogenesis, and to inhibit UVR-induced apoptosis. An important function of the MC1R is reduction of oxidative stress and activation of DNA repair pathways. The human MC1R is highly polymorphic, and MC1R variants, particularly those that cause loss of function of the expressed receptor, are associated with increased melanoma risk independently of pigmentation. These variants compromise the DNA repair and antioxidant capacities of human melanocytes. Recently, activation of ENDBR by ET-1 was reported to reduce the induction and enhance the repair of UVR-induced DNA photoproducts. We conclude that α-MSH and ET-1 and their cognate receptors MC1R and ENDBR reduce the risk for melanoma by maintaining genomic stability of melanocytes via modulating the DNA damage response to solar UVR. Elucidating the response of melanocytes to UVR should improve our understanding of the process of melanomagenesis, and lead to effective melanoma chemoprevention, as well as therapeutic strategies.

  6. Herbal tea extract combined with light-induced significant in vitro cytotoxicity of human bladder cancer cells

    Science.gov (United States)

    Nseyo, Unyime; Kim, Albert; Stavropoulos, Nicholas E.; Skalkos, Dimitris; Nseyo, U. U.; Chung, Theodore D.

    2005-04-01

    The anti-inflammatory, anti-microbial, antiviral, and antidepressant activities of the Greek herb, Hypericum Perforatum L, HP L, have been attributed to the total extract or single constituents. We investigated the use of the extract,specifically of the polar methanolic fraction (PMF) of Epirus"HPL in photodynamic therapy (PDT) alone and in combination with recombinant Interferon-a2b (IFN) and gemcitabine (GCB) in the treatment of human bladder cancer cells. The PMF was extracted from the dry herb with methanol, followed by liquid-liquid extraction with petroleum ether. T-24 bladder cancer cells were plated (105 cells/well) and placed in the incubator (370 C, 5%CO) for 24 hours prior to addition of drugs. PMF 60ug/ml was added and incubation continued. After 24 hours, the cells were subjected to laser light (630nm) treatment with 0, 1, 4 and 8 Joules. After reincubation for 24 hours, IFN, (50,000 IU) or GCB, (2ug/ml) was added to the PDT-treated cells. After this incubation cell survival was assessed by the MTT assay. PMF-PDT alone-induced percent cell kill of 0%, 8%, 44% and 80% versus 31%, 64 and 86 % for PMF-PDT and IFN, versus 63%, 80% and 88% for MPF-PDT plus GCB at 1, 2, 4 and 8 Joules respectively. IFN and GCB induced 20% and 53% cell kill respectively. Our data suggest that MPF may be an effective agent for in vitro photodynamic therapy. PMF-PDT combined with Intron A, or gemcitabine achieved improved kill of cultured bladder cancer cells. Confirmation of these results in preclinical studies may lead to clinical trials.

  7. Clinical significance of measurement of changes of serum TNF-α, IL-6 and IL-8 centent after treatment in patients with pregnancy induced hypertension (PIH)

    International Nuclear Information System (INIS)

    Wang Guiying

    2008-01-01

    Objective: To explore the clinical significance of changes of serum TNF-α, IL-6 and IL-8 levels in patients with pregnancy induced hypertension. Methods: Serum TNF-α, IL-6 and IL-8 levels were measured with RIA in 36 patients with pregnancy induced hypertension both before and after 2 weeks of treatment as well as in 35 controls. Results: Before treatment, the serum TNF-α, IL-6 and IL-8 levels were significantly higher in patients with PIH than those in the controls (P 0.05). Conclusion: The inflammatory cytokines such as TNF-α, IL-6 and IL-8 may play important roles in the pathogenesis of pregnancy induced hypertension. (authors)

  8. Significance of local cerebral glucose utilization determined by the autoradiographic (/sup 14/C)deoxyglucose method in experimentally induced coma

    Energy Technology Data Exchange (ETDEWEB)

    Sakurada, O.; Kobayashi, M.; Ueno, H.; Ishii, S. (Juntendo Univ., Tokyo (Japan). School of Medicine)

    1982-01-01

    Bilateral lesions made in the midbrain reticular formation of the rat produced behavioral akinesia. These animals neither ate nor drank. EEGs of these animals usually showed high voltage slow waves at rest. Slight EEG arousal response was demonstrated by clapping, touching and pinching only in rats with moderate impairment. Concerning the rates of local cerebral glucose utilization (LCGU) measured by means of the autoradiographic (/sup 14/C) deoxyglucose method, 13 structures exhibited significant reductions in 28 gray structures examined when compared with sham operated rats. Lesions in the midbrain reticular formation resulted in reduction of LCGU in the neocortex, ventral nucleus of the thalamus, subthalamic nucleus, and medial and lateral geniculated bodies, mamillary body, septal nucleus and caudateputamen. Structures which did not show any significant change in LCGU were those related to the paleo and archi-cortices. These findings suggest the existence of two types of ascending activating systems. Administration of 30 mg/kg of pentobarbital reduced LCGU diffusely throughout the brain. When thyrotropin releasing hormone (TRH) was administered to rats with lesions in the midbrain reticular formation, reversal of the reduction of LCGU was observed in the dorsomedial nucleus of the thalamus and the mamillary body. Reversal of LCGU in the dorsomedial nucleus of thalamus was especially significant and its level exceeded the level of the sham control value. This suggests TRH might exert its function through the dorsomedial nucleus of the thalamus and mamillary body. When TRH was administered to rats treated with pentobarbital, significant reversal was observed in the following structures: the lateral and ventral nucleus of the thalamus, dentate gyrus, caudate-putamen, nucleus accumbens, pontine gray matter, and raphe nucleus.

  9. Attenuation of diet-induced atherosclerosis in rabbits with a highly selective 15-lipoxygenase inhibitor lacking significant antioxidant properties

    OpenAIRE

    Sendobry, Sandra M; Cornicelli, Joseph A; Welch, Kathryn; Bocan, Thomas; Tait, Bradley; Trivedi, Bharat K; Colbry, Norman; Dyer, Richard D; Feinmark, Steven J; Daugherty, Alan

    1997-01-01

    15-Lipoxygenase (15-LO) has been implicated in the pathogenesis of atherosclerosis because of its localization in lesions and the many biological activities exhibited by its products. To provide further evidence for a role of 15-LO, the effects of PD 146176 on the development of atherosclerosis in cholesterol-fed rabbits were assessed. This novel drug is a specific inhibitor of the enzyme in vitro and lacks significant non specific antioxidant properties.PD 146176 inhibited rabbit reticulocyt...

  10. Temperature induces significant changes in both glycolytic reserve and mitochondrial spare respiratory capacity in colorectal cancer cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Mitov, Mihail I., E-mail: m.mitov@uky.edu [Markey Cancer Center, University of Kentucky, Lexington, KY 40536 (United States); Harris, Jennifer W. [Department of Surgery, University of Kentucky, Lexington, KY 40506 (United States); Alstott, Michael C.; Zaytseva, Yekaterina Y. [Markey Cancer Center, University of Kentucky, Lexington, KY 40536 (United States); Evers, B. Mark [Markey Cancer Center, University of Kentucky, Lexington, KY 40536 (United States); Department of Surgery, University of Kentucky, Lexington, KY 40506 (United States); Butterfield, D. Allan [Markey Cancer Center, University of Kentucky, Lexington, KY 40536 (United States); Department of Chemistry, University of Kentucky, Lexington, KY 40506 (United States)

    2017-05-15

    Thermotherapy, as a method of treating cancer, has recently attracted considerable attention from basic and clinical investigators. A number of studies and clinical trials have shown that thermotherapy can be successfully used as a therapeutic approach for various cancers. However, the effects of temperature on cancer bioenergetics have not been studied in detail with a real time, microplate based, label-free detection approach. This study investigates how changes in temperature affect the bioenergetics characteristics (mitochondrial function and glycolysis) of three colorectal cancer (CRC) cell lines utilizing the Seahorse XF96 technology. Experiments were performed at 32 °C, 37 °C and 42 °C using assay medium conditions and equipment settings adjusted to produce equal oxygen and pH levels ubiquitously at the beginning of all experiments. The results suggest that temperature significantly changes multiple components of glycolytic and mitochondrial function of all cell lines tested. Under hypothermia conditions (32 °C), the extracellular acidification rates (ECAR) of CRC cells were significantly lower compared to the same basal ECAR levels measured at 37 °C. Mitochondrial stress test for SW480 cells at 37 °C vs 42 °C demonstrated increased proton leak while all other OCR components remained unchanged (similar results were detected also for the patient-derived xenograft cells Pt.93). Interestingly, the FCCP dose response at 37 °C vs 42 °C show significant shifts in profiles, suggesting that single dose FCCP experiments might not be sufficient to characterize the mitochondrial metabolic potential when comparing groups, conditions or treatments. These findings provide valuable insights for the metabolic and bioenergetic changes of CRC cells under hypo- and hyperthermia conditions that could potentially lead to development of better targeted and personalized strategies for patients undergoing combined thermotherapy with chemotherapy.

  11. Temperature induces significant changes in both glycolytic reserve and mitochondrial spare respiratory capacity in colorectal cancer cell lines

    International Nuclear Information System (INIS)

    Mitov, Mihail I.; Harris, Jennifer W.; Alstott, Michael C.; Zaytseva, Yekaterina Y.; Evers, B. Mark; Butterfield, D. Allan

    2017-01-01

    Thermotherapy, as a method of treating cancer, has recently attracted considerable attention from basic and clinical investigators. A number of studies and clinical trials have shown that thermotherapy can be successfully used as a therapeutic approach for various cancers. However, the effects of temperature on cancer bioenergetics have not been studied in detail with a real time, microplate based, label-free detection approach. This study investigates how changes in temperature affect the bioenergetics characteristics (mitochondrial function and glycolysis) of three colorectal cancer (CRC) cell lines utilizing the Seahorse XF96 technology. Experiments were performed at 32 °C, 37 °C and 42 °C using assay medium conditions and equipment settings adjusted to produce equal oxygen and pH levels ubiquitously at the beginning of all experiments. The results suggest that temperature significantly changes multiple components of glycolytic and mitochondrial function of all cell lines tested. Under hypothermia conditions (32 °C), the extracellular acidification rates (ECAR) of CRC cells were significantly lower compared to the same basal ECAR levels measured at 37 °C. Mitochondrial stress test for SW480 cells at 37 °C vs 42 °C demonstrated increased proton leak while all other OCR components remained unchanged (similar results were detected also for the patient-derived xenograft cells Pt.93). Interestingly, the FCCP dose response at 37 °C vs 42 °C show significant shifts in profiles, suggesting that single dose FCCP experiments might not be sufficient to characterize the mitochondrial metabolic potential when comparing groups, conditions or treatments. These findings provide valuable insights for the metabolic and bioenergetic changes of CRC cells under hypo- and hyperthermia conditions that could potentially lead to development of better targeted and personalized strategies for patients undergoing combined thermotherapy with chemotherapy.

  12. A novel multi-stage subunit vaccine against paratuberculosis induces significant immunity and reduces bacterial burden in tissues (P4304)

    DEFF Research Database (Denmark)

    Thakur, Aneesh; Aagaard, Claus; Riber, Ulla

    2013-01-01

    Effective control of paratuberculosis is hindered by lack of a vaccine preventing infection, transmission and without diagnostic interference with tuberculosis. We have developed a novel multi-stage recombinant subunit vaccine in which a fusion of four early expressed MAP antigens is combined...... characterized by a significant containment of bacterial burden in gut tissues compared to non-vaccinated animals. There was no cross-reaction with bovine tuberculosis in vaccinated animals. This novel multi-stage vaccine has the potential to become a marker vaccine for paratuberculosis....

  13. Significance of determination of serum IL-8 and interferon induced protein-10 (IP-10) contents in patients with psoriasis

    International Nuclear Information System (INIS)

    Yang Shijun; Cui Jianhe; Xue Mei

    2005-01-01

    Objective: To explore the roles played by IL-8 and IP-10 in the development and pathogenesis of psoriasis. Methods: Serum IL-8 (with RIA) and IP-10 (with ELISA) contents were measured in 47 patients with psoriasis and 42 controls. Results: The serum contents of IL-8 and IP-10 were significantly higher in the patients with psoriasis than those in the controls (P<0.01). Conclusion: IL-8 and IP-10 participated in the pathogenesis of psoriasis. Possible mechanisms were discussed. (authors)

  14. Genetic deletion of the P2Y2 receptor offers significant resistance to development of lithium-induced polyuria accompanied by alterations in PGE2 signaling.

    Science.gov (United States)

    Zhang, Yue; Pop, Ioana L; Carlson, Noel G; Kishore, Bellamkonda K

    2012-01-01

    Lithium (Li)-induced polyuria is due to resistance of the medullary collecting duct (mCD) to the action of arginine vasopressin (AVP), apparently mediated by increased production of PGE(2). We previously reported that the P2Y(2) receptor (P2Y(2)-R) antagonizes the action of AVP on the mCD and may play a role in Li-induced polyuria by enhancing the production of PGE(2) in mCD. Hence, we hypothesized that genetic deletion of P2Y(2)-R should ameliorate Li-induced polyuria. Wild-type (WT) or P2Y(2)-R knockout (KO) mice were fed normal or Li-added diets for 14 days and euthanized. Li-induced polyuria, and decreases in urine osmolality and AQP2 protein abundance in the renal medulla, were significantly less compared with WT mice despite the lack of differences in Li intake or terminal serum or inner medullary tissue Li levels. Li-induced increased urinary excretion of PGE(2) was not affected in KO mice. However, prostanoid EP(3) receptor (EP3-R) protein abundance in the renal medulla of KO mice was markedly lower vs. WT mice, irrespective of the dietary regimen. The protein abundances of other EP-Rs were not altered across the groups irrespective of the dietary regimen. Ex vivo stimulation of mCD with PGE(2) generated significantly more cAMP in Li-fed KO mice (130%) vs. Li-fed WT mice (100%). Taken together, these data suggest 1) genetic deletion of P2Y(2)-R offers significant resistance to the development of Li-induced polyuria; and 2) this resistance is apparently due to altered PGE(2) signaling mediated by a marked decrease in EP3-R protein abundance in the medulla, thus attenuating the EP3-mediated decrease in cAMP levels in mCD.

  15. Significant and sustaining elevation of blood oxygen induced by Chinese cupping therapy as assessed by near-infrared spectroscopy.

    Science.gov (United States)

    Li, Ting; Li, Yaoxian; Lin, Yu; Li, Kai

    2017-01-01

    Cupping therapy has been used in traditional Chinese medicine for thousands of years to relieve muscle pain/tendency/fatigue and to cure or reduce symbols of other diseases. However, its therapeutic effect is sparsely interpreted in the language of modern physiology. To objectively evaluate its therapeutic effect, we focused on dry cupping treatment and utilized near-infrared spectroscopy (NIRS) to assess the concentration change in oxy-hemoglobin ([HbO 2 ]), deoxy-hemoglobin ([Hb]), and blood volume in the course of cupping therapy over 13 volunteers on the infraspinatus muscle, where is usually applied for shoulder pains. Both a prominent drop in [Hb] and a significant elevation in [HbO 2 ] in the tissue surrounding the cupping site were observed during both cupping and post-treatment, manifesting the enhancement of oxygen uptake. This resulting promotion indicates potential positive therapeutic effect of cupping therapy in hemodynamics for facilitating muscular functions.

  16. Smoking cessation programmes in radon affected areas: can they make a significant contribution to reducing radon-induced lung cancers?

    International Nuclear Information System (INIS)

    Denman, A.R.; Groves-Kirkby, C.J.; Timson, K.; Shield, G.; Rogers, S.; Phillips, P.S.

    2008-01-01

    Domestic radon levels in parts of the UK are sufficiently high to increase the risk of lung cancer in the occupants. Public health campaigns in Northamptonshire, a designated radon affected area with 6.3% of homes having average radon levels over the UK action level of 200 Bq m -3 , have encouraged householders to test for radon and then to carry out remediation in their homes, but have been only partially successful. Only 40% of Northamptonshire houses have been tested, and only 15% of householders finding raised levels proceed to remediate. Of those who did remediate, only 9% smoked, compared to a countywide average of 28.8%. This is unfortunate, since radon and smoking combine to place the individual at higher risk by a factor of around 4, and suggests that current strategies to reduce domestic radon exposure are not reaching those most at risk. During 2004-5, the NHS Stop Smoking Services in Northamptonshire assisted 2,808 smokers to quit to the 4-week stage, with some 30% of 4-week quitters remaining quitters at 1 year. We consider whether smoking cessation campaigns make significant contributions to radon risk reduction on their own, by assessing individual occupants' risk of developing lung cancer from knowledge of their age, gender, and smoking habits, together with he radon level in their house. The results demonstrate that smoking cessation programmes have significant added value in radon affected areas, and contribute a greater health benefit than reducing radon levels in the smokers' homes, whilst they remain smokers. Additionally, results are presented from a questionnaire-based survey of quitters, addressing their reasons for seeking help in quitting smoking, and whether knowledge of radon risks influenced this decision. The impact of these findings on future public health campaigns to reduce the impact of radon and smoking are discussed. (author)

  17. Significant change of local atomic configurations at surface of reduced activation Eurofer steels induced by hydrogenation treatments

    Energy Technology Data Exchange (ETDEWEB)

    Greculeasa, S.G.; Palade, P.; Schinteie, G. [National Institute for Materials Physics, P.O. Box MG-7, 77125, Bucharest-Magurele (Romania); Kuncser, A.; Stanciu, A. [National Institute for Materials Physics, P.O. Box MG-7, 77125, Bucharest-Magurele (Romania); University of Bucharest, Faculty of Physics, 77125, Bucharest-Magurele (Romania); Lungu, G.A. [National Institute for Materials Physics, P.O. Box MG-7, 77125, Bucharest-Magurele (Romania); Porosnicu, C.; Lungu, C.P. [National Institute for Laser, Plasma and Radiation Physics, 77125, Bucharest-Magurele (Romania); Kuncser, V., E-mail: kuncser@infim.ro [National Institute for Materials Physics, P.O. Box MG-7, 77125, Bucharest-Magurele (Romania)

    2017-04-30

    Highlights: • Engineering of Eurofer slab properties by hydrogenation treatments. • Hydrogenation modifies significantly the local atomic configurations at the surface. • Hydrogenation increases the expulsion of the Cr atoms toward the very surface. • Approaching binomial atomic distribution by hydrogenation in the next surface 100 nm. - Abstract: Reduced-activation steels such as Eurofer alloys are candidates for supporting plasma facing components in tokamak-like nuclear fusion reactors. In order to investigate the impact of hydrogen/deuterium insertion in their crystalline lattice, annealing treatments in hydrogen atmosphere have been applied on Eurofer slabs. The resulting samples have been analyzed with respect to local structure and atomic configuration both before and after successive annealing treatments, by X-ray diffractometry (XRD), scanning electron microscopy and energy dispersive spectroscopy (SEM-EDS), X-ray photoelectron spectroscopy (XPS) and conversion electron Mössbauer spectroscopy (CEMS). The corroborated data point out for a bcc type structure of the non-hydrogenated alloy, with an average alloy composition approaching Fe{sub 0.9}Cr{sub 0.1} along a depth of about 100 nm. EDS elemental maps do not indicate surface inhomogeneities in concentration whereas the Mössbauer spectra prove significant deviations from a homogeneous alloying. The hydrogenation increases the expulsion of the Cr atoms toward the surface layer and decreases their oxidation, with considerable influence on the surface properties of the steel. The hydrogenation treatment is therefore proposed as a potential alternative for a convenient engineering of the surface of different Fe-Cr based alloys.

  18. Laparoscopic limited Heller myotomy without anti-reflux procedure does not induce significant long-term gastroesophageal reflux.

    Science.gov (United States)

    Zurita Macías Valadez, L C; Pescarus, R; Hsieh, T; Wasserman, L; Apriasz, I; Hong, D; Gmora, S; Cadeddu, M; Anvari, M

    2015-06-01

    Laparoscopic Heller myotomy with partial fundoplication is the gold standard treatment for achalasia. Laparoscopic limited Heller myotomy (LLHM) with no anti-reflux procedure is another possible option. A review of prospectively collected data was performed on patients who underwent LLHM from January 1998 to December 2012. Evaluation included gastroscopy, esophageal manometry, 24-h pH-metry, and the Short Form(36) Health Survey(SF-36) questionnaire at baseline and 6 months, as well as the global symptom score at baseline, 6 months, and 5 years post-surgery. Comparison between outcomes was performed with a paired t student's test. 126 patients underwent LLHM. Of these, 60 patients had complete pre and post-operative motility studies. 57 % were female, patient mean age was 45.7 years, with a mean follow-up of 10.53 months. Mean operative time was 56.1 min, and the average length of stay was 1.7 days. At 6 months, a significant decrease in the lower esophageal sphincter resting pressure (29.1 vs. 7.1 mmHg; p < 0.001) and nadir (16.4 vs. 4.3 mmHg; p < 0.001) was observed. Normal esophageal acid exposure (total pH < 4 %) was observed in 68.3 % patients. Nevertheless, of the remaining 31.7 % with abnormal pH-metry, only 21.6 % were clinically symptomatic and all were properly controlled with medical treatment without requiring anti-reflux surgery. Significant improvement in all pre-operative symptoms was observed at 6 months and maintained over 5 years. Dysphagia score was reduced from 9.8 pre-operatively to 2.6 at 5 years (p < 0.001), heartburn score from 3.82 to 2 (p < 0.01), and regurgitation score from 7.5 to 0.8 (p < 0.001). Only one patient (0.8 %) presented with recurrent dysphagia requiring reoperation. LLHM without anti-reflux procedure is an effective long-term treatment for achalasia and does not cause symptomatic GERD in three quarters of patients. The remaining patients are well controlled on anti-reflux medications. It is believed that similar clinical

  19. Experimentally-induced immune activation in natural hosts of SIV induces significant increases in viral replication and CD4+ T cell depletion

    Energy Technology Data Exchange (ETDEWEB)

    Ribeiro, Ruy M [Los Alamos National Laboratory

    2008-01-01

    Chronically SIVagm-infected African green monkeys (AGMs) have a remarkably stable non-pathogenic disease course, with levels of immune activation in chronic SIVagm infection similar to those observed in uninfected monkeys and stable viral loads (VLs) for long periods of time. In vivo administration of lipopolysaccharide (LPS) or an IL-2/diphtheria toxin fusion protein (Ontak) to chronically SIVagm-infected AGMs triggered increases in immune activation and subsequently of viral replication and depletion of intestinal CD4{sup +} T cells. Our study indicates that circulating microbial products can increase viral replication by inducing immune activation and increasing the number of viral target cells, thus demonstrating that immune activation and T cell prolifeation are key factors in AIDS pathogenesis.

  20. Post-Harvest Induced Production of Salvianolic Acids and Significant Promotion of Antioxidant Properties in Roots of Salvia miltiorrhiza (Danshen

    Directory of Open Access Journals (Sweden)

    Guo-Jun Zhou

    2014-05-01

    Full Text Available Danshen, the dried roots of Salvia miltiorrhiza, is an extremely valued Traditional Chinese Medicine. Previously, we have demonstrated that salvianolic acid B (SaB, the important bioactive ingredient in this herb, was a post-harvest product. Here, we further reported that all salvianolic acids (SAs in the roots were post-harvest products of the drying process. In addition, the results of various radical scavenging activity assays, including lipid peroxidation (1, DPPH (2, hydroxyl (3 and superoxide (4, were significantly increased along with the accumulation of total salvianolic acids in the process. The contents of chemical targets and antioxidant activities both reached the highest value under thermal treatment at 130 °C for 80 min. In this dehydration period, contents of SaB, and sum of nine SAs increased from 0.01% to 5.51%, and 0.20% to 6.61%; and IC50 of antioxidant activity decreased from 4.85 to 2.69 (1; 7.75 to 0.43 (2; 2.57 to 1.13 (3 and 17.25 to 1.10 mg/mL. These results further supported the hypothesis that the newly harvested plant roots were still physiologically active and the secondary metabolites might be produced due to dehydration stress after harvest. Our findings supplied an important and useful theoretical basis for promoting the quality of Danshen and other medicinal plant materials.

  1. Elevated expression of the toll like receptors 2 and 4 in obese individuals: its significance for obesity-induced inflammation

    Directory of Open Access Journals (Sweden)

    Ahmad Rasheed

    2012-11-01

    Full Text Available Abstract Background Expression profile of the toll like receptors (TLRs on PBMCs is central to the regulation of proinflammatory markers. An imbalance in the TLRs expression may lead to several types of inflammatory disorders. Furthermore, the dynamic regulation of inflammatory activity and associated impaired production of cytokines by peripheral blood mononuclear cells (PBMCs in obese individulas remain poorly understood. Therefore, we determined the perturbation in TLRs (TLR2 and TLR4, their adaptor proteins (MyD88, IRAK1 and TRAF6 expression in PBMCs/subcutaneous adipose tissue (AT as well as inflammatory cytokines changes in obese individuals. Methods mRNA expression levels of TLR2, TLR4, IL-6, TNF-α and adaptor proteins were determined by RT-PCR. TLR2, TLR4 and adaptor proteins expression in AT was determined by immunohistochemistry. Results Obese and overweight individuals showed significantly increased expression of TLR2, TLR4 and MyD88 in both PBMCs and AT as compared with lean individuals (P  Conclusions TLRs and adapter proteins were overexpressed in PBMCs from obese subjects, which correlated with increased expression of TNF-α and IL-6. This association may explain a potential pathophysiological link between obesity and inflammation leading to insulin resistance.

  2. Gene-carried hepatoma targeting complex induced high gene transfection efficiency with low toxicity and significant antitumor activity

    Directory of Open Access Journals (Sweden)

    Zhao QQ

    2012-06-01

    was confirmed and the vector showed low cytotoxicity and strong targeting specificity to liver tumors in vitro. The in vivo study results showed that interleukin-12 delivered by the new gene vector CPT/DNA significantly enhanced the antitumor effect on ascites tumor-bearing imprinting control region mice as compared with polyethylenimine (25 kDa, CP, and other controls, which further demonstrate the targeting specificity of the new synthesized polymer.Conclusion: The synthesized CPT copolymer was proven to be an effective liver cancer-targeted vector for therapeutic gene delivery, which could be a potential candidate for targeted cancer gene therapy.Keywords: targeting, peptide, polyethylenimine, chitosan, antitumor

  3. The role of aryl hydrocarbon receptor signaling pathway in cardiotoxicity of acute lead intoxication in vivo and in vitro rat model.

    Science.gov (United States)

    Ansari, Mushtaq A; Maayah, Zaid H; Bakheet, Saleh A; El-Kadi, Ayman O; Korashy, Hesham M

    2013-04-05

    Lead (Pb(2+)) is a naturally occurring systemic toxicant heavy metal that affects several organs in the body including the kidneys, liver, and central nervous system. However, Pb(2+)-induced cardiotoxicity has never been investigated yet and the exact mechanism of Pb(2+) associated cardiotoxicity has not been studied. The current study was designed to investigate the potential effect of Pb(2+) to induce cardiotoxicity in vivo and in vitro rat model and to explore the molecular mechanisms and the role of aryl hydrocarbon receptor (AhR) and regulated gene, cytochrome P4501A1 (CYP1A1), in Pb(2+)-mediated cardiotoxicity. For these purposes, Wistar albino rats were treated with Pb(2+) (25, 50 and 100mg/kg, i.p.) for three days and the effects on physiological and histopathological parameters of cardiotoxicity were determined. At the in vitro level, rat cardiomyocyte H9c2 cell lines were incubated with increasing concentration of Pb(2+) (25, 50, and 100 μM) and the expression of hypertrophic genes, α- and β-myosin heavy chain (α-MHC and β-MHC), brain Natriuretic Peptide (BNP), and CYP1A1 were determined at the mRNA and protein levels using real-time PCR and Western blot analysis, respectively. The results showed that Pb(2+) significantly induced cardiotoxicity and heart failure as evidenced by increase cardiac enzymes, lactate dehydrogenase and creatine kinase and changes in histopathology in vivo. In addition, Pb(2+) treatment induced β-MHC and BNP whereas inhibited α-MHC mRNA and protein levels in vivo in a dose-dependent manner. In contrast, at the in vitro level, Pb(2+) treatment induced both β-MHC and α-MHC mRNA levels in time- and dose-dependent manner. Importantly, these changes were accompanied with a proportional increase in the expression of CYP1A1 mRNA and protein expression levels, suggesting a role for the CYP1A1 in cardiotoxicity. The direct evidence for the involvement of CYP1A1 in the induction of cardiotoxicity by Pb(2+) was evidenced by the

  4. Cobaltous chloride and hypoxia inhibit aryl hydrocarbon receptor-mediated responses in breast cancer cells

    International Nuclear Information System (INIS)

    Khan, Shaheen; Liu Shengxi; Stoner, Matthew; Safe, Stephen

    2007-01-01

    The aryl hydrocarbon receptor (AhR) is expressed in estrogen receptor (ER)-positive ZR-75 breast cancer cells. Treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces CYP1A1 protein and mRNA levels and also activates inhibitory AhR-ERα crosstalk associated with hormone-induced reporter gene expression. In ZR-75 cells grown under hypoxia, induction of these AhR-mediated responses by TCDD was significantly inhibited. This was not accompanied by decreased nuclear AhR levels or decreased interaction of the AhR complex with the CYP1A1 gene promoter as determined in a chromatin immunoprecipitation assay. Hypoxia-induced loss of Ah-responsiveness was not associated with induction of hypoxia-inducible factor-1α or other factors that sequester the AhR nuclear translocation (Arnt) protein, and overexpression of Arnt under hypoxia did not restore Ah-responsiveness. The p65 subunit of NFκB which inhibits AhR-mediated transactivation was not induced by hypoxia and was primarily cytosolic in ZR-75 cells grown under hypoxic and normoxic conditions. In ZR-75 cells maintained under hypoxic conditions for 24 h, BRCA1 (an enhancer of AhR-mediated transactivation in breast cancer cells) was significantly decreased and this contributed to loss of Ah-responsiveness. In cells grown under hypoxia for 6 h, BRCA1 was not decreased, but induction of CYP1A1 by TCDD was significantly decreased. Cotreatment of ZR-75 cells with TCDD plus the protein synthesis inhibitor cycloheximide for 6 h enhanced CYP1A1 expression in cells grown under hypoxia and normoxia. These results suggest that hypoxia rapidly induces protein(s) that inhibit Ah-responsiveness and these may be similar to constitutively expressed inhibitors of Ah-responsiveness (under normoxia) that are also inhibited by cycloheximide

  5. Clinical significance of determination of changes of serum Hcy, ET and BNP levels After treatment in patients with pregnancy induced hypertension (PIH)

    International Nuclear Information System (INIS)

    He Hongling

    2010-01-01

    Objective: To study the clinical significance of changes of serum Hcy, ET and BNP levels after treatment in patients with pregnancy induced hypertension(PIH). Methods: Serum Hcy (with ELISA), ET and BNP (with RIA) levels were determined in 32 patients with PIH both before and after treatment as well as in 35 controls. Results: Before treatment, serum Hcy, ET and BNP levels in patients with PIH were significantly higher than those in controls (P < 0.01). After 1 month of treatment the levels dropped markedly, but still remained significantly higher(P < 0.05). Conclusion: Serum Hcy, ET and BNP levels were closely related to the diseases process of PIH and were of prognostic values. (authors)

  6. 2,3,7,8-Tetrachlorodibenzo-p-dioxin increases reactive oxygen species production in human endothelial cells via induction of cytochrome P4501A1

    International Nuclear Information System (INIS)

    Kopf, P.G.; Walker, M.K.

    2010-01-01

    Studies in our laboratory have demonstrated that subchronic 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD) exposure of adult mice results in hypertension, cardiac hypertrophy, and reduced nitric oxide (NO)-mediated vasodilation. Moreover, increased superoxide anion production was observed in cardiovascular organs of TCDD-exposed mice and this increase contributed to the reduced NO-mediated vasodilation. Since cytochrome P4501A1 (CYP1A1) can contribute to some TCDD-induced toxicity, we tested the hypothesis that TCDD increases reactive oxygen species (ROS) in endothelial cells by the induction of CYP1A1. A concentration-response to 24 h TCDD exposure (10 pM-10 nM) was performed in confluent primary human aortic endothelial cells (HAECs). Oxidant-sensitive fluorescent probes dihydroethidium (DHE) and 2',7'-dichlorofluorescin diacetate (DCFH-DA), were used to measure superoxide anion, and hydrogen peroxide and hydroxyl radical, respectively. NO was also measured using the fluorescent probe diaminofluorescein-2 diacetate (DAF-2DA). These assessments were conducted in HAECs transfected with siRNA targeting the aryl hydrocarbon receptor (AhR), CYP1A1, or CYP1B1. TCDD concentration-dependently increased CYP1A1 and CYP1B1 mRNA, protein, and enzyme activity. Moreover, 1 nM TCDD maximally increased DHE (Cont = 1.0 ± 0.3; TCDD = 5.1 ± 1.0; p = 0.002) and DCFH-DA (Cont = 1.0 ± 0.2; TCDD = 4.1 ± 0.5; p = 0.002) fluorescence and maximally decreased DAF-2DA fluorescence (Cont = 1.0 ± 0.4; TCDD = 0.68 ± 0.1). siRNA targeting AhR and CYP1A1 significantly decreased TCDD-induced DHE (siAhR: Cont = 1.0 ± 0.1; TCDD = 1.3 ± 0.2; p = 0.093) (siCYP1A1: Cont = 1.0 ± 0.1; TCDD = 1.1 ± 0.1; p = 0.454) and DCFH-DA (siAhR: Cont = 1.0 ± 0.2; TCDD = 1.3 ± 0.3; p = 0.370) (siCYP1A1: Cont = 1.0 ± 0.1; TCDD = 1.3 ± 0.2; p = 0.114) fluorescence and increased DAF-2DA fluorescence (siAhR: Cont = 1.00 ± 0.03; TCDD = 0.97 ± 0.03; p = 0.481) (siCYP1A1: Cont = 1.00 ± 0.03; TCDD = 0.92 ± 0

  7. Clinically Significant Contrast Induced Acute Kidney Injury after Non-Emergent Cardiac Catheterization - Risk Factors and Impact on Length of Hospital Stay

    International Nuclear Information System (INIS)

    Kashif, W.; Yaqub, S.; Khawaja, A.

    2013-01-01

    Objective: To evaluate the frequency and risk factors associated with clinically significant contrast-induced nephropathy (CIN) in patients undergoing non-emergent coronary angiography. Study Design: Descriptive study. Place and Duration of Study: The Aga Khan University Hospital, Karachi, from January 2005 to December 2007. Methodology: Case records of patients who underwent coronary angiography with a serum creatinine of >= 1.5 mg/dl at the time of procedure were evaluated. Clinically significant contrast induced nephropathy (CSCIN) was defined as either doubling of serum creatinine from baseline value within a week following the procedure or need for emergency hemodialysis after the procedure. Results: One hundred and sixteen patients met the inclusion criteria. Mean age was 64.0 +- 11.5 years, 72% were males. Overall prevalence of CIN was 17% (rise of serum creatinine by A= 0.5 mg/dl) while that of clinically significant CIN (CSCIN) was 9.5% (11 patients). Patients with CSCIN had significantly lower left ventricular ejection fraction (p = 0.03, OR: 0.24; 95% CI = 0.06 A= 0.91) and higher prevalence of cerebrovascular disease (p < 0.001, OR: 14.66; 95% CI = 3.30 - 65.08). Mean baseline serum creatinine was significantly higher, 3.0 +- 1.5 vs. 2.0 +- 1.1 mg/dl (p = 0.03, OR: 1.47; 95% CI = 1.03 - 2.11) whereas mean GFR estimated by Cockcroft-Gault formula was significantly lower at 25 +- 7.4 vs. 41.0 +- 14.6 ml/minute (p = 0.001, OR = 0.89, 95% CI = 0.84 A= 0.95) at the time of procedure in patients with CSCIN. Mean length of hospital stay was significantly higher in this group compared to those without CIN, 9.0 +- 5.1 vs. 3.0 +- 3.2 days (p = 0.001, OR = 1.31, 95% CI = 1.12 - 1.54). Multivariate analysis revealed low GFR (p = 0.001, OR = 0.88; 95% CI = 0.82 - 0.95) and low ejection fraction (p = 0.03, OR = 0.20; 95% CI = 0.04 - 0.91) to be independent factors associated with CSCIN. No significant differences were noted between the two groups in patients with

  8. Kluyveromyces marxianus and Saccharomyces boulardii Induce Distinct Levels of Dendritic Cell Cytokine Secretion and Significantly Different T Cell Responses In Vitro.

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    Ida M Smith

    Full Text Available Interactions between members of the intestinal microbiota and the mucosal immune system can significantly impact human health, and in this context, fungi and food-related yeasts are known to influence intestinal inflammation through direct interactions with specialized immune cells in vivo. The aim of the present study was to characterize the immune modulating properties of the food-related yeast Kluyveromyces marxianus in terms of adaptive immune responses indicating inflammation versus tolerance and to explore the mechanisms behind the observed responses. Benchmarking against a Saccharomyces boulardii strain with probiotic effects documented in clinical trials, we evaluated the ability of K. marxianus to modulate human dendritic cell (DC function in vitro. Further, we assessed yeast induced DC modulation of naive T cells toward effector responses dominated by secretion of IFNγ and IL-17 versus induction of a Treg response characterized by robust IL-10 secretion. In addition, we blocked relevant DC surface receptors and investigated the stimulating properties of β-glucan containing yeast cell wall extracts. K. marxianus and S. boulardii induced distinct levels of DC cytokine secretion, primarily driven by Dectin-1 recognition of β-glucan components in their cell walls. Upon co-incubation of yeast exposed DCs and naive T cells, S. boulardii induced a potent IFNγ response indicating TH1 mobilization. In contrast, K. marxianus induced a response dominated by Foxp3+ Treg cells, a characteristic that may benefit human health in conditions characterized by excessive inflammation and positions K. marxianus as a strong candidate for further development as a novel yeast probiotic.

  9. Kluyveromyces marxianus and Saccharomyces boulardii Induce Distinct Levels of Dendritic Cell Cytokine Secretion and Significantly Different T Cell Responses In Vitro.

    Science.gov (United States)

    Smith, Ida M; Baker, Adam; Christensen, Jeffrey E; Boekhout, Teun; Frøkiær, Hanne; Arneborg, Nils; Jespersen, Lene

    2016-01-01

    Interactions between members of the intestinal microbiota and the mucosal immune system can significantly impact human health, and in this context, fungi and food-related yeasts are known to influence intestinal inflammation through direct interactions with specialized immune cells in vivo. The aim of the present study was to characterize the immune modulating properties of the food-related yeast Kluyveromyces marxianus in terms of adaptive immune responses indicating inflammation versus tolerance and to explore the mechanisms behind the observed responses. Benchmarking against a Saccharomyces boulardii strain with probiotic effects documented in clinical trials, we evaluated the ability of K. marxianus to modulate human dendritic cell (DC) function in vitro. Further, we assessed yeast induced DC modulation of naive T cells toward effector responses dominated by secretion of IFNγ and IL-17 versus induction of a Treg response characterized by robust IL-10 secretion. In addition, we blocked relevant DC surface receptors and investigated the stimulating properties of β-glucan containing yeast cell wall extracts. K. marxianus and S. boulardii induced distinct levels of DC cytokine secretion, primarily driven by Dectin-1 recognition of β-glucan components in their cell walls. Upon co-incubation of yeast exposed DCs and naive T cells, S. boulardii induced a potent IFNγ response indicating TH1 mobilization. In contrast, K. marxianus induced a response dominated by Foxp3+ Treg cells, a characteristic that may benefit human health in conditions characterized by excessive inflammation and positions K. marxianus as a strong candidate for further development as a novel yeast probiotic.

  10. Expression of cytochromes P450 1A1 and 1B1 in human lung from smokers, non-smokers, and ex-smokers

    International Nuclear Information System (INIS)

    Kim, James H.; Sherman, Mark E.; Curriero, Frank C.; Guengerich, F. Peter; Strickland, Paul T.; Sutter, Thomas R.

    2004-01-01

    Cytochromes P450 1A1 and 1B1 are known to bioactivate procarcinogens such as polycyclic aromatic hydrocarbons (PAHs) found in cigarette smoke and are inducible via an Ah receptor-mediated mechanism. The aim of this study was to examine the levels of expression of CYP1A1 and CYP1B1 in samples of lung from smokers (n = 18), non-smokers (n = 7), and ex-smokers (n = 7). Using immunoglobulin preparations of highly specific polyclonal antibodies and immunoblot analysis of microsomes from lung tissues, we determined the specific content for CYP1A1 and CYP1B1. For CYP1A1, we found median expression levels of 15.5 pmol/mg microsomal protein in smokers, 6.0 pmol/mg microsomal protein in non-smokers, and 19.0 pmol/mg microsomal protein in ex-smokers. The difference in median expression levels of smokers and ex-smokers compared to non-smokers was statistically significant. For CYP1B1, we found median expression levels of 1.8 pmol/mg microsomal protein in smokers, 1.0 pmol/mg microsomal protein in non-smokers, and 4.4 pmol/mg microsomal protein in ex-smokers. The difference in median expression levels between ex-smokers and non-smokers was statistically significant. These results suggest that levels of expression of CYP1A1 and CYP1B1 protein in lung tissues from smokers and ex-smokers are quantitatively greater than in non-smokers. By immunohistochemical analysis, we demonstrated the expression of CYP1A1 and CYP1B1 in normal human alveolar type I and II cells, ciliated columnar epithelial cells lining bronchoalveolar airways, and alveolar macrophages. These results confirm that CYP1A1 is expressed in normal human lung, appears to be induced in smokers, and show interindividual variation; the similar characteristics of CYP1B1 are demonstrated

  11. A receptor tyrosine kinase ROR1 inhibitor (KAN0439834 induced significant apoptosis of pancreatic cells which was enhanced by erlotinib and ibrutinib.

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    Amir Hossein Daneshmanesh

    Full Text Available There is a great unmet medical need in pancreatic carcinoma (PC for novel drugs with other mechanisms of action than existing. PC cells express the onco-fetal RTK ROR1, absent on most normal post-partem cells. ROR1 is involved in proliferation, survival, EMT and metastasis of tumor cells in various malignancies. A small molecule inhibitor (KAN0439834 (530 Da targeting the TK domain of ROR1 was developed and the activity in ROR1 expressing human PC cell lines (n = 8 evaluated. The effects were compared to a murine mAb against the external part of ROR1, gemcitabine, erlotinib and ibrutinib. KAN0439834 induced significant apoptosis of the tumor cells. EC50 values for KAN0439834 varied between 250-650 nM depending on the cell line. The corresponding values for erlotinib and ibrutinib were 10-40 folds higher. KAN0439834 was much more effective in inducing tumor cell death than the ROR1 mAb although both inhibited ROR1 phosphorylation and downstream non-canonical Wnt pathway molecules. Combination of KAN0439834 with erlotinib or ibrutinib had significant additive effects on tumor cell death. A first-in-class small molecule ROR1 inhibitor (KAN0439834 showed promising in vitro activity against a number of human PC cell lines. Interesting is the additive effects of erlotinib and ibrutinib which warrants further studies as both these agents are in clinical trials for pancreatic carcinoma.

  12. Crystalline silica is a negative modifier of pulmonary cytochrome P-4501A1 induction

    Energy Technology Data Exchange (ETDEWEB)

    Battelli, L.A.; Ghanem, M.M.; Kashon, M.L.; Barger, M.; Ma, J.Y.C.; Simoskevitz, R.L.; Miles, P.R.; Hubbs, A.F. [NIOSH, Morgantown, WV (United States). Health Effects Laboratory Division

    2008-07-01

    Polycyclic aromatic hydrocarbons (PAHs) are products of incomplete combustion that are commonly inhaled by workers in the dusty trades. Many PAHs are metabolized by cytochrome P-4501A1 (CYP1A1), which may facilitate excretion but may activate pulmonary carcinogens. PAHs also stimulate their own metabolism by inducing CYP1A1. Recent studies suggest that respirable coal dust exposure inhibits induction of pulmonary CYP1A1 using the model PAH {beta}-naphthoflavone. The effect of the occupational particulate respirable crystalline silica was investigated on PAH-dependent pulmonary CYP1A1 induction. Male Sprague-Dawley rats were exposed to intratracheal silica or vehicle and then intraperitoneal {beta}-naphthoflavone, a CYP1A1 inducer, and/or phenobarbital, an inducer of hepatic CYP2B1, or vehicle. {beta}-Naphthoflavone induced pulmonary CYP1A1, but silica attenuated this {beta}-naphthoflavone-induced CYP1A1 activity and also suppressed the activity of CYP2B1, the major constituitive CYP in rat lung. The magnitude of CYP activity suppression was similar regardless of silica exposure dose within a range of 5 to 20 mg/rat. Phenobarbital and beta-naphthoflavone had no effect on pulmonary CYP2B1 activity. Both enzymatic immunohistochemistry and immunofluorescent staining for CYP1A1 indicated that sites of CYP1A1 induction were nonciliated airway epithelial cells, endothelial cells, and the alveolar septum. Our findings suggest that in PAH-exposed rat lung, silica is a negative modifier of CYP1A1 induction and CYP2B1 activity.

  13. Introducing the "TCDD-inducible AhR-Nrf2 gene battery".

    Science.gov (United States)

    Yeager, Ronnie L; Reisman, Scott A; Aleksunes, Lauren M; Klaassen, Curtis D

    2009-10-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces genes via the transcription factor aryl hydrocarbon receptor (AhR), including Cyp1a1, NAD(P)H:quinone oxidoreductase 1 (Nqo1), UDP-glucuronosyltransferase 1a6 (Ugt1a6), and glutathione S-transferase a1 (Gsta1). These genes are referred to as the "AhR gene battery." However, Nqo1 is also considered a prototypical target gene of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). In mice, TCDD induction of Nrf2 and Nrf2 target, Nqo1, is dependent on AhR, and thus TCDD induction of drug-processing genes may be routed through an AhR-Nrf2 sequence. There has been speculation that Nrf2 may be involved in the TCDD induction of drug-processing genes; however, the data are not definitive. Therefore, to address whether TCDD induction of Nqo1, Ugts, and Gsts is dependent on Nrf2, we conducted the definitive experiment by administering TCDD (50 mug/kg, ip) to Nrf2-null and wild-type (WT) mice and collecting livers 24 h later to quantify the mRNA of drug-processing genes. TCDD induction of Cyp1a1 and Ugt1a1 was similar in WT and Nrf2-null mice, whereas TCDD induction of Ugt1a5 and 1a9 was blunted in Nrf2-null mice. TCDD induced Nqo1, Ugt1a6, 2b34, 2b35, 2b36, UDP-glucuronic acid-synthesizing gene UDP-glucose dehydrogenase, and Gsta1, m1, m2, m3, m6, p2, t2, and microsomal Gst1 in WT mice but not in Nrf2-null mice. Therefore, the present study demonstrates the novel finding that Nrf2 is required for TCDD induction of classical AhR battery genes Nqo1, Ugt1a6, and Gsta1, as well as most Ugt and Gst isoforms in livers of mice.

  14. Serum miR-451a Levels Are Significantly Elevated in Women With Endometriosis and Recapitulated in Baboons ( Papio anubis) With Experimentally-Induced Disease.

    Science.gov (United States)

    Nothnick, Warren B; Falcone, Tommaso; Joshi, Niraj; Fazleabas, Asgerally T; Graham, Amanda

    2017-08-01

    We have previously demonstrated that human microRNA-451a (miR-451a) endometriotic lesion expression is significantly higher compared to that of the corresponding eutopic endometrium. The objective of the current study was to examine the relationship between lesion and serum content of miR-451a and to determine the utility of serum miR-451a in distinguishing between women with and without visible signs of endometriosis. Eighty-one participants were enrolled in this study, 41 with confirmed endometriosis and 40 without visible signs of endometriosis at laparoscopy (n = 20) or symptoms of endometriosis (pain, infertility n = 20). Experimental endometriosis was also induced in 8 baboons. Blood, endometriotic lesions, and eutopic endometrial samples were collected from women undergoing laparoscopy for surgical removal of endometriosis. Blood was also collected from control participants with no signs and symptoms associated with the disease as well as from baboons prior to, and then 1, 3, 6, 9, and 15 months postinduction of endometriosis. MicroRNA-451a was assessed by quantitative real-time polymerase chain reaction in all samples. In humans, serum miR-451a levels positively correlated with endometriotic lesion miR-451a content, and sera levels were significantly higher in these participants compared to controls. The area under the curve (AUC) for miR-451a was 0.8599. In baboons, serum miR-451a reached statistically significant peak levels at 6 months postinduction of endometriosis. We conclude from this study that sera miR-451a levels positively correlated with endometriotic lesion content and are significantly greater compared to sera levels in women without visible signs or symptoms of endometriosis. MicroRNA-451a may serve as a serum diagnostic marker for endometriosis.

  15. Motavizumab, A Neutralizing Anti-Respiratory Syncytial Virus (Rsv Monoclonal Antibody Significantly Modifies The Local And Systemic Cytokine Responses Induced By Rsv In The Mouse Model

    Directory of Open Access Journals (Sweden)

    Jafri Hasan S

    2007-10-01

    Full Text Available Abstract Motavizumab (MEDI-524 is a monoclonal antibody with enhanced neutralizing activity against RSV. In mice, motavizumab suppressed RSV replication which resulted in significant reduction of clinical parameters of disease severity. We evaluated the effect of motavizumab on the local and systemic immune response induced by RSV in the mouse model. Balb/c mice were intranasally inoculated with 106.5 PFU RSV A2 or medium. Motavizumab was given once intraperitoneally (1.25 mg/mouse as prophylaxis, 24 h before virus inoculation. Bronchoalveolar lavage (BAL and serum samples were obtained at days 1, 5 (acute and 28 (long-term post inoculation and analyzed with a multiplex assay (Beadlyte Upstate, NY for simultaneous quantitation of 18 cytokines: IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, KC (similar to human IL-8, IL-10, IL-12p40, IL-12p70, IL-13, IL-17, TNF-α, MCP-1, RANTES, IFN-γ and GM-CSF. Overall, cytokine concentrations were lower in serum than in BAL samples. By day 28, only KC was detected in BAL specimens at low concentrations in all groups. Administration of motavizumab significantly reduced (p

  16. The multikinase inhibitor Sorafenib displays significant antiproliferative effects and induces apoptosis via caspase 3, 7 and PARP in B- and T-lymphoblastic cells

    International Nuclear Information System (INIS)

    Schult, Catrin; Boldt, Sonja; Wolkenhauer, Olaf; Neri, Luca Maria; Freund, Mathias; Junghanss, Christian; Dahlhaus, Meike; Ruck, Sabine; Sawitzky, Mandy; Amoroso, Francesca; Lange, Sandra; Etro, Daniela; Glass, Aenne; Fuellen, Georg

    2010-01-01

    Targeted therapy approaches have been successfully introduced into the treatment of several cancers. The multikinase inhibitor Sorafenib has antitumor activity in solid tumors and its effects on acute lymphoblastic leukemia (ALL) cells are still unclear. ALL cell lines (SEM, RS4;11 and Jurkat) were treated with Sorafenib alone or in combination with cytarabine, doxorubicin or RAD001. Cell count, apoptosis and necrosis rates, cell cycle distribution, protein phosphorylation and metabolic activity were determined. Sorafenib inhibited the proliferation of ALL cells by cell cycle arrest accompanied by down-regulation of CyclinD3 and CDK4. Furthermore, Sorafenib initiated apoptosis by cleavage of caspases 3, 7 and PARP. Apoptosis and necrosis rates increased significantly with most pronounced effects after 96 h. Antiproliferative effects of Sorafenib were associated with a decreased phosphorylation of Akt (Ser473 and Thr308), FoxO3A (Thr32) and 4EBP-1 (Ser65 and Thr70) as early as 0.5 h after treatment. Synergistic effects were seen when Sorafenib was combined with other cytotoxic drugs or a mTOR inhibitor emphasizing the Sorafenib effect. Sorafenib displays significant antileukemic activity in vitro by inducing cell cycle arrest and apoptosis. Furthermore, it influences PI3K/Akt/mTOR signaling in ALL cells

  17. A Newly Emergent Turkey Arthritis Reovirus Shows Dominant Enteric Tropism and Induces Significantly Elevated Innate Antiviral and T Helper-1 Cytokine Responses.

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    Tamer A Sharafeldin

    Full Text Available Newly emergent turkey arthritis reoviruses (TARV were isolated from tendons of lame 15-week-old tom turkeys that occasionally had ruptured leg tendons. Experimentally, these TARVs induced remarkable tenosynovitis in gastrocnemius tendons of turkey poults. The current study aimed to characterize the location and the extent of virus replication as well as the cytokine response induced by TARV during the first two weeks of infection. One-week-old male turkeys were inoculated orally with TARV (O'Neil strain. Copy numbers of viral genes were estimated in intestines, internal organs and tendons at ½, 1, 2, 3, 4, 7, 14 days Post inoculation (dpi. Cytokine profile was measured in intestines, spleen and leg tendons at 0, 4, 7 and 14 dpi. Viral copy number peaked in jejunum, cecum and bursa of Fabricius at 4 dpi. Copy numbers increased dramatically in leg tendons at 7 and 14 dpi while minimal copies were detected in internal organs and blood during the same period. Virus was detected in cloacal swabs at 1-2 dpi, and peaked at 14 dpi indicating enterotropism of the virus and its early shedding in feces. Elevation of IFN-α and IFN-β was observed in intestines at 7 dpi as well as a prominent T helper-1 response (IFN-γ at 7 and 14 dpi. IFN-γ and IL-6 were elevated in gastrocnemius tendons at 14 dpi. Elevation of antiviral cytokines in intestines occurred at 7dpi when a significant decline of viral replication in intestines was observed. T helper-1 response in intestines and leg tendons was the dominant T-helper response. These results suggest the possible correlation between viral replication and cytokine response in early infection of TARV in turkeys. Our findings provide novel insights which help elucidate viral pathogenesis in turkey tendons infected with TARV.

  18. The causes and clinical significance of exercise-induced silent myocardial ischemia evaluated by ischemic range and intensity with exercise Tl-201 myocardial SPECT

    International Nuclear Information System (INIS)

    Moriai, Naoki; Nakai, Kenji; Hiramori, Katsuhiko

    1992-01-01

    We investigated the causes and long-term prognosis of exercise-induced silent myocardial ischemia (SMI) by means of exercise Tl-201 myocardial SPECT (Ex-SPECT) in 97 patients with effort angina or old myocardial infarction (OMI). These patients were proven to have significant stenosis by coronary angiography. The subjects were divided into three groups based on the presence or absence of Tl-201 redistribution (RD) or angina during exercise testing. Group one consisted of 34 patients who had RD on Ex-SPECT and angina during exercise testing: the painful myocardial ischemia (PMI) group. The second group consisted of 38 patients who had RD on Ex-SPECT, but no angina during exercise testing: the SMI group. The third group consisted of 25 patients who had no RD: the RD (-) group. The ischemic range and intensity were quantified by the defect volume ratio (DVR) and defect severity index (DSI), respectively. Comparison of the DVR and DSI values for the PMI and SMI groups revealed that the DVR and DSI values for the SMI group were lower than those of the PMI group. Also the prognosis of the SMI group tended to be worse than that of the RD (-) group. Thus, we concluded that the SMI and PMI groups should receive identical treatment. (author)

  19. [Changes and significance of peripheral blood platelet count in tumor shrinkage induced by a low dose of CTX in T739 mice].

    Science.gov (United States)

    Li, Mo-lin; Jia, Yu-jie; Jiang, Miao-na; Shu, Xiao-hong; Li, Chuan-gang

    2008-06-01

    To establish a mouse model for BTT739 tumor-bearing mice cured by a low dose of cyclophosphamide (CTX). And then to observe the dynamic changes and significance of peripheral blood counts especially blood platelet count during tumor shrinkage induced by a low dose of CTX in T739 mice. Mouse bladder carcinoma tissues were inoculated subcutaneously into T739 mice. Seven days later, different doses of CTX or the same volume of NS were administered intraperitoneally to treat these tumor-bearing T739 mice. Tumor sizes were observed and recorded subsequently to find out the minimal dose of CTX that could cure most of these tumor-bearing mice. Then another 12 tumor-bearing mice were randomly divided into 15 mg/kg CTX treatment group and control group. Blood samples were obtained from orbital venous sinus on different times after CTX treatment. Complete blood counts were performed and the relationship between peripheral blood platelet counts and tumor shrinkage was analyzed. Within 2 weeks after CTX treatment, the speed of tumor shrinkage had a positive relationship with the dose of CTX used; but the survival rate of the tumor-bearing mice had a negative relationship with the dose of CTX used in 2 months after CTX treatment. 15 mg/kg CTX could cure most of the tumor bearing mice, while it had no remarkably inhibitive effects on peripheral blood cells. The perpherial platelet count increased to (1483.4+/-184.4)x10(9)/L in mice 6 h after CTX treatment. There was significant difference compared with that in mice of control group (1086.6+/-81.0)x10(9)/L (P0.05). CTX 15 mg/kg could cure most of bladder tumor-bearing T739 mice. The transient increase of the peripheral platelet count in 6 h after CTX treatment may relate to the antitumor effects of CTX.

  20. Gas Chromatography-Mass Spectrometry Analysis of Ulva fasciata (Green Seaweed Extract and Evaluation of Its Cytoprotective and Antigenotoxic Effects

    Directory of Open Access Journals (Sweden)

    Idania Rodeiro

    2015-01-01

    Full Text Available The chemical composition and biological properties of Ulva fasciata aqueous-ethanolic extract were examined. Five components were identified in one fraction prepared from the extract by gas chromatography-mass spectrometry, and palmitic acid and its ethyl ester accounted for 76% of the total identified components. Furthermore, we assessed the extract’s antioxidant properties by using the DPPH, ABTS, and lipid peroxidation assays and found that the extract had a moderate scavenging effect. In an experiment involving preexposition and coexposition of the extract (1–500 µg/mL and benzo[a]pyrene (BP, the extract was found to be nontoxic to C9 cells in culture and to inhibit the cytotoxicity induced by BP. As BP is biotransformed by CYP1A and CYP2B subfamilies, we explored the possible interaction of the extract with these enzymes. The extract (25–50 µg/mL inhibited CYP1A1 activity in rat liver microsomes. Analysis of the inhibition kinetics revealed a mixed-type inhibitory effect on CYP1A1 supersome. The effects of the extract on BP-induced DNA damage and hepatic CYP activity in mice were also investigated. Micronuclei induction by BP and liver CYP1A1/2 activities significantly decreased in animals treated with the extract. The results suggest that Ulva fasciata aqueous-ethanolic extract inhibits BP bioactivation and it may be a potential chemopreventive agent.

  1. Gas Chromatography-Mass Spectrometry Analysis of Ulva fasciata (Green Seaweed) Extract and Evaluation of Its Cytoprotective and Antigenotoxic Effects.

    Science.gov (United States)

    Rodeiro, Idania; Olguín, Sitlali; Santes, Rebeca; Herrera, José A; Pérez, Carlos L; Mangas, Raisa; Hernández, Yasnay; Fernández, Gisselle; Hernández, Ivones; Hernández-Ojeda, Sandra; Camacho-Carranza, Rafael; Valencia-Olvera, Ana; Espinosa-Aguirre, Jesús Javier

    2015-01-01

    The chemical composition and biological properties of Ulva fasciata aqueous-ethanolic extract were examined. Five components were identified in one fraction prepared from the extract by gas chromatography-mass spectrometry, and palmitic acid and its ethyl ester accounted for 76% of the total identified components. Furthermore, we assessed the extract's antioxidant properties by using the DPPH, ABTS, and lipid peroxidation assays and found that the extract had a moderate scavenging effect. In an experiment involving preexposition and coexposition of the extract (1-500 µg/mL) and benzo[a]pyrene (BP), the extract was found to be nontoxic to C9 cells in culture and to inhibit the cytotoxicity induced by BP. As BP is biotransformed by CYP1A and CYP2B subfamilies, we explored the possible interaction of the extract with these enzymes. The extract (25-50 µg/mL) inhibited CYP1A1 activity in rat liver microsomes. Analysis of the inhibition kinetics revealed a mixed-type inhibitory effect on CYP1A1 supersome. The effects of the extract on BP-induced DNA damage and hepatic CYP activity in mice were also investigated. Micronuclei induction by BP and liver CYP1A1/2 activities significantly decreased in animals treated with the extract. The results suggest that Ulva fasciata aqueous-ethanolic extract inhibits BP bioactivation and it may be a potential chemopreventive agent.

  2. Solid-solid phase transformation via internal stress-induced virtual melting, significantly below the melting temperature. Application to HMX energetic crystal.

    Science.gov (United States)

    Levitas, Valery I; Henson, Bryan F; Smilowitz, Laura B; Asay, Blaine W

    2006-05-25

    We theoretically predict a new phenomenon, namely, that a solid-solid phase transformation (PT) with a large transformation strain can occur via internal stress-induced virtual melting along the interface at temperatures significantly (more than 100 K) below the melting temperature. We show that the energy of elastic stresses, induced by transformation strain, increases the driving force for melting and reduces the melting temperature. Immediately after melting, stresses relax and the unstable melt solidifies. Fast solidification in a thin layer leads to nanoscale cracking which does not affect the thermodynamics or kinetics of the solid-solid transformation. Thus, virtual melting represents a new mechanism of solid-solid PT, stress relaxation, and loss of coherence at a moving solid-solid interface. It also removes the athermal interface friction and deletes the thermomechanical memory of preceding cycles of the direct-reverse transformation. It is also found that nonhydrostatic compressive internal stresses promote melting in contrast to hydrostatic pressure. Sixteen theoretical predictions are in qualitative and quantitative agreement with experiments conducted on the PTs in the energetic crystal HMX. In particular, (a) the energy of internal stresses is sufficient to reduce the melting temperature from 551 to 430 K for the delta phase during the beta --> delta PT and from 520 to 400 K for the beta phase during the delta --> beta PT; (b) predicted activation energies for direct and reverse PTs coincide with corresponding melting energies of the beta and delta phases and with the experimental values; (c) the temperature dependence of the rate constant is determined by the heat of fusion, for both direct and reverse PTs; results b and c are obtained both for overall kinetics and for interface propagation; (d) considerable nanocracking, homogeneously distributed in the transformed material, accompanies the PT, as predicted by theory; (e) the nanocracking does not

  3. Metformin induces a Senescence-associated gene Signature in Breast Cancer Cells

    Science.gov (United States)

    Williams, Christopher C.; Singleton, Brittany A.; Llopis, Shawn D.; Skripnikova, Elena V.

    2013-01-01

    Diabetic patients taking metformin have lower incidence of breast cancer than those taking other anti-diabetic medications. Additionally, triple negative breast cancer (TNBC), a form of breast cancer disproportionately afflicting premenopausal African American women, shows atypical susceptibility to metformin’s antiproliferative effect. The mechanisms involved in metformin’s function in TNBC has not yet been fully elucidated. Therefore, we sought to identify pathways regulated by metformin in using the MDA-MB-468 TNBC cell model. Metformin dose-dependently caused apoptosis, decreased cell viability, and induced cell morphology/chromatin condensation consistent with the permanent proliferative arrest. Furthermore, gene expression arrays revealed that metformin caused expression of stress markers DDIT3, CYP1A1, and GDF-15 and a concomitant reduction in PTGS1 expression. Our findings show that metformin may affect the viability and proliferative capacity of TNBC by inducing an antiproliferative gene signature, and that metformin may be effective in the treatment/prevention of TNBC. PMID:23395946

  4. Nrf2-inducing anti-oxidation stress response in the rat liver--new beneficial effect of lansoprazole.

    Science.gov (United States)

    Yamashita, Yasunobu; Ueyama, Takashi; Nishi, Toshio; Yamamoto, Yuta; Kawakoshi, Akatsuki; Sunami, Shogo; Iguchi, Mikitaka; Tamai, Hideyuki; Ueda, Kazuki; Ito, Takao; Tsuruo, Yoshihiro; Ichinose, Masao

    2014-01-01

    Lansoprazole is a potent anti-gastric ulcer drug that inhibits gastric proton pump activity. We identified a novel function for lansoprazole, as an inducer of anti-oxidative stress responses in the liver. Gastric administration of lansoprazole (10-100 mg/kg) to male Wistar rats produced a dose-dependent increase in hepatic mRNA levels of nuclear factor, erythroid-derived 2, -like 2 (Nrf2), a redox-sensitive transcription factor, at 3 h and Nrf2 immunoreactivity (IR) in whole hepatic lysates at 6 h. Conversely, the levels of Kelch-like ECH-associated protein (Keap1), which sequesters Nrf2 in the cytoplasm under un-stimulated conditions, were unchanged. Translocation of Nrf2 into the nuclei of hepatocytes was observed using western blotting and immunohistochemistry. Expression of mRNAs for Nrf2-dependent antioxidant and phase II enzymes, such as heme oxygenase 1 (HO-1), NAD (P) H dehydrogenase, quinone 1 (Nqo1), glutathione S-transferase A2 (Gsta2), UDP glucuronosyltransferase 1 family polypeptide A6 (Ugt1a6), were dose-dependently up-regulated at 3 h. Furthermore, the levels of HO-1 IR were dose-dependently increased in hepatocytes at 6 h. Subcutaneous administration of lansoprazole (30 mg/kg/day) for 7 successive days resulted in up-regulation and nuclear translocation of Nrf2 IR in hepatocytes and up-regulation of HO-1 IR in the liver. Pretreatment with lansoprazole attenuated thioacetamide (500 mg/kg)-induced acute hepatic damage via both HO-1-dependent and -independent pathways. Up-stream networks related to Nrf2 expression were investigated using microarray analysis, followed by data mining with Ingenuity Pathway Analysis. Up-regulation of the aryl hydrocarbon receptor (AhR)-cytochrome P450, family 1, subfamily a, polypeptide 1 (Cyp1a1) pathway was associated with up-regulation of Nrf2 mRNA. In conclusion, lansoprazole might have an alternative indication in the prevention and treatment of oxidative hepatic damage through the induction of both phase I and phase

  5. Nrf2-Inducing Anti-Oxidation Stress Response in the Rat Liver - New Beneficial Effect of Lansoprazole

    Science.gov (United States)

    Yamashita, Yasunobu; Ueyama, Takashi; Nishi, Toshio; Yamamoto, Yuta; Kawakoshi, Akatsuki; Sunami, Shogo; Iguchi, Mikitaka; Tamai, Hideyuki; Ueda, Kazuki; Ito, Takao; Tsuruo, Yoshihiro; Ichinose, Masao

    2014-01-01

    Lansoprazole is a potent anti-gastric ulcer drug that inhibits gastric proton pump activity. We identified a novel function for lansoprazole, as an inducer of anti-oxidative stress responses in the liver. Gastric administration of lansoprazole (10–100 mg/kg) to male Wistar rats produced a dose-dependent increase in hepatic mRNA levels of nuclear factor, erythroid-derived 2, -like 2 (Nrf2), a redox-sensitive transcription factor, at 3 h and Nrf2 immunoreactivity (IR) in whole hepatic lysates at 6 h. Conversely, the levels of Kelch-like ECH-associated protein (Keap1), which sequesters Nrf2 in the cytoplasm under un-stimulated conditions, were unchanged. Translocation of Nrf2 into the nuclei of hepatocytes was observed using western blotting and immunohistochemistry. Expression of mRNAs for Nrf2-dependent antioxidant and phase II enzymes, such as heme oxygenase 1 (HO-1), NAD (P) H dehydrogenase, quinone 1 (Nqo1), glutathione S-transferase A2 (Gsta2), UDP glucuronosyltransferase 1 family polypeptide A6 (Ugt1a6), were dose-dependently up-regulated at 3 h. Furthermore, the levels of HO-1 IR were dose-dependently increased in hepatocytes at 6 h. Subcutaneous administration of lansoprazole (30 mg/kg/day) for 7 successive days resulted in up-regulation and nuclear translocation of Nrf2 IR in hepatocytes and up-regulation of HO-1 IR in the liver. Pretreatment with lansoprazole attenuated thioacetamide (500 mg/kg)-induced acute hepatic damage via both HO-1-dependent and -independent pathways. Up-stream networks related to Nrf2 expression were investigated using microarray analysis, followed by data mining with Ingenuity Pathway Analysis. Up-regulation of the aryl hydrocarbon receptor (AhR)-cytochrome P450, family 1, subfamily a, polypeptide 1 (Cyp1a1) pathway was associated with up-regulation of Nrf2 mRNA. In conclusion, lansoprazole might have an alternative indication in the prevention and treatment of oxidative hepatic damage through the induction of both phase I and

  6. Experimentally induced, synergistic late effects of a single dose of radiation and aging: significance in LKS fraction as compared with mature blood cells.

    Science.gov (United States)

    Hirabayashi, Yoko; Tsuboi, Isao; Nakachi, Kei; Kusunoki, Yoichiro; Inoue, Tohru

    2015-03-01

    The number of murine mature blood cells recovered within 6 weeks after 2-Gy whole-body irradiation at 6 weeks of age, whereas in the case of the undifferentiated hematopoietic stem/progenitor cell (HSC/HPC) compartment [cells in the lineage-negative, c-kit-positive and stem-cell-antigen-1-positive (LKS) fraction], the numerical differences between mice with and without irradiation remained more than a year, but conclusively the cells showed numerical recovery. When mice were exposed to radiation at 6 months of age, acute damages of mature blood cells were rather milder probably because of their maturation with age; but again, cells in the LKS fraction were specifically damaged, and their numerical recovery was significantly delayed probably as a result of LKS-specific cellular damages. Interestingly, in contrast to the recovery of the number of cells in the LKS fraction, their quality was not recovered, which was quantitatively assessed on the basis of oxidative-stress-related fluorescence intensity. To investigate why the recovery in the number of cells in the LKS fraction was delayed, expression levels of genes related to cellular proliferation and apoptosis of cells in the bone marrow and LKS fraction were analyzed by real-time polymerase chain reaction (RT-PCR). In the case of 21-month-old mice after radiation exposure, Ccnd1, PiK3r1 and Fyn were overexpressed solely in cells in the LKS fraction. Because Ccnd1and PiK3r1 upregulated by aging were further upregulated by radiation, single-dose radiation seemed to induce the acceleration of aging, which is related to the essential biological responses during aging based on a lifetime-dependent relationship between a living creature and xenobiotic materials. Copyright © 2014 John Wiley & Sons, Ltd.

  7. Addition of sodium caseinate to skim milk increases nonsedimentable casein and causes significant changes in rennet-induced gelation, heat stability, and ethanol stability.

    Science.gov (United States)

    Lin, Yingchen; Kelly, Alan L; O'Mahony, James A; Guinee, Timothy P

    2017-02-01

    The protein content of skim milk was increased from 3.3 to 4.1% (wt/wt) by the addition of a blend of skim milk powder and sodium caseinate (NaCas), in which the weight ratio of skim milk powder to NaCas was varied from 0.8:0.0 to 0.0:0.8. Addition of NaCas increased the levels of nonsedimentable casein (from ∼6 to 18% of total casein) and calcium (from ∼36 to 43% of total calcium) and reduced the turbidity of the fortified milk, to a degree depending on level of NaCas added. Rennet gelation was adversely affected by the addition of NaCas at 0.2% (wt/wt) and completely inhibited at NaCas ≥0.4% (wt/wt). Rennet-induced hydrolysis was not affected by added NaCas. The proportion of total casein that was nonsedimentable on centrifugation (3,000 × g, 1 h, 25°C) of the rennet-treated milk after incubation for 1 h at 31°C increased significantly on addition of NaCas at ≥0.4% (wt/wt). Heat stability in the pH range 6.7 to 7.2 and ethanol stability at pH 6.4 were enhanced by the addition of NaCas. It is suggested that the negative effect of NaCas on rennet gelation is due to the increase in nonsedimentable casein, which upon hydrolysis by chymosin forms into small nonsedimentable particles that physically come between, and impede the aggregation of, rennet-altered para-casein micelles, and thereby inhibit the development of a gel network. Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  8. Therapeutic Non-Toxic Doses of TNF Induce Significant Regression in TNFR2-p75 Knockdown Lewis Lung Carcinoma Tumor Implants

    Science.gov (United States)

    Sasi, Sharath P.; Bae, Sanggyu; Song, Jin; Perepletchikov, Aleksandr; Schneider, Douglas; Carrozza, Joseph; Yan, Xinhua; Kishore, Raj; Enderling, Heiko; Goukassian, David A.

    2014-01-01

    Tumor necrosis factor-alpha (TNF) binds to two receptors: TNFR1/p55-cytotoxic and TNFR2/p75-pro-survival. We have shown that tumor growth in p75 knockout (KO) mice was decreased more than 2-fold in Lewis lung carcinoma (LLCs). We hypothesized that selective blocking of TNFR2/p75 LLCs may sensitize them to TNF-induced apoptosis and affect the tumor growth. We implanted intact and p75 knockdown (KD)-LLCs (>90%, using shRNA) into wild type (WT) mice flanks. On day 8 post-inoculation, recombinant murine (rm) TNF-α (12.5 ng/gr of body weight) or saline was injected twice daily for 6 days. Tumor volumes (tV) were measured daily and tumor weights (tW) on day 15, when study was terminated due to large tumors in LLC+TNF group. Tubular bones, spleens and peripheral blood (PB) were examined to determine possible TNF toxicity. There was no significant difference in tV or tW between LLC minus (-) TNF and p75KD/LLC-TNF tumors. Compared to 3 control groups, p75KD/LLC+TNF showed >2-5-fold decreases in tV (ptumors were 100% necrotic, the remaining revealed 40-60% necrosis. No toxicity was detected in bone marrow, spleen and peripheral blood. We concluded that blocking TNFR2/p75 in LLCs combined with intra-tumoral rmTNF injections inhibit LLC tumor growth. This could represent a novel and effective therapy against lung neoplasms and a new paradigm in cancer therapeutics. PMID:24664144

  9. Kluyveromyces marxianus and Saccharomyces boulardii induce distinct levels of dendritic cell cytokine secretion and significantly different T cell responses In Vitro

    DEFF Research Database (Denmark)

    Smith, Ida Mosbech; Baker, Adam; Christensen, Jeffrey E

    2016-01-01

    induction of a Treg response characterized by robust IL-10 secretion. In addition, we blocked relevant DC surface receptors and investigated the stimulating properties of β-glucan containing yeast cell wall extracts. K. marxianus and S. boulardii induced distinct levels of DC cytokine secretion, primarily...... driven by Dectin-1 recognition of β-glucan components in their cell walls. Upon co-incubation of yeast exposed DCs and naive T cells, S. boulardii induced a potent IFNγ response indicating TH1 mobilization. In contrast, K. marxianus induced a response dominated by Foxp3+ Treg cells, a characteristic...... of the present study was to characterize the immune modulating properties of the food-related yeast Kluyveromyces marxianus in terms of adaptive immune responses indicating inflammation versus tolerance and to explore the mechanisms behind the observed responses. Benchmarking against a Saccharomyces boulardii...

  10. In Vivo Imaging Reveals Significant Tumor Vascular Dysfunction and Increased Tumor Hypoxia-Inducible Factor-1α Expression Induced by High Single-Dose Irradiation in a Pancreatic Tumor Model

    Energy Technology Data Exchange (ETDEWEB)

    Maeda, Azusa [Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario (Canada); Department of Medical Biophysics, University of Toronto, Toronto, Ontario (Canada); Chen, Yonghong; Bu, Jiachuan; Mujcic, Hilda [Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario (Canada); Wouters, Bradly G. [Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario (Canada); Department of Medical Biophysics, University of Toronto, Toronto, Ontario (Canada); Department of Radiation Oncology, University of Toronto, Toronto, Ontario (Canada); DaCosta, Ralph S., E-mail: rdacosta@uhnres.utoronto.ca [Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario (Canada); Department of Medical Biophysics, University of Toronto, Toronto, Ontario (Canada); Techna Institute, University Health Network, Toronto, Ontario (Canada)

    2017-01-01

    Purpose: To investigate the effect of high-dose irradiation on pancreatic tumor vasculature and microenvironment using in vivo imaging techniques. Methods and Materials: A BxPC3 pancreatic tumor xenograft was established in a dorsal skinfold window chamber model and a subcutaneous hind leg model. Tumors were irradiated with a single dose of 4, 12, or 24 Gy. The dorsal skinfold window chamber model was used to assess tumor response, vascular function and permeability, platelet and leukocyte adhesion to the vascular endothelium, and tumor hypoxia for up to 14 days after 24-Gy irradiation. The hind leg model was used to monitor tumor size, hypoxia, and vascularity for up to 65 days after 24-Gy irradiation. Tumors were assessed histologically to validate in vivo observations. Results: In vivo fluorescence imaging revealed temporary vascular dysfunction in tumors irradiated with a single dose of 4 to 24 Gy, but most significantly with a single dose of 24 Gy. Vascular functional recovery was observed by 14 days after irradiation in a dose-dependent manner. Furthermore, irradiation with 24 Gy caused platelet and leukocyte adhesion to the vascular endothelium within hours to days after irradiation. Vascular permeability was significantly higher in irradiated tumors compared with nonirradiated controls 14 days after irradiation. This observation corresponded with increased expression of hypoxia-inducible factor-1α in irradiated tumors. In the hind leg model, irradiation with a single dose of 24 Gy led to tumor growth delay, followed by tumor regrowth. Conclusions: Irradiation of the BxPC3 tumors with a single dose of 24 Gy caused transient vascular dysfunction and increased expression of hypoxia-inducible factor-1α. Such biological changes may impact tumor response to high single-dose and hypofractionated irradiation, and further investigations are needed to better understand the clinical outcomes of stereotactic body radiation therapy.

  11. Human Tubal-Derived Mesenchymal Stromal Cells Associated with Low Level Laser Therapy Significantly Reduces Cigarette Smoke-Induced COPD in C57BL/6 mice.

    Directory of Open Access Journals (Sweden)

    Jean Pierre Schatzmann Peron

    Full Text Available Cigarette smoke-induced chronic obstructive pulmonary disease is a very debilitating disease, with a very high prevalence worldwide, which results in a expressive economic and social burden. Therefore, new therapeutic approaches to treat these patients are of unquestionable relevance. The use of mesenchymal stromal cells (MSCs is an innovative and yet accessible approach for pulmonary acute and chronic diseases, mainly due to its important immunoregulatory, anti-fibrogenic, anti-apoptotic and pro-angiogenic. Besides, the use of adjuvant therapies, whose aim is to boost or synergize with their function should be tested. Low level laser (LLL therapy is a relatively new and promising approach, with very low cost, no invasiveness and no side effects. Here, we aimed to study the effectiveness of human tube derived MSCs (htMSCs cell therapy associated with a 30mW/3J-660 nm LLL irradiation in experimental cigarette smoke-induced chronic obstructive pulmonary disease. Thus, C57BL/6 mice were exposed to cigarette smoke for 75 days (twice a day and all experiments were performed on day 76. Experimental groups receive htMSCS either intraperitoneally or intranasally and/or LLL irradiation either alone or in association. We show that co-therapy greatly reduces lung inflammation, lowering the cellular infiltrate and pro-inflammatory cytokine secretion (IL-1β, IL-6, TNF-α and KC, which were followed by decreased mucus production, collagen accumulation and tissue damage. These findings seemed to be secondary to the reduction of both NF-κB and NF-AT activation in lung tissues with a concomitant increase in IL-10. In summary, our data suggests that the concomitant use of MSCs + LLLT may be a promising therapeutic approach for lung inflammatory diseases as COPD.

  12. Kluyveromyces marxianus and Saccharomyces boulardii Induce Distinct Levels of Dendritic Cell Cytokine Secretion and Significantly Different T Cell Responses In Vitro

    NARCIS (Netherlands)

    Smith, Ida M; Baker, Adam; Christensen, Jeffrey E; Boekhout, Teun; Frøkiær, Hanne; Arneborg, Nils; Jespersen, Lene

    2016-01-01

    Interactions between members of the intestinal microbiota and the mucosal immune system can significantly impact human health, and in this context, fungi and food-related yeasts are known to influence intestinal inflammation through direct interactions with specialized immune cells in vivo. The aim

  13. Postmortem aging can significantly enhance water-holding capacity of broiler pectoralis major muscle measured by the salt-induced swelling/centrifuge method

    Science.gov (United States)

    Water-holding capacity (WHC) is one of the most important functional properties of fresh meat and can be significantly affected by postmortem muscle changes. Two experiments were carried out to evaluate the effects of postmortem aging on WHC of broiler pectoralis (p.) major muscle indicated with % s...

  14. DNA double strand break repair pathway plays a significant role in determining the radiotherapy induced normal tissue toxicity among head-and-neck and breast cancer

    International Nuclear Information System (INIS)

    Sadashiva, Satish Rao Bola; Mumbrekar, Kamalesh Dattaram; Venkatesh, Goutham Hassan; Fernandes, Donald Jerard; Bejadi, Vadhiraja Manjunath; Kapaettu, Satyamoorthy

    2014-01-01

    The ability to predict individual risk of radiotherapy induced normal tissue complications prior to the therapy may give an opportunity to personalize the treatment aiming improved therapeutic effect and quality of life. Therefore, predicting the risk of developing acute reactions before the initiation of radiation therapy may serve as a potential biomarker. DNA double-strand break (DSB) induction and its repair kinetics in lymphocytes of Head-and-Neck (n = 183) and Breast cancer (n = 132) patients undergoing chemoradiation or radiation therapy alone were analyzed by performing γ-H2AX foci, neutral comet and a modified neutral filter elution assay. Candidate radioresponsive genes like DNA repair, antioxidant pathway, profibrotic cytokine genes were screened for the common variants for their association with normal tissue toxicity outcome. Patients were stratified as non-over responders (NOR) and over responders (OR) based on their Radiation Therapy Oncology Group grading for normal tissue adverse reactions. Our results suggest that DSB repair plays a major role in the development of normal tissue adverse reactions in H and N and Breast cancer patients. The cellular (γ-H2AX analysis) and SNP analysis may have the potential to be developed into a clinically useful predictive assay for identifying the normal tissue over reactors

  15. Clinical significance of determination of changes of serum TNF-α levels, peripheral B lymphocyte count and T lymphocyte subsets distribution pattern in patients with pregnancy induced hypertension syndrome

    International Nuclear Information System (INIS)

    Zhao Wenjuan

    2006-01-01

    Objective: To explore the changes of serum TNF-α levels, peripheral B cell count and T subsets distribution pattern in patients with pregnancy induced hypertension syndrome. Methods: Serum TNF-α levels (with RIA), peripheral B cell count as well as T subsets (with monoclonal technique) were examined in 34 patients with pregnancy induced hypertension syndrome and 35 controls. Results: The serum TNF-α levels and B lymphocytes count were significantly higher than those in controls (P 3 , CD 4 , CD4/CD8 ratio were significantly lower than those in controls (P<0.01). Conclusion: Pregnancy induced hY- pertension syndrome is a kind of autoimmune diseases with abnormal immunoregulation. (authors)

  16. Role of field-induced nanostructures, zippering and size polydispersity on effective thermal transport in magnetic fluids without significant viscosity enhancement

    Science.gov (United States)

    Vinod, Sithara; Philip, John

    2017-12-01

    Magnetic nanofluids or ferrofluids exhibit extraordinary field dependant tunable thermal conductivity (k), which make them potential candidates for microelectronic cooling applications. However, the associated viscosity enhancement under an external stimulus is undesirable for practical applications. Further, the exact mechanism of heat transport and the role of field induced nanostructures on thermal transport is not clearly understood. In this paper, through systematic thermal, rheological and microscopic studies in 'model ferrofluids', we demonstrate for the first time, the conditions to achieve very high thermal conductivity to viscosity ratio. Highly stable ferrofluids with similar crystallite size, base fluid, capping agent and magnetic properties, but with slightly different size distributions, are synthesized and characterized by X-ray diffraction, small angle X-ray scattering, transmission electron microscopy, dynamic light scattering, vibrating sample magnetometer, Fourier transform infrared spectroscopy and thermo-gravimetry. The average hydrodynamic diameters of the particles were 11.7 and 10.1 nm and the polydispersity indices (σ), were 0.226 and 0.151, respectively. We observe that the system with smaller polydispersity (σ = 0.151) gives larger k enhancement (130% for 150 G) as compared to the one with σ = 0.226 (73% for 80 G). Further, our results show that dispersions without larger aggregates and with high density interfacial capping (with surfactant) can provide very high enhancement in thermal conductivity, with insignificant viscosity enhancement, due to minimal interfacial losses. We also provide experimental evidence for the effective heat conduction (parallel mode) through a large number of space filling linear aggregates with high aspect ratio. Microscopic studies reveal that the larger particles act as nucleating sites and facilitate lateral aggregation (zippering) of linear chains that considerably reduces the number density of space

  17. SIGNIFICANCE OF LACTATE DEHYDROGENASE AND ASPARTATE TRANSAMINASE AS BIOCHEMICAL MARKERS AND AS PREDICTORS OF SEVERITY OF PREGNANCY-INDUCED HYPERTENSION AND ITS COMPLICATIONS

    Directory of Open Access Journals (Sweden)

    Ramesh Sonowal

    2017-03-01

    Full Text Available BACKGROUND To compare serum Lactate Dehydrogenase (LDH and serum Aspartate Transaminase (AST of normotensive pregnant women with those of preeclamptic and eclamptic women. To determine the relationship of levels of serum lactate dehydrogenase and serum aspartate transaminase with severity of pregnancy-induced hypertension and its complications. MATERIALSAND METHODS The study was carried out on pregnant hypertensive patients attending outpatient department of Obstetrics and Gynaecology department, AMCH, Dibrugarh, Assam from 1 st July 2013 to 30 th June 2014. Normotensive pregnant women were taken as controls. Each serum sample from both the control group as well as study group was estimated for lactate dehydrogenase and aspartate transaminase using standard methods and a comparison is drawn and analysed using t-test and Chi-square test. RESULTS Serum lactate dehydrogenase and serum aspartate transaminase levels were higher in the study group in comparison to the study groups. The mean serum LDH was 198±30.03U/L in control group, whereas in preeclampsia and eclampsia, mean serum levels of LDH were 817±114U/L and 927±108U/L, respectively. The levels of the serum AST were found to be less than 600U/L in normotensive and preeclampsia patients and more than 600 U/L in eclampsia and other complications of PIH. CONCLUSION Serum lactate dehydrogenase and serum aspartate transaminase levels in patients suffering from preeclampsia and its complications are consistently higher compared to the normotensive pregnant patients. To determine the usefulness of inclusion of these enzymes along with other cardiac enzymes in the panel of investigations of pregnant women universally needs further large scale comparative studies.

  18. Insulin-Like growth factor-II (IGF-II) prevents proinflammatory cytokine-induced apoptosis and significantly improves islet survival after transplantation.

    Science.gov (United States)

    Hughes, Amy; Mohanasundaram, Daisy; Kireta, Svjetlana; Jessup, Claire F; Drogemuller, Chris J; Coates, P Toby H

    2013-03-15

    The early loss of functional islet mass (50-70%) due to apoptosis after clinical transplantation contributes to islet allograft failure. Insulin-like growth factor (IGF)-II is an antiapoptotic protein that is highly expressed in β-cells during development but rapidly decreases in postnatal life. We used an adenoviral (Ad) vector to overexpress IGF-II in isolated rat islets and investigated its antiapoptotic action against exogenous cytokines interleukin-1β- and interferon-γ-induced islet cell death in vitro. Using an immunocompromised marginal mass islet transplant model, the ability of Ad-IGF-II-transduced rat islets to restore euglycemia in nonobese diabetic/severe combined immunodeficient diabetic recipients was assessed. Ad-IGF-II transduction did not affect islet viability or function. Ad-IGF-II cytokine-treated islets exhibited decreased cell death (40% ± 2.8%) versus Ad-GFP and untransduced control islets (63.2% ± 2.5% and 53.6% ± 2.3%, respectively). Ad-IGF-II overexpression during cytokine treatment resulted in a marked reduction in terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive apoptotic cells (8.3% ± 1.4%) versus Ad-GFP control (41% ± 4.2%) and untransduced control islets (46.5% ± 6.2%). Western blot analysis confirmed that IGF-II inhibits apoptosis via activation of the phosphatidylinositol 3-kinase/Akt signaling pathway. Transplantation of IGF-II overexpressing islets under the kidney capsule of diabetic mice restored euglycemia in 77.8% of recipients compared with 18.2% and 47.5% of Ad-GFP and untransduced control islet recipients, respectively (Pislet transplant outcomes in vivo. Antiapoptotic gene transfer is a potentially powerful tool to improve islet survival after transplantation.

  19. Molecular mechanisms of the 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced inverted U-shaped dose responsiveness in anchorage independent growth and cell proliferation of human breast epithelial cells with stem cell characteristics

    International Nuclear Information System (INIS)

    Ahn, Nam-Shik; Hu, Hongbo; Park, Jin-Sung; Park, Joon-Suk; Kim, Jong-Sik; An, Sungwhan; Kong, Gu; Aruoma, Okezie I.; Lee, Yong-Soon; Kang, Kyung-Sun

    2005-01-01

    Although 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has a variety of carcinogenic and noncarcinogenic effects in experimental animals, its role in human carcinogenicity remain controversial. A simian virus 40-immortalized cell line from normal human breast epithelial cells with stem cells and luminal characteristics (M13SV1) was used to study whether TCDD can induce AIG positive colony formation and cause increased cell numbers in a inverted U-shaped dose-response manner. TCDD activated Akt, ERK2, and increased the expression of CYP1A1, PAI-2, IL-lb mRNA, and ERK2 protein levels. TCDD was able to increased phosphorylation and expression of ERK2 in same dose-response manner as AIG positive colony formation. Thus, TCDD induced tumorigenicity in M13SV1, possibly through the phosphorylation of ERK2 and/or Akt. Further, cDNA microarray with 7448 sequence-verified clones was used to profile various gene expression patterns after treatment of TCDD. Three clear patterns could be delineated: genes that were dose-dependently up-regulated, genes expressed in either U-shape and/or inverted U-shape. The fact that these genes are intrinsically related to breast epithelial cell proliferation and survival clearly suggests that they may be involved in the TCDD-induced breast tumorigenesis

  20. Clinical significance of changes of plasma endothelin vasoactive factors (ET and NO) as well as serum related interleukin (IL-6 and IL-8) levels in patients with pregnancy induced hypertension (PIH)

    International Nuclear Information System (INIS)

    Chen Ying

    2009-01-01

    Objective: To investigate the clinical etiological significance of changes of plasma endothelin (ET) and nitric oxide (NO) as well as serum interleukin-6 (IL-6) and interleukin-8 (IL-8) levels in patients with pregnancy induced hypertension. Methods: Plasma ET (with RIA), NO (with biochemistry) and serum IL-6, IL-8 (with RIA) levels were measured in 32 pregnant women with PIH, 35 normal pregnant women without PIH and 35 non-pregnant women (as controls). Results: The plasma ET, NO level were significantly higher in normal pregnant women than those in the non-pregnant women controls, while serum levels of IL-6 and IL-8 levels were only slightly higher without significance (P>0.05). Before treatment, the blood ET, IL-6 and IL- 8 levels were significantly higher in patients with pregnancy induced hypertension than those in the control (P<0.01), while plasma levels of NO were significantly decreased (P<0.01), Two weeks after treatment, the plasma ET, NO and serum IL-6 and IL-8 levels were markedly corrected with no significantly differences from those in controls. The ET levels and serum IL-6, IL-8 levels were mutually positively correlated (r=0.6097, 0.7213, P<0.01). Conclusion: Determination of changes of plasma ET and NO, serum IL-6 and IL-8 levels in patients with pregnancy induced hypertension was helpful for outcome prediction. (authors)

  1. Lithium-induced alterations in the testis of the male roseringed parakeet (Psittacula krameri) : evidence for significant structural changes and disruption in the spermatogenetic activity.

    Science.gov (United States)

    Banerji, T K; Maitra, S K; Basu, A; Hawkins, H K

    1999-02-01

    In this report, we have examined the effects of lithium on testicular morphology in a male subtropical wild avian species, the roseringed parakeet (Psittacula krameri). Adult male birds were collected during the months of February-March, a time when the testicular gametogenic activity in these seasonally breeding birds is at its peak. They were injected, intramuscularly, twice daily (07:00 and 19:00 h) with lithium chloride (Sigma Chemical Company) at a dosage of 0.5 mEq/Kg body weight either for 5 or 10 days. A significant decrease in both the absolute and relative testicular weights was evident in the lithium-treated birds as compared to those of the saline-injected control animals. Light microscopic studies of the testis in the lithium-treated animals showed a wide range of degenerative changes. These included a) a significant reduction in the diameter of seminiferous tubules; b) necrosis and exfoliation of most of the germ cells in the seminiferous tubular lumen with the exception of the spermatogonia; and c) a significant reduction in the number of mature spermatozoa in the tubular lumen. These degenerative changes were dependent on the duration of lithium treatment and were evident when the plasma lithium concentrations were well below the human therapeutic range. Leydig cell morphology was not affected by lithium however. Our results provide the first experimental evidence of lithium's adverse reproductive function in an avian species. These data provide further support to the view that lithium adversely affects the male reproductive system and that these effects extend beyond mammalian species.

  2. Significance of changes of plasma levels of AM, CGRP, sICAM-1 and THcy in patients with pregnancy induced hypertension (PIM)

    International Nuclear Information System (INIS)

    Xu Fei; Chen Daozhen; Wang Junfeng; Yang Min; Pan Donghui

    2009-01-01

    Objective: To study the relationship between changes of plasma levels of adrenomedullin(AM), calcitonin-gene-related peptide(CGRP), soluble intercellular adhesion molecule-1(sICAM-1), total homocysteine(THcy) and the progression of disease in patients with PIH. Methods: Plasma AM, CGRP(with RIA), sICAM-1(with ELISA) and THcy(with CLIA) levels were measured in 1)35 non-pregnant women 2) 35 normal pregnant women and 3) 35 women with PIH(both before and after two weeks' treatment). Results: The plasma AM levels in normal pregnant women were insignificantly higher than those in non-pregnant women (P>0.05). The plasma AM levels in patients with PIH before treatment were significantly higher than those in normal pregnant women (P 0.05). Both plasma sICAM-1 and THcy levels in normal pregnant women were insignificantly higher than those in non-pregnant women. The levels were significantly higher in patients with PIH before treatment than those in normal pregnant women and became only insignificantly higher after treatment. Conclusion: Changes of plasma levels of AM, CGRP, sICAM-1 and THcy were closely related to the disease process in patients with PIH. (authors)

  3. Cellular immunotherapy using irradiated lung cancer cell vaccine co-expressing GM-CSF and IL-18 can induce significant antitumor effects

    International Nuclear Information System (INIS)

    Tian, Hongwei; Zhang, Xiaomei; Dai, Lei; Chen, Xiaolei; Zhang, Shuang; Yang, Yang; Yu, Dechao; Wei, Yuquan; Deng, Hongxin; Shi, Gang; Yang, Guoyou; Zhang, Junfeng; Li, Yiming; Du, Tao; Wang, Jianzhou; Xu, Fen; Cheng, Lin

    2014-01-01

    Although the whole tumor cell vaccine can provide the best source of immunizing antigens, there is still a limitation that most tumors are not naturally immunogenic. Tumor cells genetically modified to secrete immune activating cytokines have been proved to be more immunogenic. IL-18 could augment proliferation of T cells and cytotoxicity of NK cells. GM-CSF could stimulate dendritic cells, macrophages and enhance presentation of tumor antigens. In our study, we used mouse GM-CSF combined with IL-18 to modify Lewis lung cancer LL/2, then investigated whether vaccination could suppress tumor growth and promote survival. The Lewis lung cancer LL/2 was transfected with co-expressing mouse GM-CSF and IL-18 plasmid by cationic liposome, then irradiated with a sublethal dose X ray (100 Gy) to prepare vaccines. Mice were subcutaneously immunized with this inactivated vaccine and then inoculated with autologous LL/2 to estimate the antitumor efficacy. The studies reported here showed that LL/2 tumor cell vaccine modified by a co-expressing mouse GM-CSF and IL-18 plasmid could significantly inhibit tumor growth and increased survival of the mice bearing LL/2 tumor whether prophylactic or adoptive immunotherapy in vivo. A significant reduction of proliferation and increase of apoptosis were also observed in the tumor treated with vaccine of co-expressing GM-CSF and IL-18. The potent antitumor effect correlated with higher secretion levels of pro-inflammatory cytokines such as IL-18, GM-CSF, interferon-γ in serum, the proliferation of CD4 + IFN-γ + , CD8 + IFN-γ + T lymphocytes in spleen and the infiltration of CD4 + , CD8 + T in tumor. Furthermore, the mechanism of tumor-specific immune response was further proved by 51 Cr cytotoxicity assay in vitro and depletion of CD4, CD8, NK immune cell subsets in vivo. The results suggested that the antitumor mechanism was mainly depended on CD4 + , CD8 + T lymphocytes. These results provide a new insight into therapeutic mechanisms

  4. Repetitive long-term hyperbaric oxygen treatment (HBOT administered after experimental traumatic brain injury in rats induces significant remyelination and a recovery of sensorimotor function.

    Directory of Open Access Journals (Sweden)

    Klaus Kraitsy

    Full Text Available Cells in the central nervous system rely almost exclusively on aerobic metabolism. Oxygen deprivation, such as injury-associated ischemia, results in detrimental apoptotic and necrotic cell loss. There is evidence that repetitive hyperbaric oxygen therapy (HBOT improves outcomes in traumatic brain-injured patients. However, there are no experimental studies investigating the mechanism of repetitive long-term HBOT treatment-associated protective effects. We have therefore analysed the effect of long-term repetitive HBOT treatment on brain trauma-associated cerebral modulations using the lateral fluid percussion model for rats. Trauma-associated neurological impairment regressed significantly in the group of HBO-treated animals within three weeks post trauma. Evaluation of somatosensory-evoked potentials indicated a possible remyelination of neurons in the injured hemisphere following HBOT. This presumption was confirmed by a pronounced increase in myelin basic protein isoforms, PLP expression as well as an increase in myelin following three weeks of repetitive HBO treatment. Our results indicate that protective long-term HBOT effects following brain injury is mediated by a pronounced remyelination in the ipsilateral injured cortex as substantiated by the associated recovery of sensorimotor function.

  5. Renal Subcapsular Transplantation of PSC-Derived Kidney Organoids Induces Neo-vasculogenesis and Significant Glomerular and Tubular Maturation In Vivo

    Directory of Open Access Journals (Sweden)

    Cathelijne W. van den Berg

    2018-03-01

    Full Text Available Summary: Human pluripotent stem cell (hPSC-derived kidney organoids may facilitate disease modeling and the generation of tissue for renal replacement. Long-term application, however, will require transferability between hPSC lines and significant improvements in organ maturation. A key question is whether time or a patent vasculature is required for ongoing morphogenesis. Here, we show that hPSC-derived kidney organoids, derived in fully defined medium conditions and in the absence of any exogenous vascular endothelial growth factor, develop host-derived vascularization. In vivo imaging of organoids under the kidney capsule confirms functional glomerular perfusion as well as connection to pre-existing vascular networks in the organoids. Wide-field electron microscopy demonstrates that transplantation results in formation of a glomerular basement membrane, fenestrated endothelial cells, and podocyte foot processes. Furthermore, compared with non-transplanted organoids, polarization and segmental specialization of tubular epithelium are observed. These data demonstrate that functional vascularization is required for progressive morphogenesis of human kidney organoids. : In this article, Van den Berg and colleagues show that PSC-derived kidney organoids contain nephron structures but remain disorganized and immature after prolonged culture. Upon transplantation, the organoids develop host-derived vascularization, functional glomerular perfusion, and connection to pre-existing vascular networks. The authors conclude that patent vasculature is required for ongoing morphogenesis and maturation of these kidney organoids. Keywords: human pluripotent stem cells, directed differentiation, kidney organoids, transplantation, intravital microscopy, vascularization, maturation

  6. Glucoraphanin, the bioprecursor of the widely extolled chemopreventive agent sulforaphane found in broccoli, induces Phase-I xenobiotic metabolizing enzymes and increases free radical generation in rat liver

    Energy Technology Data Exchange (ETDEWEB)

    Perocco, Paolo [Department of Experimental Pathology, Cancerology Section, viale Filopanti 22, I-40126, University of Bologna, Bologna (Italy); Bronzetti, Giorgio [Institute of Biology and Agricultural Biotechnology - CNR Research Area, via Moruzzi, I-56124 Pisa (Italy); Canistro, Donatella; Sapone, Andrea; Affatato, Alessandra; Pozzetti, Laura; Broccoli, Massimiliano [Department of Pharmacology, Molecular Toxicology Unit, via Irnerio 48, I-40126, University of Bologna, Bologna (Italy); Valgimigli, Luca [Department of Organic Chemistry ' A. Mangini' , Viale Risorgimento 4, I-40127, Alma-Mater Studiorum, University of Bologna, Bologna (Italy); Pedulli, Gian Franco [Department of Organic Chemistry ' A. Mangini' , Viale Risorgimento 4, I-40127, Alma-Mater Studiorum, University of Bologna, Bologna (Italy); Iori, Renato [C.R.A - Research Institute for Industrial Crops, via di Corticella 133, I-40129 Bologna (Italy); Barillari, Jessica [Institute of Biology and Agricultural Biotechnology - CNR Research Area, via Moruzzi, I-56124 Pisa (Italy)]|[C.R.A - Research Institute for Industrial Crops, via di Corticella 133, I-40129 Bologna (Italy); Sblendorio, Valeriana [Department of Pharmacology, Molecular Toxicology Unit, via Irnerio 48, I-40126, University of Bologna, Bologna (Italy); Legator, Marvin S. [Department of Preventive Medicine and Community Health, Division of Environmental Toxicology, The University of Texas Medical Branch at Galveston, 700 Harborside Drive, Galveston, TX 77555-1110 (United States); Paolini, Moreno [Department of Pharmacology, Molecular Toxicology Unit, via Irnerio 48, I-40126, University of Bologna, Bologna (Italy); Abdel-Rahman, Sherif Z. [Department of Preventive Medicine and Community Health, Division of Environmental Toxicology, The University of Texas Medical Branch at Galveston, 700 Harborside Drive, Galveston, TX 77555-1110 (United States)]. E-mail: sabdelra@utmb.edu

    2006-03-20

    Epidemiological and animal studies linking high fruit and vegetable consumption to lower cancer risk have strengthened the belief that long-term administration of isolated naturally occurring dietary constituents could reduce the risk of cancer. In recent years, metabolites derived from phytoalexins, such as glucoraphanin found in broccoli and other cruciferous vegetables (Brassicaceae), have gained much attention as potential cancer chemopreventive agents. The protective effect of these micronutrients is assumed to be due to the inhibition of Phase-I carcinogen-bioactivating enzymes and/or induction of Phase-II detoxifying enzymes, an assumption that still remains uncertain. The protective effect of glucoraphanin is thought to be due to sulforaphane, an isothiocyanate metabolite produced from glucoraphanin by myrosinase. Here we show, in rat liver, that while glucoraphanin slightly induces Phase-II enzymes, it powerfully boosts Phase-I enzymes, including activators of polycyclic aromatic hydrocarbons (PAHs), nitrosamines and olefins. Induction of the cytochrome P450 (CYP) isoforms CYP1A1/2, CYP3A1/2 and CYP2E1 was confirmed by Western immunoblotting. CYP induction was paralleled by an increase in the corresponding mRNA levels. Concomitant with this Phase-I induction, we also found that glucoraphanin generated large amount of various reactive radical species, as determined by electron paramagnetic resonance (EPR) spectrometry coupled to a radical-probe technique. This suggests that long-term uncontrolled administration of glucoraphanin could actually pose a potential health hazard.

  7. Glucoraphanin, the bioprecursor of the widely extolled chemopreventive agent sulforaphane found in broccoli, induces Phase-I xenobiotic metabolizing enzymes and increases free radical generation in rat liver

    International Nuclear Information System (INIS)

    Perocco, Paolo; Bronzetti, Giorgio; Canistro, Donatella; Valgimigli, Luca; Sapone, Andrea; Affatato, Alessandra; Pedulli, Gian Franco; Pozzetti, Laura; Broccoli, Massimiliano; Iori, Renato; Barillari, Jessica; Sblendorio, Valeriana; Legator, Marvin S.; Paolini, Moreno; Abdel-Rahman, Sherif Z.

    2006-01-01

    Epidemiological and animal studies linking high fruit and vegetable consumption to lower cancer risk have strengthened the belief that long-term administration of isolated naturally occurring dietary constituents could reduce the risk of cancer. In recent years, metabolites derived from phytoalexins, such as glucoraphanin found in broccoli and other cruciferous vegetables (Brassicaceae), have gained much attention as potential cancer chemopreventive agents. The protective effect of these micronutrients is assumed to be due to the inhibition of Phase-I carcinogen-bioactivating enzymes and/or induction of Phase-II detoxifying enzymes, an assumption that still remains uncertain. The protective effect of glucoraphanin is thought to be due to sulforaphane, an isothiocyanate metabolite produced from glucoraphanin by myrosinase. Here we show, in rat liver, that while glucoraphanin slightly induces Phase-II enzymes, it powerfully boosts Phase-I enzymes, including activators of polycyclic aromatic hydrocarbons (PAHs), nitrosamines and olefins. Induction of the cytochrome P450 (CYP) isoforms CYP1A1/2, CYP3A1/2 and CYP2E1 was confirmed by Western immunoblotting. CYP induction was paralleled by an increase in the corresponding mRNA levels. Concomitant with this Phase-I induction, we also found that glucoraphanin generated large amount of various reactive radical species, as determined by electron paramagnetic resonance (EPR) spectrometry coupled to a radical-probe technique. This suggests that long-term uncontrolled administration of glucoraphanin could actually pose a potential health hazard

  8. Studies on clinical significance of exercise-induced ST-segment depression at non-infarct-related leads in the patients with prior myocardial infarction using the stress scintigraphy

    International Nuclear Information System (INIS)

    Ohkubo, Toshitaka

    1988-01-01

    Stress Tl-201 myocardial imaging and stress radionuclide ventriculography were performed in a total of 67 patients with prior myocardial infarction (MI) to assess the clinical significance of exercise induced ST-segment depression at non-infarct-related leads on ECG during the chronic stage. The patients consisted of 12 with inferior MI with single vessel disease (SVD) that showed no precordial ST-segment depression; 7 with inferior MI with SVD accompanied by precordial ST-segment depression; 13 with inferior MI with multivessel disease (MVD); 20 with anterior MI with SVD that showed no inferior ST-segment depression; 4 with anterior MI with SVD accompanied by inferior ST-segment depression; and 11 with anterior MI with MVD. In cases of SVD, the incidence of ST-segment depression at non-infarct-related leads was higher for inferior MI (36.8%) than anterior MI (16.7%). Myocardial imaging revealed large infarct and infarct extending into the inferoseptal wall of the left ventricle (LV) in cases of exercise induced precordial ST-segment depression; and infarct extending into the lateral wall of LV in cases of exercise induced inferior ST-segment depression. In detecting MVD, stress Tl-201 myocardial imaging was superior to exercise electrocardiography and stress radionuclide ventriculography, but this was not statistically significant. Prognostic value of error rate for detecting MVD was significantly improved with a discriminant analysis. Exercise induced ST-segment depression on ECG should be of clinical significance in reflecting myocardial ischemia around an infarcted area. (Namekawa, K)

  9. The inhibition of subchondral bone lesions significantly reversed the weight-bearing deficit and the overexpression of CGRP in DRG neurons, GFAP and Iba-1 in the spinal dorsal horn in the monosodium iodoacetate induced model of osteoarthritis pain.

    Directory of Open Access Journals (Sweden)

    Degang Yu

    Full Text Available Chronic pain is the most prominent and disabling symptom of osteoarthritis (OA. Clinical data suggest that subchondral bone lesions contribute to the occurrence of joint pain. The present study investigated the effect of the inhibition of subchondral bone lesions on joint pain.Osteoarthritic pain was induced by an injection of monosodium iodoacetate (MIA into the rat knee joint. Zoledronic acid (ZOL, a third generation of bisphosphonate, was used to inhibit subchondral bone lesions. Joint histomorphology was evaluated using X-ray micro computed tomography scanning and hematoxylin-eosin staining. The activity of osteoclast in subchondral bone was evaluated using tartrate-resistant acid phosphatase staining. Joint pain was evaluated using weight-bearing asymmetry, the expression of calcitonin gene-related peptide (CGRP in the dorsal root ganglion (DRG, and spinal glial activation status using glial fibrillary acidic protein (GFAP and ionized calcium binding adaptor molecule-1 (Iba-1 immunofluorescence. Afferent neurons in the DRGs that innervated the joints were identified using retrograde fluorogold labeling.MIA injections induced significant histomorphological alterations and joint pain. The inhibition of subchondral bone lesions by ZOL significantly reduced the MIA-induced weight-bearing deficit and overexpression of CGRP in DRG neurons, GFAP and Iba-1 in the spinal dorsal horn at 3 and 6 weeks after MIA injection; however, joint swelling and synovial reaction were unaffected.The inhibition of subchondral bone lesions alleviated joint pain. Subchondral bone lesions should be a key target in the management of osteoarthritic joint pain.

  10. Significance of exercise-induced ST segment depression in patients with myocardial infarction involving the left circumflex artery. Evaluation by exercise thallium-201 myocardial single photon emission computed tomography

    International Nuclear Information System (INIS)

    Koitabashi, Norimichi; Toyama, Takuji; Hoshizaki, Hiroshi

    2000-01-01

    The significance of exercise-induced ST segment depression in patients with left circumflex artery involvement was investigated by comparing exercise electrocardiography with exercise thallium-201 single photon emission computed tomography (Tl-SPECT) and the wall motion estimated by left ventriculography. Tl-SPECT and exercise electrocardiography were simultaneously performed in 51 patients with left circumflex artery involvement (angina pectoris 30, myocardial infarction 21). In patients with myocardial infarction, exercise-induced ST depression was frequently found in the V 2 , V 3 and V 4 leads. In patients with angina pectoris, ST depression was frequently found in the II, III, aV F , V 5 and V 6 leads. There was no obvious difference in the leads of ST depression in patients with myocardial infarction with ischemia and without ischemia on Tl-SPECT images. In patients with myocardial infarction, the lateral wall motion of the infarcted area evaluated by left ventriculography was more significantly impaired in the patients with ST depression than without ST depression (p<0.01). Exercise-induced ST depression in the precordial leads possibly reflects wall motion abnormality rather than ischemia in the lateral infarcted myocardium. (author)

  11. Clinical significance of determination of changes of plasma Hcy and serum folic acid and vitamin B{sub 12} levels in patients with pregnancy induced hypertension complicated with nephr opathy

    Energy Technology Data Exchange (ETDEWEB)

    Dongxia, Zhou; Xiaoli, Pan; Fangwen, Xie; Jifeng, Fan [Shuyang County People' s Hospital, Jiangsu, Shuyang (China)

    2007-10-15

    Objective: To investigate the clinical significance of changes of plasma homocysteine (Hcy), serum folic acid and vitamin B{sub 12} levels in patients with pregnancy induced hypertension (PIH) complicated with nephropathy. Methods: Plasma Hcy levels was measured with immuno chemistry and serum folic acid and vitamin B{sub 12} levels were detected with RIA in 32 pregnant women with PIH complicated with nephrophy and 70 pregnant women with PIH but without nephrophy and 35 pregnant women without PIH (as controls). Results; The plasma Hcy levels in patients with PIH were significantly higher than those without (i.e. controls) (P<0.01), while the serum folic acid, vitaminB{sub 12} levels decreased markedly (P<0.01). Among the pregnant women with PIH, plasma Hcy levels were significantly higher and serum folic acid, B{sub 12} levels were significantly lower in the patients complicated with nepropathy than those in patients without nephropathy (P<0.01). conclusion: Determination of plasma Hcy and serum folic acid and vitaminB{sub 12} levels is clinically useful in the management in patients with pregnancy induced hypertension complicated with nephropthy. (authors)

  12. FTY720-loaded poly(DL-lactide-co-glycolide) electrospun scaffold significantly increases microvessel density over 7 days in streptozotocin-induced diabetic C57b16/J mice: preliminary results.

    Science.gov (United States)

    Bowers, D T; Chhabra, P; Langman, L; Botchwey, E A; Brayman, K L

    2011-11-01

    Nanofiber scaffolds could improve islet transplant success by physically mimicking the shape of extracellular matrix and by acting as a drug-delivery vehicle. Scaffolds implanted in alternate transplant sites must be prevascularized or very quickly vascularized following transplantation to prevent hypoxia-induced islet necrosis. The local release of the S1P prodrug FTY720 induces diameter enlargement and increases in length density. The objective of this preliminary study was to evaluate length and diameter differences between diabetic and nondiabetic animals implanted with FTY720-containing electrospun scaffolds using intravital imaging of dorsal skinfold window chambers. Electrospun mats of randomly oriented fibers we created from polymer solutions of PLAGA (50:50 LA:GA) with and without FTY720 loaded at a ratio of 1:200 (FTY720:PLAGA by wt). The implanted fiber mats were 4 mm in diameter and ∼0.2 mm thick. Increases in length density and vessel diameter were assessed by automated analysis of images over 7 days in RAVE, a Matlab program. Image analysis of repeated measures of microvessel metrics demonstrated a significant increase in the length density from day 0 to day 7 in the moderately diabetic animals of this preliminary study (P < .05). Furthermore, significant differences in length density at day 0 and day 3 were found between recently STZ-induced moderately diabetic and nondiabetic animals in response to FTY720 local release (P < .05, Student t test). Driving the islet revascularization process using local release of factors, such as FTY720, from biodegradable polymers makes an attractive system for the improvement of islet transplant success. Preliminary study results suggest that a recently induced moderately diabetic state may potentiate the mechanism by which local release of FTY720 from polymer fibers increases length density of microvessels. Therefore, local release of S1P receptor-targeted drugs is under further investigation for improvement of

  13. Glucosinolates from pak choi and broccoli induce enzymes and inhibit inflammation and colon cancer differently.

    Science.gov (United States)

    Lippmann, Doris; Lehmann, Carsten; Florian, Simone; Barknowitz, Gitte; Haack, Michael; Mewis, Inga; Wiesner, Melanie; Schreiner, Monika; Glatt, Hansruedi; Brigelius-Flohé, Regina; Kipp, Anna P

    2014-06-01

    High consumption of Brassica vegetables is considered to prevent especially colon carcinogenesis. The content and pattern of glucosinolates (GSLs) can highly vary among different Brassica vegetables and may, thus, affect the outcome of Brassica intervention studies. Therefore, we aimed to feed mice with diets containing plant materials of the Brassica vegetables broccoli and pak choi. Further enrichment of the diets by adding GSL extracts allowed us to analyze the impact of different amounts (GSL-poor versus GSL-rich) and different patterns (broccoli versus pak choi) of GSLs on inflammation and tumor development in a model of inflammation-triggered colon carcinogenesis (AOM/DSS model). Serum albumin adducts were analyzed to confirm the up-take and bioactivation of GSLs after feeding the Brassica diets for four weeks. In agreement with their high glucoraphanin content, broccoli diets induced the formation of sulforaphane-lysine adducts. Levels of 1-methoxyindolyl-3-methyl-histidine adducts derived from neoglucobrassicin were the highest in the GSL-rich pak choi group. In the colon, the GSL-rich broccoli and the GSL-rich pak choi diet up-regulated the expression of different sets of typical Nrf2 target genes like Nqo1, Gstm1, Srxn1, and GPx2. GSL-rich pak choi induced the AhR target gene Cyp1a1 but did not affect Ugt1a1 expression. Both colitis and tumor number were drastically reduced after feeding the GSL-rich pak choi diet while the other three diets had no effect. GSLs can act anti-inflammatory and anti-carcinogenic but both effects depend on the specific amount and pattern of GSLs within a vegetable. Thus, a high Brassica consumption cannot be generally considered to be cancer-preventive.

  14. Significant interactions between maternal PAH exposure and haplotypes in candidate genes on B[a]P-DNA adducts in a NYC cohort of non-smoking African-American and Dominican mothers and newborns

    Science.gov (United States)

    Tang, Deliang

    2014-01-01

    Polycyclic aromatic hydrocarbons (PAH) are a class of chemicals common in the environment. Certain PAH are carcinogenic, although the degree to which genetic variation influences susceptibility to carcinogenic PAH remains unclear. Also unknown is the influence of genetic variation on the procarcinogenic effect of in utero exposures to PAH. Benzo[a]pyrene (B[a]P) is a well-studied PAH that is classified as a probable human carcinogen. Within our New York City-based cohort, we explored interactions between maternal exposure to airborne PAH during pregnancy and maternal and newborn haplotypes (and in one case, a single-nucleotide polymorphism) in key B[a]P metabolism genes on B[a]P-DNA adducts in paired cord blood samples. The study subjects included non-smoking African-American (n = 132) and Dominican (n = 235) women with available data on maternal PAH exposure, paired cord adducts and genetic data who resided in the Washington Heights, Central Harlem and South Bronx neighborhoods of New York City. We selected seven maternal and newborn genes related to B[a]P metabolism, detoxification and repair for our analyses: CYP1A1, CYP1A2, CYP1B1, GSTM3, GSTT2, NQO1 and XRCC1. We found significant interactions between maternal PAH exposure and haplotype on cord B[a]P-DNA adducts in the following genes: maternal CYP1B1, XRCC1 and GSTM3, and newborn CYP1A2 and XRCC1 in African-Americans; and maternal XRCC1 and newborn NQO1 in Dominicans. These novel findings highlight differences in maternal and newborn genetic contributions to B[a]P-DNA adduct formation, as well as ethnic differences in gene–environment interactions, and have the potential to identify at-risk subpopulations who are susceptible to the carcinogenic potential of B[a]P. PMID:24177223

  15. Role of brain cytochrome P450 mono-oxygenases in bilirubin oxidation-specific induction and activity.

    Science.gov (United States)

    Gambaro, Sabrina E; Robert, Maria C; Tiribelli, Claudio; Gazzin, Silvia

    2016-02-01

    In the Crigler-Najjar type I syndrome, the genetic absence of efficient hepatic glucuronidation of unconjugated bilirubin (UCB) by the uridine 5'-diphospho-glucuronosyltransferase1A1 (UGT1A1) enzyme produces the rise of UCB level in blood. Its entry to central nervous system could generate toxicity and neurological damage, and even death. In the past years, a compensatory mechanism to liver glucuronidation has been indicated in the hepatic cytochromes P450 enzymes (Cyps) which are able to oxidize bilirubin. Cyps are expressed also in the central nervous system, the target of bilirubin toxicity, thus making them theoretically important to confer a protective activity toward bilirubin accumulation and neurotoxicity. We therefore investigated the functional induction (mRNA, EROD/MROD) and the ability to oxidize bilirubin of Cyp1A1, 1A2, and 2A3 in primary astrocytes cultures obtained from two rat brain region (cortex: Cx and cerebellum: Cll). We observed that Cyp1A1 was the Cyp isoform more easily induced by beta-naphtoflavone (βNF) in both Cx and Cll astrocytes, but oxidized bilirubin only after uncoupling by 3, 4,3',4'-tetrachlorobiphenyl (TCB). On the contrary, Cyp1A2 was the most active Cyp in bilirubin clearance without uncoupling, but its induction was confined only in Cx cells. Brain Cyp2A3 was not inducible. In conclusion, the exposure of astrocytes to βNF plus TCB significantly enhanced Cyp1A1 mediating bilirubin clearance, improving cell viability in both regions. These results may be a relevant groundwork for the manipulation of brain Cyps as a therapeutic approach in reducing bilirubin-induced neurological damage.

  16. Elevated blood pressure in cytochrome P4501A1 knockout mice is associated with reduced vasodilation to omega − 3 polyunsaturated fatty acids

    Energy Technology Data Exchange (ETDEWEB)

    Agbor, Larry N.; Walsh, Mary T.; Boberg, Jason R.; Walker, Mary K., E-mail: mwalker@salud.unm.edu

    2012-11-01

    In vitro cytochrome P4501A1 (CYP1A1) metabolizes omega − 3 polyunsaturated fatty acids (n − 3 PUFAs); eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), primarily to 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP), respectively. These metabolites have been shown to mediate vasodilation via increases in nitric oxide (NO) and activation of potassium channels. We hypothesized that genetic deletion of CYP1A1 would reduce vasodilatory responses to n − 3 PUFAs, but not the metabolites, and increase blood pressure (BP) due to decreases in NO. We assessed BP by radiotelemetry in CYP1A1 wildtype (WT) and knockout (KO) mice ± NO synthase (NOS) inhibitor. We also assessed vasodilation to acetylcholine (ACh), EPA, DHA, 17,18-EEQ and 19,20-EDP in aorta and mesenteric arterioles. Further, we assessed vasodilation to an NO donor and to DHA ± inhibitors of potassium channels. CYP1A1 KO mice were hypertensive, compared to WT, (mean BP in mm Hg, WT 103 ± 1, KO 116 ± 1, n = 5/genotype, p < 0.05), and exhibited a reduced heart rate (beats per minute, WT 575 ± 5; KO 530 ± 7; p < 0.05). However, BP responses to NOS inhibition and vasorelaxation responses to ACh and an NO donor were normal in CYP1A1 KO mice, suggesting that NO bioavailability was not reduced. In contrast, CYP1A1 KO mice exhibited significantly attenuated vasorelaxation responses to EPA and DHA in both the aorta and mesenteric arterioles, but normal vasorelaxation responses to the CYP1A1 metabolites, 17,18-EEQ and 19,20-EDP, and normal responses to potassium channel inhibition. Taken together these data suggest that CYP1A1 metabolizes n − 3 PUFAs to vasodilators in vivo and the loss of these vasodilators may lead to increases in BP. -- Highlights: ► CYP1A1 KO mice are hypertensive. ► CYP1A1 KO mice exhibit reduced vasodilation responses to n-3 PUFAs. ► Constitutive CYP1A1 expression regulates blood pressure and vascular function.

  17. Elevated blood pressure in cytochrome P4501A1 knockout mice is associated with reduced vasodilation to omega − 3 polyunsaturated fatty acids

    International Nuclear Information System (INIS)

    Agbor, Larry N.; Walsh, Mary T.; Boberg, Jason R.; Walker, Mary K.

    2012-01-01

    In vitro cytochrome P4501A1 (CYP1A1) metabolizes omega − 3 polyunsaturated fatty acids (n − 3 PUFAs); eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), primarily to 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP), respectively. These metabolites have been shown to mediate vasodilation via increases in nitric oxide (NO) and activation of potassium channels. We hypothesized that genetic deletion of CYP1A1 would reduce vasodilatory responses to n − 3 PUFAs, but not the metabolites, and increase blood pressure (BP) due to decreases in NO. We assessed BP by radiotelemetry in CYP1A1 wildtype (WT) and knockout (KO) mice ± NO synthase (NOS) inhibitor. We also assessed vasodilation to acetylcholine (ACh), EPA, DHA, 17,18-EEQ and 19,20-EDP in aorta and mesenteric arterioles. Further, we assessed vasodilation to an NO donor and to DHA ± inhibitors of potassium channels. CYP1A1 KO mice were hypertensive, compared to WT, (mean BP in mm Hg, WT 103 ± 1, KO 116 ± 1, n = 5/genotype, p < 0.05), and exhibited a reduced heart rate (beats per minute, WT 575 ± 5; KO 530 ± 7; p < 0.05). However, BP responses to NOS inhibition and vasorelaxation responses to ACh and an NO donor were normal in CYP1A1 KO mice, suggesting that NO bioavailability was not reduced. In contrast, CYP1A1 KO mice exhibited significantly attenuated vasorelaxation responses to EPA and DHA in both the aorta and mesenteric arterioles, but normal vasorelaxation responses to the CYP1A1 metabolites, 17,18-EEQ and 19,20-EDP, and normal responses to potassium channel inhibition. Taken together these data suggest that CYP1A1 metabolizes n − 3 PUFAs to vasodilators in vivo and the loss of these vasodilators may lead to increases in BP. -- Highlights: ► CYP1A1 KO mice are hypertensive. ► CYP1A1 KO mice exhibit reduced vasodilation responses to n-3 PUFAs. ► Constitutive CYP1A1 expression regulates blood pressure and vascular function.

  18. Oxidative stress as a significant factor for development of an adaptive response in irradiated and nonirradiated human lymphocytes after inducing the bystander effect by low-dose X-radiation

    Energy Technology Data Exchange (ETDEWEB)

    Ermakov, Aleksei V., E-mail: avePlato@mail.ru [Research Centre for Medical Genetics, Russian Academy of Medical Science, ul. Moskvorechye, 1, Moscow 115478 (Russian Federation); Konkova, Marina S.; Kostyuk, Svetlana V.; Egolina, Natalya A.; Efremova, Liudmila V.; Veiko, Natalya N. [Research Centre for Medical Genetics, Russian Academy of Medical Science, ul. Moskvorechye, 1, Moscow 115478 (Russian Federation)

    2009-10-02

    X-radiation (10 cGy) was shown to induce in human lymphocytes transposition of homologous chromosomes loci from the membrane towards the centre of the nucleus and activation of the chromosomal nucleolus-forming regions (NFRs). These effects are transmitted by means of extracellular DNA (ecDNA) fragments to nonirradiated cells (the so-called bystander effect, BE). We demonstrated that in the development of the BE an important role is played by oxidative stress (which is brought about by low radiation doses and ecDNA fragments of the culture medium of the irradiated cells), by an enzyme of apoptosis called caspase-3, and by DNA-binding receptors of the bystander cells, presumably TLR9. Proposed herein is a scheme of the development of an adaptive response and the BE on exposure to radiation. Ionizing radiation induces apoptosis of the radiosensitive fraction of cells due to the development of the 'primary' oxidative stress (OS). DNA fragments of apoptotic cells are released into the intercellular space and interact with the DNA-binding receptors of the bystander cells. This interaction activates in lymphocytes signalling pathways associated with synthesis of the reactive oxygen species and nitrogen species, i.e., induces secondary oxidative stress accompanied by apoptosis of part of the cells, etc. Hence, single exposure to radiation may be followed by relatively long-lasting in the cellular population oxidative stress contributing to the development of an adaptive response. We thus believe that ecDNA of irradiated apoptotic lymphocytes is a significant factor of stress-signalling.

  19. The use of rockfish Sebastiscus marmoratus as a sentinel species to assess petroleum hydrocarbons pollution: A case study in Quanzhou Bay, China.

    Science.gov (United States)

    Bo, Jun; Zheng, Ronghui; Kuang, Weiming; Hong, Fukun; Xie, Qing; Zhang, Yusheng

    2017-11-30

    To monitor the biological effects of marine pollution, choosing a native fish species and establishing suitable biomarkers are required. In this study, the full-length cDNA of cyp1a1 was cloned from Sebastiscus marmoratus (SM-CYP1A1). Then the dose-response and time-course induction of hepatic CYP1A1 mRNA by the crude oil water-soluble fraction (WSF) were determined. Subsequently, SM-CYP1A1 mRNA was applied to investigate the biological effect of petroleum hydrocarbon pollution in Quanzhou Bay, China. The transcription levels of hepatic CYP1A1 were significantly elevated in fish caged in the polluted sites for 2weeks compared with those of the reference site, which were correlated with the concentrations of petroleum hydrocarbon and polycyclic aromatic hydrocarbon (PAH) in the surface seawaters. The results suggest that S. marmoratus is a potential sentinel organism to monitor marine pollutants and the hepatic CYP1A1 mRNA can serve as a sensitive biomarker to organic xenobiotics in aquatic environments. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Solvothermal-assisted evaporation-induced self-assembly process for significant improvement in the textural properties of γ-Al2O3, and study dye adsorption efficiency

    Directory of Open Access Journals (Sweden)

    Sourav Ghosh

    2015-06-01

    Full Text Available A comparative study of the textural properties of γ-Al2O3 prepared by solvothermal-assisted evaporation-induced self-assembly (SA-EISA and conventional evaporation-induced self-assembly (EISA processes has been carried out using aluminum isopropoxide, triblock copolymer-type nonionic surfactant (Pluronic P123 and ethanol. The solvothermal reaction was carried out at 100 °C for 24 h followed by slow drying at 60 °C for 48 h. The synthesized products were characterized by thermogravimetry analysis (TGA, differential thermal analysis (DTA, X-ray diffraction (XRD analysis, N2 adsorption–desorption study and transmission electron microscopy (TEM. The γ-Al2O3 prepared by SA-EISA process became stable up to 1000 °C. The powder prepared by SA-EISA process resulted in a significant increase in textural properties (BET surface area, pore volume and pore diameter compared to that prepared by conventional EISA process. A better adsorption capacity for Congo red, a carcinogenic dye used in textile industry, was exhibited by the powders prepared by SA-EISA process. A proposed mechanism was illustrated for the formation of mesoporous γ-Al2O3 obtained by EISA and SA-EISA processes.

  1. Induction of cytochromes P450 1A1 and 1A2 suppresses formation of DNA adducts by carcinogenic aristolochic acid I in rats in vivo

    International Nuclear Information System (INIS)

    Dračínská, Helena; Bárta, František; Levová, Kateřina; Hudecová, Alena; Moserová, Michaela; Schmeiser, Heinz H.; Kopka, Klaus; Frei, Eva; Arlt, Volker M.; Stiborová, Marie

    2016-01-01

    Highlights: • Oxidation and reduction of aristolochic acid I (AAI) dictate its (geno)toxicity in vivo. • Cytochrome P450 (CYP) 1A1 and 1A2 are induced in rats treated with Sudan I and AAI. • Induced CYP1A enzyme activity resulted in decreased AAI-DNA adduct levels in vivo. • CYP1A1 and 1A2 mainly detoxify AAI and attenuate its genotoxicity in vivo. - Abstract: Aristolochic acid I (AAI) is a natural plant alkaloid causing aristolochic acid nephropathy, Balkan endemic nephropathy and their associated urothelial malignancies. One of the most efficient enzymes reductively activating AAI to species forming AAI-DNA adducts is cytosolic NAD(P)H:quinone oxidoreductase 1. AAI is also either reductively activated or oxidatively detoxified to 8-hydroxyaristolochic acid (AAIa) by microsomal cytochrome P450 (CYP) 1A1 and 1A2. Here, we investigated which of these two opposing CYP1A1/2-catalyzed reactions prevails in AAI metabolism in vivo. The formation of AAI-DNA adducts was analyzed in liver, kidney and lung of rats treated with AAI, Sudan I, a potent inducer of CYP1A1/2, or AAI after pretreatment with Sudan I. Compared to rats treated with AAI alone, levels of AAI-DNA adducts determined by the 32 P-postlabeling method were lower in liver, kidney and lung of rats treated with AAI after Sudan I. The induction of CYP1A1/2 by Sudan I increased AAI detoxification to its O-demethylated metabolite AAIa, thereby reducing the actual amount of AAI available for reductive activation. This subsequently resulted in lower AAI-DNA adduct levels in the rat in vivo. Our results demonstrate that CYP1A1/2-mediated oxidative detoxification of AAI is the predominant role of these enzymes in rats in vivo, thereby suppressing levels of AAI-DNA adducts.

  2. Maternal obesity alters feto-placental Cytochrome P4501A1 activity

    Science.gov (United States)

    DuBois, Barent N.; O’Tierney, Perrie; Pearson, Jacob; Friedman, Jacob E.; Thornburg, Kent; Cherala, Ganesh

    2012-01-01

    Cytochrome P4501A1 (CYP1A1), an important drug metabolizing enzyme, is expressed in human placenta throughout gestation as well as in fetal liver. Obesity, a chronic inflammatory condition, is known to alter CYP enzyme expression in non-placental tissues. In the present study, we test the hypothesis that maternal obesity alters the distribution of CYP1A1 activity in feto-placental unit. Placentas were collected from non-obese (BMI30) women at term. Livers were collected from gestation day 130 fetuses of non-human primates fed either control diet or high-fat diet (HFD). Cytosol and microsomes were collected using differential centrifugation, and incubated with 7-Ethoxyresorufin. The CYP1A1 specific activity (pmoles of resorufin formed/min/mg of protein) was measured at excitation/emission wavelength of 530/590nm. Placentas of obese women had significantly reduced microsomal CYP1A1 activity compared to non-obese women (0.046 vs. 0.082; p<0.05); however no such effect was observed on cytosolic activity. Similarly, fetal liver from HFD fed mothers had significantly reduced microsomal CYP1A1 activity (0.44±0.04 vs. 0.20±0.10; p<0.05), with no significant difference in cytosolic CYP1A1 activity (control, 1.23±0.20; HFD, 0.80±0.40). Interestingly, multiple linear regression analyses of placental efficiency indicates cytosolic CYP1A1 activity is a main effect (5.67±2.32 (β±SEM); p=0.022) along with BMI (−0.57±0.26; p=0.037), fetal gender (1.07±0.26; p<0.001), and maternal age (0.07±0.03; p=0.011). In summary, while maternal obesity affects microsomal CYP1A1 activity alone, cytosolic activity along with maternal BMI is an important determinant of placental efficiency. Together, these data suggest that maternal lifestyle could have a significant impact on CYP1A1 activity, and hints at a possible role for CYP1A1 in feto-placental growth and thereby well-being of fetus. PMID:23046808

  3. [Detection of cerebrospinal fluid anti-enterovirus 71 IgM in children with severe hand, food and mouth disease induced by enterovirus 71 infection and its clinical significance].

    Science.gov (United States)

    Wu, Yidong; Chen, Dong; Zhou, Jun; Wang, Jie; Zhao, Shiyong; Shao, Qimin; Wei, Yi

    2015-05-01

    To detect the anti-enterovirus 71 (EV71) IgM level in cerebrospinal fluid (CSF) of children with severe hand, foot and mouth disease (HFMD) induced by EV71 and then analyze the relationships among the IgM antibody levels, CSF routine examination and patients' clinical features, and thus to evaluate the clinical significance of anti-EV71 IgM as a new indicator for early diagnosis of children with severe HFMD induced by EV71. A total of 294 laboratory-confirmed cases of children with severe HFMD infected with EV71 were enrolled into the research group from March 2014 to June 2014, consisting of 53 fatal cases and 241 severe cases, and their CSF samples underwent enzyme-linked immunosorbent assay (ELISA) for anti-EV71 IgM levels, CSF routine and biochemical tests. Forty-one cases of children with severe HFMD induced by other enteroviruses were collected as antibody-testing control group during the same period. In the research group, the total positive rate of anti-EV71 IgM in 294 CSF samples of children with severe HFMD infected by EV71 was 60.2% (177/294); the positive rate of anti-EV71 IgM in the fatal HFMD subgroup was 62.3% (33/53); the positive rate of anti-EV71 IgM in the severe HFMD subgroup was 59.8% (144/241). In the control group, the results of CSF anti-EV71 IgM tests were all negative (0/41). In the research group, patients in antibody-positive subgroup (2.5±1.2) years old were younger than those in antibody-negative subgroup (2.9±1.1) years old (t=2.595, P=0.010). And within the antibody-positive subgroup, the patients ((1.9±0.7) years old) with fatal type disease were younger than those ((2.6±1.2) years old) with severe type disease (t=3.150, P=0.002). The CSF nucleated cells count and positive rates (105 (56,180) ×10(6) /L; 97.7% (173/177)) in antibody-positive subgroup were higher than those (62(30,150) ×10(6) /L; 83.8% (98/117)) in antibody-negative subgroup (Z=3.663, P=0.000; χ(2)=19.089, P=0.000). In antibody-positive subgroup, the percentage

  4. Inhibition of mitogen-activated protein kinase kinase, DNA methyltransferase, and transforming growth factor-β promotes differentiation of human induced pluripotent stem cells into enterocytes.

    Science.gov (United States)

    Kodama, Nao; Iwao, Takahiro; Kabeya, Tomoki; Horikawa, Takashi; Niwa, Takuro; Kondo, Yuki; Nakamura, Katsunori; Matsunaga, Tamihide

    2016-06-01

    We previously reported that small-molecule compounds were effective in generating pharmacokinetically functional enterocytes from human induced pluripotent stem (iPS) cells. In this study, to determine whether the compounds promote the differentiation of human iPS cells into enterocytes, we investigated the effects of a combination of mitogen-activated protein kinase kinase (MEK), DNA methyltransferase (DNMT), and transforming growth factor (TGF)-β inhibitors on intestinal differentiation. Human iPS cells cultured on feeder cells were differentiated into endodermal cells by activin A. These endodermal-like cells were then differentiated into intestinal stem cells by fibroblast growth factor 2. Finally, the cells were differentiated into enterocyte cells by epidermal growth factor and small-molecule compounds. After differentiation, mRNA expression levels and drug-metabolizing enzyme activities were measured. The mRNA expression levels of the enterocyte marker sucrase-isomaltase and the major drug-metabolizing enzyme cytochrome P450 (CYP) 3A4 were increased by a combination of MEK, DNMT, and TGF-β inhibitors. The mRNA expression of CYP3A4 was markedly induced by 1α,25-dihydroxyvitamin D3. Metabolic activities of CYP1A1/2, CYP2B6, CYP2C9, CYP2C19, CYP3A4/5, UDP-glucuronosyltransferase, and sulfotransferase were also observed in the differentiated cells. In conclusion, MEK, DNMT, and TGF-β inhibitors can be used to promote the differentiation of human iPS cells into pharmacokinetically functional enterocytes. Copyright © 2016 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

  5. Detecting Novelty and Significance

    Science.gov (United States)

    Ferrari, Vera; Bradley, Margaret M.; Codispoti, Maurizio; Lang, Peter J.

    2013-01-01

    Studies of cognition often use an “oddball” paradigm to study effects of stimulus novelty and significance on information processing. However, an oddball tends to be perceptually more novel than the standard, repeated stimulus as well as more relevant to the ongoing task, making it difficult to disentangle effects due to perceptual novelty and stimulus significance. In the current study, effects of perceptual novelty and significance on ERPs were assessed in a passive viewing context by presenting repeated and novel pictures (natural scenes) that either signaled significant information regarding the current context or not. A fronto-central N2 component was primarily affected by perceptual novelty, whereas a centro-parietal P3 component was modulated by both stimulus significance and novelty. The data support an interpretation that the N2 reflects perceptual fluency and is attenuated when a current stimulus matches an active memory representation and that the amplitude of the P3 reflects stimulus meaning and significance. PMID:19400680

  6. Significant NRC Enforcement Actions

    Data.gov (United States)

    Nuclear Regulatory Commission — This dataset provides a list of Nuclear Regulartory Commission (NRC) issued significant enforcement actions. These actions, referred to as "escalated", are issued by...

  7. Prevalence and chemotherapy-induced reactivation of occult hepatitis B virus among hepatitis B surface antigen negative patients with diffuse large B-cell lymphoma: Significance of hepatitis B core antibodies screening

    International Nuclear Information System (INIS)

    Elbedewy, T.A.; Elashtokhy, H.A.; Rabee, E.S.; Kheder, G.E.

    2015-01-01

    Background: Occult hepatitis B infection (OBI) is characterized by negative hepatitis B surface antigen (HBsAg) and detectable hepatitis B virus (HBV)-DNA in the liver and/or serum, with or without hepatitis B core antibody (anti-HBc). Anti-HBc is the most sensitive marker of previous HBV. HBV reactivation in patients under immunosuppressive treatment is life-threatening, occurring in both overt and occult HBV especially in hematological malignancies. Aim of the work: To evaluate the prevalence and chemotherapy-induced reactivation of OBI among hepatitis B surface antigen negative patients with diffuse large B-cell lymphoma (DLBCL) patients and to determine the significance of anti-HBc screening among this group of patients before receiving chemotherapy. Patients and methods: This cross-sectional study included 72 DLBCL patients negative for HBsAg, HBsAb and hepatitis C virus antibodies (anti-HCV). Patients were subjected to investigations including anti-HBc. All patients underwent alanine transaminase (ALT) monitoring before each cycle of chemotherapy and monthly for 12 months after the end of chemotherapy. Patients with suspected OBI were tested for HBV-DNA using real-time polymerase chain reaction (PCR). Results: Anti-HBc was detected in 10 of 72 HBsAg negative sera (13.89%) (95% confidence interval 6.9-22.2%). Five of the 10 anti-HBc positive patients in this study had OBI reactivation. Conclusion: The study concluded that anti-HBc screening is mandatory before chemotherapy. HBsAg-negative/anti-HBc-positive patients should be closely observed for signs of HBV reactivation through the regular monitoring of ALT. Prophylaxis lamivudine is recommended for anti-HBc positive patients before chemotherapy.

  8. Inhibition of the MEK-1/p42 MAP kinase reduces aryl hydrocarbon receptor-DNA interactions

    International Nuclear Information System (INIS)

    Yim, Sujin; Oh, Myoungsuk; Choi, Su Mi; Park, Hyunsung

    2004-01-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces expression of the cytochrome P450 1A1 gene, cyp1a1, by binding to its receptor, aryl hydrocarbon receptor (AhR). TCDD-bound AhR translocates to the nucleus and forms a heterodimer with its partner protein, AhR nuclear translocator (Arnt). The AhR/Arnt heterodimer then binds to the dioxin-response elements (DREs) in the cyp1a1 enhancer and stimulates transcription of cyp1a1. We tested whether kinase pathways are involved in this process by treating Hepa1c1c7 cells with kinase inhibitors. The MEK-1 inhibitor PD98059 reduced TCDD-induced transcription of cyp1a1. TCDD treatment results in phosphorylation of p44/p42 mitogen-activated protein kinase (MAPK), a substrate of MEK-1. Overexpression of dominant negative form of p42 MAPK suppressed TCDD-dependent transcription of a reporter gene controlled by dioxin-response elements (DREs), and pretreatment with PD98059 also blocked this transcription. PD98059 pretreatment also inhibited TCDD-induced DRE binding of the AhR/Arnt heterodimer. Together these results indicate that TCDD activates the MEK-1/p44/p42 MAPK pathway, which in turn activates AhR and so facilitates binding of AhR to the cyp1a1 DRE

  9. Application of a novel regulatable Cre recombinase system to define the role of liver and gut metabolism in drug oral bioavailability.

    Science.gov (United States)

    Henderson, Colin J; McLaughlin, Lesley A; Osuna-Cabello, Maria; Taylor, Malcolm; Gilbert, Ian; McLaren, Aileen W; Wolf, C Roland

    2015-02-01

    The relative contribution of hepatic compared with intestinal oxidative metabolism is a crucial factor in drug oral bioavailability and therapeutic efficacy. Oxidative metabolism is mediated by the cytochrome P450 mono-oxygenase system to which cytochrome P450 reductase (POR) is the essential electron donor. In order to study the relative importance of these pathways in drug disposition, we have generated a novel mouse line where Cre recombinase is driven off the endogenous Cyp1a1 gene promoter; this line was then crossed on to a floxed POR mouse. A 40 mg/kg dose of the Cyp1a1 inducer 3-methylcholanthrene (3MC) eliminated POR expression in both liver and small intestine, whereas treatment at 4 mg/kg led to a more targeted deletion in the liver. Using this approach, we have studied the pharmacokinetics of three probe drugs--paroxetine, midazolam, nelfinavir--and show that intestinal metabolism is a determinant of oral bioavailability for the two latter compounds. The Endogenous Reductase Locus (ERL) mouse represents a significant advance on previous POR deletion models as it allows direct comparison of hepatic and intestinal effects on drug and xenobiotic clearance using lower doses of a single Cre inducing agent, and in addition minimizes any cytotoxic effects, which may compromise interpretation of the experimental data.

  10. Does maternal exposure to artificial food coloring additives increase oxidative stress in the skin of rats?

    Science.gov (United States)

    Başak, K; Başak, P Y; Doğuç, D K; Aylak, F; Oğuztüzün, S; Bozer, B M; Gültekin, F

    2017-10-01

    Glutathione-S-transferase (GST) and cytochrome P450 family 1 subfamily A polypeptide 1 (CYP1A1) metabolize and detoxify carcinogens, drugs, environmental pollutants, and reactive oxygen species. Changes of GST expression in tissues and gene mutations have been reported in association with many neoplastic skin diseases and dermatoses. Widely used artificial food coloring additives (AFCAs) also reported to effect primarily behavioral and cognitive function and cause neoplastic diseases and several inflammatory skin diseases. We aimed to identify the changes in expression of GSTs, CYP1A1, and vascular endothelial growth factor (VEGF) in rat skin which were maternally exposed AFCAs. A rat model was designed to evaluate the effects of maternal exposure of AFCAs on skin in rats. "No observable adverse effect levels" of commonly used AFCAs as a mixture were given to female rats before and during gestation. Immunohistochemical expression of GSTs, CYP1A1, and VEGF was evaluated in their offspring. CYP1A1, glutathione S-transferase pi (GSTP), glutathione S-transferase alpha (GSTA), glutathione S-transferase mu (GSTM), glutathione S-transferase theta (GSTT), and VEGF were expressed by epidermal keratinocytes, dermal fibroblasts, sebaceous glands, hair follicle, and subcutaneous striated muscle in the normal skin. CYP1A1, GSTA, and GSTT were expressed at all microanatomical sites of skin in varying degrees. The expressions of CYP1A1, GSTA, GSTT, and VEGF were decreased significantly, while GSTM expression on sebaceous gland and hair follicle was increased. Maternal exposure of AFCAs apparently effects expression of the CYP1A1, GSTs, and VEGF in the skin. This prominent change of expressions might play role in neoplastic and nonneoplastic skin diseases.

  11. Regional specificity in deltamethrin induced cytochrome P450 expression in rat brain

    International Nuclear Information System (INIS)

    Yadav, Sanjay; Johri, Ashu; Dhawan, Alok; Seth, Prahlad K.; Parmar, Devendra

    2006-01-01

    Oral administration of deltamethrin (5 mg/kg x 7 or 15 or 21 days) was found to produce a time-dependent increase in the mRNA expression of xenobiotic metabolizing cytochrome P450 1A1 (CYP1A1), 1A2 and CYP2B1, 2B2 isoenzymes in rat brain. RT-PCR studies further showed that increase in the mRNA expression of these CYP isoenzymes observed after 21 days of exposure was region specific. Hippocampus exhibited maximum increase in the mRNA expression of CYP1A1, which was followed by pons-medulla, cerebellum and hypothalamus. The mRNA expression of CYP2B1 also exhibited maximum increase in the hypothalamus and hippocampus followed by almost similar increase in midbrain and cerebellum. In contrast, mRNA expression of CYP1A2 and CYP2B2, the constitutive isoenzymes exhibited relatively higher increase in pons-medulla, cerebellum and frontal cortex. Immunoblotting studies carried out with polyclonal antibody raised against rat liver CYP1A1/1A2 or CYP2B1/2B2 isoenzymes also showed increase in immunoreactivity comigrating with CYP1A1/1A2 or 2B1/2B2 in the microsomal fractions isolated from hippocampus, hypothalamus and cerebellum of rat treated with deltamethrin. Though the exact relationship of the xenobiotic metabolizing CYPs with the physiological function of the brain is yet to be clearly understood, the increase in the mRNA expression of the CYPs in the brain regions that regulate specific brain functions affected by deltamethrin have further indicated that modulation of these CYPs could be associated with the various endogenous functions of the brain

  12. 4-Hydroxy estradiol but not 2-hydroxy estradiol induces expression of hypoxia-inducible factor 1α and vascular endothelial growth factor A through phosphatidylinositol 3-kinase/Akt/FRAP pathway in OVCAR-3 and A2780-CP70 human ovarian carcinoma cells

    International Nuclear Information System (INIS)

    Gao Ning; Nester, Rebecca A.; Sarkar, Mohamadi A.

    2004-01-01

    Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix transcription factor composed of HIF-1α and HIF-1β subunits. HIF-1 expression is induced by hypoxia, growth factors, and activation of oncogenes. HIF-1 activates downstream target genes such as vascular endothelial growth factor A (VEGF-A), which plays an important role in tumor progression and angiogenesis. Estrogen exposure is considered to be the major risk factor for ovarian cancer. Estradiol (E2) is usually metabolized by CYP1A1/1A2 and CYP3A4 to the 2-hydroxy estradiol (2-OHE2) and 4-hydroxy estradiol (4-OHE2) in human liver. Many reports have suggested that the formation of 4-OHE2 is important for mammary carcinogenesis. However, the formation of 2-OHE2 may play an important role in exhibiting anticarcinogenic effects. In the present study, we have demonstrated that one of the catechol estrogen metabolites of E2, 4-OHE2, induces HIF-1α and VEGF-A expression at protein level in two human ovarian cancer cell lines, OVCAR-3 and A2780-CP70 cells, in dose- and time-dependent manners, whereas the other catechol estrogen metabolite of E2, 2-OHE2, does not alter HIF-1α and VEGF-A expression. To explore the mechanism of 4-OHE2-induced HIF-1α and VEGF-A expression, we studied whether phosphatidylinositol 3-kinase (PI3K) or mitogen-activated protein kinase (MAPK) signaling pathways are involved in 4-OHE2-induced HIF-1α and VEGF-A expression. Our findings indicate that PI3K inhibitors, LY294002 and wortmannin, inhibited HIF-1α and VEGF-A expression, whereas MAPK inhibitor, PD98059, did not alter HIF-1α and VEGF-A expression induced by 4-OHE2. 4-OHE2, but not 2-OHE2, also induced Akt phosphorylation at Ser473 in dose- and time-dependent manners, and LY294002 and wortmannin inhibited Akt phosphorylation at Ser473 induced by 4-OHE2. Our results also indicated that the mTOR/FRAP inhibitor, rapamycin, inhibited 4-OHE2-induced HIF-1α and VEGF-A expression. These results suggest that the PI3K

  13. Significant Tsunami Events

    Science.gov (United States)

    Dunbar, P. K.; Furtney, M.; McLean, S. J.; Sweeney, A. D.

    2014-12-01

    Tsunamis have inflicted death and destruction on the coastlines of the world throughout history. The occurrence of tsunamis and the resulting effects have been collected and studied as far back as the second millennium B.C. The knowledge gained from cataloging and examining these events has led to significant changes in our understanding of tsunamis, tsunami sources, and methods to mitigate the effects of tsunamis. The most significant, not surprisingly, are often the most devastating, such as the 2011 Tohoku, Japan earthquake and tsunami. The goal of this poster is to give a brief overview of the occurrence of tsunamis and then focus specifically on several significant tsunamis. There are various criteria to determine the most significant tsunamis: the number of deaths, amount of damage, maximum runup height, had a major impact on tsunami science or policy, etc. As a result, descriptions will include some of the most costly (2011 Tohoku, Japan), the most deadly (2004 Sumatra, 1883 Krakatau), and the highest runup ever observed (1958 Lituya Bay, Alaska). The discovery of the Cascadia subduction zone as the source of the 1700 Japanese "Orphan" tsunami and a future tsunami threat to the U.S. northwest coast, contributed to the decision to form the U.S. National Tsunami Hazard Mitigation Program. The great Lisbon earthquake of 1755 marked the beginning of the modern era of seismology. Knowledge gained from the 1964 Alaska earthquake and tsunami helped confirm the theory of plate tectonics. The 1946 Alaska, 1952 Kuril Islands, 1960 Chile, 1964 Alaska, and the 2004 Banda Aceh, tsunamis all resulted in warning centers or systems being established.The data descriptions on this poster were extracted from NOAA's National Geophysical Data Center (NGDC) global historical tsunami database. Additional information about these tsunamis, as well as water level data can be found by accessing the NGDC website www.ngdc.noaa.gov/hazard/

  14. Testing Significance Testing

    Directory of Open Access Journals (Sweden)

    Joachim I. Krueger

    2018-04-01

    Full Text Available The practice of Significance Testing (ST remains widespread in psychological science despite continual criticism of its flaws and abuses. Using simulation experiments, we address four concerns about ST and for two of these we compare ST’s performance with prominent alternatives. We find the following: First, the 'p' values delivered by ST predict the posterior probability of the tested hypothesis well under many research conditions. Second, low 'p' values support inductive inferences because they are most likely to occur when the tested hypothesis is false. Third, 'p' values track likelihood ratios without raising the uncertainties of relative inference. Fourth, 'p' values predict the replicability of research findings better than confidence intervals do. Given these results, we conclude that 'p' values may be used judiciously as a heuristic tool for inductive inference. Yet, 'p' values cannot bear the full burden of inference. We encourage researchers to be flexible in their selection and use of statistical methods.

  15. Safety significance evaluation system

    International Nuclear Information System (INIS)

    Lew, B.S.; Yee, D.; Brewer, W.K.; Quattro, P.J.; Kirby, K.D.

    1991-01-01

    This paper reports that the Pacific Gas and Electric Company (PG and E), in cooperation with ABZ, Incorporated and Science Applications International Corporation (SAIC), investigated the use of artificial intelligence-based programming techniques to assist utility personnel in regulatory compliance problems. The result of this investigation is that artificial intelligence-based programming techniques can successfully be applied to this problem. To demonstrate this, a general methodology was developed and several prototype systems based on this methodology were developed. The prototypes address U.S. Nuclear Regulatory Commission (NRC) event reportability requirements, technical specification compliance based on plant equipment status, and quality assurance assistance. This collection of prototype modules is named the safety significance evaluation system

  16. Predicting significant torso trauma.

    Science.gov (United States)

    Nirula, Ram; Talmor, Daniel; Brasel, Karen

    2005-07-01

    Identification of motor vehicle crash (MVC) characteristics associated with thoracoabdominal injury would advance the development of automatic crash notification systems (ACNS) by improving triage and response times. Our objective was to determine the relationships between MVC characteristics and thoracoabdominal trauma to develop a torso injury probability model. Drivers involved in crashes from 1993 to 2001 within the National Automotive Sampling System were reviewed. Relationships between torso injury and MVC characteristics were assessed using multivariate logistic regression. Receiver operating characteristic curves were used to compare the model to current ACNS models. There were a total of 56,466 drivers. Age, ejection, braking, avoidance, velocity, restraints, passenger-side impact, rollover, and vehicle weight and type were associated with injury (p < 0.05). The area under the receiver operating characteristic curve (83.9) was significantly greater than current ACNS models. We have developed a thoracoabdominal injury probability model that may improve patient triage when used with ACNS.

  17. Gas revenue increasingly significant

    International Nuclear Information System (INIS)

    Megill, R.E.

    1991-01-01

    This paper briefly describes the wellhead prices of natural gas compared to crude oil over the past 70 years. Although natural gas prices have never reached price parity with crude oil, the relative value of a gas BTU has been increasing. It is one of the reasons that the total amount of money coming from natural gas wells is becoming more significant. From 1920 to 1955 the revenue at the wellhead for natural gas was only about 10% of the money received by producers. Most of the money needed for exploration, development, and production came from crude oil. At present, however, over 40% of the money from the upstream portion of the petroleum industry is from natural gas. As a result, in a few short years natural gas may become 50% of the money revenues generated from wellhead production facilities

  18. Cytochrome b5 and epoxide hydrolase contribute to benzo[a]pyrene-DNA adduct formation catalyzed by cytochrome P450 1A1 under low NADPH:P450 oxidoreductase conditions

    International Nuclear Information System (INIS)

    Stiborová, Marie; Moserová, Michaela; Černá, Věra; Indra, Radek; Dračínský, Martin; Šulc, Miroslav; Henderson, Colin J.; Wolf, C. Roland; Schmeiser, Heinz H.; Phillips, David H.; Frei, Eva; Arlt, Volker M.

    2014-01-01

    In previous studies we had administered benzo[a]pyrene (BaP) to genetically engineered mice (HRN) which do not express NADPH:cytochrome P450 oxidoreductase (POR) in hepatocytes and observed higher DNA adduct levels in livers of these mice than in wild-type mice. To elucidate the reason for this unexpected finding we have used two different settings for in vitro incubations; hepatic microsomes from control and BaP-pretreated HRN mice and reconstituted systems with cytochrome P450 1A1 (CYP1A1), POR, cytochrome b 5 , and epoxide hydrolase (mEH) in different ratios. In microsomes from BaP-pretreated mice, in which Cyp1a1 was induced, higher levels of BaP metabolites were formed, mainly of BaP-7,8-dihydrodiol. At a low POR:CYP1A1 ratio of 0.05:1 in the reconstituted system, the amounts of BaP diones and BaP-9-ol formed were essentially the same as at an equimolar ratio, but formation of BaP-3-ol was ∼1.6-fold higher. Only after addition of mEH were BaP dihydrodiols found. Two BaP-DNA adducts were formed in the presence of mEH, but only one when CYP1A1 and POR were present alone. At a ratio of POR:CYP1A1 of 0.05:1, addition of cytochrome b 5 increased CYP1A1-mediated BaP oxidation to most of its metabolites indicating that cytochrome b 5 participates in the electron transfer from NADPH to CYP1A1 required for enzyme activity of this CYP. BaP-9-ol was formed even by CYP1A1 reconstituted with cytochrome b 5 without POR. Our results suggest that in livers of HRN mice Cyp1a1, cytochrome b 5 and mEH can effectively activate BaP to DNA binding species, even in the presence of very low amounts of POR

  19. Tumor significant dose

    International Nuclear Information System (INIS)

    Supe, S.J.; Nagalaxmi, K.V.; Meenakshi, L.

    1983-01-01

    In the practice of radiotherapy, various concepts like NSD, CRE, TDF, and BIR are being used to evaluate the biological effectiveness of the treatment schedules on the normal tissues. This has been accepted as the tolerance of the normal tissue is the limiting factor in the treatment of cancers. At present when various schedules are tried, attention is therefore paid to the biological damage of the normal tissues only and it is expected that the damage to the cancerous tissues would be extensive enough to control the cancer. Attempt is made in the present work to evaluate the concent of tumor significant dose (TSD) which will represent the damage to the cancerous tissue. Strandquist in the analysis of a large number of cases of squamous cell carcinoma found that for the 5 fraction/week treatment, the total dose required to bring about the same damage for the cancerous tissue is proportional to T/sup -0.22/, where T is the overall time over which the dose is delivered. Using this finding the TSD was defined as DxN/sup -p/xT/sup -q/, where D is the total dose, N the number of fractions, T the overall time p and q are the exponents to be suitably chosen. The values of p and q are adjusted such that p+q< or =0.24, and p varies from 0.0 to 0.24 and q varies from 0.0 to 0.22. Cases of cancer of cervix uteri treated between 1978 and 1980 in the V. N. Cancer Centre, Kuppuswamy Naidu Memorial Hospital, Coimbatore, India were analyzed on the basis of these formulations. These data, coupled with the clinical experience, were used for choice of a formula for the TSD. Further, the dose schedules used in the British Institute of Radiology fraction- ation studies were also used to propose that the tumor significant dose is represented by DxN/sup -0.18/xT/sup -0.06/

  20. Uranium chemistry: significant advances

    International Nuclear Information System (INIS)

    Mazzanti, M.

    2011-01-01

    The author reviews recent progress in uranium chemistry achieved in CEA laboratories. Like its neighbors in the Mendeleev chart uranium undergoes hydrolysis, oxidation and disproportionation reactions which make the chemistry of these species in water highly complex. The study of the chemistry of uranium in an anhydrous medium has led to correlate the structural and electronic differences observed in the interaction of uranium(III) and the lanthanides(III) with nitrogen or sulfur molecules and the effectiveness of these molecules in An(III)/Ln(III) separation via liquid-liquid extraction. Recent work on the redox reactivity of trivalent uranium U(III) in an organic medium with molecules such as water or an azide ion (N 3 - ) in stoichiometric quantities, led to extremely interesting uranium aggregates particular those involved in actinide migration in the environment or in aggregation problems in the fuel processing cycle. Another significant advance was the discovery of a compound containing the uranyl ion with a degree of oxidation (V) UO 2 + , obtained by oxidation of uranium(III). Recently chemists have succeeded in blocking the disproportionation reaction of uranyl(V) and in stabilizing polymetallic complexes of uranyl(V), opening the way to to a systematic study of the reactivity and the electronic and magnetic properties of uranyl(V) compounds. (A.C.)

  1. Meaning and significance of

    Directory of Open Access Journals (Sweden)

    Ph D Student Roman Mihaela

    2011-05-01

    Full Text Available The concept of "public accountability" is a challenge for political science as a new concept in this area in full debate and developement ,both in theory and practice. This paper is a theoretical approach of displaying some definitions, relevant meanings and significance odf the concept in political science. The importance of this concept is that although originally it was used as a tool to improve effectiveness and eficiency of public governance, it has gradually become a purpose it itself. "Accountability" has become an image of good governance first in the United States of America then in the European Union.Nevertheless,the concept is vaguely defined and provides ambiguous images of good governance.This paper begins with the presentation of some general meanings of the concept as they emerge from specialized dictionaries and ancyclopaedies and continues with the meanings developed in political science. The concept of "public accontability" is rooted in economics and management literature,becoming increasingly relevant in today's political science both in theory and discourse as well as in practice in formulating and evaluating public policies. A first conclusin that emerges from, the analysis of the evolution of this term is that it requires a conceptual clarification in political science. A clear definition will then enable an appropriate model of proving the system of public accountability in formulating and assessing public policies, in order to implement a system of assessment and monitoring thereof.

  2. Significant Radionuclides Determination

    Energy Technology Data Exchange (ETDEWEB)

    Jo A. Ziegler

    2001-07-31

    The purpose of this calculation is to identify radionuclides that are significant to offsite doses from potential preclosure events for spent nuclear fuel (SNF) and high-level radioactive waste expected to be received at the potential Monitored Geologic Repository (MGR). In this calculation, high-level radioactive waste is included in references to DOE SNF. A previous document, ''DOE SNF DBE Offsite Dose Calculations'' (CRWMS M&O 1999b), calculated the source terms and offsite doses for Department of Energy (DOE) and Naval SNF for use in design basis event analyses. This calculation reproduces only DOE SNF work (i.e., no naval SNF work is included in this calculation) created in ''DOE SNF DBE Offsite Dose Calculations'' and expands the calculation to include DOE SNF expected to produce a high dose consequence (even though the quantity of the SNF is expected to be small) and SNF owned by commercial nuclear power producers. The calculation does not address any specific off-normal/DBE event scenarios for receiving, handling, or packaging of SNF. The results of this calculation are developed for comparative analysis to establish the important radionuclides and do not represent the final source terms to be used for license application. This calculation will be used as input to preclosure safety analyses and is performed in accordance with procedure AP-3.12Q, ''Calculations'', and is subject to the requirements of DOE/RW-0333P, ''Quality Assurance Requirements and Description'' (DOE 2000) as determined by the activity evaluation contained in ''Technical Work Plan for: Preclosure Safety Analysis, TWP-MGR-SE-000010'' (CRWMS M&O 2000b) in accordance with procedure AP-2.21Q, ''Quality Determinations and Planning for Scientific, Engineering, and Regulatory Compliance Activities''.

  3. Modulation of Benzo[a]pyrene induced immunotoxicity in mice actively immunized with a B[a]P-diphtheria toxoid conjugate

    International Nuclear Information System (INIS)

    Schellenberger, Mario T.; Grova, Nathalie; Willieme, Stephanie; Farinelle, Sophie; Prodhomme, Emmanuel J.F.; Muller, Claude P.

    2009-01-01

    Benzo[a]pyrene (B[a]P) is a small molecular weight carcinogen and the prototype of polycyclic aromatic hydrocarbons (PAHs). While these compounds are primarily known for their carcinogenicity, B[a]P and its metabolites are also toxic for mammalian immune cells. To develop a prophylactic immune strategy against detrimental effects of B[a]P, we have immunized mice with a B[a]P-diphtheria toxoid conjugate vaccine. We showed that high levels of antibodies against B[a]P and its metabolites modulate the redistribution of these PAHs in the blood. After immunization, increased levels of B[a]P and its metabolites were recovered in the blood. B[a]P significantly suppressed the proliferative response of both T and B cells after a sub-acute administration, an effect that was completely reversed by vaccination. In immunized mice also the immunotoxic effect of B[a]P on IFN-γ, IL-12, TNF-α production and the reduced B cell activation was restored. Finally, our results showed that specific antibodies inhibited the induction of Cyp1a1 by B[a]P in lymphocytes and Cyp1b1 in the liver, enzymes that are known to convert the procarcinogen B[a]P to the ultimate DNA-adduct forming metabolite, a major risk factor of chemical carcinogenesis. Thus, we demonstrate that vaccination with a B[a]P conjugate vaccine based on a carrier protein used in licensed human vaccines reduces immunotoxicity and possibly other detrimental effects associated with B[a]P.

  4. Evaluation of a C57BL/6J × 129S1/SvImJ Hybrid Nestin-Thymidine Kinase Transgenic Mouse Model for Studying the Functional Significance of Exercise-Induced Adult Hippocampal Neurogenesis.

    Science.gov (United States)

    Hamilton, G F; Majdak, P; Miller, D S; Bucko, P J; Merritt, J R; Krebs, C P; Rhodes, J S

    2015-01-01

    New neurons are continuously generated in the adult hippocampus but their function remains a mystery. The nestin thymidine kinase (nestin-TK) transgenic method has been used for selective and conditional reduction of neurogenesis for the purpose of testing the functional significance of new neurons in learning, memory and motor performance. Here we explored the nestin-TK model on a hybrid genetic background (to increase heterozygosity, and "hybrid vigor"). Transgenic C57BL/6J (B6) were crossed with 129S1/SvImJ (129) producing hybrid offspring (F1) with the B6 half of the genome carrying a herpes simplex virus thymidine kinase (TK) transgene regulated by a modified nestin promoter. In the presence of exogenously administered valganciclovir, new neurons expressing TK undergo apoptosis. Female B6 nestin-TK mice ( n = 80) were evaluated for neurogenesis reduction as a positive control. Male and female F1 nestin-TK mice ( n = 223) were used to determine the impact of neurogenesis reduction on the Morris water maze (MWM) and rotarod. All mice received BrdU injections to label dividing cells and either valganciclovir or control chow, with or without a running wheel for 30 days. Both the F1 and B6 background displayed approximately 50% reduction in neurogenesis, a difference that did not impair learning and memory on the MWM or rotarod performance. Running enhanced neurogenesis and performance on the rotarod but not MWM suggesting the F1 background may not be suitable for studying pro-cognitive effects of exercise on MWM. Greater reduction of neurogenesis may be required to observe behavioral impacts. Alternatively, new neurons may not play a critical role in learning, or compensatory mechanisms in pre-existing neurons could have masked the deficits. Further work using these and other models for selectively reducing neurogenesis are needed to establish the functional significance of adult hippocampal neurogenesis in behavior.

  5. Aryl hydrocarbon receptor pathway activation enhances gastric cancer cell invasiveness likely through a c-Jun-dependent induction of matrix metalloproteinase-9

    Directory of Open Access Journals (Sweden)

    Song Xin

    2009-04-01

    Full Text Available Abstract Background Abberant aryl hydrocarbon receptor (AhR expression and AhR pathway activation are involved in gastric carcinogenesis. However, the relationship between AhR pathway activation and gastric cancer progression is still unclear. In present study, we used 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD, a classic and most potent ligand of AhR, to activate AhR pathway and investigated the effect of AhR pathway activation on human gastric cancer AGS cell invasion and explored the corresponding mechanism. Results To determine whether AhR pathway can be activated in AGS cells, we examined the expression of CYP1A1, a classic target gene of AhR pathway, following TCDD exposure. RT-PCR and western blot analysis showed that both CYP1A1 mRNA and protein expression were increased in a dose-dependent manner following TCDD treatment and AhR antagonist resveratrol (RSV could reverse this TCDD-induced CYP1A1 expression. To determine whether TCDD treatment of AGS cells results in an induction of MMP-9 expression, we detected MMP-9 mRNA using RT-PCR and detected MMP-9 enzymatic activity using gelatin zymography. The results showed that both MMP-9 mRNA expression and enzymatic activity were gradually increased with the concentration increase of TCDD in media and these changes could be reversed by RSV treatment in a dose-dependent manner. To examine whether AhR activation-induced MMP-9 expression and activity in AGS cells results in increased migration and invasion, we performed wound healing migration assay and transwell migration and invasion assay. After TCDD treatment, the migration distance and the migration and invasion abilities of AGS cells were increased with a dose-dependent manner. To demonstrate AhR activation-induced MMP-9 expression is mediated by c-Jun, siRNA transfection was performed to silence c-Jun mRNA in AGS cells. The results showed that MMP-9 mRNA expression and activity in untreated control AGS cells were very weak; After TCDD

  6. Effects of oral anorexiant sibutramine on the expression of cytochromes P450s in human hepatocytes and cancer cell lines.

    Science.gov (United States)

    Vrzal, Radim; Knoppová, Barbora; Bachleda, Petr; Dvořák, Zdeněk

    2013-12-01

    Sibutramine is a serotonin-norepinephrine reuptake inhibitor that was used for weight-loss management in obese patients. Even though it was officially withdrawn from the market in 2010, it is still present in some tainted weight-loss pills (as reported by US Food and Drug Administration). Thus, it is still reasonable to study the effects of this compound. The aim of this work was to investigate the potential of sibutramine to induce CYP1A1/CY3A4 in human cancer cell lines and CYP1A1/2, CYP2A6, CYP2B6, and CYP3A4 in human hepatocytes, a competent model of metabolically active cells. The levels of mRNA and protein of CYP1A1/1A2/3A4/2A6/2B6 were compared with the typical inducers, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and rifampicin (RIF) for CYP1A1/2 and for other CYPs, respectively. The mRNA and protein levels of all genes in either cancer cell lines or human hepatocytes were induced when treated with typical inducers but not with sibutramine. © 2013 Wiley Periodicals, Inc.

  7. Correlates of Cytochrome P450 1A1 Expression in Bottlenose Dolphin (Tursiops truncatus) Integument Biopsies

    NARCIS (Netherlands)

    Wilson, J.Y.; Wells, R.; Anguilar, A.; Borrell, A.; Tornero, V.; Reijnders, P.J.H.; Moore, M.

    2007-01-01

    Integument biopsy is a nondestructive method for sampling free-ranging cetaceans, which allows for the determination of both contaminant concentrations and biomarker responses. Cytochrome P450 1A1 (CYP1A1) expression is induced by polycyclic aromatic hydrocarbons and planar halogenated aromatic

  8. Poly(lactic-co-glycolic) acid loaded nano-insulin has greater potentials of combating arsenic induced hyperglycemia in mice: Some novel findings

    Energy Technology Data Exchange (ETDEWEB)

    Samadder, Asmita; Das, Jayeeta; Das, Sreemanti; De, Arnab; Saha, Santu Kumar; Bhattacharyya, Soumya Sundar; Khuda-Bukhsh, Anisur Rahman, E-mail: prof_arkb@yahoo.co.in

    2013-02-15

    Diabetes is a menacing problem, particularly to inhabitants of groundwater arsenic contaminated areas needing new medical approaches. This study examines if PLGA loaded nano-insulin (NIn), administered either intraperitoneally (i.p.) or through oral route, has a greater cost-effective anti-hyperglycemic potential than that of insulin in chronically arsenite-fed hyperglycemic mice. The particle size, morphology and zeta potential of nano-insulin were determined using dynamic light scattering method, scanning electronic and atomic force microscopies. The ability of the nano-insulin (NIn) to cross the blood–brain barrier (BBB) was also checked. Circular dichroic spectroscopic (CD) data of insulin and nano-insulin in presence or absence of arsenic were compared. Several diabetic markers in different groups of experimental and control mice were assessed. The mitochondrial functioning through indices like cytochrome c, pyruvate-kinase, glucokinase, ATP/ADP ratio, mitochondrial membrane potential, cell membrane potential and calcium-ion level was also evaluated. Expressions of the relevant marker proteins and mRNAs like insulin, GLUT2, GLUT4, IRS1, IRS2, UCP2, PI3, PPARγ, CYP1A1, Bcl2, caspase3 and p38 for tracking-down the signaling cascade were also analyzed. Results revealed that i.p.-injected nano-encapsulated-insulin showed better results; NIn, due to its smaller size, faster mobility, site-specific release, could cross BBB and showed positive modulation in mitochondrial signaling cascades and other downstream signaling molecules in reducing arsenic-induced-hyperglycemia. CD data indicated that nano-insulin had less distorted secondary structure as compared with that of insulin in presence of arsenic. Thus, overall analyses revealed that PLGA nano-insulin showed better efficacy in combating arsenite-induced-hyperglycemia than that of insulin and therefore, has greater potentials for use in nano-encapsulated form. - Highlights: ► PLGA encapsulated nano

  9. Poly(lactic-co-glycolic) acid loaded nano-insulin has greater potentials of combating arsenic induced hyperglycemia in mice: Some novel findings

    International Nuclear Information System (INIS)

    Samadder, Asmita; Das, Jayeeta; Das, Sreemanti; De, Arnab; Saha, Santu Kumar; Bhattacharyya, Soumya Sundar; Khuda-Bukhsh, Anisur Rahman

    2013-01-01

    Diabetes is a menacing problem, particularly to inhabitants of groundwater arsenic contaminated areas needing new medical approaches. This study examines if PLGA loaded nano-insulin (NIn), administered either intraperitoneally (i.p.) or through oral route, has a greater cost-effective anti-hyperglycemic potential than that of insulin in chronically arsenite-fed hyperglycemic mice. The particle size, morphology and zeta potential of nano-insulin were determined using dynamic light scattering method, scanning electronic and atomic force microscopies. The ability of the nano-insulin (NIn) to cross the blood–brain barrier (BBB) was also checked. Circular dichroic spectroscopic (CD) data of insulin and nano-insulin in presence or absence of arsenic were compared. Several diabetic markers in different groups of experimental and control mice were assessed. The mitochondrial functioning through indices like cytochrome c, pyruvate-kinase, glucokinase, ATP/ADP ratio, mitochondrial membrane potential, cell membrane potential and calcium-ion level was also evaluated. Expressions of the relevant marker proteins and mRNAs like insulin, GLUT2, GLUT4, IRS1, IRS2, UCP2, PI3, PPARγ, CYP1A1, Bcl2, caspase3 and p38 for tracking-down the signaling cascade were also analyzed. Results revealed that i.p.-injected nano-encapsulated-insulin showed better results; NIn, due to its smaller size, faster mobility, site-specific release, could cross BBB and showed positive modulation in mitochondrial signaling cascades and other downstream signaling molecules in reducing arsenic-induced-hyperglycemia. CD data indicated that nano-insulin had less distorted secondary structure as compared with that of insulin in presence of arsenic. Thus, overall analyses revealed that PLGA nano-insulin showed better efficacy in combating arsenite-induced-hyperglycemia than that of insulin and therefore, has greater potentials for use in nano-encapsulated form. - Highlights: ► PLGA encapsulated nano

  10. Green tea polyphenol induces significant cell death in human lung ...

    African Journals Online (AJOL)

    : 1596-5996 (print); 1596-9827 (electronic). © Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, 300001 Nigeria. .... Roswell Park Memorial Institute (RPMI)-1640 ..... Washington DC: National Academy Press. 18.

  11. Significance of radiation-induced bystander effects in radiation therapy

    International Nuclear Information System (INIS)

    Suzuki, Masao

    2014-01-01

    Since 1994, a Phase I/II clinical study and radiotherapy have carried out using carbon-ion beams produced with the Heavy Ion Medical Accelerator in Chiba (HIMAC) at National Institute of Radiological Sciences. Now we constructed the new treatment facility for the advanced carbon-ion therapy at HIMAC applying a 3D fast spot scanning system with pencil beams. In the field of fundamental biological studies for high-LET heavy ions, there are some reports regarding bystander effects after exposure to alpha particles derived from 238 Pu or He-ion microbeams. However, only limited sets of studies have examined bystander effects after exposure to different ion species heavier than helium, such as carbon ions. We have been investigating bystander cellular responses in both normal human and human tumor cells irradiated with the HIMAC carbon ions. Bystander cell-killing effect was observed in the cells harboring wild-type P53 gene, but not in the P53-mutated cells. Moreover, observed bystander effect was suppressed by treating with a specific inhibitor of gap-junction mediated cell-cell communication. There is clear evidence that the carbon-ion irradiation enables the enhanced cell killing in cells with wild-type P53 gene via gap-junction mediated bystander effect. (author)

  12. Significance of antioxidants in L-NAME-induced hypertension

    Czech Academy of Sciences Publication Activity Database

    Pecháňová, Olga; Kojšová, S.; Jendeková, L.; Paulis, L.; Janega, P.; Dovinová, I.; Dobešová, Zdenka; Šimko, F.; Babál, P.; Kuneš, Jaroslav; Zicha, Josef

    2006-01-01

    Roč. 24, č. S4 (2006), S341-S341 ISSN 0263-6352. [European Meeting on Hypertension /16./. 12.06.2006-15.06.2006, Madrid] Grant - others:VEGA(SK) 2/6148/26; VEGA(SK) 1/3429/06 Keywords : antioxidants * L-NAME * hypertension Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery

  13. Cosmic-rays induced Titan tholins and their astrobiological significances

    Science.gov (United States)

    Kobayashi, Kensei; Taniuchi, Toshinori; Hosogai, Tomohiro; Kaneko, Takeo; Takano, Yoshinori; Khare, Bishun; McKay, Chris

    Titan is the largest satellite of Saturn. It is quite unique satellite since it has a dense atmosphere composed of nitrogen and methane, and has been sometimes considered as a model of primitive Earth. In Titan atmosphere, a wide variety of organic compounds and mists made of complex organics. Such solid complex organics are often referred to as tholins. A number of laboratory experiments simulating reactions in Titan atmosphere have been conducted. In most of them, ultraviolet light and discharges (simulating actions of electrons in Saturn magnetosphere) were used, which were simulation of the reactions in upper dilute atmosphere of Titan. We examined possible formation of organic compounds in the lower dense atmosphere of Titan, where cosmic rays are major energies. A Mixture of 35 Torr of methane and 665 Torr of nitrogen was irradiated with high-energy protons (3 MeV) from a van de Graaff accelerator (TIT, Japan) or from a Tandem accelerator (TIARA, QUBS, JAEA, Japan). In some experiments, 13 C-labelled methane was used. We also performed plasma discharges in a mixture of methane (10 %) and nitrogen (90 %) to simulate the reactions in the upper atmosphere of Titan. Solid products by proton irradiation and those by plasma discharges are hereafter referred to as PI-tholins and PD-tholins, respectively. The resulting PI-tholins were observed with SEM and AFM. They were characterized by pyrolysis-GC/MS, gel permeation chromatography, FT-IR, etc. Amino acids in PI-and PD-tholins were analyzed by HPLC, GC/MS and MALDI-TOF-MS after acid hydrolysis. 18 O-Labelled water was used in some cases during hydrolysis. Filamentary and/or globular-like structures were observed by SEM and AFM. By pyrolysis-GC/MS of PI-tholins, ammonia and hydrogen cyanide were detected, which was the same as the results obtained in Titan atmosphere during the Huygens mission. A wide variety of amino acids were detected after hydrolysis of both tholins. It was proved that oxygen atoms in the amino acids in PI-tholins were incorporated from water during hydrolysis by the experiments with 18 O-Labelled water. Estimating from the G-values of amino acids and the flux of each energy in Titan atmosphere, it is strongly suggested that amino acid precursors in the form of tholins can be produced mainly in the lower Titan atmosphere by cosmic rays. The tholins containing amino acid precursors could be concentrated on some part of Titan surface by the flow of liquid methane. Amino acid precursors on the surface of Titan is promising targets in future Titan missions.

  14. Enzyme induction and cytotoxicity in human hepatocytes by chlorpyrifos and N,N-diethyl-m-toluamide (DEET).

    Science.gov (United States)

    Das, Parikshit C; Cao, Yan; Rose, Randy L; Cherrington, Nathan; Hodgson, Ernest

    2008-01-01

    Xenobiotics, including drugs and environmental chemicals, can influence cytochrome P450 (CYP) levels by altering the transcription of CYP genes. To minimize potential drug-pesticide and pesticide-pesticide interactions it is important to evaluate the potential of pesticides to induce CYP isoforms and to cause cytotoxicity in humans. The present study was designed to examine chlorpyrifos and DEET mediated induction of CYP isoforms and also to characterize their potential cytotoxic effects on primary human hepatocytes. DEET significantly induced CYP3A4, CYP2B6, CYP2A6 and CYP1A2 mRNA expression while chlorpyrifos induced CYP1A1, CYP1A2 and CYP3A4 mRNA, and to a lesser extent, CYP1B1 and CYP2B6 mRNA in primary human hepatocytes. Chlorpyrifos and DEET also mediated the expression of CYP isoforms, particularly CYP3A4, CYP2B6 and CYP1A1, as shown by CYP3A4-specific protein expression, testosterone metabolism and CYP1Al-specific activity assays. DEET is a mild, while chlorpyrifos is a relatively potent, inducer of adenylate kinase and caspase-3/7, an indicator of apoptosis, while inducing 15-20% and 25-30% cell death, respectively. Therefore, DEET and chlorpyrifos mediated induction of CYP mRNA and functional CYP isoforms together with their cytotoxic potential in human hepatocytes suggests that exposure to chlorpyrifos and/or DEET should be considered in human health impact analysis.

  15. Interaction of cytochrome P4501A1 genotypes with other risk factors and susceptibility to lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Shah, Parag P.; Singh, Arvind P.; Singh, Madhu; Mathur, Neeraj [Developmental Toxicology Division, Industrial Toxicology Research Centre, P.O. Box 80, M.G. Marg, Lucknow 226001 (India); Pant, Mohan C. [Department of Radiotherapy, King George' s Medical University, Shahmina Road, Lucknow 226001 (India); Mishra, Bhartendu N. [Department of Biotechnology, IET, Sitapur Road, Lucknow 226021 (India); Parmar, Devendra [Developmental Toxicology Division, Industrial Toxicology Research Centre, P.O. Box 80, M.G. Marg, Lucknow 226001 (India)], E-mail: parmar_devendra@hotmail.com

    2008-03-01

    Lung cancer is the most common cause of death throughout the world with cigarette smoking being established as the major etiological factor in lung cancer. Since not much information is available regarding the polymorphism in drug metabolizing enzymes and lung cancer risk in the Indian population, the present case-control study attempted to investigate the association of polymorphisms in cytochrome P450 1A1 (CYP1A1) and glutathione-S-transferase M1 (GSTM1) with risk to squamous cell carcinoma of lung malignancy. Patients suffering from lung cancer (n = 200) and visiting OPD facility of Department of Radiotherapy, King George's Medical University, Lucknow, were included in the study. Equal number (n = 200) of age and sex matched healthy individuals were also enrolled in the study. Our data revealed that the variant genotypes of CYP1A1*2A, CYP1A1*2C and CYP1A1*4 were found to be over represented in the lung cancer patients when compared to controls. CYP1A1*2A variant genotypes (combined heterozygous and mutant genotypes) revealed significant association towards the lung cancer risk (OR: 1.93, 95%CI: 1.28-2.89, p = 0.002). Likewise, GSTM1 null genotypes were found to be over represented in patients when compared to controls. Haplotype analysis revealed that CYP1A1 haplotype, C-G-C increased the lung cancer risk (OR: 3.90, 95%CI: 1.00-15.04, p = 0.025) in the patients. The lung cancer risk was increased several two-to fourfold in the patients carrying the genotype combinations of CYP1A1*2A and GSTM1 suggesting the role of gene-gene interaction in lung cancer. Cigarette smoking or tobacco chewing or alcohol consumption was also found to interact with CYP1A1 genotypes in increasing the risk to lung cancer further demonstrating the role of gene-environment interaction in development of lung cancer.

  16. Interaction of cytochrome P4501A1 genotypes with other risk factors and susceptibility to lung cancer

    International Nuclear Information System (INIS)

    Shah, Parag P.; Singh, Arvind P.; Singh, Madhu; Mathur, Neeraj; Pant, Mohan C.; Mishra, Bhartendu N.; Parmar, Devendra

    2008-01-01

    Lung cancer is the most common cause of death throughout the world with cigarette smoking being established as the major etiological factor in lung cancer. Since not much information is available regarding the polymorphism in drug metabolizing enzymes and lung cancer risk in the Indian population, the present case-control study attempted to investigate the association of polymorphisms in cytochrome P450 1A1 (CYP1A1) and glutathione-S-transferase M1 (GSTM1) with risk to squamous cell carcinoma of lung malignancy. Patients suffering from lung cancer (n = 200) and visiting OPD facility of Department of Radiotherapy, King George's Medical University, Lucknow, were included in the study. Equal number (n = 200) of age and sex matched healthy individuals were also enrolled in the study. Our data revealed that the variant genotypes of CYP1A1*2A, CYP1A1*2C and CYP1A1*4 were found to be over represented in the lung cancer patients when compared to controls. CYP1A1*2A variant genotypes (combined heterozygous and mutant genotypes) revealed significant association towards the lung cancer risk (OR: 1.93, 95%CI: 1.28-2.89, p = 0.002). Likewise, GSTM1 null genotypes were found to be over represented in patients when compared to controls. Haplotype analysis revealed that CYP1A1 haplotype, C-G-C increased the lung cancer risk (OR: 3.90, 95%CI: 1.00-15.04, p = 0.025) in the patients. The lung cancer risk was increased several two-to fourfold in the patients carrying the genotype combinations of CYP1A1*2A and GSTM1 suggesting the role of gene-gene interaction in lung cancer. Cigarette smoking or tobacco chewing or alcohol consumption was also found to interact with CYP1A1 genotypes in increasing the risk to lung cancer further demonstrating the role of gene-environment interaction in development of lung cancer

  17. Overexpression of Catalase Enhances Benzo(a)pyrene Detoxification in Endothelial Microsomes.

    Science.gov (United States)

    Yang, Fang; Yang, Hong; Ramesh, Aramandla; Goodwin, J Shawn; Okoro, Emmanuel U; Guo, ZhongMao

    2016-01-01

    We previously reported that overexpression of catalase upregulated xenobiotic- metabolizing enzyme (XME) expression and diminished benzo(a)pyrene (BaP) intermediate accumulation in mouse aortic endothelial cells (MAECs). Endoplasmic reticulum (ER) is the most active organelle involved in BaP metabolism. To examine the involvement of ER in catalase-induced BaP detoxification, we compared the level and distribution of XMEs, and the profile of BaP intermediates in the microsomes of wild-type and catalase transgenic endothelial cells. Our data showed that endothelial microsomes were enriched in cytochrome P450 (CYP) 1A1, CYP1B1 and epoxide hydrolase 1 (EH1), and contained considerable levels of quinone oxidoreductase-1 (NQO1) and glutathione S-transferase-pi (GSTP). Treatment of wild-type MAECs with 1μM BaP for 2 h increased the expression of microsomal CYP1A1, 1B1 and NQO1 by ~300, 64 and 116%, respectively. However, the same treatment did not significantly alter the expression of EH1 and GSTP. Overexpression of catalase did not significantly increase EH1, but upregulated BaP-induced expression of microsomal CYP1A1, 1B1, NQO1 and GSTP in the following order: 1A1>NQO1>GSTP>1B1. Overexpression of catalase did not alter the distribution of each of these enzymes in the microsomes. In contrast to our previous report showing lower level of BaP phenols versus BaP diols/diones in the whole-cell, this report demonstrated that the sum of microsomal BaP phenolic metabolites were ~60% greater than that of the BaP diols/diones after exposure of microsomes to BaP. Overexpression of catalase reduced the concentrations of microsomal BaP phenols and diols/diones by ~45 and 95%, respectively. This process enhanced the ratio of BaP phenol versus diol/dione metabolites in a potent manner. Taken together, upregulation of phase II XMEs and CYP1 proteins, but not EH1 in the ER might be the mechanism by which overexpression of catalase reduces the levels of all the BaP metabolites, and

  18. Resveratrol analogue 3,4,4′,5-tetramethoxystilbene inhibits growth, arrests cell cycle and induces apoptosis in ovarian SKOV‐3 and A-2780 cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Piotrowska, Hanna; Myszkowski, Krzysztof; Ziółkowska, Alicja [Department of Toxicology, Poznan University of Medical Sciences, Poznan (Poland); Kulcenty, Katarzyna [Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan (Poland); Wierzchowski, Marcin [Department of Chemical Technology of Drugs, Poznan University of Medical Sciences, Poznan (Poland); Kaczmarek, Mariusz [Department of Clinical Immunology, Poznan University of Medical Sciences, Poznan (Poland); Murias, Marek [Department of Toxicology, Poznan University of Medical Sciences, Poznan (Poland); Kwiatkowska-Borowczyk, Eliza [Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan (Poland); Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Centre, Poznan (Poland); Jodynis-Liebert, Jadwiga, E-mail: liebert@ump.edu.pl [Department of Toxicology, Poznan University of Medical Sciences, Poznan (Poland)

    2012-08-15

    In the screening studies, cytotoxicity of 12 methylated resveratrol analogues on 11 human cancer cell lines was examined. The most active compound 3,4,4′5-tetramethoxystilbene (DMU-212) and two ovarian cancer cell lines A-2780 (IC{sub 50} = 0.71 μM) and SKOV-3 (IC{sub 50} = 11.51 μM) were selected for further investigation. To determine the mechanism of DMU-212 cytotoxicity, its ability to induce apoptosis was examined. DMU-212 arrested cell cycle in the G2/M or G0/G1 phase which resulted in apoptosis of both cell lines. The expression level of 84 apoptosis-related genes was investigated. In SKOV-3 cells DMU-212 caused up-regulation of pro-apoptotic Bax, Apaf-1 and p53 genes, specific to intrinsic pathway of apoptosis, and a decrease in Bcl-2 and Bcl 2110 mRNA expressions. Conversely, in A-2780 cells an increased expression of pro-apoptotic genes Fas, FasL, TNF, TNFRSF10A, TNFRSF21, TNFRSF16 specific to extracellular mechanism of apoptosis was observed. There are no data published so far regarding the receptor mediated apoptosis induced by DMU-212. The activation of caspase-3/7 was correlated with decreased TRAF-1 and BIRC-2 expression level in A-2780 cells exposed to DMU-212. DMU-212 caused a decrease in CYP1A1 and CYP1B1 mRNA levels in A-2780 by 50% and 75%, and in SKOV-3 cells by 15% and 45%, respectively. The protein expression was also reduced in both cell lines. It is noteworthy that the expression of CYP1B1 protein was entirely inhibited in A-2780 cells treated with DMU-212. It can be suggested that different CYP1B1 expression patterns in either ovarian cell line may affect their sensitivity to cytotoxic activity of DMU-212. -- Highlights: ► DMU-212 was the most cytotoxic among 12 O-methylated resveratrol analogues. ► DMU-212 arrested cell cycle at G2/M and G0/G1phase ► DMU-212 triggered mitochondria- and receptor‐mediated apoptosis. ► DMU-212 entirely inhibited CYP1B1 protein expression in A-2780 cells.

  19. Resveratrol analogue 3,4,4′,5-tetramethoxystilbene inhibits growth, arrests cell cycle and induces apoptosis in ovarian SKOV‐3 and A-2780 cancer cells

    International Nuclear Information System (INIS)

    Piotrowska, Hanna; Myszkowski, Krzysztof; Ziółkowska, Alicja; Kulcenty, Katarzyna; Wierzchowski, Marcin; Kaczmarek, Mariusz; Murias, Marek; Kwiatkowska-Borowczyk, Eliza; Jodynis-Liebert, Jadwiga

    2012-01-01

    In the screening studies, cytotoxicity of 12 methylated resveratrol analogues on 11 human cancer cell lines was examined. The most active compound 3,4,4′5-tetramethoxystilbene (DMU-212) and two ovarian cancer cell lines A-2780 (IC 50 = 0.71 μM) and SKOV-3 (IC 50 = 11.51 μM) were selected for further investigation. To determine the mechanism of DMU-212 cytotoxicity, its ability to induce apoptosis was examined. DMU-212 arrested cell cycle in the G2/M or G0/G1 phase which resulted in apoptosis of both cell lines. The expression level of 84 apoptosis-related genes was investigated. In SKOV-3 cells DMU-212 caused up-regulation of pro-apoptotic Bax, Apaf-1 and p53 genes, specific to intrinsic pathway of apoptosis, and a decrease in Bcl-2 and Bcl 2110 mRNA expressions. Conversely, in A-2780 cells an increased expression of pro-apoptotic genes Fas, FasL, TNF, TNFRSF10A, TNFRSF21, TNFRSF16 specific to extracellular mechanism of apoptosis was observed. There are no data published so far regarding the receptor mediated apoptosis induced by DMU-212. The activation of caspase-3/7 was correlated with decreased TRAF-1 and BIRC-2 expression level in A-2780 cells exposed to DMU-212. DMU-212 caused a decrease in CYP1A1 and CYP1B1 mRNA levels in A-2780 by 50% and 75%, and in SKOV-3 cells by 15% and 45%, respectively. The protein expression was also reduced in both cell lines. It is noteworthy that the expression of CYP1B1 protein was entirely inhibited in A-2780 cells treated with DMU-212. It can be suggested that different CYP1B1 expression patterns in either ovarian cell line may affect their sensitivity to cytotoxic activity of DMU-212. -- Highlights: ► DMU-212 was the most cytotoxic among 12 O-methylated resveratrol analogues. ► DMU-212 arrested cell cycle at G2/M and G0/G1phase ► DMU-212 triggered mitochondria- and receptor‐mediated apoptosis. ► DMU-212 entirely inhibited CYP1B1 protein expression in A-2780 cells.

  20. Genotoxic effects and oxidative stress induced by organic extracts of particulate matter(PM 10)collected from a subway tunnel in Seoul, Korea.

    Science.gov (United States)

    Jung, Mi Hyun; Kim, Ha Ryong; Park, Yong Joo; Park, Duck Shin; Chung, Kyu Hyuck; Oh, Seung Min

    2012-12-12

    Particulate matter (PM) has become an important health risk factor in our society. PM can easily deposit in the bronchi and lungs, causing diverse diseases such as respiratory infections, lung cancers and cardiovascular diseases. In recent days, more and more toxicological studies have been dealing with air particles in distinctive areas including industrial areas, transportation sites, or indoors. Studies on subway PM in particular, have been recognizing PM as an important health risk factor because many people use subways as a major mode of public transportation (4 million people a day in Korea). The main aim of the present study was to evaluate the genotoxic effects of organic extract (OE) of subway PM10 and potential attribution of PAHs to these effects. Particles were collected in the subway tunnel at Kil-eum station(Line 4) for one month and then extracted with Dichloromethane (DCM). Chinese Hamster Ovary cells(CHO-K1) and human normal bronchial cells (BEAS-2B) were exposed to OE, and MN and Comet assays were conducted to analyze the genotoxicity. The results showed that OE increased DNA or chromosome damages in both cell lines. In the modified Comet assay and MN assay with free radical scavengers, we confirmed that the genotoxic effect of OE was partially due to the oxidative damage on DNA. DCFHD Aassay also indicated that OE induced ROS generation in BEAS-2B cells. PAHs [benzo(a)anthracene,benzo(k)fluoranthrene, etc.], the most well-known carcinogens in polluted air, were detected in Kil-eum PM10. In conclusion, our findings confirmed that OE of subway PM10 has genotoxic effects on normal human lung cells, and oxidative stress could be one of the major mechanisms of these genotoxic effects.In addition, some genotoxic and carcinogenic PAHs were detected in OE by GC/MS/MS, even though PAHs level was not enough to increase CYP1A1 gene. Therefore, we suggest that additive or synergistic effects by unidentified chemicals as well as PAHs contained in OE of subway

  1. Proinflammatory effects of diesel exhaust particles from moderate blend concentrations of 1st and 2nd generation biodiesel in BEAS-2B bronchial epithelial cells-The FuelHealth project.

    Science.gov (United States)

    Skuland, Tonje S; Refsnes, Magne; Magnusson, Pål; Oczkowski, Michał; Gromadzka-Ostrowska, Joanna; Kruszewski, Marcin; Mruk, Remigiusz; Myhre, Oddvar; Lankoff, Anna; Øvrevik, Johan

    2017-06-01

    Biodiesel fuel fuels are introduced at an increasing extent as a more carbon-neutral alternative to reduce CO 2 -emissions, compared to conventional diesel fuel. In the present study we have investigated the impact of increasing the use of 1st generation fatty acid methyl ester (FAME) biodiesel from current 7% blend (B7) to 20% blend (B20), or by increasing the biodiesel content by adding 2nd generation hydrotreated vegetable oil (HVO) based biodiesel (SHB; Synthetic Hydrocarbon Biofuel) on toxicity of diesel exhaust particles (DEP) in an in vitro system. Human bronchial epithelial BEAS-2B cells were exposed for 4 and 20h to DEP from B7, B20 and SHB at different concentrations, and examined for effects on gene expression of interleukin 6 (IL-6), CXCL8 (IL-8), CYP1A1 and heme oxygenase-1 (HO-1). The results show that both B20 and SHB were more potent inducers of IL-6 expression compared to B7. Only B20 induced statistically significant increases in CXCL8 expression. By comparison the rank order of potency to induce CYP1A1 was SHB>B7>B20. No statistically significant difference were observed form HO-1 expression, suggesting that the differences in cytokine responses were not due to oxidative stress. The results show that even moderate increases in biodiesel blends, from 7% to 20%, may increase the proinflammatory potential of emitted DEP in BEAS-2B cells. This effect was observed for both addition of 1st generation FAME and 2nd generation HVO biodiesel. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Metabolic intervention of aflatoxin B1 toxicity by curcumin.

    Science.gov (United States)

    Nayak, Sujatha; Sashidhar, R B

    2010-02-17

    Curcumin, bioactive principle of turmeric (Curcuma longa Linn) is an important constituent of Indian traditional medicine. Turmeric has been known to possess several therapeutic properties. The modulatory effect of dietary curcumin (0.05%, w/w) on drug metabolizing and general marker enzymes of liver and formation of AFB(1)-adducts (DNA and protein) due to dietary AFB(1) exposure for a period of 6 weeks in a rodent model, have been evaluated. Drug metabolizing enzymes CYP1A1, GSHT, UGT1A and general marker enzymes (LDH, ALT, AST, ALP and gamma-GT) of liver were estimated by standardized methods. Aflatoxin adducts (DNA and protein) were quantitated by indirect competitive ELISA. Dietary curcumin enhanced GSHT (pcurcumin in the diet normalized the altered activities of LDH and ALT. At molecular level, curcumin significantly reduced AFB(1)-N(7)-guanine adduct (pcurcumin intervention ameliorates the AFB(1) induced toxicity. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

  3. The flame retardants tetrabromobisphenol A and tetrabromobisphenol A-bisallylether suppress the induction of interleukin-2 receptor α chain (CD25) in murine splenocytes

    International Nuclear Information System (INIS)

    Pullen, Sabine; Boecker, Ronald; Tiegs, Gisa

    2003-01-01

    Polybrominated flame retardants (PBF) are frequently used additives in electronical equipment. They are ubiquitous environmental contaminants which bioaccumulate with several health effects for humans and the environment. This study investigated immunotoxic effects of the PBF tetrabromobisphenol A (TBBP A), tetrabromobisphenol A-bisallylether (TBBP A-AE), tetrabromobisphenol A-bis-(2,3-dibromopropyl-ether) (TBBP A-PE), decabromodiphenylether (DBDE), and 2,4,6-tribromophenol (TBP) in vitro. The structurally related polychlorinated aromatic hydrocarbon 3,4,3',4'-tetrachlorobiphenyl (PCB77) and dioxins mediate their immunotoxicity via the Ah-receptor gene complex. A highly relevant function of the Ah receptor, the induction of CYP 1A1 in hepatocytes of C57BL/6 mice by the established inducers 3-methylcholanthrene (MC) and PCB77 was compared to the effect of PBF by measurement of ethoxyresorufin-o-deethylase (EROD) activity. The PBF did not show any induction of CYP 1A1, while EROD activity of hepatocytes exposed to MC and PCB77 was induced 10.8- and 8.7-fold, respectively. To investigate immunotoxic effects of the flame retardants, splenocytes of C57BL/6 mice were incubated with subtoxic doses of the flame retardants and PCB77 and activated by concanavalin A (Con A). The flame retardants TBBP A and TBBP A-AE significantly inhibited the expression of interleukin-2 receptor α chain (CD25) in contrast to TBBP A-PE, DBDE, TBP, and PCB77 as shown by immunohistochemistry and quantitative analysis by laser scanning cytometry. None of the substances had any effect on the Con A-induced production of cytokines. Hence, TBBP A and TBBP A-AE may act as immunotoxic compounds by specifically inhibiting the expression of CD25

  4. Historical Significant Volcanic Eruption Locations

    Data.gov (United States)

    Department of Homeland Security — A significant eruption is classified as one that meets at least one of the following criteriacaused fatalities, caused moderate damage (approximately $1 million or...

  5. 175-169):1(13) 2016 (. Afr J Tradit Complement Altern Med and ...

    African Journals Online (AJOL)

    acer

    GP III: Rats were orally pretreated with Lyco (15 mg/kg b.w). GP IV: rats were pretreated ... via ATP depletion, which finally produce necrosis of hepatocytes. It provokes a state of .... Results obtained in table (4) showed that rats injected with Gala (GP III) caused a significant elevation in the phase I enzymes activities CYP1A1 ...

  6. Cytochrome P2A13 and P1A1 gene polymorphisms are associated with the occurrence of uterine leiomyoma.

    Science.gov (United States)

    Herr, D; Bettendorf, H; Denschlag, D; Keck, C; Pietrowski, D

    2006-10-01

    To investigate the association between the occurrence of uterine leiomyoma and two SNPs of the CYP 2A13 and CYP 1A1 genes. Prospective case control study with 132 women with clinically and surgically diagnosed uterine leiomyoma and 260 controls. Genotyping was performed by polymerase chain reaction (PCR) based amplification of CYP 2A13 and CYP 1A1 genes, and restriction fragment length polymorphism (RFLP) analysis. Comparing women with uterine leiomyoma and controls, we demonstrate statistical significant differences of allele frequency and genotype distribution for the CYP 1A1 polymorphism (P = 0.025 and P = 0.046, respectively). Furthermore, for the CYP 2A13 polymorphism we found a significant difference concerning allele frequency (P = 0.033). However, for the genotype distribution, only borderline significance was observed (P = 0.064). The CYP 2A13 and CYP 1A1 SNPs are associated with uterine leiomyoma in a Caucasian population and may contribute to the understanding of the pathogenic mechanisms of uterine leiomyoma.

  7. The influence of metabolic gene polymorphisms on urinary 1-hydroxypyrene concentration in Thai bus drivers.

    Science.gov (United States)

    Petchpoung, Krittaya; Kaojarern, Sming; Yoovathaworn, Krongtong; Sura, Thanyachai; Sirivarasai, Jintana

    2011-01-01

    Polycyclic aromatic hydrocarbons (PAHs) are associated with an increased cancer risk. CYP1A1 and GSTs enzymes are important in metabolism of PAHs. Genetic polymorphisms of these enzymes are responsible for enzyme activity and concentration variation. The objectives of this study were to evaluate association of 1-OHP concentration with genetic polymorphisms of CYP1A1 and GSTs in Thai bus drivers. The results showed that 1-OHP levels in bus drivers were significantly higher than that in the control group. Significant difference in 1-OHP was found between smokers and non-smokers, in only bus drivers. Significantly increasing of 1-OHP levels were observed in bus drivers with CYP1A1 MspI and exon 7 variants. Whereas, bus drivers with GSTP1 Val and GSTM1 null genotypes showed decreasing in excretion of 1-OHP. No association between 1-OHP and polymorphisms of GSTT1 was found. This study indicated that 1-OHP concentrations were associated with exposure to air pollution, cigarette smoking and polymorphisms of CYP1A1, GSTM1 and GSTP1 genes. Copyright © 2010 Elsevier B.V. All rights reserved.

  8. Significance evaluation in factor graphs

    DEFF Research Database (Denmark)

    Madsen, Tobias; Hobolth, Asger; Jensen, Jens Ledet

    2017-01-01

    in genomics and the multiple-testing issues accompanying them, accurate significance evaluation is of great importance. We here address the problem of evaluating statistical significance of observations from factor graph models. Results Two novel numerical approximations for evaluation of statistical...... significance are presented. First a method using importance sampling. Second a saddlepoint approximation based method. We develop algorithms to efficiently compute the approximations and compare them to naive sampling and the normal approximation. The individual merits of the methods are analysed both from....... Conclusions The applicability of saddlepoint approximation and importance sampling is demonstrated on known models in the factor graph framework. Using the two methods we can substantially improve computational cost without compromising accuracy. This contribution allows analyses of large datasets...

  9. Significant Lactic Acidosis from Albuterol

    Directory of Open Access Journals (Sweden)

    Deborah Diercks

    2018-03-01

    Full Text Available Lactic acidosis is a clinical entity that demands rapid assessment and treatment to prevent significant morbidity and mortality. With increased lactate use across many clinical scenarios, lactate values themselves cannot be interpreted apart from their appropriate clinical picture. The significance of Type B lactic acidosis is likely understated in the emergency department (ED. Given the mortality that sepsis confers, a serum lactate is an important screening study. That said, it is with extreme caution that we should interpret and react to the resultant elevated value. We report a patient with a significant lactic acidosis. Though he had a high lactate value, he did not require aggressive resuscitation. A different classification scheme for lactic acidosis that focuses on the bifurcation of the “dangerous” and “not dangerous” causes of lactic acidosis may be of benefit. In addition, this case is demonstrative of the potential overuse of lactates in the ED.

  10. Modulation of aryl hydrocarbon receptor target genes in circulating lymphocytes from dairy cows bred in a dioxin-like PCB contaminated area

    International Nuclear Information System (INIS)

    Girolami, Flavia; Spalenza, Veronica; Carletti, Monica; Sacchi, Paola; Rasero, Roberto; Nebbia, Carlo

    2013-01-01

    Animal productions (i.e. fish, eggs, milk and dairy products) represent the major source of exposure to dioxins, furans, and dioxin-like (DL) polychlorobiphenyls for humans. The negative effects of these highly toxic and persistent pollutants are mediated by the activation of the aryl hydrocarbon receptor (AHR) that elicits the transcriptional induction of several genes, including those involved in xenobiotic metabolism. Previously we demonstrated the presence and functioning of the AHR signaling pathway in primary cultures of bovine blood lymphocytes. The aim of the present study was to investigate by real time PCR the expression and the inducibility of selected target genes (i.e. AHR, AHR nuclear translocator (ARNT), AHR repressor, CYP1A1 and CYP1B1) in uncultured cells from dairy cows naturally exposed to DL-compounds. The study was carried out on two groups of animals bred in a highly polluted area and characterized by a different degree of contamination, as assessed by bulk milk TEQ values, and a control group reared in an industry free area. Bovine lymphocytes expressed only AHR, ARNT and CYP1B1 genes to a detectable level; moreover, only CYP1B1 expression appeared to be correlated to TEQ values, being higher in the most contaminated group, and decreasing along with animal decontamination. Finally, lymphocytes from exposed cows displayed a lower inducibility of both CYP1A1 and CYP1B1 after the in vitro treatment with a specific AHR ligand. In conclusion, our results indicate that DL-compound contaminated cows may display significant changes in AHR-target gene expression of circulating lymphocytes. - Highlights: ► The expression of AHR-target genes in blood bovine lymphocytes was evaluated. ► The lymphocyte CYP1B1 expression appears to be related to bulk milk TEQ values. ► Blood lymphocytes from dairy cows might represent a matrix for dioxin biomonitoring

  11. Modulation of aryl hydrocarbon receptor target genes in circulating lymphocytes from dairy cows bred in a dioxin-like PCB contaminated area

    Energy Technology Data Exchange (ETDEWEB)

    Girolami, Flavia [Department of Animal Pathology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy); Spalenza, Veronica [Department of Animal Production, Epidemiology and Ecology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy); Carletti, Monica [Department of Animal Pathology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy); Sacchi, Paola [Department of Animal Production, Epidemiology and Ecology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy); Rasero, Roberto [Department of Animal Production, Epidemiology and Ecology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy); Nebbia, Carlo [Department of Animal Pathology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy)

    2013-04-15

    Animal productions (i.e. fish, eggs, milk and dairy products) represent the major source of exposure to dioxins, furans, and dioxin-like (DL) polychlorobiphenyls for humans. The negative effects of these highly toxic and persistent pollutants are mediated by the activation of the aryl hydrocarbon receptor (AHR) that elicits the transcriptional induction of several genes, including those involved in xenobiotic metabolism. Previously we demonstrated the presence and functioning of the AHR signaling pathway in primary cultures of bovine blood lymphocytes. The aim of the present study was to investigate by real time PCR the expression and the inducibility of selected target genes (i.e. AHR, AHR nuclear translocator (ARNT), AHR repressor, CYP1A1 and CYP1B1) in uncultured cells from dairy cows naturally exposed to DL-compounds. The study was carried out on two groups of animals bred in a highly polluted area and characterized by a different degree of contamination, as assessed by bulk milk TEQ values, and a control group reared in an industry free area. Bovine lymphocytes expressed only AHR, ARNT and CYP1B1 genes to a detectable level; moreover, only CYP1B1 expression appeared to be correlated to TEQ values, being higher in the most contaminated group, and decreasing along with animal decontamination. Finally, lymphocytes from exposed cows displayed a lower inducibility of both CYP1A1 and CYP1B1 after the in vitro treatment with a specific AHR ligand. In conclusion, our results indicate that DL-compound contaminated cows may display significant changes in AHR-target gene expression of circulating lymphocytes. - Highlights: ► The expression of AHR-target genes in blood bovine lymphocytes was evaluated. ► The lymphocyte CYP1B1 expression appears to be related to bulk milk TEQ values. ► Blood lymphocytes from dairy cows might represent a matrix for dioxin biomonitoring.

  12. Modulation of aryl hydrocarbon receptor target genes in circulating lymphocytes from dairy cows bred in a dioxin-like PCB contaminated area.

    Science.gov (United States)

    Girolami, Flavia; Spalenza, Veronica; Carletti, Monica; Sacchi, Paola; Rasero, Roberto; Nebbia, Carlo

    2013-04-15

    Animal productions (i.e. fish, eggs, milk and dairy products) represent the major source of exposure to dioxins, furans, and dioxin-like (DL) polychlorobiphenyls for humans. The negative effects of these highly toxic and persistent pollutants are mediated by the activation of the aryl hydrocarbon receptor (AHR) that elicits the transcriptional induction of several genes, including those involved in xenobiotic metabolism. Previously we demonstrated the presence and functioning of the AHR signaling pathway in primary cultures of bovine blood lymphocytes. The aim of the present study was to investigate by real time PCR the expression and the inducibility of selected target genes (i.e. AHR, AHR nuclear translocator (ARNT), AHR repressor, CYP1A1 and CYP1B1) in uncultured cells from dairy cows naturally exposed to DL-compounds. The study was carried out on two groups of animals bred in a highly polluted area and characterized by a different degree of contamination, as assessed by bulk milk TEQ values, and a control group reared in an industry free area. Bovine lymphocytes expressed only AHR, ARNT and CYP1B1 genes to a detectable level; moreover, only CYP1B1 expression appeared to be correlated to TEQ values, being higher in the most contaminated group, and decreasing along with animal decontamination. Finally, lymphocytes from exposed cows displayed a lower inducibility of both CYP1A1 and CYP1B1 after the in vitro treatment with a specific AHR ligand. In conclusion, our results indicate that DL-compound contaminated cows may display significant changes in AHR-target gene expression of circulating lymphocytes. Copyright © 2013 Elsevier B.V. All rights reserved.

  13. Enantiospecific effects of ketoconazole on aryl hydrocarbon receptor.

    Directory of Open Access Journals (Sweden)

    Aneta Novotna

    Full Text Available Azole antifungal ketoconazole (KET was demonstrated to activate aryl hydrocarbon receptor (AhR. Since clinically used KET is a racemic mixture of two cis-enantiomers (2R,4S-(+-KET and (2S,4R-(--KET, we examined the effects of KET enantiomers on AhR signaling pathway. (+-KET dose-dependently activated AhR in human gene reporter cell line AZ-AHR, and displayed 5-20× higher agonist activity (efficacy, as compared to (--KET; both enantiomers were AhR antagonists with equal potency (IC50. Consistently, (+-KET strongly induced CYP1A1 mRNA and protein in human HepG2 cells, while (--KET exerted less than 10% of (+-KET activity. In primary human hepatocytes, both enantiomers preferentially induced CYP1A2 over CYP1A1 mRNA and protein, and the potency of (+-KET was slightly higher as compared to (--KET. Ligand binding assay with guinea pig liver cytosols revealed that both (+-KET and (--KET are weak ligands of AhR that displaced [3H]-TCDD with comparable potency. Similarly, both enantiomers weakly transformed AhR to DNA-binding form with similar potency, as showed by EMSA, in guinea pig liver cytosolic extracts and nuclear extracts from mouse Hepa-1 cells. We also examined effects of KET on glucocorticoid receptor (GR, a regulator of AhR activity. Both KET enantiomers antagonized GR with similar potency, as revealed by gene reporter assay in AZ-GR cell line and down-regulation of tyrosine aminotransferase mRNA in human hepatocytes. Finally, we demonstrate enantiospecific antifungal activities of KET enantiomers in six Candida spp. strains. In conclusion, the significance of current study is providing the first evidence of enatiospecific effects of cis-enantiomers of ketoconazole on AhR-CYP1A pathway.

  14. The historical significance of oak

    Science.gov (United States)

    J. V. Thirgood

    1971-01-01

    A brief history of the importance of oak in Europe, contrasting the methods used in France and Britain to propagate the species and manage the forests for continued productivity. The significance of oak as a strategic resource during the sailing-ship era is stressed, and mention is made of the early development of oak management in North America. The international...

  15. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1994-03-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (October - December 1993) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  16. Synthetic definition of biological significance

    International Nuclear Information System (INIS)

    Buffington, J.D.

    1975-01-01

    The central theme of the workshop is recounted and the views of the authors are summarized. Areas of broad agreement or disagreement, unifying principles, and research needs are identified. Authors' views are consolidated into concepts that have practical utility for the scientist making impact assessments. The need for decision-makers and managers to be cognizant of the recommendations made herein is discussed. Finally, bringing together the diverse views of the workshop participants, a conceptual definition of biological significance is synthesized

  17. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1992-11-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (July - September 1992) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  18. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1993-09-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (April--June 1993) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  19. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1990-05-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (January--March 1990) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. Also included are a number of enforcement actions that had been previously resolved but not published in this NUREG. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  20. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1991-05-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (January--March 1991) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  1. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1991-02-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (October--December 1990) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  2. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1990-03-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (October--December 1989) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  3. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1990-11-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (July--September 1990) and includes copies of letters, notices, and orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  4. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1992-08-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (April--June 1992) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  5. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1990-09-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (April--June 1990) and includes copies of letters, notices, and orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  6. Clinical significance of neonatal menstruation.

    Science.gov (United States)

    Brosens, Ivo; Benagiano, Giuseppe

    2016-01-01

    Past studies have clearly shown the existence of a spectrum of endometrial progesterone responses in neonatal endometrium, varying from proliferation to full decidualization with menstrual-like shedding. The bleedings represent, similar to what occurs in adult menstruation, a progesterone withdrawal bleeding. Today, the bleeding is completely neglected and considered an uneventful episode of no clinical significance. Yet clinical studies have linked the risk of bleeding to a series of events indicating fetal distress. The potential link between the progesterone response and major adolescent disorders requires to be investigated by prospective studies. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  7. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1993-06-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (January--March 1993) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  8. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1992-05-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (January--March 1992) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  9. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1993-12-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (July--September 1993) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  10. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1993-03-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (October--December 1992) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  11. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1991-07-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (April-June 1991) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  12. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1991-11-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (July--September 1991) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  13. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1992-03-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (October--December 1991) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  14. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1989-06-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (January--March 1989) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. Also included are a number of enforcement actions that had been previously resolved but not published in this NUREG. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  15. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1989-12-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (July--September 1989) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  16. Moral significance of phenomenal consciousness.

    Science.gov (United States)

    Levy, Neil; Savulescu, Julian

    2009-01-01

    Recent work in neuroimaging suggests that some patients diagnosed as being in the persistent vegetative state are actually conscious. In this paper, we critically examine this new evidence. We argue that though it remains open to alternative interpretations, it strongly suggests the presence of consciousness in some patients. However, we argue that its ethical significance is less than many people seem to think. There are several different kinds of consciousness, and though all kinds of consciousness have some ethical significance, different kinds underwrite different kinds of moral value. Demonstrating that patients have phenomenal consciousness--conscious states with some kind of qualitative feel to them--shows that they are moral patients, whose welfare must be taken into consideration. But only if they are subjects of a sophisticated kind of access consciousness--where access consciousness entails global availability of information to cognitive systems--are they persons, in the technical sense of the word employed by philosophers. In this sense, being a person is having the full moral status of ordinary human beings. We call for further research which might settle whether patients who manifest signs of consciousness possess the sophisticated kind of access consciousness required for personhood.

  17. Clinical significance of the fabella

    International Nuclear Information System (INIS)

    Dodevski, A.; Lazarova-Tosovska, D.; Zhivadinovik, J.; Lazareska, M.

    2012-01-01

    Full text: Introduction: There is variable number of sesamoid bones in the human body; one of them is fabella, located in the tendon of the gastrocnemius muscle. Aim of this study was to investigate the frequency of occurrence of fabella in the Macedonian population and to discuss about clinical importance of this bone. Materials and methods: We retrospectively examined radiographs of 53 patients who had knee exams undertaken for a variety of clinical reasons, performed as a part of their medical treatment. Over a time span of six months, 53 patients (38 males and 15 females, age range 19-60 years, mean age of 36.7±12.3 years) were examined. Results: In seven (13.2%) patients of 53 analyzed reports, fabella was found in the lateral tendon of gastrocnemius muscle. We did not find a significant gender or side difference in the appearance of fabella. Conclusion: Although anatomic studies emphasized a lack of significance of the fabella, this bone has been associated with a spectrum of pathology affecting the knee as fabellar syndrome, perineal nerve injury and fracture. We should think of this sesamoid bone while performing diagnostic and surgical procedures

  18. The significance of small streams

    Science.gov (United States)

    Wohl, Ellen

    2017-09-01

    Headwaters, defined here as first- and secondorder streams, make up 70%‒80% of the total channel length of river networks. These small streams exert a critical influence on downstream portions of the river network by: retaining or transmitting sediment and nutrients; providing habitat and refuge for diverse aquatic and riparian organisms; creating migration corridors; and governing connectivity at the watershed-scale. The upstream-most extent of the channel network and the longitudinal continuity and lateral extent of headwaters can be difficult to delineate, however, and people are less likely to recognize the importance of headwaters relative to other portions of a river network. Consequently, headwaters commonly lack the legal protections accorded to other portions of a river network and are more likely to be significantly altered or completely obliterated by land use.

  19. No significant fuel failures (NSFF)

    International Nuclear Information System (INIS)

    Domaratzki, Z.

    1979-01-01

    It has long been recognized that no emergency core cooling system (ECCS) could be absolutely guaranteed to prevent fuel failures. In 1976 the Atomic Energy Control Board decided that the objective for an ECCS should be to prevent fuel failures, but if the objective could not be met it should be shown that the consequences are acceptable for dual failures comprising any LOCA combined with an assumed impairment of containment. Out of the review of the Bruce A plant came the definition of 'no significant fuel failures': for any postulated LOCA combined with any one mode of containment impairment the resultant dose to a person at the edge of the exclusion zone is less than the reference dose limits for dual failures

  20. Ritual Significance in Mycenaean Hairstyles

    Directory of Open Access Journals (Sweden)

    Hsu, Florence Sheng-chieh

    2012-04-01

    Full Text Available Although the frescoes excavated from Bronze Age sites on the Greek mainland provide evidence for female figures in the Mycenaean society, the hairstyles of these figures have not been studied in detail. As in many other ancient cultures, hairstyles were not only an exhibition of beauty and fashion, but they also represented certain age groups or a person’s social status. The Mycenaeans inherited many of their hairstyles from their Minoan predecessors, although differences existed as well. It is also possible there may have been a shift in meaning for seemingly similar looking hairstyles from the Minoan to the Mycenaean periods. Female figures, which compose most of the Mycenaean figures in frescoes known to date, are fine examples for discussing the artistic representation and potential significance of Mycenaean hairstyles. By comparing with Minoan hairstyles, discussions of Mycenaean examples lead to conclusions in the relationship between hairstyles and ritual activities in the Mycenaean society.

  1. The energetic significance of cooking.

    Science.gov (United States)

    Carmody, Rachel N; Wrangham, Richard W

    2009-10-01

    While cooking has long been argued to improve the diet, the nature of the improvement has not been well defined. As a result, the evolutionary significance of cooking has variously been proposed as being substantial or relatively trivial. In this paper, we evaluate the hypothesis that an important and consistent effect of cooking food is a rise in its net energy value. The pathways by which cooking influences net energy value differ for starch, protein, and lipid, and we therefore consider plant and animal foods separately. Evidence of compromised physiological performance among individuals on raw diets supports the hypothesis that cooked diets tend to provide energy. Mechanisms contributing to energy being gained from cooking include increased digestibility of starch and protein, reduced costs of digestion for cooked versus raw meat, and reduced energetic costs of detoxification and defence against pathogens. If cooking consistently improves the energetic value of foods through such mechanisms, its evolutionary impact depends partly on the relative energetic benefits of non-thermal processing methods used prior to cooking. We suggest that if non-thermal processing methods such as pounding were used by Lower Palaeolithic Homo, they likely provided an important increase in energy gain over unprocessed raw diets. However, cooking has critical effects not easily achievable by non-thermal processing, including the relatively complete gelatinisation of starch, efficient denaturing of proteins, and killing of food borne pathogens. This means that however sophisticated the non-thermal processing methods were, cooking would have conferred incremental energetic benefits. While much remains to be discovered, we conclude that the adoption of cooking would have led to an important rise in energy availability. For this reason, we predict that cooking had substantial evolutionary significance.

  2. Sustained induction of cytochrome P4501A1 in human hepatoma cells by co-exposure to benzo[a]pyrene and 7H-dibenzo[c,g]carbazole underlies the synergistic effects on DNA adduct formation

    Energy Technology Data Exchange (ETDEWEB)

    Gábelová, Alena, E-mail: alena.gabelova@savba.sk [Cancer Research Institute, Slovak Academy of Sciences, Vlárska 7, 833 91 Bratislava (Slovakia); Poláková, Veronika [Cancer Research Institute, Slovak Academy of Sciences, Vlárska 7, 833 91 Bratislava (Slovakia); Prochazka, Gabriela [Department of Biosciences and Nutrition, Karolinska Institute, Novum, SE-141 83 Huddinge (Sweden); Department of Medical Epidemiology and Biostatistics, Karolinska Institute, SE-171 77 Stockholm (Sweden); Kretová, Miroslava; Poloncová, Katarína; Regendová, Eva; Luciaková, Katarína [Cancer Research Institute, Slovak Academy of Sciences, Vlárska 7, 833 91 Bratislava (Slovakia); Segerbäck, Dan [Department of Biosciences and Nutrition, Karolinska Institute, Novum, SE-141 83 Huddinge (Sweden)

    2013-08-15

    To gain a deeper insight into the potential interactions between individual aromatic hydrocarbons in a mixture, several benzo[a]pyrene (B[a]P) and 7H-dibenzo[c,g]carbazole (DBC) binary mixtures were studied. The biological activity of the binary mixtures was investigated in the HepG2 and WB-F344 liver cell lines and the Chinese hamster V79 cell line that stably expresses the human cytochrome P4501A1 (hCYP1A1). In the V79 cells, binary mixtures, in contrast to individual carcinogens, caused a significant decrease in the levels of micronuclei, DNA adducts and gene mutations, but not in cell survival. Similarly, a lower frequency of micronuclei and levels of DNA adducts were found in rat liver WB-F344 cells treated with a binary mixture, regardless of the exposure time. The observed antagonism between B[a]P and DBC may be due to an inhibition of Cyp1a1 expression because cells exposed to B[a]P:DBC showed a decrease in Cyp1a1 mRNA levels. In human liver HepG2 cells exposed to binary mixtures for 2 h, a reduction in micronuclei frequency was also found. However, after a 24 h treatment, synergism between B[a]P and DBC was determined based on DNA adduct formation. Accordingly, the up-regulation of CYP1A1 expression was detected in HepG2 cells exposed to B[a]P:DBC. Our results show significant differences in the response of human and rat cells to B[a]P:DBC mixtures and stress the need to use multiple experimental systems when evaluating the potential risk of environmental pollutants. Our data also indicate that an increased expression of CYP1A1 results in a synergistic effect of B[a]P and DBC in human cells. As humans are exposed to a plethora of noxious chemicals, our results have important implications for human carcinogenesis. - Highlights: • B[a]P:DBC mixtures were less genotoxic in V79MZh1A1 cells than B[a]P and DBC alone. • An antagonism between B[a]P and DBC was determined in rat liver WB-F344 cells. • The inhibition of CYP1a1 expression by B[a]P:DBC mixture

  3. Assessing Oil Spill Impacts to Cold-Water Corals of the Deep Gulf of Mexico

    Science.gov (United States)

    DeLeo, D. M.; Lengyel, S. D.; Cordes, E. E.

    2016-02-01

    The Deepwater Horizon (DWH) disaster and subsequent cleanup efforts resulted in the release of an unprecedented amount of oil and chemical dispersants in the deep waters of the Gulf of Mexico (GoM). Over the years, numerous detrimental effects have been documented including impacts to cold-water coral ecosystems. Assessing and quantifying these effects is crucial to understanding the long-term consequences to affected coral populations as well as their resilience. We conducted live exposure experiments to investigate the toxicity of oil and dispersants on two deep-sea corals, Callogorgia delta and Paramuricea type B3. For both species, the treatments containing dispersants had a more pronounced effect than oil treatments alone. In addition, RNA from unexposed and DWH spill-impacted Paramuricea biscaya was extracted and sequenced using Illumina technology. A de novo reference transcriptome was produced and used to explore stress-induced variations in gene expression. Current findings show overexpression of genes coding for Cytochrome p450 (CYP1A1), Tumor necrosis factor receptor-associated factors (TRAFs), Peroxidasin and additional genes involved in innate immunity and apoptotic pathways. CYP1A1 is involved in the metabolism of xenobiotics and has been previously used as a diagnostic tool for aquatic pollution. TRAFs are responsible for regulating pathways involved in immune and inflammatory responses and were likewise overexpressed in thermally stressed shallow-water corals. Ribosomal proteins were also significantly underexpressed. These genes among others found in our expression data serve as useful biomarker candidates for assessing and monitoring future spill impacts as resource extraction continues in the deep waters of the GoM. Our results also provide insights into the responses of deep-sea corals to toxin exposure, implications of applying dispersants to oil spills and a novel reference assembly for a relatively under-studied group of cold-water corals.

  4. Significant biases affecting abundance determinations

    Science.gov (United States)

    Wesson, Roger

    2015-08-01

    I have developed two highly efficient codes to automate analyses of emission line nebulae. The tools place particular emphasis on the propagation of uncertainties. The first tool, ALFA, uses a genetic algorithm to rapidly optimise the parameters of gaussian fits to line profiles. It can fit emission line spectra of arbitrary resolution, wavelength range and depth, with no user input at all. It is well suited to highly multiplexed spectroscopy such as that now being carried out with instruments such as MUSE at the VLT. The second tool, NEAT, carries out a full analysis of emission line fluxes, robustly propagating uncertainties using a Monte Carlo technique.Using these tools, I have found that considerable biases can be introduced into abundance determinations if the uncertainty distribution of emission lines is not well characterised. For weak lines, normally distributed uncertainties are generally assumed, though it is incorrect to do so, and significant biases can result. I discuss observational evidence of these biases. The two new codes contain routines to correctly characterise the probability distributions, giving more reliable results in analyses of emission line nebulae.

  5. Astrobiological significance of chemolithoautotrophic acidophiles

    Science.gov (United States)

    Pikuta, Elena V.; Hoover, Richard B.

    2004-02-01

    For more than a century (since Winogradsky discovered lithautotrophic bacteria) there has been a dilemma in microbiology about life that first inhabited the Earth. Which types of life forms first appeared in the primordial oceans during the earliest geological period on Earth as the primary ancestors of modern biological diversity? How did a metabolism of ancestors evolve: from lithoautotrophic to lithoheterotrophic and organoheterotrophic or from organoheterotrophic to organautotrophic and lithomixotrophic types? At the present time, it is known that chemolithoheterotrophic and chemolithoautotrophic metabolizing bacteria are wide spread in different ecosystems. On Earth the acidic ecosystems are associated with geysers, volcanic fumaroles, hot springs, deep sea hydrothermal vents, caves, acid mine drainage and other technogenic ecosystems. Bioleaching played a significant roel on a global geological scale during the Earth's formation. This important feature of bacteria has been successfully applied in industry. The lithoautotrophs include Bacteria and Archaea belonging to diverse genera containing thermophilic and mesophilic species. In this paper we discuss the lithotrophic microbial acidophiles and present some data with a description of new acidophilic iron- and sulfur-oxidizing bacterium isolated from the Chena Hot Springs in Alaska. We also consider the possible relevance of microbial acidophiles to Venus, Io, and acidic inclusions in glaciers and icy moons.

  6. Determining Semantically Related Significant Genes.

    Science.gov (United States)

    Taha, Kamal

    2014-01-01

    GO relation embodies some aspects of existence dependency. If GO term xis existence-dependent on GO term y, the presence of y implies the presence of x. Therefore, the genes annotated with the function of the GO term y are usually functionally and semantically related to the genes annotated with the function of the GO term x. A large number of gene set enrichment analysis methods have been developed in recent years for analyzing gene sets enrichment. However, most of these methods overlook the structural dependencies between GO terms in GO graph by not considering the concept of existence dependency. We propose in this paper a biological search engine called RSGSearch that identifies enriched sets of genes annotated with different functions using the concept of existence dependency. We observe that GO term xcannot be existence-dependent on GO term y, if x- and y- have the same specificity (biological characteristics). After encoding into a numeric format the contributions of GO terms annotating target genes to the semantics of their lowest common ancestors (LCAs), RSGSearch uses microarray experiment to identify the most significant LCA that annotates the result genes. We evaluated RSGSearch experimentally and compared it with five gene set enrichment systems. Results showed marked improvement.

  7. Statistically significant relational data mining :

    Energy Technology Data Exchange (ETDEWEB)

    Berry, Jonathan W.; Leung, Vitus Joseph; Phillips, Cynthia Ann; Pinar, Ali; Robinson, David Gerald; Berger-Wolf, Tanya; Bhowmick, Sanjukta; Casleton, Emily; Kaiser, Mark; Nordman, Daniel J.; Wilson, Alyson G.

    2014-02-01

    This report summarizes the work performed under the project (3z(BStatitically significant relational data mining.(3y (BThe goal of the project was to add more statistical rigor to the fairly ad hoc area of data mining on graphs. Our goal was to develop better algorithms and better ways to evaluate algorithm quality. We concetrated on algorithms for community detection, approximate pattern matching, and graph similarity measures. Approximate pattern matching involves finding an instance of a relatively small pattern, expressed with tolerance, in a large graph of data observed with uncertainty. This report gathers the abstracts and references for the eight refereed publications that have appeared as part of this work. We then archive three pieces of research that have not yet been published. The first is theoretical and experimental evidence that a popular statistical measure for comparison of community assignments favors over-resolved communities over approximations to a ground truth. The second are statistically motivated methods for measuring the quality of an approximate match of a small pattern in a large graph. The third is a new probabilistic random graph model. Statisticians favor these models for graph analysis. The new local structure graph model overcomes some of the issues with popular models such as exponential random graph models and latent variable models.

  8. Statistical Significance for Hierarchical Clustering

    Science.gov (United States)

    Kimes, Patrick K.; Liu, Yufeng; Hayes, D. Neil; Marron, J. S.

    2017-01-01

    Summary Cluster analysis has proved to be an invaluable tool for the exploratory and unsupervised analysis of high dimensional datasets. Among methods for clustering, hierarchical approaches have enjoyed substantial popularity in genomics and other fields for their ability to simultaneously uncover multiple layers of clustering structure. A critical and challenging question in cluster analysis is whether the identified clusters represent important underlying structure or are artifacts of natural sampling variation. Few approaches have been proposed for addressing this problem in the context of hierarchical clustering, for which the problem is further complicated by the natural tree structure of the partition, and the multiplicity of tests required to parse the layers of nested clusters. In this paper, we propose a Monte Carlo based approach for testing statistical significance in hierarchical clustering which addresses these issues. The approach is implemented as a sequential testing procedure guaranteeing control of the family-wise error rate. Theoretical justification is provided for our approach, and its power to detect true clustering structure is illustrated through several simulation studies and applications to two cancer gene expression datasets. PMID:28099990

  9. Making lasting memories: Remembering the significant

    Science.gov (United States)

    McGaugh, James L.

    2013-01-01

    Although forgetting is the common fate of most of our experiences, much evidence indicates that emotional arousal enhances the storage of memories, thus serving to create, selectively, lasting memories of our more important experiences. The neurobiological systems mediating emotional arousal and memory are very closely linked. The adrenal stress hormones epinephrine and corticosterone released by emotional arousal regulate the consolidation of long-term memory. The amygdala plays a critical role in mediating these stress hormone influences. The release of norepinephrine in the amygdala and the activation of noradrenergic receptors are essential for stress hormone-induced memory enhancement. The findings of both animal and human studies provide compelling evidence that stress-induced activation of the amygdala and its interactions with other brain regions involved in processing memory play a critical role in ensuring that emotionally significant experiences are well-remembered. Recent research has determined that some human subjects have highly superior autobiographic memory of their daily experiences and that there are structural differences in the brains of these subjects compared with the brains of subjects who do not have such memory. Understanding of neurobiological bases of such exceptional memory may provide additional insights into the processes underlying the selectivity of memory. PMID:23754441

  10. Detection of significant protein coevolution.

    Science.gov (United States)

    Ochoa, David; Juan, David; Valencia, Alfonso; Pazos, Florencio

    2015-07-01

    The evolution of proteins cannot be fully understood without taking into account the coevolutionary linkages entangling them. From a practical point of view, coevolution between protein families has been used as a way of detecting protein interactions and functional relationships from genomic information. The most common approach to inferring protein coevolution involves the quantification of phylogenetic tree similarity using a family of methodologies termed mirrortree. In spite of their success, a fundamental problem of these approaches is the lack of an adequate statistical framework to assess the significance of a given coevolutionary score (tree similarity). As a consequence, a number of ad hoc filters and arbitrary thresholds are required in an attempt to obtain a final set of confident coevolutionary signals. In this work, we developed a method for associating confidence estimators (P values) to the tree-similarity scores, using a null model specifically designed for the tree comparison problem. We show how this approach largely improves the quality and coverage (number of pairs that can be evaluated) of the detected coevolution in all the stages of the mirrortree workflow, independently of the starting genomic information. This not only leads to a better understanding of protein coevolution and its biological implications, but also to obtain a highly reliable and comprehensive network of predicted interactions, as well as information on the substructure of macromolecular complexes using only genomic information. The software and datasets used in this work are freely available at: http://csbg.cnb.csic.es/pMT/. pazos@cnb.csic.es Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  11. Cytochrome P450 1b1 in polycyclic aromatic hydrocarbon (PAH)-induced skin carcinogenesis: Tumorigenicity of individual PAHs and coal-tar extract, DNA adduction and expression of select genes in the Cyp1b1 knockout mouse

    Energy Technology Data Exchange (ETDEWEB)

    Siddens, Lisbeth K. [Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331 (United States); Superfund Research Center, Oregon State University, Corvallis, OR 97331 (United States); Bunde, Kristi L. [College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331 (United States); Harper, Tod A. [Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331 (United States); Linus Pauling Institute, Oregon State University, Corvallis, OR 97331 (United States); Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331 (United States); McQuistan, Tammie J. [Superfund Research Center, Oregon State University, Corvallis, OR 97331 (United States); Linus Pauling Institute, Oregon State University, Corvallis, OR 97331 (United States); Löhr, Christiane V. [Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331 (United States); College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331 (United States); Bramer, Lisa M. [Applied Statistics and Computational Modeling, Pacific Northwest National Laboratory, Richland, WA 99352 (United States); Waters, Katrina M. [Superfund Research Center, Oregon State University, Corvallis, OR 97331 (United States); Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352 (United States); Tilton, Susan C. [Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331 (United States); Superfund Research Center, Oregon State University, Corvallis, OR 97331 (United States); Krueger, Sharon K. [Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331 (United States); Superfund Research Center, Oregon State University, Corvallis, OR 97331 (United States); Linus Pauling Institute, Oregon State University, Corvallis, OR 97331 (United States); and others

    2015-09-01

    FVB/N mice wild-type, heterozygous or null for Cyp 1b1 were used in a two-stage skin tumor study comparing PAH, benzo[a]pyrene (BaP), dibenzo[def,p]chrysene (DBC), and coal tar extract (CTE, SRM 1597a). Following 20 weeks of promotion with TPA the Cyp 1b1 null mice, initiated with DBC, exhibited reductions in incidence, multiplicity, and progression. None of these effects were observed with BaP or CTE. The mechanism of Cyp 1b1-dependent alteration of DBC skin carcinogenesis was further investigated by determining expression of select genes in skin from DBC-treated mice 2, 4 and 8 h post-initiation. A significant reduction in levels of Cyp 1a1, Nqo1 at 8 h and Akr 1c14 mRNA was observed in Cyp 1b1 null (but not wt or het) mice, whereas no impact was observed in Gst a1, Nqo 1 at 2 and 4 h or Akr 1c19 at any time point. Cyp 1b1 mRNA was not elevated by DBC. The major covalent DNA adducts, dibenzo[def,p]chrysene-(±)-11,12-dihydrodiol-cis and trans-13,14-epoxide-deoxyadenosine (DBCDE-dA) were quantified by UHPLC-MS/MS 8 h post-initiation. Loss of Cyp1 b1 expression reduced DBCDE-dA adducts in the skin but not to a statistically significant degree. The ratio of cis- to trans-DBCDE-dA adducts was higher in the skin than other target tissues such as the spleen, lung and liver (oral dosing). These results document that Cyp 1b1 plays a significant role in bioactivation and carcinogenesis of DBC in a two-stage mouse skin tumor model and that loss of Cyp 1b1 has little impact on tumor response with BaP or CTE as initiators. - Highlights: • Cyp1b1 null mice exhibit lower skin cancer sensitivity to DBC but not BaP or CTE. • Cyp1b1 expression impacts expression of other PAH metabolizing enzymes. • cis/trans-DBCDE-dA ratio significantly higher in the skin than the spleen, lung or liver • Potency of DBC and CTE in mouse skin is higher than predicted by RPFs.

  12. Induced Abortion

    Science.gov (United States)

    ... Education & Events Advocacy For Patients About ACOG Induced Abortion Home For Patients Search FAQs Induced Abortion Page ... Induced Abortion FAQ043, May 2015 PDF Format Induced Abortion Special Procedures What is an induced abortion? What ...

  13. Traditional Indian spices and their health significance.

    Science.gov (United States)

    Krishnaswamy, Kamala

    2008-01-01

    India has been recognized all over the world for spices and medicinal plants. Both exhibit a wide range of physiological and pharmacological properties. Current biomedical efforts are focused on their scientific merits, to provide science-based evidence for the traditional uses and to develop either functional foods or nutraceuticals. The Indian traditional medical systems use turmeric for wound healing, rheumatic disorders, gastrointestinal symptoms, deworming, rhinitis and as a cosmetic. Studies in India have explored its anti-inflammatory, cholekinetic and anti-oxidant potentials with the recent investigations focusing on its preventive effect on precarcinogenic, anti-inflammatory and anti atherosclerotic effects in biological systems both under in vitro and in vivo conditions in animals and humans. Both turmeric and curcumin were found to increase detoxifying enzymes, prevent DNA damage, improve DNA repair, decrease mutations and tumour formation and exhibit antioxidative potential in animals. Limited clinical studies suggest that turmeric can significantly impact excretion of mutagens in urine in smokers and regress precancerous palatal lesions. It reduces DNA adducts and micronuclei in oral epithelial cells. It prevents formation of nitroso compounds both in vivo and in vitro. It delays induced cataract in diabetes and reduces hyperlipidemia in obese rats. Recently several molecular targets have been identified for therapeutic / preventive effects of turmeric. Fenugreek seeds, a rich source of soluble fiber used in Indian cuisine reduces blood glucose and lipids and can be used as a food adjuvant in diabetes. Similarly garlic, onions, and ginger have been found to modulate favourably the process of carcinogenesis.

  14. Quantifying the Clinical Significance of Cannabis Withdrawal

    Science.gov (United States)

    Allsop, David J.; Copeland, Jan; Norberg, Melissa M.; Fu, Shanlin; Molnar, Anna; Lewis, John; Budney, Alan J.

    2012-01-01

    Background and Aims Questions over the clinical significance of cannabis withdrawal have hindered its inclusion as a discrete cannabis induced psychiatric condition in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV). This study aims to quantify functional impairment to normal daily activities from cannabis withdrawal, and looks at the factors predicting functional impairment. In addition the study tests the influence of functional impairment from cannabis withdrawal on cannabis use during and after an abstinence attempt. Methods and Results A volunteer sample of 49 non-treatment seeking cannabis users who met DSM-IV criteria for dependence provided daily withdrawal-related functional impairment scores during a one-week baseline phase and two weeks of monitored abstinence from cannabis with a one month follow up. Functional impairment from withdrawal symptoms was strongly associated with symptom severity (p = 0.0001). Participants with more severe cannabis dependence before the abstinence attempt reported greater functional impairment from cannabis withdrawal (p = 0.03). Relapse to cannabis use during the abstinence period was associated with greater functional impairment from a subset of withdrawal symptoms in high dependence users. Higher levels of functional impairment during the abstinence attempt predicted higher levels of cannabis use at one month follow up (p = 0.001). Conclusions Cannabis withdrawal is clinically significant because it is associated with functional impairment to normal daily activities, as well as relapse to cannabis use. Sample size in the relapse group was small and the use of a non-treatment seeking population requires findings to be replicated in clinical samples. Tailoring treatments to target withdrawal symptoms contributing to functional impairment during a quit attempt may improve treatment outcomes. PMID:23049760

  15. Quantifying the clinical significance of cannabis withdrawal.

    Directory of Open Access Journals (Sweden)

    David J Allsop

    Full Text Available Questions over the clinical significance of cannabis withdrawal have hindered its inclusion as a discrete cannabis induced psychiatric condition in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV. This study aims to quantify functional impairment to normal daily activities from cannabis withdrawal, and looks at the factors predicting functional impairment. In addition the study tests the influence of functional impairment from cannabis withdrawal on cannabis use during and after an abstinence attempt.A volunteer sample of 49 non-treatment seeking cannabis users who met DSM-IV criteria for dependence provided daily withdrawal-related functional impairment scores during a one-week baseline phase and two weeks of monitored abstinence from cannabis with a one month follow up. Functional impairment from withdrawal symptoms was strongly associated with symptom severity (p=0.0001. Participants with more severe cannabis dependence before the abstinence attempt reported greater functional impairment from cannabis withdrawal (p=0.03. Relapse to cannabis use during the abstinence period was associated with greater functional impairment from a subset of withdrawal symptoms in high dependence users. Higher levels of functional impairment during the abstinence attempt predicted higher levels of cannabis use at one month follow up (p=0.001.Cannabis withdrawal is clinically significant because it is associated with functional impairment to normal daily activities, as well as relapse to cannabis use. Sample size in the relapse group was small and the use of a non-treatment seeking population requires findings to be replicated in clinical samples. Tailoring treatments to target withdrawal symptoms contributing to functional impairment during a quit attempt may improve treatment outcomes.

  16. PPARalpha-dependent modulation of hepatic CYP1A by clofibric acid in rats.

    Science.gov (United States)

    Shaban, Zein; El-Shazly, Samir; Ishizuka, Mayumi; Kimura, Kazuhiro; Kazusaka, Akio; Fujita, Shoichi

    2004-09-01

    Fibrates, hypolipidemic drugs, have been reported to suppress the metabolic activities of cytochrome P450 1A1 and 1A2 in rats but the mechanism has not been elucidated. In the present study we tested the hypothesis that the inhibitory effect of fibrates on arylhydrocarbon receptor (AhR) function may be due to their stimulatory effects on PPARalpha. Sudan III (S.III) treatment induced CYP 1A1 and CYP 1A2 protein expression, mRNA and their metabolic activities, methoxyresorufin-O-demethylase (MROD) and ethoxyresorufin-O-deethylase (EROD), in Wistar rats higher than those in the control. Co-treatment of rats with S.III and clofibric acid (CA) caused a 40-50% decrease in the induced levels of CYP1A1 and CYP1A2 protein, mRNA expression and their metabolic activities and reduced AhR protein expression. When we treated HepG2 cells with S.III and/or CA, no suppressive effect on S.III-induced CYP1A1 protein expression due to CA was found. HepG2 cells were transiently transfected with increasing concentrations of PPARalpha mammalian expression vector and exposed to the same treatment. CA co-treatment with S.III decreased AhR protein and S.III-induced CYP1A1 protein expression with increasing dose of PPARalpha transfected into HepG2 cells. Our results demonstrate that the suppressive effect of fibrates on CYP1A is PPARalpha-dependent and suggest that PPARalpha has an inhibitory effect on AhR function.

  17. NAD(P)H:quinone oxidoreductase expression in Cyp1a-knockout and CYP1A-humanized mouse lines and its effect on bioactivation of the carcinogen aristolochic acid I

    Energy Technology Data Exchange (ETDEWEB)

    Levova, Katerina; Moserova, Michaela [Department of Biochemistry, Faculty of Science, Charles University, Prague (Czech Republic); Nebert, Daniel W. [Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati (United States); Phillips, David H. [Analytical and Environmental Sciences Division, MRC-HPA Centre for Environment and Health, King' s College London, London (United Kingdom); Frei, Eva [Division of Preventive Oncology, National Center for Tumor Diseases, German Cancer Research Center (DKFZ), Heidelberg (Germany); Schmeiser, Heinz H. [Research Group Genetic Alterations in Carcinogenesis, German Cancer Research Center (DKFZ), Heidelberg (Germany); Arlt, Volker M. [Analytical and Environmental Sciences Division, MRC-HPA Centre for Environment and Health, King' s College London, London (United Kingdom); Stiborova, Marie, E-mail: stiborov@natur.cuni.cz [Department of Biochemistry, Faculty of Science, Charles University, Prague (Czech Republic)

    2012-12-15

    Aristolochic acid causes a specific nephropathy (AAN), Balkan endemic nephropathy, and urothelial malignancies. Using Western blotting suitable to determine protein expression, we investigated in several transgenic mouse lines expression of NAD(P)H:quinone oxidoreductase (NQO1)—the most efficient cytosolic enzyme that reductively activates aristolochic acid I (AAI). The mouse tissues used were from previous studies [Arlt et al., Chem. Res. Toxicol. 24 (2011) 1710; Stiborova et al., Toxicol. Sci. 125 (2012) 345], in which the role of microsomal cytochrome P450 (CYP) enzymes in AAI metabolism in vivo had been determined. We found that NQO1 levels in liver, kidney and lung of Cyp1a1(−/−), Cyp1a2(−/−) and Cyp1a1/1a2(−/−) knockout mouse lines, as well as in two CYP1A-humanized mouse lines harboring functional human CYP1A1 and CYP1A2 and lacking the mouse Cyp1a1/1a2 orthologs, differed from NQO1 levels in wild-type mice. NQO1 protein and enzymic activity were induced in hepatic and renal cytosolic fractions isolated from AAI-pretreated mice, compared with those in untreated mice. Furthermore, this increase in hepatic NQO1 enzyme activity was associated with bioactivation of AAI and elevated AAI-DNA adduct levels in ex vivo incubations of cytosolic fractions with DNA and AAI. In conclusion, AAI appears to increase its own metabolic activation by inducing NQO1, thereby enhancing its own genotoxic potential. Highlights: ► NAD(P)H:quinone oxidoreductase expression in Cyp1a knockout and humanized CYP1A mice ► Reductive activation of the nephrotoxic and carcinogenic aristolochic acid I (AAI) ► NAD(P)H:quinone oxidoreductase is induced in mice treated with AAI. ► Induced hepatic enzyme activity resulted in elevated AAI-DNA adduct levels.

  18. NAD(P)H:quinone oxidoreductase expression in Cyp1a-knockout and CYP1A-humanized mouse lines and its effect on bioactivation of the carcinogen aristolochic acid I

    International Nuclear Information System (INIS)

    Levova, Katerina; Moserova, Michaela; Nebert, Daniel W.; Phillips, David H.; Frei, Eva; Schmeiser, Heinz H.; Arlt, Volker M.; Stiborova, Marie

    2012-01-01

    Aristolochic acid causes a specific nephropathy (AAN), Balkan endemic nephropathy, and urothelial malignancies. Using Western blotting suitable to determine protein expression, we investigated in several transgenic mouse lines expression of NAD(P)H:quinone oxidoreductase (NQO1)—the most efficient cytosolic enzyme that reductively activates aristolochic acid I (AAI). The mouse tissues used were from previous studies [Arlt et al., Chem. Res. Toxicol. 24 (2011) 1710; Stiborova et al., Toxicol. Sci. 125 (2012) 345], in which the role of microsomal cytochrome P450 (CYP) enzymes in AAI metabolism in vivo had been determined. We found that NQO1 levels in liver, kidney and lung of Cyp1a1(−/−), Cyp1a2(−/−) and Cyp1a1/1a2(−/−) knockout mouse lines, as well as in two CYP1A-humanized mouse lines harboring functional human CYP1A1 and CYP1A2 and lacking the mouse Cyp1a1/1a2 orthologs, differed from NQO1 levels in wild-type mice. NQO1 protein and enzymic activity were induced in hepatic and renal cytosolic fractions isolated from AAI-pretreated mice, compared with those in untreated mice. Furthermore, this increase in hepatic NQO1 enzyme activity was associated with bioactivation of AAI and elevated AAI-DNA adduct levels in ex vivo incubations of cytosolic fractions with DNA and AAI. In conclusion, AAI appears to increase its own metabolic activation by inducing NQO1, thereby enhancing its own genotoxic potential. Highlights: ► NAD(P)H:quinone oxidoreductase expression in Cyp1a knockout and humanized CYP1A mice ► Reductive activation of the nephrotoxic and carcinogenic aristolochic acid I (AAI) ► NAD(P)H:quinone oxidoreductase is induced in mice treated with AAI. ► Induced hepatic enzyme activity resulted in elevated AAI-DNA adduct levels.

  19. Mercury modulates the cytochrome P450 1a1, 1a2 and 1b1 in C57BL/6J mice: in vivo and in vitro studies

    International Nuclear Information System (INIS)

    Amara, Issa E.A.; Anwar-Mohamed, Anwar; Abdelhamid, Ghada; El-Kadi, Ayman O.S.

    2013-01-01

    In the current study C57BL/6J mice were injected intraperitoneally with Hg 2+ in the absence and presence of TCDD. After 6 and 24 h the liver was harvested and the expression of Cyps was determined. In vitro, isolated hepatocytes were incubated with TCDD in the presence and absence of Hg 2+ . At the in vivo level, Hg 2+ significantly decreased the TCDD-mediated induction of Cyps at 6 h while potentiating their levels at 24 h. In vitro, Hg 2+ significantly inhibited the TCDD-mediated induction of Cyp1a1 in a concentration- and time-dependent manner. Interestingly, Hg 2+ increased the serum hemoglobin (Hb) levels in mice treated for 24 h. Upon treatment of isolated hepatocytes with Hb alone, there was an increase in the AhR-dependent luciferase activity with a subsequent increase in Cyp1a1 protein and catalytic activity levels. Importantly, when hepatocytes were treated for 2 h with Hg 2+ in the presence of TCDD, then the medium was replaced with new medium containing Hb, there was potentiation of the TCDD-mediated effect. In addition, Hg 2+ increased heme oxygenase-1 (HO-1) mRNA, which coincided with a decrease in the Cyp1a1 activity level. When the competitive HO-1 inhibitor, tin mesoporphyrin was applied to the hepatocytes there was a partial restoration of Hg 2+ -mediated inhibition of Cyp1a1 activity. In conclusion, we demonstrate for the first time that there is a differential modulation of the TCDD-mediated induction of Cyp1a1 by Hg 2+ in C57BL/6J mice livers and isolated hepatocytes. Moreover, this study implicates Hb as an in vivo specific modulator of Cyp1 family. -- Highlights: ► In vivo, Hg 2+ decreased the Cyps at 6 h while potentiating their levels at 24 h. ► In vitro, Hg 2+ significantly inhibited the TCDD-mediated induction of Cyps. ► Hg 2+ increased the serum Hb levels in animals treated for 24 h. ► Hb potentiated the TCDD-mediated effect on Cyps. ► Tin mesoporphyrin partially restored Hg 2+ -mediated inhibition of Cyp1a1.

  20. Curcumin significantly enhances dual PI3K/Akt and mTOR inhibitor NVP-BEZ235-induced apoptosis in human renal carcinoma Caki cells through down-regulation of p53-dependent Bcl-2 expression and inhibition of Mcl-1 protein stability.

    Directory of Open Access Journals (Sweden)

    Bo Ram Seo

    Full Text Available The PI3K/Akt and mTOR signaling pathways are important for cell survival and growth, and they are highly activated in cancer cells compared with normal cells. Therefore, these signaling pathways are targets for inducing cancer cell death. The dual PI3K/Akt and mTOR inhibitor NVP-BEZ235 completely inhibited both signaling pathways. However, NVP-BEZ235 had no effect on cell death in human renal carcinoma Caki cells. We tested whether combined treatment with natural compounds and NVP-BEZ235 could induce cell death. Among several chemopreventive agents, curcumin, a natural biologically active compound that is extracted from the rhizomes of Curcuma species, markedly induced apoptosis in NVP-BEZ235-treated cells. Co-treatment with curcumin and NVP-BEZ235 led to the down-regulation of Mcl-1 protein expression but not mRNA expression. Ectopic expression of Mcl-1 completely inhibited curcumin plus NVP-NEZ235-induced apoptosis. Furthermore, the down-regulation of Bcl-2 was involved in curcumin plus NVP-BEZ235-induced apoptosis. Curcumin or NVP-BEZ235 alone did not change Bcl-2 mRNA or protein expression, but co-treatment reduced Bcl-2 mRNA and protein expression. Combined treatment with NVP-BEZ235 and curcumin reduced Bcl-2 expression in wild-type p53 HCT116 human colon carcinoma cells but not p53-null HCT116 cells. Moreover, Bcl-2 expression was completely reversed by treatment with pifithrin-α, a p53-specific inhibitor. Ectopic expression of Bcl-2 also inhibited apoptosis in NVP-BE235 plus curcumin-treated cells. In contrast, NVP-BEZ235 combined with curcumin did not have a synergistic effect on normal human skin fibroblasts and normal human mesangial cells. Taken together, combined treatment with NVP-BEZ235 and curcumin induces apoptosis through p53-dependent Bcl-2 mRNA down-regulation at the transcriptional level and Mcl-1 protein down-regulation at the post-transcriptional level.

  1. Impact significance determination-Back to basics

    International Nuclear Information System (INIS)

    Lawrence, David P.

    2007-01-01

    Impact significance determination is widely recognized as a vital and critical EIA activity. But impact significance related concepts are poorly understood. And the quality of approaches for impact significance determination in EIA practice remains highly variable. This article seeks to help establish a sound and practical conceptual foundation for formulating and evaluating impact significance determination approaches. It addresses the nature (what is impact significance?), the core characteristics (what are the major properties of significance determination?), the rationale (why are impact significance determinations necessary?), the procedural and substantive objectives (what do impact significance determinations seek to achieve?), and the process for making impact significance judgments (how is impact significance determination conducted?). By identifying fundamental attributes and key distinctions associated with impact significance determinations, a basis is provided for designing and evaluating impact significance determination procedures at both the regulatory and applied levels

  2. Differential effects of omeprazole and lansoprazole enantiomers on aryl hydrocarbon receptor in human hepatocytes and cell lines.

    Science.gov (United States)

    Novotna, Aneta; Srovnalova, Alzbeta; Svecarova, Michaela; Korhonova, Martina; Bartonkova, Iveta; Dvorak, Zdenek

    2014-01-01

    Proton pump inhibitors omeprazole and lansoprazole contain chiral sulfur atom and they are administered as a racemate, i.e. equimolar mixture of S- and R-enantiomers. The enantiopure drugs esomeprazole and dexlansoprazole have been developed and introduced to clinical practice due to their improved clinical and therapeutic properties. Since omeprazole and lansoprazole are activators of aryl hydrocarbon receptor (AhR) and inducers of CYP1A genes, we examined their enantiospecific effects on AhR-CYP1A pathway in human cancer cells and primary human hepatocytes. We performed gene reporter assays for transcriptional activity of AhR, RT-PCR analyses for CYP1A1/2 mRNAs, western blots for CYP1A1/2 proteins and EROD assay for CYP1A1/2 catalytic activity. Lansoprazole and omeprazole enantiomers displayed differential effects on AhR-CYP1A1/2 pathway. In general, S-enantiomers were stronger activators of AhR and inducers of CYP1A genes as compared to R-enantiomers in lower concentrations, i.e. 1-10 µM for lansoprazole and 10-100 µM for omeprazole. In contrast, R-enantiomers were stronger AhR activators and CYP1A inducers than S-enantiomers in higher concentrations, i.e. 100 µM for lansoprazole and 250 µM for omeprazole. In conclusion, we provide the first evidence of enantiospecific effects of omeprazole and lansoprazole on AhR signaling pathway.

  3. Prognostic significance of nonsustained ventricular tachycardia after revascularization.

    Science.gov (United States)

    Mittal, Suneet; Lomnitz, David J; Mirchandani, Sunil; Stein, Kenneth M; Markowitz, Steven M; Slotwiner, David J; Iwai, Sei; Das, Mithilesh K; Lerman, Bruce B

    2002-04-01

    Two randomized trials (Multicenter Automatic Defibrillator Implantation Trial [MADIT] and Multicenter Unsustained Tachycardia Trial [MUSTT]) suggest that implantable cardioverter defibrillator (ICD) placement is associated with improved survival in patients with coronary artery disease, depressed left ventricular function, and nonsustained ventricular tachycardia (VT) who also have inducible sustained VT. However, neither study directly addresses the management of such patients who develop nonsustained VT early after revascularization. We evaluated 109 consecutive patients who underwent electrophysiologic testing to evaluate nonsustained VT, which occurred 5 +/- 4 days following revascularization. Sustained monomorphic VT was inducible in 46 (42%) patients; these patients received an ICD. The remaining 63 (58%) noninducible patients received neither antiarrhythmic drug therapy nor an ICD. During 27 +/- 12 months of follow-up, 15 (33%) of 45 patients with an implanted ICD received at least one appropriate therapy from the device and 26 (24%) of the 109 study patients died. The 1- and 2-year freedom from ventricular tachycardia/fibrillation or sudden death in noninducible patients (97% and 93%) was significantly greater than that of inducible patients (84% and 71%; P = 0.001). However, no difference was observed in total mortality. Patients with nonsustained VT during the early postrevascularization period who have inducible VT have a high incidence of arrhythmic events. Although this study was not designed to assess the impact of ICD placement on the total mortality of inducible patients, the finding that one third of these patients received appropriate ICD therapy suggests that the device may have a protective effect in these patients.

  4. Lithostratigraphic development and neotectonic significance of the ...

    Indian Academy of Sciences (India)

    by debris flows and sediment gravity flows, as small coalescing alluvial fans in front of the scarps. These deposits suggest ..... ble size clasts embedded in matrix of medium to fine sand. ...... sequences of the Golmud River and their environmental implications; Quat. ... human-induced changes in the Bolivian Chaco?; Proc.

  5. Indole-3-carbinol induces G1 cell cycle arrest and apoptosis through aryl hydrocarbon receptor in THP-1 monocytic cell line.

    Science.gov (United States)

    Mohammadi, Saeed; Seyedhosseini, Fakhri Sadat; Behnampour, Nasser; Yazdani, Yaghoub

    2017-10-01

    The role of aryl hydrocarbon receptor (AhR) in carcinogenesis has been studied recently. Indole-3-carbinol (I3C) is an AhR agonist and a potential anticancer agent. Here, we investigated the effects of I3C on cell cycle progression and apoptosis through activation of AhR on THP-1 acute myeloid leukemia (AML) cell line. MTT viability assay was used to measure the cytotoxic effects of I3C on THP-1 cells. Apoptosis and cell cycle assays were investigated using flow cytometry. Real time RT-PCR was conducted to measure the alterations in the expression of AhR gene, key genes associated with AhR activation (IL1β and CYP1A1) and major genes involved in cell cycle regulation and apoptosis including P27, P21, CDK2, P53, BCL2 and FasR. Our findings revealed that I3C inhibits the proliferation of THP-1 cells in a dose- and time-dependent manner with minimal toxicity over normal monocytes. The AhR target genes (CYP1A1, IL1β) were overexpressed upon I3C treatment (p cycle arrest was also observed using flow cytometry. G1-acting cell cycle genes (P21, P27 and P53) were overexpressed (p cycle arrest in a dose- and time-dependent manner. Therefore, AhR could be targeted as a novel treatment possibility in AML.

  6. Creating Significant Learning Experiences across Disciplines

    Science.gov (United States)

    Levine, Laura E.; Fallahi, Carolyn R.; Nicoll-Senft, Joan M.; Tessier, Jack T.; Watson, Cheryl L.; Wood, Rebecca M.

    2008-01-01

    The purpose of this study was to use Fink's (2003) taxonomy of significant learning to redesign courses and assess student learning. Significant improvements were found across the semester for students in the six courses, but there were differences in which taxa showed improvement in each course. The meta-analysis showed significant, positive…

  7. 23 CFR 630.1010 - Significant projects.

    Science.gov (United States)

    2010-04-01

    ... 23 Highways 1 2010-04-01 2010-04-01 false Significant projects. 630.1010 Section 630.1010 Highways... PRECONSTRUCTION PROCEDURES Work Zone Safety and Mobility § 630.1010 Significant projects. (a) A significant project is one that, alone or in combination with other concurrent projects nearby is anticipated to cause...

  8. Significance levels for studies with correlated test statistics.

    Science.gov (United States)

    Shi, Jianxin; Levinson, Douglas F; Whittemore, Alice S

    2008-07-01

    When testing large numbers of null hypotheses, one needs to assess the evidence against the global null hypothesis that none of the hypotheses is false. Such evidence typically is based on the test statistic of the largest magnitude, whose statistical significance is evaluated by permuting the sample units to simulate its null distribution. Efron (2007) has noted that correlation among the test statistics can induce substantial interstudy variation in the shapes of their histograms, which may cause misleading tail counts. Here, we show that permutation-based estimates of the overall significance level also can be misleading when the test statistics are correlated. We propose that such estimates be conditioned on a simple measure of the spread of the observed histogram, and we provide a method for obtaining conditional significance levels. We justify this conditioning using the conditionality principle described by Cox and Hinkley (1974). Application of the method to gene expression data illustrates the circumstances when conditional significance levels are needed.

  9. Phase I metabolic genes and risk of lung cancer: multiple polymorphisms and mRNA expression.

    Directory of Open Access Journals (Sweden)

    Melissa Rotunno

    2009-05-01

    Full Text Available Polymorphisms in genes coding for enzymes that activate tobacco lung carcinogens may generate inter-individual differences in lung cancer risk. Previous studies had limited sample sizes, poor exposure characterization, and a few single nucleotide polymorphisms (SNPs tested in candidate genes. We analyzed 25 SNPs (some previously untested in 2101 primary lung cancer cases and 2120 population controls from the Environment And Genetics in Lung cancer Etiology (EAGLE study from six phase I metabolic genes, including cytochrome P450s, microsomal epoxide hydrolase, and myeloperoxidase. We evaluated the main genotype effects and genotype-smoking interactions in lung cancer risk overall and in the major histology subtypes. We tested the combined effect of multiple SNPs on lung cancer risk and on gene expression. Findings were prioritized based on significance thresholds and consistency across different analyses, and accounted for multiple testing and prior knowledge. Two haplotypes in EPHX1 were significantly associated with lung cancer risk in the overall population. In addition, CYP1B1 and CYP2A6 polymorphisms were inversely associated with adenocarcinoma and squamous cell carcinoma risk, respectively. Moreover, the association between CYP1A1 rs2606345 genotype and lung cancer was significantly modified by intensity of cigarette smoking, suggesting an underlying dose-response mechanism. Finally, increasing number of variants at CYP1A1/A2 genes revealed significant protection in never smokers and risk in ever smokers. Results were supported by differential gene expression in non-tumor lung tissue samples with down-regulation of CYP1A1 in never smokers and up-regulation in smokers from CYP1A1/A2 SNPs. The significant haplotype associations emphasize that the effect of multiple SNPs may be important despite null single SNP-associations, and warrants consideration in genome-wide association studies (GWAS. Our findings emphasize the necessity of post

  10. Methodology, theoretical framework and scholarly significance: An ...

    African Journals Online (AJOL)

    Methodology, theoretical framework and scholarly significance: An overview ... AFRICAN JOURNALS ONLINE (AJOL) · Journals · Advanced Search ... Keywords: Legal Research, Methodology, Theory, Pedagogy, Legal Training, Scholarship ...

  11. Impact significance determination-Pushing the boundaries

    International Nuclear Information System (INIS)

    Lawrence, David P.

    2007-01-01

    Impact significance determination practice tends to be highly variable. Too often insufficient consideration is given to good practice insights. Also, impact significance determinations are frequently narrowly defined addressing, for example, only individual, negative impacts, focusing on bio-physical impacts, and not seeking to integrate either the Precautionary Principle or sustainability. This article seeks to extend the boundaries of impact significance determination practice by providing an overview of good general impact significance practices, together with stakeholder roles and potential methods for addressing significance determination challenges. Relevant thresholds, criteria, contextual considerations and support methods are also highlighted. The analysis is then extended to address how impact significance determination practices change for positive as compared with negative impacts, for cumulative as compared with individual impacts, for socio-economic as compared with bio-physical impacts, when the Precautionary Principle is integrated into the process, and when sustainability contributions drive the EIA process and related impact significance determinations. These refinements can assist EIA practitioners in ensuring that the scope and nature of impact significance determinations reflect the broadened scope of emerging EIA requirements and practices. Suggestions are included for further refining and testing of the proposed changes to impact significance determination practice

  12. Regionally Significant Ecological Areas - MLCCS derived 2008

    Data.gov (United States)

    Minnesota Department of Natural Resources — This is an analysis of regionally significant Terrestrial and Wetland Ecological Areas in the seven county metropolitan area. Individual forest, grassland and...

  13. Central Region Regionally Ecological Significant Areas

    Data.gov (United States)

    Minnesota Department of Natural Resources — This is an analysis of regionally significant Terrestrial and Wetland Ecological Areas in the seven county metropolitan area. Individual forest, grassland and...

  14. Targeted Multiplex Imaging Mass Spectrometry with Single Chain Fragment Variable (scfv) Recombinant Antibodies

    Science.gov (United States)

    Thiery, Gwendoline; Mernaugh, Ray L.; Yan, Heping; Spraggins, Jeffrey M.; Yang, Junhai; Parl, Fritz F.; Caprioli, Richard M.

    2012-10-01

    Recombinant scfv antibodies specific for CYP1A1 and CYP1B1 P450 enzymes were combined with targeted imaging mass spectrometry to simultaneously detect the P450 enzymes present in archived, paraffin-embedded, human breast cancer tissue sections. By using CYP1A1 and CYP1B1 specific scfv, each coupled to a unique reporter molecule (i.e., a mass tag) it was possible to simultaneously detect multiple antigens within a single tissue sample with high sensitivity and specificity using mass spectrometry. The capability of imaging multiple antigens at the same time is a significant advance that overcomes technical barriers encountered when using present day approaches to develop assays that can simultaneously detect more than a single antigen in the same tissue sample.

  15. The thresholds for statistical and clinical significance

    DEFF Research Database (Denmark)

    Jakobsen, Janus Christian; Gluud, Christian; Winkel, Per

    2014-01-01

    BACKGROUND: Thresholds for statistical significance are insufficiently demonstrated by 95% confidence intervals or P-values when assessing results from randomised clinical trials. First, a P-value only shows the probability of getting a result assuming that the null hypothesis is true and does...... not reflect the probability of getting a result assuming an alternative hypothesis to the null hypothesis is true. Second, a confidence interval or a P-value showing significance may be caused by multiplicity. Third, statistical significance does not necessarily result in clinical significance. Therefore...... of the probability that a given trial result is compatible with a 'null' effect (corresponding to the P-value) divided by the probability that the trial result is compatible with the intervention effect hypothesised in the sample size calculation; (3) adjust the confidence intervals and the statistical significance...

  16. What if there were no significance tests?

    CERN Document Server

    Harlow, Lisa L; Steiger, James H

    2013-01-01

    This book is the result of a spirited debate stimulated by a recent meeting of the Society of Multivariate Experimental Psychology. Although the viewpoints span a range of perspectives, the overriding theme that emerges states that significance testing may still be useful if supplemented with some or all of the following -- Bayesian logic, caution, confidence intervals, effect sizes and power, other goodness of approximation measures, replication and meta-analysis, sound reasoning, and theory appraisal and corroboration. The book is organized into five general areas. The first presents an overview of significance testing issues that sythesizes the highlights of the remainder of the book. The next discusses the debate in which significance testing should be rejected or retained. The third outlines various methods that may supplement current significance testing procedures. The fourth discusses Bayesian approaches and methods and the use of confidence intervals versus significance tests. The last presents the p...

  17. Apoptosis and Bax expression are increased by coal dust in the polycyclic aromatic hydrocarbon-exposed lung

    Energy Technology Data Exchange (ETDEWEB)

    Ghanem, M.M.; Battelli, L.A.; Mercer, R.R.; Scabilloni, J.F.; Kashon, M.L.; Ma, J.Y.C.; Nath, J.; Hubbs, A.F.

    2006-09-15

    Miners inhaling respirable coal dust (CD) frequently develop coal workers' pneumoconiosis. Many coal miners are also exposed to polycyclic aromatic hydrocarbon (PAH) components of diesel engine exhaust and cigarette smoke, which may contribute to lung disease in these workers. Recently, apoptosis was reported to play a critical role in the development of another pneumoconiosis of miners, silicosis. In addition, CID was reported to suppress cytochrome P450 1A1 (CYP1A1) induction by PAHs. We exposed rats intratracheally to 0.0, 2.5, 10.0, 20.0, or 40.0 mg/rat CD and, 11 days later, to intraperitoneal P-naphthoflavone (BNF), a PAH. In another group of rats exposed to CD and BNF, caspase activity was inhibited by injection of the pan-caspase inhibitor Q-VD-OPH (quinoline-Val-Asp (OMe)-CH{sub 2}-OPH). In rats exposed to BNF, CD exposure increased alveolar expression of the proapoptotic mediator Bax but decreased CYP1A1 induction relative to BNF exposure alone. Pan-caspase inhibition decreased CD-associated Bax expression and apoptosis but did not restore CYP1A1 activity. Further, CD-induced lung inflammation and alveolar epithelial cell hypertrophy and hyperplasia were not suppressed by caspase inhibition. It is concluded that combined BNF and CD exposure increased Bax expression and apoptosis in the lung, but Bax and apoptosis were not the major determinants of early lung injury in this model.

  18. Mining Significant Semantic Locations from GPS Data

    DEFF Research Database (Denmark)

    Cao, Xin; Cong, Gao; Jensen, Christian Søndergaard

    2010-01-01

    With the increasing deployment and use of GPS-enabled devices, massive amounts of GPS data are becoming available. We propose a general framework for the mining of semantically meaningful, significant locations, e.g., shopping malls and restaurants, from such data. We present techniques capable...... of extracting semantic locations from GPS data. We capture the relationships between locations and between locations and users with a graph. Significance is then assigned to locations using random walks over the graph that propagates significance among the locations. In doing so, mutual reinforcement between...

  19. Discovering the Significance of Scientific Design Practice

    DEFF Research Database (Denmark)

    Pries-Heje, Jan; Baskerville, Richard

    2016-01-01

    This paper discusses and defines the achievement of significance in design science research. We review the values and processes of old-science and how this mode of science attacks the complexity of scientific knowledge production through analysis. We then explain how new-science attacks...... the complexity of scientific knowledge production through synthesis. The work argues that significance of the new-science contribution in design science can be obfuscated when wrapped in old-science. This understanding helps reveal how new-science, such as design science research, constitutes its significance...

  20. Mining significant semantic locations from GPS data

    DEFF Research Database (Denmark)

    Cao, Xin; Cong, Gao; Jensen, Christian S.

    2010-01-01

    With the increasing deployment and use of GPS-enabled devices, massive amounts of GPS data are becoming available. We propose a general framework for the mining of semantically meaningful, significant locations, e.g., shopping malls and restaurants, from such data. We present techniques capable...... of extracting semantic locations from GPS data. We capture the relationships between locations and between locations and users with a graph. Significance is then assigned to locations using random walks over the graph that propagates significance among the locations. In doing so, mutual reinforcement between...

  1. SRS Process Facility Significance Fire Frequency

    Energy Technology Data Exchange (ETDEWEB)

    Sarrack, A.G. [Westinghouse Savannah River Company, AIKEN, SC (United States)

    1995-10-01

    This report documents the method and assumptions of a study performed to determine a site generic process facility significant fire initiator frequency and explains the proper way this value should be used.

  2. Can a significance test be genuinely Bayesian?

    OpenAIRE

    Pereira, Carlos A. de B.; Stern, Julio Michael; Wechsler, Sergio

    2008-01-01

    The Full Bayesian Significance Test, FBST, is extensively reviewed. Its test statistic, a genuine Bayesian measure of evidence, is discussed in detail. Its behavior in some problems of statistical inference like testing for independence in contingency tables is discussed.

  3. 40 CFR 1508.27 - Significantly.

    Science.gov (United States)

    2010-07-01

    ... Register of Historic Places or may cause loss or destruction of significant scientific, cultural, or... cultural resources, park lands, prime farmlands, wetlands, wild and scenic rivers, or ecologically critical...

  4. Economically Significant Sites - OSPR [ds356

    Data.gov (United States)

    California Natural Resource Agency — This point data set shows locations of Economically Significant Sites along the California coast from Del Norte to San Diego counties. Data for locating these points...

  5. Contribution of radiodiagnosis to genetically significant dose

    International Nuclear Information System (INIS)

    Pele, J.M.; Ouvrard, R.

    Surveys were carried out in France on 33,000 X-ray medical examinations. The genetically significant dose to the whole population from roentgenography and fluoroscopy, for typical examinations, should be about 65mrads [fr

  6. SRS Process Facility Significance Fire Frequency

    International Nuclear Information System (INIS)

    Sarrack, A.G.

    1995-10-01

    This report documents the method and assumptions of a study performed to determine a site generic process facility significant fire initiator frequency and explains the proper way this value should be used

  7. SIGWX Charts - High Level Significant Weather

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — High level significant weather (SIGWX) forecasts are provided for the en-route portion of international flights. NOAA's National Weather Service Aviation Center...

  8. Modulation of xenobiotic biotransformation system and hormonal responses in Atlantic salmon (Salmo salar) after exposure to tributyltin (TBT).

    Science.gov (United States)

    Mortensen, Anne Skjetne; Arukwe, Augustine

    2007-04-01

    Multiple biological effects of tributyltin (TBT) on juvenile salmon have been investigated. Fish were exposed for 7 days to waterborne TBT at nominal concentrations of 50 and 250 microg/L dissolved in dimethyl sulfoxide (DMSO). Hepatic samples were analyzed for gene expression patterns in the hormonal and xenobiotic biotransformation pathways using validated real-time PCR method. Immunochemical and several cytochrome P450 (CYP)-mediated enzyme activity (ethoxyresorufin: EROD, benzyloxyresorufin: BROD, methoxyresorufin: MROD and pentoxyresorufin: PROD) assays were analyzed. Our data show that TBT produced concentration-specific decrease of estrogen receptor-alpha (ERalpha), vitellogenin (Vtg), zona radiata protein (Zr-protein) and increase of estrogen receptor-beta (ERbeta) and androgen receptor-beta (ARbeta) in the hormonal pathway. In the xenobiotic biotransformation pathway, TBT produced apparent increase and decrease at respective low and high concentration, on aryl hydrocarbon receptor-alpha (AhRalpha), AhR nuclear translocator (ARNT) and AhR repressor (AhRR) mRNA. The expression of CYP1A1 and GST showed a TBT concentration-dependent decrease. The AhRbeta, CYP3A and uridine diphosphoglucuronosyl transferase (UGT) mRNA expressions were significantly induced after exposure to TBT. Immunochemical analysis of CYP3A and CYP1A1 protein levels confirmed the TBT effects observed at the transcriptional levels. The effect of TBT on the biotransformation enzyme gene expressions partially co-related but did not directly parallel enzyme activity levels for EROD, BROD, MROD and PROD. In general, these findings confirm previous reports on the endocrine effects of TBT, in addition to effects on hepatic CYP1A isoenzyme at the transcriptional level that transcends to protein and enzymatic levels. The induced expression patterns of CYP3A and UGT mRNA after TBT exposure, suggest the involvement of CYP3A and UGT in TBT metabolism in fish. The effect of TBT on CYP3A is proposed to

  9. Asymptomatic bacteriuria. Clinical significance and management.

    Science.gov (United States)

    Raz, Raul

    2003-10-01

    The clinical significance and management of asymptomatic bacteriuria (ASB) differs according to different groups of patients. ASB requires antibiotic treatment in pregnant women, children aged 5-6 years and prior to invasive genitourinary procedures. However, there is a consensus that ASB in the elderly, healthy school girls and young women, diabetic women and patients with indwelling catheters or intermittent catheterization has no clinical significance and antibiotic prescription is not indicated.

  10. Formal conditions for the significance-effect

    DEFF Research Database (Denmark)

    Thellefsen, Torkild Leo; Sørensen, Bent; Thellefsen, Martin

    2006-01-01

    The significance-effect is the right effect of meaning caused upon an interpreting mind. The right effect is understood as the right interpretation of an intended meaning caused by a sign communicated by an utterer. In the article, which is inspired by Charles S. Peirce's doctrine of signs, his s...... semeiotics and his theory of communication, we account for the formal conditions that have to be present for the release of the significance-effect....

  11. Significance of Hemispheric Security for Mexico

    Science.gov (United States)

    2003-04-07

    La Seguridad Internacional, la Nueva Geopolitica Continental y Mexico ,” Seminario Internacional sobre Misiones de Paz, Seguridad y Defensa, Rio de...USAWC STRATEGY RESEARCH PROJECT SIGNIFICANCE OF HEMISPHERIC SECURITY FOR MEXICO by LTC Enrique Garcia Jaramillo Cavalry, Mexican Army COL Joseph R...xx-xx-2002 to xx-xx-2003 4. TITLE AND SUBTITLE Significance of Hemispheric Security for Mexico Unclassified 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c

  12. Building stones can be of geoheritage significance

    Science.gov (United States)

    Brocx, Margaret; Semeniuk, Vic

    2017-04-01

    Building stones have generally been assigned values according to their cultural, aesthetic, and rarity significance, amongst other criteria, but they also may have geoheritage significance. This is akin to the geoheritage significance ascribed to minerals and fossils housed as ex situ specimens in museums. We proffer the notion that building stones can be of geoheritage value particularly where they comprise permanent buildings, they illustrate significant windows into the history of the Earth, and they can be visited as an ex situ museum locality (e.g., the "Blue Granite" of Iceland) for education as part of building-stone tours. For some rocks the quarries that supplied the building stone are no longer in existence and hence the building stones provide the only record of that type of material; for other rocks, the building stone may illustrate features in the lithology no longer present in the quarry itself (e.g., rare and large xenoliths). Building stones are particularly significant as they are often polished and manifest structures, fabrics, and textures not evident in outcrop. We illustrate here examples of building stone of geoheritage significance using Australian and International examples. Australian designated stones could include the "Sydney Sandstone" or "Victorian Bluestone". For international examples, there is the famous "Carrara Marble" in Italy and the widely known "Portland Limestone" from southern England, the latter having been utilized for St Pauls Cathedral in London and the UN building in New York City.

  13. Total sleep deprivation does not significantly degrade semantic encoding.

    Science.gov (United States)

    Honn, K A; Grant, D A; Hinson, J M; Whitney, P; Van Dongen, Hpa

    2018-01-17

    Sleep deprivation impairs performance on cognitive tasks, but it is unclear which cognitive processes it degrades. We administered a semantic matching task with variable stimulus onset asynchrony (SOA) and both speeded and self-paced trial blocks. The task was administered at the baseline and 24 hours later after 30.8 hours of total sleep deprivation (TSD) or matching well-rested control. After sleep deprivation, the 20% slowest response times (RTs) were significantly increased. However, the semantic encoding time component of the RTs remained at baseline level. Thus, the performance impairment induced by sleep deprivation on this task occurred in cognitive processes downstream of semantic encoding.

  14. 3, 3'-Diindolylmethane alleviates steatosis and the progression of NASH partly through shifting the imbalance of Treg/Th17 cells to Treg dominance.

    Science.gov (United States)

    Liu, Yun; She, Weimin; Wang, Fuping; Li, Jing; Wang, Jiyao; Jiang, Wei

    2014-12-01

    This study was designed to discuss the effects of 3, 3'-diindolylmethane (DIM) on methionine-choline-deficient (MCD)-diet induced mouse nonalcoholic steatohepatitis (NASH) and the potential mechanisms. NASH mice were administrated with or without DIM at different concentrations for 8 weeks. Both the in-vivo and in-vitro effects of DIM on Treg/Th17 imbalance during NASH progression were analyzed. The in-vivo blocking of CD25 or IL-17 was performed to respectively deplete respective function of Treg or Th17 subset. Besides, with the assistance of AhR antagonist CH223191 and anti-TLR4 neutralizing antibody, we designed the in-vitro DIM-incubation experiments to discuss the roles of aryl hydrocarbon receptor (AhR) (CYP1A1, CYP1B1) and toll-like receptor 4 (TLR4) on DIM's effects when shifting Treg/Th17 imbalance. Notably, in NASH mouse models, DIM alleviated hepatic steatosis and inflammation, and shifted the Treg/Th17 imbalance from MCD diet-induced Th17 dominance to Treg dominance. In-vitro, DIM not only significantly up-regulated the mRNAs of Foxp3 (Treg-specific) in purified spleen CD4(+) T cells, but also enhanced the immunosuppressive function of these Treg cells. Besides, DIM significantly up-regulated the proteins of CYP1A1 and CYP1B1 whereas down-regulated those of TLR4 on CD4(+) T cells from MCD-diet mice. Moreover, blocking AhR attenuated while blocking TLR4 enhanced the effects of DIM when regulating Treg/Th17 imbalance. Conclusively, DIM could be used as a potential therapeutic candidate to treat NASH based on its dramatic induction of Treg dominance to alleviate intra-hepatic inflammation, suggesting us a clue that the dietary cruciferous vegetables (containing abundant DIM) might exist as a protective factor for patients with NASH-related liver diseases. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Significance of Lead Residues in Mallard Tissues

    Science.gov (United States)

    Longcore, J.R.; Locke, L.N.; Bagley, George E.; Andrews, R.

    1974-01-01

    Tissues of adult, lead-dosed mallards that either died or were sacrificed were analyzed for lead. Lead levels in brains, tibiae, and breast muscle of ducks that died and in tibiae of ducks that were sacrificed increased significantly from dosage until death. Lead in the heart, lung, and blood from sacrificed ducks decreased significantly from dosage until death. Lead concentrations in tissues from ducks in the two groups were not significantly different except for the liver, kidney, and lung. Average lead levels in the livers and kidneys of ducks that died were significantly higher than those in ducks that were sacrificed. The mean concentration of lead in the lungs of the ducks sacrificed was significantly higher than the mean level in the lungs of ducks that died. Measurements of the lead concentrations in this study, when compared with lead levels reported in the literature for avian and non-avian species, showed that arbitrary diagnostic levels indicating lead poisoning could be set. In mallard ducks, lead levels exceeding 3 ppm in the brain, 6 to 20 ppm in the kidney or liver, or 10 ppm in clotted blood from the heart indicated acute exposure to lead.

  16. Polymorphisms of cytochrome P450 1A1, glutathione s-transferases M1 and T1 genes in ouangolodougou (Northern Ivory Coast

    Directory of Open Access Journals (Sweden)

    Alfredo Santovito

    2010-01-01

    Full Text Available In this study, the frequencies of CYP1A1, GSTM1, and GSTT1 gene polymorphisms were determined in 133 healthy individuals from Ouangolodougou, a small rural town situated in the north of the Ivory Coast. As appeared in several published studies, ethnic differences in these frequencies have been found to play an important role in the metabolism of a relevant number of human carcinogens. In the studied sample, the frequencies of Ile/Ile (wild type, Ile/Val (heterozygous variant, and Val/Val (homozygous variant CYP1A1 genotypes were 0.271, 0.692, and 0.037, respectively. Frequencies of GSTM1 and GSTT1 null genotypes were 0.361 and 0.331, respectively. No significant differences were noted between men and women. In contrast to published data for Africans, CYP1A1 *Val Allele frequency (0.383 was significantly high (p < 0.001 in this specific population. For the GSTT1 null genotype, no differences were found between the studied and other African populations, the contrary to what occurred for the GSTM1 null genotype in relation to Gambia and Egypt.

  17. Clinical significance of anismus in encopresis.

    Science.gov (United States)

    Catto-Smith, A G; Nolan, T M; Coffey, C M

    1998-09-01

    Treatments designed to relieve paradoxical contraction of the anal sphincters during defecation (anismus) have had limited success in children with encopresis. This has raised doubts as to the clinical relevance of this diagnosis in childhood as anorectal dysfunction. Our aim was to determine whether, in patients who had treatment-resistant encopresis, the presence of electromyographic anismus was associated with increased faecal retention. Sixty-eight children with soiling (mean age 8.7+/-2.06 years) were assessed by clinical examination, abdominal radiography and then with anorectal manometry. Patients with electromyographic anismus (n=32; 47%) had significantly increased radiographic rectal faecal retention and were significantly less likely to be able to defecate water-filled balloons. There were no significant differences in response to prior therapy, history of primary encopresis, behavioural adjustment or in sociodemographic data. Our results suggest that electromyographic anismus is associated with obstructed defecation and faecal retention.

  18. Statistical significance of cis-regulatory modules

    Directory of Open Access Journals (Sweden)

    Smith Andrew D

    2007-01-01

    Full Text Available Abstract Background It is becoming increasingly important for researchers to be able to scan through large genomic regions for transcription factor binding sites or clusters of binding sites forming cis-regulatory modules. Correspondingly, there has been a push to develop algorithms for the rapid detection and assessment of cis-regulatory modules. While various algorithms for this purpose have been introduced, most are not well suited for rapid, genome scale scanning. Results We introduce methods designed for the detection and statistical evaluation of cis-regulatory modules, modeled as either clusters of individual binding sites or as combinations of sites with constrained organization. In order to determine the statistical significance of module sites, we first need a method to determine the statistical significance of single transcription factor binding site matches. We introduce a straightforward method of estimating the statistical significance of single site matches using a database of known promoters to produce data structures that can be used to estimate p-values for binding site matches. We next introduce a technique to calculate the statistical significance of the arrangement of binding sites within a module using a max-gap model. If the module scanned for has defined organizational parameters, the probability of the module is corrected to account for organizational constraints. The statistical significance of single site matches and the architecture of sites within the module can be combined to provide an overall estimation of statistical significance of cis-regulatory module sites. Conclusion The methods introduced in this paper allow for the detection and statistical evaluation of single transcription factor binding sites and cis-regulatory modules. The features described are implemented in the Search Tool for Occurrences of Regulatory Motifs (STORM and MODSTORM software.

  19. How do we make sense of significance?

    DEFF Research Database (Denmark)

    Lyhne, Ivar; Kørnøv, Lone

    2013-01-01

    Determination of significance is widely recognised as an important step in environmental assessment (EA) processes. The prescriptive literature and guidance on significance determination is comprehensive within the field of EA, whereas descriptive and explorative studies of how we go about making......' sense-making, including important differences in the way individuals screen and scope. These patterns concern what we notice, how fast we frame the choice, and when we are critical about the provided information. The indications provide a basis for reflections on practice and on how to organise EA...

  20. Genetic variation in hormone metabolizing genes and risk of testicular germ cell tumors.

    Science.gov (United States)

    Figueroa, Jonine D; Sakoda, Lori C; Graubard, Barry I; Chanock, Stephen; Rubertone, Mark V; Erickson, R Loren; McGlynn, Katherine A

    2008-11-01

    Testicular germ cell tumors (TGCT) that arise in young men are composed of two histologic types, seminomas and nonseminomas. Risk patterns for the two types appear to be similar and may be related to either endogenous or exogenous hormonal exposures in utero. Why similar risk patterns would result in different histologic types is unclear, but could be related to varying genetic susceptibility profiles. Genetic variation in hormone metabolizing genes could potentially modify hormonal exposures, and thereby affect which histologic type a man develops. To examine this hypothesis, 33 single nucleotide polymorphisms (SNPs) in four hormone metabolism candidate genes (CYP1A1, CYP17A1, HSD17B1, HSD17B4) and the androgen receptor gene (AR) were genotyped. Associations with TGCT were evaluated among 577 TGCT cases (254 seminoma, 323 nonseminoma) and 707 controls from the US Servicemen's Testicular Tumor Environmental and Endocrine Determinants (STEED) study. There were no significant associations with TGCT overall based on a test using an additive model. However, compared to homozygotes of the most common allele, two nonredundant SNPs in CYP1A1 were inversely associated with nonseminoma: CYP1A1 promoter SNP rs4886605 OR = 0.75 (95% CI = 0.54-1.04) among the heterozygotes and OR = 0.37, 95% CI = 0.12-1.11 among the homozygotes with a p-value for trend = 0.02; rs2606345 intron 1 SNP, OR = 0.69 (95% CI = 0.51-0.93) among heterozygotes and OR = 0.70 (95% CI = 0.42-1.17) among homozygotes, with a p-value for trend = 0.02. Caution in interpretation is warranted until findings are replicated in other studies; however, the results suggest that genetic variation in CYP1A1 may be associated with nonseminoma.

  1. Changing relationships with significant others: Reflections of ...

    African Journals Online (AJOL)

    Symbolic interactionism provides the framework for analysing the building of relationships between elite athletes and their significant others. In-depth interviews were conducted with elite throwers and decathlon athletes. The sample included current (n=15) and retired (n=5) student-athletes, parents (n=5), coaches (n=2) ...

  2. Mycotoxins: significance to global economics and health

    Science.gov (United States)

    Mycotoxins are fungal metabolites produced my micro-fungi (molds and mildews) that have significant impacts on global economics and health. Some of these metabolites are beneficial, but most are harmful and have been associated with well-known epidemics dating back to medieval times. The terms ‘myco...

  3. Incidence and Significance of Haematemesis in Cirrhosis

    African Journals Online (AJOL)

    1974-06-08

    Jun 8, 1974 ... veloped encephalopathy and coma. It was found that more patients fell into the latter group (50 cases) than into the group with haematemesis (with or without encephalopathy). (45 cases), but there was no significant difference in the mortality rate of the groups. s. Afr. Med. l., 48, 1155 (1974). It has for some ...

  4. Encounter Probability of Significant Wave Height

    DEFF Research Database (Denmark)

    Liu, Z.; Burcharth, H. F.

    The determination of the design wave height (often given as the significant wave height) is usually based on statistical analysis of long-term extreme wave height measurement or hindcast. The result of such extreme wave height analysis is often given as the design wave height corresponding to a c...

  5. The Significance of the Nursery School

    Science.gov (United States)

    Gesell, Arnold

    2017-01-01

    From the standpoint of mental health and perhaps even from the standpoint of human culture, the complete realization of the educational possibilities of the preschool child is of foundational significance. Normative and comparative studies performed at a psychological clinic at Yale examining norms of development in children from one month to five…

  6. Scope and Significance of Eating Disorders.

    Science.gov (United States)

    Mitchell, James E.; Eckert, Elke D.

    1987-01-01

    Describes the increasing prevalence of anorexia nervosa and bulimia in many industrialized societies, and their association with significant morbidity and mortality. Discusses the genetic risks for the development of anorexia nervosa, and treatment strategies. Of these, pharmacotherapy and psychotherapy, particularly those incorporating…

  7. Soil physicochemical properties and their significance for ...

    African Journals Online (AJOL)

    Soil physicochemical properties and their significance for sustainable sugarcane production in Kesem Allaideghe plains irrigation project area, Eastern Ethiopia. ... In order to improve soil structure and water availability, addition of gypsum, plant residues and organic matter are recommended. Keywords: Soil survey ...

  8. Petrochemistry and geotectonic significance of enderbite ...

    African Journals Online (AJOL)

    Petrochemistry and geotectonic significance of enderbite-charnockite association in the Pan-African Obudu plateau, southeastern Nigeria. VU Ukaegbu, FT Beka. Abstract. No Abstract. Journal of Mining and Geology Vol. 43 (1) 2007: pp. 1-14. Full Text: EMAIL FULL TEXT EMAIL FULL TEXT · DOWNLOAD FULL TEXT ...

  9. The Historical Significance of the Universal Declaration.

    Science.gov (United States)

    Eide, Asbjorn

    1998-01-01

    Explains the historical significance of the Universal Declaration of Human Rights. Focuses on the initiative for the Declaration and its elaboration, the precursors to modern human rights, the foundation of the Declaration, the rights contained in the Universal Declaration, three modes of human rights analysis, and global governance and human…

  10. Bullying in Academe: Prevalent, Significant, and Incessant

    Science.gov (United States)

    Cassell, Macgorine A.

    2011-01-01

    This paper examines the top-down perspective of bullying and mobbing of professors by analyzing why it is prevalent, significant, and incessant and then proposes a framework to produce a caring, respectful, and safe environment for professors to engage in their teaching, scholarship, and service. The author suggests that the failure of…

  11. Cystic echinococcosis: prevalence and economic significance in ...

    African Journals Online (AJOL)

    A cross-sectional study was conducted from November 2015 to April 2016 at ELFORA export abattoir to determine the prevalence, cyst viability, organ distribution and economic significance of small ruminant cystic echinococcosis. A total of 850 small ruminants (400 sheep and 450 goats), were examined for the presence of ...

  12. Significance of Literature in Foreign Language Teaching

    Science.gov (United States)

    Babaee, Ruzbeh; Yahya, Wan Roselezam Bt Wan

    2014-01-01

    This research aims to consider literature as a significant tool for teaching fundamental language skills including speaking, listening, reading and writing. Reasons for the use of literature in language classrooms and major factors for choosing appropriate kinds of literary texts in such classes should be highlighted in order to make readers aware…

  13. 32 CFR 651.39 - Significance.

    Science.gov (United States)

    2010-07-01

    ... existing pollution standards; cause water, air, noise, soil, or underground pollution; impair visibility... Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) ENVIRONMENTAL QUALITY ENVIRONMENTAL ANALYSIS OF ARMY ACTIONS (AR 200-2) Environmental Assessment § 651.39 Significance. (a) If the...

  14. [Current clinical significance of anaerobic bacteremia].

    Science.gov (United States)

    Jirsa, Roman; Marešová, Veronika; Brož, Zdeněk

    2010-10-01

    to estimate tje current clinical significance of anaerobic bacteremia in a group of Czech hospitals. this retrospective analysis comprised 8 444 anaerobic blood cultures in patients admitted to four Czech hospitals between 2004 and 2007. in 16 patients, blood cultures yielded significant anaerobic bacteria. Thus, anaerobic bacteremia accounted for less than 2 % of clinically significant bacteremia. Four patients (18 %) died but none of the deaths could be clearly attributable to anaerobic bacteria in the bloodstream. The most common comorbidities predisposing to anaerobic bacteremia and the most frequent sources of infection were similar to those reported by other authors. The majority of anaerobic bacteremia cases were due to gram-negative bacteria, followed by Clostridium perfringens and, surprisingly, Eubacterium spp. (particularly Eubacterium lentum). anaerobic bacteremia remains rare. The comparison of our data with those by other authors suggests that (despite the reported high mortality) the actual clinical significance of anaerobic bacteremia is rather controversial and that the anaerobic bacteremia might not correspond to more serious pathogenic role of the anaerobic bacteria as the source of infection.

  15. Discovering the Significance of Scientific Design Practice

    DEFF Research Database (Denmark)

    Pries-Heje, Jan; Baskerville, Richard

    This paper aims at discussing and defining what it is that makes design science research significant. First it reviews the values and processes of old science and how this attacks complexity through analysis. It then shows how new science attacks complexity through synthesis. Then the paper argue...

  16. Induced Seismicity

    Science.gov (United States)

    Keranen, Katie M.; Weingarten, Matthew

    2018-05-01

    The ability of fluid-generated subsurface stress changes to trigger earthquakes has long been recognized. However, the dramatic rise in the rate of human-induced earthquakes in the past decade has created abundant opportunities to study induced earthquakes and triggering processes. This review briefly summarizes early studies but focuses on results from induced earthquakes during the past 10 years related to fluid injection in petroleum fields. Study of these earthquakes has resulted in insights into physical processes and has identified knowledge gaps and future research directions. Induced earthquakes are challenging to identify using seismological methods, and faults and reefs strongly modulate spatial and temporal patterns of induced seismicity. However, the similarity of induced and natural seismicity provides an effective tool for studying earthquake processes. With continuing development of energy resources, increased interest in carbon sequestration, and construction of large dams, induced seismicity will continue to pose a hazard in coming years.

  17. In vitro evaluation of the genotoxicity of polycyclic aromatic hydrocarbons-coated onto airborne PM{sub 2.5}; Genotoxicite des hydrocarbures aromatiques polycycliques adsorbes a la surface d'un aerosol urbano-industriel PM{sub 2.5}

    Energy Technology Data Exchange (ETDEWEB)

    Billet, S.; Abbas, I.; Verdin, A.; Shirali, P.; Garcon, G. [Universite du Littoral, LCE-EA2598, Lab. de Recherche en toxicologie Industrielle et Environnementale, Maison de la Recherche en Environnement Industriel de Dunkerque, 59 - Dunkerque (France); Le Goff, J.; Andre, V.; Sichel, F. [Caen Univ. Basse Normandie et Centre Regional de Lutte Contre le Cancer Francois Baclesse, UPRES-EA 1772, Groupe Regional d' Etudes sur le Cancer, 14 (France); Cazier, F. [Universite du Littoral, Centre Commun de Mesures, Maison de la Recherche en Environnement Industriel de Dunkerque, 59 (France)

    2009-01-15

    Polycyclic aromatic hydrocarbons (PAH) represent a family of chemical compounds including a number of members recognized for their carcinogenicity. Their presence is often detected in mixtures very complex and heterogeneous, such as Particulate Matter (PM). However, the genotoxicity of such aerosols has been rarely studied. To improve the knowledge of the underlying mechanisms of action involved in air pollution Particulate Matter (PM)-induced toxicity in human lungs, a PM sampling was realized in Dunkerque. We were interested in the metabolic activation of Polycyclic Aromatic Hydrocarbons (PAH)-coated onto air pollution PM, and, thereafter, the formation of PAH-DNA adducts in a human lung epithelial cell model (A549 cell line). Cells were exposed to Dunkerque city's PM{sub 2.5} at their Lethal Concentrations at 10% and 50% (i.e. LC{sub 10} = 23.72 {mu}g/mL or 6.33 {mu}g/cm{sup 2}, and LC{sub 50} =118.60 {mu}g/mL or 31.63 {mu}g/cm{sup 2}), and the study of Cytochrome P450 (CYP)1A1 gene expression (i.e. RT-PCR) and protein activity (i.e. EROD activity), and the formation of PAH-DNA adducts (i.e. {sup 32}P-post-labelling), were investigated after 24, 48 and 72 h. Negative (i.e. TiO{sub 2} or desorbed PM, dPM; EgLC{sub 10} = 19.42 {mu}g/mL or 5.18 {mu}g/cm{sup 2}, and EgLC{sub 50} = 97.13 {mu}g/mL or 25.90 {mu}g/cm{sup 2}), and positive (i.e. benzo(a)pyrene; 1 {mu}M) controls were included in the experimental design. Statistically significant increases of CYP1A1 gene expression and protein activity were observed in A549 cells, 24, 48 and 72 h after their exposure to dPM, suggesting thereby that the employed outgassing method was not efficient enough to remove total PAH. Both the CYP1A1 gene expression and EROD activity were highly induced 24, 48 and 72 h after cell exposure to PM. However, only very low levels of PAH-DNA adducts, also not reliably quantifiable, were reported 72 h after cell exposure to dPM, and, particularly, PM. The relatively low levels of PAH

  18. Andrographolide Ameliorates Beta-Naphthoflavone-Induced CYP1A Enzyme Activity and Lipid Peroxidation in Hamsters with Acute Opisthorchiasis.

    Science.gov (United States)

    Udomsuk, Latiporn; Chatuphonprasert, Waranya; Jarukamjorn, Kanokwan; Sithithaworn, Paiboon

    2016-01-01

    Opisthorchis viverrini (OV) infection generates oxidative stress/free radicals and is considered as a primary cause ofcholangiocarcinoma since it primarily triggers sclerosing cholangitis. In this study, the impacts of andrographolide on acute opisthorchaisis in β-naphthoflavone (BNF)-exposed hamsters were investigated. Ethoxyresorufin O-deethylase (EROD) and methoxyresorufin O-demethylase (MROD) activities and Thiobarbituric acid reaction substances (TBARS) assay of andrographolide in acute opisthorchiasis in the BNF-exposed hamsters were assessed. The results showed that andrographolide ameliorated the hepatic CYP1A1 and CYP1A2 activities by decreases of the specific enzymatic reactions of EROD and MROD, respectively, in the BNF-exposed hamsters. Moreover, andrographolide lowered the formation of malondialdehyde in the livers and brains of the hamsters. These observations revealed the promising chemo-protective and antioxidant activities of andrographolide via suppression of the specific EROD and MROD reactions and lipid peroxidation against acute opisthorchiasis in the BNF-exposed hamsters.

  19. Significant incidents in nuclear fuel cycle facilities

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-03-01

    In contrast to nuclear power plants, events in nuclear fuel cycle facilities are not well documented. The INES database covers all the nuclear fuel cycle facilities; however, it was developed in the early 1990s and does not contain information on events prior to that. The purpose of the present report is to collect significant events and analyze them in order to give a safety related overview of nuclear fuel cycle facilities. Significant incidents were selected using the following criteria: release of radioactive material or exposure to radiation; degradation of items important to safety; and deficiencies in design, quality assurance, etc. which include criticality incidents, fire, explosion, radioactive release and contamination. This report includes an explanation, where possible, of root causes, lessons learned and action taken. 4 refs, 4 tabs.

  20. Significant incidents in nuclear fuel cycle facilities

    International Nuclear Information System (INIS)

    1996-03-01

    In contrast to nuclear power plants, events in nuclear fuel cycle facilities are not well documented. The INES database covers all the nuclear fuel cycle facilities; however, it was developed in the early 1990s and does not contain information on events prior to that. The purpose of the present report is to collect significant events and analyze them in order to give a safety related overview of nuclear fuel cycle facilities. Significant incidents were selected using the following criteria: release of radioactive material or exposure to radiation; degradation of items important to safety; and deficiencies in design, quality assurance, etc. which include criticality incidents, fire, explosion, radioactive release and contamination. This report includes an explanation, where possible, of root causes, lessons learned and action taken. 4 refs, 4 tabs

  1. Respiratory neuroplasticity - Overview, significance and future directions.

    Science.gov (United States)

    Fuller, David D; Mitchell, Gordon S

    2017-01-01

    Neuroplasticity is an important property of the neural system controlling breathing. However, our appreciation for its importance is still relatively new, and we have much to learn concerning different forms of plasticity, their underlying mechanisms, and their biological and clinical significance. In this brief review, we discuss several well-studied models of respiratory plasticity, including plasticity initiated by inactivity in the respiratory system, intermittent and sustained hypoxia, and traumatic injury to the spinal cord. Other aspects of respiratory plasticity are considered in other contributions to this special edition of Experimental Neurology on respiratory plasticity. Finally, we conclude with discussions concerning the biological and clinical significance of respiratory motor plasticity, and areas in need of future research effort. Copyright © 2016. Published by Elsevier Inc.

  2. Dual purpose or not? The significant factors

    International Nuclear Information System (INIS)

    Bak, W.; Roland, V.

    1999-01-01

    The development of spent fuel storage systems requires consideration of many factors in making design decisions. A significant issue affecting the design is the need to incorporate transportability of the canister or cask system design, which results in major changes to the storage system design. This paper presents a review of the significant factors affecting storage system design to incorporate transportation requirements and looks at the trends in both the United States and Europe where Transnucleaire and its US affiliated companies Transnuclear Inc., Transnuclear West and PacTec are active. A discussion is also presented relative to the pros and cons of whether the spent fuel storage system vendor should anticipate these transportation needs in the design of their systems. (author)

  3. Cross wavelet analysis: significance testing and pitfalls

    Directory of Open Access Journals (Sweden)

    D. Maraun

    2004-01-01

    Full Text Available In this paper, we present a detailed evaluation of cross wavelet analysis of bivariate time series. We develop a statistical test for zero wavelet coherency based on Monte Carlo simulations. If at least one of the two processes considered is Gaussian white noise, an approximative formula for the critical value can be utilized. In a second part, typical pitfalls of wavelet cross spectra and wavelet coherency are discussed. The wavelet cross spectrum appears to be not suitable for significance testing the interrelation between two processes. Instead, one should rather apply wavelet coherency. Furthermore we investigate problems due to multiple testing. Based on these results, we show that coherency between ENSO and NAO is an artefact for most of the time from 1900 to 1995. However, during a distinct period from around 1920 to 1940, significant coherency between the two phenomena occurs.

  4. Significance and radioimmunoassay of gastric inhibitory polypeptide

    International Nuclear Information System (INIS)

    Zheng Ping; Zeng Minde; Yuan Jimin

    1995-01-01

    We have established the GIP Radioimmunoassay which has high sensitivity and specificity by labelling with iodogen and purified with HPLC. Using this method, the plasma GIP level was measured in 64 cases of which there are 10 normal individuals, 25 cases of diabetes and 29 cases of liver cirrhosis . The results showed that the plasma GIP level was significantly increased in patients with liver cirrhosis and correlated to degree of glucose tolerance damage

  5. Prevalence of significant bacteriuria among symptomatic and ...

    African Journals Online (AJOL)

    Data were analyzed using the Statistical Package for Social Sciences (SPSS) version 16.0 (SPSS, Inc., Chicago, Ill). Results: A total of 100 consenting participants were recruited into the study. The mean age was: 23.42 ± 8.31 years and a range of 14‑50 years. Only 9% (9/100) had significant bacteriuria while 44.4% (4/9) ...

  6. Impact significance determination-Designing an approach

    International Nuclear Information System (INIS)

    Lawrence, David P.

    2007-01-01

    The question of how best to go about determining the significance of impacts has, to date, only been addressed in a partial and preliminary way. The assumption tends to be made that it is either only necessary to provide explicit, justified reasons for a judgment about significance and/or to explicitly apply a prescribed procedure-a procedure usually involving the staged application of thresholds and/or criteria. The detailed attributes, strengths and limitations of such approaches and possible alternative approaches have yet to be explored systematically. This article addresses these deficiencies by analyzing the characteristics, specific methods and positive and negative tendencies of three general impact significance determination approaches-the technical approach, the collaborative approach and the reasoned argumentation approach. A range of potential composite approaches are also described. With an enhanced understanding of these approaches, together with potential combinations, EIA practitioners and other EIA participants can be in a better position to select an approach appropriate to their needs, to reinforce the positive tendencies and offset the negative tendencies of the selected approach and to combine the best qualities of more than one approach

  7. Significance of postoperative irradiation for breast cancer

    International Nuclear Information System (INIS)

    Murai, Nobuko; Ogami, Koji; Nishikawa, Kiyoshi; Koga, Kenji; Waki, Norio; Higashi, Hidefumi; Hayashi, Asami; Shibata, Koichiro; Watanabe, Katsuji

    1986-01-01

    From 1978 through 1983, 27 patients were treated with surgery followed by irradiation (irradiated group) and 29 with surery alone (non-irradiated group). In the irradiated group, 10 had stage II and 17 stage III; in the non-irradiated group, 25 had stage II and 4 stage III. The most common histology was medullary tubular carcinoma (MTC). There was no significant difference in survivals at 3 years and 5 years between the groups. Similarly, no significant difference was seen among stage II patients. Patients with MTC tended to have worse survivals in the irradiated group than in the non-irradiated group, with no statistically significant difference. Among stage II patients, no major differences in local recurrence were seen between the groups; the incidence of distant metastases tended to be high in the irradiated group. The incidence of both local recurrence and distant metastases for stage III patients showed a tendency to be higher in the irradiated group than in the non-irradiated group. The results indicated no apparent benifit of postoperative irradiation for breast cancer. A randomized clinical trial is needed for the evaluation of postoperative irradiation for breast cancer. (Namekawa, K.)

  8. Clinical significance of dental root canal microflora.

    Science.gov (United States)

    Gomes, B P; Lilley, J D; Drucker, D B

    1996-01-01

    Previous work by this group has shown that a significant association exists between pain and the presence of either Prevotella or Peptostreptococcus spp. in dental root canals. The aim of this study was to examine a more extensive series of canals microbiologically, to determine whether any other particular endodontic symptoms or clinical signs showed specific associations with individual bacterial species. Seventy root canals were examined microbiologically and clinical data collected to investigate in detail such associations. Of the canals studied, 37 were associated with pain, 49 with tenderness to percussion, 23 with swelling, six with purulent exudate and 57 presented with wet root canals. Anaerobes were isolated from 70.3% of painful canals and from 29.7% of pain-free canals. Significant associations were found between (a) pain and either Prevotella spp. or peptostreptococci, both with P spp. (P Eubacterium spp. (P spp. or Pstr. micros, both with P spp. (each P Eubacterium, Peptostreptococcus, Prevotella or Propionibacterium (each P < 0.05). It was concluded that several different endodontic clinical signs and symptoms are significantly associated with specific bacterial species.

  9. Waterborne gemfibrozil challenges the hepatic antioxidant defense system and down-regulates peroxisome proliferator-activated receptor beta (PPARβ) mRNA levels in male goldfish (Carassius auratus)

    International Nuclear Information System (INIS)

    Mimeault, C.; Trudeau, V.L.; Moon, T.W.

    2006-01-01

    The lipid regulator gemfibrozil (GEM) is one of many human pharmaceuticals found in the aquatic environment. We previously demonstrated that GEM bioconcentrates in blood and reduces plasma testosterone levels in goldfish (Carassius auratus). In this study, we address the potential of an environmentally relevant waterborne concentration of GEM (1.5 μg/l) to induce oxidative stress in goldfish liver and whether this may be linked to GEM acting as a peroxisome proliferator (PP). We also investigate the autoregulation of the peroxisome proliferator-activated receptors (PPARs) as a potential index of exposure. The three PPAR subtypes (α, β, and γ) were amplified from goldfish liver cDNA. Goldfish exposed to a concentration higher (1500 μg/l) than environmentally relevant for 14 and 28 days significantly reduce hepatic PPARβ mRNA levels (p < 0.001). Levels of CYP1A1 mRNA were unchanged. GEM exposure significantly induced the antioxidant defense enzymes catalase (p < 0.001), glutathione peroxidase (p < 0.001) and glutathione-S-transferase (p = 0.006) but not acyl-CoA oxidase or glutathione reductase. As GEM exposure failed to increase levels of thiobarbituric reactive substances (TBARS), we conclude that a sub-chronic exposure to GEM upregulates the antioxidant defense status of the goldfish as an adaptive response to this human pharmaceutical

  10. Identification of sequence motifs significantly associated with antisense activity

    Directory of Open Access Journals (Sweden)

    Peek Andrew S

    2007-06-01

    mediators to speed the process along like the RNA Induced Silencing Complex (RISC in RNAi. The independence of motif position and antisense activity also allows us to bypass consideration of this feature in the modelling process, promoting model efficiency and reducing the chance of overfitting when predicting antisense activity. The increase in SVR correlation with significant features compared to nearest-neighbour features indicates that thermodynamics alone is likely not the only factor in determining antisense efficiency.

  11. Assessing the significance of Heidegger's Black Notebooks

    Directory of Open Access Journals (Sweden)

    J. Malpas

    2018-03-01

    Full Text Available The publication of Heidegger's Black Notebooks (Schwarze Hefte has provoked a storm of controversy. Much of this has centred on the pro-Nazi and anti-Semitic comments the volumes contain. But these aspects of the Notebooks are perhaps the least surprising and important. This essay offers a summary overview of the issues to which the Notebooks give rise, at the same time as it also aims to provide a preliminary assessment of their overall significance, especially in relation to what they show about the nature and development of Heidegger's thinking from the early 1930s to the late 1940s.

  12. Os odontoideum: a significant radiographic finding

    International Nuclear Information System (INIS)

    Choit, Rachel L.; Reilly, Christopher W.; Jamieson, Douglas H.

    2005-01-01

    Os odontoideum can lead to instability of the atlantoaxial joint and places the spinal cord at significant risk for acute catastrophic events after minor trauma or chronic neurological change. We present two cases of os odontoideum in pediatric patients that were not appreciated at earlier remote imaging but were, in retrospect, detectable. One patient presented with an acute spinal cord injury. Incorporating assessment of dens integrity into the evaluation algorithm for all pediatric cervical spine studies should lead to early detection of os odontoideum lesions and allow referral to appropriate clinical spinal services for evaluation, surveillance and possible surgery to prevent future complications. (orig.)

  13. Detecting significant changes in protein abundance

    Directory of Open Access Journals (Sweden)

    Kai Kammers

    2015-06-01

    Full Text Available We review and demonstrate how an empirical Bayes method, shrinking a protein's sample variance towards a pooled estimate, leads to far more powerful and stable inference to detect significant changes in protein abundance compared to ordinary t-tests. Using examples from isobaric mass labelled proteomic experiments we show how to analyze data from multiple experiments simultaneously, and discuss the effects of missing data on the inference. We also present easy to use open source software for normalization of mass spectrometry data and inference based on moderated test statistics.

  14. Perspectives on Gandhi’s Significance Today

    Directory of Open Access Journals (Sweden)

    Michael Simpson

    2016-12-01

    Full Text Available Gandhi’s example has inspired countless political struggles worldwide over the past century. We might then ask how his thought has been transferred and translated when taken out of the particular historical and geographic context in which he lived. How have Gandhi’s ideas been changed or altered when adopted in different contexts? Which aspects of Gandhi’s thinking remain most relevant to struggles for social and environmental justice today? These are just a few of the questions that were discussed at the “Perspectives on Gandhi’s Significance Workshop” hosted by Reed College in Portland Oregon (USA, on April 16th, 2016.

  15. Sucralfate significantly reduces ciprofloxacin concentrations in serum.

    OpenAIRE

    Garrelts, J C; Godley, P J; Peterie, J D; Gerlach, E H; Yakshe, C C

    1990-01-01

    The effect of sucralfate on the bioavailability of ciprofloxacin was evaluated in eight healthy subjects utilizing a randomized, crossover design. The area under the concentration-time curve from 0 to 12 h was reduced from 8.8 to 1.1 micrograms.h/ml by sucralfate (P less than 0.005). Similarly, the maximum concentration of ciprofloxacin in serum was reduced from 2.0 to 0.2 micrograms/ml (P less than 0.005). We conclude that concurrent ingestion of sucralfate significantly reduces the concentr...

  16. Significant events caused by extraneous acts

    International Nuclear Information System (INIS)

    Verlaeken, J.

    1987-01-01

    The operating experience feedback system of VINCOTTE, called ARIANE, consists, among others, of preparing synthesis reports on specific safety concerns. A recent report deals with significant events caused by extranous acts. Events attributable to human error are numerous. Confusion errors have already been analysed in several publications (NES IRS 664 etc.). However, are described here some ten incidents where extranous acts occurred: ZION 2 (September 76), OYSTER CREEK (May 79), PALISADES (January 81), CATAWBA (August 85), etc. The contributing factors for these unfortunate initiatives are explained; several resort to psychological influences. Corrective actions are discussed, and some general lessons are drawn. (author)

  17. Medical significance of the essential biological metals

    International Nuclear Information System (INIS)

    Davies, I.J.T.

    1977-01-01

    The medical significance of the essential biological metals such as zinc, copper and molybdenum as well as their nutritional and biochemical importance are reviewed. The following topics are treated: biochemical actions of the essential biological metals; the concept of essentiality; the development of knowledge about the essential biological metals. Data are given on zinc deficiency and hypogonadismi in humans, zinc and acrodermatitis enterophatica, zinc and the skin, zinc in diabetes mellitus, zinc and insulin, zinc and the liver; copper functions, copper deficiency - ''sway back'' in sheep, copper and haemopoiesis, copper and the function of blood vessels; molybdenum and dental caries in humans, oesophageal carcinoma and molybdenum deficiency in humans. (T.G.)

  18. Non-destructive testing: significant facts

    International Nuclear Information System (INIS)

    Espejo, Hector; Ruch, Marta C.

    2006-01-01

    In the last fifty years different organisations, both public and private, have been assigned to the mission of introducing into the country the most relevant aspects of the modern technological discipline 'Non Destructive Testing' (NDT) through a manifold of activities, such as training and education, research, development, technical assistance and services, personnel qualification/certification and standardisation. A review is given of the significant facts in this process, in which the Argentine Atomic Energy Commission, CNEA, played a leading part, a balance of the accomplishments is made and a forecast of the future of the activity is sketched. (author) [es

  19. Os odontoideum: a significant radiographic finding

    Energy Technology Data Exchange (ETDEWEB)

    Choit, Rachel L.; Reilly, Christopher W. [BC Children' s Hospital, Department of Orthopaedics, Vancouver, BC (Canada); Jamieson, Douglas H. [BC Children' s Hospital, Department of Radiology, Vancouver (Canada)

    2005-08-01

    Os odontoideum can lead to instability of the atlantoaxial joint and places the spinal cord at significant risk for acute catastrophic events after minor trauma or chronic neurological change. We present two cases of os odontoideum in pediatric patients that were not appreciated at earlier remote imaging but were, in retrospect, detectable. One patient presented with an acute spinal cord injury. Incorporating assessment of dens integrity into the evaluation algorithm for all pediatric cervical spine studies should lead to early detection of os odontoideum lesions and allow referral to appropriate clinical spinal services for evaluation, surveillance and possible surgery to prevent future complications. (orig.)

  20. Significant exposures to isoeugenol derivaties in perfumes

    DEFF Research Database (Denmark)

    Rastogi, Suresh Chandra; Johansen, Jeanne Duus

    2008-01-01

    in perfumes/aftershaves. MATERIALS AND METHODS: 29 international brand perfumes/aftershaves were analysed for the target fragrance ingredient by gas chromatography-mass spectrometry. All samples were analysed in duplicate at detection levels of 1-5 p.p.m. RESULTS: 16 products (55%) contained isoeugenol...... was not detected in any of the investigated products. CONCLUSIONS: Isoeugenyl acetate is present in perfumes/aftershaves, in some products in significant amounts. This may lead to elicitation of contact allergy in isoeugenol-sensitized individuals and may contribute to unchanged levels of isoeugenol sensitization....

  1. pancreatic steatosis: diagnosis and clinical significance

    Directory of Open Access Journals (Sweden)

    Murat Daðdeviren

    2017-03-01

    Full Text Available Pancreatic steatosis (PS, with increased use of abdominal imaging in recent years generally appears as incidental. But it is a condition that is often overlooked. The reason for this is not yet fully demonstrated the clinical significance of PS while. However, in recent years, there are some studies conducted on the relationship with ps and other disease such as diabetes, metabolic syndrome, acute and chronic pancreatitis and pancreatic cancer. In this review, the etiology, diagnosis, treatment and clinical characteristics of ps were evaluated in the light of recent literature and current approaches. [J Contemp Med 2017; 7(1.000: 107-112

  2. Significance of abolishing British National Oil Corporation

    Energy Technology Data Exchange (ETDEWEB)

    Mabro, R

    1985-04-01

    The decision to abolish British National Oil Corporation has greater significance than any commentator, so far, has cared to admit. Mr. Mabro says the Government has done much more than get rid of an institution it had previously weakened and emasculated; in effect, it had abdicated its responsibilities for the pricing of North Sea oil. He further observes that these moves may be consistent with the tenets of a simplistic free-market ideology: they betray, however, a lack of understanding of the economics of oil, and of the UK economic interest in oil.

  3. Sonographic ally Detected Architectural Distortion: Clinical Significance

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Shin Kee; Seo, Bo Kyoung; Yi, Ann; Cha, Sang Hoon; Kim, Baek Hyun; Cho, Kyu Ran; Kim, Young Sik; Son, Gil Soo; Kim, Young Soo; Kim, Hee Young [Korea University Ansan Hospital, Ansan (Korea, Republic of)

    2008-12-15

    Architectural distortion is a suspicious abnormality for the diagnosis of breast cancer. The aim of this study was to investigate the clinical significance of sonographic ally detected architectural distortion. From January 2006 to June 2008, 20 patients were identified who had sonographic ally detected architectural distortions without a history of trauma or surgery and abnormal mammographic findings related to an architectural distortion. All of the lesions were pathologically verified. We evaluated the clinical and pathological findings and then assessed the clinical significance of the sonographic ally detected architectural distortions. Based on the clinical findings, one (5%) of the 20 patients had a palpable lump and the remaining 19 patients had no symptoms. No patient had a family history of breast cancer. Based on the pathological findings, three (15%) patients had malignancies. The malignant lesions included invasive ductal carcinomas (n = 2) and ductal carcinoma in situ (n = 1). Four (20%) patients had high-risk lesions: atypical ductal hyperplasia (n = 3) and lobular carcinoma in situ (n = 1). The remaining 13 (65%) patients had benign lesions, however, seven (35%) out of 13 patients had mild-risk lesions (three intraductal papillomas, three moderate or florid epithelial hyperplasia and one sclerosing adenosis). Of the sonographic ally detected architectural distortions, 35% were breast cancers or high-risk lesions and 35% were mild-risk lesions. Thus, a biopsy might be needed for an architectural distortion without an associated mass as depicted on breast ultrasound, even though the mammographic findings are normal

  4. Adaptive significance of root grafting in trees

    Energy Technology Data Exchange (ETDEWEB)

    Loehle, C.; Jones, R.

    1988-12-31

    Root grafting has long been observed in forest trees but the adaptive significance of this trait has not been fully explained. Various authors have proposed that root grafting between trees contributes to mechanical support by linking adjacent root systems. Keeley proposes that this trait would be of greatest advantage in swamps where soils provide poor mechanical support. He provides as evidence a greenhouse study of Nyssa sylvatica Marsh in which seedlings of swamp provenance formed between-individual root grafts more frequently than upland provenance seedlings. In agreement with this within-species study, Keeley observed that arid zone species rarely exhibit grafts. Keeley also demonstrated that vines graft less commonly than trees, and herbs never do. Since the need for mechanical support coincides with this trend, these data seem to support his model. In this paper, the authors explore the mechanisms and ecological significance of root grafting, leading to predictions of root grafting incidence. Some observations support and some contradict the mechanical support hypothesis.

  5. Could patients' coughing have communicative significance?

    Science.gov (United States)

    Bailey, Julia V

    2008-01-01

    Medical discourse positions patients with coughs and colds negatively, so consulting health services with 'minor' respiratory illness is therefore more accountable than for other medical problems. Patients face dilemmas since they must persuade doctors of the doctorability of their illness without being seen as hypochondriacal, and they risk losing face if doctors decide that there is nothing much wrong. It is known that the placement of non-lexical features of talk such as laughing or crying can have interactional meaning. Using a data set of video-recorded doctor-patient cough and cold consultations, this study explores whether patients' coughing could have communicative significance. The study is a qualitative analysis of 33 consultations drawing on a constructionist, sociolinguistic analytic approach. Coughing is co-ordinated with talk rather than occurring randomly. Coughing helps patients to demonstrate the doctorability of their symptoms and to legitimize their claims for medical attention. Coughing is also associated with resistance to 'no problem' diagnoses, resulting in changes in the trajectory of talk (for example, soliciting more explanation from doctors and/or re-negotiation of doctors' investigation or treatment plans). Coughing is undoubtedly a manifestation of respiratory illness, but also has communicative significance in consultations for coughs and colds.

  6. Significance and popularity in music production

    Science.gov (United States)

    Monechi, Bernardo; Gravino, Pietro; Servedio, Vito D. P.; Tria, Francesca; Loreto, Vittorio

    2017-07-01

    Creative industries constantly strive for fame and popularity. Though highly desirable, popularity is not the only achievement artistic creations might ever acquire. Leaving a longstanding mark in the global production and influencing future works is an even more important achievement, usually acknowledged by experts and scholars. `Significant' or `influential' works are not always well known to the public or have sometimes been long forgotten by the vast majority. In this paper, we focus on the duality between what is successful and what is significant in the musical context. To this end, we consider a user-generated set of tags collected through an online music platform, whose evolving co-occurrence network mirrors the growing conceptual space underlying music production. We define a set of general metrics aiming at characterizing music albums throughout history, and their relationships with the overall musical production. We show how these metrics allow to classify albums according to their current popularity or their belonging to expert-made lists of important albums. In this way, we provide the scientific community and the public at large with quantitative tools to tell apart popular albums from culturally or aesthetically relevant artworks. The generality of the methodology presented here lends itself to be used in all those fields where innovation and creativity are in play.

  7. Sonographic ally Detected Architectural Distortion: Clinical Significance

    International Nuclear Information System (INIS)

    Kim, Shin Kee; Seo, Bo Kyoung; Yi, Ann; Cha, Sang Hoon; Kim, Baek Hyun; Cho, Kyu Ran; Kim, Young Sik; Son, Gil Soo; Kim, Young Soo; Kim, Hee Young

    2008-01-01

    Architectural distortion is a suspicious abnormality for the diagnosis of breast cancer. The aim of this study was to investigate the clinical significance of sonographic ally detected architectural distortion. From January 2006 to June 2008, 20 patients were identified who had sonographic ally detected architectural distortions without a history of trauma or surgery and abnormal mammographic findings related to an architectural distortion. All of the lesions were pathologically verified. We evaluated the clinical and pathological findings and then assessed the clinical significance of the sonographic ally detected architectural distortions. Based on the clinical findings, one (5%) of the 20 patients had a palpable lump and the remaining 19 patients had no symptoms. No patient had a family history of breast cancer. Based on the pathological findings, three (15%) patients had malignancies. The malignant lesions included invasive ductal carcinomas (n = 2) and ductal carcinoma in situ (n = 1). Four (20%) patients had high-risk lesions: atypical ductal hyperplasia (n = 3) and lobular carcinoma in situ (n = 1). The remaining 13 (65%) patients had benign lesions, however, seven (35%) out of 13 patients had mild-risk lesions (three intraductal papillomas, three moderate or florid epithelial hyperplasia and one sclerosing adenosis). Of the sonographic ally detected architectural distortions, 35% were breast cancers or high-risk lesions and 35% were mild-risk lesions. Thus, a biopsy might be needed for an architectural distortion without an associated mass as depicted on breast ultrasound, even though the mammographic findings are normal

  8. Significance and popularity in music production.

    Science.gov (United States)

    Monechi, Bernardo; Gravino, Pietro; Servedio, Vito D P; Tria, Francesca; Loreto, Vittorio

    2017-07-01

    Creative industries constantly strive for fame and popularity. Though highly desirable, popularity is not the only achievement artistic creations might ever acquire. Leaving a longstanding mark in the global production and influencing future works is an even more important achievement, usually acknowledged by experts and scholars. 'Significant' or 'influential' works are not always well known to the public or have sometimes been long forgotten by the vast majority. In this paper, we focus on the duality between what is successful and what is significant in the musical context. To this end, we consider a user-generated set of tags collected through an online music platform, whose evolving co-occurrence network mirrors the growing conceptual space underlying music production. We define a set of general metrics aiming at characterizing music albums throughout history, and their relationships with the overall musical production. We show how these metrics allow to classify albums according to their current popularity or their belonging to expert-made lists of important albums. In this way, we provide the scientific community and the public at large with quantitative tools to tell apart popular albums from culturally or aesthetically relevant artworks. The generality of the methodology presented here lends itself to be used in all those fields where innovation and creativity are in play.

  9. Origin and significance of defects in welds

    International Nuclear Information System (INIS)

    Lundin, C.D.

    1984-01-01

    In the past 10 to 15 years significant advances have taken place in the understanding of the origin and nature of weld discontinuities. The furthering of the knowledge of hot cracking, cold cracking, lamellar tearing and porosity formation is due to the development and utilization of sophisticated techniques for microscopy and microanalysis and the concerted efforts of many researchers in the U.S. and abroad. Concurrent with the progress toward better definition of the metallurgical mechanisms for discontinuity formation, the development of the fracture mechanics approach for the assessment of the significance of the discontinuities was brought into focus. It is the marriage of the metallurgical understanding of formation and the mechanics assessment of relevance that permits discontinuities to be treated with a new degree of sophistication. The many types of cracking and porosity formation were the subjects of numerous studies in the intervening years. This presentation will treat the various types of weld discontinuities which have their origin closely related to a metallurgical mechanism. Emphasis will be placed on hot cracking, and porosity formation with information presented on cold cracking, reheat cracking and lamellar tearing. The employment of the newer metallurgical tools will be discussed in terms of their utilization in determining the cause of discontinuity formation

  10. Ciprofibrate, clofibric acid and respective glycinate derivatives. Effects of a four-week treatment on male lean and obese Zucker rats.

    Science.gov (United States)

    Lupp, Amelie; Karge, Elke; Deufel, Thomas; Oelschlägers, Herbert; Fleck, Christian

    2008-01-01

    Fibrates are widely prescribed in hyperlpidemic patients to prevent atherosclerosis. Their therapeutic use, however, can be associated with adverse effects like gastrointestinal disorders, myalgia, myositis and hepatotoxicity. In rodents large doses can even cause hepatocellular carcinoma. Additionally, interactions with the biotransformation of other compounds at the cytochrome P450 (CYP) system have been observed. Thus, the discovery of new substances or derivatives with less side effects is of great interest. In the present study the influence of a four-week daily oral administration of 2 mg/kg body weight ciprofibrate (CAS 52214-84-3) or of 100 mg/kg body weight clofibric acid (CAS 882-09-7) was compared to that of the respective doses of their newly synthesized glycine conjugates in adult male lean and obese Zucker rats. Although obese rats displayed distinctly higher serum lipid concentrations, after fibrate treatment values were significantly lowered in lean animals only. Livers of obese rats were significantly enlarged, histologically showing a fine-droplet like fatty degeneration and an increase in glycogen content, but no signs of inflammation. After fibrate administration histologically a hypertrophy, an eosinophilia, a reduced glycogen content and also hepatocyteapoptosis were observed. Livers of obese rats displayed higher CYP1A1 andCYP2E1 expression, but lower immunostaining for CYP2B1 and CYP3A2. No differences between the two groups of rats were seen with respect to CYP4A1 expression. Due to fibrate treatment especially CYP2E1 and CYP4A1, but also CYP1A1, 2B1 and 3A2 were induced. Resulting CYP mediated monooxygenase activities were also elevated in most cases. In general, effects of clofibric acid and clofibric acid glycinate (CAS 4896-55-3) were less distinct than those of ciprofibrate and its glycinate (CAS 640772-36-7). With no parameterinvestigated major differences were seen between the parent fibrates and their glycine conjugates. Thus, the

  11. Arcuate foramen and its clinical significance

    International Nuclear Information System (INIS)

    Cakmark, O.; Gurdal, E.; Cavdar, S.; Ekinci, G.; Yildiz, E.

    2005-01-01

    The present study determines the degree of ossification of the posterior atlanto-occipital membrane in dry bone, plane lateral cervical spine radiographs and computer tomography (CT). The average length, width and the area of the arcuate foramen were measured on dry bone and on cervical CT. Further, age, gender and complaints of the patients of shoulder and arm pain, neck pain, headache, vertigo, and lacrimation in relation to the presence of bony complete or incomplete arcuate foramen were evaluated. From February 2004 to January 2005 60 dry atlases were obtained from the Anatomy Department, University of Marmara, Istanbul, Turkey and 416 lateral cervical spine radiographs were obtained from the Radiology department for neurological and orthopedic evaluations. Each complete arcuate foramen was calculated with the aid of Clemex Vision PE demo version computer program. Among the 60 dry atlases examined 7 (11.7%) had complete and 2 (3.3 %) had incomplete bony bridge formation. Of the 416 plane lateral cervical spine radiographs examined, 30 (7.2%) had complete and 26 (6.25%) had incomplete bony bridge formation. Of the 30 complete arcuate foramen 24 (80%) were females and 6 (20%) were males. The frequency of having a complete arcuate foramen in females was 8.45%, and in males it was 4.55%. Further, of the 26 incomplete arcuate foramen 20 (76.9%) were females and 6 (23.1%) were males. The frequency of having an incomplete arcuate foramen in females was 7%, and in males was 4.55%. The statistical evaluations showed that patients with complete arcuate foramen had significant complaints of shoulder-arm pain (p=0.0072), neck pain (p=0.0072) and vertigo (p=0.0598) compared to patients with incomplete arcuate foramen. The patients with complete arcuate foramen had a headache ratio of 12:30 and this ratio was 2:26 in patients with incomplete arcuate foramen and the difference between complete and incomplete arcuate foramen was statistically significant (p=0.0062). Further

  12. Regional and global significance of nuclear energy

    International Nuclear Information System (INIS)

    Schilling, H.D.

    1995-01-01

    Measures to combat poverty and improve the standard of living in countries of the Third World will inevitably boost global demand for energy, and energy conservation measures will not be able to offset this increase. Nuclear energy will regain significance in the framework of approaches adopted to resolve the energy problem, which primarily is an ecologic problem created by an extremely large flow of materials. The extraordinarily high energy density of nuclear fuels can contribute to markedly reduce the flow of materials; and at that, electric energy is an efficient substitute for primary energy forms. Thus nuclear electricity generation is of double benefit to the ecology. Engineering goals in nuclear technology thus gain a service aspect, with progress in power plant engineering and design aiming not only at enhanced engineered safety, but also at regaining public acceptance of and confidence in nuclear power plant technology. (orig./UA) [de

  13. Response to a spill of national significance

    International Nuclear Information System (INIS)

    Jensen, D.S.; Pond, R.; Johnson, M.H.

    1993-01-01

    Responding to a spill of national significance (SONS), such as the 1989 Exxon Valdez spill, requires an augmenting organization to support the local response organization. The US Coast Guard has developed SONS protocol to be better prepared to respond to these infrequent catastrophic spills. A flag-level Coast Guard officer assumes the role of national incident commander (NIC) and federal on-scene coordinator (OSC), and is supported by a national incident task force (NITF). The major role of the NITF is to develop a national response strategy, acquire response resources and allocate them efficiently, and effectively deal with many peripheral national issues. Unified command concepts have been incorporated into the NITF and its primary organizational elements. In addition, frequent training and exercising is essential to keep the SONS protocol's preparedness at an acceptable level

  14. The significance of vector magnetic field measurements

    Science.gov (United States)

    Hagyard, M. J.

    1990-01-01

    Observations of four flaring solar active regions, obtained during 1980-1986 with the NASA Marshall vector magnetograph (Hagyard et al., 1982 and 1985), are presented graphically and characterized in detail, with reference to nearly simultaneous Big Bear Solar Observatory and USAF ASW H-alpha images. It is shown that the flares occurred where local photospheric magnetic fields differed most from the potential field, with initial brightening on either side of a magnetic-neutral line near the point of maximum angular shear (rather than that of maximum magnetic-field strength, typically 1 kG or greater). Particular emphasis is placed on the fact that these significant nonpotential features were detected only by measuring all three components of the vector magnetic field.

  15. Global warming: the significance of methane

    International Nuclear Information System (INIS)

    Dessus, B.; Le Treut, H.; Laponche, B.

    2008-01-01

    the concept of Global Warming Potential (GWP) indicates the relative contribution to global warming over a given period (for example 100 years) of a pulse emission at the start of the period of 1 kg of a specific greenhouse gas (GHG) in comparison to the contribution, over the same period, of an emission of 1 kg of CO 2 . The GWPs calculated for different time intervals take into account the differences in atmospheric lifetimes of the different GHGs. Using the '100-year GWP' to measure non CO 2 GHG emissions is not well suited to the case of permanent or long lifetime measures whose effectiveness is to be assessed at a given time horizon. In this context, it contributes to significantly playing down the importance of reducing emissions of GHGs with short atmospheric lifetimes. Thus, for example, methane which is not emitted over the period 2020- 2100 as a result of a landfill site being closed in 2020 will have an impact (as opposed to if the site remained in operation) that would be far greater towards 2100 compared to a CO 2 emission source that has also been stopped permanently and whose climate impact is measured in an equivalent manner. Using the GWP is only appropriate if applied year after year to time horizons considered to be of concern or decisive by climate studies, thus in particular 2050, 2100 and 2150. This is all the more significant as climate experts' current concerns lead them not only to advocate long-term stabilisation of GHG concentrations but also to avoid as far as possible intermediate excess of these concentrations over the coming century. Finally, it is noted that CH 4 prevention policies implemented in the short term may continue to have a long-term impact greater than merely taking into account the current GWP would imply. To more or less ignore the impact of CH 4 as it is unsuitable for accounting purposes affects the exclusive character of the link that may exist between the issue of GHGs and that of energy. Furthermore, if the

  16. Bayesian approaches for detecting significant deterioration

    International Nuclear Information System (INIS)

    Roed, Willy; Aven, Terje

    2009-01-01

    Risk indicators can provide useful input to risk management processes and are given increased attention in the Norwegian petroleum industry. Examples include indicators expressing the proportion of test failures of safety and barrier systems. Such indicators give valuable information about the performance of the systems and provide a basis for trend evaluations. Early warning of a possible deterioration is essential due to the importance of the systems in focus, but what should be the basis for the warning criterion? This paper presents and discusses several Bayesian approaches for the establishment of a warning criterion to disclose significant deterioration. The Norwegian petroleum industry is the starting point for this paper, but the study is relevant for other application areas as well

  17. Swiss solar power statistics 2007 - Significant expansion

    International Nuclear Information System (INIS)

    Hostettler, T.

    2008-01-01

    This article presents and discusses the 2007 statistics for solar power in Switzerland. A significant number of new installations is noted as is the high production figures from newer installations. The basics behind the compilation of the Swiss solar power statistics are briefly reviewed and an overview for the period 1989 to 2007 is presented which includes figures on the number of photovoltaic plant in service and installed peak power. Typical production figures in kilowatt-hours (kWh) per installed kilowatt-peak power (kWp) are presented and discussed for installations of various sizes. Increased production after inverter replacement in older installations is noted. Finally, the general political situation in Switzerland as far as solar power is concerned are briefly discussed as are international developments.

  18. THRESHOLD OF SIGNIFICANCE IN STRESS MANAGEMENT

    Directory of Open Access Journals (Sweden)

    Elena RUSE

    2015-12-01

    Full Text Available Stress management is the individual's ability to handle any situation, external conditions, to match the demands of the external environment. The researchers revealed several stages in the stress response. A first phase was called ‘‘alert reaction'' or ‘‘immediate reaction to stress‘‘, phase in which there are physiological modifications and manifestations that occur under psychological aspect. Adaptation phase is the phase in which the reactions from the first phase diminishes or disappears. Exhaustion phase is related to the diversity of stress factors and time and may exceed the resources of the human body to adapt. Influencing factors may be: limited, cognitive, perceptual, and a priori. But there is a threshold of significance in stress management. Once the reaction to external stimuli occurs, awareness is needed. The capability effect occurs, any side effect goes away and comes out the ''I AM'' effect.

  19. The insignificance of statistical significance testing

    Science.gov (United States)

    Johnson, Douglas H.

    1999-01-01

    Despite their use in scientific journals such as The Journal of Wildlife Management, statistical hypothesis tests add very little value to the products of research. Indeed, they frequently confuse the interpretation of data. This paper describes how statistical hypothesis tests are often viewed, and then contrasts that interpretation with the correct one. I discuss the arbitrariness of P-values, conclusions that the null hypothesis is true, power analysis, and distinctions between statistical and biological significance. Statistical hypothesis testing, in which the null hypothesis about the properties of a population is almost always known a priori to be false, is contrasted with scientific hypothesis testing, which examines a credible null hypothesis about phenomena in nature. More meaningful alternatives are briefly outlined, including estimation and confidence intervals for determining the importance of factors, decision theory for guiding actions in the face of uncertainty, and Bayesian approaches to hypothesis testing and other statistical practices.

  20. Significance and potential benefits of the CTBT

    International Nuclear Information System (INIS)

    Sato, M.

    1999-01-01

    This presentation is based on the Treaty stipulation on international cooperation: 'The States parties undertake to promote cooperation among themselves to facilitate and participate in the fullest possible exchange relating to technologies used in the verification of the Non-proliferation Treaty in order to enable States to strengthen national implementation of verification measures; and to enable States to benefit from the application of such technologies for peaceful purposes'. Political significance of the Treaty and the potential benefits of participating in the CTBT regime are exposed. It is concluded that international cooperation under the CTBT regime is an element in broadening Treaty support and participation, thereby contributing to an early establishment and the efficient operation of the Treaty verification regime. The PTS will assist the States Signatories to facilitate and promote cooperation among themselves in the fullest exchange of information relating to verification-related technologies so that they may benefit from participation in the Treaty regime

  1. Risk control and the minimum significant risk

    International Nuclear Information System (INIS)

    Seiler, F.A.; Alvarez, J.L.

    1996-01-01

    Risk management implies that the risk manager can, by his actions, exercise at least a modicum of control over the risk in question. In the terminology of control theory, a management action is a control signal imposed as feedback on the system to bring about a desired change in the state of the system. In the terminology of risk management, an action is taken to bring a predicted risk to lower values. Even if it is assumed that the management action taken is 100% effective and that the projected risk reduction is infinitely well known, there is a lower limit to the desired effects that can be achieved. It is based on the fact that all risks, such as the incidence of cancer, exhibit a degree of variability due to a number of extraneous factors such as age at exposure, sex, location, and some lifestyle parameters such as smoking or the consumption of alcohol. If the control signal is much smaller than the variability of the risk, the signal is lost in the noise and control is lost. This defines a minimum controllable risk based on the variability of the risk over the population considered. This quantity is the counterpart of the minimum significant risk which is defined by the uncertainties of the risk model. Both the minimum controllable risk and the minimum significant risk are evaluated for radiation carcinogenesis and are shown to be of the same order of magnitude. For a realistic management action, the assumptions of perfectly effective action and perfect model prediction made above have to be dropped, resulting in an effective minimum controllable risk which is determined by both risk limits. Any action below that effective limit is futile, but it is also unethical due to the ethical requirement of doing more good than harm. Finally, some implications of the effective minimum controllable risk on the use of the ALARA principle and on the evaluation of remedial action goals are presented

  2. Prognostic significance of serum bilirubin in stroke

    International Nuclear Information System (INIS)

    Arslan, A.; Ismail, M.; Khan, F.; Khan, A.; Khattak, M.B.; Anwar, M.J.

    2011-01-01

    Background: Oxidative injury is an important cause of the neurologic lesion in stroke. Serum bilirubin is considered a natural antioxidant that may affect the prognosis of stroke. The purpose of this study was to evaluate the prognostic significance of bilirubin in stroke patients. Methods: A prospective cross-sectional study was conducted in Medical Units of Khyber Teaching Hospital, Peshawar. Inpatients admitted with acute attack of stroke were included in this study. Data regarding serum bilirubin and concurrent cerebrovascular risk factors were collected. National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) were used to analyse stroke's severity and functional outcomes, respectively. Results: Hypertension