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Sample records for dioxin modulates expression

  1. Dioxin exposure of human CD34+ hemopoietic cells induces gene expression modulation that recapitulates its in vivo clinical and biological effects

    International Nuclear Information System (INIS)

    Fracchiolla, Nicola Stefano; Todoerti, Katia; Bertazzi, Pier Alberto; Servida, Federica; Corradini, Paolo; Carniti, Cristiana; Colombi, Antonio; Cecilia Pesatori, Angela; Neri, Antonino; Deliliers, Giorgio Lambertenghi

    2011-01-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has a large number of biological effects, including skin, cardiovascular, neurologic diseases, diabetes, infertility, cancers and immunotoxicity. We analysed the in vitro TCDD effects on human CD34 + cells and tested the gene expression modulation by means of microarray analyses before and after TCDD exposure. We identified 257 differentially modulated probe sets, identifying 221 well characterized genes. A large part of these resulted associated to cell adhesion and/or angiogenesis and to transcription regulation. Synaptic transmission and visual perception functions, with the particular involvement of the GABAergic pathway were also significantly modulated. Numerous transcripts involved in cell cycle or cell proliferation, immune response, signal transduction, ion channel activity or calcium ion binding, tissue development and differentiation, female or male fertility or in several metabolic pathways were also affected after dioxin exposure. The transcriptional profile induced by TCDD treatment on human CD34 + cells strikingly reproduces the clinical and biological effects observed in individuals exposed to dioxin and in biological experimental systems. Our data support a role of dioxin in the neoplastic transformation of hemopoietic stem cells and in immune modulation processes after in vivo exposure, as indicated by the epidemiologic data in dioxin accidentally exposed populations, providing a molecular basis for it. In addition, TCDD alters genes associated to glucidic and lipidic metabolisms, to GABAergic transmission or involved in male and female fertility, thus providing a possible explanation of the diabetogenic, dyslipidemic, neurologic and fertility effects induced by TCDD in vivo exposure.

  2. Dioxin modulates expression of receptor for activated C kinase (RACK-1) in developing neurons

    Energy Technology Data Exchange (ETDEWEB)

    Yang, J.H.; Kim, S.Y.; Lee, H.G.; Kim, M.Y.; Lee, J.H.; Chae, W.G. [Catholic Univ. of Daegu, Dept. of Pharmacology/Toxicology, Daegu (Korea)

    2004-09-15

    TCDD is sensitive to the central nerve system of the developing brain. The TCDD-induced neurodevelopmental deficits include the cognitive disability and motor dysfunction. While TCDD may lead to neurodevelopmental and neurobehavioral deficit, it is not known which molecular substances are intracellular targets for TCDD. Since TCDD accumulates in brain and the brain contains the Ah receptor, it is possible that TCDD may act at the target site such as cerebellum, which is responsible for cognitive abilities and motor function. A recent in vitro studies using cerebellar granule cells demonstrated a translocation of PKC-{alpha} and {epsilon} following the TCDD or PCB exposure. One of the most pivotal second messenger molecules involved in neuronal function and development is protein kinase C (PKC). PKC signaling pathways have been implicated as an important factor in learning and memory processes. PKC signaling events are optimized by the adaptor proteins, which organize PKCs near their selective substrates and away from others. RACK-1(receptor for activated C-kinase) is one of adaptor proteins that anchor the activated PKC at the site of translocation 6. RACKs bind PKC only in the presence of PKC activators. RACKs are 30- and 36-kDa proteins located in cytoskeletal compartment and play a key role in PKC activation and in membrane amchoring. Since different PKC isoforms translocate to distinct subcellular sites on activation, it is suggested that isoform-specific RACK may be present. Activation of certain PKC isoforms (PKC-a and {beta}II) is preferentially associated with RACK-1. While TCDD modulates PKC signaling pathway, role of RACK-1 on TCDD-mediated signaling pathway is not known. To identify the intracellular target for TCDD and understand a mechanism of signaling pathway in the developing brain, the present study attempted to analyze effects of RACK-1 in the cerebellar granule cells following TCDD exposure.

  3. Constitutive expression of the AHR signaling pathway in a bovine mammary epithelial cell line and modulation by dioxin-like PCB and other AHR ligands.

    Science.gov (United States)

    Girolami, Flavia; Spalenza, Veronica; Manzini, Livio; Carletti, Monica; Nebbia, Carlo

    2015-01-05

    Environmental pollutants, such as dioxin-like (DL) PCBs, benzo(a) pyrene (B[a]P), and flavonoids are aryl hydrocarbon receptor (AHR) ligands and may be excreted in dairy milk. The expression of AHR-target genes, particularly those involved in xenobiotic biotransformation, and their modulation by two DL-PCBs, B[a]P, and β-naphthoflavone was investigated in a bovine mammary epithelial cell line (BME-UV). As assessed by quantitative PCR, BME-UV cells expressed a functional AHR signaling pathway. All the AHR ligands induced a concentration-related increase in the transcription of cytochrome P450 1A1 and 1B1, known to be implicated in the bioactivation of several xenobiotics. Conversely, genes encoding for antioxidant and detoxifying enzymes, like quinone oxidoreductase or glutathione S-transferase A2, were not affected or even depressed. This study demonstrates the occurrence and the modulation by different AHR-ligands of genes involved in xenobiotic metabolism in BME-UV cells, with the potential generation of (re) active metabolites that may damage mammary tissue and/or affect animal or human health via the contaminated milk. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  4. Patterns of dioxin-altered mRNA expression in livers of dioxin-sensitive versus dioxin-resistant rats

    Energy Technology Data Exchange (ETDEWEB)

    Franc, Monique A. [University of Toronto, Department of Pharmacology and Toxicology, Medical Sciences Building, Toronto, ON (Canada); Johnson and Johnson Pharmaceutical Research and Development, Department of Pharmacogenomics, 1000 Route 202 South, P.O. Box 300, Raritan, NJ (United States); Moffat, Ivy D.; Boutros, Paul C.; Okey, Allan B. [University of Toronto, Department of Pharmacology and Toxicology, Medical Sciences Building, Toronto, ON (Canada); Tuomisto, Jouni T.; Tuomisto, Jouko [National Public Health Institute, Department of Environmental Health, Centre for Environmental Health Risk Analysis, Kuopio (Finland); Pohjanvirta, Raimo [University of Helsinki, Department of Food and Environmental Hygiene, Faculty of Veterinary Medicine, Helsinki (Finland)

    2008-11-15

    Dioxins exert their major toxicologic effects by binding to the aryl hydrocarbon receptor (AHR) and altering gene transcription. Numerous dioxin-responsive genes previously were identified both by conventional biochemical and molecular techniques and by recent mRNA expression microarray studies. However, of the large set of dioxin-responsive genes the specific genes whose dysregulation leads to death remain unknown. To identify specific genes that may be involved in dioxin lethality we compared changes in liver mRNA levels following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in three strains/lines of dioxin-sensitive rats with changes in three dioxin-resistant rat strains/lines. The three dioxin-resistant strains/lines all harbor a large deletion in the transactivation domain of the aryl hydrocarbon receptor (AHR). Despite this deletion, many genes exhibited a ''Type-I'' response - that is, their responses were similar in dioxin-sensitive and dioxin-resistant rats. Several genes that previously were well established as being dioxin-responsive or under AHR regulation emerged as Type-I responses (e.g. CYP1A1, CYP1A2, CYP1B1 and Gsta3). In contrast, a relatively small number of genes exhibited a Type-II response - defined as a difference in responsiveness between dioxin-sensitive and dioxin-resistant rat strains. Type-II genes include: malic enzyme 1, ubiquitin C, cathepsin L, S-adenosylhomocysteine hydrolase and ferritin light chain 1. In silico searches revealed that AH response elements are conserved in the 5'-flanking regions of several genes that respond to TCDD in both the Type-I and Type-II categories. The vast majority of changes in mRNA levels in response to 100 {mu}g/kg TCDD were strain-specific; over 75% of the dioxin-responsive clones were affected in only one of the six strains/lines. Selected genes were assessed by quantitative RT-PCR in dose-response and time-course experiments and responses of some genes were

  5. Effect of dioxin exposure on aromatase expression in ovariectomized rats

    International Nuclear Information System (INIS)

    Ye Lan; Leung, Lai K.

    2008-01-01

    Because of their persistence in the environment dioxins are one of the most concerned classes of carcinogens. Displaying both pro- and anti-agonistic properties to some hormone receptors, the pollutants are also known to be endocrine disruptors. Humans can be exposed to this pollutant through contaminated food, air, drinking water, etc. The female hormone estrogen may initiate various physiological functions, and excessive exposure to this hormone is a documented risk factor for carcinogenesis. Cyp19 (aromatase) catalyses the last step of estrogen biosynthesis, while cyp1a1 can hydroxylate and deactivate the hormone. In the present study, we investigated the effect of 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD) on aromatase expression in the brain and adipose tissue in ovariectomized Sprague Dawley rats. Female rats were given 2.5 μg/kg TCDD p.o. before and after ovariectomy. Real-time PCR and western blot analysis indicated that pre-ovariectomy administration of TCDD could significantly reduce aromatase expression in the brain but increase the expression in the adipose tissue. In addition, increased plasma estrogen level and uterine weight were observed in these rats. These parameters did not change in rats with post-ovariectomy TCDD treatment. Our results suggested that the timing of exposure to the toxicant could determine the estrogenicity of TCDD. No correlation between cyp1a1 and cyp19 expression was observed

  6. Dioxin induces expression of hsa-miR-146b-5p in human neuroblastoma cells.

    Science.gov (United States)

    Xu, Tuan; Xie, Heidi Q; Li, Yunping; Xia, Yingjie; Sha, Rui; Wang, Lingyun; Chen, Yangsheng; Xu, Li; Zhao, Bin

    2018-01-01

    Dioxin can cause a series of neural toxicological effects. MicroRNAs (miRs) play important roles in regulating nervous system function and mediating cellular responses to environmental pollutants, such as dioxin. Hsa-miR-146b-5p appears to be involved in neurodegenerative diseases and brain tumors. However, little is known about effects of dioxin on the expression of hsa-miR-146b-5p. We found that the hsa-miR-146b-5p expression and its promoter activity were significantly increased in dioxin treated SK-N-SH cells, a human-derived neuroblastoma cell line. Potential roles of hsa-miR-146b-5p in mediating neural toxicological effects of dioxin may be due to the regulation of certain target genes. We further confirmed that hsa-miR-146b-5p significantly suppressed acetylcholinesterase (AChE) activity and targeted the 3'-untranslated region of the AChE T subunit, which has been down-regulated in dioxin treated SK-N-SH cells. Functional bioinformatic analysis showed that the known and predicted target genes of hsa-miR-146b-5p were involved in some brain functions or cyto-toxicities related to known dioxin effects, including synapse transmission, in which AChE may serve as a responsive gene for mediating the effect. Copyright © 2017. Published by Elsevier B.V.

  7. 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.

    Science.gov (United States)

    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.

  8. Express Detection of Pentachlorophenol as Dioxins Precursor in Natural Water

    Directory of Open Access Journals (Sweden)

    Vitalia S. Krikounova

    2002-01-01

    Full Text Available A rapid detection method for the pesticide pentachlorophenol (PCP — polarization fluoroimmunoassay (PFIA — in the dynamic range of 10–9,000 ppb was developed. PCP may form polychlorinated dibenzo-p-dioxins, making environmental monitoring of this compound an issue of great importance. In order to optimize the PFIA procedure, a number of fluorescein-labeled PCP derivatives and similar compounds (tracers were synthesized, and the influence of their structure on PFIA characteristics was studied. Also, two antisera were tested in developing PFIA for PCP. The developed method is highly specific for PCP and can be used for its determination in water samples at a level down to 10 ppb. Total time of the assay for 10 samples is about 7 min. The assay provides a useful and a highly practical screening tool for the processing of large numbers of samples and for the preliminary estimation of potential dioxins contamination in water resources.

  9. Microarray analysis of gene expression in peripheral blood mononuclear cells from dioxin-exposed human subjects

    International Nuclear Information System (INIS)

    McHale, Cliona M.; Zhang, Luoping; Hubbard, Alan E.; Zhao, Xin; Baccarelli, Andrea; Pesatori, Angela C.; Smith, Martyn T.; Landi, Maria Teresa

    2007-01-01

    Tetrachlorodibenzo-p-dioxin (TCDD) is classified as a human carcinogen and exerts toxic effects on the skin (chloracne). Effects on reproductive, immunological, and endocrine systems have also been observed in animal models. TCDD acts through the aryl hydrocarbon receptor (AhR) pathway influencing largely unknown gene networks. An industrial accident in Seveso, Italy in 1976 exposed thousands of people to substantial quantities of TCDD. Twenty years after the exposure, this study examines global gene expression in the mononuclear cells of 26 Seveso female never smokers, with similar age, alcohol consumption, use of medications, and background plasma levels of 22 dioxin congeners unrelated to the Seveso accident. Plasma dioxin levels were still elevated in the exposed subjects. We performed analyses in two different comparison groups. The first included high-exposed study subjects compared with individuals with background TCDD levels (average plasma levels 99.4 and 6.7 ppt, respectively); the second compared subjects who developed chloracne after the accident, and those who did not develop this disease. Overall, we observed a modest alteration of gene expression based on dioxin levels or on chloracne status. In the comparison between high levels and background levels of TCDD, four histone genes were up-regulated and modified expression of HIST1H3H was confirmed by real-time PCR. In the comparison between chloracne case-control subjects, five hemoglobin genes were up-regulated. Pathway analysis revealed two major networks for each comparison, involving cell proliferation, apoptosis, immunological and hematological disease, and other pathways. Further examination of the role of these genes in dioxin induced-toxicity is warranted

  10. PCB 126 and Other Dioxin-Like PCBs Specifically Suppress Hepatic PEPCK Expression via the Aryl Hydrocarbon Receptor

    Science.gov (United States)

    Zhang, Wenshuo; Sargis, Robert M.; Volden, Paul A.; Carmean, Christopher M.; Sun, Xiao J.; Brady, Matthew J.

    2012-01-01

    Dioxins and dioxin-like compounds encompass a group of structurally related heterocyclic compounds that bind to and activate the aryl hydrocarbon receptor (AhR). The prototypical dioxin is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly toxic industrial byproduct that incites numerous adverse physiological effects. Global commercial production of the structurally similar polychlorinated biphenyls (PCBs), however, commenced early in the 20th century and continued for decades; dioxin-like PCBs therefore contribute significantly to total dioxin-associated toxicity. In this study, PCB 126, the most potent dioxin-like PCB, was evaluated with respect to its direct effects on hepatic glucose metabolism using primary mouse hepatocytes. Overnight treatment with PCB 126 reduced hepatic glycogen stores in a dose-dependent manner. Additionally, PCB 126 suppressed forskolin-stimulated gluconeogenesis from lactate. These effects were independent of acute toxicity, as PCB 126 did not increase lactate dehydrogenase release nor affect lipid metabolism or total intracellular ATP. Interestingly, provision of cells with glycerol instead of lactate as the carbon source completely restored hepatic glucose production, indicating specific impairment in the distal arm of gluconeogenesis. In concordance with this finding, PCB 126 blunted the forskolin-stimulated increase in phosphoenolpyruvate carboxykinase (PEPCK) mRNA levels without affecting glucose-6-phosphatase expression. Myricetin, a putative competitive AhR antagonist, reversed the suppression of PEPCK induction by PCB 126. Furthermore, other dioxin-like PCBs demonstrated similar effects on PEPCK expression in parallel with their ability to activate AhR. It therefore appears that AhR activation mediates the suppression of PEPCK expression by dioxin-like PCBs, suggesting a role for these pollutants as disruptors of energy metabolism. PMID:22615911

  11. PCB 126 and other dioxin-like PCBs specifically suppress hepatic PEPCK expression via the aryl hydrocarbon receptor.

    Directory of Open Access Journals (Sweden)

    Wenshuo Zhang

    Full Text Available Dioxins and dioxin-like compounds encompass a group of structurally related heterocyclic compounds that bind to and activate the aryl hydrocarbon receptor (AhR. The prototypical dioxin is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, a highly toxic industrial byproduct that incites numerous adverse physiological effects. Global commercial production of the structurally similar polychlorinated biphenyls (PCBs, however, commenced early in the 20(th century and continued for decades; dioxin-like PCBs therefore contribute significantly to total dioxin-associated toxicity. In this study, PCB 126, the most potent dioxin-like PCB, was evaluated with respect to its direct effects on hepatic glucose metabolism using primary mouse hepatocytes. Overnight treatment with PCB 126 reduced hepatic glycogen stores in a dose-dependent manner. Additionally, PCB 126 suppressed forskolin-stimulated gluconeogenesis from lactate. These effects were independent of acute toxicity, as PCB 126 did not increase lactate dehydrogenase release nor affect lipid metabolism or total intracellular ATP. Interestingly, provision of cells with glycerol instead of lactate as the carbon source completely restored hepatic glucose production, indicating specific impairment in the distal arm of gluconeogenesis. In concordance with this finding, PCB 126 blunted the forskolin-stimulated increase in phosphoenolpyruvate carboxykinase (PEPCK mRNA levels without affecting glucose-6-phosphatase expression. Myricetin, a putative competitive AhR antagonist, reversed the suppression of PEPCK induction by PCB 126. Furthermore, other dioxin-like PCBs demonstrated similar effects on PEPCK expression in parallel with their ability to activate AhR. It therefore appears that AhR activation mediates the suppression of PEPCK expression by dioxin-like PCBs, suggesting a role for these pollutants as disruptors of energy metabolism.

  12. Assays of dioxins and dioxin-like compounds in actually contaminated soils using transgenic tobacco plants carrying a recombinant mouse aryl hydrocarbon receptor-mediated β-glucuronidase reporter gene expression system.

    Science.gov (United States)

    Inui, Hideyuki; Gion, Keiko; Utani, Yasushi; Wakai, Taketo; Kodama, Susumu; Eun, Heesoo; Kim, Yun-Seok; Ohkawa, Hideo

    2012-01-01

    The transgenic tobacco plant XD4V-26 carrying the recombinant mouse aryl hydrocarbon receptor XD4V-mediated β-glucuronidase (GUS) reporter gene expression system was used for assay of dioxins and dioxin-like compounds consisting of polychlorinated dibenzeno-p-dioxins, polychlorinated dibenzofurans, and coplanar polychlorinated biphenyls (Co-PCBs) in actually contaminated soils. The transgenic tobacco plant XD4V-26 showed a significant dose-dependent induced GUS activity when cultured on MS medium containing PCB126 [toxic equivalency factor (TEF) = 0.1]. In contrast, PCB169 and PCB180, which have 0.03 of TEF and unassigned TEF values, respectively, did not significantly induce GUS activity under the same conditions as with PCB126. When the tobacco plants were cultivated for up to 5 weeks on actually contaminated soils with dioxins and dioxin-like compounds collected from the periphery of an incinerator used for disposal of residential and industrial wastes, GUS activity in the leaves was dose-dependently increased. The plants clearly detected 360 pg-TEQ g(-1) of dioxins and dioxin-like compounds in this assay. There was a positive correlation between GUS activity and TEQ value of dioxins and dioxin-like compounds in the plants. This assay does not require any extraction and purification processes for the actually contaminated soil samples.

  13. 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.)

  14. The dioxins; Les dioxines

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1999-01-01

    This complete report on the dioxins, after a recall of the dioxins impacts on health, the emissions sources and the researches on these pollutants control and monitoring, details four studies. The first one deals with the dioxins emissions evolution in the atmosphere. The distribution of the emissions in function of the different sources is detailed. The second one concerns results of dioxins measures coming from municipal wastes incineration plants. A list of every french plants, of a 6 tons per hour capacity, is given with the corresponding emissions. Some installations requiring to be in conformity with standards are presented. The third study presents dioxins measures in the milk nearby municipal wastes incinerators. The last one is devoted to the monitoring, the biological effects on health and the regulations. (A.L.B.)

  15. New insights to the role of aryl hydrocarbon receptor in bone phenotype and in dioxin-induced modulation of bone microarchitecture and material properties

    International Nuclear Information System (INIS)

    Herlin, Maria; Finnilä, Mikko A.J.; Zioupos, Peter; Aula, Antti; Risteli, Juha; Miettinen, Hanna M.; Jämsä, Timo; Tuukkanen, Juha; Korkalainen, Merja; Håkansson, Helen; Viluksela, Matti

    2013-01-01

    Bone is a target for high affinity aryl hydrocarbon receptor (AHR) ligands, such as dioxins. Although bone morphology, mineral density and strength are sensitive endpoints of dioxin toxicity, less is known about effects on bone microarchitecture and material properties. This study characterizes TCDD-induced modulations of bone tissue, and the role of AHR in dioxin-induced bone toxicity and for normal bone phenotype. Six AHR-knockout (Ahr −/− ) and wild-type (Ahr +/+ ) mice of both genders were exposed to TCDD weekly for 10 weeks, at a total dose of 200 μg/kg bw. Bones were examined with micro-computed tomography, nanoindentation and biomechanical testing. Serum levels of bone remodeling markers were analyzed, and the expression of genes related to osteogenic differentiation was profiled using PCR array. In Ahr +/+ mice, TCDD-exposure resulted in harder bone matrix, thinner and more porous cortical bone, and a more compact trabecular bone compartment. Bone remodeling markers and altered expression of a number of osteogenesis related genes indicated imbalanced bone remodeling. Untreated Ahr −/− mice displayed a slightly modified bone phenotype as compared with untreated Ahr +/+ mice, while TCDD exposure caused only a few changes in bones of Ahr −/− mice. Part of the effects of both TCDD-exposure and AHR-deficiency were gender dependent. In conclusion, exposure of adult mice to TCDD resulted in harder bone matrix, thinner cortical bone, mechanically weaker bones and most notably, increased trabecular bone volume fraction in Ahr +/+ mice. AHR is involved in bone development of a normal bone phenotype, and is crucial for manifestation of TCDD-induced bone alterations. - Highlights: • TCDD disrupts bone remodeling resulting in altered cortical and trabecular bone. • In trabecular bone an anabolic effect is observed. • Cortical bone is thinner, more porous, harder, stiffer and mechanically weaker. • AHR ablation results in increased trabecular bone

  16. New insights to the role of aryl hydrocarbon receptor in bone phenotype and in dioxin-induced modulation of bone microarchitecture and material properties

    Energy Technology Data Exchange (ETDEWEB)

    Herlin, Maria, E-mail: maria.herlin@ki.se [Institute of Environmental Medicine, Karolinska Institutet, Stockholm (Sweden); Finnilä, Mikko A.J., E-mail: mikko.finnila@oulu.fi [Department of Medical Technology, Institute of Biomedicine, University of Oulu, Oulu (Finland); Department of Anatomy and Cell Biology, Institute of Biomedicine, University of Oulu, Oulu (Finland); Zioupos, Peter, E-mail: p.zioupos@cranfield.ac.uk [Biomechanics Laboratories, Department of Engineering and Applied Science, Cranfield University, Shrivenham SN6 8LA (United Kingdom); Aula, Antti, E-mail: antti.aula@gmail.com [Department of Medical Physics, Imaging Centre, Tampere University Hospital, Tampere (Finland); Department of Biomedical Engineering, Tampere University of Technology, Tampere (Finland); Risteli, Juha, E-mail: juha.risteli@ppshp.fi [Department of Clinical Chemistry, Oulu University Hospital, Oulu (Finland); Miettinen, Hanna M., E-mail: hanna.miettinen@crl.com [Department of Environmental Health, National Institute for Health and Welfare, Kuopio (Finland); Jämsä, Timo, E-mail: timo.jamsa@oulu.fi [Department of Medical Technology, Institute of Biomedicine, University of Oulu, Oulu (Finland); Department of Diagnostic Radiology, Oulu University Hospital, Oulu (Finland); Tuukkanen, Juha, E-mail: juha.tuukkanen@oulu.fi [Department of Anatomy and Cell Biology, Institute of Biomedicine, University of Oulu, Oulu (Finland); Korkalainen, Merja, E-mail: merja.korkalainen@thl.fi [Department of Environmental Health, National Institute for Health and Welfare, Kuopio (Finland); Håkansson, Helen, E-mail: Helen.Hakansson@ki.se [Institute of Environmental Medicine, Karolinska Institutet, Stockholm (Sweden); Viluksela, Matti, E-mail: matti.viluksela@thl.fi [Department of Environmental Health, National Institute for Health and Welfare, Kuopio (Finland); Department of Environmental Science, University of Eastern Finland, Kuopio (Finland)

    2013-11-15

    Bone is a target for high affinity aryl hydrocarbon receptor (AHR) ligands, such as dioxins. Although bone morphology, mineral density and strength are sensitive endpoints of dioxin toxicity, less is known about effects on bone microarchitecture and material properties. This study characterizes TCDD-induced modulations of bone tissue, and the role of AHR in dioxin-induced bone toxicity and for normal bone phenotype. Six AHR-knockout (Ahr{sup −/−}) and wild-type (Ahr{sup +/+}) mice of both genders were exposed to TCDD weekly for 10 weeks, at a total dose of 200 μg/kg bw. Bones were examined with micro-computed tomography, nanoindentation and biomechanical testing. Serum levels of bone remodeling markers were analyzed, and the expression of genes related to osteogenic differentiation was profiled using PCR array. In Ahr{sup +/+} mice, TCDD-exposure resulted in harder bone matrix, thinner and more porous cortical bone, and a more compact trabecular bone compartment. Bone remodeling markers and altered expression of a number of osteogenesis related genes indicated imbalanced bone remodeling. Untreated Ahr{sup −/−} mice displayed a slightly modified bone phenotype as compared with untreated Ahr{sup +/+} mice, while TCDD exposure caused only a few changes in bones of Ahr{sup −/−} mice. Part of the effects of both TCDD-exposure and AHR-deficiency were gender dependent. In conclusion, exposure of adult mice to TCDD resulted in harder bone matrix, thinner cortical bone, mechanically weaker bones and most notably, increased trabecular bone volume fraction in Ahr{sup +/+} mice. AHR is involved in bone development of a normal bone phenotype, and is crucial for manifestation of TCDD-induced bone alterations. - Highlights: • TCDD disrupts bone remodeling resulting in altered cortical and trabecular bone. • In trabecular bone an anabolic effect is observed. • Cortical bone is thinner, more porous, harder, stiffer and mechanically weaker. • AHR ablation

  17. Modulating effects of thyroid state on the induction of biotransformation enzymes byu 2,3,7,8-tetrachlorodibenzo-p-dioxin.

    NARCIS (Netherlands)

    Schuur, A.G.; Tacken, P.J.; Visser, T.J.; Brouwer, A.

    1998-01-01

    In this study we investigated to what extent the induction of detoxification enzymes by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is modulated by concomitant TCDD-induced changes in thyroid state. Euthyroid (Eu) male Sprague-Dawley rats, surgically thyroidectomized (Tx) rats and Tx rats receiving

  18. Modulation of gene expression made easy

    DEFF Research Database (Denmark)

    Solem, Christian; Jensen, Peter Ruhdal

    2002-01-01

    A new approach for modulating gene expression, based on randomization of promoter (spacer) sequences, was developed. The method was applied to chromosomal genes in Lactococcus lactis and shown to generate libraries of clones with broad ranges of expression levels of target genes. In one example...... that the method can be applied to modulating the expression of native genes on the chromosome. We constructed a series of strains in which the expression of the las operon, containing the genes pfk, pyk, and ldh, was modulated by integrating a truncated copy of the pfk gene. Importantly, the modulation affected...

  19. Relative effect potency estimates of dioxin-like activity for dioxins, furans, and dioxin-like PCBs in adults based on cytochrome P450 1A1 and 1B1 gene expression in blood

    NARCIS (Netherlands)

    Wimmerová, Soňa; van den Berg, Martin; Chovancová, Jana; Patayová, Henrieta; Jusko, Todd A; van Duursen, Majorie B M; Palkovičová Murínová, Ľubica; Canton, Rocio F; van Ede, Karin I; Trnovec, Tomáš

    2016-01-01

    BACKGROUND: In the risk assessment of PCDDs, PCDFs, and dioxin-like (DL) PCBs, regulatory authorities support the use of the toxic equivalency factor (TEF)-scheme derived from a heterogeneous data set of the relative effect potency (REPs) estimates. OBJECTIVES: We sought to determine REPs for

  20. Effect of dioxins on regulation of tyrosine hydroxylase gene expression by aryl hydrocarbon receptor: a neurotoxicology study

    Directory of Open Access Journals (Sweden)

    Akahoshi Eiichi

    2009-06-01

    Full Text Available Abstract Background Dioxins and related compounds are suspected of causing neurological disruption. Epidemiological studies indicated that exposure to these compounds caused neurodevelopmental disturbances such as learning disability and attention deficit hyperactivity disorder, which are thought to be closely related to dopaminergic dysfunction. Although the molecular mechanism of their actions has not been fully investigated, a major participant in the process is aryl hydrocarbon receptor (AhR. This study focused on the effect of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD exposure on the regulation of TH, a rate-limiting enzyme of dopamine synthesis, gene expression by AhR. Methods N2a-Rβ cells were established by transfecting murine neuroblastoma Neuro2a with the rat AhR cDNA. TH expression induced by TCDD was assessed by RT-PCR and Western blotting. Participation of AhR in TCDD-induced TH gene expression was confirmed by suppressing AhR expression using the siRNA method. Catecholamines including dopamine were measured by high-performance liquid chromatography. A reporter gene assay was used to identify regulatory motifs in the promoter region of TH gene. Binding of AhR with the regulatory motif was confirmed by an electrophoretic mobility shift assay (EMSA. Results Induction of TH by TCDD through AhR activation was detected at mRNA and protein levels. Induced TH protein was functional and its expression increased dopamine synthesis. The reporter gene assay and EMSA indicated that AhR directly regulated TH gene expression. Regulatory sequence called aryl hydrocarbon receptor responsive element III (AHRE-III was identified upstream of the TH gene from -285 bp to -167 bp. Under TCDD exposure, an AhR complex was bound to AHRE-III as well as the xenobiotic response element (XRE, though AHRE-III was not identical to XRE, the conventional AhR-binding motif. Conclusion Our results suggest TCDD directly regulate the dopamine system by TH gene

  1. 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

  2. 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.

  3. Sphingomonas wittichii Strain RW1 Genome-Wide Gene Expression Shifts in Response to Dioxins and Clay.

    Directory of Open Access Journals (Sweden)

    Benli Chai

    Full Text Available Sphingomonas wittichii strain RW1 (RW1 is one of the few strains that can grow on dibenzo-p-dioxin (DD. We conducted a transcriptomic study of RW1 using RNA-Seq to outline transcriptional responses to DD, dibenzofuran (DF, and the smectite clay mineral saponite with succinate as carbon source. The ability to grow on DD is rare compared to growth on the chemically similar DF even though the same initial dioxygenase may be involved in oxidation of both substrates. Therefore, we hypothesized the reason for this lies beyond catabolic pathways and may concern genes involved in processes for cell-substrate interactions such as substrate recognition, transport, and detoxification. Compared to succinate (SUC as control carbon source, DF caused over 240 protein-coding genes to be differentially expressed, whereas more than 300 were differentially expressed with DD. Stress response genes were up-regulated in response to both DD and DF. This effect was stronger with DD than DF, suggesting a higher toxicity of DD compared to DF. Both DD and DF caused changes in expression of genes involved in active cross-membrane transport such as TonB-dependent receptor proteins, but the patterns of change differed between the two substrates. Multiple transcription factor genes also displayed expression patterns distinct to DD and DF growth. DD and DF induced the catechol ortho- and the salicylate/gentisate pathways, respectively. Both DD and DF induced the shared down-stream aliphatic intermediate compound pathway. Clay caused category-wide down-regulation of genes for cell motility and chemotaxis, particularly those involved in the synthesis, assembly and functioning of flagella. This is an environmentally important finding because clay is a major component of soil microbes' microenvironment influencing local chemistry and may serve as a geosorbent for toxic pollutants. Similar to clay, DD and DF also affected expression of genes involved in motility and chemotaxis.

  4. Perinatal exposure to dioxins and dioxin-like compounds and infant growth and body mass index at seven years

    DEFF Research Database (Denmark)

    Iszatt, N.; Stigum, H; Govarts, Eva

    2016-01-01

    Background Dioxins and dioxin-like compounds are endocrine disrupting chemicals (EDCs). Experimental studies suggest perinatal exposure to EDCs results in later obesity. However, the few epidemiological investigations on dioxins are inconclusive. We investigated perinatal exposure to dioxins...... and dioxin-like compounds, infant growth and body mass index (BMI) in childhood. Methods We pooled data from 3 European birth cohorts (Belgian, Norwegian, Slovak) with exposure assessment in cord blood or breast milk. Two cohorts had dioxin-like toxicity assessed using dioxin-responsive chemical......-activated luciferase expression (DR-CALUX) bioassay and one cohort had measured concentrations of dioxins, furans and dioxin-like polychlorinated biphenols with CALUX relative potency values applied. Growth was cohort- and sex-specific change in weight-for-age z-score between birth and 24 months (N = 367). BMI...

  5. Dioxin emissions and sources

    International Nuclear Information System (INIS)

    1994-01-01

    The papers presented at the seminar discussed dioxin emissions and sources, dioxin pollution of soils, waste water and sewage sludge, stocktaking of emission sources, and exposure and risk analyses for dioxin and other pollutants. (EF) [de

  6. Dioxin-induced retardation of development through a reduction in the expression of pituitary hormones and possible involvement of an aryl hydrocarbon receptor in this defect: A comparative study using two strains of mice with different sensitivities to dioxin

    International Nuclear Information System (INIS)

    Takeda, Tomoki; Taura, Junki; Hattori, Yukiko; Ishii, Yuji; Yamada, Hideyuki

    2014-01-01

    We have previously revealed that treating pregnant rats with 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD) reduces the expression of gonadotropins and growth hormone (GH) in the fetal and neonatal pituitary. A change in gonadotropin expression impairs the testicular expression of steroidogenic proteins in perinatal pups, and imprint defects in sexual behavior after reaching maturity. In this study, we examined whether TCDD also affects the expression of gonadotropin and GH in mice using C57BL/6J and DBA/2J strains which express the aryl hydrocarbon receptor (Ahr) exhibiting a different affinity for TCDD. When pregnant C57BL/6J mice at gestational day (GD) 12 were given oral TCDD (0.2–20 μg/kg), all doses significantly attenuated the pituitary expression of gonadotropin mRNAs in fetuses at GD18. On the other hand, in DBA/2J mice, a much higher dose of TCDD (20 μg/kg) was needed to produce a significant attenuation. Such reduction in the C57BL/6J strain continued until at least postnatal day (PND) 4. In agreement with this, TCDD reduced the testicular expression of steroidogenic proteins in C57BL/6J neonates at PND2 and 4, although the same did not occur in the fetal testis and ovary. Furthermore, TCDD reduced the perinatal expression of GH, litter size and the body weight of newborn pups only in the C57BL/6J strain. These results suggest that 1) also in mice, maternal exposure to TCDD attenuates gonadotropin-regulated steroidogenesis and GH expression leading to the impairment of pup development and sexual immaturity; and 2) Ahr activation during the late fetal and early postnatal stages is required for these defects. - Highlights: • The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on mouse growth was studied. • TCDD reduced the levels of luteinizing hormone and growth hormone in perinatal pups. • Maternal exposure to TCDD also attenuated testicular steroidogenesis in pups. • The above effects of TCDD were more pronounced in C57BL/6J than in DBA/2J

  7. Dioxin-induced retardation of development through a reduction in the expression of pituitary hormones and possible involvement of an aryl hydrocarbon receptor in this defect: A comparative study using two strains of mice with different sensitivities to dioxin

    Energy Technology Data Exchange (ETDEWEB)

    Takeda, Tomoki; Taura, Junki; Hattori, Yukiko; Ishii, Yuji; Yamada, Hideyuki, E-mail: hyamada@phar.kyushu-u.ac.jp

    2014-08-01

    We have previously revealed that treating pregnant rats with 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD) reduces the expression of gonadotropins and growth hormone (GH) in the fetal and neonatal pituitary. A change in gonadotropin expression impairs the testicular expression of steroidogenic proteins in perinatal pups, and imprint defects in sexual behavior after reaching maturity. In this study, we examined whether TCDD also affects the expression of gonadotropin and GH in mice using C57BL/6J and DBA/2J strains which express the aryl hydrocarbon receptor (Ahr) exhibiting a different affinity for TCDD. When pregnant C57BL/6J mice at gestational day (GD) 12 were given oral TCDD (0.2–20 μg/kg), all doses significantly attenuated the pituitary expression of gonadotropin mRNAs in fetuses at GD18. On the other hand, in DBA/2J mice, a much higher dose of TCDD (20 μg/kg) was needed to produce a significant attenuation. Such reduction in the C57BL/6J strain continued until at least postnatal day (PND) 4. In agreement with this, TCDD reduced the testicular expression of steroidogenic proteins in C57BL/6J neonates at PND2 and 4, although the same did not occur in the fetal testis and ovary. Furthermore, TCDD reduced the perinatal expression of GH, litter size and the body weight of newborn pups only in the C57BL/6J strain. These results suggest that 1) also in mice, maternal exposure to TCDD attenuates gonadotropin-regulated steroidogenesis and GH expression leading to the impairment of pup development and sexual immaturity; and 2) Ahr activation during the late fetal and early postnatal stages is required for these defects. - Highlights: • The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on mouse growth was studied. • TCDD reduced the levels of luteinizing hormone and growth hormone in perinatal pups. • Maternal exposure to TCDD also attenuated testicular steroidogenesis in pups. • The above effects of TCDD were more pronounced in C57BL/6J than in DBA/2J

  8. 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.

  9. Dioxin Exposure Initiative

    Science.gov (United States)

    The Dioxin Exposure Initiative (DEI) is no longer active. This page contains a summary of the dioxin exposure initiative with illustrations, contact and background information.Originally supported by scientist Matthew Lorber, who retired in Mar 2017.

  10. 2,3,7,8-Tetrachlorodibenzo-p-dioxin induces apoptotic cell death and cytochrome P4501A expression in developing Fundulus heteroclitus embryos

    Science.gov (United States)

    Toomey, B.H.; Bello, S.; Hahn, M.E.; Cantrell, S.; Wright, P.; Tillitt, D.E.; Di Giulio, R.T.

    2001-01-01

    Fundulus heteroclitus embryos were exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during early development using nanoinjection or water bath exposure. TCDD caused developmental abnormalities that included hemorrhaging, loss of vascular integrity, edema, stunted development and death. The LC50 and LD50 of TCDD for Fundulus embryos were ???19.7??9.5 pg TCDD/??l (water bath) and 0.25??0.09 ng TCDD/g embryo (nanoinjection). To identify a possible cause for these developmental abnormalities we analyzed the effects of TCDD on apoptotic cell death and cytochrome P4501A (CYP1A) expression in the embryos. TCDD exposure increased apoptotic cell death in several tissues including brain, eye, gill, kidney, tail, intestine, heart, and vascular tissue. CYP1A expression was also increased in the TCDD-exposed embryos predominantly in liver, kidney, gill, heart, intestine, and in vascular tissues throughout the embryo. There was co-occurrence of TCDD-induced apoptosis and CYP1A expression in some, but not all, cell types. In addition the dose response relationships for apoptosis and mortality were similar, while CYP1A expression appeared more sensitive to TCDD induction. Copyright ?? 2001 Elsevier Science B.V.

  11. 2,3,7,8-tetrachlorodibenzo-p-dioxin decrease expression of aryl hydrocarbon receptor in peripheral lymphocyte of β-thalassemia major patients.

    Science.gov (United States)

    Ghatrehsamani, Mahdi; Soleimani, Masoud; Esfahani, Behjat Al-Sadat Moayedi; Hakemi, Mazdak Ganjalikhani; Shirzad, Hedayatollah; Eskandari, Nahid; Adib, Minoo

    2015-01-01

    β-thalassemia major is a hereditary disease with inefficient erythropoiesis. Level of inflammatory cytokine is elevated in these patients. In this study, we investigate the effect of aryl hydrocarbon receptor (AhR) ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), on the expression of inflammatory mediators in β-thalassemia major patient's lymphocytes. Peripheral blood mononuclear cells of patients and healthy participants was isolated and cultured in favor of lymphocytes increment. Based on the treatment, we divided the cell into four groups. The orders of group's treatments were no treatment, tumor necrosis factor-α (TNF-α) treatment, TNF-α and TCDD treatment, TCDD treatment in Group 1-4, respectively. After cell culture, we extracted the cells RNA and converted them to cDNA. Real-time polymerase chain reaction was performed to assessment relative expression of caspase-1, NLRP3, and AhR. We compared all patient groups with equal healthy (control) groups. Results showed that expression of caspase-1 in patients (Groups 1 and 2) was significantly lower than healthy individuals (P 0.05). Expression of AhR in other groups of patients (3 and 4) was significantly lower than control groups (P < 0.05). Expression of caspase-1 in Group 4 was significantly larger than the control group (P < 0.001). We show here that chronic inflammation decrease caspase-1 expression and exposure of human lymphocytes to TCDD promote caspase-1 expression. Furthermore, activation of AhR with TCDD decreases AhR expression in lymphocytes of β-thalassemia major disease.

  12. Low-dose dioxins alter gene expression related to cholesterol biosynthesis, lipogenesis, and glucose metabolism through the aryl hydrocarbon receptor-mediated pathway in mouse liver

    International Nuclear Information System (INIS)

    Sato, Shoko; Shirakawa, Hitoshi; Tomita, Shuhei; Ohsaki, Yusuke; Haketa, Keiichi; Tooi, Osamu; Santo, Noriaki; Tohkin, Masahiro; Furukawa, Yuji; Gonzalez, Frank J.; Komai, Michio

    2008-01-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a common environmental contaminant. TCDD binds and activates the transcription factor aryl hydrocarbon receptor (AHR), leading to adverse biological responses via the alteration of the expression of various AHR target genes. Although small amounts of TCDD are consumed via contaminated daily foodstuffs and environmental exposures, the effects of low-dose TCDD on gene expression in animal tissues have not been clarified, while a number of genes affected by high-dose TCDD were reported. In this study, we comprehensively analyzed gene expression profiles in livers of C57BL/6N mice that were orally administered relatively low doses of TCDD (5, 50, or 500 ng/kg body weight (bw) day -1 ) for 18 days. The hepatic TCDD concentrations, measured by gas chromatography-mass spectrometry, were 1.2, 17, and 1063 pg toxicity equivalent quantity (TEQ)/g, respectively. The mRNA level of the cytochrome P450 CYP1A1 was significantly increased by treatment with only TCDD 500 ng/kg bw day -1 . DNA microarray and quantitative RT-PCR analyses revealed changes in the expression of genes involved in the circadian rhythm, cholesterol biosynthesis, fatty acid synthesis, and glucose metabolism in the liver with at all doses of TCDD employed. However, repression of expression of genes involved in energy metabolism was not observed in the livers of Ahr-null mice that were administered the same dose of TCDD. These results indicate that changes in gene expression by TCDD are mediated by AHR and that exposure to low-dose TCDD could affect energy metabolism via alterations of gene expression

  13. Effects of short-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin on microRNA expression in zebrafish embryos

    International Nuclear Information System (INIS)

    Jenny, Matthew J.; Aluru, Neelakanteswar; Hahn, Mark E.

    2012-01-01

    Although many drugs and environmental chemicals are teratogenic, the mechanisms by which most toxicants disrupt embryonic development are not well understood. MicroRNAs, single-stranded RNA molecules of ∼ 22 nt that regulate protein expression by inhibiting mRNA translation and promoting mRNA sequestration or degradation, are important regulators of a variety of cellular processes including embryonic development and cellular differentiation. Recent studies have demonstrated that exposure to xenobiotics can alter microRNA expression and contribute to the mechanisms by which environmental chemicals disrupt embryonic development. In this study we tested the hypothesis that developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a well-known teratogen, alters microRNA expression during zebrafish development. We exposed zebrafish embryos to DMSO (0.1%) or TCDD (5 nM) for 1 h at 30 hours post fertilization (hpf) and measured microRNA expression using several methods at 36 and 60 hpf. TCDD caused strong induction of CYP1A at 36 hpf (62-fold) and 60 hpf (135-fold) as determined by real-time RT-PCR, verifying the effectiveness of the exposure. MicroRNA expression profiles were determined using microarrays (Agilent and Exiqon), next-generation sequencing (SOLiD), and real-time RT-PCR. The two microarray platforms yielded results that were similar but not identical; both showed significant changes in expression of miR-451, 23a, 23b, 24 and 27e at 60 hpf. Multiple analyses were performed on the SOLiD sequences yielding a total of 16 microRNAs as differentially expressed by TCDD in zebrafish embryos. However, miR-27e was the only microRNA to be identified as differentially expressed by all three methods (both microarrays, SOLiD sequencing, and real-time RT-PCR). These results suggest that TCDD exposure causes modest changes in expression of microRNAs, including some (miR-451, 23a, 23b, 24 and 27e) that are critical for hematopoiesis and cardiovascular

  14. Computational expressions for signals in frequency-modulation spectroscopy.

    Science.gov (United States)

    Di Rosa, Michael D; Reiten, M T

    2015-06-01

    General expressions for the signals in frequency-modulation spectroscopy (FMS) appear in the literature but are often reduced to simple analytical equations following the assumption of a weak modulation index. This is little help to the experimentalist who wants to predict signals for modulation depths of the order of unity or greater, where strong FMS signals reside. Here, we develop general formulas for FMS signals in the case of an absorber with a Voigt line shape and then link these expressions to an example and existing numerical code for the line shape. The resulting computational recipe is easy to implement and exercised here to show where the larger FMS signals are found over the coordinates of modulation index and modulation frequency. One can also estimate from provided curves the in-phase FMS signal over a wide range of modulation parameters at either the Lorentzian-broadening or Doppler-broadening limit, or anywhere in between by interpolation.

  15. Expression of the C-terminal family 22 carbohydratebinding module ...

    African Journals Online (AJOL)

    ... not reveal marked cell wall phenotype. In addition, there were no observable changes in the height or the appearance of the transgenic plants expressing the CBM22-2 module. The results indicate that the family 22 carbohydrate binding module is not a potential candidate for use in in planta modification of the cell wall.

  16. Dioxin in Danish air

    Energy Technology Data Exchange (ETDEWEB)

    Vikelsoe, J.; Andersen, H.V. [National Environmental Research Inst., Roskilde (Denmark)

    2004-09-15

    To gain more knowledge about dioxin levels, sources and emissions in Denmark, the Danish government year 2001 initiated the Danish Dioxin Monitoring Program. The program is a series of investigations, comprising soil, compost, percolate, bio-ash, incineration of municipal and hazardous waste, deposition, air, lake and fjord sediment as well as cows milk and human milk. The present paper describes the preliminary results for the continued investigation of air. Deposition of dioxin over land or sea is of major importance for the human exposure, which takes place mainly from food intake. The dioxin are emitted mainly to the atmosphere, therefore air measurements are well suited for tracking the transport and fate of dioxin from sources to exposure. Whereas measurements from chimneys has been frequently used to estimate the industrial emission from point sources such as incinerators, air measurements also include emission from diffuse sources such as larger urban or industrial regions, residential quarters, and from evaporation. Furthermore, emission measurements must be done on known sources, whereas air measurements include contribution from unknown source. The major drawbacks of air measurements are the long duration required (years), and the results depends on meteorological conditions, such as temperature, rainfall, wind speed and direction. The purpose of the present study has been to measure dioxins in Danish air, emphasizing - background concentrations and annual variation - difference between urban, rural and residential zones - influence from local sources and long range transport - connection between dioxin in air and deposition.

  17. Effect of dioxin on normal and leukemic human hematopoietic cells

    Energy Technology Data Exchange (ETDEWEB)

    Lambertenghi-Deliliers, G.; Soligo, D. [Univ. degli Studi, Milan (Italy). Dipt. die Ematologia, Ospedale Maggiore Policlinico IRCCS; Fracchiolla, N.S. [Ospedale Maggiore Policlinico IRCCS, Milan (Italy). Dipt. di Ematologia; Servida, F. [Fondazione Matarelli, Milan (Italy); Bertazzi, P.A. [Istituti Clinici di Perfezionamento, Milan (Italy). Dipt. di Medicina del Lavoro

    2004-09-15

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) arises from chlorination of phenolic substrates or from partial combustion of organic materials in the presence of chlorine sources. TCDD has a large number of biological effects such as long-lasting skin disease, cardiovascular disease, diabete and cancer. TCDD is the prototypical agonist of the aryl hydrocarbon receptor (AhR), a member of the erb-A family that also includes the receptors for steroids, thyroid hormones, peroxisome proliferators and retinoids. When bound to dioxin, the AhR can bind to DNA and alter the expression of some genes including cytokines and growth factors. In this study, we analyzed the effect of escalating doses of TCDD on human CD34{sup +} progenitor cells from the leukapheresis of normal donors stimulated with G-CSF as well as the human myeloid leukemic cell lines HL60 (promyelocytic leukemia) and K562 (chronic myelogenous leukemia). The possible specific modulation of gene expression induced by the TCDD exposure was then tested by means of microarray analyses.

  18. Dioxin and Dioxin-Like Compounds Toxic Equivalency Information

    Science.gov (United States)

    EPA requires that, in addition to the total grams released for the entire dioxin and dioxin-like compounds category, TRI facilities must report the quantity for each individual member on a new Form R Schedule 1.

  19. Enhancing the response of CALUX and CAFLUX cell bioassays for quantitative detection of dioxin-like compounds

    Science.gov (United States)

    ZHAO, Bin; BASTON, David S.; KHAN, Elaine; SORRENTINO, Claudio; DENISON, Michael S.

    2011-01-01

    Reporter genes produce a protein product in transfected cells that can be easily measured in intact or lysed cells and they have been extensively used in numerous basic and applied research applications. Over the past 10 years, reporter gene assays have been widely accepted and used for analysis of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related dioxin-like compounds in various types of matrices, such as biological, environmental, food and feed samples, given that high-resolution instrumental analysis techniques are impractical for large-scale screening analysis. The most sensitive cell-based reporter gene bioassay systems developed are the mechanism-based CALUX (Chemically Activated Luciferase Expression) and CAFLUX (Chemically Activated Fluorescent Expression) bioassays, which utilize recombinant cell lines containing stably transfected dioxin (AhR)-responsive firefly luciferase or enhanced green fluorescent protein (EGFP) reporter genes, respectively. While the current CALUX and CAFLUX bioassays are very sensitive, increasing their lower limit of sensitivity, magnitude of response and dynamic range for chemical detection would significantly increase their utility, particularly for those samples that contain low levels of dioxin-like HAHs (i.e., serum). In this study, we report that the addition of modulators of cell signaling pathways or modification of cell culture conditions results in significant improvement in the magnitude and overall responsiveness of the existing CALUX and CAFLUX cell bioassays. PMID:21394221

  20. Using the dioxin receptor-calux in vitro bioassay to screen marine harbor sediments for compounds with a dioxin-like mode of action

    NARCIS (Netherlands)

    Stronkhorst, J.; Leonards, P.E.G.; Murk, A.J.

    2002-01-01

    The presence of dioxin-like compounds in sediments from harbors and reference sites along the Dutch coast was investigated using the dioxin receptor–chemically activated luciferase gene expression (DR-CALUX) bioassay. The DR-CALUX response varied between 0.2 and 136 ng/kg dry weight expressed in

  1. Dioxins, furans and dioxin-like PCBs in human blood: causes or consequences of diabetic nephropathy?

    Science.gov (United States)

    Everett, Charles J; Thompson, Olivia M

    2014-07-01

    Nephropathy, or kidney disease, is a major, potential complication of diabetes. We assessed the association of 6 chlorinated dibenzo-p-dioxins, 9 chlorinated dibenzofurans and 8 polychlorinated biphenyls (PCBs) in blood with diabetic nephropathy in the 1999-2004 National Health and Nutrition Examination Survey (unweighted N=2588, population estimate=117,658,357). Diabetes was defined as diagnosed or undiagnosed (glycohemoglobin ≥ 6.5%) and nephropathy defined as urinary albumin to creatinine ratio >30 mg/g, representing microalbuminuria or macroalbuminuria. For the 8 chemicals analyzed separately, values above the 75th percentile were considered elevated, whereas for the other 15 compounds values above the maximum limit of detection were considered elevated. Seven of 8 dioxins and dioxin-like compounds, analyzed separately, were found to be associated with diabetic nephropathy. The chemicals associated with diabetic nephropathy were: 1,2,3,6,7,8-Hexachlorodibenzo-p-dioxin; 1,2,3,4,6,7,8,9-Octachlorodibenzo-p-dioxin; 2,3,4,7,8-Pentachlorodibenzofuran; PCB 126; PCB 169; PCB 118; and PCB 156. Three of the 8 dioxins and dioxin-like compounds; 1,2,3,4,6,7,8,9-Octachlorodibenzo-p-dioxin; 2,3,4,7,8-Pentachlorodibenzofuran and PCB 118; expressed as log-transformed continuous variables; were associated with diabetes without nephropathy. When 4 or more of the 23 chemicals were elevated the odds ratios were 7.00 (95% CI=1.80-27.20) for diabetic nephropathy and 2.13 (95% CI=0.95-4.78) for diabetes without nephropathy. Log-transformed toxic equivalency (TEQ) was associated with both diabetic nephropathy, and diabetes without nephropathy, the odds ratios were 2.35 (95% CI=1.57-3.52) for diabetic nephropathy, and 1.44 (95% CI=1.11-1.87) for diabetes without nephropathy. As the kidneys function to remove waste products from the blood, diabetic nephropathy could be either the cause or the consequence (or both) of exposure to dioxins, furans and dioxin-like PCBs. Copyright © 2014

  2. Dynamic modulation of phosphoprotein expression in ovarian cancer xenograft models

    International Nuclear Information System (INIS)

    Koussounadis, Antonis; Langdon, Simon P.; Um, Inhwa; Kay, Charlene; Francis, Kyle E.; Harrison, David J.; Smith, V. Anne

    2016-01-01

    The dynamic changes that occur in protein expression after treatment of a cancer in vivo are poorly described. In this study we measure the effect of chemotherapy over time on the expression of a panel of proteins in ovarian cancer xenograft models. The objective was to identify phosphoprotein and other protein changes indicative of pathway activation that might link with drug response. Two xenograft models, platinum-responsive OV1002 and platinum-unresponsive HOX424, were used. Treatments were carboplatin and carboplatin-paclitaxel. Expression of 49 proteins over 14 days post treatment was measured by quantitative immunofluorescence and analysed by AQUA. Carboplatin treatment in the platinum-sensitive OV1002 model triggered up-regulation of cell cycle, mTOR and DDR pathways, while at late time points WNT, invasion, EMT and MAPK pathways were modulated. Estrogen receptor-alpha (ESR1) and ERBB pathways were down-regulated early, within 24 h from treatment administration. Combined carboplatin-paclitaxel treatment triggered a more extensive response in the OV1002 model modulating expression of 23 of 49 proteins. Therefore the cell cycle and DDR pathways showed similar or more pronounced changes than with carboplatin alone. In addition to expression of pS6 and pERK increasing, components of the AKT pathway were modulated with pAKT increasing while its regulator PTEN was down-regulated early. WNT signaling, EMT and invasion markers were modulated at later time points. Additional pathways were also observed with the NFκB and JAK/STAT pathways being up-regulated. ESR1 was down-regulated as was HER4, while further protein members of the ERBB pathway were upregulated late. By contrast, in the carboplatin-unresponsive HOX 424 xenograft, carboplatin only modulated expression of MLH1 while carboplatin-paclitaxel treatment modulated ESR1 and pMET. Thirteen proteins were modulated by carboplatin and a more robust set of changes by carboplatin-paclitaxel. Early changes included

  3. Determination of relative assay response factors for toxic chlorinated and bromiated dioxins/furans using an enyme immunoassay (EIA) and a chemically-activated luciferase gene expression cell bioassay (CALUX)

    Science.gov (United States)

    Determination of dioxin-like activity requires knowledge of both the concentration and toxicity to evaluate the risk of adverse human health and environmental effects. The dioxin-like response of several polybrominated dibenzo-p-dioxins/furans (PBDDs/Fs) and polybrominated/chlori...

  4. Dioxin-like activity of brominated dioxins as individual compounds or mixtures in in vitro reporter gene assays with rat and mouse hepatoma cell lines.

    Science.gov (United States)

    Suzuki, G; Nakamura, M; Michinaka, C; Tue, N M; Handa, H; Takigami, H

    2017-10-01

    In vitro reporter gene assays detecting dioxin-like compounds have been developed and validated since the middle 1990's, and applied to the determination of dioxin-like activities in various samples for their risk management. Data on characterizing the potency of individual brominated dioxins and their activity in mixture with chlorinated dioxins are still limited on the cell-based assay. This study characterized the dioxin-like activities of the 32 brominated dioxins, such as polybrominated dibenzo-p-dioxins, polybrominated dibenzofurans (PBDFs), coplanar polybrominated biphenyls, mixed halogenated dibenzo-p-dioxins and dibenzofurans (PXDFs), as a sole component or in a mixture by DR-CALUX (dioxin-responsive chemically activated luciferase expression) using the rat hepatoma H4IIE cell line and XDS-CALUX (xenobiotic detection systems-chemically activated luciferase expression) assays using the mouse hepatoma H1L6.1 cell line. The 2,3,7,8-TCDD-relative potencies (REPs) of most of the brominated dioxins were within a factor of 10 of the WHO toxicity equivalency factor (WHO-TEF) for the chlorinated analogues. The REPs of a few PXDFs were an order of magnitude higher than the corresponding WHO-TEFs, indicating their toxicological importance. Results with reconstituted mixtures suggest that the activity of brominated and chlorinated dioxins in both CALUX assays was dose-additive. Thus, obtained results indicated the applicability of the CALUX assays as screening tools of brominated dioxins together with their chlorinated analogues. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on signal transduction pathway-related protein expression in liver and cerebrum of rhesus monkey

    Energy Technology Data Exchange (ETDEWEB)

    Ohta, Mari; Akema, Satoshi; Tsuzuki, Masami; Kubota, Shunichiro [Tokyo Univ. (Japan); Korenaga, Tatsumi; Fukusato, Toshio [Teikyo Univ. of School of Medicine, Tokyo (Japan); Asaoka, Kazuo [Kyoto Univ. (Japan); Murata, Nobuo [Teikyo Univ. of School of Medicine, Kawasaki (Japan); Nomizu, Motoyoshi [Hokkaido Univ., Sapporo (Japan); Arima, Akihiro [Shin Nippon Biomedical Laboratories, Ltd., Kagoshima (Japan)

    2004-09-15

    2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to produce a wide range of toxic and biochemical effects in experimental animals, including immunological dysfunctions, chloracne, tetragenecity and carcinogenesis. Recently, the potential impact of dioxins on neurological disorders with particular focus on attention deficit hyperactivity disorder (ADHD) are concerned. Although a lot of information is available from studies in rodents, not much is known of the low dose effects of TCDD in non-human primates. In higher animals, dioxins are metabolized slowly, as evidenced by the estimated TCDD half-life of 5.8 to 14.1 years. Therefore, it is necessary to investigate the long-term effects of TCDD on human health. Considering the pronounced species differences observed in some studies of TCDD, the studies using primates are needed for assessment of TCDD exposure on human health. We have been studying the metabolism and the effects of single administration of TCDD on pregnant monkey (F0) and F1 rhesus monkey. The focus of the present study is to study the effects of TCDD on signal transduction pathway-related protein levels in various organs, especially in liver and brain of F0 monkeys.

  6. Emotion Unchained: Facial Expression Modulates Gaze Cueing under Cognitive Load.

    Science.gov (United States)

    Pecchinenda, Anna; Petrucci, Manuel

    2016-01-01

    Direction of eye gaze cues spatial attention, and typically this cueing effect is not modulated by the expression of a face unless top-down processes are explicitly or implicitly involved. To investigate the role of cognitive control on gaze cueing by emotional faces, participants performed a gaze cueing task with happy, angry, or neutral faces under high (i.e., counting backward by 7) or low cognitive load (i.e., counting forward by 2). Results show that high cognitive load enhances gaze cueing effects for angry facial expressions. In addition, cognitive load reduces gaze cueing for neutral faces, whereas happy facial expressions and gaze affected object preferences regardless of load. This evidence clearly indicates a differential role of cognitive control in processing gaze direction and facial expression, suggesting that under typical conditions, when we shift attention based on social cues from another person, cognitive control processes are used to reduce interference from emotional information.

  7. Survey of serum concentrations of dioxins, furans, and coplanar polychlorinated biphenyls in a small non-random sample of U.S. residents

    Energy Technology Data Exchange (ETDEWEB)

    Grassman, J. [Brooklyn Coll. CUNY, Health and Nutrition Sciences, Brooklyn, New York, NY (United States); Patterson, D.G. Jr.; Needham, L.L. [National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA (United States); Spencer, D.L.; Masten, S.A. [Environmental Toxicology Program, National Inst. of Environmental Health Sciences, Research Triangle Park, NC (United States)

    2004-09-15

    This cross sectional assessment of serum dioxin concentrations was conducted as part of a larger study to examine the relationship between dioxin exposure and gene expression in peripheral blood mononuclear cells. Recent reports indicate that environmental levels of dioxins have declined since the mid-1980's. Except for the recent National Health and Nutrition Examination Survey (NHANES), there has been little systematic surveillance of serum dioxins levels in the US general population. Here, we report the serum concentrations of 22 congeners of dioxins and dioxin-like compounds and their relationship with age, sex, smoking, and meat consumption.

  8. In utero exposure to dioxins and dioxin-like compounds and anogenital distance in newborns and infants.

    Science.gov (United States)

    Vafeiadi, Marina; Agramunt, Silvia; Papadopoulou, Eleni; Besselink, Harrie; Mathianaki, Kleopatra; Karakosta, Polyxeni; Spanaki, Ariana; Koutis, Antonis; Chatzi, Leda; Vrijheid, Martine; Kogevinas, Manolis

    2013-01-01

    Anogenital distance in animals is used as a measure of fetal androgen action. Prenatal exposure to dioxins and dioxin-like compounds in rodents causes reproductive changes in male offspring and decreases anogenital distance. We assessed whether in utero exposure to dioxins and dioxin-like compounds adversely influences anogenital distance in newborns and young children (median age, 16 months; range, 1-31 months). We measured anogenital distance among participants of the "Rhea" mother-child cohort study in Crete and the Hospital del Mar (HMAR) cohort in Barcelona. Anogenital distance (AGD; anus to upper penis), anoscrotal distance (ASD; anus to scrotum), and penis width (PW) were measured in 119 newborn and 239 young boys; anoclitoral (ACD; anus to clitoris) and anofourchetal distance (AFD; anus to fourchette) were measured in 118 newborn and 223 young girls. We estimated plasma dioxin-like activity in maternal blood samples collected at delivery with the Dioxin-Responsive Chemically Activated LUciferase eXpression (DR CALUX®) bioassay. Anogenital distances were sexually dimorphic, being longer in males than females. Plasma dioxin-like activity was negatively associated with AGD in male newborns. The estimated change in AGD per 10 pg CALUX®-toxic equivalent/g lipid increase was -0.44 mm (95% CI: -0.80, -0.08) after adjusting for confounders. Negative but smaller and nonsignificant associations were observed for AGD in young boys. No associations were found in girls. Male infants may be susceptible to endocrine-disrupting effects of dioxins. Our findings are consistent with the experimental animal evidence used by the Food and Agriculture Organization/World Health Organization to set recommendations for human dioxin intake.

  9. Determination of relative assay response factors for toxic chlorinated and brominated dioxins/furans using an enzyme immunoassay (EIA) and a chemically-activated luciferase gene expression cell bioassay (CALUX).

    Science.gov (United States)

    Samara, Fatin; Gullett, Brian K; Harrison, Robert O; Chu, Andrew; Clark, George C

    2009-04-01

    Determination of toxic activity requires knowledge of both the concentration and toxicity to evaluate the risk for adverse human health and environmental effects. A chemically-activated luciferase gene expression cell bioassay system (CALUX) and an antibody-based method enzyme immunoassay (EIA) were used to detect the dioxin-like response of several polybrominated, polychlorinated, and polybrominated/chlorinated dibenzo-p-dioxins/furans (PBDDs/Fs, PCDDs/Fs, and PBCDDs/Fs, respectively). It has been suggested that the biological activity of the brominated and mixed bromo/chloro compounds is similar to their chlorinated analogues (measured by binding to the Ah receptor). PBDD/F, PCDD/F, and PBCDD/F laboratory standards exhibited biological activity ranging over three orders of magnitude. The highest relative potency (REP) values from CALUX analysis, when compared to 2,3,7,8-TCDD, were 2,3,7,8-TBDD at 0.99 (+/-0.07), 1,2,3,7,8-PeCDD at 0.69, and 2-Br-3,7,8-TriCDD at 0.72 (+/-0.02). Cross-reactivities were calculated using EIA for several PBDDs/Fs and PBCDDs. The highest percent cross-reactivity was found for 2,3,7,8-TBDD at 138 (+/-34%), and 2,3,7-TriBDD at 84 (+/-36%).

  10. Global deposition of airborne dioxin.

    Science.gov (United States)

    Booth, Shawn; Hui, Joe; Alojado, Zoraida; Lam, Vicky; Cheung, William; Zeller, Dirk; Steyn, Douw; Pauly, Daniel

    2013-10-15

    We present a global dioxin model that simulates one year of atmospheric emissions, transport processes, and depositions to the earth's terrestrial and marine habitats. We map starting emission levels for each land area, and we also map the resulting deposits to terrestrial and marine environments. This model confirms that 'hot spots' of deposition are likely to be in northern Europe, eastern North America, and in parts of Asia with the highest marine dioxin depositions being the northeast and northwest Atlantic, western Pacific, northern Indian Ocean and the Mediterranean. It also reveals that approximately 40% of airborne dioxin emissions are deposited to marine environments and that many countries in Africa receive more dioxin than they produce, which results in these countries being disproportionately impacted. Since human exposure to dioxin is largely through diet, this work highlights food producing areas that receive higher atmospheric deposits of dioxin than others. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. In Utero Exposure to Compounds with Dioxin-like Activity and Birth Outcomes

    DEFF Research Database (Denmark)

    Vafeiadi, Marina; Agramunt, Silvia; Pedersen, Marie

    2014-01-01

    BACKGROUND: Maternal exposure to dioxins and dioxin-like compounds may affect fetal growth and development. We evaluated the association between in utero dioxin-like activity and birth outcomes in a prospective European mother-child study. METHODS: We measured dioxin-like activity in maternal...... and cord blood plasma samples collected at delivery using the Dioxin-Responsive Chemically Activated LUciferase eXpression (DR CALUX) bioassay in 967 mother-child pairs, in Denmark, Greece, Norway, Spain, and England. Multiple linear regression models were used to investigate the associations with birth...... weight, gestational age, and head circumference. RESULTS: Plasma dioxin-like activity was higher in maternal sample than in cord samples. Birth weight was lower with medium (-58 g [95% confidence interval (CI) = -176 to 62]) and high (-82 g [-216 to 53]) tertiles of exposure (cord blood) compared...

  12. Functional modules by relating protein interaction networks and gene expression.

    Science.gov (United States)

    Tornow, Sabine; Mewes, H W

    2003-11-01

    Genes and proteins are organized on the basis of their particular mutual relations or according to their interactions in cellular and genetic networks. These include metabolic or signaling pathways and protein interaction, regulatory or co-expression networks. Integrating the information from the different types of networks may lead to the notion of a functional network and functional modules. To find these modules, we propose a new technique which is based on collective, multi-body correlations in a genetic network. We calculated the correlation strength of a group of genes (e.g. in the co-expression network) which were identified as members of a module in a different network (e.g. in the protein interaction network) and estimated the probability that this correlation strength was found by chance. Groups of genes with a significant correlation strength in different networks have a high probability that they perform the same function. Here, we propose evaluating the multi-body correlations by applying the superparamagnetic approach. We compare our method to the presently applied mean Pearson correlations and show that our method is more sensitive in revealing functional relationships.

  13. Dynamic zebrafish interactome reveals transcriptional mechanisms of dioxin toxicity.

    Directory of Open Access Journals (Sweden)

    Andrey Alexeyenko

    2010-05-01

    Full Text Available In order to generate hypotheses regarding the mechanisms by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin causes toxicity, we analyzed global gene expression changes in developing zebrafish embryos exposed to this potent toxicant in the context of a dynamic gene network. For this purpose, we also computationally inferred a zebrafish (Danio rerio interactome based on orthologs and interaction data from other eukaryotes.Using novel computational tools to analyze this interactome, we distinguished between dioxin-dependent and dioxin-independent interactions between proteins, and tracked the temporal propagation of dioxin-dependent transcriptional changes from a few genes that were altered initially, to large groups of biologically coherent genes at later times. The most notable processes altered at later developmental stages were calcium and iron metabolism, embryonic morphogenesis including neuronal and retinal development, a variety of mitochondria-related functions, and generalized stress response (not including induction of antioxidant genes. Within the interactome, many of these responses were connected to cytochrome P4501A (cyp1a as well as other genes that were dioxin-regulated one day after exposure. This suggests that cyp1a may play a key role initiating the toxic dysregulation of those processes, rather than serving simply as a passive marker of dioxin exposure, as suggested by earlier research.Thus, a powerful microarray experiment coupled with a flexible interactome and multi-pronged interactome tools (which are now made publicly available for microarray analysis and related work suggest the hypothesis that dioxin, best known in fish as a potent cardioteratogen, has many other targets. Many of these types of toxicity have been observed in mammalian species and are potentially caused by alterations to cyp1a.

  14. Dioxins, dioxin-like PCBs and non-dioxin-like PCBs in foodstuffs : occurrence and dietary intake in the Netherlands

    NARCIS (Netherlands)

    Baars, A.J.; Bakker, M.I.; Baumann, R.A.; Boon, P.E.; Freijer, J.I.; Hoogenboom, L.A.P.; Klaveren, van J.D.; Liem, A.K.D.; Traag, W.A.; Vries, de J.

    2004-01-01

    Data on occurrence of dioxins (polychlorinated dibenzo-p-dioxins [PCDDs] and dibenzofurans [PCDFs]), dioxin-like PCBs (polychlorinated non-ortho and mono-ortho biphenyls) and non-dioxin-like PCBs (as represented by the so-called indicator-PCBs: congeners 28, 52, 101, 118, 138, 153 and 180) in food

  15. Perinatal exposure to dioxins and dioxin-like compounds and infant growth and body mass index at seven years: A pooled analysis of three European birth cohorts.

    Science.gov (United States)

    Iszatt, Nina; Stigum, Hein; Govarts, Eva; Murinova, Lubica Palkovicova; Schoeters, Greet; Trnovec, Tomas; Legler, Juliette; Thomsen, Cathrine; Koppen, Gudrun; Eggesbø, Merete

    2016-09-01

    Dioxins and dioxin-like compounds are endocrine disrupting chemicals (EDCs). Experimental studies suggest perinatal exposure to EDCs results in later obesity. However, the few epidemiological investigations on dioxins are inconclusive. We investigated perinatal exposure to dioxins and dioxin-like compounds, infant growth and body mass index (BMI) in childhood. We pooled data from 3 European birth cohorts (Belgian, Norwegian, Slovak) with exposure assessment in cord blood or breast milk. Two cohorts had dioxin-like toxicity assessed using dioxin-responsive chemical-activated luciferase expression (DR-CALUX) bioassay and one cohort had measured concentrations of dioxins, furans and dioxin-like polychlorinated biphenols with CALUX relative potency values applied. Growth was cohort- and sex-specific change in weight-for-age z-score between birth and 24months (N=367). BMI was calculated at around 7years (median 7.17, interquartile range [IQR] 7.00-7.37years, N=251), and overweight defined according to international standards for children equivalent to adult BMI >25kg/m(2) (Cole and Lobstein, 2012). We fitted multivariate models using generalized estimating equations, and tested effect modification by sex, breastfeeding and cohort. Results per 10pgCALUXTEQ/g lipid increase in exposure. Dioxin exposure was highest in the Belgian and lowest in the Norwegian cohort; median (IQR) of the pooled sample 13 (12.0) pgCALUXTEQ/g lipid. Perinatal exposure to dioxins and dioxin-like compounds appeared associated with increased growth between 0 and 24months (adjusted estimate for change in z-score: β=0.07, 95% CI: -0.01, 0.14). At 7years, dioxins exposure was associated with a statistically significant increase in BMI in girls (adjusted estimate for BMI units β=0.49, 95% CI: 0.07, 0.91) but not in boys (β=-0.03, 95% CI: -0.55, 0.49) (p-interaction=0.044). Furthermore, girls had a 54% (-6%, 151%) increased risk of overweight at 7years (p-interaction=0.023). Perinatal exposure to

  16. Symbiont modulates expression of specific gene categories in Angomonas deanei

    Directory of Open Access Journals (Sweden)

    Luciana Loureiro Penha

    Full Text Available Trypanosomatids are parasites that cause disease in humans, animals, and plants. Most are non-pathogenic and some harbor a symbiotic bacterium. Endosymbiosis is part of the evolutionary process of vital cell functions such as respiration and photosynthesis. Angomonas deanei is an example of a symbiont-containing trypanosomatid. In this paper, we sought to investigate how symbionts influence host cells by characterising and comparing the transcriptomes of the symbiont-containing A. deanei (wild type and the symbiont-free aposymbiotic strains. The comparison revealed that the presence of the symbiont modulates several differentially expressed genes. Empirical analysis of differential gene expression showed that 216 of the 7625 modulated genes were significantly changed. Finally, gene set enrichment analysis revealed that the largest categories of genes that downregulated in the absence of the symbiont were those involved in oxidation-reduction process, ATP hydrolysis coupled proton transport and glycolysis. In contrast, among the upregulated gene categories were those involved in proteolysis, microtubule-based movement, and cellular metabolic process. Our results provide valuable information for dissecting the mechanism of endosymbiosis in A. deanei.

  17. Fear modulates visual awareness similarly for facial and bodily expressions

    Directory of Open Access Journals (Sweden)

    Bernard M.C. Stienen

    2011-11-01

    Full Text Available BackgroundSocial interaction depends on a multitude of signals carrying information about the emotional state of others. Past research has focused on the perception of facial expressions while perception of whole body signals has only been studied recently. The relative importance of facial and bodily signals is still poorly understood. In order to better understand the relative contribution of affective signals from the face only or from the rest of the body we used a binocular rivalry experiment. This method seems to be perfectly suitable to contrast two classes of stimuli to test our processing sensitivity to either stimulus and to address the question how emotion modulates this sensitivity. We report in this paper two behavioral experiments addressing these questions.MethodIn the first experiment we directly contrasted fearful, angry and neutral bodies and faces. We always presented bodies in one eye and faces in the other simultaneously for 60 seconds and asked participants to report what they perceived. In the second experiment we focused specifically on the role of fearful expressions of faces and bodies.ResultsTaken together the two experiments show that there is no clear bias towards either the face or body when the expression of the body and face are neutral or angry. However, the perceptual dominance in favor of either the face of the body is a function of the stimulus class expressing fear.

  18. Fetal exposure markers of dioxins and dioxin-like PCBs.

    Science.gov (United States)

    Lampa, Erik; Eguchi, Akifumi; Todaka, Emiko; Mori, Chisato

    2018-04-01

    Fetal exposure to polychlorinated biphenyls (PCBs), polychlorinated-p-dibenzodioxins (PCDDs), and polychlorinated dibenzofurans (PCDFs) have been associated with a number of adverse health outcomes. Although the placenta acts as a barrier between the mother and the fetus, these contaminants transfer through the placenta exposing the fetus. Several studies have investigated placental transfer, but few have assessed the co-variation among these contaminants. Maternal blood, cord blood, and cord tissue were collected from 41 Japanese mother-infant pairs and analyzed for dioxin-like PCBs and PCDD/Fs. Hierarchical cluster analysis followed by principal component analysis were used to assess the co-variation. Two stable clusters of dioxin-like PCBs were found in maternal and cord blood. One cluster of low/medium chlorinated dioxin-like PCBs was present in all three matrices with 2,3',4,4',5-PeCB(#118) and 3,3',4,4',5-PeCB(#126) explaining the majority of the clusters' variances. Medium/high chlorinated dioxin-like PCBs clustered in maternal blood and cord blood but not in cord tissue. 2,3,4,4',5-PeCB(#114) and 2,3,3',4,4',5,5'-HpCB(#189) explained the majority of the clusters' variances. There was a substantial correlation between the sum of dioxin-like PCBs and total PCDD/F in all three matrices. The sum of the four suggested PCBs plus 3,3',4,4'-TeCB(#77) correlated well with total PCDD/F in all three matrices. Apart from the dioxin-like PCBs, little co-variation existed among the studied contaminants. The five PCBs can be used as fetal exposure markers for dioxin and dioxin-like PCBs in maternal and cord blood respectively. In cord tissue, more higher chlorinated dioxin-like PCBs need to be measured as well.

  19. Troponin T isoform expression is modulated during Atlantic Halibut metamorphosis

    Directory of Open Access Journals (Sweden)

    Llewellyn Lynda

    2007-06-01

    Full Text Available Abstract Background Flatfish metamorphosis is a thyroid hormone (TH driven process which leads to a dramatic change from a symmetrical larva to an asymmetrical juvenile. The effect of THs on muscle and in particular muscle sarcomer protein genes is largely unexplored in fish. The change in Troponin T (TnT, a pivotal protein in the assembly of skeletal muscles sarcomeres and a modulator of calcium driven muscle contraction, during flatfish metamophosis is studied. Results In the present study five cDNAs for halibut TnT genes were cloned; three were splice variants arising from a single fast TnT (fTnT gene; a fourth encoded a novel teleost specific fTnT-like cDNA (AfTnT expressed exclusively in slow muscle and the fifth encoded the teleost specific sTnT2. THs modified the expression of halibut fTnT isoforms which changed from predominantly basic to acidic isoforms during natural and T4 induced metamorphosis. In contrast, expression of red muscle specific genes, AfTnT and sTnT2, did not change during natural metamorphosis or after T4 treatment. Prior to and after metamorphosis no change in the dorso-ventral symmetry or temporal-spatial expression pattern of TnT genes and muscle fibre organization occurred in halibut musculature. Conclusion Muscle organisation in halibut remains symmetrical even after metamorphosis suggesting TH driven changes are associated with molecular adaptations. We hypothesize that species specific differences in TnT gene expression in teleosts underlies different larval muscle developmental programs which better adapts them to the specific ecological constraints.

  20. Sarcoptes scabiei mites modulate gene expression in human skin equivalents.

    Directory of Open Access Journals (Sweden)

    Marjorie S Morgan

    Full Text Available The ectoparasitic mite, Sarcoptes scabiei that burrows in the epidermis of mammalian skin has a long co-evolution with its hosts. Phenotypic studies show that the mites have the ability to modulate cytokine secretion and expression of cell adhesion molecules in cells of the skin and other cells of the innate and adaptive immune systems that may assist the mites to survive in the skin. The purpose of this study was to identify genes in keratinocytes and fibroblasts in human skin equivalents (HSEs that changed expression in response to the burrowing of live scabies mites. Overall, of the more than 25,800 genes measured, 189 genes were up-regulated >2-fold in response to scabies mite burrowing while 152 genes were down-regulated to the same degree. HSEs differentially expressed large numbers of genes that were related to host protective responses including those involved in immune response, defense response, cytokine activity, taxis, response to other organisms, and cell adhesion. Genes for the expression of interleukin-1α (IL-1α precursor, IL-1β, granulocyte/macrophage-colony stimulating factor (GM-CSF precursor, and G-CSF precursor were up-regulated 2.8- to 7.4-fold, paralleling cytokine secretion profiles. A large number of genes involved in epithelium development and keratinization were also differentially expressed in response to live scabies mites. Thus, these skin cells are directly responding as expected in an inflammatory response to products of the mites and the disruption of the skin's protective barrier caused by burrowing. This suggests that in vivo the interplay among these skin cells and other cell types, including Langerhans cells, dendritic cells, lymphocytes and endothelial cells, is responsible for depressing the host's protective response allowing these mites to survive in the skin.

  1. Sarcoptes scabiei Mites Modulate Gene Expression in Human Skin Equivalents

    Science.gov (United States)

    Morgan, Marjorie S.; Arlian, Larry G.; Markey, Michael P.

    2013-01-01

    The ectoparasitic mite, Sarcoptes scabiei that burrows in the epidermis of mammalian skin has a long co-evolution with its hosts. Phenotypic studies show that the mites have the ability to modulate cytokine secretion and expression of cell adhesion molecules in cells of the skin and other cells of the innate and adaptive immune systems that may assist the mites to survive in the skin. The purpose of this study was to identify genes in keratinocytes and fibroblasts in human skin equivalents (HSEs) that changed expression in response to the burrowing of live scabies mites. Overall, of the more than 25,800 genes measured, 189 genes were up-regulated >2-fold in response to scabies mite burrowing while 152 genes were down-regulated to the same degree. HSEs differentially expressed large numbers of genes that were related to host protective responses including those involved in immune response, defense response, cytokine activity, taxis, response to other organisms, and cell adhesion. Genes for the expression of interleukin-1α (IL-1α) precursor, IL-1β, granulocyte/macrophage-colony stimulating factor (GM-CSF) precursor, and G-CSF precursor were up-regulated 2.8- to 7.4-fold, paralleling cytokine secretion profiles. A large number of genes involved in epithelium development and keratinization were also differentially expressed in response to live scabies mites. Thus, these skin cells are directly responding as expected in an inflammatory response to products of the mites and the disruption of the skin’s protective barrier caused by burrowing. This suggests that in vivo the interplay among these skin cells and other cell types, including Langerhans cells, dendritic cells, lymphocytes and endothelial cells, is responsible for depressing the host’s protective response allowing these mites to survive in the skin. PMID:23940705

  2. Personality traits modulate neural responses to emotions expressed in music.

    Science.gov (United States)

    Park, Mona; Hennig-Fast, Kristina; Bao, Yan; Carl, Petra; Pöppel, Ernst; Welker, Lorenz; Reiser, Maximilian; Meindl, Thomas; Gutyrchik, Evgeny

    2013-07-26

    Music communicates and evokes emotions. The number of studies on the neural correlates of musical emotion processing is increasing but few have investigated the factors that modulate these neural activations. Previous research has shown that personality traits account for individual variability of neural responses. In this study, we used functional magnetic resonance imaging (fMRI) to investigate how the dimensions Extraversion and Neuroticism are related to differences in brain reactivity to musical stimuli expressing the emotions happiness, sadness and fear. 12 participants (7 female, M=20.33 years) completed the NEO-Five Factor Inventory (NEO-FFI) and were scanned while performing a passive listening task. Neurofunctional analyses revealed significant positive correlations between Neuroticism scores and activations in bilateral basal ganglia, insula and orbitofrontal cortex in response to music expressing happiness. Extraversion scores were marginally negatively correlated with activations in the right amygdala in response to music expressing fear. Our findings show that subjects' personality may have a predictive power in the neural correlates of musical emotion processing and should be considered in the context of experimental group homogeneity. Copyright © 2013 Elsevier B.V. All rights reserved.

  3. 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.

  4. Risk assessments of polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, and dioxin-like polychlorinated biphenyls in food

    DEFF Research Database (Denmark)

    Larsen, John Christian

    2006-01-01

    -p-dioxin (TCDD). The toxic responses include dermal toxicity, immunotoxicity, carcinogenicity, and reproductive and developmental toxicity. Toxic equivalency factors have been established for the other PCDD, PCDF and dioxin-like PCB relative to TCDD, and the combined toxicity of a sample can be expressed...... as toxic equivalent (WHO-TEQ). The EC Scientific Committee for Food evaluated these compounds in 2001. The assessment used the most sensitive adverse toxicological end-points of TCDD in experimental animals. These were developmental and reproductive effects in the male offspring of rats administered TCDD......,3,7,8-substituted PCDD and PCDF, and the dioxin-like PCB, and expressed as a group tolerable weekly intake of 14 pg WHC-TEQ/kg bw. The FAO/WHO Joint Expert Committee on Food Additives (JECFA) performed a similar assessment whereas the US Environmental Protection Agency (US EPA) has paid more attention to human data...

  5. The dioxins in broad daylight; Les dioxines au grand jour

    Energy Technology Data Exchange (ETDEWEB)

    Claveri, B.; Mersch, J. [BioMonitor, 57 - Florange (France)

    2001-07-01

    In the framework of the Eco-Industries 2000 meeting, the ATEE organized a colloquium on the dioxins in the environment. This book presents the seven papers proposed at this colloquium bringing information on the dioxins and the furans molecular structure, their biological impacts on the environment, the monitoring and regulations in the domain and some example of remedial actions in the metal and wood industry. (A.L.B.)

  6. Multiple upstream modules regulate zebrafish myf5 expression

    Directory of Open Access Journals (Sweden)

    Weng Chih-Wei

    2007-01-01

    that the cell lineage-specific expression of myf5 is delicately orchestrated by multiple modules within the distal upstream region. This study provides an insight to understand the molecular control of myf5 and myogenesis in the zebrafish.

  7. A survey of dioxin-like contaminants in fish from recreational fishing.

    Science.gov (United States)

    Heimstad, Eldbjørg Sofie; Grønstøl, Gaute; Hetland, Karl Torstein; Alarcon, Javier Martinez; Rylander, Charlotta; Mariussen, Espen

    2015-08-01

    The dioxin and dioxin-like compounds are regarded as one of the most toxic group of environmental contaminants. Food for the commercial market is regularly monitored for their dioxin levels and the concentration allowed in food is strictly regulated. Less is known about locally caught fish from recreational fishing, which is often brought home for consumption. This can be fish caught from nearby lakes or streams or fish with marine origin close to industrial areas or harbours that are not regularly monitored for their dioxin levels. In this study, we established collaboration with schools in 13 countries. We received 203 samples of 29 different fish species of which Atlantic cod was the most abundant followed by brown trout and pollock. In general, the majority of samples from the participating countries had low concentrations (between 0.1 and 0.2 pg/g chemical-activated luciferase gene expression toxic equivalency wet weight (CALUX TEQ w.w.)) of dioxins and dioxin-like PCBs. Only 18 samples had concentrations above 1 pg/g CALUX TEQ w.w., and only 2 dab samples had concentration above maximum levels set by the European Commission. The Atlantic cod samples showed a significant reduction in the concentrations of dioxins with increasing latitude indicating less contamination of dioxin and dioxin-like compounds in the north of Norway. The results indicate that a moderate consumption of self-caught fish at presumed non-contaminated sites does not represent a major risk for exposure to dioxins or dioxin-like compounds at concentrations associated with adverse health effects. Recreational fishermen should, however, obtain knowledge about local fish consumption advice.

  8. Contact inhibition and interferon (IFN)-modulated gene expression

    Energy Technology Data Exchange (ETDEWEB)

    Kulesh, D.A.

    1986-01-01

    The relationship between cell morphology, proliferation and contact inhibition was studied in normal and malignant human cells which varied in their sensitivity to contact inhibition. Their ability to proliferate was examined under conditions where the cells were constrained into different shapes. Cell proliferation was quantitated by labeling indices, which were inferred by autoradiography, and by total cell counts. The normal cells (JHU-1, IMR-90) were dependent on cell shape for proliferation capability while the transformed cells (RT4, HT1080) were shape-dependent for proliferation. Interferon (IFN) induced shape-dependent proliferation and contact inhibition in the transformed cells when used at subantiproliferative concentrations. This ability of B-IFN to confer a level of proliferation control which is characteristic of normal fibroblasts suggests a possible relationship between gene expression mediated by IFN and those genes involved in the maintenance of regulated cell proliferation. To evaluate this possibility, cDNA libraries were constructed from IFN-treated and untreated HT1080 cells. The resulting 10 IFN-induced and 11 IFN-repressed sequences were then differentially rescreened using /sup 32/P-cDNA probes. This screening resulted in the identification of at least four cDNA sequences which appeared to be proliferation regulated as well as IFN-modulated. These cloned, regulated cDNA sequences were then used as /sup 32/P-labeled probes to study both the gene expression at the mRNA level employing Northern blotting and slot blotting techniques.

  9. Proteomic Profiling of the Dioxin-Degrading Bacterium Sphingomonas wittichii RW1

    Directory of Open Access Journals (Sweden)

    David R. Colquhoun

    2012-01-01

    Full Text Available Sphingomonas wittichii RW1 is a bacterium of interest due to its ability to degrade polychlorinated dioxins, which represent priority pollutants in the USA and worldwide. Although its genome has been fully sequenced, many questions exist regarding changes in protein expression of S. wittichii RW1 in response to dioxin metabolism. We used difference gel electrophoresis (DIGE and matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS to identify proteomic changes induced by growth on dibenzofuran, a surrogate for dioxin, as compared to acetate. Approximately 10% of the entire putative proteome of RW1 could be observed. Several components of the dioxin and dibenzofuran degradation pathway were shown to be upregulated, thereby highlighting the utility of using proteomic analyses for studying bioremediation agents. This is the first global protein analysis of a microorganism capable of utilizing the carbon backbone of both polychlorinated dioxins and dibenzofurans as the sole source for carbon and energy.

  10. Dioxin-like exposures and effects on estrogenic and androgenic exposures and micronuclei frequency in mother-newborn pairs

    DEFF Research Database (Denmark)

    Pedersen, Marie; Halldorsson, Thorhallur I; Mathiesen, Line

    2010-01-01

    In utero exposure to environmental dioxin-like, estrogen and androgen compounds can cause adverse health effects. Little is known about potential interactions in vivo between dioxin-like compounds, estrogens and androgens during fetal development in humans. Therefore we explored the potential...... interactions in vivo between dioxin-like compounds, estrogens, androgens using chemical-activated luciferase expression (CALUX)(R) bioassays in maternal and umbilical cord blood plasma concurrently collected at the time of planned Caesarean section from 98 healthy pregnancies. The dioxin-like activity was also...... determined after placental transfer of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the ex vivo human placenta perfusion system. Similar dioxin-like activity in maternal and cord blood (37 versus 33pg CALUX(R)-TEQ/g plasma lipids, P>0.05) was detected and it demonstrates transplacental transfer. Increased...

  11. Alteration of keratinocyte differentiation and senescence by the tumor promoter dioxin

    International Nuclear Information System (INIS)

    Ray, Soma S.; Swanson, Hollie I.

    2003-01-01

    Exposure to the environmental contaminant dioxin, elicits a variety of responses, which includes tumor promotion, embryotoxicity/teratogenesis, and carcinogenesis in both animals and humans. Many of the effects of dioxin are mediated by the aryl hydrocarbon receptor (AHR), a ligand-activated bHLH (basic helix-loop-helix)/PAS transcription factor. We initiated this study to determine whether dioxin's tumor-promoting activities may lie in its ability to alter proliferation, differentiation, and/or senescence using normal human epidermal keratinocytes (HEKs). Here, we report that dioxin appears to accelerate differentiation as measured by flow cytometry and by increased expression of the differentiation markers involucrin and filaggrin. In addition, dioxin appears to increase proliferation as indicated by an increase in NADH/NADPH production and changes in cell cycle. Finally, dioxin decreases SA (senescence associated) β-galactosidase staining, an indicator of senescence, in the differentiating keratinocytes. These changes were accompanied by decreases in the expression levels of key cell cycle regulatory proteins p53, p16 INK4a , and p14 ARF . Our findings support the idea that dioxin may exert its tumor-promoting actions, in part, by downregulating the expression levels of key tumor suppressor proteins, which may impair the cell's ability to maintain its appropriate cellular status

  12. AN ASSESSMENT OF DIOXIN LEVELS IN PROCESSED ...

    Science.gov (United States)

    The presence of dioxin-like compounds in ball clay was discovered in 1996 as a result of an investigation to determine the sources of elevated levels of dioxin found in two chicken fat samples from a national survey of poultry. The investigation indicated that soybean meal added to chicken feed was the source of dioxin contamination. Further investigation showed that the dioxin contamination came from the mixing of a natural clay known as

  13. Dioxin formation from waste incineration.

    Science.gov (United States)

    Shibamoto, Takayuki; Yasuhara, Akio; Katami, Takeo

    2007-01-01

    There has been great concern about dioxins-polychlorinated dibenzo dioxins (PCDDs), polychlorinated dibenzo furans (PCDFs), and polychlorinated biphenyls (PCBs)-causing contamination in the environment because the adverse effects of these chemicals on human health have been known for many years. Possible dioxin-contamination has received much attention recently not only by environmental scientists but also by the public, because dioxins are known to be formed during the combustion of industrial and domestic wastes and to escape into the environment via exhaust gases from incinerators. Consequently, there is a pressing need to investigate the formation mechanisms or reaction pathways of these chlorinated chemicals to be able to devise ways to reduce their environmental contamination. A well-controlled small-scale incinerator was used for the experiments in the core references of this review. These articles report the investigation of dioxin formation from the combustion of various waste-simulated samples, including different kinds of paper, various kinds of wood, fallen leaves, food samples, polyethylene (PE), polystyrene (PS), polyvinyl chloride (PVC), polyvinylidene chloride, polyethylene tetraphthalate (PET), and various kinds of plastic products. These samples were also incinerated with inorganic chlorides (NaCl, KCl, CuCI2, MgCl2, MnCl2, FeCl2, CoCl2, fly ash, and seawater) or organic chlorides (PVC, chlordane, and pentachlorophenol) to investigate the role of chlorine content and/or the presence of different metals in dioxin formation. Some samples, such as newspapers, were burned after they were impregnated with NaCl or PVC, as well as being cocombusted with chlorides. The roles of incineration conditions, including chamber temperatures, O2 concentrations, and CO concentrations, in dioxin formation were also investigated. Dioxins (PCDDs, PCDFs, and coplanar-PCBs) formed in the exhaust gases from a controlled small-scale incinerator, where experimental waste

  14. Co-expression modules construction by WGCNA and identify potential prognostic markers of uveal melanoma.

    Science.gov (United States)

    Wan, Qi; Tang, Jing; Han, Yu; Wang, Dan

    2018-01-01

    Uveal melanoma is an aggressive cancer which has a high percentage recurrence and with a worse prognosis. Identify the potential prognostic markers of uveal melanoma may provide information for early detection of recurrence and treatment. RNA sequence data of uveal melanoma and patient clinic traits were obtained from The Cancer Genome Atlas (TCGA) database. Co-expression modules were built by weighted gene co -expression network analysis (WGCNA) and applied to investigate the relationship underlying modules and clinic traits. Besides, functional enrichment analysis was performed on these co-expression genes from interested modules. First, using WGCNA, identified 21 co-expression modules were constructed by the 10975 genes from the 80 human uveal melanoma samples. The number of genes in these modules ranged from 42 to 5091. Found four co -expression modules significantly correlated with three clinic traits (status, recurrence and recurrence Time). Module red, and purple positively correlated with patient's life status and recurrence Time. Module green positively correlates with recurrence. The result of functional enrichment analysis showed that the module magenta was mainly enriched genetic material assemble processes, the purple module was mainly enriched in tissue homeostasis and melanosome membrane and the module red was mainly enriched metastasis of cell, suggesting its critical role in the recurrence and development of the disease. Additionally, identified the hug gene (top connectivity with other genes) in each module. The hub gene SLC17A7, NTRK2, ABTB1 and ADPRHL1 might play a vital role in recurrence of uveal melanoma. Our findings provided the framework of co-expression gene modules of uveal melanoma and identified some prognostic markers might be detection of recurrence and treatment for uveal melanoma. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. A single administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin that produces reduced food and water intake induces long-lasting expression of corticotropin-releasing factor, arginine vasopressin, and proopiomelanocortin in rat brain

    International Nuclear Information System (INIS)

    Moon, Bo-Hyun; Hong, Chang Gwun; Kim, Soo-Young; Kim, Hyun-Ju; Shin, Seung Keon; Kang, Seungwoo; Lee, Kuem-Ju; Kim, Yong-Ku; Lee, Min-Soo; Shin, Kyung-Ho

    2008-01-01

    The mechanism by which a single administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) reduces food and water intake is unclear. We examined whether such a food and water intake-reducing single administration of TCDD induced changes in corticotropin-releasing factor (CRF), arginine vasopressin (AVP), and proopiomelanocortin (POMC) expression in rat brain. To observe time-dependent changes in these neuropeptides, male Sprague-Dawley rats were given TCDD (50 μg/kg) and terminated 1, 2, 4, or 7 days later. In addition, to observe dose-dependent changes in feeding and neuropeptides, rats were also given a range of TCDD doses (12.5, 25, or 50 μg/kg) and terminated 14 days later. TCDD suppressed food and water intake over 14 days in a dose-dependent manner. TCDD treatment also increased CRF and POMC mRNA levels in the hypothalamic paraventricular nucleus (PVN) and arcuate nucleus, respectively, in a dose- and time-dependent manner. These increases were related to decreased food intake following TCDD administration. TCDD treatment increased AVP and CRF mRNA levels in the PVN, and these increases were related to decreased water intake. Interestingly, the increases in CRF, AVP and POMC expression were observed 7 to 14 days after TCDD administration. These results suggest that a single administration of TCDD induced long-lasting increases in CRF, AVP, and POMC mRNA levels in the hypothalamus and that these changes are related to reduced food and water intake 7 to 14 days after TCDD administration

  16. Dioxins, Furans and PCBs in Recycled Water for Indirect Potable Reuse

    Directory of Open Access Journals (Sweden)

    Clemencia Rodriguez

    2008-12-01

    Full Text Available An assessment of potential health impacts of dioxin and dioxin-like compounds in recycled water for indirect potable reuse was conducted. Toxic equivalency factors (TEFs for 2,3,7,8-substituted polychlorinated dibenzo-p-dioxins (PCDD and dibenzofurans (PCDFs and dioxin-like polychlorinated biphenyls (PCBs congeners have been developed by the World Health Organization to simplify the risk assessment of complex mixtures. Samples of secondary treated wastewater in Perth, Australia were examined pre-and post-tertiary treatment in one full-scale and one pilot water reclamation plant. Risk quotients (RQs were estimated by expressing the middle-bound toxic equivalent (TEQ and the upper-bound TEQ concentration in each sampling point as a function of the estimated health target value. The results indicate that reverse osmosis (RO is able to reduce the concentration of PCDD, PCDF and dioxin-like PCBs and produce water of high quality (RQ after RO=0.15. No increased human health risk from dioxin and dioxin-like compounds is anticipated if highly treated recycled water is used to augment drinking water supplies in Perth. Recommendations for a verification monitoring program are offered.

  17. Dioxins, Furans and PCBs in Recycled Water for Indirect Potable Reuse

    Science.gov (United States)

    Rodriguez, Clemencia; Cook, Angus; Devine, Brian; Van Buynder, Paul; Lugg, Richard; Linge, Kathryn; Weinstein, Philip

    2008-01-01

    An assessment of potential health impacts of dioxin and dioxin-like compounds in recycled water for indirect potable reuse was conducted. Toxic equivalency factors (TEFs) for 2,3,7,8-substituted polychlorinated dibenzo-p-dioxins (PCDD) and dibenzofurans (PCDFs) and dioxin-like polychlorinated biphenyls (PCBs) congeners have been developed by the World Health Organization to simplify the risk assessment of complex mixtures. Samples of secondary treated wastewater in Perth, Australia were examined pre-and post-tertiary treatment in one full-scale and one pilot water reclamation plant. Risk quotients (RQs) were estimated by expressing the middle-bound toxic equivalent (TEQ) and the upper-bound TEQ concentration in each sampling point as a function of the estimated health target value. The results indicate that reverse osmosis (RO) is able to reduce the concentration of PCDD, PCDF and dioxin-like PCBs and produce water of high quality (RQ after RO=0.15). No increased human health risk from dioxin and dioxin-like compounds is anticipated if highly treated recycled water is used to augment drinking water supplies in Perth. Recommendations for a verification monitoring program are offered. PMID:19151430

  18. Developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin alters DNA methyltransferase (dnmt) expression in zebrafish (Danio rerio)

    International Nuclear Information System (INIS)

    Aluru, Neelakanteswar; Kuo, Elaine; Helfrich, Lily W.; Karchner, Sibel I.; Linney, Elwood A.; Pais, June E.; Franks, Diana G.

    2015-01-01

    DNA methylation is one of the most important epigenetic modifications involved in the regulation of gene expression. The DNA methylation reaction is catalyzed by DNA methyltransferases (DNMTs). Recent studies have demonstrated that toxicants can affect normal development by altering DNA methylation patterns, but the mechanisms of action are poorly understood. Hence, we tested the hypothesis that developmental exposure to TCDD affects dnmt gene expression patterns. Zebrafish embryos were exposed to 5 nM TCDD for 1 h from 4 to 5 h post-fertilization (hpf) and sampled at 12, 24, 48, 72, and 96 hpf to determine dnmt gene expression and DNA methylation patterns. We performed a detailed analysis of zebrafish dnmt gene expression during development and in adult tissues. Our results demonstrate that dnmt3b genes are highly expressed in early stages of development, and dnmt3a genes are more abundant in later stages. TCDD exposure upregulated dnmt1 and dnmt3b2 expression, whereas dnmt3a1, 3b1, and 3b4 are downregulated following exposure. We did not observe any TCDD-induced differences in global methylation or hydroxymethylation levels, but the promoter methylation of aryl hydrocarbon receptor (AHR) target genes was altered. In TCDD-exposed embryos, AHR repressor a (ahrra) and c-fos promoters were differentially methylated. To characterize the TCDD effects on DNMTs, we cloned the dnmt promoters with xenobiotic response elements and conducted AHR transactivation assays using a luciferase reporter system. Our results suggest that ahr2 can regulate dnmt3a1, dnmt3a2, and dnmt3b2 expression. Overall, we demonstrate that developmental exposure to TCDD alters dnmt expression and DNA methylation patterns. - Highlights: • TCDD altered the dnmt expression in a gene and developmental time-specific manner. • TCDD hypermethylated ahrra and hypomethylated c-fos proximal promoter regions. • Functional analysis suggests that ahr2 can regulate dnmt3a1, 3a2, and 3b2 expression. • Dnmt

  19. Developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin alters DNA methyltransferase (dnmt) expression in zebrafish (Danio rerio)

    Energy Technology Data Exchange (ETDEWEB)

    Aluru, Neelakanteswar, E-mail: naluru@whoi.edu [Biology Department and Woods Hole Center for Oceans and Human Health, Woods Hole Oceanographic Institution, Woods Hole, MA 02543 (United States); Kuo, Elaine [Biology Department and Woods Hole Center for Oceans and Human Health, Woods Hole Oceanographic Institution, Woods Hole, MA 02543 (United States); Stanford University, 450 Serra Mall, Stanford, CA 94305 (United States); Helfrich, Lily W. [Biology Department and Woods Hole Center for Oceans and Human Health, Woods Hole Oceanographic Institution, Woods Hole, MA 02543 (United States); Northwestern University, 633 Clark St, Evanston, IL 60208 (United States); Karchner, Sibel I. [Biology Department and Woods Hole Center for Oceans and Human Health, Woods Hole Oceanographic Institution, Woods Hole, MA 02543 (United States); Linney, Elwood A. [Department of Molecular Genetics and Microbiology, Duke University Medical Center, Box 3020, Durham, NC 27710 (United States); Pais, June E. [New England Biolabs, 240 County Road, Ipswich, MA 01938 (United States); Franks, Diana G. [Biology Department and Woods Hole Center for Oceans and Human Health, Woods Hole Oceanographic Institution, Woods Hole, MA 02543 (United States)

    2015-04-15

    DNA methylation is one of the most important epigenetic modifications involved in the regulation of gene expression. The DNA methylation reaction is catalyzed by DNA methyltransferases (DNMTs). Recent studies have demonstrated that toxicants can affect normal development by altering DNA methylation patterns, but the mechanisms of action are poorly understood. Hence, we tested the hypothesis that developmental exposure to TCDD affects dnmt gene expression patterns. Zebrafish embryos were exposed to 5 nM TCDD for 1 h from 4 to 5 h post-fertilization (hpf) and sampled at 12, 24, 48, 72, and 96 hpf to determine dnmt gene expression and DNA methylation patterns. We performed a detailed analysis of zebrafish dnmt gene expression during development and in adult tissues. Our results demonstrate that dnmt3b genes are highly expressed in early stages of development, and dnmt3a genes are more abundant in later stages. TCDD exposure upregulated dnmt1 and dnmt3b2 expression, whereas dnmt3a1, 3b1, and 3b4 are downregulated following exposure. We did not observe any TCDD-induced differences in global methylation or hydroxymethylation levels, but the promoter methylation of aryl hydrocarbon receptor (AHR) target genes was altered. In TCDD-exposed embryos, AHR repressor a (ahrra) and c-fos promoters were differentially methylated. To characterize the TCDD effects on DNMTs, we cloned the dnmt promoters with xenobiotic response elements and conducted AHR transactivation assays using a luciferase reporter system. Our results suggest that ahr2 can regulate dnmt3a1, dnmt3a2, and dnmt3b2 expression. Overall, we demonstrate that developmental exposure to TCDD alters dnmt expression and DNA methylation patterns. - Highlights: • TCDD altered the dnmt expression in a gene and developmental time-specific manner. • TCDD hypermethylated ahrra and hypomethylated c-fos proximal promoter regions. • Functional analysis suggests that ahr2 can regulate dnmt3a1, 3a2, and 3b2 expression. • Dnmt

  20. Computational integration of homolog and pathway gene module expression reveals general stemness signatures.

    Directory of Open Access Journals (Sweden)

    Martina Koeva

    Full Text Available The stemness hypothesis states that all stem cells use common mechanisms to regulate self-renewal and multi-lineage potential. However, gene expression meta-analyses at the single gene level have failed to identify a significant number of genes selectively expressed by a broad range of stem cell types. We hypothesized that stemness may be regulated by modules of homologs. While the expression of any single gene within a module may vary from one stem cell type to the next, it is possible that the expression of the module as a whole is required so that the expression of different, yet functionally-synonymous, homologs is needed in different stem cells. Thus, we developed a computational method to test for stem cell-specific gene expression patterns from a comprehensive collection of 49 murine datasets covering 12 different stem cell types. We identified 40 individual genes and 224 stemness modules with reproducible and specific up-regulation across multiple stem cell types. The stemness modules included families regulating chromatin remodeling, DNA repair, and Wnt signaling. Strikingly, the majority of modules represent evolutionarily related homologs. Moreover, a score based on the discovered modules could accurately distinguish stem cell-like populations from other cell types in both normal and cancer tissues. This scoring system revealed that both mouse and human metastatic populations exhibit higher stemness indices than non-metastatic populations, providing further evidence for a stem cell-driven component underlying the transformation to metastatic disease.

  1. Effect of ARA9 on dioxin receptor mediated transcription

    International Nuclear Information System (INIS)

    Lees, M.J.; Whitelaw, M.L.

    2002-01-01

    The dioxin (Aryl hydrocarbon) receptor (DR) is a unique bHLH transcription factor which is activated by binding of planar aromatic hydrocarbons typified by dioxin (TCDD). The active receptor is key to metabolism of aryl hydrocarbon xenobiotics by being a potent inducer of CYP1A1 gene activity. Chlorinated dioxins are inert to metabolism and initiate multifarious toxicities, including potent tumour promotion. These ill-effects are mediated by the activated DR and we are studying the mechanisms by which the ligand binding domain of the DR controls activity of the protein. The DR ligand binding domain resides within a PAS (Per/Arnt/Sim homology) region which is contiguous with the bHLH. The latent bHLH/PAS dioxin receptor (DR) is found in the cytoplasm of most mammalian cell types in a complex with heat shock protein 90, a novel immunophilin like protein termed ARA9/XAP2/AIP, and the co-chaperone p23. Here we use antisense ARA9 constructs to reveal that in the absence of ARA9, the DR is unable to form a transcriptionally active complex. Co-expression of antisense ARA9 with a form of the DR which is constitutively targeted to the nucleus leads to dramatically decreased levels of the nuclear DR protein, implying that ARA9 may function beyond its currently proposed role in cytoplasmic retention of the latent DR

  2. Dioxins - essential characteristics. Pt. 3

    International Nuclear Information System (INIS)

    Brunn, H.

    1993-01-01

    'The dioxins' is the name of a large family of environmentally significant chemicals which, being stereoisomers of 2,3,7,8 TCDD, are all assumed to have similar effects. They include PCDD, PCDF, PBDD, PBDF, and possibly also a whole number of PCBs. Altogether, average ingestion of dioxins and furans in Germany amounts to a toxicity equivalent of 93.5 pg TCDD per person and day, 24.6 pg of which are 2,3,7,8 TCDD. Assuming the average weight of an adult to be 70 kg, this means an average ingestion of 1.3 pg TE/kg body weight and day. Fuerst et al. obtained similar results in their study on dioxin ingestion, average daily intake of dioxins and furans amounting to 85 pg TE per person. This is equivalent to an intake of 1.2 pg TE/kg body weight and day. Breaking down daily PCDD and PCDF intake by food category, the authors obtained the following data: Meat and meat products (beef, veal pork, chicken): 27.5 pg TE/person and day; fish and fish products 27 pg TE/person and day; milk and dairy products (milk, cheese, butter) 26.9 pg TE/person and day; vegetable oils (salad oil, margarine) 3.8 pg TE/person and day. This amounts to an overall intake of 85 pg TE/person and day. (orig./EF) [de

  3. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces matrix metalloproteinase (MMP) expression and invasion in A2058 melanoma cells

    International Nuclear Information System (INIS)

    Villano, C.M.; Murphy, K.A.; Akintobi, A.; White, L.A.

    2006-01-01

    There has been a 34% increase in melanoma related mortality in the United States from 1973 to 1992. Although few successful treatments for malignant melanoma exist, it is known that genetic susceptibility and environmental factors contribute to the initiation and progression of melanoma. Excessive UV exposure is considered the main etiological factor in melanoma initiation, however, epidemiological and experimental evidence suggests that exposure to environmental carcinogens contribute to melanoma. We propose that exposure to environmental chemicals that activate the aryl hydrocarbon receptor pathway contribute to melanoma progression, specifically through stimulation of the expression and activity of the matrix metalloproteinases (MMPs). Therefore, we investigated the effect of AhR activation on normal human melanocytes and several melanoma cell lines. The data presented here demonstrate that normal melanocytes and melanoma cells express the AhR and Arnt and are responsive to activation by TCDD. Furthermore, activation of this pathway in transformed melanoma cells (A2058) results in increased expression and activity of MMP-1, MMP-2 and MMP-9, as well as increased invasion using in vitro invasion assays. Furthermore, TCDD-induced expression of the MMP-1 promoter in melanoma cells appears to require different elements than those required in untransformed cells, indicating that this pathway may have multiple mechanisms for activation of MMP expression

  4. Epigenetic Editing: targeted rewriting of epigenetic marks to modulate expression of selected target genes.

    NARCIS (Netherlands)

    de Groote, M.L.; Verschure, P.J.; Rots, M.G.

    2012-01-01

    Despite significant advances made in epigenetic research in recent decades, many questions remain unresolved, especially concerning cause and consequence of epigenetic marks with respect to gene expression modulation (GEM). Technologies allowing the targeting of epigenetic enzymes to predetermined

  5. Epigenetic Editing : targeted rewriting of epigenetic marks to modulate expression of selected target genes

    NARCIS (Netherlands)

    de Groote, Marloes L.; Verschure, Pernette J.; Rots, Marianne G.

    2012-01-01

    Despite significant advances made in epigenetic research in recent decades, many questions remain unresolved, especially concerning cause and consequence of epigenetic marks with respect to gene expression modulation (GEM). Technologies allowing the targeting of epigenetic enzymes to predetermined

  6. AKIP1 expression modulates mitochondrial function in rat neonatal cardiomyocytes

    NARCIS (Netherlands)

    Yu, Hongjuan; Tigchelaar, Wardit; Koonen, Debby P. Y.; Patel, Hemal H.; de Boer, Rudolf A.; van Gilst, Wiek H.; Westenbrink, B. Daan; Sillje, Herman H. W.

    2013-01-01

    A kinase interacting protein 1 (AKIP1) is a molecular regulator of protein kinase A and nuclear factor kappa B signalling. Recent evidence suggests AKIP1 is increased in response to cardiac stress, modulates acute ischemic stress response, and is localized to mitochondria in cardiomyocytes. The

  7. Expression of an expansin carbohydrate-binding module affects ...

    African Journals Online (AJOL)

    Expansins are believed to be involved in disrupting the non-covalent adhesion of cellulose to matrix polysaccharides, thereby promoting wall creep. We have targeted a putative potato expansin (EXPA) carbohydrate-binding module (CBM) to the cell walls of tobacco plants. Histological examinations and electron ...

  8. Reproduction of European eel jeopardised by high levels of dioxins and dioxin-like PCBs?

    Science.gov (United States)

    Geeraerts, C; Focant, J-F; Eppe, G; De Pauw, E; Belpaire, C

    2011-09-01

    Dioxins, furans and dioxin-like polychlorinated biphenyls (PCBs) were analysed in muscle tissue from yellow phased European eel (Anguilla anguilla) from 38 sites in Belgium. Dioxin concentrations in eel vary considerably between sampling locations, indicating that yellow eel is a good indicator of local pollution levels. Measured levels of dioxin-like PCBs are much higher than those of the dioxins and furans. In the majority of the sites, eel has levels considered to be detrimental for their reproduction. Field levels of dioxin and dioxin-like PCBs are therefore suggested as an additional causal factor contributing to the decline of the European eel. 42% of the sampling sites show especially dioxin-like PCB levels exceeding the European consumption level (with a factor 3 on average). Human consumption of eel, especially in these highly contaminated sites, seems unjustified. Copyright © 2011 Elsevier B.V. All rights reserved.

  9. Human exposure to dioxin from combustion sources

    International Nuclear Information System (INIS)

    Hattemer-Frey, H.A.; Travis, C.C.

    1988-01-01

    Because of their extreme toxicity, much concern and debate has arisen about the nature and extent of human exposure to dioxin. Since municipal solid waste (MSW) incinerators are known to emit polychorinated dibenzo-p-dioxins (PCDDs) and polycholorinated dibenzofurnas (PCDFs) many people who live near MSW incinerators fear that they will be exposed to high levels of dioxin and subsequently develop cancer. What is often overlooked in this debate, however, is the fact that the general population is continuously being exposed to trace amounts of dioxin as exemplified by the fact that virtually all human adipose tissue samples contain dioxin at levels of 3 parts per trillion (ppt) or greater. This paper provides a perspective on MSW incineration as a source of human exposure to dioxin by comparing this exposure source with exposure to background environmental contamination and evaluates some of the potential key sources of PCDD/PCDF input into the enviroment. 32 refs., 3 tabs

  10. Software for Data Acquisition AMC Module with PCI Express Interface

    CERN Document Server

    Szachowalow, S; Makowski, D; Butkowski, L

    2010-01-01

    Free Electron Laser in Hamburg (FLASH) and XRay Free Electron Laser (XFEL) are linear accelerators that require a complex and accurate Low Level Radio Frequency (LLRF) control system. Currently working systems are based on aged Versa Module Eurocard (VME) architecture. One of the alternatives for the VME bus is the Advanced Telecommunications and Computing Architecture (ATCA) standard. The ATCA based LLRF controller mainly consists of a few ATCA carrier boards and several Advanced Mezzanine Cards (AMC). AMC modules are available in variety of functions such as: ADC, DAC, data storage, data links and even CPU cards. This paper focuses on the software that allows user to collect and plot the data from commercially available TAMC900 board.

  11. A fuzzy network module extraction technique for gene expression data

    Indian Academy of Sciences (India)

    2014-05-01

    expression network from the distance matrix. The distance matrix is .... mental process, cellular component assembly involved in ..... the molecules are present in the network. User can ... hsa05213:Endometrial cancer. 24. 0.07.

  12. Maternal diet, prenatal exposure to dioxin-like compounds and birth outcomes in a European prospective mother-child study (NewGeneris).

    Science.gov (United States)

    Papadopoulou, Eleni; Kogevinas, Manolis; Botsivali, Maria; Pedersen, Marie; Besselink, Harrie; Mendez, Michelle A; Fleming, Sarah; Hardie, Laura J; Knudsen, Lisbeth E; Wright, John; Agramunt, Silvia; Sunyer, Jordi; Granum, Berit; Gutzkow, Kristine B; Brunborg, Gunnar; Alexander, Jan; Meltzer, Helle Margrete; Brantsæter, Anne Lise; Sarri, Katerina; Chatzi, Leda; Merlo, Domenico F; Kleinjans, Jos C; Haugen, Margaretha

    2014-06-15

    Maternal diet can result in exposure to environmental contaminants including dioxins which may influence foetal growth. We investigated the association between maternal diet and birth outcomes by defining a dioxin-rich diet. We used validated food frequency questionnaires to assess the diet of pregnant women from Greece, Spain, United Kingdom, Denmark and Norway and estimated plasma dioxin-like activity by the Dioxin-Responsive Chemically Activated LUciferase eXpression (DR-CALUX®) bioassay in 604 maternal blood samples collected at delivery. We applied reduced rank regression to identify a dioxin-rich dietary pattern based on dioxin-like activity (DR-CALUX®) levels in maternal plasma, and calculated a dioxin-diet score as an estimate of adherence to this dietary pattern. In the five country population, dioxin-diet score was characterised by high consumption of red and white meat, lean and fatty fish, low-fat dairy and low consumption of salty snacks and high-fat cheese, during pregnancy. The upper tertile of the dioxin-diet score was associated with a change in birth weight of -121g (95% confidence intervals: -232, -10g) compared to the lower tertile after adjustment for confounders. A small non-significant reduction in gestational age was also observed (-1.4days, 95% CI: -3.8, 1.0days). Our results suggest that maternal diet might contribute to the exposure of the foetus to dioxins and dioxin-like compounds and may be related to reduced birth weight. More studies are needed to develop updated dietary guidelines for women of reproductive age, aiming to the reduction of dietary exposure to persistent organic pollutants as dioxins and dioxin-like compounds. Copyright © 2014 Elsevier B.V. All rights reserved.

  13. Network statistics of genetically-driven gene co-expression modules in mouse crosses

    Directory of Open Access Journals (Sweden)

    Marie-Pier eScott-Boyer

    2013-12-01

    Full Text Available In biology, networks are used in different contexts as ways to represent relationships between entities, such as for instance interactions between genes, proteins or metabolites. Despite progress in the analysis of such networks and their potential to better understand the collective impact of genes on complex traits, one remaining challenge is to establish the biologic validity of gene co-expression networks and to determine what governs their organization. We used WGCNA to construct and analyze seven gene expression datasets from several tissues of mouse recombinant inbred strains (RIS. For six out of the 7 networks, we found that linkage to module QTLs (mQTLs could be established for 29.3% of gene co-expression modules detected in the several mouse RIS. For about 74.6% of such genetically-linked modules, the mQTL was on the same chromosome as the one contributing most genes to the module, with genes originating from that chromosome showing higher connectivity than other genes in the modules. Such modules (that we considered as genetically-driven had network statistic properties (density, centralization and heterogeneity that set them apart from other modules in the network. Altogether, a sizeable portion of gene co-expression modules detected in mouse RIS panels had genetic determinants as their main organizing principle. In addition to providing a biologic interpretation validation for these modules, these genetic determinants imparted on them particular properties that set them apart from other modules in the network, to the point that they can be predicted to a large extent on the basis of their network statistics.

  14. Dioxins in processes of incineration of wastes

    International Nuclear Information System (INIS)

    Perez John; Espinel Jorge; Ocampo Alonso; Londono Carlos

    2001-01-01

    This paper is a door to come into the subject of dioxins, which is a little bit known in Colombia. In this way, in order to clarify and to get a wider knowledge about dioxins and waste incineration process, it has been divided in three main sections. The first one gives a basic information about origin, effects on the human health and a chemical definition of dioxins; in the second one the main kind of incinerator processes are given to know, also a deeper knowledge of reaction formation. The last part emphasizes options to control dioxins emissions in incineration systems

  15. Radiolytic decomposition of dioxins in liquid wastes

    International Nuclear Information System (INIS)

    Zhao Changli; Taguchi, M.; Hirota, K.; Takigami, M.; Kojima, T.

    2006-01-01

    The dioxins including polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) are some of the most toxic persistent organic pollutants. These chemicals have widely contaminated the air, water, and soil. They would accumulate in the living body through the food chains, leading to a serious public health hazard. In the present study, radiolytic decomposition of dioxins has been investigated in liquid wastes, including organic waste and waste-water. Dioxin-containing organic wastes are commonly generated in nonane or toluene. However, it was found that high radiation doses are required to completely decompose dioxins in the two solvents. The decomposition was more efficient in ethanol than in nonane or toluene. The addition of ethanol to toluene or nonane could achieve >90% decomposition of dioxins at the dose of 100 kGy. Thus, dioxin-containing organic wastes can be treated as regular organic wastes after addition of ethanol and subsequent γ-ray irradiation. On the other hand, radiolytic decomposition of dioxins easily occurred in pure-water than in waste-water, because the reaction species is largely scavenged by the dominant organic materials in waste-water. Dechlorination was not a major reaction pathway for the radiolysis of dioxin in water. In addition, radiolytic mechanism and dechlorinated pathways in liquid wastes were also discussed. (authors)

  16. Mere social categorization modulates identification of facial expressions of emotion.

    Science.gov (United States)

    Young, Steven G; Hugenberg, Kurt

    2010-12-01

    The ability of the human face to communicate emotional states via facial expressions is well known, and past research has established the importance and universality of emotional facial expressions. However, recent evidence has revealed that facial expressions of emotion are most accurately recognized when the perceiver and expresser are from the same cultural ingroup. The current research builds on this literature and extends this work. Specifically, we find that mere social categorization, using a minimal-group paradigm, can create an ingroup emotion-identification advantage even when the culture of the target and perceiver is held constant. Follow-up experiments show that this effect is supported by differential motivation to process ingroup versus outgroup faces and that this motivational disparity leads to more configural processing of ingroup faces than of outgroup faces. Overall, the results point to distinct processing modes for ingroup and outgroup faces, resulting in differential identification accuracy for facial expressions of emotion. PsycINFO Database Record (c) 2010 APA, all rights reserved.

  17. Isomer pattern and elimination of dioxins in workers exposed at a municipal waste incineration plant

    Science.gov (United States)

    YAMAMOTO, Kenya; KUDO, Mitsuhiro; ARITO, Heihachiro; OGAWA, Yasutaka; TAKATA, Tsutomu

    2015-01-01

    The aim of this study was to clarify patterns of serum concentrations of dioxins in the employees of a waste incineration plant and to estimate elimination rates and half-lives of serum dioxin isomers, and the maximum serum concentrations of dioxin isomers at the time of plant shutdown. Sixteen subjects participating 3 times or more in annual health examinations during an 8-yr period from 2000 to 2007 were recruited for this study. Serum concentrations of dioxins expressed as TEQ/g lipid decreased gradually after plant shutdown with the highest decrease observed in polychlorinated dibenzofurans (PCDFs) followed by polychlorinated deibenzo-p-dioxins (PCDDs) and then coplanar PCBs. The serum toxic equivalency (TEQ) concentrations of PCDF and PCDD congeners in the employees were higher than those in the general population survey by the Ministry of the Environment, Japan, whereas the serum concentrations of coplanar PCBs were similar to those in the general population. The estimated half-lives and elimination rates of PCDDs and PCDFs in the highly exposed workers increased compared with the moderately exposed workers. The estimated geometric mean serum concentrations of PCDDs, PCDFs and total dioxins at the time of plant shutdown were 35, 53 and 107 pg TEQ/g lipid, respectively. PMID:26118856

  18. Characterization of chemically induced liver injuries using gene co-expression modules.

    Directory of Open Access Journals (Sweden)

    Gregory J Tawa

    Full Text Available Liver injuries due to ingestion or exposure to chemicals and industrial toxicants pose a serious health risk that may be hard to assess due to a lack of non-invasive diagnostic tests. Mapping chemical injuries to organ-specific damage and clinical outcomes via biomarkers or biomarker panels will provide the foundation for highly specific and robust diagnostic tests. Here, we have used DrugMatrix, a toxicogenomics database containing organ-specific gene expression data matched to dose-dependent chemical exposures and adverse clinical pathology assessments in Sprague Dawley rats, to identify groups of co-expressed genes (modules specific to injury endpoints in the liver. We identified 78 such gene co-expression modules associated with 25 diverse injury endpoints categorized from clinical pathology, organ weight changes, and histopathology. Using gene expression data associated with an injury condition, we showed that these modules exhibited different patterns of activation characteristic of each injury. We further showed that specific module genes mapped to 1 known biochemical pathways associated with liver injuries and 2 clinically used diagnostic tests for liver fibrosis. As such, the gene modules have characteristics of both generalized and specific toxic response pathways. Using these results, we proposed three gene signature sets characteristic of liver fibrosis, steatosis, and general liver injury based on genes from the co-expression modules. Out of all 92 identified genes, 18 (20% genes have well-documented relationships with liver disease, whereas the rest are novel and have not previously been associated with liver disease. In conclusion, identifying gene co-expression modules associated with chemically induced liver injuries aids in generating testable hypotheses and has the potential to identify putative biomarkers of adverse health effects.

  19. Affective priming using facial expressions modulates liking for abstract art.

    Science.gov (United States)

    Flexas, Albert; Rosselló, Jaume; Christensen, Julia F; Nadal, Marcos; Olivera La Rosa, Antonio; Munar, Enric

    2013-01-01

    We examined the influence of affective priming on the appreciation of abstract artworks using an evaluative priming task. Facial primes (showing happiness, disgust or no emotion) were presented under brief (Stimulus Onset Asynchrony, SOA = 20 ms) and extended (SOA = 300 ms) conditions. Differences in aesthetic liking for abstract paintings depending on the emotion expressed in the preceding primes provided a measure of the priming effect. The results showed that, for the extended SOA, artworks were liked more when preceded by happiness primes and less when preceded by disgust primes. Facial expressions of happiness, though not of disgust, exerted similar effects in the brief SOA condition. Subjective measures and a forced-choice task revealed no evidence of prime awareness in the suboptimal condition. Our results are congruent with findings showing that the affective transfer elicited by priming biases evaluative judgments, extending previous research to the domain of aesthetic appreciation.

  20. Affective priming using facial expressions modulates liking for abstract art.

    Directory of Open Access Journals (Sweden)

    Albert Flexas

    Full Text Available We examined the influence of affective priming on the appreciation of abstract artworks using an evaluative priming task. Facial primes (showing happiness, disgust or no emotion were presented under brief (Stimulus Onset Asynchrony, SOA = 20 ms and extended (SOA = 300 ms conditions. Differences in aesthetic liking for abstract paintings depending on the emotion expressed in the preceding primes provided a measure of the priming effect. The results showed that, for the extended SOA, artworks were liked more when preceded by happiness primes and less when preceded by disgust primes. Facial expressions of happiness, though not of disgust, exerted similar effects in the brief SOA condition. Subjective measures and a forced-choice task revealed no evidence of prime awareness in the suboptimal condition. Our results are congruent with findings showing that the affective transfer elicited by priming biases evaluative judgments, extending previous research to the domain of aesthetic appreciation.

  1. AKIP1 expression modulates mitochondrial function in rat neonatal cardiomyocytes.

    Directory of Open Access Journals (Sweden)

    Hongjuan Yu

    Full Text Available A kinase interacting protein 1 (AKIP1 is a molecular regulator of protein kinase A and nuclear factor kappa B signalling. Recent evidence suggests AKIP1 is increased in response to cardiac stress, modulates acute ischemic stress response, and is localized to mitochondria in cardiomyocytes. The mitochondrial function of AKIP1 is, however, still elusive. Here, we investigated the mitochondrial function of AKIP1 in a neonatal cardiomyocyte model of phenylephrine (PE-induced hypertrophy. Using a seahorse flux analyzer we show that PE stimulated the mitochondrial oxygen consumption rate (OCR in cardiomyocytes. This was partially dependent on PE mediated AKIP1 induction, since silencing of AKIP1 attenuated the increase in OCR. Interestingly, AKIP1 overexpression alone was sufficient to stimulate mitochondrial OCR and in particular ATP-linked OCR. This was also true when pyruvate was used as a substrate, indicating that it was independent of glycolytic flux. The increase in OCR was independent of mitochondrial biogenesis, changes in ETC density or altered mitochondrial membrane potential. In fact, the respiratory flux was elevated per amount of ETC, possibly through enhanced ETC coupling. Furthermore, overexpression of AKIP1 reduced and silencing of AKIP1 increased mitochondrial superoxide production, suggesting that AKIP1 modulates the efficiency of electron flux through the ETC. Together, this suggests that AKIP1 overexpression improves mitochondrial function to enhance respiration without excess superoxide generation, thereby implicating a role for AKIP1 in mitochondrial stress adaptation. Upregulation of AKIP1 during different forms of cardiac stress may therefore be an adaptive mechanism to protect the heart.

  2. CD147 Promotes CXCL1 Expression and Modulates Liver Fibrogenesis

    Directory of Open Access Journals (Sweden)

    Wen-Pu Shi

    2018-04-01

    Full Text Available Activated hepatic stellate cells (HSCs release pro-inflammatory and pro-fibrogenic factors. CXC chemokine-ligand-1 (CXCL1 is expressed on HSCs. We previously found that the CD147 is overexpressed in activated HSCs. In this study, we showed an important role of CD147 in promoting liver fibrosis by activating HSCs and upregulating expression of chemokines. Specifically, we found that CD147 specific deletion in HSCs mice alleviated CCl4-induced liver fibrosis and inhibited HSCs activation. Overexpression of CD147 upregulated the secretion of CXCL1. Meanwhile, CXCL1 promoted HSCs activation through autocrine. Treating with PI3K/AKT inhibitor could effectively suppress CD147-induced CXCL1 expression. Taken together, these findings suggest that CD147 regulates CXCL1 release in HSCs by PI3K/AKT signaling. Inhibition of CD147 attenuates CCl4-induced liver fibrosis and inflammation. Therefore, administration of targeting CD147 could be a promising therapeutic strategy in liver fibrosis.

  3. Alterations in integrin expression modulates invasion of pancreatic cancer cells.

    LENUS (Irish Health Repository)

    Walsh, Naomi

    2009-01-01

    BACKGROUND: Factors mediating the invasion of pancreatic cancer cells through the extracellular matrix (ECM) are not fully understood. METHODS: In this study, sub-populations of the human pancreatic cancer cell line, MiaPaCa-2 were established which displayed differences in invasion, adhesion, anoikis, anchorage-independent growth and integrin expression. RESULTS: Clone #3 displayed higher invasion with less adhesion, while Clone #8 was less invasive with increased adhesion to ECM proteins compared to MiaPaCa-2. Clone #8 was more sensitive to anoikis than Clone #3 and MiaPaCa-2, and displayed low colony-forming efficiency in an anchorage-independent growth assay. Integrins beta 1, alpha 5 and alpha 6 were over-expressed in Clone #8. Using small interfering RNA (siRNA), integrin beta1 knockdown in Clone #8 cells increased invasion through matrigel and fibronectin, increased motility, decreased adhesion and anoikis. Integrin alpha 5 and alpha 6 knockdown also resulted in increased motility, invasion through matrigel and decreased adhesion. CONCLUSION: Our results suggest that altered expression of integrins interacting with different extracellular matrixes may play a significant role in suppressing the aggressive invasive phenotype. Analysis of these clonal populations of MiaPaCa-2 provides a model for investigations into the invasive properties of pancreatic carcinoma.

  4. Multiple Functional Variants in cis Modulate PDYN Expression.

    Science.gov (United States)

    Babbitt, Courtney C; Silverman, Jesse S; Haygood, Ralph; Reininga, Jennifer M; Rockman, Matthew V; Wray, Gregory A

    2010-02-01

    Understanding genetic variation and its functional consequences within cis-regulatory regions remains an important challenge in human genetics and evolution. Here, we present a fine-scale functional analysis of segregating variation within the cis-regulatory region of prodynorphin, a gene that encodes an endogenous opioid precursor with roles in cognition and disease. In order to characterize the functional consequences of segregating variation in cis in a region under balancing selection in different human populations, we examined associations between specific polymorphisms and gene expression in vivo and in vitro. We identified five polymorphisms within the 5' flanking region that affect transcript abundance: a 68-bp repeat recognized in prior studies, as well as two microsatellites and two single nucleotide polymorphisms not previously implicated as functional variants. The impact of these variants on transcription differs by brain region, sex, and cell type, implying interactions between cis genotype and the differentiated state of cells. The effects of individual variants on expression level are not additive in some combinations, implying epistatic interactions between nearby variants. These data reveal an unexpectedly complex relationship between segregating genetic variation and its expression-trait consequences and highlights the importance of close functional scrutiny of natural genetic variation within even relatively well-studied cis-regulatory regions.

  5. Melatonin modulates adiponectin expression on murine colitis with sleep deprivation.

    Science.gov (United States)

    Kim, Tae Kyun; Park, Young Sook; Baik, Haing-Woon; Jun, Jin Hyun; Kim, Eun Kyung; Sull, Jae Woong; Sung, Ho Joong; Choi, Jin Woo; Chung, Sook Hee; Gye, Myung Chan; Lim, Ju Yeon; Kim, Jun Bong; Kim, Seong Hwan

    2016-09-07

    To determine adiponectin expression in colonic tissue of murine colitis and systemic cytokine expression after melatonin treatments and sleep deprivation. The following five groups of C57BL/6 mice were used in this study: (1) group I, control; (2) group II, 2% DSS induced colitis for 7 d; (3) group III, 2% DSS induced colitis and melatonin treatment; (4) group IV, 2% DSS induced colitis with sleep deprivation (SD) using specially designed and modified multiple platform water baths; and (5) group V, 2% DSS induced colitis with SD and melatonin treatment. Melatonin (10 mg/kg) or saline was intraperitoneally injected daily to mice for 4 d. The body weight was monitored daily. The degree of colitis was evaluated histologically after sacrificing the mice. Immunohistochemical staining and Western blot analysis was performed using anti-adiponectin antibody. After sampling by intracardiac punctures, levels of serum cytokines were measured by ELISA. Sleep deprivation in water bath exacerbated DSS induced colitis and worsened weight loss. Melatonin injection not only alleviated the severity of mucosal injury, but also helped survival during stressful condition. The expression level of adiponectin in mucosa was decreased in colitis, with the lowest level observed in colitis combined with sleep deprivation. Melatonin injection significantly (P sleep deprivation.

  6. 2,3,7,8-Tetrachlorodibenzo-p-dioxin induced autophagy in a bovine kidney cell line

    International Nuclear Information System (INIS)

    Fiorito, Filomena; Ciarcia, Roberto; Granato, Giovanna Elvira; Marfe, Gabriella; Iovane, Valentina; Florio, Salvatore; De Martino, Luisa; Pagnini, Ugo

    2011-01-01

    Highlights: ► TCDD induces cell proliferation in MDBK cells. ► TCDD provokes morphological cell death in MDBK cells. ► TCDD induces autophagy in MDBK cells. ► TCDD induces a down-regulation of telomerase activity, bTERT, c-Myc in MDBK cells. ► TCDD induces an up-regulation of p53 and p21 protein levels in MDBK cells. -- Abstract: The administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to a variety of cultured cells may alter their ability to proliferate and die. In a previous study we demonstrated that TCDD induced proliferation in Madin-Darby Bovine Kidney (MDBK) cells where no signs of apoptosis were observed, but herein, analysis of MDBK cell morphology, in a large number of exposed cells, revealed some alterations, as expanded cytoplasm, an increase of intercellular spaces and many pyknotic nuclei. Hence, the aim of the current study was to elucidate the influences of dioxin on cell proliferation and cell death. We found that dioxin increased proliferation, as well as, activated cell death with autophagy, as we detected by increased amount of LC3-II, an autophagosome marker. Furthermore, formation of acidic vesicular organelles was observed by fluorescence microscopy following staining with the lysosomotropic agent acridine orange. These results were accompanied by down-regulation of telomerase activity, bTERT and c-Myc. Key tumor-suppressor protein p53 and expression of cell cycle inhibitor p21Waf1/Cip1 were activated after TCDD exposure. These changes occurred with activation of ATM phosphorylation in the presence of a decrease in Mdm2 protein levels. Taken together, these results support the idea that TCDD in MDBK cells, may exert its action, in part, by enhancing cell proliferation, but also by modulating the incidence of induced cell death with autophagy.

  7. Origins and transport of aquatic dioxins in the Japanese watershed: soil contamination, land use, and soil runoff events.

    Science.gov (United States)

    Kanematsu, Masakazu; Shimizu, Yoshihisa; Sato, Keisuke; Kim, Suejin; Suzuki, Tasuma; Park, Baeksoo; Saino, Reiko; Nakamura, Masafumi

    2009-06-15

    Significant dioxins accumulations in Japanese forests and paddy fields have been observed, and surface soil runoff caused by rainfall and irrigation (i.e., soil puddling in paddy fields) results in dioxins input into the aquatic environment. An extensive investigation into the origins and transport of aquatic dioxins in the Yasu watershed, Japan was conducted considering surface soil contamination level, land use, and type of soil runoff event (i.e., irrigation runoff [IR], rainfall runoff [RR], and base flow [BF]). Combined use of the chemically activated luciferase expression (CALUX) assay together with high-resolution gas chromatography and high-resolution mass spectrometry (HRGC/HRMS) efficiently enabled this study, so that origins, transport, and dynamic movement of aquatic dioxins in the watershed were revealed. The particulate organic carbon normalized particulate-dioxins WHO-toxic equivalent (TEQ) concentration predicted by the CALUX assay (Spar) was found to be a convenient molecular marker to indicate origins of aquatic dioxins and clearly reflect surface soil contamination level, land use, and soil runoff events. Using experimental results and theoretical modeling, the annual loading amount of dioxins at the middle reach of the river was estimated to be 0.458 mg WHO-TEQ in 2004. More than 96.6% of the annual loading amount was attributed to RR and derived almost evenly from forest and paddy fields at the study location. Because the annual loading amount at the middle reach is less than 0.5% of the total dioxins accumulated in the upper basin, dioxins runoff from the Japanese watershed will continue. This study shows that the combined use of the bioassay with HRGC/HRMS can provide new insights into dioxins transport and fate in the environment.

  8. The Need and Potential of Biosensors to Detect Dioxins and Dioxin-Like Polychlorinated Biphenyls along the Milk, Eggs and Meat Food Chain

    Directory of Open Access Journals (Sweden)

    Aize Kijlstra

    2011-12-01

    Full Text Available Dioxins and dioxin-like polychlorinated biphenyls (DL-PCBs are hazardous toxic, ubiquitous and persistent chemical compounds, which can enter the food chain and accumulate up to higher trophic levels. Their determination requires sophisticated methods, expensive facilities and instruments, well-trained personnel and expensive chemical reagents. Ideally, real-time monitoring using rapid detection methods should be applied to detect possible contamination along the food chain in order to prevent human exposure. Sensor technology may be promising in this respect. This review gives the state of the art for detecting possible contamination with dioxins and DL-PCBs along the food chain of animal-source foods. The main detection methods applied (i.e., high resolution gas-chromatography combined with high resolution mass-spectrometry (HRGC/HRMS and the chemical activated luciferase gene expression method (CALUX bioassay, each have their limitations. Biosensors for detecting dioxins and related compounds, although still under development, show potential to overcome these limitations. Immunosensors and biomimetic-based biosensors potentially offer increased selectivity and sensitivity for dioxin and DL-PCB detection, while whole cell-based biosensors present interpretable biological results. The main shortcoming of current biosensors, however, is their detection level: this may be insufficient as limits for dioxins and DL-PCBs for food and feedstuffs are in pg per gram level. In addition, these contaminants are normally present in fat, a difficult matrix for biosensor detection. Therefore, simple and efficient extraction and clean-up procedures are required which may enable biosensors to detect dioxins and DL-PCBs contamination along the food chain.

  9. The Need and Potential of Biosensors to Detect Dioxins and Dioxin-Like Polychlorinated Biphenyls along the Milk, Eggs and Meat Food Chain

    Science.gov (United States)

    Chobtang, Jeerasak; de Boer, Imke J. M.; Hoogenboom, Ron L. A. P.; Haasnoot, Willem; Kijlstra, Aize; Meerburg, Bastiaan G.

    2011-01-01

    Dioxins and dioxin-like polychlorinated biphenyls (DL-PCBs) are hazardous toxic, ubiquitous and persistent chemical compounds, which can enter the food chain and accumulate up to higher trophic levels. Their determination requires sophisticated methods, expensive facilities and instruments, well-trained personnel and expensive chemical reagents. Ideally, real-time monitoring using rapid detection methods should be applied to detect possible contamination along the food chain in order to prevent human exposure. Sensor technology may be promising in this respect. This review gives the state of the art for detecting possible contamination with dioxins and DL-PCBs along the food chain of animal-source foods. The main detection methods applied (i.e., high resolution gas-chromatography combined with high resolution mass-spectrometry (HRGC/HRMS) and the chemical activated luciferase gene expression method (CALUX bioassay)), each have their limitations. Biosensors for detecting dioxins and related compounds, although still under development, show potential to overcome these limitations. Immunosensors and biomimetic-based biosensors potentially offer increased selectivity and sensitivity for dioxin and DL-PCB detection, while whole cell-based biosensors present interpretable biological results. The main shortcoming of current biosensors, however, is their detection level: this may be insufficient as limits for dioxins and DL-PCBs for food and feedstuffs are in pg per gram level. In addition, these contaminants are normally present in fat, a difficult matrix for biosensor detection. Therefore, simple and efficient extraction and clean-up procedures are required which may enable biosensors to detect dioxins and DL-PCBs contamination along the food chain. PMID:22247688

  10. The need and potential of biosensors to detect dioxins and dioxin-like polychlorinated biphenyls along the milk, eggs and meat food chain.

    Science.gov (United States)

    Chobtang, Jeerasak; de Boer, Imke J M; Hoogenboom, Ron L A P; Haasnoot, Willem; Kijlstra, Aize; Meerburg, Bastiaan G

    2011-01-01

    Dioxins and dioxin-like polychlorinated biphenyls (DL-PCBs) are hazardous toxic, ubiquitous and persistent chemical compounds, which can enter the food chain and accumulate up to higher trophic levels. Their determination requires sophisticated methods, expensive facilities and instruments, well-trained personnel and expensive chemical reagents. Ideally, real-time monitoring using rapid detection methods should be applied to detect possible contamination along the food chain in order to prevent human exposure. Sensor technology may be promising in this respect. This review gives the state of the art for detecting possible contamination with dioxins and DL-PCBs along the food chain of animal-source foods. The main detection methods applied (i.e., high resolution gas-chromatography combined with high resolution mass-spectrometry (HRGC/HRMS) and the chemical activated luciferase gene expression method (CALUX bioassay)), each have their limitations. Biosensors for detecting dioxins and related compounds, although still under development, show potential to overcome these limitations. Immunosensors and biomimetic-based biosensors potentially offer increased selectivity and sensitivity for dioxin and DL-PCB detection, while whole cell-based biosensors present interpretable biological results. The main shortcoming of current biosensors, however, is their detection level: this may be insufficient as limits for dioxins and DL-PCBs for food and feedstuffs are in pg per gram level. In addition, these contaminants are normally present in fat, a difficult matrix for biosensor detection. Therefore, simple and efficient extraction and clean-up procedures are required which may enable biosensors to detect dioxins and DL-PCBs contamination along the food chain.

  11. Serum dioxin concentration and age at Menarche

    Energy Technology Data Exchange (ETDEWEB)

    Warner, M.; Samuels, S.; Eskenazi, B. [Univ. of California at Berkeley (United States); Mocarelli, P.; Gerthoux, P.M. [Univ. of Milano-Biococca (Italy); Needham, L.; Patterson, D. Jr. [Centers for Disease Control and Prevention (United States)

    2004-09-15

    To date, no epidemiologic studies have examined the association of TCDD exposure and age at menarche. Three studies, however, have examined the relation of dioxin-like compounds to pubertal development, with inconsistent conclusions. A study of daughters of Michigan women who had consumed polybrominated biphenyls (PBB) in food in 1973, found an earlier age at menarche among daughters whose mothers had higher serum PBB levels 8. No differences were found in age at menarche of Taiwanese women who were exposed postnatally (but premenarche) to PCBs and PCDFs via consumption of contaminated rice oil (Yu-Cheng) compared to unexposed 9. In Flemish adolescents, there was no relation of age at menarche with current serum levels of dioxin-like compounds as measured by Chemical Activated LUciferase gene eXpression bioassay toxic equivalents (CALUX-TEQ) or individual PCB congeners 118, 153, and 180 10. On July 10, 1976, as a result of a chemical explosion, residents of Seveso, Italy experienced the highest levels of TCDD exposure in a human population. Twenty years later (1996-1998), the Seveso Women's Health Study (SWHS), a retrospective cohort study, was initiated to determine whether the women were at higher risk for reproductive disease. Among participants in SWHS, we have observed that TCDD levels are associated with an increase in menstrual cycle length among those who were premenarcheal at exposure, but not in those who were postmenarcheal at exposure 11. Consistent with animal studies 12, this suggests that females may be particularly susceptible to the effects of TCDD during early stages of development, e.g. in utero or pre-pubertal. Thus, here we examine the association of individual serum TCDD and age of menarche among women who were premenarcheal in 1976, at the time of explosion.

  12. Dietary intake of dioxins, furans and dioxin-like PCBs in Austria.

    Science.gov (United States)

    Rauscher-Gabernig, Elke; Mischek, Daniela; Moche, Wolfgang; Prean, Michael

    2013-01-01

    Human exposure to polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and dioxin-like PCBs (dl-PCBs) should be assessed regularly. In order to evaluate the contamination levels in various food products on the Austrian market and to assess the dietary exposure of the Austrian population for the first time, a national monitoring programme was conducted from 2005 to 2011. The 235 food products comprised meat, poultry, game and offal, fish and fish products, milk and dairy products, eggs, animal fats and vegetable oils. To estimate the dietary intakes of PCDD/Fs and dl-PCBs, mean concentrations in food were combined with the respective food consumption data from the Austrian food consumption survey. Estimated dietary intakes were expressed as toxic equivalents (WHO-TEQs 1998). The mean intakes for PCDD/Fs and dl-PCBs were estimated as 0.77, 0.75 and 0.61 pg WHO-TEQ kg(-1) bw day(-1) for children, women and men, respectively. The main contributors to total intake were milk and dairy products followed by fish and fish products for children and women, and meat, poultry, game and offal for men (65% and 15% for children, 67% and 14% for women, and 63% and 19% for men, respectively). Comparison of the estimated dietary intakes with the toxicological reference values shows that both children and adults are well below those values.

  13. Optical modulation of transgene expression in retinal pigment epithelium

    Science.gov (United States)

    Palanker, D.; Lavinsky, D.; Chalberg, T.; Mandel, Y.; Huie, P.; Dalal, R.; Marmor, M.

    2013-03-01

    Over a million people in US alone are visually impaired due to the neovascular form of age-related macular degeneration (AMD). The current treatment is monthly intravitreal injections of a protein which inhibits Vascular Endothelial Growth Factor, thereby slowing progression of the disease. The immense financial and logistical burden of millions of intravitreal injections signifies an urgent need to develop more long-lasting and cost-effective treatments for this and other retinal diseases. Viral transfection of ocular cells allows creation of a "biofactory" that secretes therapeutic proteins. This technique has been proven successful in non-human primates, and is now being evaluated in clinical trials for wet AMD. However, there is a critical need to down-regulate gene expression in the case of total resolution of retinal condition, or if patient has adverse reaction to the trans-gene products. The site for genetic therapy of AMD and many other retinal diseases is the retinal pigment epithelium (RPE). We developed and tested in pigmented rabbits, an optical method to down-regulate transgene expression in RPE following vector delivery, without retinal damage. Microsecond exposures produced by a rapidly scanning laser vaporize melanosomes and destroy a predetermined fraction of the RPE cells selectively. RPE continuity is restored within days by migration and proliferation of adjacent RPE, but since the transgene is not integrated into the nucleus it is not replicated. Thus, the decrease in transgene expression can be precisely determined by the laser pattern density and further reduced by repeated treatment without affecting retinal structure and function.

  14. Radiation-modulated gene expression in C. elegans

    International Nuclear Information System (INIS)

    Nelson, G.A.; Bayeta, E.; Perez, C.; Lloyd, E.; Jones, T.; Smith, A.; Tian, J.

    2003-01-01

    Full text: We use the nematode C. elegans to characterize the genotoxic and cytotoxic effects of ionizing radiation with emphasis effects of charged particle radiation and have described the fluence vs. response relationships for mutation, chromosome aberration and certain developmental errors. These endpoints quantify the biological after repair and compensation pathways have completed their work. In order to address the control of these reactions we have turned to gene expression profiling to identify genes that uniquely respond to high LET species or respond differentially as a function of radiation properties. We have employed whole genome microarray methods to map gene expression following exposure to gamma rays, protons and accelerated iron ions. We found that 599 of 17871 genes analyzed showed differential expression 3 hrs after exposure to 3 Gy of at least one radiation types. 193 were up-regulated, 406 were down-regulated, and 90% were affected by only one species of radiation. Genes whose transcription levels responded significantly mapped to definite statistical clusters that were unique for each radiation type. We are now trying to establish the functional relationships of the genes their relevance to mitigation of radiation-induced damage. Three approaches are being used. First, bioinformatics tools are being used to determine the roles of genes in co-regulated gene sets. Second, we are applying the technique of RNA interference to determine whether our radiation-induced genes affect cell survival (measured in terms of embryo survival) and chromosome aberration (intestinal anaphase bridges). Finally we are focussing on the response of the most strongly-regulated gene in our data set. This is the autosomal gene, F36D3.9, whose predicted structure is that of a cysteine protease resembling cathepsin B. An enzymological approach is being used to characterize this gene at the protein level. This work was supported by NASA Cooperative Agreement NCC9-149

  15. Optøjer og dioxiner

    DEFF Research Database (Denmark)

    Berg, Rolf W.

    2008-01-01

    brintatomer er udskiftet med chlor (såkaldt chlor-substitueret dioxin), man tænker på, når man snakker om dioxin (se boks). Dioxiner er ekstremt giftige stoffer. Indtagelse of nogle få milligram regnes for dødelig for en voksen person. Det er dog ikke realistisk at blive udsat for så meget dioxin, og der...... findes ingen kendte dødsfald på grund of akut dioxinforgiftning. Til gengæld kan dioxin påvirke et bestemt proteinsystem ved navn aryl hydrocarbon receptor (AhR), give fosterskader og sandsynligvis fremkalde kræftsygdomme. Dioxin og brande. Dioxiner dannes let som reaktionsprodukter ved kemiske...... flammerne til røgen, mens resten blev tilbage i asken. Røgen spredes over store områder, og dioxinen falder ned lidt overalt. Forholdene betyder meget for dioxindannelsen, idet dårlig og ustabil forbrænding ved lave temperaturer (som det ofte er tilfældet ved brande) vil give relativt mere dioxin. Desuden...

  16. Dioxin in the atmosphere of Denmark

    Energy Technology Data Exchange (ETDEWEB)

    Vikelsoee, J.; Hovmand, M.F.; Andersen, Helle V.; Bossi, R.; Johansen, Elsebeth; Chrillesen, M.A.

    2006-03-15

    Occurrence and geographical distribution of dioxin was investigated in air and deposition at selected locations in Denmark, three forest sites in the background area, a city site in Copenhagen and a village site. At two sites simultaneously determination of dioxins concentrations in the ambient atmosphere and bulk precipitation were carried out during a period of three years. (au)

  17. Dioxins and polyvinylchloride in combustion and fires.

    Science.gov (United States)

    Zhang, Mengmei; Buekens, Alfons; Jiang, Xuguang; Li, Xiaodong

    2015-07-01

    This review on polyvinylchloride (PVC) and dioxins collects, collates, and compares data from selected sources on the formation of polychlorinated dibenzofurans (PCDFs) and dibenzo-p-dioxins (PCDDs), or in brief dioxins, in combustion and fires. In professional spheres, the incineration of PVC as part of municipal solid waste is seldom seen as a problem, since deep flue gas cleaning is required anyhow. Conversely, with its high content of chlorine, PVC is frequently branded as a major chlorine donor and spitefully leads to substantial formation of dioxins during poorly controlled or uncontrolled combustion and open fires. Numerous still ill-documented and diverse factors of influence may affect the formation of dioxins during combustion: on the one hand PVC-compounds represent an array of materials with widely different formulations; on the other hand these may all be exposed to fires of different nature and consequences. Hence, attention should be paid to PVC with respect to the ignition and development of fires, as well as attenuating the emission of objectionable compounds, such as carbon monoxide, hydrogen chloride, polycyclic aromatic hydrocarbons, and dioxins. This review summarises available dioxin emissions data, gathers experimental and simulation studies of fires and combustion tests involving PVC, and identifies and analyses the effects of several local factors of influence, affecting the formation of dioxins during PVC combustion. © The Author(s) 2015.

  18. Modulation of PML protein expression regulates JCV infection

    International Nuclear Information System (INIS)

    Gasparovic, Megan L.; Maginnis, Melissa S.; O'Hara, Bethany A.; Dugan, Aisling S.; Atwood, Walter J.

    2009-01-01

    JC virus (JCV) is a human polyomavirus that infects the majority of the human population worldwide. It is responsible for the fatal demyelinating disease Progressive Multifocal Leukoencephalopathy. JCV binds to cells using the serotonin receptor 5-HT 2A R and α(2-6)- or α(2-3)-linked sialic acid. It enters cells using clathrin-dependent endocytosis and traffics to the early endosome and possibly to the endoplasmic reticulum. Viral DNA is then delivered to the nucleus where transcription, replication, and assembly of progeny occur. We found that the early regulatory protein large T antigen accumulates in microdomains in the nucleus adjacent to ND-10 or PML domains. This observation prompted us to explore the role of these domains in JCV infection. We found that a reduction of nuclear PML enhanced virus infection and that an increase in nuclear PML reduced infection. Infection with JCV did not directly modulate nuclear levels of PML but our data indicate that a host response involving interferon beta is likely to restrict virus infection by increasing nuclear PML.

  19. Levels, profiles and risk assessment of polychlorinated biphenyls, dibenzo-p-dioxins and dibenzofurans in breast milk from North China

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, J.H.; Sun, S.J.; Horiguchi, H.; Kayama, F. [Dept. of Environ. Medicine, Jichi Medical School, Kawachi-gun (Japan)]|[CREST-JST, Kawaguchi, Saitama (Japan); Nakamura, M. [Hiyoshi Corp., Omihachiman, Shiga (Japan); Li Li; Ge Jun [Hospital of gynaecology and maternity of Shijiazhuang, Hebei Province (China); Ma Yu-Xia [Dept. of Hygienic Food, Collection of Public Health, Hebei Medical Univ. (China); Hou Xiu-Jun [The Second Hospital of Luanxian, Hebei Province (China); Clark, G. [Xenobiotic Detection System International Inc., Durham, NC (United States)

    2004-09-15

    China have produced and used organochlorine pesticides with low purity in a large quantity. However, there is little information on the environmental levels of organohalogens contamination as well as body burden of these chemicals, especially in Mainland China. After recent rapid growth of economy in China, health effects of persistent organohalogens are of growing concern. To assess mother's body burden and perinatal exposure of dioxins and pesticides, we collected breast milk specimens from Shijiazhuang urban and Tangshan rural area, Hebei Province, North China, and measured dioxins by DIPS-CALUX{sup circledR} bioassay (Dioxin and PCB specific Chemical-Activated LUciferase gene eXpression cell bioassay system).

  20. Dynamic functional modules in co-expressed protein interaction networks of dilated cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Oyang Yen-Jen

    2010-10-01

    Full Text Available Abstract Background Molecular networks represent the backbone of molecular activity within cells and provide opportunities for understanding the mechanism of diseases. While protein-protein interaction data constitute static network maps, integration of condition-specific co-expression information provides clues to the dynamic features of these networks. Dilated cardiomyopathy is a leading cause of heart failure. Although previous studies have identified putative biomarkers or therapeutic targets for heart failure, the underlying molecular mechanism of dilated cardiomyopathy remains unclear. Results We developed a network-based comparative analysis approach that integrates protein-protein interactions with gene expression profiles and biological function annotations to reveal dynamic functional modules under different biological states. We found that hub proteins in condition-specific co-expressed protein interaction networks tended to be differentially expressed between biological states. Applying this method to a cohort of heart failure patients, we identified two functional modules that significantly emerged from the interaction networks. The dynamics of these modules between normal and disease states further suggest a potential molecular model of dilated cardiomyopathy. Conclusions We propose a novel framework to analyze the interaction networks in different biological states. It successfully reveals network modules closely related to heart failure; more importantly, these network dynamics provide new insights into the cause of dilated cardiomyopathy. The revealed molecular modules might be used as potential drug targets and provide new directions for heart failure therapy.

  1. Modulation of the osteosarcoma expression phenotype by microRNAs.

    Directory of Open Access Journals (Sweden)

    Heidi M Namløs

    Full Text Available BACKGROUND: Osteosarcomas are the most common primary malignant tumors of bone and show multiple and complex genomic aberrations. miRNAs are non-coding RNAs capable of regulating gene expression at the post transcriptional level, and miRNAs and their target genes may represent novel therapeutic targets or biomarkers for osteosarcoma. In order to investigate the involvement of miRNAs in osteosarcoma development, global microarray analyses of a panel of 19 human osteosarcoma cell lines was performed. PRINCIPAL FINDINGS: We identified 177 miRNAs that were differentially expressed in osteosarcoma cell lines relative to normal bone. Among these, miR-126/miR-126*, miR-142-3p, miR-150, miR-223, miR-486-5p and members of the miR-1/miR-133a, miR-144/miR-451, miR-195/miR-497 and miR-206/miR-133b clusters were found to be downregulated in osteosarcoma cell lines. All miRNAs in the paralogous clusters miR-17-92, miR-106b-25 and miR-106a-92 were overexpressed. Furthermore, the upregulated miRNAs included miR-9/miR-9*, miR-21*, miR-31/miR-31*, miR-196a/miR-196b, miR-374a and members of the miR-29 and miR-130/301 families. The most interesting inversely correlated miRNA/mRNA pairs in osteosarcoma cell lines included miR-9/TGFBR2 and miR-29/p85α regulatory subunit of PI3K. PTEN mRNA correlated inversely with miR-92a and members of the miR-17 and miR-130/301 families. Expression profiles of selected miRNAs were confirmed in clinical samples. A set of miRNAs, miR-1, miR-18a, miR-18b, miR-19b, miR-31, miR-126, miR-142-3p, miR-133b, miR-144, miR-195, miR-223, miR-451 and miR-497 was identified with an intermediate expression level in osteosarcoma clinical samples compared to osteoblasts and bone, which may reflect the differentiation level of osteosarcoma relative to the undifferentiated osteoblast and fully differentiated normal bone. SIGNIFICANCE: This study provides an integrated analysis of miRNA and mRNA in osteosarcoma, and gives new insight into the complex

  2. Chloroquine mediated modulation of Anopheles gambiae gene expression.

    Directory of Open Access Journals (Sweden)

    Patrícia Abrantes

    2008-07-01

    Full Text Available Plasmodium development in the mosquito is crucial for malaria transmission and depends on the parasite's interaction with a variety of cell types and specific mosquito factors that have both positive and negative effects on infection. Whereas the defensive response of the mosquito contributes to a decrease in parasite numbers during these stages, some components of the blood meal are known to favor infection, potentiating the risk of increased transmission. The presence of the antimalarial drug chloroquine in the mosquito's blood meal has been associated with an increase in Plasmodium infectivity for the mosquito, which is possibly caused by chloroquine interfering with the capacity of the mosquito to defend against the infection.In this study, we report a detailed survey of the Anopheles gambiae genes that are differentially regulated by the presence of chloroquine in the blood meal, using an A. gambiae cDNA microarray. The effect of chloroquine on transcript abundance was evaluated separately for non-infected and Plasmodium berghei-infected mosquitoes. Chloroquine was found to affect the abundance of transcripts that encode proteins involved in a variety of processes, including immunity, apoptosis, cytoskeleton and the response to oxidative stress. This pattern of differential gene expression may explain the weakened mosquito defense response which accounts for the increased infectivity observed in chloroquine-treated mosquitoes.The results of the present study suggest that chloroquine can interfere with several putative mosquito mechanisms of defense against Plasmodium at the level of gene expression and highlight the need for a better understanding of the impacts of antimalarial agents on parasite transmission.

  3. Modulation of GLO1 Expression Affects Malignant Properties of Cells

    Directory of Open Access Journals (Sweden)

    Antje Hutschenreuther

    2016-12-01

    Full Text Available The energy metabolism of most tumor cells relies on aerobic glycolysis (Warburg effect characterized by an increased glycolytic flux that is accompanied by the increased formation of the cytotoxic metabolite methylglyoxal (MGO. Consequently, the rate of detoxification of this reactive glycolytic byproduct needs to be increased in order to prevent deleterious effects to the cells. This is brought about by an increased expression of glyoxalase 1 (GLO1 that is the rate-limiting enzyme of the MGO-detoxifying glyoxalase system. Here, we overexpressed GLO1 in HEK 293 cells and silenced it in MCF-7 cells using shRNA. Tumor-related properties of wild type and transformed cells were compared and key glycolytic enzyme activities assessed. Furthermore, the cells were subjected to hypoxic conditions to analyze the impact on cell proliferation and enzyme activities. Our results demonstrate that knockdown of GLO1 in the cancer cells significantly reduced tumor-associated properties such as migration and proliferation, whereas no functional alterations where found by overexpression of GLO1 in HEK 293 cells. In contrast, hypoxia caused inhibition of cell growth of all cells except of those overexpressing GLO1. Altogether, we conclude that GLO1 on one hand is crucial to maintaining tumor characteristics of malignant cells, and, on the other hand, supports malignant transformation of cells in a hypoxic environment when overexpressed.

  4. Spaceflight modulates gene expression in the whole blood of astronauts.

    Science.gov (United States)

    Barrila, Jennifer; Ott, C Mark; LeBlanc, Carly; Mehta, Satish K; Crabbé, Aurélie; Stafford, Phillip; Pierson, Duane L; Nickerson, Cheryl A

    2016-01-01

    Astronauts are exposed to a unique combination of stressors during spaceflight, which leads to alterations in their physiology and potentially increases their susceptibility to disease, including infectious diseases. To evaluate the potential impact of the spaceflight environment on the regulation of molecular pathways mediating cellular stress responses, we performed a first-of-its-kind pilot study to assess spaceflight-related gene-expression changes in the whole blood of astronauts. Using an array comprised of 234 well-characterized stress-response genes, we profiled transcriptomic changes in six astronauts (four men and two women) from blood preserved before and immediately following the spaceflight. Differentially regulated transcripts included those important for DNA repair, oxidative stress, and protein folding/degradation, including HSP90AB1 , HSP27 , GPX1 , XRCC1 , BAG-1 , HHR23A , FAP48 , and C-FOS . No gender-specific differences or relationship to number of missions flown was observed. This study provides a first assessment of transcriptomic changes occurring in the whole blood of astronauts in response to spaceflight.

  5. Emotional Intensity Modulates the Integration of Bimodal Angry Expressions: ERP Evidence

    Directory of Open Access Journals (Sweden)

    Zhihui Pan

    2017-06-01

    Full Text Available Integration of information from face and voice plays a central role in social interactions. The present study investigated the modulation of emotional intensity on the integration of facial-vocal emotional cues by recording EEG for participants while they were performing emotion identification task on facial, vocal, and bimodal angry expressions varying in emotional intensity. Behavioral results showed the rates of anger and reaction speed increased as emotional intensity across modalities. Critically, the P2 amplitudes were larger for bimodal expressions than for the sum of facial and vocal expressions for low emotional intensity stimuli, but not for middle and high emotional intensity stimuli. These findings suggested that emotional intensity modulates the integration of facial-vocal angry expressions, following the principle of Inverse Effectiveness (IE in multimodal sensory integration.

  6. Comprehensive evaluation of dioxins and dioxin-like compounds in surface soils and river sediments from e-waste-processing sites in a village in northern Vietnam: Heading towards the environmentally sound management of e-waste

    OpenAIRE

    Go Suzuki; Masayuki Someya; Hidenori Matsukami; Nguyen Minh Tue; Natsuyo Uchida; Le Huu Tuyen; Pham Hung Viet; Shin Takahashi; Shinsuke Tanabe; Abraham Brouwer; Hidetaka Takigami

    2016-01-01

    The management of electronic waste (e-waste), which can be a source of both useful materials and toxic substances, depending on the processing method, is important for promoting material cycling. In this study, we used the dioxin-responsive chemical-activated luciferase gene expression (DR-CALUX) assay combined with gas chromatography–high-resolution mass spectrometry to evaluate the levels of dioxin-like compounds in surface soils and river sediments collected in and around an e-waste-proces...

  7. Module discovery by exhaustive search for densely connected, co-expressed regions in biomolecular interaction networks.

    Directory of Open Access Journals (Sweden)

    Recep Colak

    2010-10-01

    Full Text Available Computational prediction of functionally related groups of genes (functional modules from large-scale data is an important issue in computational biology. Gene expression experiments and interaction networks are well studied large-scale data sources, available for many not yet exhaustively annotated organisms. It has been well established, when analyzing these two data sources jointly, modules are often reflected by highly interconnected (dense regions in the interaction networks whose participating genes are co-expressed. However, the tractability of the problem had remained unclear and methods by which to exhaustively search for such constellations had not been presented.We provide an algorithmic framework, referred to as Densely Connected Biclustering (DECOB, by which the aforementioned search problem becomes tractable. To benchmark the predictive power inherent to the approach, we computed all co-expressed, dense regions in physical protein and genetic interaction networks from human and yeast. An automatized filtering procedure reduces our output which results in smaller collections of modules, comparable to state-of-the-art approaches. Our results performed favorably in a fair benchmarking competition which adheres to standard criteria. We demonstrate the usefulness of an exhaustive module search, by using the unreduced output to more quickly perform GO term related function prediction tasks. We point out the advantages of our exhaustive output by predicting functional relationships using two examples.We demonstrate that the computation of all densely connected and co-expressed regions in interaction networks is an approach to module discovery of considerable value. Beyond confirming the well settled hypothesis that such co-expressed, densely connected interaction network regions reflect functional modules, we open up novel computational ways to comprehensively analyze the modular organization of an organism based on prevalent and largely

  8. Module discovery by exhaustive search for densely connected, co-expressed regions in biomolecular interaction networks.

    Science.gov (United States)

    Colak, Recep; Moser, Flavia; Chu, Jeffrey Shih-Chieh; Schönhuth, Alexander; Chen, Nansheng; Ester, Martin

    2010-10-25

    Computational prediction of functionally related groups of genes (functional modules) from large-scale data is an important issue in computational biology. Gene expression experiments and interaction networks are well studied large-scale data sources, available for many not yet exhaustively annotated organisms. It has been well established, when analyzing these two data sources jointly, modules are often reflected by highly interconnected (dense) regions in the interaction networks whose participating genes are co-expressed. However, the tractability of the problem had remained unclear and methods by which to exhaustively search for such constellations had not been presented. We provide an algorithmic framework, referred to as Densely Connected Biclustering (DECOB), by which the aforementioned search problem becomes tractable. To benchmark the predictive power inherent to the approach, we computed all co-expressed, dense regions in physical protein and genetic interaction networks from human and yeast. An automatized filtering procedure reduces our output which results in smaller collections of modules, comparable to state-of-the-art approaches. Our results performed favorably in a fair benchmarking competition which adheres to standard criteria. We demonstrate the usefulness of an exhaustive module search, by using the unreduced output to more quickly perform GO term related function prediction tasks. We point out the advantages of our exhaustive output by predicting functional relationships using two examples. We demonstrate that the computation of all densely connected and co-expressed regions in interaction networks is an approach to module discovery of considerable value. Beyond confirming the well settled hypothesis that such co-expressed, densely connected interaction network regions reflect functional modules, we open up novel computational ways to comprehensively analyze the modular organization of an organism based on prevalent and largely available large

  9. Arginase expression modulates nitric oxide production in Leishmania (Leishmania) amazonensis.

    Science.gov (United States)

    Acuña, Stephanie Maia; Aoki, Juliana Ide; Laranjeira-Silva, Maria Fernanda; Zampieri, Ricardo Andrade; Fernandes, Juliane Cristina Ribeiro; Muxel, Sandra Marcia; Floeter-Winter, Lucile Maria

    2017-01-01

    Arginase is an enzyme that converts L-arginine to urea and L-ornithine, an essential substrate for the polyamine pathway supporting Leishmania (Leishmania) amazonensis replication and its survival in the mammalian host. L-arginine is also the substrate of macrophage nitric oxide synthase 2 (NOS2) to produce nitric oxide (NO) that kills the parasite. This competition can define the fate of Leishmania infection. The transcriptomic profiling identified a family of oxidoreductases in L. (L.) amazonensis wild-type (La-WT) and L. (L.) amazonensis arginase knockout (La-arg-) promastigotes and axenic amastigotes. We highlighted the identification of an oxidoreductase that could act as nitric oxide synthase-like (NOS-like), due to the following evidences: conserved domain composition, the participation of NO production during the time course of promastigotes growth and during the axenic amastigotes differentiation, regulation dependence on arginase activity, as well as reduction of NO amount through the NOS activity inhibition. NO quantification was measured by DAF-FM labeling analysis in a flow cytometry. We described an arginase-dependent NOS-like activity in L. (L.) amazonensis and its role in the parasite growth. The increased detection of NO production in the mid-stationary and late-stationary growth phases of La-WT promastigotes could suggest that this production is an important factor to metacyclogenesis triggering. On the other hand, La-arg- showed an earlier increase in NO production compared to La-WT, suggesting that NO production can be arginase-dependent. Interestingly, La-WT and La-arg- axenic amastigotes produced higher levels of NO than those observed in promastigotes. As a conclusion, our work suggested that NOS-like is expressed in Leishmania in the stationary growth phase promastigotes and amastigotes, and could be correlated to metacyclogenesis and amastigotes growth in a dependent way to the internal pool of L-arginine and arginase activity.

  10. ROMA: representation and quantification of module activity from target expression data

    Directory of Open Access Journals (Sweden)

    Loredana eMartignetti

    2016-02-01

    Full Text Available In many analysis of high-throughput data in systems biology, there is a need to quantify the activity of a set of genes in individual samples. A typical example is the case where it is necessary to estimate the activity of a transcription factor (which is often not directly measurable from the expression of its target genes. We present here ROMA (Representation and quantification Of Module Activities Java software, designed for fast and robust computation of the activity of gene sets (or modules with coordinated expression. ROMA activity quantification is based on the simplest uni-factor linear model of gene regulation that approximates the expression data of a gene set by its first principal component.The proposed algorithm implements novel functionalities: it provides several method modifications for principal components computation, including weighted, robust and centered methods; it distinguishes overdispersed modules (based on the variance explained by the first principal component and coordinated modules (based on the significance of the spectral gap; finally, it computes statistical significance of the estimated module overdispersion or coordination.ROMA can be applied in many contexts, from estimating differential activities of transcriptional factors to findingoverdispersed pathways in single-cell transcriptomics data. We describe here the principles of ROMA providing several practical examples of its use.ROMA source code is available at https://github.com/sysbio-curie/Roma.

  11. Modulators of inhibitor of growth (ING) family expression in development and disease.

    Science.gov (United States)

    Maher, Stacey K; Helbing, Caren C

    2009-05-01

    The inhibitor of growth (ING) gene family proteins regulate many critical cellular processes such as cell proliferation and growth, apoptosis, DNA repair, senescence, angiogenesis, and drug resistance. Their transcripts and proteins are differentially expressed in health and disease and there is evidence for developmental regulation. The vast majority of studies have characterized ING levels in the context of cancer. However, relatively little attention has been paid to the expression of ING family members in other contexts. This review summarizes the findings from human and animal model systems that provide insight into the factors influencing the expression of these important proteins. We examine the influence of cell cycle and aging as well as genotoxic stress on ING expression levels and evaluate several emerging areas of inquiry demonstrating that ING gene activity may be modulated by factors such as the p53 tumor suppressor, DNA methylation, and ING proteins themselves with external factors such as hormones, reactive oxygen species, TGFbeta signalling, and other proteins of pathological significance also influencing ING levels. We then briefly discuss the influence of post-translational modification and changes in subcellular localization as it pertains to modulation of ING expression. Understanding how ING expression is modulated represents a vital aspect of effective drug targeting strategies.

  12. Expression of biomarkers modulating prostate cancer angiogenesis: Differential expression of annexin II in prostate carcinomas from India and USA

    Directory of Open Access Journals (Sweden)

    Dinda Amit K

    2003-10-01

    Full Text Available Abstract Background Prostate cancer (PCa incidences vary with genetic, geographical and ethnic dietary background of patients while angiogenesis is modulated through exquisite interplay of tumor-stromal interactions of biological macromolecules. We hypothesized that comprehensive analysis of four biomarkers modulating angiogenesis in PCa progression in two diverse populations might explain the variance in the incidence rates. Results Immunohistochemical analysis of 42 PCa biopsies reveals that though Anx-II expression is lost in both the Indian and American population with Gleason scores (GS ranging between 6 and 10, up to 25 % of cells in the entire high grade (GS > 8 PD PCa samples from US show intense focal membrane staining for Anx-II unlike similarly graded specimens from India. Consistent with this observation, the prostate cancer cell lines PC-3, DU-145 and MDA PCa 2A, but not LNCaP-R, LNCAP-UR or MDA PCa 2B cell lines, express Anx-II. Transcriptional reactivation of Anx-II gene with Aza-dC could not entirely account for loss of Anx-II protein in primary PCa. Cyclooxygenase-2 (COX-2 was moderately expressed in most of high grade PIN and some MD PCa and surrounding stroma. COX-2 was not expressed in PD PCa (GS ~7–10, while adjacent smooth muscles cells stained weakly positive. Decorin expression was observed only in high grade PIN but not in any of the prostate cancers, atrophy or BPH while stromal areas of BPH stained intensively for DCN and decreased with advancing stages of PCa. Versican expression was weak in most of the MD PCa, moderate in all of BPH, moderately focal in PD PC, weak and focal in PIN, atrophy and adjacent stroma. Conclusions Expression of pro- and anti-angiogenic modulators changes with stage of PCa but correlates with angiogenic status. Focal membrane staining of Anx-II reappears in high grade PCa specimens only from US indicating differential expression of Anx-II. COX-2 stained stronger in American specimens

  13. Soil dioxin concentrations in Baden-Wuerttemberg

    International Nuclear Information System (INIS)

    Wolf, D.

    1993-01-01

    Soil dioxin levels in Baden-Wuerttemberg are generally low. Where high dioxin concentrations have been reported like in Rastatt, Rheinfelden, Crailsheim-Maulach and Eppingen these phenomena are local. Already at less than 100 metres distance, drastically lower concentrations are measured. At 1500 to 2000 metres distance the values are back to the ordinary background level. A programme for detecting sources of emission in the entire state revealed no further sites of heavy contamination. For this assessment of soil dioxin concentrations in Baden-Wuerttemberg 1275 soil samples were used, which is a vast amount also in comparison with nation-wide surveys. The average dioxin content in farmland is about 1 ng I-TEq/kg m T . Soil dioxin concentrations are the higher the greater the density of settlements and industry. In cities they are about three to five times higher than the ubiquitous background concentration. The highest concentrations measured were 5-20 ng I-TE/kg in garden soils in cities. Sewage sludge may be a significant source of dioxin contamination for farmland, far beyond the ubiquitous background concentration. Automobile exhaust gas caused higher soil contamination within 10 m along both sides of the roads as a function of traffic. Because scavengers in gasoline are now prohibited and catalysts are becoming more and more common the rate of additional dioxin and furan contamination due to traffic will decrease. Currently, traffic-related emissions in Baden-Wuerttemberg are well below 2 g I-TEq. (orig./EF) [de

  14. Module discovery by exhaustive search for densely connected, co-expressed regions in biomolecular networks

    NARCIS (Netherlands)

    R. Colak; F. Moser; J. Shu; A. Schönhuth (Alexander); N. Chen; M. Ester

    2010-01-01

    htmlabstractBackground Computational prediction of functionally related groups of genes (functional modules) from large-scale data is an important issue in computational biology. Gene expression experiments and interaction networks are well studied large-scale data sources, available for many not

  15. Epithelial expression of TLR4 is modulated in COPD and by steroids, salmeterol and cigarette smoke

    Directory of Open Access Journals (Sweden)

    Dorscheid Delbert R

    2007-11-01

    Full Text Available Abstract The toll-like receptors (TLRs are a key component of host defense in the respiratory epithelium. Cigarette smoking is associated with increased susceptibility to infection, while COPD is characterised by bacterial colonisation and infective exacerbations. We found reduced TLR4 gene expression in the nasal epithelium of smokers compared with non-smoking controls, while TLR2 expression was unchanged. Severe COPD was associated with reduced TLR4 expression compared to less severe disease, with good correlation between nasal and tracheal expression. We went on to examine the effect of potential modulators of TLR4 expression in respiratory epithelium pertinent to airways disease. Using an airway epithelial cell line, we found a dose-dependent downregulation in TLR4 mRNA and protein expression by stimulation with cigarette smoke extracts. Treatment with the corticosteroids fluticasone and dexamethasone resulted in a dose-dependent reduction in TLR4 mRNA and protein. The functional significance of this effect was demonstrated by impaired IL-8 and HBD2 induction in response to LPS. Stimulation with salmeterol (10-6 M caused upregulation of TLR4 membrane protein presentation with no upregulation of mRNA, suggesting a post-translational effect. The effect of dexamethasone and salmeterol in combination was additive, with downregulation of TLR4 gene expression, and no change in membrane receptor expression. Modulation of TLR4 in respiratory epithelium may have important implications for airway inflammation and infection in response to inhaled pathogens.

  16. Third-generation Ah receptor-responsive luciferase reporter plasmids: amplification of dioxin-responsive elements dramatically increases CALUX bioassay sensitivity and responsiveness.

    Science.gov (United States)

    He, Guochun; Tsutsumi, Tomoaki; Zhao, Bin; Baston, David S; Zhao, Jing; Heath-Pagliuso, Sharon; Denison, Michael S

    2011-10-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and related dioxin-like chemicals are widespread and persistent environmental contaminants that produce diverse toxic and biological effects through their ability to bind to and activate the Ah receptor (AhR) and AhR-dependent gene expression. The chemically activated luciferase expression (CALUX) system is an AhR-responsive recombinant luciferase reporter gene-based cell bioassay that has been used in combination with chemical extraction and cleanup methods for the relatively rapid and inexpensive detection and relative quantitation of dioxin and dioxin-like chemicals in a wide variety of sample matrices. Although the CALUX bioassay has been validated and used extensively for screening purposes, it has some limitations when screening samples with very low levels of dioxin-like chemicals or when there is only a small amount of sample matrix for analysis. Here, we describe the development of third-generation (G3) CALUX plasmids with increased numbers of dioxin-responsive elements, and stable transfection of these new plasmids into mouse hepatoma (Hepa1c1c7) cells has produced novel amplified G3 CALUX cell bioassays that respond to TCDD with a dramatically increased magnitude of luciferase induction and significantly lower minimal detection limit than existing CALUX-type cell lines. The new G3 CALUX cell lines provide a highly responsive and sensitive bioassay system for the detection and relative quantitation of very low levels of dioxin-like chemicals in sample extracts.

  17. Levels of dioxins and dioxin-like PCBs in food and feed in Europe

    Energy Technology Data Exchange (ETDEWEB)

    Gallani, B.; Verstraete, F. [European Commission, DG SANCO, Brussels (Belgium); Boix, A.; Holst, C. von; Anklam, E. [European Commission, Joint Research Centre, Geel (Belgium)

    2004-09-15

    Regulation (EC) No 466/2001 as amended by Council Regulation (EC) No 2375/2001 of November 2001 setting maximum levels for certain contaminants in foodstuffs, inter alia dioxins, stipulates that foodstuffs should not, when placed on the market, contain higher contaminant levels than those specified in that Regulation. The Regulation also states that the Commission shall review Section 5 of Annex I, which outlines the maximum levels for dioxins and furans in food, by 31 December 2004 at the latest, in the light of new data on the presence of dioxins and dioxin-like PCBs, in particular with a view to the inclusion of dioxin-like PCBs in the levels to be set. Section 5 of Annex I shall be further reviewed by 31 December 2006 at the latest with the aim of significantly reducing the maximum levels. An EC Recommended Monitoring Programme for Food (Ref 1) was discussed to provide the Commission with the necessary data to make it possible to meet these commitments. A considerable amount of data was received by the Commission on the occurrence of dioxins and dioxin-like PCBs in food and was analysed to determine whether any patterns emerge in the ratios between dioxins and dioxin-like PCBs in certain food types or in certain areas. Directive 2002/32/EC of the European Parliament and of the Council as amended by Commission Directive 2003/57/EC of 17 June 2003 on undesirable substances in animal feed establishes maximum levels for dioxins in several feed materials and compound feeding stuffs. Similar revision clauses to the Regulation on food apply to this Directive on feeding stuffs. A monitoring programme similar to the one recommended for food was discussed for undesirable substances in animal feed (Ref 2). Data submitted by Member states on the occurrence of dioxins and dioxin-like PCBs in feed have also been analysed to determine whether any patterns emerge in the ratios between dioxins and dioxin-like PCBs in certain feedstuffs or in certain areas. This paper describes

  18. Nigribactin, a Novel Siderophore from Vibrio nigripulchritudo, Modulates Staphylococcus aureus Virulence Gene Expression

    DEFF Research Database (Denmark)

    Nielsen, Anita; Månsson, Maria; Wietz, Matthias

    2012-01-01

    Staphylococcus aureus is a serious human pathogen that employs a number of virulence factors as part of its pathogenesis. The purpose of the present study was to explore marine bacteria as a source of compounds that modulate virulence gene expression in S. aureus. During the global marine Galathea...... 3 expedition, a strain collection was established comprising bacteria that express antimicrobial activity against Vibrio anguillarum and/or Staphylococcus aureus. Within this collection we searched colony material, culture supernatants, and cell extracts for virulence modulating activity showing......, enterobactin, failed to influence S. aureus virulence gene expression. This study shows that marine microorganisms produce compounds with potential use in therapeutic strategies targeting virulence rather than viability of human pathogens....

  19. Posed versus spontaneous facial expressions are modulated by opposite cerebral hemispheres.

    Science.gov (United States)

    Ross, Elliott D; Pulusu, Vinay K

    2013-05-01

    Clinical research has indicated that the left face is more expressive than the right face, suggesting that modulation of facial expressions is lateralized to the right hemisphere. The findings, however, are controversial because the results explain, on average, approximately 4% of the data variance. Using high-speed videography, we sought to determine if movement-onset asymmetry was a more powerful research paradigm than terminal movement asymmetry. The results were very robust, explaining up to 70% of the data variance. Posed expressions began overwhelmingly on the right face whereas spontaneous expressions began overwhelmingly on the left face. This dichotomy was most robust for upper facial expressions. In addition, movement-onset asymmetries did not predict terminal movement asymmetries, which were not significantly lateralized. The results support recent neuroanatomic observations that upper versus lower facial movements have different forebrain motor representations and recent behavioral constructs that posed versus spontaneous facial expressions are modulated preferentially by opposite cerebral hemispheres and that spontaneous facial expressions are graded rather than non-graded movements. Published by Elsevier Ltd.

  20. 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.

  1. Modulated molecular beam mass spectrometry: A generalized expression for the ''reaction product vector'' for linear systems

    International Nuclear Information System (INIS)

    Chang, H.; Weinberg, W.H.

    1977-01-01

    A generalized expression is developed that relates the ''reaction product vector'', epsilon exp(-iphi), to the kinetic parameters of a linear system. The formalism is appropriate for the analysis of modulated molecular beam mass spectrometry data and facilitates the correlation of experimental results to (proposed) linear models. A study of stability criteria appropriate for modulated molecular beam mass spectrometry experiments is also presented. This investigation has led to interesting inherent limitations which have not heretofore been emphasized, as well as a delineation of the conditions under which stable chemical oscillations may occur in the reacting system

  2. Peripheral myelin protein-22 (PMP22 modulates alpha 6 integrin expression in the human endometrium

    Directory of Open Access Journals (Sweden)

    Braun Jonathan

    2011-04-01

    Full Text Available Abstract Background PMP22, a member of the GAS3 family of tetraspan proteins, is associated with a variety of neurological diseases. Previous studies have shown that PMP22 is expressed in proliferative endometrium, but its function within this tissue is poorly understood. In this study, we first characterized the expression of PMP22 in the human menstrual cycle and began to characterize its function in the endometrium. Methods Using a combination of immunohistochemistry and quantitative PCR, we characterized the expression of PMP22 in both proliferative and secretory endometrium. Differences in PMP22 expression between proliferative and secretory endometrium were determined using a Mann-Whitney U test. In order to investigate the influence of PMP22 on α6 integrin expression, cells were created that ectopically overexpressed PMP22 or expressed a siRNA to inhibit its expression. These cells were analyzed for changes in integrins and binding to extracellular matrices. Results In this study, we show that PMP22 expression is higher in proliferative phase than secretory phase. Functionally, we have begun to characterize the functional significance of this expression. Previous studies have suggested a link between PMP22 and α6 integrin, and therefore we asked whether PMP22 could associate or potentially modulate the expression of α6 integrin. Expression of both PMP22 and α6 integrin were detectable in endometrial epithelial and stromal cells, and we show that both proteins can associate and colocalize with each other. To understand if PMP22 directly altered the expression of a6 integrin, we examined cell lines with modulated levels of the protein. Overexpression of PMP22 was sufficient to increase α6 integrin surface expression with a concominant increase in binding to the extracellular matrix laminin, while a reduction in PMP22 suppressed α6 integrin surface expression. Conclusion These findings suggest a physiologic role for PMP22 on the

  3. Peripheral myelin protein-22 (PMP22) modulates alpha 6 integrin expression in the human endometrium.

    Science.gov (United States)

    Rao, Rajiv G; Sudhakar, Deepthi; Hogue, Claire P; Amici, Stephanie; Gordon, Lynn K; Braun, Jonathan; Notterpek, Lucia; Goodglick, Lee; Wadehra, Madhuri

    2011-04-25

    PMP22, a member of the GAS3 family of tetraspan proteins, is associated with a variety of neurological diseases. Previous studies have shown that PMP22 is expressed in proliferative endometrium, but its function within this tissue is poorly understood. In this study, we first characterized the expression of PMP22 in the human menstrual cycle and began to characterize its function in the endometrium. Using a combination of immunohistochemistry and quantitative PCR, we characterized the expression of PMP22 in both proliferative and secretory endometrium. Differences in PMP22 expression between proliferative and secretory endometrium were determined using a Mann-Whitney U test. In order to investigate the influence of PMP22 on α6 integrin expression, cells were created that ectopically overexpressed PMP22 or expressed a siRNA to inhibit its expression. These cells were analyzed for changes in integrins and binding to extracellular matrices. In this study, we show that PMP22 expression is higher in proliferative phase than secretory phase. Functionally, we have begun to characterize the functional significance of this expression. Previous studies have suggested a link between PMP22 and α6 integrin, and therefore we asked whether PMP22 could associate or potentially modulate the expression of α6 integrin. Expression of both PMP22 and α6 integrin were detectable in endometrial epithelial and stromal cells, and we show that both proteins can associate and colocalize with each other. To understand if PMP22 directly altered the expression of a6 integrin, we examined cell lines with modulated levels of the protein. Overexpression of PMP22 was sufficient to increase α6 integrin surface expression with a concominant increase in binding to the extracellular matrix laminin, while a reduction in PMP22 suppressed α6 integrin surface expression. These findings suggest a physiologic role for PMP22 on the expression of α6 integrin. We predict that this may be important for the

  4. Clofazimine modulates the expression of lipid metabolism proteins in Mycobacterium leprae-infected macrophages.

    Science.gov (United States)

    Degang, Yang; Akama, Takeshi; Hara, Takeshi; Tanigawa, Kazunari; Ishido, Yuko; Gidoh, Masaichi; Makino, Masahiko; Ishii, Norihisa; Suzuki, Koichi

    2012-01-01

    Mycobacterium leprae (M. leprae) lives and replicates within macrophages in a foamy, lipid-laden phagosome. The lipids provide essential nutrition for the mycobacteria, and M. leprae infection modulates expression of important host proteins related to lipid metabolism. Thus, M. leprae infection increases the expression of adipophilin/adipose differentiation-related protein (ADRP) and decreases hormone-sensitive lipase (HSL), facilitating the accumulation and maintenance of lipid-rich environments suitable for the intracellular survival of M. leprae. HSL levels are not detectable in skin smear specimens taken from leprosy patients, but re-appear shortly after multidrug therapy (MDT). This study examined the effect of MDT components on host lipid metabolism in vitro, and the outcome of rifampicin, dapsone and clofazimine treatment on ADRP and HSL expression in THP-1 cells. Clofazimine attenuated the mRNA and protein levels of ADRP in M. leprae-infected cells, while those of HSL were increased. Rifampicin and dapsone did not show any significant effects on ADRP and HSL expression levels. A transient increase of interferon (IFN)-β and IFN-γ mRNA was also observed in cells infected with M. leprae and treated with clofazimine. Lipid droplets accumulated by M. leprae-infection were significantly decreased 48 h after clofazimine treatment. Such effects were not evident in cells without M. leprae infection. In clinical samples, ADRP expression was decreased and HSL expression was increased after treatment. These results suggest that clofazimine modulates lipid metabolism in M. leprae-infected macrophages by modulating the expression of ADRP and HSL. It also induces IFN production in M. leprae-infected cells. The resultant decrease in lipid accumulation, increase in lipolysis, and activation of innate immunity may be some of the key actions of clofazimine.

  5. Piper betle L. Modulates Senescence-Associated Genes Expression in Replicative Senescent Human Diploid Fibroblasts

    Directory of Open Access Journals (Sweden)

    Lina Wati Durani

    2017-01-01

    Full Text Available Piper betle (PB is a traditional medicine that is widely used to treat different diseases around Asian region. The leaf extracts contain various bioactive compounds, which were reported to have antidiabetic, antibacterial, anti-inflammatory, antioxidant, and anticancer effects. In this study, the effect of PB aqueous extracts on replicative senescent human diploid fibroblasts (HDFs was investigated by determining the expressions of senescence-associated genes using quantitative PCR. Our results showed that PB extracts at 0.4 mg/ml can improve cell proliferation of young (143%, presenescent (127.3%, and senescent (157.3% HDFs. Increased expressions of PRDX6, TP53, CDKN2A, PAK2, and MAPK14 were observed in senescent HDFs compared to young and/or presenescent HDFs. Treatment with PB extracts modulates the transcriptional profile changes in senescent HDFs. By contrast, expressions of SOD1 increased, whereas GPX1, PRDX6, TP53, CDKN2A, PAK2, and MAPK14 were decreased in PB-treated senescent HDFs compared to untreated senescent HDFs. In conclusion, this study indicates the modulation of PB extracts on senescence-associated genes expression of replicative senescent HDFs. Further studies warrant determining the mechanism of PB in modulating replicative senescence of HDFs through these signaling pathways.

  6. Piper betle L. Modulates Senescence-Associated Genes Expression in Replicative Senescent Human Diploid Fibroblasts.

    Science.gov (United States)

    Durani, Lina Wati; Khor, Shy Cian; Tan, Jen Kit; Chua, Kien Hui; Mohd Yusof, Yasmin Anum; Makpol, Suzana

    2017-01-01

    Piper betle (PB) is a traditional medicine that is widely used to treat different diseases around Asian region. The leaf extracts contain various bioactive compounds, which were reported to have antidiabetic, antibacterial, anti-inflammatory, antioxidant, and anticancer effects. In this study, the effect of PB aqueous extracts on replicative senescent human diploid fibroblasts (HDFs) was investigated by determining the expressions of senescence-associated genes using quantitative PCR. Our results showed that PB extracts at 0.4 mg/ml can improve cell proliferation of young (143%), presenescent (127.3%), and senescent (157.3%) HDFs. Increased expressions of PRDX6 , TP53 , CDKN2A , PAK2 , and MAPK14 were observed in senescent HDFs compared to young and/or presenescent HDFs. Treatment with PB extracts modulates the transcriptional profile changes in senescent HDFs. By contrast, expressions of SOD1 increased, whereas GPX1 , PRDX6 , TP53 , CDKN2A , PAK2 , and MAPK14 were decreased in PB-treated senescent HDFs compared to untreated senescent HDFs. In conclusion, this study indicates the modulation of PB extracts on senescence-associated genes expression of replicative senescent HDFs. Further studies warrant determining the mechanism of PB in modulating replicative senescence of HDFs through these signaling pathways.

  7. PCDD/F, dioxin-like and markers PCBs in trouts from French aquaculture

    Energy Technology Data Exchange (ETDEWEB)

    Marchand, P.; Matayron, G.; Gade, C.; Le Bizec, B.; Andre, F. [LABERCA-ENVN, Nantes (France)

    2004-09-15

    Since the introduction of 12 ''dioxin-like'' polychlorinated biphenyls (PCBs) into the assessment of a tolerable daily intake (TDI) for polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) by the World Health Organization (WHO) in 1998, the analytical determination of nonand mono-ortho PCBs is of increasing interest in the scientific community. The European Commission has already published a regulation that sets maximum limits for dioxins in foodstuffs (Council Regulation 2375/01/EC amending Commission regulation (EC) N 466/2001 setting maximum levels for certain contaminants in foodstuffs). As an additional feature of the reduction strategy for this group of compounds, the European Commission has planned to include the dioxinlike PCBs in the limit values for food and feeding stuffs starting at the end of 2004. The LABERCA (French National Reference Laboratory for dioxins and dioxin-like PCBs (DL-PCBs)) and the CIPA (French Interprofessional Committee for Aquaculture products) reported levels in French farmed trout according to WHO-TEQ expression and sum of Markers PCBs (m-PCBs). It must be emphasized that this survey only represents a snapshot in time. The results cannot be used to determine the potential contamination of other batches that have not been tested. However, the fish samples were taken from 58 aquaculture sites and 10 fishes were pooled from each site. It is the reason why the results can be interpreted as a good indicative of the contamination levels in farmed trout produced in France.

  8. Applicability of the CALUX bioassay for screening of dioxin levels in human milk samples

    DEFF Research Database (Denmark)

    Laier, P.; Cederberg, Tommy Licht; Larsen, John Christian

    2003-01-01

    The CALUX (chemically activated luciferase expression) bioassay based on rat hepatoma (H4IIE) cells is a sensitive assay for the detection of Ah receptor agonists like 2,3,7,8-substituted chlorinated dibenzo-p-dioxins and dibenzofurans and related PCBs. In this paper, the assay was optimized...... and applied for monitoring levels of dioxins in human milk samples. Combination effects of dioxin-like compounds were evaluated by testing potential mechanisms of interaction between seven of the major dioxin-like compounds in human milk using the isobole method. Results showed that the compounds acted...... lower REP in CALUX. The total dioxin-like activity was determined in 16 Danish human milk samples and was in the range 20.5-55.8 pg TEQ g(-1) fat. These values were compared with TEQs obtained from GC/MS analysis (range 14.8-43.6 pg TEQ-g(-1) fat) that overall were a little lower than CALUX TEQs...

  9. Meta-analysis of peripheral blood gene expression modules for COPD phenotypes.

    Directory of Open Access Journals (Sweden)

    Dominik Reinhold

    Full Text Available Chronic obstructive pulmonary disease (COPD occurs typically in current or former smokers, but only a minority of people with smoking history develops the disease. Besides environmental factors, genetics is an important risk factor for COPD. However, the relationship between genetics, environment and phenotypes is not well understood. Sample sizes for genome-wide expression studies based on lung tissue have been small due to the invasive nature of sample collection. Increasing evidence for the systemic nature of the disease makes blood a good alternative source to study the disease, but there have also been few large-scale blood genomic studies in COPD. Due to the complexity and heterogeneity of COPD, examining groups of interacting genes may have more relevance than identifying individual genes. Therefore, we used Weighted Gene Co-expression Network Analysis to find groups of genes (modules that are highly connected. However, module definitions may vary between individual data sets. To alleviate this problem, we used a consensus module definition based on two cohorts, COPDGene and ECLIPSE. We studied the relationship between the consensus modules and COPD phenotypes airflow obstruction and emphysema. We also used these consensus module definitions on an independent cohort (TESRA and performed a meta analysis involving all data sets. We found several modules that are associated with COPD phenotypes, are enriched in functional categories and are overrepresented for cell-type specific genes. Of the 14 consensus modules, three were strongly associated with airflow obstruction (meta p ≤ 0.0002, and two had some association with emphysema (meta p ≤ 0.06; some associations were stronger in the case-control cohorts, and others in the cases-only subcohorts. Gene Ontology terms that were overrepresented included "immune response" and "defense response." The cell types whose type-specific genes were overrepresented in modules (p < 0.05 included

  10. Mode of action of dioxin-like versus non-dioxin-like PCBs

    Energy Technology Data Exchange (ETDEWEB)

    Schoeters, G. [VITO (Flemish Institute for Technological Research), Dept. of Environemental Toxicology (Belgium)]|[Antwerp Univ. (Belgium); Birnbaum, L. [United States Environmental Protection Agency, Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory (United States)

    2004-09-15

    Exposure of humans to polychlorinated biphenyls has been associated with different adverse effects such as immune impairment, changes in hormone levels, reproductive and neuropsychological changes and cancer. It is difficult to attribute the observed effects to either dioxin-like, non-dioxin-like PCBs or to both. All known human exposures are mixed, comprising dioxin and non-dioxin like PCB congeners as well as dioxins and furans. The purpose of this work was to evaluate, based on mechanistic data available in the open literature, whether non-dioxin like PCBs (NDL-PCBs) themselves may pose specific health risks. It is clear that dioxin and NDL-PCBs differ in the spectrum of metabolizing enzymes they induce, but the mechanistic links to health of these biochemical changes remain unclear at the moment. NDL-PCBs also cause immunotoxicity and tumor promotion via different mechanisms than do dioxin-like PCBs. We focus on neurotoxicity which has been associated with developmental exposure to PCBs and which is considered as one of the most sensitive adverse health effects.

  11. Contamination of free-range chicken eggs with dioxins and dioxin-like polychlorinated biphenyls

    NARCIS (Netherlands)

    Schoeters, G.; Hoogenboom, L.A.P.

    2006-01-01

    Dioxins and dioxin-like (DL) polychlorinated biphenyls (PCB) are persistent organic pollutants that enter the body mainly by food intake. A small margin exists between current exposure levels in the human population and the levels causing biological effects. Therefore, stringent control of

  12. Dietary exposure to dioxins and dioxin-like PCBs in The Netherlands anno 2004

    NARCIS (Netherlands)

    Mul, de A.; Bakker, M.I.; Zeilmaker, M.J.; Traag, W.A.; Leeuwen, van S.P.J.; Hoogenboom, L.A.P.; Boon, P.E.; Klaveren, van J.D.

    2008-01-01

    In this study, representative occurrence data for PCDD/Fs and dioxin-like PCBs in food were obtained and used to estimate dietary exposure of the Dutch population. Food composite samples were analyzed as well as single fish and vegetables samples. Total dioxin concentrations in animal products

  13. Dioxin and dioxin-like PCB exposure of non-breastfed Dutch infants.

    NARCIS (Netherlands)

    Weijs, P J M; Bakker, Martine I; Korver, K R; Goor Ghanaviztchi, K van; Wijnen, Joop H van

    2006-01-01

    The exposure of humans to PCDD/Fs (polychlorinated dibenzo-p-dioxins and dibenzofurans) and dioxin-like PCBs (dl-PCBs, i.e. polychlorinated non-ortho and mono-ortho biphenyls) occurs predominantly via the intake of food. Young children have a relatively high intake of these substances, due to their

  14. Proanthocyanidins modulate microRNA expression in human HepG2 cells.

    Directory of Open Access Journals (Sweden)

    Anna Arola-Arnal

    Full Text Available Mi(croRNAs are small non-coding RNAs of 18-25 nucleotides in length that modulate gene expression at the post-transcriptional level. These RNAs have been shown to be involved in a several biological processes, human diseases and metabolic disorders. Proanthocyanidins, which are the most abundant polyphenol class in the human diet, have positive health effects on a variety of metabolic disorders such as inflammation, obesity, diabetes and insulin resistance. The present study aimed to evaluate whether proanthocyanidin-rich natural extracts modulate miRNA expression. Using microarray analysis and Q-PCR, we investigated miRNA expression in HepG2 cells treated with proanthocyanidins. Our results showed that when HepG2 cells were treated with grape seed proanthocyanidin extract (GSPE, cocoa proanthocyanidin extract (CPE or pure epigallocatechin gallate isolated from green tea (EGCG, fifteen, six and five differentially expressed miRNAs, respectively, were identified out of 904 mRNAs. Specifically, miR-30b* was downregulated by the three treatments, and treatment with GSPE or CPE upregulated miR-1224-3p, miR-197 and miR-532-3p. Therefore, these results provide evidence of the capacity of dietary proanthocyanidins to influence microRNA expression, suggesting a new mechanism of action of proanthocyanidins.

  15. C. albicans Growth, Transition, Biofilm Formation, and Gene Expression Modulation by Antimicrobial Decapeptide KSL-W

    Science.gov (United States)

    2013-11-07

    RESEARCH ARTICLE Open Access C. albicans growth, transition, biofilm formation, and gene expression modulation by antimicrobial decapeptide KSL-W...at the end of the article © 2013 Theberge et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the...microbial growth and plaque formation by surfactant drugs. J Periodontal Res 1978, 13:474–485. 36. Semlali A, Leung KP, Curt S, Rouabhia M

  16. Modulation of neural circuits underlying temporal production by facial expressions of pain

    OpenAIRE

    Ballotta, Daniela; Lui, Fausta; Porro, Carlo Adolfo; Nichelli, Paolo Frigio; Benuzzi, Francesca

    2018-01-01

    According to the Scalar Expectancy Theory, humans are equipped with a biological internal clock, possibly modulated by attention and arousal. Both emotions and pain are arousing and can absorb attentional resources, thus causing distortions of temporal perception. The aims of the present single-event fMRI study were to investigate: a) whether observation of facial expressions of pain interferes with time production; and b) the neural network subserving this kind of temporal distortions. Thirt...

  17. The dioxines in environment and health; Les dioxines dans l'environnement et la sante

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2003-06-15

    Dioxines and furans are chlorinated polycyclic aromatic hydrocarbons. Their half life in environment are 10 years. their half life in human organism is 7 years. The techniques to measure and identify these components are complex. Dioxines emissions come from incomplete combustion. 60% of dioxines emissions come from domestic wastes incineration. Soils contamination is made by atmospheric particulates deposit. Dioxines are low soluble in water. The principal mode of exposure for man is the food chain (90 to 95% of global exposure). The effects of dioxines are cancer appearance, increase of congenital malformations, decrease of sex ratio at birth (excess of girls ), decrease of fertility, decrease of birth weight, late on sexual maturity and neurological development. Among other toxic effects are an increase of cardio vascular diseases and increase of lipid rate in blood. (N.C.)

  18. Gene Expression Measurement Module (GEMM) - a fully automated, miniaturized instrument for measuring gene expression in space

    Science.gov (United States)

    Karouia, Fathi; Ricco, Antonio; Pohorille, Andrew; Peyvan, Kianoosh

    2012-07-01

    The capability to measure gene expression on board spacecrafts opens the doors to a large number of experiments on the influence of space environment on biological systems that will profoundly impact our ability to conduct safe and effective space travel, and might also shed light on terrestrial physiology or biological function and human disease and aging processes. Measurements of gene expression will help us to understand adaptation of terrestrial life to conditions beyond the planet of origin, identify deleterious effects of the space environment on a wide range of organisms from microbes to humans, develop effective countermeasures against these effects, determine metabolic basis of microbial pathogenicity and drug resistance, test our ability to sustain and grow in space organisms that can be used for life support and in situ resource utilization during long-duration space exploration, and monitor both the spacecraft environment and crew health. These and other applications hold significant potential for discoveries in space biology, biotechnology and medicine. Accordingly, supported by funding from the NASA Astrobiology Science and Technology Instrument Development Program, we are developing a fully automated, miniaturized, integrated fluidic system for small spacecraft capable of in-situ measuring microbial expression of thousands of genes from multiple samples. The instrument will be capable of (1) lysing bacterial cell walls, (2) extracting and purifying RNA released from cells, (3) hybridizing it on a microarray and (4) providing electrochemical readout, all in a microfluidics cartridge. The prototype under development is suitable for deployment on nanosatellite platforms developed by the NASA Small Spacecraft Office. The first target application is to cultivate and measure gene expression of the photosynthetic bacterium Synechococcus elongatus, i.e. a cyanobacterium known to exhibit remarkable metabolic diversity and resilience to adverse conditions

  19. Gene Regulation, Modulation, and Their Applications in Gene Expression Data Analysis

    Directory of Open Access Journals (Sweden)

    Mario Flores

    2013-01-01

    Full Text Available Common microarray and next-generation sequencing data analysis concentrate on tumor subtype classification, marker detection, and transcriptional regulation discovery during biological processes by exploring the correlated gene expression patterns and their shared functions. Genetic regulatory network (GRN based approaches have been employed in many large studies in order to scrutinize for dysregulation and potential treatment controls. In addition to gene regulation and network construction, the concept of the network modulator that has significant systemic impact has been proposed, and detection algorithms have been developed in past years. Here we provide a unified mathematic description of these methods, followed with a brief survey of these modulator identification algorithms. As an early attempt to extend the concept to new RNA regulation mechanism, competitive endogenous RNA (ceRNA, into a modulator framework, we provide two applications to illustrate the network construction, modulation effect, and the preliminary finding from these networks. Those methods we surveyed and developed are used to dissect the regulated network under different modulators. Not limit to these, the concept of “modulation” can adapt to various biological mechanisms to discover the novel gene regulation mechanisms.

  20. Growing functional modules from a seed protein via integration of protein interaction and gene expression data

    Directory of Open Access Journals (Sweden)

    Dimitrakopoulou Konstantina

    2007-10-01

    Full Text Available Abstract Background Nowadays modern biology aims at unravelling the strands of complex biological structures such as the protein-protein interaction (PPI networks. A key concept in the organization of PPI networks is the existence of dense subnetworks (functional modules in them. In recent approaches clustering algorithms were applied at these networks and the resulting subnetworks were evaluated by estimating the coverage of well-established protein complexes they contained. However, most of these algorithms elaborate on an unweighted graph structure which in turn fails to elevate those interactions that would contribute to the construction of biologically more valid and coherent functional modules. Results In the current study, we present a method that corroborates the integration of protein interaction and microarray data via the discovery of biologically valid functional modules. Initially the gene expression information is overlaid as weights onto the PPI network and the enriched PPI graph allows us to exploit its topological aspects, while simultaneously highlights enhanced functional association in specific pairs of proteins. Then we present an algorithm that unveils the functional modules of the weighted graph by expanding a kernel protein set, which originates from a given 'seed' protein used as starting-point. Conclusion The integrated data and the concept of our approach provide reliable functional modules. We give proofs based on yeast data that our method manages to give accurate results in terms both of structural coherency, as well as functional consistency.

  1. Gene Expression Measurement Module (GEMM) - A Fully Automated, Miniaturized Instrument for Measuring Gene Expression in Space

    Science.gov (United States)

    Pohorille, Andrew; Peyvan, Kia; Karouia, Fathi; Ricco, Antonio

    2012-01-01

    The capability to measure gene expression on board spacecraft opens the door to a large number of high-value experiments on the influence of the space environment on biological systems. For example, measurements of gene expression will help us to understand adaptation of terrestrial life to conditions beyond the planet of origin, identify deleterious effects of the space environment on a wide range of organisms from microbes to humans, develop effective countermeasures against these effects, and determine the metabolic bases of microbial pathogenicity and drug resistance. These and other applications hold significant potential for discoveries in space biology, biotechnology, and medicine. Supported by funding from the NASA Astrobiology Science and Technology Instrument Development Program, we are developing a fully automated, miniaturized, integrated fluidic system for small spacecraft capable of in-situ measurement of expression of several hundreds of microbial genes from multiple samples. The instrument will be capable of (1) lysing cell walls of bacteria sampled from cultures grown in space, (2) extracting and purifying RNA released from cells, (3) hybridizing the RNA on a microarray and (4) providing readout of the microarray signal, all in a single microfluidics cartridge. The device is suitable for deployment on nanosatellite platforms developed by NASA Ames' Small Spacecraft Division. To meet space and other technical constraints imposed by these platforms, a number of technical innovations are being implemented. The integration and end-to-end technological and biological validation of the instrument are carried out using as a model the photosynthetic bacterium Synechococcus elongatus, known for its remarkable metabolic diversity and resilience to adverse conditions. Each step in the measurement process-lysis, nucleic acid extraction, purification, and hybridization to an array-is assessed through comparison of the results obtained using the instrument with

  2. H-ferritin-regulated microRNAs modulate gene expression in K562 cells.

    Directory of Open Access Journals (Sweden)

    Flavia Biamonte

    Full Text Available In a previous study, we showed that the silencing of the heavy subunit (FHC offerritin, the central iron storage molecule in the cell, is accompanied by a modification in global gene expression. In this work, we explored whether different FHC amounts might modulate miRNA expression levels in K562 cells and studied the impact of miRNAs in gene expression profile modifications. To this aim, we performed a miRNA-mRNA integrative analysis in K562 silenced for FHC (K562shFHC comparing it with K562 transduced with scrambled RNA (K562shRNA. Four miRNAs, namely hsa-let-7g, hsa-let-7f, hsa-let-7i and hsa-miR-125b, were significantly up-regulated in silenced cells. The remarkable down-regulation of these miRNAs, following FHC expression rescue, supports a specific relation between FHC silencing and miRNA-modulation. The integration of target predictions with miRNA and gene expression profiles led to the identification of a regulatory network which includes the miRNAs up-regulated by FHC silencing, as well as91 down-regulated putative target genes. These genes were further classified in 9 networks; the highest scoring network, "Cell Death and Survival, Hematological System Development and Function, Hematopoiesis", is composed by 18 focus molecules including RAF1 and ERK1/2. We confirmed that, following FHC silencing, ERK1/2 phosphorylation is severely impaired and that RAF1 mRNA is significantly down-regulated. Taken all together, our data indicate that, in our experimental model, FHC silencing may affect RAF1/pERK1/2 levels through the modulation of a specific set of miRNAs and add new insights in to the relationship among iron homeostasis and miRNAs.

  3. Serum Dioxin and Memory Among Veterans of Operation Ranch Hand

    National Research Council Canada - National Science Library

    Patches, Johnson; Cary, Martin; Grubbs, William; Jackson, William; Robinson, Julie; Pavuk, Marian

    2007-01-01

    The authors used the Wechsler Memory Scale and the Wechsler Memory Scale-Revised to assess memory among Air Force veterans exposed to Agent Orange and its contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin...

  4. Endogenous angiotensin II modulates nNOS expression in renovascular hypertension

    Directory of Open Access Journals (Sweden)

    T.M.C. Pereira

    2009-07-01

    Full Text Available Nitric oxide (NO influences renal blood flow mainly as a result of neuronal nitric oxide synthase (nNOS. Nevertheless, it is unclear how nNOS expression is modulated by endogenous angiotensin II, an inhibitor of NO function. We tested the hypothesis that the angiotensin II AT1 receptor and oxidative stress mediated by NADPH oxidase contribute to the modulation of renal nNOS expression in two-kidney, one-clip (2K1C hypertensive rats. Experiments were performed on male Wistar rats (150 to 170 g body weight divided into 2K1C (N = 19 and sham-operated (N = 19 groups. nNOS expression in kidneys of 2K1C hypertensive rats (N = 9 was compared by Western blotting to that of 2K1C rats treated with low doses of the AT1 antagonist losartan (10 mg·kg-1·day-1; N = 5 or the superoxide scavenger tempol (0.2 mmol·kg-1·day-1; N = 5, which still remain hypertensive. After 28 days, nNOS expression was significantly increased by 1.7-fold in the clipped kidneys of 2K1C rats and by 3-fold in the non-clipped kidneys of 2K1C rats compared with sham rats, but was normalized by losartan. With tempol treatment, nNOS expression increased 2-fold in the clipped kidneys and 1.4-fold in the non-clipped kidneys compared with sham rats. The changes in nNOS expression were not followed by changes in the enzyme activity, as measured indirectly by the cGMP method. In conclusion, AT1 receptors and oxidative stress seem to be primary stimuli for increased nNOS expression, but this up-regulation does not result in higher enzyme activity.

  5. Dynamic modulation of thymidylate synthase gene expression and fluorouracil sensitivity in human colorectal cancer cells.

    Directory of Open Access Journals (Sweden)

    Kentaro Wakasa

    Full Text Available Biomarkers have revolutionized cancer chemotherapy. However, many biomarker candidates are still in debate. In addition to clinical studies, a priori experimental approaches are needed. Thymidylate synthase (TS expression is a long-standing candidate as a biomarker for 5-fluorouracil (5-FU treatment of cancer patients. Using the Tet-OFF system and a human colorectal cancer cell line, DLD-1, we first constructed an in vitro system in which TS expression is dynamically controllable. Quantitative assays have elucidated that TS expression in the transformant was widely modulated, and that the dynamic range covered 15-fold of the basal level. 5-FU sensitivity of the transformant cells significantly increased in response to downregulated TS expression, although being not examined in the full dynamic range because of the doxycycline toxicity. Intriguingly, our in vitro data suggest that there is a linear relationship between TS expression and the 5-FU sensitivity in cells. Data obtained in a mouse model using transformant xenografts were highly parallel to those obtained in vitro. Thus, our in vitro and in vivo observations suggest that TS expression is a determinant of 5-FU sensitivity in cells, at least in this specific genetic background, and, therefore, support the possibility of TS expression as a biomarker for 5-FU-based cancer chemotherapy.

  6. Hepatic transcriptomic responses to TCDD in dioxin-sensitive and dioxin-resistant rats during the onset of toxicity

    International Nuclear Information System (INIS)

    Boutros, Paul C.; Yao, Cindy Q.; Watson, John D.; Wu, Alexander H.; Moffat, Ivy D.; Prokopec, Stephenie D.; Smith, Ashley B.; Okey, Allan B.; Pohjanvirta, Raimo

    2011-01-01

    The dioxin congener 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes a wide range of toxic effects in rodent species, all of which are mediated by a ligand-dependent transcription-factor, the aryl hydrocarbon receptor (AHR). The Han/Wistar (Kuopio) (H/W) strain shows exceptional resistance to many TCDD-induced toxicities; the LD 50 of > 9600 μg/kg for H/W rats is higher than for any other wild-type mammal known. We previously showed that this resistance primarily results from H/W rats expressing a variant AHR isoform that has a substantial portion of the AHR transactivation domain deleted. Despite this large deletion, H/W rats are not entirely refractory to the effects of TCDD; the variant AHR in these animals remains fully competent to up-regulate well-known dioxin-inducible genes. TCDD-sensitive (Long-Evans, L-E) and resistant (H/W) rats were treated with either corn-oil (with or without feed-restriction) or 100 μg/kg TCDD for either four or ten days. Hepatic transcriptional profiling was done using microarrays, and was validated by RT-PCR analysis of 41 genes. A core set of genes was altered in both strains at all time points tested, including CYP1A1, CYP1A2, CYP1B1, Nqo1, Aldh3a1, Tiparp, Exoc3, and Inmt. Outside this core, the strains differed significantly in the breadth of response: three-fold more genes were altered in L-E than H/W rats. At ten days almost all expressed genes were dysregulated in L-E rats, likely reflecting emerging toxic responses. Far fewer genes were affected by feed-restriction, suggesting that only a minority of the TCDD-induced changes are secondary to the wasting syndrome.

  7. Dopamine transporter polymorphism modulates oculomotor function and DAT1 mRNA expression in schizophrenia.

    Science.gov (United States)

    Wonodi, Ikwunga; Hong, L Elliot; Stine, O Colin; Mitchell, Braxton D; Elliott, Amie; Roberts, Rosalinda C; Conley, Robert R; McMahon, Robert P; Thaker, Gunvant K

    2009-03-05

    Smooth pursuit eye movement (SPEM) deficit is an established schizophrenia endophenotype with a similar neurocognitive construct to working memory. Frontal eye field (FEF) neurons controlling SPEM maintain firing when visual sensory information is removed, and their firing rates directly correlate with SPEM velocity. We previously demonstrated a paradoxical association between a functional polymorphism of dopamine signaling (COMT gene) and SPEM. Recent evidence implicates the dopamine transporter gene (DAT1) in modulating cortical dopamine and associated neurocognitive functions. We hypothesized that DAT1 10/10 genotype, which reduces dopamine transporter expression and increases extracellular dopamine, would affect SPEM. We examined the effects of DAT1 genotype on: Clinical diagnosis in the study sample (n = 418; 190 with schizophrenia), SPEM measures in a subgroup with completed oculomotor measures (n = 200; 87 schizophrenia), and DAT1 gene expression in FEF tissue obtained from postmortem brain samples (n = 32; 16 schizophrenia). DAT1 genotype was not associated with schizophrenia. DAT1 10/10 genotype was associated with better SPEM in healthy controls, intermediate SPEM in unaffected first-degree relatives of schizophrenia subjects, and worse SPEM in schizophrenia subjects. In the gene expression study, DAT1 10/10 genotype was associated with significantly reduced DAT1 mRNA transcript in FEF tissue from healthy control donors (P < 0.05), but higher expression in schizophrenia donors. Findings suggest regulatory effects of another gene(s) or etiological factor in schizophrenia, which modulate DAT1 gene function. 2008 Wiley-Liss, Inc.

  8. The bromodomain protein LEX-1 acts with TAM-1 to modulate gene expression in C. elegans.

    Science.gov (United States)

    Tseng, Rong-Jeng; Armstrong, Kristin R; Wang, Xiaodong; Chamberlin, Helen M

    2007-11-01

    In many organisms, repetitive DNA serves as a trigger for gene silencing. However, some gene expression is observed from repetitive genomic regions such as heterochromatin, suggesting mechanisms exist to modulate the silencing effects. From a genetic screen in C. elegans, we have identified mutations in two genes important for expression of repetitive sequences: lex-1 and tam-1. Here we show that lex-1 encodes a protein containing an ATPase domain and a bromodomain. LEX-1 is similar to the yeast Yta7 protein, which maintains boundaries between silenced and active chromatin. tam-1 has previously been shown to encode a RING finger/B-box protein that modulates gene expression from repetitive DNA. We find that lex-1, like tam-1, acts as a class B synthetic multivulva (synMuv) gene. However, since lex-1 and tam-1 mutants have normal P granule localization, it suggests they act through a mechanism distinct from other class B synMuvs. We observe intragenic (interallelic) complementation with lex-1 and a genetic interaction between lex-1 and tam-1, data consistent with the idea that the gene products function in the same biological process, perhaps as part of a protein complex. We propose that LEX-1 and TAM-1 function together to influence chromatin structure and to promote expression from repetitive sequences.

  9. Modulation of SOCS protein expression influences the interferon responsiveness of human melanoma cells

    International Nuclear Information System (INIS)

    Lesinski, Gregory B; Zimmerer, Jason M; Kreiner, Melanie; Trefry, John; Bill, Matthew A; Young, Gregory S; Becknell, Brian; Carson, William E III

    2010-01-01

    Endogenously produced interferons can regulate the growth of melanoma cells and are administered exogenously as therapeutic agents to patients with advanced cancer. We investigated the role of negative regulators of interferon signaling known as suppressors of cytokine signaling (SOCS) in mediating interferon-resistance in human melanoma cells. Basal and interferon-alpha (IFN-α) or interferon-gamma (IFN-γ)-induced expression of SOCS1 and SOCS3 proteins was evaluated by immunoblot analysis in a panel of n = 10 metastatic human melanoma cell lines, in human embryonic melanocytes (HEM), and radial or vertical growth phase melanoma cells. Over-expression of SOCS1 and SOCS3 proteins in melanoma cells was achieved using the PINCO retroviral vector, while siRNA were used to inhibit SOCS1 and SOCS3 expression. Tyr 701 -phosphorylated STAT1 (P-STAT1) was measured by intracellular flow cytometry and IFN-stimulated gene expression was measured by Real Time PCR. SOCS1 and SOCS3 proteins were expressed at basal levels in melanocytes and in all melanoma cell lines examined. Expression of the SOCS1 and SOCS3 proteins was also enhanced following stimulation of a subset of cell lines with IFN-α or IFN-γ. Over-expression of SOCS proteins in melanoma cell lines led to significant inhibition of Tyr 701 -phosphorylated STAT1 (P-STAT1) and gene expression following stimulation with IFN-α (IFIT2, OAS-1, ISG-15) or IFN-γ (IRF1). Conversely, siRNA inhibition of SOCS1 and SOCS3 expression in melanoma cells enhanced their responsiveness to interferon stimulation. These data demonstrate that SOCS proteins are expressed in human melanoma cell lines and their modulation can influence the responsiveness of melanoma cells to IFN-α and IFN-γ

  10. DIOXINS AND ENDOMETRIOSIS: COHORT STUDY OF WOMEN IN WEST VIRGINIA

    Science.gov (United States)

    Kanawha Valley of West Virginia has a history of 2,3,7,8-tetrachlorodibenzo-p-dioxin contamination (dioxin, TCDD). The bulk of the dioxin found in this area appears to be derived from the production of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and the disposal of associated wa...

  11. Galunisertib suppresses the staminal phenotype in hepatocellular carcinoma by modulating CD44 expression.

    Science.gov (United States)

    Rani, Bhavna; Malfettone, Andrea; Dituri, Francesco; Soukupova, Jitka; Lupo, Luigi; Mancarella, Serena; Fabregat, Isabel; Giannelli, Gianluigi

    2018-03-07

    Cancer stem cells (CSCs) niche in the tumor microenvironment is responsible for cancer recurrence and therapy failure. To better understand its molecular and biological involvement in hepatocellular carcinoma (HCC) progression, one can design more effective therapies and tailored then to individual patients. While sorafenib is currently the only approved drug for first-line treatment of advanced stage HCC, its role in modulating the CSC niche is estimated to be small. By contrast, transforming growth factor (TGF)-β pathway seems to influence the CSC and thus may impact hallmarks of HCC, such as liver fibrosis, cirrhosis, and tumor progression. Therefore, blocking this pathway may offer an appealing and druggable target. In our study, we have used galunisertib (LY2157299), a selective ATP-mimetic inhibitor of TGF-β receptor I (TGFβI/ALK5) activation, currently under clinical investigation in HCC patients. Because the drug resistance is mainly mediated by CSCs, we tested the effects of galunisertib on stemness phenotype in HCC cells to determine whether TGF-β signaling modulates CSC niche and drug resistance. Galunisertib modulated the expression of stemness-related genes only in the invasive (HLE and HLF) HCC cells inducing a decreased expression of CD44 and THY1. Furthermore, galunisertib also reduced the stemness-related functions of invasive HCC cells decreasing the formation of colonies, liver spheroids and invasive growth ability. Interestingly, CD44 loss of function mimicked the galunisertib effects on HCC stemness-related functions. Galunisertib treatment also reduced the expression of stemness-related genes in ex vivo human HCC specimens. Our observations are the first evidence that galunisertib effectiveness overcomes stemness-derived aggressiveness via decreased expression CD44 and THY1.

  12. The expression of melanopsin and clock genes in Xenopus laevis melanophores and their modulation by melatonin

    Energy Technology Data Exchange (ETDEWEB)

    Bluhm, A.P.C.; Obeid, N.N.; Castrucci, A.M.L.; Visconti, M.A. [Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP (Brazil)

    2012-05-25

    Vertebrates have a central clock and also several peripheral clocks. Light responses might result from the integration of light signals by these clocks. The dermal melanophores of Xenopus laevis have a photoreceptor molecule denominated melanopsin (OPN4x). The mechanisms of the circadian clock involve positive and negative feedback. We hypothesize that these dermal melanophores also present peripheral clock characteristics. Using quantitative PCR, we analyzed the pattern of temporal expression of Opn4x and the clock genes Per1, Per2, Bmal1, and Clock in these cells subjected to a 14-h light:10-h dark (14L:10D) regime or constant darkness (DD). Also, in view of the physiological role of melatonin in the dermal melanophores of X. laevis, we determined whether melatonin modulates the expression of these clock genes. These genes show a time-dependent expression pattern when these cells are exposed to 14L:10D, which differs from the pattern observed under DD. Cells kept in DD for 5 days exhibited overall increased mRNA expression for Opn4x and Clock, and a lower expression for Per1, Per2, and Bmal1. When the cells were kept in DD for 5 days and treated with melatonin for 1 h, 24 h before extraction, the mRNA levels tended to decrease for Opn4x and Clock, did not change for Bmal1, and increased for Per1 and Per2 at different Zeitgeber times (ZT). Although these data are limited to one-day data collection, and therefore preliminary, we suggest that the dermal melanophores of X. laevis might have some characteristics of a peripheral clock, and that melatonin modulates, to a certain extent, melanopsin and clock gene expression.

  13. The expression of melanopsin and clock genes in Xenopus laevis melanophores and their modulation by melatonin

    International Nuclear Information System (INIS)

    Bluhm, A.P.C.; Obeid, N.N.; Castrucci, A.M.L.; Visconti, M.A.

    2012-01-01

    Vertebrates have a central clock and also several peripheral clocks. Light responses might result from the integration of light signals by these clocks. The dermal melanophores of Xenopus laevis have a photoreceptor molecule denominated melanopsin (OPN4x). The mechanisms of the circadian clock involve positive and negative feedback. We hypothesize that these dermal melanophores also present peripheral clock characteristics. Using quantitative PCR, we analyzed the pattern of temporal expression of Opn4x and the clock genes Per1, Per2, Bmal1, and Clock in these cells subjected to a 14-h light:10-h dark (14L:10D) regime or constant darkness (DD). Also, in view of the physiological role of melatonin in the dermal melanophores of X. laevis, we determined whether melatonin modulates the expression of these clock genes. These genes show a time-dependent expression pattern when these cells are exposed to 14L:10D, which differs from the pattern observed under DD. Cells kept in DD for 5 days exhibited overall increased mRNA expression for Opn4x and Clock, and a lower expression for Per1, Per2, and Bmal1. When the cells were kept in DD for 5 days and treated with melatonin for 1 h, 24 h before extraction, the mRNA levels tended to decrease for Opn4x and Clock, did not change for Bmal1, and increased for Per1 and Per2 at different Zeitgeber times (ZT). Although these data are limited to one-day data collection, and therefore preliminary, we suggest that the dermal melanophores of X. laevis might have some characteristics of a peripheral clock, and that melatonin modulates, to a certain extent, melanopsin and clock gene expression

  14. Anaerobic reductive dehalogenation of polychlorinated dioxins

    Energy Technology Data Exchange (ETDEWEB)

    Bunge, Michael [Aarhus Univ. (DK). Dept. of Biological Sciences, Microbiology, and Interdisciplinary Nanoscience Centre (iNANO); Lechner, Ute [Halle-Wittenberg Univ., Halle (Germany). Inst. of Biology/Microbiology

    2009-09-15

    Polychlorinated dibenzo-p-dioxins and -furans (PCDD/Fs) are among the most harmful environmental contaminants. Their widespread distribution due to unintentional or unknown release coincides with environmental persistence, acute and chronic toxicity to living organisms, and long-term effects due to the compounds' tendency for bioaccumulation and biomagnification. While microbial aerobic degradation of PCDD/Fs is mainly reported for the turnover of low chlorinated congeners, this review focuses on anaerobic reductive dehalogenation, which may constitute a potential remediation strategy for polychlorinated compounds in soils and sediments. Microorganisms in sediments and in microcosms or enrichment cultures have been shown to be involved in the reductive dechlorination of dioxins. Bacteria related to the genus Dehalococcoides are capable of the reductive transformation of dioxins leading to lower chlorinated dioxins including di- and monochlorinated congeners. Thus, reductive dehalogenation might be one of the very few mechanisms able to mediate the turnover of polychlorinated dioxins by reducing their toxicity and paving the way for a subsequent breakdown of the carbon skeleton. (orig.)

  15. A mouse strain less responsive to dioxin-induced prostaglandin E2 synthesis is resistant to the onset of neonatal hydronephrosis.

    Science.gov (United States)

    Aida-Yasuoka, Keiko; Yoshioka, Wataru; Kawaguchi, Tatsuya; Ohsako, Seiichiroh; Tohyama, Chiharu

    2014-10-01

    Dioxin is a ubiquitous environmental pollutant that induces toxicity when bound to the aryl hydrocarbon receptor (AhR). Significant differences in susceptibility of mouse strains to dioxin toxicity are largely accounted for by the dissociation constant of binding to dioxins of AhR subtypes encoded by different alleles. We showed that cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1), components of a prostanoid synthesis pathway, play essential roles in the onset of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced hydronephrosis of neonatal mice. Although C57BL/6J and BALB/cA mice harbor AhR receptors highly responsive to TCDD, they were found by chance to differ significantly in the incidence of TCDD-induced hydronephrosis. Therefore, the goal of the present study was to determine the molecular basis of this difference in susceptibility to TCDD toxicity. For this purpose, we administered C57BL/6J and BALB/cA dams' TCDD at an oral dose of 15 or 80 μg/kg on postnatal day (PND) 1 to expose pups to TCDD via lactation, and the pups' kidneys were collected on PND 7. The incidence of hydronephrosis in C57BL/6J pups (64%) was greater than in BALB/cA pups (0%, p hydronephrosis in these mouse strains paralleled the levels of renal mPGES-1 mRNA and early growth response 1 (Egr-1) that modulates mPGES-1 gene expression, as well as PGE2 concentrations in urine. Although these mouse strains possess AhR alleles tightly bound to TCDD, their difference in incidence and severity of hydronephrosis can be explained, in part, by differences in the expression of mPGES-1 and Egr-1. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  16. Influence of cAMP on reporter bioassays for dioxin and dioxin-like compounds

    International Nuclear Information System (INIS)

    Kasai, Ayumi; Yao, Jian; Yamauchi, Kozue; Hiramatsu, Nobuhiko; Hayakawa, Kunihiro; Meng, Yiman; Maeda, Shuichiro; Kitamura, Masanori

    2006-01-01

    In reporter assays for detection of dioxins, the dioxin-responsive element (DRE) is generally used as a sensor sequence. In several systems, the CYP1A1 promoter containing DREs (DRE cyp ) is inserted into a part of the long terminal repeat of mouse mammary tumor virus (LTR MMTV ) to improve sensitivity of assays. We found that DRE cyp -LTR MMTV responds not only to dioxins and dioxin-like compounds but also to forskolin, a cAMP-elevating agent. This effect was dose-dependent and reproduced by other cAMP-elevating agents including 8-bromo-cAMP and 3-isobutyl-methylxanthine. The cAMP response element (CRE) and CRE-like sequences were absent in DRE cyp -LTR MMTV and not involved in this process. In contrast to the effect of dioxin, the activation of DRE cyp -LTR MMTV by cAMP was independent of the aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor for DRE. Furthermore, neither DRE cyp , LTR MMTV nor the consensus sequence of DRE alone was activated in response to cAMP. These data elucidated for the first time that the combination of DRE cyp with LTR MMTV causes a peculiar response to cAMP and suggested that use of AhR antagonists is essential to exclude false-positive responses of DRE cyp -LTR MMTV -based bioassays for detection and quantification of dioxins and dioxin-like compounds

  17. Environmental pollution by dioxin and its biodegradation; Dioxin ni yoru kankyo osen to sono biseibutsu bunkai

    Energy Technology Data Exchange (ETDEWEB)

    Nojiri, H.; Yamane, H.; Omori, T. [Tokyo Univ. (Japan)

    1998-10-20

    Polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and coplanar polychlorinated biphenyls (Co-PCBs) exhibit similar chemical and biological properties. Because of their highly toxic activity, the pollution with these compounds, which are called dioxin-related compounds, is one of the most serious environmental problems. In this review, we described the analytical methods of dioxin-related compounds in environmental samples, especially in the exhaust gas from the incineration site of municipal solid waste. In addition, we described the present situation of environmental pollution by dioxin-related compounds, including pollution levels in environmental, human, and food samples, daily intakes, and risk assessment. On the other hand, a number of microorganisms have been reported which are able to degrade dioxin-related compounds including PCDDs and PCDFs. These microorganisms are classified into two groups, lignin-degrading white rot fungi and the dioxin-degrading bacteria. We also described the degradation pathways of dioxin-related compounds in these microorganisms, and their degradative enzymes. 47 refs., 5 figs., 4 tabs.

  18. Expression of aryl hydrocarbon receptor 1 (AHR1), AHR1 nuclear translocator 1 (ARNT1) and CYP1 family monooxygenase mRNAs and their activity in chicken ovarian follicles following in vitro exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

    Science.gov (United States)

    Antos, Piotr A; Błachuta, Małgorzata; Hrabia, Anna; Grzegorzewska, Agnieszka K; Sechman, Andrzej

    2015-09-02

    The aim of this in vitro study was to determine the effect of TCDD and luteinizing hormone (LH) on mRNA expression of aryl hydrocarbon receptor 1 (AHR1), AHR1 nuclear translocator 1 (ARNT1), and the CYP1 family monooxygenases (CYP1A4, CYP1A5, CYP1B1), and to assess the basal and TCDD-induced activity of these enzymes in chicken ovarian follicles. White (WF) and yellowish (YF) prehierarchical follicles and fragments of the theca (TL) and granulosa (GL) layers of the 3 largest preovulatory follicles (F3-F1) were exposed to TCDD (10nM), ovine LH (oLH; 10ng/mL) or a combination of TCDD (10nM) and oLH (10ng/mL), and increasing doses of TCDD (0.01-100nM). AHR1 and ARNT1 mRNA transcripts were found in all examined follicles. The effect of TCDD and oLH on AHR1 and ARNT1 mRNA expression depended on the maturational state of the follicle. CYP1A4 was predominantly expressed in the GL of the F3-F1 follicles; in comparison with the WF, a higher level of CYP1A5 mRNA was found both in the GL and TL of F3-F1 follicles. Alternatively, the highest level of CYP1B1 mRNA was noticed in the WF follicles. In different developmental stages of the follicle TCDD and oLH induced a different CYP1 isoform. TCDD increased EROD and MROD activities in all the investigated ovarian follicles. In conclusion, AHR1 and ARNT1 mRNA expression indicate that the chicken ovary is a target tissue for dioxin and dioxin-like compounds. The expression of CYP1-family genes and TCDD-inducible EROD and MROD activities in ovarian follicles suggest the possibility of xenobiotic detoxification in the chicken ovary. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  19. Modulation of cytokine expression in human macrophages by endocrine-disrupting chemical Bisphenol-A

    International Nuclear Information System (INIS)

    Liu, Yanzhen; Mei, Chenfang; Liu, Hao; Wang, Hongsheng; Zeng, Guoqu; Lin, Jianhui; Xu, Meiying

    2014-01-01

    Highlights: • Effects of BPA on the cytokines expression of human macrophages were investigated. • BPA increased pro-inflammation cytokines TNF-α and IL-6 production. • BPA decreased anti-inflammation IL-10 and TGF-β production. • ERα/β/ERK/NF-κB signaling involved in BPA-mediated cytokines expression. - Abstract: Exposure to environmental endocrine-disrupting chemical Bisphenol-A (BPA) is often associated with dysregulated immune homeostasis, but the mechanisms remain unclear. In the present study, the effects of BPA on the cytokines responses of human macrophages were investigated. Treatment with BPA increased pro-inflammation cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production, but decreased anti-inflammation cytokines interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) production in THP1 macrophages, as well as in primary human macrophages. BPA effected cytokines expression through estrogen receptor α/β (ERα/β)-dependent mechanism with the evidence of ERα/β antagonist reversed the expression of cytokines. We also identified that activation of extracellular regulated protein kinases (ERK)/nuclear factor κB (NF-κB) signal cascade marked the effects of BPA on cytokines expression. Our results indicated that BPA effected inflammatory responses of macrophages via modulating of cytokines expression, and provided a new insight into the link between exposure to BPA and human health

  20. Modulation of gene expression in heart and liver of hibernating black bears (Ursus americanus).

    Science.gov (United States)

    Fedorov, Vadim B; Goropashnaya, Anna V; Tøien, Øivind; Stewart, Nathan C; Chang, Celia; Wang, Haifang; Yan, Jun; Showe, Louise C; Showe, Michael K; Barnes, Brian M

    2011-03-31

    Hibernation is an adaptive strategy to survive in highly seasonal or unpredictable environments. The molecular and genetic basis of hibernation physiology in mammals has only recently been studied using large scale genomic approaches. We analyzed gene expression in the American black bear, Ursus americanus, using a custom 12,800 cDNA probe microarray to detect differences in expression that occur in heart and liver during winter hibernation in comparison to summer active animals. We identified 245 genes in heart and 319 genes in liver that were differentially expressed between winter and summer. The expression of 24 genes was significantly elevated during hibernation in both heart and liver. These genes are mostly involved in lipid catabolism and protein biosynthesis and include RNA binding protein motif 3 (Rbm3), which enhances protein synthesis at mildly hypothermic temperatures. Elevated expression of protein biosynthesis genes suggests induction of translation that may be related to adaptive mechanisms reducing cardiac and muscle atrophies over extended periods of low metabolism and immobility during hibernation in bears. Coordinated reduction of transcription of genes involved in amino acid catabolism suggests redirection of amino acids from catabolic pathways to protein biosynthesis. We identify common for black bears and small mammalian hibernators transcriptional changes in the liver that include induction of genes responsible for fatty acid β oxidation and carbohydrate synthesis and depression of genes involved in lipid biosynthesis, carbohydrate catabolism, cellular respiration and detoxification pathways. Our findings show that modulation of gene expression during winter hibernation represents molecular mechanism of adaptation to extreme environments.

  1. Modulation of cytokine expression in human macrophages by endocrine-disrupting chemical Bisphenol-A

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Yanzhen; Mei, Chenfang [State Key Laboratory of Applied Microbiology Southern China, Guangzhou 510070 (China); Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Institute of Microbiology, Guangzhou 510070 (China); Liu, Hao [Affiliated Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou 510095 (China); Wang, Hongsheng [Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006 (China); Zeng, Guoqu; Lin, Jianhui [State Key Laboratory of Applied Microbiology Southern China, Guangzhou 510070 (China); Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Institute of Microbiology, Guangzhou 510070 (China); Xu, Meiying, E-mail: xumy@gdim.cn [State Key Laboratory of Applied Microbiology Southern China, Guangzhou 510070 (China); Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Institute of Microbiology, Guangzhou 510070 (China)

    2014-09-05

    Highlights: • Effects of BPA on the cytokines expression of human macrophages were investigated. • BPA increased pro-inflammation cytokines TNF-α and IL-6 production. • BPA decreased anti-inflammation IL-10 and TGF-β production. • ERα/β/ERK/NF-κB signaling involved in BPA-mediated cytokines expression. - Abstract: Exposure to environmental endocrine-disrupting chemical Bisphenol-A (BPA) is often associated with dysregulated immune homeostasis, but the mechanisms remain unclear. In the present study, the effects of BPA on the cytokines responses of human macrophages were investigated. Treatment with BPA increased pro-inflammation cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production, but decreased anti-inflammation cytokines interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) production in THP1 macrophages, as well as in primary human macrophages. BPA effected cytokines expression through estrogen receptor α/β (ERα/β)-dependent mechanism with the evidence of ERα/β antagonist reversed the expression of cytokines. We also identified that activation of extracellular regulated protein kinases (ERK)/nuclear factor κB (NF-κB) signal cascade marked the effects of BPA on cytokines expression. Our results indicated that BPA effected inflammatory responses of macrophages via modulating of cytokines expression, and provided a new insight into the link between exposure to BPA and human health.

  2. Manipulation of colony environment modulates honey bee aggression and brain gene expression.

    Science.gov (United States)

    Rittschof, C C; Robinson, G E

    2013-11-01

    The social environment plays an essential role in shaping behavior for most animals. Social effects on behavior are often linked to changes in brain gene expression. In the honey bee (Apis mellifera L.), social modulation of individual aggression allows colonies to adjust the intensity with which they defend their hive in response to predation threat. Previous research has showed social effects on both aggression and aggression-related brain gene expression in honey bees, caused by alarm pheromone and unknown factors related to colony genotype. For example, some bees from less aggressive genetic stock reared in colonies with genetic predispositions toward increased aggression show both increased aggression and more aggressive-like brain gene expression profiles. We tested the hypothesis that exposure to a colony environment influenced by high levels of predation threat results in increased aggression and aggressive-like gene expression patterns in individual bees. We assessed gene expression using four marker genes. Experimentally induced predation threats modified behavior, but the effect was opposite of our predictions: disturbed colonies showed decreased aggression. Disturbed colonies also decreased foraging activity, suggesting that they did not habituate to threats; other explanations for this finding are discussed. Bees in disturbed colonies also showed changes in brain gene expression, some of which paralleled behavioral findings. These results show that bee aggression and associated molecular processes are subject to complex social influences. © 2013 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  3. Keep calm! Gender differences in mental rotation performance are modulated by habitual expressive suppression.

    Science.gov (United States)

    Fladung, Anne-Katharina; Kiefer, Markus

    2016-11-01

    Men have been frequently found to perform more accurately than women in mental rotation tasks. However, men and women also differ with regard to the habitual use of emotion regulation strategies, particularly with regard to expressive suppression, i.e., the suppression of emotional expression in behavior. As emotional suppression is more often used by men, emotion regulation strategies might be a variable modulating gender differences in mental rotation performance. The present study, therefore, examined the influences of gender and emotion regulation strategies on mental rotation performance accuracy and feedback processing. Twenty-eight men and 28 women matched for relevant demographic variables performed mental rotation tasks of varying difficulty over a prolonged time. Emotional feedback was given immediately after each trial. Results showed that women reported to use expressive suppression less frequently than men. Women made more errors in the mental rotation task than men confirming earlier demonstrations of gender differences. Furthermore, women were more impaired by the negative feedback as indicated by the increased likelihood of subsequent errors compared with men. Task performance of women not habitually using expressive suppression was most inferior and most strongly influenced by failure feedback compared with men. Women using expressive suppression more habitually did not significantly differ in mental rotation accuracy and feedback processing from men. Hence, expressive suppression reduces gender differences in mental rotation accuracy by improving cognitive performance following failure feedback.

  4. Concentrations of dioxins and dioxine-like PCBs in feed material in the Netherlands, 2001-11

    NARCIS (Netherlands)

    Adamse, P.; Fels-Klerx, van der H.J.; Schoss, S.; Jong, de J.; Hoogenboom, L.A.P.

    2015-01-01

    This study aimed to obtain insights into contamination of feed materials used in the Netherlands with dioxins (polychlorinated dibenzo-p-dioxins and dibenzofurans) and dioxin-like polychlorinated biphenyls (PCBs). Monitoring results from the period 2001-11, covering in total 4938 samples, were

  5. RNA-based, transient modulation of gene expression in human haematopoietic stem and progenitor cells

    Science.gov (United States)

    Diener, Yvonne; Jurk, Marion; Kandil, Britta; Choi, Yeong-Hoon; Wild, Stefan; Bissels, Ute; Bosio, Andreas

    2015-01-01

    Modulation of gene expression is a useful tool to study the biology of haematopoietic stem and progenitor cells (HSPCs) and might also be instrumental to expand these cells for therapeutic approaches. Most of the studies so far have employed stable gene modification by viral vectors that are burdensome when translating protocols into clinical settings. Our study aimed at exploring new ways to transiently modify HSPC gene expression using non-integrating, RNA-based molecules. First, we tested different methods to deliver these molecules into HSPCs. The delivery of siRNAs with chemical transfection methods such as lipofection or cationic polymers did not lead to target knockdown, although we observed more than 90% fluorescent cells using a fluorochrome-coupled siRNA. Confocal microscopic analysis revealed that despite extensive washing, siRNA stuck to or in the cell surface, thereby mimicking a transfection event. In contrast, electroporation resulted in efficient, siRNA-mediated protein knockdown. For transient overexpression of proteins, we used optimised mRNA molecules with modified 5′- and 3′-UTRs. Electroporation of mRNA encoding GFP resulted in fast, efficient and persistent protein expression for at least seven days. Our data provide a broad-ranging comparison of transfection methods for hard-to-transfect cells and offer new opportunities for DNA-free, non-integrating gene modulation in HSPCs. PMID:26599627

  6. Longitudinal analysis of calorie restriction on rat taste bud morphology and expression of sweet taste modulators.

    Science.gov (United States)

    Cai, Huan; Daimon, Caitlin M; Cong, Wei-Na; Wang, Rui; Chirdon, Patrick; de Cabo, Rafael; Sévigny, Jean; Maudsley, Stuart; Martin, Bronwen

    2014-05-01

    Calorie restriction (CR) is a lifestyle intervention employed to reduce body weight and improve metabolic functions primarily via reduction of ingested carbohydrates and fats. Taste perception is highly related to functional metabolic status and body adiposity. We have previously shown that sweet taste perception diminishes with age; however, relatively little is known about the effects of various lengths of CR upon taste cell morphology and function. We investigated the effects of CR on taste bud morphology and expression of sweet taste-related modulators in 5-, 17-, and 30-month-old rats. In ad libitum (AL) and CR rats, we consistently found the following parameters altered significantly with advancing age: reduction of taste bud size and taste cell numbers per taste bud and reduced expression of sonic hedgehog, type 1 taste receptor 3 (T1r3), α-gustducin, and glucagon-like peptide-1 (GLP-1). In the oldest rats, CR affected a significant reduction of tongue T1r3, GLP-1, and α-gustducin expression compared with age-matched AL rats. Leptin receptor immunopositive cells were elevated in 17- and 30-month-old CR rats compared with age-matched AL rats. These alterations of sweet taste-related modulators, specifically during advanced aging, suggest that sweet taste perception may be altered in response to different lengths of CR.

  7. Waning of "conditioned pain modulation": a novel expression of subtle pronociception in migraine.

    Science.gov (United States)

    Nahman-Averbuch, Hadas; Granovsky, Yelena; Coghill, Robert C; Yarnitsky, David; Sprecher, Elliot; Weissman-Fogel, Irit

    2013-01-01

    To assess the decay of the conditioned pain modulation (CPM) response along repeated applications as a possible expression of subtle pronociception in migraine. One of the most explored mechanisms underlying the pain modulation system is "diffuse noxious inhibitory controls," which is measured psychophysically in the lab by the CPM paradigm. There are contradicting reports on CPM response in migraine, questioning whether migraineurs express pronociceptive pain modulation. Migraineurs (n = 26) and healthy controls (n = 35), all females, underwent 3 stimulation series, consisting of repeated (1) "test-stimulus" (Ts) alone that was given first followed by (2) parallel CPM application (CPM-parallel), and (3) sequential CPM application (CPM-sequential), in which the Ts is delivered during or following the conditioning-stimulus, respectively. In all series, the Ts repeated 4 times (0-3). In the CPM series, repetition "0" consisted of the Ts-alone that was followed by 3 repetitions of the Ts with a conditioning-stimulus application. Although there was no difference between migraineurs and controls for the first CPM response in each series, we found waning of CPM-parallel efficiency along the series for migraineurs (P = .005 for third vs first CPM), but not for controls. Further, greater CPM waning in the CPM-sequential series was correlated with less reported extent of pain reduction by episodic medication (r = 0.493, P = .028). Migraineurs have subtle deficits in endogenous pain modulation which requires a more challenging test protocol than the commonly used single CPM. Waning of CPM response seems to reveal this pronociceptive state. The clinical relevance of the CPM waning effect is highlighted by its association with clinical parameters of migraine. © 2013 American Headache Society.

  8. Cigarette smoke modulates expression of human rhinovirus-induced airway epithelial host defense genes.

    Directory of Open Access Journals (Sweden)

    David Proud

    Full Text Available Human rhinovirus (HRV infections trigger acute exacerbations of chronic obstructive pulmonary disease (COPD and asthma. The human airway epithelial cell is the primary site of HRV infection and responds to infection with altered expression of multiple genes, the products of which could regulate the outcome to infection. Cigarette smoking aggravates asthma symptoms, and is also the predominant risk factor for the development and progression of COPD. We, therefore, examined whether cigarette smoke extract (CSE modulates viral responses by altering HRV-induced epithelial gene expression. Primary cultures of human bronchial epithelial cells were exposed to medium alone, CSE alone, purified HRV-16 alone or to HRV-16+ CSE. After 24 h, supernatants were collected and total cellular RNA was isolated. Gene array analysis was performed to examine mRNA expression. Additional experiments, using real-time RT-PCR, ELISA and/or western blotting, validated altered expression of selected gene products. CSE and HRV-16 each induced groups of genes that were largely independent of each other. When compared to gene expression in response to CSE alone, cells treated with HRV+CSE showed no obvious differences in CSE-induced gene expression. By contrast, compared to gene induction in response to HRV-16 alone, cells exposed to HRV+CSE showed marked suppression of expression of a number of HRV-induced genes associated with various functions, including antiviral defenses, inflammation, viral signaling and airway remodeling. These changes were not associated with altered expression of type I or type III interferons. Thus, CSE alters epithelial responses to HRV infection in a manner that may negatively impact antiviral and host defense outcomes.

  9. Modulation of epithelial sodium channel (ENaC expression in mouse lung infected with Pseudomonas aeruginosa

    Directory of Open Access Journals (Sweden)

    Radzioch Danuta

    2005-01-01

    Full Text Available Abstract Background The intratracheal instillation of Pseudomonas aeruginosa entrapped in agar beads in the mouse lung leads to chronic lung infection in susceptible mouse strains. As the infection generates a strong inflammatory response with some lung edema, we tested if it could modulate the expression of genes involved in lung liquid clearance, such as the α, β and γ subunits of the epithelial sodium channel (ENaC and the catalytic subunit of Na+-K+-ATPase. Methods Pseudomonas aeruginosa entrapped in agar beads were instilled in the lung of resistant (BalB/c and susceptible (DBA/2, C57BL/6 and A/J mouse strains. The mRNA expression of ENaC and Na+-K+-ATPase subunits was tested in the lung by Northern blot following a 3 hours to 14 days infection. Results The infection of the different mouse strains evoked regulation of α and β ENaC mRNA. Following Pseudomonas instillation, the expression of αENaC mRNA decreased to a median of 43% on days 3 and 7 after infection and was still decreased to a median of 45% 14 days after infection (p 1Na+-K+-ATPase mRNA, the catalytic subunit of the sodium pump, was recorded. The distinctive expression profiles of the three subunits were not different, between the susceptible and resistant mouse strains. Conclusions These results show that Pseudomonas infection, by modulating ENaC subunit expression, could influence edema formation and clearance in infected lungs.

  10. CVD-associated non-coding RNA, ANRIL, modulates expression of atherogenic pathways in VSMC

    International Nuclear Information System (INIS)

    Congrains, Ada; Kamide, Kei; Katsuya, Tomohiro; Yasuda, Osamu; Oguro, Ryousuke; Yamamoto, Koichi; Ohishi, Mitsuru; Rakugi, Hiromi

    2012-01-01

    Highlights: ► ANRIL maps in the strongest susceptibility locus for cardiovascular disease. ► Silencing of ANRIL leads to altered expression of tissue remodeling-related genes. ► The effects of ANRIL on gene expression are splicing variant specific. ► ANRIL affects progression of cardiovascular disease by regulating proliferation and apoptosis pathways. -- Abstract: ANRIL is a newly discovered non-coding RNA lying on the strongest genetic susceptibility locus for cardiovascular disease (CVD) in the chromosome 9p21 region. Genome-wide association studies have been linking polymorphisms in this locus with CVD and several other major diseases such as diabetes and cancer. The role of this non-coding RNA in atherosclerosis progression is still poorly understood. In this study, we investigated the implication of ANRIL in the modulation of gene sets directly involved in atherosclerosis. We designed and tested siRNA sequences to selectively target two exons (exon 1 and exon 19) of the transcript and successfully knocked down expression of ANRIL in human aortic vascular smooth muscle cells (HuAoVSMC). We used a pathway-focused RT-PCR array to profile gene expression changes caused by ANRIL knock down. Notably, the genes affected by each of the siRNAs were different, suggesting that different splicing variants of ANRIL might have distinct roles in cell physiology. Our results suggest that ANRIL splicing variants play a role in coordinating tissue remodeling, by modulating the expression of genes involved in cell proliferation, apoptosis, extra-cellular matrix remodeling and inflammatory response to finally impact in the risk of cardiovascular disease and other pathologies.

  11. CVD-associated non-coding RNA, ANRIL, modulates expression of atherogenic pathways in VSMC

    Energy Technology Data Exchange (ETDEWEB)

    Congrains, Ada; Kamide, Kei [Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine (Japan); Katsuya, Tomohiro [Clinical Gene Therapy, Osaka University Graduate School of Medicine (Japan); Yasuda, Osamu [Department of Cardiovascular Clinical and Translational Research, Kumamoto University Hospital (Japan); Oguro, Ryousuke; Yamamoto, Koichi [Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine (Japan); Ohishi, Mitsuru, E-mail: ohishi@geriat.med.osaka-u.ac.jp [Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine (Japan); Rakugi, Hiromi [Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine (Japan)

    2012-03-23

    Highlights: Black-Right-Pointing-Pointer ANRIL maps in the strongest susceptibility locus for cardiovascular disease. Black-Right-Pointing-Pointer Silencing of ANRIL leads to altered expression of tissue remodeling-related genes. Black-Right-Pointing-Pointer The effects of ANRIL on gene expression are splicing variant specific. Black-Right-Pointing-Pointer ANRIL affects progression of cardiovascular disease by regulating proliferation and apoptosis pathways. -- Abstract: ANRIL is a newly discovered non-coding RNA lying on the strongest genetic susceptibility locus for cardiovascular disease (CVD) in the chromosome 9p21 region. Genome-wide association studies have been linking polymorphisms in this locus with CVD and several other major diseases such as diabetes and cancer. The role of this non-coding RNA in atherosclerosis progression is still poorly understood. In this study, we investigated the implication of ANRIL in the modulation of gene sets directly involved in atherosclerosis. We designed and tested siRNA sequences to selectively target two exons (exon 1 and exon 19) of the transcript and successfully knocked down expression of ANRIL in human aortic vascular smooth muscle cells (HuAoVSMC). We used a pathway-focused RT-PCR array to profile gene expression changes caused by ANRIL knock down. Notably, the genes affected by each of the siRNAs were different, suggesting that different splicing variants of ANRIL might have distinct roles in cell physiology. Our results suggest that ANRIL splicing variants play a role in coordinating tissue remodeling, by modulating the expression of genes involved in cell proliferation, apoptosis, extra-cellular matrix remodeling and inflammatory response to finally impact in the risk of cardiovascular disease and other pathologies.

  12. Emissions of chlorinated dioxins and furans

    International Nuclear Information System (INIS)

    Broeker, G.; Bruckmann, P.; Gliwa, H.

    1994-01-01

    Already now the estimated daily average input of about 2 pg I-TEQ/kg body weight for an adult exceeds the preventive value of 1 pg I-TEQ/(kg x d) proposed by the Federal Environmental Agency (UBA) and the Federal Health Office (BGA), although the intervention value of 10 pg/(kg x d) also proposed by UBA and BGA has not been reached yet. To be able to take well-aimed measures to reduce dioxin emissions into the environment, it is necessary to collect sufficient information about the sources, the history of origins and the efficiency of control measures. The high number of investigations conducted into waste incineration plants, which can be explained by increasing public awareness of the disposal problem, gave the impression that waste incineration is one of the major causes of dioxin emissions into the environment. Analyses of the ambient air situation revealed that there is a considerable lack of information about the sources of dioxin emissions. For example, systematic investigations in North Rhine-Westphalia, which have not been finished yet, identified sintering plants as the main dioxin emittors. It can be concluded already now that control measures are indispensable for these plants to improve the ambient air situation; a few waste gas cleaning methods were tested. The realisation of the 17th Order Implementing the Federal Immission Control Act (17th BImSchV) (emission control of dioxins from waste incineration plants), the 19th BImSchV (prohibition of Cl and Br additions to fuels) and the further spread of the controlled catalytic coverter for passenger cars will make industrial dioxin sources even more relevant. This underlines the necessity for control measures in this field. (orig.) [de

  13. Expression of Versican 3′-Untranslated Region Modulates Endogenous MicroRNA Functions

    Science.gov (United States)

    Lee, Daniel Y.; Jeyapalan, Zina; Fang, Ling; Yang, Jennifer; Zhang, Yaou; Yee, Albert Y.; Li, Minhui; Du, William W.; Shatseva, Tatiana; Yang, Burton B.

    2010-01-01

    Background Mature microRNAs (miRNAs) are single-stranded RNAs that regulate post-transcriptional gene expression. In our previous study, we have shown that versican 3′UTR, a fragment of non-coding transcript, has the ability to antagonize miR-199a-3p function thereby regulating expression of the matrix proteins versican and fibronectin, and thus resulting in enhanced cell-cell adhesion and organ adhesion. However, the impact of this non-coding fragment on tumorigenesis is yet to be determined. Methods and Findings Using computational prediction confirmed with in vitro and in vivo experiments, we report that the expression of versican 3′UTR not only antagonizes miR-199a-3p but can also lower its steady state expression. We found that expression of versican 3′UTR in a mouse breast carcinoma cell line, 4T1, decreased miR-199a-3p levels. The decrease in miRNA activity consequently translated into differences in tumor growth. Computational analysis indicated that both miR-199a-3p and miR-144 targeted a cell cycle regulator, Rb1. In addition, miR-144 and miR-136, which have also been shown to interact with versican 3′UTR, was found to target PTEN. Expression of Rb1 and PTEN were up-regulated synergistically in vitro and in vivo, suggesting that the 3′UTR binds and modulates miRNA activities, freeing Rb1 and PTEN mRNAs for translation. In tumor formation assays, cells transfected with the 3′UTR formed smaller tumors compared with cells transfected with a control vector. Conclusion Our results demonstrated that a 3′UTR fragment can be used to modulate miRNA functions. Our study also suggests that miRNAs in the cancer cells are more susceptible to degradation, due to its interaction with a non-coding 3′UTR. This non-coding component of mRNA may be used retrospectively to modulate miRNA activities. PMID:21049042

  14. Expression of versican 3'-untranslated region modulates endogenous microRNA functions.

    Science.gov (United States)

    Lee, Daniel Y; Jeyapalan, Zina; Fang, Ling; Yang, Jennifer; Zhang, Yaou; Yee, Albert Y; Li, Minhui; Du, William W; Shatseva, Tatiana; Yang, Burton B

    2010-10-25

    Mature microRNAs (miRNAs) are single-stranded RNAs that regulate post-transcriptional gene expression. In our previous study, we have shown that versican 3'UTR, a fragment of non-coding transcript, has the ability to antagonize miR-199a-3p function thereby regulating expression of the matrix proteins versican and fibronectin, and thus resulting in enhanced cell-cell adhesion and organ adhesion. However, the impact of this non-coding fragment on tumorigenesis is yet to be determined. Using computational prediction confirmed with in vitro and in vivo experiments, we report that the expression of versican 3'UTR not only antagonizes miR-199a-3p but can also lower its steady state expression. We found that expression of versican 3'UTR in a mouse breast carcinoma cell line, 4T1, decreased miR-199a-3p levels. The decrease in miRNA activity consequently translated into differences in tumor growth. Computational analysis indicated that both miR-199a-3p and miR-144 targeted a cell cycle regulator, Rb1. In addition, miR-144 and miR-136, which have also been shown to interact with versican 3'UTR, was found to target PTEN. Expression of Rb1 and PTEN were up-regulated synergistically in vitro and in vivo, suggesting that the 3'UTR binds and modulates miRNA activities, freeing Rb1 and PTEN mRNAs for translation. In tumor formation assays, cells transfected with the 3'UTR formed smaller tumors compared with cells transfected with a control vector. Our results demonstrated that a 3'UTR fragment can be used to modulate miRNA functions. Our study also suggests that miRNAs in the cancer cells are more susceptible to degradation, due to its interaction with a non-coding 3'UTR. This non-coding component of mRNA may be used retrospectively to modulate miRNA activities.

  15. Expression of versican 3'-untranslated region modulates endogenous microRNA functions.

    Directory of Open Access Journals (Sweden)

    Daniel Y Lee

    Full Text Available BACKGROUND: Mature microRNAs (miRNAs are single-stranded RNAs that regulate post-transcriptional gene expression. In our previous study, we have shown that versican 3'UTR, a fragment of non-coding transcript, has the ability to antagonize miR-199a-3p function thereby regulating expression of the matrix proteins versican and fibronectin, and thus resulting in enhanced cell-cell adhesion and organ adhesion. However, the impact of this non-coding fragment on tumorigenesis is yet to be determined. METHODS AND FINDINGS: Using computational prediction confirmed with in vitro and in vivo experiments, we report that the expression of versican 3'UTR not only antagonizes miR-199a-3p but can also lower its steady state expression. We found that expression of versican 3'UTR in a mouse breast carcinoma cell line, 4T1, decreased miR-199a-3p levels. The decrease in miRNA activity consequently translated into differences in tumor growth. Computational analysis indicated that both miR-199a-3p and miR-144 targeted a cell cycle regulator, Rb1. In addition, miR-144 and miR-136, which have also been shown to interact with versican 3'UTR, was found to target PTEN. Expression of Rb1 and PTEN were up-regulated synergistically in vitro and in vivo, suggesting that the 3'UTR binds and modulates miRNA activities, freeing Rb1 and PTEN mRNAs for translation. In tumor formation assays, cells transfected with the 3'UTR formed smaller tumors compared with cells transfected with a control vector. CONCLUSION: Our results demonstrated that a 3'UTR fragment can be used to modulate miRNA functions. Our study also suggests that miRNAs in the cancer cells are more susceptible to degradation, due to its interaction with a non-coding 3'UTR. This non-coding component of mRNA may be used retrospectively to modulate miRNA activities.

  16. Ocean acidification modulates expression of genes and physiological performance of a marine diatom

    Science.gov (United States)

    Li, Y.; Zhuang, S.; Wu, Y.; Ren, H.; Cheng, F.; Lin, X.; Wang, K.; Beardall, J.; Gao, K.

    2015-09-01

    Ocean Acidification (OA) is known to affect various aspects of the physiological performance of diatoms, but there is little information on the underlining molecular mechanisms involved. Here, we show that in the model diatom Phaeodactylum tricornutum expression of the genes related to light harvesting, carbon acquisition and carboxylation, nitrite assimilation and ATP synthesis are modulated by OA. Growth and photosynthetic carbon fixation were enhanced by elevated CO2 (1000 μatm) under both constant indoor and fluctuating outdoor light regimes. The genetic expression of nitrite reductase (NiR) was up-regulated by OA regardless of light levels and/or regimes. The transcriptional expression of fucoxanthin chlorophyll a/c protein (lhcf type (FCP)) and mitochondrial ATP synthase (mtATP synthase) genes were also enhanced by OA, but only under high light intensity. OA treatment decreased the expression of β-carbonic anhydrase (β-CA) along with down-regulation of CO2 concentrating mechanisms (CCMs). Additionally, the genes for these proteins (NiR, FCP, mtATP synthase, β-CA) showed diel expressions either under constant indoor light or fluctuating sunlight. Thus, OA enhanced photosynthetic and growth rates by stimulating nitrogen assimilation and indirectly by down-regulating the energy-costly inorganic carbon acquisition process.

  17. Aging Selectively Modulates Vitamin C Transporter Expression Patterns in the Kidney.

    Science.gov (United States)

    Forman, Katherine; Martínez, Fernando; Cifuentes, Manuel; Bertinat, Romina; Salazar, Katterine; Nualart, Francisco

    2017-09-01

    In the kidney, vitamin C is reabsorbed from the glomerular ultrafiltrate by sodium-vitamin C cotransporter isoform 1 (SVCT1) located in the brush border membrane of the proximal tubules. Although we know that vitamin C levels decrease with age, the adaptive physiological mechanisms used by the kidney for vitamin C reabsorption during aging remain unknown. In this study, we used an animal model of accelerated senescence (SAMP8 mice) to define the morphological alterations and aging-induced changes in the expression of vitamin C transporters in renal tissue. Aging induced significant morphological changes, such as periglomerular lymphocytic infiltrate and glomerular congestion, in the kidneys of SAMP8 mice, although no increase in collagen deposits was observed using 2-photon microscopy analysis and second harmonic generation. The most characteristic histological alteration was the dilation of intracellular spaces in the basolateral region of proximal tubule epithelial cells. Furthermore, a combination of laser microdissection, qRT-PCR, and immunohistochemical analyses allowed us to determine that SVCT1 expression specifically increased in the proximal tubules from the outer strip of the outer medulla (segment S3) and cortex (segment S2) during aging and that these tubules also express GLUT1. We conclude that aging modulates vitamin C transporter expression and that renal over-expression of SVCT1 enhances vitamin C reabsorption in aged animals that may synthesize less vitamin C. J. Cell. Physiol. 232: 2418-2426, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  18. Cholesterol can modulate mitochondrial aquaporin-8 expression in human hepatic cells.

    Science.gov (United States)

    Danielli, Mauro; Capiglioni, Alejo M; Marrone, Julieta; Calamita, Giuseppe; Marinelli, Raúl A

    2017-05-01

    Hepatocyte mitochondrial aquaporin-8 (mtAQP8) works as a multifunctional membrane channel protein that facilitates the uptake of ammonia for its detoxification to urea as well as the mitochondrial release of hydrogen peroxide. Since early oligonucleotide microarray studies in liver of cholesterol-fed mice showed an AQP8 downregulation, we tested whether alterations of cholesterol content per se modulate mtAQP8 expression in human hepatocyte-derived Huh-7 cells. Cholesterol loading with methyl-β-cyclodextrin (mβCD):cholesterol complexes downregulated the proteolytic activation of cholesterol-responsive sterol regulatory element-binding protein (SREBP) transcriptions factors 1 and 2, and the expression of the target gene 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). Under such conditions, mtAQP8 mRNA and protein expressions were significantly reduced. In contrast, cholesterol depletion using mβCD alone increased SREBP-1 and 2 activation and upregulated HMGCR and mtAQP8 mRNA and protein expressions. The results suggest that cholesterol can regulate transcriptionally human hepatocyte mtAQP8 expression likely via SREBPs. The functional implications of our findings are discussed. © 2017 IUBMB Life, 69(5):341-346, 2017. © 2017 International Union of Biochemistry and Molecular Biology.

  19. Expression of measles virus nucleoprotein induces apoptosis and modulates diverse functional proteins in cultured mammalian cells.

    Directory of Open Access Journals (Sweden)

    Ashima Bhaskar

    Full Text Available BACKGROUND: Measles virus nucleoprotein (N encapsidates the viral RNA, protects it from endonucleases and forms a virus specific template for transcription and replication. It is the most abundant protein during viral infection. Its C-terminal domain is intrinsically disordered imparting it the flexibility to interact with several cellular and viral partners. PRINCIPAL FINDINGS: In this study, we demonstrate that expression of N within mammalian cells resulted in morphological transitions, nuclear condensation, DNA fragmentation and activation of Caspase 3 eventuating into apoptosis. The rapid generation of intracellular reactive oxygen species (ROS was involved in the mechanism of cell death. Addition of ascorbic acid (AA or inhibitor of caspase-3 in the extracellular medium partially reversed N induced apoptosis. We also studied the protein profile of cells expressing N protein. MS analysis revealed the differential expression of 25 proteins out of which 11 proteins were up regulated while 14 show signs of down regulation upon N expression. 2DE results were validated by real time and semi quantitative RT-PCR analysis. CONCLUSION: These results show the pro-apoptotic effects of N indicating its possible development as an apoptogenic tool. Our 2DE results present prima facie evidence that the MV nucleoprotein interacts with or causes differential expression of a wide range of cellular factors. At this stage it is not clear as to what the adaptive response of the host cell is and what reflects a strategic modulation exerted by the virus.

  20. Oxygen Modulates Human Decidual Natural Killer Cell Surface Receptor Expression and Interactions with Trophoblasts1

    Science.gov (United States)

    Wallace, Alison E.; Goulwara, Sonu S.; Whitley, Guy S.; Cartwright, Judith E.

    2014-01-01

    Decidual natural killer (dNK) cells have been shown to both promote and inhibit trophoblast behavior important for decidual remodeling in pregnancy and have a distinct phenotype compared to peripheral blood NK cells. We investigated whether different levels of oxygen tension, mimicking the physiological conditions of the decidua in early pregnancy, altered cell surface receptor expression and activity of dNK cells and their interactions with trophoblast. dNK cells were isolated from terminated first-trimester pregnancies and cultured in oxygen tensions of 3%, 10%, and 21% for 24 h. Cell surface receptor expression was examined by flow cytometry, and the effects of secreted factors in conditioned medium (CM) on the trophoblast cell line SGHPL-4 were assessed in vitro. SGHPL-4 cells treated with dNK cell CM incubated in oxygen tensions of 10% were significantly more invasive (P cells treated with dNK cell CM incubated in oxygen tensions of 3% or 21%. After 24 h, a lower percentage of dNK cells expressed CD56 at 21% oxygen (P cells expressed NKG2D at 10% oxygen (P oxygen tensions, with large patient variation. This study demonstrates dNK cell phenotype and secreted factors are modulated by oxygen tension, which induces changes in trophoblast invasion and endovascular-like differentiation. Alterations in dNK cell surface receptor expression and secreted factors at different oxygen tensions may represent regulation of function within the decidua during the first trimester of pregnancy. PMID:25232021

  1. Modulation of Mast Cell Toll-Like Receptor 3 Expression and Cytokines Release by Histamine

    Directory of Open Access Journals (Sweden)

    Guogang Xie

    2018-05-01

    Full Text Available Background/Aims: As a major inflammatory molecule released from mast cell activation, histamine has been reported to regulate TLRs expression and cytokine production in inflammatory cells present in the microenvironment. In this study, we determined the ability of histamine to modulate TLRs expression and cytokine production in mast cells. Methods: HMC-1 and P815 cells were exposed to various concentrations of histamine in the presence or absence of histamine antagonist for 2, 6 or 16 h. The effect of histamine on the expression of TLR3 protein and mRNA was analyzed by flow cytometry、 RT-PCR and immunofluorescent microscopy. Furthermore, we also examined the effect of histamine on the secretion of MCP-1 and IL-13 from mast cells by ELISA. Results: The amplification of TLR3 mRNA and protein expression in mast cells was observed after incubation with histamine, which was accompanied by increasing secretion of IL-13 and MCP-1 via H1 receptor. The signaling pathways of PI3K/ Akt and Erk1/2/MAPK contributed to these induction effects. Conclusion: These results demonstrate that histamine up-regulates the expression of TLR3 and secretion of IL-13 and MCP-1 in mast cells, thus identifying a new mechanism for the histamine inducing allergic response.

  2. Emissions and dioxins formation from waste incinerators

    International Nuclear Information System (INIS)

    Carbone, A.I.; Zagaroli, M.

    1989-01-01

    This paper describes current knowledge on dioxins formation and emission from waste incinerators. The pertinent Italian law and effects on man health are dealt with, too. The picture of existing municipal incinerators is presented concerning both the actual emission levels and the monitored levels in the environment. Sampling and analysis systems of these organic chlorinated micro-pollutants and current theories on precursors, formation mechanisms, and influence of different parameters are also described. The last section deals with some of the techniques that can be used to reduce dioxins formation and emission from municipal incinerators. (author)

  3. Modulation of expression and activity of intestinal multidrug resistance-associated protein 2 by xenobiotics

    Energy Technology Data Exchange (ETDEWEB)

    Tocchetti, Guillermo Nicolás [Instituto de Fisiología Experimental, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, CONICET, Suipacha 570, 2000 Rosario (Argentina); Rigalli, Juan Pablo [Instituto de Fisiología Experimental, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, CONICET, Suipacha 570, 2000 Rosario (Argentina); Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg (Germany); Arana, Maite Rocío; Villanueva, Silvina Stella Maris [Instituto de Fisiología Experimental, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, CONICET, Suipacha 570, 2000 Rosario (Argentina); Mottino, Aldo Domingo, E-mail: amottino@unr.edu.ar [Instituto de Fisiología Experimental, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, CONICET, Suipacha 570, 2000 Rosario (Argentina)

    2016-07-15

    The multidrug resistance-associated protein 2 (MRP2/ABCC2) is a transporter that belongs to the ATP-binding cassette (ABC) superfamily. In the intestine, it is localized to the apical membrane of the enterocyte and plays a key role in limiting the absorption of xenobiotics incorporated orally. MRP2 may also play a role in systemic clearance of xenobiotics available from the serosal side of the intestine. MRP2 transports a wide range of substrates, mainly organic anions conjugated with glucuronic acid, glutathione and sulfate and its expression can be modulated by xenobiotics at transcriptional- and post-transcriptional levels. Transcriptional regulation is usually mediated by a group of nuclear receptors. The pregnane X receptor (PXR) is a major member of this group. Relevant drugs described to up-regulate intestinal MRP2 via PXR are rifampicin, spironolactone and carbamazepine, among others. The constitutive androstane receptor (CAR, NR1I3) was also reported to modulate MRP2 expression, phenobarbital being a typical activator. Dietary compounds, including micronutrients and other natural products, are also capable of regulating intestinal MRP2 expression transcriptionally. We have given them particular attention since the composition of the food ingested daily is not necessarily supervised and may result in interactions with therapeutic drugs. Post-transcriptional regulation of MRP2 activity by xenobiotics, e.g. as a consequence of inhibitory actions, is also described in this review. Unfortunately, only few studies report on drug-drug or nutrient-drug interactions as a consequence of modulation of intestinal MRP2 activity by xenobiotics. Future clinical studies are expected to identify additional interactions resulting in changes in efficacy or safety of therapeutic drugs. - Highlights: • Intestinal MRP2 (ABCC2) expression and activity can be regulated by xenobiotics. • PXR and CAR are major MRP2 modulators through a transcriptional mechanism. • Rifampicin

  4. Relationship between dioxin concentration and particle size for suspended sediment

    Energy Technology Data Exchange (ETDEWEB)

    Kitamura, K.; Sakurai, T.; Choi, J.W.; Suzuki, N.; Morita, M. [National Inst. for Environmental Studies, Tsukuba (Japan)

    2004-09-15

    The purpose of the present study was to find out how the amounts of adsorbed dioxins, i.e., polychlorinated dibenzo-p-dioxins/dibenzofurans (PCDDs/Fs), mono-ortho-polychlorinated biphenyls (PCBs) and non-ortho-PCBs, vary with the particle size of suspended sediment. As dioxins are hydrophobic, they tend to adsorb onto particles suspended in water, and the determination of which dioxin congeners readily dissolve in water or adsorb onto particles is central to the characterization of dioxin behavior in water/sediment systems. Presumably suspension of sediments and the size of the particles govern the transfer of dioxins to aquatic organisms. Therefore, in the present study, we investigated the relationship between the amount of dioxins and the particle-size distribution of resuspended, rather than settled, sediment.

  5. Sucralfate modulates uPAR and EGFR expression in an experimental rat model of cervicitis.

    Science.gov (United States)

    Mannari, C; Santi, S; Migliori, M; Filippi, C; Origlia, N; Sansò, M; Boldrini, E; Giovannini, L

    2008-01-01

    Sucralfate is a drug used in the treatment of gastric and duodenal ulcer; it is cytoprotective and able to increase the bioavailability of several growth factors, modulating the wound healing process. In this study we tested the possible therapeutic effect of Sucralfate in the treatment of ulcerative lesions occurring in uterine cervix; to investigate such effect we used an experimental rat model of cervicitis in which the uPAR and EGFR expression were evaluated. Cervicitis was induced in wild and ovariectomized Wistar female rats by an acetic acid-soaked tampon. The animals were divided into two main groups (4 and 7 days) and Sucralfate was administered topically until the day they were sacrificed. In order to distinguish physiological and drug-induced healing, quantitative and qualitative uPAR and EGFR expression were evaluated by using Western blot and Immunohistochemistry techniques. Western blot analysis demonstrated an increased expression of both receptors after 4 days from wounding in wild and ovariectomized animals. In particular in ovariectomized animals the expression of uPAR and EGFR increased after 4 days while it reduced following the administration of Sucralfate. In wild rats the same was observed for uPAR expression, while EGFR was different; in fact, its expression increased significantly at day 4 in the animals treated with the drug and only at day 7 in those untreated. Immunohistochemistry highlighted a noteworthy epithelial colocalization of EGFR and uPAR after 4 days in the animals treated with Sucralfate. We conclude that Sucralfate can promote the healing of ulcerative cervicitis and moreover, it reduces the normal healing time because of its modulatory property on uPAR and EGFR expression.

  6. Store-operated Ca2+ Entry Modulates the Expression of Enamel Genes.

    Science.gov (United States)

    Nurbaeva, M K; Eckstein, M; Snead, M L; Feske, S; Lacruz, R S

    2015-10-01

    Dental enamel formation is an intricate process tightly regulated by ameloblast cells. The correct spatiotemporal patterning of enamel matrix protein (EMP) expression is fundamental to orchestrate the formation of enamel crystals, which depend on a robust supply of Ca2+. In the extracellular milieu, Ca2+ -EMP interactions occur at different levels. Despite its recognized role in enamel development, the molecular machinery involved in Ca2+ homeostasis in ameloblasts remains poorly understood. A common mechanism for Ca2+ influx is store-operated Ca2+ entry (SOCE). We evaluated the possibility that Ca2+ influx in enamel cells might be mediated by SOCE and the Ca2+ release-activated Ca2+ (CRAC) channel, the prototypical SOCE channel. Using ameloblast-like LS8 cells, we demonstrate that these cells express Ca2+ -handling molecules and mediate Ca2+ influx through SOCE. As a rise in the cytosolic Ca2+ concentration is a versatile signal that can modulate gene expression, we assessed whether SOCE in enamel cells had any effect on the expression of EMPs. Our results demonstrate that stimulating LS8 cells or murine primary enamel organ cells with thapsigargin to activate SOCE leads to increased expression of Amelx, Ambn, Enam, Mmp20. This effect is reversed when cells are treated with a CRAC channel inhibitor. These data indicate that Ca2+ influx in LS8 cells and enamel organ cells is mediated by CRAC channels and that Ca2+ signals enhance the expression of EMPs. Ca2+ plays an important role not only in mineralizing dental enamel but also in regulating the expression of EMPs. © International & American Associations for Dental Research 2015.

  7. Arabidopsis ATRX Modulates H3.3 Occupancy and Fine-Tunes Gene Expression

    KAUST Repository

    Duc, Céline

    2017-07-07

    Histones are essential components of the nucleosome, the major chromatin subunit that structures linear DNA molecules and regulates access of other proteins to DNA. Specific histone chaperone complexes control the correct deposition of canonical histones and their variants to modulate nucleosome structure and stability. In this study, we characterize the Arabidopsis Alpha Thalassemia-mental Retardation X-linked (ATRX) ortholog and show that ATRX is involved in histone H3 deposition. Arabidopsis ATRX mutant alleles are viable, but show developmental defects and reduced fertility. Their combination with mutants of the histone H3.3 chaperone HIRA (Histone Regulator A) results in impaired plant survival, suggesting that HIRA and ATRX function in complementary histone deposition pathways. Indeed, ATRX loss of function alters cellular histone H3.3 pools and in consequence modulates the H3.1/H3.3 balance in the cell. H3.3 levels are affected especially at genes characterized by elevated H3.3 occupancy, including the 45S ribosomal DNA (45S rDNA) loci, where loss of ATRX results in altered expression of specific 45S rDNA sequence variants. At the genome-wide scale, our data indicate that ATRX modifies gene expression concomitantly to H3.3 deposition at a set of genes characterized both by elevated H3.3 occupancy and high expression. Altogether, our results show that ATRX is involved in H3.3 deposition and emphasize the role of histone chaperones in adjusting genome expression.

  8. Dioxin exposure in breast milk and infant neurodevelopment in Vietnam.

    Science.gov (United States)

    Tai, Pham The; Nishijo, Muneko; Anh, Nguyen Thi Nguyet; Maruzeni, Shoko; Nakagawa, Hideaki; Van Luong, Hoang; Anh, Tran Hai; Honda, Ryumon; Kido, Teruhiko; Nishijo, Hisao

    2013-09-01

    Dioxin levels in the breast milk of mothers residing near hot spots of dioxin contamination areas in South Vietnam remain much higher than in unsprayed areas, suggesting that fetuses and breast-fed infants may be exposed to high levels of dioxins. The present study investigated the association of infant neurodevelopment in early infancy and dioxin exposure during the perinatal period. The study involved 216 mother-infant pairs living near the Da Nang airbase, a dioxin contaminated area in Vietnam. Mothers and infants were followed from birth until infants were 4 months old. Dioxin levels in breast milk were measured to estimate the perinatal dioxin exposure, including the infant daily dioxin intake (DDI) via breastfeeding. Infant neurodevelopmental parameters, including cognitive, language and motor domains were assessed at approximately 4 months using the Bayley Scales of Infant and Toddler Development, third edition (Bayley-III). The level of 2,3,7,8-tetrachlorodibenzo-p-dioxin and polychlorinated dibenzo-p-dioxins/furans-toxic equivalents in breast milk and the infant DDI showed significant inverse correlations with neurodevelopmental scores. When the subjects were divided into four groups according to dioxin levels in breast milk, the moderate and high DDI groups had significantly lower cognitive, composite motor and fine motor scores, and the high polychlorinated dibenzo-p-dioxins/furans-toxic equivalents group had significantly lower fine motor score than the low exposure group. For all domains, neurodevelopmental scores were decreased with increase in the level of 2,3,7,8-tetrachlorodibenzo-p-dioxin. The present study demonstrates a considerable impact of perinatal dioxin exposure on neurodevelopment in 4-month-old infants living in contaminated areas in Vietnam.

  9. FORMATION OF DIOXINS AND FURANS DURING MUNICIPAL SOLID WASTE GASIFICATION

    Directory of Open Access Journals (Sweden)

    E. J. Lopes

    2015-03-01

    Full Text Available Abstract Thermal treatment is an interesting strategy to dispose of municipal solid waste: it reduces the volume and weight of the material dumped in landfills and generates alternative energy. However, the process emits pollutants, such as dioxins and furans. The present study evaluated MSW gasification-combustion integrated technologies in terms of dioxin and furan emission; and compared the obtained data with literature results on incineration, to point out which operational features differentiate the release of pollutants by these two processes. The results show that the process of integrated gasification and combustion emitted 0.28 ng N-1 m-3, expressed in TEQ (Total Equivalent Toxicity, of PCDD/F, less than the maximum limits allowed by local and international laws, whereas incineration normally affords values above these limits and requires a gas treatment system. The distinct operational conditions of the two thermal processes, especially those related to temperature and the presence of oxygen and fixed carbon, led to a lower PCDD/F emission in gasification.

  10. Culture modulates the brain response to human expressions of emotion: electrophysiological evidence.

    Science.gov (United States)

    Liu, Pan; Rigoulot, Simon; Pell, Marc D

    2015-01-01

    To understand how culture modulates on-line neural responses to social information, this study compared how individuals from two distinct cultural groups, English-speaking North Americans and Chinese, process emotional meanings of multi-sensory stimuli as indexed by both behaviour (accuracy) and event-related potential (N400) measures. In an emotional Stroop-like task, participants were presented face-voice pairs expressing congruent or incongruent emotions in conditions where they judged the emotion of one modality while ignoring the other (face or voice focus task). Results indicated that while both groups were sensitive to emotional differences between channels (with lower accuracy and higher N400 amplitudes for incongruent face-voice pairs), there were marked group differences in how intruding facial or vocal cues affected accuracy and N400 amplitudes, with English participants showing greater interference from irrelevant faces than Chinese. Our data illuminate distinct biases in how adults from East Asian versus Western cultures process socio-emotional cues, supplying new evidence that cultural learning modulates not only behaviour, but the neurocognitive response to different features of multi-channel emotion expressions. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Transplantation of bone marrow mononuclear cells modulates hippocampal expression of growth factors in chronically epileptic animals.

    Science.gov (United States)

    Zanirati, Gabriele; Azevedo, Pamella Nunes; Marinowic, Daniel Rodrigo; Rodrigues, Felipe; de Oliveira Dias, Ana Christina; Venturin, Gianina Teribele; Greggio, Samuel; Simão, Fabrício; DaCosta, Jaderson Costa

    2015-05-01

    In previous studies, transplantation of bone marrow mononuclear cells (BMMCs) in epileptic animals has been found to be neuroprotective. However, the mechanism by which the BMMCs act remains unclear. We hypothesize that BMMCs may provide neuroprotection to the epileptic brain through trophic support. To test our hypothesis, we studied the temporal expression of neurotrophins after BMMC transplantation in the epileptic rat hippocampus. Chronically epileptic rats were intravenously transplanted with 1 × 10(7) BMMCs isolated from GFP transgenic mice. Expression levels of BDNF, GDNF, NGF, VEGF, and TGF-β1, and their receptors, were evaluated by ELISA and/or qRT-PCR analysis. Our data revealed increased protein expression of BDNF, GDNF, NGF, and VEGF and reduced levels of TGF-β1 in the hippocampus of transplanted epileptic animals. Additionally, an increase in the mRNA expression of BDNF, GDNF, and VEGF, a reduction in TGF-β1, and a decrease in mRNA levels of the TrkA and TGFR-β1 receptors were also observed. The gain provided by transplanted BMMCs in the epileptic brain may be related to the ability of these cells in modulating the network of neurotrophins and angiogenic signals. © 2015 John Wiley & Sons Ltd.

  12. 5-HTTLPR modulates the recognition accuracy and exploration of emotional facial expressions

    Directory of Open Access Journals (Sweden)

    Sabrina eBoll

    2014-07-01

    Full Text Available Individual genetic differences in the serotonin transporter-linked polymorphic region (5-HTTLPR have been associated with variations in the sensitivity to social and emotional cues as well as altered amygdala reactivity to facial expressions of emotion. Amygdala activation has further been shown to trigger gaze changes towards diagnostically relevant facial features. The current study examined whether altered socio-emotional reactivity in variants of the 5-HTTLPR promoter polymorphism reflects individual differences in attending to diagnostic features of facial expressions. For this purpose, visual exploration of emotional facial expressions was compared between a low (n=39 and a high (n=40 5-HTT expressing group of healthy human volunteers in an eye tracking paradigm. Emotional faces were presented while manipulating the initial fixation such that saccadic changes towards the eyes and towards the mouth could be identified. We found that the low versus the high 5-HTT group demonstrated greater accuracy with regard to emotion classifications, particularly when faces were presented for a longer duration. No group differences in gaze orientation towards diagnostic facial features could be observed. However, participants in the low 5-HTT group exhibited more and faster fixation changes for certain emotions when faces were presented for a longer duration and overall face fixation times were reduced for this genotype group. These results suggest that the 5-HTT gene influences social perception by modulating the general vigilance to social cues rather than selectively affecting the pre-attentive detection of diagnostic facial features.

  13. Human MiR-544a Modulates SELK Expression in Hepatocarcinoma Cell Lines.

    Directory of Open Access Journals (Sweden)

    Nicoletta Potenza

    Full Text Available Hepatocellular carcinoma (HCC is a multi-factorial cancer with a very poor prognosis; therefore, there are several investigations aimed at the comprehension of the molecular mechanisms leading to development and progression of HCC and at the definition of new therapeutic strategies. We have recently evaluated the expression of selenoproteins in HCC cell lines in comparison with normal hepatocytes. Recent results have shown that some of them are down- and others up-regulated, including the selenoprotein K (SELK, whose expression was also induced by sodium selenite treatment on cells. However, so far very few studies have been dedicated to a possible effect of microRNAs on the expression of selenoproteins and their implication in HCC. In this study, the analysis of SELK 3'UTR by bioinformatics tools led to the identification of eight sites potentially targeted by human microRNAs. They were then subjected to a validation test based on luciferase reporter constructs transfected in HCC cell lines. In this functional screening, miR-544a was able to interact with SELK 3'UTR suppressing the reporter activity. Transfection of a miR-544a mimic or inhibitor was then shown to decrease or increase, respectively, the translation of the endogenous SELK mRNA. Intriguingly, miR-544a expression was found to be modulated by selenium treatment, suggesting a possible role in SELK induction by selenium.

  14. 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.

  15. IBTK Differently Modulates Gene Expression and RNA Splicing in HeLa and K562 Cells

    Directory of Open Access Journals (Sweden)

    Giuseppe Fiume

    2016-11-01

    Full Text Available The IBTK gene encodes the major protein isoform IBTKα that was recently characterized as substrate receptor of Cul3-dependent E3 ligase, regulating ubiquitination coupled to proteasomal degradation of Pdcd4, an inhibitor of translation. Due to the presence of Ankyrin-BTB-RCC1 domains that mediate several protein-protein interactions, IBTKα could exert expanded regulatory roles, including interaction with transcription regulators. To verify the effects of IBTKα on gene expression, we analyzed HeLa and K562 cell transcriptomes by RNA-Sequencing before and after IBTK knock-down by shRNA transduction. In HeLa cells, 1285 (2.03% of 63,128 mapped transcripts were differentially expressed in IBTK-shRNA-transduced cells, as compared to cells treated with control-shRNA, with 587 upregulated (45.7% and 698 downregulated (54.3% RNAs. In K562 cells, 1959 (3.1% of 63128 mapped RNAs were differentially expressed in IBTK-shRNA-transduced cells, including 1053 upregulated (53.7% and 906 downregulated (46.3%. Only 137 transcripts (0.22% were commonly deregulated by IBTK silencing in both HeLa and K562 cells, indicating that most IBTKα effects on gene expression are cell type-specific. Based on gene ontology classification, the genes responsive to IBTK are involved in different biological processes, including in particular chromatin and nucleosomal organization, gene expression regulation, and cellular traffic and migration. In addition, IBTK RNA interference affected RNA maturation in both cell lines, as shown by the evidence of alternative 3′- and 5′-splicing, mutually exclusive exons, retained introns, and skipped exons. Altogether, these results indicate that IBTK differently modulates gene expression and RNA splicing in HeLa and K562 cells, demonstrating a novel biological role of this protein.

  16. The HTLV-I tax protein transcriptionally modulates OX40 antigen expression.

    Science.gov (United States)

    Pankow, R; Dürkop, H; Latza, U; Krause, H; Kunzendorf, U; Pohl, T; Bulfone-Paus, S

    2000-07-01

    OX40 is a member of the TNF receptor family, expressed on activated T cells. It is the only costimulatory T cell molecule known to be specifically up-regulated in human T cell leukemia virus type-I (HTLV-I)-producing cells. In a T cell line, OX40 surface expression was shown to be induced by HTLV-I Tax alone. To understand molecular mechanisms of OX40 gene regulation and modulation by HTLV-I Tax, we have cloned the human OX40 gene and analyzed its 5'-flanking region. By reporter gene analysis with progressive 5' deletions from nucleotides -1259 to -64, we have defined a 157-bp DNA fragment as a minimal promoter for constitutive expression. In addition, we show that in the OX40+ cell line, Co, Tax is able to further increase OX40 surface expression. Up-regulation of OX40 promoter activity by Tax requires two upstream NF-kappaB sites, which are not active in the constitutive OX40 expression. Their deletion abrogates Tax responsiveness in reporter gene analysis. The site-directed mutagenesis of each NF-kappaB site demonstrates that cooperative NF-kappaB binding is a prerequisite for Tax-directed activity as neither site alone is sufficient for a full Tax responsiveness of the OX40 promoter. Upon Tax expression, both sites bind p65 and c-Rel. These data provide new insight into the direct regulation of OX40 by Tax and add to our understanding of the possible role of the OX40/OX40 ligand system in the proliferation of HTLV-I+ T cells.

  17. Modulation of microRNA editing, expression and processing by ADAR2 deaminase in glioblastoma.

    Science.gov (United States)

    Tomaselli, Sara; Galeano, Federica; Alon, Shahar; Raho, Susanna; Galardi, Silvia; Polito, Vinicia Assunta; Presutti, Carlo; Vincenti, Sara; Eisenberg, Eli; Locatelli, Franco; Gallo, Angela

    2015-01-13

    ADAR enzymes convert adenosines to inosines within double-stranded RNAs, including microRNA (miRNA) precursors, with important consequences on miRNA retargeting and expression. ADAR2 activity is impaired in glioblastoma and its rescue has anti-tumoral effects. However, how ADAR2 activity may impact the miRNome and the progression of glioblastoma is not known. By integrating deep-sequencing and array approaches with bioinformatics analyses and molecular studies, we show that ADAR2 is essential to edit a small number of mature miRNAs and to significantly modulate the expression of about 90 miRNAs in glioblastoma cells. Specifically, the rescue of ADAR2 activity in cancer cells recovers the edited miRNA population lost in glioblastoma cell lines and tissues, and rebalances expression of onco-miRNAs and tumor suppressor miRNAs to the levels observed in normal human brain. We report that the major effect of ADAR2 is to reduce the expression of a large number of miRNAs, most of which act as onco-miRNAs. ADAR2 can edit miR-222/221 and miR-21 precursors and decrease the expression of the corresponding mature onco-miRNAs in vivo and in vitro, with important effects on cell proliferation and migration. Our findings disclose an additional layer of complexity in miRNome regulation and provide information to better understand the impact of ADAR2 editing enzyme in glioblastoma. We propose that ADAR2 is a key factor for maintaining edited-miRNA population and balancing the expression of several essential miRNAs involved in cancer.

  18. Modulation of gene expression in heart and liver of hibernating black bears (Ursus americanus

    Directory of Open Access Journals (Sweden)

    Yan Jun

    2011-03-01

    Full Text Available Abstract Background Hibernation is an adaptive strategy to survive in highly seasonal or unpredictable environments. The molecular and genetic basis of hibernation physiology in mammals has only recently been studied using large scale genomic approaches. We analyzed gene expression in the American black bear, Ursus americanus, using a custom 12,800 cDNA probe microarray to detect differences in expression that occur in heart and liver during winter hibernation in comparison to summer active animals. Results We identified 245 genes in heart and 319 genes in liver that were differentially expressed between winter and summer. The expression of 24 genes was significantly elevated during hibernation in both heart and liver. These genes are mostly involved in lipid catabolism and protein biosynthesis and include RNA binding protein motif 3 (Rbm3, which enhances protein synthesis at mildly hypothermic temperatures. Elevated expression of protein biosynthesis genes suggests induction of translation that may be related to adaptive mechanisms reducing cardiac and muscle atrophies over extended periods of low metabolism and immobility during hibernation in bears. Coordinated reduction of transcription of genes involved in amino acid catabolism suggests redirection of amino acids from catabolic pathways to protein biosynthesis. We identify common for black bears and small mammalian hibernators transcriptional changes in the liver that include induction of genes responsible for fatty acid β oxidation and carbohydrate synthesis and depression of genes involved in lipid biosynthesis, carbohydrate catabolism, cellular respiration and detoxification pathways. Conclusions Our findings show that modulation of gene expression during winter hibernation represents molecular mechanism of adaptation to extreme environments.

  19. Modulation of neural circuits underlying temporal production by facial expressions of pain.

    Science.gov (United States)

    Ballotta, Daniela; Lui, Fausta; Porro, Carlo Adolfo; Nichelli, Paolo Frigio; Benuzzi, Francesca

    2018-01-01

    According to the Scalar Expectancy Theory, humans are equipped with a biological internal clock, possibly modulated by attention and arousal. Both emotions and pain are arousing and can absorb attentional resources, thus causing distortions of temporal perception. The aims of the present single-event fMRI study were to investigate: a) whether observation of facial expressions of pain interferes with time production; and b) the neural network subserving this kind of temporal distortions. Thirty healthy volunteers took part in the study. Subjects were asked to perform a temporal production task and a concurrent gender discrimination task, while viewing faces of unknown people with either pain-related or neutral expressions. Behavioural data showed temporal underestimation (i.e., longer produced intervals) during implicit pain expression processing; this was accompanied by increased activity of right middle temporal gyrus, a region known to be active during the perception of emotional and painful faces. Psycho-Physiological Interaction analyses showed that: 1) the activity of middle temporal gyrus was positively related to that of areas previously reported to play a role in timing: left primary motor cortex, middle cingulate cortex, supplementary motor area, right anterior insula, inferior frontal gyrus, bilateral cerebellum and basal ganglia; 2) the functional connectivity of supplementary motor area with several frontal regions, anterior cingulate cortex and right angular gyrus was correlated to the produced interval during painful expression processing. Our data support the hypothesis that observing emotional expressions distorts subjective time perception through the interaction of the neural network subserving processing of facial expressions with the brain network involved in timing. Within this frame, middle temporal gyrus appears to be the key region of the interplay between the two neural systems.

  20. Modulation of neural circuits underlying temporal production by facial expressions of pain.

    Directory of Open Access Journals (Sweden)

    Daniela Ballotta

    Full Text Available According to the Scalar Expectancy Theory, humans are equipped with a biological internal clock, possibly modulated by attention and arousal. Both emotions and pain are arousing and can absorb attentional resources, thus causing distortions of temporal perception. The aims of the present single-event fMRI study were to investigate: a whether observation of facial expressions of pain interferes with time production; and b the neural network subserving this kind of temporal distortions. Thirty healthy volunteers took part in the study. Subjects were asked to perform a temporal production task and a concurrent gender discrimination task, while viewing faces of unknown people with either pain-related or neutral expressions. Behavioural data showed temporal underestimation (i.e., longer produced intervals during implicit pain expression processing; this was accompanied by increased activity of right middle temporal gyrus, a region known to be active during the perception of emotional and painful faces. Psycho-Physiological Interaction analyses showed that: 1 the activity of middle temporal gyrus was positively related to that of areas previously reported to play a role in timing: left primary motor cortex, middle cingulate cortex, supplementary motor area, right anterior insula, inferior frontal gyrus, bilateral cerebellum and basal ganglia; 2 the functional connectivity of supplementary motor area with several frontal regions, anterior cingulate cortex and right angular gyrus was correlated to the produced interval during painful expression processing. Our data support the hypothesis that observing emotional expressions distorts subjective time perception through the interaction of the neural network subserving processing of facial expressions with the brain network involved in timing. Within this frame, middle temporal gyrus appears to be the key region of the interplay between the two neural systems.

  1. Modulation of neural circuits underlying temporal production by facial expressions of pain

    Science.gov (United States)

    Lui, Fausta; Porro, Carlo Adolfo; Nichelli, Paolo Frigio; Benuzzi, Francesca

    2018-01-01

    According to the Scalar Expectancy Theory, humans are equipped with a biological internal clock, possibly modulated by attention and arousal. Both emotions and pain are arousing and can absorb attentional resources, thus causing distortions of temporal perception. The aims of the present single-event fMRI study were to investigate: a) whether observation of facial expressions of pain interferes with time production; and b) the neural network subserving this kind of temporal distortions. Thirty healthy volunteers took part in the study. Subjects were asked to perform a temporal production task and a concurrent gender discrimination task, while viewing faces of unknown people with either pain-related or neutral expressions. Behavioural data showed temporal underestimation (i.e., longer produced intervals) during implicit pain expression processing; this was accompanied by increased activity of right middle temporal gyrus, a region known to be active during the perception of emotional and painful faces. Psycho-Physiological Interaction analyses showed that: 1) the activity of middle temporal gyrus was positively related to that of areas previously reported to play a role in timing: left primary motor cortex, middle cingulate cortex, supplementary motor area, right anterior insula, inferior frontal gyrus, bilateral cerebellum and basal ganglia; 2) the functional connectivity of supplementary motor area with several frontal regions, anterior cingulate cortex and right angular gyrus was correlated to the produced interval during painful expression processing. Our data support the hypothesis that observing emotional expressions distorts subjective time perception through the interaction of the neural network subserving processing of facial expressions with the brain network involved in timing. Within this frame, middle temporal gyrus appears to be the key region of the interplay between the two neural systems. PMID:29447256

  2. IBTK Differently Modulates Gene Expression and RNA Splicing in HeLa and K562 Cells.

    Science.gov (United States)

    Fiume, Giuseppe; Scialdone, Annarita; Rizzo, Francesca; De Filippo, Maria Rosaria; Laudanna, Carmelo; Albano, Francesco; Golino, Gaetanina; Vecchio, Eleonora; Pontoriero, Marilena; Mimmi, Selena; Ceglia, Simona; Pisano, Antonio; Iaccino, Enrico; Palmieri, Camillo; Paduano, Sergio; Viglietto, Giuseppe; Weisz, Alessandro; Scala, Giuseppe; Quinto, Ileana

    2016-11-07

    The IBTK gene encodes the major protein isoform IBTKα that was recently characterized as substrate receptor of Cul3-dependent E3 ligase, regulating ubiquitination coupled to proteasomal degradation of Pdcd4, an inhibitor of translation. Due to the presence of Ankyrin-BTB-RCC1 domains that mediate several protein-protein interactions, IBTKα could exert expanded regulatory roles, including interaction with transcription regulators. To verify the effects of IBTKα on gene expression, we analyzed HeLa and K562 cell transcriptomes by RNA-Sequencing before and after IBTK knock-down by shRNA transduction. In HeLa cells, 1285 (2.03%) of 63,128 mapped transcripts were differentially expressed in IBTK -shRNA-transduced cells, as compared to cells treated with control-shRNA, with 587 upregulated (45.7%) and 698 downregulated (54.3%) RNAs. In K562 cells, 1959 (3.1%) of 63128 mapped RNAs were differentially expressed in IBTK -shRNA-transduced cells, including 1053 upregulated (53.7%) and 906 downregulated (46.3%). Only 137 transcripts (0.22%) were commonly deregulated by IBTK silencing in both HeLa and K562 cells, indicating that most IBTKα effects on gene expression are cell type-specific. Based on gene ontology classification, the genes responsive to IBTK are involved in different biological processes, including in particular chromatin and nucleosomal organization, gene expression regulation, and cellular traffic and migration. In addition, IBTK RNA interference affected RNA maturation in both cell lines, as shown by the evidence of alternative 3'- and 5'-splicing, mutually exclusive exons, retained introns, and skipped exons. Altogether, these results indicate that IBTK differently modulates gene expression and RNA splicing in HeLa and K562 cells, demonstrating a novel biological role of this protein.

  3. CLOSURE OF A DIOXIN INCINERATION FACILITY

    Science.gov (United States)

    The U.S. Environmental Protection Agency Mobile Incineration System, whihc was operated at the Denney Farm site in southwestern Miissouri between October 1985 and June 1989, treated almost six million kilograms of dioxin-contaminated wastes from eight area sites. At the conclusi...

  4. Radioimmunoassay for chlorinated dibenzo-p-dioxins

    International Nuclear Information System (INIS)

    Albro, P.W.; Chae, K.; Luster, M.I.; Mckinney, J.D.

    1980-01-01

    The invention provides a double-antibody radioimmunoassay method for the determination of chlorinated dibenzo-p-dioxins, particularly, 2,3,7,8-tetrachlorodibenzo-p-dioxin, in environmental samples including animal tissues such as monkey liver and adipose tissues. The limit of detection is approximately 25 picograms for 2,3,7,8-tetrachlorodibenzo-pdioxin. Assuming an appropriate cleanup procedure is used, chlorinated dibenzofurans are the only likely interferences, and these can be distinguished through the use of two antisers of different dibenzo-furan/dibenzodioxin selectivities. The invention includes the preparation of a reproducible antigen, an appropriate radiolabeled hapten, and effective sample extracts. A feature of the assay method is the use of a nonionic detergent (e.g., ''cutscum'' or ''triton x-305'') to solubilize the extremely hydrophobic dibenzo-p-dioxins in a manner permitting their binding by antibodies. The immunoassay is applicable to screening samples in order to minimize the demand for mass spectrometric screening, and to routine monitoring for exposure to known chlorinated dibenzo-p-dioxins in potentially contaminated environments

  5. DIOXINS AND ENDOMETRIOSIS: A PLAUSIBLE HYPOTHESIS

    Science.gov (United States)

    A potential connection exists between the increasing prevalence of endometriosis and exposure to organochlorine chemicals. There is evidence that dioxin (2,3,7,8-TCDD) can increase the incidence and severity of the disease in monkeys and can promote the growth or survival of end...

  6. Consequences of 40 Years' Dioxin Intoxication

    Czech Academy of Sciences Publication Activity Database

    Pelclová, D.; Fenclová, Z.; Dubská, Z.; Malík, J.; Navrátil, Tomáš

    2009-01-01

    Roč. 47, č. 5 (2009), s. 494-494 ISSN 1556-3650. [The International Congress of the European Association of Poison Centres and Clinical Toxicologists /29./. 12.05.2009-15.05.2009, Stockholm] Institutional research plan: CEZ:AV0Z40400503 Keywords : dioxins * intoxication Subject RIV: CF - Physical ; Theoretical Chemistry

  7. Coxiella burnetii Nine Mile II proteins modulate gene expression of monocytic host cells during infection

    Directory of Open Access Journals (Sweden)

    Shaw Edward I

    2010-09-01

    Full Text Available Abstract Background Coxiella burnetii is an intracellular bacterial pathogen that causes acute and chronic disease in humans. Bacterial replication occurs within enlarged parasitophorous vacuoles (PV of eukaryotic cells, the biogenesis and maintenance of which is dependent on C. burnetii protein synthesis. These observations suggest that C. burnetii actively subverts host cell processes, however little is known about the cellular biology mechanisms manipulated by the pathogen during infection. Here, we examined host cell gene expression changes specifically induced by C. burnetii proteins during infection. Results We have identified 36 host cell genes that are specifically regulated when de novo C. burnetii protein synthesis occurs during infection using comparative microarray analysis. Two parallel sets of infected and uninfected THP-1 cells were grown for 48 h followed by the addition of chloramphenicol (CAM to 10 μg/ml in one set. Total RNA was harvested at 72 hpi from all conditions, and microarrays performed using Phalanx Human OneArray™ slides. A total of 784 (mock treated and 901 (CAM treated THP-1 genes were up or down regulated ≥2 fold in the C. burnetii infected vs. uninfected cell sets, respectively. Comparisons between the complementary data sets (using >0 fold, eliminated the common gene expression changes. A stringent comparison (≥2 fold between the separate microarrays revealed 36 host cell genes modulated by C. burnetii protein synthesis. Ontological analysis of these genes identified the innate immune response, cell death and proliferation, vesicle trafficking and development, lipid homeostasis, and cytoskeletal organization as predominant cellular functions modulated by C. burnetii protein synthesis. Conclusions Collectively, these data indicate that C. burnetii proteins actively regulate the expression of specific host cell genes and pathways. This is in addition to host cell genes that respond to the presence of the

  8. Attenuation of doxorubicin-induced cardiotoxicity by esculetin through modulation of Bmi-1 expression.

    Science.gov (United States)

    Xu, Fan; Li, Xiao; Liu, Lanfang; Xiao, Xu; Zhang, Li; Zhang, Shenglin; Lin, Pingping; Wang, Xiaojie; Wang, Yongwei; Li, Qingshan

    2017-09-01

    The protective effects and mechanisms of esculetin on doxorubicin (DOX)-induced injury of H9c2 cells were investigated. H9c2 cells were cultured and the logarithmic growth phase of the cells was divided into a control group, a DOX group and an esculetin + DOX group. Cell viability was detected by MTT assay. Annexin V-PI (AV-PI) double staining flow cytometry was carried out to detect cell apoptosis. Intracellular reactive oxygen species (ROS) were detected by flow cytometry. Transmission electron microscope (TEM) was used to evaluate cell ultrastructure. Cleaved caspase-3, cleaved PARP, Bcl-2, Bid and Bmi-1 proteins levels were investigated by western blot analysis. Bmi-1 siRNA was used to detect the role of Bmi-1 in the protective effects of esculetin against DOX-induced toxicity in H9c2 cells. The MTT and AV-PI double staining results showed that esculetin significantly increased H9c2 cell viability. Compared with the control group, the levels of cleaved caspase-3, cleaved PARP, Bid and ROS levels were significantly decreased, but the expression of Bcl-2 and Bmi-1 were significantly increased in the esculetin + DOX group. TEM showed that the cell structure of the mitochondria was protected by esculetin. The results of Bmi-1 siRNA showed that esculetin could protect DOX-induced cardiotoxicity by modulating Bmi-1 expression. Esculetin can protect DOX-induced cardiotoxicity and the effects may be attributable to modulation of Bmi-1 expression, provoking intracellular ROS accumulation, protecting the structure of mitochondria and reducing cell apoptosis.

  9. Radiotherapy modulates expression of EGFR, ERCC1 and p53 in cervical cancer

    Energy Technology Data Exchange (ETDEWEB)

    Almeida, V.H. de; Melo, A.C. de; Nogueira-Rodrigues, A.; Pimenta-Inada, H.K.; Alves, F.G.; Moralez, G.; Thiago, L.S.; Ferreira, C.G.; Sternberg, C., E-mail: diretoriaexecutiva@sboc.org.br [Instituto Nacional de Câncer (INCA), Rio de Janeiro, RJ (Brazil); Meira, D.D. [Universidade Federal do Espírito Santo (UFES), Vitória, ES (Brazil); Pires, A.C. [Fonte Medicina Diagnóstica, Niterói, RJ (Brazil)

    2018-02-01

    Cervical cancer is a public health problem and the molecular mechanisms underlying radioresistance are still poorly understood. Here, we evaluated the modulation of key molecules involved in cell proliferation, cell cycle and DNA repair in cervical cancer cell lines (CASKI and C33A) and in malignant tissues biopsied from 10 patients before and after radiotherapy. The expression patterns of epidermal growth factor receptor (EGFR), excision repair cross-complementation group 1 (ERCC1) and p53 were evaluated in cancer cell lines by quantitative PCR and western blotting, and in human malignant tissues by immunohistochemistry. The mutation status of TP53 gene was evaluated by direct sequencing. Among cell lines, absent or weak modulations of EGFR, ERCC1 and p53 were observed after exposure to 1.8 Gy. Conversely, increased expressions of p53 (5/10 patients; P=0.0239), ERCC1 (5/10 patients; P=0.0294) and EGFR (4/10 patients; P=0.1773) were observed in malignant tissues after radiotherapy with the same radiation dose. TP53 mutations were found only in one patient. Here we show that a single dose of radiotherapy induced EGFR, ERCC1 and p53 expression in malignant tissues from cervical cancer patients but not in cancer cell lines, highlighting the gap between in vitro and in vivo experimental models. Studies on larger patient cohorts are needed to allow an interpretation that an up regulation of p53, EGFR and ERCC1 may be part of a radioresistance mechanism. (author)

  10. Michigan dioxin exposure study: planning phase and protocol development

    Energy Technology Data Exchange (ETDEWEB)

    Adriaens, P. [Univ. of Michigan, Coll. of Engineering, Ann Arbor (United States); Garabrant, D.; Franzblau, A. [Univ. of Michigan, School for Public Health, Ann Arbor (United States); Gillespie, B. [Univ. of Michigan, Center for Statistics, Ann Arbor (United States); Lepowski, J. [Univ. of Michigan, Inst. for Social Research, Ann Arbor (United States)

    2004-09-15

    The University of Michigan has been commissioned to conduct one of the largest environmental epidemiology studies (700 residents) of dioxin exposure among the population of Michigan to describe the pattern of serum dioxin levels among adults and to understand the factors that explain variation in serum dioxin levels. The study is being undertaken (2004-2006) in response to concerns among the population of Midland and Saginaw Counties that dioxins from the Dow Chemical Company facilities in Midland have resulted in contamination of areas of the City of Midland and have contaminated the sediments in the Tittabawassee River flood plain. There is concern that body burdens of dioxins are elevated because of environmental contamination. The appropriate way to respond to these concerns is to measure the serum dioxin levels in a probability sample of the population in the region and to estimate each individual's past exposure to various factors that are believed to contribute to the body burden of dioxins. By measuring factors that reflect potential exposure to dioxins through air, water, soil, food intake, occupations, and various recreational activities, we can identify the factors that correlate with (and explain variation in) serum dioxin levels. The central goal of the study is to determine which factors explain variation in serum dioxin levels, and to quantify how much variation each factor explains. This paper provides information on the planning phase, study scope and objectives.

  11. Oleocanthal Modulates Estradiol-Induced Gene Expression Involving Estrogen Receptor α.

    Science.gov (United States)

    Keiler, Annekathrin Martina; Djiogue, Sefirin; Ehrhardt, Tino; Zierau, Oliver; Skaltsounis, Leandros; Halabalaki, Maria; Vollmer, Günter

    2015-09-01

    Oleocanthal is a bioactive compound from olive oil. It has attracted considerable attention as it is anti-inflammatory, antiproliferative, and has been shown to possess neuroprotective properties in vitro and in vivo. Delineated from its polyphenolic structure, the aim of this study was to characterize oleocanthal towards estrogenic properties. This might contribute to partly explain the beneficial effects described for the Mediterranean diet. Estrogenic properties of oleocanthal were assessed by different methods: a) stimulation of reporter gene activity in MVLN or RNDA cells either expressing estrogen receptor α or β, b) stimulation of luciferase reporter gene activity in U2OS osteosarcoma cells expressing estrogen receptor α or β, and c) elucidation of the impact on estradiol-induced gene expression in U2OS cells transduced with both estrogen receptors. Depending on the cell line origin, oleocanthal inhibited luciferase activity (MVLN, U2OS-estrogen receptor β) or weakly induced reporter gene activity at 10 µM in U2OS-estrogen receptor α cells. However, oleocanthal inhibited stimulation of luciferase activity by estradiol from both estrogen receptors. Oleocanthal, if given alone, did not stimulate gene expression in U2OS cells, but it significantly modulated the response of estradiol. Oleocanthal enhanced the effect of estradiol on the regulation of those genes, which are believed to be regulated through heterodimeric estrogen receptors. As the estrogenic response pattern of oleocanthal is rather unique, we compared the results obtained with oleacein. Oleocanthal binds to both estrogen receptors inducing estradiol-agonistic or antiagonistic effects depending on the cell line. Regarding regulation of gene expression in U2OS-estrogen receptor α/β cells, oleocanthal and oleacein enhanced estradiol-mediated regulation of heterodimer-regulated genes. Georg Thieme Verlag KG Stuttgart · New York.

  12. Phorbol diesters and transferrin modulate lymphoblastoid cell transferrin receptor expression by two different mechanisms

    International Nuclear Information System (INIS)

    Alcantara, O.; Phillips, J.L.; Boldt, D.H.

    1986-01-01

    Expression of transferrin receptors (TfR) by activated lymphocytes is necessary for lymphocyte DNA synthesis and proliferation. Regulation of TfR expression, therefore, is a mechanism by which the lymphocyte's proliferative potential may be directed and controlled. The authors studied mechanisms by which lymphoblastoid cells modulate TfR expression during treatment with phorbol diesters or iron transferrin (FeTf), agents which cause downregulation of cell surface TfR. Phorbol diester-induced TfR downregulation occurred rapidly, being detectable at 2 min and reaching maximal decreases of 50% by 15 min. It was inhibited by cold but not by agents that destabilize cytoskeletal elements. Furthermore, this downregulation was reversed rapidly by washing or by treatment with the membrane interactive agent, chlorpromazine. In contrast, FeTf-induced TfR downregulation occurred slowly. Decreased expression of TfR was detectable only after 15 min and maximal downregulation was achieved after 60 min. Although FeTf-induced downregulation also was inhibited by cold, it was inhibited in addition by a group of microtubule destabilizing agents (colchicine, vinblastine, podophyllotoxin) or cytochalasin B, a microfilament inhibitor. Furthermore, FeTf-induced downregulation was not reversed readily by washing or by treatment with chlorpromazine. Phorbol diesters cause TfR downregulation by a cytoskeleton-independent mechanism. These data indicate that TfR expression is regulated by two independent mechanisms in lymphoblastoid cells, and they provide the possibility that downregulation of TfR by different mechanisms may result in different effects in these cells

  13. Modulation of gene expression in Actinobacillus pleuropneumoniae exposed to bronchoalveolar fluid.

    Directory of Open Access Journals (Sweden)

    Abdul G Lone

    Full Text Available BACKGROUND: Actinobacillus pleuropneumoniae, the causative agent of porcine contagious pleuropneumonia, is an important pathogen of swine throughout the world. It must rapidly overcome the innate pulmonary immune defenses of the pig to cause disease. To better understand this process, the objective of this study was to identify genes that are differentially expressed in a medium that mimics the lung environment early in the infection process. METHODS AND PRINCIPAL FINDINGS: Since bronchoalveolar lavage fluid (BALF contains innate immune and other components found in the lungs, we examined gene expression of a virulent serovar 1 strain of A. pleuropneumoniae after a 30 min exposure to BALF, using DNA microarrays and real-time PCR. The functional classes of genes found to be up-regulated most often in BALF were those encoding proteins involved in energy metabolism, especially anaerobic metabolism, and in cell envelope, DNA, and protein biosynthesis. Transcription of a number of known virulence genes including apxIVA and the gene for SapF, a protein which is involved in resistance to antimicrobial peptides, was also up-regulated in BALF. Seventy-nine percent of the genes that were up-regulated in BALF encoded a known protein product, and of these, 44% had been reported to be either expressed in vivo and/or involved in virulence. CONCLUSIONS: The results of this study suggest that in early stages of infection, A. pleuropneumoniae may modulate expression of genes involved in anaerobic energy generation and in the synthesis of proteins involved in cell wall biogenesis, as well as established virulence factors. Given that many of these genes are thought to be expressed in vivo or involved in virulence, incubation in BALF appears, at least partially, to simulate in vivo conditions and may provide a useful medium for the discovery of novel vaccine or therapeutic targets.

  14. Activity of Tachykinin1-Expressing Pet1 Raphe Neurons Modulates the Respiratory Chemoreflex.

    Science.gov (United States)

    Hennessy, Morgan L; Corcoran, Andrea E; Brust, Rachael D; Chang, YoonJeung; Nattie, Eugene E; Dymecki, Susan M

    2017-02-15

    Homeostatic control of breathing, heart rate, and body temperature relies on circuits within the brainstem modulated by the neurotransmitter serotonin (5-HT). Mounting evidence points to specialized neuronal subtypes within the serotonergic neuronal system, borne out in functional studies, for the modulation of distinct facets of homeostasis. Such functional differences, read out at the organismal level, are likely subserved by differences among 5-HT neuron subtypes at the cellular and molecular levels, including differences in the capacity to coexpress other neurotransmitters such as glutamate, GABA, thyrotropin releasing hormone, and substance P encoded by the Tachykinin-1 ( Tac1 ) gene. Here, we characterize in mice a 5-HT neuron subtype identified by expression of Tac1 and the serotonergic transcription factor gene Pet1 , referred to as the Tac1-Pet1 neuron subtype. Transgenic cell labeling showed Tac1-Pet1 soma resident largely in the caudal medulla. Chemogenetic [clozapine -N- oxide (CNO)-hM4Di] perturbation of Tac1-Pet1 neuron activity blunted the ventilatory response of the respiratory CO 2 chemoreflex, which normally augments ventilation in response to hypercapnic acidosis to restore normal pH and PCO 2 Tac1-Pet1 axonal boutons were found localized to brainstem areas implicated in respiratory modulation, with highest density in motor regions. These findings demonstrate that the activity of a Pet1 neuron subtype with the potential to release both 5-HT and substance P is necessary for normal respiratory dynamics, perhaps via motor outputs that engage muscles of respiration and maintain airway patency. These Tac1-Pet1 neurons may act downstream of Egr2-Pet1 serotonergic neurons, which were previously established in respiratory chemoreception, but do not innervate respiratory motor nuclei. SIGNIFICANCE STATEMENT Serotonin (5-HT) neurons modulate physiological processes and behaviors as diverse as body temperature, respiration, aggression, and mood. Using

  15. RANK ligand signaling modulates the matrix metalloproteinase-9 gene expression during osteoclast differentiation

    International Nuclear Information System (INIS)

    Sundaram, Kumaran; Nishimura, Riko; Senn, Joseph; Youssef, Rimon F.; London, Steven D.; Reddy, Sakamuri V.

    2007-01-01

    the absence of RANKL. Taken together, our results suggest that RANKL signals through TRAF6 and that NFATc1 is a downstream effector of RANKL signaling to modulate MMP-9 gene expression during osteoclast differentiation

  16. Bmi-1 expression modulates non-small cell lung cancer progression

    Science.gov (United States)

    Xiong, Dan; Ye, Yunlin; Fu, Yujie; Wang, Jinglong; Kuang, Bohua; Wang, Hongbo; Wang, Xiumin; Zu, Lidong; Xiao, Gang; Hao, Mingang; Wang, Jianhua

    2015-01-01

    Previous studies indicate that the role of B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) is responsible for multiple cancer progression. However, Bmi-1 in controlling gene expression in non-small cell lung cancer (NSCLC) development is not well explored. Here we report that the Bmi-1 level is highly increased in primary NSCLC tissues compared to matched adjacent non-cancerous tissues and required for lung tumor growth in xenograft model. Furthermore, we also demonstrate that Bmi-1 level is lower in matched involved lymph node cancerous tissues than the respective primary NSCLC tissues. We find that Bmi-1 does not affect cell cycle and apoptosis in lung cancer cell lines as it does not affect the expression of p16/p19, Pten, AKT and P-AKT. Mechanistic analyses note that reduction of Bmi-1 expression inversely regulates invasion and metastasis of NSCLC cells in vitro and in vivo, followed by induction of epithelial-mesenchymal transition (EMT). Using genome microarray assays, we find that RNAi-mediated silence of Bmi-1 modulates some important molecular genetics or signaling pathways, potentially associated with NSCLC development. Taken together, our findings disclose for the first time that Bmi-1 level accumulates strongly in early stage and then declines in late stage, which is potentially important for NSCLC cell invasion and metastasis during progression. PMID:25880371

  17. Insertional inactivation of a chromosomal locus that modulates expression of potential virulence determinants in Staphylococcus aureus.

    Science.gov (United States)

    Cheung, A L; Wolz, C; Yeaman, M R; Bayer, A S

    1995-06-01

    A single insertion of transposon Tn551 into a unique chromosomal locus of Staphylococcus aureus ISP479C has resulted in a pleiotropic effect on the expression of both extracellular and cell wall proteins. In particular, the expression of cell wall protein A and clumping activity with fibrinogen were rendered undetectable in the mutant 1E3 compared with the parent. The secretion of alpha-hemolysin in mutant 1E3 was modestly increased. Southern blot and phenotypic analyses indicated that this locus is distinct from agr, xpr, and sar, three previously described global regulatory loci. Transduction experiments demonstrated that the genotype associated with mutant 1E3 could be transferred back into the parental strain ISP479C. The transductant 1E3-2 displayed a phenotypic profile similar to that of the original mutant. Northern (RNA) blot studies showed that this locus may be involved in modulating target genes at the mRNA level. In the rabbit endocarditis model, there was a significant decrease in both the infectivity rate and intravegetation bacterial density with mutant 1E3 compared with the parent at an inoculum of 10(3) CFU. Since protein A and the fibrinogen-binding protein(s) are major surface proteins that may mediate bacterial adhesion to host tissues, this locus may be an important genetic element involved in the expression of virulence determinants in S. aureus.

  18. Exosomes from asbestos-exposed cells modulate gene expression in mesothelial cells.

    Science.gov (United States)

    Munson, Phillip; Lam, Ying-Wai; Dragon, Julie; MacPherson, Maximilian; Shukla, Arti

    2018-03-19

    Asbestos exposure is a determinate cause of many diseases, such as mesothelioma, fibrosis, and lung cancer, and poses a major human health hazard. At this time, there are no identified biomarkers to demarcate asbestos exposure before the presentation of disease and symptoms, and there is only limited understanding of the underlying biology that governs asbestos-induced disease. In our study, we used exosomes, 30-140 nm extracellular vesicles, to gain insight into these knowledge gaps. As inhaled asbestos is first encountered by lung epithelial cells and macrophages, we hypothesize that asbestos-exposed cells secrete exosomes with signature proteomic cargo that can alter the gene expression of mesothelial cells, contributing to disease outcomes like mesothelioma. In the present study using lung epithelial cells (BEAS2B) and macrophages (THP-1), we first show that asbestos exposure causes changes in abundance of some proteins in the exosomes secreted from these cells. Furthermore, exposure of human mesothelial cells (HPM3) to these exosomes resulted in gene expression changes related to epithelial-to-mesenchymal transition and other cancer-related genes. This is the first report to indicate that asbestos-exposed cells secrete exosomes with differentially abundant proteins and that those exosomes have a gene-altering effect on mesothelial cells.-Munson, P., Lam, Y.-W., Dragon, J. MacPherson, M., Shukla, A. Exosomes from asbestos-exposed cells modulate gene expression in mesothelial cells.

  19. Micro-fluidic module for blood cell separation for gene expression radiobiological assays

    International Nuclear Information System (INIS)

    Brengues, Muriel; Gu, Jian; Zenhausern, Frederic

    2015-01-01

    Advances in molecular techniques have improved discovery of biomarkers associated with radiation exposure. Gene expression techniques have been demonstrated as effective tools for biodosimetry, and different assay platforms with different chemistries are now available. One of the main challenges is to integrate the sample preparation processing of these assays into micro-fluidic platforms to be fully automated for point-of-care medical countermeasures in the case of a radiological event. Most of these assays follow the same workflow processing that comprises first the collection of blood samples followed by cellular and molecular sample preparation. The sample preparation is based on the specific reagents of the assay system and depends also on the different subsets of cells population and the type of biomarkers of interest. In this article, the authors present a module for isolation of white blood cells from peripheral blood as a prerequisite for automation of gene expression assays on a micro-fluidic cartridge. For each sample condition, the gene expression platform can be adapted to suit the requirements of the selected assay chemistry (authors)

  20. Exposure assessment of dioxins and dioxin-like PCBs in pasteurised bovine milk using probabilistic modelling.

    Science.gov (United States)

    Adekunte, Adefunke O; Tiwari, Brijesh K; O'Donnell, Colm P

    2010-09-01

    Quantitative exposure assessment is a useful technique to investigate the risk from contaminants in the food chain. The objective of this study was to develop a probabilistic exposure assessment model for dioxins (PCDD/Fs) and dioxin-like PCBs (DL-PCBs) in pasteurised bovine milk. Mean dioxins and DL-PCBs (non-ortho and mono-ortho PCBs) concentrations (pg WHO-TEQ g(-1)) in bovine milk were estimated as 0.06 ± 0.07 pg WHO-TEQ g(-1) for dioxins and 0.08 ± 0.07 pg WHO-TEQ g(-1) for DL-PCBs using Monte Carlo simulation. The simulated model estimated mean exposure for dioxins was 0.19 ± 0.29 pg WHO-TEQ kg(-1)bw d(-1) and 0.14 ± 0.22 pg WHO-TEQ kg(-1) bw d(-1) and for DL-PCBs was 0.25 ± 0.30 pg WHO-TEQ kg(-1) bw d(-1) and 0.19 ± 0.22 pg WHO-TEQ kg(-1) bw d(-1) for men and women, respectively. This study showed that the mean dioxins and DL-PCBs exposure from consumption of pasteurised bovine milk is below the provisional maximum tolerable monthly intake of 70 pg TEQ kg(-1) bw month(-1) (equivalent of 2.3 pg TEQ kg(-1) bw d(-1)) recommended by the Joint FAO/WHO Expert Committee on Food Additives and Contaminants (JECFA). Results from this study also showed that the estimated dioxins and DL-PCBs concentration in pasteurised bovine milk is comparable to those reported in previous studies. Copyright © 2010 Elsevier Ltd. All rights reserved.

  1. Serotonin receptors expressed in Drosophila mushroom bodies differentially modulate larval locomotion.

    Directory of Open Access Journals (Sweden)

    Bryon Silva

    Full Text Available Drosophila melanogaster has been successfully used as a simple model to study the cellular and molecular mechanisms underlying behaviors, including the generation of motor programs. Thus, it has been shown that, as in vertebrates, CNS biogenic amines (BA including serotonin (5HT participate in motor control in Drosophila. Several evidence show that BA systems innervate an important association area in the insect brain previously associated to the planning and/or execution of motor programs, the Mushroom Bodies (MB. The main objective of this work is to evaluate the contribution of 5HT and its receptors expressed in MB to motor behavior in fly larva. Locomotion was evaluated using an automated tracking system, in Drosophila larvae (3(rd-instar exposed to drugs that affect the serotonergic neuronal transmission: alpha-methyl-L-dopa, MDMA and fluoxetine. In addition, animals expressing mutations in the 5HT biosynthetic enzymes or in any of the previously identified receptors for this amine (5HT1AR, 5HT1BR, 5HT2R and 5HT7R were evaluated in their locomotion. Finally, RNAi directed to the Drosophila 5HT receptor transcripts were expressed in MB and the effect of this manipulation on motor behavior was assessed. Data obtained in the mutants and in animals exposed to the serotonergic drugs, suggest that 5HT systems are important regulators of motor programs in fly larvae. Studies carried out in animals pan-neuronally expressing the RNAi for each of the serotonergic receptors, support this idea and further suggest that CNS 5HT pathways play a role in motor control. Moreover, animals expressing an RNAi for 5HT1BR, 5HT2R and 5HT7R in MB show increased motor behavior, while no effect is observed when the RNAi for 5HT1AR is expressed in this region. Thus, our data suggest that CNS 5HT systems are involved in motor control, and that 5HT receptors expressed in MB differentially modulate motor programs in fly larvae.

  2. Dietary Nutrients and Bioactive Substances Modulate Heat Shock Protein (HSP) Expression: A Review.

    Science.gov (United States)

    Moura, Carolina Soares; Lollo, Pablo Christiano Barboza; Morato, Priscila Neder; Amaya-Farfan, Jaime

    2018-05-28

    Interest in the heat shock proteins (HSPs), as a natural physiological toolkit of living organisms, has ranged from their chaperone function in nascent proteins to the remedial role following cell stress. As part of the defence system, HSPs guarantee cell tolerance against a variety of stressors, including exercise, oxidative stress, hyper and hypothermia, hyper and hypoxia and improper diets. For the past couple of decades, research on functional foods has revealed a number of substances likely to trigger cell protection through mechanisms that involve the induction of HSP expression. This review will summarize the occurrence of the most easily inducible HSPs and describe the effects of dietary proteins, peptides, amino acids, probiotics, high-fat diets and other food-derived substances reported to induce HSP response in animals and humans studies. Future research may clarify the mechanisms and explore the usefulness of this natural alternative of defense and the modulating mechanism of each substance.

  3. Salmonella modulation of host cell gene expression promotes its intracellular growth.

    Directory of Open Access Journals (Sweden)

    Sebastian Hannemann

    Full Text Available Salmonella Typhimurium has evolved a complex functional interface with its host cell largely determined by two type III secretion systems (T3SS, which through the delivery of bacterial effector proteins modulate a variety of cellular processes. We show here that Salmonella Typhimurium infection of epithelial cells results in a profound transcriptional reprogramming that changes over time. This response is triggered by Salmonella T3SS effector proteins, which stimulate unique signal transduction pathways leading to STAT3 activation. We found that the Salmonella-stimulated changes in host cell gene expression are required for the formation of its specialized vesicular compartment that is permissive for its intracellular replication. This study uncovers a cell-autonomous process required for Salmonella pathogenesis potentially opening up new avenues for the development of anti-infective strategies that target relevant host pathways.

  4. Salmonella modulation of host cell gene expression promotes its intracellular growth.

    Science.gov (United States)

    Hannemann, Sebastian; Gao, Beile; Galán, Jorge E

    2013-01-01

    Salmonella Typhimurium has evolved a complex functional interface with its host cell largely determined by two type III secretion systems (T3SS), which through the delivery of bacterial effector proteins modulate a variety of cellular processes. We show here that Salmonella Typhimurium infection of epithelial cells results in a profound transcriptional reprogramming that changes over time. This response is triggered by Salmonella T3SS effector proteins, which stimulate unique signal transduction pathways leading to STAT3 activation. We found that the Salmonella-stimulated changes in host cell gene expression are required for the formation of its specialized vesicular compartment that is permissive for its intracellular replication. This study uncovers a cell-autonomous process required for Salmonella pathogenesis potentially opening up new avenues for the development of anti-infective strategies that target relevant host pathways.

  5. Evidence of Rapid Modulation by Social Information of Subjective, Physiological, and Neural Responses to Emotional Expressions.

    Science.gov (United States)

    Mermillod, Martial; Grynberg, Delphine; Pio-Lopez, Léo; Rychlowska, Magdalena; Beffara, Brice; Harquel, Sylvain; Vermeulen, Nicolas; Niedenthal, Paula M; Dutheil, Frédéric; Droit-Volet, Sylvie

    2017-01-01

    Recent research suggests that conceptual or emotional factors could influence the perceptual processing of stimuli. In this article, we aimed to evaluate the effect of social information (positive, negative, or no information related to the character of the target) on subjective (perceived and felt valence and arousal), physiological (facial mimicry) as well as on neural (P100 and N170) responses to dynamic emotional facial expressions (EFE) that varied from neutral to one of the six basic emotions. Across three studies, the results showed reduced ratings of valence and arousal of EFE associated with incongruent social information (Study 1), increased electromyographical responses (Study 2), and significant modulation of P100 and N170 components (Study 3) when EFE were associated with social (positive and negative) information (vs. no information). These studies revealed that positive or negative social information reduces subjective responses to incongruent EFE and produces a similar neural and physiological boost of the early perceptual processing of EFE irrespective of their congruency. In conclusion, the article suggests that the presence of positive or negative social context modulates early physiological and neural activity preceding subsequent behavior.

  6. Modulation of cathepsin G expression in severe atopic dermatitis following medium-dose UVA1 phototherapy

    Directory of Open Access Journals (Sweden)

    Altmeyer Peter

    2002-08-01

    Full Text Available Abstract Background During the last decade, medium-dose UVA1 phototherapy (50 J/cm2 has achieved great value within the treatment of severe atopic dermatitis (AD. The purpose of our study was to investigate to what extent UVA1 irradiation is able to modulate the status of protease activity by the use of a monoclonal antibody labeling cathepsin G. Methods In order to further elucidate the mechanisms by which medium-dose UVA1 irradiation leads to an improvement of skin status in patients with AD, biopsy specimens from 15 patients before and after treatment were analyzed immunohistochemically for proteolytic activation. Results Compared to lesional skin of patients with AD before UVA1 irradiation, the number of cells positive for cathepsin G within the dermal infiltrate decreased significantly after treatment. The decrease of cathepsin G+ cells was closely linked to a substantial clinical improvement in skin condition. Conclusions In summary, our findings demonstrated that medium-dose UVA1 irradiation leads to a modulation of the expression of cathepsin G in the dermal inflammatory infiltrate in patients with severe AD. Cathepsin G may attack laminin, proteoglycans, collagen I and insoluble fibronectin, to provoke proinflammatory events, to degrade the basement membrane, to destroy the tissue inhibitor of metalloproteinases and to increase the endothelial permeability. Therefore, its down-regulation by UVA1 phototherapy may induce the reduction of skin inflammation as well as improvement of the skin condition.

  7. Modulation of cathepsin G expression in severe atopic dermatitis following medium-dose UVA1 phototherapy

    Science.gov (United States)

    Breuckmann, Frank; von Kobyletzki, Gregor; Avermaete, Annelies; Kreuter, Alexander; Altmeyer, Peter; Gambichler, Thilo

    2002-01-01

    Background During the last decade, medium-dose UVA1 phototherapy (50 J/cm2) has achieved great value within the treatment of severe atopic dermatitis (AD). The purpose of our study was to investigate to what extent UVA1 irradiation is able to modulate the status of protease activity by the use of a monoclonal antibody labeling cathepsin G. Methods In order to further elucidate the mechanisms by which medium-dose UVA1 irradiation leads to an improvement of skin status in patients with AD, biopsy specimens from 15 patients before and after treatment were analyzed immunohistochemically for proteolytic activation. Results Compared to lesional skin of patients with AD before UVA1 irradiation, the number of cells positive for cathepsin G within the dermal infiltrate decreased significantly after treatment. The decrease of cathepsin G+ cells was closely linked to a substantial clinical improvement in skin condition. Conclusions In summary, our findings demonstrated that medium-dose UVA1 irradiation leads to a modulation of the expression of cathepsin G in the dermal inflammatory infiltrate in patients with severe AD. Cathepsin G may attack laminin, proteoglycans, collagen I and insoluble fibronectin, to provoke proinflammatory events, to degrade the basement membrane, to destroy the tissue inhibitor of metalloproteinases and to increase the endothelial permeability. Therefore, its down-regulation by UVA1 phototherapy may induce the reduction of skin inflammation as well as improvement of the skin condition. PMID:12204095

  8. DLEC1 Expression Is Modulated by Epigenetic Modifications in Hepatocelluar Carcinoma Cells: Role of HBx Genotypes

    International Nuclear Information System (INIS)

    Niu, Dandan; Feng, Huixing; Chen, Wei Ning

    2010-01-01

    Deleted in Lung and Esophageal Cancer 1 (DLEC1) is a functional tumor suppressor gene (TSG). It has been found to be silenced in a variety of human cancers including hepatocellular carcinoma (HCC). The silencing of DLEC1 can be modulated by epigenetic modifications, such as DNA hypermethylation and histone hypoacetylation. In the case of HCC, hepatitis B virus X protein (HBx) has been implicated in methylation of target promoters resulting in the down-regulation of tumor suppressor genes, which in turn contributes to the development of HCC. In the present study, we first established a cell system in which epigenetic modifications can be modulated using inhibitors of either DNA methylation or histone deacetylation. The cell system was used to reveal that the expression of DLEC1 was upregulated by HBx in a genotype-dependent manner. In particular, HBx genotype A was found to decrease DNA methylation of the DLEC1 promoter. Our results have provided new insights on the impact of HBx in HCC development by epigenetic modifications

  9. Evidence of Rapid Modulation by Social Information of Subjective, Physiological, and Neural Responses to Emotional Expressions

    Directory of Open Access Journals (Sweden)

    Martial Mermillod

    2018-01-01

    Full Text Available Recent research suggests that conceptual or emotional factors could influence the perceptual processing of stimuli. In this article, we aimed to evaluate the effect of social information (positive, negative, or no information related to the character of the target on subjective (perceived and felt valence and arousal, physiological (facial mimicry as well as on neural (P100 and N170 responses to dynamic emotional facial expressions (EFE that varied from neutral to one of the six basic emotions. Across three studies, the results showed reduced ratings of valence and arousal of EFE associated with incongruent social information (Study 1, increased electromyographical responses (Study 2, and significant modulation of P100 and N170 components (Study 3 when EFE were associated with social (positive and negative information (vs. no information. These studies revealed that positive or negative social information reduces subjective responses to incongruent EFE and produces a similar neural and physiological boost of the early perceptual processing of EFE irrespective of their congruency. In conclusion, the article suggests that the presence of positive or negative social context modulates early physiological and neural activity preceding subsequent behavior.

  10. MicroRNA-338 Attenuates Cortical Neuronal Outgrowth by Modulating the Expression of Axon Guidance Genes.

    Science.gov (United States)

    Kos, Aron; Klein-Gunnewiek, Teun; Meinhardt, Julia; Loohuis, Nikkie F M Olde; van Bokhoven, Hans; Kaplan, Barry B; Martens, Gerard J; Kolk, Sharon M; Aschrafi, Armaz

    2017-07-01

    MicroRNAs (miRs) are small non-coding RNAs that confer robustness to gene networks through post-transcriptional gene regulation. Previously, we identified miR-338 as a modulator of axonal outgrowth in sympathetic neurons. In the current study, we examined the role of miR-338 in the development of cortical neurons and uncovered its downstream mRNA targets. Long-term inhibition of miR-338 during neuronal differentiation resulted in reduced dendritic complexity and altered dendritic spine morphology. Furthermore, monitoring axon outgrowth in cortical cells revealed that miR-338 overexpression decreased, whereas inhibition of miR-338 increased axonal length. To identify gene targets mediating the observed phenotype, we inhibited miR-338 in cortical neurons and performed whole-transcriptome analysis. Pathway analysis revealed that miR-338 modulates a subset of transcripts involved in the axonal guidance machinery by means of direct and indirect gene targeting. Collectively, our results implicate miR-338 as a novel regulator of cortical neuronal maturation by fine-tuning the expression of gene networks governing cortical outgrowth.

  11. Interleukin 6 deficiency modulates the hypothalamic expression of energy balance regulating peptides during pregnancy in mice.

    Science.gov (United States)

    Pazos, Patricia; Lima, Luis; Casanueva, Felipe F; Diéguez, Carlos; García, María C

    2013-01-01

    Pregnancy is associated with hyperphagia, increased adiposity and multiple neuroendocrine adaptations. Maternal adipose tissue secretes rising amounts of interleukin 6 (IL6), which acts peripherally modulating metabolic function and centrally increasing energy expenditure and reducing body fat. To explore the role of IL6 in the central mechanisms governing dam's energy homeostasis, early, mid and late pregnant (gestational days 7, 13 and 18) wild-type (WT) and Il6 knockout mice (Il6-KO) were compared with virgin controls at diestrus. Food intake, body weight and composition as well as indirect calorimetry measurements were performed in vivo. Anabolic and orexigenic peptides: neuropeptide Y (Npy) and agouti-related peptide (Agrp); and catabolic and anorectic neuropeptides: proopiomelanocortin (Pomc), corticotrophin and thyrotropin-releasing hormone (Crh and Trh) mRNA levels were determined by in situ hybridization. Real time-PCR and western-blot were used for additional tissue gene expression and protein studies. Non-pregnant Il6-KO mice were leaner than WT mice due to a decrease in fat but not in lean body mass. Pregnant Il6-KO mice had higher fat accretion despite similar body weight gain than WT controls. A decreased fat utilization in absence of Il6 might explain this effect, as shown by increased respiratory exchange ratio (RER) in virgin Il6-KO mice. Il6 mRNA levels were markedly enhanced in adipose tissue but reduced in hypothalamus of mid and late pregnant WT mice. Trh expression was also stimulated at gestational day 13 and lack of Il6 blunted this effect. Conversely, in late pregnant mice lessened hypothalamic Il6 receptor alpha (Il6ra), Pomc and Crh mRNA were observed. Il6 deficiency during this stage up-regulated Npy and Agrp expression, while restoring Pomc mRNA levels to virgin values. Together these results demonstrate that IL6/IL6Ra system modulates Npy/Agrp, Pomc and Trh expression during mouse pregnancy, supporting a role of IL6 in the central

  12. Weighted gene co-expression network analysis of expression data of monozygotic twins identifies specific modules and hub genes related to BMI.

    Science.gov (United States)

    Wang, Weijing; Jiang, Wenjie; Hou, Lin; Duan, Haiping; Wu, Yili; Xu, Chunsheng; Tan, Qihua; Li, Shuxia; Zhang, Dongfeng

    2017-11-13

    The therapeutic management of obesity is challenging, hence further elucidating the underlying mechanisms of obesity development and identifying new diagnostic biomarkers and therapeutic targets are urgent and necessary. Here, we performed differential gene expression analysis and weighted gene co-expression network analysis (WGCNA) to identify significant genes and specific modules related to BMI based on gene expression profile data of 7 discordant monozygotic twins. In the differential gene expression analysis, it appeared that 32 differentially expressed genes (DEGs) were with a trend of up-regulation in twins with higher BMI when compared to their siblings. Categories of positive regulation of nitric-oxide synthase biosynthetic process, positive regulation of NF-kappa B import into nucleus, and peroxidase activity were significantly enriched within GO database and NF-kappa B signaling pathway within KEGG database. DEGs of NAMPT, TLR9, PTGS2, HBD, and PCSK1N might be associated with obesity. In the WGCNA, among the total 20 distinct co-expression modules identified, coral1 module (68 genes) had the strongest positive correlation with BMI (r = 0.56, P = 0.04) and disease status (r = 0.56, P = 0.04). Categories of positive regulation of phospholipase activity, high-density lipoprotein particle clearance, chylomicron remnant clearance, reverse cholesterol transport, intermediate-density lipoprotein particle, chylomicron, low-density lipoprotein particle, very-low-density lipoprotein particle, voltage-gated potassium channel complex, cholesterol transporter activity, and neuropeptide hormone activity were significantly enriched within GO database for this module. And alcoholism and cell adhesion molecules pathways were significantly enriched within KEGG database. Several hub genes, such as GAL, ASB9, NPPB, TBX2, IL17C, APOE, ABCG4, and APOC2 were also identified. The module eigengene of saddlebrown module (212 genes) was also significantly

  13. Third-Generation Ah Receptor–Responsive Luciferase Reporter Plasmids: Amplification of Dioxin-Responsive Elements Dramatically Increases CALUX Bioassay Sensitivity and Responsiveness

    Science.gov (United States)

    He, Guochun; Tsutsumi, Tomoaki; Zhao, Bin; Baston, David S.; Zhao, Jing; Heath-Pagliuso, Sharon; Denison, Michael S.

    2011-01-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and related dioxin-like chemicals are widespread and persistent environmental contaminants that produce diverse toxic and biological effects through their ability to bind to and activate the Ah receptor (AhR) and AhR-dependent gene expression. The chemically activated luciferase expression (CALUX) system is an AhR-responsive recombinant luciferase reporter gene–based cell bioassay that has been used in combination with chemical extraction and cleanup methods for the relatively rapid and inexpensive detection and relative quantitation of dioxin and dioxin-like chemicals in a wide variety of sample matrices. Although the CALUX bioassay has been validated and used extensively for screening purposes, it has some limitations when screening samples with very low levels of dioxin-like chemicals or when there is only a small amount of sample matrix for analysis. Here, we describe the development of third-generation (G3) CALUX plasmids with increased numbers of dioxin-responsive elements, and stable transfection of these new plasmids into mouse hepatoma (Hepa1c1c7) cells has produced novel amplified G3 CALUX cell bioassays that respond to TCDD with a dramatically increased magnitude of luciferase induction and significantly lower minimal detection limit than existing CALUX-type cell lines. The new G3 CALUX cell lines provide a highly responsive and sensitive bioassay system for the detection and relative quantitation of very low levels of dioxin-like chemicals in sample extracts. PMID:21775728

  14. Citizen participatory dioxin monitoring campaign by pine needles as biomonitor of ambient air dioxin pollution

    Energy Technology Data Exchange (ETDEWEB)

    Komichi, I.; Takatori, A. [Environmental Research Institute Inc., Tokyo (Japan); Aoyama, T. [Musashi Institute of Technology, Yokohama (Japan). Faculty of Environment and Informations; Vrzic, B. [Maxxam Analytics Inc. HRMS Laboratory, Waterloo, ON (Canada)

    2004-09-15

    The needle-type leaves of Japanese black pine trees (hereafter abbreviated as pine needles) have been used as an effective bio-monitor of ambient air pollution. Miyata Laboratory of Setsunan University has reported that the pine needles accumulate PCDDs and PCDFs (hereafter abbreviated as D/F) through photosynthesis and respiration during their lifetime. On the basis of this study, we have revealed the correlation between ambient air and pine needle concentrations to be estimated at or near 1:10 by analyzing long term continuous ambient dioxin monitoring data and that of pine needles sampled from the same area as ambient air in the Kanagawa Prefecture in 1999. Since then, the citizen groups of each local area all over Japan have started monitoring the ambient air dioxin concentration levels by using pine needles. Samples analyzed during these 5 years totaled more than 650 throughout Japan. The results of these citizen participatory environmental monitoring activities are the tremendous effects achieved in reducing the dioxin levels. This occurs through observation of the dioxin emission sources such as Municipal Solid Waste Incineration Plants as well as the Industrial Waste Incineration plants, which exist in numbers exceeding several thousands in Japan. This short paper will present the results of 56 municipalities of western Japan where ambient air dioxin levels have improved steadily against local averages during these 5 years.

  15. Biomonitoring of organic airborne pollutants in particular dioxins and furans

    International Nuclear Information System (INIS)

    Nobel, W.; Maier-Reiter, W.; Sommer, B.; Finkbeiner, M.

    1992-01-01

    Standardised grass and borecole cultures were used as bioindicators in the course of planning procedures for emitters. The studies show that such standardised cultures are suitable cumulative indicators of the dioxin and furan content of the atmosphere. Accumulation of dioxins and furans at the site are also evident in the naturally growing vegetation. The levels found for dioxins and furans are calculated by estimating health risks by means of a model of pollutant transfer within the human food chain. (orig.) [de

  16. Modulation of keratinocyte expression of antioxidants by 4-hydroxynonenal, a lipid peroxidation end product

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Ruijin [Pharmacology and Toxicology and Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ (United States); Heck, Diane E. [Environmental Health Science, New York Medical College, Valhalla, NY (United States); Mishin, Vladimir; Black, Adrienne T. [Pharmacology and Toxicology and Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ (United States); Shakarjian, Michael P. [Environmental Health Science, New York Medical College, Valhalla, NY (United States); Kong, Ah-Ng Tony; Laskin, Debra L. [Pharmacology and Toxicology and Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ (United States); Laskin, Jeffrey D., E-mail: jlaskin@eohsi.rutgers.edu [Environmental and Occupational Medicine, Rutgers University-Robert Wood Johnson Medical School, Piscataway, NJ (United States)

    2014-03-01

    4-Hydroxynonenal (4-HNE) is a lipid peroxidation end product generated in response to oxidative stress in the skin. Keratinocytes contain an array of antioxidant enzymes which protect against oxidative stress. In these studies, we characterized 4-HNE-induced changes in antioxidant expression in mouse keratinocytes. Treatment of primary mouse keratinocytes and PAM 212 keratinocytes with 4-HNE increased mRNA expression for heme oxygenase-1 (HO-1), catalase, NADPH:quinone oxidoreductase (NQO1) and glutathione S-transferase (GST) A1-2, GSTA3 and GSTA4. In both cell types, HO-1 was the most sensitive, increasing 86–98 fold within 6 h. Further characterization of the effects of 4-HNE on HO-1 demonstrated concentration- and time-dependent increases in mRNA and protein expression which were maximum after 6 h with 30 μM. 4-HNE stimulated keratinocyte Erk1/2, JNK and p38 MAP kinases, as well as PI3 kinase. Inhibition of these enzymes suppressed 4-HNE-induced HO-1 mRNA and protein expression. 4-HNE also activated Nrf2 by inducing its translocation to the nucleus. 4-HNE was markedly less effective in inducing HO-1 mRNA and protein in keratinocytes from Nrf2 −/− mice, when compared to wild type mice, indicating that Nrf2 also regulates 4-HNE-induced signaling. Western blot analysis of caveolar membrane fractions isolated by sucrose density centrifugation demonstrated that 4-HNE-induced HO-1 is localized in keratinocyte caveolae. Treatment of the cells with methyl-β-cyclodextrin, which disrupts caveolar structure, suppressed 4-HNE-induced HO-1. These findings indicate that 4-HNE modulates expression of antioxidant enzymes in keratinocytes, and that this can occur by different mechanisms. Changes in expression of keratinocyte antioxidants may be important in protecting the skin from oxidative stress. - Highlights: • Lipid peroxidation generates 4-hydroxynonenal, a reactive aldehyde. • 4-HNE induces antioxidant proteins in mouse keratinocytes. • Induction of

  17. Cyp1a reporter zebrafish reveals target tissues for dioxin

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Kun-Hee [Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju (Korea, Republic of); Department of Microbiology, Chonnam National University Medical School, Gwangju (Korea, Republic of); Park, Hye-Jeong [Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju (Korea, Republic of); Kim, Jin Hee [Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju (Korea, Republic of); Department of Microbiology, Chonnam National University Medical School, Gwangju (Korea, Republic of); Kim, Suhyun [Graduate School of Medicine, Korea University, Ansan (Korea, Republic of); Williams, Darren R. [New Drug Targets Laboratory, School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju (Korea, Republic of); Kim, Myeong-Kyu [Department of Neurology, Chonnam National University Medical School, Gwangju (Korea, Republic of); Jung, Young Do [Department of Biochemistry, Chonnam National University Medical School, Gwangju (Korea, Republic of); Teraoka, Hiroki [School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu (Japan); Park, Hae-Chul [Graduate School of Medicine, Korea University, Ansan (Korea, Republic of); Choy, Hyon E., E-mail: hyonchoy@chonnam.ac.kr [Department of Microbiology, Chonnam National University Medical School, Gwangju (Korea, Republic of); Shin, Boo Ahn, E-mail: bashin@chonnam.ac.kr [Department of Microbiology, Chonnam National University Medical School, Gwangju (Korea, Republic of); Choi, Seok-Yong, E-mail: zebrafish@chonnam.ac.kr [Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju (Korea, Republic of); School of Biological Sciences and Technology, Chonnam National University, Gwangju (Korea, Republic of)

    2013-06-15

    Highlights: •2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic anthropogenic substance ever identified. •Transgenic cyp1a reporter zebrafish reveals target tissues for TCDD. •The retinal bipolar cells, otic vesicle, lateral line, pancreas, cloaca and pectoral fin bud are novel targets in zebrafish for TCDD. •Our findings will further understanding of human health risks by TCDD. -- Abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the unintentional byproduct of various industrial processes, is classified as human carcinogen and could disrupt reproductive, developmental and endocrine systems. Induction of cyp1a1 is used as an indicator of TCDD exposure. We sought to determine tissues that are vulnerable to TCDD toxicity using a transgenic zebrafish (Danio rerio) model. We inserted a nuclear enhanced green fluorescent protein gene (EGFP) into the start codon of a zebrafish cyp1a gene in a fosmid clone using DNA recombineering. The resulting recombineered fosmid was then used to generate cyp1a reporter zebrafish, embryos of which were exposed to TCDD. Expression pattern of EGFP in the reporter zebrafish mirrored that of endogenous cyp1a mRNA. In addition, exposure of the embryos to TCDD at as low as 10 pM for 72 h, which does not elicit morphological abnormalities of embryos, markedly increased GFP expression. Furthermore, the reporter embryos responded to other AhR ligands as well. Exposure of the embryos to TCDD revealed previously reported (the cardiovascular system, liver, pancreas, kidney, swim bladder and skin) and unreported target tissues (retinal bipolar cells, otic vesicle, lateral line, cloaca and pectoral fin bud) for TCDD. Transgenic cyp1a reporter zebrafish we have developed can further understanding of ecotoxicological relevance and human health risks by TCDD. In addition, they could be used to identify agonists of AhR and antidotes to TCDD toxicity.

  18. Comparisons of dioxin levels of cucumber varieties and cultivation periods

    Energy Technology Data Exchange (ETDEWEB)

    Eun, H.; Watanabe, E.; Ishii, Y.; Ueji, M. [National Inst. for Agro-Environmental Sciences, Tsukuba (Japan); Narita, I.; Nakamura, K. [Saitama Prefecture Agriculture and Forestry Research Center, Saitama (Japan)

    2004-09-15

    According to a 2001 survey on Daily Intake in Japan, the total dioxins intake of a person in Japan amounts to 1.68 pg-TEQ per kg of body weight/day on average. The sharing a percentage of agricultural crops was about 3%in Japanese TDI amounts. However, all cases collect samples from supermarkets to estimate TDI of dioxins, which make it difficult to understand under what environment, food samples were pretreated and cultivated. Especially, TDI values in agricultural crops are probably dependent on the collection situation. In the agricultural environment, some reports indicate that dioxins have accumulated in paddy and upland in Japan due to the past use of some types of agricultural chemicals, which contained dioxins as impurities. Furthermore, taking the atmospheric pathway, for example, dioxins in the ambient air are associated with particulate matter and fall to the ground, contaminating agricultural land. Thus, it has been emphasized that dioxin compounds have a possibility to have adverse effect on vegetables. However, there is little understanding related to this fact in the country and worldwide. Empirical studies conducted in Japan and abroad have reported low residual concentrations of dioxins in cucumbers (Cucumis sativus L.), a member of the gourd family. However, there have been extremely few instances of research involving overall comparisons of cultivation environments. Thus, we studied the persistence of dioxins in cucumbers of different varieties cultivated outdoors over varying cultivation periods, conducting thorough experiments to elucidate the actual conditions and mechanisms of dioxin contamination of cucumbers.

  19. Common commercial and consumer products contain activators of the aryl hydrocarbon (dioxin receptor.

    Directory of Open Access Journals (Sweden)

    Bin Zhao

    Full Text Available Activation of the Ah receptor (AhR by halogenated aromatic hydrocarbons (HAHs, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin, can produce a wide variety of toxic and biological effects. While recent studies have shown that the AhR can bind and be activated by structurally diverse chemicals, how widespread of these AhR agonists are in environmental, biological and synthetic materials remains to be determined. Using AhR-based assays, we demonstrate the presence of potent AhR agonists in a variety of common commercial and consumer items. Solvent extracts of paper, rubber and plastic products contain chemicals that can bind to and stimulate AhR DNA binding and/or AhR-dependent gene expression in hepatic cytosol, cultured cell lines, human epidermis and zebrafish embryos. In contrast to TCDD and other persistent dioxin-like HAHs, activation of AhR-dependent gene expression by these extracts was transient, suggesting that the agonists are metabolically labile. Solvent extracts of rubber products produce AhR-dependent developmental toxicity in zebrafish in vivo, and inhibition of expression of the metabolic enzyme CYP1A, significantly increased their toxic potency. Although the identity of the responsible AhR-active chemicals and their toxicological impact remain to be determined, our data demonstrate that AhR active chemicals are widely distributed in everyday products.

  20. Response inhibition is modulated by functional cerebral asymmetries for facial expression perception

    Directory of Open Access Journals (Sweden)

    Sebastian eOcklenburg

    2013-11-01

    Full Text Available The efficacy of executive functions is critically modulated by information processing in earlier cognitive stages. For example, initial processing of verbal stimuli in the language-dominant left-hemisphere leads to more efficient response inhibition than initial processing of verbal stimuli in the non-dominant right hemisphere. However, it is unclear whether this organizational principle is specific for the language system, or a general principle that also applies to other types of lateralized cognition. To answer this question, we investigated the neurophysiological correlates of early attentional processes, facial expression perception and response inhibition during tachistoscopic presentation of facial ‘Go’ and ‘Nogo’ stimuli in the left and the right visual field. Participants committed fewer false alarms after Nogo-stimulus presentation in the left compared to the right visual field. This right-hemispheric asymmetry on the behavioral level was also reflected in the neurophysiological correlates of face perception, specifically in a right-sided asymmetry in the N170 amplitude. Moreover, the right-hemispheric dominance for facial expression processing also affected event-related potentials typically related to response inhibition, namely the Nogo-N2 and Nogo-P3. These findings show that an effect of hemispheric asymmetries in early information processing on the efficacy of higher cognitive functions is not limited to left-hemispheric language functions, but can be generalized to predominantly right-hemispheric functions.

  1. Senescence-Induced Alterations of Laminin Chain Expression Modulate Tumorigenicity of Prostate Cancer Cells1

    Science.gov (United States)

    Sprenger, Cynthia C T; Drivdahl, Rolf H; Woodke, Lillie B; Eyman, Daniel; Reed, May J; Carter, William G; Plymate, Stephen R

    2008-01-01

    Prostate cancer is an age-associated epithelial cancer, and as such, it contributes significantly to the mortality of the elderly. Senescence is one possible mechanism by which the body defends itself against various epithelial cancers. Senescent cells alter the microenvironment, in part, through changes to the extracellular matrix. Laminins (LMs) are extracellular proteins important to both the structure and function of the microenvironment. Overexpression of the senescence-associated gene mac25 in human prostate cancer cells resulted in increased mRNA levels of the LM α4 and β2 chains compared to empty vector control cells. The purpose of this study was to examine the effects of these senescence-induced LM chains on tumorigenicity of prostate cancer cells. We created stable M12 human prostate cancer lines overexpressing either the LM α4 or β2 chain or both chains. Increased expression of either the LM α4 or β2 chain resulted in increased in vitro migration and in vivo tumorigenicity of those cells, whereas high expression of both chains led to decreased in vitro proliferation and in vivo tumorigenicity compared to M12 control cells. This study demonstrates that senescent prostate epithelial cells can alter the microenvironment and that these changes modulate progression of prostate cancer. PMID:19048114

  2. Senescence-Induced Alterations of Laminin Chain Expression Modulate Tumorigenicity of Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Cynthia C.T. Sprenger

    2008-12-01

    Full Text Available Prostate cancer is an age-associated epithelial cancer, and as such, it contributes significantly to the mortality of the elderly. Senescence is one possible mechanism by which the body defends itself against various epithelial cancers. Senescent cells alter the microenvironment, in part, through changes to the extracellular matrix. Laminins (LMs are extracellular proteins important to both the structure and function of the microenvironment. Overexpression of the senescence-associated gene mac25 in human prostate cancer cells resulted in increased mRNA levels of the LM α4 and β2 chains compared to empty vector control cells. The purpose of this study was to examine the effects of these senescence-induced LM chains on tumorigenicity of prostate cancer cells. We created stable M12 human prostate cancer lines overexpressing either the LM α4 or β2 chain or both chains. Increased expression of either the LM α4 or β2 chain resulted in increased in vitro migration and in vivo tumorigenicity of those cells, whereas high expression of both chains led to decreased in vitro proliferation and in vivo tumorigenicity compared to M12 control cells. This study demonstrates that senescent prostate epithelial cells can alter the microenvironment and that these changes modulate progression of prostate cancer.

  3. Uncovering co-expression gene network modules regulating fruit acidity in diverse apples.

    Science.gov (United States)

    Bai, Yang; Dougherty, Laura; Cheng, Lailiang; Zhong, Gan-Yuan; Xu, Kenong

    2015-08-16

    Acidity is a major contributor to fruit quality. Several organic acids are present in apple fruit, but malic acid is predominant and determines fruit acidity. The trait is largely controlled by the Malic acid (Ma) locus, underpinning which Ma1 that putatively encodes a vacuolar aluminum-activated malate transporter1 (ALMT1)-like protein is a strong candidate gene. We hypothesize that fruit acidity is governed by a gene network in which Ma1 is key member. The goal of this study is to identify the gene network and the potential mechanisms through which the network operates. Guided by Ma1, we analyzed the transcriptomes of mature fruit of contrasting acidity from six apple accessions of genotype Ma_ (MaMa or Mama) and four of mama using RNA-seq and identified 1301 fruit acidity associated genes, among which 18 were most significant acidity genes (MSAGs). Network inferring using weighted gene co-expression network analysis (WGCNA) revealed five co-expression gene network modules of significant (P acidity. Overall, this study provides important insight into the Ma1-mediated gene network controlling acidity in mature apple fruit of diverse genetic background.

  4. Anaerobic transformation of chlorinated dioxins by microorganisms

    Energy Technology Data Exchange (ETDEWEB)

    Adrian, L. [Fachgebiet Technische Biochemie, Technische Univ. Berlin (Germany); Lechner, U. [Inst. fuer Mikrobiologie, Martin-Luther-Univ. Halle-Wittenberg (Germany)

    2004-09-15

    Mixed bacterial cultures catalyze diverse chlorodioxin-dehalogenation pathways. Some of these pathways lead to relatively harmless end products, which can undergo further biological degradation e.g. by aerobic bacteria. However, the possible formation of highly toxic products is a critical problem for a bioremediation approach but also for untreated sites where such dechlorination reactions can occur. Bioaugmentation with suitable pure or mixed cultures is promising. This has recently been demonstrated in a tetrachloroethene-contaminated groundwater using a Dehalococcoidescontaining inoculum that almost completely converted tetrachloroethene to ethene without accumulation of the toxic intermediate vinyl chloride. With Dehalococcoides sp. strain CBDB1 the first bacterium is now known, that grows by dehalorespiration with dioxins. Learning from the physiology and biochemistry of this bacterium will help us to understand the role of these bacteria in the environment and to predict the fate of dioxin pollution.

  5. The dioxins - essential characteristics. Pt. 1

    International Nuclear Information System (INIS)

    Brunn, H.

    1993-01-01

    Polychlorinated dibenzo-p-dioxins (PCDD) belong to the group of persistent chlorinated hydrocarbons. They are predominantly of anthropogenic origin, except for those originating from fires caused by lightning or volcanic eruption. PCDD, according to the present knowledge, are absolutely useless. They are toxic, lipophilic, hardly degradable, and therefore ubiquitous in environment and food chain. PCDD have also been found in breast milk. Because their carcinogenic mechanism of action is little known, the toxicological evaluation of PCDD is still incomplete. Even lowest concentrations of PCDD may be detrimental to health. These characteristics are reason with enough to group PCDD not with xenobiotics, but with harmful substances. Closely related to PCDD in their origin and characteristics are polychlorinated dibenzofuranes (PCDF), which therefore are frequently ranked among ''the dioxins'': Essential characteristics of PCDD and PCDF are discussed. (orig.) [de

  6. An Exploratory Study: Assessment of Modeled Dioxin ...

    Science.gov (United States)

    EPA has released an external review draft entitled, An Exploratory Study: Assessment of Modeled Dioxin Exposure in Ceramic Art Studios(External Review Draft). The public comment period and the external peer-review workshop are separate processes that provide opportunities for all interested parties to comment on the document. In addition to consideration by EPA, all public comments submitted in accordance with this notice will also be forwarded to EPA’s contractor for the external peer-review panel prior to the workshop. EPA has realeased this draft document solely for the purpose of pre-dissemination peer review under applicable information quality guidelines. This document has not been formally disseminated by EPA. It does not represent and should not be construed to represent any Agency policy or determination. The purpose of this report is to describe an exploratory investigation of potential dioxin exposures to artists/hobbyists who use ball clay to make pottery and related products.

  7. Full-length huntingtin levels modulate body weight by influencing insulin-like growth factor 1 expression

    DEFF Research Database (Denmark)

    Pouladi, Mahmoud A; Xie, Yuanyun; Skotte, Niels Henning

    2010-01-01

    of the IGF-1 pathway in mediating the effect of htt on body weight. IGF-1 expression was examined in transgenic mouse lines expressing different levels of FL wild-type (WT) htt (YAC18 mice), FL mutant htt (YAC128 and BACHD mice) and truncated mutant htt (shortstop mice). We demonstrate that htt influences...... body weight by modulating the IGF-1 pathway. Plasma IGF-1 levels correlate with body weight and htt levels in the transgenic YAC mice expressing human htt. The effect of htt on IGF-1 expression is independent of CAG size. No effect on body weight is observed in transgenic YAC mice expressing...... and decreases the body weight of YAC128 animals to WT levels. Furthermore, given the ubiquitous expression of IGF-1 within the central nervous system, we also examined the impact of FL htt levels on IGF-1 expression in different regions of the brain, including the striatum, cerebellum of YAC18, YAC128...

  8. Determination of the levels of dioxin and dioxin-like compounds in the Australian population by analysis of pooled human breast milk

    Energy Technology Data Exchange (ETDEWEB)

    Harden, F.; Mueller, J.F.; Toms, L.M.L.; Moore, M. [National Research Centre for Environmental Toxicology, The Univ. of Queensland, Brisbane (Australia); Burniston, D.; Symons, R. [AGAL, Sydney (Australia); Ahokas, J. [RMIT, Melbourne (Australia); Fuerst, P. [State Lab. of NRW, Muenster (Germany); Paepke, O. [ERGO Forschungsgesellschaft, Hamburg (Germany)

    2004-09-15

    Dioxin-like compounds are ubiquitously distributed and humans are exposed to them via various sources but primarily through food. They can be detected in air, water, soil, sediment and biota. These compounds are lipid soluble, poorly eliminated and thus can accumulate in human adipose tissue. They can cross the placenta and are also transferred to breast milk during the lactation process. Therefore infants are exposed ante and postnatally. Since PCDD/PCDF concentration in blood and human milk are very similar when concentrations are expressed on a lipid basis, human milk provides a good monitoring tool of exposure for a given population in a given area. Previously the WHO has co-ordinated international studies on dioxin-like compounds in breast milk. These were conducted in 1987/88, 1992/93 and 2001. In summary, these studies demonstrated that levels of dioxins in breast milk are relatively high in industrialised countries when compared to non-industrialised countries that PCDD/PCDFs were higher in human milk from mothers with their first child and that the levels decrease over a given lactation period. The present study aims to examine the levels of these compounds in primiparae women throughout Australia.

  9. Cannabidiol Modulates the Expression of Alzheimer’s Disease-Related Genes in Mesenchymal Stem Cells

    Directory of Open Access Journals (Sweden)

    Rosaliana Libro

    2016-12-01

    Full Text Available Mesenchymal stem cells (MSCs have emerged as a promising tool for the treatment of several neurodegenerative disorders, including Alzheimer’s disease (AD. The main neuropathological hallmarks of AD are senile plaques, composed of amyloid beta (Aβ, and neurofibrillary tangles, formed by hyperphosphorylated tau. However, current therapies for AD have shown limited efficacy. In this study, we evaluated whether pre-treatment with cannabidiol (CBD, at 5 μM concentration, modulated the transcriptional profile of MSCs derived from gingiva (GMSCs in order to improve their therapeutic potential, by performing a transcriptomic analysis by the next-generation sequencing (NGS platform. By comparing the expression profiles between GMSCs treated with CBD (CBD-GMSCs and control GMSCs (CTR-GMSCs, we found that CBD led to the downregulation of genes linked to AD, including genes coding for the kinases responsible of tau phosphorylation and for the secretases involved in Aβ generation. In parallel, immunocytochemistry analysis has shown that CBD inhibited the expression of GSK3β, a central player in AD pathogenesis, by promoting PI3K/Akt signalling. In order to understand through which receptor CBD exerted these effects, we have performed pre-treatments with receptor antagonists for the cannabinoid receptors (SR141716A and AM630 or for the vanilloid receptor 1 (TRPVI. Here, we have proved that TRPV1 was able to mediate the modulatory effect of CBD on the PI3K/Akt/GSK3β axis. In conclusion, we have found that pre-treatment with CBD prevented the expression of proteins potentially involved in tau phosphorylation and Aβ production in GMSCs. Therefore, we suggested that GMSCs preconditioned with CBD possess a molecular profile that might be more beneficial for the treatment of AD.

  10. 3D-printed gelatin scaffolds of differing pore geometry modulate hepatocyte function and gene expression.

    Science.gov (United States)

    Lewis, Phillip L; Green, Richard M; Shah, Ramille N

    2018-03-15

    Three dimensional (3D) printing is highly amenable to the fabrication of tissue-engineered organs of a repetitive microstructure such as the liver. The creation of uniform and geometrically repetitive tissue scaffolds can also allow for the control over cellular aggregation and nutrient diffusion. However, the effect of differing geometries, while controlling for pore size, has yet to be investigated in the context of hepatocyte function. In this study, we show the ability to precisely control pore geometry of 3D-printed gelatin scaffolds. An undifferentiated hepatocyte cell line (HUH7) demonstrated high viability and proliferation when seeded on 3D-printed scaffolds of two different geometries. However, hepatocyte specific functions (albumin secretion, CYP activity, and bile transport) increases in more interconnected 3D-printed gelatin cultures compared to a less interconnected geometry and to 2D controls. Additionally, we also illustrate the disparity between gene expression and protein function in simple 2D culture modes, and that recreation of a physiologically mimetic 3D environment is necessary to induce both expression and function of cultured hepatocytes. Three dimensional (3D) printing provides tissue engineers the ability spatially pattern cells and materials in precise geometries, however the biological effects of scaffold geometry on soft tissues such as the liver have not been rigorously investigated. In this manuscript, we describe a method to 3D print gelatin into well-defined repetitive geometries that show clear differences in biological effects on seeded hepatocytes. We show that a relatively simple and widely used biomaterial, such as gelatin, can significantly modulate biological processes when fabricated into specific 3D geometries. Furthermore, this study expands upon past research into hepatocyte aggregation by demonstrating how it can be manipulated to enhance protein function, and how function and expression may not precisely correlate in

  11. Kaempferol modulates Angiopoietin-like protein 2 expression to lessen the mastitis in mice.

    Science.gov (United States)

    Xiao, Hong-Bo; Sui, Guo-Guang; Lu, Xiang-Yang; Sun, Zhi-Liang

    2017-11-22

    Mastitis is inflammation of a breast (or udder). Angiopoietin-like protein 2 (ANGPTL2) has been found as a key inflammatory mediator in mastitis. Purpose of this research was to investigate the mechanisms about repressing effect of kaempferol on mastitis. Forty mice were randomly divided into 4 groups (n = 10): C57BL/6J control mice, untreated murine mastitis, 10 mg/kg kaempferol treated murine mastitis (ip), and 30 mg/kg kaempferol treated murine mastitis (ip). Primary cultured mouse mammary epithelial cells (MMEC) were indiscriminately divided into seven groups including control group, 10 mmol/L vehicle of kaempferol group, 10 μmol/L kaempferol treated group, 20 μg/mL LPS treated group, 1 μmol/L kaempferol plus LPS treated group, 3 μmol/L kaempferol plus LPS treated group, and 10 μmol/L kaempferol plus LPS treated group. In murine mastitis, kaempferol (10 or 30 mg/kg) treatment prevented mastitis development, decreased myeloperoxidase (MPO) production, interleukin (IL)-6 level, tumour necrosis factor-α (TNF-α) concentration, and ANGPTL2 expression. In MMEC, kaempferol (1, 3, or 10 μM) reduced MPO production, TNF-α concentration, IL-6 level, and ANGPTL2 expression. The results in present study show that kaempferol modulates the expression of ANGPTL2 to lessen the mastitis in mice. Copyright © 2018 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.

  12. Podophyllum hexandrum (Himalayan mayapple) extract provides radioprotection by modulating the expression of proteins associated with apoptosis.

    Science.gov (United States)

    Kumar, Raj; Singh, Pankaj Kumar; Sharma, Ashok; Prasad, Jagdish; Sagar, Ravinder; Singh, Surender; Arora, Rajesh; Sharma, Rakesh Kumar

    2005-08-01

    demonstrated that P. hexandrum extract provides protection from gamma-radiation by the modulation of expression of proteins associated with cell death.

  13. Ras GTPases Modulate Morphogenesis, Sporulation and Cellulase Gene Expression in the Cellulolytic Fungus Trichoderma reesei

    Science.gov (United States)

    Zhang, Jiwei; Zhang, Yanmei; Zhong, Yaohua; Qu, Yinbo; Wang, Tianhong

    2012-01-01

    Background The model cellulolytic fungus Trichoderma reesei (teleomorph Hypocrea jecorina) is capable of responding to environmental cues to compete for nutrients in its natural saprophytic habitat despite its genome encodes fewer degradative enzymes. Efficient signalling pathways in perception and interpretation of environmental signals are indispensable in this process. Ras GTPases represent a kind of critical signal proteins involved in signal transduction and regulation of gene expression. In T. reesei the genome contains two Ras subfamily small GTPases TrRas1 and TrRas2 homologous to Ras1 and Ras2 from S. cerevisiae, but their functions remain unknown. Methodology/Principal Findings Here, we have investigated the roles of GTPases TrRas1 and TrRas2 during fungal morphogenesis and cellulase gene expression. We show that both TrRas1 and TrRas2 play important roles in some cellular processes such as polarized apical growth, hyphal branch formation, sporulation and cAMP level adjustment, while TrRas1 is more dominant in these processes. Strikingly, we find that TrRas2 is involved in modulation of cellulase gene expression. Deletion of TrRas2 results in considerably decreased transcription of cellulolytic genes upon growth on cellulose. Although the strain carrying a constitutively activated TrRas2G16V allele exhibits increased cellulase gene transcription, the cbh1 and cbh2 expression in this mutant still strictly depends on cellulose, indicating TrRas2 does not directly mediate the transmission of the cellulose signal. In addition, our data suggest that the effect of TrRas2 on cellulase gene is exerted through regulation of transcript abundance of cellulase transcription factors such as Xyr1, but the influence is independent of cAMP signalling pathway. Conclusions/Significance Together, these findings elucidate the functions for Ras signalling of T. reesei in cellular morphogenesis, especially in cellulase gene expression, which contribute to deciphering the

  14. Dioxin air emission inventory 1990-2004

    Energy Technology Data Exchange (ETDEWEB)

    Capral Henriksen, T; Illerup, J B; Nielsen, Ole-Kenneth [DMU, Dept. of Policy Analysis (Denmark)

    2006-12-15

    The present Danish dioxin air emission inventory shows that the emission has been reduced from 68.6 g I-TEQ in 1990 to 22.0 g I-TEQ in 2004, or about 68% over this period. Most of the significant reductions have been achieved in the industrial sector, where emissions have been reduced from 14.67 g I-TEQ in 1990 to 0.17 g I-TEQ in 2004; a reduction of almost 99%. Lower emissions from steel and aluminium reclamation industries form the major part of the reduction within industry. Emissions from waste incineration reduced from 32.5 g I-TEQ in 1990 to 2.1 g ITEQ in 2004; which is approx. 94%. This is due to installation of dioxin abatement equipment in incineration plants. The most important source of emission in 2004 is residential wood combustion, at 8.5 g I-TEQ, or around 40% of the total emission. In 2004, accidental fires, which are estimated to emit 6.1 g I-TEQ/year, are the second most important source, contributing with around 28% of the total emission. The present dioxin emission inventory for Denmark shows how emissions in 2004 come from sources other than waste incineration plants and industry, which were the largest sources in 1990. (au)

  15. Possible additional exposure to dioxin and dioxin-like compounds from waste incineration. Biomonitoring using human milk and animal samples

    Energy Technology Data Exchange (ETDEWEB)

    Sampaio, C.; M. Fatima Reis; J. Pereira Miguel [Inst. of Preventive Medicine, Univ. of Lisbon (Portugal); Murk, A. [Wageningen Univ., Dept. of Toxicology (Netherlands)

    2004-09-15

    In the ambit of an Environmental Health Survey Program relative to a MSW facility, which has been operating near to Lisbon since 1999 a biomonitoring study using human breast milk has been performed. Specific aims of this study were: (1) determine whether living in the vicinity of the incinerator increases dioxin maternal body burden and accordingly perinatal (intra-uterus and lactacional) exposure; (2) to investigate the possibility of increased human exposure to dioxins and dioxin-like compounds via locally produced food items from animal origin. Therefore, levels of dioxins and dioxin-like compounds have been determined in human milk samples collected in the vicinity of the incinerator and in a control area, for comparison. From the same areas, cow and sheep milk and eggs from free-range chickens have also been collected to get an indication of possible local additional exposure to air-borne dioxins via the food chain. Analyses of TCDD-equivalents (TEQs) were mainly performed with a reporter gene assay for dioxin-like activity, the DR-CALUX bioassay (Dioxin Responsive Chemical Activated LUciferase gene eXpression).To determine congeners profile, some human milk samples have also been analysed for PCDD/Fs and relevant dioxin-like PCBs, by using high-resolution gas chromatography and high-resolution mass spectrometry (HRGC/HRMS). Both the Ethics Committees of the Faculty of Medicine, University of Lisbon, and of the Maternity Dr. Alfredo da Costa have approved the study protocol.

  16. Radiolytic degradation of octachlorodibenzo-p-dioxin and octachlorodibenzofuran in organic solvents and treatment of dioxin-containing liquid wastes

    International Nuclear Information System (INIS)

    Zhao Changli; Hirota, Koichi; Taguchi, Mitsumasa; Takigami, Machiko; Kojima, Takuji

    2007-01-01

    Degradations of octachlorodibenzo-p-dioxin (OCDD) and octachlorodibenzofuran (OCDF) were studied by 60 Co γ-ray in organic solvents: ethanol, n-nonane, and toluene. Both OCDD and OCDF were degraded more efficiently in ethanol than in n-nonane or toluene. The degradation is mainly attributed to electrons and in part to solvent radicals. The addition of ethanol to dioxin-containing liquid wastes enhanced effectively the degradation of dioxins; the liquid wastes did not exhibit the dioxin toxicity at a dose of 100 kGy

  17. The Modulation of Mimicry by Ethnic Group-Membership and Emotional Expressions.

    Directory of Open Access Journals (Sweden)

    Birgit Rauchbauer

    Full Text Available Mimicry has been ascribed affiliative functions. In three experiments, we used a newly developed social-affective mimicry task (SAMT to investigate mimicry´s modulation by emotional facial expressions (happy, angry and ethnic group-membership (White in-group, Black out-group. Experiment 1 established the main consistent effect across experiments, which was enhanced mimicry to angry out-group faces compared to angry in-group faces. Hence the SAMT was useful for experimentally investigating the modulation of mimicry. Experiment 2 demonstrated that these effects were not confounded by general aspects of response conflict, as a Simon task resulted in different response patterns than the SAMT. Experiment 2 and pooled analysis of Experiments 1 and 2 also corroborated the finding of enhanced mimicry to angry out-group faces. Experiment 3 tested whether this effect was related to perceptions of threat, by framing angry persons as physically threatening, or not. Selective enhancement of mimicry to out-group persons framed as physically threatening confirmed this hypothesis. Further support for the role of threat was derived from implicit measures showing, in all experiments, that black persons were more strongly associated with threat. Furthermore, enhanced mimicry was consistently related to response facilitation in the execution of congruent movements. This suggests that mimicry acted as a social congruency signal. Our findings suggest that mimicry may serve as an appeasement signal in response to negative affiliative intent. This extends previous models of mimicry, which have predominantly focused on its role in reciprocating affiliation. It suggests that mimicry might not only be used to maintain and establish affiliative bonds, but also to ameliorate a negative social situation.

  18. MicroRNA-1185 Promotes Arterial Stiffness though Modulating VCAM-1 and E-Selectin Expression

    Directory of Open Access Journals (Sweden)

    Haoyuan Deng

    2017-04-01

    Full Text Available Background/Aims: Atherosclerosis is the primary cause of cardiovascular ischaemic events; arterial stiffness is a characteristic of the atherosclerotic process. MicroRNAs (miRNAs have been revealed as crucial modulators of atherosclerosis. However, the role of arterial stiffness-related miRNAs in the atherosclerotic process is still unclear. Methods: Four hundred six participants from Northern China were enrolled in this study. Circulating miR-1185 and adhesion molecule levels were measured. Multiple linear regression models were used to evaluate the association of miR-1185 levels with brachial-ankle pulse wave velocity (baPWV and adhesion molecule levels. A mediation analysis was also performed to examine the mediating effect. Cell adhesion molecule levels were measured in primary human umbilical vein endothelial cells (pHUVECs and human umbilical vein smooth cells (HUVSMCs transfected with miR-1185 or co-transfected with a miR-1185 inhibitor. Results: miR-1185 was independently correlated with arterial stiffness. A positive relationship between miR-1185 and vascular cell adhesion molecule-1 (VCAM-1 and E-selectin levels was observed. VCAM- 1 and E-selectin partially mediated the correlation between miR-1185 and arterial stiffness. miR-1185 induced a significant increase in the VCAM-1 and E-selectin levels in pHUVECs and HUVSMCs in vitro. According to our mechanistic analysis, VCAM-1 and E-selectin mediated miR-1185-induced arterial stiffening. Conclusions: miR-1185 modulated the expression of VCAM-1 and E-selectin to promote arterial stiffening, suggesting that miR-1185 plays a crucial role in the development of atherosclerosis and may serve as a novel therapeutic target for atherosclerosis.

  19. Bifidobacterium breve - HT-29 cell line interaction: modulation of TNF-α induced gene expression.

    Science.gov (United States)

    Boesten, R J; Schuren, F H J; Willemsen, L E M; Vriesema, A; Knol, J; De Vos, W M

    2011-06-01

    To provide insight in the molecular basis for intestinal host-microbe interactions, we determined the genome-wide transcriptional response of human intestinal epithelial cells following exposure to cells of Bifidobacterium breve. To select an appropriate test system reflecting inflammatory conditions, the responsiveness to TNF-α was compared in T84, Caco-2 and HT-29 cells. The highest TNF-α response was observed in HT-29 cells and this cell line was selected for exposure to the B. breve strains M-16V, NR246 and UCC2003. After one hour of bacterial pre-incubation followed by two hours of additional TNF-α stimulation, B. breve M-16V (86%), but to a much lesser extent strains NR246 (50%) or UCC2003 (32%), showed a strain-specific reduction of the HT-29 transcriptional response to the inflammatory treatment. The most important functional groups of genes that were transcriptionally suppressed by the presence of B. breve M-16V, were found to be involved in immune regulation and apoptotic processes. About 54% of the TNF-α induced genes were solely suppressed by the presence of B. breve M-16V. These included apoptosis-related cysteine protease caspase 7 (CASP7), interferon regulatory factor 3 (IRF3), amyloid beta (A4) precursor proteinbinding family A member 1 (APBA1), NADPH oxidase (NOX5), and leukemia inhibitory factor receptor (LIFR). The extracellular IL-8 concentration was determined by an immunological assay but did not change significantly, indicating that B. breve M-16V only partially modulates the TNF-α pathway. In conclusion, this study shows that B. breve strains modulate gene expression in HT-29 cells under inflammatory conditions in a strain-specific way.

  20. Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on adipogenic differentiation and insulin-induced glucose uptake in 3T3-L1 cells

    Energy Technology Data Exchange (ETDEWEB)

    Hsu, Hsin-Fen [Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan (China); Tsou, Tsui-Chun, E-mail: tctsou@nhri.org.tw [Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan (China); Chao, How-Ran [Department of Environmental Science and Engineering, National Pingtung University of Science and Technology, Neipu 912, Pingtung, Taiwan (China); Kuo, Ya-Ting; Tsai, Feng-Yuan; Yeh, Szu-Ching [Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan (China)

    2010-10-15

    Dioxin exposure has been positively associated with human type II diabetes. Because lipophilic dioxins accumulate mainly in adipose tissue, this study aimed to determine if dioxins induce metabolic dysfunction in fat cells. Using 3T3-L1 cells as an in vitro model, we analyzed the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a model dioxin, on adipogenic differentiation, glucose uptake, and lipolysis. TCDD inhibited adipogenic differentiation, as determined by using oil droplet formation and adipogenic marker gene expression, including PPAR{gamma} (peroxisome proliferator-activated receptor {gamma}), C/EBP{alpha} (CCAAT/enhancer-binding protein {alpha}), and Glut4 (glucose transporter type 4). Effects of TCDD on glucose uptake were evaluated using fully differentiated 3T3-L1 adipocytes, revealing that TCDD significantly attenuated insulin-induced glucose uptake dose dependently. Inhibition of aryl hydrocarbon receptor (AhR) by {alpha}-naphthoflavone ({alpha}-NF), an AhR inhibitor, did not prevent the inhibitory effect of TCDD on glucose uptake, suggesting that TCDD attenuates insulin-induced glucose uptake in an AhR-independent manner. Effects of TCDD on lipolysis were determined using glycerol release assay. We found that TCDD had no marked effect on isoproterenol-induced glycerol release in fully differentiated 3T3-L1 adipocytes. These results provide in vitro evidence of TCDD's effects on fat cell metabolism, suggesting dioxin exposure in development of insulin resistance and type II diabetes.

  1. Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on adipogenic differentiation and insulin-induced glucose uptake in 3T3-L1 cells

    International Nuclear Information System (INIS)

    Hsu, Hsin-Fen; Tsou, Tsui-Chun; Chao, How-Ran; Kuo, Ya-Ting; Tsai, Feng-Yuan; Yeh, Szu-Ching

    2010-01-01

    Dioxin exposure has been positively associated with human type II diabetes. Because lipophilic dioxins accumulate mainly in adipose tissue, this study aimed to determine if dioxins induce metabolic dysfunction in fat cells. Using 3T3-L1 cells as an in vitro model, we analyzed the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a model dioxin, on adipogenic differentiation, glucose uptake, and lipolysis. TCDD inhibited adipogenic differentiation, as determined by using oil droplet formation and adipogenic marker gene expression, including PPARγ (peroxisome proliferator-activated receptor γ), C/EBPα (CCAAT/enhancer-binding protein α), and Glut4 (glucose transporter type 4). Effects of TCDD on glucose uptake were evaluated using fully differentiated 3T3-L1 adipocytes, revealing that TCDD significantly attenuated insulin-induced glucose uptake dose dependently. Inhibition of aryl hydrocarbon receptor (AhR) by α-naphthoflavone (α-NF), an AhR inhibitor, did not prevent the inhibitory effect of TCDD on glucose uptake, suggesting that TCDD attenuates insulin-induced glucose uptake in an AhR-independent manner. Effects of TCDD on lipolysis were determined using glycerol release assay. We found that TCDD had no marked effect on isoproterenol-induced glycerol release in fully differentiated 3T3-L1 adipocytes. These results provide in vitro evidence of TCDD's effects on fat cell metabolism, suggesting dioxin exposure in development of insulin resistance and type II diabetes.

  2. Dioxin formation and control in a gasification-melting plant.

    Science.gov (United States)

    Kawamoto, Katsuya; Miyata, Haruo

    2015-10-01

    We investigated dioxin formation and removal in a commercial thermal waste treatment plant employing a gasification and melting process that has become widespread in the last decade in Japan. The aim was to clarify the possibility of dioxin formation in a process operation at high temperatures and the applicability of catalytic decomposition of dioxins. Also, the possible use of dioxin surrogate compounds for plant monitoring was further evaluated. The main test parameter was the influence of changes in the amount and type of municipal solid waste (MSW) supplied to the thermal waste treatment plant which from day to day operation is a relevant parameter also from commercial perspective. Here especially, the plastic content on dioxin release was assessed. The following conclusions were reached: (1) disturbance of combustion by adding plastic waste above the capability of the system resulted in a considerable increase in dioxin content of the flue gas at the inlet of the bag house and (2) bag filter equipment incorporating a catalytic filter effectively reduced the gaseous dioxin content below the standard of 0.1 ng toxic equivalency (TEQ)/m(3) N, by decomposition and partly adsorption, as was revealed by total dioxin mass balance and an increased levels in the fly ash. Also, the possible use of organohalogen compounds as dioxin surrogate compounds for plant monitoring was further evaluated. The levels of these surrogates did not exceed values corresponding to 0.1 ng TEQ/m(3) N dioxins established from former tests. This further substantiated that surrogate measurement therefore can well reflect dioxin levels.

  3. Dioxin contamination in the soil. South of Vietnam

    Energy Technology Data Exchange (ETDEWEB)

    Mai, Tuan Anh; Tarradellas, J.; DeAlancastro, F.; Grandjean, D. [CECOTOX-ISTE-ENAC-EPFL, Lausanne (Switzerland); Doan, Thanh Vu; Huynh, Thi Minh Hang [National Univ. of Hochiminh City, Inst. for Environment and Resources (Viet Nam)

    2004-09-15

    Dioxin is a common name given to a group of persistent and very toxic chemicals, also known as dioxins and furans. These chemicals include 75 chlorinated dibenzo-p-dioxins and 135 chlorinated dibenzo furans. The most toxic of these compounds is 2,3,7,8-tetrachlorodibenzo-p-dioxin and the isomers with chlorines substituted in the 2,3,7,8 positions. Dioxin in the environment is measured and reported in terms of 2,3,7,8-TCDD equivalents, which are the actual concentrations of each dioxin or furan congener multiplied by its relative toxicity. The amount of dioxin in a sample is the sum of the concentration of 2,3,7,8-TCDD and 2,3,7,8-TCDD-equivalents. The problem of dioxin contamination in South of Vietnam has been reported in many documents as a typical case because there are many areas affected by the toxic chemicals from US-Vietnam War. Although the War ended in 1975, to date no large-scale epidemiological study has been performed to assess the effects of the herbicides used on the Vietnamese people and ecosystem. Nowadays, the study on this problem is relatively difficult because many times passed (over 28 years) and every thing has been changed (not in origin form): a grand part of dioxin had been degraded or transfered into biological food web. In addition, the document collection and sampling planning are not easy work due to the complete formalities or military secrets. In this paper we present our primary result on dioxin contamination of three selected areas, including: Ma Da Forest, Cam Lo District - Quang Tri Province and Da Nang Airport. These are also the common names that reported in the documents related to the dioxin contamination problem.

  4. Galanin-Expressing GABA Neurons in the Lateral Hypothalamus Modulate Food Reward and Noncompulsive Locomotion.

    Science.gov (United States)

    Qualls-Creekmore, Emily; Yu, Sangho; Francois, Marie; Hoang, John; Huesing, Clara; Bruce-Keller, Annadora; Burk, David; Berthoud, Hans-Rudolf; Morrison, Christopher D; Münzberg, Heike

    2017-06-21

    The lateral hypothalamus (LHA) integrates reward and appetitive behavior and is composed of many overlapping neuronal populations. Recent studies associated LHA GABAergic neurons (LHA GABA ), which densely innervate the ventral tegmental area (VTA), with modulation of food reward and consumption; yet, LHA GABA projections to the VTA exclusively modulated food consumption, not reward. We identified a subpopulation of LHA GABA neurons that coexpress the neuropeptide galanin (LHA Gal ). These LHA Gal neurons also modulate food reward, but lack direct VTA innervation. We hypothesized that LHA Gal neurons may represent a subpopulation of LHA GABA neurons that mediates food reward independent of direct VTA innervation. We used chemogenetic activation of LHA Gal or LHA GABA neurons in mice to compare their role in feeding behavior. We further analyzed locomotor behavior to understand how differential VTA connectivity and transmitter release in these LHA neurons influences this behavior. LHA Gal or LHA GABA neuronal activation both increased operant food-seeking behavior, but only activation of LHA GABA neurons increased overall chow consumption. Additionally, LHA Gal or LHA GABA neuronal activation similarly induced locomotor activity, but with striking differences in modality. Activation of LHA GABA neurons induced compulsive-like locomotor behavior; while LHA Gal neurons induced locomotor activity without compulsivity. Thus, LHA Gal neurons define a subpopulation of LHA GABA neurons without direct VTA innervation that mediate noncompulsive food-seeking behavior. We speculate that the striking difference in compulsive-like locomotor behavior is also based on differential VTA innervation. The downstream neural network responsible for this behavior and a potential role for galanin as neuromodulator remains to be identified. SIGNIFICANCE STATEMENT The lateral hypothalamus (LHA) regulates motivated feeding behavior via GABAergic LHA neurons. The molecular identity of LHA

  5. Aryl Hydrocarbon Receptor Antagonists Mitigate the Effects of Dioxin on Critical Cellular Functions in Differentiating Human Osteoblast-Like Cells

    Directory of Open Access Journals (Sweden)

    Chawon Yun

    2018-01-01

    Full Text Available The inhibition of bone healing in humans is a well-established effect associated with cigarette smoking, but the underlying mechanisms are still unclear. Recent work using animal cell lines have implicated the aryl hydrocarbon receptor (AhR as a mediator of the anti-osteogenic effects of cigarette smoke, but the complexity of cigarette smoke mixtures makes understanding the mechanisms of action a major challenge. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin is a high-affinity AhR ligand that is frequently used to investigate biological processes impacted by AhR activation. Since there are dozens of AhR ligands present in cigarette smoke, we utilized dioxin as a prototype ligand to activate the receptor and explore its effects on pro-osteogenic biomarkers and other factors critical to osteogenesis using a human osteoblast-like cell line. We also explored the capacity for AhR antagonists to protect against dioxin action in this context. We found dioxin to inhibit osteogenic differentiation, whereas co-treatment with various AhR antagonists protected against dioxin action. Dioxin also negatively impacted cell adhesion with a corresponding reduction in the expression of integrin and cadherin proteins, which are known to be involved in this process. Similarly, the dioxin-mediated inhibition of cell migration correlated with reduced expression of the chemokine receptor CXCR4 and its ligand, CXCL12, and co-treatment with antagonists restored migratory capacity. Our results suggest that AhR activation may play a role in the bone regenerative response in humans exposed to AhR activators, such as those present in cigarette smoke. Given the similarity of our results using a human cell line to previous work done in murine cells, animal models may yield data relevant to the human setting. In addition, the AhR may represent a potential therapeutic target for orthopedic patients who smoke cigarettes, or those who are exposed to secondhand smoke or other

  6. Characterization of connective tissue growth factor expression in primary cultures of human tubular epithelial cells: modulation by hypoxia

    NARCIS (Netherlands)

    Kroening, Sven; Neubauer, Emily; Wullich, Bernd; Aten, Jan; Goppelt-Struebe, Margarete

    2010-01-01

    Kroening S, Neubauer E, Wullich B, Aten J, Goppelt-Struebe M. Characterization of connective tissue growth factor expression in primary cultures of human tubular epithelial cells: modulation by hypoxia. Am J Physiol Renal Physiol 298:F796-F806, 2010. First published December 23, 2009;

  7. Fresh Frozen Plasma Modulates Brain Gene Expression in a Swine Model of Traumatic Brain Injury and Shock

    DEFF Research Database (Denmark)

    Sillesen, Martin; Bambakidis, Ted; Dekker, Simone E

    2017-01-01

    BACKGROUND: Resuscitation with fresh frozen plasma (FFP) decreases brain lesion size and swelling in a swine model of traumatic brain injury and hemorrhagic shock. We hypothesized that brain gene expression profiles after traumatic brain injury and hemorrhagic shock would be modulated by FFP resu...

  8. C. albicans growth, transition, biofilm formation, and gene expression modulation by antimicrobial decapeptide KSL-W

    Science.gov (United States)

    2013-01-01

    Background Antimicrobial peptides have been the focus of much research over the last decade because of their effectiveness and broad-spectrum activity against microbial pathogens. These peptides also participate in inflammation and the innate host defense system by modulating the immune function that promotes immune cell adhesion and migration as well as the respiratory burst, which makes them even more attractive as therapeutic agents. This has led to the synthesis of various antimicrobial peptides, including KSL-W (KKVVFWVKFK-NH2), for potential clinical use. Because this peptide displays antimicrobial activity against bacteria, we sought to determine its antifungal effect on C. albicans. Growth, hyphal form, biofilm formation, and degradation were thus examined along with EFG1, NRG1, EAP1, HWP1, and SAP 2-4-5-6 gene expression by quantitative RT-PCR. Results This study demonstrates that KSL-W markedly reduced C. albicans growth at both early and late incubation times. The significant effect of KSL-W on C. albicans growth was observed beginning at 10 μg/ml after 5 h of contact by reducing C. albicans transition and at 25 μg/ml by completely inhibiting C. albicans transition. Cultured C. albicans under biofilm-inducing conditions revealed that both KSL-W and amphotericin B significantly decreased biofilm formation at 2, 4, and 6 days of culture. KSL-W also disrupted mature C. albicans biofilms. The effect of KSL-W on C. albicans growth, transition, and biofilm formation/disruption may thus occur through gene modulation, as the expression of various genes involved in C. albicans growth, transition and biofilm formation were all downregulated when C. albicans was treated with KSL-W. The effect was greater when C. albicans was cultured under hyphae-inducing conditions. Conclusions These data provide new insight into the efficacy of KSL-W against C. albicans and its potential use as an antifungal therapy. PMID:24195531

  9. Curcumin is a potent modulator of microglial gene expression and migration

    Directory of Open Access Journals (Sweden)

    Aslanidis Alexander

    2011-09-01

    Full Text Available Abstract Background Microglial cells are important effectors of the neuronal innate immune system with a major role in chronic neurodegenerative diseases. Curcumin, a major component of tumeric, alleviates pro-inflammatory activities of these cells by inhibiting nuclear factor kappa B (NFkB signaling. To study the immuno-modulatory effects of curcumin on a transcriptomic level, DNA-microarray analyses were performed with resting and LPS-challenged microglial cells after short-term treatment with curcumin. Methods Resting and LPS-activated BV-2 cells were stimulated with curcumin and genome-wide mRNA expression patterns were determined using DNA-microarrays. Selected qRT-PCR analyses were performed to confirm newly identified curcumin-regulated genes. The migration potential of microglial cells was determined with wound healing assays and transwell migration assays. Microglial neurotoxicity was estimated by morphological analyses and quantification of caspase 3/7 levels in 661W photoreceptors cultured in the presence of microglia-conditioned medium. Results Curcumin treatment markedly changed the microglial transcriptome with 49 differentially expressed transcripts in a combined analysis of resting and activated microglial cells. Curcumin effectively triggered anti-inflammatory signals as shown by induced expression of Interleukin 4 and Peroxisome proliferator activated receptor α. Several novel curcumin-induced genes including Netrin G1, Delta-like 1, Platelet endothelial cell adhesion molecule 1, and Plasma cell endoplasmic reticulum protein 1, have been previously associated with adhesion and cell migration. Consequently, curcumin treatment significantly inhibited basal and activation-induced migration of BV-2 microglia. Curcumin also potently blocked gene expression related to pro-inflammatory activation of resting cells including Toll-like receptor 2 and Prostaglandin-endoperoxide synthase 2. Moreover, transcription of NO synthase 2 and

  10. Curcumin is a potent modulator of microglial gene expression and migration

    Science.gov (United States)

    2011-01-01

    Background Microglial cells are important effectors of the neuronal innate immune system with a major role in chronic neurodegenerative diseases. Curcumin, a major component of tumeric, alleviates pro-inflammatory activities of these cells by inhibiting nuclear factor kappa B (NFkB) signaling. To study the immuno-modulatory effects of curcumin on a transcriptomic level, DNA-microarray analyses were performed with resting and LPS-challenged microglial cells after short-term treatment with curcumin. Methods Resting and LPS-activated BV-2 cells were stimulated with curcumin and genome-wide mRNA expression patterns were determined using DNA-microarrays. Selected qRT-PCR analyses were performed to confirm newly identified curcumin-regulated genes. The migration potential of microglial cells was determined with wound healing assays and transwell migration assays. Microglial neurotoxicity was estimated by morphological analyses and quantification of caspase 3/7 levels in 661W photoreceptors cultured in the presence of microglia-conditioned medium. Results Curcumin treatment markedly changed the microglial transcriptome with 49 differentially expressed transcripts in a combined analysis of resting and activated microglial cells. Curcumin effectively triggered anti-inflammatory signals as shown by induced expression of Interleukin 4 and Peroxisome proliferator activated receptor α. Several novel curcumin-induced genes including Netrin G1, Delta-like 1, Platelet endothelial cell adhesion molecule 1, and Plasma cell endoplasmic reticulum protein 1, have been previously associated with adhesion and cell migration. Consequently, curcumin treatment significantly inhibited basal and activation-induced migration of BV-2 microglia. Curcumin also potently blocked gene expression related to pro-inflammatory activation of resting cells including Toll-like receptor 2 and Prostaglandin-endoperoxide synthase 2. Moreover, transcription of NO synthase 2 and Signal transducer and activator

  11. ConGEMs: Condensed Gene Co-Expression Module Discovery Through Rule-Based Clustering and Its Application to Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Saurav Mallik

    2017-12-01

    Full Text Available For transcriptomic analysis, there are numerous microarray-based genomic data, especially those generated for cancer research. The typical analysis measures the difference between a cancer sample-group and a matched control group for each transcript or gene. Association rule mining is used to discover interesting item sets through rule-based methodology. Thus, it has advantages to find causal effect relationships between the transcripts. In this work, we introduce two new rule-based similarity measures—weighted rank-based Jaccard and Cosine measures—and then propose a novel computational framework to detect condensed gene co-expression modules ( C o n G E M s through the association rule-based learning system and the weighted similarity scores. In practice, the list of evolved condensed markers that consists of both singular and complex markers in nature depends on the corresponding condensed gene sets in either antecedent or consequent of the rules of the resultant modules. In our evaluation, these markers could be supported by literature evidence, KEGG (Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology annotations. Specifically, we preliminarily identified differentially expressed genes using an empirical Bayes test. A recently developed algorithm—RANWAR—was then utilized to determine the association rules from these genes. Based on that, we computed the integrated similarity scores of these rule-based similarity measures between each rule-pair, and the resultant scores were used for clustering to identify the co-expressed rule-modules. We applied our method to a gene expression dataset for lung squamous cell carcinoma and a genome methylation dataset for uterine cervical carcinogenesis. Our proposed module discovery method produced better results than the traditional gene-module discovery measures. In summary, our proposed rule-based method is useful for exploring biomarker modules from transcriptomic data.

  12. ConGEMs: Condensed Gene Co-Expression Module Discovery Through Rule-Based Clustering and Its Application to Carcinogenesis.

    Science.gov (United States)

    Mallik, Saurav; Zhao, Zhongming

    2017-12-28

    For transcriptomic analysis, there are numerous microarray-based genomic data, especially those generated for cancer research. The typical analysis measures the difference between a cancer sample-group and a matched control group for each transcript or gene. Association rule mining is used to discover interesting item sets through rule-based methodology. Thus, it has advantages to find causal effect relationships between the transcripts. In this work, we introduce two new rule-based similarity measures-weighted rank-based Jaccard and Cosine measures-and then propose a novel computational framework to detect condensed gene co-expression modules ( C o n G E M s) through the association rule-based learning system and the weighted similarity scores. In practice, the list of evolved condensed markers that consists of both singular and complex markers in nature depends on the corresponding condensed gene sets in either antecedent or consequent of the rules of the resultant modules. In our evaluation, these markers could be supported by literature evidence, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway and Gene Ontology annotations. Specifically, we preliminarily identified differentially expressed genes using an empirical Bayes test. A recently developed algorithm-RANWAR-was then utilized to determine the association rules from these genes. Based on that, we computed the integrated similarity scores of these rule-based similarity measures between each rule-pair, and the resultant scores were used for clustering to identify the co-expressed rule-modules. We applied our method to a gene expression dataset for lung squamous cell carcinoma and a genome methylation dataset for uterine cervical carcinogenesis. Our proposed module discovery method produced better results than the traditional gene-module discovery measures. In summary, our proposed rule-based method is useful for exploring biomarker modules from transcriptomic data.

  13. Detection of expression and modulation of multidrug-resistance (MDR) and establishment of a new bioassay

    International Nuclear Information System (INIS)

    Berger, W.

    1993-08-01

    The present thesis deals with the resistance of human malignant cells against cellular toxicity of anticancer drugs, a phenomenon representing one of the major obstacles to successful chemotherapy. One mechanism underlying a cross-resistance to different drugs called multidrug resistance (MDR) is characterized by the expression of an active transport protein (P-glycoprotein), causing decreased intracellular drug retention and cytotoxicity. The main subjects of the present work were to establish different detection methods for MDR and its modulation (by substances blocking activity of P-glycoprotein) including immunological methods (immunocytochemistry, radioimmunoassay), molecular biology (slot-blot analysis, in-situ hybridization) and functional assays (drug-accumulation analysis, drug-cytotoxicity analysis). The methods were evaluated and compared using human and mouse MDR control cell lines and human tumor cell lines established in our laboratory. In cell lines derived from human melanoma - a malignancy insensitive to chemotherapy - expression of P-glycoprotein of relatively low transporting activity was detected by different methods in 8 of 33 cases. Furthermore a new sensitive in vitro assay for the functional detection of MDR was established using the biological features of cytochalasins, a microfilament disrupting substance group. These compounds were shown to be substrates for the P-glycoprotein efflux pump and their effects on cell division (blockade of cytokinesis resulting in multinucleate cells) correlated with MDR-activity of the tested cells. With this new assay P-glycoprotein activity can be demonstrated and analysed over a wide range of resistance against different cytotoxic drugs. Therefore it may by a suitable tool for research and diagnosis in the field of drug resistance

  14. Thyroid hormone modulates the extracellular matrix organization and expression in cerebellar astrocyte: effects on astrocyte adhesion.

    Science.gov (United States)

    Trentin, Andréa Gonçalves; De Aguiar, Cláudia Beatriz Nedel Mendes; Garcez, Ricardo Castilho; Alvarez-Silva, Marcio

    2003-06-01

    The effects of thyroid hormone (T(3)) on extracellular matrix (ECM) expression and organization in cerebellar astrocytes were studied. Control astrocytes exhibit laminin immunostaining distributed in a punctate configuration and fibronectin concentrated in focal points at the cell surface. These cells attach to the substratum by membrane points, as shown by scanning microscopy, possibly by focal points stained to fibronectin. In contrast, after T(3) treatment, laminin assumes a fibrillary pattern and fibronectin becomes organized in filaments homogeneously distributed on the cell surface; the cells acquire a very flat and spread morphology. T(3) treatment also modulates astrocyte adhesion. In addition, increased expression of both laminin and fibronectin was detected by Western blot. These alterations in fibronectin and/or laminin production and organization may be involved in the flat and spread morphology and in altered adhesion. We observed that fibroblast growth factor-2 (FGF(2)) added to cultures had similar effects to those described to T(3). Neutralizing antibodies against FGF(2) reversed T(3) effects on fibronectin and laminin distribution. We also observed that cerebellar neurons co-cultured on T(3)-treated astrocytes had an increase in the number of cells and presented longer neurites. Thus, we propose a novel mechanism of the effect of thyroid hormone on cerebellar development mediated by astrocytes: T(3) may induce astrocyte secretion of growth factors, mainly FGF(2), that autocrinally stimulate astrocyte proliferation, reorganization in ECM proteins, and alterations in cell spreading and adhesion. These effects may indirectly influence neuronal development. Copyright 2003 Wiley-Liss, Inc.

  15. Standard Chinese: A Modular Approach. Resource Modules: Pronunciation and Romanization, Numbers, Classroom Expressions, Time and Dates.

    Science.gov (United States)

    Defense Language Inst., Monterey, CA.

    Texts in spoken Standard Chinese were developed to improve and update Chinese materials to reflect current usage in Beijing and Taipei. The focus is on communicating in Chinese in practical situations. The overall course is organized into 10 situational modules, student workbooks for each module, and resource modules. This text contains resource…

  16. Optimizing bulk milk dioxin monitoring based on costs and effectiveness

    NARCIS (Netherlands)

    Lascano Alcoser, V.; Velthuis, A.G.J.; Fels-Klerx, van der H.J.; Hoogenboom, L.A.P.; Oude Lansink, A.G.J.M.

    2013-01-01

    Dioxins are environmental pollutants, potentially present in milk products, which have negative consequences for human health and for the firms and farms involved in the dairy chain. Dioxin monitoring in feed and food has been implemented to detect their presence and estimate their levels in food

  17. Emission of Dioxins from Danish Wood-Stoves

    DEFF Research Database (Denmark)

    Vikelsøe, J.; Madsen, Henrik; Hansen, K.

    1994-01-01

    The main purpose of the investigation was to estimate the annual dioxin emission from Danish wood-stoves. 4 stoves of different designs and 3 types of fuel were tested in 2 operating conditions. Sampling was carried out in a dilution tunnel, making reproducible sampling possible. The dioxin...

  18. Dioxin emissions into the air in the Netherlands

    NARCIS (Netherlands)

    Koning, J. de

    1996-01-01

    In 1989 in The Netherlands elevated dioxin concentrations were found in cow's milk originating from areas a.o. located near Municipal Solid Waste Combustion (MSWC) facilities. This induced the Dutch government to set up an extensive programme for making an inventory of all possible dioxin sources in

  19. Review of State Soil Cleanup Levels for Dioxin (December 2009)

    Science.gov (United States)

    This final report summarizes a survey of state soil cleanup levels for dioxin and characterizes the science underlying these values. The objective of this project was to summarize existing state cleanup levels for dioxin in soil, together with their scientific bases where availa...

  20. Effects of Epigenetic Modulation on Reporter Gene Expression: Implications for Stem Cell Imaging

    Science.gov (United States)

    Krishnan, Manickam; Park, Jinha M.; Cao, Feng; Wang, Dongxu; Paulmurugan, Ramasay; Tseng, Jeffrey R.; Gonzalgo, Mark L.; Gambhir, Sanjiv S.; Wu, Joseph C.

    2013-01-01

    Tracking stem cell localization, survival, differentiation, and proliferation following transplantation in living subjects is essential for understanding stem cell biology and physiology. In this study, we investigated the long-term stability of reporter gene expression in an embryonic rat cardiomyoblast cell line and the role of epigenetic modulation on reversing reporter gene silencing. Cells were stably transfected with plasmids carrying cytomegalovirus promoter driving firefly luciferase reporter gene (CMV-Fluc) and passaged repeatedly for 3–8 months. Within the highest expressor clone, the firefly luciferase activity decreased progressively from passage-1 (843±28) to passage-20 (250±10) to passage-40 (44±3) to passage-60 (3±1 RLU/µg) (P<0.05 vs. passage-1). Firefly luciferase activity was maximally rescued by treatment with 5-azacytidine (DNA methyltransferase inhibitor) compared to trichostatin A (histone deacetylase inhibitor) and retinoic acid (transcriptional activator) (P<0.05). Increasing dosages of 5-azacytidine treatment led to higher levels of firefly luciferase mRNA (RT-PCR) and protein (Western blots) and inversely lower levels of methylation in the CMV promoter (DNA nucleotide sequence). These in vitro results were extended to in vivo bioluminescence imaging (BLI) of cell transplant in living animals. Cells treated with 5-azacytidine were monitored for 2 weeks compared to 1 week for untreated cells (P<0.05). These findings should have important implications for reporter gene-based imaging of stem cell transplantation. PMID:16246867

  1. Polycystin-1 C-terminal Cleavage Is Modulated by Polycystin-2 Expression*

    Science.gov (United States)

    Bertuccio, Claudia A.; Chapin, Hannah C.; Cai, Yiqiang; Mistry, Kavita; Chauvet, Veronique; Somlo, Stefan; Caplan, Michael J.

    2009-01-01

    Autosomal dominant polycystic kidney disease is caused by mutations in the genes encoding polycystin-1 (PC-1) and polycystin-2 (PC-2). PC-1 cleavage releases its cytoplasmic C-terminal tail (CTT), which enters the nucleus. To determine whether PC-1 CTT cleavage is influenced by PC-2, a quantitative cleavage assay was utilized, in which the DNA binding and activation domains of Gal4 and VP16, respectively, were appended to PC-1 downstream of its CTT domain (PKDgalvp). Cells cotransfected with the resultant PKDgalvp fusion protein and PC-2 showed an increase in luciferase activity and in CTT expression, indicating that the C-terminal tail of PC-1 is cleaved and enters the nucleus. To assess whether CTT cleavage depends upon Ca2+ signaling, cells transfected with PKDgalvp alone or together with PC-2 were incubated with several agents that alter intracellular Ca2+ concentrations. PC-2 enhancement of luciferase activity was not altered by any of these treatments. Using a series of PC-2 C-terminal truncated mutations, we identified a portion of the PC-2 protein that is required to stimulate PC-1 CTT accumulation. These data demonstrate that release of the CTT from PC-1 is influenced and stabilized by PC-2. This effect is independent of Ca2+ but is regulated by sequences contained within the PC-2 C-terminal tail, suggesting a mechanism through which PC-1 and PC-2 may modulate a novel signaling pathway. PMID:19491093

  2. Salmonella Modulates Metabolism During Growth under Conditions that Induce Expression of Virulence Genes

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Young-Mo; Schmidt, Brian; Kidwai, Afshan S.; Jones, Marcus B.; Deatherage, Brooke L.; Brewer, Heather M.; Mitchell, Hugh D.; Palsson, Bernhard O.; McDermott, Jason E.; Heffron, Fred; Smith, Richard D.; Peterson, Scott N.; Ansong, Charles; Hyduke, Daniel R.; Metz, Thomas O.; Adkins, Joshua N.

    2013-04-05

    Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative pathogen that uses complex mechanisms to invade and proliferate within mammalian host cells. To investigate possible contributions of metabolic processes in S. Typhimurium grown under conditions known to induce expression of virulence genes, we used a metabolomics-driven systems biology approach coupled with genome scale modeling. First, we identified distinct metabolite profiles associated with bacteria grown in either rich or virulence-inducing media and report the most comprehensive coverage of the S. Typhimurium metabolome to date. Second, we applied an omics-informed genome scale modeling analysis of the functional consequences of adaptive alterations in S. Typhimurium metabolism during growth under our conditions. Excitingly, we observed possible sequestration of metabolites recently suggested to have immune modulating roles. Modeling efforts highlighted a decreased cellular capability to both produce and utilize intracellular amino acids during stationary phase culture in virulence conditions, despite significant abundance increases for these molecules as observed by our metabolomics measurements. Model-guided analysis suggested that alterations in metabolism prioritized other activities necessary for pathogenesis instead, such as lipopolysaccharide biosynthesis.

  3. Dioxin body burden among blood donors before and after the Belgian dioxin/PCB incident

    Energy Technology Data Exchange (ETDEWEB)

    Debacker, N.; Sasse, A.; Wouwe, N. Van; Windal, I.; Carbonnelle, S.; Overmeire, I. Van; Sartor, F.; Goeyens, L.; Oyen, H. Van [Scientific Inst. of Public Health, Brussels (Belgium); Eppe, G.; Xhrouet, C.; Pauw, E. De [Centre of Analysis of Residues in Traces, Luik (Belgium)

    2004-09-15

    In spring 1999, Belgium faced a severe food contamination when about 50 kg of PCBs containing 1 g of dioxins were introduced in the food chain. The possible public health impact of this food chain contamination was subject of a debate between different scientists. According to Vrijens et al. and Bernard et al. there was no significant public health impact, whereas van Larebeke et al. presumed the opposite claiming a significant increase of cancer incidence. These risk assessments were based on measurements of dioxins/PCBs in contaminated foods and nutritional habits observed in a selected group of adolescents (14-18 years old) using simulation techniques or on the estimation of the incremental cancer risk associated with the incremental levels of exposure to dioxins/PCBs during the incident. In the meantime, an epidemiological survey has been carried out in order to measure the dioxin levels in plasma samples collected before and after the incident. The aim of this paper is to report the preliminary results of this epidemiological survey.

  4. Overview of Dioxin Kinetics and Application of Dioxin Physiologically Based Phannacokinetic (PBPK) Models to Risk Assessment

    Science.gov (United States)

    The available data on the pharmacokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in animals and humans have been thoroughly reviewed in literature. It is evident based on these reviews and other analyses that three distinctive features of TCDD play important roles in dete...

  5. Global analysis of glycoproteins identifies markers of endotoxin tolerant monocytes and GPR84 as a modulator of TNFα expression.

    Science.gov (United States)

    Müller, Mario M; Lehmann, Roland; Klassert, Tilman E; Reifenstein, Stella; Conrad, Theresia; Moore, Christoph; Kuhn, Anna; Behnert, Andrea; Guthke, Reinhard; Driesch, Dominik; Slevogt, Hortense

    2017-04-12

    Exposure of human monocytes to lipopolysaccharide (LPS) induces a temporary insensitivity to subsequent LPS challenges, a cellular state called endotoxin tolerance. In this study, we investigated the LPS-induced global glycoprotein expression changes of tolerant human monocytes and THP-1 cells to identify markers and glycoprotein targets capable to modulate the immunosuppressive state. Using hydrazide chemistry and LC-MS/MS analysis, we analyzed glycoprotein expression changes during a 48 h LPS time course. The cellular snapshots at different time points identified 1491 glycoproteins expressed by monocytes and THP-1 cells. Label-free quantitative analysis revealed transient or long-lasting LPS-induced expression changes of secreted or membrane-anchored glycoproteins derived from intracellular membrane coated organelles or from the plasma membrane. Monocytes and THP-1 cells demonstrated marked differences in glycoproteins differentially expressed in the tolerant state. Among the shared differentially expressed glycoproteins G protein-coupled receptor 84 (GPR84) was identified as being capable of modulating pro-inflammatory TNFα mRNA expression in the tolerant cell state when activated with its ligand Decanoic acid.

  6. Channel catfish (Ictalurus punctatus) leukocytes express estrogen receptor isoforms ERα and ERβ2 and are functionally modulated by estrogens.

    Science.gov (United States)

    Iwanowicz, Luke R; Stafford, James L; Patiño, Reynaldo; Bengten, Eva; Miller, Norman W; Blazer, Vicki S

    2014-09-01

    Estrogens are recognized as modulators of immune responses in mammals and teleosts. While it is known that the effects of estrogens are mediated via leukocyte-specific estrogen receptors (ERs) in humans and mice, leucocyte-specific estrogen receptor expression and the effects of estrogens on this cell population is less explored and poorly understood in teleosts. Here in, we verify that channel catfish (Ictalurus punctaus) leukocytes express ERα and ERβ2. Transcripts of these isoforms were detected in tissue-associated leukocyte populations by PCR, but ERβ2 was rarely detected in PBLs. Expression of these receptors was temporally regulated in PBLs following polyclonal activation by concanavalin A, lipopolysaccharide or alloantigen based on evaluation by quantitative and end-point PCR. Examination of long-term leukocyte cell lines demonstrated that these receptors are differentially expressed depending on leukocyte lineage and phenotype. Expression of ERs was also temporally dynamic in some leukocyte lineages and may reflect stage of cell maturity. Estrogens affect the responsiveness of channel catfish peripheral blood leukocytes (PBLs) to mitogens in vitro. Similarly, bactericidal activity and phorbol 12-myristate 13-acetate induced respiratory burst was modulated by 17β-estradiol. These actions were blocked by the pure ER antagonist ICI 182780 indicating that response is, in part, mediated via ERα. In summary, estrogen receptors are expressed in channel catfish leukocytes and participate in the regulation of the immune response. This is the first time leukocyte lineage expression has been reported in teleost cell lines. Published by Elsevier Ltd.

  7. Dioxins levels in Australia. Key findings of studies

    Energy Technology Data Exchange (ETDEWEB)

    Ivory, A.; Mobbs, C. [Australian Government Department of the Environment and Heritage (Australia)

    2004-09-15

    The Australian Government established the National Dioxins Program (NDP) in 2001 to improve knowledge about levels of dioxins in Australia. The program aims to determine levels, assess the risks to Australians and the environment, and to consider appropriate management actions. Starting in mid 2001and completed in 2004, the studies constituted the largest survey of dioxin levels ever undertaken in Australia. The findings will contribute to debate on how to deal with dioxins in Australia, as well as helping to meet obligations under the Stockholm Convention on Persistent Organic Pollutants, which Australia ratified on 20 May 2004. These studies will also contribute to a better understanding about dioxins in the southern hemisphere. This paper provides a summary of the key findings of these studies and the risk assessments.

  8. Comprehensive evaluation of dioxins and dioxin-like compounds in surface soils and river sediments from e-waste-processing sites in a village in northern Vietnam: Heading towards the environmentally sound management of e-waste

    Directory of Open Access Journals (Sweden)

    Go Suzuki

    2016-06-01

    Full Text Available The management of electronic waste (e-waste, which can be a source of both useful materials and toxic substances, depending on the processing method, is important for promoting material cycling. In this study, we used the dioxin-responsive chemical-activated luciferase gene expression (DR-CALUX assay combined with gas chromatography–high-resolution mass spectrometry to evaluate the levels of dioxin-like compounds in surface soils and river sediments collected in and around an e-waste-processing village in northern Vietnam. The WHO-TEQs (Toxic equivalents of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs, coplanar polychlorinated biphenyls (Co-PCBs, and polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/Fs in soils collected in January 2012 ranged from 0.29 to 310 pg/g (median 2.9 pg/g, n = 32, and the WHO-TEQs in sediments ranged from 0.96 to 58 pg/g (median 4.4 pg/g, n = 8. Dioxin-like activities (CALUX-TEQs [2,3,7,8-TCDD equivalent] in soils collected in January 2012, 2013, and 2014 ranged from <30 to 4300 pg/g (median <30 pg/g, n = 96, and the activities in sediments ranged from <30 to 4000 pg/g (median 33 pg/g, n = 24. Dioxin-like compounds accumulated in samples collected around e-waste-processing areas such as open-burning sites and e-waste-processing workshops, and the compounds may be transported from their sources to surrounding areas over the course of several years. Some of the CALUX-TEQs, but not WHO-TEQs, values were higher than the maximum acceptable WHO-TEQs promulgated by various authorities, indicating that all dioxin-like compounds should be evaluated in samples collected from e-waste-processing areas. Our findings suggest that open burning and open storage of e-waste should be prohibited and that wastewater treatment should be implemented at each workshop to reduce contamination by dioxin-like compounds from e-waste.

  9. Modulation of radiation-induced base excision repair pathway gene expression by melatonin

    Directory of Open Access Journals (Sweden)

    Saeed Rezapoor

    2017-01-01

    Full Text Available Objective: Approximately 70% of all cancer patients receive radiotherapy. Although radiotherapy is effective in killing cancer cells, it has adverse effects on normal cells as well. Melatonin (MLT as a potent antioxidant and anti-inflammatory agent has been proposed to stimulate DNA repair capacity. We investigated the capability of MLT in the modification of radiation-induced DNA damage in rat peripheral blood cells. Materials and Methods: In this experimental study, male rats (n = 162 were divided into 27 groups (n = 6 in each group including: irradiation only, vehicle only, vehicle with irradiation, 100 mg/kg MLT alone, 100 mg/kg MLT plus irradiation in 3 different time points, and control. Subsequently, they were irradiated with a single whole-body X-ray radiation dose of 2 and 8 Gy at a dose rate of 200 MU/min. Rats were given an intraperitoneal injection of MLT or the same volume of vehicle alone 1 h prior to irradiation. Blood samples were also taken 8, 24, and 48 h postirradiation, in order to measure the 8-oxoguanine glycosylase1 (Ogg1, Apex1, and Xrcc1 expression using quantitative real-time-polymerase chain reaction. Results: Exposing to the ionizing radiation resulted in downregulation of Ogg1, Apex1, and Xrcc1 gene expression. The most obvious suppression was observed in 8 h after exposure. Pretreatments with MLT were able to upregulate these genes when compared to the irradiation-only and vehicle plus irradiation groups (P < 0.05 in all time points. Conclusion: Our results suggested that MLT in mentioned dose may result in modulation of Ogg1, Apex1, and Xrcc1 gene expression in peripheral blood cells to reduce X-ray irradiation-induced DNA damage. Therefore, administration of MLT may increase the normal tissue tolerance to radiation through enhancing the cell DNA repair capacity. We believed that MLT could play a radiation toxicity reduction role in patients who have undergone radiation treatment as a part of cancer radiotherapy.

  10. AN ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA) FOR DETERMINING DIOXINS IN SEDIMENT AND SOIL SAMPLES

    Science.gov (United States)

    The dioxins comprise a family of compounds chemically referred to as polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). The most toxic of these compounds is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a known human carcinogen. Dioxins are formed ...

  11. Dioxins, dibenzofurans, dioxin-like PCBs, and DDE in U.S. fast food, 1995.

    Science.gov (United States)

    Schecter, A; Li, L

    1997-01-01

    Food, especially dairy products, meat, and fish, is the primary source of environmental exposure to dioxins in the general population. Little data exists on dioxin levels in the popular and widely consumed "fast foods". Data presented in a previously published pilot study was limited to measuring only the levels of dioxins and dibenzofurans in three types of U.S. fast food. This study adds to the previous paper by presenting data, in addition to dioxins and dibenzofurans, on the closely related dioxin-like polychlorinated biphenyls (PCBs), and the persistent metabolite of DDT, 1,1-dichloro-2,2-bis (p-chlorophenyl) ethylene (DDE), in four types of popular U.S. fast food. These include McDonald's Big Mac Hamburger, Pizza Hut's Personal Pan Pizza Supreme, Kentucky Fried Chicken (KFC) three piece original recipe mixed dark and white meat luncheon package, and Häagen-Daz chocolate-chocolate chip ice cream. Dioxin plus dibenzofuran dioxin toxic equivalents (TEQ) ranged from 0.03 to 0.28 TEQ pg/g wet or whole weight for the Big Mac, from 0.03 to 0.29 for the Pizza, from 0.01 to 0.31 for the KFC, and from 0.03 to 0.49 TEQ pg/g for the ice cream. Daily TEQ consumption per kilogram body weight (kg/BW), assuming an average 65 kg adult and a 20 kg child, from one serving of each of these fast food ranged between 0.046 and 1.556 pg/kg in adults whereas in children the values were between 0.15 and 5.05 pg/kg. Total measured PCDD/Fs in the Big Mac, Personal Pan Pizza, KFC, and the Häagen-Daz ice cream varied from 0.58 to 9.31 pg/g. Measured DDE levels in the fast foods ranged from 180 to 3170 pg/g. Total mono-ortho PCB levels ranged up to 500 pg/g or 1.28 TEQ pg/g for the KFC and for di-ortho PCBs up to 740 pg/g or 0.014 TEQ pg/g for the pizza sample. Total PCB values in the four samples ranged up to 1170 pg/g or 1.29 TEQ pg/g for the chicken sample.

  12. Matrix factorization reveals aging-specific co-expression gene modules in the fat and muscle tissues in nonhuman primates

    Science.gov (United States)

    Wang, Yongcui; Zhao, Weiling; Zhou, Xiaobo

    2016-10-01

    Accurate identification of coherent transcriptional modules (subnetworks) in adipose and muscle tissues is important for revealing the related mechanisms and co-regulated pathways involved in the development of aging-related diseases. Here, we proposed a systematically computational approach, called ICEGM, to Identify the Co-Expression Gene Modules through a novel mathematical framework of Higher-Order Generalized Singular Value Decomposition (HO-GSVD). ICEGM was applied on the adipose, and heart and skeletal muscle tissues in old and young female African green vervet monkeys. The genes associated with the development of inflammation, cardiovascular and skeletal disorder diseases, and cancer were revealed by the ICEGM. Meanwhile, genes in the ICEGM modules were also enriched in the adipocytes, smooth muscle cells, cardiac myocytes, and immune cells. Comprehensive disease annotation and canonical pathway analysis indicated that immune cells, adipocytes, cardiomyocytes, and smooth muscle cells played a synergistic role in cardiac and physical functions in the aged monkeys by regulation of the biological processes associated with metabolism, inflammation, and atherosclerosis. In conclusion, the ICEGM provides an efficiently systematic framework for decoding the co-expression gene modules in multiple tissues. Analysis of genes in the ICEGM module yielded important insights on the cooperative role of multiple tissues in the development of diseases.

  13. I thought that I heard you laughing: Contextual facial expressions modulate the perception of authentic laughter and crying.

    Science.gov (United States)

    Lavan, Nadine; Lima, César F; Harvey, Hannah; Scott, Sophie K; McGettigan, Carolyn

    2015-01-01

    It is well established that categorising the emotional content of facial expressions may differ depending on contextual information. Whether this malleability is observed in the auditory domain and in genuine emotion expressions is poorly explored. We examined the perception of authentic laughter and crying in the context of happy, neutral and sad facial expressions. Participants rated the vocalisations on separate unipolar scales of happiness and sadness and on arousal. Although they were instructed to focus exclusively on the vocalisations, consistent context effects were found: For both laughter and crying, emotion judgements were shifted towards the information expressed by the face. These modulations were independent of response latencies and were larger for more emotionally ambiguous vocalisations. No effects of context were found for arousal ratings. These findings suggest that the automatic encoding of contextual information during emotion perception generalises across modalities, to purely non-verbal vocalisations, and is not confined to acted expressions.

  14. Identifying modules of coexpressed transcript units and their organization of Saccharopolyspora erythraea from time series gene expression profiles.

    Directory of Open Access Journals (Sweden)

    Xiao Chang

    Full Text Available BACKGROUND: The Saccharopolyspora erythraea genome sequence was released in 2007. In order to look at the gene regulations at whole transcriptome level, an expression microarray was specifically designed on the S. erythraea strain NRRL 2338 genome sequence. Based on these data, we set out to investigate the potential transcriptional regulatory networks and their organization. METHODOLOGY/PRINCIPAL FINDINGS: In view of the hierarchical structure of bacterial transcriptional regulation, we constructed a hierarchical coexpression network at whole transcriptome level. A total of 27 modules were identified from 1255 differentially expressed transcript units (TUs across time course, which were further classified in to four groups. Functional enrichment analysis indicated the biological significance of our hierarchical network. It was indicated that primary metabolism is activated in the first rapid growth phase (phase A, and secondary metabolism is induced when the growth is slowed down (phase B. Among the 27 modules, two are highly correlated to erythromycin production. One contains all genes in the erythromycin-biosynthetic (ery gene cluster and the other seems to be associated with erythromycin production by sharing common intermediate metabolites. Non-concomitant correlation between production and expression regulation was observed. Especially, by calculating the partial correlation coefficients and building the network based on Gaussian graphical model, intrinsic associations between modules were found, and the association between those two erythromycin production-correlated modules was included as expected. CONCLUSIONS: This work created a hierarchical model clustering transcriptome data into coordinated modules, and modules into groups across the time course, giving insight into the concerted transcriptional regulations especially the regulation corresponding to erythromycin production of S. erythraea. This strategy may be extendable to studies

  15. Identifying modules of coexpressed transcript units and their organization of Saccharopolyspora erythraea from time series gene expression profiles.

    Science.gov (United States)

    Chang, Xiao; Liu, Shuai; Yu, Yong-Tao; Li, Yi-Xue; Li, Yuan-Yuan

    2010-08-12

    The Saccharopolyspora erythraea genome sequence was released in 2007. In order to look at the gene regulations at whole transcriptome level, an expression microarray was specifically designed on the S. erythraea strain NRRL 2338 genome sequence. Based on these data, we set out to investigate the potential transcriptional regulatory networks and their organization. In view of the hierarchical structure of bacterial transcriptional regulation, we constructed a hierarchical coexpression network at whole transcriptome level. A total of 27 modules were identified from 1255 differentially expressed transcript units (TUs) across time course, which were further classified in to four groups. Functional enrichment analysis indicated the biological significance of our hierarchical network. It was indicated that primary metabolism is activated in the first rapid growth phase (phase A), and secondary metabolism is induced when the growth is slowed down (phase B). Among the 27 modules, two are highly correlated to erythromycin production. One contains all genes in the erythromycin-biosynthetic (ery) gene cluster and the other seems to be associated with erythromycin production by sharing common intermediate metabolites. Non-concomitant correlation between production and expression regulation was observed. Especially, by calculating the partial correlation coefficients and building the network based on Gaussian graphical model, intrinsic associations between modules were found, and the association between those two erythromycin production-correlated modules was included as expected. This work created a hierarchical model clustering transcriptome data into coordinated modules, and modules into groups across the time course, giving insight into the concerted transcriptional regulations especially the regulation corresponding to erythromycin production of S. erythraea. This strategy may be extendable to studies on other prokaryotic microorganisms.

  16. Dioxins and dioxin-like PCBs in fish in general and in particular from Baltic Sea

    Energy Technology Data Exchange (ETDEWEB)

    Karl, H. [Federal Research Centre for Nutrition and Food, Hamburg (Germany); Ruoff, U. [Federal Research Centre For Nutrition and Food, Kiel (Germany)

    2004-09-15

    Commission Regulation No 466/2001 establishes maximum levels for dioxins in foodstuffs, foreseeing to review the maximum levels by 31 December 2006 and to include dioxin-like PCBs in the levels to be set. Fish is known to accumulate dioxins and dioxin related compounds in the lipid phase of their tissue. To collect information of the actual contamination levels in fish species on the German market, samples were taken from fishing grounds important for the supply and in particular from the Baltic Sea. Sampling concentrates on fish species with higher fat content like mackerel (Scomber scombrus), salmon (Salmo salar), trout (Oncorhynchus mykiss), red fish (Sebastes sp.) and herring (Clupea harengus), because lean fish species are known to be less contaminated. Herring is the most important fat fish species for the German fish processing industry with a market share of 19% in 2001. The annual demand is approximately 149.000 t. Herring and other fish species accumulate PCDD/Fs with increasing age and dioxin levels in the edible part of eastern Baltic herring exceeds the maximum limit of 4 ng WHOPCDD/ F-TEQ/kg wet weight (w.w.) at ages of 4 - 6 years, corresponding to sizes of approximately 17 - 18 cm and a weight of 40 g, respectively. Hence Isosaari recommended to use preferably young fish from this area for human consumption. However, the German herring industry is based on the processing of large herring with a minimum weight of > 85g up to 250g. Therefore our interest focused on herring sizes of potential interest for the German processing industry. Samples were collected in September 1999 within two weeks covering an area from the Skagerrak to the Coast of Latvia. Additionally the contamination levels in sprat (Sprattus sprattus), flounder, brown trout (Salmo trutta) and in spring spawning herring from commercial landings around the area of Ruegen have been analysed.

  17. Modulation of gene expression as a new skin anti-aging strategy.

    Science.gov (United States)

    Talbourdet, Sylvie; Sadick, Neil S; Lazou, Kristell; Bonnet-Duquennoy, Mathilde; Kurfurst, Robin; Neveu, Michele; Heusèle, Catherine; André, Patrice; Schnebert, Sylvianne; Draelos, Zoe D; Perrier, Eric

    2007-06-01

    human epidermis model showed that some genes modulated by treatment with the Malva sylvestris extract are also regulated by RA treatment indicating a similar activity at the mRNA level. In the single-center study, a facial skin care product containing the Aframomum angustifolium seed extract significantly improved the homogeneity of the skin. The areas of the detected objects (skin imperfections) decreased significantly on each studied area of the face and the variance decreased significantly over the entire face. In the 2-center study, 28% percent of the subjects reported a greater than 50% overall global improvement in their skin by the end of the study compared to 11% of the subjects after 4 weeks of treatment. Seventy-six percent of subjects said they would purchase the cream. The authors developed a low-density DNA chip method that permitted the study of the transcriptional effect of Malva Sylvestris extract and of Aframomum angustrifolium seed extract. The gene expression profiles obtained demonstrate the anti-aging properties of these compounds. An in vivo single-center study, performed and analyzed with an assay based on image processing analysis, demonstrated the antiwrinkle activity of a formulation containing the Aframomum angustifolium seed extract. The data obtained in the 2-center study suggests that the cosmeceutical containing Aframomum angustifolium seed extract produces a global rejuvenation effect in terms of redness, pigmentation, and fine lines similar to that noted utilizing an intense pulse light source.

  18. Concentrations of dioxins and dioxin-like PCBs in feed materials in the Netherlands, 2001-11.

    Science.gov (United States)

    Adamse, Paulien; Van der Fels-Klerx, H J Ine; Schoss, Stefanie; de Jong, Jacob; Hoogenboom, Ron L A P

    2015-01-01

    This study aimed to obtain insights into contamination of feed materials used in the Netherlands with dioxins (polychlorinated dibenzo-p-dioxins and dibenzofurans) and dioxin-like polychlorinated biphenyls (PCBs). Monitoring results from the period 2001-11, covering in total 4938 samples, were statistically analysed and evaluated against the statutory limits set at the beginning or during this period. The percentage of samples exceeding maximum levels set within the European Union for either dioxins or the sum of dioxins and dioxin-like PCBs were below 1% for most feed categories, except for fish meal (4.1%), clay minerals (binders and anti-caking agents) (3.4%), and vegetable oils and byproducts (1.7%). For most feed categories, non-compliance with the action threshold (roughly 33% lower than maximum levels) for either dioxins or dioxin-like PCBs was up to three times higher than non-compliance with the respective maximum levels. Exceedance of action thresholds was just above 1% for animal fat, pre-mixtures and feed materials of plant origin excluding vegetable oils. For the categories fish meal, clay minerals, and vegetable oils and byproducts, the action thresholds were exceeded by 5.0%, 9.8% and 3.0% of the samples, respectively. In general, the percentages of samples that exceeded the action thresholds and maximum levels were lower than those reported for the European Union by the European Food Safety Authority (EFSA). In most of the feed materials, there seems to be a decreasing trend in concentrations of dioxins or dioxin-like PCBs over the years. However, a lowering of the limits of quantification during this period and the low concentrations in most samples precludes drawing strong conclusions.

  19. Long non-coding RNAs as novel expression signatures modulate DNA damage and repair in cadmium toxicology

    Science.gov (United States)

    Zhou, Zhiheng; Liu, Haibai; Wang, Caixia; Lu, Qian; Huang, Qinhai; Zheng, Chanjiao; Lei, Yixiong

    2015-10-01

    Increasing evidence suggests that long non-coding RNAs (lncRNAs) are involved in a variety of physiological and pathophysiological processes. Our study was to investigate whether lncRNAs as novel expression signatures are able to modulate DNA damage and repair in cadmium(Cd) toxicity. There were aberrant expression profiles of lncRNAs in 35th Cd-induced cells as compared to untreated 16HBE cells. siRNA-mediated knockdown of ENST00000414355 inhibited the growth of DNA-damaged cells and decreased the expressions of DNA-damage related genes (ATM, ATR and ATRIP), while increased the expressions of DNA-repair related genes (DDB1, DDB2, OGG1, ERCC1, MSH2, RAD50, XRCC1 and BARD1). Cadmium increased ENST00000414355 expression in the lung of Cd-exposed rats in a dose-dependent manner. A significant positive correlation was observed between blood ENST00000414355 expression and urinary/blood Cd concentrations, and there were significant correlations of lncRNA-ENST00000414355 expression with the expressions of target genes in the lung of Cd-exposed rats and the blood of Cd exposed workers. These results indicate that some lncRNAs are aberrantly expressed in Cd-treated 16HBE cells. lncRNA-ENST00000414355 may serve as a signature for DNA damage and repair related to the epigenetic mechanisms underlying the cadmium toxicity and become a novel biomarker of cadmium toxicity.

  20. Modulation of tenascin Genes expression in pig skin and muscular fibrosis after ionizing radiation

    Energy Technology Data Exchange (ETDEWEB)

    Geffrotin, C.; Tricaud, Y.; Castelli, M.; Crechet, F.; Lefaix, J.L.; Vaiman, M. [Institut National de Recherches Agronomiques (INRA-CEA-DSV-DRR) Laboratoire de Radiologie Appliquee, 78 - Jouy-en-Josas (France)

    1997-03-01

    To study mechanisms leading to radiation-induced fibrosis, a complication which may occur after radiotherapy or radiation accidents, a model of local irradiation of skin in pig has been set up. It is characterized by the development of a cutaneous and muscular fibrosis within 5 months following a single dose of at least 140 Grays at the point of application of a collimated {sup 192}Ir source (2 cm in diameter). Accumulation of myo-fibroblasts, increased synthesis and deposition of components of the extra cellular matrix (ECM), such as collagens, fibronectin and hyaluronan were described in this model. We present here a study of the expression of the tenascin C and X (TN-C and TN-X) molecules which belong to a new family of glycoproteins of the ECM that has never been analysed in this context. A single dose of 160 Grays (0,6 Gy/mn) at the point of application of the {sup 192}Ir source was delivered on the right thigh of 4 Large While pigs. The animals were killed 9 to 11 months after irradiation and samples from unirradiated skin, repaired fibrotic skin and underlying muscular fibrotic tissue were recovered. TN-C and TN-X RNAs were analysed by the RNase protection and Northern blot methods using porcine cDNA probes. Analysis of TN-C protein was performed by Western blot technique using a polyclonal antibody raised against human TN-C. RNAs and proteins were quantified with the PhosphorImager SI and the Imaging Densitometer GS-700 from Biorad respectively. In conclusion, these data confirmed our previous observations about the independence of the regulatory mechanisms involved in the level of TN-X and TN-C mRNAs. As the TN-C gene is highly expressed both at the RNA and the protein levels, its products might play an important role both in the initiation and the chronic extension of radiation-induced fibrosis by modulating mechanism such as adhesion, migration or proliferation of cells. (authors)

  1. Mechanical stretch modulates microRNA 21 expression, participating in proliferation and apoptosis in cultured human aortic smooth muscle cells.

    Directory of Open Access Journals (Sweden)

    Jian tao Song

    Full Text Available OBJECTIVES: Stretch affects vascular smooth muscle cell proliferation and apoptosis, and several responsible genes have been proposed. We tested whether the expression of microRNA 21 (miR-21 is modulated by stretch and is involved in stretch-induced proliferation and apoptosis of human aortic smooth muscle cells (HASMCs. METHODS AND RESULTS: RT-PCR revealed that elevated stretch (16% elongation, 1 Hz increased miR-21 expression in cultured HASMCs, and moderate stretch (10% elongation, 1 Hz decreased the expression. BrdU incorporation assay and cell counting showed miR-21 involved in the proliferation of HASMCs mediated by stretch, likely by regulating the expression of p27 and phosphorylated retinoblastoma protein (p-Rb. FACS analysis revealed that the complex of miR-21 and programmed cell death protein 4 (PDCD4 participated in regulating apoptosis with stretch. Stretch increased the expression of primary miR-21 and pre-miR-21 in HASMCs. Electrophoretic mobility shift assay (EMSA demonstrated that stretch increased NF-κB and AP-1 activities in HASMCs, and blockade of AP-1 activity by c-jun siRNA significantly suppressed stretch-induced miR-21 expression. CONCLUSIONS: Cyclic stretch modulates miR-21 expression in cultured HASMCs, and miR-21 plays important roles in regulating proliferation and apoptosis mediated by stretch. Stretch upregulates miR-21 expression at least in part at the transcription level and AP-1 is essential for stretch-induced miR-21 expression.

  2. Inventory of U.S. 2012 dioxin emissions to atmosphere.

    Science.gov (United States)

    Dwyer, Henri; Themelis, Nickolas J

    2015-12-01

    In 2006, the U.S. EPA published an inventory of dioxin emissions for the U.S. covering the period from 1987-2000. This paper is an updated inventory of all U.S. dioxin emissions to the atmosphere in the year 2012. The sources of emissions of polychlorinated dibenzodioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs), collectively referred to in this paper as "dioxins", were separated into two classes: controlled industrial and open burning sources. Controlled source emissions decreased 95.5% from 14.0 kg TEQ in 1987 to 0.6 kg in 2012. Open burning source emissions increased from 2.3 kg TEQ in 1987 to 2.9 kg in 2012. The 2012 dioxin emissions from 53 U.S. waste-to-energy (WTE) power plants were compiled on the basis of detailed data obtained from the two major U.S. WTE companies, representing 84% of the total MSW combusted (27.4 million metric tons). The dioxin emissions of all U.S. WTE plants in 2012 were 3.4 g TEQ and represented 0.54% of the controlled industrial dioxin emissions, and 0.09% of all dioxin emissions from controlled and open burning sources. Copyright © 2015. Published by Elsevier Ltd.

  3. Formation of dioxins and furans during combustion of treated wood

    Energy Technology Data Exchange (ETDEWEB)

    Tame, Nigel W.; Dlugogorski, Bogdan Z.; Kennedy, Eric M. [Process Safety and Environment Protection Research Group, School of Engineering, The University of Newcastle, Callaghan, NSW 2308 (Australia)

    2007-08-15

    Polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/F, dioxin) are produced in combustion of wood treated with copper-based preservatives. This review summarises and analyses the pertinent literature on the role of preservatives in the formation of dioxin in the low-temperature, vitiated environment that exists in the domestic combustion of wood, and in large-scale fires. Until recently, the role of preservatives was not thoroughly examined in the literature with respect to fires, as incineration attracted most of the research focus. However, latest studies have demonstrated that some current and emerging wood preservatives significantly increase dioxin formation during combustion in domestic stoves and in fires. The following pathways are identified: (i) copper, a common biocide that is chemically bound to the wood, is an important dioxin catalyst, (ii) preservative metals promote smouldering of wood char following cessation of flaming, providing the required temperature environment for dioxin formation, and (iii) chlorinated organics added as secondary preservative components yield dioxin precursors upon thermal decomposition. These conclusions indicate that it remains hazardous to dispose of preservative impregnated timber via domestic combustion even if arsenic is not present. (author)

  4. The proficiency testing of determination of dioxins in food

    Energy Technology Data Exchange (ETDEWEB)

    Matsuda, R.; Tsutsumi, T.; Maitani, T. [National Institute of Health Sciences, Tokyo (Japan); Toyoda, M. [Jissen Womens Univ., Hino (Japan)

    2004-09-15

    Food intake is the main route of human dioxin exposure, making the determination of dioxins in food indispensable for risk assessment and risk management of dioxins. The uncertainty of analytical results, however, can be very great because of the low concentration of the analytes and complicated cleanup procedures. The risk assessment of dioxins based on analytical results also suffers from a similar degree of uncertainty. The Ministry of Health, Labor and Welfare of Japan has published ''Guideline for the Determination of Dioxins in Food'' to standardize the analytical procedures. The guideline contains the quality assurance procedures to obtain reliable analytical results and recommends participation in the relevant proficiency testing scheme. The proficiency testing provides the fair evaluation of the analytical results. The central science laboratory in England and the food and drug safety center in Japan offer the proficiency testing on food. The National Institute of Health Sciences of Japan (NIHS) also has carried out proficiency testing of dioxins in food since 1998 to assure the quality of analytical results for dioxins. In this presentation we will show the results of 5 rounds of proficiency testing.

  5. Association of dioxins, furans and dioxin-like PCBs in human blood with nephropathy among US teens and young adults.

    Science.gov (United States)

    Everett, Charles J; Thompson, Olivia M

    2016-06-01

    We assessed the association of three chlorinated dibenzo-p-dioxins, a chlorinated dibenzofuran, and four dioxin-like polychlorinated biphenyls (PCBs) in human blood with nephropathy (microalbuminuria or macroalbuminuria) among teens and young adults (12-30 years old) having normal glycohemoglobin (A1c Dioxins, furans and dioxin-like PCBs in human blood: causes or consequences of diabetic nephropathy? Environ Res 2014;132:126-31), the cut-offs for these chemicals being considered elevated, were defined as the 75th percentile. Using these same cut-offs again, the proportion of those with one or more of the eight dioxin-like compounds elevated was 9.9%. The four chemicals associated with nephropathy were 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin, PCB 126, PCB 169, and PCB 156. The proportion with one or more of these four dioxin-like chemicals elevated was 3.9% (unweighted n=46) and the odds ratio (OR) for nephropathy was 7.1 [95% confidence interval (CI) 1.8-28.1]. The association was strong among females (OR 17.4, 95% CI 3.4-88.6), but among males there were no cases of nephropathy when one or more of the four dioxin-like chemicals were elevated, and therefore no association. In a separate analysis, elevated toxic equivalency, defined using the eight dioxin-like chemicals (TEQ8), was associated with nephropathy. TEQ8 ≥50.12 fg/g included 2.6% of the sample (unweighted n=28) and had an OR of 5.8 (95% 1.3-25.9) for nephropathy. As found in the analysis of one or more of four dioxin-like chemicals elevated, TEQ8 ≥50.12 fg/g was associated with nephropathy among females (OR 11.9, 95% CI 1.6-87.2), but not males. Trends for least-squares means also differed by gender, but there were no significant differences in mean TEQ8 between normal subjects and those having nephropathy in either males or females. We also evaluated pre-diabetes (A1c 5.7-6.4%) without nephropathy and found no associations when one or more of four dioxin-like compounds were elevated, or when TEQ8 was

  6. S187. SEARCHING FOR BRAIN CO-EXPRESSION MODULES THAT CONTRIBUTE DISPROPORTIONATELY TO THE COMMON POLYGENIC RISK FOR SCHIZOPHRENIA

    Science.gov (United States)

    Costas, Javier; Paramo, Mario; Arrojo, Manuel

    2018-01-01

    Abstract Background Genomic research has revealed that schizophrenia is a highly polygenic disease. Recent estimates indicate that at least 71% of genomic segments of 1 Mb include one or more risk loci for schizophrenia (Loh et al., Nature Genet 2015). This extremely high polygenicity represents a challenge to decipher the biological basis of schizophrenia, as it is expected that any set of SNPs with enough size will be associated with the disorder. Among the different gene sets available for study (such as those from Gene Ontology, KEGG pathway, Reactome pathways or protein protein interaction datasets), those based on brain co-expression networks represent putative functional relationships in the relevant tissue. The aim of this work was to identify brain co-expression networks that contribute disproportionately to the common polygenic risk for schizophrenia to get more insight on schizophrenia etiopathology. Methods We analyzed a case -control dataset consisting of 582 schizophrenia patients from Galicia, NW Spain, and 591 ancestrally matched controls, genotyped with the Illumina PsychArray. Using as discovery sample the summary results from the largest GWAS of schizophrenia to date (Psychiatric Genomics Consortium, SCZ2), we generated polygenic risk scores (PRS) in our sample based on SNPs located at genes belonging to brain co-expression modules determined by the CommonMind Consortium (Fromer et al., Nature Neurosci 2016). PRS were generated using the clumping procedure of PLINK, considering several different thresholds to select SNPs from the discovery sample. In order to test if any specific module increased risk to schizophrenia more than expected by their size, we generated up to 10,000 random permutations of the same number of SNPs, matched by frequency, distance to nearest gene, number of SNPs in LD and gene density, using SNPsnap. Results As expected, most modules with enough number of independent SNPs belonging to them showed a significant increase in

  7. Impression or expression? The influence of self-monitoring on the social modulation of motor contagion.

    Science.gov (United States)

    Roberts, James W; Bennett, Simon J; Hayes, Spencer J

    2018-04-01

    Social primes (pro-social, anti-social) can modulate mimicry behaviour. To date, these social modulation effects have been explained by the primed incentive to affiliate with another (Social Top-Down Response Modulation; STORM) and the primed active-self-concept leading to behaviour that is either consistent or inconsistent with the primed-construct (Active-Self account). This study was designed to explore the explanatory power of each of these accounts and thereby gain a greater understanding of how social modulation unfolds. To do this, we assessed social modulation of motor contagion in individuals high or low in self-monitoring. It was reasoned that high self-monitors would modulate mimicry according to the primed social incentive, whereas low self-monitors would modulate according to the primed active-self-concept. Participants were primed with a pro-social and anti-social cue in the first-person and third-person perspective. Next, they completed an interpersonal observation-execution task featuring the simultaneous observation and execution of arm movements that were either congruent or incongruent to each other. Results showed increased incongruent movement deviation (motor contagion) for the anti-social compared to the pro-social prime in the high self-monitors only. Findings support the STORM account of mimicry by showing observers modulate behaviour based on the social incentive underpinning an interpersonal exchange.

  8. Kaempferol inhibits vascular smooth muscle cell migration by modulating BMP-mediated miR-21 expression.

    Science.gov (United States)

    Kim, Kwangho; Kim, Sunghwan; Moh, Sang Hyun; Kang, Hara

    2015-09-01

    Bioflavonoids are known to induce cardioprotective effects by inhibiting vascular smooth muscle cell (VSMC) proliferation and migration. Kaempferol has been shown to inhibit VSMC proliferation. However, little is known about the effect of kaempferol on VSMC migration and the underlying molecular mechanisms. Our studies provide the first evidence that kaempferol inhibits VSMC migration by modulating the BMP4 signaling pathway and microRNA expression levels. Kaempferol activates the BMP signaling pathway, induces miR-21 expression and downregulates DOCK4, 5, and 7, leading to inhibition of cell migration. Moreover, kaempferol antagonizes the PDGF-mediated pro-migratory effect. Therefore, our study uncovers a novel regulatory mechanism of VSMC migration by kaempferol and suggests that miRNA modulation by kaempferol is a potential therapy for cardiovascular diseases.

  9. Radiolytic treatment of dioxin contaminated soils

    International Nuclear Information System (INIS)

    Gray, K.A.; Hilarides, R.J.

    1995-01-01

    Recent work in our laboratory has demonstrated that γ-radiolysis is a feasible method by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can be converted to products of negligible toxicity. In the presence of 25% water, 2.5% non-ionic surfactant and at a dose of 800 kGy greater than 98% destruction was achieved in a standard soil artificially contaminated with 100 ppb TCDD. By-product analysis has illustrated that the destruction occurs via step-wise reductive dechlorination producing a suite of lesser chlorinated dioxins. These results in combination with scavenger studies, target theory calculations and yields indicate that direct radiation effects account for the major route of destruction. Radiolysis has also been conducted on a real soil contaminated with TCDD and other chlorinated aromatic compounds verifying the results of model studies. Based on the data of these experiments some designs of batch gamma systems are considered and a discussion of estimated capital and operating costs associated with γ-radiolysis is presented. Given the high costs of the alternatives (i.e. incineration), radiolysis appears to be not only technically feasible, but it may also be economically competitive. (author)

  10. PI3K/AKT signaling modulates transcriptional expression of EWS/FLI1 through specificity protein 1.

    Science.gov (United States)

    Giorgi, Chiara; Boro, Aleksandar; Rechfeld, Florian; Lopez-Garcia, Laura A; Gierisch, Maria E; Schäfer, Beat W; Niggli, Felix K

    2015-10-06

    Ewing sarcoma (ES) is the second most frequent bone cancer in childhood and is characterized by the presence of the balanced translocation t(11;22)(q24;q12) in more than 85% of cases, generating a dysregulated transcription factor EWS/FLI1. This fusion protein is an essential oncogenic component of ES development which is necessary for tumor cell maintenance and represents an attractive therapeutic target. To search for modulators of EWS/FLI1 activity we screened a library of 153 targeted compounds and identified inhibitors of the PI3K pathway to directly modulate EWS/FLI1 transcription. Surprisingly, treatment of four different ES cell lines with BEZ235 resulted in down regulation of EWS/FLI1 mRNA and protein by ~50% with subsequent modulation of target gene expression. Analysis of the EWS/FLI1 promoter region (-2239/+67) using various deletion constructs identified two 14 bp minimal elements as being important for EWS/FLI1 transcription. We identified SP1 as modulator of EWS/FLI1 gene expression and demonstrated direct binding to one of these regions in the EWS/FLI1 promoter by EMSA and ChIP experiments. These results provide the first insights on the transcriptional regulation of EWS/FLI1, an area that has not been investigated so far, and offer an additional molecular explanation for the known sensitivity of ES cell lines to PI3K inhibition.

  11. bc-GenExMiner 3.0: new mining module computes breast cancer gene expression correlation analyses.

    Science.gov (United States)

    Jézéquel, Pascal; Frénel, Jean-Sébastien; Campion, Loïc; Guérin-Charbonnel, Catherine; Gouraud, Wilfried; Ricolleau, Gabriel; Campone, Mario

    2013-01-01

    We recently developed a user-friendly web-based application called bc-GenExMiner (http://bcgenex.centregauducheau.fr), which offered the possibility to evaluate prognostic informativity of genes in breast cancer by means of a 'prognostic module'. In this study, we develop a new module called 'correlation module', which includes three kinds of gene expression correlation analyses. The first one computes correlation coefficient between 2 or more (up to 10) chosen genes. The second one produces two lists of genes that are most correlated (positively and negatively) to a 'tested' gene. A gene ontology (GO) mining function is also proposed to explore GO 'biological process', 'molecular function' and 'cellular component' terms enrichment for the output lists of most correlated genes. The third one explores gene expression correlation between the 15 telomeric and 15 centromeric genes surrounding a 'tested' gene. These correlation analyses can be performed in different groups of patients: all patients (without any subtyping), in molecular subtypes (basal-like, HER2+, luminal A and luminal B) and according to oestrogen receptor status. Validation tests based on published data showed that these automatized analyses lead to results consistent with studies' conclusions. In brief, this new module has been developed to help basic researchers explore molecular mechanisms of breast cancer. DATABASE URL: http://bcgenex.centregauducheau.fr

  12. Representational momentum in dynamic facial expressions is modulated by the level of expressed pain: Amplitude and direction effects.

    Science.gov (United States)

    Prigent, Elise; Amorim, Michel-Ange; de Oliveira, Armando Mónica

    2018-01-01

    Humans have developed a specific capacity to rapidly perceive and anticipate other people's facial expressions so as to get an immediate impression of their emotional state of mind. We carried out two experiments to examine the perceptual and memory dynamics of facial expressions of pain. In the first experiment, we investigated how people estimate other people's levels of pain based on the perception of various dynamic facial expressions; these differ both in terms of the amount and intensity of activated action units. A second experiment used a representational momentum (RM) paradigm to study the emotional anticipation (memory bias) elicited by the same facial expressions of pain studied in Experiment 1. Our results highlighted the relationship between the level of perceived pain (in Experiment 1) and the direction and magnitude of memory bias (in Experiment 2): When perceived pain increases, the memory bias tends to be reduced (if positive) and ultimately becomes negative. Dynamic facial expressions of pain may reenact an "immediate perceptual history" in the perceiver before leading to an emotional anticipation of the agent's upcoming state. Thus, a subtle facial expression of pain (i.e., a low contraction around the eyes) that leads to a significant positive anticipation can be considered an adaptive process-one through which we can swiftly and involuntarily detect other people's pain.

  13. Laminin and collagen modulate expression of the small leucine-rich proteoglycan fibromodulin in rat anterior pituitary gland.

    Science.gov (United States)

    Syaidah, Rahimi; Horiguchi, Kotaro; Fujiwara, Ken; Tsukada, Takehiro; Kikuchi, Motoshi; Yashiro, Takashi

    2013-11-01

    The anterior pituitary is a complex organ consisting of five types of hormone-producing cells, non–hormone-producing cells such as folliculostellate (FS) cells and vascular cells (endothelial cells and pericytes). We have previously shown that FS cells and pericytes produce fibromodulin, a small leucine-rich proteoglycan (SLRP). SLRPs are major proteoglycans of the extracellular matrix (ECM) and are important in regulating cell signaling pathways and ECM assembly. However, the mechanism regulating fibromodulin expression in the anterior pituitary has not been elucidated. Here, we investigate whether fibromodulin expression is modulated by major anterior pituitary ECM components such as laminin and type I collagen. Using transgenic rats expressing green fluorescent protein (GFP) specifically in FS cells, we examine fibromodulin expression in GFP-positive (FS cells) and GFP-negative cells (e.g., pericytes, endocrine cells and endothelial cells). Immunostaining and Western blot analysis were used to assess protein expression in the presence and absence of laminin or type I collagen. We confirmed fibromodulin expression in the pituitary and observed the up-regulation of fibromodulin in FS cells in the presence of ECM components. However, neither laminin nor type I collagen affected expression in GFP-negative cells. This suggests that laminin and type I collagen support the function of FS cells by increasing fibromodulin protein expression in the anterior pituitary.

  14. The need and Potential of Biosensors to Detect Dioxins and Dioxin-Like Polychlorinated Biphenyls along the Milk, Eggs and Meat Food Chain

    NARCIS (Netherlands)

    Chobtang, J.; Boer, de I.J.M.; Hoogenboom, L.A.P.; Haasnoot, W.; Kijlstra, A.; Meerburg, B.G.

    2011-01-01

    Dioxins and dioxin-like polychlorinated biphenyls (DL-PCBs) are hazardous toxic, ubiquitous and persistent chemical compounds, which can enter the food chain and accumulate up to higher trophic levels. Their determination requires sophisticated methods, expensive facilities and instruments,

  15. Impact of Perinatal Dioxin Exposure on Infant Growth: A Cross-Sectional and Longitudinal Studies in Dioxin-Contaminated Areas in Vietnam

    Science.gov (United States)

    Nishijo, Muneko; Tai, Pham The; Nakagawa, Hideaki; Maruzeni, Shoko; Anh, Nguyen Thi Nguyet; Van Luong, Hoang; Anh, Tran Hai; Honda, Ryumon; Morikawa, Yuko; Kido, Teruhiko; Nishijo, Hisao

    2012-01-01

    Dioxin exposure levels remain elevated in residents living around former US Air Force bases in Vietnam, indicating potential adverse impacts on infant growth. In this study, 210 mother–infant pairs in dioxin-contaminated areas in Vietnam were recruited at the infants’ birth and followed up for 4 months. Perinatal dioxin exposure levels were estimated by measurement of polychlorinated dibenzo-p-dioxins/furans toxic equivalent (PCDDs/Fs-TEQ) in breast milk. The infants’ size was measured at birth and 1 and 4 months after birth, and neurodevelopment was evaluated using the Bayley Scales III at 4 months of age. Among 4 dioxin groups (dioxin levels. Only in boys, cognitive, language, and fine motor scores in the ≥75 percentile group were significantly lower than those in the other groups. These results suggested a considerable impact of perinatal dioxin exposure on infant growth, particularly in boys exposed to dioxins at high level of PCDDs/Fs-TEQ. PMID:22815734

  16. Effect of vitamin B12 on cleft palate induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin and dexamethasone in mice*

    Science.gov (United States)

    Zhao, Shu-fan; Chai, Mao-zhou; Wu, Min; He, Yong-hong; Meng, Tian; Shi, Bing

    2014-01-01

    The purpose of this study was to investigate the effect of vitamin B12 on palatal development by co-administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dexamethasone (DEX). We examined the morphological and histological features of the palatal shelf and expression levels of key signaling molecules (transforming growth factor-β3 (TGF-β3) and TGF-β type I receptor (activin receptor-like kinase 5, ALK5)) during palatogenesis among a control group (Group A), TCDD+DEX exposed group (Group B), and TCDD+DEX+vitamin B12 exposed group (Group C). While we failed to find that vitamin B12 decreased the incidence of cleft palate induced by TCDD+DEX treatment, the expression levels of key signaling molecules (TGF-β3 and ALK5) during palatogenesis were significantly modulated. In TCDD+DEX exposed and TCDD+DEX+vitamin B12 exposed groups, palatal shelves could not contact in the midline due to their small sizes. Our results suggest that vitamin B12 may inhibit the expression of some cleft palate inducers such as TGF-β3 and ALK5 in DEX+TCDD exposed mice, which may be beneficial against palatogenesis to some degree, even though we were unable to observe a protective role of vitamin B12 in morphological and histological alterations of palatal shelves induced by DEX and TCDD. PMID:24599693

  17. Effect of vitamin B12 on cleft palate induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin and dexamethasone in mice.

    Science.gov (United States)

    Zhao, Shu-Fan; Chai, Mao-Zhou; Wu, Min; He, Yong-Hong; Meng, Tian; Shi, Bing

    2014-03-01

    The purpose of this study was to investigate the effect of vitamin B12 on palatal development by co-administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dexamethasone (DEX). We examined the morphological and histological features of the palatal shelf and expression levels of key signaling molecules (transforming growth factor-β3 (TGF-β3) and TGF-β type I receptor (activin receptor-like kinase 5, ALK5)) during palatogenesis among a control group (Group A), TCDD+DEX exposed group (Group B), and TCDD+DEX+vitamin B12 exposed group (Group C). While we failed to find that vitamin B12 decreased the incidence of cleft palate induced by TCDD+DEX treatment, the expression levels of key signaling molecules (TGF-β3 and ALK5) during palatogenesis were significantly modulated. In TCDD+DEX exposed and TCDD+DEX+vitamin B12 exposed groups, palatal shelves could not contact in the midline due to their small sizes. Our results suggest that vitamin B12 may inhibit the expression of some cleft palate inducers such as TGF-β3 and ALK5 in DEX+TCDD exposed mice, which may be beneficial against palatogenesis to some degree, even though we were unable to observe a protective role of vitamin B12 in morphological and histological alterations of palatal shelves induced by DEX and TCDD.

  18. Haloperidol induces pharmacoepigenetic response by modulating miRNA expression, global DNA methylation and expression profiles of methylation maintenance genes and genes involved in neurotransmission in neuronal cells.

    Directory of Open Access Journals (Sweden)

    Babu Swathy

    Full Text Available Haloperidol has been extensively used in various psychiatric conditions. It has also been reported to induce severe side effects. We aimed to evaluate whether haloperidol can influence host methylome, and if so what are the possible mechanisms for it in neuronal cells. Impact on host methylome and miRNAs can have wide spread alterations in gene expression, which might possibly help in understanding how haloperidol may impact treatment response or induce side effects.SK-N-SH, a neuroblasoma cell line was treated with haloperidol at 10μm concentration for 24 hours and global DNA methylation was evaluated. Methylation at global level is maintained by methylation maintenance machinery and certain miRNAs. Therefore, the expression of methylation maintenance genes and their putative miRNA expression profiles were assessed. These global methylation alterations could result in gene expression changes. Therefore genes expressions for neurotransmitter receptors, regulators, ion channels and transporters were determined. Subsequently, we were also keen to identify a strong candidate miRNA based on biological and in-silico approach which can reflect on the pharmacoepigenetic trait of haloperidol and can also target the altered neuroscience panel of genes used in the study.Haloperidol induced increase in global DNA methylation which was found to be associated with corresponding increase in expression of various epigenetic modifiers that include DNMT1, DNMT3A, DNMT3B and MBD2. The expression of miR-29b that is known to putatively regulate the global methylation by modulating the expression of epigenetic modifiers was observed to be down regulated by haloperidol. In addition to miR-29b, miR-22 was also found to be downregulated by haloperidol treatment. Both these miRNA are known to putatively target several genes associated with various epigenetic modifiers, pharmacogenes and neurotransmission. Interestingly some of these putative target genes involved in

  19. Haloperidol induces pharmacoepigenetic response by modulating miRNA expression, global DNA methylation and expression profiles of methylation maintenance genes and genes involved in neurotransmission in neuronal cells.

    Science.gov (United States)

    Swathy, Babu; Banerjee, Moinak

    2017-01-01

    Haloperidol has been extensively used in various psychiatric conditions. It has also been reported to induce severe side effects. We aimed to evaluate whether haloperidol can influence host methylome, and if so what are the possible mechanisms for it in neuronal cells. Impact on host methylome and miRNAs can have wide spread alterations in gene expression, which might possibly help in understanding how haloperidol may impact treatment response or induce side effects. SK-N-SH, a neuroblasoma cell line was treated with haloperidol at 10μm concentration for 24 hours and global DNA methylation was evaluated. Methylation at global level is maintained by methylation maintenance machinery and certain miRNAs. Therefore, the expression of methylation maintenance genes and their putative miRNA expression profiles were assessed. These global methylation alterations could result in gene expression changes. Therefore genes expressions for neurotransmitter receptors, regulators, ion channels and transporters were determined. Subsequently, we were also keen to identify a strong candidate miRNA based on biological and in-silico approach which can reflect on the pharmacoepigenetic trait of haloperidol and can also target the altered neuroscience panel of genes used in the study. Haloperidol induced increase in global DNA methylation which was found to be associated with corresponding increase in expression of various epigenetic modifiers that include DNMT1, DNMT3A, DNMT3B and MBD2. The expression of miR-29b that is known to putatively regulate the global methylation by modulating the expression of epigenetic modifiers was observed to be down regulated by haloperidol. In addition to miR-29b, miR-22 was also found to be downregulated by haloperidol treatment. Both these miRNA are known to putatively target several genes associated with various epigenetic modifiers, pharmacogenes and neurotransmission. Interestingly some of these putative target genes involved in neurotransmission

  20. Levels of polychlorinated dibenzo(p)dioxins, dibenzofurans and dioxin-like PCBs in Irish farmed salmon

    Energy Technology Data Exchange (ETDEWEB)

    Gruemping, R.; Hamm, S.; Stegemann, D.; Maulshagen, A. [eurofins/GfA, Muenster (Germany)

    2004-09-15

    A recent survey published by Hites in the journal Science compared the level of organochlorine contaminants including PCBs and dioxins in farmed versus wild salmon collected from around the world. Most organochlorine substances analysed in the study show a significantly higher concentration level in farmed than in wild salmon. While dioxin and PCB levels of wild fish mainly reflect the contamination level of the environment in which the fish is grown, the dioxin and PCB concentration in farmed fish may mainly be attributed to the fish feed used. In January 2004, the Irish Sea Fisheries Board (BIM) conducted the present study on the concentration of Polychlorinated Dibenzo(p)dioxins (PCDDs), Dibenzofurans (PCDFs) and dioxinlike PCBs (WHO-PCBs) in farmed salmon from two locations in Ireland. The present study should examine whether the PCDD/F and WHO-PCB levels of Irish farmed salmon correlate to the dioxin data for farmed Atlantic salmon from other countries in Northern Europe (e.g. Scotland, Faroe Islands and Norway) presented in the study by Hites. In the Hites survey, raw salmon filets with skin on were tested. Since PCBs, dioxins and other organic pollutants are mainly bound to the fish fat, a reduction of fat content by removal of the skin was supposed to lower the amount of organic contaminants. Thus, the effect of skin removal on the dioxin and PCB levels was also examined in the present study. In addition, the influence of cooking the fish meat was investigated.

  1. Equine Chorionic Gonadotropin Modulates the Expression of Genes Related to the Structure and Function of the Bovine Corpus Luteum.

    Science.gov (United States)

    Sousa, Liza Margareth Medeiros de Carvalho; Mendes, Gabriela Pacheco; Campos, Danila Barreiro; Baruselli, Pietro Sampaio; Papa, Paula de Carvalho

    2016-01-01

    We hypothesized that stimulatory and superovulatory treatments, using equine chorionic gonadotropin (eCG), modulate the expression of genes related to insulin, cellular modelling and angiogenesis signaling pathways in the bovine corpus luteum (CL). Therefore, we investigated: 1-the effect of these treatments on circulating insulin and somatomedin C concentrations and on gene and protein expression of INSR, IGF1 and IGFR1, as well as other insulin signaling molecules; 2-the effects of eCG on gene and protein expression of INSR, IGF1, GLUT4 and NFKB1A in bovine luteal cells; and 3-the effect of stimulatory and superovulatory treatments on gene and protein expression of ANG, ANGPT1, NOS2, ADM, PRSS2, MMP9 and PLAU. Serum insulin did not differ among groups (P = 0.96). However, serum somatomedin C levels were higher in both stimulated and superovulated groups compared to the control (P = 0.01). In stimulated cows, lower expression of INSR mRNA and higher expression of NFKB1A mRNA and IGF1 protein were observed. In superovulated cows, lower INSR mRNA expression, but higher INSR protein expression and higher IGF1, IGFR1 and NFKB1A gene and protein expression were observed. Expression of angiogenesis and cellular modelling pathway-related factors were as follows: ANGPT1 and PLAU protein expression were higher and MMP9 gene and protein expression were lower in stimulated animals. In superovulated cows, ANGPT1 mRNA expression was higher and ANG mRNA expression was lower. PRSS2 gene and protein expression were lower in both stimulated and superovulated animals related to the control. In vitro, eCG stimulated luteal cells P4 production as well as INSR and GLUT4 protein expression. In summary, our results suggest that superovulatory treatment induced ovarian proliferative changes accompanied by increased expression of genes providing the CL more energy substrate, whereas stimulatory treatment increased lipogenic activity, angiogenesis and plasticity of the extracellular matrix

  2. Equine Chorionic Gonadotropin Modulates the Expression of Genes Related to the Structure and Function of the Bovine Corpus Luteum.

    Directory of Open Access Journals (Sweden)

    Liza Margareth Medeiros de Carvalho Sousa

    Full Text Available We hypothesized that stimulatory and superovulatory treatments, using equine chorionic gonadotropin (eCG, modulate the expression of genes related to insulin, cellular modelling and angiogenesis signaling pathways in the bovine corpus luteum (CL. Therefore, we investigated: 1-the effect of these treatments on circulating insulin and somatomedin C concentrations and on gene and protein expression of INSR, IGF1 and IGFR1, as well as other insulin signaling molecules; 2-the effects of eCG on gene and protein expression of INSR, IGF1, GLUT4 and NFKB1A in bovine luteal cells; and 3-the effect of stimulatory and superovulatory treatments on gene and protein expression of ANG, ANGPT1, NOS2, ADM, PRSS2, MMP9 and PLAU. Serum insulin did not differ among groups (P = 0.96. However, serum somatomedin C levels were higher in both stimulated and superovulated groups compared to the control (P = 0.01. In stimulated cows, lower expression of INSR mRNA and higher expression of NFKB1A mRNA and IGF1 protein were observed. In superovulated cows, lower INSR mRNA expression, but higher INSR protein expression and higher IGF1, IGFR1 and NFKB1A gene and protein expression were observed. Expression of angiogenesis and cellular modelling pathway-related factors were as follows: ANGPT1 and PLAU protein expression were higher and MMP9 gene and protein expression were lower in stimulated animals. In superovulated cows, ANGPT1 mRNA expression was higher and ANG mRNA expression was lower. PRSS2 gene and protein expression were lower in both stimulated and superovulated animals related to the control. In vitro, eCG stimulated luteal cells P4 production as well as INSR and GLUT4 protein expression. In summary, our results suggest that superovulatory treatment induced ovarian proliferative changes accompanied by increased expression of genes providing the CL more energy substrate, whereas stimulatory treatment increased lipogenic activity, angiogenesis and plasticity of the

  3. Protein Kinase CK2 Expression Predicts Relapse Survival in ERα Dependent Breast Cancer, and Modulates ERα Expression in Vitro

    Directory of Open Access Journals (Sweden)

    Marlon D. Williams

    2015-12-01

    Full Text Available The heterotetrameric protein kinase CK2 has been associated with oncogenic transformation, and our previous studies have shown that it may affect estrogenic signaling. Here, we investigate the role of the protein kinase CK2 in regulating ERα (estrogen receptor α signaling in breast cancer. We determined the correlation of CK2α expression with relapse free breast cancer patient survival utilizing Kaplan Meier Plotter (kmplot.com/analysis/ to mine breast cancer microarrays repositories. Patients were stratified according to ERα status, histological grade, and hormonal therapy. Luciferase reporter assays and flow cytometry were implemented to determine the impact of CK2 inhibition on ERE-mediated gene expression and expression of ERα protein. CK2α expression is associated with shorter relapse free survival among ERα (+ patients with grade 1 or 2 tumors, as well as among those patients receiving hormonal therapy. Biochemical inhibition of CK2 activity results in increased ER-transactivation as well as increased expression among ERα (+ and ERα (− breast cancer cell lines. These findings suggest that CK2 may contribute to estrogen-independent cell proliferation and breast tumor progression, and may potentially serve as a biomarker and pharmacological target in breast cancer.

  4. Striking similarity in the gene expression levels of individual Myc module members among ESCs, EpiSCs, and partial iPSCs.

    Directory of Open Access Journals (Sweden)

    Masataka Hirasaki

    Full Text Available Predominant transcriptional subnetworks called Core, Myc, and PRC modules have been shown to participate in preservation of the pluripotency and self-renewality of embryonic stem cells (ESCs. Epiblast stem cells (EpiSCs are another cell type that possesses pluripotency and self-renewality. However, the roles of these modules in EpiSCs have not been systematically examined to date. Here, we compared the average expression levels of Core, Myc, and PRC module genes between ESCs and EpiSCs. EpiSCs showed substantially higher and lower expression levels of PRC and Core module genes, respectively, compared with those in ESCs, while Myc module members showed almost equivalent levels of average gene expression. Subsequent analyses revealed that the similarity in gene expression levels of the Myc module between these two cell types was not just overall, but striking similarities were evident even when comparing the expression of individual genes. We also observed equivalent levels of similarity in the expression of individual Myc module genes between induced pluripotent stem cells (iPSCs and partial iPSCs that are an unwanted byproduct generated during iPSC induction. Moreover, our data demonstrate that partial iPSCs depend on a high level of c-Myc expression for their self-renewal properties.

  5. Genes and co-expression modules common to drought and bacterial stress responses in Arabidopsis and rice.

    Directory of Open Access Journals (Sweden)

    Rafi Shaik

    Full Text Available Plants are simultaneously exposed to multiple stresses resulting in enormous changes in the molecular landscape within the cell. Identification and characterization of the synergistic and antagonistic components of stress response mechanisms contributing to the cross talk between stresses is of high priority to explore and enhance multiple stress responses. To this end, we performed meta-analysis of drought (abiotic, bacterial (biotic stress response in rice and Arabidopsis by analyzing a total of 386 microarray samples belonging to 20 microarray studies and identified approximately 3100 and 900 DEGs in rice and Arabidopsis, respectively. About 38.5% (1214 and 28.7% (272 DEGs were common to drought and bacterial stresses in rice and Arabidopsis, respectively. A majority of these common DEGs showed conserved expression status in both stresses. Gene ontology enrichment analysis clearly demarcated the response and regulation of various plant hormones and related biological processes. Fatty acid metabolism and biosynthesis of alkaloids were upregulated and, nitrogen metabolism and photosynthesis was downregulated in both stress conditions. WRKY transcription family genes were highly enriched in all upregulated gene sets while 'CO-like' TF family showed inverse relationship of expression between drought and bacterial stresses. Weighted gene co-expression network analysis divided DEG sets into multiple modules that show high co-expression and identified stress specific hub genes with high connectivity. Detection of consensus modules based on DEGs common to drought and bacterial stress revealed 9 and 4 modules in rice and Arabidopsis, respectively, with conserved and reversed co-expression patterns.

  6. The use of the DR CALUX bioassay and indicator polychlorinated biphenyls for screening of elevated levels of dioxins and dioxin-like polychlorinated biphenyls in eel.

    NARCIS (Netherlands)

    Hoogenboom, Ron; Bovee, Toine; Traag, Win A; Hoogerbrugge, Ronald; Baumann, Bert; Portier, Liza; Weg, Guido van de; Vries, Jaap de

    2006-01-01

    The DR CALUX bioassay is a very suitable screening method for dioxins and dioxin-like-PCBs in feed and food. This was, e. g. demonstrated in a survey in the Netherlands to control the dioxin levels in eel. The DR CALUX assay, but also indicator polychlorinated biphenyls (PCB) were evaluated as a

  7. Per a 10 protease activity modulates CD40 expression on dendritic cell surface by nuclear factor-kappaB pathway.

    Science.gov (United States)

    Goel, C; Kalra, N; Dwarakanath, B S; Gaur, S N; Arora, N

    2015-05-01

    Serine protease activity of Per a 10 from Periplaneta americana modulates dendritic cell (DC) functions by a mechanism(s) that remains unclear. In the present study, Per a 10 protease activity on CD40 expression and downstream signalling was evaluated in DCs. Monocyte-derived DCs from cockroach-allergic patients were treated with proteolytically active/heat-inactivated Per a 10. Stimulation with active Per a 10 demonstrated low CD40 expression on DCs surface (P Per a 10, suggesting cleavage of CD40. Per a 10 activity reduced the interleukin (IL)-12 and interferon (IFN)-γ secretion by DCs (P Per a 10, indicating that low CD40 expression is associated with low levels of IL-12 secretion. Active Per a 10 stimulation caused low nuclear factor-kappa B (NF-κB) activation in DCs compared to heat-inactivated Per a 10. Inhibition of the NF-κB pathway suppressed the CD40 expression and IL-12 secretion by DCs, further indicating that NF-κB is required for CD40 up-regulation. CD40 expression activated the tumour necrosis factor (TNF) receptor-associated factor 6 (TRAF6), thereby suggesting its involvement in NF-κB activation. Protease activity of Per a 10 induced p38 mitogen-activated protein kinase (MAPK) activation that showed no significant effect on CD40 expression by DCs. However, inhibiting p38 MAPK or NF-κB suppressed the secretion of IL-12, IFN-γ, IL-6 and TNF-α by DCs. Such DCs further reduced the secretion of IL-4, IL-6, IL-12 and TNF-α by CD4(+) T cells. In conclusion, protease activity of Per a 10 reduces CD40 expression on DCs. CD40 down-regulation leads to low NF-κB levels, thereby modulating DC-mediated immune responses. © 2014 British Society for Immunology.

  8. Vitamin A and feeding statuses modulate the insulin-regulated gene expression in Zucker lean and fatty primary rat hepatocytes.

    Directory of Open Access Journals (Sweden)

    Wei Chen

    Full Text Available Unattended hepatic insulin resistance predisposes individuals to dyslipidemia, type 2 diabetes and many other metabolic complications. The mechanism of hepatic insulin resistance at the gene expression level remains unrevealed. To examine the effects of vitamin A (VA, total energy intake and feeding conditions on the insulin-regulated gene expression in primary hepatocytes of Zucker lean (ZL and fatty (ZF rats, we analyze the expression levels of hepatic model genes in response to the treatments of insulin and retinoic acid (RA. We report that the insulin- and RA-regulated glucokinase, sterol regulatory element-binding protein-1c and cytosolic form of phosphoenolpyruvate carboxykinase expressions are impaired in hepatocytes of ZF rats fed chow or a VA sufficient (VAS diet ad libitum. The impairments are partially corrected when ZF rats are fed a VA deficient (VAD diet ad libitum or pair-fed a VAS diet to the intake of their VAD counterparts in non-fasting conditions. Interestingly in the pair-fed ZL and ZF rats, transient overeating on the last day of pair-feeding regimen changes the expression levels of some VA catabolic genes, and impairs the insulin- and RA-regulated gene expression in hepatocytes. These results demonstrate that VA and feeding statuses modulate the hepatic insulin sensitivity at the gene expression level.

  9. Ethanol extract of Portulaca oleracea L. protects against hypoxia-induced neuro damage through modulating endogenous erythropoietin expression.

    Science.gov (United States)

    Wanyin, Wang; Liwei, Dong; Lin, Jia; Hailiang, Xin; Changquan, Ling; Min, Li

    2012-04-01

    In addition to its role in erythropoiesis, erythropoietin is also appreciated for its neuroprotective effects, and it has been suggested for treatment of some ischemic-hypoxic neurovascular diseases. The protective effects of endogenous erythropoietin in the brain give rise to the hypothesis that modulating erythropoietin expression might be a better way for treatment of ischemia-hypoxia neurovascular diseases. We have found that ethanol extract of Portulaca oleracea L. (EEPO) could increase erythropoietin expression in hypoxic mouse brain in our previous study. The present study is to investigate whether EEPO exerts its neuroprotective effects against hypoxia injury through regulating endogenous erythropoietin expression. The results demonstrated that EEPO decreased the serum neuron specific enolase level in hypoxia mice and the activity of caspase-3 in neuron, increased the neuron viability and attenuated the pathological damages caused by the hypoxia condition. Importantly, we also found that EEPO stimulated the endogenous erythropoietin expression at both mRNA and protein levels. Using the conditioned medium containing soluble erythropoietin receptor, we found that the neuroprotective effects of EEPO were dependent, at least partly, on erythropoietin expression. Although EEPO did not affect transcription of hypoxia inducible factor-1α (HIF-1α), it did stabilize expression of HIF-1α. It is concluded that EEPO has neuroprotective effects against hypoxia injury, which is at least partly through stimulating endogenous erythropoietin expression by stabilizing HIF-1α. Copyright © 2012 Elsevier Inc. All rights reserved.

  10. The endogenous retroviral insertion in the human complement C4 gene modulates the expression of homologous genes by antisense inhibition.

    Science.gov (United States)

    Schneider, P M; Witzel-Schlömp, K; Rittner, C; Zhang, L

    2001-02-01

    Intron 9 contains the complete endogenous retrovirus HERV-K(C4) as a 6.4-kb insertion in 60% of human C4 genes. The retroviral insertion is in reverse orientation to the C4 coding sequence. Therefore, expression of C4 could lead to the transcription of an antisense RNA, which might protect against exogenous retroviral infections. To test this hypothesis, open reading frames from the HERV sequence were subcloned in sense orientiation into a vector allowing expression of a beta-galactosidase fusion protein. Mouse L cells which had been stably transfected with either the human C4A or C4B gene both carrying the HERV insertion (LC4 cells), and L(Tk-) cells without the C4 gene were transiently transfected either with a retroviral construct or with the wild-type vector. Expression was monitored using an enzymatic assay. We demonstrated that (1) HERV-K(C4) antisense mRNA transcripts are present in cells constitutively expressing C4, (2) expression of retroviral-like constructs is significantly downregulated in cells expressing C4, and (3) this downregulation is further modulated in a dose-dependent fashion following interferon-gamma stimulation of C4 expression. These results support the hypothesis of a genomic antisense strategy mediated by the HERV-K(C4) insertion as a possible defense mechanism against exogenous retroviral infections.

  11. Nutrient Induced Type 2 and Chemical Induced Type 1 Experimental Diabetes Differently Modulate Gastric GLP-1 Receptor Expression

    Directory of Open Access Journals (Sweden)

    Olga Bloch

    2015-01-01

    Full Text Available T2DM patients demonstrate reduced GLP-1 receptor (GLP-1R expression in their gastric glands. Whether induced T2DM and T1DM differently affect the gastric GLP-1R expression is not known. This study assessed extrapancreatic GLP-1R system in glandular stomach of rodents with different types of experimental diabetes. T2DM and T1DM were induced in Psammomys obesus (PO by high-energy (HE diet and by streptozotocin (STZ in Sprague Dawly (SD rats, respectively. GLP-1R expression was determined in glandular stomach by RT PCR and immunohistomorphological analysis. The mRNA expression and cellular association of the GLP-1R in principal glands were similar in control PO and SD rats. However, nutrient and chemical induced diabetes resulted in opposite alterations of glandular GLP-1R expression. Diabetic PO demonstrated increased GLP-1R mRNA expression, intensity of cellular GLP-1R immunostaining, and frequency of GLP-1R positive cells in the neck area of principal glands compared with controls. In contrast, SD diabetic rats demonstrated decreased GLP-1 mRNA, cellular GLP-1R immunoreactivity, and frequency of GLP-1R immunoreactive cells in the neck area compared with controls. In conclusion, nutrient and chemical induced experimental diabetes result in distinct opposite alterations of GLP-1R expression in glandular stomach. These results suggest that induced T1DM and T2DM may differently modulate GLP-1R system in enteropancreatic axis.

  12. Step into the groove : engineered transcription factors as modulators of gene expression

    NARCIS (Netherlands)

    Visser, A.E.; Verschure, P.J.; Gommans, W.M.; Haisma, H.J.; Rots, M.G.

    2006-01-01

    Increasing knowledge about the influence of dysregulated gene expression in causing numerous diseases opens up new possibilities for the development of innovative therapeutics. In this chapter, we first describe different mechanisms of misregulated gene expression resulting in various

  13. The look of fear and anger: facial maturity modulates recognition of fearful and angry expressions.

    Science.gov (United States)

    Sacco, Donald F; Hugenberg, Kurt

    2009-02-01

    The current series of studies provide converging evidence that facial expressions of fear and anger may have co-evolved to mimic mature and babyish faces in order to enhance their communicative signal. In Studies 1 and 2, fearful and angry facial expressions were manipulated to have enhanced babyish features (larger eyes) or enhanced mature features (smaller eyes) and in the context of a speeded categorization task in Study 1 and a visual noise paradigm in Study 2, results indicated that larger eyes facilitated the recognition of fearful facial expressions, while smaller eyes facilitated the recognition of angry facial expressions. Study 3 manipulated facial roundness, a stable structure that does not vary systematically with expressions, and found that congruency between maturity and expression (narrow face-anger; round face-fear) facilitated expression recognition accuracy. Results are discussed as representing a broad co-evolutionary relationship between facial maturity and fearful and angry facial expressions. (c) 2009 APA, all rights reserved

  14. Galanin-Expressing GABA Neurons in the Lateral Hypothalamus Modulate Food Reward and Noncompulsive Locomotion

    OpenAIRE

    Qualls-Creekmore, Emily; Yu, Sangho; Francois, Marie; Hoang, John; Huesing, Clara; Bruce-Keller, Annadora; Burk, David; Berthoud, Hans-Rudolf; Morrison, Christopher D.; Münzberg, Heike

    2017-01-01

    The lateral hypothalamus (LHA) integrates reward and appetitive behavior and is composed of many overlapping neuronal populations. Recent studies associated LHA GABAergic neurons (LHAGABA), which densely innervate the ventral tegmental area (VTA), with modulation of food reward and consumption; yet, LHAGABA projections to the VTA exclusively modulated food consumption, not reward. We identified a subpopulation of LHAGABA neurons that coexpress the neuropeptide galanin (LHAGal). These LHAGal n...

  15. Small-molecule screen identifies modulators of EWS/FLI1 target gene expression and cell survival in Ewing's sarcoma.

    Science.gov (United States)

    Boro, Aleksandar; Prêtre, Kathya; Rechfeld, Florian; Thalhammer, Verena; Oesch, Susanne; Wachtel, Marco; Schäfer, Beat W; Niggli, Felix K

    2012-11-01

    Ewing's sarcoma family of tumors (EFT) is characterized by the presence of chromosomal translocations leading to the expression of oncogenic transcription factors such as, in the majority of cases, EWS/FLI1. Because of its key role in Ewing's sarcoma development and maintenance, EWS/FLI1 represents an attractive therapeutic target. Here, we characterize PHLDA1 as a novel direct target gene whose expression is repressed by EWS/FLI1. Using this gene and additional specific well-characterized target genes such as NROB1, NKX2.2 and CAV1, all activated by EWS/FLI1, as a read-out system, we screened a small-molecule compound library enriched for FDA-approved drugs that modulated the expression of EWS/FLI1 target genes. Among a hit-list of nine well-known drugs such as camptothecin, fenretinide, etoposide and doxorubicin, we also identified the kinase inhibitor midostaurin (PKC412). Subsequent experiments demonstrated that midostaurin is able to induce apoptosis in a panel of six Ewing's sarcoma cell lines in vitro and can significantly suppress xenograft tumor growth in vivo. These results suggest that midostaurin might be a novel drug that is active against Ewing's cells, which might act by modulating the expression of EWS/FLI1 target genes. Copyright © 2012 UICC.

  16. Dioxins and environment Dioxinas y medio ambiente

    Directory of Open Access Journals (Sweden)

    Jimena García Lobo

    2011-12-01

    Full Text Available With the generic term of dioxin is named the groups of the polychlorinated dibenzo-p-dioxins (PCDD and the polychlorinated dibenzofuran (PCDF, typical representans of the persistent organic compounds (POPs. They are obtained as not desired secondary products from several industrial process in which chlorine is used in some of its phases. The dioxins have centrated in the last decade an important part if the medical investigations in environmental health do to its notable toxicity, since they are one of the more powerful toxic chemical substances created by mankind, characterized for affecting the nervous and inmunitary system, being implicated into appearance of difference types of cancer and causing the appearance of several endocrine disorders, because of what they have been nowadays classified as endocrine disruptors. On degradation, bioaccumulation and on a large scale atmospheric transport capacity between the several environmental phases, make them to be considerate nowadays as dangerous compounds for human beings.Con el término genérico dioxinas se designa al grupo de las dibenzo-p-dioxinas policloradas (PCDD y de los dibenzofuranos policlorados (PCDF, representantes típicos de los compuestos orgánicos persistentes (COPs. Se obtienen como productos secundarios no deseados de diversos procesos industriales en los que se emplea cloro en alguna de sus etapas. Las dioxinas han centrado en la última década una parte importante de la investigación médica en salud ambiental debido a su notable toxicidad, ya que son las sustancias químicas peligrosas más potentes creadas por el hombre, afectando al sistema nervioso e inmunitario, estando implicadas en la aparición de distintos tipos de cáncer y provocando la aparición de alteraciones hormonales, clasificándose actualmente como disruptores endocrinos. Por otra parte, su persistencia en el medio ambiente, resistencia a la degradación, bioacumulación y capacidad de transporte atmosf

  17. MicroRNAs expression in ox-LDL treated HUVECs: MiR-365 modulates apoptosis and Bcl-2 expression

    Energy Technology Data Exchange (ETDEWEB)

    Qin, Bing; Xiao, Bo [Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008 (China); Liang, Desheng [State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078 (China); Xia, Jian; Li, Ye [Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008 (China); Yang, Huan, E-mail: yangh69@yahoo.cn [Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008 (China)

    2011-06-24

    Highlights: {yields} We evaluated the role of miRNAs in ox-LDL induced apoptosis in ECs. {yields} We found 4 up-regulated and 11 down-regulated miRNAs in apoptotic ECs. {yields} Target genes of the dysregulated miRNAs regulate ECs apoptosis and atherosclerosis. {yields} MiR-365 promotes ECs apoptosis via suppressing Bcl-2 expression. {yields} MiR-365 inhibitor alleviates ECs apoptosis induced by ox-LDL. -- Abstract: Endothelial cells (ECs) apoptosis induced by oxidized low-density lipoprotein (ox-LDL) is thought to play a critical role in atherosclerosis. MicroRNAs (miRNAs) are a class of noncoding RNAs that posttranscriptionally regulate the expression of genes involved in diverse cell functions, including differentiation, growth, proliferation, and apoptosis. However, whether miRNAs are associated with ox-LDL induced apoptosis and their effect on ECs is still unknown. Therefore, this study evaluated potential miRNAs and their involvement in ECs apoptosis in response to ox-LDL stimulation. Microarray and qRT-PCR analysis performed on human umbilical vein endothelial cells (HUVECs) exposed to ox-LDL identified 15 differentially expressed (4 up- and 11 down-regulated) miRNAs. Web-based query tools were utilized to predict the target genes of the differentially expressed miRNAs, and the potential target genes were classified into different function categories with the gene ontology (GO) term and KEGG pathway annotation. In particular, bioinformatics analysis suggested that anti-apoptotic protein B-cell CLL/lymphoma 2 (Bcl-2) is a target gene of miR-365, an apoptomir up-regulated by ox-LDL stimulation in HUVECs. We further showed that transfection of miR-365 inhibitor partly restored Bcl-2 expression at both mRNA and protein levels, leading to a reduction of ox-LDL-mediated apoptosis in HUVECs. Taken together, our findings indicate that miRNAs participate in ox-LDL-mediated apoptosis in HUVECs. MiR-365 potentiates ox-LDL-induced ECs apoptosis by regulating the

  18. Transcriptomics identifies differences between ultrapure non-dioxin-like polychlorinated biphenyls (PCBs) and dioxin-like PCB126 in cultured peripheral blood mononuclear cells

    International Nuclear Information System (INIS)

    Wens, B.; De Boever, P.; Maes, M.; Hollanders, K.; Schoeters, G.

    2011-01-01

    Polychlorinated biphenyls (PCBs) remain ubiquitously present in human lipids despite the ban on their production and use. Their presence can be chemically monitored in peripheral blood samples of the general population. We tested whether in vitro exposure to different PCB congeners induced different gene expression profiles in peripheral blood cells. We have isolated peripheral blood mononuclear cells (PBMC) from whole blood of 8 healthy individuals and exposed these cells in vitro to individual non-dioxin-like (NDL)-PCB congeners (PCB52, 138 or 180; 10 μM) or dioxin-like (DL)-PCB congener PCB126 (1 μM) during 18 h. Differential gene expression response was measured using Agilent whole-human genome microarrays. Two-way ANOVA analysis of the data showed that both gender and PCB exposure are important factors influencing gene expression responses in blood cells. Hierarchical cluster analysis of genes influenced by PCB exposure, revealed that DL-PCB126 induced a different gene expression response compared to the NDL-PCBs. Biological interpretation of the results revealed that exposure to PCB126 induced the AhR signaling pathway, whereas the induction of nuclear receptor pathways by the NDL-PCBs was limited in blood cells. Nevertheless, molecular responses of blood cells to individual PCB congeners revealed significantly expressed genes that play a role in biological functions and processes known to be affected by PCB exposure in vivo. Observed gene expression changes in this in vitro model were found to be related to hepatotoxicity, immune and inflammatory response and disturbance of lipid and cholesterol homeostasis.

  19. Dihydroxylation of 4-substituted 1,2-dioxines

    DEFF Research Database (Denmark)

    Robinson, Tony V; Pedersen, Daniel Sejer; Taylor, Dennis K

    2009-01-01

    The synthesis of 2-C-branched erythritol derivatives, including the plant sugar (+/-)-2-C-methylerythritol 2, was achieved through a dihydroxylation/reduction sequence on a series of 4-substituted 1,2-dioxines 3. The asymmetric dihydroxylation of 1,2-dioxines was examined, providing access...... to optically enriched dihydroxy 1,2-dioxanes 4. The synthesized 1,2-dioxanes were converted to other erythro sugar analogues and tetrahydrofurans through controlled cleavage of the endoperoxide linkage....

  20. Modulation of expression of Programmed Death-1 by administration of probiotic Dahi in DMH-induced colorectal carcinogenesis in rats.

    Science.gov (United States)

    Mohania, Dheeraj; Kansal, Vinod K; Kumar, Manoj; Nagpal, Ravinder; Yamashiro, Yuichiro; Marotta, Francesco

    2013-09-01

    Interaction of probiotic bacteria with the host immune system elicits beneficial immune modulating effects. Although, there are many published studies on interaction of probiotics with immune system focusing on activation of immune system by bacterial cell wall through the engagement of Toll-like receptor family; very few studies have focused on molecules involved in the T-cell activation, and not much work has been executed to study the correlation of probiotics and programmed death-1 in colorectal carcinogenesis in animal models. Hence, the present study was carried out to assess the effect of probiotic Dahi on expression of programmed death (PD-1) in colorectum of 1, 2-dimethylhydrazine treated Wistar rats. DMH was injected subcutaneously at the rate of 40 mg/kg body weight per animal twice a week for 2 weeks. A total of 168 male Wistar rats were randomly allocated to seven groups, each group having twenty-four animals. The rats were euthanized at the 8th, 16th and 32nd week of the experiment and examined for the expression of PD-1 in colorectal tissues by immunohistochemical staining. Expression of PD-1 was observed in colorectal tissues of normal and DMH-treated rats. Feeding rats with probiotic Dahi or the treatment with piroxicam decreased the expression of PD-1 in DMH-induced colorectal mucosa, and the combined treatment with probiotic Dahi and piroxicam was significantly more effective in reducing the expression of PD-1. PD-1 expressed independent of carcinogen administration in normal colonic mucosa and may play a role in modulation of immune response in DMH-induced colorectal carcinogenesis. The present study suggests that probiotic Dahi can be used as an effective chemopreventive agent in the management of colorectal cancer.

  1. Loss of Pnn expression attenuates expression levels of SR family splicing factors and modulates alternative pre-mRNA splicing in vivo

    International Nuclear Information System (INIS)

    Chiu Yali; Ouyang Pin

    2006-01-01

    SR and SR-related proteins have been implicated as trans-acting factors that play an important role in splice selection and are involved at specific stages of spliceosome formation. A well-established property of SR protein splicing factors is their ability to influence selection of alternative splice sites in a concentration-dependent manner. Identification of molecules that regulate SR family protein expression is therefore of vital importance in RNA biology. Here we report that depletion of Pnn expression, a SR-related protein with functions involved in pre-mRNA splicing and mRNA export, induces reduced expression of a subset of cellular proteins, especially that of SR family proteins, including SC35, SRm300, SRp55, and SRp40, but not that of other nuclear proteins, such as p53, Mdm2, and ki67. Knocking down Pnn expression was achieved in vitro by siRNA transfection. Expression levels of SR and SR-related proteins in Pnn-depleted cells as compared to those in control cells were evaluated by immunofluorescent staining and Western blot with specific antibodies. In addition, we also demonstrate that loss of Pnn expression could modulate splice site selection of model reporter gene in vivo. Our finding is significant in terms of regulation of SR protein cellular concentration because it reveals that Pnn may play a general role in the control of the cellular amount of family SR proteins through down-regulation of its own expression, thereby providing us with a better understanding of the cellular mechanism by which Pnn fulfills its biological function

  2. Modulation of gene expression by nutritional state and hormones in Bombyx larvae in relation to its growth period.

    Science.gov (United States)

    Thounaojam, Bembem; Keshan, Bela

    2017-11-01

    Insect growth and development are mainly regulated via synchronization of many extrinsic and intrinsic factors such as nutrition and hormones. Previously we have demonstrated that larval growth period influences the effect of insulin on the accumulation of glycogen in the fat body of Bombyx larvae. In the present study we demonstrate that Bombyx larvae at the terminal growth period (TGP, after critical weight) had a significantly greater increase in the expression level of Akt in the fat body than at the active growth period (AGP, before critical weight). The larvae at TGP also showed an increase in the expression level of ecdysone receptors (EcRB1 and USP1) and ecdysone-induced early genes (E75A and broad). The treatment of bovine insulin and methoprene to larvae at AGP induced the transcript levels of Akt, irrespective of the nutritional status of the larvae. However, in larvae at TGP, insulin repressed the transcript level of Akt. On contrary, 20-hydroxyecdysone (20E) induced the expression level of Akt in TGP larvae, but at feeding only. Insulin and 20E thus showed an antagonistic action on the Akt expression level in TGP larvae under feeding. The studies thus showed that larval growth period influences the expression level of Akt and ecdysone receptors in Bombyx. Further, the growth period and nutrition modulate the effect of exogenous hormones on Akt expression. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. COUP-TFI mitotically regulates production and migration of dentate granule cells and modulates hippocampal Cxcr4 expression.

    Science.gov (United States)

    Parisot, Joséphine; Flore, Gemma; Bertacchi, Michele; Studer, Michèle

    2017-06-01

    Development of the dentate gyrus (DG), the primary gateway for hippocampal inputs, spans embryonic and postnatal stages, and involves complex morphogenetic events. We have previously identified the nuclear receptor COUP-TFI as a novel transcriptional regulator in the postnatal organization and function of the hippocampus. Here, we dissect its role in DG morphogenesis by inactivating it in either granule cell progenitors or granule neurons. Loss of COUP-TFI function in progenitors leads to decreased granule cell proliferative activity, precocious differentiation and increased apoptosis, resulting in a severe DG growth defect in adult mice. COUP-TFI-deficient cells express high levels of the chemokine receptor Cxcr4 and migrate abnormally, forming heterotopic clusters of differentiated granule cells along their paths. Conversely, high COUP-TFI expression levels downregulate Cxcr4 expression, whereas increased Cxcr4 expression in wild-type hippocampal cells affects cell migration. Finally, loss of COUP-TFI in postmitotic cells leads to only minor and transient abnormalities, and to normal Cxcr4 expression. Together, our results indicate that COUP-TFI is required predominantly in DG progenitors for modulating expression of the Cxcr4 receptor during granule cell neurogenesis and migration. © 2017. Published by The Company of Biologists Ltd.

  4. N-MYC down-regulated-like proteins regulate meristem initiation by modulating auxin transport and MAX2 expression.

    Science.gov (United States)

    Mudgil, Yashwanti; Ghawana, Sanjay; Jones, Alan M

    2013-01-01

    N-MYC down-regulated-like (NDL) proteins interact with the Gβ subunit (AGB1) of the heterotrimeric G protein complex and play an important role in AGB1-dependent regulation of lateral root formation by affecting root auxin transport, auxin gradients and the steady-state levels of mRNA encoding the PIN-FORMED 2 and AUXIN 1 auxin transport facilitators. Auxin transport in aerial tissue follows different paths and utilizes different transporters than in roots; therefore, in the present study, we analyzed whether NDL proteins play an important role in AGB1-dependent, auxin-mediated meristem development. Expression levels of NDL gene family members need to be tightly regulated, and altered expression (both over-expression and down-regulation) confers ectopic growth. Over-expression of NDL1 disrupts vegetative and reproductive organ development. Reduced expression of the NDL gene family members results in asymmetric leaf emergence, twinning of rosette leaves, defects in leaf formation, and abnormal silique distribution. Reduced expression of the NDL genes in the agb1-2 (null allele) mutant rescues some of the abnormal phenotypes, such as silique morphology, silique distribution, and peduncle angle, suggesting that proper levels of NDL proteins are maintained by AGB1. We found that all of these abnormal aerial phenotypes due to altered NDL expression were associated with increases in basipetal auxin transport, altered auxin maxima and altered MAX2 expression within the inflorescence stem. NDL proteins, together with AGB1, act as positive regulators of meristem initiation and branching. AGB1 and NDL1 positively regulate basipetal inflorescence auxin transport and modulate MAX2 expression in shoots, which in turn regulates organ and lateral meristem formation by the establishment and maintenance of auxin gradients.

  5. N-MYC down-regulated-like proteins regulate meristem initiation by modulating auxin transport and MAX2 expression.

    Directory of Open Access Journals (Sweden)

    Yashwanti Mudgil

    Full Text Available N-MYC down-regulated-like (NDL proteins interact with the Gβ subunit (AGB1 of the heterotrimeric G protein complex and play an important role in AGB1-dependent regulation of lateral root formation by affecting root auxin transport, auxin gradients and the steady-state levels of mRNA encoding the PIN-FORMED 2 and AUXIN 1 auxin transport facilitators. Auxin transport in aerial tissue follows different paths and utilizes different transporters than in roots; therefore, in the present study, we analyzed whether NDL proteins play an important role in AGB1-dependent, auxin-mediated meristem development.Expression levels of NDL gene family members need to be tightly regulated, and altered expression (both over-expression and down-regulation confers ectopic growth. Over-expression of NDL1 disrupts vegetative and reproductive organ development. Reduced expression of the NDL gene family members results in asymmetric leaf emergence, twinning of rosette leaves, defects in leaf formation, and abnormal silique distribution. Reduced expression of the NDL genes in the agb1-2 (null allele mutant rescues some of the abnormal phenotypes, such as silique morphology, silique distribution, and peduncle angle, suggesting that proper levels of NDL proteins are maintained by AGB1. We found that all of these abnormal aerial phenotypes due to altered NDL expression were associated with increases in basipetal auxin transport, altered auxin maxima and altered MAX2 expression within the inflorescence stem.NDL proteins, together with AGB1, act as positive regulators of meristem initiation and branching. AGB1 and NDL1 positively regulate basipetal inflorescence auxin transport and modulate MAX2 expression in shoots, which in turn regulates organ and lateral meristem formation by the establishment and maintenance of auxin gradients.

  6. Multivariate Analysis and Prediction of Dioxin-Furan ...

    Science.gov (United States)

    Peer Review Draft of Regional Methods Initiative Final Report Dioxins, which are bioaccumulative and environmentally persistent, pose an ongoing risk to human and ecosystem health. Fish constitute a significant source of dioxin exposure for humans and fish-eating wildlife. Current dioxin analytical methods are costly, time-consuming, and produce hazardous by-products. A Danish team developed a novel, multivariate statistical methodology based on the covariance of dioxin-furan congener Toxic Equivalences (TEQs) and fatty acid methyl esters (FAMEs) and applied it to North Atlantic Ocean fishmeal samples. The goal of the current study was to attempt to extend this Danish methodology to 77 whole and composite fish samples from three trophic groups: predator (whole largemouth bass), benthic (whole flathead and channel catfish) and forage fish (composite bluegill, pumpkinseed and green sunfish) from two dioxin contaminated rivers (Pocatalico R. and Kanawha R.) in West Virginia, USA. Multivariate statistical analyses, including, Principal Components Analysis (PCA), Hierarchical Clustering, and Partial Least Squares Regression (PLS), were used to assess the relationship between the FAMEs and TEQs in these dioxin contaminated freshwater fish from the Kanawha and Pocatalico Rivers. These three multivariate statistical methods all confirm that the pattern of Fatty Acid Methyl Esters (FAMEs) in these freshwater fish covaries with and is predictive of the WHO TE

  7. Documents for Recommended Toxicity Equivalency Factors for Human Health Risk Assessments of Dioxin and Dioxin-Like Compounds

    Science.gov (United States)

    This document describes the U.S. Environmental Protection Agency’s (U.S. EPA’s) updated approach for evaluating the human health risks from exposures to environmental media containing dioxin-like compounds (DLCs).

  8. Modulating ectopic gene expression levels by using retroviral vectors equipped with synthetic promoters

    OpenAIRE

    Ferreira, Joshua P.; Peacock, Ryan W. S.; Lawhorn, Ingrid E. B.; Wang, Clifford L.

    2011-01-01

    The human cytomegalovirus and elongation factor 1α promoters are constitutive promoters commonly employed by mammalian expression vectors. These promoters generally produce high levels of expression in many types of cells and tissues. To generate a library of synthetic promoters capable of generating a range of low, intermediate, and high expression levels, the TATA and CAAT box elements of these promoters were mutated. Other promoter variants were also generated by random mutagenesis. Evalua...

  9. Ionic modulation of QPX stability as a nano-switch regulating gene expression in neurons

    Science.gov (United States)

    Baghaee Ravari, Soodeh

    G-quadruplexes (G-QPX) have been the subject of intense research due to their unique structural configuration and potential applications, particularly their functionality in biological process as a novel type of nano--switch. They have been found in critical regions of the human genome such as telomeres, promoter regions, and untranslated regions of RNA. About 50% of human DNA in promoters has G-rich regions with the potential to form G-QPX structures. A G-QPX might act mechanistically as an ON/OFF switch, regulating gene expression, meaning that the formation of G-QPX in a single strand of DNA disrupts double stranded DNA, prevents the binding of transcription factors (TF) to their recognition sites, resulting in gene down-regulation. Although there are numerous studies on biological roles of G-QPXs in oncogenes, their potential formation in neuronal cells, in particular upstream of transcription start sites, is poorly investigated. The main focus of this research is to identify stable G-QPXs in the 97bp active promoter region of the choline acetyltransferase (ChAT) gene, the terminal enzyme involved in synthesis of the neurotransmitter acetylcholine, and to clarify ionic modulation of G-QPX nanostructures through the mechanism of neural action potentials. Different bioinformatics analyses (in silico), including the QGRS, quadparser and G4-Calculator programs, have been used to predict stable G-QPX in the active promoter region of the human ChAT gene, located 1000bp upstream from the TATA box. The results of computational studies (using those three different algorithms) led to the identification of three consecutive intramolecular G-QPX structures in the negative strand (ChAT G17-2, ChAT G17, and ChAT G29) and one intramolecular G-QPX structure in the positive strand (ChAT G30). Also, the results suggest the possibility that nearby G-runs in opposed DNA strands with a short distance of each other may be able to form a stable intermolecular G-QPX involving two DNA

  10. Health risk assessment of exposure to dioxin-like PCBs and dioxins in the City of Menen (Belgium)

    Energy Technology Data Exchange (ETDEWEB)

    Nouwen, J.; Provoost, J.; Cornelis, C.; Bronders, J.; Fre, R. de; Clauvenbergern, R. van [Flemish Insitute for Technological Research (Vito) (Belgium)

    2004-09-15

    The City of Menen is a well-outlined residential area located in the neighbourhood of two waste incinerators. The waste incinerators (Menen (Belgium) and Roncq (France)) are in full operation since the eighties. Emission measurements indicate that they fulfil the European Union dioxin emission standard of 0.1 ng TEQ/m{sup 3}. Despite this, new deposition measurements and analysis of milk in this region indicate a high burden of the local environment with dioxin-like polychlorinated biphenyls (dioxin-like PCBs) and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs). It should be noted that formerly the City of Menen was also surrounded by other potential dioxin sources, among them a dye factory, some small illegal cable burning houses, a pressed board manufacturer, and a metal recycling plant. Before 1984, fly ashes of the waste incinerator were locally used as road materials and transported. This could be a secondary source. Additionally the Environmental Inspection has regularly noticed some large open waste fires in this region and follows up the situation. On request of the Public Waste Agency of Flanders (OVAM) an inventory of all dioxin measurements within the city area was made. The ratio of the dioxin-like PCBs compared to the PCDD/Fs in these measurement results was unexpectedly high. As a consequence of this and in order to achieve an optimal risk assessment for the people living in the City of Menen an additional sampling of soil, vegetables and eggs was carried out. This article focuses on the relative amounts of dioxin-like PCBs and PCDD/Fs in the different media and the consequences for the outcome of the risk assessment.

  11. Modulating ectopic gene expression levels by using retroviral vectors equipped with synthetic promoters.

    Science.gov (United States)

    Ferreira, Joshua P; Peacock, Ryan W S; Lawhorn, Ingrid E B; Wang, Clifford L

    2011-12-01

    The human cytomegalovirus and elongation factor 1α promoters are constitutive promoters commonly employed by mammalian expression vectors. These promoters generally produce high levels of expression in many types of cells and tissues. To generate a library of synthetic promoters capable of generating a range of low, intermediate, and high expression levels, the TATA and CAAT box elements of these promoters were mutated. Other promoter variants were also generated by random mutagenesis. Evaluation using plasmid vectors integrated at a single site in the genome revealed that these various synthetic promoters were capable of expression levels spanning a 40-fold range. Retroviral vectors were equipped with the synthetic promoters and evaluated for their ability to reproduce the graded expression demonstrated by plasmid integration. A vector with a self-inactivating long terminal repeat could neither reproduce the full range of expression levels nor produce stable expression. Using a second vector design, the different synthetic promoters enabled stable expression over a broad range of expression levels in different cell lines. The online version of this article (doi:10.1007/s11693-011-9089-0) contains supplementary material, which is available to authorized users.

  12. Dioxin induces genomic instability in mouse embryonic fibroblasts.

    Directory of Open Access Journals (Sweden)

    Merja Korkalainen

    Full Text Available Ionizing radiation and certain other exposures have been shown to induce genomic instability (GI, i.e., delayed genetic damage observed many cell generations later in the progeny of the exposed cells. The aim of this study was to investigate induction of GI by a nongenotoxic carcinogen, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD. Mouse embryonic fibroblasts (C3H10T1/2 were exposed to 1, 10 or 100 nM TCDD for 2 days. Micronuclei (MN and expression of selected cancer-related genes were assayed both immediately and at a delayed point in time (8 days. For comparison, similar experiments were done with cadmium, a known genotoxic agent. TCDD treatment induced an elevated frequency of MN at 8 days, but not directly after the exposure. TCDD-induced alterations in gene expression were also mostly delayed, with more changes observed at 8 days than at 2 days. Exposure to cadmium produced an opposite pattern of responses, with pronounced effects immediately after exposure but no increase in MN and few gene expression changes at 8 days. Although all responses to TCDD alone were delayed, menadione-induced DNA damage (measured by the Comet assay, was found to be increased directly after a 2-day TCDD exposure, indicating that the stability of the genome was compromised already at this time point. The results suggested a flat dose-response relationship consistent with dose-response data reported for radiation-induced GI. These findings indicate that TCDD, although not directly genotoxic, induces GI, which is associated with impaired DNA damage response.

  13. Conjugated Linoleic Acid Supplementation under a High-Fat Diet Modulates Stomach Protein Expression and Intestinal Microbiota in Adult Mice.

    Directory of Open Access Journals (Sweden)

    Alice Chaplin

    Full Text Available The gastrointestinal tract constitutes a physiological interface integrating nutrient and microbiota-host metabolism. Conjugated linoleic acids (CLA have been reported to contribute to decreased body weight and fat accretion. The modulation by dietary CLA of stomach proteins related to energy homeostasis or microbiota may be involved, although this has not been previously analysed. This is examined in the present study, which aims to underline the potential mechanisms of CLA which contribute to body weight regulation. Adult mice were fed either a normal fat (NF, 12% kJ content as fat or a high-fat (HF, 43% kJ content as fat diet. In the latter case, half of the animals received daily oral supplementation of CLA. Expression and content of stomach proteins and specific bacterial populations from caecum were analysed. CLA supplementation was associated with an increase in stomach protein expression, and exerted a prebiotic action on both Bacteroidetes/Prevotella and Akkermansia muciniphila. However, CLA supplementation was not able to override the negative effects of HF diet on Bifidobacterium spp., which was decreased in both HF and HF+CLA groups. Our data show that CLA are able to modulate stomach protein expression and exert a prebiotic effect on specific gut bacterial species.

  14. Conjugated Linoleic Acid Supplementation under a High-Fat Diet Modulates Stomach Protein Expression and Intestinal Microbiota in Adult Mice.

    Science.gov (United States)

    Chaplin, Alice; Parra, Pilar; Serra, Francisca; Palou, Andreu

    2015-01-01

    The gastrointestinal tract constitutes a physiological interface integrating nutrient and microbiota-host metabolism. Conjugated linoleic acids (CLA) have been reported to contribute to decreased body weight and fat accretion. The modulation by dietary CLA of stomach proteins related to energy homeostasis or microbiota may be involved, although this has not been previously analysed. This is examined in the present study, which aims to underline the potential mechanisms of CLA which contribute to body weight regulation. Adult mice were fed either a normal fat (NF, 12% kJ content as fat) or a high-fat (HF, 43% kJ content as fat) diet. In the latter case, half of the animals received daily oral supplementation of CLA. Expression and content of stomach proteins and specific bacterial populations from caecum were analysed. CLA supplementation was associated with an increase in stomach protein expression, and exerted a prebiotic action on both Bacteroidetes/Prevotella and Akkermansia muciniphila. However, CLA supplementation was not able to override the negative effects of HF diet on Bifidobacterium spp., which was decreased in both HF and HF+CLA groups. Our data show that CLA are able to modulate stomach protein expression and exert a prebiotic effect on specific gut bacterial species.

  15. Spermine modulates the expression of two probable polyamine transporter genes and determines growth responses to cadaverine in Arabidopsis.

    Science.gov (United States)

    Sagor, G H M; Berberich, Thomas; Kojima, Seiji; Niitsu, Masaru; Kusano, Tomonobu

    2016-06-01

    Two genes, LAT1 and OCT1 , are likely to be involved in polyamine transport in Arabidopsis. Endogenous spermine levels modulate their expression and determine the sensitivity to cadaverine. Arabidopsis spermine (Spm) synthase (SPMS) gene-deficient mutant was previously shown to be rather resistant to the diamine cadaverine (Cad). Furthermore, a mutant deficient in polyamine oxidase 4 gene, accumulating about twofold more of Spm than wild type plants, showed increased sensitivity to Cad. It suggests that endogenous Spm content determines growth responses to Cad in Arabidopsis thaliana. Here, we showed that Arabidopsis seedlings pretreated with Spm absorbs more Cad and has shorter root growth, and that the transgenic Arabidopsis plants overexpressing the SPMS gene are hypersensitive to Cad, further supporting the above idea. The transgenic Arabidopsis overexpressing L-Amino acid Transporter 1 (LAT1) absorbed more Cad and showed increased Cad sensitivity, suggesting that LAT1 functions as a Cad importer. Recently, other research group reported that Organic Cation Transporter 1 (OCT1) is a causal gene which determines the Cad sensitivity of various Arabidopsis accessions. Furthermore, their results suggested that OCT1 is involved in Cad efflux. Thus we monitored the expression of OCT1 and LAT1 during the above experiments. Based on the results, we proposed a model in which the level of Spm content modulates the expression of OCT1 and LAT1, and determines Cad sensitivity of Arabidopsis.

  16. The prelimbic cortex uses higher-order cues to modulate both the acquisition and expression of conditioned fear.

    Directory of Open Access Journals (Sweden)

    Melissa Judith Sharpe

    2015-01-01

    Full Text Available The prelimbic (PL cortex allows rodents to adapt their responding under changing experimental circumstances. In line with this, the PL cortex has been implicated in strategy set shifting, attentional set shifting, the resolution of response conflict, and the modulation of attention towards predictive stimuli. One interpretation of this research is that the PL cortex is involved in using information garnered from higher-order cues in the environment to modulate how an animal responds to environmental stimuli. However, data supporting this view of PL function in the aversive domain are lacking. In the following experiments, we attempted to answer two questions. Firstly, we wanted to investigate whether the role of the PL cortex in using higher-order cues to influence responding generalizes across appetitive and aversive domains. Secondly, as much of the research has focused on a role for the PL cortex in performance, we wanted to assess whether this region is also involved in the acquisition of hierarchal associations which facilitate an ability to use higher-order cues to modulate responding. In order to answer these questions, we assessed the impact of PL inactivation during both the acquisition and expression of a contextual bi-conditional discrimination. A contextual bi-conditional discrimination involves presenting two stimuli. In one context, one stimulus is paired with shock while the other is presented without shock. In another context, these contingencies are reversed. Thus, animals have to use the present contextual cues to disambiguate the significance of the stimulus and respond appropriately. We found that PL inactivation disrupted both the encoding and expression of these context-dependent associations. This supports a role for the PL cortex in allowing higher-order cues to modulate both learning about, and responding towards, different cues. We discuss these findings in the broader context of functioning in the medial prefrontal

  17. ABA Represses the Expression of Cell Cycle Genes and May Modulate the Development of Endodormancy in Grapevine Buds

    Directory of Open Access Journals (Sweden)

    Ricardo Vergara

    2017-05-01

    Full Text Available Recently, the plant hormone abscisic acid (ABA has been implicated as a key player in the regulation of endodormancy (ED in grapevine buds (Vitis vinifera L. In this study, we show that in the vine, the expression of genes related to the biosynthesis of ABA (VvNCED1; VvNCED2 and the content of ABA are significantly higher in the latent bud than at the shoot apex, while the expression of an ABA catabolic gene (VvA8H3 showed no significant difference between either organ. A negative correlation between the content of ABA and transcript levels of cell cycle genes (CCG was found in both tissues. This result suggested that ABA may negatively regulate the expression of CCG in meristematic tissues of grapevines. To test this proposition, the effect of ABA on the expression of CCG was analyzed in two meristematic tissues of the vine: somatic embryos and shoot apexes. The results indicated that cell cycle progression is repressed by ABA in both organs, since it down-regulated the expression of genes encoding cyclin-dependent kinases (VvCDKB1, VvCDKB2 and genes encoding cyclins of type A (VvCYCA1, VvCYCA2, VvCYCA3, B (VvCYCB, and D (VvCYCD3.2a and up-regulated the expression of VvICK5, a gene encoding an inhibitor of CDKs. During ED, the content of ABA increased, and the expression of CCG decreased. Moreover, the dormancy-breaking compound hydrogen cyanamide (HC reduced the content of ABA and up-regulated the expression of CCG, this last effect was abolished when HC and ABA were co-applied. Taken together, these results suggest that ABA-mediated repression of CCG transcription may be part of the mechanism through which ABA modulates the development of ED in grapevine buds.

  18. P53 family members modulate the expression of PRODH, but not PRODH2, via intronic p53 response elements.

    Directory of Open Access Journals (Sweden)

    Ivan Raimondi

    Full Text Available The tumor suppressor p53 was previously shown to markedly up-regulate the expression of the PRODH gene, encoding the proline dehydrogenase (PRODH enzyme, which catalyzes the first step in proline degradation. Also PRODH2, which degrades 4-hydroxy-L-proline, a product of protein (e.g. collagen catabolism, was recently described as a p53 target. Here, we confirmed p53-dependent induction of endogenous PRODH in response to genotoxic damage in cell lines of different histological origin. We established that over-expression of TAp73β or TAp63β is sufficient to induce PRODH expression in p53-null cells and that PRODH expression parallels the modulation of endogenous p73 by genotoxic drugs in several cell lines. The p53, p63, and p73-dependent transcriptional activation was linked to specific intronic response elements (REs, among those predicted by bioinformatics tools and experimentally validated by a yeast-based transactivation assay. p53 occupancy measurements were validated in HCT116 and MCF7 human cell lines. Conversely, PRODH2 was not responsive to p63 nor p73 and, at best, could be considered a weak p53 target. In fact, minimal levels of PRODH2 transcript induction by genotoxic stress was observed exclusively in one of four p53 wild-type cell lines tested. Consistently, all predicted p53 REs in PRODH2 were poor matches to the p53 RE consensus and showed very weak responsiveness, only to p53, in the functional assay. Taken together, our results highlight that PRODH, but not PRODH2, expression is under the control of p53 family members, specifically p53 and p73. This supports a deeper link between proteins of the p53-family and metabolic pathways, as PRODH modulates the balance of proline and glutamate levels and those of their derivative alpha-keto-glutarate (α-KG under normal and pathological (tumor conditions.

  19. Impact of perinatal dioxin exposure on infant growth: a cross-sectional and longitudinal studies in dioxin-contaminated areas in Vietnam.

    Science.gov (United States)

    Nishijo, Muneko; Tai, Pham The; Nakagawa, Hideaki; Maruzeni, Shoko; Anh, Nguyen Thi Nguyet; Luong, Hoang Van; Anh, Tran Hai; Honda, Ryumon; Morikawa, Yuko; Kido, Teruhiko; Nishijo, Hisao

    2012-01-01

    Dioxin exposure levels remain elevated in residents living around former US Air Force bases in Vietnam, indicating potential adverse impacts on infant growth. In this study, 210 mother-infant pairs in dioxin-contaminated areas in Vietnam were recruited at the infants' birth and followed up for 4 months. Perinatal dioxin exposure levels were estimated by measurement of polychlorinated dibenzo-p-dioxins/furans toxic equivalent (PCDDs/Fs-TEQ) in breast milk. The infants' size was measured at birth and 1 and 4 months after birth, and neurodevelopment was evaluated using the Bayley Scales III at 4 months of age. Among 4 dioxin groups (language, and fine motor scores in the ≥75 percentile group were significantly lower than those in the other groups. These results suggested a considerable impact of perinatal dioxin exposure on infant growth, particularly in boys exposed to dioxins at high level of PCDDs/Fs-TEQ.

  20. Potencies of red seabream AHR1- and AHR2-mediated transactivation by dioxins: implication of both AHRs in dioxin toxicity.

    Science.gov (United States)

    Bak, Su-Min; Iida, Midori; Hirano, Masashi; Iwata, Hisato; Kim, Eun-Young

    2013-03-19

    To evaluate species- and isoform-specific responses to dioxins and related compounds (DRCs) via aryl hydrocarbon receptor (AHR) in the red seabream ( Pagrus major ), we constructed a reporter gene assay system. Each expression plasmid of red seabream AHR1 (rsAHR1) and AHR2 (rsAHR2) together with a reporter plasmid containing red seabream CYP1A 5'-flanking region were transfected into COS-7 cells. The cells were treated with graded concentrations of seven DRC congeners including 2,3,7,8-TCDD, 1,2,3,7,8-PeCDD, 1,2,3,4,7,8-HxCDD, 2,3,7,8-TCDF, 2,3,4,7,8-PeCDF, 1,2,3,4,7,8-HxCDF, and PCB126. Both rsAHR1 and rsAHR2 exhibited dose-dependent responses for all the tested congeners. The rsAHR isoform-specific TCDD induction equivalency factors (rsAHR1- and rsAHR2-IEFs) were calculated on the basis of 2,3,7,8-TCDD relative potency derived from the dose-response of each congener. The rsAHR1-IEFs of PeCDD, HxCDD, TCDF, PeCDF, and HxCDF were estimated as 0.17, 0.29, 2.5, 1.5, and 0.27, respectively. For PCB126, no rsAHR1-IEF was given because of less than 10% 2,3,7,8-TCDD maximum response. The rsAHR2-IEFs of PeCDD, HxCDD, TCDF, PeCDF, HxCDF, and PCB126 were estimated as 0.38, 0.13, 1.5, 0.93, 0.20, and 0.0085, respectively. The rsAHR1/2-IEF profiles were different from WHO toxic equivalency factors for fish. In silico docking simulations supported that both rsAHRs have potentials to bind to these congeners. These results suggest that dioxin toxicities may be mediated by both rsAHRs in red seabreams.

  1. Green tea catechins potentiate the effect of antibiotics and modulate adherence and gene expression in Porphyromonas gingivalis.

    Science.gov (United States)

    Fournier-Larente, Jade; Morin, Marie-Pierre; Grenier, Daniel

    2016-05-01

    A number of studies have brought evidence that green tea catechins may contribute to periodontal health. The objective of this study was to investigate the ability of a green tea extract and its principal constituent epigallocatechin-3-gallate (EGCG) to potentiate the antibacterial effects of antibiotics (metronidazole, tetracycline) against Porphyromonas gingivalis, and to modulate the adherence to oral epithelial cells and expression of genes coding for virulence factors and the high temperature requirement A (HtrA) stress protein in P. gingivalis. A broth microdilution assay was used to determine the antibacterial activity of the green tea extract and EGCG. The synergistic effects of either compounds in association with metronidazole or tetracycline were evaluated using the checkerboard technique. A fluorescent assay was used to determine bacterial adherence to oral epithelial cells. The modulation of gene expression in P. gingivalis was evaluated by quantitative RT-PCR. The Vibrio harveyi bioassay was used for monitoring quorum sensing inhibitory activity. The MIC values of the green tea extract on P. gingivalis ranged from 250 to 1000 μg/ml, while those of EGCG ranged from 125 to 500 μg/ml. A marked synergistic effect on P. gingivalis growth was observed for the green tea extract or EGCG in combination with metronidazole. Both the green tea extract and EGCG caused a dose-dependent inhibition of P. gingivalis adherence to oral epithelial cells. On the one hand, green tea extract and EGCG dose-dependently inhibited the expression of several P. gingivalis genes involved in host colonization (fimA, hagA, hagB), tissue destruction (rgpA, kgp), and heme acquisition (hem). On the other hand, both compounds increased the expression of the stress protein htrA gene. The ability of the green tea extract and EGCG to inhibit quorum sensing may contribute to the modulation of gene expression. This study explored the preventive and therapeutic potential of green tea

  2. Arabidopsis ATRX Modulates H3.3 Occupancy and Fine-Tunes Gene Expression

    KAUST Repository

    Duc, Cé line; Benoit, Matthias; Dé tourné , Gwé naë lle; Simon, Lauriane; Poulet, Axel; Jung, Matthieu; Veluchamy, Alaguraj; Latrasse, David; Le Goff, Samuel; Cotterell, Sylviane; Tatout, Christophe; Benhamed, Moussa; Probst, Aline V.

    2017-01-01

    , including the 45S ribosomal DNA (45S rDNA) loci, where loss of ATRX results in altered expression of specific 45S rDNA sequence variants. At the genome-wide scale, our data indicate that ATRX modifies gene expression concomitantly to H3.3 deposition at a set

  3. CCR5 in Multiple Sclerosis : expression, regulation, and modulation by statins

    NARCIS (Netherlands)

    Kuipers, Hedwich Fardau

    2007-01-01

    Activation of microglia, the macrophages of the central nervous system, is a key element in multiple sclerosis (MS) lesion development and is characterized by enhanced expression of both classes of major histocompatibility complex (MHC) molecules. This enhanced expression results from increased

  4. Does Gaze Direction Modulate Facial Expression Processing in Children with Autism Spectrum Disorder?

    Science.gov (United States)

    Akechi, Hironori; Senju, Atsushi; Kikuchi, Yukiko; Tojo, Yoshikuni; Osanai, Hiroo; Hasegawa, Toshikazu

    2009-01-01

    Two experiments investigated whether children with autism spectrum disorder (ASD) integrate relevant communicative signals, such as gaze direction, when decoding a facial expression. In Experiment 1, typically developing children (9-14 years old; n = 14) were faster at detecting a facial expression accompanying a gaze direction with a congruent…

  5. Recognizing the SINEs of Infection: Regulation of Retrotransposon Expression and Modulation of Host Cell Processes

    Directory of Open Access Journals (Sweden)

    William Dunker

    2017-12-01

    Full Text Available Short interspersed elements (SINEs are a family of retrotransposons evolutionarily derived from cellular RNA polymerase III transcripts. Over evolutionary time, SINEs have expanded throughout the human genome and today comprise ~11% of total chromosomal DNA. While generally transcriptionally silent in healthy somatic cells, SINE expression increases during a variety of types of stresses, including DNA virus infection. The relevance of SINE expression to viral infection was largely unexplored, however, recent years have seen great progress towards defining the impact of SINE expression on viral replication and host gene expression. Here we review the origin and diversity of SINE elements and their transcriptional control, with an emphasis on how their expression impacts host cell biology during viral infection.

  6. Reduction-sensitive lipopolyamines as a novel nonviral gene delivery system for modulated release of DNA with improved transgene expression.

    Science.gov (United States)

    Byk, G; Wetzer, B; Frederic, M; Dubertret, C; Pitard, B; Jaslin, G; Scherman, D

    2000-11-16

    We have designed and synthesized original cationic lipids for modulated release of DNA from cationic lipid/DNA complexes. Our rationale was that modulated degradation of the lipids during or after penetration into the cell could improve the trafficking of DNA to the nucleus resulting in increased transgene expression. The new reduction-sensitive lipopolyamines (RSL) harbor a disulfide bridge within different positions in the backbone of the lipids as biosensitive function. A useful synthetic method was developed to obtain, with very good yields and reproducibility, unsymmetrical disulfide-bridged molecules, starting from symmetrical disulfides and thiols. The new lipopolyamines are good candidates as carriers of therapeutic genes for in vivo gene delivery. To optimize the transfection efficiency in these novel series, we have carried out structure-activity relationship studies by placing the disulfide bridge at different positions in the backbone of the cationic lipid and by systematic variation of lipid chain length. Results indicate that the transfection level can be modulated as a function of the location of the disulfide bridge in the molecule. We suggest that an early release of DNA during or after penetration into the cell, probably promoted by reduction of a disulfide bridge placed between the polyamine and the lipid, implies a total loss of transfection efficiency. On the other hand, proper modulation of DNA release by inserting the disulfide bridge between one lipid chain and the rest of the molecule brings about increased transfection efficiency as compared to previously described nondegradable lipopolyamine analogues. Finally, preliminary physicochemical characterization of the complexes demonstrates that DNA release from complexes can be modulated as a function of the surrounding reducing conditions of the complexes and of the localization of the disulfide bridge within the lipopolyamine. Our results suggest that RSL is a promising new approach for gene

  7. CpG preconditioning regulates miRNA expression that modulates genomic reprogramming associated with neuroprotection against ischemic injury

    Science.gov (United States)

    Vartanian, Keri B; Mitchell, Hugh D; Stevens, Susan L; Conrad, Valerie K; McDermott, Jason E; Stenzel-Poore, Mary P

    2015-01-01

    Cytosine-phosphate-guanine (CpG) preconditioning reprograms the genomic response to stroke to protect the brain against ischemic injury. The mechanisms underlying genomic reprogramming are incompletely understood. MicroRNAs (miRNAs) regulate gene expression; however, their role in modulating gene responses produced by CpG preconditioning is unknown. We evaluated brain miRNA expression in response to CpG preconditioning before and after stroke using microarray. Importantly, we have data from previous gene microarrays under the same conditions, which allowed integration of miRNA and gene expression data to specifically identify regulated miRNA gene targets. CpG preconditioning did not significantly alter miRNA expression before stroke, indicating that miRNA regulation is not critical for the initiation of preconditioning-induced neuroprotection. However, after stroke, differentially regulated miRNAs between CpG- and saline-treated animals associated with the upregulation of several neuroprotective genes, implicating these miRNAs in genomic reprogramming that increases neuroprotection. Statistical analysis revealed that the miRNA targets were enriched in the gene population regulated in the setting of stroke, implying that miRNAs likely orchestrate this gene expression. These data suggest that miRNAs regulate endogenous responses to stroke and that manipulation of these miRNAs may have the potential to acutely activate novel neuroprotective processes that reduce damage. PMID:25388675

  8. Novel antidepressant candidate RO-05 modulated glucocorticoid receptors activation and FKBP5 expression in chronic mild stress model in rats.

    Science.gov (United States)

    Xing, Y; Hou, J; Meng, Q; Yang, M; Kurihara, H; Tian, J

    2015-04-02

    In this study, a novel TRI (triple reuptake inhibitors) antidepressant candidate RO-05 (4-[1-[1-(benzoyloxy)cyclohexyl]-2-(dimethylamino)ethyl]-phenyl benzoate) was investigated in TST (tail suspension test), FST (forced swimming test) and CMS (chronic mild stress) model. Results showed RO-05 significantly decreased the immobility time in FST and TST at 4.5-, 9-, 18-mg/kg in rats and 9-, 18-, 36-mg/kg in mice. Chronic administration of 18-mg/kg RO-05 improved the behavioral index, anhedonia and normalized the hyperactivity of HPA (hypothalamic-pituitary-adrenal axis) of CMS rats. We further investigated the possible mechanisms of RO-05 in the CMS model. Eighteen milligrams per kilogram of RO-05 chronic administration significantly reversed the increase of mRNA and protein expression of FKBP5 in the CMS rat hippocampus, which facilitated the activation of GR- (glucocorticoid receptor) and GR-responsive gene Foxo1 expression. RO-05 also elevated the expression of BDNF (brain-derived neurotrophic factor) in CMS rat hippocampus. In summary, our results indicated that RO-05 is a promising antidepressant candidate. The possible antidepressant mechanisms of RO-05 were the modulation of FKBP5 expression, GR activation, corresponding inhibition of HPA axis hyperactivity, and the increase of BDNF expression. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  9. Catalase expression is modulated by vancomycin and ciprofloxacin and influences the formation of free radicals in Staphylococcus aureus cultures

    DEFF Research Database (Denmark)

    Wang, Ying; Hougaard, Anni Bygvrå; Paulander, Wilhelm Erik Axel

    2015-01-01

    Detection of free radicals in biological systems is challenging due to their short half-lives. We have applied electron spin resonance (ESR) spectroscopy combined with spin traps using the probes PBN (N-tert-butyl-α-phenylnitrone) and DMPO (5,5-dimethyl-1-pyrroline N-oxide) to assess free radical...... that in S. aureus, bactericidal antibiotics modulate catalase expression, which in turn influences the formation of free radicals in the surrounding broth medium. If similar regulation is found in other bacterial species, it might explain why bactericidal antibiotics are perceived as inducing formation...... of free radicals....

  10. An emotion-based facial expression word activates laughter module in the human brain: a functional magnetic resonance imaging study.

    Science.gov (United States)

    Osaka, Naoyuki; Osaka, Mariko; Kondo, Hirohito; Morishita, Masanao; Fukuyama, Hidenao; Shibasaki, Hiroshi

    2003-04-10

    We report an fMRI experiment demonstrating that visualization of onomatopoeia, an emotion-based facial expression word, highly suggestive of laughter, heard by the ear, significantly activates both the extrastriate visual cortex near the inferior occipital gyrus and the premotor (PM)/supplementary motor area (SMA) in the superior frontal gyrus while non-onomatopoeic words under the same task that did not imply laughter do not activate these areas in humans. We tested the specific hypothesis that an activation in extrastriate visual cortex and PM/SMA would be modulated by image formation of onomatopoeia implying laughter and found the hypothesis to be true. Copyright 2003 Elsevier Science Ireland Ltd.

  11. Experience Modulates the Effects of Histone Deacetylase Inhibitors on Gene and Protein Expression in the Hippocampus: Impaired Plasticity in Aging.

    Science.gov (United States)

    Sewal, Angila S; Patzke, Holger; Perez, Evelyn J; Park, Pul; Lehrmann, Elin; Zhang, Yongqing; Becker, Kevin G; Fletcher, Bonnie R; Long, Jeffrey M; Rapp, Peter R

    2015-08-19

    The therapeutic potential of histone deacetylase inhibitor (HDACi) treatment has attracted considerable attention in the emerging area of cognitive neuroepigenetics. The possibility that ongoing cognitive experience importantly regulates the cell biological effects of HDACi administration, however, has not been systematically examined. In an initial experiment addressing this issue, we tested whether water maze training influences the gene expression response to acute systemic HDACi administration in the young adult rat hippocampus. Training powerfully modulated the response to HDACi treatment, increasing the total number of genes regulated to nearly 3000, including many not typically linked to neural plasticity, compared with neuroepigenetics. Copyright © 2015 the authors 0270-6474/15/3511730-14$15.00/0.

  12. Modulation of expression of HLA components at the cell surface induced by anti-β2m reagents

    International Nuclear Information System (INIS)

    Ceppellini, R.; Malavasi, F.; Garotta, G.; Trucco, M.

    1981-01-01

    Antibodies against lymphocyte surface components are able to rearrange profoundly the topography of the cell membrane with a different modulation of surface antigens. Of particular interest is the effect of anti-β2m reagents, which are able to suppress completely the reactivity of epitopes carried by the two chains of the ABC dimers, while the expressivity of other antigens, such as DR, is significantly increased. These results have been obtained with immunoradiobinding under a varity of conditions, thus confirming the validity of the ''bb'' (β2m blanketing) test. (author)

  13. Modulation of the expression of chondroitin sulfate proteoglycan in stimulated human monocytes

    International Nuclear Information System (INIS)

    Uhlin-Hansen, L.; Eskeland, T.; Kolset, S.O.

    1989-01-01

    Proteoglycan biosynthesis was studied in human monocytes and monocyte-derived macrophages (MDM) after exposure to typical activators of the monocyte/macrophage system: interferon-gamma (IFN-gamma), lipopolysaccharide (LPS), and phorbol 12-myristate 13-acetate (PMA). By morphological examination, both monocytes and MDM were stimulated by these activators. Treatment with IFN-gamma resulted in a slight decrease in the expression of [35S]chondroitin sulfate proteoglycan (CSPG) in both monocytes and MDM, whereas LPS treatment increased the [35S]CSPG expression 1.8 and 2.2 times, respectively. PMA, in contrast, decreased the CSPG expression 0.4 times in monocytes, whereas MDM were stimulated to increase the biosynthesis 1.9 times. An increase in the sulfate density of the chondroitin sulfate chains was evident following differentiation of monocytes into MDM due to the expression of disulfated disaccharide units of the chondroitin sulfate E type (CS-E). However, monocytes exposed to PMA did also express disaccharides of the chondroitin sulfate E type. Furthermore, the expression of CS-E in MDM was increased 2 times following PMA treatment. An inactive phorbol ester, phorbol 12,13-diacetate, did not affect the expression of CS-E in either monocytes or MDM when compared with control cultures, suggesting that protein kinase C-dependent signal pathways may be involved in the regulation of sulfation of CSPG. Exposure to LPS or IFN-gamma did not lead to any changes in the sulfation of the chondroitin sulfate chains

  14. Alcohol Consumption Modulates Host Defense in Rhesus Macaques by Altering Gene Expression in Circulating Leukocytes.

    Science.gov (United States)

    Barr, Tasha; Girke, Thomas; Sureshchandra, Suhas; Nguyen, Christina; Grant, Kathleen; Messaoudi, Ilhem

    2016-01-01

    Several lines of evidence indicate that chronic alcohol use disorder leads to increased susceptibility to several viral and bacterial infections, whereas moderate alcohol consumption decreases the incidence of colds and improves immune responses to some pathogens. In line with these observations, we recently showed that heavy ethanol intake (average blood ethanol concentrations > 80 mg/dl) suppressed, whereas moderate alcohol consumption (blood ethanol concentrations consumption. To uncover the molecular basis for impaired immunity with heavy alcohol consumption and enhanced immune response with moderate alcohol consumption, we performed a transcriptome analysis using PBMCs isolated on day 7 post-modified vaccinia Ankara vaccination, the earliest time point at which we detected differences in T cell and Ab responses. Overall, chronic heavy alcohol consumption reduced the expression of immune genes involved in response to infection and wound healing and increased the expression of genes associated with the development of lung inflammatory disease and cancer. In contrast, chronic moderate alcohol consumption upregulated the expression of genes involved in immune response and reduced the expression of genes involved in cancer. To uncover mechanisms underlying the alterations in PBMC transcriptomes, we profiled the expression of microRNAs within the same samples. Chronic heavy ethanol consumption altered the levels of several microRNAs involved in cancer and immunity and known to regulate the expression of mRNAs differentially expressed in our data set. Copyright © 2015 by The American Association of Immunologists, Inc.

  15. AtMYB44 regulates WRKY70 expression and modulates antagonistic interaction between salicylic acid and jasmonic acid signaling.

    Science.gov (United States)

    Shim, Jae Sung; Jung, Choonkyun; Lee, Sangjoon; Min, Kyunghun; Lee, Yin-Won; Choi, Yeonhee; Lee, Jong Seob; Song, Jong Tae; Kim, Ju-Kon; Choi, Yang Do

    2013-02-01

    The role of AtMYB44, an R2R3 MYB transcription factor, in signaling mediated by jasmonic acid (JA) and salicylic acid (SA) is examined. AtMYB44 is induced by JA through CORONATINE INSENSITIVE 1 (COI1). AtMYB44 over-expression down-regulated defense responses against the necrotrophic pathogen Alternaria brassicicola, but up-regulated WRKY70 and PR genes, leading to enhanced resistance to the biotrophic pathogen Pseudomonas syringae pv. tomato DC3000. The knockout mutant atmyb44 shows opposite effects. Induction of WRKY70 by SA is reduced in atmyb44 and npr1-1 mutants, and is totally abolished in atmyb44 npr1-1 double mutants, showing that WRKY70 is regulated independently through both NPR1 and AtMYB44. AtMYB44 over-expression does not change SA content, but AtMYB44 over-expression phenotypes, such as retarded growth, up-regulated PR1 and down-regulated PDF1.2 are reversed by SA depletion. The wrky70 mutation suppressed AtMYB44 over-expression phenotypes, including up-regulation of PR1 expression and down-regulation of PDF1.2 expression. β-estradiol-induced expression of AtMYB44 led to WRKY70 activation and thus PR1 activation. AtMYB44 binds to the WRKY70 promoter region, indicating that AtMYB44 acts as a transcriptional activator of WRKY70 by directly binding to a conserved sequence element in the WRKY70 promoter. These results demonstrate that AtMYB44 modulates antagonistic interaction by activating SA-mediated defenses and repressing JA-mediated defenses through direct control of WRKY70. © 2012 The Authors The Plant Journal © 2012 Blackwell Publishing Ltd.

  16. RhoA signaling modulates cyclin D1 expression in human lung fibroblasts; implications for idiopathic pulmonary fibrosis

    Directory of Open Access Journals (Sweden)

    Hoban PR

    2006-06-01

    Full Text Available Abstract Background Idiopathic Pulmonary Fibrosis (IPF is a debilitating disease characterized by exaggerated extracellular matrix deposition and aggressive lung structural remodeling. Disease pathogenesis is driven by fibroblastic foci formation, consequent on growth factor overexpression and myofibroblast proliferation. We have previously shown that both CTGF overexpression and myofibroblast formation in IPF cell lines are dependent on RhoA signaling. As RhoA-mediated regulation is also involved in cell cycle progression, we hypothesise that this pathway is key to lung fibroblast turnover through modulation of cyclin D1 kinetic expression. Methods Cyclin D1 expression was compared in primary IPF patient-derived fibroblasts and equivalent normal control cells. Quantitative real time PCR was employed to examine relative expression levels of cyclin D1 mRNA; protein expression was confirmed by western blotting. Effects of Rho signaling were investigated using transient transfection of constitutively active and dominant negative RhoA constructs as well as pharmacological inhibitors. Cellular proliferation of lung fibroblasts was determined by BrdU incorporation ELISA. To further explore RhoA regulation of cyclin D1 in lung fibroblasts and associated cell cycle progression, an established Rho inhibitor, Simvastatin, was incorporated in our studies. Results Cyclin D1 expression was upregulated in IPF compared to normal lung fibroblasts under exponential growth conditions (p Conclusion These findings report for the first time that cyclin D1 expression is deregulated in IPF through a RhoA dependent mechanism that influences lung fibroblast proliferation. This potentially unravels new molecular targets for future anti-IPF strategies; accordingly, Simvastatin inhibition of Rho-mediated cyclin D1 expression in IPF fibroblasts merits further exploitation.

  17. Interactions between beta subunits of the KCNMB family and Slo3: beta4 selectively modulates Slo3 expression and function.

    Directory of Open Access Journals (Sweden)

    Cheng-Tao Yang

    2009-07-01

    Full Text Available The pH and voltage-regulated Slo3 K(+ channel, a homologue of the Ca(2+- and voltage-regulated Slo1 K(+ channel, is thought to be primarily expressed in sperm, but the properties of Slo3 studied in heterologous systems differ somewhat from the native sperm KSper pH-regulated current. There is the possibility that critical partners that regulate Slo3 function remain unidentified. The extensive amino acid identity between Slo3 and Slo1 suggests that auxiliary beta subunits regulating Slo1 channels might coassemble with and modulate Slo3 channels. Four distinct beta subunits composing the KCNMB family are known to regulate the function and expression of Slo1 Channels.To examine the ability of the KCNMB family of auxiliary beta subunits to regulate Slo3 function, we co-expressed Slo3 and each beta subunit in heterologous expression systems and investigated the functional consequences by electrophysiological and biochemical analyses. The beta4 subunit produced an 8-10 fold enhancement of Slo3 current expression in Xenopus oocytes and a similar enhancement of Slo3 surface expression as monitored by YFP-tagged Slo3 or biotin labeled Slo3. Neither beta1, beta2, nor beta3 mimicked the ability of beta4 to increase surface expression, although biochemical tests suggested that all four beta subunits are competent to coassemble with Slo3. Fluorescence microscopy from beta4 KO mice, in which an eGFP tag replaced the deleted exon, revealed that beta4 gene promoter is active in spermatocytes. Furthermore, quantitative RT-PCR demonstrated that beta4 and Slo3 exhibit comparable mRNA abundance in both testes and sperm.These results argue that, for native mouse Slo3 channels, the beta4 subunit must be considered as a potential interaction partner and, furthermore, that KCNMB subunits may have functions unrelated to regulation of the Slo1 alpha subunit.

  18. Dioxins and endometriosis: cohort study of women in West Virginia

    Energy Technology Data Exchange (ETDEWEB)

    Diliberto, J.; Birnbaum, L. [U.S. Environmental Protection Agency, NHEERL, ETD, Research Triangle Park, NC (United States); Staats, D.A. [West Virginia Dept. of Environmental Protection, Charleston, WV (United States); Staats, D.A.; Becker, J.; Jude, D.; Chouinard, S.C.; Smith, T. [Marshall Univ. Medical Center, Huntington, WV (United States); Sirinek, L. [West Virginia Dept. of Environmental Protection, Wheeling, WV (United States); Clark, G. [Xenobiotic Detection Systems Inc., Durham, NC (United States); Landy, R. [U.S. Environmental Protection Agency, Region 3, ESC, Ft. Meade, MD (United States)

    2004-09-15

    The women in this endometriosis/dioxin health study reside in the Kanawha/Ohio River Valley area of West Virginia and comprise a potential cluster (cohort) of individuals who have been exposed to dioxins (dioxin and dioxin-like chemicals) at background levels higher than those seen in other areas of the United States. The emissions from an unique constellation of chemical industries appear to have led to high levels of environmental dioxin contaminants. In addition, this area has a high incidence of endometriosis. Previous animal studies, both in nonhuman primates and rodents, have demonstrated a correlation between dioxin exposure and endometriosis. Human epidemiology studies have suggested an association but have not demonstrated a statistically significant correlation, possibly due to limitations in study design such as insufficient numbers, measurement of only TCDD rather than total equivalents to TCDD (TEQs), and/or lack of surgical ascertainment of endometriosis. The present study is addressing these issues. Thus, we have the unusual congruence of identified emission sources and high background levels of dioxins and a potentially related elevation of endometriosis. Endometriosis is a condition suffered by women in which the endometrial tissue, that usually lines the uterus, migrates to other areas. Most commonly it is found in the abdomen, bladder, ovaries or bowel. Patients with endometriosis experience pelvic pain, irregular bleeding, infertility and other problems. Immune suppression has been associated with severe endometriosis. This debilitating condition is a poorly understood disease. In the United States, this condition affects millions of women in their reproductive years and is showing up more frequently in very young women. Endometriosis will seriously impact future fertility and health care utilization. Data suggest that the rate of endometriosis in the Kanawha and Ohio River valleys is higher than is seen in other regions of the United States.

  19. Dioxin inhalation doses from wood combustion in indoor cookfires

    Science.gov (United States)

    Northcross, Amanda L.; Katharine Hammond, S.; Canuz, Eduardo; Smith, Kirk R.

    2012-03-01

    Approximately 3 billion people worldwide rely on solid biomass fuels for household cooking and space heating, and approximately 50-60% use wood, often indoors in poorly ventilated situations. Daily exposures to high concentrations of smoke from cookstoves inside kitchens create large smoke exposures for women cooks and their small children. The smoke from burning the wood fuel contains hundred of toxic compounds, including dioxins and furans some of the most toxic compounds known to science. Health effects from exposure to dioxins include reproductive and developmental problems, damage the immune system, interference with hormones and also cause cancer. This study measured concentrations of dioxins and furans in a typical Guatemalan village home during open cookfires. Measured concentrations averaged 0.32 ± 0.07 ng m-3 over 31 fires. A Monte Carlo simulation was conducted using parameter estimates based on 8 years of research experience in the study area. The estimated total daily intake of 17 particle phase dioxin and furans for women, a 5-year-old child and a 6-month-old infant were 1.2 (S.D. = 0.4), 1.7 (S.D. = 0.7) and 2.0 (S.D. = 0.5) respectively. The 46% of babies have and estimated total daily intake (TDI) which exceed the WHO TDI guideline for dioxins and furans, 3% of women and 26% of 5-year-old children based solely inhalation of particle phase dioxins in woodsmoke from an open cooking fire. These values maybe underestimates, as they did not include gas phase concentrations or ingestion of dioxins and furans through food, which is the largest route of exposure in the developed world.

  20. Microbiota-Derived Short-Chain Fatty Acids Modulate Expression of Campylobacter jejuni Determinants Required for Commensalism and Virulence.

    Science.gov (United States)

    Luethy, Paul M; Huynh, Steven; Ribardo, Deborah A; Winter, Sebastian E; Parker, Craig T; Hendrixson, David R

    2017-05-09

    Campylobacter jejuni promotes commensalism in the intestinal tracts of avian hosts and diarrheal disease in humans, yet components of intestinal environments recognized as spatial cues specific for different intestinal regions by the bacterium to initiate interactions in either host are mostly unknown. By analyzing a C. jejuni acetogenesis mutant defective in converting acetyl coenzyme A (Ac-CoA) to acetate and commensal colonization of young chicks, we discovered evidence for in vivo microbiota-derived short-chain fatty acids (SCFAs) and organic acids as cues recognized by C. jejuni that modulate expression of determinants required for commensalism. We identified a set of C. jejuni genes encoding catabolic enzymes and transport systems for amino acids required for in vivo growth whose expression was modulated by SCFAs. Transcription of these genes was reduced in the acetogenesis mutant but was restored upon supplementation with physiological concentrations of the SCFAs acetate and butyrate present in the lower intestinal tracts of avian and human hosts. Conversely, the organic acid lactate, which is abundant in the upper intestinal tract where C. jejuni colonizes less efficiently, reduced expression of these genes. We propose that microbiota-generated SCFAs and lactate are cues for C. jejuni to discriminate between different intestinal regions. Spatial gradients of these metabolites likely allow C. jejuni to locate preferred niches in the lower intestinal tract and induce expression of factors required for intestinal growth and commensal colonization. Our findings provide insights into the types of cues C. jejuni monitors in the avian host for commensalism and likely in humans to promote diarrheal disease. IMPORTANCE Campylobacter jejuni is a commensal of the intestinal tracts of avian species and other animals and a leading cause of diarrheal disease in humans. The types of cues sensed by C. jejuni to influence responses to promote commensalism or

  1. Characterization of human septic sera induced gene expression modulation in human myocytes

    Science.gov (United States)

    Hussein, Shaimaa; Michael, Paul; Brabant, Danielle; Omri, Abdelwahab; Narain, Ravin; Passi, Kalpdrum; Ramana, Chilakamarti V.; Parrillo, Joseph E.; Kumar, Anand; Parissenti, Amadeo; Kumar, Aseem

    2009-01-01

    To gain a better understanding of the gene expression changes that occurs during sepsis, we have performed a cDNA microarray study utilizing a tissue culture model that mimics human sepsis. This study utilized an in vitro model of cultured human fetal cardiac myocytes treated with 10% sera from septic patients or 10% sera from healthy volunteers. A 1700 cDNA expression microarray was used to compare the transcription profile from human cardiac myocytes treated with septic sera vs normal sera. Septic sera treatment of myocytes resulted in the down-regulation of 178 genes and the up-regulation of 4 genes. Our data indicate that septic sera induced cell cycle, metabolic, transcription factor and apoptotic gene expression changes in human myocytes. Identification and characterization of gene expression changes that occur during sepsis may lead to the development of novel therapeutics and diagnostics. PMID:19684886

  2. The time course of face processing: startle eyeblink response modulation by face gender and expression.

    Science.gov (United States)

    Duval, Elizabeth R; Lovelace, Christopher T; Aarant, Justin; Filion, Diane L

    2013-12-01

    The purpose of this study was to investigate the effects of both facial expression and face gender on startle eyeblink response patterns at varying lead intervals (300, 800, and 3500ms) indicative of attentional and emotional processes. We aimed to determine whether responses to affective faces map onto the Defense Cascade Model (Lang et al., 1997) to better understand the stages of processing during affective face viewing. At 300ms, there was an interaction between face expression and face gender with female happy and neutral faces and male angry faces producing inhibited startle. At 3500ms, there was a trend for facilitated startle during angry compared to neutral faces. These findings suggest that affective expressions are perceived differently in male and female faces, especially at short lead intervals. Future studies investigating face processing should take both face gender and expression into account. © 2013.

  3. Increasing plant growth by modulating omega-amidase expression in plants

    Science.gov (United States)

    Unkefer, Pat J.; Anderson, Penelope S.; Knight, Thomas J.

    2015-06-30

    The present disclosure relates to compositions and methods for increasing the leaf-to-root ratio of the signal metabolite 2-oxoglutaramate and related proline molecules in plants by modulating levels of .omega.-amidase to increase nitrogen use efficiency, resulting in enhanced growth, faster growth rates, greater seed and fruit/pod yields, earlier and more productive flowering, increased tolerance to high salt conditions, and increased biomass yields.

  4. Modulation of IgE-dependent COX-2 gene expression by reactive oxygen species in human neutrophils.

    Science.gov (United States)

    Vega, Antonio; Chacón, Pedro; Alba, Gonzalo; El Bekay, Rajaa; Martín-Nieto, José; Sobrino, Francisco

    2006-07-01

    Cyclooxygenase (COX) is a key enzyme in prostaglandin (PG) synthesis. Up-regulation of its COX-2 isoform is responsible for the increased PG release, taking place under inflammatory conditions, and also, is thought to be involved in allergic and inflammatory diseases. In the present work, we demonstrate that COX-2 expression becomes highly induced by anti-immunoglobulin E (IgE) antibodies and by antigens in human neutrophils from allergic patients. This induction was detected at mRNA and protein levels and was accompanied by a concomitant PGE(2) and thromboxane A(2) release. We also show evidence that inhibitors of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, such as 4-(2-aminoethyl)benzenesulphonyl fluoride and 4-hydroxy-3-methoxyaceto-phenone, completely cancelled anti-IgE-induced COX-2 protein up-regulation, suggesting that this process is mediated by reactive oxygen species (ROS) derived from NADPH oxidase activity. Moreover, the mitogen-activated protein kinases (MAPKs), p38 and extracellular signal-regulated kinase, and also, the transcription factor, nuclear factor (NF)-kappaB, are involved in the up-regulation of COX-2 expression, as specific chemical inhibitors of these two kinases, such as SB203580 and PD098059, and of the NF-kappaB pathway, such as N(alpha)-benzyloxycarbonyl-l-leucyl-l-leucyl-l-leucinal, abolished IgE-dependent COX-2 induction. Evidence is also presented, using Fe(2)(+)/Cu(2)(+) ions, that hydroxyl radicals generated from hydrogen peroxide through Fenton reactions could constitute candidate modulators able to directly trigger anti-IgE-elicited COX-2 expression through MAPK and NF-kappaB pathways. Present results underscore a new role for ROS as second messengers in the modulation of COX-2 expression by human neutrophils in allergic conditions.

  5. GNC and CGA1 Modulate Chlorophyll Biosynthesis and Glutamate Synthase (GLU1/Fd-GOGAT) Expression in Arabidopsis

    Science.gov (United States)

    Hudson, Darryl; Guevara, David; Yaish, Mahmoud W.; Hannam, Carol; Long, Nykoll; Clarke, Joseph D.; Bi, Yong-Mei; Rothstein, Steven J.

    2011-01-01

    Chloroplast development is an important determinant of plant productivity and is controlled by environmental factors including amounts of light and nitrogen as well as internal phytohormones including cytokinins and gibberellins (GA). The paralog GATA transcription factors GNC and CGA1/GNL up-regulated by light, nitrogen and cytokinin while also being repressed by GA signaling. Modifying the expression of these genes has previously been shown to influence chlorophyll content in Arabidopsis while also altering aspects of germination, elongation growth and flowering time. In this work, we also use transgenic lines to demonstrate that GNC and CGA1 exhibit a partially redundant control over chlorophyll biosynthesis. We provide novel evidence that GNC and CGA1 influence both chloroplast number and leaf starch in proportion to their transcript level. GNC and CGA1 were found to modify the expression of chloroplast localized GLUTAMATE SYNTHASE (GLU1/Fd-GOGAT), which is the primary factor controlling nitrogen assimilation in green tissue. Altering GNC and CGA1 expression was also found to modulate the expression of important chlorophyll biosynthesis genes (GUN4, HEMA1, PORB, and PORC). As previously demonstrated, the CGA1 transgenic plants demonstrated significantly altered timing to a number of developmental events including germination, leaf production, flowering time and senescence. In contrast, the GNC transgenic lines we analyzed maintain relatively normal growth phenotypes outside of differences in chloroplast development. Despite some evidence for partial divergence, results indicate that regulation of both GNC and CGA1 by light, nitrogen, cytokinin, and GA acts to modulate nitrogen assimilation, chloroplast development and starch production. Understanding the mechanisms controlling these processes is important for agricultural biotechnology. PMID:22102866

  6. Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

    International Nuclear Information System (INIS)

    Ivanov, Vladimir N.; Partridge, Michael A.; Johnson, Geoffrey E.; Huang, Sarah X.L.; Zhou, Hongning; Hei, Tom K.

    2008-01-01

    Although many human melanomas express the death receptors TRAIL-R2/DR5 or TRAIL-R1/DR4 on cell surface, they often exhibit resistance to exogenous TRAIL. One of the main contributors to TRAIL-resistance of melanoma cells is upregulation of transcription factors STAT3 and NF-κB that control the expression of antiapoptotic genes, including cFLIP and Bcl-xL. On the other hand, the JNK-cJun pathway is involved in the negative regulation of cFLIP (a caspase-8 inhibitor) expression. Our observations indicated that resveratrol, a polyphenolic phytoalexin, decreased STAT3 and NF-κB activation, while activating JNK-cJun that finally suppressed expression of cFLIP and Bcl-xL proteins and increased sensitivity to exogenous TRAIL in DR5-positive melanomas. Interestingly, resveratrol did not increase surface expression of DR5 in human melanomas, while γ-irradiation or sodium arsenite treatment substantially upregulated DR5 expression. Hence, an initial increase in DR5 surface expression (either by γ-irradiation or arsenite), and subsequent downregulation of antiapoptotic cFLIP and Bcl-xL (by resveratrol), appear to constitute an efficient approach to reactivate apoptotic death pathways in TRAIL-resistant human melanomas. In spite of partial suppression of mitochondrial function and the mitochondrial death pathway, melanoma cells still retain the potential to undergo the DR5-mediated, caspase-8-dependent death pathway that could be accelerated by either an increase in DR5 surface expression or suppression of cFLIP. Taken together, these results suggest that resveratrol, in combination with TRAIL, may have a significant efficacy in the treatment of human melanomas

  7. Characterization of human septic sera induced gene expression modulation in human myocytes

    OpenAIRE

    Hussein, Shaimaa; Michael, Paul; Brabant, Danielle; Omri, Abdelwahab; Narain, Ravin; Passi, Kalpdrum; Ramana, Chilakamarti V.; Parrillo, Joseph E.; Kumar, Anand; Parissenti, Amadeo; Kumar, Aseem

    2009-01-01

    To gain a better understanding of the gene expression changes that occurs during sepsis, we have performed a cDNA microarray study utilizing a tissue culture model that mimics human sepsis. This study utilized an in vitro model of cultured human fetal cardiac myocytes treated with 10% sera from septic patients or 10% sera from healthy volunteers. A 1700 cDNA expression microarray was used to compare the transcription profile from human cardiac myocytes treated with septic sera vs normal sera....

  8. Hormonal modulation of breast cancer gene expression: implications for intrinsic subtyping in pre-menopausal women

    OpenAIRE

    Sarah M Bernhardt; Pallave Dasari; David Walsh; Amanda R Townsend; Amanda R Townsend; Timothy J Price; Timothy J Price; Wendy V Ingman

    2016-01-01

    Clinics are increasingly adopting gene expression profiling to diagnose breast cancer subtype, providing an intrinsic, molecular portrait of the tumour. For example, the PAM50-based Prosigna test quantifies expression of 50 key genes to classify breast cancer subtype, and this method of classification has been demonstrated to be superior over traditional immunohistochemical methods that detect proteins, to predict risk of disease recurrence. However, these tests were largely developed and val...

  9. Hormonal Modulation of Breast Cancer Gene Expression: Implications for Intrinsic Subtyping in Premenopausal Women

    OpenAIRE

    Bernhardt, Sarah M.; Dasari, Pallave; Walsh, David; Townsend, Amanda R.; Price, Timothy J.; Ingman, Wendy V.

    2016-01-01

    Clinics are increasingly adopting gene-expression profiling to diagnose breast cancer subtype, providing an intrinsic, molecular portrait of the tumor. For example, the PAM50-based Prosigna test quantifies expression of 50 key genes to classify breast cancer subtype, and this method of classification has been demonstrated to be superior over traditional immunohistochemical methods that detect proteins, to predict risk of disease recurrence. However, these tests were largely developed and vali...

  10. Vaccine-induced modulation of gene expression in turbot peritoneal cells. A microarray approach.

    Science.gov (United States)

    Fontenla, Francisco; Blanco-Abad, Verónica; Pardo, Belén G; Folgueira, Iria; Noia, Manuel; Gómez-Tato, Antonio; Martínez, Paulino; Leiro, José M; Lamas, Jesús

    2016-07-01

    We used a microarray approach to examine changes in gene expression in turbot peritoneal cells after injection of the fish with vaccines containing the ciliate parasite Philasterides dicentrarchi as antigen and one of the following adjuvants: chitosan-PVMMA microspheres, Freund́s complete adjuvant, aluminium hydroxide gel or Matrix-Q (Isconova, Sweden). We identified 374 genes that were differentially expressed in all groups of fish. Forty-two genes related to tight junctions and focal adhesions and/or actin cytoskeleton were differentially expressed in free peritoneal cells. The profound changes in gene expression related to cell adherence and cytoskeleton may be associated with cell migration and also with the formation of cell-vaccine masses and their attachment to the peritoneal wall. Thirty-five genes related to apoptosis were differentially expressed. Although most of the proteins coded by these genes have a proapoptotic effect, others are antiapoptotic, indicating that both types of signals occur in peritoneal leukocytes of vaccinated fish. Interestingly, many of the genes related to lymphocytes and lymphocyte activity were downregulated in the groups injected with vaccine. We also observed decreased expression of genes related to antigen presentation, suggesting that macrophages (which were abundant in the peritoneal cavity after vaccination) did not express these during the early inflammatory response in the peritoneal cavity. Finally, several genes that participate in the inflammatory response were differentially expressed, and most participated in resolution of inflammation, indicating that an M2 macrophage response is generated in the peritoneal cavity of fish one day post vaccination. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. FOXP3 expression is modulated by TGF-β1/NOTCH1 pathway in human melanoma

    Science.gov (United States)

    Skarmoutsou, Eva; Bevelacqua, Valentina; D'Amico, Fabio; Russo, Angela; Spandidos, Demetrios A.; Scalisi, Aurora

    2018-01-01

    Forkhead box protein 3 (FOXP3) transcription factor is expressed by immune cells and several human cancers and is associated with tumor aggressiveness and unfavorable clinical outcomes. NOTCH and transforming growth factor-β (TGF-β) protumorigenic effects are mediated by FOXP3 expression in several cancer models; however, their interaction and role in melanoma is unknown. We investigated TGF-β-induced FOXP3 gene expression during NOTCH1 signaling inactivation. Primary (WM35) and metastatic melanoma (A375 and A2058) cell lines and normal melanocytes (NHEM) were used. FOXP3 subcellular distribution was evaluated by immuno cytochemical analysis. Gene expression levels were assessed by reverse transcription-quantitative polymerase chain reaction. Protein levels were assessed by western blot analysis. The γ-secretase inhibitor (GSI) was used for NOTCH1 inhibition and recombinant human (rh)TGF-β was used for melanoma cell stimulation. Cell proliferation and viability were respectively assessed by MTT and Trypan blue dye assays. FOXP3 mRNA and protein levels were progressively higher in WM35, A375 and A2058 cell lines compared to NHEM and their levels were further increased after stimulation with rh-TGF-β. TGF-β-mediated FOXP3 expression was mediated by NOTCH1 signaling. Inhibition of NOTCH1 with concomitant rh-TGF-β stimulation determined the reduction in gene expression and protein level of FOXP3. Finally, melanoma cell line proliferation and viability were reduced by NOTCH1 inhibition. The results show that nn increase in FOXP3 expression in metastatic melanoma cell lines is a potential marker of tumor aggressiveness and metastasis. NOTCH1 is a central mediator of TGF-β-mediated FOXP3 expression and NOTCH1 inhibition produces a significant reduction of melanoma cell proliferation and viability. PMID:29620159

  12. BMP signaling modulates hepcidin expression in zebrafish embryos independent of hemojuvelin.

    Directory of Open Access Journals (Sweden)

    Yann Gibert

    2011-01-01

    Full Text Available Hemojuvelin (Hjv, a member of the repulsive-guidance molecule (RGM family, upregulates transcription of the iron regulatory hormone hepcidin by activating the bone morphogenetic protein (BMP signaling pathway in mammalian cells. Mammalian models have identified furin, neogenin, and matriptase-2 as modifiers of Hjv's function. Using the zebrafish model, we evaluated the effects of hjv and its interacting proteins on hepcidin expression during embryonic development. We found that hjv is strongly expressed in the notochord and somites of the zebrafish embryo and that morpholino knockdown of hjv impaired the development of these structures. Knockdown of hjv or other hjv-related genes, including zebrafish orthologs of furin or neogenin, however, failed to decrease hepcidin expression relative to liver size. In contrast, overexpression of bmp2b or knockdown of matriptase-2 enhanced the intensity and extent of hepcidin expression in zebrafish embryos, but this occurred in an hjv-independent manner. Furthermore, we demonstrated that zebrafish hjv can activate the human hepcidin promoter and enhance BMP responsive gene expression in vitro, but is expressed at low levels in the zebrafish embryonic liver. Taken together, these data support an alternative mechanism for hepcidin regulation during zebrafish embryonic development, which is independent of hjv.

  13. Integrated analysis of microRNA and gene expression profiles reveals a functional regulatory module associated with liver fibrosis.

    Science.gov (United States)

    Chen, Wei; Zhao, Wenshan; Yang, Aiting; Xu, Anjian; Wang, Huan; Cong, Min; Liu, Tianhui; Wang, Ping; You, Hong

    2017-12-15

    Liver fibrosis, characterized with the excessive accumulation of extracellular matrix (ECM) proteins, represents the final common pathway of chronic liver inflammation. Ever-increasing evidence indicates microRNAs (miRNAs) dysregulation has important implications in the different stages of liver fibrosis. However, our knowledge of miRNA-gene regulation details pertaining to such disease remains unclear. The publicly available Gene Expression Omnibus (GEO) datasets of patients suffered from cirrhosis were extracted for integrated analysis. Differentially expressed miRNAs (DEMs) and genes (DEGs) were identified using GEO2R web tool. Putative target gene prediction of DEMs was carried out using the intersection of five major algorithms: DIANA-microT, TargetScan, miRanda, PICTAR5 and miRWalk. Functional miRNA-gene regulatory network (FMGRN) was constructed based on the computational target predictions at the sequence level and the inverse expression relationships between DEMs and DEGs. DAVID web server was selected to perform KEGG pathway enrichment analysis. Functional miRNA-gene regulatory module was generated based on the biological interpretation. Internal connections among genes in liver fibrosis-related module were determined using String database. MiRNA-gene regulatory modules related to liver fibrosis were experimentally verified in recombinant human TGFβ1 stimulated and specific miRNA inhibitor treated LX-2 cells. We totally identified 85 and 923 dysregulated miRNAs and genes in liver cirrhosis biopsy samples compared to their normal controls. All evident miRNA-gene pairs were identified and assembled into FMGRN which consisted of 990 regulations between 51 miRNAs and 275 genes, forming two big sub-networks that were defined as down-network and up-network, respectively. KEGG pathway enrichment analysis revealed that up-network was prominently involved in several KEGG pathways, in which "Focal adhesion", "PI3K-Akt signaling pathway" and "ECM

  14. The temporal expression pattern of alpha-synuclein modulates olfactory neurogenesis in transgenic mice.

    Directory of Open Access Journals (Sweden)

    Sebastian R Schreglmann

    Full Text Available Adult neurogenesis mirrors the brain´s endogenous capacity to generate new neurons throughout life. In the subventricular zone/ olfactory bulb system adult neurogenesis is linked to physiological olfactory function and has been shown to be impaired in murine models of neuronal alpha-Synuclein overexpression. We analyzed the degree and temporo-spatial dynamics of adult olfactory bulb neurogenesis in transgenic mice expressing human wild-type alpha-Synuclein (WTS under the murine Thy1 (mThy1 promoter, a model known to have a particularly high tg expression associated with impaired olfaction.Survival of newly generated neurons (NeuN-positive in the olfactory bulb was unchanged in mThy1 transgenic animals. Due to decreased dopaminergic differentiation a reduction in new dopaminergic neurons within the olfactory bulb glomerular layer was present. This is in contrast to our previously published data on transgenic animals that express WTS under the control of the human platelet-derived growth factor β (PDGF promoter, that display a widespread decrease in survival of newly generated neurons in regions of adult neurogenesis, resulting in a much more pronounced neurogenesis deficit. Temporal and quantitative expression analysis using immunofluorescence co-localization analysis and Western blots revealed that in comparison to PDGF transgenic animals, in mThy1 transgenic animals WTS is expressed from later stages of neuronal maturation only but at significantly higher levels both in the olfactory bulb and cortex.The dissociation between higher absolute expression levels of alpha-Synuclein but less severe impact on adult olfactory neurogenesis in mThy1 transgenic mice highlights the importance of temporal expression characteristics of alpha-Synuclein on the maturation of newborn neurons.

  15. SIRT-1 regulates TGF-β-induced dermal fibroblast migration via modulation of Cyr61 expression.

    Science.gov (United States)

    Kwon, Eun-Jeong; Park, Eun-Jung; Yu, Hyeran; Huh, Jung-Sik; Kim, Jinseok; Cho, Moonjae

    2018-05-01

    SIRT1 is a NAD-dependent protein deacetylase that participates in cellular regulation. The increased migration of fibroblasts is an important phenotype in fibroblast activation. The role of SIRT1 in cell migration remains controversial as to whether SIRT1 acts as an activator or suppressor of cell migration. Therefore, we have established the role of SIRT1 in the migration of human dermal fibroblasts and explored targets of SIRT1 during dermal fibroblast migration. SIRT1 and Cyr61 were expressed in human dermal fibroblasts and the stimulation with TGF-β further induced their expression. Treatment with resveratrol (RSV), a SIRT1 agonist, or overexpression of SIRT1 also promoted the expression Cyr61 in human dermal fibroblasts, whereas the inhibition of SIRT1 activity by nicotinamide or knockdown of SIRT1 decreased the level of Cyr61, as well as TGF-β or RSV-induced Cyr61 expression. Blocking of ERK signaling by PD98509 reduced the expression of Cyr61 induced by TGF-β or RSV. TGF-β, RSV, or SIRT1 overexpression enhanced β-catenin as well as Cyr61 expression. This stimulation was reduced by the Wnt inhibitor XAV939. RSV increased migration and nicotinamide attenuated RSV-induced migration of human dermal fibroblasts. Furthermore, SIRT1 overexpression promoted cell migration, whereas blocking Cyr61 attenuated SIRT1-stimulated migration of human dermal fibroblasts. SIRT1 increased cell migration by stimulating Cyr61 expression and the ERK and Wnt/β-catenin signaling. SIRT1-induced Cyr61 activity is very important for human dermal fibroblasts migration.

  16. IGF-1 modulates gene expression of proteins involved in inflammation, cytoskeleton, and liver architecture.

    Science.gov (United States)

    Lara-Diaz, V J; Castilla-Cortazar, I; Martín-Estal, I; García-Magariño, M; Aguirre, G A; Puche, J E; de la Garza, R G; Morales, L A; Muñoz, U

    2017-05-01

    Even though the liver synthesizes most of circulating IGF-1, it lacks its receptor under physiological conditions. However, according to previous studies, a damaged liver expresses the receptor. For this reason, herein, we examine hepatic histology and expression of genes encoding proteins of the cytoskeleton, extracellular matrix, and cell-cell molecules and inflammation-related proteins. A partial IGF-1 deficiency murine model was used to investigate IGF-1's effects on liver by comparing wild-type controls, heterozygous igf1 +/- , and heterozygous mice treated with IGF-1 for 10 days. Histology, microarray for mRNA gene expression, RT-qPCR, and lipid peroxidation were assessed. Microarray analyses revealed significant underexpression of igf1 in heterozygous mice compared to control mice, restoring normal liver expression after treatment, which then normalized its circulating levels. IGF-1 receptor mRNA was overexpressed in Hz mice liver, while treated mice displayed a similar expression to that of the controls. Heterozygous mice showed overexpression of several genes encoding proteins related to inflammatory and acute-phase proteins and underexpression or overexpression of genes which coded for extracellular matrix, cytoskeleton, and cell junction components. Histology revealed an altered hepatic architecture. In addition, liver oxidative damage was found increased in the heterozygous group. The mere IGF-1 partial deficiency is associated with relevant alterations of the hepatic architecture and expression of genes involved in cytoskeleton, hepatocyte polarity, cell junctions, and extracellular matrix proteins. Moreover, it induces hepatic expression of the IGF-1 receptor and elevated acute-phase and inflammation mediators, which all resulted in liver oxidative damage.

  17. Quantification of gene expression modulation at the human genome wide induced by low doses of ionizing radiations

    International Nuclear Information System (INIS)

    Nosel, Ingrid

    2013-01-01

    The main goal of this study is to identify the molecular mechanisms involved in the response to low doses of ionizing radiation by using oligonucleotide micro-arrays. The results presented in this study demonstrate the relevance of this tool in the characterization of changes in gene expression at low doses of g radiation. All experimentations conducted were conducted on T CD4+ human lymphocytes. From this model we tried to characterize in 600 minutes after irradiation the molecular players in response to a dose range of 5 and 500 mGy. In this study, we highlight two types of molecular response. First, a dose-dependent response to irradiation involving groups of genes whose proteins are implicated in the response to DNA damage and in the p53 signaling pathway. The expression of the majority of the genes is modulated from 100 mGy. The second type of response is independent of the irradiation dose and the proteins encoded are involved in the mechanism of oxidative phosphorylation. Some of these genes could potentially be regulated by a family of transcription factor with an ETS domain. These ETS factors are known to be potential targets of the MAPKinase pathway. All these genes are modulated from 5 mGy and are therefore potential molecular players involved in the cellular response to ionizing stress with a low intensity. (author)

  18. Ovarian steroid hormones modulate the expression of progesterone receptors and histone acetylation patterns in uterine leiomyoma cells.

    Science.gov (United States)

    Sant'Anna, Gabriela Dos Santos; Brum, Ilma Simoni; Branchini, Gisele; Pizzolato, Lolita Schneider; Capp, Edison; Corleta, Helena von Eye

    2017-08-01

    Uterine leiomyomas are the most common benign smooth muscle cell tumors in women. Estrogen (E2), progesterone (P4) and environmental factors play important roles in the development of these tumors. New treatments, such as mifepristone, have been proposed. We evaluated the gene expression of total (PRT) and B (PRB) progesterone receptors, and the histone acetyltransferase (HAT) and deacetylase (HDAC) activity after treatment with E2, P4 and mifepristone (RU486) in primary cell cultures from uterine leiomyoma and normal myometrium. Compared to myometrium, uterine leiomyoma cells showed an increase in PRT mRNA expression when treated with E2, and increase in PRB mRNA expression when treated with E2 and P4. Treatment with mifepristone had no significant impact on mRNA expression in these cells. The HDAC activity was higher in uterine leiomyoma compared to myometrial cells after treatment with E2 and E2 + P4 + mifepristone. HAT activity was barely detectable. Our results suggest that ovarian steroid hormones modulate PR, and mifepristone was unable to decrease PRT and PRB mRNA. The higher activity of HDAC leiomyoma cells could be involved in transcriptional repression of genes implicated in normal myometrium cell function, contributing to the maintenance and growth of uterine leiomyoma.

  19. Biphenyl Modulates the Expression and Function of Respiratory Oxidases in the Polychlorinated-Biphenyls Degrader Pseudomonas pseudoalcaligenes KF707

    Directory of Open Access Journals (Sweden)

    Federica Sandri

    2017-06-01

    Full Text Available Pseudomonas pseudoalcaligenes KF707 is a soil bacterium which is known for its capacity to aerobically degrade harmful organic compounds such as polychlorinated biphenyls (PCBs using biphenyl as co-metabolite. Here we provide the first genetic and functional analysis of the KF707 respiratory terminal oxidases in cells grown with two different carbon sources: glucose and biphenyl. We identified five terminal oxidases in KF707: two c(caa3 type oxidases (Caa3 and Ccaa3, two cbb3 type oxidases (Cbb31 and Cbb32, and one bd type cyanide-insensitive quinol oxidase (CIO. While the activity and expression of both Cbb31 and Cbb32 oxidases was prevalent in glucose grown cells as compared to the other oxidases, the activity and expression of the Caa3 oxidase increased considerably only when biphenyl was used as carbon source in contrast to the Cbb32 oxidase which was repressed. Further, the respiratory activity and expression of CIO was up-regulated in a Cbb31 deletion strain as compared to W.T. whereas the CIO up-regulation was not present in Cbb32 and C(caa3 deletion mutants. These results, together, reveal that both function and expression of cbb3 and caa3 type oxidases in KF707 are modulated by biphenyl which is the co-metabolite needed for the activation of the PCBs-degradation pathway.

  20. Gene expression changes of single skeletal muscle fibers in response to modulation of the mitochondrial calcium uniporter (MCU

    Directory of Open Access Journals (Sweden)

    Francesco Chemello

    2015-09-01

    Full Text Available The mitochondrial calcium uniporter (MCU gene codifies for the inner mitochondrial membrane (IMM channel responsible for mitochondrial Ca2+ uptake. Cytosolic Ca2+ transients are involved in sarcomere contraction through cycles of release and storage in the sarcoplasmic reticulum. In addition cytosolic Ca2+ regulates various signaling cascades that eventually lead to gene expression reprogramming. Mitochondria are strategically placed in close contact with the ER/SR, thus cytosolic Ca2+ transients elicit large increases in the [Ca2+] of the mitochondrial matrix ([Ca2+]mt. Mitochondrial Ca2+ uptake regulates energy production and cell survival. In addition, we recently showed that MCU-dependent mitochondrial Ca2+ uptake controls skeletal muscle trophism. In the same report, we dissected the effects of MCU-dependent mitochondrial Ca2+ uptake on gene expression through microarray gene expression analysis upon modulation of MCU expression by in vivo AAV infection. Analyses were performed on single skeletal muscle fibers at two time points (7 and 14 days post-AAV injection. Raw and normalized data are available on the GEO database (http://www.ncbi.nlm.nih.gov/geo/ (GSE60931.

  1. Ionizing radiation modulates the surface expression of human leukocyte antigen-G in a human melanoma cell line

    Energy Technology Data Exchange (ETDEWEB)

    Michelin, S.; Gallegos, C.E.; Dubner, D. [Radiopathology Laboratory, Nuclear Regulatory Authority, Buenos Aires (Argentina); Favier, B.; Carosella, E.D. [CEA, I2BM, Hopital Saint-Louis, IUH, Service de Recherches en Hemato-Immunologie, Paris (France)

    2009-07-01

    Human leukocyte antigen G (HLA-G) is a nonclassical HLA class I molecule involved in fetus protection from the maternal immune system, transplant tolerance, and viral and tumoral immune escape. Tumor-specific HLA-G expression has been described for a wide variety of malignancies, including melanomas. The aim of this study was to evaluate whether ionizing radiation (IR) could modulate the surface expression of HLA-G1 in a human melanoma cell line that expresses endogenously membrane-bound HLA-G1. For this purpose, cells were exposed to increasing doses of {gamma}-irradiation (0-20 Gy) and HLA-G1 levels at the plasma membrane were analyzed at different times postirradiation by flow cytometry. HLA-G total expression and the presence of the soluble form of HLA-G1 (sHLA-G1) in the culture medium of irradiated cells were also evaluated. IR was capable of down regulating cell surface and total HLA-G levels, with a concomitant increase of sHLA-G1 in the medium. These results could indicate that {gamma}-irradiation decreases HLA-G1 surface levels by enhancing the proteolytic cleavage of this molecule. (authors)

  2. Ionizing radiation modulates the surface expression of human leukocyte antigen-G in a human melanoma cell line

    International Nuclear Information System (INIS)

    Michelin, S.; Gallegos, C.E.; Dubner, D.; Favier, B.; Carosella, E.D.

    2009-01-01

    Human leukocyte antigen G (HLA-G) is a nonclassical HLA class I molecule involved in fetus protection from the maternal immune system, transplant tolerance, and viral and tumoral immune escape. Tumor-specific HLA-G expression has been described for a wide variety of malignancies, including melanomas. The aim of this study was to evaluate whether ionizing radiation (IR) could modulate the surface expression of HLA-G1 in a human melanoma cell line that expresses endogenously membrane-bound HLA-G1. For this purpose, cells were exposed to increasing doses of γ-irradiation (0-20 Gy) and HLA-G1 levels at the plasma membrane were analyzed at different times postirradiation by flow cytometry. HLA-G total expression and the presence of the soluble form of HLA-G1 (sHLA-G1) in the culture medium of irradiated cells were also evaluated. IR was capable of down regulating cell surface and total HLA-G levels, with a concomitant increase of sHLA-G1 in the medium. These results could indicate that γ-irradiation decreases HLA-G1 surface levels by enhancing the proteolytic cleavage of this molecule. (authors)

  3. miR-342 regulates BRCA1 expression through modulation of ID4 in breast cancer.

    Directory of Open Access Journals (Sweden)

    Elisabetta Crippa

    Full Text Available A miRNAs profiling on a group of familial and sporadic breast cancers showed that miRNA-342 was significantly associated with estrogen receptor (ER levels. To investigate at functional level the role of miR-342 in the pathogenesis of breast cancer, we focused our attention on its "in silico" predicted putative target gene ID4, a transcription factor of the helix-loop-helix protein family whose expression is inversely correlated with that of ER. ID4 is expressed in breast cancer and can negatively regulate BRCA1 expression. Our results showed an inverse correlation between ID4 and miR-342 as well as between ID4 and BRCA1 expression. We functionally validated the interaction between ID4 and miR-342 in a reporter Luciferase system. Based on these findings, we hypothesized that regulation of ID4 mediated by miR-342 could be involved in the pathogenesis of breast cancer by downregulating BRCA1 expression. We functionally demonstrated the interactions between miR-342, ID4 and BRCA1 in a model provided by ER-negative MDA-MB-231 breast cancer cell line that presented high levels of ID4. Overexpression of miR-342 in these cells reduced ID4 and increased BRCA1 expression, supporting a possible role of this mechanism in breast cancer. In the ER-positive MCF7 and in the BRCA1-mutant HCC1937 cell lines miR-342 over-expression only reduced ID4. In the cohort of patients we studied, a correlation between miR-342 and BRCA1 expression was found in the ER-negative cases. As ER-negative cases were mainly BRCA1-mutant, we speculate that the mechanism we demonstrated could be involved in the decreased expression of BRCA1 frequently observed in non BRCA1-mutant breast cancers and could be implicated as a causal factor in part of the familial cases grouped in the heterogeneous class of non BRCA1 or BRCA2-mutant cases (BRCAx. To validate this hypothesis, the study should be extended to a larger cohort of ER-negative cases, including those belonging to the BRCAx class.

  4. Tissue-specific expression of aryl hydrocarbon receptor and putative developmental regulatory modules in Baltic salmon yolk-sac fry

    Energy Technology Data Exchange (ETDEWEB)

    Vuori, Kristiina A. [Centre of Excellence in Evolutionary Genetics and Physiology, Department of Biology, University of Turku, FI-20014 Turku (Finland)], E-mail: kristiina.vuori@utu.fi; Nordlund, Eija [Department of Information Technology, University of Turku, and Turku Centre for Computer Science (TUCS), FI-20014 Turku (Finland); Kallio, Jenny [Centre of Excellence in Evolutionary Genetics and Physiology, Department of Biology, University of Turku, FI-20014 Turku (Finland); Salakoski, Tapio [Department of Information Technology, University of Turku, and Turku Centre for Computer Science (TUCS), FI-20014 Turku (Finland); Nikinmaa, Mikko [Centre of Excellence in Evolutionary Genetics and Physiology, Department of Biology, University of Turku, FI-20014 Turku (Finland)

    2008-04-08

    The aryl hydrocarbon receptor (AhR) is an ancient protein that is conserved in vertebrates and invertebrates, indicating its important function throughout evolution. AhR has been studied largely because of its role in toxicology-gene expression via AhR is induced by many aromatic hydrocarbons in mammals. Recently, however, it has become clear that AhR is involved in various aspects of development such as cell proliferation and differentiation, and cell motility and migration. The mechanisms by which AhR regulates these various functions remain poorly understood. Across-species comparative studies of AhR in invertebrates, non-mammalian vertebrates and mammals may help to reveal the multiple functions of AhR. Here, we have studied AhR during larval development of Baltic salmon (Salmon salar). Our results indicate that AhR protein is expressed in nervous system, liver and muscle tissues. We also present putative regulatory modules and module-matching genes, produced by chromatin immunoprecipitation (ChIP) cloning and in silico analysis, which may be associated with evolutionarily conserved functions of AhR during development. For example, the module NFKB-AHRR-CREB found from salmon ChIP sequences is present in human ULK3 (regulating formation of granule cell axons in mouse and axon outgrowth in Caernohabditis elegans) and SRGAP1 (GTPase-activating protein involved in the Slit/Robo pathway) promoters. We suggest that AhR may have an evolutionarily conserved role in neuronal development and nerve cell targeting, and in Wnt signaling pathway.

  5. Tissue-specific expression of aryl hydrocarbon receptor and putative developmental regulatory modules in Baltic salmon yolk-sac fry

    International Nuclear Information System (INIS)

    Vuori, Kristiina A.; Nordlund, Eija; Kallio, Jenny; Salakoski, Tapio; Nikinmaa, Mikko

    2008-01-01

    The aryl hydrocarbon receptor (AhR) is an ancient protein that is conserved in vertebrates and invertebrates, indicating its important function throughout evolution. AhR has been studied largely because of its role in toxicology-gene expression via AhR is induced by many aromatic hydrocarbons in mammals. Recently, however, it has become clear that AhR is involved in various aspects of development such as cell proliferation and differentiation, and cell motility and migration. The mechanisms by which AhR regulates these various functions remain poorly understood. Across-species comparative studies of AhR in invertebrates, non-mammalian vertebrates and mammals may help to reveal the multiple functions of AhR. Here, we have studied AhR during larval development of Baltic salmon (Salmon salar). Our results indicate that AhR protein is expressed in nervous system, liver and muscle tissues. We also present putative regulatory modules and module-matching genes, produced by chromatin immunoprecipitation (ChIP) cloning and in silico analysis, which may be associated with evolutionarily conserved functions of AhR during development. For example, the module NFKB-AHRR-CREB found from salmon ChIP sequences is present in human ULK3 (regulating formation of granule cell axons in mouse and axon outgrowth in Caernohabditis elegans) and SRGAP1 (GTPase-activating protein involved in the Slit/Robo pathway) promoters. We suggest that AhR may have an evolutionarily conserved role in neuronal development and nerve cell targeting, and in Wnt signaling pathway

  6. Mercury exposure induces cytoskeleton disruption and loss of renal function through epigenetic modulation of MMP9 expression.

    Science.gov (United States)

    Khan, Hafizurrahman; Singh, Radha Dutt; Tiwari, Ratnakar; Gangopadhyay, Siddhartha; Roy, Somendu Kumar; Singh, Dhirendra; Srivastava, Vikas

    2017-07-01

    Mercury is one of the major heavy metal pollutants occurring in elemental, inorganic and organic forms. Due to ban on most inorganic mercury containing products, human exposure to mercury generally occurs as methylmercury (MeHg) by consumption of contaminated fish and other sea food. Animal and epidemiological studies indicate that MeHg affects neural and renal function. Our study is focused on nephrotoxic potential of MeHg. In this study, we have shown for the first time how MeHg could epigenetically modulate matrix metalloproteinase 9(MMP9) to promote nephrotoxicity using an animal model of sub chronic MeHg exposure. MeHg caused renal toxicity as was seen by increased levels of serum creatinine and expression of early nephrotoxicity markers (KIM-1, Clusterin, IP-10, and TIMP). MeHg exposure also correlated strongly with induction of MMP9 mRNA and protein in a dose dependent manner. Further, while induction of MMP9 promoted cytoskeleton disruption and loss of cell-cell adhesion (loss of F-actin, Vimentin and Fibronectin), inhibition of MMP9 was found to reduce these disruptions. Mechanistic studies by ChIP analysis showed that MeHg modulated MMP9 by promoting demethylation of its regulatory region to increase its expression. Bisulfite sequencing identified critical CpGs in the first exon of MMP9 which were demethylated following MeHg exposure. ChIP studies also showed loss of methyl binding protein, MeCP2 and transcription factor PEA3 at the demethylated site confirming decreased CpG methylation. Our studies thus show how MeHg could epigenetically modulate MMP9 to promote cytoskeleton disruption leading to loss of renal function. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Dioxines en PCB's in Chinese wolhandkrab; invloed van grootte en variatie door het seizoen

    NARCIS (Netherlands)

    Kotterman, M.J.J.; Vries, de P.; Leeuwen, van S.P.J.; Hoogenboom, L.A.P.

    2015-01-01

    De monitoringsstudies naar de vervuilingsgraad van Chinese Wolhandkrab (WHK) die vanaf 2010 in Nederlandse wateren worden uitgevoerd tonen aan dat de WHK sterk vervuild kan zijn met polychloordibenzo-p-dioxines en -furanen (PCDD/F's, verderop aangeduid als 'dioxines'), met dioxine-achtige

  8. Formation and removal of dioxins in a MSWI during different operating periods

    Energy Technology Data Exchange (ETDEWEB)

    Wang, H.C.; Hwang, J.F. [Center for Environmental, Safety, and Health Technology, Industrial Technology Research Institute, Hsin-Chu (Taiwan). Environmental Health and Air Pollution Division; Chang, M.B.; Chi, K.H. [National Central University, Chungli (Taiwan). Graduate Inst. of Environmental Engineering

    2004-09-15

    There was little literature to report the dioxin emission concentrations and characteristics during start-up and burndown periods. This research aims to establish the databases of dioxin concentrations in the flue gas and evaluate the dioxin removal efficiencies by air pollution control devices (APCDs) at different operating periods (during start-up, normal operating and burn down periods).

  9. A chain model for dioxins: from emission to cow's milk

    NARCIS (Netherlands)

    Slob W; Klepper O; van Jaarsveld JA

    1993-01-01

    A chain model for dioxins is discussed relating dioxin levels in cow's milk to emissions. It was used to explain the elevated dioxin concentrations found in cow's milk at various MSW incinerators. It also served as an aid in the selection of locations for milk analyses in still

  10. INFLUENCE OF SHORT-TERM DIETARY MEASURES ON DIOXIN CONCENTRATIONS IN HUMAN-MILK

    NARCIS (Netherlands)

    PLUIM, HJ; BOERSMA, ER; KRAMER, [No Value; OLIE, K; VANDERSLIKKE, JW; KOPPE, JG

    Breast-feeding may expose infants to high levels of toxic chlorinated dioxins. To diminish intake of these lipophilic compounds by the baby, two diets were tested for their ability to reduce concentrations of dioxins in human milk. The diets were a low-fat/high-carbohydrate/low-dioxin diet (about

  11. 75 FR 17857 - Removal of Obsolete References to Herbicides Containing Dioxin

    Science.gov (United States)

    2010-04-08

    ... Herbicides Containing Dioxin AGENCY: Department of Veterans Affairs. ACTION: Final rule. SUMMARY: The... health effects of exposure to herbicides containing dioxin and radiation to remove the obsolete references to herbicides containing dioxin. This final rule reflects changes made by the Agent Orange Act of...

  12. Effect of flock Size on Dioxin Levels in eggs from Chickens kept Outside

    NARCIS (Netherlands)

    Kijlstra, A.; Traag, W.A.; Hoogenboom, L.A.P.

    2007-01-01

    To decrease dioxin uptake by the general population the European Union (EU) has set limits to the dioxin content of many foodstuffs including eggs. Eggs from free foraging chickens are known to have a higher dioxin content compared with confined laying hens, and the question is whether these eggs

  13. DNA methylation modulates H19 and IGF2 expression in porcine female eye

    Directory of Open Access Journals (Sweden)

    Dongxu Wang

    2017-03-01

    Full Text Available Abstract The sexually dimorphic expression of H19/IGF2 is evolutionarily conserved. To investigate whether the expression of H19/IGF2 in the female porcine eye is sex-dependent, gene expression and methylation status were evaluated using quantitative real-time PCR (qPCR and bisulfite sequencing PCR (BSP. We hypothesized that H19/IGF2 might exhibit a different DNA methylation status in the female eye. In order to evaluate our hypothesis, parthenogenetic (PA cells were used for analysis by qPCR and BSP. Our results showed that H19 and IGF2 were over-expressed in the female eye compared with the male eye (3-fold and 2-fold, respectively. We observed a normal monoallelic methylation pattern for H19 differentially methylated regions (DMRs. Compared with H19 DMRs, IGF2 DMRs showed a different methylation pattern in the eye. Taken together, these results suggest that elevated expression of H19/IGF2 is caused by a specific chromatin structure that is regulated by the DNA methylation status of IGF2 DMRs in the female eye.

  14. DNA methylation modulates H19 and IGF2 expression in porcine female eye

    Science.gov (United States)

    Wang, Dongxu; Wang, Guodong; Yang, Hao; Liu, Haibo; Li, Cuie; Li, Xiaolan; Lin, Chao; Song, Yuning; Li, Zhanjun; Liu, Dianfeng

    2017-01-01

    Abstract The sexually dimorphic expression of H19/IGF2 is evolutionarily conserved. To investigate whether the expression of H19/IGF2 in the female porcine eye is sex-dependent, gene expression and methylation status were evaluated using quantitative real-time PCR (qPCR) and bisulfite sequencing PCR (BSP). We hypothesized that H19/IGF2 might exhibit a different DNA methylation status in the female eye. In order to evaluate our hypothesis, parthenogenetic (PA) cells were used for analysis by qPCR and BSP. Our results showed that H19 and IGF2 were over-expressed in the female eye compared with the male eye (3-fold and 2-fold, respectively). We observed a normal monoallelic methylation pattern for H19 differentially methylated regions (DMRs). Compared with H19 DMRs, IGF2 DMRs showed a different methylation pattern in the eye. Taken together, these results suggest that elevated expression of H19/IGF2 is caused by a specific chromatin structure that is regulated by the DNA methylation status of IGF2 DMRs in the female eye. PMID:28266684

  15. Expression of modulators of extracellular matrix structure after anterior cruciate ligament injury.

    Science.gov (United States)

    Haslauer, Carla M; Proffen, Benedikt L; Johnson, Victor M; Murray, Martha M

    2014-01-01

    The ability of the anterior cruciate ligament (ACL) to heal after injury declines within the first 2 weeks after ACL rupture. To begin to explore the mechanism behind this finding, we quantified the expression of genes for collagen I and III, decorin, tenascin-C, and alpha smooth muscle actin, as well as matrix metalloproteinase (MMP)-1 and -13 gene expression within multiple tissues of the knee joint after ACL injury in a large animal model over a 2-week postinjury period. Gene expression of collagen I and III, decorin, and MMP-1 was highest in the synovium, whereas the highest MMP-13 gene expression levels were found in the ACL. The gene expression for collagen and decorin increased over the 2 weeks to levels approaching that in the ligament and synovium; however, no significant increase in either of the MMPs was found in the provisional scaffold. This suggests that although the ACL and synovium up-regulate both anabolic and catabolic factors, the provisional scaffold is primarily anabolic in function. The relative lack of provisional scaffold formation within the joint environment may thus be one of the key reasons for ACL degradation after injury. © 2014 by the Wound Healing Society.

  16. A rapid and reagent-free bioassay for the detection of dioxin-like compounds and other aryl hydrocarbon receptor (AhR) agonists using autobioluminescent yeast.

    Science.gov (United States)

    Xu, Tingting; Young, Anna; Marr, Enolia; Sayler, Gary; Ripp, Steven; Close, Dan

    2018-02-01

    An autonomously bioluminescent Saccharomyces cerevisiae BLYAhS bioreporter was developed in this study for the simple and rapid detection of dioxin-like compounds (DLCs) and aryl hydrocarbon receptor (AhR) agonists. This recombinant yeast reporter was based on a synthetic bacterial luciferase reporter gene cassette (lux) that can produce the luciferase as well as the enzymes capable of self-synthesizing the requisite substrates for bioluminescent production from endogenous cellular metabolites. As a result, bioluminescent signal production is generated continuously and autonomously without cell lysis or exogenous reagent addition. By linking the expression of the autobioluminescent lux reporter cassette to AhR activation via the use of a dioxin-responsive promoter, the S. cerevisiae BLYAhS bioreporter emitted a bioluminescent signal in response to DLC exposure in a dose-responsive manner. The model dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), could be detected within 4 h with a half maximal effective concentration (EC 50 ) of ~ 8.1 nM and a lower detection limit of 500 pM. The autobioluminescent response of BLYAhS to other AhR agonists, including 2,3,7,8-tetrachlorodibenzofuran (TCDF), polychlorinated bisphenyl congener 126 (PCB-126) and 169 (PCB-169), 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin (HxCDD), 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD), benzo[a]pyrene (BaP), and β-naphthoflavone (bNF), were also characterized in this study. The non-destructive and reagent-free nature of the BLYAhS reporter assay facilitated near-continuous, automated signal acquisition without additional hands-on effort and cost, providing a simple and cost-effective method for rapid DLC detection.

  17. Peptides Trapping Dioxins: A Docking-Based Inverse Screening Approach

    Directory of Open Access Journals (Sweden)

    German Perez

    2013-01-01

    Full Text Available A rapid and cost-effective computational methodology for designing and rationalizing the selection of small peptides as receptors for dioxin-like compounds was proposed. The backbone of the dioxin Ah receptor binding site was used to design a series of penta- and hexapeptide libraries, with 1400 elements in total. Peptide flexibility was considered and 10 conformers were found to be a good option to represent peptide conformational space with fair speed-accuracy ratio. Each peptide conformer was treated as a possible receptor, generating a dedicated box and then running a docking process using as ligands a family of 76 dibenzo-p-dioxins and 113 dibenzofurans mono- and polychlorinated. Significant predictions were confirmed by comparing primary structure of top and bottom ranked peptides binding dioxins confirming that scrambled positions of the same amino acids gave completely different predicted binding. The hexapeptide EWFQPW, with the best binding score, was chosen as selective sorbent material in solid-phase extraction. The retention performances were tested using the 2,3,7,8-tetrachlorodibenzo-p-dioxin and two polychlorinated biphenyls in order to verify the hexapeptide specificity. The solid-phase extraction experimental procedure was optimized, and analytical parameters of hexapeptide sorbent material were compared with the resin without hexapeptide and a commercial reversed phase cartridge.

  18. Infection by chikungunya virus modulates the expression of several proteins in Aedes aegypti salivary glands

    Directory of Open Access Journals (Sweden)

    Tchankouo-Nguetcheu Stephane

    2012-11-01

    Full Text Available Abstract Background Arthropod-borne viral infections cause several emerging and resurging infectious diseases. Among the diseases caused by arboviruses, chikungunya is responsible for a high level of severe human disease worldwide. The salivary glands of mosquitoes are the last barrier before pathogen transmission. Methods We undertook a proteomic approach to characterize the key virus/vector interactions and host protein modifications that occur in the salivary glands that could be responsible for viral transmission by using quantitative two-dimensional electrophoresis. Results We defined the protein modulations in the salivary glands of Aedes aegypti that were triggered 3 and 5 days after an oral infection (3 and 5 DPI with chikungunya virus (CHIKV. Gel profile comparisons showed that CHIKV at 3 DPI modulated the level of 13 proteins, and at 5 DPI 20 proteins. The amount of 10 putatively secreted proteins was regulated at both time points. These proteins were implicated in blood-feeding or in immunity, but many have no known function. CHIKV also modulated the quantity of proteins involved in several metabolic pathways and in cell signalling. Conclusion Our study constitutes the first analysis of the protein response of Aedes aegypti salivary glands infected with CHIKV. We found that the differentially regulated proteins in response to viral infection include structural proteins and enzymes for several metabolic pathways. Some may favour virus survival, replication and transmission, suggesting a subversion of the insect cell metabolism by arboviruses. For example, proteins involved in blood-feeding such as the short D7, an adenosine deaminase and inosine-uridine preferring nucleoside hydrolase, may favour virus transmission by exerting an increased anti-inflammatory effect. This would allow the vector to bite without the bite being detected. Other proteins, like the anti-freeze protein, may support vector protection.

  19. Polydimethylsiloxane (PDMS) modulates CD38 expression, absorbs retinoic acid and may perturb retinoid signalling.

    Science.gov (United States)

    Futrega, Kathryn; Yu, Jianshi; Jones, Jace W; Kane, Maureen A; Lott, William B; Atkinson, Kerry; Doran, Michael R

    2016-04-21

    Polydimethylsiloxane (PDMS) is the most commonly used material in the manufacture of customized cell culture devices. While there is concern that uncured PDMS oligomers may leach into culture medium and/or hydrophobic molecules may be absorbed into PDMS structures, there is no consensus on how or if PDMS influences cell behaviour. We observed that human umbilical cord blood (CB)-derived CD34(+) cells expanded in standard culture medium on PDMS exhibit reduced CD38 surface expression, relative to cells cultured on tissue culture polystyrene (TCP). All-trans retinoic acid (ATRA) induces CD38 expression, and we reasoned that this hydrophobic molecule might be absorbed by PDMS. Through a series of experiments we demonstrated that ATRA-mediated CD38 expression was attenuated when cultures were maintained on PDMS. Medium pre-incubated on PDMS for extended durations resulted in a time-dependant reduction of ATRA in the medium and increasingly attenuated CD38 expression. This indicated a time-dependent absorption of ATRA into the PDMS. To better understand how PDMS might generally influence cell behaviour, Ingenuity Pathway Analysis (IPA) was used to identify potential upstream regulators. This analysis was performed for differentially expressed genes in primary cells including CD34(+) haematopoietic progenitor cells, mesenchymal stromal cells (MSC), and keratinocytes, and cell lines including prostate cancer epithelial cells (LNCaP), breast cancer epithelial cells (MCF-7), and myeloid leukaemia cells (KG1a). IPA predicted that the most likely common upstream regulator of perturbed pathways was ATRA. We demonstrate here that ATRA is absorbed by PDMS in a time-dependent manner and results in the concomitant reduced expression of CD38 on the cell surface of CB-derived CD34(+) cells.