Applications of NMR spectroscopy to xenobiotic metabolism

International Nuclear Information System (INIS)

Harris, T.M.

1989-01-01

Recent years have seen high field NMR spectrometers become commonplace in research laboratories. At the same time, major advances in methodology for structural analysis have occurred, particularly notable among these being the development of two-dimensional spectroscopic techniques. Many applications have been made of NMR spectroscopy in the study of xenobiotic metabolic processes. This deals with two specific applications which have been made in the author's laboratory and involve mechanistic studies of the reactions of the carcinogens ethylene dibromide and aflatoxin with DNA

Xenobiotic metabolism in human skin and 3D human skin reconstructs: A review

NARCIS (Netherlands)

Gibbs, S.; Sandt, J.J.M. van de; Merk, H.F.; Lockley, D.J.; Pendlington, R.U.; Pease, C.K.

2007-01-01

In this review, we discuss and compare studies of xenobiotic metabolism in both human skin and 3D human skin reconstructs. In comparison to the liver, the skin is a less studied organ in terms of characterising metabolic capability. While the skin forms the major protective barrier to environmental

Intrinsic Xenobiotic Metabolizing Enzyme Activities in Early Life Stages of Zebrafish (Danio rerio).

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Otte, Jens C; Schultz, Bernadette; Fruth, Daniela; Fabian, Eric; van Ravenzwaay, Bennard; Hidding, Björn; Salinas, Edward R

2017-09-01

Early life stages of zebrafish (Danio rerio, zf) are gaining attention as an alternative invivo test system for drug discovery, early developmental toxicity screenings and chemical testing in ecotoxicological and toxicological testing strategies. Previous studies have demonstrated transcriptional evidence for xenobiotic metabolizing enzymes (XME) during early zf development. However, elaborate experiments on XME activities during development are incomplete. In this work, the intrinsic activities of representative phase I and II XME were monitored by transformation of putative zf model substrates analyzed using photometry and high pressure liquid chromatography techniques. Six different defined stages of zf development (between 2.5 h postfertilization (hpf) to 120 hpf) were investigated by preparing a subcellular fraction from whole organism homogenates. We demonstrated that zf embryos as early as 2.5 hpf possess intrinsic metabolic activities for esterase, Aldh, Gst, and Cyp1a above the methodological detection limit. The activities of the enzymes Cyp3a and Nat were measurable during later stages in development. Activities represent dynamic patterns during development. The role of XME activities revealed in this work is relevant for the assessing toxicity in this test system and therefore contributes to a valuable characterization of zf embryos as an alternative testing organism in toxicology. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Retrofit Strategies for Incorporating Xenobiotic Metabolism into High Throughput Screening Assays (EMGS)

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The US EPA’s ToxCast program is designed to assess chemical perturbations of molecular and cellular endpoints using a variety of high-throughput screening (HTS) assays. However, existing HTS assays have limited or no xenobiotic metabolism which could lead to a mischaracterization...

LC-MS-BASED METABOLOMICS OF XENOBIOTIC-INDUCED TOXICITIES

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Chi Chen

2013-01-01

Full Text Available Xenobiotic exposure, especially high-dose or repeated exposure of xenobiotics, can elicit detrimental effects on biological systems through diverse mechanisms. Changes in metabolic systems, including formation of reactive metabolites and disruption of endogenous metabolism, are not only the common consequences of toxic xenobiotic exposure, but in many cases are the major causes behind development of xenobiotic-induced toxicities (XIT. Therefore, examining the metabolic events associated with XIT generates mechanistic insights into the initiation and progression of XIT, and provides guidance for prevention and treatment. Traditional bioanalytical platforms that target only a few suspected metabolites are capable of validating the expected outcomes of xenobiotic exposure. However, these approaches lack the capacity to define global changes and to identify unexpected events in the metabolic system. Recent developments in high-throughput metabolomics have dramatically expanded the scope and potential of metabolite analysis. Among all analytical techniques adopted for metabolomics, liquid chromatography-mass spectrometry (LC-MS has been most widely used for metabolomic investigations of XIT due to its versatility and sensitivity in metabolite analysis. In this review, technical platform of LC-MS-based metabolomics, including experimental model, sample preparation, instrumentation, and data analysis, are discussed. Applications of LC-MS-based metabolomics in exploratory and hypothesis-driven investigations of XIT are illustrated by case studies of xenobiotic metabolism and endogenous metabolism associated with xenobiotic exposure.

Pharmacokinetic interplay of phase II metabolism and transport: a theoretical study.

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Wu, Baojian

2012-01-01

Understanding of the interdependence of cytochrome P450 enzymes and P-glycoprotein in disposition of drugs (also termed "transport-metabolism interplay") has been significantly advanced in recent years. However, whether such "interplay" exists between phase II metabolic enzymes and efflux transporters remains largely unknown. The objective of this article is to explore the role of efflux transporters (acting on the phase II metabolites) in disposition of the parent drug in Caco-2 cells, liver, and intestine via simulations utilizing a catenary model (for Caco-2 system) and physiologically based pharmacokinetic (PBPK) models (for the liver and intestine). In all three models, "transport-metabolism interplay" (i.e., inhibition of metabolite efflux decreases the metabolism) can be observed only when futile recycling (or deconjugation) occurred. Futile recycling appeared to bridge the two processes (i.e., metabolite formation and excretion) and enable the interplay thereof. Without futile recycling, metabolite formation was independent on its downstream process excretion, thus impact of metabolite excretion on its formation was impossible. Moreover, in liver PBPK model with futile recycling, impact of biliary metabolite excretion on the exposure of parent drug [(systemic (reservoir) area under the concentration-time curve (AUC(R1))] was limited; a complete inhibition of efflux resulted in AUC(R1) increases of less than 1-fold only. In intestine PBPK model with futile recycling, even though a complete inhibition of efflux could result in large elevations (e.g., 3.5-6.0-fold) in AUC(R1), an incomplete inhibition of efflux (e.g., with a residual activity of ≥ 20% metabolic clearance) saw negligible increases (interplay between phase II enzymes and efflux transporters. Those studying such "interplay" are encouraged to adequately consider potential consequences of inhibition of efflux transporters in humans. Copyright © 2011 Wiley-Liss, Inc.

Transgenic plants for enhanced biodegradation and phytoremediation of organic xenobiotics.

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Abhilash, P C; Jamil, Sarah; Singh, Nandita

2009-01-01

Phytoremediation--the use of plants to clean up polluted soil and water resources--has received much attention in the last few years. Although plants have the inherent ability to detoxify xenobiotics, they generally lack the catabolic pathway for the complete degradation of these compounds compared to microorganisms. There are also concerns over the potential for the introduction of contaminants into the food chain. The question of how to dispose of plants that accumulate xenobiotics is also a serious concern. Hence the feasibility of phytoremediation as an approach to remediate environmental contamination is still somewhat in question. For these reasons, researchers have endeavored to engineer plants with genes that can bestow superior degradation abilities. A direct method for enhancing the efficacy of phytoremediation is to overexpress in plants the genes involved in metabolism, uptake, or transport of specific pollutants. Furthermore, the expression of suitable genes in root system enhances the rhizodegradation of highly recalcitrant compounds like PAHs, PCBs etc. Hence, the idea to amplify plant biodegradation of xenobiotics by genetic manipulation was developed, following a strategy similar to that used to develop transgenic crops. Genes from human, microbes, plants, and animals are being used successfully for this venture. The introduction of these genes can be readily achieved for many plant species using Agrobacterium tumefaciens-mediated plant transformation or direct DNA methods of gene transfer. One of the promising developments in transgenic technology is the insertion of multiple genes (for phase 1 metabolism (cytochrome P450s) and phase 2 metabolism (GSH, GT etc.) for the complete degradation of the xenobiotics within the plant system. In addition to the use of transgenic plants overexpressed with P450 and GST genes, various transgenic plants expressing bacterial genes can be used for the enhanced degradation and remediation of herbicides, explosives

Elucidation of xenobiotic metabolism pathways in human skin and human skin models by proteomic profiling.

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Sven van Eijl

Full Text Available BACKGROUND: Human skin has the capacity to metabolise foreign chemicals (xenobiotics, but knowledge of the various enzymes involved is incomplete. A broad-based unbiased proteomics approach was used to describe the profile of xenobiotic metabolising enzymes present in human skin and hence indicate principal routes of metabolism of xenobiotic compounds. Several in vitro models of human skin have been developed for the purpose of safety assessment of chemicals. The suitability of these epidermal models for studies involving biotransformation was assessed by comparing their profiles of xenobiotic metabolising enzymes with those of human skin. METHODOLOGY/PRINCIPAL FINDINGS: Label-free proteomic analysis of whole human skin (10 donors was applied and analysed using custom-built PROTSIFT software. The results showed the presence of enzymes with a capacity for the metabolism of alcohols through dehydrogenation, aldehydes through dehydrogenation and oxidation, amines through oxidation, carbonyls through reduction, epoxides and carboxylesters through hydrolysis and, of many compounds, by conjugation to glutathione. Whereas protein levels of these enzymes in skin were mostly just 4-10 fold lower than those in liver and sufficient to support metabolism, the levels of cytochrome P450 enzymes were at least 300-fold lower indicating they play no significant role. Four epidermal models of human skin had profiles very similar to one another and these overlapped substantially with that of whole skin. CONCLUSIONS/SIGNIFICANCE: The proteomics profiling approach was successful in producing a comprehensive analysis of the biotransformation characteristics of whole human skin and various in vitro skin models. The results show that skin contains a range of defined enzymes capable of metabolising different classes of chemicals. The degree of similarity of the profiles of the in vitro models indicates their suitability for epidermal toxicity testing. Overall, these

Expression profiles of genes involved in xenobiotic metabolism and disposition in human renal tissues and renal cell models

Energy Technology Data Exchange (ETDEWEB)

Van der Hauwaert, Cynthia; Savary, Grégoire [EA4483, Université de Lille 2, Faculté de Médecine de Lille, Pôle Recherche, 59045 Lille (France); Buob, David [Institut de Pathologie, Centre de Biologie Pathologie Génétique, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille (France); Leroy, Xavier; Aubert, Sébastien [Institut de Pathologie, Centre de Biologie Pathologie Génétique, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille (France); Institut National de la Santé et de la Recherche Médicale, UMR837, Centre de Recherche Jean-Pierre Aubert, Equipe 5, 59045 Lille (France); Flamand, Vincent [Service d' Urologie, Hôpital Huriez, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille (France); Hennino, Marie-Flore [EA4483, Université de Lille 2, Faculté de Médecine de Lille, Pôle Recherche, 59045 Lille (France); Service de Néphrologie, Hôpital Huriez, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille (France); Perrais, Michaël [Institut National de la Santé et de la Recherche Médicale, UMR837, Centre de Recherche Jean-Pierre Aubert, Equipe 5, 59045 Lille (France); and others

2014-09-15

Numerous xenobiotics have been shown to be harmful for the kidney. Thus, to improve our knowledge of the cellular processing of these nephrotoxic compounds, we evaluated, by real-time PCR, the mRNA expression level of 377 genes encoding xenobiotic-metabolizing enzymes (XMEs), transporters, as well as nuclear receptors and transcription factors that coordinate their expression in eight normal human renal cortical tissues. Additionally, since several renal in vitro models are commonly used in pharmacological and toxicological studies, we investigated their metabolic capacities and compared them with those of renal tissues. The same set of genes was thus investigated in HEK293 and HK2 immortalized cell lines in commercial primary cultures of epithelial renal cells and in proximal tubular cell primary cultures. Altogether, our data offers a comprehensive description of kidney ability to process xenobiotics. Moreover, by hierarchical clustering, we observed large variations in gene expression profiles between renal cell lines and renal tissues. Primary cultures of proximal tubular epithelial cells exhibited the highest similarities with renal tissue in terms of transcript profiling. Moreover, compared to other renal cell models, Tacrolimus dose dependent toxic effects were lower in proximal tubular cell primary cultures that display the highest metabolism and disposition capacity. Therefore, primary cultures appear to be the most relevant in vitro model for investigating the metabolism and bioactivation of nephrotoxic compounds and for toxicological and pharmacological studies. - Highlights: • Renal proximal tubular (PT) cells are highly sensitive to xenobiotics. • Expression of genes involved in xenobiotic disposition was measured. • PT cells exhibited the highest similarities with renal tissue.

Xenobiotics and the Glucocorticoid Receptor

International Nuclear Information System (INIS)

Gulliver, Linda S M

2017-01-01

Glucocorticoid Receptor (GR) is present in virtually every human cell type. Representing a nuclear receptor superfamily, GR has several different isoforms essentially acting as ligand-dependent transcription factors, regulating glucocorticoid-responsive gene expression in both a positive and a negative manner. Although the natural ligand of the Glucocorticoid Receptor, glucocorticoids (GC) represent only some of the multiple ligands for GR. Xenobiotics, ubiquitous in the environment, bind to GR and are also capable of activating or repressing GR gene expression, thereby modulating GR cell and tissue-specific downstream effects in a multitude of ways that include responses to inflammatory, allergic, metabolic, neoplastic and autoimmune processes. Many xenobiotics, if inadequately metabolized by xenobiotic metabolizing enzymes and not wholly eliminated, could have deleterious toxic effects with potentially lethal consequences. This review examines GR, the genomic and non-genomic actions of natural and synthetic GC and the body's handling of xenobiotic compounds, before reviewing what is presently known about GR's interactions with many of the more commonly encountered and some of the less well known GR-associated xenobiotics. GR promiscuity and crosstalk with other signaling pathways is discussed, alongside novel roles for GR that include mood disorder and addiction. A knowledge of GR interactions with xenobiotics is increasingly relevant when considering aging populations and the related prevalence of neoplastic disease, together with growing concerns around human exposure to mixtures of chemicals in the environment. Furthermore, escalating rates of obesity, Type 2 diabetes; autoimmune, allergy, addiction and mood disorder-related pathologies, require novel targeted interventions and GR appears a promising pharmacological candidate. - Highlights: • Biological impact of xenobiotics acting through Glucocorticoid Receptor. • Promiscuity of Glucocorticoid

Xenobiotics and the Glucocorticoid Receptor

Energy Technology Data Exchange (ETDEWEB)

Gulliver, Linda S M, E-mail: linda.gulliver@otago.ac.nz

2017-03-15

Glucocorticoid Receptor (GR) is present in virtually every human cell type. Representing a nuclear receptor superfamily, GR has several different isoforms essentially acting as ligand-dependent transcription factors, regulating glucocorticoid-responsive gene expression in both a positive and a negative manner. Although the natural ligand of the Glucocorticoid Receptor, glucocorticoids (GC) represent only some of the multiple ligands for GR. Xenobiotics, ubiquitous in the environment, bind to GR and are also capable of activating or repressing GR gene expression, thereby modulating GR cell and tissue-specific downstream effects in a multitude of ways that include responses to inflammatory, allergic, metabolic, neoplastic and autoimmune processes. Many xenobiotics, if inadequately metabolized by xenobiotic metabolizing enzymes and not wholly eliminated, could have deleterious toxic effects with potentially lethal consequences. This review examines GR, the genomic and non-genomic actions of natural and synthetic GC and the body's handling of xenobiotic compounds, before reviewing what is presently known about GR's interactions with many of the more commonly encountered and some of the less well known GR-associated xenobiotics. GR promiscuity and crosstalk with other signaling pathways is discussed, alongside novel roles for GR that include mood disorder and addiction. A knowledge of GR interactions with xenobiotics is increasingly relevant when considering aging populations and the related prevalence of neoplastic disease, together with growing concerns around human exposure to mixtures of chemicals in the environment. Furthermore, escalating rates of obesity, Type 2 diabetes; autoimmune, allergy, addiction and mood disorder-related pathologies, require novel targeted interventions and GR appears a promising pharmacological candidate. - Highlights: • Biological impact of xenobiotics acting through Glucocorticoid Receptor. • Promiscuity of Glucocorticoid

Microbial transformation of xenobiotics for environmental ...

African Journals Online (AJOL)

Microbial transformation of xenobiotics for environmental bioremediation. ... anaerobic and reductive biotransformation by co-metabolic processes and an overview of ... of xenobiotic compounds in context to the modern day biotechnology.

Hepatic xenobiotic metabolizing enzyme and transporter gene expression through the life stages of the mouse.

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Janice S Lee

Full Text Available BACKGROUND: Differences in responses to environmental chemicals and drugs between life stages are likely due in part to differences in the expression of xenobiotic metabolizing enzymes and transporters (XMETs. No comprehensive analysis of the mRNA expression of XMETs has been carried out through life stages in any species. RESULTS: Using full-genome arrays, the mRNA expression of all XMETs and their regulatory proteins was examined during fetal (gestation day (GD 19, neonatal (postnatal day (PND 7, prepubescent (PND32, middle age (12 months, and old age (18 and 24 months in the C57BL/6J (C57 mouse liver and compared to adults. Fetal and neonatal life stages exhibited dramatic differences in XMET mRNA expression compared to the relatively minor effects of old age. The total number of XMET probe sets that differed from adults was 636, 500, 84, 5, 43, and 102 for GD19, PND7, PND32, 12 months, 18 months and 24 months, respectively. At all life stages except PND32, under-expressed genes outnumbered over-expressed genes. The altered XMETs included those in all of the major metabolic and transport phases including introduction of reactive or polar groups (Phase I, conjugation (Phase II and excretion (Phase III. In the fetus and neonate, parallel increases in expression were noted in the dioxin receptor, Nrf2 components and their regulated genes while nuclear receptors and regulated genes were generally down-regulated. Suppression of male-specific XMETs was observed at early (GD19, PND7 and to a lesser extent, later life stages (18 and 24 months. A number of female-specific XMETs exhibited a spike in expression centered at PND7. CONCLUSIONS: The analysis revealed dramatic differences in the expression of the XMETs, especially in the fetus and neonate that are partially dependent on gender-dependent factors. XMET expression can be used to predict life stage-specific responses to environmental chemicals and drugs.

Pigs in Toxicology: Breed Differences in Metabolism and Background Findings.

Science.gov (United States)

Helke, Kristi L; Nelson, Keith N; Sargeant, Aaron M; Jacob, Binod; McKeag, Sean; Haruna, Julius; Vemireddi, Vimala; Greeley, Melanie; Brocksmith, Derek; Navratil, Nicole; Stricker-Krongrad, Alain; Hollinger, Charlotte

2016-06-01

Both a rodent and a nonrodent species are required for evaluation in nonclinical safety studies conducted to support human clinical trials. Historically, dogs and nonhuman primates have been the nonrodent species of choice. Swine, especially the miniature swine or minipigs, are increasingly being used in preclinical safety as an alternate nonrodent species. The pig is an appropriate option for these toxicology studies based on metabolic pathways utilized in xenobiotic biotransformation. Both similarities and differences exist in phase I and phase II biotransformation pathways between humans and pigs. There are numerous breeds of pigs, yet only a few of these breeds are characterized with regard to both xenobiotic-metabolizing enzymes and background pathology findings. Some specific differences in these enzymes based on breed and sex are known. Although swine have been used extensively in biomedical research, there is also a paucity of information in the current literature detailing the incidence of background lesions and differences between commonly used breeds. Here, the xenobiotic-metabolizing enzymes are compared between humans and pigs, and minipig background pathology changes are reviewed with emphasis on breed differences. © The Author(s) 2016.

Xenobiotic-contaminated diets affect hepatic lipid metabolism: Implications for liver steatosis in Sparus aurata juveniles

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Maradonna, F.; Nozzi, V. [Dipartimento di Scienze della Vita e dell’Ambiente, Università Politecnica delle Marche, 60131 Ancona (Italy); Santangeli, S. [Dipartimento di Scienze della Vita e dell’Ambiente, Università Politecnica delle Marche, 60131 Ancona (Italy); INBB Consorzio Interuniversitario di Biosistemi e Biostrutture, 00136 Roma (Italy); Traversi, I. [Dipartimento di Scienze della Terra, dell’Ambiente e della Vita, Università di Genova, 16132 Genova (Italy); Gallo, P. [INBB Consorzio Interuniversitario di Biosistemi e Biostrutture, 00136 Roma (Italy); Dipartimento di Chimica, Istituto Zooprofilattico Sperimentale del Mezzogiorno, 80055 Portici, Napoli (Italy); Fattore, E. [Dipartimento Ambiente e Salute, IRCCS–Istituto di Ricerche Farmacologiche “Mario Negri”, 20156 Milano (Italy); Mita, D.G. [INBB Consorzio Interuniversitario di Biosistemi e Biostrutture, 00136 Roma (Italy); Mandich, A. [INBB Consorzio Interuniversitario di Biosistemi e Biostrutture, 00136 Roma (Italy); Dipartimento di Scienze della Terra, dell’Ambiente e della Vita, Università di Genova, 16132 Genova (Italy); Carnevali, O., E-mail: o.carnevali@univpm.it [Dipartimento di Scienze della Vita e dell’Ambiente, Università Politecnica delle Marche, 60131 Ancona (Italy); INBB Consorzio Interuniversitario di Biosistemi e Biostrutture, 00136 Roma (Italy)

2015-10-15

Highlights: • Diets contaminated with NP, BPA, or t-OP affect lipid metabolism. • Xenobiotic-contaminated diets induce metabolic disorders. • Hepatic metabolic disorders may be related to environmental pollution. - Abstract: The metabolic effects induced by feed contaminated with a lower or a higher concentration of -nonylpnenol (NP), 4-tert-octylphenol (t-OP) or bisphenol A (BPA), three environmental endocrine disruptors, were assessed in juvenile sea bream liver. Histological analysis demonstrated that all these three xenobiotics induced hepatic lipid accumulation and steatosis. These findings prompted analysis of the expression of the major molecules involved in lipid metabolism: peroxisome proliferator activated receptors (which is encoded by ppars), fatty acid synthase (encoded by fas), lipoprotein lipase (encoded by lpl) and hormone-sensitive lipase (encoded by hsl). The enzymes encoded by ppars and fas are in fact responsible for lipid accumulation, whereas lpl- and hsl- encoded proteins play a pivotal role in fat mobilization. The three xenobiotics modulated ppar mRNA expression: pparα mRNA expression was induced by the higher dose of each contaminant; pparβ mRNA expression was upregulated by the lower doses and in BPA2 fish ppary mRNA overexpression was induced by all pollutants. These data agreed with the lipid accumulation profiles documented by histology. Fas mRNA levels were modulated by the two NP doses and the higher BPA concentration. Lpl mRNA was significantly upregulated in all experimental groups except for BPA1 fish while hsl mRNA was significantly downregulated in all groups except for t-OP2 and BPA1 fish. The plasma concentrations of cortisol, the primary stress biomarker, were correlated with the levels of pepck mRNA level. This gene encodes phosphoenolpyruvate carboxykinase which is one of the key enzymes of gluconeogenesis. Pepck mRNA was significantly overexpressed in fish exposed to NP2 and both t-OP doses. Finally, the genes

Xenobiotic-contaminated diets affect hepatic lipid metabolism: Implications for liver steatosis in Sparus aurata juveniles

International Nuclear Information System (INIS)

Maradonna, F.; Nozzi, V.; Santangeli, S.; Traversi, I.; Gallo, P.; Fattore, E.; Mita, D.G.; Mandich, A.; Carnevali, O.

2015-01-01

Highlights: • Diets contaminated with NP, BPA, or t-OP affect lipid metabolism. • Xenobiotic-contaminated diets induce metabolic disorders. • Hepatic metabolic disorders may be related to environmental pollution. - Abstract: The metabolic effects induced by feed contaminated with a lower or a higher concentration of -nonylpnenol (NP), 4-tert-octylphenol (t-OP) or bisphenol A (BPA), three environmental endocrine disruptors, were assessed in juvenile sea bream liver. Histological analysis demonstrated that all these three xenobiotics induced hepatic lipid accumulation and steatosis. These findings prompted analysis of the expression of the major molecules involved in lipid metabolism: peroxisome proliferator activated receptors (which is encoded by ppars), fatty acid synthase (encoded by fas), lipoprotein lipase (encoded by lpl) and hormone-sensitive lipase (encoded by hsl). The enzymes encoded by ppars and fas are in fact responsible for lipid accumulation, whereas lpl- and hsl- encoded proteins play a pivotal role in fat mobilization. The three xenobiotics modulated ppar mRNA expression: pparα mRNA expression was induced by the higher dose of each contaminant; pparβ mRNA expression was upregulated by the lower doses and in BPA2 fish ppary mRNA overexpression was induced by all pollutants. These data agreed with the lipid accumulation profiles documented by histology. Fas mRNA levels were modulated by the two NP doses and the higher BPA concentration. Lpl mRNA was significantly upregulated in all experimental groups except for BPA1 fish while hsl mRNA was significantly downregulated in all groups except for t-OP2 and BPA1 fish. The plasma concentrations of cortisol, the primary stress biomarker, were correlated with the levels of pepck mRNA level. This gene encodes phosphoenolpyruvate carboxykinase which is one of the key enzymes of gluconeogenesis. Pepck mRNA was significantly overexpressed in fish exposed to NP2 and both t-OP doses. Finally, the genes

Rb and p53 Liver Functions Are Essential for Xenobiotic Metabolism and Tumor Suppression

NARCIS (Netherlands)

Nantasanti, Sathidpak; Toussaint, Mathilda J. M.; Youssef, Sameh A.; Tooten, Peter C. J.; de Bruin, Alain

2016-01-01

The tumor suppressors Retinoblastoma (Rb) and p53 are frequently inactivated in liver diseases, such as hepatocellular carcinomas (HCC) or infections with Hepatitis B or C viruses. Here, we discovered a novel role for Rb and p53 in xenobiotic metabolism, which represent a key function of the liver

Comparison of xenobiotic-metabolising human, porcine, rodent, and piscine cytochrome P450

International Nuclear Information System (INIS)

Burkina, Viktoriia; Rasmussen, Martin Krøyer; Pilipenko, Nadezhda; Zamaratskaia, Galia

2017-01-01

Highlights: • The percent identity of porcine, murine and piscine CYPs was compared with human CYPs. • Main similarities and differences were reviewed. • Understanding of molecular mechanisms of CYP system will provide further insights into the CYP regulatory processes, and responses to different factors. - Abstract: Cytochrome P450 proteins (CYP450s) are present in most domains of life and play a critical role in the metabolism of endogenous compounds and xenobiotics. The effects of exposure to xenobiotics depend heavily on the expression and activity of drug-metabolizing CYP450s, which is determined by species, genetic background, age, gender, diet, and exposure to environmental pollutants. Numerous reports have investigated the role of different vertebrate CYP450s in xenobiotic metabolism. Model organisms provide powerful experimental tools to investigate Phase I metabolism. The aim of the present review is to compare the existing data on human CYP450 proteins (1–3 families) with those found in pigs, mice, and fish. We will highlight differences and similarities and identify research gaps which need to be addressed in order to use these species as models that mimic human traits. Moreover, we will discuss the roles of nuclear receptors in the cellular regulation of CYP450 expression in select organisms.

A Liver-Centric Multiscale Modeling Framework for Xenobiotics.

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James P Sluka

Full Text Available We describe a multi-scale, liver-centric in silico modeling framework for acetaminophen pharmacology and metabolism. We focus on a computational model to characterize whole body uptake and clearance, liver transport and phase I and phase II metabolism. We do this by incorporating sub-models that span three scales; Physiologically Based Pharmacokinetic (PBPK modeling of acetaminophen uptake and distribution at the whole body level, cell and blood flow modeling at the tissue/organ level and metabolism at the sub-cellular level. We have used standard modeling modalities at each of the three scales. In particular, we have used the Systems Biology Markup Language (SBML to create both the whole-body and sub-cellular scales. Our modeling approach allows us to run the individual sub-models separately and allows us to easily exchange models at a particular scale without the need to extensively rework the sub-models at other scales. In addition, the use of SBML greatly facilitates the inclusion of biological annotations directly in the model code. The model was calibrated using human in vivo data for acetaminophen and its sulfate and glucuronate metabolites. We then carried out extensive parameter sensitivity studies including the pairwise interaction of parameters. We also simulated population variation of exposure and sensitivity to acetaminophen. Our modeling framework can be extended to the prediction of liver toxicity following acetaminophen overdose, or used as a general purpose pharmacokinetic model for xenobiotics.

[THE SYSTEM OF XENOBIOTICS BIOTRANSFORMATION OF HELMINTHS. RESEMBLANCE AND DIFFERENSES FROM SIMILAR HOST SYSTEMS (REWEW)].

Science.gov (United States)

Smirnov, L P; Borvinskaya, E V; Suhovskaya, I V

2016-01-01

The three phases system xenobiotic biotransformation in cells as prokaryotes as eukaryotes was formed during the process of evolution. Clear and managed function of all three links of this system guarantee the survival of living organisms at alteration of chemical component of environment. Oxidation, reduction or hydrolysis of xenobiotics realize in phase I by insertion or opening reactive and hydrophilic groups in structure of drug molecule. In phase II xenobiotics or their metabolites from phase I conjugate with endogenic compounds, main of there are glutathione, glucuronic acid, amino acids and sulphates. Active transport of substrata, metabolites and conjugates through cell lipid membranes special transport proteins carry out (phase III). The system of xenobiotics biotransformation of helminths has essential differences from the same of vertebrate hosts. In particular, parasites do not reveal the activity of prime oxidases of phase I, such as CYP or FMO, in spite of the genes of these enzymes in DNA. As this phenomenon displays mainly in adult helminths, living in guts of vertebrates, then the hypothesis was formulated that this effect is related with adaptation to conditions of strong deficiency of oxygen, arise in a process of evolution (Kotze et al., 2006). Literature data testify the existence in helminths of unique forms of enzymes of phase II, the investigation of which present doubtless interest in relation with possible role in adaptation to parasitic mode of life. Notwithstanding that many of helminths GST in greater or lesser degree similar with enzymes of M, P, S and О classes of other organisms, nevertheless they have essential structural differences as compared with enzymes of hosts that makes perspective the search of specific anthelminthics vaccines. Transport of xenobiotics is now considered phase III of biotransformation. It was shown that proteins of this phase (ATP binding cassette transporters (ABC ) of parasites) play a key role in efflux

Interplay of drug metabolizing enzymes with cellular transporters.

Science.gov (United States)

Böhmdorfer, Michaela; Maier-Salamon, Alexandra; Riha, Juliane; Brenner, Stefan; Höferl, Martina; Jäger, Walter

2014-11-01

Many endogenous and xenobiotic substances and their metabolites are substrates for drug metabolizing enzymes and cellular transporters. These proteins may not only contribute to bioavailability of molecules but also to uptake into organs and, consequently, to overall elimination. The coordinated action of uptake transporters, metabolizing enzymes, and efflux pumps, therefore, is a precondition for detoxification and elimination of drugs. As the understanding of the underlying mechanisms is important to predict alterations in drug disposal, adverse drug reactions and, finally, drug-drug interactions, this review illustrates the interplay between selected uptake/efflux transporters and phase I/II metabolizing enzymes.

Rb and p53 Liver Functions Are Essential for Xenobiotic Metabolism and Tumor Suppression.

Directory of Open Access Journals (Sweden)

Sathidpak Nantasanti

Full Text Available The tumor suppressors Retinoblastoma (Rb and p53 are frequently inactivated in liver diseases, such as hepatocellular carcinomas (HCC or infections with Hepatitis B or C viruses. Here, we discovered a novel role for Rb and p53 in xenobiotic metabolism, which represent a key function of the liver for metabolizing therapeutic drugs or toxins. We demonstrate that Rb and p53 cooperate to metabolize the xenobiotic 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC. DDC is metabolized mainly by cytochrome P450 (Cyp3a enzymes resulting in inhibition of heme synthesis and accumulation of protoporphyrin, an intermediate of heme pathway. Protoporphyrin accumulation causes bile injury and ductular reaction. We show that loss of Rb and p53 resulted in reduced Cyp3a expression decreased accumulation of protoporphyrin and consequently less ductular reaction in livers of mice fed with DDC for 3 weeks. These findings provide strong evidence that synergistic functions of Rb and p53 are essential for metabolism of DDC. Because Rb and p53 functions are frequently disabled in liver diseases, our results suggest that liver patients might have altered ability to remove toxins or properly metabolize therapeutic drugs. Strikingly the reduced biliary injury towards the oxidative stress inducer DCC was accompanied by enhanced hepatocellular injury and formation of HCCs in Rb and p53 deficient livers. The increase in hepatocellular injury might be related to reduce protoporphyrin accumulation, because protoporphrin is well known for its anti-oxidative activity. Furthermore our results indicate that Rb and p53 not only function as tumor suppressors in response to carcinogenic injury, but also in response to non-carcinogenic injury such as DDC.

Phosphorylation of Isoflavones by Bacillus subtilis BCRC 80517 May Represent Xenobiotic Metabolism.

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Hsu, Chen; Wu, Bo-Yuan; Chang, Yu-Chuan; Chang, Chi-Fon; Chiou, Tai-Ying; Su, Nan-Wei

2018-01-10

The soy isoflavones daidzein (DAI) and genistein (GEN) have beneficial effects on human health. However, their oral bioavailability is hampered by their low aqueous solubility. Our previous study revealed two water-soluble phosphorylated conjugates of isoflavones, daidzein 7-O-phosphate and genistein 7-O-phosphate, generated via biotransformation by Bacillus subtilis BCRC80517 cultivated with isoflavones. In this study, two novel derivatives of isoflavones, daidzein 4'-O-phosphate and genistein 4'-O-phosphate, were identified by HPLC-ESI-MS/MS and 1 H, 13 C, and 31 P NMR, and their biotransformation roadmaps were proposed. Primarily, isoflavone glucosides were deglycosylated and then phosphorylated predominantly into 7-O-phosphate conjugates with traces of 4'-O-phosphate conjugates. Inevitably, trace quantities of glucosides were converted into 6″-O-succinyl glucosides. GEN was more efficiently phosphorylated than DAI. Nevertheless, the presence of GEN prolonged the time until the exponential phase of cell growth, whereas the other isoflavones showed little effect on cell growth. Our findings provide new insights into the novel microbial phosphorylation of isoflavones involved in xenobiotic metabolism.

[Effects of berberine on the recovery of rat liver xenobiotic-metabolizing enzymes after partial hepatectomy].

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Zverinsky, I V; Zverinskaya, H G; Sutsko, I P; Telegin, P G; Shlyahtun, A G

2015-01-01

We have studied the effect of berberine on the recovery processes of liver xenobiotic-metabolizing function during its compensatory growth after 70% partial hepatectomy. It was found the hepatic ability to metabolize foreign substances are not restored up to day 8. Administration of berberine (10 mg/kg intraperitoneally) for 6 days led to normalization of both cytochrome P450-dependent and flavin-containing monooxygenases. It is suggested that in the biotransformation of berberine involved not only cytochrome P450, but also flavin-containing monooxygenases.

Short-term hepatic effects of depleted uranium on xenobiotic and bile acid metabolizing cytochrome P450 enzymes in the rat

International Nuclear Information System (INIS)

Gueguen, Y.; Souidi, M.; Baudelin, C.; Dudoignon, N.; Grison, S.; Dublineau, I.; Marquette, C.; Voisin, P.; Gourmelon, P.; Aigueperse, J.

2006-01-01

The toxicity of uranium has been demonstrated in different organs, including the kidneys, skeleton, central nervous system, and liver. However, few works have investigated the biological effects of uranium contamination on important metabolic function in the liver. In vivo studies were conducted to evaluate its effects on cytochrome P450 (CYP) enzymes involved in the metabolism of cholesterol and xenobiotics in the rat liver. The effects of depleted uranium (DU) contamination on Sprague-Dawley were measured at 1 and 3 days after exposure. Biochemical indicators characterizing liver and kidney functions were measured in the plasma. The DU affected bile acid CYP activity: 7α-hydroxycholesterol plasma level decreased by 52% at day 3 whereas microsomal CYP7A1 activity in the liver did not change significantly and mitochondrial CYP27A1 activity quintupled at day 1. Gene expression of the nuclear receptors related to lipid metabolism (FXR and LXR) also changed, while PPARα mRNA levels did not. The increased mRNA levels of the xenobiotic-metabolizing CYP3A enzyme at day 3 may be caused by feedback up-regulation due to the decreased CYP3A activity at day 1. CAR mRNA levels, which tripled on day 1, may be involved in this up-regulation, while mRNA levels of PXR did not change. These results indicate that high levels of depleted uranium, acting through modulation of the CYP enzymes and some of their nuclear receptors, affect the hepatic metabolism of bile acids and xenobiotics. (orig.)

Xenobiotic-metabolizing enzymes in plants and their role in uptake and biotransformation of veterinary drugs in the environment.

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Bártíková, Hana; Skálová, Lenka; Stuchlíková, Lucie; Vokřál, Ivan; Vaněk, Tomáš; Podlipná, Radka

2015-08-01

Many various xenobiotics permanently enter plants and represent potential danger for their organism. For that reason, plants have evolved extremely sophisticated detoxification systems including a battery of xenobiotic-metabolizing enzymes. Some of them are similar to those in humans and animals, but there are several plant-specific ones. This review briefly introduces xenobiotic-metabolizing enzymes in plants and summarizes present information about their action toward veterinary drugs. Veterinary drugs are used worldwide to treat diseases and protect animal health. However, veterinary drugs are also unwantedly introduced into environment mostly via animal excrements, they persist in the environment for a long time and may impact on the non-target organisms. Plants are able to uptake, transform the veterinary drugs to non- or less-toxic compounds and store them in the vacuoles and cell walls. This ability may protect not only plant themselves but also other organisms, predominantly invertebrates and wild herbivores. The aim of this review is to emphasize the importance of plants in detoxification of veterinary drugs in the environment. The results of studies, which dealt with transport and biotransformation of veterinary drugs in plants, are summarized and evaluated. In conclusion, the risks and consequences of veterinary drugs in the environment and the possibilities of phytoremediation technologies are considered and future perspectives are outlined.

Metabolism of clofibric acid in zebrafish embryos (Danio rerio) as determined by liquid chromatography-high resolution-mass spectrometry.

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Brox, Stephan; Seiwert, Bettina; Haase, Nora; Küster, Eberhard; Reemtsma, Thorsten

2016-01-01

The zebrafish embryo (ZFE) is increasingly used in ecotoxicology research but detailed knowledge of its metabolic potential is still limited. This study focuses on the xenobiotic metabolism of ZFE at different life-stages using the pharmaceutical compound clofibric acid as study compound. Liquid chromatography with quadrupole-time-of-flight mass spectrometry (LC-QToF-MS) is used to detect and to identify the transformation products (TPs). In screening experiments, a total of 18 TPs was detected and structure proposals were elaborated for 17 TPs, formed by phase I and phase II metabolism. Biotransformation of clofibric acid by the ZFE involves conjugation with sulfate or glucuronic acid, and, reported here for the first time, with carnitine, taurine, and aminomethanesulfonic acid. Further yet unknown cyclization products were identified using non-target screening that may represent a new detoxification pathway. Sulfate containing TPs occurred already after 3h of exposure (7hpf), and from 48h of exposure (52hpf) onwards, all TPs were detected. The detection of these TPs indicates the activity of phase I and phase II enzymes already at early life-stages. Additionally, the excretion of one TP into the exposure medium was observed. The results of this study outline the high metabolic potential of the ZFE with respect to the transformation of xenobiotics. Similarities but also differences to other test systems were observed. Biotransformation of test chemicals in toxicity testing with ZFE may therefore need further consideration. Copyright © 2016 Elsevier Inc. All rights reserved.

Concentrations, patterns and metabolites of organochlorine pesticides in relation to xenobiotic phase I and II enzyme activities in ringed seals (Phoca hispida) from Svalbard and the Baltic Sea

International Nuclear Information System (INIS)

Routti, Heli; Bavel, Bert van; Letcher, Robert J.; Arukwe, Augustine; Chu Shaogang; Gabrielsen, Geir W.

2009-01-01

The present study investigates the concentrations and patterns of organochlorine pesticides (OCPs) and their metabolites in liver and plasma of two ringed seal populations (Phoca hispida): lower contaminated Svalbard population and more contaminated Baltic Sea population. Among OCPs, p,p'-DDE and sum-chlordanes were the highest in concentration. With increasing hepatic contaminant concentrations and activities of xenobiotic-metabolizing enzymes, the concentrations of 3-methylsulfonyl-p,p'-DDE and the concentration ratios of pentachlorophenol/hexachlorobenzene increased, and the toxaphene pattern shifted more towards persistent Parlar-26 and -50 and less towards more biodegradable Parlar-44. Relative concentrations of the chlordane metabolites, oxychlordane and -heptachlorepoxide, to sum-chlordanes were higher in the seals from Svalbard compared to the seals from the Baltic, while the trend was opposite for cis- and trans-nonachlor. The observed differences in the OCP patterns in the seals from the two populations are probably related to the catalytic activity of xenobiotic-metabolizing enzymes, and also to differences in dietary exposure. - Contrasting patterns of organochlorine pesticides in two ringed seal populations.

Concentrations, patterns and metabolites of organochlorine pesticides in relation to xenobiotic phase I and II enzyme activities in ringed seals (Phoca hispida) from Svalbard and the Baltic Sea

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Routti, Heli, E-mail: heli.routti@npolar.n [Norwegian Polar Institute, Polar Environmental Centre, 9296 Tromso (Norway); Centre of Excellence in Evolutionary Genetics and Physiology, Department of Biology, University of Turku, 20014 Turku (Finland); Bavel, Bert van [MTM Research Centre, Orebro University, 70182 Orebro (Sweden); Letcher, Robert J. [Wildlife Toxicology and Disease Program, Wildlife and Landscape Science Directorate, Science and Technology Branch, Environment Canada, National Wildlife Research Centre, Carleton University, Ottawa, Ontario K1A 0H3 (Canada); Arukwe, Augustine [Department of Biology, Norwegian University of Science and Technology, 7491 Trondheim (Norway); Chu Shaogang [Wildlife Toxicology and Disease Program, Wildlife and Landscape Science Directorate, Science and Technology Branch, Environment Canada, National Wildlife Research Centre, Carleton University, Ottawa, Ontario K1A 0H3 (Canada); Gabrielsen, Geir W. [Norwegian Polar Institute, Polar Environmental Centre, 9296 Tromso (Norway)

2009-08-15

The present study investigates the concentrations and patterns of organochlorine pesticides (OCPs) and their metabolites in liver and plasma of two ringed seal populations (Phoca hispida): lower contaminated Svalbard population and more contaminated Baltic Sea population. Among OCPs, p,p'-DDE and sum-chlordanes were the highest in concentration. With increasing hepatic contaminant concentrations and activities of xenobiotic-metabolizing enzymes, the concentrations of 3-methylsulfonyl-p,p'-DDE and the concentration ratios of pentachlorophenol/hexachlorobenzene increased, and the toxaphene pattern shifted more towards persistent Parlar-26 and -50 and less towards more biodegradable Parlar-44. Relative concentrations of the chlordane metabolites, oxychlordane and -heptachlorepoxide, to sum-chlordanes were higher in the seals from Svalbard compared to the seals from the Baltic, while the trend was opposite for cis- and trans-nonachlor. The observed differences in the OCP patterns in the seals from the two populations are probably related to the catalytic activity of xenobiotic-metabolizing enzymes, and also to differences in dietary exposure. - Contrasting patterns of organochlorine pesticides in two ringed seal populations.

Yinchenhao Decoction Ameliorates Alpha-Naphthylisothiocyanate Induced Intrahepatic Cholestasis in Rats by Regulating Phase II Metabolic Enzymes and Transporters

Directory of Open Access Journals (Sweden)

Ya-Xiong Yi

2018-05-01

Full Text Available Yinchenhao Decoction (YCHD, a famous traditional Chinese formula, has been used for treating cholestasis for 1000s of years. The cholagogic effect of YCHD has been widely reported, but its pharmacodynamic material and underlying therapeutic mechanism remain unclear. By using ultra-high-performance liquid chromatography (UHPLC-quadrupole time-of-flight mass spectrometry, 11 original active components and eight phase II metabolites were detected in rats after oral administration of YCHD, including three new phase II metabolites. And it indicated that phase II metabolism was one of the major metabolic pathway for most active components in YCHD, which was similar to the metabolism process of bilirubin. It arouses our curiosity that whether the metabolism process of YCHD has any relationship with its cholagogic effects. So, a new method for simultaneous quantitation of eight active components and four phase II metabolites of rhein, emodin, genipin, and capillarisin has been developed and applied for their pharmacokinetic study in both normal and alpha-naphthylisothiocyanate (ANIT-induced intrahepatic cholestasis rats. The results indicated the pharmacokinetic behaviors of most components of YCHD were inhibited, which was hypothesized to be related to different levels of metabolic enzymes and transporters in rat liver. So dynamic changes of intrahepatic enzyme expression in cholestasis and YCHD treated rats have been monitored by an UHPLC-tandem mass spectrometry method. The results showed expression levels of UDP-glucuronosyltransferase 1-1 (UGT1A1, organic anion-transporting polypeptide 1A4 (OATP1A4, multidrug resistance-associated protein 2 (MRP2, multidrug resistance protein 1, sodium-dependent taurocholate cotransporter, and organic anion-transporting polypeptide 1A2 were significantly inhibited in cholestasis rats, which would account for reducing the drug absorption and the metabolic process of YCHD in cholestatic rats. A high dose (12 g/kg of

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

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Vinay K Tripathi

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

Towards a continuous two-phase partitioning bioreactor for xenobiotic removal

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Tomei, M.Concetta, E-mail: tomei@irsa.cnr.it [Water Research Institute, C.N.R., Via Salaria km 29.300, CP 10, 00015 Monterotondo Stazione, Rome (Italy); Mosca Angelucci, Domenica [Water Research Institute, C.N.R., Via Salaria km 29.300, CP 10, 00015 Monterotondo Stazione, Rome (Italy); Daugulis, Andrew J. [Department of Chemical Engineering, Queen’s University, Kingston, Ontario K7 L 3N6 (Canada)

2016-11-05

Highlights: • A prototype of a continuous two-phase partitioning bioreactor was investigated. • The bioreactor contained coiled tubing of a selected extruded polymer, Hytrel 8206. • Mass transfer and removal of a xenobiotic, 4-cholorophenol, were investigated. • Removal efficiencies in the tubing wastewater stream were always ≥ 96%. • Presence of polymer tubing buffered increasing in organic load to the hybrid system. - Abstract: The removal of a xenobiotic (4-chlorophenol) from contaminated water was investigated in a simulated continuous two-phase partitioning bioreactor (C-TPPB), fitted with coiled tubing comprised of a specifically-selected extruded polymer, Hytrel 8206. Wastewater flowed inside the tubing, the pollutant diffused through the tubing wall, and was removed in the aqueous bioreactor phase at typical biological removal rates in the C-TTPB simulated by varying aqueous phase throughput to the reactor. Operating over a range of influent substrate concentrations (500–1500 mg L{sup −1}) and hydraulic retention times in the tubing (4–8 h), overall mass transfer coefficients were 1.7–3.5 × 10{sup −7} m s{sup −1}, with the highest value corresponding to the highest tubing flow rate. Corresponding mass transfer rates are of the same order as biological removal rates, and thus do not limit the removal process. The C-TPPB showed good performance over all organic and hydraulic loading ranges, with removal efficiencies of 4CP in the tubing wastewater stream always ≥96%. Additionally, the presence of the Hytrel tubing was able to buffer increases in organic loading to the hybrid system, enhancing overall process stability. Biological testing of the C-TPPB confirmed the abiotic test results demonstrating even higher 4-chlorophenol removal efficiency (∼99%) in the tubing stream.

High-throughput metagenomic analysis of petroleum-contaminated soil microbiome reveals the versatility in xenobiotic aromatics metabolism.

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Bao, Yun-Juan; Xu, Zixiang; Li, Yang; Yao, Zhi; Sun, Jibin; Song, Hui

2017-06-01

The soil with petroleum contamination is one of the most studied soil ecosystems due to its rich microorganisms for hydrocarbon degradation and broad applications in bioremediation. However, our understanding of the genomic properties and functional traits of the soil microbiome is limited. In this study, we used high-throughput metagenomic sequencing to comprehensively study the microbial community from petroleum-contaminated soils near Tianjin Dagang oilfield in eastern China. The analysis reveals that the soil metagenome is characterized by high level of community diversity and metabolic versatility. The metageome community is predominated by γ-Proteobacteria and α-Proteobacteria, which are key players for petroleum hydrocarbon degradation. The functional study demonstrates over-represented enzyme groups and pathways involved in degradation of a broad set of xenobiotic aromatic compounds, including toluene, xylene, chlorobenzoate, aminobenzoate, DDT, methylnaphthalene, and bisphenol. A composite metabolic network is proposed for the identified pathways, thus consolidating our identification of the pathways. The overall data demonstrated the great potential of the studied soil microbiome in the xenobiotic aromatics degradation. The results not only establish a rich reservoir for novel enzyme discovery but also provide putative applications in bioremediation. Copyright © 2016. Published by Elsevier B.V.

Functioning of Microsomal Cytochrome P450s: Murburn Concept Explains the Metabolism of Xenobiotics in Hepatocytes.

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Manoj, Kelath Murali; Parashar, Abhinav; Gade, Sudeep K; Venkatachalam, Avanthika

2016-01-01

Using oxygen and NADPH, the redox enzymes cytochrome P450 (CYP) and its reductase (CPR) work in tandem to carry out the phase I metabolism of a vast majority of drugs and xenobiotics. As per the erstwhile understanding of the catalytic cycle, binding of the substrate to CYP's heme distal pocket allows CPR to pump electrons through a CPR-CYP complex. In turn, this trigger (a thermodynamic push of electrons) leads to the activation of oxygen at CYP's heme-center, to give Compound I, a two-electron deficient enzyme reactive intermediate. The formation of diffusible radicals and reactive oxygen species (DROS, hitherto considered an undesired facet of the system) was attributed to the heme-center. Recently, we had challenged these perceptions and proposed the murburn ("mured burning" or "mild unrestricted burning") concept to explain heme enzymes' catalytic mechanism, electron-transfer phenomena and the regulation of redox equivalents' consumption. Murburn concept incorporates a one-electron paradigm, advocating obligatory roles for DROS. The new understanding does not call for high-affinity substrate-binding at the heme distal pocket of the CYP (the first and the most crucial step of the erstwhile paradigm) or CYP-CPR protein-protein complexations (the operational backbone of the erstwhile cycle). Herein, the dynamics of reduced nicotinamide nucleotides' consumption, peroxide formation and depletion, product(s) formation, etc. was investigated with various controls, by altering reaction variables, environments and through the incorporation of diverse molecular probes. In several CYP systems, control reactions lacking the specific substrate showed comparable or higher peroxide in milieu, thereby discrediting the foundations of the erstwhile hypothesis. The profiles obtained by altering CYP:CPR ratios and the profound inhibitions observed upon the incorporation of catalytic amounts of horseradish peroxidase confirm the obligatory roles of DROS in milieu, ratifying

In Vivo Exposure of Kaempferol Is Driven by Phase II Metabolic Enzymes and Efflux Transporters.

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Zheng, Liang; Zhu, Lijun; Zhao, Min; Shi, Jian; Li, Yuhuan; Yu, Jia; Jiang, Huangyu; Wu, Jinjun; Tong, Yunli; Liu, Yuting; Hu, Ming; Lu, Linlin; Liu, Zhongqiu

2016-09-01

Kaempferol is a well-known flavonoid; however, it lacks extensive pharmacokinetic studies. Phase II metabolic enzymes and efflux transporters play an important role in the disposition of flavonoids. This study aimed to investigate the mechanism by which phase II metabolic enzymes and efflux transporters determine the in vivo exposure of kaempferol. Pharmacokinetic analysis in Sprague-Dawley rats revealed that kaempferol was mostly biotransformed to conjugates, namely, kaempferol-3-glucuronide (K-3-G), kaempferol-7-glucuronide (K-7-G), and kaempferol-7-sulfate, in plasma. K-3-G represented the major metabolite. Compared with that in wild-type mice, pharmacokinetics in knockout FVB mice demonstrated that the absence of multidrug resistance protein 2 (MRP2) and breast cancer resistance protein (BCRP) significantly increased the area under the curve (AUC) of the conjugates. The lack of MRP1 resulted in a much lower AUC of the conjugates. Intestinal perfusion in rats revealed that the glucuronide conjugates were mainly excreted in the small intestine, but 7-sulfate was mainly excreted in the colon. In Caco-2 monolayers, K-7-G efflux toward the apical (AP) side was significantly higher than K-3-G efflux. In contrast, K-3-G efflux toward the basolateral (BL) side was significantly higher than K-7-G efflux. The BL-to-AP efflux was significantly reduced in the presence of the MRP2 inhibitor LTC4. The AP-to-BL efflux was significantly decreased in the presence of the BL-side MRPs inhibitor MK571. The BCRP inhibitor Ko143 decreased the glucuronide conjugate efflux. Therefore, kaempferol is mainly exposed as K-3-G in vivo, which is driven by phase II metabolic enzymes and efflux transporters (i.e., BCRP and MRPs).

Effect of thiabendazole on some rat hepatic xenobiotic metabolising enzymes

NARCIS (Netherlands)

Price, R.J.; Scott, M.P.; Walters, D.G.; Stierum, R.H.; Groten, J.P.; Meredith, C.; Lake, B.G.

2004-01-01

The effect of thiabendazole (TB) on some rat hepatic xenobiotic metabolising enzymes has been investigated. Male Sprague-Dawley rats were fed control diet or diets containing 102-5188 ppm TB for 28 days. As a positive control for induction of hepatic xenobiotic metabolism, rats were also fed diets

Drug and xenobiotic biotransformation in the blood-brain barrier: A neglected issue.

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José A.G. Agúndez

2014-10-01

Full Text Available Drug biotransformation is a crucial mechanism for facilitating the elimination of chemicals from the organism and for decreasing their pharmacological activity. Published evidence suggests that brain drug metabolism may play a role in the development of adverse drug reactions and in the clinical response to drugs and xenobiotics. The blood-brain barrier (BBB has been regarded mainly as a physical barrier for drugs and xenobiotics, and little attention has been paid to BBB as a drug-metabolizing barrier. The presence of drug metabolizing enzymes in the BBB is likely to have functional implications because local metabolism may inactivate drugs or may modify the drug's ability to cross the BBB, thus modifying the drug response and the risk of developing adverse drug reactions. In this perspective paper, we discuss the expression of relevant xenobiotic metabolizing enzymes in the brain and in the BBB, and we cover current advances and future directions on the potential role of these BBB drug-metabolizing enzymes as modifiers of drug response.

Effects of dietary components on testosterone metabolism via UDP‐glucuronosyltransferase (UGT

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Carl eJenkinson

2013-07-01

Full Text Available The potential interference in testosterone metabolism through ingested substances has ramifications for: i a range of pathologies such as prostate cancer, ii medication contra-indications, iii disruption to the endocrine system, and iv potential confounding effects on doping tests. Conjugation of anabolic steroids during phase II metabolism, mainly driven by UDP-glucuronosyltransferase (UGT 2B7, 2B15 and 2B17, has been shown to be impaired in vitro by a range of compounds including xenobiotics and pharmaceuticals. Following early reports on the effects of a range of xenobiotics on UGT activity in vitro, the work was extended to reveal similar effects with common non-steroidal anti-inflammatory drugs. Notably, recent studies have evidenced inhibitory effects of the common foodstuffs green tea and red wine, along with their constituent flavonoids and catechins. This review amalgamates the existing evidence for the inhibitory effects of various pharmaceutical and dietary substances on the rate of UGT glucuronidation of testosterone; and evaluates the potential consequences for health linked to steroid levels, interaction with treatment drugs metabolised by the UGT enzyme and steroid abuse in sport.

Influence of frequently used industrial solvents and monomers of plastics on xenobiotic metabolism

Energy Technology Data Exchange (ETDEWEB)

Gut, I. (Institut Hygieny a Epidemiologie, Prague (Czechoslovakia))

1983-11-01

In male Wistar rats, inhalation of benzene, toluene, or styrene induced a dose-dependent increase of the in vitro hepatic microsomal metabolism of benzene, but toluene metabolism and microsomal cytochrome P-450 level were little affected. In phenobarbital pretreated rats the solvents induced increased biotransformation of benzene metabolism toluene, but relatively less than in controls, and benzene and toluene inhalation actually caused an apparent destruction of cytochrome P-450. In vivo rates of metabolism of toluene and styrene were in good agreement with the in vitro hepatic microsomal biotransformation of benzene or toluene, but benzene metabolism not due to inhibition of benzene metabolism in vivo caused by benzene metabolites. In simultaneously administered two solvents, toluene, styrene or xylene markedly inhibited metabolism of benzene-/sup 14/C, but toluene-/sup 14/C metabolsim was little affected by coadministered benzene, styrene or xylene. Various industrial solvents inhibited metabolism of acrylonitrile along the oxidative pathway leading to thiocyanate, but actually increased the rate of the conjugative pathway beginning with cyanoethylation of glutathion and the final products. Various derivatives of benzene had low inhibiting effect on antipyrine metabolism and clinical significance of such effect is of little significance. Inhibition of benzene metabolism by toluene followed in significantly decreased myelotoxicity of benzene, but the modification of acrylonitrile metabolism and pharmacokinetics by organic solvents given at low doses markedly increased lethal effects of acrylonitrile. The prediction of in vivo rates of metabolism based on the in vitro rates of hepatic microsomal metabolism is therefore possible, provided the inhibiting potency of the xenobiotic and/or its metabolites, self-induction of their metabolism, as well as differences in their pharmacokinetics are considered.

Systematic Analysis Reveals that Cancer Mutations Converge on Deregulated Metabolism of Arachidonate and Xenobiotics

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Francesco Gatto

2016-07-01

Full Text Available Mutations are the basis of the clonal evolution of most cancers. Nevertheless, a systematic analysis of whether mutations are selected in cancer because they lead to the deregulation of specific biological processes independent of the type of cancer is still lacking. In this study, we correlated the genome and transcriptome of 1,082 tumors. We found that nine commonly mutated genes correlated with substantial changes in gene expression, which primarily converged on metabolism. Further network analyses circumscribed the convergence to a network of reactions, termed AraX, that involves the glutathione- and oxygen-mediated metabolism of arachidonic acid and xenobiotics. In an independent cohort of 4,462 samples, all nine mutated genes were consistently correlated with the deregulation of AraX. Among all of the metabolic pathways, AraX deregulation represented the strongest predictor of patient survival. These findings suggest that oncogenic mutations drive a selection process that converges on the deregulation of the AraX network.

The effects of multiply ionizing gamma irradiations on the xenobiotic metabolizing system in the liver of rats

International Nuclear Information System (INIS)

Zavodnik, L.B.; Buko, V.U.

2009-01-01

The aim of the work was the studying the effect of multiply low doses of gamma-irradiation in a total doze 1 and 2 Gy on processes lipid peroxidation and xenobiotics metabolizing in rat liver. It was shown the multiply irradiation causes the expressed activation of lipid peroxidation, by increase of TBARS level and dien conjugates. The system of microsomal oxidations was broken at the same time. (authors)

Xenobiotics and the Human Gut Microbiome: Metatranscriptomics Reveal the Active Players

OpenAIRE

Ursell, Luke K.; Knight, Rob

2013-01-01

The human gut microbiome plays an important role in the metabolism of xenobiotics. In a recent issue of Cell, Maurice et al. identify the active members of the gut microbiome and show how gene expression profiles change within the gut microbial community in response to antibiotics and host-targeted xenobiotics.

In vitro approach to studying cutaneous metabolism and disposition of topically applied xenobiotics

International Nuclear Information System (INIS)

Kao, J.; Hall, J.; Shugart, L.R.; Holland, J.M.

1984-01-01

The extent to which cutaneous metabolism may be involved in the penetration and fate of topically applied xenobiotics was examined by metabolically viable and structurally intact mouse skin in organ culture. Evidence that skin penetration of certain chemicals is coupled to cutaneous metabolism was based upon observations utilizing [ 14 C]benzo[a]pyrene (BP). As judged by the recovery of radioactivity in the culture medium 24 hr after in vitro topical application of [ 14 C]BP to the skin from both control and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced C3H mice, skin penetration of BP was higher in the induced tissue. All classes of metabolites of BP were found in the culture medium; water-soluble metabolites predominated and negligible amounts of unmetabolized BP were found. As shown by enzymatic hydrolysis of the medium, TCDD induction resulted in shifting the cutaneous metabolism of BP toward the synthesis of more water-soluble conjugates. Differences in the degree of covalent binding of BP, via diol epoxide intermediates to epidermal DNA, from control and induced tissues were observed. These differences may reflect a change in the pathways of metabolism as a consequence of TCDD induction. These results indicated that topically applied BP is metabolized by the skin during its passage through the skin; and the degree of percutaneous penetration and disposition of BP was dependent upon the metabolic status of the tissue. This suggests that cutaneous metabolism may play an important role in the translocation and subsequent physiological disposition of topically applied BP. 33 references, 5 figures, 2 tables

Modulation of Xenobiotic Metabolizing Enzyme and Transporter Gene Expression in Primary Cultures of Human Hepatocytes by ToxCast Chemicals

Science.gov (United States)

ToxCast chemicals were assessed for induction or suppression of xenobiotic metabolizing enzyme and transporter gene expression using primary human hepatocytes. The mRNA levels of 14 target and 2 control genes were measured: ABCB1, ABCB11, ABCG2, SLCO1B1, CYP1A1, CYP1A2, CYP2B6, C...

The effect of selected metals on the central metabolic pathways in ...

African Journals Online (AJOL)

compounds, interfere with xenobiotic metabolic pathways, and may also affect glycolysis, the Krebs cycle, oxidative phosphorylation, protein amino acid metabolism as well as carbohydrate and lipid metabolism. Therefore, in this review, we discuss the two phases of the central metabolic pathways, as well as how metals ...

Approaching Resonant Absorption of Environmental Xenobiotics Harmonic Oscillation by Linear Structures

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Cornelia A. Bulucea

2012-03-01

Full Text Available Over the last several decades, it has become increasingly accepted that the term xenobiotic relates to environmental impact, since environmental xenobiotics are understood to be substances foreign to a biological system, which did not exist in nature before their synthesis by humans. In this context, xenobiotics are persistent pollutants such as dioxins and polychlorinated biphenyls, as well as plastics and pesticides. Dangerous and unstable situations can result from the presence of environmental xenobiotics since their harmful effects on humans and ecosystems are often unpredictable. For instance, the immune system is extremely vulnerable and sensitive to modulation by environmental xenobitics. Various experimental assays could be performed to ascertain the immunotoxic potential of environmental xenobiotics, taking into account genetic factors, the route of xenobiotic penetration, and the amount and duration of exposure, as well as the wave shape of the xenobiotic. In this paper, we propose an approach for the analysis of xenobiotic metabolism using mathematical models and corresponding methods. This study focuses on a pattern depicting mathematically modeled processes of resonant absorption of a xenobiotic harmonic oscillation by an organism modulated as an absorbing oscillator structure. We represent the xenobiotic concentration degree through a spatial concentration vector, and we model and simulate the oscillating regime of environmental xenobiotic absorption. It is anticipated that the results could be used to facilitate the assessment of the processes of environmental xenobiotic absorption, distribution, biotransformation and removal within the framework of compartmental analysis, by establishing appropriate mathematical models and simulations.

Systemic responses to inhaled ozone in mice: cachexia and down-regulation of liver xenobiotic metabolizing genes

Energy Technology Data Exchange (ETDEWEB)

Last, Jerold A [Pulmonary and Critical Care Medicine, School of Medicine, Toxic Substances Program, 1131 Surge I, University of California, Davis, CA 95616-8723 (United States); Gohil, Kishorchandra [Pulmonary and Critical Care Medicine, School of Medicine, Toxic Substances Program, 1131 Surge I, University of California, Davis, CA 95616-8723 (United States); Mathrani, Vivek C [Pulmonary and Critical Care Medicine, School of Medicine, Toxic Substances Program, 1131 Surge I, University of California, Davis, CA 95616-8723 (United States); Kenyon, Nicholas J [Pulmonary and Critical Care Medicine, School of Medicine, Toxic Substances Program, 1131 Surge I, University of California, Davis, CA 95616-8723 (United States)

2005-10-15

Rats or mice acutely exposed to high concentrations of ozone show an immediate and significant weight loss, even when allowed free access to food and water. The mechanisms underlying this systemic response to ozone have not been previously elucidated. We have applied the technique of global gene expression analysis to the livers of C57BL mice acutely exposed to ozone. Mice lost up to 14% of their original body weight, with a 42% decrease in total food consumption. We previously had found significant up-regulation of genes encoding proliferative enzymes, proteins related to acute phase reactions and cytoskeletal functions, and other biomarkers of a cachexia-like inflammatory state in lungs of mice exposed to ozone. These results are consistent with a general up-regulation of different gene families responsive to NF-{kappa}B in the lungs of the exposed mice. In the present study, we observed significant down-regulation of different families of mRNAs in the livers of the exposed mice, including genes related to lipid and fatty acid metabolism, and to carbohydrate metabolism in this tissue, consistent with a systemic cachexic response. Several interferon-dependent genes were down-regulated in the liver, suggesting a possible role for interferon as a signaling molecule between lung and liver. In addition, transcription of several mRNAs encoding enzymes of xenobiotic metabolism in the livers of mice exposed to ozone was decreased, suggesting cytokine-mediated suppression of cytochrome P450 expression. This finding may explain a previously controversial report from other investigators more than 20 years ago of prolongation of pentobarbital sleeping time in mice exposed to ozone.

Systemic responses to inhaled ozone in mice: cachexia and down-regulation of liver xenobiotic metabolizing genes

International Nuclear Information System (INIS)

Last, Jerold A.; Gohil, Kishorchandra; Mathrani, Vivek C.; Kenyon, Nicholas J.

2005-01-01

Rats or mice acutely exposed to high concentrations of ozone show an immediate and significant weight loss, even when allowed free access to food and water. The mechanisms underlying this systemic response to ozone have not been previously elucidated. We have applied the technique of global gene expression analysis to the livers of C57BL mice acutely exposed to ozone. Mice lost up to 14% of their original body weight, with a 42% decrease in total food consumption. We previously had found significant up-regulation of genes encoding proliferative enzymes, proteins related to acute phase reactions and cytoskeletal functions, and other biomarkers of a cachexia-like inflammatory state in lungs of mice exposed to ozone. These results are consistent with a general up-regulation of different gene families responsive to NF-κB in the lungs of the exposed mice. In the present study, we observed significant down-regulation of different families of mRNAs in the livers of the exposed mice, including genes related to lipid and fatty acid metabolism, and to carbohydrate metabolism in this tissue, consistent with a systemic cachexic response. Several interferon-dependent genes were down-regulated in the liver, suggesting a possible role for interferon as a signaling molecule between lung and liver. In addition, transcription of several mRNAs encoding enzymes of xenobiotic metabolism in the livers of mice exposed to ozone was decreased, suggesting cytokine-mediated suppression of cytochrome P450 expression. This finding may explain a previously controversial report from other investigators more than 20 years ago of prolongation of pentobarbital sleeping time in mice exposed to ozone

Triclocarban mediates induction of xenobiotic metabolism through activation of the constitutive androstane receptor and the estrogen receptor alpha.

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Mei-Fei Yueh

Full Text Available Triclocarban (3,4,4'-trichlorocarbanilide, TCC is used as a broad-based antimicrobial agent that is commonly added to personal hygiene products. Because of its extensive use in the health care industry and resistance to degradation in sewage treatment processes, TCC has become a significant waste product that is found in numerous environmental compartments where humans and wildlife can be exposed. While TCC has been linked to a range of health and environmental effects, few studies have been conducted linking exposure to TCC and induction of xenobiotic metabolism through regulation by environmental sensors such as the nuclear xenobiotic receptors (XenoRs. To identify the ability of TCC to activate xenobiotic sensors, we monitored XenoR activities in response to TCC treatment using luciferase-based reporter assays. Among the XenoRs in the reporter screening assay, TCC promotes both constitutive androstane receptor (CAR and estrogen receptor alpha (ERα activities. TCC treatment to hUGT1 mice resulted in induction of the UGT1A genes in liver. This induction was dependent upon the constitutive active/androstane receptor (CAR because no induction occurred in hUGT1Car(-/- mice. Induction of the UGT1A genes by TCC corresponded with induction of Cyp2b10, another CAR target gene. TCC was demonstrated to be a phenobarbital-like activator of CAR in receptor-based assays. While it has been suggested that TCC be classified as an endocrine disruptor, it activates ERα leading to induction of Cyp1b1 in female ovaries as well as in promoter activity. Activation of ERα by TCC in receptor-based assays also promotes induction of human CYP2B6. These observations demonstrate that TCC activates nuclear xenobiotic receptors CAR and ERα both in vivo and in vitro and might have the potential to alter normal physiological homeostasis. Activation of these xenobiotic-sensing receptors amplifies gene expression profiles that might represent a mechanistic base for

Liver genomic responses to ciguatoxin: evidence for activation of phase I and phase II detoxification pathways following an acute hypothermic response in mice.

Science.gov (United States)

Morey, Jeanine S; Ryan, James C; Bottein Dechraoui, Marie-Yasmine; Rezvani, Amir H; Levin, Edward D; Gordon, Christopher J; Ramsdell, John S; Van Dolah, Frances M

2008-06-01

Ciguatoxins (CTX) are polyether neurotoxins that target voltage-gated sodium channels and are responsible for ciguatera, the most common fish-borne food poisoning in humans. This study characterizes the global transcriptional response of mouse liver to a symptomatic dose (0.26 ng/g) of the highly potent Pacific ciguatoxin-1 (P-CTX-1). At 1 h post-exposure 2.4% of features on a 44K whole genome array were differentially expressed (p or = 1.5 and p < or = 0.0001 in at least one time point) and a trend set of 1550 genes were used for further analysis. Early gene expression was likely influenced prominently by an acute 4 degrees C decline in core body temperature by 1 h, which resolved by 8 h following exposure. An initial downregulation of 32 different solute carriers, many involved in sodium transport, was observed. Differential gene expression in pathways involving eicosanoid biosynthesis and cholesterol homeostasis was also noted. Cytochrome P450s (Cyps) were of particular interest due to their role in xenobiotic metabolism. Twenty-seven genes, mostly members of Cyp2 and Cyp4 families, showed significant changes in expression. Many Cyps underwent an initial downregulation at 1 h but were quickly and strongly upregulated at 4 and 24 h post-exposure. In addition to Cyps, increases in several glutathione S-transferases were observed, an indication that both phase I and phase II metabolic reactions are involved in the hepatic response to CTX in mice.

Cytotoxic effects and aromatase inhibition by xenobiotic endocrine disrupters alone and in combination

International Nuclear Information System (INIS)

Benachour, Nora; Moslemi, Safa; Sipahutar, Herbert; Seralini, Gilles-Eric

2007-01-01

Xenobiotics may cause long-term adverse effects in humans, especially at the embryonic level, raising questions about their levels of exposure, combined effects, and crucial endpoints. We are interested in the possible interactions between xenobiotic endocrine disrupters, cellular viability and androgen metabolism. Accordingly, we tested aroclor 1254 (A1254), atrazine (AZ), o,p'-DDT, vinclozolin (VZ), p,p'-DDE, bisphenol A (BPA), chlordecone (CD), nonylphenol (NP), tributylin oxide (TBTO), and diethylstilbestrol (DES) for cellular toxicity against human embryonic 293 cells, and activity against cellular aromatase, but also on placental microsomes and on the purified equine enzyme. Cellular viability was affected in 24 h by all the xenobiotics with a threshold at 50 μM (except for TBTO and DES, 10 μM threshold), and aromatase was inhibited at non-toxic doses. In combination synergism was observed reducing the threshold values of toxicity to 4-10 μM, and aromatase activity by 50% in some cases. In placental microsomes the most active xenobiotics rapidly inhibited microsomal aromatase in a manner independent of NADPH metabolism. Prolonged exposures to low doses in cells generally amplified by 50 times aromatase inhibition. These xenobiotics may act by inhibition of the active site or by allosteric effects on the enzyme. Bioaccumulation is a feature of some xenobiotics, especially chlordecone, DDT and DDE, and low level chronic exposures can also affect cell signaling mechanisms. This new information about the mechanism of action of these xenobiotics will assist in improved molecular design with a view to providing safer compounds for use in the (human) environment

CHANGING METABOLIC FUNCTIONS IN EXPERIMENTAL ANIMALS AFTER INTRODUCTION OF THE XENOBIOTIC, IMMUNOTROPIC DRUG AND PROBIOTIC

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Zvyagintseva O.V.

2015-05-01

Saccharomyces cerevisiae. The peripheral blood leukocytes were cultured according to the method of Hereford in medium 199 with the addition of fetal calf serum in the absence and in the presence of T-cell mitogen – phytohemagglutinin. Results and discussion. In all studied groups (introduction of the xenobiotic, "Fungidol", probiotic experimental animals revealed a significant increase in the concentrations of ceruloplasmin and haptoglobin on the average in 1,5 times in comparison with the control, indicating the development of the inflammatory process after the toxic action of copper sulphate. During administration of sulphate of copper, the experimental animals showed a reduction in the index of completion of phagocytosis, indicating a failure of the process of endocytosis of bacterial antigens and reduced stimulation index due to the low activity of NADPoxidase system of phagocytes. The introduction of xenobiotic animals was increased 1,2 times compared with the control (23,33±1,38 % the number of transformed cells in the background of mitogenic inducer of cell proliferation. The proliferative activity of hemolytic after the joint action of the xenobiotic and immunotropic drug in cell culture with the mitogen was the highest and exceeded 1,5 times control (23,33±1,38%. After the introduction of copper sulfate and probiotic proliferative activity of hemolytic was also significantly higher spontaneous. Introduction biologic response modifier substance to a greater extent than probiotics stimulate a protective immune processes aimed at combating the negative effect of the xenobiotic. Conclusion. Thus, the introduction of copper sulfate launches in animals a cascade of reactions aimed at the disruption of homeostasis. It is a violation of various physiological processes of digestion, respiration, cell differentiation, water-salt metabolism, metabolism of carbohydrates, proteins, lipids, detoxification of exogenous substrates and metabolites, production of biologically active

The metabolism of aflatoxin B1 by hepatocytes isolated from rats following the in vivo administration of some xenobiotics

International Nuclear Information System (INIS)

Metcalfe, S.A.; Neal, G.E.

1983-01-01

Isolated rat hepatocytes, an intact cellular system capable of performing phase I and phase II metabolism, have been used to investigate metabolism of aflatoxin B1. These cells were found to metabolise [ 14 C]aflatoxin B1 to aflatoxins M1 and Q1, and to radiolabelled polar material, presumably conjugates, as analysed by h.p.l.c., t.l.c. and radioactive determination. In vivo administration of the mixed function oxidase inducers, phenobarbitone and 3-methylcholanthrene, resulted in enhanced hepatocyte phase I (microsomal) metabolism of aflatoxin B1. In contrast to metabolism of AFB1 by in vitro subcellular systems increased production of polar material (conjugated metabolites) derived from [ 14 C]aflatoxin B1 was also detected in hepatocytes isolated from these pretreated animals. Formation of aflatoxin Q1 by isolated hepatocytes appeared to be mediated by cytochrome P450-linked enzymes whereas cytochrome P448-linked enzymes were apparently involved in aflatoxin M1 production. Chronic feeding of aflatoxin B1 to rats enhanced hepatocyte production of conjugated material only and did not elevate cellular cytochrome P450 levels, thus suggesting that aflatoxin B1 is not an inducer of its own primary metabolism

Altered carbohydrate, lipid, and xenobiotic metabolism by liver from rats flown on Cosmos 1887

Science.gov (United States)

Merrill, A. H. Jr; Hoel, M.; Wang, E.; Mullins, R. E.; Hargrove, J. L.; Jones, D. P.; Popova, I. A.; Merrill AH, J. r. (Principal Investigator)

1990-01-01

To determine the possible biochemical effects of prolonged weightlessness on liver function, samples of liver from rats that had flown aboard Cosmos 1887 were analyzed for protein, glycogen, and lipids as well as the activities of a number of key enzymes involved in metabolism of these compounds and xenobiotics. Among the parameters measured, the major differences were elevations in the glycogen content and hydroxymethylglutaryl-CoA (HMG-CoA) reductase activities for the rats flown on Cosmos 1887 and decreases in the amount of microsomal cytochrome P-450 and the activities of aniline hydroxylase and ethylmorphine N-demethylase, cytochrome P-450-dependent enzymes. These results support the earlier finding of differences in these parameters and suggest that altered hepatic function could be important during spaceflight and/or the postflight recovery period.

Transposable elements are enriched within or in close proximity to xenobiotic-metabolizing cytochrome P450 genes

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Li Xianchun

2007-03-01

Full Text Available Abstract Background Transposons, i.e. transposable elements (TEs, are the major internal spontaneous mutation agents for the variability of eukaryotic genomes. To address the general issue of whether transposons mediate genomic changes in environment-adaptation genes, we scanned two alleles per each of the six xenobiotic-metabolizing Helicoverpa zea cytochrome P450 loci, including CYP6B8, CYP6B27, CYP321A1, CYP321A2, CYP9A12v3 and CYP9A14, for the presence of transposon insertions by genome walking and sequence analysis. We also scanned thirteen Drosophila melanogaster P450s genes for TE insertions by in silico mapping and literature search. Results Twelve novel transposons, including LINEs (long interspersed nuclear elements, SINEs (short interspersed nuclear elements, MITEs (miniature inverted-repeat transposable elements, one full-length transib-like transposon, and one full-length Tcl-like DNA transpson, are identified from the alleles of the six H. zea P450 genes. The twelve transposons are inserted into the 5'flanking region, 3'flanking region, exon, or intron of the six environment-adaptation P450 genes. In D. melanogaster, seven out of the eight Drosophila P450s (CYP4E2, CYP6A2, CYP6A8, CYP6A9, CYP6G1, CYP6W1, CYP12A4, CYP12D1 implicated in insecticide resistance are associated with a variety of transposons. By contrast, all the five Drosophila P450s (CYP302A1, CYP306A1, CYP307A1, CYP314A1 and CYP315A1 involved in ecdysone biosynthesis and developmental regulation are free of TE insertions. Conclusion These results indicate that TEs are selectively retained within or in close proximity to xenobiotic-metabolizing P450 genes.

Genomics and the prediction of xenobiotic toxicity

International Nuclear Information System (INIS)

Meyer, Urs-A.; Gut, Josef

2002-01-01

The systematic identification and functional analysis of human genes is revolutionizing the study of disease processes and the development and rational use of drugs. It increasingly enables medicine to make reliable assessments of the individual risk to acquire a particular disease, raises the number and specificity of drug targets and explains interindividual variation of the effectiveness and toxicity of drugs. Mutant alleles at a single gene locus for more than 20 drug metabolizing enzymes are some of the best studied individual risk factors for adverse drug reactions and xenobiotic toxicity. Increasingly, genetic polymorphisms of transporter and receptor systems are also recognized as causing interindividual variation in drug response and drug toxicity. However, pharmacogenetic and toxicogenetic factors rarely act alone; they produce a phenotype in concert with other variant genes and with environmental factors. Environmental factors may affect gene expression in many ways. For instance, numerous drugs induce their own and the metabolism of other xenobiotics by interacting with nuclear receptors such as AhR, PPAR, PXR and CAR. Genomics is providing the information and technology to analyze these complex situations to obtain individual genotypic and gene expression information to assess the risk of toxicity

Differential roles of phase I and phase II enzymes in 3,4-methylendioxymethamphetamine-induced cytotoxicity.

NARCIS (Netherlands)

Antolino Lobo, I.; Meulenbelt, J.; Nijmeijer, S.M.; Scherpenisse, P.; van den Berg, M.; van Duursen, M.B.M.

2010-01-01

Metabolism plays an important role in the toxic effects caused by 3,4-methylenedioxymethamphetamine (MDMA). Most research has focused on the involvement of CYP2D6 enzyme in MDMA bioactivation, and less is known about the contribution of other cytochrome P450 (P450) and phase II metabolism. In this

Absolute Configuration of (-)-2-(4-Hydroxyphenyl)propionic acid: Stereochemistry of Soy Isoflavone Metabolism

Energy Technology Data Exchange (ETDEWEB)

Kim, Mihyang; Han, Jaehong [Chung-Ang Univ., Seoul (Korea, Republic of)

2014-06-15

We have elucidated stereochemistry of (-)-2-HPPA. Determination of (R)-2-HPPA stereochemistry also provided stereochemical information of genistein metabolism. Considering the stereochemistry of 2-HPPA, the precursor of (R)-2-HPPA should be (R)-6'-hydroxy-O-DMA. Besides, it is clear that only (S)-dihydrogenistein is the possible precursor of (R)-6'-hydroxy-O-DMA. Therefore, genistein metabolism is suggested to follow the same stereochemical pathway like daidzein. Biotransformation of natural products by human intestinal bacteria has recently drawn a significant interest, due to the emerging strong correlation between gut microbiota and human health. Microbial metabolism of natural products by intestinal bacteria in small intestine and colon proceeds the phase I and II xenobiotic metabolisms in the liver. The metabolites were found to exhibit different biological activities, and affect human etiology. For example, many beneficial effects of dietary polyphenols in human health are attributed to the microbial metabolites produced by intestinal bacteria and the modulation of gut microbiota composition.

Absolute Configuration of (-)-2-(4-Hydroxyphenyl)propionic acid: Stereochemistry of Soy Isoflavone Metabolism

International Nuclear Information System (INIS)

Kim, Mihyang; Han, Jaehong

2014-01-01

We have elucidated stereochemistry of (-)-2-HPPA. Determination of (R)-2-HPPA stereochemistry also provided stereochemical information of genistein metabolism. Considering the stereochemistry of 2-HPPA, the precursor of (R)-2-HPPA should be (R)-6'-hydroxy-O-DMA. Besides, it is clear that only (S)-dihydrogenistein is the possible precursor of (R)-6'-hydroxy-O-DMA. Therefore, genistein metabolism is suggested to follow the same stereochemical pathway like daidzein. Biotransformation of natural products by human intestinal bacteria has recently drawn a significant interest, due to the emerging strong correlation between gut microbiota and human health. Microbial metabolism of natural products by intestinal bacteria in small intestine and colon proceeds the phase I and II xenobiotic metabolisms in the liver. The metabolites were found to exhibit different biological activities, and affect human etiology. For example, many beneficial effects of dietary polyphenols in human health are attributed to the microbial metabolites produced by intestinal bacteria and the modulation of gut microbiota composition

Estimation of aerial deposition and foliar uptake of xenobiotics: Assessment of current models

Energy Technology Data Exchange (ETDEWEB)

Link, S.O.; Fellows, R.J.; Cataldo, D.A.; Droppo, J.G.; Van Voris, P.

1987-10-01

This report reviews existing mathematical and/or computer simulation models that estimate xenobiotic deposition to and transport through (both curricular and stomatal) vegetative surfaces. The report evaluates the potential for coupling the best of those models to the existing Uptake, Translocation, Accumulation, and Biodegradation model to be used for future xenobiotic exposure assessments. Here xenobiotic compounds are defined as airborne contaminants, both organic and gaseous pollutants, that are introduced into the environment by man. Specifically this document provides a detailed review of the state-of-the-art models that addressed aerial deposition of particles and gases to foliage; foliar and cuticular transport, metabolism, and uptake of organic xenobiotics; and stomatal transport of gaseous and volatile organic xenobiotic pollutants. Where detailed information was available, parameters for each model are provided on a chemical by chemical as well as species by species basis. Sufficient detail is provided on each model to assess the potential for adapting or coupling the model to the existing UTAB plant exposure model. 126 refs., 6 figs., 10 tabs.

Polymorphisms in xenobiotic metabolizing enzymes and diet influence colorectal adenoma risk.

Science.gov (United States)

Northwood, Emma L; Elliott, Faye; Forman, David; Barrett, Jennifer H; Wilkie, Murray J V; Carey, Francis A; Steele, Robert J C; Wolf, Roland; Bishop, Timothy; Smith, Gillian

2010-05-01

We have earlier shown that diet and xenobiotic metabolizing enzyme genotypes influence colorectal cancer risk, and now investigate whether similar associations are seen in patients with premalignant colorectal adenomas (CRA), recruited during the pilot phase of the Scottish Bowel Screening Programme. Nineteen polymorphisms in 13 genes [cytochrome P450 (P450), glutathione S-transferase (GST), N-acetyl transferase, quinone reductase (NQ01) and microsomal epoxide hydrolase (EPHX1) genes] were genotyped using multiplex PCR or Taqman-based allelic discrimination assays and analyzed in conjunction with diet, assessed by food frequency questionnaire, in a case-control study [317 CRA cases (308 cases genotyped), 296 controls]. Findings significant at a nominal 5% level are reported. CRA risk was inversely associated with fruit (P=0.02, test for trend) and vegetable (P=0.001, test for trend) consumption. P450 CYP2C9*3 heterozygotes had reduced CRA risk compared with homozygotes for the reference allele [odds ratio (OR): 0.60; 95% confidence interval (CI): 0.36-0.99], whereas CYP2D6*4 homozygotes (OR: 2.72; 95% CI: 1.18-6.27) and GSTM1 'null' individuals (OR: 1.43; 95% CI: 1.04-1.98) were at increased risk. The protective effect of fruit consumption was confined to GSTP1 (Ala114Val) reference allele homozygotes (OR: 0.49; 95% CI: 0.34-0.71, P=0.03 for interaction). CRA risk was not associated with meat consumption, although a significant interaction between red meat consumption and EPHX1 (His139Arg) genotype was noted (P=0.02 for interaction). We report the novel associations between P450 genotype and CRA risk, and highlight the risk association with GSTM1 genotype, common to our CRA and cancer case-control series. In addition, we report a novel modifying influence of GSTP1 genotype on dietary chemoprevention. These novel findings require independent confirmation.

Comparative liver accumulation of dioxin-like compounds in sheep and cattle: Possible role of AhR-mediated xenobiotic metabolizing enzymes.

Science.gov (United States)

Girolami, F; Spalenza, V; Benedetto, A; Manzini, L; Badino, P; Abete, M C; Nebbia, C

2016-11-15

PCDDs, PCDFs, and PCBs are persistent organic pollutants (POPs) that accumulate in animal products and may pose serious health problems. Those able to bind the aryl hydrocarbon receptor (AhR), eliciting a plethora of toxic responses, are defined dioxin-like (DL) compounds, while the remainders are called non-DL (NDL). An EFSA opinion has highlighted the tendency of ovine liver to specifically accumulate DL-compounds to a greater extent than any other farmed ruminant species. To examine the possible role in such an accumulation of xenobiotic metabolizing enzymes (XME) involved in DL-compound biotransformation, liver samples were collected from ewes and cows reared in an area known for low dioxin contamination. A related paper reported that sheep livers had about 5-fold higher DL-compound concentrations than cattle livers, while the content of the six marker NDL-PCBs did not differ between species. Specimens from the same animals were subjected to gene expression analysis for AhR, AhR nuclear translocator (ARNT) and AhR-dependent oxidative and conjugative pathways; XME protein expression and activities were also investigated. Both AhR and ARNT mRNA levels were about 2-fold lower in ovine samples and the same occurred for CYP1A1 and CYP1A2, being approximately 3- and 9-fold less expressed in sheep compared to cattle, while CYP1B1 could be detectable in cattle only. The results of the immunoblotting and catalytic activity (most notably EROD) measurements of the CYP1A family enzymes were in line with the gene expression data. By contrast, phase II enzyme expression and activities in sheep were higher (UGT1A) or similar (GSTA1, NQO1) to those recorded in cattle. The overall low expression of CYP1 family enzymes in the sheep is in line with the observed liver accumulation of DL-compounds and is expected to affect the kinetics and the dynamics of other POPs such as many polycyclic aromatic hydrocarbons, as well as of toxins (e.g. aflatoxins) or drugs (e.g. benzimidazole

Xenobiotic/medium chain fatty acid: CoA ligase - a critical review on its role in fatty acid metabolism and the detoxification of benzoic acid and aspirin.

Science.gov (United States)

van der Sluis, Rencia; Erasmus, Elardus

2016-10-01

Activation of fatty acids by the acyl-CoA synthetases (ACSs) is the vital first step in fatty acid metabolism. The enzymatic and physiological characterization of the human xenobiotic/medium chain fatty acid: CoA ligases (ACSMs) has been severely neglected even though xenobiotics, such as benzoate and salicylate, are detoxified through this pathway. This review will focus on the nomenclature and substrate specificity of the human ACSM ligases; the biochemical and enzymatic characterization of ACSM1 and ACSM2B; the high sequence homology of the ACSM2 genes (ACSM2A and ACSM2B) as well as what is currently known regarding disease association studies. Several discrepancies exist in the current literature that should be taken note of. For example, the single nucleotide polymorphisms (SNPs) reported to be associated with aspirin metabolism and multiple risk factors of metabolic syndrome are incorrect. Kinetic data on the substrate specificity of the human ACSM ligases are non-existent and currently no data exist on the influence of SNPs on the enzyme activity of these ligases. One of the biggest obstacles currently in the field is that glycine conjugation is continuously studied as a one-step process, which means that key regulatory factors of the two individual steps remain unknown.

Impact of environmental exposures on ovarian function and role of xenobiotic metabolism during ovotoxicity

Energy Technology Data Exchange (ETDEWEB)

Bhattacharya, Poulomi; Keating, Aileen F., E-mail: akeating@iastate.edu

2012-06-15

The mammalian ovary is a heterogeneous organ and contains oocyte-containing follicles at varying stages of development. The most immature follicular stage, the primordial follicle, comprises the ovarian reserve and is a finite number, defined at the time of birth. Depletion of all follicles within the ovary leads to reproductive senescence, known as menopause. A number of chemical classes can destroy follicles, thus hastening entry into the menopausal state. The ovarian response to chemical exposure can determine the extent of ovotoxicity that occurs. Enzymes capable of bioactivating as well as detoxifying xenobiotics are expressed in the ovary and their impact on ovotoxicity has been partially characterized for trichloroethylene, 7,12-dimethylbenz[a]anthracene, and 4-vinylcyclohexene. This review will discuss those studies, as well as illustrate where knowledge gaps remain for chemicals that have also been established as ovotoxicants. -- Highlights: ► Summary of ovotoxicant action during ovotoxicity. ► Discussion of impact of biotransformation on chemical toxicity. ► Identification of knowledge gaps in chemical metabolism.

Impact of environmental exposures on ovarian function and role of xenobiotic metabolism during ovotoxicity

International Nuclear Information System (INIS)

Bhattacharya, Poulomi; Keating, Aileen F.

2012-01-01

The mammalian ovary is a heterogeneous organ and contains oocyte-containing follicles at varying stages of development. The most immature follicular stage, the primordial follicle, comprises the ovarian reserve and is a finite number, defined at the time of birth. Depletion of all follicles within the ovary leads to reproductive senescence, known as menopause. A number of chemical classes can destroy follicles, thus hastening entry into the menopausal state. The ovarian response to chemical exposure can determine the extent of ovotoxicity that occurs. Enzymes capable of bioactivating as well as detoxifying xenobiotics are expressed in the ovary and their impact on ovotoxicity has been partially characterized for trichloroethylene, 7,12-dimethylbenz[a]anthracene, and 4-vinylcyclohexene. This review will discuss those studies, as well as illustrate where knowledge gaps remain for chemicals that have also been established as ovotoxicants. -- Highlights: ► Summary of ovotoxicant action during ovotoxicity. ► Discussion of impact of biotransformation on chemical toxicity. ► Identification of knowledge gaps in chemical metabolism.

Acetaminophen induces xenobiotic-metabolizing enzymes in rat: Impact of a uranium chronic exposure.

Science.gov (United States)

Rouas, Caroline; Souidi, Maâmar; Grandcolas, Line; Grison, Stephane; Baudelin, Cedric; Gourmelon, Patrick; Pallardy, Marc; Gueguen, Yann

2009-11-01

The extensive use of uranium in civilian and military applications increases the risk of human chronic exposure. Uranium is a slightly radioactive heavy metal with a predominantly chemical toxicity, especially in kidney but also in liver. Few studies have previously shown some effects of uranium on xenobiotic-metabolizing enzymes (XME) that might disturb drug pharmacokinetic. The aim of this study was to determine whether a chronic (9 months) non-nephrotoxic low dose exposure to depleted uranium (DU, 1mg/rat/day) could modify the liver XME, using a single non-hepatotoxic acetaminophen (APAP) treatment (50mg/kg). Most of XME analysed were induced by APAP treatment at the gene expression level but at the protein level only CYP3A2 was significantly increased 3h after APAP treatment in DU-exposed rats whereas it remained at a basal level in unexposed rats. In conclusion, these results showed that a chronic non-nephrotoxic DU exposure specially modify CYP3A2 after a single therapeutic APAP treatment. Copyright © 2009 Elsevier B.V. All rights reserved.

Cadmium, cobalt and lead cause stress response, cell cycle deregulation and increased steroid as well as xenobiotic metabolism in primary normal human bronchial epithelial cells which is coordinated by at least nine transcription factors

Energy Technology Data Exchange (ETDEWEB)

Glahn, Felix; Wiese, Jan; Foth, Heidi [Martin-Luther-University, Halle-Wittenberg, Institute of Environmental Toxicology, Halle/Saale (Germany); Schmidt-Heck, Wolfgang; Guthke, Reinhard [Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, Jena (Germany); Zellmer, Sebastian; Gebhardt, Rolf [University of Leipzig, Institute of Biochemistry, Medical Faculty, Leipzig (Germany); Golka, Klaus; Degen, Gisela H.; Hermes, Matthias; Schormann, Wiebke; Brulport, Marc; Bauer, Alexander; Bedawy, Essam [IfADo, Leibniz Research Centre for Working Environment and Human Factors, Dortmund (Germany); Hergenroeder, Roland [ISAS, Institute for Analytical Sciences, Dortmund (Germany); Lehmann, Thomas [Translational Centre for Regenerative Medicine, Leipzig (Germany); Hengstler, Jan G. [IfADo, Leibniz Research Centre for Working Environment and Human Factors, Dortmund (Germany)

2008-08-15

Workers occupationally exposed to cadmium, cobalt and lead have been reported to have increased levels of DNA damage. To analyze whether in vivo relevant concentrations of heavy metals cause systematic alterations in RNA expression patterns, we performed a gene array study using primary normal human bronchial epithelial cells. Cells were incubated with 15{mu}g/l Cd(II), 25{mu}g/l Co(II) and 550{mu}g/l Pb(II) either with individual substances or in combination. Differentially expressed genes were filtered out and used to identify enriched GO categories as well as KEGG pathways and to identify transcription factors whose binding sites are enriched in a given set of promoters. Interestingly, combined exposure to Cd(II), Co(II) and Pb(II) caused a coordinated response of at least seven stress response-related transcription factors, namely Oct-1, HIC1, TGIF, CREB, ATF4, SRF and YY1. A stress response was further corroborated by up regulation of genes involved in glutathione metabolism. A second major response to heavy metal exposure was deregulation of the cell cycle as evidenced by down regulation of the transcription factors ELK-1 and the Ets transcription factor GABP, as well as deregulation of genes involved in purine and pyrimidine metabolism. A third and surprising response was up regulation of genes involved in steroid metabolism, whereby promoter analysis identified up regulation of SRY that is known to play a role in sex determination. A forth response was up regulation of xenobiotic metabolising enzymes, particularly of dihydrodiol dehydrogenases 1 and 2 (AKR1C1, AKR1C2). Incubations with individual heavy metals showed that the response of AKR1C1 and AKR1C2 was predominantly caused by lead. In conclusion, we have shown that in vivo relevant concentrations of Cd(II), Co(II) and Pb(II) cause a complex and coordinated response in normal human bronchial epithelial cells. This study gives an overview of the most responsive genes. (orig.)

Coactivator PGC-1α regulates the fasting inducible xenobiotic-metabolizing enzyme CYP2A5 in mouse primary hepatocytes

International Nuclear Information System (INIS)

Arpiainen, Satu; Jaervenpaeae, Sanna-Mari; Manninen, Aki; Viitala, Pirkko; Lang, Matti A.; Pelkonen, Olavi; Hakkola, Jukka

2008-01-01

The nutritional state of organisms and energy balance related diseases such as diabetes regulate the metabolism of xenobiotics such as drugs, toxins and carcinogens. However, the mechanisms behind this regulation are mostly unknown. The xenobiotic-metabolizing cytochrome P450 (CYP) 2A5 enzyme has been shown to be induced by fasting and by glucagon and cyclic AMP (cAMP), which mediate numerous fasting responses. Peroxisome proliferator-activated receptor γ coactivator (PGC)-1α triggers many of the important hepatic fasting effects in response to elevated cAMP levels. In the present study, we were able to show that cAMP causes a coordinated induction of PGC-1α and CYP2A5 mRNAs in murine primary hepatocytes. Furthermore, the elevation of the PGC-1α expression level by adenovirus mediated gene transfer increased CYP2A5 transcription. Co-transfection of Cyp2a5 5' promoter constructs with the PGC-1α expression vector demonstrated that PGC-1α is able to activate Cyp2a5 transcription through the hepatocyte nuclear factor (HNF)-4α response element in the proximal promoter of the Cyp2a5 gene. Chromatin immunoprecipitation assays showed that PGC-1α binds, together with HNF-4α, to the same region at the Cyp2a5 proximal promoter. In conclusion, PGC-1α mediates the expression of CYP2A5 induced by cAMP in mouse hepatocytes through coactivation of transcription factor HNF-4α. This strongly suggests that PGC-1α is the major factor mediating the fasting response of CYP2A5

The Mediator subunit MDT-15 confers metabolic adaptation to ingested material.

Directory of Open Access Journals (Sweden)

Stefan Taubert

2008-02-01

Full Text Available In eukaryotes, RNA polymerase II (Pol(II dependent gene expression requires accessory factors termed transcriptional coregulators. One coregulator that universally contributes to Pol(II-dependent transcription is the Mediator, a multisubunit complex that is targeted by many transcriptional regulatory factors. For example, the Caenorhabditis elegans Mediator subunit MDT-15 confers the regulatory actions of the sterol response element binding protein SBP-1 and the nuclear hormone receptor NHR-49 on fatty acid metabolism. Here, we demonstrate that MDT-15 displays a broader spectrum of activities, and that it integrates metabolic responses to materials ingested by C. elegans. Depletion of MDT-15 protein or mutation of the mdt-15 gene abrogated induction of specific detoxification genes in response to certain xenobiotics or heavy metals, rendering these animals hypersensitive to toxin exposure. Intriguingly, MDT-15 appeared to selectively affect stress responses related to ingestion, as MDT-15 functional defects did not abrogate other stress responses, e.g., thermotolerance. Together with our previous finding that MDT-15:NHR-49 regulatory complexes coordinate a sector of the fasting response, we propose a model whereby MDT-15 integrates several transcriptional regulatory pathways to monitor both the availability and quality of ingested materials, including nutrients and xenobiotic compounds.

Intake of Hydrolyzed Casein is Associated with Reduced Body Fat Accretion and Enhanced Phase II Metabolism in Obesity Prone C57BL/6J Mice

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Clausen, Morten Rahr; Zhang, Xumin; Yde, Christian C.; Ditlev, Ditte B.; Lillefosse, Haldis H.; Madsen, Lise; Kristiansen, Karsten; Liaset, Bjørn; Bertram, Hanne C.

2015-01-01

The amount and form of dietary casein have been shown to affect energy metabolism and lipid accumulation in mice, but the underlying mechanisms are not fully understood. We investigated 48 hrs urinary metabolome, hepatic lipid composition and gene expression in male C57BL/6J mice fed Western diets with 16 or 32 energy% protein in the form of extensively hydrolyzed or intact casein. LC-MS based metabolomics revealed a very strong impact of casein form on the urinary metabolome. Evaluation of the discriminatory metabolites using tandem mass spectrometry indicated that intake of extensively hydrolyzed casein modulated Phase II metabolism associated with an elevated urinary excretion of glucuronic acid- and sulphate conjugated molecules, whereas glycine conjugated molecules were more abundant in urine from mice fed the intact casein diets. Despite the differences in the urinary metabolome, we observed no differences in hepatic expression of genes involved in Phase II metabolism, but it was observed that expression of Abcc3 encoding ATP binding cassette c3 (transporter of glucuronic acid conjugates) was increased in livers of mice fed hydrolyzed casein. As glucuronic acid is derived from glucose and sulphate is derived from cysteine, our metabolomic data provided evidence for changes in carbohydrate and amino acid metabolism and we propose that this modulation of metabolism was associated with the reduced glucose and lipid levels observed in mice fed the extensively hydrolyzed casein diets. PMID:25738501

The SafeBoosC Phase II Randomised Clinical Trial

DEFF Research Database (Denmark)

Pellicer, Adelina; Greisen, Gorm; Benders, Manon

2013-01-01

Near-infrared spectroscopy-derived regional tissue oxygen saturation of haemoglobin (rStO2) reflects venous oxygen saturation. If cerebral metabolism is stable, rStO2 can be used as an estimate of cerebral oxygen delivery. The SafeBoosC phase II randomised clinical trial hypothesises that the bur...

Small Business Innovation Research GRC Phase I, Phase II, and Post-Phase II Opportunity Assessment for 2015

Science.gov (United States)

Nguyen, Hung D.; Steele, Gynelle C.

2016-01-01

This report outlines the 2015 Small Business Innovation Research/Small Business Technology Transfer (SBIR/STTR) Phase I, Phase II, and Post-Phase II opportunity contract award results associated with NASA's Aeronautics Research Mission Directorate (ARMD), Human Exploration and Operations Mission Directorate (HEOMD), Science Mission Directorate (SMD), and Space Technology Mission Directorate (STMD) for NASA Glenn Research Center. The report also highlights the number of Phase I, Phase II, and Post-Phase II contracts awarded by mission directorate. The 2015 Phase I contract awards to companies in Ohio and their corresponding technologies are also discussed.

Polychlorinated Biphenyl-Xenobiotic Nuclear Receptor Interactions Regulate Energy Metabolism, Behavior, and Inflammation in Non-alcoholic-Steatohepatitis.

Science.gov (United States)

Wahlang, Banrida; Prough, Russell A; Falkner, K Cameron; Hardesty, Josiah E; Song, Ming; Clair, Heather B; Clark, Barbara J; States, J Christopher; Arteel, Gavin E; Cave, Matthew C

2016-02-01

Polychlorinated biphenyls (PCBs) are environmental pollutants associated with non-alcoholic-steatohepatitis (NASH), diabetes, and obesity. We previously demonstrated that the PCB mixture, Aroclor 1260, induced steatohepatitis and activated nuclear receptors in a diet-induced obesity mouse model. This study aims to evaluate PCB interactions with the pregnane-xenobiotic receptor (Pxr: Nr1i2) and constitutive androstane receptor (Car: Nr1i3) in NASH. Wild type C57Bl/6 (WT), Pxr(-/-) and Car(-/-) mice were fed the high fat diet (42% milk fat) and exposed to a single dose of Aroclor 1260 (20 mg/kg) in this 12-week study. Metabolic phenotyping and analysis of serum, liver, and adipose was performed. Steatohepatitis was pathologically similar in all Aroclor-exposed groups, while Pxr(-/-) mice displayed higher basal pro-inflammatory cytokine levels. Pxr repressed Car expression as evident by increased basal Car/Cyp2b10 expression in Pxr(-/-) mice. Both Pxr(-/-) and Car(-/-) mice showed decreased basal respiratory exchange rate (RER) consistent with preferential lipid metabolism. Aroclor increased RER and carbohydrate metabolism, associated with increased light cycle activity in both knockouts, and decreased food consumption in the Car(-/-) mice. Aroclor exposure improved insulin sensitivity in WT mice but not glucose tolerance. The Aroclor-exposed, Pxr(-/-) mice displayed increased gluconeogenic gene expression. Lipid-oxidative gene expression was higher in WT and Pxr(-/-) mice although RER was not changed, suggesting PCB-mediated mitochondrial dysfunction. Therefore, Pxr and Car regulated inflammation, behavior, and energy metabolism in PCB-mediated NASH. Future studies should address the 'off-target' effects of PCBs in steatohepatitis. Published by Oxford University Press on behalf of the Society of Toxicology 2015. This work is written by US Government employees and is in the public domain in the US.

Current knowledge of detoxification mechanisms of xenobiotic in honey bees.

Science.gov (United States)

Gong, Youhui; Diao, Qingyun

2017-01-01

The western honey bee Apis mellifera is the most important managed pollinator species in the world. Multiple factors have been implicated as potential causes or factors contributing to colony collapse disorder, including honey bee pathogens and nutritional deficiencies as well as exposure to pesticides. Honey bees' genome is characterized by a paucity of genes associated with detoxification, which makes them vulnerable to specific pesticides, especially to combinations of pesticides in real field environments. Many studies have investigated the mechanisms involved in detoxification of xenobiotics/pesticides in honey bees, from primal enzyme assays or toxicity bioassays to characterization of transcript gene expression and protein expression in response to xenobiotics/insecticides by using a global transcriptomic or proteomic approach, and even to functional characterizations. The global transcriptomic and proteomic approach allowed us to learn that detoxification mechanisms in honey bees involve multiple genes and pathways along with changes in energy metabolism and cellular stress response. P450 genes, is highly implicated in the direct detoxification of xenobiotics/insecticides in honey bees and their expression can be regulated by honey/pollen constitutes, resulting in the tolerance of honey bees to other xenobiotics or insecticides. P450s is also a key detoxification enzyme that mediate synergism interaction between acaricides/insecticides and fungicides through inhibition P450 activity by fungicides or competition for detoxification enzymes between acaricides. With the wide use of insecticides in agriculture, understanding the detoxification mechanism of insecticides in honey bees and how honeybees fight with the xenobiotis or insecticides to survive in the changing environment will finally benefit honeybees' management.

Short-term calorie restriction feminizes the mRNA profiles of drug metabolizing enzymes and transporters in livers of mice

International Nuclear Information System (INIS)

Fu, Zidong Donna; Klaassen, Curtis D.

2014-01-01

Calorie restriction (CR) is one of the most effective anti-aging interventions in mammals. A modern theory suggests that aging results from a decline in detoxification capabilities and thus accumulation of damaged macromolecules. The present study aimed to determine how short-term CR alters mRNA profiles of genes that encode metabolism and detoxification machinery in the liver. Male C57BL/6 mice were fed CR (0, 15, 30, or 40%) diets for one month, followed by mRNA quantification of 98 xenobiotic processing genes (XPGs) in the liver, including 7 uptake transporters, 39 phase-I enzymes, 37 phase-II enzymes, 10 efflux transporters, and 5 transcription factors. In general, 15% CR did not alter mRNAs of most XPGs, whereas 30 and 40% CR altered over half of the XPGs (32 increased and 29 decreased). CR up-regulated some phase-I enzymes (fold increase), such as Cyp4a14 (12), Por (2.3), Nqo1 (1.4), Fmo2 (5.4), and Fmo3 (346), and numerous number of phase-II enzymes, such as Sult1a1 (1.2), Sult1d1 (2.0), Sult1e1 (33), Sult3a1 (2.2), Gsta4 (1.3), Gstm2 (1.3), Gstm3 (1.7), and Mgst3 (2.2). CR feminized the mRNA profiles of 32 XPGs in livers of male mice. For instance, CR decreased the male-predominantly expressed Oatp1a1 (97%) and increased the female-predominantly expressed Oatp1a4 (11). In conclusion, short-term CR alters the mRNA levels of over half of the 98 XPGs quantified in livers of male mice, and over half of these alterations appear to be due to feminization of the liver. - Highlights: • Utilized a graded CR model in male mice • The mRNA profiles of xenobiotic processing genes (XPGs) in liver were investigated. • CR up-regulates many phase-II enzymes. • CR tends to feminize the mRNA profiles of XPGs

Short-term calorie restriction feminizes the mRNA profiles of drug metabolizing enzymes and transporters in livers of mice

Energy Technology Data Exchange (ETDEWEB)

Fu, Zidong Donna [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Klaassen, Curtis D., E-mail: cklaasse@kumc.edu [Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160 (United States)

2014-01-01

Calorie restriction (CR) is one of the most effective anti-aging interventions in mammals. A modern theory suggests that aging results from a decline in detoxification capabilities and thus accumulation of damaged macromolecules. The present study aimed to determine how short-term CR alters mRNA profiles of genes that encode metabolism and detoxification machinery in the liver. Male C57BL/6 mice were fed CR (0, 15, 30, or 40%) diets for one month, followed by mRNA quantification of 98 xenobiotic processing genes (XPGs) in the liver, including 7 uptake transporters, 39 phase-I enzymes, 37 phase-II enzymes, 10 efflux transporters, and 5 transcription factors. In general, 15% CR did not alter mRNAs of most XPGs, whereas 30 and 40% CR altered over half of the XPGs (32 increased and 29 decreased). CR up-regulated some phase-I enzymes (fold increase), such as Cyp4a14 (12), Por (2.3), Nqo1 (1.4), Fmo2 (5.4), and Fmo3 (346), and numerous number of phase-II enzymes, such as Sult1a1 (1.2), Sult1d1 (2.0), Sult1e1 (33), Sult3a1 (2.2), Gsta4 (1.3), Gstm2 (1.3), Gstm3 (1.7), and Mgst3 (2.2). CR feminized the mRNA profiles of 32 XPGs in livers of male mice. For instance, CR decreased the male-predominantly expressed Oatp1a1 (97%) and increased the female-predominantly expressed Oatp1a4 (11). In conclusion, short-term CR alters the mRNA levels of over half of the 98 XPGs quantified in livers of male mice, and over half of these alterations appear to be due to feminization of the liver. - Highlights: • Utilized a graded CR model in male mice • The mRNA profiles of xenobiotic processing genes (XPGs) in liver were investigated. • CR up-regulates many phase-II enzymes. • CR tends to feminize the mRNA profiles of XPGs.

Identification of phase-II metabolites of flavonoids by liquid chromatography-ion-mobility spectrometry-mass spectrometry.

Science.gov (United States)

Chalet, Clément; Hollebrands, Boudewijn; Janssen, Hans-Gerd; Augustijns, Patrick; Duchateau, Guus

2018-01-01

Flavonoids are a class of natural compounds with a broad range of potentially beneficial health properties. They are subjected to an extensive intestinal phase-II metabolism, i.e., conjugation to glucuronic acid, sulfate, and methyl groups. Flavonoids and their metabolites can interact with drug transporters and thus interfere with drug absorption, causing food-drug interactions. The site of metabolism plays a key role in the activity, but the identification of the various metabolites remains a challenge. Here, we developed an analytical method to identify the phase-II metabolites of structurally similar flavonoids. We used liquid chromatography-ion-mobility spectrometry-mass spectrometry (LC-IMS-MS) analysis to identify phase-II metabolites of flavonols, flavones, and catechins produced by HT29 cells. We showed that IMS could bring valuable structural information on the different positional isomers of the flavonols and flavones. The position of the glucuronide moiety had a strong influence on the collision cross section (CCS) of the metabolites, with only minor contribution of hydroxyl and methyl moieties. For the catechins, fragmentation data obtained from MS/MS analysis appeared more useful than IMS to determine the structure of the metabolites, mostly due to the high number of metabolites formed. Nevertheless, CCS information as a molecular fingerprint proved to be useful to identify peaks from complex mixtures. LC-IMS-MS thus appears as a valuable tool for the identification of phase-II metabolites of flavonoids. Graphical abstract Structural identification of phase-II metabolites of flavonoids using LC-IMS-MS.

Prediction of bacterial growth on xenobiotics

DEFF Research Database (Denmark)

Brock, Andreas Libonati; Kästner, Matthias; Trapp, Stefan

2016-01-01

to attain predictions closer to the experimentally observed yields [3]. However, this knowledge is seldom known for xenobiotics in the environment but is needed to assess the turnover leading to biomass production, i.e. for sludge production or biogenic residues. The objectives of the present study were...... method, we evaluated it with both simple substrates (e.g. acetate, methanol, and glyoxylate) and xenobiotics (e.g 2,4-D, linuron, carbofuran, carbon tetrachloride, and toluene). Experimental data for the simple substrates were taken from [4], for xenobiotics from [6] and own experimental data. For simple...... substrates, our approach predicts yields close to experimental values and also for xenobiotics the yield predictions for most of the compounds are close to the experimentally obtained values.Overall, with our method we were able to obtain yield predictions close to experimental values with a minimum of input...

Xenobiotic-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models.

Science.gov (United States)

Oesch, F; Fabian, E; Guth, K; Landsiedel, R

2014-12-01

The exposure of the skin to medical drugs, skin care products, cosmetics, and other chemicals renders information on xenobiotic-metabolizing enzymes (XME) in the skin highly interesting. Since the use of freshly excised human skin for experimental investigations meets with ethical and practical limitations, information on XME in models comes in the focus including non-human mammalian species and in vitro skin models. This review attempts to summarize the information available in the open scientific literature on XME in the skin of human, rat, mouse, guinea pig, and pig as well as human primary skin cells, human cell lines, and reconstructed human skin models. The most salient outcome is that much more research on cutaneous XME is needed for solid metabolism-dependent efficacy and safety predictions, and the cutaneous metabolism comparisons have to be viewed with caution. Keeping this fully in mind at least with respect to some cutaneous XME, some models may tentatively be considered to approximate reasonable closeness to human skin. For dermal absorption and for skin irritation among many contributing XME, esterase activity is of special importance, which in pig skin, some human cell lines, and reconstructed skin models appears reasonably close to human skin. With respect to genotoxicity and sensitization, activating XME are not yet judgeable, but reactive metabolite-reducing XME in primary human keratinocytes and several reconstructed human skin models appear reasonably close to human skin. For a more detailed delineation and discussion of the severe limitations see the "Overview and Conclusions" section in the end of this review.

[Study of enzymes of xenobiotic metabolism in the evaluation of quality of protein-containing wheat germ flakes and wallpaper flour].

Science.gov (United States)

Martinchuk, A N; E En Gyn; Safronova, A M; Peskova, E V

1991-01-01

Intake of wheat upholstery meal by growing rats was attended by a sharp decrease in the content and activity of xenobiotic metabolism enzymes in the hepatic microsomes, that was caused by the low biological value of the meal proteins. Hepatic microsomes of the rats that were fed with wheat germ flakes showed increased specific content of cytochromes P-450 and b5, but the total blood protein content per 100 g of body mass was lower than during casein consumption. No significant changes were detected in hydroxylation rate of benz(a)pyrene, aniline and ethylmorphine. During consumption of wheat germ flakes induction of UDP-glucuronide-transferase was detected in hepatic microsomes. Wheat germ flakes induced a 5-fold increase of Se-dependent glutathione peroxidase activity. Wheat germ flakes produced no significant effect on glutathione-S-aryltransferase and glutathione reductase activity.

Molecular, cellular, and tissue impact of depleted uranium on xenobiotic-metabolizing enzymes.

Science.gov (United States)

Gueguen, Yann; Rouas, Caroline; Monin, Audrey; Manens, Line; Stefani, Johanna; Delissen, Olivia; Grison, Stéphane; Dublineau, Isabelle

2014-02-01

Enzymes that metabolize xenobiotics (XME) are well recognized in experimental models as representative indicators of organ detoxification functions and of exposure to toxicants. As several in vivo studies have shown, uranium can alter XME in the rat liver or kidneys after either acute or chronic exposure. To determine how length or level of exposure affects these changes in XME, we continued our investigation of chronic rat exposure to depleted uranium (DU, uranyl nitrate). The first study examined the effect of duration (1-18 months) of chronic exposure to DU, the second evaluated dose dependence, from a level close to that found in the environment near mining sites (0.2 mg/L) to a supra-environmental dose (120 mg/L, 10 times the highest level naturally found in the environment), and the third was an in vitro assessment of whether DU exposure directly affects XME and, in particular, CYP3A. The experimental in vivo models used here demonstrated that CYP3A is the enzyme modified to the greatest extent: high gene expression changed after 6 and 9 months. The most substantial effects were observed in the liver of rats after 9 months of exposure to 120 mg/L of DU: CYP3A gene and protein expression and enzyme activity all decreased by more than 40 %. Nonetheless, no direct effect of DU by itself was observed after in vitro exposure of rat microsomal preparations, HepG2 cells, or human primary hepatocytes. Overall, these results probably indicate the occurrence of regulatory or adaptive mechanisms that could explain the indirect effect observed in vivo after chronic exposure.

Multiple resistance to carcinogens and xenobiotics: P-glycoproteins as universal detoxifiers.

Science.gov (United States)

Efferth, Thomas; Volm, Manfred

2017-07-01

The detoxification of toxic substances is of general relevance in all biological systems. The plethora of exogenous xenobiotic compounds and endogenous toxic metabolic products explains the evolutionary pressure of all organisms to develop molecular mechanisms to detoxify and excrete harmful substances from the body. P-glycoprotein and other members of the ATP-binding cassette (ABC) transporter family extrude innumerous chemical compounds out of cells. Their specific expression in diverse biological contexts cause different phenotypes: (1) multidrug resistance (MDR) and thus failure of cancer chemotherapy, (2) avoidance of accumulation of carcinogens and prevention of carcinogenesis in healthy tissues, (3) absorption, distribution, metabolization and excretion (ADME) of pharmacological drugs in human patients, (4) protection from environmental toxins in aquatic organisms (multi-xenobiotic resistance, MXR). Hence ABC-transporters may have opposing effects for organismic health reaching from harmful in MDR of tumors to beneficial for maintenance of health in MXR. While their inhibition by specific inhibitors may improve treatment success in oncology and avoid carcinogenesis, blocking of ABC-transporter-driven efflux by environmental pollutants leads to ecotoxicological consequences in marine biotopes. Poisoned seafood may enter the food-chain and cause intoxications in human beings. As exemplified with ABC-transporters, joining forces in interdisciplinary research may, therefore, be a wise strategy to fight problems in human medicine and environmental sciences.

Differences in the expression of xenobiotic-metabolizing enzymes between islets derived from the ventral and dorsal anlage of the pancreas.

Science.gov (United States)

Standop, Jens; Ulrich, Alexis B; Schneider, Matthias B; Büchler, Markus W; Pour, Parviz M

2002-01-01

Chronic pancreatitis and pancreatic cancer have been linked to the exposure of environmental chemicals (xenobiotics), which generally require metabolic activation to highly reactive toxic or carcinogenic intermediates. The primary enzyme system involved is made up of numerous cytochrome P450 mono-oxygenases (CYP). Glutathione S-transferases (GST) belong to the enzyme systems that catalyze the conjugation of the reactive intermediates produced by CYPs to less toxic or readily excretable metabolites. Because the majority of chronic pancreatitis and pancreatic cancers develop in the organ's head, we compared the expression of selected CYP and GST enzymes between the tissues deriving from the ventral anlage (head) and dorsal anlage (corpus, tail). A total of 20 normal pancreatic tissue specimen from organ donors and early autopsy cases were processed immunohistochemically by using antibodies to CYP 1A1, 1A2, 2B6, 2C8/9/19, 2D6, 2E1, 3A1, 3A2 and 3A4, GST-alpha, GST-mu and GST-pi, and the NADPH cytochrome P450 oxido-reductase (NA-OR), the specificity of which has been verified in our previous study by Western blot and RT-PCR analyses. In all pancreatic regions, most of the enzymes were expressed in islet cells. However, more islets in the head region expressed CYP 2B6, 2C8/9/19, 2E1 and the NA-OR, than those in the body and tail. Moreover, the expression of CYP 2B6 and 2E1 was restricted to the pancreatic polypeptide (PP) cells, and the concentration of CYP 3A1 and 3A4 was stronger in PP cells than in other islet cells. On the other hand, GST-mu and GST-pi were expressed primarily in islet cells of the body and tail. The greater content of xenobiotic-metabolizing and carcinogen-activating CYP enzymes and a lower expression of detoxifying GST enzymes in the head of the pancreas could be one reason for the greater susceptibility of this region for inflammatory and malignant diseases. Copyright 2002 S. Karger AG, Basel and IAP

Role of Free Radicals, Oxidative Stress and Xenobiotics in Carcinogenesis by Environmental Pollutants

Directory of Open Access Journals (Sweden)

Dibyajyoti Saha

2014-09-01

Full Text Available Carcinogenesis by many small molecular weight chemicals involves either a direct action of the chemical on cellular DNA or metabolism of the parent chemical to an active or ultimate form, which can than react with cellular DNA to produce a permanent chemical change in a DNA structure. A free radical is an atom or molecule that has one or more unpaired electron(s. These are highly reactive species capable of wide spread, indiscriminate oxidation and per oxidation of proteins, lipids and DNA which can lead to significant cellular damage and even tissue and/or organ failure. . Oxidative stress is a leading cause to damage cells by oxidation. The rate at which oxidative damage is induced (input and the rate at which it is efficiently repaired and removed (output. Xenobiotics are a compound that is foreign to the body. Xenobiotics can produce a variety of biological effects, including pharmacologic responses, toxicity, genes, immunologic reactions and cancer. Oxidative stress is a leading cause to damage cells by oxidation. The rate at which oxidative damage is induced (input and the rate at which it is efficiently repaired and removed (output. This communication highlights the role of carcinogens as environmental pollutants with the possible mechanism of free radicals, oxidative stress and xenobiotics.

Norepinephrine metabolism in neuronal cultures is increased by angiotensin II

International Nuclear Information System (INIS)

Sumners, C.; Shalit, S.L.; Kalberg, C.J.; Raizada, M.K.

1987-01-01

In this study the authors have examined the actions of angiotensin II (ANG II) on catecholamine metabolism in neuronal brain cell cultures prepared from the hypothalamus and brain stem. Neuronal cultures prepared from the brains of 1-day-old Sprague-Dawley rats exhibit specific neuronal uptake mechanisms for both norepinephrine (NE) and dopamine (DA), and also monoamine oxidase (MAO) and catechol O-methyltransferase (COMT) activity. Separate neuronal uptake sites for NE and DA were identified by using specific neuronal uptake inhibitors for each amine. In previous studies, they determined that ANG II (10 nM-1 μM) stimulates increased neuronal [ 3 H]NE uptake by acting as specific receptors. They have confirmed these results here and in addition have shown that ANG II has not significant effects on neuronal [ 3 H]DA uptake. These results suggest that the actions of ANG II are restricted to the NE transporter in neuronal cultures. It is possible that ANG II stimulates the intraneuronal metabolism of at least part of the NE that is taken up, because the peptide stimulates MAO activity, an effect mediated by specific ANG II receptors. ANG II had no effect on COMT activity in neuronal cultures. Therefore, the use of neuronal cultures of hypothalamus and brain stem they have determined that ANG II can specifically alter NE metabolism in these areas, while apparently not altering DA metabolism

Microbial Dark Matter Phase II: Stepping deeper into unknown territory

Energy Technology Data Exchange (ETDEWEB)

Jarett, Jessica; Dunfield, Peter; Peura, Sari; Wielen, Paul van der; Hedlund, Brian; Elshahed, Mostafa; Kormas, Konstantinos; Stott, Andreas Teske8, Matt; Birkeland, Nils-Kare; Zhang, Chuanlun; Rengefors, Karin; Lindemann, Stephen; Ravin, Nikolai V.; Spear, John; Hallam, Steven; Crowe, Sean; Steele, Jillian; Goudeau, Danielle; Malmstrom, Rex; Kyrpides, Nikos; Stepanauskas, Ramunas; Woyke, Tanja

2014-10-27

Currently available microbial genomes are of limited phylogenetic breadth due to our historical inability to cultivate most microorganisms in the laboratory. The first phase of the Microbial Dark Matter project used single-cell genomics to sequence 201 single cells from uncultivated lineages, and was able to resolve new superphyla and reveal novel metabolic features in bacteria and archaea. However, many fundamental questions about the evolution and function of microbes remain unanswered, and many candidate phyla remain uncharacterized. Phase II of the Microbial Dark Matter project will target candidate phyla with no sequenced representatives at a variety of new sites using a combination of single-cell sequencing and shotgun metagenomics approaches.

Metabolism and interactions of pesticides in human and animal in vitro hepatic models

OpenAIRE

Abass, K. M. (Khaled M.)

2010-01-01

Abstract Risk assessment of chemicals needs reliable scientific information and one source of information is the characterization of the metabolic fate and toxicokinetics of a chemical. Metabolism is often the most important factor contributing to toxicokinetics. Cytochrome P450 (CYP) enzymes are a superfamily of microsomal proteins playing a pivotal role in xenobiotic metabolism. In the present study, pesticides were used as representative xenobiotics since exposure to pesticides is ...

Extent of cutaneous metabolism during percutaneous absorption of xenobiotics.

Science.gov (United States)

Bronaugh, R L; Stewart, R F; Storm, J E

1989-07-01

In vitro percutaneous absorption studies generally do not determine whether biotransformation occurs during passage of a substance through the skin. Since it has recently been demonstrated that several chemicals are metabolized during skin permeation, we investigated the metabolism of five additional compounds (14C-labeled) after application to fuzzy rat skin: caffeine, p,p'-DDT, butylated hydroxytoluene (BHT), salicylic acid, and acetyl ethyl tetramethyltetralin (AETT). The viability of skin was maintained with a tissue culture medium. Radioactivity of each substrate and any metabolites in skin and receptor fluid was measured so that the absorption and metabolism of water-insoluble compounds would be accurately determined. Percutaneous absorption ranged from a low of 13% of the applied dose for BHT to a high of 49% for DDT. BHT was metabolized in skin to 4-hydroxy-BHT and an unknown metabolite. Of the absorbed radioisotope, 6.6% was isolated in biotransformed products found mainly in the receptor fluid. AETT was also metabolized during absorption, with 1.9% of the absorbed radioisotope found in two unknown peaks. Caffeine, DDT, and salicylic acid were not metabolized during skin permeation. Skin and liver microsomal metabolism was measured for all compounds except DDT. Metabolism in skin was observed only for the compounds also biotransformed in the diffusion cell; BHT and AETT were metabolized at 113 and 2.5 pmol/min/mg protein, respectively. In this study, as in others, skin metabolism was substantially less than the corresponding metabolism in liver. Therefore, a low rate of liver metabolism such as that found for caffeine, salicylic acid, and DDT might often be predictive of the absence of measurable metabolism during skin permeation. It seems likely that for many compounds, the biotransformations in skin will be small in terms of the percentage of absorbed material that is metabolized. Nevertheless, with potent compounds, even small quantities of a metabolite

Influence of non-hydrophobic factors on the sorption of ionizable xenobiotics to solids

DEFF Research Database (Denmark)

Lützhøft, Hans-Christian Holten; Franco, Antonio; Trapp, Stefan

2011-01-01

It is well known that xenobiotics sorp to solid phases like soil and sediment, depending on their inherent properties and environmental conditions. Traditionally it was accepted, that the hydrophobicity of the chemical, i.e. the log KOW, as well as the solid’s content of organic carbon (OC) were...

Modulation of xenobiotic metabolising enzymes by anticarcinogens-focus on glutathione S-transferases and their role as targets of dietary chemoprevention in colorectal carcinogenesis

Energy Technology Data Exchange (ETDEWEB)

Pool-Zobel, Beatrice [Department of Nutritional Toxicology, Institute for Nutrition, Friedrich Schiller University Jena, 07743 Jena (Germany)]. E-mail: b8pobe@uni-jena.de; Veeriah, Selvaraju [Department of Nutritional Toxicology, Institute for Nutrition, Friedrich Schiller University Jena, 07743 Jena (Germany); Boehmer, Frank-D. [Institute of Molecular Cell Biology, University Hospital, Friedrich Schiller University Jena, 07743 Jena (Germany)

2005-12-11

There is evidence that consumption of certain dietary ingredients may favourably modulate biotransformation of carcinogens. Associated with this is the hypothesis that the risk for developing colorectal cancer could be reduced, since its incidence is related to diet. Two main groups of biotransformation enzymes metabolize carcinogens, namely Phase I enzymes, which convert hydrophobic compounds to more water-soluble moieties, and Phase II enzymes (e.g. glutathione S-transferases [GST]), which primarily catalyze conjugation reactions. The conjugation of electrophilic Phase I intermediates with glutathione, for instance, frequently results in detoxification. Several possible colon carcinogens may serve as substrates for GST isoenzymes that can have marked substrate specificity. The conjugated products could be less toxic/genotoxic if GSTs are induced, thereby reducing exposure. Thus, numerous studies have shown that the induction of GSTs by antioxidants enables experimental animals to tolerate exposure to carcinogens. One important mechanism of GST induction involves an antioxidant-responsive response element (ARE) and the transcription factor nuclear factor E2-related factor 2 (Nrf2), which is bound to the Kelch-like ECH associated protein 1 (Keap1) in the cytoplasm. Antioxidants may disrupt the Keap-Nrf2 complex, allowing Nrf2 to translocate to the nucleus and mediate expression of Phase II genes via interaction with the ARE. GSTs are also induced by butyrate, a product of gut flora-derived fermentation of plant foods, which may act via different mechanisms, e.g. by increasing histone acetylation. GSTs are expressed with high inter-individual variability in human colonocytes, which points to large differences in cellular susceptibility to xenobiotics. Enhancing expression of GSTs in human colon tissue could therefore contribute to reducing cancer risks. However, it has not been demonstrated in humans that this mechanism is associated with cancer prevention. In the

Modulation of xenobiotic metabolising enzymes by anticarcinogens-focus on glutathione S-transferases and their role as targets of dietary chemoprevention in colorectal carcinogenesis

International Nuclear Information System (INIS)

Pool-Zobel, Beatrice; Veeriah, Selvaraju; Boehmer, Frank-D.

2005-01-01

There is evidence that consumption of certain dietary ingredients may favourably modulate biotransformation of carcinogens. Associated with this is the hypothesis that the risk for developing colorectal cancer could be reduced, since its incidence is related to diet. Two main groups of biotransformation enzymes metabolize carcinogens, namely Phase I enzymes, which convert hydrophobic compounds to more water-soluble moieties, and Phase II enzymes (e.g. glutathione S-transferases [GST]), which primarily catalyze conjugation reactions. The conjugation of electrophilic Phase I intermediates with glutathione, for instance, frequently results in detoxification. Several possible colon carcinogens may serve as substrates for GST isoenzymes that can have marked substrate specificity. The conjugated products could be less toxic/genotoxic if GSTs are induced, thereby reducing exposure. Thus, numerous studies have shown that the induction of GSTs by antioxidants enables experimental animals to tolerate exposure to carcinogens. One important mechanism of GST induction involves an antioxidant-responsive response element (ARE) and the transcription factor nuclear factor E2-related factor 2 (Nrf2), which is bound to the Kelch-like ECH associated protein 1 (Keap1) in the cytoplasm. Antioxidants may disrupt the Keap-Nrf2 complex, allowing Nrf2 to translocate to the nucleus and mediate expression of Phase II genes via interaction with the ARE. GSTs are also induced by butyrate, a product of gut flora-derived fermentation of plant foods, which may act via different mechanisms, e.g. by increasing histone acetylation. GSTs are expressed with high inter-individual variability in human colonocytes, which points to large differences in cellular susceptibility to xenobiotics. Enhancing expression of GSTs in human colon tissue could therefore contribute to reducing cancer risks. However, it has not been demonstrated in humans that this mechanism is associated with cancer prevention. In the

Design of Phase II Non-inferiority Trials.

Science.gov (United States)

Jung, Sin-Ho

2017-09-01

With the development of inexpensive treatment regimens and less invasive surgical procedures, we are confronted with non-inferiority study objectives. A non-inferiority phase III trial requires a roughly four times larger sample size than that of a similar standard superiority trial. Because of the large required sample size, we often face feasibility issues to open a non-inferiority trial. Furthermore, due to lack of phase II non-inferiority trial design methods, we do not have an opportunity to investigate the efficacy of the experimental therapy through a phase II trial. As a result, we often fail to open a non-inferiority phase III trial and a large number of non-inferiority clinical questions still remain unanswered. In this paper, we want to develop some designs for non-inferiority randomized phase II trials with feasible sample sizes. At first, we review a design method for non-inferiority phase III trials. Subsequently, we propose three different designs for non-inferiority phase II trials that can be used under different settings. Each method is demonstrated with examples. Each of the proposed design methods is shown to require a reasonable sample size for non-inferiority phase II trials. The three different non-inferiority phase II trial designs are used under different settings, but require similar sample sizes that are typical for phase II trials.

An activated sludge modeling framework for xenobiotic trace chemicals (ASM-X): assessment of diclofenac and carbamazepine.

Science.gov (United States)

Plósz, Benedek Gy; Langford, Katherine H; Thomas, Kevin V

2012-11-01

Conventional models for predicting the fate of xenobiotic organic trace chemicals, identified, and calibrated using data obtained in batch experiments spiked with reference substances, can be limited in predicting xenobiotic removal in wastewater treatment plants (WWTPs). At stake is the level of model complexity required to adequately describe a general theory of xenobiotic removal in WWTPs. In this article, we assess the factors that influence the removal of diclofenac and carbamazepine in activated sludge, and evaluate the complexity required for the model to effectively predict their removal. The results are generalized to previously published cases. Batch experimental results, obtained under anoxic and aerobic conditions, were used to identify extensions to, and to estimate parameter values of the activated sludge modeling framework for Xenobiotic trace chemicals (ASM-X). Measurement and simulation results obtained in the batch experiments, spiked with the diclofenac and carbamazepine content of preclarified municipal wastewater shows comparably high biotransformation rates in the presence of growth substrates. Forward dynamic simulations were performed using full-scale data obtained from Bekkelaget WWTP (Oslo, Norway) to evaluate the model and to estimate the level of re-transformable xenobiotics present in the influent. The results obtained in this study demonstrate that xenobiotic loading conditions can significantly influence the removal capacity of WWTPs. We show that the trace chemical retransformation in upstream sewer pipes can introduce considerable error in assessing the removal efficiency of a WWTP, based only on parent compound concentration measurements. The combination of our data with those from the literature shows that solids retention time (SRT) can enhance the biotransformation of diclofenac, which was not the case for carbamazepine. Model approximation of the xenobiotic concentration, detected in the solid phase, suggest that between

Potential for anaerobic conversion of xenobiotics

DEFF Research Database (Denmark)

Mogensen, Anders Skibsted; Dolfing, J.; Haagensen, Frank

2003-01-01

This review covers the latest research on the anaerobic biodegradation of aromatic xenobiotic compounds, with emphasis on surfactants, polycyclic aromatic hydrocarbons, phthalate esters, polychlorinated biphenyls, halogenated phenols, and pesticides. The versatility of anaerobic reactor systems...... regarding the treatment of xenobiotics is shown with the focus on the UASB reactor, but the applicability of other reactor designs for treatment of hazardous waste is also included. Bioaugmentation has proved to be a viable technique to enhance a specific activity in anaerobic reactors and recent research...

Investigation of the role of the enzymes of xenobiotic metabolism in the resistance of insects to insecticides

International Nuclear Information System (INIS)

Leonova, I.N.; Nedel'kina, S.V.; Naumova, N.B.; Salganik, R.I.

1986-01-01

The activity of three enzyme systems of xenobiotic metabolism: cytochrome P-450-dependent monooxygenases, nonspecific esterases, and glutathione S-transferases, was investigated on a sensitive strain (S) of the housefly M. domestica L. and strains resistant to tetrametrin (R/sub tetr/), permetrin (R/sub perm/), mecarbenyl (R/sub mec/), and chlorophos (R/sub chlor/). In the strains R/sub tetr/ and R/sub mec/, in comparison with strain S, an increase of 2.7 and 2.3-fold, respectively, in the activity of microsomal monooxygenases was observed. The position of the maxima of the CO-differential spectra of cytochrome P-450 in all the investigated resistant strains, with the exception of R/sub chlor/, is shifted by 1-2 nm in the shortwave direction. The activity of glutathione S-transferases in the strain R/sub tetr/ proved elevated in comparison with the strain S. The data of an investigation of the total esterase activity and the data of starch gel electrophoresis are evidence of quantitative and qualitative differences between the strains. For all the resistant strains except for R/sub mec/, supplementary zones of esterase activity appear. The data obtained are discussed in connection with the resistance of the insects to insecticides

Centrifuge workers study. Phase II, completion report

International Nuclear Information System (INIS)

Wooten, H.D.

1994-09-01

Phase II of the Centrifuge Workers Study was a follow-up to the Phase I efforts. The Phase I results had indicated a higher risk than expected among centrifuge workers for developing bladder cancer when compared with the risk in the general population for developing this same type of cancer. However, no specific agent could be identified as the causative agent for these bladder cancers. As the Phase II Report states, Phase I had been limited to workers who had the greatest potential for exposure to substances used in the centrifuge process. Phase II was designed to expand the survey to evaluate the health of all employees who had ever worked in Centrifuge Program Departments 1330-1339 but who had not been interviewed in Phase I. Employees in analytical laboratories and maintenance departments who provided support services for the Centrifuge Program were also included in Phase II. In December 1989, the Oak Ridge Associated Universities (ORAU), now known as Oak Ridge Institute for Science and Education (ORISE), was contracted to conduct a follow-up study (Phase II). Phase H of the Centrifuge Workers Study expanded the survey to include all former centrifuge workers who were not included in Phase I. ORISE was chosen because they had performed the Phase I tasks and summarized the corresponding survey data therefrom

Centrifuge workers study. Phase II, completion report

Energy Technology Data Exchange (ETDEWEB)

Wooten, H.D.

1994-09-01

Phase II of the Centrifuge Workers Study was a follow-up to the Phase I efforts. The Phase I results had indicated a higher risk than expected among centrifuge workers for developing bladder cancer when compared with the risk in the general population for developing this same type of cancer. However, no specific agent could be identified as the causative agent for these bladder cancers. As the Phase II Report states, Phase I had been limited to workers who had the greatest potential for exposure to substances used in the centrifuge process. Phase II was designed to expand the survey to evaluate the health of all employees who had ever worked in Centrifuge Program Departments 1330-1339 but who had not been interviewed in Phase I. Employees in analytical laboratories and maintenance departments who provided support services for the Centrifuge Program were also included in Phase II. In December 1989, the Oak Ridge Associated Universities (ORAU), now known as Oak Ridge Institute for Science and Education (ORISE), was contracted to conduct a follow-up study (Phase II). Phase H of the Centrifuge Workers Study expanded the survey to include all former centrifuge workers who were not included in Phase I. ORISE was chosen because they had performed the Phase I tasks and summarized the corresponding survey data therefrom.

Carcinogen-induced mdr overexpression is associated with xenobiotic resistance in rat preneoplastic liver nodules and hepatocellular carcinomas.

Science.gov (United States)

Fairchild, C R; Ivy, S P; Rushmore, T; Lee, G; Koo, P; Goldsmith, M E; Myers, C E; Farber, E; Cowan, K H

1987-11-01

We have previously reported the isolation of a human breast cancer cell line resistant to doxorubicin (adriamycin; AdrR MCF-7 cells) that has also developed the phenotype of multidrug resistance (MDR). MDR in this cell line is associated with increased expression of mdr (P glycoprotein) gene sequences. The development of MDR in AdrR MCF-7 cells is also associated with changes in the expression of several phase I and phase II drug-detoxifying enzymes. These changes are remarkably similar to those associated with development of xenobiotic resistance in rat hyperplastic liver nodules, a well-studied model system of chemical carcinogenesis. Using an mdr-encoded cDNA sequence isolated from AdrR MCF-7 cells, we have examined the expression of mdr sequences in rat livers under a variety of experimental conditions. The expression of mdr increased 3-fold in regenerating liver. It was also elevated (3- to 12-fold) in several different samples of rat hyperplastic nodules and in four of five hepatomas that developed in this system. This suggests that overexpression of mdr, a gene previously associated with resistance to antineoplastic agents, may also be involved in the development of resistance to xenobiotics in rat hyperplastic nodules. In addition, although the acute administration of 2-acetylaminofluorene induced an 8-fold increase in hepatic mdr-encoded RNA, performance of a partial hepatectomy either before or after administration of 2-acetylaminofluorene resulted in a greater than 80-fold increase in mdr gene expression over that in normal untreated livers. This represents an important in vivo model system in which to study the acute regulation of this drug resistance gene.

Sample Exchange Evaluation (SEE) Report - Phase II

Energy Technology Data Exchange (ETDEWEB)

Winters, W.I.

1994-09-28

This report describes the results from Phase II of the Sample Exchange Evaluation (SEE) Program, a joint effort to compare analytical laboratory performance on samples from the Hanford Site`s high-level waste tanks. In Phase II, the program has been expanded to include inorganic constituents in addition to radionuclides. Results from Phase II that exceeded 20% relative percent difference criteria are identified.

Sample Exchange Evaluation (SEE) Report - Phase II

International Nuclear Information System (INIS)

Winters, W.I.

1994-01-01

This report describes the results from Phase II of the Sample Exchange Evaluation (SEE) Program, a joint effort to compare analytical laboratory performance on samples from the Hanford Site's high-level waste tanks. In Phase II, the program has been expanded to include inorganic constituents in addition to radionuclides. Results from Phase II that exceeded 20% relative percent difference criteria are identified

Military Family Coping Project - Phase II

Science.gov (United States)

2015-05-01

Anxiety, Life Satisfaction , Addiction, Trauma 4 The Military Family Coping Project reflects two phases. The first consisted of a series of focus...need for and guided the work of the Military Family Coping Project Phase II funded by TATRC. The Military Family Coping Project Phase II was...solidarity. For the purposes of family functioning analyses, married and unmarried soldiers were analyzed separately because marital status affects

Lowbush wild blueberries have the potential to modify gut microbiota and xenobiotic metabolism in the rat colon.

Directory of Open Access Journals (Sweden)

Alison Lacombe

Full Text Available The gastrointestinal tract is populated by an array of microbial species that play an important role in metabolic and immune functions. The composition of microorganisms is influenced by the components of the host's diet and can impact health. In the present study, dietary enrichment of lowbush wild blueberries (LWB was examined to determine their effect on colon microbial composition and their potential in promoting gut health. The microbial composition and functional potential of the colon microbiota from Sprague Dawley rats fed control diets (AIN93 and LWB-enriched diets (AIN93+8% LWB powder substituting for dextrose for 6 weeks were assessed using Illumina shotgun sequencing and bioinformatics tools. Our analysis revealed an alteration in the relative abundance of 3 phyla and 22 genera as representing approximately 14 and 8% of all phyla and genera identified, respectively. The LWB-enriched diet resulted in a significant reduction in the relative abundance of the genera Lactobacillus and Enterococcus. In addition, hierarchal analysis revealed a significant increase in the relative abundance of the phylum Actinobacteria, the order Actinomycetales, and several novel genera under the family Bifidobacteriaceae and Coriobacteriaceae, in the LWB group. Functional annotation of the shotgun sequences suggested that approximately 9% of the 4709 Kyoto Encyclopaedia of Gene and Genome (KEGG hits identified were impacted by the LWB-diet. Open Reading Frames (ORFs assigned to KEGG category xenobiotics biodegradation and metabolism were significantly greater in the LWB-enriched diet compared to the control and included the pathway for benzoate degradation [PATH:ko00362] and glycosaminoglycan degradation [PATH:ko00531]. Moreover, the number of ORFs assigned to the bacterial invasion of epithelial cells [PATH:ko05100] pathway was approximately 8 fold lower in the LWB group compared to controls. This study demonstrated that LWBs have the potential to promote

Phase II clinical development of new drugs

CERN Document Server

Ting, Naitee; Ho, Shuyen; Cappelleri, Joseph C

2017-01-01

This book focuses on how to appropriately plan and develop a Phase II program, and how to design Phase II clinical trials and analyze their data. It provides a comprehensive overview of the entire drug development process and highlights key questions that need to be addressed for the successful execution of Phase II, so as to increase its success in Phase III and for drug approval. Lastly it warns project team members of the common potential pitfalls and offers tips on how to avoid them.

Induction of expression of two phenotypic markers of pulmonary type II cells in a cultured cell line

International Nuclear Information System (INIS)

Henderson, R.F.; Waide, J.J.; Scott, G.G.

1994-01-01

The functions of pulmonary type II cells, such as synthesis of pulmonary surfactant and metabolism of inhaled xenobiotics, can be studied in primary isolates of lung cells. However, isolated type II cells, when cultured, quickly lose the phenotypic expressions characteristics of type II cells, including surfactant lipid and protein synthesis and alkaline phosphatase (AP) activity. A cultured cell line that maintained expression of type II cell markers of differentiation would be advantageous for the study of such functions as surfactant synthesis and secretion. Such a cell line would allow generation of a large number of homogeneous cells for study. The purpose of the current study was to induce markers of differentiated type II cells in a cultured cell line to facilitate studies of factors that control surfactant synthesis and secretion

(Systemic) phototoxicity of drugs and other xenobiotics.

Science.gov (United States)

Beijersbergen van Henegouwen, G M

1991-08-01

Xenobiotics extensively used in drugs, cosmetics, food and agricultural chemicals can produce adverse biological effects. These toxic effects are separated into classes, e.g. hepatotoxicity, genotoxicity and neurotoxicity. Skin allergy, part of immunotoxicity, is also a subdivision of toxicology. When light is an essential condition for toxicity, the xenobiotic is called phototoxic. Thus it fits into the logic of toxicology that photoallergic compounds are a subdivision of phototoxic compounds. Phototoxicons as a group do not differ from the group of phototherapeutics with regard to their eventual biological effects. The primary photoreactions, secondary molecular processes, biomolecules involved and cellular and tissue damage are similar. The difference between the two groups is in the appreciation of the photobiological effects: adverse vs. desired. The aim of research is to determine the part of the molecular structure which makes a given compound phototoxic. With that knowledge the structure of the phototoxicon can be changed. This can result in a derivative which still has the desired properties of the parent compound, but is no longer phototoxic. This aim can be reached by combining data from both in vitro and in vivo research. The variety and number of phototoxic compounds is large. This, together with the limited research effort devoted to this subject so far, means that for most phototoxic xenobiotics a relationship between structure and in vivo photoreactivity is not available. In this review, emphasis is placed on xenobiotics whose in vitro and in vivo photochemistry have been studied. Furthermore, possible phototoxic effects which do not concern the skin but involve inner organs (systemic effects) are considered. References in this review mostly concern investigations over the last 10 years. For older literature or for additional information, references to other reviews are given. Important groups of phototoxic xenobiotics not dealt with in this article

Improved xenobiotic metabolism and reduced susceptibility to cancer in gluten-sensitive macaques upon introduction of a gluten-free diet.

Directory of Open Access Journals (Sweden)

Karol Sestak

2011-04-01

Full Text Available A non-human primate (NHP model of gluten sensitivity was employed to study the gene perturbations associated with dietary gluten changes in small intestinal tissues from gluten-sensitive rhesus macaques (Macaca mulatta.Stages of remission and relapse were accomplished in gluten-sensitive animals by administration of gluten-free (GFD and gluten-containing (GD diets, as described previously. Pin-head-sized biopsies, obtained non-invasively by pediatric endoscope from duodenum while on GFD or GD, were used for preparation of total RNA and gene profiling, using the commercial Rhesus Macaque Microarray (Agilent Technologies,targeting expression of over 20,000 genes.When compared with normal healthy control, gluten-sensitive macaques showed differential gene expressions induced by GD. While observed gene perturbations were classified into one of 12 overlapping categories--cancer, metabolism, digestive tract function, immune response, cell growth, signal transduction, autoimmunity, detoxification of xenobiotics, apoptosis, actin-collagen deposition, neuronal and unknown function--this study focused on cancer-related gene networks such as cytochrome P450 family (detoxification function and actin-collagen-matrix metalloproteinases (MMP genes.A loss of detoxification function paralleled with necessity to metabolize carcinogens was revealed in gluten-sensitive animals while on GD. An increase in cancer-promoting factors and a simultaneous decrease in cancer-preventing factors associated with altered expression of actin-collagen-MMP gene network were noted. In addition, gluten-sensitive macaques showed reduced number of differentially expressed genes including the cancer-associated ones upon withdrawal of dietary gluten. Taken together, these findings indicate potentially expanded utility of gluten-sensitive rhesus macaques in cancer research.

Aerospace Systems Monitor, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — Proposal Title: Aerospace Systems Monitor PHASE 1 Technical Abstract: This Phase II STTR project will continue development and commercialization of the Aerospace...

An enhanced in vivo stable isotope labeling by amino acids in cell culture (SILAC) model for quantification of drug metabolism enzymes.

Science.gov (United States)

MacLeod, A Kenneth; Fallon, Padraic G; Sharp, Sheila; Henderson, Colin J; Wolf, C Roland; Huang, Jeffrey T-J

2015-03-01

Many of the enzymes involved in xenobiotic metabolism are maintained at a low basal level and are only synthesized in response to activation of upstream sensor/effector proteins. This induction can have implications in a variety of contexts, particularly during the study of the pharmacokinetics, pharmacodynamics, and drug-drug interaction profile of a candidate therapeutic compound. Previously, we combined in vivo SILAC material with a targeted high resolution single ion monitoring (tHR/SIM) LC-MS/MS approach for quantification of 197 peptide pairs, representing 51 drug metabolism enzymes (DME), in mouse liver. However, as important enzymes (for example, cytochromes P450 (Cyp) of the 1a and 2b subfamilies) are maintained at low or undetectable levels in the liver of unstimulated metabolically labeled mice, quantification of these proteins was unreliable. In the present study, we induced DME expression in labeled mice through synchronous ligand-mediated activation of multiple upstream nuclear receptors, thereby enhancing signals for proteins including Cyps 1a, 2a, 2b, 2c, and 3a. With this enhancement, 115 unique, lysine-containing, Cyp-derived peptides were detected in the liver of a single animal, as opposed to 56 in a pooled sample from three uninduced animals. A total of 386 peptide pairs were quantified by tHR/SIM, representing 68 Phase I, 30 Phase II, and eight control proteins. This method was employed to quantify changes in DME expression in the hepatic cytochrome P450 reductase null (HRN) mouse. We observed compensatory induction of several enzymes, including Cyps 2b10, 2c29, 2c37, 2c54, 2c55, 2e1, 3a11, and 3a13, carboxylesterase (Ces) 2a, and glutathione S-transferases (Gst) m2 and m3, along with down-regulation of hydroxysteroid dehydrogenases (Hsd) 11b1 and 17b6. Using DME-enhanced in vivo SILAC material with tHR/SIM, therefore, permits the robust analysis of multiple DME of importance to xenobiotic metabolism, with improved utility for the study of

Host genes related to paneth cells and xenobiotic metabolism are associated with shifts in human ileum-associated microbial composition.

Directory of Open Access Journals (Sweden)

Tianyi Zhang

Full Text Available The aim of this study was to integrate human clinical, genotype, mRNA microarray and 16 S rRNA sequence data collected on 84 subjects with ileal Crohn's disease, ulcerative colitis or control patients without inflammatory bowel diseases in order to interrogate how host-microbial interactions are perturbed in inflammatory bowel diseases (IBD. Ex-vivo ileal mucosal biopsies were collected from the disease unaffected proximal margin of the ileum resected from patients who were undergoing initial intestinal surgery. Both RNA and DNA were extracted from the mucosal biopsy samples. Patients were genotyped for the three major NOD2 variants (Leufs1007, R702W, and G908R and the ATG16L1T300A variant. Whole human genome mRNA expression profiles were generated using Agilent microarrays. Microbial composition profiles were determined by 454 pyrosequencing of the V3-V5 hypervariable region of the bacterial 16 S rRNA gene. The results of permutation based multivariate analysis of variance and covariance (MANCOVA support the hypothesis that host mucosal Paneth cell and xenobiotic metabolism genes play an important role in host microbial interactions.

Addressing the Impact of Environmental Xenobiotics in Coal-Fired Flue Gas

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Cornelia A. Bulucea

2015-03-01

Full Text Available Dangerous and unstable situations can result from the presence of environmental xenobiotics since their harmful effects on humans and ecosystems are often unpredictable, and building awareness of the environmental risk should be a main concern of humankind. The environmental xenobiotics in the flue gas from a fossil fuel-fired electrical generating station, such as particulate matter (PM, sulfur dioxide (SO2, nitrogen oxides (NOx, and carbon dioxide (CO2, are analyzed in this study, since these xenobiotics are persistent pollutants. Mathematical models of the environmental pollutant vector, estimating the emission factors specific to fossil fuel combustion, are applied to the operation of thermal units in the Turceni electrical generating station, each of which produces a net electrical power of 330 MW. For each stack gas component in the pollutant vector, emission factors and pollutant concentrations are determined. A pattern is also examined depicting the mathematically modelled processes of resonant absorption of an environmental xenobiotic harmonic oscillation by an organism modulated as an absorbing oscillator structure. The xenobiotic concentration degree is represented through a spatial concentration vector, which allows further modelling and simulation of the oscillating regime of environmental xenobiotic absorption.

Conservation and divergence of chemical defense system in the tunicate Oikopleura dioica revealed by genome wide response to two xenobiotics

Directory of Open Access Journals (Sweden)

Yadetie Fekadu

2012-02-01

Full Text Available Abstract Background Animals have developed extensive mechanisms of response to xenobiotic chemical attacks. Although recent genome surveys have suggested a broad conservation of the chemical defensome across metazoans, global gene expression responses to xenobiotics have not been well investigated in most invertebrates. Here, we performed genome survey for key defensome genes in Oikopleura dioica genome, and explored genome-wide gene expression using high density tiling arrays with over 2 million probes, in response to two model xenobiotic chemicals - the carcinogenic polycyclic aromatic hydrocarbon benzo[a]pyrene (BaP the pharmaceutical compound Clofibrate (Clo. Results Oikopleura genome surveys for key genes of the chemical defensome suggested a reduced repertoire. Not more than 23 cytochrome P450 (CYP genes could be identified, and neither CYP1 family genes nor their transcriptional activator AhR was detected. These two genes were present in deuterostome ancestors. As in vertebrates, the genotoxic compound BaP induced xenobiotic biotransformation and oxidative stress responsive genes. Notable exceptions were genes of the aryl hydrocarbon receptor (AhR signaling pathway. Clo also affected the expression of many biotransformation genes and markedly repressed genes involved in energy metabolism and muscle contraction pathways. Conclusions Oikopleura has the smallest number of CYP genes among sequenced animal genomes and lacks the AhR signaling pathway. However it appears to have basic xenobiotic inducible biotransformation genes such as a conserved genotoxic stress response gene set. Our genome survey and expression study does not support a role of AhR signaling pathway in the chemical defense of metazoans prior to the emergence of vertebrates.

Two Horizontally Transferred Xenobiotic Resistance Gene Clusters Associated with Detoxification of Benzoxazolinones by Fusarium Species

Science.gov (United States)

Glenn, Anthony E.; Davis, C. Britton; Gao, Minglu; Gold, Scott E.; Mitchell, Trevor R.; Proctor, Robert H.; Stewart, Jane E.; Snook, Maurice E.

2016-01-01

Microbes encounter a broad spectrum of antimicrobial compounds in their environments and often possess metabolic strategies to detoxify such xenobiotics. We have previously shown that Fusarium verticillioides, a fungal pathogen of maize known for its production of fumonisin mycotoxins, possesses two unlinked loci, FDB1 and FDB2, necessary for detoxification of antimicrobial compounds produced by maize, including the γ-lactam 2-benzoxazolinone (BOA). In support of these earlier studies, microarray analysis of F. verticillioides exposed to BOA identified the induction of multiple genes at FDB1 and FDB2, indicating the loci consist of gene clusters. One of the FDB1 cluster genes encoded a protein having domain homology to the metallo-β-lactamase (MBL) superfamily. Deletion of this gene (MBL1) rendered F. verticillioides incapable of metabolizing BOA and thus unable to grow on BOA-amended media. Deletion of other FDB1 cluster genes, in particular AMD1 and DLH1, did not affect BOA degradation. Phylogenetic analyses and topology testing of the FDB1 and FDB2 cluster genes suggested two horizontal transfer events among fungi, one being transfer of FDB1 from Fusarium to Colletotrichum, and the second being transfer of the FDB2 cluster from Fusarium to Aspergillus. Together, the results suggest that plant-derived xenobiotics have exerted evolutionary pressure on these fungi, leading to horizontal transfer of genes that enhance fitness or virulence. PMID:26808652

Effects of tin-protoporphyrin administration on hepatic xenobiotic metabolizing enzymes in the juvenile rat

International Nuclear Information System (INIS)

Stout, D.L.; Becker, F.F.

1988-01-01

The heme analogue tin-protoporphyrin IX (SnP) is a potent inhibitor of microsomal heme oxygenase. Administration of SnP to neonatal rats can prevent hyperbilirubinemia by blocking the postnatal increase of heme oxygenase activity. Apparently innocuous at therapeutic doses, it is of potential clinical value for chemoprevention of neonatal jaundice. We found that when 50-g male Sprague-Dawley rats were treated daily with 50 mumol of SnP/kg sc for 6 days, hepatic microsomal cytochromes b5 and P-450 were significantly diminished. Cytochrome P-450 reductase, two P-450-dependent monooxygenases, aminopyrine demethylase and benzo(a)pyrene hydroxylase, and catalase, a peroxisomal hemoprotein, were also significantly diminished. These results suggested that SnP might significantly affect the metabolism of other xenobiotics. This possibility was confirmed by the finding that hexobarbital-induced sleep lasted 4 times longer in SnP-treated rats than in controls. Inhibition of protein synthesis by SnP was ruled out as the cause of hemoprotein loss when administration of [ 3 H]leucine to SnP-treated and control rats demonstrated that proteins of the microsomal, cytosolic, and plasma membrane fractions of the livers from both groups incorporated similar levels of leucine. When 55 FeCl 3 and [2- 14 C]glycine were administered to measure heme synthesis, heme extract from the livers of SnP-treated rats contained 4 times more label from iron and glycine than did heme from control livers. Despite the apparent increased rate of heme synthesis in SnP-treated rats, each of the three cell fractions demonstrated a significant loss of heme but contained sizable amounts of SnP. These findings suggest that SnP causes a decrease of functional hemoprotein and partial loss of enzymic activity by displacing intracellular heme

Mutagenic activation and detoxification of benzo[a]pyrene in vitro by hepatic cytochrome P450 1A1 and phase II enzymes in three meat-producing animals.

Science.gov (United States)

Darwish, W; Ikenaka, Y; Eldaly, E; Ishizuka, M

2010-01-01

The mutagenic activation activity of hepatic microsomes from three meat-producing animals (cattle, deer and horses) was compared with those of rats as a reference species. In the Ames Salmonella typhimurium TA98 assay, the liver microsomes of all examined animals mutagenically activated benzo[a]pyrene, an ideal promutagens, in terms of production of histidine-independent revertant colonies. The microsomes of horses had the highest ability to produce revertant colonies of the examined animals under both low and high substrate concentrations. Inhibition of this mutagenic activity using alpha-naphthoflavone, anti-rat CYP1A1, CYP3A2 and CYP2E1 antibodies suggests that this activity was mainly because of CYP1A1 in these animals as well as in rats. The addition of co-factors for two phase II enzymes, microsomal UDP glucoronosyl transferase and cytosolic glutathione-S-transferase, reduced the production of the revertant colonies in a concentration-dependent manner. Interestingly, horses had the highest reduction rate among the examined animals, suggesting that phase II enzymes play a great role in producing a state of balance between the bioactivation and detoxification of xenobiotics in these meat-producing animals. This report is the first to investigate the mutagenic activation activity of the hepatic microsomes and the role of phase II enzymes against this activity in meat-producing animals. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Status of Gerda Phase II

Energy Technology Data Exchange (ETDEWEB)

Wagner, Victoria [Max-Planck-Institut fuer Kernphysik, Heidelberg (Germany); Collaboration: GERDA-Collaboration

2016-07-01

The GERDA experiment is designed to search for neutrinoless double beta (0νββ) decay of {sup 76}Ge. In Phase I of the experiment a background index (BI) of 10{sup -2} cts/(keV.kg.yr) was reached. No signal has been found and a lower limit on the half-life of 2.1.10{sup 25} yr (at 90% C.L.) is extracted. The aim of Phase II is to double the Ge mass and further reduce the BI by an order of magnitude to explore half-lives of about 10{sup 26} yr. Thirty new Broad Energy Germanium (BEGe) detectors have been produced. These detectors are distinct for their improved energy resolution and enhanced pulse shape discrimination of signal from background events. Further background reduction will be reached by an active veto to read out argon scintillation light. The Phase II commissioning showed that two of the major background components, external γ-rays from {sup 214}Bi and {sup 208}Tl decays, can be suppressed up to two orders of magnitude. This talk presents the current status of the GERDA Phase II upgrade.

Human gut microbiota plays a role in the metabolism of drugs.

Science.gov (United States)

Jourova, Lenka; Anzenbacher, Pavel; Anzenbacherova, Eva

2016-09-01

The gut microbiome, an aggregate genome of trillions of microorganisms residing in the human gastrointestinal tract, is now known to play a critical role in human health and predisposition to disease. It is also involved in the biotransformation of xenobiotics and several recent studies have shown that the gut microbiota can affect the pharmacokinetics of orally taken drugs with implications for their oral bioavailability. Review of Pubmed, Web of Science and Science Direct databases for the years 1957-2016. Recent studies make it clear that the human gut microbiota can play a major role in the metabolism of xenobiotics and, the stability and oral bioavailability of drugs. Over the past 50 years, more than 30 drugs have been identified as a substrate for intestinal bacteria. Questions concerning the impact of the gut microbiota on drug metabolism, remain unanswered or only partially answered, namely (i) what are the molecular mechanisms and which bacterial species are involved? (ii) What is the impact of host genotype and environmental factors on the composition and function of the gut microbiota, (iii) To what extent is the composition of the intestinal microbiome stable, transmissible, and resilient to perturbation? (iv) Has past exposure to a given drug any impact on future microbial response, and, if so, for how long? Answering such questions should be an integral part of pharmaceutical research and personalised health care.

Improved Xenobiotic Metabolism and Reduced Susceptibility to Cancer in Gluten-Sensitive Macaques upon Introduction of a Gluten-Free Diet

Science.gov (United States)

Sestak, Karol; Conroy, Lauren; Aye, Pyone P.; Mehra, Smriti; Doxiadis, Gaby G.; Kaushal, Deepak

2011-01-01

Background A non-human primate (NHP) model of gluten sensitivity was employed to study the gene perturbations associated with dietary gluten changes in small intestinal tissues from gluten-sensitive rhesus macaques (Macaca mulatta). Methodology Stages of remission and relapse were accomplished in gluten-sensitive animals by administration of gluten-free (GFD) and gluten-containing (GD) diets, as described previously. Pin-head-sized biopsies, obtained non-invasively by pediatric endoscope from duodenum while on GFD or GD, were used for preparation of total RNA and gene profiling, using the commercial Rhesus Macaque Microarray (Agilent Technologies),targeting expression of over 20,000 genes. Principal Findings When compared with normal healthy control, gluten-sensitive macaques showed differential gene expressions induced by GD. While observed gene perturbations were classified into one of 12 overlapping categories - cancer, metabolism, digestive tract function, immune response, cell growth, signal transduction, autoimmunity, detoxification of xenobiotics, apoptosis, actin-collagen deposition, neuronal and unknown function - this study focused on cancer-related gene networks such as cytochrome P450 family (detoxification function) and actin-collagen-matrix metalloproteinases (MMP) genes. Conclusions/Significance A loss of detoxification function paralleled with necessity to metabolize carcinogens was revealed in gluten-sensitive animals while on GD. An increase in cancer-promoting factors and a simultaneous decrease in cancer-preventing factors associated with altered expression of actin-collagen-MMP gene network were noted. In addition, gluten-sensitive macaques showed reduced number of differentially expressed genes including the cancer-associated ones upon withdrawal of dietary gluten. Taken together, these findings indicate potentially expanded utility of gluten-sensitive rhesus macaques in cancer research. PMID:21533263

PXR as a mediator of herb–drug interaction

Directory of Open Access Journals (Sweden)

Brett C. Hogle

2018-04-01

Full Text Available Medicinal herbs have been a part of human medicine for thousands of years. The herb–drug interaction is an extension of drug–drug interaction, in which the consumptions of herbs cause alterations in the metabolism of drugs the patients happen to take at the same time. The pregnane X receptor (PXR has been established as one of the most important transcriptional factors that regulate the expression of phase I enzymes, phase II enzymes, and drug transporters in the xenobiotic responses. Since its initial discovery, PXR has been implicated in multiple herb–drug interactions that can lead to alterations of the drug's pharmacokinetic properties and cause fluctuating therapeutic efficacies, possibly leading to complications. Regions of the world that heavily incorporate herbalism into their primary health care and people turning to alternative medicines as a personal choice could be at risk for adverse reactions or unintended results from these interactions. This article is intended to highlight our understanding of the PXR-mediated herb–drug interactions. Keywords: Drug metabolism, Herb–drug interaction, PXR, St. John's Wort, Xenobiotics

Antioxidant Functions of the Aryl Hydrocarbon Receptor

Directory of Open Access Journals (Sweden)

Cornelia Dietrich

2016-01-01

Full Text Available The aryl hydrocarbon receptor (AhR is a transcription factor belonging to the basic helix-loop-helix/PER-ARNT-SIM family. It is activated by a variety of ligands, such as environmental contaminants like polycyclic aromatic hydrocarbons or dioxins, but also by naturally occurring compounds and endogenous ligands. Binding of the ligand leads to dimerization of the AhR with aryl hydrocarbon receptor nuclear translocator (ARNT and transcriptional activation of several xenobiotic phase I and phase II metabolizing enzymes. It is generally accepted that the toxic responses of polycyclic aromatic hydrocarbons, dioxins, and structurally related compounds are mediated by activation of the AhR. A multitude of studies indicate that the AhR operates beyond xenobiotic metabolism and exerts pleiotropic functions. Increasing evidence points to a protective role of the AhR against carcinogenesis and oxidative stress. Herein, I will highlight data demonstrating a causal role of the AhR in the antioxidant response and present novel findings on potential AhR-mediated antioxidative mechanisms.

Test of GERDA Phase II detector assembly

Energy Technology Data Exchange (ETDEWEB)

Bode, Tobias; Gusev, Konstantin [Technische Universitaet Muenchen (Germany); Schwingenheuer, Bernhard; Wagner, Victoria [Max-Planck Institut fuer Kernphysik, Heidelberg (Germany); Collaboration: GERDA-Collaboration

2014-07-01

The GERDA experiment searches for the lepton number violating neutrinoless double beta decay (0νββ) of {sup 76}Ge. The experiment uses HPGe detectors enriched in {sup 76}Ge as source and detection material. In GERDA Phase I five BEGe detectors were operated successfully. These detectors are distinguished for improved energy resolution and enhanced pulse shape discrimination (PSD) against background events. In Phase II additional 25 BEGe detectors will be installed. New electronics and radio-pure low-mass holders were specially designed for Phase II. Prior to the installation in GERDA all BEGe detectors are tested in their final assembly in the LNGS underground laboratory. This talk presents the mechanics and performance of the GERDA Phase II detector assembly.

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

Energy Technology Data Exchange (ETDEWEB)

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

2006-03-20

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

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

International Nuclear Information System (INIS)

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

2006-01-01

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

Polymorphisms of xenobiotic metabolizing enzymes in bladder cancer patients of the Semmelweis University Budapest, Hungary.

Science.gov (United States)

Ebbinghaus, Dörte; Bánfi, Gergely; Selinski, Silvia; Blaszkewicz, Meinolf; Bürger, Hannah; Hengstler, Jan G; Nyirády, Péter; Golka, Klaus

2017-01-01

Polymorphic xenobiotic metabolizing enzymes such as N-acetyltransferase 2 (NAT2) or glutathione S-transferase M1 (GSTM1) are known to modulate bladder cancer risk. As no apparent data were available from Hungary, a former member of the eastern European economic organization, a study was performed in Budapest. In total, 182 bladder cancer cases and 78 cancer-free controls were investigated by questionnaire. Genotypes of NAT2, GSTM1, GSTT1, rs1058396 and rs17674580 were determined by standard methods. Current smokers' crude odds ratio (OR) (3.43) and former smokers crude OR (2.36) displayed a significantly increased bladder cancer risk. The risk rose by a factor of 1.56 per 10 pack years. Exposure to fumes was associated with an elevated bladder cancer risk (23% cases, 13% controls). Sixty-four % of the cases and 59% of controls were slow NAT2 acetylators. It was not possible to establish a particular impact of NAT2*6A and *7B genotypes (15 cases, 8%, 5 controls, 7%). GSTT1 exerted no marked influence on bladder cancer (negative 21% cases vs. 22% controls). The portion of GSTM1 negative bladder cancer patients was increased (63% cases vs. 54% controls). The SLC14A1 SNPs rs1058396[AG/GG] and the nearby rs17674580[CT/TT] occurred more frequently in cases (79% and 68%) than controls (77% and 55%). The portion of GSTM1 negative bladder cancer patients is comparable with portions reported from other industrialized areas like Lutherstadt Wittenberg/Germany (58%), Dortmund/Germany (70%), Brescia/Italy (66%) or an occupational case-control series in Germany (56%). Data indicate that GSTM1 is a susceptibility factor for environmentally triggered bladder cancer rather than for smoking-mediated bladder cancer.

Light contamination during the dark phase in "photoperiodically controlled" animal rooms: effect on tumor growth and metabolism in rats.

Science.gov (United States)

Dauchy, R T; Sauer, L A; Blask, D E; Vaughan, G M

1997-10-01

Enhanced neoplastic growth and metabolism have been reported in animals maintained in a constant light (24L:0D) environment. Results from this laboratory indicate that tumor growth is directly dependent upon increased ambient blood concentrations of arachidonic and linoleic acids, particularly linoleic acid. Tumor linoleic acid utilization and production if its putative mitogenic metabolite, 13-hydroxyoctadecadienoic acid (13-HODE), are suppressed by the circadian neurohormone melatonin, the production of which is itself regulated by light in all mammals. This study was performed to determine whether minimal light contamination (0.2 lux) in an animal room during an otherwise normal dark phase may disrupt normal circadian production of melatonin and affect tumor growth and metabolism. Animals of groups I (12L:12D), II (12L:12-h light-contaminated dark phase), and III (24L:0D) had plasma total fatty acid (TFA), linoleic acid (LA), and melatonin concentrations measured prior to tumor implantation; groups I and II had daily cycles in plasma TFA and LA values, whereas group III had constant values throughout the day. The integrated mean TFA and LA values for the entire day were similar in all groups. Although group-I animals had a normal nocturnal surge of melatonin (127.0 pg/ml) at 2400 h, the nocturnal amplitude was suppressed in group-II animals (16.0 pg/ml); circadian variation in melatonin concentration was not seen in group-III animals (7.4 pg/ml). At 12 weeks of age, rats had the Morris hepatoma 7288CTC implanted as "tissue-isolated" tumors grown subcutaneously. Latency to onset of palpable tumor mass for groups I, II, and III was 11, 9, and 5 days respectively. Tumor growth rates were 0.72 +/- 0.09, 1.30 +/- 0.15, and 1.48 +/- 0.17 g/d (mean +/- SD, n = 6/group) in groups I, II, and III respectively. Arteriovenous difference measurements for TFA and LA across the tumors were 4.22 +/- 0.89 and 0.83 +/- 0.18 (group I), 8.26 +/- 0.66 and 1.64 +/- 0.13 (group II

Metabolic Phase I (CYPs) and Phase II (GSTs) Gene Polymorphisms and Their Interaction with Environmental Factors in Nasopharyngeal Cancer from the Ethnic Population of Northeast India.

Science.gov (United States)

Singh, Seram Anil; Ghosh, Sankar Kumar

2017-09-26

Multiple genetic and environmental factors and their interaction are believed to contribute in the pathogenesis of Nasopharyngeal Cancer (NPC). We investigate the role of Metabolic Phase I (CYPs) and Phase II (GSTs) gene polymorphisms, gene-gene and gene-environmental interaction in modulating the susceptibility to NPC in Northeast India. To determine the association of metabolic gene polymorphisms and environmental habits, 123 cases and 189 controls blood/swab samples were used for PCR and confirmed by Sanger sequencing. Analysis for GSTM1 and GSTT1 gene polymorphism was done by multiplex PCR. The T3801C in the 3'- flanking region of CYP1A1 gene was detected by PCR-RFLP method. The Logistic regression analysis was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI). The GSTM1 null genotype alone (OR = 2.76) was significantly associated with NPC risk (P < 0.0001). The combinations of GSTM1 null and GSTT1 null genotypes also higher, 3.77 fold (P < 0.0001), risk of NPC, while GSTM1 null genotype along with CYP1A1 T3801C TC + CC genotype had 3.22 (P = 0.001) fold risk. The most remarkable risk was seen among individual carrying GSTM1 null, GSTT1 null genotypes and CYP1A1 T3801C TC + CC genotypes (OR = 5.71, P = 0.001). Further; analyses demonstrate an enhanced risk of NPC in smoked meat (OR = 5.56, P < 0.0001) and fermented fish consumers (OR = 5.73, P < 0.0001) carrying GSTM1 null genotype. An elevated risk of NPC was noted in smokers (OR = 12.67, P < 0.0001) and chewers (OR = 5.68, P < 0.0001) with GSTM1 null genotype. However, smokers had the highest risk of NPC among individuals carrying GSTT1 null genotype (OR = 4.46, P = 0.001) or CYP1A1 T3801C TC + CC genotype (OR = 7.13, P < 0.0001). The association of null genotypes and mutations of metabolic neutralizing genes along with the environmental habits (tobacco smokers and chewers, smoke meat, fermented fishes) can be used as a possible biomarker for

Design and Performance of a Xenobiotic Metabolism Database Manager for Building Metabolic Pathway Databases

Science.gov (United States)

A major challenge for scientists and regulators is accounting for the metabolic activation of chemicals that may lead to increased toxicity. Reliable forecasting of chemical metabolism is a critical factor in estimating a chemical’s toxic potential. Research is underway to develo...

129I Interlaboratory comparison: phase I and phase II

International Nuclear Information System (INIS)

Caffee, M. W.; Roberts, M. L.

1999-01-01

An interlaboratory comparison exercise for 129 I was organized and conducted. Nine laboratories participated in the exercise to either a full or limited extent. In Phase I of the comparison, 11 samples were measured. The suite of samples contained both synthetic ''standard type'' materials (i.e., AgI) and environmental materials. The isotopic 129 I/ 127 I ratios of the samples varied from 10 -8 to 10 -14 . In this phase, each laboratory was responsible for its own chemical preparation of the samples. In Phase I, the 129 I AMS measurements for prepared AgI were in good agreement. However, large discrepancies were seen in 129 I AMS measurements of environmental samples. Because of the large discrepancies seen in the Phase I 129 I intercomparison, a subsequent study was conducted. In Phase II of the 129 I intercomparison, three separate laboratories prepared AgI from two environmental samples (IAEA 375 soil and maples leaves). Each laboratory used its own chemical preparation method with each of the methods being distinctly different. The resulting six samples (two sets of three) were then re-distributed to the participating 129 I AMS facilities and 129 I/ 127 I ratios measured. Results and discussion of both the Phase I and Phase II interlaboratory comparison are presented

Transcriptional expression analysis of ABC efflux transporters and xenobiotic-metabolizing enzymes in the Chinese rare minnow.

Science.gov (United States)

Yuan, Lilai; Lv, Biping; Zha, Jinmiao; Wang, Zijian

2014-05-01

In the present study, the cDNA fragments of five ABC transporter genes (ABCB1, ABCB11, ABCC1, ABCC2, and ABCG2) in the rare minnow were cloned, and their tissue-specific expression patterns were evaluated across eight rare minnow tissues (liver, gill, intestine, kidney, spleen, brain, skin, and muscle). Furthermore, the transcriptional effects on these ABC transporter genes and five xenobiotic-metabolizing enzyme genes (CYP1A, GSTm, GSTp1, GCLC, and UGT1a) were determined in the rare minnow liver after 12 days of pyrene exposure. Basal expression analysis showed that the tissues with high expression of the ABC transporters included the liver, kidney, and intestine. Moreover, the most highly expressed of the ABC genes were ABCB1 and ABCC2 in all eight of the tissues tested. The ABCB11 gene was almost exclusively expressed in the liver of the rare minnow, whereas ABCC1 and ABCG2 showed weak expression in all eight tissues compared to ABCB1 and ABCC2. Our results provide the first thorough examination of the expression patterns of toxicologically relevant ABC transporters in the rare minnow and serve as a necessary basis for further studies of these ABC transporters in fish. Furthermore, synergistic up-regulation of CYP1A, GSTp1, GCLC, UGT1a, and ABCC2 was observed in the rare minnow liver following pyrene exposure, while GSTm, ABCB1, ABCB11, ABCC1, and ABCG2 were not significantly affected (p ABC transporters by pyrene suggests a possible involvement and cooperation of these genes in the detoxification process in rare minnows. Copyright © 2014 Elsevier B.V. All rights reserved.

Upgrade for Phase II of the Gerda experiment

Science.gov (United States)

Agostini, M.; Bakalyarov, A. M.; Balata, M.; Barabanov, I.; Baudis, L.; Bauer, C.; Bellotti, E.; Belogurov, S.; Belyaev, S. T.; Benato, G.; Bettini, A.; Bezrukov, L.; Bode, T.; Borowicz, D.; Brudanin, V.; Brugnera, R.; Caldwell, A.; Cattadori, C.; Chernogorov, A.; D'Andrea, V.; Demidova, E. V.; Di Marco, N.; Domula, A.; Doroshkevich, E.; Egorov, V.; Falkenstein, R.; Frodyma, N.; Gangapshev, A.; Garfagnini, A.; Grabmayr, P.; Gurentsov, V.; Gusev, K.; Hakenmüller, J.; Hegai, A.; Heisel, M.; Hemmer, S.; Hiller, R.; Hofmann, W.; Hult, M.; Inzhechik, L. V.; Ioannucci, L.; Janicskó Csáthy, J.; Jochum, J.; Junker, M.; Kazalov, V.; Kermaïdic, Y.; Kihm, T.; Kirpichnikov, I. V.; Kirsch, A.; Kish, A.; Klimenko, A.; Kneißl, R.; Knöpfle, K. T.; Kochetov, O.; Kornoukhov, V. N.; Kuzminov, V. V.; Laubenstein, M.; Lazzaro, A.; Lebedev, V. I.; Lehnert, B.; Lindner, M.; Lippi, I.; Lubashevskiy, A.; Lubsandorzhiev, B.; Lutter, G.; Macolino, C.; Majorovits, B.; Maneschg, W.; Medinaceli, E.; Miloradovic, M.; Mingazheva, R.; Misiaszek, M.; Moseev, P.; Nemchenok, I.; Nisi, S.; Panas, K.; Pandola, L.; Pelczar, K.; Pullia, A.; Ransom, C.; Riboldi, S.; Rumyantseva, N.; Sada, C.; Salamida, F.; Salathe, M.; Schmitt, C.; Schneider, B.; Schönert, S.; Schreiner, J.; Schütz, A.-K.; Schulz, O.; Schwingenheuer, B.; Selivanenko, O.; Shevchik, E.; Shirchenko, M.; Simgen, H.; Smolnikov, A.; Stanco, L.; Vanhoefer, L.; Vasenko, A. A.; Veresnikova, A.; von Sturm, K.; Wagner, V.; Wegmann, A.; Wester, T.; Wiesinger, C.; Wojcik, M.; Yanovich, E.; Zhitnikov, I.; Zhukov, S. V.; Zinatulina, D.; Zsigmond, A. J.; Zuber, K.; Zuzel, G.

2018-05-01

The Gerda collaboration is performing a sensitive search for neutrinoless double beta decay of ^{76}Ge at the INFN Laboratori Nazionali del Gran Sasso, Italy. The upgrade of the Gerda experiment from Phase I to Phase II has been concluded in December 2015. The first Phase II data release shows that the goal to suppress the background by one order of magnitude compared to Phase I has been achieved. Gerda is thus the first experiment that will remain "background-free" up to its design exposure (100 kg year). It will reach thereby a half-life sensitivity of more than 10^{26} year within 3 years of data collection. This paper describes in detail the modifications and improvements of the experimental setup for Phase II and discusses the performance of individual detector components.

Effects of brussels sprouts, indole 3-carbinol and phenobarbital on xenobiotic metabolism and in vivo DNA binding of aflatoxin B1 in the rat

International Nuclear Information System (INIS)

Salbe, A.D.; Bjeldanes, L.F.

1986-01-01

Cruciferous vegetables have been shown to be potent inducers of xenobiotic-metabolizing enzymes in the rat and this may offer protection against chemical carcinogenesis. Adult, male, SD rats were fed on purified diets supplemented with 25% freeze-dried Brussels sprouts or 250 ppm idole 3-carbinol (I3C) for 2 weeks, or given phenobarbital (PB, 1 mg/ml) in the drinking water for 7 days prior to killing. Brussels sprouts caused a 50% decrease (p 3 H] aflatoxin B 1 (AFB 1 ) to liver DNA, and increased intestinal and hepatic glutathione S-transferase (GST) activity. Hepatic monooxygenase activity was not altered in this group but greater than 2-fold increases in intestinal aryl hydrocarbon hydroxylase (AHH) and ethoxycoumarin O-deethylase (ECD) activities were found. I3C did not decrease AFB 1 binding, nor did it increase hepatic or intestinal GST activity. I3C did increase both intestinal AHH and ECD activities. PB treatment significantly decreased AFB 1 binding by 60%, and significantly elevated hepatic but not intestinal GST activity. Hepatic AHH and ECD activities were also elevated in this group, while intestinal AHH and ECD activities were decreased. These results emphasize the importance of GST activity in the detoxification of AFB 1 and suggest a less important role for intestinal monooxygenase activity in the metabolism of this hepatocarcinogen

AS IMPLICAÇÕES DO POLIMORFISMO GENÉTICO DO GENE GST NA PATOGÊNESE DO DIABETES MELLITUS TIPO 2

Directory of Open Access Journals (Sweden)

Angela Adamski da Silva Reis

2011-01-01

Full Text Available Type 2 Diabetes mellitus (T2DM is a disease characterized by chronic hyperglycemia associated with metabolic complications, clinical and social, resulting from the aging population, increasing urbanization and the adoption of unhealthy lifestyles such as sedentary lifestyles, poor diet and especially obesity. Complex diseases like diabetes, are determined by three main factors: the lifestyle, environmental exposure and genetic susceptibility. Thegenetic contribution is important evidence in the development of T2DM. Several polymorphisms of genes responsible for encoding enzymes involved in the biotransformation of xenobiotics are related to the development of atherosclerosis, cancer and type 2 diabetes. In the pathogenesis of T2DM, it is observed that oxidative stress contributes to decreased production and reduced ability of insulin to stimulate glucose uptake. In this sense, the polymorphism ofenzymes of xenobiotic metabolism phase II has been extensively studied in a wide variety of diseases, especially in determining genetic susceptibility to cancer and response to chemotherapy.

Arachidonate metabolism increases as rat alveolar type II cells differentiate in vitro

International Nuclear Information System (INIS)

Lipchik, R.J.; Chauncey, J.B.; Paine, R.; Simon, R.H.; Peters-Golden, M.

1990-01-01

Rat type II alveolar epithelial cells are known to undergo morphological and functional changes when maintained in culture for several days. Having previously demonstrated that these cells can deacylate free arachidonic acid (AA) and metabolize it to products of the cyclooxygenase pathway, the present study was undertaken to determine whether in vitro differentiation was accompanied by alterations in the availability and metabolism of AA. We assessed the constitutive and ionophore A23187-induced deacylation and metabolism of endogenous AA, as well as the metabolism of exogenously supplied AA, in primary cultures of rat type II cells at days 2, 4, and 7 after isolation. Levels of free endogenous AA were increased at day 4, whereas eicosanoid synthesis, predominantly prostaglandin E2 and prostacyclin, increased markedly only at day 7. A similar time course of augmentation of prostanoid release was seen in response to exogenous AA. Type II cells cultured on fibronectin, intended to hasten cell flattening and spreading, demonstrated accelerated increases in available free AA in response to A23187; cells cultured on basement membrane derived from Engelbreth-Holm-Swarm mouse sarcoma, known to maintain the type II phenotype, exhibited diminished levels of available free AA. From these findings, we conclude that alterations in arachidonate metabolism are linked to alterations in cellular phenotype. The potentiation of eicosanoid synthesis accompanying in vitro differentiation suggests a possible role for the alveolar epithelium in the modulation of inflammation and fibrosis in the distal lung

40 CFR 72.73 - State issuance of Phase II permits.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 16 2010-07-01 2010-07-01 false State issuance of Phase II permits. 72.73 Section 72.73 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) PERMITS REGULATION Acid Rain Phase II Implementation § 72.73 State issuance of Phase II permits...

Status of the Gerda phase II experiment

Energy Technology Data Exchange (ETDEWEB)

Lazzaro, Andrea [Physik-Department and Excellence Cluster Universe, Technische Universitaet Muenchen (Germany); Collaboration: GERDA-Collaboration

2016-07-01

The Gerda experiment searches for the neutrinoless double beta decay (0νββ) in {sup 76}Ge. The first phase of the experiment collected 21.6 kg. yr of exposure with a background index (BI) of 0.01 cts/(keV . kg . yr). No signal was observed and a lower limit for the 0νββ half-life was set to T{sup 0νββ}{sub 1/2} < 2.1 . 10{sup 25} yr (90% C.L). The apparatus has now been upgraded to the Phase II configuration. In Phase II 38 kg of HPGe detectors will be operated to reach an exposure of 100 kg . yr. The goal of Gerda Phase II is to lower the BI to 10{sup -3} cts/(keV . kg . y), in order to reach the sensitivity for T{sup 0νββ}{sub 1/2} = O(10{sup 26}) yr. The additional target mass is constituted of 30 custom made BEGe detectors with higher energy resolution and better pulse shape discrimination performance. The detectors are operated in new radio-pure low-mass holders. The liquid argon surrounding the detectors has been instrumented to veto the background events which produce scintillation light. In this talk the current status and the performance of the Gerda Phase II are presented.

Lunar Health Monitor, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — During the Phase II Lunar Health Monitor program, Orbital Research will develop a second generation wearable sensor suite for astronaut physiologic monitoring. The...

Cysteine Addition Promotes Sulfide Production and 4-Fold Hg(II)-S Coordination in Actively Metabolizing Escherichia coli.

Science.gov (United States)

Thomas, Sara A; Gaillard, Jean-François

2017-04-18

The bacterial uptake of mercury(II), Hg(II), is believed to be energy-dependent and is enhanced by cysteine in diverse species of bacteria under aerobic and anaerobic conditions. To gain insight into this Hg(II) biouptake pathway, we have employed X-ray absorption spectroscopy (XAS) to investigate the relationship between exogenous cysteine, cellular metabolism, cellular localization, and Hg(II) coordination in aerobically respiring Escherichia coli (E. coli). We show that cells harvested in exponential growth phase consistently display mixtures of 2-fold and 4-fold Hg(II) coordination to sulfur (Hg-S 2 and Hg-S 4 ), with added cysteine enhancing Hg-S 4 formation. In contrast, cells in stationary growth phase or cells treated with a protonophore causing a decrease in cellular ATP predominantly contain Hg-S 2 , regardless of cysteine addition. Our XAS results favor metacinnabar (β-HgS) as the Hg-S 4 species, which we show is associated with both the cell envelope and cytoplasm. Additionally, we observe that added cysteine abiotically oxidizes to cystine and exponentially growing E. coli degrade high cysteine concentrations (100-1000 μM) into sulfide. Thermodynamic calculations confirm that cysteine-induced sulfide biosynthesis can promote the formation of dissolved and particulate Hg(II)-sulfide species. This report reveals new complexities arising in Hg(II) bioassays with cysteine and emphasizes the need for considering changes in chemical speciation as well as growth stage.

78 FR 76789 - Additional Connect America Fund Phase II Issues

Science.gov (United States)

2013-12-19

... inspection and copying during normal business hours in the FCC Reference Information Center, Portals II, 445... Phase I to Phase II. 2. Timing of Phase II Support Disbursements. In the USF/ICC Transformation Order... language in paragraph 180 of the USF/ICC Transformation Order. We now seek to more fully develop the record...

Probability of success for phase III after exploratory biomarker analysis in phase II.

Science.gov (United States)

Götte, Heiko; Kirchner, Marietta; Sailer, Martin Oliver

2017-05-01

The probability of success or average power describes the potential of a future trial by weighting the power with a probability distribution of the treatment effect. The treatment effect estimate from a previous trial can be used to define such a distribution. During the development of targeted therapies, it is common practice to look for predictive biomarkers. The consequence is that the trial population for phase III is often selected on the basis of the most extreme result from phase II biomarker subgroup analyses. In such a case, there is a tendency to overestimate the treatment effect. We investigate whether the overestimation of the treatment effect estimate from phase II is transformed into a positive bias for the probability of success for phase III. We simulate a phase II/III development program for targeted therapies. This simulation allows to investigate selection probabilities and allows to compare the estimated with the true probability of success. We consider the estimated probability of success with and without subgroup selection. Depending on the true treatment effects, there is a negative bias without selection because of the weighting by the phase II distribution. In comparison, selection increases the estimated probability of success. Thus, selection does not lead to a bias in probability of success if underestimation due to the phase II distribution and overestimation due to selection cancel each other out. We recommend to perform similar simulations in practice to get the necessary information about the risk and chances associated with such subgroup selection designs. Copyright © 2017 John Wiley & Sons, Ltd.

Oxygen-Methane Thruster, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — Two main innovations will be developed in the Phase II effort that are fundamentally associated with our gaseous oxygen/gaseous methane RCS thruster. The first...

OSAS Surgery and Postoperative Discomfort: Phase I Surgery versus Phase II Surgery

Directory of Open Access Journals (Sweden)

Giulio Gasparini

2015-01-01

Full Text Available Introduction. This study aims to investigate the reasons that discourage the patients affected by OSAS to undergo orthognathic surgery and compares the postoperative discomfort of phase I (soft tissue surgery and phase II (orthognathic surgery procedures for treatment of OSAS. Material and Methods. A pool of 46 patients affected by OSAS was divided into two groups: “surgery patients” who accepted surgical treatments of their condition and “no surgery patients” who refused surgical procedures. The “surgery patients” group was further subdivided into two arms: patients who accepted phase I procedures (IP and those who accepted phase II (IIP. To better understand the motivations behind the refusal of II phase procedures, we asked the patients belonging to both the IP group and “no surgery” group to indicate the main reason that influenced their decision to avoid II phase procedures. We also monitored and compared five parameters of postoperative discomfort: pain, painkiller assumption, length of hospitalization, foreign body sensation, and diet assumption following IP and IIP procedures. Results. The main reason to avoid IIP procedures was the concern of a more severe postoperative discomfort. Comparison of the postoperative discomfort following IP versus IIP procedures showed that the former scored worse in 4 out of 5 parameters analyzed. Conclusion. IIP procedures produce less postoperative discomfort. IIP procedures, namely, orthognathic surgery, should be the first choice intervention in patients affected by OSAS and dentoskeletal malformation.

Studies on defense mechanism against xenobiotics in rats, using gold as a model

International Nuclear Information System (INIS)

Sugawa-Katayama, Yohko; Kojima, Akiko; Nakano, Yukihiro.

1994-01-01

For self-protection, a living organism has a special mechanism to prevent xenobiotics from being absorbed through the gastrointestinal tract. This led to the present study on the defense mechanism of the gastrointestinal tract where foods are digested and absorbed. The results obtained from this study showed that 1) starvation caused an insufficiency of the defense mechanism against xenobiotics in jejunal absorptive cells and Kupffer cells, 2) after refeeding diets, a reparative process occurred at the damaged cell sites, resulting in recovery of the defense mechanism against xenobiotics, and 3) a 5% fat diet seemed to be the best fat level for recovery of the defense mechanism against xenobiotics. In the nutritional point of view, the 5% fat diet is equivalent to 0.11 in fat energy ratio (fat energy/total energy of the diet). These data suggest that a diet with a much lower fat energy (equivalent to 0.11) can give a good effect on recovery of the defense mechanism against xenobiotics in the gastrointestinal tract and the liver. (author)

Chemopreventive effect of natural dietary compounds on xenobiotic-induced toxicity

Directory of Open Access Journals (Sweden)

Jia-Ching Wu

2017-01-01

Full Text Available Contaminants (or pollutants that affect human health have become an important issue, spawning a myriad of studies on how to prevent harmful contaminant-induced effects. Recently, a variety of biological functions of natural dietary compounds derived from consumed foods and plants have been demonstrated in a number of studies. Natural dietary compounds exhibited several beneficial effects for the prevention of disease and the inhibition of chemically-induced carcinogenesis. Contaminant-induced toxicity and carcinogenesis are mostly attributed to the mutagenic activity of reactive metabolites and the disruption of normal biological functions. Therefore, the metabolic regulation of hazardous chemicals is key to reducing contaminant-induced adverse health effects. Moreover, promoting contaminant excretion from the body through Phase I and II metabolizing enzymes is also a useful strategy for reducing contaminant-induced toxicity. This review focuses on summarizing the natural dietary compounds derived from common dietary foods and plants and their possible mechanisms of action in the prevention/suppression of contaminant-induced toxicity.

Barriers to participation in a phase II cardiac rehabilitation programme.

Science.gov (United States)

Mak, Y M W; Chan, W K; Yue, C S S

2005-12-01

To identify barriers to participation in a phase II cardiac rehabilitation programme and measures that may enhance participation. Prospective study. Regional hospital, Hong Kong. Cardiac patients recruited for a phase I cardiac rehabilitation programme from July 2002 to January 2003. Reasons for not participating in a phase II cardiac rehabilitation programme. Of the 193 patients recruited for a phase I cardiac rehabilitation programme, 152 (79%) patients, with a mean age of 70.3 years (standard deviation, 11.9 years), did not proceed to phase II programme. Eleven (7%) deaths occurred before commencement of phase II and 74 (49%) patients were considered physically unfit. Reasons for the latter included fractures, pain, or degenerative changes in the lower limbs (24%), and co-morbidities such as cerebrovascular accident (19%), chronic renal failure (11%), congestive heart failure (9%), and unstable angina (8%). Phase II rehabilitation was postponed until after completion of scheduled cardiac interventions in 13% of patients. Failure of physicians to arrange the pre-phase II exercise stress test as per protocol was reported in 7% of patients. Other reasons were reported: work or time conflicts (16%), non-compliance with cardiac treatment (5%), financial constraints (4%), self-exercise (3%), fear after exercise stress testing (3%), and patients returning to their original cardiologists for treatment (3%). A significant (79%) proportion of patients did not proceed to a phase II cardiac rehabilitation programme for a variety of reasons. These included physical unfitness, work or time conflicts, and need to attend scheduled cardiac interventions. Further studies are required to determine how to overcome obstacles to cardiac rehabilitation.

Integrated modelling of two xenobiotic organic compounds

DEFF Research Database (Denmark)

Lindblom, Erik Ulfson; Gernaey, K.V.; Henze, Mogens

2006-01-01

This paper presents a dynamic mathematical model that describes the fate and transport of two selected xenobiotic organic compounds (XOCs) in a simplified representation. of an integrated urban wastewater system. A simulation study, where the xenobiotics bisphenol A and pyrene are used as reference...... compounds, is carried out. Sorption and specific biological degradation processes are integrated with standardised water process models to model the fate of both compounds. Simulated mass flows of the two compounds during one dry weather day and one wet weather day are compared for realistic influent flow...... rate and concentration profiles. The wet weather day induces resuspension of stored sediments, which increases the pollutant load on the downstream system. The potential of the model to elucidate important phenomena related to origin and fate of the model compounds is demonstrated....

The biochemistry and molecular biology of xenobiotic polymer degradation by microorganisms.

Science.gov (United States)

Kawai, Fusako

2010-01-01

Research on microbial degradation of xenobiotic polymers has been underway for more than 40 years. It has exploited a new field not only in applied microbiology but also in environmental microbiology, and has greatly contributed to polymer science by initiating the design of biodegradable polymers. Owing to the development of analytical tools and technology, molecular biological and biochemical advances have made it possible to prospect for degrading microorganisms in the environment and to determine the mechanisms involved in biodegradation when xenobiotic polymers are introduced into the environment and are exposed to microbial attack. In this review, the molecular biological and biochemical aspects of the microbial degradation of xenobiotic polymers are summarized, and possible applications of potent microorganisms, enzymes, and genes in environmental biotechnology are suggested.

Animal models of toxicology testing: the role of pigs.

Science.gov (United States)

Helke, Kristi L; Swindle, Marvin Michael

2013-02-01

In regulatory toxicological testing, both a rodent and non-rodent species are required. Historically, dogs and non-human primates (NHP) have been the species of choice of the non-rodent portion of testing. The pig is an appropriate option for these tests based on metabolic pathways utilized in xenobiotic biotransformation. This review focuses on the Phase I and Phase II biotransformation pathways in humans and pigs and highlights the similarities and differences of these models. This is a growing field and references are sparse. Numerous breeds of pigs are discussed along with specific breed differences in these enzymes that are known. While much available data are presented, it is grossly incomplete and sometimes contradictory based on methods used. There is no ideal species to use in toxicology. The use of dogs and NHP in xenobiotic testing continues to be the norm. Pigs present a viable and perhaps more reliable model of non-rodent testing.

First results from GERDA Phase II

Science.gov (United States)

Agostini, M.; Allardt, M.; Bakalyarov, A. M.; Balata, M.; Barabanov, I.; Baudis, L.; Bauer, C.; Bellotti, E.; Belogurov, S.; Belyaev, S. T.; Benato, G.; Bettini, A.; Bezrukov, L.; Bode, T.; Borowicz, D.; Brudanin, V.; Brugnera, R.; Caldwell, A.; Cattadori, C.; Chernogorov, A.; D'Andrea, V.; Demidova, E. V.; Di Marco, N.; Domula, A.; Doroshkevich, E.; Egorov, V.; Falkenstein, R.; Frodyma, N.; Gangapshev, A.; Garfagnini, A.; Gooch, C.; Grabmayr, P.; Gurentsov, V.; Gusev, K.; Hakenmüller, J.; Hegai, A.; Heisel, M.; Hemmer, S.; Hofmann, W.; Hult, M.; Inzhechik, L. V.; Janicskó Csáthy, J.; Jochum, J.; Junker, M.; Kazalov, V.; Kihm, T.; Kirpichnikov, I. V.; Kirsch, A.; Kish, A.; Klimenko, A.; Kneißl, R.; Knöpfle, K. T.; Kochetov, O.; Kornoukhov, V. N.; Kuzminov, V. V.; Laubenstein, M.; Lazzaro, A.; Lebedev, V. I.; Lehnert, B.; Liao, H. Y.; Lindner, M.; Lippi, I.; Lubashevskiy, A.; Lubsandorzhiev, B.; Lutter, G.; Macolino, C.; Majorovits, B.; Maneschg, W.; Medinaceli, E.; Miloradovic, M.; Mingazheva, R.; Misiaszek, M.; Moseev, P.; Nemchenok, I.; Palioselitis, D.; Panas, K.; Pandola, L.; Pelczar, K.; Pullia, A.; Riboldi, S.; Rumyantseva, N.; Sada, C.; Salamida, F.; Salathe, M.; Schmitt, C.; Schneider, B.; Schönert, S.; Schreiner, J.; Schulz, O.; Schütz, A.-K.; Schwingenheuer, B.; Selivanenko, O.; Shevchik, E.; Shirchenko, M.; Simgen, H.; Smolnikov, A.; Stanco, L.; Vanhoefer, L.; Vasenko, A. A.; Veresnikova, A.; von Sturm, K.; Wagner, V.; Wegmann, A.; Wester, T.; Wiesinger, C.; Wojcik, M.; Yanovich, E.; Zhitnikov, I.; Zhukov, S. V.; Zinatulina, D.; Zuber, K.; Zuzel, G.

2017-09-01

Gerda is designed for a background-free search of 76Ge neutrinoless double-β decay, using bare Ge detectors in liquid Ar. The experiment was upgraded after the successful completion of Phase I to double the target mass and further reduce the background. Newly-designed Ge detectors were installed along with LAr scintillation sensors. Phase II of data-taking started in Dec 2015 with approximately 36 kg of Ge detectors and is currently ongoing. The first results based on 10.8 kg· yr of exposure are presented. The background goal of 10-3 cts/(keV· kg· yr) is achieved and a search for neutrinoless double-β decay is performed by combining Phase I and II data. No signal is found and a new limit is set at T1/20ν > 5.3 \\cdot {1025} yr (90% C.L.).

Xenobiotics that affect oxidative phosphorylation alter differentiation of human adipose-derived stem cells at concentrations that are found in human blood

Directory of Open Access Journals (Sweden)

Laura Llobet

2015-11-01

Full Text Available Adipogenesis is accompanied by differentiation of adipose tissue-derived stem cells to adipocytes. As part of this differentiation, biogenesis of the oxidative phosphorylation system occurs. Many chemical compounds used in medicine, agriculture or other human activities affect oxidative phosphorylation function. Therefore, these xenobiotics could alter adipogenesis. We have analyzed the effects on adipocyte differentiation of some xenobiotics that act on the oxidative phosphorylation system. The tested concentrations have been previously reported in human blood. Our results show that pharmaceutical drugs that decrease mitochondrial DNA replication, such as nucleoside reverse transcriptase inhibitors, or inhibitors of mitochondrial protein synthesis, such as ribosomal antibiotics, diminish adipocyte differentiation and leptin secretion. By contrast, the environmental chemical pollutant tributyltin chloride, which inhibits the ATP synthase of the oxidative phosphorylation system, can promote adipocyte differentiation and leptin secretion, leading to obesity and metabolic syndrome as postulated by the obesogen hypothesis.

IFPA meeting 2015 workshop report III: nanomedicine applications and exosome biology, xenobiotics and endocrine disruptors and pregnancy, and lipid.

Science.gov (United States)

Albrecht, C; Caniggia, I; Clifton, V; Göhner, C; Harris, L; Hemmings, D; Jawerbaum, A; Johnstone, E; Jones, H; Keelan, J; Lewis, R; Mitchell, M; Murthi, P; Powell, T; Saffery, R; Smith, R; Vaillancourt, C; Wadsack, C; Salomon, C

2016-12-01

Workshops are an important part of the IFPA annual meeting, as they allow for discussion of specialized topics. At the IFPA meeting 2015 there were twelve themed workshops, three of which are summarized in this report. These workshops were related to various aspects of placental biology but collectively covered areas of pregnancy pathologies and placental metabolism: 1) nanomedicine applications and exosome biology; 2) xenobiotics and endocrine disruptors and pregnancy; 3) lipid mediators and placental function. Copyright © 2016. Published by Elsevier Ltd.

Measurements of radioactive and xenobiotic substances in the biosphere in the Netherlands 1983

International Nuclear Information System (INIS)

1983-01-01

In this annual report the results and conclusions are given of measurements of radioactive and xenobiotic substances in the biosphere of the Netherlands. The measurements are coordinated by the Coordinating Committee for the Monitoring of Radioactive and Xenobiotic Substances (CCRX)

The time point of β-catenin knockout in hepatocytes determines their response to xenobiotic activation of the constitutive androstane receptor

International Nuclear Information System (INIS)

Ganzenberg, Katrin; Singh, Yasmin; Braeuning, Albert

2013-01-01

The constitutive androstane receptor (CAR) controls the expression of drug-metabolizing enzymes and regulates hepatocyte proliferation. Studies with transgenic mice with an early postnatal conditional hepatocyte-specific knockout of the β-catenin gene Ctnnb1 revealed that β-catenin deficiency decreases the magnitude of induction of drug-metabolizing enzymes by CAR activators, abrogates zonal differences in the hepatocytes’ susceptibility to these compounds, and impacts on hepatocyte proliferation. These data, however, do not allow distinguishing between effects caused by β-catenin deficiency during postnatal liver development and acute effects of β-catenin deficiency in the adult animal at the time point of CAR activation. Therefore, CAR activation was now studied in a different mouse model allowing for the hepatocyte-specific knockout of β-catenin in adult mice. Treatment of these mice with 3 mg/kg body weight of the model CAR activator 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) confirmed previous findings related to the coordinate regulation of drug metabolism by β-catenin and CAR. More importantly, the present study clarified that the impact of β-catenin signaling on CAR-mediated enzyme induction in the liver is not merely due to developmental defects caused by a postnatal lack of β-catenin, but depends on the presence of β-catenin at the time point of xenobiotic treatment. The study also revealed interesting differences between the two mouse models: hepatic zonation of TCPOBOP-dependent induction of drug-metabolizing enzymes was restored in mice with late knockout of β-catenin, and the strong proliferative response of female mice was exclusively abolished when using animals with a late β-catenin knockout. This suggests a β-catenin-dependent postnatal priming of hepatocytes during postnatal liver development, later affecting the proliferative response of adult animals to CAR-activating xenobiotics

Metabolism Retrofit Strategies for ToxCast Assays (BOSC)

Science.gov (United States)

The EPA’s ToxCast program utilizes a wide variety of high-throughput screening assays (HTS) to assess chemical perturbations of molecular and cellular endpoints. A limitation of many HTS assays used for toxicity assessment is the lack of xenobiotic metabolism (XM) which precludes...

SIMMER-II analysis of transition-phase experiments

International Nuclear Information System (INIS)

Wehner, T.R.; Bell, C.R.

1985-01-01

Analyses of Los Alamos transition-phase experiments with the SIMMER-II computer code are reported. These transient boilup experiments simulated the recriticality-induced transient motion of a boiling pool of molten fuel, molten steel and steel vapor, within a subassembly duct in a liquid-metal fast breeder reactor during the transition phase of a core-disruptive accident. The two purposes of these experiments were to explore and reach a better understanding of fast reactor safety issues, and to provide data for SIMMER-II verification. Experimental data, consisting of four pressure traces and a high-speed movie, were recorded for four sets of initial conditions. For three of the four cases, SIMMER-II-calculated pressures compared reasonably well with the experimental pressures. After a modification to SIMMER-II's liquid-vapor drag correlation, the comparison for the fourth case was reasonable also. 12 refs., 4 figs

40 CFR 73.20 - Phase II early reduction credits.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 16 2010-07-01 2010-07-01 false Phase II early reduction credits. 73.20 Section 73.20 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) SULFUR DIOXIDE ALLOWANCE SYSTEM Allowance Allocations § 73.20 Phase II early reduction credits...

The Gerda Phase II detector assembly

Energy Technology Data Exchange (ETDEWEB)

Bode, Tobias; Schoenert, Stefan [Physik-Department E15, Technische Universitaet Muenchen (Germany); Schwingenheuer, Bernhard [Max-Planck-Institut fuer Kernphysik, Heidelberg (Germany); Collaboration: GERDA-Collaboration

2013-07-01

Phase II of the Gerda (Germanium Detector Array) experiment will continue the search for the neutrinoless double beta decay (0νββ) of {sup 76}Ge. Prerequisites for Phase II are an increased target mass and a reduced background index of < 10 {sup -3} cts/(keV.kg.yr). Major hardware upgrades to achieve these requirements are scheduled for 2013. They include the deployment of a new radio pure low mass detector assembly. The structural properties of available radio-pure materials and reduction of mass necessitate a change of the electrical contacting used to bias and read-out the detectors. The detector assembly design and the favored contacting solution are presented.

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

Directory of Open Access Journals (Sweden)

Orsolya Palócz

2017-06-01

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

Design of clinical trials Phase I and II with radiopharmaceuticals

International Nuclear Information System (INIS)

Giannone, C.A.; Soroa, V.E.

2015-01-01

We presented some usual designs for clinical studies in Phase I and Phase II. For Phase I we considered the 3 + 3 Classic design, designs with accelerated titration and those with dose escalation schemes with overdose control (EWOC). For Phase II designs with efficacy outcomes are presented. The design proposed by Fleming is discussed as well as those with inclusion of patients in two stages: Gehan’s design and the Optimal two–stage Simon’s design. We also discussed the design of combined endpoints of efficacy and safety of Bryant and Day with an application example of therapeutically Lu-177. Finally some proposals for phase II trials with control group are considered. (authors) [es

Use of biomarkers to evaluate the ecological risk of xenobiotics associated with agriculture.

Science.gov (United States)

Lima, Liana Bezerra Dias de; Morais, Paula Benevides de; Andrade, Ricardo Lopes Tortorela de; Mattos, Luciana Vieira; Moron, Sandro Estevan

2018-06-01

This research aimed to evaluate the ecological risk of xenobiotics associated with agricultural activities by determining metal contents and biomarker responses using tucunaré (Cichla sp.) as a bioindicator. The work was conducted in the southwest region of the state of Tocantins, in the cities of Lagoa da Confusão and Pium. Water samples and specimens of Cichla sp. were collected in the Javaés and Formoso Rivers at three collection points (A, B and C). The concentrations of Cd, Pb, Cu, Cr, Mn, Ni and Zn in water and fish were analyzed. In fish, genotoxic, biochemical (glucose serum levels, AST (aspartate aminotransferase) and ALT (alanine aminotransferase) and histological (gills and liver) biomarkers were assessed. In the water, the Cr and Mn concentrations at the three collection points exceeded the values for Class 1 rivers. In the muscle, Cr was above the maximum limit allowed for human consumption at the three collection points, although the values at Points B and C were not significantly different from that at Point A (p > 0.05). At the three collection points, the micronucleus test revealed a low frequency of micronuclei. Significant hyperglycemia and a decrease in the AST activity of the fish collected at Point C was observed. In the gills, the most frequent alterations were at Stages I and II, which indicated mild to moderate damage, and epithelial detachment was the most frequent variation. In the liver tissue, the most frequently observed histological changes were at Stages I and II and included cytoplasmic vacuolization, nuclear hypertrophy, dilated sinusoids and bile stagnation. The integrated evaluation of these biomarkers indicated that fish collected from areas with intense agricultural activities presented adaptive responses that were likely caused by the availability and bioaccumulation of certain xenobiotics in the environment. Copyright © 2018 Elsevier Ltd. All rights reserved.

Symposium overview: alterations in cytokine receptors by xenobiotics.

Science.gov (United States)

Cohen, M D; Schook, L B; Oppenheim, J J; Freed, B M; Rodgers, K E

1999-04-01

A symposium entitled Alterations in Cytokine Receptors by Xenobiotics was held at the 37th Annual Meeting of the Society of Toxicology (SOT) in Seattle, Washington. The symposium was sponsored by the Immunotoxicology Specialty Section of SOT and was designed to present information on the effect of several different classes of xenobiotics on various aspects of receptor function (i.e., post-receptor signal transduction of receptor expression), or the involvement of cytokine receptors in the action of the toxicant under consideration. This symposium brought together scientists in the area of receptor immunobiology whose expertise in receptor modulation encompassed those major signaling agents involved in the normal immune response, i.e., proinflammatory cytokines, chemokines, interleukins, and interferons. The following is a summary of each of the individual presentations.

Effect of Nine Diets on Xenobiotic Transporters in Livers of Mice

Science.gov (United States)

Guo, Ying; Cui, Julia Yue; Lu, Hong; Klaassen, Curtis D.

2017-01-01

1. Lifestyle diseases are often caused by inappropriate nutrition habits and attempted to be treated by polypharmacotherapy. Therefore, it is important to determine whether differences in diet affect the disposition of drugs. Xenobiotic transporters in the liver are essential in drug disposition. 2. In the current study, mice were fed one of 9 diets for 3 weeks. The mRNAs of 23 known xenobiotic transporters in livers of mice were quantified by microarray analysis, and validated by branched DNA assay. The mRNAs of 15 transporters were altered by at least one diet. Diet-restriction (10) and the atherogenic diet (10) altered the expression of the most number of transporters, followed by western diet (8), high-fat diet (4), lab chow (2), high-fructose diet (2) and EFA-deficient diet (2), whereas the low n-3 FA diet had no effect on these transporters. Seven of the 11 xenobiotic transporters in the Slc family, three of 4 in the Abcb family, two of 4 in the Abcc family and all 3 in the Abcg family were changed significantly. 3. This first comprehensive study indicates that xenobiotic transporters are altered by diet, and suggests there are likely diet-drug interactions due to changes in the expression of drug transporters. PMID:25566878

Optimal dose selection accounting for patient subpopulations in a randomized Phase II trial to maximize the success probability of a subsequent Phase III trial.

Science.gov (United States)

Takahashi, Fumihiro; Morita, Satoshi

2018-02-08

Phase II clinical trials are conducted to determine the optimal dose of the study drug for use in Phase III clinical trials while also balancing efficacy and safety. In conducting these trials, it may be important to consider subpopulations of patients grouped by background factors such as drug metabolism and kidney and liver function. Determining the optimal dose, as well as maximizing the effectiveness of the study drug by analyzing patient subpopulations, requires a complex decision-making process. In extreme cases, drug development has to be terminated due to inadequate efficacy or severe toxicity. Such a decision may be based on a particular subpopulation. We propose a Bayesian utility approach (BUART) to randomized Phase II clinical trials which uses a first-order bivariate normal dynamic linear model for efficacy and safety in order to determine the optimal dose and study population in a subsequent Phase III clinical trial. We carried out a simulation study under a wide range of clinical scenarios to evaluate the performance of the proposed method in comparison with a conventional method separately analyzing efficacy and safety in each patient population. The proposed method showed more favorable operating characteristics in determining the optimal population and dose.

HPC Benchmark Suite NMx, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — In the phase II effort, Intelligent Automation Inc., (IAI) and University of Central Florida (UCF) propose to develop a comprehensive numerical test suite for...

Xenobiotics enhance laccase activity in alkali-tolerant γ-proteobacterium JB.

Science.gov (United States)

Singh, Gursharan; Batish, Mona; Sharma, Prince; Capalash, Neena

2009-01-01

Various genotoxic textile dyes, xenobiotics, substrates (10 µM) and agrochemicals (100 µg/ml) were tested for enhancement of alkalophilic laccase activity in γ-proteobacterium JB. Neutral Red, Indigo Carmine, Naphthol Base Bordears and Sulphast Ruby dyes increased the activity by 3.7, 2.7, 2.6 and 2.3 fold respectively. Xenobiotics/substrates like p-toluidine, 8-hydroxyquinoline and anthracine increased it by 3.4, 2.8 and 2.3 fold respectively. Atrazine and trycyclozole pesticides enhanced the activity by 1.95 and 1.5 fold respectively.

Horonobe Underground Research Laboratory project. Synthesis of phase II (construction phase) investigations to a depth of 350 m

International Nuclear Information System (INIS)

Sato, Toshinori; Sasamoto, Hiroshi; Ishii, Eiichi; Matsuoka, Toshiyuki; Hayano, Akira; Miyakawa, Kazuya; Fujita, Tomoo; Tanai, Kenji; Nakayama, Masashi; Takeda, Masaki; Yokota, Hideharu; Aoyagi, Kazuhei; Ohno, Hirokazu; Shigeta, Naotaka; Hanamuro, Takahiro; Ito, Hiroaki

2017-03-01

The Horonobe Underground Research Laboratory (URL) Project is being pursued by the Japan Atomic Energy Agency (JAEA) to enhance the reliability of relevant disposal technologies through investigations of the deep geological environment within the host sedimentary formations at Horonobe, northern Hokkaido. The project consists of two major research areas, 'Geoscientific Research' and 'R and D on Geological Disposal', and proceeds in three overlapping phases, 'Phase I: Surface-based investigation', 'Phase II: Construction' and 'Phase III: Operation', over a period of 20 years. This report summarizes the results of the Phase II investigations carried out from April 2005 to June 2014 to a depth of 350 m. Integration of work from different disciplines into a 'geosynthesis' ensures that the Phase II goals have been successfully achieved and identifies key issues that need to be addressed in the Phase II investigations. Efforts are made to summarize as many lessons learnt from the Phase II investigations and other technical achievements as possible to form a 'knowledge base' that will reinforce the technical basis for both implementation and the formulation of safety regulations. (author)

Crew Cerebral Oxygen Monitor, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — This Phase II SBIR proposal is aimed at developing a non-invasive, optical method for monitoring crew member state of awareness in operational environments. All...

Xenobiotic Receptor-Mediated Regulation of Intestinal Barrier Function and Innate Immunity

Directory of Open Access Journals (Sweden)

Harmit S. Ranhotra

2016-07-01

Full Text Available The molecular basis for the regulation of the intestinal barrier is a very fertile research area. A growing body of knowledge supports the targeting of various components of intestinal barrier function as means to treat a variety of diseases, including the inflammatory bowel diseases. Herein, we will summarize the current state of knowledge of key xenobiotic receptor regulators of barrier function, highlighting recent advances, such that the field and its future are succinctly reviewed. We posit that these receptors confer an additional dimension of host-microbe interaction in the gut, by sensing and responding to metabolites released from the symbiotic microbiota, in innate immunity and also in host drug metabolism. The scientific evidence for involvement of the receptors and its molecular basis for the control of barrier function and innate immunity regulation would serve as a rationale towards development of non-toxic probes and ligands as drugs.

Short-term calorie restriction feminizes the mRNA profiles of drug metabolizing enzymes and transporters in livers of mice.

Science.gov (United States)

Fu, Zidong Donna; Klaassen, Curtis D

2014-01-01

Calorie restriction (CR) is one of the most effective anti-aging interventions in mammals. A modern theory suggests that aging results from a decline in detoxification capabilities and thus accumulation of damaged macromolecules. The present study aimed to determine how short-term CR alters mRNA profiles of genes that encode metabolism and detoxification machinery in the liver. Male C57BL/6 mice were fed CR (0, 15, 30, or 40%) diets for one month, followed by mRNA quantification of 98 xenobiotic processing genes (XPGs) in the liver, including 7 uptake transporters, 39 phase-I enzymes, 37 phase-II enzymes, 10 efflux transporters, and 5 transcription factors. In general, 15% CR did not alter mRNAs of most XPGs, whereas 30 and 40% CR altered over half of the XPGs (32 increased and 29 decreased). CR up-regulated some phase-I enzymes (fold increase), such as Cyp4a14 (12), Por (2.3), Nqo1 (1.4), Fmo2 (5.4), and Fmo3 (346), and numerous number of phase-II enzymes, such as Sult1a1 (1.2), Sult1d1 (2.0), Sult1e1 (33), Sult3a1 (2.2), Gsta4 (1.3), Gstm2 (1.3), Gstm3 (1.7), and Mgst3 (2.2). CR feminized the mRNA profiles of 32 XPGs in livers of male mice. For instance, CR decreased the male-predominantly expressed Oatp1a1 (97%) and increased the female-predominantly expressed Oatp1a4 (11). In conclusion, short-term CR alters the mRNA levels of over half of the 98 XPGs quantified in livers of male mice, and over half of these alterations appear to be due to feminization of the liver. Copyright © 2013 Elsevier Inc. All rights reserved.

Phase II Final Report

Energy Technology Data Exchange (ETDEWEB)

Schuknecht, Nate [Project Manager; White, David [Principle Investigator; Hoste, Graeme [Research Engineer

2014-09-11

The SkyTrough DSP will advance the state-of-the-art in parabolic troughs for utility applications, with a larger aperture, higher operating temperature, and lower cost. The goal of this project was to develop a parabolic trough collector that enables solar electricity generation in the 2020 marketplace for a 216MWe nameplate baseload power plant. This plant requires an LCOE of 9¢/kWhe, given a capacity factor of 75%, a fossil fuel limit of 15%, a fossil fuel cost of $6.75/MMBtu, $25.00/kWht thermal storage cost, and a domestic installation corresponding to Daggett, CA. The result of our optimization was a trough design of larger aperture and operating temperature than has been fielded in large, utility scale parabolic trough applications: 7.6m width x 150m SCA length (1,118m2 aperture), with four 90mm diameter × 4.7m receivers per mirror module and an operating temperature of 500°C. The results from physical modeling in the System Advisory Model indicate that, for a capacity factor of 75%: The LCOE will be 8.87¢/kWhe. SkyFuel examined the design of almost every parabolic trough component from a perspective of load and performance at aperture areas from 500 to 2,900m2. Aperture-dependent design was combined with fixed quotations for similar parts from the commercialized SkyTrough product, and established an installed cost of $130/m2 in 2020. This project was conducted in two phases. Phase I was a preliminary design, culminating in an optimum trough size and further improvement of an advanced polymeric reflective material. This phase was completed in October of 2011. Phase II has been the detailed engineering design and component testing, which culminated in the fabrication and testing of a single mirror module. Phase II is complete, and this document presents a summary of the comprehensive work.

Improved Metal-Polymeric Laminate Radiation Shielding, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — In this proposed Phase II program, builds on the phase I feaibility where a multifunctional lightweight radiation shield composite was developed and fabricated. This...

Performance of BEGe detectors for GERDA Phase II

Energy Technology Data Exchange (ETDEWEB)

Lazzaro, Andrea [Physik-Department E15, Technische Universitaet Muenchen (Germany); Collaboration: GERDA-Collaboration

2015-07-01

After the end of the data-taking for GERDA Phase I, the apparatus has been upgraded to fulfill the requirements of the second phase. Phase II sensitivity will be driven by 30 custom made BEGe detectors. This detectors are now available and can be operated in phaseII configuration in the GERDA cryostat together with the liquid argon scintillation veto. The performances of BEGe detectors in liquid argon are presented in this talk. Besides the spectroscopy capability, the focus will be placed on the expectations in terms of background rejection via pulse shape discrimination (PSD). In particular the main goal the BEGe's pulse shape analysis is to discriminate surface events produced by beta emitters (e.g. {sup 42}K) present in the liquid Ar.

Toxicity of xenobiotics during sulfate, iron, and nitrate reduction in primary sewage sludge suspensions

DEFF Research Database (Denmark)

Elsgaard, Lars

2010-01-01

The effect and persistence of six organic xenobiotics was tested under sulfate-, iron-, and nitrate-reducing conditions in primary sewage sludge suspensions. The xenobiotics tested were acenaphthene, phenanthrene, di(2-ethylhexyl)phthalate (DEHP), 4-nonylphenol (4-NP), linear alkylbenzene sulfonate...

Innovation in the Sky, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — This Phase II proposal presents a scope of work to develop reliable Sense and Avoid for BVLOS Unmanned Aerial Vehicle [UAV] operations. We first analyze a) the...

Kursk Operation Simulation and Validation Exercise - Phase II (KOSAVE II)

National Research Council Canada - National Science Library

Bauman, Walter

1998-01-01

... (KOSAVE) Study (KOSAVE II) documents, in this report a statistical record of the Kursk battle, as represented in the KDB, for use as both a standalone descriptive record for historians, and as a baseline for a subsequent Phase...

Nano-Phase Powder Based Exothermic Braze Repair Technology For RCC Materials, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — The Phase II project will advance innovative, cost effective and reliable nano-phase exothermic RCC joining processes (ExoBrazeTM) in order to be able to reinforce...

Polymorphisms in phase I and phase II genes and breast cancer risk and relations to persistent organic pollutant exposure

DEFF Research Database (Denmark)

Ghisari, Mandana; Eiberg, Hans; Long, Manhai

2014-01-01

BACKGROUND: We have previously reported that chemicals belonging to the persistent organic pollutants (POPs) such as perfluorinated compounds (PFAS) and polychlorinated biphenyls (PCBs) are risk factors in Breast Cancer (BC) development in Greenlandic Inuit women. The present case-control study...... on BC risk in Greenlandic Inuit women. METHODS: The study population consisted of 31 BC cases and 115 matched controls, with information on serum levels of POPs. Genotyping was conducted for CYP1A1 (Ile462Val; rs1048943), CYP1B1 (Leu432Val; rs1056836), COMT (Val158Met; rs4680), CYP17A1 (A1> A2; rs743572...... aimed to investigate the main effect of polymorphisms in genes involved in xenobiotic metabolism and estrogen biosynthesis, CYP1A1, CYP1B1, COMT and CYP17, CYP19 and the BRCA1 founder mutation in relation to BC risk and to explore possible interactions between the gene polymorphisms and serum POP levels...

The Role of Cytochromes P450 in Infection

Directory of Open Access Journals (Sweden)

Elisavet Stavropoulou

2018-01-01

Full Text Available Cytochromes are expressed in many different tissues of the human body. They are found mostly in intestinal and hepatic tissues. Cytochromes P450 (CYPs are enzymes that oxidize substances using iron and are able to metabolize a large variety of xenobiotic substances. CYP enzymes are linked to a wide array of reactions including and O-dealkylation, S-oxidation, epoxidation, and hydroxylation. The activity of the typical P450 cytochrome is influenced by a variety of factors, such as genus, environment, disease state, herbicide, alcohol, and herbal medications. However, diet seems to play a major role. The mechanisms of action of dietary chemicals, macro- and micronutrients on specific CYP isoenzymes have been extensively studied. Dietary modulation has effects upon the metabolism of xenobiotics. Cytochromes harbor intra- or interindividual and intra- or interethnic genetic polymorphisms. Bacteria were shown to express CYP-like genes. The tremendous metabolic activity of the microbiota is associated to its abundant pool of CYP enzymes, which catalyze phase I and II reactions in drug metabolism. Disease states, intestinal disturbances, aging, environmental toxic effects, chemical exposures or nutrition modulate the microbial metabolism of a drug before absorption. A plethora of effects exhibited by most of CYP enzymes can resemble those of proinflammatory cytokines and IFNs. Moreover, they are involved in the initiation and persistence of pathologic pain by directly activating sensory neurons and inflammatory cytokines.

First results of GERDA Phase II and consistency with background models

Science.gov (United States)

Agostini, M.; Allardt, M.; Bakalyarov, A. M.; Balata, M.; Barabanov, I.; Baudis, L.; Bauer, C.; Bellotti, E.; Belogurov, S.; Belyaev, S. T.; Benato, G.; Bettini, A.; Bezrukov, L.; Bode1, T.; Borowicz, D.; Brudanin, V.; Brugnera, R.; Caldwell, A.; Cattadori, C.; Chernogorov, A.; D'Andrea, V.; Demidova, E. V.; Di Marco, N.; Domula, A.; Doroshkevich, E.; Egorov, V.; Falkenstein, R.; Frodyma, N.; Gangapshev, A.; Garfagnini, A.; Gooch, C.; Grabmayr, P.; Gurentsov, V.; Gusev, K.; Hakenmüller, J.; Hegai, A.; Heisel, M.; Hemmer, S.; Hofmann, W.; Hult, M.; Inzhechik, L. V.; Janicskó Csáthy, J.; Jochum, J.; Junker, M.; Kazalov, V.; Kihm, T.; Kirpichnikov, I. V.; Kirsch, A.; Kish, A.; Klimenko, A.; Kneißl, R.; Knöpfle, K. T.; Kochetov, O.; Kornoukhov, V. N.; Kuzminov, V. V.; Laubenstein, M.; Lazzaro, A.; Lebedev, V. I.; Lehnert, B.; Liao, H. Y.; Lindner, M.; Lippi, I.; Lubashevskiy, A.; Lubsandorzhiev, B.; Lutter, G.; Macolino, C.; Majorovits, B.; Maneschg, W.; Medinaceli, E.; Miloradovic, M.; Mingazheva, R.; Misiaszek, M.; Moseev, P.; Nemchenok, I.; Palioselitis, D.; Panas, K.; Pandola, L.; Pelczar, K.; Pullia, A.; Riboldi, S.; Rumyantseva, N.; Sada, C.; Salamida, F.; Salathe, M.; Schmitt, C.; Schneider, B.; Schönert, S.; Schreiner, J.; Schulz, O.; Schütz, A.-K.; Schwingenheuer, B.; Selivanenko, O.; Shevzik, E.; Shirchenko, M.; Simgen, H.; Smolnikov, A.; Stanco, L.; Vanhoefer, L.; Vasenko, A. A.; Veresnikova, A.; von Sturm, K.; Wagner, V.; Wegmann, A.; Wester, T.; Wiesinger, C.; Wojcik, M.; Yanovich, E.; Zhitnikov, I.; Zhukov, S. V.; Zinatulina, D.; Zuber, K.; Zuzel, G.

2017-01-01

The GERDA (GERmanium Detector Array) is an experiment for the search of neutrinoless double beta decay (0νββ) in 76Ge, located at Laboratori Nazionali del Gran Sasso of INFN (Italy). GERDA operates bare high purity germanium detectors submersed in liquid Argon (LAr). Phase II of data-taking started in Dec 2015 and is currently ongoing. In Phase II 35 kg of germanium detectors enriched in 76Ge including thirty newly produced Broad Energy Germanium (BEGe) detectors is operating to reach an exposure of 100 kg·yr within about 3 years data taking. The design goal of Phase II is to reduce the background by one order of magnitude to get the sensitivity for T1/20ν = O≤ft( {{{10}26}} \\right){{ yr}}. To achieve the necessary background reduction, the setup was complemented with LAr veto. Analysis of the background spectrum of Phase II demonstrates consistency with the background models. Furthermore 226Ra and 232Th contamination levels consistent with screening results. In the first Phase II data release we found no hint for a 0νββ decay signal and place a limit of this process T1/20ν > 5.3 \\cdot {1025} yr (90% C.L., sensitivity 4.0·1025 yr). First results of GERDA Phase II will be presented.

Study of Stationary Phase Metabolism Via Isotopomer Analysis of Amino Acids from an Isolated Protein

Energy Technology Data Exchange (ETDEWEB)

Shaikh, AfshanS.; Tang, YinjieJ.; Mukhopadhyay, Aindrila; Martin, Hector Garcia; Gin, Jennifer; Benke, Peter; Keasling, Jay D.

2009-09-14

Microbial production of many commercially important secondary metabolites occurs during stationary phase, and methods to measure metabolic flux during this growth phase would be valuable. Metabolic flux analysis is often based on isotopomer information from proteinogenic amino acids. As such, flux analysis primarily reflects the metabolism pertinent to the growth phase during which most proteins are synthesized. To investigate central metabolism and amino acids synthesis activity during stationary phase, addition of fully 13C-labeled glucose followed by induction of green fluorescent protein (GFP) expression during stationary phase was used. Our results indicate that Escherichia coli was able to produce new proteins (i.e., GFP) in the stationary phase, and the amino acids in GFP were mostly from degraded proteins synthesized during the exponential growth phase. Among amino acid biosynthetic pathways, only those for serine, alanine, glutamate/glutamine, and aspartate/asparagine had significant activity during the stationary phase.

Generation Z: Adolescent Xenobiotic Abuse in the 21st Century.

Science.gov (United States)

Eggleston, William; Stork, Christine

2015-12-01

NMDA receptor antagonists include the prescription medication ketamine, the illicit xenobiotics PCP, MXE, and other novel PCP analogs, and the OTC medication DXM. The NMDA receptor antagonist most commonly abused by adolescents in the United States is DXM. These xenobiotics cause dissociative effects by non-competitively inhibiting the action of glutamate at the NMDA receptor. Additionally, these agents modulate the actions of monoamine neurotransmitters, agonize opioid receptors, and inhibit nitric oxide synthase. Patients typically present with sympathomimetic and neuropsychiatric clinical manifestations after abuse of NMDA receptor antagonists. Treatment is generally symptomatic and supportive. Interventions include benzodiazepines, propofol, fluids, antiemetics, aggressive cooling, and respiratory support.

DESIGN AND PERFORMANCE OF A XENOBIOTIC METABOLISM DATABASE MANAGER FOR METABOLIC SIMULATOR ENHANCEMENT AND CHEMICAL RISK ANALYSIS

Science.gov (United States)

A major uncertainty that has long been recognized in evaluating chemical toxicity is accounting for metabolic activation of chemicals resulting in increased toxicity. In silico approaches to predict chemical metabolism and to subsequently screen and prioritize chemicals for risk ...

Oxygen and xenobiotic reductase activities of cytochrome P450.

NARCIS (Netherlands)

Goeptar, A.R.; Scheerens, H.; Vermeulen, N.P.E.

1995-01-01

The oxygen reductase and xenobiotic reductase activities of cytochrome P450 (P450) are reviewed. During the oxygen reductase activity of P450, molecular oxygen is reduced to superoxide anion radicals (O

Application of probiotics in the xenobiotic detoxification therapy

Energy Technology Data Exchange (ETDEWEB)

Urban, P L [Isotope Laboratory, Faculty of Biology, Warsaw University, Warsaw (Poland); Kuthan, R T [2 Plant Pathogenesis Group, Institute of Biochemistry and Biophysics, Polish Academy of Science, Warsaw (Poland)

2004-07-01

Many applications of probiotics have been described up to date. In this paper, it is hypothesized that probiotic microorganisms can also be used to decrease the xenobiotics intake in humans. The use of probiotic bacteria (e.g. strains of Lactobacillus sp. and Bifidobacterium Sp.) and Yeasts (Saccharomyces sp.) gives the opportunity for detoxification of various elements and compounds, considered as contaminants, directly in the lumen of human intestine. Some of these microorganisms ar known to accumulate cesium, strontium and heavy metals to a great extent and also bind mycotoxins. Certainly, during the up-coming years, their native or genetically modified strains will be a part of treatment protocols in detoxication therapy. The utilization of probiotics, in the both therapy and nutrition of people living in the countries suffering from high food contamination, could result in the reduction of annual xenobiotic dose to be incorporated in their organisms. (author)

Application of probiotics in the xenobiotic detoxification therapy

International Nuclear Information System (INIS)

Urban, P.L.; Kuthan, R.T.

2004-01-01

Many applications of probiotics have been described up to date. In this paper, it is hypothesized that probiotic microorganisms can also be used to decrease the xenobiotics intake in humans. The use of probiotic bacteria (e.g. strains of Lactobacillus sp. and Bifidobacterium Sp.) and Yeasts (Saccharomyces sp.) gives the opportunity for detoxification of various elements and compounds, considered as contaminants, directly in the lumen of human intestine. Some of these microorganisms ar known to accumulate cesium, strontium and heavy metals to a great extent and also bind mycotoxins. Certainly, during the up-coming years, their native or genetically modified strains will be a part of treatment protocols in detoxication therapy. The utilization of probiotics, in the both therapy and nutrition of people living in the countries suffering from high food contamination, could result in the reduction of annual xenobiotic dose to be incorporated in their organisms. (author)

Single Electron Transistor Platform for Microgravity Proteomics, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — This Phase II program builds from the successful Phase I efforts to demonstrate that Quantum Logic Devices' nanoelectronic platform for biological detection could...

Review and evaluation of the effects of xenobiotic chemicals on microorganisms in soil. [139 references

Energy Technology Data Exchange (ETDEWEB)

Hicks, R.J.; Van Voris, P.

1988-02-01

The primary objective was to review and evaluate the relevance and quality of existing xenobiotic data bases and test methods for evaluating direct and indirect effects (both adverse and beneficial) of xenobiotics on the soil microbial community; direct and indirect effects of the soil microbial community on xenobiotics; and adequacy of test methods used to evaluate these effects and interactions. Xenobiotic chemicals are defined here as those compounds, both organic and inorganic, produced by man and introduced into the environment at concentrations that cause undesirable effects. Because soil serves as the main repository for many of these chemicals, it therefore has a major role in determining their ultimate fate. Once released, the distribution of xenobiotics between environmental compartments depends on the chemodynamic properties of the compounds, the physicochemical properties of the soils, and the transfer between soil-water and soil-air interfaces and across biological membranes. Abiotic and biotic processes can transform the chemical compound, thus altering its chemical state and, subsequently, its toxicity and reactivity. Ideally, the conversion is to carbon dioxide, water, and mineral elements, or at least, to some harmless substance. However, intermediate transformation products, which can become toxic pollutants in their own right, can sometimes be formed. 139 refs., 6 figs., 11 tabs.

U10 : Trusted Truck(R) II (phase B).

Science.gov (United States)

2009-01-01

Phase B of the Trusted Truck II project built on the system developed in Phase A (or Year 1). For the implementation portion of the project, systems were added to the trailer to provide additional diagnostic trailer data that can be sent to the TTM...

Durability of lightweight concrete : Phase II : wetting and drying tests, Phase III : freezing and thawing tests.

Science.gov (United States)

1966-12-01

This report describes a laboratory research program on the durability of lightweight concrete. Two phases of a three phase study are covered by this report, while the remaining phase is still under study. The two phases being reported are Phase II - ...

Murine Automated Urine Sampler (MAUS), Phase II

Data.gov (United States)

National Aeronautics and Space Administration — This SBIR Phase II effort involves the development of a novel rodent spaceflight habitat, focusing on care and monitoring of mice for gravitational physiology...

Triclosan affects the microbial community in simulated sewage-drain-field soil and slows down xenobiotic degradation

Energy Technology Data Exchange (ETDEWEB)

Svenningsen, Hanne [Department of Geochemistry, Geological Survey of Denmark and Greenland (GEUS), Oster Voldgade 10, DK-1350 Copenhagen K (Denmark); Department of Biology, University of Copenhagen, Solvgade 83H, DK-1307 Copenhagen K (Denmark); Henriksen, Trine [Department of Geochemistry, Geological Survey of Denmark and Greenland (GEUS), Oster Voldgade 10, DK-1350 Copenhagen K (Denmark); Prieme, Anders [Department of Biology, University of Copenhagen, Solvgade 83H, DK-1307 Copenhagen K (Denmark); Johnsen, Anders R., E-mail: arj@geus.dk [Department of Geochemistry, Geological Survey of Denmark and Greenland (GEUS), Oster Voldgade 10, DK-1350 Copenhagen K (Denmark)

2011-06-15

Effects of the common antibacterial agent triclosan on microbial communities and degradation of domestic xenobiotics were studied in simulated sewage-drain-field soil. Cultivable microbial populations decreased 22-fold in the presence of 4 mg kg{sup -1} of triclosan, and triclosan-resistant Pseudomonas strains were strongly enriched. Exposure to triclosan also changed the general metabolic profile (Ecoplate substrate profiling) and the general profile (T-RFLP) of the microbial community. Triclosan degradation was slow at all concentrations tested (0.33-81 mg kg{sup -1}) during 50-days of incubation. Mineralization experiments ({sup 14}C-tracers) and chemical analyses (LC-MS/MS) showed that the persistence of a linear alkylbenzene sulfonate (LAS) and a common analgesic (ibuprofen) increased with increasing triclosan concentrations (0.16-100 mg kg{sup -1}). The largest effect was seen for LAS mineralization which was severely reduced by 0.16 mg kg{sup -1} of triclosan. Our findings indicate that environmentally realistic concentrations of triclosan may affect the efficiency of biodegradation in percolation systems. - Highlights: > Triclosan may enter the soil environment through sewage. > Triclosan impacts the microbial community in sewage-drain-field soil. > Triclosan-resistant pseudomonads are strongly enriched. > Degradation of co-occurring LAS and ibuprofen is reduced. - Environmentally realistic triclosan concentrations in percolation systems may reduce the biodegradation of other xenobiotics and select for triclosan-resistant bacteria.

Triclosan affects the microbial community in simulated sewage-drain-field soil and slows down xenobiotic degradation

International Nuclear Information System (INIS)

Svenningsen, Hanne; Henriksen, Trine; Prieme, Anders; Johnsen, Anders R.

2011-01-01

Effects of the common antibacterial agent triclosan on microbial communities and degradation of domestic xenobiotics were studied in simulated sewage-drain-field soil. Cultivable microbial populations decreased 22-fold in the presence of 4 mg kg -1 of triclosan, and triclosan-resistant Pseudomonas strains were strongly enriched. Exposure to triclosan also changed the general metabolic profile (Ecoplate substrate profiling) and the general profile (T-RFLP) of the microbial community. Triclosan degradation was slow at all concentrations tested (0.33-81 mg kg -1 ) during 50-days of incubation. Mineralization experiments ( 14 C-tracers) and chemical analyses (LC-MS/MS) showed that the persistence of a linear alkylbenzene sulfonate (LAS) and a common analgesic (ibuprofen) increased with increasing triclosan concentrations (0.16-100 mg kg -1 ). The largest effect was seen for LAS mineralization which was severely reduced by 0.16 mg kg -1 of triclosan. Our findings indicate that environmentally realistic concentrations of triclosan may affect the efficiency of biodegradation in percolation systems. - Highlights: → Triclosan may enter the soil environment through sewage. → Triclosan impacts the microbial community in sewage-drain-field soil. → Triclosan-resistant pseudomonads are strongly enriched. → Degradation of co-occurring LAS and ibuprofen is reduced. - Environmentally realistic triclosan concentrations in percolation systems may reduce the biodegradation of other xenobiotics and select for triclosan-resistant bacteria.

Apoptosis (programmed cell death) as an indicator of xenobiotic toxicity

International Nuclear Information System (INIS)

Bond, G.P.

1989-01-01

Xenobiotics alter the frequency and pattern of apoptosis (programmed cell death). Preliminary studies identified the mouse liver, with normally low levels of apoptosis, as a preferable test system to the chicken embryo limb, with normally high levels of apoptosis. The major purposes of these investigations, using the apoptogen and necrogen 1,1-dichloroethylene (DCE), were to determine if increases in apoptosis, (1) could be quantified as a direct result of treatment, (2) were dose- and time-dependent, (3) were independent of necrosis, (4) were associated with mitosis in the control of cell numbers and (5) were limited to specific areas of the liver. To these ends, food-deprived female, CF-1 mice were administered DCE ip under varying experimental conditions. Increased apoptosis occurred in a dose- and time-dependent manner after treatment with 12.5, 40, and 125 mg/kg for 0.5, 1, 2, 4 and 8 hr. Peak effects were observed at 4 hr. Apoptosis occurred only in the midzonal/pericentral areas of the liver. At 12.5 mg/kg, there were no effects on biochemical (alanine transaminase) and morphological indices of necrosis, establishing apoptosis as a separate phenomenon from necrosis. Increased 3 H-thymidine incorporation (DNA synthesis), mitosis and the percentage of octaploid hepatocytes occurred from 24-48 hr after treatment with the apoptotic but non-necrotic dose of 40 mg/kg. Apoptosis only occurred in the midzonal/pericentral areas of the liver after multiple doses with DCE, indicating the zonal selectivity of the response. In conclusion, apoptosis, a normally occurring homeostatic process associated with mitosis in the control of cell numbers, is affected by selected xenobiotics in a dose-dependent manner. Xenobiotic-induced apoptosis in the liver occurs at low doses of xenobiotics which cause no other effects on tissue structure or function

High Resolution Autostereoscopic Cockpit Display, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — During this Phase II program Dimension Technologies Inc. (DTI) proposes to design and build an autostereoscopic (glasses-free 3D) LCD based aircraft cockpit display...

Complex exercise rehabilitation program for women of the II period of age with metabolic syndrome

OpenAIRE

Lee, Eun-Ok; Olga, Kozyreva

2013-01-01

The purpose of this study was to develop a complex exercise program integrating Eastern and Western complex exercise rehabilitation programs in order to examine the effects of it on the human body with the subjects for women of the II period of mature age with metabolic syndrome. The subjects of this study are 60 II period of mature aged women with metabolic syndrome living in G City, and the experimental group conducted Taekwon-aerobic exercise, European rehabilitation gymnastics, gym ball e...

Silver Biocide Analysis & Control Device, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — Rapid, accurate measurement and process control of silver ion biocide concentrations in future space missions is needed. The purpose of the Phase II program is to...

Performance of the LAr scintillation veto of Gerda Phase II

Energy Technology Data Exchange (ETDEWEB)

Wiesinger, Christoph [Physik-Department and Excellence Cluster Universe, Technische Universitaet Muenchen, James-Franck-Strasse, 85748 Garching (Germany); Collaboration: GERDA-Collaboration

2016-07-01

Gerda is an experiment to search for the neutrinoless double beta decay in {sup 76}Ge. Results of Phase I have been published in summer 2013 and Gerda has been upgraded to Phase II. To reach the aspired background index of ∝10{sup -3} cts/(keV.kg.yr) for Phase II active background-suppression techniques are applied, including an active liquid argon (LAr) veto. It has been demonstrated with the LArGe test facility that the detection of argon scintillation light can be used to effectively suppress background events in the germanium detectors, which simultaneously deposit energy in the LAr. The light instrumentation consisting of photomultiplier tubes (PMT) and wavelength-shifting fibers connected to silicon photomultipliers (SiPM) has been installed in Gerda. In this talk the low background design of the LAr veto and its performance during Phase II start-up is reported.

Natural variations in xenobiotic-metabolizing enzymes: developing tools for coral monitoring

Science.gov (United States)

Rougée, L. R. A.; Richmond, R. H.; Collier, A. C.

2014-06-01

The continued deterioration of coral reefs worldwide demonstrates the need to develop diagnostic tools for corals that go beyond general ecological monitoring and can identify specific stressors at sublethal levels. Cellular diagnostics present an approach to defining indicators (biomarkers) that have the potential to reflect the impact of stress at the cellular level, allowing for the detection of intracellular changes in corals prior to outright mortality. Detoxification enzymes, which may be readily induced or inhibited by environmental stressors, present such a set of indicators. However, in order to apply these diagnostic tools for the detection of stress, a detailed understanding of their normal, homeostatic levels within healthy corals must first be established. Herein, we present molecular and biochemical evidence for the expression and activity of major Phase I detoxification enzymes cytochrome P450 (CYP450), CYP2E1, and CYP450 reductase, as well as the Phase II enzymes UDP, glucuronosyltransferase (UGT), β-glucuronidase, glutathione- S-transferase (GST), and arylsulfatase C (ASC) in the coral Pocillopora damicornis. Additionally, we characterized enzyme expression and activity variations over a reproductive cycle within a coral's life history to determine natural endogenous changes devoid of stress exposure. Significant changes in enzyme activity over the coral's natural lunar reproductive cycle were observed for CYP2E1 and CYP450 reductase as well as UGT and GST, while β-glucuronidase and ASC did not fluctuate significantly. The data represent a baseline description of `health' for the expression and activity of these enzymes that can be used toward understanding the impact of environmental stressors on corals. Such knowledge can be applied to address causes of coral reef ecosystem decline and to monitor effectiveness of mitigation strategies. Achieving a better understanding of cause-and-effect relationships between putative stressors and biological

Treatment of groundwater containing Mn(II), Fe(II), As(III) and Sb(III) by bioaugmented quartz-sand filters.

Science.gov (United States)

Bai, Yaohui; Chang, Yangyang; Liang, Jinsong; Chen, Chen; Qu, Jiuhui

2016-12-01

High concentrations of iron (Fe(II)) and manganese (Mn(II)) often occur simultaneously in groundwater. Previously, we demonstrated that Fe(II) and Mn(II) could be oxidized to biogenic Fe-Mn oxides (BFMO) via aeration and microbial oxidation, and the formed BFMO could further oxidize and adsorb other pollutants (e.g., arsenic (As(III)) and antimony (Sb(III))). To apply this finding to groundwater remediation, we established four quartz-sand columns for treating groundwater containing Fe(II), Mn(II), As(III), and Sb(III). A Mn-oxidizing bacterium (Pseudomonas sp. QJX-1) was inoculated into two parallel bioaugmented columns. Long-term treatment (120 d) showed that bioaugmentation accelerated the formation of Fe-Mn oxides, resulting in an increase in As and Sb removal. The bioaugmented columns also exhibited higher overall treatment effect and anti-shock load capacity than that of the non-bioaugmented columns. To clarify the causal relationship between the microbial community and treatment effect, we compared the biomass of active bacteria (reverse-transcribed real-time PCR), bacterial community composition (Miseq 16S rRNA sequencing) and community function (metagenomic sequencing) between the bioaugmented and non-bioaugmented columns. Results indicated that the QJX1 strain grew steadily and attached onto the filter material surface in the bioaugmented columns. In general, the inoculated strain did not significantly alter the composition of the indigenous bacterial community, but did improve the relative abundances of xenobiotic metabolism genes and Mn oxidation gene. Thus, bioaugmentation intensified microbial degradation/utilization for the direct removal of pollutants and increased the formation of Fe-Mn oxides for the indirect removal of pollutants. Our study provides an alternative method for the treatment of groundwater containing high Fe(II), Mn(II) and As/Sb. Copyright © 2016 Elsevier Ltd. All rights reserved.

PBFA [Particle Beam Fusion Accelerator] II: The pulsed power characterization phase

International Nuclear Information System (INIS)

Martin, T.H.; Turman, B.N.; Goldstein, S.A.

1987-01-01

The Particle Beam Fusion Accelerator II, PBFA II, is now the largest pulsed power device in operation. This paper summarizes its first year and a half of operation for the Department of Energy (DOE) Inertial Confinement Fusion (ICF) program. Thirty-six separate modules provide 72 output pulses that combine to form a 100 TW output pulse at the accelerator center. PBFA II was successfully test fired for the first time on December 11, 1985. This test completed the construction phase (Phase 1) within the expected schedule and budget. The accelerator checkout phase then started (Phase 2). The first priority during checkout was to bring the Phase 1 subsystems into full operation. The accelerator was first tested to determine overall system performance. Next, subsystems that were not performing adequately were modified. The accelerator is now being used for ion diode studies. 32 refs

Rapid metabolism of exogenous angiotensin II by catecholaminergic neuronal cells in culture media.

Science.gov (United States)

Basu, Urmi; Seravalli, Javier; Madayiputhiya, Nandakumar; Adamec, Jiri; Case, Adam J; Zimmerman, Matthew C

2015-02-01

Angiotensin II (AngII) acts on central neurons to increase neuronal firing and induce sympathoexcitation, which contribute to the pathogenesis of cardiovascular diseases including hypertension and heart failure. Numerous studies have examined the precise AngII-induced intraneuronal signaling mechanism in an attempt to identify new therapeutic targets for these diseases. Considering the technical challenges in studying specific intraneuronal signaling pathways in vivo, especially in the cardiovascular control brain regions, most studies have relied on neuronal cell culture models. However, there are numerous limitations in using cell culture models to study AngII intraneuronal signaling, including the lack of evidence indicating the stability of AngII in culture media. Herein, we tested the hypothesis that exogenous AngII is rapidly metabolized in neuronal cell culture media. Using liquid chromatography-tandem mass spectrometry, we measured levels of AngII and its metabolites, Ang III, Ang IV, and Ang-1-7, in neuronal cell culture media after administration of exogenous AngII (100 nmol/L) to a neuronal cell culture model (CATH.a neurons). AngII levels rapidly declined in the media, returning to near baseline levels within 3 h of administration. Additionally, levels of Ang III and Ang-1-7 acutely increased, while levels of Ang IV remained unchanged. Replenishing the media with exogenous AngII every 3 h for 24 h resulted in a consistent and significant increase in AngII levels for the duration of the treatment period. These data indicate that AngII is rapidly metabolized in neuronal cell culture media, and replenishing the media at least every 3 h is needed to sustain chronically elevated levels. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

The SafeBoosC Phase II Randomised Clinical Trial : A Treatment Guideline for Targeted Near-Infrared-Derived Cerebral Tissue Oxygenation versus Standard Treatment in Extremely Preterm Infants

NARCIS (Netherlands)

Pellicer, Adelina; Greisen, Gorm; Benders, Manon; Claris, Olivier; Dempsey, Eugene; Fumagalli, Monica; Gluud, Christian; Hagmann, Cornelia; Hellstroem-Westas, Lena; Hyttel-Sorensen, Simon; Lemmers, Petra; Naulaers, Gunnar; Pichler, Gerhard; Roll, Claudia; van Bel, Frank; van Oeveren, Wim; Skoog, Maria; Wolf, Martin; Austin, Topun

2013-01-01

Near-infrared spectroscopy-derived regional tissue oxygen saturation of haemoglobin (rSto(2)) reflects venous oxygen saturation. If cerebral metabolism is stable, rSto(2) can be used as an estimate of cerebral oxygen delivery. The SafeBoosC phase II randomised clinical trial hypothesises that the

Titanium Heat Pipe Thermal Plane, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — The objective of the Phase II program is to complete the development of the titanium heat pipe thermal plane and establish all necessary steps for production of this...

Space-Ready Advanced Imaging System, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — In this Phase II effort Toyon will increase the state-of-the-art for video/image systems. This will include digital image compression algorithms as well as system...

Malignant pleural mesothelioma: a phase II trial with docetaxel.

Science.gov (United States)

Vorobiof, D A; Rapoport, B L; Chasen, M R; Abratt, R P; Cronje, N; Fourie, L; McMichael, G; Hacking, D

2002-03-01

Current cytotoxic therapy has been of limited benefit to patients with malignant pleural mesothelioma. Single agent chemotherapy has been extensively evaluated in small series of phase II clinical trials, with disappointing responses. Docetaxel, an effective taxane in the treatment of advanced breast cancer and non-small-cell lung cancer, was administered intravenously at a dose of 100 mg/m2 every 3 weeks to 30 chemotherapy naive patients with malignant pleural mesothelioma in a prospective multi-institutional phase II clinical trial. An objective response rate (partial responses) of 10% was documented. Additionally, 21% of the patients had minor responses (intention-to-treat analysis). Three patients died within 2 weeks post-first cycle of therapy, although only one patient's death was directly attributed to the investigational drug, whilst in the majority of the patients, manageable and treatable toxicities were encountered. In this phase II clinical trial, docetaxel proved to be mildly effective in the treatment of patients with malignant pleural mesothelioma.

Conversion of Phase II Unsteady Aerodynamics Experiment Data to Common Format; TOPICAL

International Nuclear Information System (INIS)

Hand, M. M.

1999-01-01

A vast amount of aerodynamic, structural, and turbine performance data were collected during three phases of the National Renewable Energy Laboratory's Unsteady Aerodynamics Experiment (UAE). To compare data from the three phases, a similar format of engineering unit data is required. The process of converting Phase II data from a previous engineering unit format to raw integer counts is discussed. The integer count files can then be input to the new post-processing software, MUNCH. The resulting Phase II engineering unit files are in a common format with current and future UAE engineering unit files. An additional objective for changing the file format was to convert the Phase II data from English units to SI units of measurement

Metabolism of a new synthetic progestagen, Org 2969, in female volunteers

International Nuclear Information System (INIS)

Viinikka, L.; Ylikorkala, O.; Vihko, R.; Hasenack, H.G.; Nieuwenhuyse, H.

1980-01-01

The metabolism of a new synthetic progestagen, Org 2969 was studied in 4 healthy female volunteers. During the first part of the study (Phase I), the volunteers ingested 50 μg (about 0.1 mCi) of [16- 3 H]Org 2969 together with 50 μg of ethinyloestradiol as a single dose. During the second part of the study (Phase II), a 10-day pre-treatment with the same dosage of non-radioactive compound preceded the administration of the radioactive steroid. A peak level of total radioactivity, representing 3.16-5.02% of the dose given/l of serum, was achieved within 2-3 h in Phase I. During Phase II, the corresponding figures were 4.54-5.13% after 1.5-3 h. The difference was mainly due to an increase of freely-extractable steroids during Phase II. The difference can at least partly be explained by assuming a change in the kinetics of the metabolism of Org 2969 by pre-treatment with Org 2969 and ethinyloestradiol. The mean recovery of radioactivity in urine and faeces was 83.0%/48.1%/34.9% (total/urine/faeces) of the total dose in Phase I and 76.1%/45.2%/30.9% during Phase II. The differences in the total excretion and in the radioactivity excreted in the faeces were significant. (author)

Kilowatt isotope power system. Phase II plan. Volume I. Phase II program plan

International Nuclear Information System (INIS)

1978-01-01

The development of a Kilowatt Isotope Power System (KIPS) was begun in 1975 for the purpose of satisfying the power requirements of satellites in the 1980's. The KIPS is a 238 PuO 2 -fueled organic Rankine cycle turbine power system to provide a design output of 500 to 2000 W. Phase II of the overall 3-phase KIPS program is described. This volume presents a program plan for qualifying the organic Rankine power system for flight test in 1982. The program plan calls for the design and fabrication of the proposed flight power system; conducting a development and a qualification program including both environmental and endurance testing, using an electrical and a radioisotope heat source; planning for flight test and spacecraft integration; and continuing ground demonstration system testing to act as a flight system breadboard and to accumulate life data

Reclaimable Thermally Reversible Polymers for AM Feedstock, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — CRG proposes to continue efforts from the 2016 NASA SBIR Phase I topic H5.04 Reclaimable Thermally Reversible Polymers for AM Feedstock. In Phase II, CRG will refine...

Do heavy metals and metalloids influence the detoxification of organic xenobiotics in plants?

Science.gov (United States)

Schröder, Peter; Lyubenova, Lyudmila; Huber, Christian

2009-11-01

Mixed pollution with trace elements and organic industrial compounds is characteristic for many spill areas and dumping sites. The danger for the environment and human health from such sites is large, and sustainable remediation strategies are urgently needed. Phytoremediation seems to be a cheap and environmentally sound option for the removal of unwanted compounds, and the hyperaccumulation of trace elements and toxic metals is seemingly independent from the metabolism of organic xenobiotics. However, stress reactions, ROS formation and depletion of antioxidants will also cause alterations in xenobiotic detoxification. Here, we investigate the capability of plants to detoxify chlorophenols via glutathione conjugation in a mixed pollution situation. Typha latifolia and Phragmites australis plants for the present study were grown under greenhouse conditions in experimental ponds. A Picea abies L. suspension culture was grown in a growth chamber. Cadmium sulphate, sodium arsenate and lead chloride in concentrations from 10 to 500 microM were administered to plants. Enzymes of interest for the present study were: glutathione transferase (GST), glutathione reductase, ascorbate peroxidase and peroxidase. Measurements were performed according to published methods. GST spectrophotometric assays included the model substrates CDNB, DCNB, NBC, NBoC and the herbicide Fluorodifen. Heavy metals lead to visible stress symptoms in higher plants. Besides one long-term experiment of 72 days duration, the present study shows time and concentration-dependent plant alterations already after 24 and 72 h Cd incubation. P. abies spruce cell cultures react to CdSO(4) and Na(2)HAsO(4) with an oxidative burst, similar to that observed after pathogen attack or elicitor treatment. Cd application resulted in a reduction in GSH and GSSG contents. When a heavy metal mixture containing Na(2)HAsO(4), CdSO(4) and PbCl(2) was applied to cultures, both GSH and GSSG levels declined. Incubation with

A new research journal to understand the interactions of xenobiotics with living organisms

Directory of Open Access Journals (Sweden)

François Gagné

2012-10-01

Full Text Available Since its creation in January 2011, the Journal of Xenobiotics (published by PAGEPress, Italy is devoted to the publication of novel research articles in the fields of the occurrence and biochemical effects of xenobiotics on all living organisms. Although xenobiotics are defined firstly as compounds that are foreign to life, compounds of natural origins occuring at concentrations that are not usually found, could also be considered as foreigners since their enhanced occurrence may affect non-target organisms. In this sense, products derived from natural products are well known to have either a beneficial (natural products used as food additives and many pharmaceuticals or detrimental (cyanotoxins impact on the health of an organism. The journal recognizes that these compounds could be either harmful or beneficial to organisms and the interplay between these two aspects is of particular interest...

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

Neutrinoless double beta decay in GERDA Phase II

International Nuclear Information System (INIS)

Macolino, C.

2014-01-01

The GERmanium Detector Array, GERDA, is designed to search for neutrinoless double beta (0νββ) decay of 76 Ge and it is installed in the Laboratori Nazionali del Gran Sasso (LNGS) of INFN, Italy. The GERDA experiment has completed the Phase I with a total collected exposure of 21.6 kg yr and a background index (BI) of the order of BI ≃ 10 −2 cts/(keVkg yr). No excess of events from 0νββ decay has been observed and a lower limit on the half-life on the 0νββ decay for 76 Ge has been estimated: T 0ν 1 /2 > 2.1·10 25 yr at 90% CL. The goal of GERDA Phase II is to reach the target sensitivity of T 0ν 1 /2 ≃ 1.4 · 10 26 yr, with an increased total mass of the enriched material and a reduced background level. In this paper the results from GERDA Phase I and the major improvements planned for Phase II are discussed.

A steerable/distance enhanced penetrometer delivery system: Phase II. Topical report

International Nuclear Information System (INIS)

Amini, A.; Shenhar, J.; Lum, K.D.

1996-05-01

This report summarizes the phase II work on the Position Location Device (POLO) for penetrometers. Phase II was carried out to generate an integrated design of a full-scale steerable/distance enhanced penetrometer delivery system. Steering provides for the controlled and directional use of the penetrometer, while vibratory thrusting can provide greater penetration ability

In vitro phase I metabolism of gamabufotalin and arenobufagin: Reveal the effect of substituent group on metabolic stability.

Science.gov (United States)

Feng, Yujie; Wang, Chao; Tian, Xiangge; Huo, Xiaokui; Feng, Lei; Sun, Chengpeng; Ge, Guangbo; Yang, Ling; Ning, Jing; Ma, Xiaochi

2017-09-01

Bufadienolides are a major class of bioactive compounds derived from amphibian skin secretion. Gamabufotalin (GB) and arenobufagin (AB) are among the top of the intensively investigated natural bufadienolides for their outstanding biological activities. This study aimed to characterize the phase I metabolism of GB and AB with respect to the metabolic profiles, enzymes involved, and catalytic efficacy, thereafter tried to reveal substituent effects on metabolism. Two mono-hydroxylated products of GB and AB were detected in the incubation mixtures, and they were accurately identified as 1- and 5-hydroxylated bufadienolides by NMR and HPLC-MS techniques. Reaction phenotyping studies demonstrated that CYP3A mediated the metabolism of the two bufadienolides with a high specific selectivity. Further kinetic evaluation demonstrated that the metabolism stability of GB and AB were better than other reported bufadienolides. Additionally, the CYP3A5 preference for hydroxylation of AB was observed, which was different to the selectivity of CYP3As for bufadienolides suggested by our previous report. This study can provide important data for elucidating the phase I metabolism of GB and AB and can lead to a better understanding of the bufadienolide-CYP3A interaction which is helpful for preclinical development and rational use of bufadienolides. Copyright © 2017 Elsevier B.V. All rights reserved.

Metabolic and clinical effects of Ramadan fasting in patients with type II diabetes

International Nuclear Information System (INIS)

Yarahmadi, S.; Larijani, B.; Bastanhagh, M.H.; Pajouhi, M.; Bardar, J. R.; Zahedi, F.; Zendehdel, K.; Akrami, S.M.

2003-01-01

Objective: To evaluate the effects of fasting on anthropometric indices and carbohydrate and lipid metabolism in patients with type II diabetes. Results: Daily cholesterol intake increased in all subjects (p 0.01). Blood pressure, fasting blood glucose and serum fructosamine did not change during the study. Plasma insulin (p < 0.05), C-peptide (p < 0.01) and insulin resistance (p < 0.01) decreased only in men. Total and LDL cholesterol increased significantly in all subjects during the study. Conclusion: Ramadan fasting does not alter carbohydrate metabolism or tissue insulin sensitivity in patients with type II diabetes given appropriate dietary education and rescheduling of oral hypoglycaemic medication. Lipid profile is unfavorably altered due to changes in both diet and biochemical response to starvation. (author)

X-ray diffraction study of phase transitions in iron(II) trisnioximate hexadecylboronate clathrochelate complex

International Nuclear Information System (INIS)

Vorontsov, I.I.; Antipin, M.Yu.; Dubovik, I.I.; Papkov, V.S.; Potekhin, K.A.; Voloshin, Ya.Z.; Stash, A.I.; Belsky, V.K.

2001-01-01

Crystals of the iron(II) nioximate hexadecylboronate clathrochelate complex-FeNx 3 (BHd ) 2 [tris(μ-1,2-cyclohexanedionedioximato-O:O ' )di-n-hexadecyldiborato(2-) - N,'''N''',N''',N''',N''',N ' ]iron(II) - are investigated by differential scanning calorimetry and X-ray diffraction. Two structural phase transitions are revealed at T cr1 = 290(3) K and T cr2 = 190(3) K. The crystal structures of phases I, II, and III are determined by X-ray diffraction analysis at 303, 243, and 153 K, respectively. It is demonstrated that the I ↔ II phase transition is due to a change in the system of translations, and the II ↔ III phase transition is accompanied only by a jumpwise change in the unit cell parameters. The possible mechanisms of phase transitions are discussed in terms of geometry and molecular packing of FeNx 3 (BHd) 2 in all three phases

Xenobiotic effects on intestinal stem cell proliferation in adult honey bee (Apis mellifera L) workers.

Science.gov (United States)

Forkpah, Cordelia; Dixon, Luke R; Fahrbach, Susan E; Rueppell, Olav

2014-01-01

The causes of the current global decline in honey bee health are unknown. One major group of hypotheses invokes the pesticides and other xenobiotics to which this important pollinator species is often exposed. Most studies have focused on mortality or behavioral deficiencies in exposed honey bees while neglecting other biological functions and target organs. The midgut epithelium of honey bees presents an important interface between the insect and its environment. It is maintained by proliferation of intestinal stem cells throughout the adult life of honey bees. We used caged honey bees to test multiple xenobiotics for effects on the replicative activity of the intestinal stem cells under laboratory conditions. Most of the tested compounds did not alter the replicative activity of intestinal stem cells. However, colchicine, methoxyfenozide, tetracycline, and a combination of coumaphos and tau-fluvalinate significantly affected proliferation rate. All substances except methoxyfenozide decreased proliferation rate. Thus, the results indicate that some xenobiotics frequently used in apiculture and known to accumulate in honey bee hives may have hitherto unknown physiological effects. The nutritional status and the susceptibility to pathogens of honey bees could be compromised by the impacts of xenobiotics on the maintenance of the midgut epithelium. This study contributes to a growing body of evidence that more comprehensive testing of xenobiotics may be required before novel or existing compounds can be considered safe for honey bees and other non-target species.

In silico identification and construction of microbial gene clusters associated with biodegradation of xenobiotic compounds.

Science.gov (United States)

Awasthi, Garima; Kumari, Anjani; Pant, Aditya Bhushan; Srivastava, Prachi

2018-01-01

Chemical substances not showing any importance in existence of biological systems and causing serious health hazards may be designated as Xenobiotic compound. Elimination or degradation of these unwanted substances is a major issue of concern for current time research. Process of biodegradation is a very important aspect of current research as discussed in current manuscript. Current study focuses on the detailed mining of data for the construction of microbial consortia for wide range of xenobiotics compounds. Intensive literature search was done for the construction of this library. Desired data was retrieved from NCBI in fasta format. Data was analysed through homology approaches by using BLAST. This homology based searched enriched with a great vision that not only bacterial population but many other cheap and potential sources are available for different xenobiotic degradation. Though it was focused that bacterial population covers a major part of biodegradation which is near about 90.6% but algae and fungi are also showing promising future in degradation of some important xenobiotic compounds. Analysis of data reveals that Pseudomonas putida has potential for degrading maximum compounds. Establishment of correlation through cluster analysis signifies that Pseudomonas putida, Aspergillus niger and Skeletonema costatum can have combined traits that can be used in finding out actual evolutionary relationship between these species. These findings may also givea new outcome in terms of much cheaper and eco-friendly source in the area of biodegradation of specified xenobiotic compounds. Copyright © 2017 Elsevier Ltd. All rights reserved.

High Performance Wafer-Based Capillary Electrochromatography, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — The Phase II research comprises designing, constructing, and testing a chip-based capillary electrochromatography (CEC) prototype for separation and analysis of...

Pavement performance evaluation, phase II : data collection.

Science.gov (United States)

2008-12-01

Phase I and II of this study tested approximately 1500 rehabilitated pavements (asphalt and PCC) : throughout the State. These pavements ranged from 5 to 15 years old and were intended to develop a : snapshot of how various rehabilitations were perfo...

Metabolic profiling detects early effects of environmental and lifestyle exposure to cadmium in a human population

OpenAIRE

Ellis, James K; Athersuch, Toby J; Thomas, Laura DK; Teichert, Friederike; Pérez-Trujillo, Miriam; Svendsen, Claus; Spurgeon, David J; Singh, Rajinder; Järup, Lars; Bundy, Jacob G; Keun, Hector C

2012-01-01

Background: The ‘exposome’ represents the accumulation of all environmental exposures across a lifetime. Topdown strategies are required to assess something this comprehensive, and could transform our understanding of how environmental factors affect human health. Metabolic profiling (metabonomics/metabolomics) defines an individual’s metabolic phenotype, which is influenced by genotype, diet, lifestyle, health and xenobiotic exposure, and could also reveal intermediate biomarkers...

Dead layer and active volume determination for GERDA Phase II detectors

Energy Technology Data Exchange (ETDEWEB)

Lehnert, Bjoern [TU Dresden (Germany); Collaboration: GERDA-Collaboration

2013-07-01

The GERDA experiment investigates the neutrinoless double beta decay of {sup 76}Ge and is currently running Phase I of its physics program. Using the same isotope as the Heidelberg Moscow (HDM) experiment, GERDA aims to directly test the claim of observation by a subset of the HDM collaboration. For the update to Phase II of the experiment in 2013, the collaboration organized the production of 30 new Broad Energy Germanium (BEGe) type detectors from original 35 kg enriched material and tested their performance in the low background laboratory HADES in SCK.CEN, Belgium. With additional 20 kg of detectors, GERDA aims to probe the degenerated hierarchy scenario. One of the crucial detector parameters is the active volume (AV) fraction which directly enters into all physics analysis. This talk presents the methodology of dead layer and AV determination with different calibration sources such as {sup 241}Am, {sup 133}Ba, {sup 60}Co and {sup 228}Th and the results obtained for the new Phase II detectors. Furthermore, the AV fraction turned out to be the largest systematic uncertainty in the analysis of Phase I data which makes it imperative to reduce its uncertainty for Phase II. This talk addresses the major contributions to the AV uncertainty and gives an outlook for improvements in Phase II analysis.

Chemical Screening for Bioactivated Electrophilic Metabolites Using Alginate Immobilization of Metabolic Enzymes (AIME) (SOT)

Science.gov (United States)

The US EPA's ToxCast program is designed to assess chemical perturbations of molecular and cellular endpoints using a variety of high-throughput screening (HTS) assays. However, existing HTS assays have limited or no xenobiotic metabolism which could lead to a mischaracterization...

Reassessing Phase II Heart Failure Clinical Trials: Consensus Recommendations

Science.gov (United States)

Butler, Javed; Hamo, Carine E.; Udelson, James E.; O’Connor, Christopher; Sabbah, Hani N.; Metra, Marco; Shah, Sanjiv J.; Kitzman, Dalane W.; Teerlink, John; Bernstein, Harold S.; Brooks, Gabriel; Depre, Christophe; DeSouza, Mary M.; Dinh, Wilfried; Donovan, Mark; Frische-Danielson, Regina; Frost, Robert J.; Garza, Dahlia; Gohring, Udo-Michael; Hellawell, Jennifer; Hsia, Judith; Ishihara, Shiro; Kay-Mugford, Patricia; Koglin, Joerg; Kozinn, Marc; Larson, Christopher J.; Mayo, Martha; Gan, Li-Ming; Mugnier, Pierrre; Mushonga, Sekayi; Roessig, Lothar; Russo, Cesare; Salsali, Afshin; Satler, Carol; Shi, Victor; Ticho, Barry; van der Laan, Michael; Yancy, Clyde; Stockbridge, Norman; Gheorghiade, Mihai

2017-01-01

The increasing burden and the continued suboptimal outcomes for patients with heart failure underlines the importance of continued research to develop novel therapeutics for this disorder. This can only be accomplished with successful translation of basic science discoveries into direct human application through effective clinical trial design and execution that results in a substantially improved clinical course and outcomes. In this respect, phase II clinical trials play a pivotal role in determining which of the multitude of potential basic science discoveries should move to the large and expansive registration trials in humans. A critical examination of the phase II trials in heart failure reveals multiple shortcomings in their concept, design, execution, and interpretation. To further a dialogue regarding the challenges and potential for improvement and the role of phase II trials in patients with heart failure, the Food and Drug Administration facilitated a meeting on October 17th 2016 represented by clinicians, researchers, industry members, and regulators. This document summarizes the discussion from this meeting and provides key recommendations for future directions. PMID:28356300

Modelling the Fate of Xenobiotic Trace Chemicals via Wastewater Treatment and Agricultural Resource Reuse

DEFF Research Database (Denmark)

Polesel, Fabio

the comprehension of XTC fate, and thus the predictive capabilities of fate models: (i) at process scale, with a focus on sorption and biological transformation of XTCs in biological treatment systems; (ii) in full-scale WWTPs, assessing the impact of retransformation and WWTP operation on XTC elimination; and (iii......) in integrated WWTP-agricultural systems. Different modelling tools, suiting the specific purposes of our investigations, were developed, extended and/or innovatively applied. Fate models used as reference in this thesis include: the Activated Sludge Modelling framework for Xenobiotics (ASM-X); the generic WWTP...... model SimpleTreat Activity; and the dynamic soil-plant model for fate prediction in agricultural systems. Experimental and model-based observations were combined to assess sorption of ionizable XTCs onto activated sludge and XTC biotransformation in moving bed biofilm reactors (MBBRs). Most XTCs...

Influence of xenobiotics on the microbiological and agrochemical parameters of soddy-podzolic soil

Science.gov (United States)

Vakkerov-Kouzova, N. D.

2010-08-01

We studied the influence of various chemical compounds, i.e., azobenzene (an insecticide and acaricide), nitrification inhibitors (DCD, dicyandiamide and DMPP, and 3,4-dimetylpyrazolphosphate), and inhibitors of urease activity (HQ-hydroquinone), on the agrochemical and microbiological parameters of a soddy-podzolic soil. It is proved that these xenobiotics are able to influence the agrochemical parameters (the pH and the content of NO{3/-} and NH{4/+}, the microbial activity (the basal respiration, the microbial mass carbon, and the microbial quotient), and the number of bacteria of different physiological groups in soddypodzolic soil. The influence of the xenobiotics was preserved for some time, which testified to their persistence in the soil. Upon cultivating the soil microorganisms in different media, the growth of the heterotrophic bacteria was inhibited, the radial growth velocity was slowed down, and the sporogenesis of the micromycetes was retarded. The toxic effect of the xenobiotics was higher with their increasing concentrations.

Does circadian disruption play a role in the metabolic-hormonal link to delayed lactogenesis II?

Directory of Open Access Journals (Sweden)

Manjie eFu

2015-02-01

Full Text Available Breastfeeding improves maternal and child health. The American Academy of Pediatrics recommends exclusive breastfeeding for six months, with continued breastfeeding for at least one year. However, in the US, only 18.8% of infants are exclusively breastfed until six months of age. For mothers who initiate breastfeeding, the early postpartum period sets the stage for sustained breastfeeding. Mothers who experience breastfeeding problems in the early postpartum period are more likely to discontinue breastfeeding within two weeks. A major risk factor for shorter breastfeeding duration is delayed lactogenesis II (i.e. onset of milk coming in more than 72 h postpartum. Recent studies report a metabolic-hormonal link to delayed lactogenesis II. This is not surprising because around the time of birth the mother’s entire metabolism changes to direct nutrients to mammary glands. Circadian and metabolic systems are closely linked, and our rodent studies suggest circadian clocks coordinate hormonal and metabolic changes to support lactation. Molecular and environmental disruption of the circadian system decreases a dam’s ability to initiate lactation and negatively impacts milk production. Circadian and metabolic systems evolved to be functional and adaptive when lifestyles and environmental exposures were quite different from modern times. We now have artificial lights, longer work days, and increases in shift work. Disruption in the circadian system due to shift work, jet lag, sleep disorders and other modern life style choices are associated with metabolic disorders, obesity, and impaired reproduction. We hypothesize delayed lactogenesis II is related to disruption of the mother’s circadian system. Here we review literature that supports this hypothesis, and describe interventions that may help to increase breastfeeding success.

A methodology for ranking and hazard identification of xenobiotic organic compounds in urban stormwater

DEFF Research Database (Denmark)

Baun, Anders; Eriksson, Eva; Ledin, Anna

2006-01-01

The paper presents a novel methodology (RICH, Ranking and Identification of Chemical Hazards) for ranking and identification of xenobiotic organic compounds of environmental concern in stormwater discharged to surface water. The RICHmethod is illustrated as a funnel fitted with different filters...... in hazard/risk assessments, a justified list of stormwater priority pollutants which must be included in hazard/risk assessments, and a list of compounds which may be present in discharged stormwater, but cannot be evaluated due to lack of data. The procedure was applied to 233 xenobiotic organic chemicals...... with xenobiotic organic compounds (XOCs) found in urban stormwater, but it may be transferred to other environmental compartments and problems. Thus, the RICH procedure can be used as a stand-alone tool for selection of potential priority pollutants or it can be integrated in larger priority setting frameworks....

Individualization of treatments with drugs metabolized by CES1: combining genetics and metabolomics

DEFF Research Database (Denmark)

Rasmussen, Henrik B.; Bjerre, Ditte; Linnet, Kristian

2015-01-01

CES1 is involved in the hydrolysis of ester group-containing xenobiotic and endobiotic compounds including several essential and commonly used drugs. The individual variation in the efficacy and tolerability of many drugs metabolized by CES1 is considerable. Hence, there is a large interest in in...

Apolipoprotein C-II and C-III metabolism in a kindred of familial hypobetalipoproteinemia

International Nuclear Information System (INIS)

Malmendier, C.L.; Delcroix, C.; Lontie, J.F.; Dubois, D.Y.

1991-01-01

Three affected members of a kindred with asymptomatic hypobetalipoproteinemia (HBL) showed low levels of triglycerides, low-density lipoprotein (LDL)-cholesterol, and apolipoproteins (apo) B, C-II, and C-III. Turnover of iodine-labeled apo C-II and apo C-III associated in vitro to plasma lipoproteins was studied after intravenous injection. Radioactivity in plasma and lipoproteins (95% recovered in high-density lipoprotein [HDL] density range) and in 24-hour urine samples was observed for 16 days. A parallelism of the slowest slopes of plasma decay curves was observed between apo C-II and apo C-III, indicating a partial common catabolic route. Urine/plasma radioactivity ratio (U/P) varied with time, suggesting heterogeneity of metabolic pathways. A new compartmental model using the SAAM program was built, not only fitting simultaneously plasma and urine data, but also taking into account the partial common metabolism of lipoprotein particles (LP) containing apo C-II and apo C-III. The low apo C-II and C-III plasma concentrations observed in HBL compared with normal resulted from both an increased catabolism and a reduced synthesis, these changes being more marked for apo C-III. The modifications in the rate constants of the different pathways calculated from the new model are in favor of an increased direct removal of particles following the fast pathway, likely in the very-low-density lipoprotein (VLDL) density range

Lightweight Thermally Stable Multi-Meter Aperture Submillimeter Reflectors, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — The objective of the Phase II effort will be an affordable demonstrated full-scale design for a thermally stable multi-meter submillimeter reflector. The Phase I...

Pressure Controlled Heat Pipe for Precise Temperature Control, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — The principal Phase II objective is to refine and further develop the prototype PCHP into a useful thermal management tool. The Phase I program established the...

Toward an Integrated Psychological Approach - Phase II

International Development Research Centre (IDRC) Digital Library (Canada)

Trauma, Development and Peacebuilding : Toward an Integrated Psychological Approach - Phase II. Over the past decade, the peace, conflict and development community has begun to question the value of medicalized approaches such as post-traumatic stress disorder (PTSD) in dealing with aftermath of political violence ...

Diagnosis-Driven Prognosis for Decision Making, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — In Phase II, the QSI-Vanderbilt team seeks to develop a system-level diagnostics and prognostic process that incorporates a "sense and respond capability," which...

Novel Instrumentation for Rocket Propulsion Systems, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — The objective of the proposed SBIR Phase II program is to develop, deploy and deliver novel laser-based instruments that provide rapid, in situ, simultaneous...

Mercury Oxidation via Catalytic Barrier Filters Phase II

Energy Technology Data Exchange (ETDEWEB)

Wayne Seames; Michael Mann; Darrin Muggli; Jason Hrdlicka; Carol Horabik

2007-09-30

In 2004, the Department of Energy National Energy Technology Laboratory awarded the University of North Dakota a Phase II University Coal Research grant to explore the feasibility of using barrier filters coated with a catalyst to oxidize elemental mercury in coal combustion flue gas streams. Oxidized mercury is substantially easier to remove than elemental mercury. If successful, this technique has the potential to substantially reduce mercury control costs for those installations that already utilize baghouse barrier filters for particulate removal. Completed in 2004, Phase I of this project successfully met its objectives of screening and assessing the possible feasibility of using catalyst coated barrier filters for the oxidation of vapor phase elemental mercury in coal combustion generated flue gas streams. Completed in September 2007, Phase II of this project successfully met its three objectives. First, an effective coating method for a catalytic barrier filter was found. Second, the effects of a simulated flue gas on the catalysts in a bench-scale reactor were determined. Finally, the performance of the best catalyst was assessed using real flue gas generated by a 19 kW research combustor firing each of three separate coal types.

Compact 2-Micron Transmitter for Remote Sensing Applications, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — In this Phase II effort we propose to work with NASA to extend the Phase I achievements, which focused on design and development of very compact master and...

Hyperglycemia and anthocyanin inhibit quercetin metabolism in HepG2 cells

Science.gov (United States)

A high glucose (Glu) milieu promotes generation of reactive oxygen species, which may not only cause cellular damage, but also modulate phase II enzymes that are responsible for the metabolism of flavonoids. Thus, we examined the effect of a high Glu milieu on quercetin (Q) metabolism in HepG2 cells...

Compact, High Accuracy CO2 Monitor, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — This Small Business Innovative Research Phase II proposal seeks to develop a low cost, robust, highly precise and accurate CO2 monitoring system. This system will...

Cytochrome P450 CYP1A1: wider roles in cancer progression and prevention

International Nuclear Information System (INIS)

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

2009-01-01

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

Justice at work and metabolic syndrome: the Whitehall II study.

Science.gov (United States)

Gimeno, David; Tabák, Adám G; Ferrie, Jane E; Shipley, Martin J; De Vogli, Roberto; Elovainio, Marko; Vahtera, Jussi; Marmot, Michael G; Kivimäki, Mika

2010-04-01

Growing evidence shows that high levels of justice are beneficial for employee health, although biological mechanisms underlying this association are yet to be clarified. We aim to test whether high justice at work protects against metabolic syndrome. A prospective cohort study of 20 civil service departments in London (the Whitehall II study) including 6123 male and female British civil servants aged 35-55 years without prevalent coronary heart disease at baseline (1985-1990). Perceived justice at work was determined by means of questionnaire on two occasions between 1985 and 1990. Follow-up for metabolic syndrome and its components occurring from 1990 to 2004 was based on clinical assessments on three occasions over more than 18 years. Cox proportional hazard models adjusted for age, ethnicity and employment grade showed that men who experienced a high level of justice at work had a lower risk of incident metabolic syndrome than employees with a low level of justice (HR 0.75; 95% CI 0.63 to 0.89). There was little evidence of an association between organisational justice and metabolic syndrome or its components in women (HR 0.88; 95% CI 0.67 to 1.17). Our prospective findings provide evidence of an association between high levels of justice at work and the development of metabolic syndrome in men.

Effect of CAR activation on selected metabolic pathways in normal and hyperlipidemic mouse livers.

Science.gov (United States)

Rezen, Tadeja; Tamasi, Viola; Lövgren-Sandblom, Anita; Björkhem, Ingemar; Meyer, Urs A; Rozman, Damjana

2009-08-19

Detoxification in the liver involves activation of nuclear receptors, such as the constitutive androstane receptor (CAR), which regulate downstream genes of xenobiotic metabolism. Frequently, the metabolism of endobiotics is also modulated, resulting in potentially harmful effects. We therefore used 1,4-Bis [2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) to study the effect of CAR activation on mouse hepatic transcriptome and lipid metabolome under conditions of diet-induced hyperlipidemia. Using gene expression profiling with a dedicated microarray, we show that xenobiotic metabolism, PPARalpha and adipocytokine signaling, and steroid synthesis are the pathways most affected by TCPOBOP in normal and hyperlipidemic mice. TCPOBOP-induced CAR activation prevented the increased hepatic and serum cholesterol caused by feeding mice a diet containing 1% cholesterol. We show that this is due to increased bile acid metabolism and up-regulated removal of LDL, even though TCPOBOP increased cholesterol synthesis under conditions of hyperlipidemia. Up-regulation of cholesterol synthesis was not accompanied by an increase in mature SREBP2 protein. As determined by studies in CAR -/- mice, up-regulation of cholesterol synthesis is however CAR-dependent; and no obvious CAR binding sites were detected in promoters of cholesterogenic genes. TCPOBOP also affected serum glucose and triglyceride levels and other metabolic processes in the liver, irrespective of the diet. Our data show that CAR activation modulates hepatic metabolism by lowering cholesterol and glucose levels, through effects on PPARalpha and adiponectin signaling pathways, and by compromising liver adaptations to hyperlipidemia.

Phase II beam lines at the National Synchrotron Light Source

International Nuclear Information System (INIS)

Thomlinson, W.

1984-06-01

The expansion of the National Synchrotron Light Source has been funded by the US Department of Energy. The Phase II program consists of both increased conventional facilities and six new beam lines. In this paper, an overview of the six beam lines which will be constructed during Phase II is presented. For five of the lines special radiation sources are necessary and the designs of four of the devices are complete. The relevant parameters of the insertion devices under construction and development are presented

Sears Point Tidal Marsh Restoration Project: Phase II

Science.gov (United States)

Information about the SFBWQP Sears Point Tidal Marsh Restoration Project: Phase II, part of an EPA competitive grant program to improve SF Bay water quality focused on restoring impaired waters and enhancing aquatic resources.

Study of the GERDA Phase II background spectrum

Science.gov (United States)

Agostini, M.; Allardt, M.; Bakalyarov, A. M.; Balata, M.; Barabanov, I.; Baudis, L.; Bauer, C.; Bellotti, E.; Belogurov, S.; Belyaev, S. T.; Benato, G.; Bettini, A.; Bezrukov, L.; Bode, T.; Borowicz, D.; Brudanin, V.; Brugnera, R.; Caldwell, A.; Cattadori, C.; Chernogorov, A.; D'Andrea, V.; Demidova, E. V.; Di Marco, N.; Domula, A.; Doroshkevich, E.; Egorov, V.; Falkenstein, R.; Frodyma, N.; Gangapshev, A.; Garfagnini, A.; Gooch, C.; Grabmayr, P.; Gurentsov, V.; Gusev, K.; Hakenmüller, J.; Hegai, A.; Heisel, M.; Hemmer, S.; Hofmann, W.; Hult, M.; Inzhechik, L. V.; Janicskó Csáthy, J.; Jochum, J.; Junker, M.; Kazalov, V.; Kihm, T.; Kirpichnikov, I. V.; Kirsch, A.; Kish, A.; Klimenko, A.; Kneißl, R.; Knöpfle, K. T.; Kochetov, O.; Kornoukhov, V. N.; Kuzminov, V. V.; Laubenstein, M.; Lazzaro, A.; Lebedev, V. I.; Lehnert, B.; Liao, H. Y.; Lindner, M.; Lippi, I.; Lubashevskiy, A.; Lubsandorzhiev, B.; Lutter, G.; Macolino, C.; Majorovits, B.; Maneschg, W.; Medinaceli, E.; Miloradovic, M.; Mingazheva, R.; Misiaszek, M.; Moseev, P.; Nemchenok, I.; Palioselitis, D.; Panas, K.; Pandola, L.; Pelczar, K.; Pullia, A.; Riboldi, S.; Rumyantseva, N.; Sada, C.; Salamida, F.; Salathe, M.; Schmitt, C.; Schneider, B.; Schönert, S.; Schreiner, J.; Schulz, O.; Schütz, A.-K.; Schwingenheuer, B.; Selivanenko, O.; Shevzik, E.; Shirchenko, M.; Simgen, H.; Smolnikov, A.; Stanco, L.; Vanhoefer, L.; Vasenko, A. A.; Veresnikova, A.; von Sturm, K.; Wagner, V.; Wegmann, A.; Wester, T.; Wiesinger, C.; Wojcik, M.; Yanovich, E.; Zhitnikov, I.; Zhukov, S. V.; Zinatulina, D.; Zuber, K.; Zuzel, G.

2017-09-01

The Gerda experiment, located at the Laboratori Nazionali del Gran Sasso (LNGS) of INFN in Italy, searches for the neutrinoless double beta (0νββ) decay of 76Ge. Gerda Phase II is aiming to reach a sensitivity for the 0νββ half life of 1026 yr in ˜ 3 years of physics data taking with 100 kg·yr of exposure and a background index of ˜ 10-3 cts/(keV·kg·yr). After 6 months of acquisition a first data release with 10.8 kg·yr of exposure is performed, showing that the design background is achieved. In this work a study of the Phase II background spectrum, the main spectral structures and the background sources will be presented and discussed.

Carboxylesterases in lipid metabolism: from mouse to human

Directory of Open Access Journals (Sweden)

Jihong Lian

2017-07-01

Full Text Available ABSTRACT Mammalian carboxylesterases hydrolyze a wide range of xenobiotic and endogenous compounds, including lipid esters. Physiological functions of carboxylesterases in lipid metabolism and energy homeostasis in vivo have been demonstrated by genetic manipulations and chemical inhibition in mice, and in vitro through (overexpression, knockdown of expression, and chemical inhibition in a variety of cells. Recent research advances have revealed the relevance of carboxylesterases to metabolic diseases such as obesity and fatty liver disease, suggesting these enzymes might be potential targets for treatment of metabolic disorders. In order to translate pre-clinical studies in cellular and mouse models to humans, differences and similarities of carboxylesterases between mice and human need to be elucidated. This review presents and discusses the research progress in structure and function of mouse and human carboxylesterases, and the role of these enzymes in lipid metabolism and metabolic disorders.

Status report of the Gerda Phase II startup

Science.gov (United States)

D'Andrea, Valerio; Gerda Collaboration

2017-01-01

The GERmanium Detector Array (GERDA) experiment, located at the Laboratori Nazionali del Gran Sasso (LNGS) of INFN, searches for 0νββ of 76Ge . Germanium diodes enriched to ˜ 86 % in the double beta emitter 76Ge ( enrGe are exposed being both source and detector of 0νββ decay. This process is considered a powerful probe to address still open issues in the neutrino sector of the (beyond) Standard Model of particle Physics. Since 2013, at the completion of the first experimental phase (Phase I), the GERDA setup has been upgraded to perform its next step (Phase II). The aim is to reach a sensitivity to the 0νββ decay half-life larger than 10^{26} yr in about 3 years of physics data taking, exposing a detector mass of about 35 kg of enrGe with a background index of about 10^{-3} cts/(keV . kg . yr). One of the main new implementations is the liquid argon (LAr) scintillation light read-out, to veto those events that only partially deposit their energy both in Ge and in the surrounding LAr. In this paper the GERDA Phase II expected goals, the upgraded items and few selected features from the first 2016 physics and calibration runs will be presented. The main Phase I achievements will be also reviewed.

UltraSail Solar Sail Flight Experiment, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — A team of CU Aerospace, the University of Illinois, and ManTech SRS Technologies proposes Phase II development of a 3 kg CubeSat spacecraft for initial flight test...

ABC transporters and xenobiotic defense systems in early life stages of rainbow trout (Oncorhynchus mykiss).

Science.gov (United States)

Kropf, Christian; Segner, Helmut; Fent, Karl

2016-01-01

Embryos of oviparous fish, in contrast to (ovo) viviparous species, develop in the aquatic environment, and therefore need solute transport systems at their body surfaces for maintaining internal homeostasis and defending against potentially harmful substances. We hypothesized that solute transporters undergo changes in tissue distribution from the embryo to the larval stage. We therefore studied the mRNA profiles of eight ABC transporters (abcb1a, abcb1b, abcc1, abcc2, abcc3, abcc4, abcc5, abcg2) and three solute carriers (oatp1d, putative oatp2 putative, mate1) in different body regions (head, yolk sac epithelium, abdominal viscera, skin/muscles) of developing rainbow trout. Additionally, we investigated mRNA levels of phase I (cyp1a, cyp3a) and phase II (gstp, putative ugt1, putative ugt2) biotransformation enzymes. The study covered the developmental period from the eleuthero-embryo stage to the first-feeding larval stage (1-20days post-hatch, dph). At 1dph, transcripts of abcc2, abcc4, abcg2, cyp3a, gstp, putative mate1, and putative oatp2 occurred primarily in the yolk sac epithelium, whereas at later stages expression of these genes was predominantly observed in the abdominal viscera. The functional activity of ABC transporters in fish early life stages was assessed by rhodamine B accumulation assays. Finally, we investigated the potential impact of xenobiotics (clotrimazole, clofibric acid) on the ABC and biotransformation systems of trout early life stages. While clofibric acid had no effect, clotrimazole lead to an increased rhodamine B accumulation. The results provide evidence that the transition from the eleuthero-embryo to the larval stage is accompanied by a major alteration in tissue expression of ABC transporters. Copyright © 2016 Elsevier Inc. All rights reserved.

Status of the GERDA Phase II upgrade

Science.gov (United States)

Wagner, Victoria

2016-06-01

The GERDA experiment is designed to search for neutrinoless double beta (0νββ) decay of 76Ge. In Phase I of the experiment a background index of 10-2 cts/(keV.kg.yr) was reached. A lower limit on the half-life of the 0νββ decay of 76Ge was set to 2.1.1025 yr (at 90% C.L.). The aim of Phase II is to reach a sensitivity of the half-life of about 1026 yr. To increase the exposure thirty new Broad Energy Germanium (BEGe) detectors have been produced. These detectors are distinct for their improved energy resolution and enhanced pulse shape discrimination of signal from background events. Further background reduction will be reached by a light instrumentation to read out argon scintillation light. In April 2015 the light instrumentation together with eight BEGe detectors has been successfully deployed in the GERDA cryostat. In a commissioning run it was shown that two of the major background components, external γ-rays from 214Bi and 208Tl decays, were suppressed up to two orders of magnitude. We are confident to reach a background index of 10-3 cts/(keV.kg.yr) which is the design goal for GERDA Phase II.

Testosterone metabolism in the estuarine mysid Neomysis integer (Crustacea; Mysidacea) following tributyltin exposure.

Science.gov (United States)

Verslycke, Tim; Poelmans, Sofie; De Wasch, Katia; Vercauteren, Jordy; Devos, Christophe; Moens, Luc; Sandra, Patrick; De Brabander, Hubert F; Janssen, Colin R

2003-09-01

Current evidence suggests that the biocide tributyltin (TBT) causes the development of imposex, a state of pseudohermaphrodism in which females exhibit functional secondary male characteristics, by altering the biotransformation or elimination of testosterone. Imposex in gastropods following TBT exposure is the most complete example of the effects of an endocrine disrupter on marine invertebrates. Previous studies have demonstrated that the estuarine mysid Neomysis integer converts testosterone into multiple polar and nonpolar metabolites resulting from both phase I and phase II biotransformations. In this study, the effects of TBT chloride (TBTCl) on the phase I and II testosterone metabolism of N. integer were evaluated. The TBTCl was highly toxic to N. integer (96-h median lethal concentration [LC50] of 164 ng/L). To assess the effects on testosterone metabolism, mysids were exposed for 96 h to different concentrations of TBTCl (control, 10, 100, and 1,000 ng/L), and testosterone elimination as polar hydroxylated, nonpolar oxido-reduced, and glucose- and sulfate-conjugated metabolites was examined. The TBTCl differentially affected testosterone metabolism. The effect of TBTCl on phase I metabolism was unclear and has been shown to vary among species, likely depending on the inducibility or presence of certain P450 isozyme families. Reductase activity and metabolic androgenization were induced in the 10-ng/L treatment, whereas higher concentrations resulted in a reduction of sulfate conjugation. The exact mechanisms underlying TBT-induced imposex and alterations in the steroid metabolism need to be further elucidated.

Solid-phase extraction of Mn(II), Co(II), Ni(II), Cu(II), Cd(II) and Pb(II) ions from environmental samples by flame atomic absorption spectrometry (FAAS)

Energy Technology Data Exchange (ETDEWEB)

Duran, Celal [Department of Chemistry, Faculty of Art and Science, Karadeniz Technical University, 61080 Trabzon (Turkey); Gundogdu, Ali [Department of Chemistry, Faculty of Art and Science, Karadeniz Technical University, 61080 Trabzon (Turkey); Bulut, Volkan Numan [Department of Chemistry, Giresun Faculty of Art and Science, Karadeniz Technical University, 28049 Giresun (Turkey); Soylak, Mustafa [Department of Chemistry, Faculty of Art and Science, Erciyes University, 38039 Kayseri (Turkey)]. E-mail: soylak@erciyes.edu.tr; Elci, Latif [Department of Chemistry, Faculty of Art and Science, Pamukkale University, 20020 Denizli (Turkey); Sentuerk, Hasan Basri [Department of Chemistry, Faculty of Art and Science, Karadeniz Technical University, 61080 Trabzon (Turkey); Tuefekci, Mehmet [Department of Chemistry, Faculty of Art and Science, Karadeniz Technical University, 61080 Trabzon (Turkey)

2007-07-19

A new method using a column packed with Amberlite XAD-2010 resin as a solid-phase extractant has been developed for the multi-element preconcentration of Mn(II), Co(II), Ni(II), Cu(II), Cd(II), and Pb(II) ions based on their complex formation with the sodium diethyldithiocarbamate (Na-DDTC) prior to flame atomic absorption spectrometric (FAAS) determinations. Metal complexes sorbed on the resin were eluted by 1 mol L{sup -1} HNO{sub 3} in acetone. Effects of the analytical conditions over the preconcentration yields of the metal ions, such as pH, quantity of Na-DDTC, eluent type, sample volume and flow rate, foreign ions etc. have been investigated. The limits of detection (LOD) of the analytes were found in the range 0.08-0.26 {mu}g L{sup -1}. The method was validated by analyzing three certified reference materials. The method has been applied for the determination of trace elements in some environmental samples.

Enhanced tolerance and remediation of anthracene by transgenic tobacco plants expressing a fungal glutathione transferase gene

International Nuclear Information System (INIS)

Dixit, Prachy; Mukherjee, Prasun K.; Sherkhane, Pramod D.; Kale, Sharad P.; Eapen, Susan

2011-01-01

Highlights: → Transgenic plants expressing a TvGST gene were tested for tolerance, uptake and degradation of anthracene. → Transgenic plants were more tolerant to anthracene and take up more anthracene from soil and solutions compared to control plants. → Using in vitro T 1 seedlings, we showed that anthracene-a three fused benzene ring compound was phytodegraded to naphthalene derivatives, having two benzene rings. → This is the first time that a transgenic plant was shown to have the potential to phytodegrade anthracene. - Abstract: Plants can be used for remediation of polyaromatic hydrocarbons, which are known to be a major concern for human health. Metabolism of xenobiotic compounds in plants occurs in three phases and glutathione transferases (GST) mediate phase II of xenobiotic transformation. Plants, although have GSTs, they are not very efficient for degradation of exogenous recalcitrant xenobiotics including polyaromatic hydrocarbons. Hence, heterologous expression of efficient GSTs in plants may improve their remediation and degradation potential of xenobiotics. In the present study, we investigated the potential of transgenic tobacco plants expressing a Trichoderma virens GST for tolerance, remediation and degradation of anthracene-a recalcitrant polyaromatic hydrocarbon. Transgenic plants with fungal GST showed enhanced tolerance to anthracene compared to control plants. Remediation of 14 C uniformly labeled anthracene from solutions and soil by transgenic tobacco plants was higher compared to wild-type plants. Transgenic plants (T 0 and T 1 ) degraded anthracene to naphthalene derivatives, while no such degradation was observed in wild-type plants. The present work has shown that in planta expression of a fungal GST in tobacco imparted enhanced tolerance as well as higher remediation potential of anthracene compared to wild-type plants.

Metabolism of nasally instilled benzo(a)pyrene and dihydrosafrole in dogs and monkeys

International Nuclear Information System (INIS)

Petridou-Fischer, J.; Whaley, S.; Dahl, A.

1987-01-01

Cytochrome P-450 monooxygenases are found in the nasal cavities of a variety of species and could play an important role in the metabolism of inhaled airborne xenobiotics. The object of this study was to examine the metabolism of 14 C-benzo(a)pyrene (BaP) and 3 H-dihydrosafrole (DHS) deposited at the ethmoid and maxillary turbinate regions in Beagle dogs and Cynomolgus monkeys. While the animals were anesthetized, either compound was instilled at 10 minute intervals for 2 hours through catheters positioned at each region. Cotton swab samples of mucus from the nasopharynx were collected at 30 minute intervals during instillation. Metabolites in mucus were identified using high pressure liquid chromatography. Results showed that both regions in both species were capable of metabolizing BaP and DHS. BaP metabolites identified in the mucus were dihydrodiols, quinones, phenols, and tetrols. DHS metabolites were 2-methoxy-4-propyl-phenol, 2-methoxy-4-(2-propenyl)benzene, and 3,4-methylenedioxy-1-(1-hydroxypropyl)benzene. Radioactivity was found in urine and feces of animals treated with either compound, and was detected in the blood of animals treated with DHS. No differences were noted for the nasal metabolism between the two species. This study indicated that not only the nasal tissues, but also the alimentary tract, may be exposed to metabolites of inhaled xenobiotics carried by the mucus

Functional proteomic analysis of corticosteroid pharmacodynamics in rat liver: Relationship to hepatic stress, signaling, energy regulation, and drug metabolism.

Science.gov (United States)

Ayyar, Vivaswath S; Almon, Richard R; DuBois, Debra C; Sukumaran, Siddharth; Qu, Jun; Jusko, William J

2017-05-08

Corticosteroids (CS) are anti-inflammatory agents that cause extensive pharmacogenomic and proteomic changes in multiple tissues. An understanding of the proteome-wide effects of CS in liver and its relationships to altered hepatic and systemic physiology remains incomplete. Here, we report the application of a functional pharmacoproteomic approach to gain integrated insight into the complex nature of CS responses in liver in vivo. An in-depth functional analysis was performed using rich pharmacodynamic (temporal-based) proteomic data measured over 66h in rat liver following a single dose of methylprednisolone (MPL). Data mining identified 451 differentially regulated proteins. These proteins were analyzed on the basis of temporal regulation, cellular localization, and literature-mined functional information. Of the 451 proteins, 378 were clustered into six functional groups based on major clinically-relevant effects of CS in liver. MPL-responsive proteins were highly localized in the mitochondria (20%) and cytosol (24%). Interestingly, several proteins were related to hepatic stress and signaling processes, which appear to be involved in secondary signaling cascades and in protecting the liver from CS-induced oxidative damage. Consistent with known adverse metabolic effects of CS, several rate-controlling enzymes involved in amino acid metabolism, gluconeogenesis, and fatty-acid metabolism were altered by MPL. In addition, proteins involved in the metabolism of endogenous compounds, xenobiotics, and therapeutic drugs including cytochrome P450 and Phase-II enzymes were differentially regulated. Proteins related to the inflammatory acute-phase response were up-regulated in response to MPL. Functionally-similar proteins showed large diversity in their temporal profiles, indicating complex mechanisms of regulation by CS. Clinical use of corticosteroid (CS) therapy is frequent and chronic. However, current knowledge on the proteome-level effects of CS in liver and

Metagenomic analysis of an ecological wastewater treatment plant's microbial communities and their potential to metabolize pharmaceuticals.

Science.gov (United States)

Balcom, Ian N; Driscoll, Heather; Vincent, James; Leduc, Meagan

2016-01-01

Pharmaceuticals and other micropollutants have been detected in drinking water, groundwater, surface water, and soil around the world. Even in locations where wastewater treatment is required, they can be found in drinking water wells, municipal water supplies, and agricultural soils. It is clear conventional wastewater treatment technologies are not meeting the challenge of the mounting pressures on global freshwater supplies. Cost-effective ecological wastewater treatment technologies have been developed in response. To determine whether the removal of micropollutants in ecological wastewater treatment plants (WWTPs) is promoted by the plant-microbe interactions, as has been reported for other recalcitrant xenobiotics, biofilm microbial communities growing on the surfaces of plant roots were profiled by whole metagenome sequencing and compared to the microbial communities residing in the wastewater. In this study, the concentrations of pharmaceuticals and personal care products (PPCPs) were quantified in each treatment tank of the ecological WWTP treating human wastewater at a highway rest stop and visitor center in Vermont. The concentrations of detected PPCPs were substantially greater than values reported for conventional WWTPs likely due to onsite recirculation of wastewater. The greatest reductions in PPCPs concentrations were observed in the anoxic treatment tank where Bacilli dominated the biofilm community. Benzoate degradation was the most abundant xenobiotic metabolic category identified throughout the system. Collectively, the microbial communities residing in the wastewater were taxonomically and metabolically more diverse than the immersed plant root biofilm. However, greater heterogeneity and higher relative abundances of xenobiotic metabolism genes was observed for the root biofilm.

Why is coronary collateral growth impaired in type II diabetes and the metabolic syndrome?

Science.gov (United States)

Rocic, Petra

2012-01-01

Type II diabetes and the metabolic syndrome are strong predictors of severity of occlusive coronary disease and poorer outcomes of coronary revascularization therapies. Coronary collateral growth can provide an alternative or accessory pathway of revascularization. However, collateral growth is impaired in type II diabetes and the metabolic syndrome. Although many factors necessary for collateral growth are known and many interventions have shown promising results in animal studies, not a single attempt to induce coronary collateral growth in human clinical trials has led to satisfactory results. Accordingly, the first part of this review outlines the known deleterious effects of diabetes and the metabolic syndrome on factors necessary for collateral growth, including pro-angiogenic growth factors, endothelial function, the redox state of the coronary circulation, intracellular signaling, leukocytes and bone marrow-derived progenitors cells. The second section highlights the gaps in our current knowledge of how these factors interact with the radically altered environment of the coronary circulation in diabetes and the metabolic syndrome. The interplay between these pathologies and inadequately explored areas related to the temporal regulation of collateral remodeling and the roles of the extracellular matrix, vascular cell phenotype and pro-inflammatory cytokines are emphasized with implications to development of efficient therapies. PMID:22342811

Ultraflat Tip-Tilt-Piston MEMS Deformable Mirror, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — This proposal describes a Phase II SBIR project to develop high-resolution, ultraflat micromirror array devices using advanced silicon surface micromachining...

Steam generator tube integrity program: Phase II, Final report

Energy Technology Data Exchange (ETDEWEB)

Kurtz, R.J.; Bickford, R.L.; Clark, R.A.; Morris, C.J.; Simonen, F.A.; Wheeler, K.R.

1988-08-01

The Steam Generator Tube Integrity Program (SGTIP) was a three phase program conducted for the US Nuclear Regulatory Commission (NRC) by Pacific Northwest Laboratory (PNL). The first phase involved burst and collapse testing of typical steam generator tubing with machined defects. The second phase of the SGTIP continued the integrity testing work of Phase I, but tube specimens were degraded by chemical means rather than machining methods. The third phase of the program used a removed-from-service steam generator as a test bed for investigating the reliability and effectiveness of in-service nondestructive eddy-current inspection methods and as a source of service degraded tubes for validating the Phase I and Phase II data on tube integrity. This report describes the results of Phase II of the SGTIP. The object of this effort included burst and collapse testing of chemically defected pressurized water reactor (PWR) steam generator tubing to validate empirical equations of remaining tube integrity developed during Phase I. Three types of defect geometries were investigated: stress corrosion cracking (SCC), uniform thinning and elliptical wastage. In addition, a review of the publicly available leak rate data for steam generator tubes with axial and circumferential SCC and a comparison with an analytical leak rate model is presented. Lastly, nondestructive eddy-current (EC) measurements to determine accuracy of defect depth sizing using conventional and alternate standards is described. To supplement the laboratory EC data and obtain an estimate of EC capability to detect and size SCC, a mini-round robin test utilizing several firms that routinely perform in-service inspections was conducted.

Steam generator tube integrity program: Phase II, Final report

International Nuclear Information System (INIS)

Kurtz, R.J.; Bickford, R.L.; Clark, R.A.; Morris, C.J.; Simonen, F.A.; Wheeler, K.R.

1988-08-01

The Steam Generator Tube Integrity Program (SGTIP) was a three phase program conducted for the US Nuclear Regulatory Commission (NRC) by Pacific Northwest Laboratory (PNL). The first phase involved burst and collapse testing of typical steam generator tubing with machined defects. The second phase of the SGTIP continued the integrity testing work of Phase I, but tube specimens were degraded by chemical means rather than machining methods. The third phase of the program used a removed-from-service steam generator as a test bed for investigating the reliability and effectiveness of in-service nondestructive eddy-current inspection methods and as a source of service degraded tubes for validating the Phase I and Phase II data on tube integrity. This report describes the results of Phase II of the SGTIP. The object of this effort included burst and collapse testing of chemically defected pressurized water reactor (PWR) steam generator tubing to validate empirical equations of remaining tube integrity developed during Phase I. Three types of defect geometries were investigated: stress corrosion cracking (SCC), uniform thinning and elliptical wastage. In addition, a review of the publicly available leak rate data for steam generator tubes with axial and circumferential SCC and a comparison with an analytical leak rate model is presented. Lastly, nondestructive eddy-current (EC) measurements to determine accuracy of defect depth sizing using conventional and alternate standards is described. To supplement the laboratory EC data and obtain an estimate of EC capability to detect and size SCC, a mini-round robin test utilizing several firms that routinely perform in-service inspections was conducted

DrugMetZ DB: an anthology of human drug metabolizing Chytochrome P450 enzymes.

Science.gov (United States)

Antony, Tresa Remya Thomas; Nagarajan, Shanthi

2006-11-14

Understandings the basics of Cytochrome P450 (P450 or CYP) will help to discern drug metabolism. CYP, a super-family of heme-thiolate proteins, are found in almost all living organisms and is involved in the biotransformation of a diverse range of xenobiotics, therapeutic drugs and toxins. Here, we describe DrugMetZ DB, a database for CYP metabolizing drugs. The DB is implemented in MySQL, PHP and HTML. www.bicpu.edu.in/DrugMetZDB/

Reconfigurable L-band Radar Transceiver using Digital Signal Synthesis, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — This Phase II proposal, builds upon the extensive research and digital radar design that has been successfully completed during the Phase I contract. Key innovations...

Single Photon Sensitive HgCdTe Avalanche Photodiode Detector (APD), Phase II

Data.gov (United States)

National Aeronautics and Space Administration — Leveraging Phase I SBIR successes, in Phase II, a single photon sensitive LIDAR receiver will be fabricated and delivered to NASA. In Phase I, high-gain,...

Metabolic studies of Hg-203 on chlamydomonas reinhardi

International Nuclear Information System (INIS)

Macka, W.; Stehlik, G.; Wihlidal, H.; Washuettl, J.; Bancher, E.

1977-09-01

Vegetative cultures of the green algae Chlamydomonas reinhardi WT + in the log-phase reduce mercury(II)-nitrate to elemental mercury which is removed from the cell suspension by the stream of gas bubbling through it. Monomethyl and dimethyl mercury as intermediate metabolic compounds are to be excluded, because none of them could be found in the algae, the nutrient medium or the gas phase. (author)

Status report of the Gerda Phase II startup

International Nuclear Information System (INIS)

D’Andrea, Valerio

2017-01-01

The GERmanium Detector Array (Gerda) experiment, located at the Laboratori Nazionali del Gran Sasso (LNGS) of INFN, searches for 0νββ of "7"6Ge. Germanium diodes enriched to ∼ 86 % in the double beta emitter "7"6Ge ("e"n"rGe) are exposed being both source and detector of 0νββ decay. This process is considered a powerful probe to address still open issues in the neutrino sector of the (beyond) Standard Model of particle Physics. Since 2013, at the completion of the first experimental phase (Phase I), the Gerda setup has been upgraded to perform its next step (Phase II). The aim is to reach a sensitivity to the 0νββ decay half life larger than 10"2"6 yr in about 3 years of physics data taking, exposing a detector mass of about 35 kg of "e"n"rGe with a background index of about 10"−"3cts/(keV·kg·yr). One of the main new implementations is the liquid argon (LAr) scintillation light read-out, to veto those events that only partially deposit their energy both in Ge and in the surrounding LAr. In this paper the Gerda Phase II expected goals, the upgraded items and few selected features from the first 2016 physics and calibration runs will be presented. The main Phase I achievements will be also reviewed.

LHC Experiments Phase II - TDRs Approval Process

CERN Document Server

Forti, F

2017-01-01

The overall review process and steps of Phase II were described in CERN-LHCC-2015-077. As experiments submit detailed technical design reports (TDRs), the LHCC and UCG work in close connection to ensure a timely review of the scientific and technical feasibility as well as of the budget and schedule of the upgrade programme.

Shape Memory Alloy-Based Periodic Cellular Structures, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — This SBIR Phase II effort will continue to develop and demonstrate an innovative shape memory alloy (SMA) periodic cellular structural technology. Periodic cellular...

Status of the GERDA Phase II upgrade

Energy Technology Data Exchange (ETDEWEB)

Wagner, Victoria [Max-Planck-Insitut für Kernphysik, Heidelberg (Germany)

2016-06-21

The GERDA experiment is designed to search for neutrinoless double beta (0νββ) decay of {sup 76}Ge. In Phase I of the experiment a background index of 10{sup −2} cts/(keV·kg·yr) was reached. A lower limit on the half-life of the 0νββ decay of {sup 76}Ge was set to 2.1·10{sup 25} yr (at 90% C.L.). The aim of Phase II is to reach a sensitivity of the half-life of about 10{sup 26} yr. To increase the exposure thirty new Broad Energy Germanium (BEGe) detectors have been produced. These detectors are distinct for their improved energy resolution and enhanced pulse shape discrimination of signal from background events. Further background reduction will be reached by a light instrumentation to read out argon scintillation light. In April 2015 the light instrumentation together with eight BEGe detectors has been successfully deployed in the GERDA cryostat. In a commissioning run it was shown that two of the major background components, external γ-rays from {sup 214}Bi and {sup 208}Tl decays, were suppressed up to two orders of magnitude. We are confident to reach a background index of 10{sup −3} cts/(keV·kg·yr) which is the design goal for GERDA Phase II.

Status of the GERDA Phase II upgrade

International Nuclear Information System (INIS)

Wagner, Victoria

2016-01-01

The GERDA experiment is designed to search for neutrinoless double beta (0νββ) decay of "7"6Ge. In Phase I of the experiment a background index of 10"−"2 cts/(keV·kg·yr) was reached. A lower limit on the half-life of the 0νββ decay of "7"6Ge was set to 2.1·10"2"5 yr (at 90% C.L.). The aim of Phase II is to reach a sensitivity of the half-life of about 10"2"6 yr. To increase the exposure thirty new Broad Energy Germanium (BEGe) detectors have been produced. These detectors are distinct for their improved energy resolution and enhanced pulse shape discrimination of signal from background events. Further background reduction will be reached by a light instrumentation to read out argon scintillation light. In April 2015 the light instrumentation together with eight BEGe detectors has been successfully deployed in the GERDA cryostat. In a commissioning run it was shown that two of the major background components, external γ-rays from "2"1"4Bi and "2"0"8Tl decays, were suppressed up to two orders of magnitude. We are confident to reach a background index of 10"−"3 cts/(keV·kg·yr) which is the design goal for GERDA Phase II.

Instrument for Airborne Measurement of Carbonyl Sulfide, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — In this Phase II SBIR program, Southwest Sciences will continue the development of small, low power instrumentation for real-time direct measurement of carbonyl...

High Radiation Resistance Inverted Metamorphic Solar Cell, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — The innovation in this SBIR Phase II project is the development of a unique triple junction inverted metamorphic technology (IMM), which will enable the...

Multi-Channel Tunable Source for Atomic Sensors, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — This Phase II SBIR will seek to develop a prototype laser source suitable for atomic interferometry from compact, robust, integrated components. AdvR's design is...

Organ slices as an in vitro test system for drug metabolism in human liver, lung and kidney

NARCIS (Netherlands)

Olinga, Peter; de Jager, M.H; Meijer, D.K F; Groothuis, Geny; Merema, M.T.

1999-01-01

Metabolism of xenobiotics occurs mainly in the liver, but in addition, the lungs and kidneys may contribute considerably. The choice of the animal species during drug development as a predictive model for the human condition is often inadequate due to large interspecies differences. Therefore, a

The NEA Forum on Stakeholder Confidence - Phase I Lessons and Phase II Activities

Energy Technology Data Exchange (ETDEWEB)

Brown, Peter [Natural Resources Canada, Ottawa (Canada). Uranium and Radioactive Waste Div.; Pescatore, Claudio [Nuclear Energy Agency, Paris (France)

2006-09-15

The Forum on Stakeholder Confidence (FSC) was created under a mandate from the OECD Nuclear Energy Agency (NEA) Radioactive Waste Management Committee (RWMC) to facilitate the sharing of international experience in addressing the societal dimension of radioactive waste management. It explores means of ensuring an effective dialogue with the public, and considers ways to strengthen confidence in decision-making processes. The Forum was launched in August 2000 and completed its first phase in 00 . Major findings and principles for action were published under the title of 'Learning and Adapting to Societal Requirements'. Activities of the FSC were also reported at Valdor 2003. In the second mandate of the FSC, there is continued use of a variety of tools and formats to allow dialogue among stakeholders in an atmosphere of mutual trust: national workshops and community visits, topical sessions, and desk and interview studies. In Phase II, the FSC is exploring: the link between research, development and demonstration and stakeholder confidence; cultural and organisational changes in RWM institutions; the role of media relations and outreach opportunities; tools and processes to help society prepare and manage decisions through stakeholder involvement; and increasing the value of waste management facilities to local communities. Workshops have been held in Germany and Spain. A large set of publications makes both Phase I and Phase II findings widely available.

The NEA Forum on Stakeholder Confidence - Phase I Lessons and Phase II Activities

International Nuclear Information System (INIS)

Brown, Peter

2006-01-01

The Forum on Stakeholder Confidence (FSC) was created under a mandate from the OECD Nuclear Energy Agency (NEA) Radioactive Waste Management Committee (RWMC) to facilitate the sharing of international experience in addressing the societal dimension of radioactive waste management. It explores means of ensuring an effective dialogue with the public, and considers ways to strengthen confidence in decision-making processes. The Forum was launched in August 2000 and completed its first phase in 00 . Major findings and principles for action were published under the title of 'Learning and Adapting to Societal Requirements'. Activities of the FSC were also reported at Valdor 2003. In the second mandate of the FSC, there is continued use of a variety of tools and formats to allow dialogue among stakeholders in an atmosphere of mutual trust: national workshops and community visits, topical sessions, and desk and interview studies. In Phase II, the FSC is exploring: the link between research, development and demonstration and stakeholder confidence; cultural and organisational changes in RWM institutions; the role of media relations and outreach opportunities; tools and processes to help society prepare and manage decisions through stakeholder involvement; and increasing the value of waste management facilities to local communities. Workshops have been held in Germany and Spain. A large set of publications makes both Phase I and Phase II findings widely available

Insights into CYP2B6-mediated drug–drug interactions

Directory of Open Access Journals (Sweden)

William D. Hedrich

2016-09-01

Full Text Available Mounting evidence demonstrates that CYP2B6 plays a much larger role in human drug metabolism than was previously believed. The discovery of multiple important substrates of CYP2B6 as well as polymorphic differences has sparked increasing interest in the genetic and xenobiotic factors contributing to the expression and function of the enzyme. The expression of CYP2B6 is regulated primarily by the xenobiotic receptors constitutive androstane receptor (CAR and pregnane X receptor (PXR in the liver. In addition to CYP2B6, these receptors also mediate the inductive expression of CYP3A4, and a number of important phase II enzymes and drug transporters. CYP2B6 has been demonstrated to play a role in the metabolism of 2%–10% of clinically used drugs including widely used antineoplastic agents cyclophosphamide and ifosfamide, anesthetics propofol and ketamine, synthetic opioids pethidine and methadone, and the antiretrovirals nevirapine and efavirenz, among others. Significant inter-individual variability in the expression and function of the human CYP2B6 gene exists and can result in altered clinical outcomes in patients receiving treatment with CYP2B6-substrate drugs. These variances arise from a number of sources including genetic polymorphism, and xenobiotic intervention. In this review, we will provide an overview of the key players in CYP2B6 expression and function and highlight recent advances made in assessing clinical ramifications of important CYP2B6-mediated drug–drug interactions.

Recession-Tolerant Sensors for Thermal Protection Systems, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — The Phase II project will develop a suite of diagnostic sensors using Direct Write technology to measure temperature, surface recession depth, and heat flux of an...

Androgen metabolism in invertebrates and its modulation by xenoandrogens: a comparative study.

Science.gov (United States)

Janer, G; Leblanc, G A; Porte, C

2005-04-01

Marisa cornuarietis (Mollusc), Hyalella azteca (Crustacean), and Paracentrotus lividus (Echinoderm) demonstrated the ability to metabolize androgens through different pathways catalyzed by 5alpha-reductases (5alpha-R), hydroxysteroid dehydrogenases (HSD), hydroxylases, sulfotransferases (SULT), and fatty-acid acyl-CoA acyltransferases (ATAT). Interspecies differences and tissue-specific distribution of those enzymatic activities were observed. Xenobiotics, such as triphenyltin, tributyltin, and fenarimol, interfered with some of the pathways studied, namely, testosterone sulfation, testosterone esterification, and 5alpha-R activity. The work evidenced different sensitivity of those pathways to androgenic compounds, together with interphyla differences in androgen metabolism.

Development of ceramics based fuel, Phase II; Razvoj goriva na bazi keramike, II faza

Energy Technology Data Exchange (ETDEWEB)

Ristic, M M [Institute of Nuclear Sciences Vinca, Laboratorija za reaktorske materijale, Beograd (Serbia and Montenegro)

1962-12-15

Phase II of this task covers the following: testing the changes of UO{sub 2} properties during sintering; interpretation of results obtained from the analysis of the sintering process kinetics; fabrication of UO{sub 2} samples with cladding by vibrational compacting.

Ground Processing Optimization Using Artificial Intelligence Techniques, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — The ultimate goal is the automation of a large amount of KSC's planning, scheduling, and execution decision making. Phase II will result in a complete full-scale...

Lightweight Metal RubberTM Sensors and Interconnects, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — The objective of this NASA Phase II program is to develop and increase the Technology Readiness Level of multifunctional Metal RubberTM (MRTM) materials that can be...

16th Carbonyl Metabolism Meeting: from enzymology to genomics

Directory of Open Access Journals (Sweden)

Maser Edmund

2012-12-01

Full Text Available Abstract The 16th International Meeting on the Enzymology and Molecular Biology of Carbonyl Metabolism, Castle of Ploen (Schleswig-Holstein, Germany, July 10–15, 2012, covered all aspects of NAD(P-dependent oxido-reductases that are involved in the general metabolism of xenobiotic and physiological carbonyl compounds. Starting 30 years ago with enzyme purification, structure elucidation and enzyme kinetics, the Carbonyl Society members have meanwhile established internationally recognized enzyme nomenclature systems and now consider aspects of enzyme genomics and enzyme evolution along with their roles in diseases. The 16th international meeting included lectures from international speakers from all over the world.

Performance of the LAr scintillation veto of GERDA Phase II

Energy Technology Data Exchange (ETDEWEB)

Wiesinger, Christoph [Technische Universitaet Muenchen, Physik Dept. E15, James-Franck-Strasse, 85748 Garching (Germany); Collaboration: GERDA-Collaboration

2015-07-01

Gerda is an experiment to search for the neutrinoless double beta decay in {sup 76}Ge. Results of Phase I have been published in summer 2013 and Gerda is upgraded to Phase II. To reach the aspired background index of ≤ 10{sup -3} cts/(keV.kg.yr) for Phase II active background-suppression techniques are applied, including an active liquid argon (LAr) veto. It has been demonstrated with the LArGe test facility that the detection of argon scintillation light can be used to effectively suppress background events in the germanium, which simultaneously deposit energy in the LAr. The light instrumentation consisting of photomultiplier tubes (PMT) and wavelength-shifting fibers connected to silicon multipliers (SiPM) has been installed in Gerda. In this talk the low background design of the LAr veto and its performance during the commissioning runs are reported.

The SafeBoosC phase II clinical trial

DEFF Research Database (Denmark)

Riera, Joan; Hyttel-Sorensen, Simon; Bravo, María Carmen

2016-01-01

BACKGROUND: The SafeBoosC phase II randomised clinical trial recently demonstrated the benefits of a combination of cerebral regional tissue oxygen saturation (rStO2) by near-infrared spectroscopy (NIRS) and a treatment guideline to reduce the oxygen imbalance in extremely preterm infants. AIMS: ...

Effect of Blood Glucose Fluctuation on Some Trace Elements and Aldosterone Hormone among Type II Diabetic Patients with Metabolic Syndrome

International Nuclear Information System (INIS)

Ezz El-Arab, A.; El Fouly, A.H.; Mahmoud, H.H.

2014-01-01

There is accumulating evidence determine that the metabolism of some trace elements is altered in diabetes mellitus (DM) type II. The current study aimed to evaluate the effect of serum blood glucose fluctuation during (Random, Fasting and Postprandial 2 hours state) on some trace elements such as Cadmium (Cd), Chromium (Cr), Manganese (Mn), Magnesium (Mg), Zinc (Zn), Copper (Cu), Sodium (Na), Potassium (K), and Aldosterone hormone in type II Diabetic patients associated with metabolic syndrome in comparison with healthy volunteers. The International Diabetes Federation (IFD) consensus the diagnosis of metabolic syndrome according to central obesity, lipid profile, blood glucose level and blood pressure. A significant change was observed in trace elements level (Cd, Cr, Mg, Mn, Zn, Cu, Na, and K) and Aldosterone hormone as a result of glucose fluctuation among type II diabetic patients.

Advanced Technology Cloud Particle Probe for UAS, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — In Phase II SPEC will design, fabricate and flight test a state-of-the-art combined cloud particle probe called the Hawkeye. Hawkeye is the culmination of two...

Composite Structure Monitoring using Direct Write Sensors, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — This NASA SBIR Phase II project seeks to develop and demonstrate a suite of sensor products to monitor the health of composite structures. Sensors will be made using...

Improved Lunar and Martian Regolith Simulant Production, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — The technical objective of the Phase II project is to provide a more complete investigation of the long-term needs of the simulant community based on the updated...

Evidence for induction of cytochrome P-450I in patients with tropical chronic pancreatitis.

Science.gov (United States)

Chaloner, C; Sandle, L N; Mohan, V; Snehalatha, C; Viswanathan, M; Braganza, J M

1990-06-01

Theophylline kinetics, as an in vivo probe for the potentially toxic cytochrome P-450I pathway of drug metabolism, were studied in 11 healthy volunteers and 11 patients with calcific chronic pancreatitis at Madras, South India. Theophylline clearance was faster in the patients than controls [median 69 (range 39-114) vs 45 (33-56) ml h-1 kg-1, p = 0.003]. In keeping with this finding, detailed social histories identified a higher exposure level in the patients to xenobiotics that are inducers of cytochrome P-450I and/or yield reactive metabolites upon processing thereby (score 7, 4-11 vs 3, 2-9, p = 0.002). However, the concentration of D-glucaric acid in urine, as a marker of phase II conjugating pathways of drug metabolism, was similar in patients and controls. This pattern of drug metabolism could predispose to oxidant stress: hence micronutrient antioxidant supplements may have therapeutic (or even prophylactic) value in tropical chronic pancreatitis.

Xenobiotic Modulation of Human Mammary Epithelial Cell Gap Junctional Intercellular Communication and Growth

National Research Council Canada - National Science Library

Ruch, Randall

1999-01-01

.... These agents also inhibit gap junctional intercellular communication (GJIC). This inhibition may contribute to the enhancement of breast epithelial growth and breast cancer formation by xenobiotics...

TNX GeoSiphon Cell (TGSC-1) Phase II Single Cell Deployment/Demonstration Final Report

Energy Technology Data Exchange (ETDEWEB)

Phifer, M.A.

1999-04-15

This Phase II final report documents the Phase II testing conducted from June 18, 1998 through November 13, 1998, and it focuses on the application of the siphon technology as a sub-component of the overall GeoSiphon Cell technology. [Q-TPL-T-00004

Spray Forming Aluminum - Final Report (Phase II)

Energy Technology Data Exchange (ETDEWEB)

D. D. Leon

1999-07-08

The U.S. Department of Energy - Office of Industrial Technology (DOE) has an objective to increase energy efficient and enhance competitiveness of American metals industries. To support this objective, ALCOA Inc. entered into a cooperative program to develop spray forming technology for aluminum. This Phase II of the DOE Spray Forming Program would translate bench scale spray forming technology into a cost effective world class process for commercialization. Developments under DOE Cooperative Agreement No. DE-FC07-94ID13238 occurred during two time periods due to budgetary constraints; April 1994 through September 1996 and October 1997 and December 1998. During these periods, ALCOA Inc developed a linear spray forming nozzle and specific support processes capable of scale-up for commercial production of aluminum sheet alloy products. Emphasis was given to alloys 3003 and 6111, both being commercially significant alloys used in the automotive industry. The report reviews research performed in the following areas: Nozzel Development, Fabrication, Deposition, Metal Characterization, Computer Simulation and Economics. With the formation of a Holding Company, all intellectual property developed in Phases I and II of the Project have been documented under separate cover for licensing to domestic producers.

Magnetically-modified natural biogenic iron oxides for organic xenobiotics removal

Czech Academy of Sciences Publication Activity Database

Šafařík, Ivo; Filip, J.; Horská, Kateřina; Nowakova, M.; Tuček, J.; Šafaříková, Miroslava; Hashimoto, H.; Takada, J.; Zbořil, R.

2015-01-01

Roč. 12, č. 2 (2015), s. 673-682 ISSN 1735-1472 R&D Projects: GA MŠk(CZ) LH11111; GA MŠk LH12190 Institutional support: RVO:67179843 Keywords : Biogenic iron oxides * Leptothrix ochracea * Magnetic fluid * Magnetic adsorbents * Xenobiotics Subject RIV: EI - Biotechnology ; Bionics Impact factor: 2.344, year: 2015

Involvement of hepatic xenobiotic related genes in bromadiolone resistance in wild Norway rats, Rattus norvegicus (Berk.)

DEFF Research Database (Denmark)

Markussen, Mette Drude; Heiberg, Ann-Charlotte; Alsbo, Carsten

2007-01-01

To examine the role of xenobiotic relevant genes in bromadiolone resistance in wild Norway rats (Rattus norvegicus) we compared the constitutive liver gene expression and expression upon bromadiolone administration in bromadiolone resistant and anticoagulant susceptible female rats using a LNA...... expressed in resistant than susceptible rats upon bromadiolone exposure. To establish how bromadiolone affected xenobiotic gene expression in the two strains we compared bromadiolone expression profiles to saline profiles of both strains. Bromadiolone mediated significant up-regulation of Cyp2e1 and Cyp3a3...... expression in the resistant rats whereas the rodenticide conferred down-regulation of Cyp2e1, Cyp3a3 and Gpox1 and induction of Cyp2c12 expression in susceptible rats. Cyp2c13 and Cyp3a2 expression were markedly suppressed in both strains upon treatment. This suggests that xenobiotic relevant enzymes play...

Space Qualified Non-Destructive Evaluation and Structural Health Monitoring Technology, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — Encouraged by Phase I accomplishments, the proposed Phase II program will significantly mature and align the development of a Space Qualified Non-Destructive...

Solid phase selective separation and preconcentration of Cu(II) by Cu(II)-imprinted polymethacrylic microbeads.

Science.gov (United States)

Dakova, Ivanka; Karadjova, Irina; Ivanov, Ivo; Georgieva, Ventsislava; Evtimova, Bisera; Georgiev, George

2007-02-12

Ion-imprinted polymer (IIP) particles are prepared by copolymerization of methacrylic acid as monomer, trimethylolpropane trimethacrylate as crosslinking agent and 2,2'-azo-bis-isobutyronitrile as initiator in the presence of Cu(II), a Cu(II)-4-(2-pyridylazo)resorcinol (Cu(II)-PAR) complex, and PAR only. A batch procedure is used for the determination of the characteristics of the Cu(II) solid phase extraction from the IIP produced. The results obtained show that the Cu(II)-PAR IIP has the greatest adsorption capacity (37.4 micromol g(-1) of dry copolymer) among the IIPs investigated. The optimal pH value for the quantitative preconcentration is 7, and full desorption is achieved by 1 M HNO(3). The selectivity coefficients (S(Cu/Me)) for Me=Ni(II), Co(II) are 45.0 and 38.5, respectively. It is established that Cu(II)-PAR IIPs can be used repeatedly without a considerable adsorption capacity loss. The determination of Cu(II) ions in seawater shows that the interfering matrix does not influence the preconcentration and selectivity values of the Cu(II)-PAR IIPs. The detection and quantification limits are 0.001 micromol L(-1) (3sigma) and 0.003 micromol L(-1) (6sigma), respectively.

South Bay Salt Pond Restoration, Phase II at Ravenswood

Science.gov (United States)

Information about the South Bay Salt Pond Restoration Project: Phase II Construction at Ravenswood, part of an EPA competitive grant program to improve SF Bay water quality focused on restoring impaired waters and enhancing aquatic resources.

InGaN High Temperature Photovoltaic Cells, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — The objectives of this Phase II project are to develop InGaN photovoltaic cells for high temperature and/or high radiation environments to TRL 4 and to define the...

Cash Impact of the Consumable Item Transfer, Phase II

National Research Council Canada - National Science Library

1998-01-01

...). This report is the third in a series of reports regarding the consumable item transfer (CIT), phase II. The Deputy Secretary of Defense directed the transfer of the management of consumable items to Defense Logistics Agency...

A Tool for Predicting Regulatory Approval After Phase II Testing of New Oncology Compounds.

Science.gov (United States)

DiMasi, J A; Hermann, J C; Twyman, K; Kondru, R K; Stergiopoulos, S; Getz, K A; Rackoff, W

2015-11-01

We developed an algorithm (ANDI) for predicting regulatory marketing approval for new cancer drugs after phase II testing has been conducted, with the objective of providing a tool to improve drug portfolio decision-making. We examined 98 oncology drugs from the top 50 pharmaceutical companies (2006 sales) that first entered clinical development from 1999 to 2007, had been taken to at least phase II development, and had a known final outcome (research abandonment or regulatory marketing approval). Data on safety, efficacy, operational, market, and company characteristics were obtained from public sources. Logistic regression and machine-learning methods were used to provide an unbiased approach to assess overall predictability and to identify the most important individual predictors. We found that a simple four-factor model (activity, number of patients in the pivotal phase II trial, phase II duration, and a prevalence-related measure) had high sensitivity and specificity for predicting regulatory marketing approval. © 2015 American Society for Clinical Pharmacology and Therapeutics.

ANALYSIS OF POLYMORPHISM OF THE GENES OF THE PHASE II OF XENOBIOTICS BIOTRANSFORMATION (GSTM1, GSTT1 IN THE SHORIANS AND ALIEN POPULATION OF THE KEMEROVO REGION: THE PROBLEM OF THE DIFFERENCES IN MORTALITY RATE FROM MALIGNANT NEOPLASMS

Directory of Open Access Journals (Sweden)

Фаина Анисимовна Лузина

2017-10-01

Conclusions. The reduced frequency of the deletion variants of the genes of xenobiotics biotransformation (GSTM1, GSTT1 in the Shorians allows predicting the risk of disease incidence and mortality rates from oncologic pathology at the population level. Under the same ecological conditions of the urban environment mortality rates from MNP among the Shorians occupy a lower rank in the structure of the main classes of death causes in the comparison with the population of Novokuznetsk.

Mechanical Engineering and Design of the LHC Phase II Collimators

CERN Document Server

Bertarelli, A; Gentini, L; Mariani, N; Perret, R; Timmins, M A

2010-01-01

Phase II collimators will complement the existing system to improve the expected high RF impedance and limited efficiency of Phase I jaws. An international collaborative effort has been launched to identify novel advanced materials responding to the very challenging requirements of the new collimators. Complex numerical calculations simulating extreme conditions and experimental tests are in progress. In parallel, an innovative modular design concept of the jaw assembly is being developed to allow fitting in alternative materials, minimizing the thermally induced deformations, withstanding accidents and accepting high radiation doses. Phase II jaw assembly is made up of a molybdenum back-stiffener ensuring high geometrical stability and a modular jaw split in threes sectors. Each sector is equipped with a high-efficiency independent cooling circuit. Beam position monitors (BPM) are embedded in the jaws to fasten setup time and improve beam monitoring. An adjustment system will permit to fine-tune the jaw flat...

Investigation of runoff generation from anthropogenic sources with dissolved xenobiotics

Science.gov (United States)

Krein, A.; Pailler, J.; Guignard, C.; Iffly, J.; Pfister, L.; Hoffmann, L.

2009-04-01

In the experimental Mess basin (35 km2, Luxembourg) dissolved xenobiotics in surface water are used to study the influences of anthropogenic sources like separated sewer systems on runoff generation. Emerging contaminants like pharmaceuticals are of growing interest because of their use in large quantities in human and veterinary medicine. The amounts reaching surface waters depend on rainfall patterns, hydraulic conditions, consumption, metabolism, degradation, and disposal. The behaviour of endocrine disruptors including pharmaceuticals in the aquatic environment is widely unknown. The twelve molecules analyzed belong to three families: the estrogens, the antibiotics (sulfonamides, tetracyclines), and the painkillers (ibuprofen, diclofenac). Xenobiotics can be used as potential environmental tracers for untreated sewerage. Our results show that the concentrations are highly variable during flood events. The highest concentrations are reached in the first flush period, mainly during the rising limb of the flood hydrographs. As a result of the kinematic wave effect the concentration peak occurs in some cases a few hours after the discharge maximum. In floodwater (eleven floods, 66 samples) the highest concentrations were measured for ibuprofen (g/l range), estrone, and diclofenac (all ng/l range). From the tetracycline group, essentially tetracycline itself is of relevance, while the sulfonamides are mainly represented by sulfamethoxazole (all in ng/l range). In the Mess River the pharmaceuticals fluxes during flood events proved to be influenced by hydrological conditions. Different pharmaceuticals showed their concentration peaks during different times of a flood event. An example is the estrone peak that - during summer flash floods - often occurred one to two hours prior to the largest concentrations of the painkillers. This suggests for more sources than the sole storm drainage through the spillway of the single sewage water treatment plant, different

Acute Phase Proteins and Variables of Protein Metabolism in Dairy Cows during the Pre- and Postpartal Period

Directory of Open Access Journals (Sweden)

Cs. Tóthová

2008-01-01

Full Text Available The objective of the present study was to compare the concentrations of acute phase proteins and selected variables of protein metabolism in dairy cows of the Slovak Spotted breed from 4 weeks before parturition to 10 weeks after parturition. Acute phase proteins - haptoglobin (Hp and serum amyloid A (SAA - and variables of protein metabolism - total proteins, albumin, urea, creatinine, total immunoglobulins - were evaluated in blood serum. Significant differences were found in average values of the Hp and SAA concentrations in several groups during the monitored period (P P P P P P P P P < 0.001. The above mentioned results indicate that in the time around parturition there are significant changes in concentrations of acute phase proteins, as well as in the whole protein metabolism of dairy cows. These facts suggest that the postparturient period is a critical biological phase, throughout which there is the highest incidence of metabolic disorders.

Enhanced tolerance and remediation of anthracene by transgenic tobacco plants expressing a fungal glutathione transferase gene

Energy Technology Data Exchange (ETDEWEB)

Dixit, Prachy; Mukherjee, Prasun K.; Sherkhane, Pramod D.; Kale, Sharad P. [Nuclear Agriculture and Biotechnology Division, Bhabha Atomic Research Centre, Mumbai 400085 (India); Eapen, Susan, E-mail: eapenhome@yahoo.com [Nuclear Agriculture and Biotechnology Division, Bhabha Atomic Research Centre, Mumbai 400085 (India)

2011-08-15

Highlights: {yields} Transgenic plants expressing a TvGST gene were tested for tolerance, uptake and degradation of anthracene. {yields} Transgenic plants were more tolerant to anthracene and take up more anthracene from soil and solutions compared to control plants. {yields} Using in vitro T{sub 1} seedlings, we showed that anthracene-a three fused benzene ring compound was phytodegraded to naphthalene derivatives, having two benzene rings. {yields} This is the first time that a transgenic plant was shown to have the potential to phytodegrade anthracene. - Abstract: Plants can be used for remediation of polyaromatic hydrocarbons, which are known to be a major concern for human health. Metabolism of xenobiotic compounds in plants occurs in three phases and glutathione transferases (GST) mediate phase II of xenobiotic transformation. Plants, although have GSTs, they are not very efficient for degradation of exogenous recalcitrant xenobiotics including polyaromatic hydrocarbons. Hence, heterologous expression of efficient GSTs in plants may improve their remediation and degradation potential of xenobiotics. In the present study, we investigated the potential of transgenic tobacco plants expressing a Trichoderma virens GST for tolerance, remediation and degradation of anthracene-a recalcitrant polyaromatic hydrocarbon. Transgenic plants with fungal GST showed enhanced tolerance to anthracene compared to control plants. Remediation of {sup 14}C uniformly labeled anthracene from solutions and soil by transgenic tobacco plants was higher compared to wild-type plants. Transgenic plants (T{sub 0} and T{sub 1}) degraded anthracene to naphthalene derivatives, while no such degradation was observed in wild-type plants. The present work has shown that in planta expression of a fungal GST in tobacco imparted enhanced tolerance as well as higher remediation potential of anthracene compared to wild-type plants.

Yeast and mammalian metabolism continuous monitoring by using pressure recording as an assessment technique for xenobiotic agent effects

Science.gov (United States)

Milani, Marziale; Ballerini, Monica; Ferraro, Lorenzo; Marelli, E.; Mazza, Francesca; Zabeo, Matteo

2002-06-01

Our work is devoted to the study of Saccharomyces cerevisiae and human lymphocytes cellular metabolism in order to develop a reference model to assess biological systems responses to chemical or physical agents exposure. CO2 variations inside test-tubes are measured by differential pressure sensors; pressure values are subsequently converted in voltage. The system allows to test up to 16 samples at the same time. Sampling manages up to 100 acquisitions per second. Values are recorded by a data acquisition card connected to a computer. This procedure leads to a standard curve (pressure variation versus time), typical of the cellular line, that describe cellular metabolism. The longest time lapse used is of 170 h. Different phases appear in this curve: an initial growth up to a maximum, followed by a decrement that leads to a typical depression (pressure value inside the test-tubes is lower than the initial one) after about 35 h from the beginning of yeast cells. The curve is reproducible within an experimental error of 4%. The analysis of many samples and the low cost of the devices allow a good statistical significance of the data. In particular as a test we will compare two sterilizing agents effects: UV radiation and amuchina.

Post Process Characterization of Friction Stir Welded Components, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — Luna Innovations Incorporated proposes in this STTR Phase II project to continue development and validation of Luna's amplitude-dependent, nonlinear ultrasonic...

Photosystem II excitation pressure and photosynthetic carbon metabolism in Chlorella vulgaris

International Nuclear Information System (INIS)

Savitch, L.V.; Maxwell, D.P.; Huner, N.P.A.

1996-01-01

Chlorella vulgaris grown at 5 degrees C/150 micromoles m -2 s -1 mimics cells grown under high irradiance (27 degrees C/2200 micromoles m -2 s -1 ). This has been rationalized through the suggestion that both populations of cells were exposed to comparable photosystem II (PSII) excitation pressures measured as the chlorophyll a fluorescence quenching parameter, 1 - qP (D.P. Maxwell, S. Falk, N.P.A. Huner [1995] Plant Physiol 107: 687-694). To assess the possible role(s) of feedback mechanisms on PSII excitation pressure, stromal and cytosolic carbon metabolism were examined. Sucrose phosphate synthase and fructose-1,6-bisphosphatase activities as well as the ratios of fructose-1,6-bisphosphate/fructose-6 phosphate and sucrose/starch indicated that cells grown at 27 degrees C/2200 micromoles m -2 s -1 appeared to exhibit a restriction in starch metabolism. In contrast, cells grown at 5 degrees C/150 micromoles-1 m -2 s -1 appeared to exhibit a restriction in the sucrose metabolism based on decreased cytosolic fructose-1,6-bisphosphatase and sucrose phosphate synthase activities as well as a low sucrose/starch ratio. These metabolic restrictions may feedback on photosynthetic electron transport and, thus, contribute to the observed PSII excitation pressure. We conclude that, although PSII excitation pressure may reflect redox regulation of photosynthetic acclimation to light and temperature in C. vulgaris, it cannot be considered the primary redox signal. Alternative metabolic sensing/signaling mechanisms are discussed

LAr instrumentation for Gerda phase II

Energy Technology Data Exchange (ETDEWEB)

Wegmann, Anne [Max-Planck-Institut fuer Kernphysik, Heidelberg (Germany); Collaboration: GERDA-Collaboration

2015-07-01

Gerda is an experiment to search for the neutrinoless double beta decay of {sup 76}Ge. Results of Phase I have been published in summer 2013. Currently the commissioning of Gerda Phase II is ongoing. To reach the aspired background index of ≤10{sup -3} cts/(keV.kg.yr) active background-suppression techniques will be applied, including an active liquid argon veto (LAr veto). It has been demonstrated by the LArGe test facility that the detection of argon scintillation light can be used to effectively suppress background events in the germanium, which simultaneously deposit energy in LAr. The light instrumentation consisting of photomultiplier tubes (PMT) and wavelength-shifting fibers connected to silicon multipliers (SiPM) has been installed in Gerda. In this talk the low background design of the LAr veto and its performance during the commissioning runs are reported.

Stability of cytochromes P450 and phase II conjugation systems in precision-cut rat lung slices cultured up to 72 h.

Science.gov (United States)

Umachandran, Meera; Ioannides, Costas

2006-07-05

The objective of the present study was to evaluate the stability of cytochrome P450 enzymes and of the conjugation enzyme systems epoxide hydrolase, glucuronosyl transferase, sulphotransferase and glutathione S-transferase in precision-cut rat lung slices incubated in RPMI media for different time periods up to 72 h. Moreover, the effect of culturing of lung slices on total glutathione levels and glutathione reductase was also investigated. Monitoring of cytochrome P450 activity was achieved using established diagnostic probes, but when activity in the lung was low the maintenance of the various enzymes in culture was determined immunologically using Western blotting. The dealkylation of pentoxyresorufin declined markedly during the first 4h of incubation but in the case of ethoxyresorufin loss of activity was more gradual and less severe. Western blot analysis revealed that the rate of decrease in cytochrome P450 apoprotein levels was isoform-specific with CYP2E1 being the most stable and CYP3A the least stable. Generally, phase II activities, especially cytosolic sulphotransferase, were relatively more stable throughout the incubation period compared with cytochromes P450. Finally, glutathione reductase activity and total glutathione levels were maintained throughout the 72 h incubation. The present studies indicate that xenobiotic-metabolising enzymes in precision-cut rat lung slices decline in culture, but the rate of loss differs and depends on the nature of the enzyme.

Bile Acid Metabolism and Signaling

Science.gov (United States)

Chiang, John Y. L.

2015-01-01

Bile acids are important physiological agents for intestinal nutrient absorption and biliary secretion of lipids, toxic metabolites, and xenobiotics. Bile acids also are signaling molecules and metabolic regulators that activate nuclear receptors and G protein-coupled receptor (GPCR) signaling to regulate hepatic lipid, glucose, and energy homeostasis and maintain metabolic homeostasis. Conversion of cholesterol to bile acids is critical for maintaining cholesterol homeostasis and preventing accumulation of cholesterol, triglycerides, and toxic metabolites, and injury in the liver and other organs. Enterohepatic circulation of bile acids from the liver to intestine and back to the liver plays a central role in nutrient absorption and distribution, and metabolic regulation and homeostasis. This physiological process is regulated by a complex membrane transport system in the liver and intestine regulated by nuclear receptors. Toxic bile acids may cause inflammation, apoptosis, and cell death. On the other hand, bile acid-activated nuclear and GPCR signaling protects against inflammation in liver, intestine, and macrophages. Disorders in bile acid metabolism cause cholestatic liver diseases, dyslipidemia, fatty liver diseases, cardiovascular diseases, and diabetes. Bile acids, bile acid derivatives, and bile acid sequestrants are therapeutic agents for treating chronic liver diseases, obesity, and diabetes in humans. PMID:23897684

Options Study - Phase II

Energy Technology Data Exchange (ETDEWEB)

R. Wigeland; T. Taiwo; M. Todosow; W. Halsey; J. Gehin

2010-09-01

The Options Study has been conducted for the purpose of evaluating the potential of alternative integrated nuclear fuel cycle options to favorably address the issues associated with a continuing or expanding use of nuclear power in the United States. The study produced information that can be used to inform decisions identifying potential directions for research and development on such fuel cycle options. An integrated nuclear fuel cycle option is defined in this study as including all aspects of the entire nuclear fuel cycle, from obtaining natural resources for fuel to the ultimate disposal of used nuclear fuel (UNF) or radioactive wastes. Issues such as nuclear waste management, especially the increasing inventory of used nuclear fuel, the current uncertainty about used fuel disposal, and the risk of nuclear weapons proliferation have contributed to the reluctance to expand the use of nuclear power, even though it is recognized that nuclear power is a safe and reliable method of producing electricity. In this Options Study, current, evolutionary, and revolutionary nuclear energy options were all considered, including the use of uranium and thorium, and both once-through and recycle approaches. Available information has been collected and reviewed in order to evaluate the ability of an option to clearly address the challenges associated with the current implementation and potential expansion of commercial nuclear power in the United States. This Options Study is a comprehensive consideration and review of fuel cycle and technology options, including those for disposal, and is not constrained by any limitations that may be imposed by economics, technical maturity, past policy, or speculated future conditions. This Phase II report is intended to be used in conjunction with the Phase I report, and much information in that report is not repeated here, although some information has been updated to reflect recent developments. The focus in this Options Study was to

Multifunctional Metal/Polymer Composite Fiber for Space Applications, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — In this Small Business Innovation Research Phase II Program, Syscom Technology, Inc. will implement an integrated processing scheme to fabricate a conductive...

Biotransformation and induction: implications for toxicity, bioaccumulation and monitoring of environmental xenobiotics in fish

International Nuclear Information System (INIS)

Kleinow, K.M.; Melancon, M.J.; Lech, J.J.

1987-01-01

Biotransformation of xenobiotics in fish occurs by many of the same reactions as in mammals. These reactions have been shown to affect the bioaccumulation, persistence, residue dynamics, and toxicity of select chemicals in fish. P-450-dependent monooxygenase activity of fish can be induced by polycyclic aromatic hydrocarbons, but phenobarbital-type agents induce poorly, if at all. Fish monooxygenase activity exhibits ideal temperature compensation and sex-related variation. Induction of monooxygenase activity by polycyclic aromatic hydrocarbons can result in qualitative as well as quantitative changes in the metabolic profile of a chemical. Induction can also alter toxicity. In addition, multiple P-450 isozymes have been described for several fish species. The biotransformation productions of certain chemicals have been related to specific P-450 isozymes, and the formation of these products can be influenced by induction. Exposure of fish to low levels of certain environmental contaminants has resulted in induction of specific monooxygenase activities and monitoring of such activities has been suggested as a means of identifying areas of pollutant exposure in the wild

A Nanodroplet Processor for Advanced Microencapsulated Drug Formulations, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — During this Phase II program we propose to build on the key aspects of the nanodroplet encapsulation technology to demonstrate optimized formulation and...

Nature and Nurture in the Early-Life Origins of Metabolic Syndrome.

Science.gov (United States)

Gonzalez-Bulnes, Antonio; Astiz, Susana; Ovilo, Cristina; Garcia-Contreras, Consolacion; Vazquez-Gomez, Marta

The combination of genetic background together with food excess and lack of exercise has become the cornerstone of metabolic disorders associated to lifestyle. The scenario is furthermore reinforced by their interaction with other environmental factors (stress, sleeping patterns, education, culture, rural versus urban locations, and xenobiotics, among others) inducing epigenetic changes in the exposed individuals. The immediate consequence is the development of further alterations like obesity and metabolic syndrome, and other adverse health conditions (type-2 diabetes, cardiovascular diseases, cancer, reproductive, immune and neurological disorders). Thus, having in mind the impact of the metabolic syndrome on the worldwide public health, the present review affords the relative roles and the interrelationships of nature (genetic predisposition to metabolic syndrome) and nurture (lifestyle and environmental effects causing epigenetic changes), on the establishment of the metabolic disorders in women; disorders that may evolve to metabolic syndrome prior or during pregnancy and may be transmitted to their descendants.

Animal bioavailability of defined xenobiotic lignin metabolites

International Nuclear Information System (INIS)

Sandermann, H. Jr.; Arjmand, M.; Gennity, I.; Winkler, R.; Struble, C.B.; Aschbacher, P.W.

1990-01-01

Lignin has been recognized as a major component of bound pesticide residues in plants and is thought to be undigestible in animals. Two defined ring-U- 14 C-labeled chloroaniline/lignin metabolites have now been fed to rats, where a release of ∼66% of the bound xenobiotic occurred in the form of simple chloroaniline derivatives. The observed high degree of bioavailability indicates that bound pesticidal residues may possess ecotoxicological significance. In parallel studies, the white-rot fungus Phanerochaete chrysosporium was more efficient, and a soil system was much less efficient, in the degradation of the [ring-U- 14 C]chloroaniline/lignin metabolites

Project NOAH: Regulating modern sea-level rise. Phase II: Jerusalem Underground

Science.gov (United States)

Newman, Walter S.; Fairbridge, Rhodes W.

This proposal builds a high-speed inter-urban express between Jerusalem and Tel Aviv, generates 1500 megawatts of hydroelectric energy, curtails littoral erosion, builds a port along the Israeli Mediterranean coast and demands peaceful cooperation on both sides of the Jordan River. Phase II represents a pilot project demonstrating the feasibility of continuing to regulate world sea-level by a new series of water regulation schemes. Phase I previously described all those projects already completed or underway which have inadvertently and/or unintentionally served the purpose of sea-level regulation. These forms of Phase I sea-level regulation include large and small reservoirs, irrigation projects, water infiltration schemes, farm ponds, and swimming and reflecting pools. All these water storage projects have already exercised a very appreciable brake on 20th century sea-level rise. Phase II outlines a high-visibility proposal which will serve to illustrate the viability of “Project NOAH”.

The fetal/neonatal mouse liver exhibits transcriptional features of the adult pancreas.

Science.gov (United States)

Metabolic homeostasis of the organism is maintained by the liver’s ability to detoxify and eliminate xenobiotics through the expression of xenobiotic metabolism enxymes (XME). The fetus and neonate have been hypothesized to exhibit increased sensitivity to xenobiotic toxicity. T...

ColoLipidGene: signature of lipid metabolism-related genes to predict prognosis in stage-II colon cancer patients

Science.gov (United States)

Vargas, Teodoro; Moreno-Rubio, Juan; Herranz, Jesús; Cejas, Paloma; Molina, Susana; González-Vallinas, Margarita; Mendiola, Marta; Burgos, Emilio; Aguayo, Cristina; Custodio, Ana B.; Machado, Isidro; Ramos, David; Gironella, Meritxell; Espinosa-Salinas, Isabel; Ramos, Ricardo; Martín-Hernández, Roberto; Risueño, Alberto; De Las Rivas, Javier; Reglero, Guillermo; Yaya, Ricardo; Fernández-Martos, Carlos; Aparicio, Jorge; Maurel, Joan; Feliu, Jaime; de Molina, Ana Ramírez

2015-01-01

Lipid metabolism plays an essential role in carcinogenesis due to the requirements of tumoral cells to sustain increased structural, energetic and biosynthetic precursor demands for cell proliferation. We investigated the association between expression of lipid metabolism-related genes and clinical outcome in intermediate-stage colon cancer patients with the aim of identifying a metabolic profile associated with greater malignancy and increased risk of relapse. Expression profile of 70 lipid metabolism-related genes was determined in 77 patients with stage II colon cancer. Cox regression analyses using c-index methodology was applied to identify a metabolic-related signature associated to prognosis. The metabolic signature was further confirmed in two independent validation sets of 120 patients and additionally, in a group of 264 patients from a public database. The combined analysis of these 4 genes, ABCA1, ACSL1, AGPAT1 and SCD, constitutes a metabolic-signature (ColoLipidGene) able to accurately stratify stage II colon cancer patients with 5-fold higher risk of relapse with strong statistical power in the four independent groups of patients. The identification of a group of 4 genes that predict survival in intermediate-stage colon cancer patients allows delineation of a high-risk group that may benefit from adjuvant therapy, and avoids the toxic and unnecessary chemotherapy in patients classified as low-risk group. PMID:25749516

FALSIRE Phase II. CSNI project for Fracture Analyses of Large-Scale International Reference Experiments (Phase II). Comparison report

International Nuclear Information System (INIS)

Sievers, J.; Schulz, H.; Bass, R.; Pugh, C.; Keeney, J.

1996-11-01

A summary of Phase II of the Project for Fracture Analysis of Large-Scale International Reference Experiments (FALSIRE) is presented. A FALSIRE II Workshop focused on analyses of reference fracture experiments. More than 30 participants representing 22 organizations from 12 countries took part in the workshop. Final results for 45 analyses of the reference experiments were received from the participating analysts. For each experiment, analysis results provided estimates of variables that include temperature, crack-mouth-opening displacement, stress, strain, and applied K and J values. The data were sent electronically to the Organizing Committee, who assembled the results into a comparative data base using a special-purpose computer program. A comparative assessment and discussion of the analysis results are presented in the report. Generally, structural responses of the test specimens were predicted with tolerable scatter bands. (orig./DG)

Multifunctional Aerogel Thermal Protection Systems for Hypersonic Vehicles, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — The overall objective of the Phase II project is to develop lightweight reinforced aerogel materials for use as the core structural insulation material in...

Prediction of cytochrome P450 mediated metabolism

DEFF Research Database (Denmark)

Olsen, Lars; Oostenbrink, Chris; Jørgensen, Flemming Steen

2015-01-01

Cytochrome P450 enzymes (CYPs) form one of the most important enzyme families involved in the metabolism of xenobiotics. CYPs comprise many isoforms, which catalyze a wide variety of reactions, and potentially, a large number of different metabolites can be formed. However, it is often hard...... to rationalize what metabolites these enzymes generate. In recent years, many different in silico approaches have been developed to predict binding or regioselective product formation for the different CYP isoforms. These comprise ligand-based methods that are trained on experimental CYP data and structure...

Phase I and II feasibility study report for the 300-FF-5 operable unit

Energy Technology Data Exchange (ETDEWEB)

NONE

1993-12-31

The purpose of this Phase I/II feasibility study is to assemble and screen a list of alternatives for remediation of the 300-FF-5 operable site on the Hanford Reservation. This screening is based on information gathered in the Phase I Remedial Investigation (RI) and on currently available information on remediation technologies. The alternatives remaining after screening provide a range of response actions for remediation. In addition, key data needs are identified for collection during a Phase II RI (if necessary). This Phase I/II FS represents a primary document as defined by the Tri-Party Agreement, but will be followed by a Phase III FS that will further develop the alternatives and provide a detailed evaluation of them. The following remedial action objectives were identified for the 300-FF-5 operable unit: Limit current human exposure to contaminated groundwater in the unit; Limit discharge of contaminated groundwater to the Columbia River; Reduce contaminant concentrations in groundwater below acceptable levels by the year 2018.

Phase I and II feasibility study report for the 300-FF-5 operable unit

International Nuclear Information System (INIS)

1993-01-01

The purpose of this Phase I/II feasibility study is to assemble and screen a list of alternatives for remediation of the 300-FF-5 operable site on the Hanford Reservation. This screening is based on information gathered in the Phase I Remedial Investigation (RI) and on currently available information on remediation technologies. The alternatives remaining after screening provide a range of response actions for remediation. In addition, key data needs are identified for collection during a Phase II RI (if necessary). This Phase I/II FS represents a primary document as defined by the Tri-Party Agreement, but will be followed by a Phase III FS that will further develop the alternatives and provide a detailed evaluation of them. The following remedial action objectives were identified for the 300-FF-5 operable unit: Limit current human exposure to contaminated groundwater in the unit; Limit discharge of contaminated groundwater to the Columbia River; Reduce contaminant concentrations in groundwater below acceptable levels by the year 2018

Deployable Engine Air-Brake for Drag Management Applications, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — ATA Engineering, Inc., (ATA) proposes a Phase II SBIR program to demonstrate an innovative engine air-brake (EAB) technology that uses a deployable swirl vane...

Small Business Innovation Research, Post-Phase II Opportunity Assessment

Science.gov (United States)

Nguyen, Hung D.; Steele, Gynelle C.

2015-01-01

This report outlines current Small Business Innovation Research (SBIR) Post-Phase II opportunity contract award results for the SBIR technology program from 2007 to 2011 for NASA's Aeronautics Research Mission Directorate (ARMD), Human Exploration and Operations Mission Directorate (HEOMD), Science Mission Directorate (SMD), and Space Technology Mission Directorate (STMD). The report provides guidelines for incorporating SBIR technology into NASA programs and projects and provides a quantitative overview of the post-Phase II award patterns that correspond with each mission directorate at NASA Glenn Research Center (GRC). In recent years, one of NASA's goals has been to not only transfer SBIR technologies to commercial industries, but to ensure that NASA mission directorates incorporate SBIR technologies into their program and project activities. Before incorporating technologies into MD programs, it is important to understand each mission directorate structure because each directorate has different objectives and needs. The directorate program structures follow.

RadSTraM: Radiological Source Tracking and Monitoring, Phase II Final Report

Energy Technology Data Exchange (ETDEWEB)

Warren, Tracy A [ORNL; Walker, Randy M [ORNL; Hill, David E [ORNL; Gross, Ian G [ORNL; Smith, Cyrus M [ORNL; Abercrombie, Robert K [ORNL

2008-12-01

This report focuses on the technical information gained from the Radiological Source Tracking and Monitoring (RadSTraM) Phase II investigation and its implications. The intent of the RadSTraM project was to determine the feasibility of tracking radioactive materials in commerce, particularly International Atomic Energy Agency (IAEA) Category 3 and 4 materials. Specifically, Phase II of the project addressed tracking radiological medical isotopes in commerce. These categories of materials are susceptible to loss or theft but the problem is not being addressed by other agencies.

RadSTraM: Radiological Source Tracking and Monitoring, Phase II Final Report

International Nuclear Information System (INIS)

Warren, Tracy A.; Walker, Randy M.; Hill, David E.; Gross, Ian G.; Smith, Cyrus M.; Abercrombie, Robert K.

2008-01-01

This report focuses on the technical information gained from the Radiological Source Tracking and Monitoring (RadSTraM) Phase II investigation and its implications. The intent of the RadSTraM project was to determine the feasibility of tracking radioactive materials in commerce, particularly International Atomic Energy Agency (IAEA) Category 3 and 4 materials. Specifically, Phase II of the project addressed tracking radiological medical isotopes in commerce. These categories of materials are susceptible to loss or theft but the problem is not being addressed by other agencies

Live-cell Imaging Approaches for the Investigation of Xenobiotic-Induced Oxidant Stress

Science.gov (United States)

BACKGROUND: Oxidant stress is arguably a universal feature in toxicology. Research studies on the role of oxidant stress induced by xenobiotic exposures have typically relied on the identification of damaged biomolecules using a variety of conventional biochemical and molecular t...

Cunninghamella Biotransformation--Similarities to Human Drug Metabolism and Its Relevance for the Drug Discovery Process.

Science.gov (United States)

Piska, Kamil; Żelaszczyk, Dorota; Jamrozik, Marek; Kubowicz-Kwaśny, Paulina; Pękala, Elżbieta

2016-01-01

Studies of drug metabolism are one of the most significant issues in the process of drug development, its introduction to the market and also in treatment. Even the most promising molecule may show undesirable metabolic properties that would disqualify it as a potential drug. Therefore, such studies are conducted in the early phases of drug discovery and development process. Cunninghamella is a filamentous fungus known for its catalytic properties, which mimics mammalian drug metabolism. It has been proven that C. elegans carries at least one gene coding for a CYP enzyme closely related to the CYP51 family. The transformation profile of xenobiotics in Cunninghamella spp. spans a number of reactions catalyzed by different mammalian CYP isoforms. This paper presents detailed data on similar biotransformation drug products in humans and Cunninghamella spp. and covers the most important aspects of preparative biosynthesis of metabolites, since this model allows to obtain metabolites in sufficient quantities to conduct the further detailed investigations, as quantification, structure analysis and pharmacological activity and toxicity testing. The metabolic activity of three mostly used Cunninghamella species in obtaining hydroxylated, dealkylated and oxidated metabolites of different drugs confirmed its convergence with human biotransformation. Though it cannot replace the standard methods, it can provide support in the field of biotransformation and identifying metabolic soft spots of new chemicals and in predicting possible metabolic pathways. Another aspect is the biosynthesis of metabolites. In this respect, techniques using Cunninghamella spp. seem to be competitive to the chemical methods currently used.

Research Paper ISSN 0189-6016©2008

African Journals Online (AJOL)

AJTCAM

inflammatory, antitumor and antioxidant properties (Sharada et al., 1996; Bhattacharya et al., ... Withaferin-A (WA) was extracted and isolated from commercially available Withania somnifera root ..... Chemomodulatory efficacy of Basil leaf (Ocimum ... In vitro human phase I metabolism of xenobiotics I: pesticides and related.

Triglyceride-rich lipoprotein metabolism in women: roles of apoC-II and apoC-III.

Science.gov (United States)

Ooi, Esther M; Chan, Dick C; Hodson, Leanne; Adiels, Martin; Boren, Jan; Karpe, Fredrik; Fielding, Barbara A; Watts, Gerald F; Barrett, P Hugh R

2016-08-01

Experimental data suggest that apolipoprotein (apo) C-II and C-III regulate triglyceride-rich lipoprotein (TRL) metabolism, but there are limited studies in humans. We investigated the metabolic associations of TRLs with apoC-II and apoC-III concentrations and kinetics in women. The kinetics of plasma apoC-II, apoC-III and very low-density lipoprotein (VLDL) apoB-100 and triglycerides were measured in the postabsorptive state using stable isotopic techniques and compartmental modelling in 60 women with wide-ranging body mass index (19·5-32·9 kg/m(2) ). Plasma apoC-II and apoC-III concentrations were positively associated with the concentrations of plasma triglycerides, VLDL1 - and VLDL2 -apoB-100 and triglyceride (all P triglyceride concentration and VLDL1 triglyceride PR, while apoC-II fractional catabolic rate (FCR) was positively associated with VLDL1 triglyceride FCR (all P triglyceride kinetics. ApoC-III PR, but not FCR, was positively associated with VLDL1 triglyceride, and VLDL2 -apoB-100 and triglyceride concentrations (all P triglyceride kinetics. In multivariable analysis, including homoeostasis model assessment score, menopausal status and obesity, apoC-II concentration was significantly associated with plasma triglyceride, VLDL1 -apoB-100 and VLDL1 triglyceride concentrations and PR. Using the same multivariable analysis, apoC-III was significantly associated with plasma triglyceride and VLDL1 - and VLDL2 -apoB-100 and triglyceride concentrations and FCR. In women, plasma apoC-II and apoC-III concentrations are regulated by their respective PR and are significant, independent determinants of the kinetics and plasma concentrations of TRLs. © 2016 Stichting European Society for Clinical Investigation Journal Foundation.

Metabolism of six CYP probe substrates in fetal hepatocytes

Directory of Open Access Journals (Sweden)

Abdul Naveed Shaik

2016-06-01

Full Text Available Cytochrome P-450 (CYP are the most common drug metabolizing enzymes and are abundantly expressed in liver apart from kidney, lungs, intestine, brain etc. Their expression levels change with physiological conditions and disease states. The expression of these CYPs is less in human foetus and neonates compared to adults, which results in lower clearance of xenobiotics in infants and neonates compared to adults. Hepatocytes are the cells which are largely used to study these CYPs. We have isolated hepatocytes from aborted foetus to study the metabolism of six probe substrates: phenacetin, diclofenac, S-mephenytoin, dextromethorphan, nifedipine and testosterone. The results obtained show the expression of various CYPs (CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4 in human foetus and their involvement in metabolism of CYP probe substrates.

Depleted uranium: Metabolic disruptor?; Uranium appauvri: perturbateur metabolique?

Energy Technology Data Exchange (ETDEWEB)

Souidi, Maamar; Dublineau, Isabelle; Lestaevel, Philippe [Institut de Radioprotection et de Surete Nucleaire - IRSN, Direction de la radioprotection de l' homme, Laboratoire de radiotoxicologie experimentale, Service de radiobiologie et d' epidemiologie, BP 17, 92262 Fontenay-aux-Roses cedex (France)

2011-11-15

The presence of uranium in the environment can lead to long-term contamination of the food chain and of water intended for human consumption and thus raises many questions about the scientific and societal consequences of this exposure on population health. Although the biological effects of chronic low-level exposure are poorly understood, results of various recent studies show that contamination by depleted uranium (DU) induces subtle but significant biological effects at the molecular level in organs including the brain, liver, kidneys and testicles. For the first time, it has been demonstrated that DU induces effects on several metabolic pathways, including those metabolizing vitamin D, cholesterol, steroid hormones, acetylcholine and xenobiotics. This evidence strongly suggests that DU might well interfere with many metabolic pathways. It might thus contribute, together with other man-made substances in the environment, to increased health risks in some regions. (authors)

Avian species differences in the intestinal absorption of xenobiotics (PCB, dieldrin, Hg2+)

Science.gov (United States)

Serafin, J.A.

1984-01-01

1. Intestinal absorption of a polychlorinated biphenyl, dieldrin, and mercury (from HgCl2) was measured in adult Northern bobwhites, Eastern screech owls, American kestrels, black-crowned night-herons and mallards in vivo by an in situ luminal perfusion technique.2. Bobwhites, screech owls and kestrels absorbed much more of each xenobiotic than black-crowned night-herons and mallards.3. Mallards absorbed less dieldrin and mercury than black-crowned night-herons.4. Mercury absorption by kestrels was more than twice that in screech owls and eight times that observed in mallards.5. Pronounced differences in xenobiotic absorption rates between bobwhites, screech owls and kestrels on the one hand, and black-crowned night-herons and mallards on the other, raise the possibility that absorptive ability may be associated with the phylogenetic classification of birds.

The influence of single application of paracetamol and/or N-acetylcysteine on rats subchronic exposed to trichloroethylene vapours. I. Effect on hepatic moonooxygenase system dependent of cytochrome P450

Directory of Open Access Journals (Sweden)

Andrzej Plewka

2012-06-01

Full Text Available Background: There is a number of factors which potentially affect occurrence of toxic change in liver after overdosing of paracetamol. Hepatic metabolism of trichloroethylene has primary impact on hepatotoxic effect of this solvent. This means that the combined exposure to these xenobiotics can be particularly harmful for human. The influence of N-acetylcysteine (NAC as a protective factor after paracetamol intoxication was studies. Materials and method: Tests were carried out on rats which were treated with trichloroethylene, paracetamol and/or N-acetylcysteine. In the hepatic microsomal fraction activity of the components of cytochrome P450- dependent monooxygenases was determined Results: Paracetamol slightly stimulated cytochrome P450 having no effect on reductase activity cooperating with it. Cytochrome b5 and its reductase were inhibited by this compound. Trichloroethylene was the inhibitor of compounds of II microsomal electron transport chain. N-acetylcysteine inhibited activity of reductase of NADH-cytochrome b5. Conclusions: Tested doses of the xenobiotics influenced on II microsomal electron transport chain. Protective influence of N-acetylcysteine was better if this compound was applied 2 hours after exposure on xenobiotics

[Hypothetical link between endometriosis and xenobiotics-associated genetically modified food].

Science.gov (United States)

Aris, A; Paris, K

2010-12-01

Endometriosis is an oestrogen-dependent inflammatory disease affecting 10 % of reproductive-aged women. Often accompanied by chronic pelvic pain and infertility, endometriosis rigorously interferes with women's quality of life. Although the pathophysiology of endometriosis remains unclear, a growing body of evidence points to the implication of environmental toxicants. Over the last decade, an increase in the incidence of endometriosis has been reported and coincides with the introduction of genetically modified foods in our diet. Even though assessments of genetically modified food risk have not indicated any hazard on human health, xenobiotics-associated genetically modified food, such as pesticides residues and xenoproteins, could be harmful in the long-term. The "low-dose hypothesis", accumulation and biotransformation of pesticides-associated genetically modified food and the multiplied toxicity of pesticides-formulation adjuvants support this hypothesis. This review summarizes toxic effects (in vitro and on animal models) of some xenobiotics-associated genetically modified food, such as glyphosate and Cry1Ab protein, and extrapolates on their potential role in the pathophysiology of endometriosis. Their roles as immune toxicants, pro-oxidants, endocrine disruptors and epigenetic modulators are discussed. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

PERM Hypothesis: The Fundamental Machinery Able to Elucidate the Role of Xenobiotics and Hormesis in Cell Survival and Homeostasis

Directory of Open Access Journals (Sweden)

Salvatore Chirumbolo

2017-01-01

Full Text Available In this article the Proteasome, Endoplasmic Reticulum and Mitochondria (PERM hypothesis is discussed. The complex machinery made by three homeostatic mechanisms involving the proteasome (P, endoplasmic reticulum (ER and mitochondria (M is addressed in order to elucidate the beneficial role of many xenobiotics, either trace metals or phytochemicals, which are spread in the human environment and in dietary habits, exerting their actions on the mechanisms underlying cell survival (apoptosis, cell cycle regulation, DNA repair and turnover, autophagy and stress response. The “PERM hypothesis” suggests that xenobiotics can modulate this central signaling and the regulatory engine made fundamentally by the ER, mitochondria and proteasome, together with other ancillary components such as peroxisomes, by acting on the energetic balance, redox system and macromolecule turnover. In this context, reactive species and stressors are fundamentally signalling molecules that could act as negative-modulating signals if PERM-mediated control is offline, impaired or dysregulated, as occurs in metabolic syndrome, degenerative disorders, chronic inflammation and cancer. Calcium is an important oscillatory input of this regulation and, in this hypothesis, it might play a role in maintaining the correct rhythm of this PERM modulation, probably chaotic in its nature, and guiding cells to a more drastic decision, such as apoptosis. The commonest effort sustained by cells is to maintain their survival balance and the proterome has the fundamental task of supporting this mechanism. Mild stress is probably the main stimulus in this sense. Hormesis is therefore re-interpreted in the light of this hypothetical model and that experimental evidence arising from flavonoid and hormesis reasearch.

Performance of GERDA phase II BEGe detectors

Energy Technology Data Exchange (ETDEWEB)

Wagner, Victoria [Max-Planck Institut fuer Kernphysik (Germany); Collaboration: GERDA-Collaboration

2015-07-01

The GERDA experiment searches for the lepton number violating neutrinoless double beta (0νββ) decay of {sup 76}Ge. GERDA uses HPGe detectors enriched in {sup 76}Ge as source and detection material. The experiment proceeds in two phases. In Phase I a background index of 10{sup -2} cts/(keV.kg.yr) was reached and a new lower limit on the half-life of the 0νββ decay of {sup 76}Ge was set to 2.1.10{sup 25} yr (at 95% C.L.). In Phase II the background index will be lowered by an order of magnitude and a sensitivity of 10{sup 26} yr will be reached. In order to achieve this goal 30 new custom-made broad energy germanium (BEGe) detectors and a liquid argon scintillation light veto will be deployed. Five BEGe detectors have been operated successfully in Phase I and demonstrated their improved energy resolution and enhanced pulse shape discrimination (PSD) against background events. Special designed electronics will further improve energy resolution and PSD performance. The first results from commissioning of the new BEGe detectors are presented in this talk.

Removal of Antibiotics in Biological Wastewater Treatment Systems—A Critical Assessment Using the Activated Sludge Modeling Framework for Xenobiotics (ASM-X)

DEFF Research Database (Denmark)

Polesel, Fabio; Andersen, Henrik Rasmus; Trapp, Stefan

2016-01-01

Many scientific studies present removal efficiencies for pharmaceuticals in laboratory-, pilot-, and full-scale wastewater treatment plants, based on observations that may be impacted by theoretical and methodological approaches used. In this Critical Review, we evaluated factors influencing...... observed removal efficiencies of three antibiotics (sulfamethoxazole, ciprofloxacin, tetracycline) in pilot- and full-scale biological treatment systems. Factors assessed include (i) retransformation to parent pharmaceuticals from e.g., conjugated metabolites and analogues, (ii) solid retention time (SRT......), (iii) fractions sorbed onto solids, and (iv) dynamics in influent and effluent loading. A recently developed methodology was used, relying on the comparison of removal efficiency predictions (obtained with the Activated Sludge Model for Xenobiotics (ASM-X)) with representative measured data from...

Mass fluxes and spatial trends of xenobiotics in the waters of the city of Halle, Germany

International Nuclear Information System (INIS)

Reinstorf, F.; Strauch, G.; Schirmer, K.; Glaeser, H.-R.; Moeder, M.; Wennrich, R.; Osenbrueck, K.; Schirmer, M.

2008-01-01

The behaviour and the effects of xenobiotics including pharmaceuticals and fragrances in the environment are widely unknown. In order to improve our knowledge, field investigations and modelling approaches for the entire area of the city of Halle/Saale, Germany, were performed. The distribution of the concentration values and mass fluxes are exemplified using indicators such as Bisphenol A, t-Nonylphenol, Carbamacepine, Galaxolide, Tonalide, Gadolinium and isotopes. Concentrations at a magnitude of ng/L to μg/L were found ubiquitously in the ground and surface waters. Using the concentration values, the impact of the city concerning the indicators was not always evident. Only the assessment of the mass fluxes shows significant urban impacts along the city passage. The calculation of the mass fluxes shows increasing values for all investigated xenobiotics during the city passage; only Bisphenol A stagnates. A balance model of water and indicator mass fluxes was built up for the entire city area. - Xenobiotics are ubiquitous in the investigated urban aquatic system and are quantified by a large scale mass balance to find spatial trends

Xenobiotic Modulation of Human Mammary Epithelial Cell Gap junctional Intercellular Communication and Growth

National Research Council Canada - National Science Library

Ruch, Randall

1998-01-01

...), phthalate esters, and dioxin have been implicated in this increase. Many xenobiotics such as DDT and PCBs have weak estrogenic activity and may enhance breast cancer formation by an estrogenic effect on breast epithelial cell growth...

Xenobiotic Modulation of Human Mammary Epithelial Cell Gap Junctional Intercellular Communication and Growth

National Research Council Canada - National Science Library

Ruch, Randall

1997-01-01

...), phthalate esters, and dioxin have been implicated in this increase. Many xenobiotics such as DDT and PCBs have weak estrogenic activity and may enhance breast cancer formation by an estrogenic effect on breast epithelial cell growth...

Search for neutrinoless double beta decay with GERDA phase II

Science.gov (United States)

Agostini, M.; Bakalyarov, A. M.; Balata, M.; Barabanov, I.; Baudis, L.; Bauer, C.; Bellotti, E.; Belogurov, S.; Bettini, A.; Bezrukov, L.; Bode, T.; Borowicz, D.; Brudanin, V.; Brugnera, R.; Caldwell, A.; Cattadori, C.; Chernogorov, A.; D'Andrea, V.; Demidova, E. V.; Di Marco, N.; Domula, A.; Doroshkevich, E.; Egorov, V.; Falkenstein, R.; Gangapshev, A.; Garfagnini, A.; Gooch, C.; Grabmayr, P.; Gurentsov, V.; Gusev, K.; Hakenmüller, J.; Hegai, A.; Heisel, M.; Hemmer, S.; Hofmann, W.; Hult, M.; Inzhechik, L. V.; Csáthy, J. Janicskó; Jochum, J.; Junker, M.; Kazalov, V.; Kihm, T.; Kirpichnikov, I. V.; Kirsch, A.; Kish, A.; Klimenko, A.; Kneißl, R.; Knies, J.; Knöpfle, K. T.; Kochetov, O.; Kornoukhov, V. N.; Kuzminov, V. V.; Laubenstein, M.; Lazzaro, A.; Lebedev, V. I.; Liao, H. Y.; Lindner, M.; Lippi, I.; Lubashevskiy, A.; Lubsandorzhiev, B.; Lutter, G.; Majorovits, B.; Maneschg, W.; Marissens, G.; Miloradovic, M.; Mingazheva, R.; Misiaszek, M.; Moseev, P.; Nemchenok, I.; Panas, K.; Pandola, L.; Pelczar, K.; Pullia, A.; Ransom, C.; Reissfelder, M.; Riboldi, S.; Rumyantseva, N.; Sada, C.; Salamida, F.; Schmitt, C.; Schneider, B.; Schönert, S.; Schreiner, J.; Schulz, O.; Schütz, A.-K.; Schwingenheuer, B.; Seitz, H.; Selivanenko, O.; Shevchik, E.; Shirchenko, M.; Simgen, H.; Smolnikov, A.; Stanco, L.; Vanhoefer, L.; Vasenko, A. A.; Veresnikova, A.; von Sturm, K.; Wagner, V.; Wegmann, A.; Wester, T.; Wiesinger, C.; Wojcik, M.; Yanovich, E.; Zhitnikov, I.; Zhukov, S. V.; Zinatulina, D.; Zuber, K.; Zuzel, G.

2017-10-01

The GERmanium Detector Array (gerda) experiment, located at the Gran Sasso underground laboratory in Italy, is one of the leading experiments for the search of 0νββ decay. In Phase II of the experiment 35.6 kg of enriched germanium detectors are operated. The application of active background rejection methods, such as a liquid argon scintillation light read-out and pulse shape discrimination of germanium detector signals, allowed to reduce the background index to the intended level of 10-3 cts/(keV.kg.yr). In the first five month of data taking 10.8 kg yr of exposure were accumulated. No signal has been found and together with data from Phase I a new limit for the neutrinoless double beta decay half-life of 76Ge of 5.3 . 1025 yr at 90% C.L. was established in June 2016. Phase II data taking is ongoing and will allow the exploration of half-lifes in the 1026 yr regime. The current status of data taking and an update on the background index are presented.

Geraniol Pharmacokinetics, Bioavailability and Its Multiple Effects on the Liver Antioxidant and Xenobiotic-Metabolizing Enzymes

Directory of Open Access Journals (Sweden)

Barbara Pavan

2018-01-01

Full Text Available Geraniol is a natural monoterpene showing anti-inflammatory, antioxidant, neuroprotective and anticancer effects. No pharmacokinetic and bioavailability data on geraniol are currently available. We therefore performed a systematic study to identify the permeation properties of geraniol across intestinal cells, and its pharmacokinetics and bioavailability after intravenous and oral administration to rats. In addition, we systematically investigated the potential hepatotoxic effects of high doses of geraniol on hepatic phase I, phase II and antioxidant enzymatic activities and undertook a hematochemical analysis on mice. Permeation studies performed via HPLC evidenced geraniol permeability coefficients across an in vitro model of the human intestinal wall for apical to basolateral and basolateral to apical transport of 13.10 ± 2.3 × 10-3 and 2.1 ± 0.1⋅× 10-3 cm/min, respectively. After intravenous administration of geraniol to rats (50 mg/kg, its concentration in whole blood (detected via HPLC decreased following an apparent pseudo-first order kinetics with a half-life of 12.5 ± 1.5 min. The absolute bioavailability values of oral formulations (50 mg/kg of emulsified geraniol or fiber-adsorbed geraniol were 92 and 16%, respectively. Following emulsified oral administration, geraniol amounts in the cerebrospinal fluid of rats ranged between 0.72 ± 0.08 μg/mL and 2.6 ± 0.2 μg/mL within 60 min. Mice treated with 120 mg/kg of geraniol for 4 weeks showed increased anti-oxidative defenses with no signs of liver toxicity. CYP450 enzyme activities appeared only slightly affected by the high dosage of geraniol.

Pretest Predictions for Phase II Ventilation Tests

International Nuclear Information System (INIS)

Yiming Sun

2001-01-01

The objective of this calculation is to predict the temperatures of the ventilating air, waste package surface, and concrete pipe walls that will be developed during the Phase II ventilation tests involving various test conditions. The results will be used as inputs to validating numerical approach for modeling continuous ventilation, and be used to support the repository subsurface design. The scope of the calculation is to identify the physical mechanisms and parameters related to thermal response in the Phase II ventilation tests, and describe numerical methods that are used to calculate the effects of continuous ventilation. The calculation is limited to thermal effect only. This engineering work activity is conducted in accordance with the ''Technical Work Plan for: Subsurface Performance Testing for License Application (LA) for Fiscal Year 2001'' (CRWMS M and O 2000d). This technical work plan (TWP) includes an AP-2.21Q, ''Quality Determinations and Planning for Scientific, Engineering, and Regulatory Compliance Activities'', activity evaluation (CRWMS M and O 2000d, Addendum A) that has determined this activity is subject to the YMP quality assurance (QA) program. The calculation is developed in accordance with the AP-3.12Q procedure, ''Calculations''. Additional background information regarding this activity is contained in the ''Development Plan for Ventilation Pretest Predictive Calculation'' (DP) (CRWMS M and O 2000a)

Balneotherapy and platelet glutathione metabolism in type II diabetic patients

Science.gov (United States)

Ohtsuka, Yoshinori; Yabunaka, Noriyuki; Watanabe, Ichiro; Noro, Hiroshi; Agishi, Yuko

1996-09-01

Effects of balneotherapy on platelet glutathione metabolism were investigated in 12 type II (non-insulin-dependent) diabetic patients. Levels of the reduced form of glutathione (GSH) on admission were well correlated with those of fasting plasma glucose (FPG; r=0.692, Pbalneotherapy, the mean level of GSH showed no changes; however, in well-controlled patients (FPG 150 mg/dl), the value decreased ( Pbalneotherapy, the activity increased in 5 patients, decreased in 3 patients and showed no changes (alteration within ±3%) in all the other patients. From these findings in diabetic patients we concluded: (1) platelet GSH synthesis appeared to be induced in response to oxidative stress; (2) lowered GPX activities indicated that the antioxidative defense system was impaired; and (3) platelet glutathione metabolism was partially improved by 4 weeks balneotherapy, an effect thought to be dependent on the control status of plasma glucose levels. It is suggested that balneotherapy is beneficial for patients whose platelet antioxidative defense system is damaged, such as those with diabetes mellitus and coronary heart disease.

Maintenance of drug metabolism and transport functions in human precision-cut liver slices during prolonged incubation for 5 days

NARCIS (Netherlands)

Starokozhko, Viktoriia; Vatakuti, Suresh; Schievink, Bauke; Merema, Marjolijn T.; Asplund, Annika; Synnergren, Jane; Aspegren, Anders; Groothuis, Geny M. M.

Human precision-cut liver slices (hPCLS) are a valuable ex vivo model that can be used in acute toxicity studies. However, a rapid decline in metabolic enzyme activity limits their use in studies that require a prolonged xenobiotic exposure. The aim of the study was to extend the viability and

South Bay Salt Pond Tidal Wetland Restoration Phase II Planning

Science.gov (United States)

Information about the SFBWQP South Bay Salt Pond Tidal Wetland Restoration Phase II Planning project, part of an EPA competitive grant program to improve SF Bay water quality focused on restoring impaired waters and enhancing aquatic re

An Experimental Evaluation of Hyperactivity and Food Additives. 1977-Phase II.

Science.gov (United States)

Harley, J. Preston; And Others

Phase II of a study on the effectiveness of B. Feingold's recommended diet for hyperactive children involved the nine children (mean age 9 years) who had shown the "best" response to diet manipulation in Phase I. Each child served as his own control and was challenged with specified amounts of placebo and artificial color containing food…

Searching Neutrinoless Double Beta Decay with GERDA Phase II

Science.gov (United States)

Agostini, M.; Bakalyarov, A. M.; Balata, M.; Barabanov, I.; Baudis, L.; Bauer, C.; Bellotti, E.; Belogurov, S.; Bettini, A.; Bezrukov, L.; Bode, T.; Brudanin, V.; Brugnera, R.; Caldwell, A.; Cattadori, C.; Chernogorov, A.; Comellato, T.; D’Andrea, V.; Demidova, E. V.; di Marco, N.; Domula, A.; Doroshkevich, E.; Egorov, V.; Falkenstein, R.; Gangapshev, A.; Garfagnini, A.; Giordano, M.; Gooch, C.; Grabmayr, P.; Gurentsov, V.; Gusev, K.; Hahne, C.; Hakenmüller, J.; Hegai, A.; Heisel, M.; Hemmer, S.; Hiller, R.; Hofmann, W.; Holl, P.; Hult, M.; Inzhechik, L. V.; Ioannucci, L.; Csáthy, J. Janicskó; Jochum, J.; Junker, M.; Kazalov, V.; Kermaidic, Y.; Kihm, T.; Kirpichnikov, I. V.; Kirsch, A.; Kish, A.; Klimenko, A.; Kneißl, R.; Knöpfle, K. T.; Kochetov, O.; Kornoukhov, V. N.; Kuzminov, V. V.; Laubenstein, M.; Lazzaro, A.; Lindner, M.; Lippi, I.; Lubashevskiy, A.; Lubsandorzhiev, B.; Lutter, G.; Macolino, C.; Majorovits, B.; Maneschg, W.; Marissens, G.; Miloradovic, M.; Mingazheva, R.; Misiaszek, M.; Moseev, P.; Nemchenok, I.; Nisi, S.; Panas, K.; Pandola, L.; Pelczar, K.; Pullia, A.; Ransom, C.; Reissfelder, M.; Riboldi, S.; Rumyantseva, N.; Sada, C.; Sala, E.; Salamida, F.; Schmitt, C.; Schneider, B.; Schreiner, J.; Schulz, O.; Schweisshelm, B.; Schwingenheuer, B.; Schönert, S.; Schütz, A.-K.; Seitz, H.; Selivanenko, O.; Shevchik, E.; Shirchenko, M.; Simgen, H.; Smolnikov, A.; Stanco, L.; Vanhoefer, L.; Vasenko, A. A.; Veresnikova, A.; von Sturm, K.; Wagner, V.; Wegmann, A.; Wester, T.; Wiesinger, C.; Wojcik, M.; Yanovich, E.; Zhitnikov, I.; Zhukov, S. V.; Zinatulina, D.; Zschocke, A.; Zsigmond, A. J.; Zuber, K.; Zuzel, G.

An observation of neutrinoless double beta (0νββ) decay would allow to shed light onto the nature of neutrinos. GERDA (GERmanium Detector Array) aims to discover this process in a background-free search using 76Ge. The experiment is located at the Laboratori Nazionali del Gran Sasso (LNGS) of the Istituto Nazionale di Fisica Nucleare (INFN) in Italy. Bare, isotopically enriched, high purity germanium detectors are operated in liquid argon. GERDA follows a staged approach. In Phase II 35.6 kg of enriched germanium detectors are operated since December 2015. The application of active background rejection methods, such as a liquid argon scintillation light read-out and pulse shape discrimination of germanium detector signals, allows to reduce the background index to the intended level of 10‑3 cts/(keVṡkgṡyr). No evidence for the 0νββ decay has been found in 23.2 kgṡyr of Phase II data, and together with data from Phase I the up-to-date most stringent half-life limit for this process in 76Ge has been established, at a median sensitivity of 5.8ṡ1025yr the 90% C.L. lower limit is 8.0ṡ1025yr.

Occurrence of xenobiotics in gray water and removal in three biological treatment systems

NARCIS (Netherlands)

Hernandez Leal, L.; Vieno, N.; Temmink, B.G.; Zeeman, G.; Buisman, C.J.N.

2010-01-01

Eighteen selected xenobiotics related to personal care and household chemicals (UV-filters, fragrances, preservatives, biocides, surfactants) were measured in gray water from 32 houses and in effluents of three different biological treatment systems (aerobic, anaerobic, and combined anaerobic +

Phase I/II Pilot Study of Mixed Chimerism to Treat Inherited Metabolic Disorders

Science.gov (United States)

2017-11-15

Hurler Syndrome (MPS I); Hurler-Scheie Syndrome; Hunter Syndrome (MPS II); Sanfilippo Syndrome (MPS III); Krabbe Disease (Globoid Leukodystrophy); Metachromatic Leukodystrophy (MLD); Adrenoleukodystrophy (ALD and AMN); Sandhoff Disease; Tay Sachs Disease; Pelizaeus Merzbacher (PMD); Niemann-Pick Disease; Alpha-mannosidosis

PWR steam generator chemical cleaning. Phase II. Final report

International Nuclear Information System (INIS)

1980-01-01

Two techniques believed capable of chemically dissolving the corrosion products in the annuli between tubes and support plates were developed in laboratory work in Phase I of this project and were pilot tested in Indian Point Unit No. 1 steam generators. In Phase II, one of the techniques was shown to be inadequate on an actual sample taken from an Indian Point Unit No. 2 steam generator. The other technique was modified slightly, and it was demonstrated that the tube/support plate annulus could be chemically cleaned effectively

From the selfish gene to selfish metabolism: revisiting the central dogma.

Science.gov (United States)

de Lorenzo, Víctor

2014-03-01

The standard representation of the Central Dogma (CD) of Molecular Biology conspicuously ignores metabolism. However, both the metabolites and the biochemical fluxes behind any biological phenomenon are encrypted in the DNA sequence. Metabolism constrains and even changes the information flow when the DNA-encoded instructions conflict with the homeostasis of the biochemical network. Inspection of adaptive virulence programs and emergence of xenobiotic-biodegradation pathways in environmental bacteria suggest that their main evolutionary drive is the expansion of their metabolic networks towards new chemical landscapes rather than perpetuation and spreading of their DNA sequences. Faulty enzymatic reactions on suboptimal substrates often produce reactive oxygen species (ROS), a process that fosters DNA diversification and ultimately couples catabolism of the new chemicals to growth. All this calls for a revision of the CD in which metabolism (rather than DNA) has the leading role. © 2014 WILEY Periodicals, Inc.

The metabolism of anabolic-androgenic steroids in the greyhound.

Science.gov (United States)

McKinney, Andrew R; Cawley, Adam T; Young, E Bruce; Kerwick, Carmel M; Cunnington, Karen; Stewart, Rhiannon T; Ambrus, Joseph I; Willis, Anthony C; McLeod, Malcolm D

2013-04-01

Effective control of the use of anabolic-androgenic steroids (AASs) in animal sports is essential in order to ensure both animal welfare and integrity. In order to better police their use in Australian and New Zealand greyhound racing, thorough metabolic studies have been carried out on a range of registered human and veterinary AASs available in the region. Canine metabolic data are presented for the AASs boldenone, danazol, ethylestrenol, mesterolone, methandriol, nandrolone and norethandrolone. The principal Phase I metabolic processes observed were the reduction of A-ring unsaturations and/or 3-ketones with either 3α,5β- or 3β,5α-stereochemistry, the oxidation of secondary 17β-hydroxyl groups and 16α-hydroxylation. The Phase II β-glucuronylation of sterol metabolites was extensive. The presented data have enabled the effective analysis of AASs and their metabolites in competition greyhound urine samples.

Impact of metabolism and growth phase on the hydrogen isotopic composition of microbial fatty acids

Science.gov (United States)

Heinzelmann, Sandra M.; Villanueva, Laura; Sinke-Schoen, Danielle; Sinninghe Damsté, Jaap S.; Schouten, Stefan; van der Meer, Marcel T. J.

2015-01-01

Microorganisms are involved in all elemental cycles and therefore it is important to study their metabolism in the natural environment. A recent technique to investigate this is the hydrogen isotopic composition of microbial fatty acids, i.e., heterotrophic microorganisms produce fatty acids enriched in deuterium (D) while photoautotrophic and chemoautotrophic microorganisms produce fatty acids depleted in D compared to the water in the culture medium (growth water). However, the impact of factors other than metabolism have not been investigated. Here, we evaluate the impact of growth phase compared to metabolism on the hydrogen isotopic composition of fatty acids of different environmentally relevant microorganisms with heterotrophic, photoautotrophic and chemoautotrophic metabolisms. Fatty acids produced by heterotrophs are enriched in D compared to growth water with εlipid/water between 82 and 359‰ when grown on glucose or acetate, respectively. Photoautotrophs (εlipid/water between −149 and −264‰) and chemoautotrophs (εlipid/water between −217 and −275‰) produce fatty acids depleted in D. Fatty acids become, in general, enriched by between 4 and 46‰ with growth phase which is minor compared to the influence of metabolisms. Therefore, the D/H ratio of fatty acids is a promising tool to investigate community metabolisms in nature. PMID:26005437

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

Science.gov (United States)

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

2011-01-01

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

Acute and Chronic Plasma Metabalomic and Liver Transcriptomic Stress Effects in a Mouse Model with Features of Post-Traumatic Stress Disorder

Science.gov (United States)

2015-01-28

trends is that at both 24 hr time points and the 1.5 wks time point, the HPA had already become desensitized , potentially involving attenuated release...points To explore metabolic alterations occurring at 24 hrs that potentially persisted out to 1.5 and 4 wks, we used random forests (RF) to classify...NR0B2, SLC27A3, SREBF1) Inhibition of cholesterol and lipid metabolism and transport; activation of Phase I metabolizing enzymes ->lipid and xenobiotic

An FPGA-based trigger for the phase II of the MEG experiment

Energy Technology Data Exchange (ETDEWEB)

Baldini, A. [Istituto Nazionale di Fisica Nucleare, Pisa (Italy); Bemporad, C.; Cei, F. [Istituto Nazionale di Fisica Nucleare, Pisa (Italy); Dipartimento di Fisica, Università di Pisa (Italy); Galli, L.; Grassi, M.; Morsani, F. [Istituto Nazionale di Fisica Nucleare, Pisa (Italy); Nicolò, D., E-mail: donato.nicolo@pi.infn.it [Istituto Nazionale di Fisica Nucleare, Pisa (Italy); Dipartimento di Fisica, Università di Pisa (Italy); Ritt, S. [Paul Scherrer Institut, Villigen AG (Switzerland); Venturini, M. [Istituto Nazionale di Fisica Nucleare, Pisa (Italy); Scuola Normale Superiore, Pisa (Italy)

2016-07-11

For the phase II of MEG, we are going to develop a combined trigger and DAQ system. Here we focus on the former side, which operates an on-line reconstruction of detector signals and event selection within 450 μs from event occurrence. Trigger concentrator boards (TCB) are under development to gather data from different crates, each connected to a set of detector channels, to accomplish higher-level algorithms to issue a trigger in the case of a candidate signal event. We describe the major features of the new system, in comparison with phase I, as well as its performances in terms of selection efficiency and background rejection. - Highlights: • A new, two-level trigger scheme for the phase-II of the MEG experiment is presented. • Improvements with respect to phase-I are underlined. • The role of detector upgrades and the use of a new generation of FPGA as well are emphasized.

Finite Element Models for Electron Beam Freeform Fabrication Process, Phase II

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National Aeronautics and Space Administration — This Small Business Innovation Research Phase II proposal offers to develop a comprehensive computer simulation methodology based on the finite element method for...

Toxicokinetics of drugs of abuse: current knowledge of the isoenzymes involved in the human metabolism of tetrahydrocannabinol, cocaine, heroin, morphine, and codeine.

Science.gov (United States)

Maurer, Hans H; Sauer, Christoph; Theobald, Denis S

2006-06-01

This review summarizes the major metabolic pathways of the drugs of abuse, tetrahydrocannabinol, cocaine, heroin, morphine, and codeine, in humans including the involvement of isoenzymes. This knowledge may be important for predicting their possible interactions with other xenobiotics, understanding pharmaco-/toxicokinetic and pharmacogenetic variations, toxicological risk assessment, developing suitable toxicological analysis procedures, and finally for understanding certain pitfalls in drug testing. The detection times of these drugs and/or their metabolites in biological samples are summarized and the implications of the presented data on the possible interactions of drugs of abuse with other xenobiotics, ie, inhibition or induction of individual polymorphic and nonpolymorphic isoenzymes, discussed.

Effect of cerebral blood flow on consciousness and outcome after head injury. Assessment by jugular bulb venous metabolism and IMP-SPECT

Energy Technology Data Exchange (ETDEWEB)

Imaizumi, Shigeki; Onuma, Takehide; Motohashi, Osamu; Kameyama, Motonobu; Ishii, Kiyoshi [Sendai City Hospital (Japan)

2002-10-01

This study was performed to elucidate the therapeutical value of arteriojugularvenous oxygen difference (AVDO{sub 2}) in the ultra-emergent period after head injury. Rational therapeutic strategy after severe head injury needs information concerning the dynamical change of cerebral blood flow (CBF) and metabolism. We monitored the cerebral venous metabolism within 6 hours after head injury until the day IMP-SPECT was performed. Whole brain cerebral blood flow detected by IMP-SPECT and AVDO{sub 2} at the same day was compared, which restored to the period within 6 hours after head injury. From this procedure, we could outline cerebral blood flow conditions by only AVDO{sub 2} without IMP-SPECT in the ultra-emergent period. Eighty-six patients with head injury who were carried to our emergency center in the period of recent 2 years aged ranging from 15 to 94 years were the subjects. They all performed jugular bulb cannulation within 6 hours after the accident (Martin's phase I: day 0) to know saturation of jugular vein (SjO{sub 2}), AVDO{sub 2} and AVL. They were monitored until the day IMP-SPECT was performed (Martin's phase II; day 1-3 or phase III; day 4-15). The correlation between CBF and AVDO{sub 2}. The effect of CBF and cerebral venous metabolism on consciousness and outcome was also analyzed. CBF and AVDO{sub 2} in phase II and III were reversely correlated (p<0.0001). Normal CBF corresponded with 5.0 vol% in AVDO{sub 2}. AVDO{sub 2} in all cases changed 6.2 vol% at phase I, 4.5 vol% at phase II and 5.1 vol% at phase III. Glasgow comascale (GCS) on admission under 8 (n=47) and over 9 (n=39) significantly differed in AVDO{sub 2} and CBF in the period of II and III. The patients with favorable consciousness showed low AVDO{sub 2} and hyperemia afterwards. Dead cases in phase I (n=19) showed high AVDO{sub 2} and low SjO{sub 2}. The patients with severe disability (SD) (n=13) showed high AVDO{sub 2} and low CBF and the patients with good recovery (GR

Effects of Curcuma xanthorrhiza Extracts and Their Constituents on Phase II Drug-metabolizing Enzymes Activity.

Science.gov (United States)

Salleh, Nurul Afifah Mohd; Ismail, Sabariah; Ab Halim, Mohd Rohaimi

2016-01-01

Curcuma xanthorrhiza is a native Indonesian plant and traditionally utilized for a range of illness including liver damage, hypertension, diabetes, and cancer. The study determined the effects of C. xanthorrhiza extracts (ethanol and aqueous) and their constituents (curcumene and xanthorrhizol) on UDP-glucuronosyltransferase (UGT) and glutathione transferase (GST) activities. The inhibition studies were evaluated both in rat liver microsomes and in human recombinant UGT1A1 and UGT2B7 enzymes. p-nitrophenol and beetle luciferin were used as the probe substrates for UGT assay while 1-chloro-2,4-dinitrobenzene as the probe for GST assay. The concentrations of extracts studied ranged from 0.1 to 1000 μg/mL while for constituents ranged from 0.01 to 500 μM. In rat liver microsomes, UGT activity was inhibited by the ethanol extract (IC 50 =279.74 ± 16.33 μg/mL). Both UGT1A1 and UGT2B7 were inhibited by the ethanol and aqueous extracts with IC 50 values ranging between 9.59-22.76 μg/mL and 110.71-526.65 μg/Ml, respectively. Rat liver GST and human GST Pi-1 were inhibited by ethanol and aqueous extracts, respectively (IC 50 =255.00 ± 13.06 μg/mL and 580.80 ± 18.56 μg/mL). Xanthorrhizol was the better inhibitor of UGT1A1 (IC 50 11.30 ± 0.27 μM) as compared to UGT2B7 while curcumene did not show any inhibition. For GST, both constituents did not show any inhibition. These findings suggest that C. xanthorrhiza have the potential to cause herb-drug interaction with drugs that are primarily metabolized by UGT and GST enzymes. Findings from this study would suggest which of Curcuma xanthorrhiza extracts and constituents that would have potential interactions with drugs which are highly metabolized by UGT and GST enzymes. Further clinical studies can then be designed if needed to evaluate the in vivo pharmacokinetic relevance of these interactions Abbreviations Used : BSA: Bovine serum albumin, CAM: Complementary and alternative medicine, cDNA: Complementary

XenoSite: accurately predicting CYP-mediated sites of metabolism with neural networks.

Science.gov (United States)

Zaretzki, Jed; Matlock, Matthew; Swamidass, S Joshua

2013-12-23

Understanding how xenobiotic molecules are metabolized is important because it influences the safety, efficacy, and dose of medicines and how they can be modified to improve these properties. The cytochrome P450s (CYPs) are proteins responsible for metabolizing 90% of drugs on the market, and many computational methods can predict which atomic sites of a molecule--sites of metabolism (SOMs)--are modified during CYP-mediated metabolism. This study improves on prior methods of predicting CYP-mediated SOMs by using new descriptors and machine learning based on neural networks. The new method, XenoSite, is faster to train and more accurate by as much as 4% or 5% for some isozymes. Furthermore, some "incorrect" predictions made by XenoSite were subsequently validated as correct predictions by revaluation of the source literature. Moreover, XenoSite output is interpretable as a probability, which reflects both the confidence of the model that a particular atom is metabolized and the statistical likelihood that its prediction for that atom is correct.

Chemical carcinogenesis in feral fish: uptake, activation, and detoxication of organic xenobiotics

International Nuclear Information System (INIS)

Varanasi, U.; Stein, J.E.; Nishimoto, M.; Reichert, W.L.; Collier, T.K.

1987-01-01

The high prevalance of liver neoplasms in English sole (Parophrys vetulus) and substantially lower prevalence of neoplasms in a closely related species, starry flounder (Platichthys stellatus) captured from industrialized waterways, provide a unique opportunity to compare biochemical processes involved in chemical carcinogenesis in feral fish species. Because levels of aromatic hydrocarbons (AHs) in urban sediments are correlated with prevalences of liver neoplasms in English sole, the authors have initiated detailed studies to evaluate the effects of endogenous and exogenous factors on uptake, activation and detoxication of carcinogenic AHs, such as benzo[a]pyrene (BaP), using spectroscopic, chromatographic, and radiometric techniques. The results obtained thus far show that sole readily takes up AHs associated with sediment from urban areas and that the presence of other xenobiotics, such as PCBs, in sediment increases tissue concentrations of BaP metabolites. Extensive metabolism of BaP occurred whether sole was exposed to this AH via sediment, per os, or intraperitoneally. Substantial modification of hepatic DNA occurred and persisted for a period of 2-4 weeks after a single exposure to BaP. The level of covalent binding of BaP intermediates to hepatic DNA was 10-fold higher in juvenile than adult sole and 90-fold higher in juvenile sole than in Sprague-Dawley rat, a species which is resistant to BaP-induced hepatocarcinogenesis. These results, along with the authors findings that hepatic GST activity in flounder was two times higher than in sole, demonstrate that microsomal metabolism of BaP does not accurately reflect the differences in the ability of these fish to form BaP-DNA adducts in vivo and also suggest that detoxication of reactive intermediates is an important factor in determining the levels of DNA modification by AHs and resulting toxic effects in feral fish

Influence of bacterial N-acyl-homoserinelactones on growth parameters, pigments, antioxidative capacities and the xenobiotic phase II detoxification enzymes in barley and yam bean

Directory of Open Access Journals (Sweden)

Christine eGoetz-Roesch

2015-04-01

Full Text Available Bacteria are able to communicate with each other and sense their environment in a population density dependent mechanism known as quorum sensing (QS. N-acyl-homoserine lactones (AHLs are the QS signalling compounds of Gram-negative bacteria which are frequent colonizers of rhizospheres. While cross-kingdom signalling and AHL-dependent gene expression in plants has been confirmed, the responses of enzyme activities in the eukaryotic host upon AHLs are unknown. Since AHL are thought to be used as so-called plant boosters or strengthening agents, which might change their resistance towards radiation and/or xenobiotic stress, we have examined the plants’ pigment status and their antioxidative and detoxifying capacities upon AHL treatment. Because the yield of a crop plant should not be negatively influenced, we have also checked for growth and root parameters.We investigated the influence of three different AHLs, namely N-hexanoyl- (C6-HSL, N-octanoyl- (C8-HSL and N-decanoyl- homoserine lactone (C10-HSL on two agricultural crop plants. The AHL-effects on Hordeum vulgare (L. as an example of a monocotyledonous crop and on the tropical leguminous crop plant Pachyrhizus erosus (L were compared. While plant growth and pigment contents in both plants showed only small responses to the applied AHLs, AHL treatment triggered tissue- and compound-specific changes in the activity of important detoxification enzymes. The activity of dehydroascorbate reductase (DHAR in barley shoots after C10-HSL treatment for instance increased up to 384% of control plant levels, whereas superoxide dismutase (SOD activity in barley roots was decreased down to 23% of control levels upon C6-HSL treatment. Other detoxification enzymes reacted similarly within this range, with interesting clusters of positive or negative answers towards AHL treatment. In general the changes on the enzyme level were more severe in barley than in yam bean which might be due to the different

Quality of reporting in oncology phase II trials: A 5-year assessment through systematic review.

Science.gov (United States)

Langrand-Escure, Julien; Rivoirard, Romain; Oriol, Mathieu; Tinquaut, Fabien; Rancoule, Chloé; Chauvin, Frank; Magné, Nicolas; Bourmaud, Aurélie

2017-01-01

Phase II clinical trials are a cornerstone of the development in experimental treatments They work as a "filter" for phase III trials confirmation. Surprisingly the attrition ratio in Phase III trials in oncology is significantly higher than in any other medical specialty. This suggests phase II trials in oncology fail to achieve their goal. Objective The present study aims at estimating the quality of reporting in published oncology phase II clinical trials. A literature review was conducted among all phase II and phase II/III clinical trials published during a 5-year period (2010-2015). All articles electronically published by three randomly-selected oncology journals with Impact-Factors>4 were included: Journal of Clinical Oncology, Annals of Oncology and British Journal of Cancer. Quality of reporting was assessed using the Key Methodological Score. 557 articles were included. 315 trials were single-arm studies (56.6%), 193 (34.6%) were randomized and 49 (8.8%) were non-randomized multiple-arm studies. The Methodological Score was equal to 0 (lowest level), 1, 2, 3 (highest level) respectively for 22 (3.9%), 119 (21.4%), 270 (48.5%) and 146 (26.2%) articles. The primary end point is almost systematically reported (90.5%), while sample size calculation is missing in 66% of the articles. 3 variables were independently associated with reporting of a high standard: presence of statistical design (p-value <0.001), multicenter trial (p-value = 0.012), per-protocol analysis (p-value <0.001). Screening was mainly performed by a sole author. The Key Methodological Score was based on only 3 items, making grey zones difficult to translate. This literature review highlights the existence of gaps concerning the quality of reporting. It therefore raised the question of the suitability of the methodology as well as the quality of these trials, reporting being incomplete in the corresponding articles.

Advanced materials for future Phase II LHC collimators

CERN Document Server

Dallocchio, A; Arnau Izquierdo, G; Artoos, K

2009-01-01

Phase I collimators, equipped with Carbon-Carbon jaws, effectively met specifications for the early phase of LHC operation. However, the choice of carbon-based materials is expected to limit the nominal beam intensity mainly because of the high RF impedance and limited efficiency of the collimators. Moreover, C/C may be degraded by high radiation doses. To overcome these limitations, new Phase II secondary collimators will complement the existing system. Their extremely challenging requirements impose a thorough material investigation effort aiming at identifying novel materials combining very diverse properties. Relevant figures of merit have been identified to classify materials: Metal-diamonds composites look a promising choice as they combine good thermal, structural and stability properties. Molybdenum is interesting for its good thermal stability. Ceramics with non-conventional RF performances are also being evaluated. The challenges posed by the development and industrialization of these materials are ...

How competitive are EU electricity markets? An assessment of ETS Phase II

International Nuclear Information System (INIS)

Castagneto-Gissey, Giorgio

2014-01-01

This paper studies the interactions between electricity and carbon allowance prices in the year-ahead energy markets of France, Germany, United Kingdom and the Nordic countries, during Phase II of the EU ETS. VAR and Granger-causality methods are used to analyze causal interfaces, whereas the volatility of electricity prices is studied with basic and asymmetric AR-GARCH models. Among the main results, the marginal rate at which carbon prices feed into electricity prices is shown to be ca. 135% in the EEX and Nord Pool markets, where electricity and carbon prices display bidirectional causality, and 109% in the UK. Therefore, generators in these markets internalized the cost of freely allotted emission allowances into their electricity prices considerably more than the proportionate increase in costs justified by effective carbon intensity. Moreover, electricity prices in France are found to Granger-cause the carbon price. This study also shows how European electricity prices are deeply linked to coal prices among other factors, both in terms of levels and volatility, regardless of the underlying fuel mix, and that coal was marginally more profitable than gas for electricity generation. EU policies aimed at increasing the carbon price are likely to be crucial in limiting the externalities involved in the transition to a low-carbon system. - Highlights: • The interactions between electricity and carbon prices during Phase II are investigated. • This work also studies the determinants of EU electricity price levels and volatilities. • Nord Pool, APX UK and EEX carbon cost pass-through rates emphasize low electricity market competitiveness. • Powernext electricity prices Granger-cause the Phase II carbon price. • Coal was marginally more profitable than gas during Phase II

Fiber Coupled Pulse Shaper for Sub-Nanosecond Pulse Lidar, Phase II

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National Aeronautics and Space Administration — This Small Business Innovation Research Phase II effort will develop an all-diode laser and fiber optic based, single frequency, sub-nanosecond pulsed laser source...

The evolutionarily conserved mediator subunit MDT-15/MED15 links protective innate immune responses and xenobiotic detoxification.

Directory of Open Access Journals (Sweden)

Read Pukkila-Worley

2014-05-01

Full Text Available Metazoans protect themselves from environmental toxins and virulent pathogens through detoxification and immune responses. We previously identified a small molecule xenobiotic toxin that extends survival of Caenorhabditis elegans infected with human bacterial pathogens by activating the conserved p38 MAP kinase PMK-1 host defense pathway. Here we investigate the cellular mechanisms that couple activation of a detoxification response to innate immunity. From an RNAi screen of 1,420 genes expressed in the C. elegans intestine, we identified the conserved Mediator subunit MDT-15/MED15 and 28 other gene inactivations that abrogate the induction of PMK-1-dependent immune effectors by this small molecule. We demonstrate that MDT-15/MED15 is required for the xenobiotic-induced expression of p38 MAP kinase PMK-1-dependent immune genes and protection from Pseudomonas aeruginosa infection. We also show that MDT-15 controls the induction of detoxification genes and functions to protect the host from bacteria-derived phenazine toxins. These data define a central role for MDT-15/MED15 in the coordination of xenobiotic detoxification and innate immune responses.

The evolutionarily conserved mediator subunit MDT-15/MED15 links protective innate immune responses and xenobiotic detoxification.

Science.gov (United States)

Pukkila-Worley, Read; Feinbaum, Rhonda L; McEwan, Deborah L; Conery, Annie L; Ausubel, Frederick M

2014-05-01

Metazoans protect themselves from environmental toxins and virulent pathogens through detoxification and immune responses. We previously identified a small molecule xenobiotic toxin that extends survival of Caenorhabditis elegans infected with human bacterial pathogens by activating the conserved p38 MAP kinase PMK-1 host defense pathway. Here we investigate the cellular mechanisms that couple activation of a detoxification response to innate immunity. From an RNAi screen of 1,420 genes expressed in the C. elegans intestine, we identified the conserved Mediator subunit MDT-15/MED15 and 28 other gene inactivations that abrogate the induction of PMK-1-dependent immune effectors by this small molecule. We demonstrate that MDT-15/MED15 is required for the xenobiotic-induced expression of p38 MAP kinase PMK-1-dependent immune genes and protection from Pseudomonas aeruginosa infection. We also show that MDT-15 controls the induction of detoxification genes and functions to protect the host from bacteria-derived phenazine toxins. These data define a central role for MDT-15/MED15 in the coordination of xenobiotic detoxification and innate immune responses.

Metabolism of acetaminophen (paracetamol) in plants--two independent pathways result in the formation of a glutathione and a glucose conjugate.

Science.gov (United States)

Huber, Christian; Bartha, Bernadett; Harpaintner, Rudolf; Schröder, Peter

2009-03-01

Pharmaceuticals and their metabolites are detected in the aquatic environment and our drinking water supplies. The need for high quality drinking water is one of the most challenging problems of our times, but still only little knowledge exists on the impact of these compounds on ecosystems, animals, and man. Biological waste water treatment in constructed wetlands is an effective and low-cost alternative, especially for the treatment of non-industrial, municipal waste water. In this situation, plants get in contact with pharmaceutical compounds and have to tackle their detoxification. The mechanisms for the detoxification of xenobiotics in plants are closely related to the mammalian system. An activation reaction (phase I) is followed by a conjugation (phase II) with hydrophilic molecules like glutathione or glucose. Phase III reactions can be summarized as storage, degradation, and transport of the xenobiotic conjugate. Until now, there is no information available on the fate of pharmaceuticals in plants. In this study, we want to investigate the fate and metabolism of N-acetyl-4-aminophenol (paracetamol) in plant tissues using the cell culture of Armoracia rusticana L. as a model system. A hairy root culture of A. rusticana was treated with acetaminophen in a liquid culture. The formation and identification of metabolites over time were analyzed using HPLC-DAD and LC-MSn techniques. With LC-MS technique, we were able to detect paracetamol and identify three of its metabolites in root cells of A. rusticana. Six hours after incubation with 1 mM of acetaminophen, the distribution of acetaminophen and related metabolites in the cells resulted in 18% paracetamol, 64% paracetamol-glucoside, 17% paracetamol glutathione, and 1% of the corresponding cysteine conjugate. The formation of two independently formed metabolites in plant root cells again revealed strong similarities between plant and mammalian detoxification systems. The detoxification mechanism of

An Instrument for Inspecting Aspheric Optical Surfaces and Components, Phase II

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National Aeronautics and Space Administration — This is a Phase II SBIR proposal to develop an extremely versatile optical inspection tool for aspheric optical components and optics that are not easily inspected...

2-Phase NSGA II: An Optimized Reward and Risk Measurements Algorithm in Portfolio Optimization

Directory of Open Access Journals (Sweden)

Seyedeh Elham Eftekharian

2017-11-01

Full Text Available Portfolio optimization is a serious challenge for financial engineering and has pulled down special attention among investors. It has two objectives: to maximize the reward that is calculated by expected return and to minimize the risk. Variance has been considered as a risk measure. There are many constraints in the world that ultimately lead to a non–convex search space such as cardinality constraint. In conclusion, parametric quadratic programming could not be applied and it seems essential to apply multi-objective evolutionary algorithm (MOEA. In this paper, a new efficient multi-objective portfolio optimization algorithm called 2-phase NSGA II algorithm is developed and the results of this algorithm are compared with the NSGA II algorithm. It was found that 2-phase NSGA II significantly outperformed NSGA II algorithm.

Microbially-accelerated consolidation of oil sands tailings. Pathway II: solid phase biogeochemistry

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Tariq eSiddique

2014-03-01

Full Text Available Consolidation of clay particles in aqueous tailings suspensions is a major obstacle to effective management of oil sands tailings ponds in northern Alberta, Canada. We have observed that microorganisms indigenous to the tailings ponds accelerate consolidation of mature fine tailings (MFT during active metabolism by using two biogeochemical pathways. In Pathway I, microbes alter porewater chemistry to indirectly increase consolidation of MFT. Here, we describe Pathway II comprising significant, direct and complementary biogeochemical reactions with MFT mineral surfaces. An anaerobic microbial community comprising Bacteria (predominantly Clostridiales, Synergistaceae and Desulfobulbaceae and Archaea (Methanolinea/Methanoregula and Methanosaeta transformed FeIII minerals in MFT to amorphous FeII minerals during methanogenic metabolism of an added organic substrate. Synchrotron analyses suggested that ferrihydrite (5Fe2O3. 9H2O and goethite (α-FeOOH were the dominant FeIII minerals in MFT. The formation of amorphous iron sulfide (FeS and possibly green rust entrapped and masked electronegative clay surfaces in amended MFT. Both Pathways I and II reduced the surface charge potential (repulsive forces of the clay particles in MFT, which aided aggregation of clays and formation of networks of pores, as visualized using cryo-scanning electron microscopy. These reactions facilitated the egress of porewater from MFT and increased consolidation of tailings solids. These results have large-scale implications for management and reclamation of oil sands tailings ponds, a burgeoning environmental issue for the public and government regulators.

Microbially-accelerated consolidation of oil sands tailings. Pathway II: solid phase biogeochemistry.

Science.gov (United States)

Siddique, Tariq; Kuznetsov, Petr; Kuznetsova, Alsu; Li, Carmen; Young, Rozlyn; Arocena, Joselito M; Foght, Julia M

2014-01-01

Consolidation of clay particles in aqueous tailings suspensions is a major obstacle to effective management of oil sands tailings ponds in northern Alberta, Canada. We have observed that microorganisms indigenous to the tailings ponds accelerate consolidation of mature fine tailings (MFT) during active metabolism by using two biogeochemical pathways. In Pathway I, microbes alter porewater chemistry to indirectly increase consolidation of MFT. Here, we describe Pathway II comprising significant, direct and complementary biogeochemical reactions with MFT mineral surfaces. An anaerobic microbial community comprising Bacteria (predominantly Clostridiales, Synergistaceae, and Desulfobulbaceae) and Archaea (Methanolinea/Methanoregula and Methanosaeta) transformed Fe(III) minerals in MFT to amorphous Fe(II) minerals during methanogenic metabolism of an added organic substrate. Synchrotron analyses suggested that ferrihydrite (5Fe2O3. 9H2O) and goethite (α-FeOOH) were the dominant Fe(III) minerals in MFT. The formation of amorphous iron sulfide (FeS) and possibly green rust entrapped and masked electronegative clay surfaces in amended MFT. Both Pathways I and II reduced the surface charge potential (repulsive forces) of the clay particles in MFT, which aided aggregation of clays and formation of networks of pores, as visualized using cryo-scanning electron microscopy (SEM). These reactions facilitated the egress of porewater from MFT and increased consolidation of tailings solids. These results have large-scale implications for management and reclamation of oil sands tailings ponds, a burgeoning environmental issue for the public and government regulators.

Phased Retrofits in Existing Homes in Florida Phase II: Shallow Plus Retrofits

Energy Technology Data Exchange (ETDEWEB)

Sutherland, K. [Building America Partnership for Improved Residential Construction, Cocoa, FL (United States); Parker, D. [Building America Partnership for Improved Residential Construction, Cocoa, FL (United States); Martin, E. [Building America Partnership for Improved Residential Construction, Cocoa, FL (United States); Chasar, D. [Building America Partnership for Improved Residential Construction, Cocoa, FL (United States); Amos, B. [Building America Partnership for Improved Residential Construction, Cocoa, FL (United States)

2016-02-03

The BAPIRC team and Florida Power and Light (FPL) electric utility pursued a pilot phased energy-efficiency retrofit program in Florida by creating detailed data on the energy and economic performance of two levels of retrofit - simple and deep. For this Phased Deep Retrofit (PDR) project, a total of 56 homes spread across the utility partner's territory in east central Florida, southeast Florida, and southwest Florida were instrumented between August 2012 and January 2013, and received simple pass-through retrofit measures during the period of March 2013 - June 2013. Ten of these homes received a deeper package of retrofits during August 2013 - December 2013. A full account of Phase I of this project, including detailed home details and characterization, is found in Parker et al, 2015 (currently in draft). Phase II of this project, which is the focus of this report, applied the following additional retrofit measures to select homes that received a shallow retrofit in Phase I: a) Supplemental mini-split heat pump (MSHP) (6 homes); b) Ducted and space coupled Heat Pump Water Heater (8 homes); c) Exterior insulation finish system (EIFS) (1 homes); d) Window retrofit (3 homes); e) Smart thermostat (21 homes: 19 NESTs; 2 Lyrics); f) Heat pump clothes dryer (8 homes); g) Variable speed pool pump (5 homes).

Caelyx (TM) in malignant mesothelioma : A phase II EORTC study

NARCIS (Netherlands)

Baas, P; van Meerbeeck, J; Groen, H; Schouwink, H; Burgers, S; Daamen, S; Giaccone, G

Background: The use of doxorubicin has shown some activity in malignant mesothelioma but prolonged administration is hampered by cardiotoxicity. Caelyx(TM), a new liposomal and pegylated form of doxorubicin has shown a better pharmacokinetic and toxic profile then doxorubicin. In a phase II study,

Bile Acid Signaling in Metabolic Disease and Drug Therapy

Science.gov (United States)

Li, Tiangang

2014-01-01

Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates hepatobiliary secretion of lipids, lipophilic metabolites, and xenobiotics. In the intestine, bile acids are essential for the absorption, transport, and metabolism of dietary fats and lipid-soluble vitamins. Extensive research in the last 2 decades has unveiled new functions of bile acids as signaling molecules and metabolic integrators. The bile acid–activated nuclear receptors farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, vitamin D receptor, and G protein–coupled bile acid receptor play critical roles in the regulation of lipid, glucose, and energy metabolism, inflammation, and drug metabolism and detoxification. Bile acid synthesis exhibits a strong diurnal rhythm, which is entrained by fasting and refeeding as well as nutrient status and plays an important role for maintaining metabolic homeostasis. Recent research revealed an interaction of liver bile acids and gut microbiota in the regulation of liver metabolism. Circadian disturbance and altered gut microbiota contribute to the pathogenesis of liver diseases, inflammatory bowel diseases, nonalcoholic fatty liver disease, diabetes, and obesity. Bile acids and their derivatives are potential therapeutic agents for treating metabolic diseases of the liver. PMID:25073467

Advances in drug metabolism and pharmacogenetics research in Australia.

Science.gov (United States)

Mackenzie, Peter I; Somogyi, Andrew A; Miners, John O

2017-02-01

Metabolism facilitates the elimination, detoxification and excretion in urine or bile (as biotransformation products) of a myriad of structurally diverse drugs and other chemicals. The metabolism of drugs, non-drug xenobiotics and many endogenous compounds is catalyzed by families of drug metabolizing enzymes (DMEs). These include the hemoprotein-containing cytochromes P450, which function predominantly as monooxygenases, and conjugation enzymes that transfer a sugar, sulfate, acetate or glutathione moiety to substrates containing a suitable acceptor functional group. Drug and chemical metabolism, especially the enzymes that catalyse these reactions, has been the research focus of several groups in Australia for over four decades. In this review, we highlight the role of recent and current drug metabolism research in Australia, including elucidation of the structure and function of enzymes from the various DME families, factors that modulate enzyme activity in humans (e.g. drug-drug interactions, gene expression and genetic polymorphism) and the application of in vitro approaches for the prediction of drug metabolism parameters in humans, along with the broader pharmacological/clinical pharmacological and toxicological significance of drug metabolism and DMEs and their relevance to drug discovery and development, and to clinical practice. Copyright © 2016 Elsevier Ltd. All rights reserved.

A catalogue of polymorphisms related to xenobiotic metabolism and cancer susceptibility.

Science.gov (United States)

Gemignani, Federica; Landi, Stefano; Vivant, Franck; Zienolddiny, Shanbeh; Brennan, Paul; Canzian, Federico

2002-08-01

High-throughput genotyping technology of multiple genes based on large samples of cases and controls are likely to be important in identifying common genes which have a moderate effect on the development of specific diseases. We present here a comprehensive list of 313 known experimentally confirmed polymorphisms in 54 genes which are particularly relevant for metabolism of drugs, alcohol, tobacco, and other potential carcinogens. We have compiled a catalog with a standardized format that summarizes the genetic and biochemical properties of the selected polymorphisms. We have also confirmed or redesigned experimental conditions for simplex or multiplex PCR amplification of a subset of 168 SNPs of particular interest, which will provide the basis for the design of assays compatible with high-throughput genotyping.

The Simplest Flowchart Stating the Mechanisms for Organic Xenobiotics-induced Toxicity: Can it Possibly be Accepted as a "Central Dogma" for Toxic Mechanisms?

Science.gov (United States)

Park, Yeong-Chul; Lee, Sundong; Cho, Myung-Haing

2014-09-01

Xenobiotics causing a variety of toxicity in biological systems could be classified as two types, inorganic and organic chemicals. It is estimated that the organic xenobiotics are responsible for approximately 80~90% of chemical-induced toxicity in human population. In the class for toxicology, we have encountered some difficulties in explaining the mechanisms of toxicity caused especially by organic chemicals. Here, a simple flowchart was introduced for explaining the mechanism of toxicity caused by organic xenobiotics, as the central dogma of molecular biology. This flowchart, referred to as a central dogma, was described based on a view of various aspects as follows: direct-acting chemicals vs. indirect-acting chemicals, cytochrome P450-dependent vs. cytochrome P450-independent biotransformation, reactive intermediates, reactivation, toxicokinetics vs. toxicodynamics, and reversibility vs. irreversibility. Thus, the primary objective of this flowchart is to help better understanding of the organic xenobiotics-induced toxic mechanisms, providing a major pathway for toxicity occurring in biological systems.

Phase equilibrium measurements and the tuning behavior of new sII clathrate hydrates

Energy Technology Data Exchange (ETDEWEB)

Shin, Woongchul; Park, Seongmin; Ro, Hyeyoon; Koh, Dong-Yeun; Seol, Jiwoong [Department of Chemical and Biomolecular Engineering (BK21 Program), KAIST, Daejeon 305-701 (Korea, Republic of); Lee, Huen, E-mail: h_lee@kaist.ac.kr [Department of Chemical and Biomolecular Engineering (BK21 Program), KAIST, Daejeon 305-701 (Korea, Republic of); Graduate School of EEWS, KAIST, Daejeon 305-701 (Korea, Republic of)

2012-01-15

Graphical abstract: Pyrrolidine and piperidine act as sII clathrate hydrate formers under methane gas. Highlights: > New sII clathrate hydrate formers were proposed: pyrrolidine and piperidine. > Formation of gas hydrate with methane as help gas was confirmed. > NMR, Raman, and XRD patterns were analyzed to identify the hydrate structures. > We measured (L + H + V) phase equilibrium with proposed hydrate formers. > Tuning phenomena increase gas storage in (pyrrolidine + CH{sub 4}) clathrate hydrates. - Abstract: We suggest two types of new amine-type sII formers: pyrrolidine and piperidine. These guest compounds fail to form clathrate hydrate structures with host water, but instead have to combine with light gaseous guest molecules (methane) for enclathration. First, two binary clathrate hydrates of (pyrrolidine + methane) and (piperidine + methane) were synthesized at various amine concentrations. {sup 13}C NMR and Raman analysis were done to identify the clathrate hydrate structure and guest distribution over sII-S and sII-L cages. XRD was also used to find the exact structure and corresponding cell parameters. At a dilute pyrrolidine concentration of less than 5.56 mol%, the tuning phenomenon is observed such that methane molecules surprisingly occupy sII-L cages. At the critical guest concentration of about 0.1 mol%, the cage occupancy ratio reaches the maximum of approximately 0.5. At very dilute guest concentration below 0.1 mol%, the methane molecules fail to occupy large cages on account of their rarefied distribution in the network. Direct-release experiments were performed to determine the actual guest compositions in the clathrate hydrate phases. Finally, we measured the clathrate hydrate phase equilibria of (pyrrolidine + methane) and (piperidine + methane).

Phase equilibrium measurements and the tuning behavior of new sII clathrate hydrates

International Nuclear Information System (INIS)

Shin, Woongchul; Park, Seongmin; Ro, Hyeyoon; Koh, Dong-Yeun; Seol, Jiwoong; Lee, Huen

2012-01-01

Graphical abstract: Pyrrolidine and piperidine act as sII clathrate hydrate formers under methane gas. Highlights: → New sII clathrate hydrate formers were proposed: pyrrolidine and piperidine. → Formation of gas hydrate with methane as help gas was confirmed. → NMR, Raman, and XRD patterns were analyzed to identify the hydrate structures. → We measured (L + H + V) phase equilibrium with proposed hydrate formers. → Tuning phenomena increase gas storage in (pyrrolidine + CH 4 ) clathrate hydrates. - Abstract: We suggest two types of new amine-type sII formers: pyrrolidine and piperidine. These guest compounds fail to form clathrate hydrate structures with host water, but instead have to combine with light gaseous guest molecules (methane) for enclathration. First, two binary clathrate hydrates of (pyrrolidine + methane) and (piperidine + methane) were synthesized at various amine concentrations. 13 C NMR and Raman analysis were done to identify the clathrate hydrate structure and guest distribution over sII-S and sII-L cages. XRD was also used to find the exact structure and corresponding cell parameters. At a dilute pyrrolidine concentration of less than 5.56 mol%, the tuning phenomenon is observed such that methane molecules surprisingly occupy sII-L cages. At the critical guest concentration of about 0.1 mol%, the cage occupancy ratio reaches the maximum of approximately 0.5. At very dilute guest concentration below 0.1 mol%, the methane molecules fail to occupy large cages on account of their rarefied distribution in the network. Direct-release experiments were performed to determine the actual guest compositions in the clathrate hydrate phases. Finally, we measured the clathrate hydrate phase equilibria of (pyrrolidine + methane) and (piperidine + methane).

F/H Area Effluent Treatment Facility. Phase II. CAC basic data

International Nuclear Information System (INIS)

Collins, W.W.; O'Leary, C.D.

1984-01-01

Project objectives and requirements are listed for both Phase I and II. Schedule is listed with startup targeted for 1989. Storage facilities will be provided for both chemical and radioactive effluents. 8 figs., 19 tabs

Modeling antibiotic and cytotoxic effects of the dimeric isoquinoline IQ-143 on metabolism and its regulation in Staphylococcus aureus, Staphylococcus epidermidis and human cells

Science.gov (United States)

2011-01-01

Background Xenobiotics represent an environmental stress and as such are a source for antibiotics, including the isoquinoline (IQ) compound IQ-143. Here, we demonstrate the utility of complementary analysis of both host and pathogen datasets in assessing bacterial adaptation to IQ-143, a synthetic analog of the novel type N,C-coupled naphthyl-isoquinoline alkaloid ancisheynine. Results Metabolite measurements, gene expression data and functional assays were combined with metabolic modeling to assess the effects of IQ-143 on Staphylococcus aureus, Staphylococcus epidermidis and human cell lines, as a potential paradigm for novel antibiotics. Genome annotation and PCR validation identified novel enzymes in the primary metabolism of staphylococci. Gene expression response analysis and metabolic modeling demonstrated the adaptation of enzymes to IQ-143, including those not affected by significant gene expression changes. At lower concentrations, IQ-143 was bacteriostatic, and at higher concentrations bactericidal, while the analysis suggested that the mode of action was a direct interference in nucleotide and energy metabolism. Experiments in human cell lines supported the conclusions from pathway modeling and found that IQ-143 had low cytotoxicity. Conclusions The data suggest that IQ-143 is a promising lead compound for antibiotic therapy against staphylococci. The combination of gene expression and metabolite analyses with in silico modeling of metabolite pathways allowed us to study metabolic adaptations in detail and can be used for the evaluation of metabolic effects of other xenobiotics. PMID:21418624

Imitation of phase I oxidative metabolism of anabolic steroids by titanium dioxide photocatalysis.

Science.gov (United States)

Ruokolainen, Miina; Valkonen, Minna; Sikanen, Tiina; Kotiaho, Tapio; Kostiainen, Risto

2014-12-18

The aim of this study was to investigate the feasibility of titanium dioxide (TiO2) photocatalysis for oxidation of anabolic steroids and for imitation of their phase I metabolism. The photocatalytic reaction products of five anabolic steroids were compared to their phase I in vitro metabolites produced by human liver microsomes (HLM). The same main reaction types - hydroxylation, dehydrogenation and combination of these two - were observed both in TiO2 photocatalysis and in microsomal incubations. Several isomers of each product type were formed in both systems. Based on the same mass, retention time and similarity of the product ion spectra, many of the products observed in HLM reactions were also formed in TiO2 photocatalytic reactions. However, products characteristic to only either one of the systems were also formed. In conclusion, TiO2 photocatalysis is a rapid, simple and inexpensive method for imitation of phase I metabolism of anabolic steroids and production of metabolite standards. Copyright © 2014 Elsevier B.V. All rights reserved.

Urban Integrated Industrial Cogeneration Systems Analysis. Phase II final report

Energy Technology Data Exchange (ETDEWEB)

1984-01-01

Through the Urban Integrated Industrial Cogeneration Systems Analysis (UIICSA), the City of Chicago embarked upon an ambitious effort to identify the measure the overall industrial cogeneration market in the city and to evaluate in detail the most promising market opportunities. This report discusses the background of the work completed during Phase II of the UIICSA and presents the results of economic feasibility studies conducted for three potential cogeneration sites in Chicago. Phase II focused on the feasibility of cogeneration at the three most promising sites: the Stockyards and Calumet industrial areas, and the Ford City commercial/industrial complex. Each feasibility case study considered the energy load requirements of the existing facilities at the site and the potential for attracting and serving new growth in the area. Alternative fuels and technologies, and ownership and financing options were also incorporated into the case studies. Finally, site specific considerations such as development incentives, zoning and building code restrictions and environmental requirements were investigated.

MULTIFUNCTIONAL, SELF-HEALING HYBRIDSIL MATERIALS FOR EVA SPACE SUIT PRESSURE GARMENT SYSTEMS, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — A Phase II SBIR transition of NanoSonic's high flex HybridSil space suit bladder and glove materials will provide a pivotal funding bridge toward Phase III...

Monolithic, High-Speed Fiber-Optic Switching Array for Lidar, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — This NASA SBIR Phase II effort will develop a 1 x 10 prototype non-mechanical fiber optic switch for use with high power lasers. The proposed optical device is a...

The skin function: a factor of anti-metabolic syndrome

Directory of Open Access Journals (Sweden)

Zhou Shi-Sheng

2012-04-01

Full Text Available Abstract The body’s total antioxidant capacity represents a sum of the antioxidant capacity of various tissues/organs. A decrease in the body’s antioxidant capacity may induce oxidative stress and subsequent metabolic syndrome, a clustering of risk factors for type 2 diabetes and cardiovascular disease. The skin, the largest organ of the body, is one of the major components of the body’s total antioxidant defense system, primarily through its xenobiotic/drug biotransformation system, reactive oxygen species-scavenging system, and sweat glands- and sebaceous glands-mediated excretion system. Notably, unlike other contributors, the skin contribution is variable, depending on lifestyles and ambient temperature or seasonal variations. Emerging evidence suggests that decreased skin’s antioxidant and excretory functions (e.g., due to sedentary lifestyles and low ambient temperature may increase the risk for metabolic syndrome. This review focuses on the relationship between the variability of skin-mediated detoxification and elimination of exogenous and endogenous toxic substances and the development of metabolic syndrome. The potential role of sebum secretion in lipid and cholesterol homeostasis and its impact on metabolic syndrome, and the association between skin disorders (acanthosis nigricans, acne, and burn and metabolic syndrome are also discussed.

Assessment of the impact of xenobiotic pollutants on the marine organisms: Molecular biomarker approach

Digital Repository Service at National Institute of Oceanography (India)

Sarkar, A.

of the organisms to xenobiotic compounds being transformed into reactive oxygen species. Most importantly, the occurrence of DNA strand breaks in marine organisms leading to the loss of DNA integrity is a significant biomarker of marine pollution. The measurement...

Effects of Curcuma xanthorrhiza Extracts and Their Constituents on Phase II Drug-metabolizing Enzymes Activity

Science.gov (United States)

Salleh, Nurul Afifah Mohd; Ismail, Sabariah; Ab Halim, Mohd Rohaimi

2016-01-01

Background: Curcuma xanthorrhiza is a native Indonesian plant and traditionally utilized for a range of illness including liver damage, hypertension, diabetes, and cancer. Objective: The study determined the effects of C. xanthorrhiza extracts (ethanol and aqueous) and their constituents (curcumene and xanthorrhizol) on UDP-glucuronosyltransferase (UGT) and glutathione transferase (GST) activities. Materials and Methods: The inhibition studies were evaluated both in rat liver microsomes and in human recombinant UGT1A1 and UGT2B7 enzymes. p-nitrophenol and beetle luciferin were used as the probe substrates for UGT assay while 1-chloro-2,4-dinitrobenzene as the probe for GST assay. The concentrations of extracts studied ranged from 0.1 to 1000 μg/mL while for constituents ranged from 0.01 to 500 μM. Results: In rat liver microsomes, UGT activity was inhibited by the ethanol extract (IC50 =279.74 ± 16.33 μg/mL). Both UGT1A1 and UGT2B7 were inhibited by the ethanol and aqueous extracts with IC50 values ranging between 9.59–22.76 μg/mL and 110.71–526.65 μg/Ml, respectively. Rat liver GST and human GST Pi-1 were inhibited by ethanol and aqueous extracts, respectively (IC50 =255.00 ± 13.06 μg/mL and 580.80 ± 18.56 μg/mL). Xanthorrhizol was the better inhibitor of UGT1A1 (IC50 11.30 ± 0.27 μM) as compared to UGT2B7 while curcumene did not show any inhibition. For GST, both constituents did not show any inhibition. Conclusion: These findings suggest that C. xanthorrhiza have the potential to cause herb-drug interaction with drugs that are primarily metabolized by UGT and GST enzymes. SUMMARY Findings from this study would suggest which of Curcuma xanthorrhiza extracts and constituents that would have potential interactions with drugs which are highly metabolized by UGT and GST enzymes. Further clinical studies can then be designed if needed to evaluate the in vivo pharmacokinetic relevance of these interactions Abbreviations Used: BSA: Bovine serum albumin

Prospera Digital Phase II: Financial inclusion for low-income women ...

International Development Research Centre (IDRC) Digital Library (Canada)

Prospera Digital Phase II: Financial inclusion for low-income women in Mexico ... a research network in Latin America, to identify barriers and opportunities to scale up ... Call for new OWSD Fellowships for Early Career Women Scientists now open ... conference of McGill's Institute for the Study of International Development.

Phase II cancer clinical trials for biomarker-guided treatments.

Science.gov (United States)

Jung, Sin-Ho

2018-01-01

The design and analysis of cancer clinical trials with biomarker depend on various factors, such as the phase of trials, the type of biomarker, whether the used biomarker is validated or not, and the study objectives. In this article, we demonstrate the design and analysis of two Phase II cancer clinical trials, one with a predictive biomarker and the other with an imaging prognostic biomarker. Statistical testing methods and their sample size calculation methods are presented for each trial. We assume that the primary endpoint of these trials is a time to event variable, but this concept can be used for any type of endpoint.

Causalities between CO2, electricity, and other energy variables during phase I and phase II of the EU ETS

International Nuclear Information System (INIS)

Keppler, Jan Horst; Mansanet-Bataller, Maria

2010-01-01

The topic of this article is the analysis of the interplay between daily carbon, electricity and gas price data with the European Union Emission Trading System (EU ETS) for CO 2 emissions. In a first step we have performed Granger causality tests for Phase I of the EU ETS (January 2005 until December 2007) and the first year of Phase II of the EU ETS (2008). The analysis includes both spot and forward markets - given the close interactions between the two sets of markets. The results show that during Phase I coal and gas prices, through the clean dark and spark spread, impacted CO 2 futures prices, which in return Granger caused electricity prices. During the first year of the Phase II, the short-run rent capture theory (in which electricity prices Granger cause CO 2 prices) prevailed. On the basis of the qualitative results of the Granger causality tests we obtained the formulation testable equations for quantitative analysis. Standard OLS regressions yielded statistically robust and theoretically coherent results. (author)

The first preparative solution phase synthesis of melanotan II

Directory of Open Access Journals (Sweden)

2008-10-01

Full Text Available Melanotan II is a synthetic cyclic heptapeptide used to prevent a sunlight-induced skin cancer by stimulating the skin tanning process. In this paper we report the first solution phase synthesis of the title compound. The hexapeptide sequence has been assembled by [(2+2+1+1] scheme. After removing the orthogonal protection, a carbodiimide mediated lactamization, involving the ε-amino group of lysine and γ-carboxy group of aspartic acid, led to a cyclic intermediate. Appending N-acetylnorleucine concluded the assembly of melanotan II molecule. Protection of the lateral groups in arginine and tryptophan was omitted for atom and step economy reasons. The total synthesis of melanotan II was accomplished in 12 steps with 2.6% overall yield, affording >90% pure peptide without using preparative chromatography.

Bioanalytical methods for determination of tamoxifen and its phase I metabolites: A review

International Nuclear Information System (INIS)

Teunissen, S.F.; Rosing, H.; Schinkel, A.H.; Schellens, J.H.M.; Beijnen, J.H.

2010-01-01

The selective estrogen receptor modulator tamoxifen is used in the treatment of early and advanced breast cancer and in selected cases for breast cancer prevention in high-risk subjects. The cytochrome P450 enzyme system and flavin-containing monooxygenase are responsible for the extensive metabolism of tamoxifen into several phase I metabolites that vary in toxicity and potencies towards estrogen receptor (ER) alpha and ER beta. An extensive overview of publications on the determination of tamoxifen and its phase I metabolites in biological samples is presented. In these publications techniques were used such as capillary electrophoresis, liquid, gas and thin layer chromatography coupled with various detection techniques (mass spectrometry, ultraviolet or fluorescence detection, liquid scintillation counting and nuclear magnetic resonance spectroscopy). A trend is seen towards the use of liquid chromatography coupled to mass spectrometry (LC-MS). State-of-the-art LC-MS equipment allowed for identification of unknown metabolites and quantification of known metabolites reaching lower limit of quantification levels in the sub pg mL -1 range. Although tamoxifen is also metabolized into phase II metabolites, the number of publications reporting on phase II metabolism of tamoxifen is scarce. Therefore the focus of this review is on phase I metabolites of tamoxifen. We conclude that in the past decades tamoxifen metabolism has been studied extensively and numerous metabolites have been identified. Assays have been developed for both the identification and quantification of tamoxifen and its metabolites in an array of biological samples. This review can be used as a resource for method transfer and development of analytical methods used to support pharmacokinetic and pharmacodynamic studies of tamoxifen and its phase I metabolites.

Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia.

Science.gov (United States)

von Stackelberg, Arend; Locatelli, Franco; Zugmaier, Gerhard; Handgretinger, Rupert; Trippett, Tanya M; Rizzari, Carmelo; Bader, Peter; O'Brien, Maureen M; Brethon, Benoît; Bhojwani, Deepa; Schlegel, Paul Gerhardt; Borkhardt, Arndt; Rheingold, Susan R; Cooper, Todd Michael; Zwaan, Christian M; Barnette, Phillip; Messina, Chiara; Michel, Gérard; DuBois, Steven G; Hu, Kuolung; Zhu, Min; Whitlock, James A; Gore, Lia

2016-12-20

Purpose Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19 on B-cell lymphoblasts. We evaluated the safety, pharmacokinetics, recommended dosage, and potential for efficacy of blinatumomab in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Methods This open-label study enrolled children treatment cycles. Primary end points were maximum-tolerated dosage (phase I) and complete remission rate within the first two cycles (phase II). Results We treated 49 patients in phase I and 44 patients in phase II. Four patients had dose-limiting toxicities in cycle 1 (phase I). Three experienced grade 4 cytokine-release syndrome (one attributed to grade 5 cardiac failure); one had fatal respiratory failure. The maximum-tolerated dosage was 15 µg/m 2 /d. Blinatumomab pharmacokinetics was linear across dosage levels and consistent among age groups. On the basis of the phase I data, the recommended blinatumomab dosage for children with relapsed/refractory ALL was 5 µg/m 2 /d for the first 7 days, followed by 15 µg/m 2 /d thereafter. Among the 70 patients who received the recommended dosage, 27 (39%; 95% CI, 27% to 51%) achieved complete remission within the first two cycles, 14 (52%) of whom achieved complete minimal residual disease response. The most frequent grade ≥ 3 adverse events were anemia (36%), thrombocytopenia (21%), and hypokalemia (17%). Three patients (4%) and one patient (1%) had cytokine-release syndrome of grade 3 and 4, respectively. Two patients (3%) interrupted treatment after grade 2 seizures. Conclusion This trial, which to the best of our knowledge was the first such trial in pediatrics, demonstrated antileukemic activity of single-agent blinatumomab with complete minimal residual disease response in children with relapsed/refractory BCP-ALL. Blinatumomab may represent an important new treatment option in this setting, requiring further investigation in curative indications.

In vitro metabolism of benzo[a]pyrene-7,8-dihydrodiol and dibenzo[def,p]chrysene-11,12 diol in rodent and human hepatic microsomes

Energy Technology Data Exchange (ETDEWEB)

Smith, Jordan N.; Mehinagic, Denis; Nag, Subhasree; Crowell, Susan R.; Corley, Richard A.

2017-03-01

Polycyclic aromatic hydrocarbons (PAHs) are contaminants that are ubiquitously found in the environment, produced through combustion of organic matter or petrochemicals, and many of which are procarcinogens. The prototypic PAH, benzo[a]pyrene (B[a]P) and the highly carcinogenic dibenzo[def,p]chrysene (DBC) are metabolically activated by isoforms of the P450 enzyme superfamily producing benzo[a]pyrene-7,8-dihydrodiol (B[a]P diol), dibenzo[def,p]chrysene-11,12 diol (DBC diol). Each of these diols can be further metabolized by cytochrome P450 enzymes to highly reactive diol-epoxide metabolites that readily react with DNA or by phase II conjugation facilitating excretion. To complement prior in vitro metabolism studies with parent B[a]P and DBC, both phase I metabolism and phase II glucuronidation of B[a]P diol and DBC diol were measured in hepatic microsomes from female B6129SF1/J mice, male Sprague-Dawley rats, and female humans. Metabolic parameters, including intrinsic clearance and Michaelis-Menten kinetics were calculated from substrate depletion data. Mice and rats demonstrated similar B[a]P diol phase I metabolic rates. Compared to rodents, human phase I metabolism of B[a]P diol demonstrated lower overall metabolic capacity, lower intrinsic clearance at higher substrate concentrations (>0.14 µM), and higher intrinsic clearance at lower substrate concentrations (<0.07 µM). Rates of DBC diol metabolism did not saturate in mice or humans and were highest overall in mice. Higher affinity constants and lower capacities were observed for DBC diol glucuronidation compared to B[a]P diol glucuronidation; however, intrinsic clearance values for these compounds were consistent within each species. Kinetic parameters reported here will be used to extend physiologically based pharmacokinetic (PBPK) models to include the disposition of B[a]P and DBC metabolites in animal models and humans to support future human health risk assessments.

Identification of phase I and II metabolites of the new designer drug α-pyrrolidinohexiophenone (α-PHP) in human urine by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS).

Science.gov (United States)

Paul, Michael; Bleicher, Sergej; Guber, Susanne; Ippisch, Josef; Polettini, Aldo; Schultis, Wolfgang

2015-11-01

Pyrrolidinophenones represent one emerging class of newly encountered drugs of abuse, also known as 'new psychoactive substances', with stimulating psychoactive effects. In this work, we report on the detection of the new designer drug α-pyrrolidinohexiophenone (α-PHP) and its phase I and II metabolites in a human urine sample of a drug abuser. Determination and structural elucidation of these metabolites have been achieved by liquid chromatography electrospray ionisation quadrupole time-of-flight mass spectrometry (LC-ESI-QTOF-MS). By tentative identification, the exact and approximate structures of 19 phase I metabolites and nine phase II glucuronides were elucidated. Major metabolic pathways revealed the reduction of the ß-keto moieties to their corresponding alcohols, didesalkylation of the pyrrolidine ring, hydroxylation and oxidation of the aliphatic side chain leading to n-hydroxy, aldehyde and carboxylate metabolites, and oxidation of the pyrrolidine ring to its lactam followed by ring cleavage and additional hydroxylation, reduction and oxidation steps and combinations thereof. The most abundant phase II metabolites were glucuronidated ß-keto-reduced alcohols. Besides the great number of metabolites detected in this sample, α-PHP is still one of the most abundant ions together with its ß-keto-reduced alcoholic dihydro metabolite. Monitoring of these metabolites in clinical and forensic toxicology may unambiguously prove the abuse of the new designer drug α-PHP. Copyright © 2015 John Wiley & Sons, Ltd.

The Simplest Flowchart Stating the Mechanisms for Organic Xenobiotics-induced Toxicity: Can it Possibly be Accepted as a “Central Dogma” for Toxic Mechanisms?

Science.gov (United States)

Lee, Sundong; Cho, Myung-Haing

2014-01-01

Xenobiotics causing a variety of toxicity in biological systems could be classified as two types, inorganic and organic chemicals. It is estimated that the organic xenobiotics are responsible for approximately 80~90% of chemical-induced toxicity in human population. In the class for toxicology, we have encountered some difficulties in explaining the mechanisms of toxicity caused especially by organic chemicals. Here, a simple flowchart was introduced for explaining the mechanism of toxicity caused by organic xenobiotics, as the central dogma of molecular biology. This flowchart, referred to as a central dogma, was described based on a view of various aspects as follows: direct-acting chemicals vs. indirect-acting chemicals, cytochrome P450-dependent vs. cytochrome P450-independent biotransformation, reactive intermediates, reactivation, toxicokinetics vs. toxicodynamics, and reversibility vs. irreversibility. Thus, the primary objective of this flowchart is to help better understanding of the organic xenobiotics-induced toxic mechanisms, providing a major pathway for toxicity occurring in biological systems. PMID:25343011

Lightweight Design of an HTS Coil for the VASIMR Experiment, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — In this Phase II SBIR contract Tai-Yang Research Company of Tennessee proposes to design, fabricate, and test an ultra-lightweight High Temperature Superconducting...

[Study on the phase II metabolites of phenoprolamine hydrochloride in rat bile by LC/DAD/MSD].

Science.gov (United States)

Ding, L; Zhang, Z X; Ni, P Z; Wang, G J; An, D K

2001-06-01

To study the phase II metabolites of phenoprolamine hydrochloride (DDPH) in rat bile. DDPH was administered by i.p. to bile duct-cannulated rats. Bile samples were collected before drug administration and up to 12 h after drug administration. After being purified and enriched with C-18 SPE columns the rat bile samples were analyzed by LC/DAD/MSD to identify the peaks of phase II metabolites. The fractions of phase II metabolites were prepared by HPLC and treated with beta-glucuronidase, and then were purified and enriched with C-18 SPE columns and analyzed by LC/DAD/MSD. The corresponding reference standards of DDPH phase I metabolites were analyzed by LC/DAD/MSD under identical conditions. The peaks M7, M8 and M9 in the chromatograms of rat bile samples were the phase II metabolites of DDPH and the enzymatic hydrolysates of M7, M8 and M9 were 1-(2, 6-dimethyl-4-hydroxyphenoxy)-2-(3, 4-methoxyphenylethylamino)-propane (M3), 1-(2, 6-dimethyl-3-hydroxyphenoxy)-2-(3, 4-methoxyphenylethylamino)-propane (M2) and 1-(2,6-dimethylphenoxy)-2-(3-methoxy-4-hydroxyphenylethyl-amino)-propane (M1) respectively. beta-1-O-[3,5-dimethyl-4-[-2-methyl-2-(3,4-dimethoxy-phenylethylamino)- ethoxy]-phenyl]-glucuronic acid (M7, glucuronide of M3), beta-1-O-[2, 4-dimethyl-3-[2-methyl-2-(3, 4-dimethoxy-phenylethylamino)-ethoxy]-phenyl]-glucuronic acid (M8, glucuronide of M2) and beta-1-O-[2-methoxy-4-[1-methyl-2-(2, 6-dimethylphenoxy)-ethylamino-ethyl]-phenyl]-glucuronic acid (M9, glucuronide of M1) were the phase II metabolites of DDPH in rat bile.

Life cycle and economic efficiency analysis phase II : durable pavement markings.

Science.gov (United States)

2011-04-01

This report details the Phase II analysis of the life cycle and economic efficiency of inlaid tape : and thermoplastic. Waterborne paint was included as a non-durable for comparison purposes : only. In order to find the most economical product for sp...

Magnetic sensor for nondestructive evaluation of deteriorated prestressing strand : phase II.

Science.gov (United States)

2011-08-01

This report gives an account of the execution and achievements in Phase II of the project completed through August 2011. The main objective of this project is to advance the practical development of a nondestructive testing and evaluation method usin...

Drug discovery strategies in the field of tumor energy metabolism: Limitations by metabolic flexibility and metabolic resistance to chemotherapy.

Science.gov (United States)

Amoedo, N D; Obre, E; Rossignol, R

2017-08-01

The search for new drugs capable of blocking the metabolic vulnerabilities of human tumors has now entered the clinical evaluation stage, but several projects already failed in phase I or phase II. In particular, very promising in vitro studies could not be translated in vivo at preclinical stage and beyond. This was the case for most glycolysis inhibitors that demonstrated systemic toxicity. A more recent example is the inhibition of glutamine catabolism in lung adenocarcinoma that failed in vivo despite a strong addiction of several cancer cell lines to glutamine in vitro. Such contradictory findings raised several questions concerning the optimization of drug discovery strategies in the field of cancer metabolism. For instance, the cell culture models in 2D or 3D might already show strong limitations to mimic the tumor micro- and macro-environment. The microenvironment of tumors is composed of cancer cells of variegated metabolic profiles, supporting local metabolic exchanges and symbiosis, but also of immune cells and stroma that further interact with and reshape cancer cell metabolism. The macroenvironment includes the different tissues of the organism, capable of exchanging signals and fueling the tumor 'a distance'. Moreover, most metabolic targets were identified from their increased expression in tumor transcriptomic studies, or from targeted analyses looking at the metabolic impact of particular oncogenes or tumor suppressors on selected metabolic pathways. Still, very few targets were identified from in vivo analyses of tumor metabolism in patients because such studies are difficult and adequate imaging methods are only currently being developed for that purpose. For instance, perfusion of patients with [ 13 C]-glucose allows deciphering the metabolomics of tumors and opens a new area in the search for effective targets. Metabolic imaging with positron emission tomography and other techniques that do not involve [ 13 C] can also be used to evaluate tumor

Phase-II Associative Memory ASIC Specifications

CERN Document Server

Stabile, Alberto; Warren, Matthew; Green, Barry; Konstantinidis, Nikolaos; Motuk, Halil Erdem; Frontini, Luca; Liberali, Valentino; Crescioli, Francesco; Fedi, Giacomo; Sotiropoulou, Calliope-louisa; De Canio, Francesco; Traversi, Gianluca; Shojaii, Seyed Ruhollah; Kubota, Takashi; Calderini, Giovanni; Palla, Fabrizio; Checcucci, Bruno; Spiller, Laurence Anthony; Mcnamara, Peter Charles

2018-01-01

This documents defines the specifications for the Associative Memory ASIC for Phase-II. The work-flow toward the final ASIC is organized in the following three steps • AM08 prototype: small area MPW prototype to test all the full custom features, the VHDL logic and the I/O. This chip must be fully functional with smaller memory area than the final ASIC; • AM09pre pre-production: full area ASIC to be fabricated with a full-mask set pilot run. Production corner wafers will be created; • AM09 production: full area ASIC with refinements for the mass production. The AM09 will be developed built on the AM08 extending the memory area, therefore the specification of both versions must be compatible.

Purification and H-1 NMR spectroscopic characterization of phase II metabolites of tolfenamic acid

DEFF Research Database (Denmark)

Sidelmann, U. G.; Christiansen, E.; Krogh, L.

1997-01-01

samples obtained on days 7 to 10 from a human volunteer after oral administration of 200 mg of the drug three times per day (steady-state plasma concentration). The metabolites of tolfenamic acid were initially concentrated by preparative solid phase extraction (PSPE) chromatography, thereby removing...... the endogenous polar compounds that are present in the urine. The individual metabolites were purified by preparative high performance liquid chromatography (HPLC) and then identified using H-1 NMR, Both one- and two-dimensional NMR experiments were performed to identify the phase II metabolites of tolfenamic......), and N-(2-methyl-4-hydroxyphenyl)-anthranilic acid (11) were identified. The phase II metabolites (5-11) had not previously been identified in urine from humans administered tolfenamic acid. The phase I metabolites of the glucuronides 7, 8, 10, and 11 were identified here for the first time. An HPLC...

Metabolism of a new synthetic progestagen, Org 2969, in female volunteers. The distribution and excretion of radioactivity after an oral dose of the labelled drug

Energy Technology Data Exchange (ETDEWEB)

Viinikka, L; Ylikorkala, O; Vihko, R [Oulu Univ. (Finland); Hasenack, H G; Nieuwenhuyse, H [Organon Scientific Development Group, Organon Int., Oss, The Netherlands

1980-01-01

The metabolism of a new synthetic progestagen, Org 2969 was studied in 4 healthy female volunteers. During the first part of the study (Phase I), the volunteers ingested 50 ..mu..g (about 0.1 mCi) of (16-/sup 3/H)Org 2969 together with 50 ..mu..g of ethinyloestradiol as a single dose. During the second part of the study (Phase II), a 10-day pre-treatment with the same dosage of non-radioactive compound preceded the administration of the radioactive steroid. A peak level of total radioactivity, representing 3.16-5.02% of the dose given/l of serum, was achieved within 2-3 h in Phase I. During Phase II, the corresponding figures were 4.54-5.13% after 1.5-3 h. The difference was mainly due to an increase of freely-extractable steroids during Phase II. The difference can at least partly be explained by assuming a change in the kinetics of the metabolism of Org 2969 by pre-treatment with Org 2969 and ethinyloestradiol. The mean recovery of radioactivity in urine and faeces was 83.0%/48.1%/34.9% (total/urine/faeces) of the total dose in Phase I and 76.1%/45.2%/30.9% during Phase II. The differences in the total excretion and in the radioactivity excreted in the faeces were significant.

A Fire Safety Certification System for Board and Care Operators and Staff. SBIR Phase II: Final Report.

Science.gov (United States)

Walker, Bonnie L.

This report describes Phase II of a project which developed a system for delivering fire safety training to board and care providers who serve adults with developmental disabilities. Phase II focused on developing and pilot testing a "train the trainers" workshop for instructors and field testing the provider's workshop. Evaluation of…

Expanded Operational Temperature Range for Space Rated Li-Ion Batteries, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — Quallion's Phase II proposal calls for expanding the nominal operation range of its space rated lithium ion cells, while maintaining their long life capabilities. To...

OrFPGA: An Empirical Performance Tuning Tool for FPGA Designs, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — In this Phase II STTR project, RNET and its subcontractors are proposing to fully develop an empirical performance optimization tool called OrFPGA that efficiently...

Battery Separator Membrane Having a Selectable Thermal Shut-Down Temperature, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — This Small Business Innovation Research Phase II proposal to NASA requests $596,750.96 support for Policell Technologies, Inc. to develop a series of separator...

Efficient Integration, Validation and Troubleshooting in Multimodal Distributed Diagnostic Schemes, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — In general, development and validation of diagnostic models for complex safety critical systems are time and cost intensive jobs. The proposed Phase-II effort will...

Plasma-wall Interaction Studies in the Start-up Phase of TJ-II

International Nuclear Information System (INIS)

De la Cal, E.; Tabares, F.L.; Tafalla, D.

1998-01-01

The aim of this work is to present some first plasma-wall interaction studies made during the first experimental campaign of TJ-II. The different sections contain independent contributions presented orally in the fusion division of the Euratom-Ciemat association during 1998: I. Density limit during the start-up phase of TJ-II : are we limited by radiation?. II. Temporal evolution of oxygen in the plasma during an experimental day. III. The contribution of helium to the plasma electron density IV. First studies of the S.O.L. diffusion coefficient and its dependence with the boundary plasma parameters. (Author) 3 refs

Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase-II: A Phase II Randomized Trial.

Science.gov (United States)

Okonkwo, David O; Shutter, Lori A; Moore, Carol; Temkin, Nancy R; Puccio, Ava M; Madden, Christopher J; Andaluz, Norberto; Chesnut, Randall M; Bullock, M Ross; Grant, Gerald A; McGregor, John; Weaver, Michael; Jallo, Jack; LeRoux, Peter D; Moberg, Dick; Barber, Jason; Lazaridis, Christos; Diaz-Arrastia, Ramon R

2017-11-01

A relationship between reduced brain tissue oxygenation and poor outcome following severe traumatic brain injury has been reported in observational studies. We designed a Phase II trial to assess whether a neurocritical care management protocol could improve brain tissue oxygenation levels in patients with severe traumatic brain injury and the feasibility of a Phase III efficacy study. Randomized prospective clinical trial. Ten ICUs in the United States. One hundred nineteen severe traumatic brain injury patients. Patients were randomized to treatment protocol based on intracranial pressure plus brain tissue oxygenation monitoring versus intracranial pressure monitoring alone. Brain tissue oxygenation data were recorded in the intracranial pressure -only group in blinded fashion. Tiered interventions in each arm were specified and impact on intracranial pressure and brain tissue oxygenation measured. Monitors were removed if values were normal for 48 hours consecutively, or after 5 days. Outcome was measured at 6 months using the Glasgow Outcome Scale-Extended. A management protocol based on brain tissue oxygenation and intracranial pressure monitoring reduced the proportion of time with brain tissue hypoxia after severe traumatic brain injury (0.45 in intracranial pressure-only group and 0.16 in intracranial pressure plus brain tissue oxygenation group; p injury after severe traumatic brain injury based on brain tissue oxygenation and intracranial pressure values was consistent with reduced mortality and increased proportions of patients with good recovery compared with intracranial pressure-only management; however, the study was not powered for clinical efficacy. Management of severe traumatic brain injury informed by multimodal intracranial pressure and brain tissue oxygenation monitoring reduced brain tissue hypoxia with a trend toward lower mortality and more favorable outcomes than intracranial pressure-only treatment. A Phase III randomized trial to assess

Experimental studies on the in vivo disposition and metabolism of toxic oil syndrome xenobiotics using dual-labelled fatty acid anilides

International Nuclear Information System (INIS)

Rodiguez Farre, E.; Vera, N. de; Cristofol, R.M.; Planas, A.; Camon, L.

1986-01-01

The outbreak of mass poisoning affecting more than 20000 people in Spain in 1981, has been related to the consumption of adulterated rapesseed oil containing fatty acid anilides (FAA). The aim of this study was to define the biological kinetics and metabolism of (ring-U- 3 H)- or (ring-U 3 H, carboxyl- 14 C)-oleic and linoleic acid anilides (OA and LA), given intragastrically to mice. Nearly 60% of OA and 54% of LA were absorbed mainly via the portal vein. The remaining fraction was detected in 24 h faeces mainly as the parent compound. A fraction of radiotracer was absorbed via the lymphatic system. Computer-fitted time activity curves showed different tissue radiotracer uptake followed by slow monoexponential elimination phase for both FAA. The highest retention was exhibited by spleen, lung and thymus. Anilide ring tritium was excreted mainly in the urine, where only small amounts of the carboxyl- 14 C -label were detected. TLC autoradiography of urine showed the same metabolic pattern for both OA and LA. About 50% of hydrolyzed was identified by mass spectrometry as true paracetamol. These results indicate that FAA were hydrolized by a first-pass effect mainly in the liver or in the intestinal wall. The major metabolites of FAA observed in our studies were the same as those reported to be present in urine and tissues of TOS patients. (Author)

Inflammation's Association with Metabolic Profiles before and after a Twelve-Week Clinical Trial in Drug-Naïve Patients with Bipolar II Disorder.

Directory of Open Access Journals (Sweden)

Sheng-Yu Lee

Full Text Available Inflammation is thought to be involved in the pathophysiology of bipolar disorder (BP and metabolic syndrome. Prior studies evaluated the association between metabolic profiles and cytokines only during certain mood states instead of their changes during treatment. We enrolled drug-naïve patients with BP-II and investigated the correlation between changes in mood symptoms and metabolic indices with changes in plasma cytokine levels after 12 weeks of pharmacological treatment. Drug-naïve patients (n = 117 diagnosed with BP-II according to DSM-IV criteria were recruited. Metabolic profiles (cholesterol, triglyceride, HbA1C, fasting serum glucose, body mass index (BMI and plasma cytokines (TNF-α, CRP, IL-6, and TGF-β were measured at baseline and 2, 8, and 12 weeks post-treatment. To adjust within-subject dependence over repeated assessments, multiple linear regressions with generalized estimating equation methods were used. Seventy-six (65.0% patients completed the intervention. Changes in plasma CRP were significantly associated with changes in BMI (P = 1.7E-7 and triglyceride (P = 0.005 levels. Changes in plasma TGF-β1 were significantly associated with changes in BMI (P = 8.2E-6, cholesterol (P = 0.004, and triglyceride (P = 0.006 levels. However, changes in plasma TNF-α and IL-6 were not associated with changes in any of the metabolic indices. Changes in Hamilton Depression Rating Scale scores were significantly associated with changes in IL-6 (P = 0.003 levels; changes in Young Mania Rating Scale scores were significantly associated with changes in CRP (P = 0.006 and TNF-α (P = 0.039 levels. Plasma CRP and TGF-β1 levels were positively correlated with several metabolic indices in BP-II after 12 weeks of pharmacological intervention. We also hypothesize that clinical symptoms are correlated with certain cytokines. These new findings might be important evidence that inflammation is the pathophysiology

Solid State Transmitters for Water Vapor and Ozone DIAL Systems, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — The focus of this Select Phase II program is to build and deliver laser components both for airborne water vapor and ozone DIAL systems. Specifically, Fibertek...

Scaled Model Technology for Flight Research of General Aviation Aircraft, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — Our proposed future Phase II activities are aimed at developing a scientifically based "tool box" for flight research using scaled models. These tools will be of...

Coordinated Control of Multi-Agent Systems in Rapidly Varying Environments, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — The main objective of this Phase II STTR project is to develop advanced control algorithms that enable multiple autonomous agents to perform complex tasks in rapidly...

ABC transporters in fish species: a review

Directory of Open Access Journals (Sweden)

Marta eFerreira

2014-07-01

Full Text Available ATP-binding cassette (ABC proteins were first recognized for their role in multidrug resistance (MDR in chemotherapeutic treatments, which is a major impediment for the successful treatment of many forms of malignant tumors in humans. These proteins, highly conserved throughout vertebrate species, were later related to cellular detoxification and accounted as responsible for protecting aquatic organisms from xenobiotic insults in the so-called multixenobiotic resistance mechanism (MXR. In recent years, research on these proteins in aquatic species has highlighted their importance in the detoxification mechanisms in fish thus it is of extreme added value to continue these studies. Several transporters have been pointed out as relevant in the ecotoxicological context associated to the transport of xenobiotics, such as P-glycoproteins (Pgps, multidrug-resistance-associated proteins (MRPs 1-5 and breast resistance associated protein (BCRP. In mammals, several nuclear receptors have been identified as mediators of phase I and II metabolizing enzymes and ABC transporters. In aquatic species, knowledge on co-regulation of detoxification mechanism is scarce and needs to be addressed. The interaction of emergent contaminants, with chemosensitizer potential, with ABC transporters in aquatic organisms can compromise detoxification processes and have population effects and should be studied in more detail. This review intends to summarize the recent advances in research on MXR mechanisms in fish species, focusing in 1 regulation and functioning of ABC proteins; 2 cooperation with phase I and II biotransformation enzymes; and 3 ecotoxicological relevance and information on emergent pollutants with ability to modulate ABC transporters expression and activity. Several lines of evidence are clear suggesting the important role of these transporters in detoxification mechanisms and must be further investigated in fish.