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Sample records for actively toxic pfiesteria

  1. Field ecology of toxic Pfiesteria complex species and a conservative analysis of their role in estuarine fish kills.

    PubMed Central

    Glasgow, H B; Burkholder, J M; Mallin, M A; Deamer-Melia, N J; Reed, R E

    2001-01-01

    Within the past decade, toxic Pfiesteria outbreaks have been documented in poorly flushed, eutrophic areas of the largest and second largest estuaries on the U.S. mainland. Here we summarize a decadal field effort in fish kill assessment, encompassing kills related to Pfiesteria (49 major kills in North Carolina estuaries since 1991 and 4 in Maryland estuaries in 1997) and to other factors such as low oxygen stress (79 major fish kills in North Carolina estuaries). The laboratory and field data considered in developing our protocols are described, including toxic Pfiesteria behavior, environmental conditions conducive to toxic Pfiesteria activity, and impacts of toxic clonal Pfiesteria on fish health. We outline the steps of the standardized fish bioassay procedure that has been used since 1991 to diagnose whether actively toxic Pfiesteria was present during estuarine fish kills. Detailed data are given for a 1998 toxic Pfiesteria outbreak in the Neuse Estuary in North Carolina to illustrate of the full suite of diagnostic steps completed. We demonstrate that our conservative approach in implicating toxic Pfiesteria involvement in fish kills has biased in favor of causes other than Pfiesteria. Data are summarized from experiments that have shown stimulation of toxic Pfiesteria strains by nutrient (N, P) enrichment, supporting field observations of highest abundance of toxic strains in eutrophic estuaries. On the basis of a decade of research on toxic Pfiesteria, we present a conceptual model of the seasonal dynamics of toxic strains as affected by changing food resources and weather patterns. We also recommend protocols and research approaches that will strengthen the science of fish kill assessment related to Pfiesteria and/or other causative factors. PMID:11677181

  2. Species of the toxic Pfiesteria complex, and the importance of functional type in data interpretation.

    PubMed Central

    Burkholder, J M; Glasgow, H B; Deamer-Melia, N J; Springer, J; Parrow, M W; Zhang, C; Cancellieri, P J

    2001-01-01

    We describe the two species of the toxic Pfiesteria complex to date (Pfiesteria piscicida and Pfiesteria shumwayae), their complex life cycles, and the characteristics required for inclusion within this complex. These species resemble P. piscicida Steidinger & Burkholder and also have a) strong attraction to fresh fish tissues and excreta, b) toxic activity stimulated by live fish, and c) production of toxin that can cause fish death and disease. Amoeboid stages were verified in 1992-1997 by our laboratory (various stages from toxic cultures) and that of K. Steidinger and co-workers (filose amoebae in nontoxic cultures), and in 2000 by H. Marshall and co-workers (various stages from toxic cultures), from clonal Pfiesteria spp. cultures, using species-specific polymerase chain reaction-based molecular probes with cross-confirmation by an independent specialist. Data were provided from tests of the hypothesis that Pfiesteriastrains differ in response to fresh fish mucus and excreta, algal prey, and inorganic nutrient (N, P) enrichment, depending on functional type or toxicity status. There are three functional types: TOX-A, in actively toxic, fish-killing mode; TOX-B, temporarily nontoxic, without access to live fish for days to weeks, but capable of toxic activity if fish are added; and NON-IND, noninducible with negligible toxicity in the presence of live fish. NON-IND Pfiesteria attained highest zoospore production on algal prey without or without inorganic nitrogen or inorganic phosphorus enrichment. TOX-B Pfiesteria was intermediate and TOX-A was lowest in zoospore production on algal prey with or without nutrients. TOX-A Pfiesteria spp. showed strong behavioral attraction to fresh fish mucus and excreta in short-term trials, with intermediate attraction of TOX-B zoospores and relatively low attraction of NON-IND cultures when normalized for cell density. The data for these clones indicated a potentially common predatory behavioral response, although differing

  3. Characterization of Ichthyocidal Activity of Pfiesteria piscicida: Dependence on the Dinospore Cell Density

    PubMed Central

    Drgon, Tomás; Saito, Keiko; Gillevet, Patrick M.; Sikaroodi, Masoumeh; Whitaker, Brent; Krupatkina, Danara N.; Argemi, Federico; Vasta, Gerardo R.

    2005-01-01

    The ichthyocidal activity of Pfiesteria piscicida dinospores was examined in an aquarium bioassay format by exposing fish to either Pfiesteria-containing environmental sediments or clonal P. piscicida. The presence of Pfiesteria spp. and the complexity of the microbial assemblage in the bioassay were assessed by molecular approaches. Cell-free water from bioassays that yielded significant fish mortality failed to show ichthyocidal activity. Histopathological examination of moribund and dead fish failed to reveal the skin lesions reported elsewhere. Fish larvae within “cages” of variable mesh sizes were killed in those where the pore size exceeded that of Pfiesteria dinospores. In vitro exposure of fish larvae to clonal P. piscicida indicated that fish mortality was directly proportional to the dinospore cell density. Dinospores clustered around the mouth, eyes, and operculi, suggesting that fish health may be affected by their direct interaction with skin, gill epithelia, or mucous surfaces. Molecular fingerprinting revealed the presence of a very diverse microbial community of bacteria, protists, and fungi within bioassay aquaria containing environmental sediments. Some components of the microbial community were identified as potential fish pathogens, preventing the rigorous identification of Pfiesteria spp. as the only cause of fish death. In summary, our results strongly suggest (i) that this aquarium bioassay format, which has been extensively reported in the literature, is unsuitable to accurately assess the ichthyocidal activity of Pfiesteria spp. and (ii) that the ichthyocidal activity of Pfiesteria spp. is mostly due to direct interactions of the zoospores with fish skin and gill epithelia rather than to soluble factors. PMID:15640229

  4. PFIESTERIA SHUMWAYAE KILLS FISH BY MICROPREDATION NOT ECOTOXIN SECRETION

    EPA Science Inventory

    Massive fish kills in mid-Atlantic USA estuaries involving several million Atlantic menhaden, Brevoortia tyrannus,have been attributed to dinoflagellates of the toxic Pfiesteria complex (TPC). Potent ichthyotoxins secreted during Pfiesteria blooms are thought to be responsible fo...

  5. Lack of Evidence for Contact Sensitization by Pfiesteria Extract

    PubMed Central

    Patterson, Rachel M.; Noga, Edward; Germolec, Dori

    2007-01-01

    Background Members of the estuarine dinoflagellate genus Pfiesteria are reported to have been responsible for massive fish kills in the southeastern United States. Some reports suggest that exposure to waters having Pfiesteria blooms or occupation-related exposure might result in Pfiesteria-induced dermal irritation and inflammation. Although the toxin has not been isolated and purified, the original data suggested both hydrophilic and hydrophobic toxic components. Some investigators propose that dermonecrotic properties are associated with a hydrophobic fraction. Objectives A bioactive C18-bound putative toxin (CPE) extracted from Pfiesteria-laden aquarium water during active fish-killing conditions was examined in the present study to evaluate its potential to produce inflammation and dermal sensitization and to determine whether the inflammation and dermatitis reported in early human exposure studies were allergic or irritant in nature. Results This fraction was cytotoxic to mouse Neuro-2A cells and primary human epidermal keratinocytes (NHEK) at a concentration of 1 mg/mL. Balb/C mice exposed to 50–200% CPE by skin painting exhibited a 6–10% increase in ear swelling relative to vehicle-treated mice in a primary irritancy assay. There was no increase in lymph node cell proliferation as measured using the local lymph node assay. Exposure to CPE in culture up-regulated interleukin-8 in NHEK, whereas granulocyte macrophage–colony-stimulating factor and tumor necrosis factor α were only minimally altered. Conclusions This study suggests that CPE is cytotoxic to keratinocytes in culture at high concentrations and that it induces mild, localized irritation but not dermal sensitization. PMID:17637917

  6. PFIESTERIA PISCICIDA IMPACTS

    EPA Science Inventory

    Recent evidence suggests that the estuarine dinofageflate, Pfiesteria piscicida, may release a toxin(s) which kills fish and adversely affects human health in laboratory and environmental settings. The potential for Pfresferia-like organisms to adversely impact estuarine ecosys...

  7. Metal Complexes And Free Radical Toxins Produced By Pfiesteria Piscicida

    SciTech Connect

    Moeller, P.D.R.; Beauchesne, K.R.; Huncik, K.M.; Davis, W.C.; Christopher, S.J.; Riggs-Gelasco, P.; Gelasco, A.K.

    2009-06-03

    Metal-containing organic toxins produced by Pfiesteria piscicida were characterized, for the first time, by corroborating data obtained from five distinct instrumental methods: nuclear magnetic resonance spectroscopy (NMR), inductively coupled plasma mass spectrometry (ICPMS), liquid chromatography particle beam glow discharge mass spectrometry (LC/PB-GDMS), electron paramagnetic resonance spectroscopy (EPR), and X-ray absorption spectroscopy (XAS). The high toxicity of the metal-containing toxins is due to metal-mediated free radical production. This mode of activity explains the toxicity of Pfiesteria, as well as previously reported difficulty in observing the molecular target, due to the ephemeral nature of radical species. The toxins are highly labile in purified form, maintaining activity for only 2-5 days before all activity is lost. The multiple toxin congeners in active extracts are also susceptible to decomposition in the presence of white light, pH variations, and prolonged heat. These findings represent the first formal isolation and characterization of a radical forming toxic organic-ligated metal complex isolated from estuarine/marine dinoflagellates. These findings add to an increased understanding regarding the active role of metals interacting with biological systems in the estuarine environment, as well as their links and implications to human health.

  8. Metal Complexes and Free Radical Toxins Produced by Pfiesteria piscicida

    SciTech Connect

    Moeller,P.; Beauchesne, K.; Huncik, K.; Davis, W.; Christopher, S.; Riggs-Gelasco, P.; Gelasco, A.

    2007-01-01

    Metal-containing organic toxins produced by Pfiesteria piscicida were characterized, for the first time, by corroborating data obtained from five distinct instrumental methods: nuclear magnetic resonance spectroscopy (NMR), inductively coupled plasma mass spectrometry (ICP-MS), liquid chromatography particle beam glow discharge mass spectrometry (LC/PB-GDMS), electron paramagnetic resonance spectroscopy (EPR), and X-ray absorption spectroscopy (XAS). The high toxicity of the metal-containing toxins is due to metal-mediated free radical production. This mode of activity explains the toxicity of Pfiesteria, as well as previously reported difficulty in observing the molecular target, due to the ephemeral nature of radical species. The toxins are highly labile in purified form, maintaining activity for only 2-5 days before all activity is lost. The multiple toxin congeners in active extracts are also susceptible to decomposition in the presence of white light, pH variations, and prolonged heat. These findings represent the first formal isolation and characterization of a radical forming toxic organic-ligated metal complex isolated from estuarine/marine dinoflagellates. These findings add to an increased understanding regarding the active role of metals interacting with biological systems in the estuarine environment, as well as their links and implications to human health.

  9. Etiology and pathogenesis of skin ulcers in menhaden, Brevoortia tyrannis: does Pfiesteria piscicida play a role?

    USGS Publications Warehouse

    Blazer, V.; Vogelbein, W.K.; Densmore, C.; Kator, H.; Zwerner, D.; Lilley, J.

    2000-01-01

    The toxic dinoflagellate, Pfiesteria piscicida, is widely blamed for adverse human health effects, acute fish kills and skin lesion events in fishes, particularly menhaden, Brevoortia tyrannis, inhabiting coastal waters from Delaware to North Carolina, USA. In response, we initiated studies to clarify the etiology and pathogenesis of presumed 'Pfiesteria-specific' menhaden skin lesions. Histopathologically, all lesions (>150 fish examined) were associated with a highly invasive and pathogenic fungus eliciting severe tissue necrosis and intense granulomatous inflammation. Severity and extent of the host response indicates that ulcers were at least 1 week old or older. Maryland and Virginia currently use menhaden ulcers as one of several indicators of local Pfiesteria activity. However, their chronic nature, advanced age, and consistent fungal involvement suggest that their use for this purpose may not be valid. We recently isolated an Aphanomyces sp. from the menhaden lesions which by appearance in culture, temperature growth curves, pathogenicity studies in snakehead and positive immunohistochemical staining with polyclonal antibodies suggest the infectious agent is A. invadans (cause of epizootic ulcerative syndrome in Asia, Japan and Australia) or a very closely related species. Ongoing research will address pathogenicity of the fungus in menhaden, genetic comparisons of isolates, and the role of environmental stressors, including P. piscicida, in initiation of the infection. Copyright (C) 2000.

  10. Identification of amoebae implicated in the life cycle of Pfiesteria and Pfiesteria-like dinoflagellates

    USGS Publications Warehouse

    Peglar, M.T.; Nerad, T.A.; Anderson, O.R.; Gillevet, P.M.

    2004-01-01

    This study was undertaken to assess whether amoebae commonly found in mesohaline environments are in fact stages in the life cycles of Pfiesteria and Pfiesteria-like dinoflagellates. Primary isolations of amoebae and dinoflagellates were made from water and sediment samples from five tributaries of the Chesapeake Bay. Additional amoebae were also cloned from bioassay aquaria where fish mortality was attributed to Pfiesteria. Electron microscopy and small subunit (SSU) rRNA gene sequence analysis of these isolates clearly demonstrated that the commonly depicted amoeboid form of Pfiesteria is very likely a species of Korotnevella and is unrelated to Pfiesteria or Pfiesteria-like dinoflagellates. We have determined that the Pfiesteria and Pfiesteria-like dinoflagellates examined in this study undergo a typical homothallic life cycle without amoeboid stages. Furthermore, we have demonstrated that cloned amoebae sharing morphological characteristics described for stages in the life cycle of Pfiesteria do not transform into dinozoites. The strict clonal isolation and cultivation techniques used in this study substantially support the conclusion that the amoebae and some of the flagellates depicted in the life cycle of Pfiesteria are environmental contaminants of the Pfiesteria culture system and that the Ambush Predator Hypothesis needs to be rigorously reevaluated.

  11. CHEMOSENSORY ATTRACTION OF ZOOSPORES OF THE ESTUARINE DINOFLAGELLATES, PFIESTERIA PISCICIDA AND P. SHUMWAYAE, TO FINFISH MUCUS AND EXCRETA. (R825551)

    EPA Science Inventory

    Toxic strains of the estuarine dinoflagellates, Pfiesteria piscicida and P. shumwayae, can cause fish death and disease, whereas other estuarine `lookalike' species such as cryptoperidiniopsoids have not been ichthyotoxic under ecologically rel...

  12. Pfiesteria: review of the science and identification of research gaps. Report for the National Center for Environmental Health, Centers for Disease Control and Prevention.

    PubMed Central

    Samet, J; Bignami, G S; Feldman, R; Hawkins, W; Neff, J; Smayda, T

    2001-01-01

    In connection with the CDC National Conference on Pfiesteria, a multidisciplinary panel evaluated Pfiesteria-related research. The panel set out what was known and what was not known about adverse effects of the organism on estuarine ecology, fish, and human health; assessed the methods used in Pfiesteria research; and offered suggestions to address data gaps. The panel's expertise covered dinoflagellate ecology; fish pathology and toxicology; laboratory measurement of toxins, epidemiology, and neurology. The panel evaluated peer-reviewed and non-peer-reviewed literature available through June 2000 in a systematic conceptual framework that moved from the source of exposure, through exposure research and dose, to human health effects. Substantial uncertainties remain throughout the conceptual framework the panel used to guide its evaluation. Firm evidence demonstrates that Pfiesteria is toxic to fish, but the specific toxin has not been isolated or characterized. Laboratory and field evidence indicate that the organism has a complex life cycle. The consequences of human exposure to Pfiesteria toxin and the magnitude of the human health problem remain obscure. The patchwork of approaches used in clinical evaluation and surrogate measures of exposure to the toxin are major limitations of this work. To protect public health, the panel suggests that priority be given research that will provide better insight into the effects of Pfiesteria on human health. Key gaps include the identity and mechanism of action of the toxin(s), the incomplete description of effects of exposure in invertebrates, fish, and humans, and the nature and extent of exposures that place people at risk. PMID:11687383

  13. PFIESTERIA PISCICIDA-INDUCED COGNITIVE EFFECTS: VISUAL SIGNAL DETECTION PERFORMANCE AND REVERSAL.

    EPA Science Inventory

    Humans exposed to Pfiesteria piscicida report cognitive impairment. In a rat model, we showed that exposure to Pfiesteria impaired learning a new task, but not performance of previously-learned behavior. In this study, we characterized the behavioral effects of Pfiesteria in rats...

  14. Pfiesteria-related educational products and information resources available to the public, health officials, and researchers.

    PubMed Central

    Kleindinst, J L; Anderson, D M

    2001-01-01

    Public and political concerns about Pfiesteria from 1997 to the present vastly exceed the attention given to other harmful algal bloom (HAB) issues in the United States. To some extent, the intense focus on Pfiesteria has served to increase attention on HABs in general. Given the strong and continuing public, political, and research interests in Pfiesteria piscicida Steidinger & Burkholder and related organisms, there is a clear need for information and resources of many different types. This article provides information on Pfiesteria-related educational products and information resources available to the general public, health officials, and researchers. These resources are compiled into five categories: reports; website resources; state outreach and communication programs; fact sheets; and training manuals and documentaries. Over the last few years there has been rapid expansion in the amount of Pfiesteria-related information available, particularly on the Internet, and it is scattered among many different sources. PMID:11677177

  15. Emerging areas of research reported during the CDC National Conference on Pfiesteria: from biology to public health.

    PubMed

    Rubin, C; McGeehin, M A; Holmes, A K; Backer, L; Burreson, G; Earley, M C; Griffith, D; Levine, R; Litaker, W; Mei, J; Naeher, L; Needham, L; Noga, E; Poli, M; Rogers, H S

    2001-10-01

    Since its identification in 1996, the marine dinoflagellate Pfiesteria piscicida Steidinger & Burkholder has been the focus of intense scientific inquiry in disciplines ranging from estuarine ecology to epidemiology and from molecular biology to public health. Despite these research efforts, the extent of human exposure and the degree of human illness directly associated with Pfiesteria is still in the process of being defined. Unfortunately, during this same time Pfiesteria has also stimulated media coverage that in some instances jumped ahead of the science to conclude that Pfiesteria presents a widespread threat to human health. Political and economic forces also came into play when the tourism and seafood industries were adversely impacted by rumors of toxin-laden water in estuaries along the east coast of the United States. Amid this climate of evolving science and public concern, Pfiesteria has emerged as a highly controversial public health issue. In October 2000 Centers for Disease Control and Prevention sponsored the National Conference on Pfiesteria: From Biology to Public Health to bring together Pfiesteria researchers from many disparate disciplines. The goal of this meeting was to describe the state of the science and identify directions for future research. In preparation for the conference an expert peer-review panel was commissioned to review the existing literature and identify research gaps; the summary of their review is published in this monograph. During the meeting primary Pfiesteria researchers presented previously unpublished results. The majority of those presentations are included as peer-reviewed articles in this monograph. The discussion portion of the conference focused upon researcher-identified research gaps. This article details the discussion segments of the conference and makes reference to the presentations as it describes emerging areas of Pfiesteria research. PMID:11677172

  16. Emerging areas of research reported during the CDC National Conference on Pfiesteria: from biology to public health.

    PubMed Central

    Rubin, C; McGeehin, M A; Holmes, A K; Backer, L; Burreson, G; Earley, M C; Griffith, D; Levine, R; Litaker, W; Mei, J; Naeher, L; Needham, L; Noga, E; Poli, M; Rogers, H S

    2001-01-01

    Since its identification in 1996, the marine dinoflagellate Pfiesteria piscicida Steidinger & Burkholder has been the focus of intense scientific inquiry in disciplines ranging from estuarine ecology to epidemiology and from molecular biology to public health. Despite these research efforts, the extent of human exposure and the degree of human illness directly associated with Pfiesteria is still in the process of being defined. Unfortunately, during this same time Pfiesteria has also stimulated media coverage that in some instances jumped ahead of the science to conclude that Pfiesteria presents a widespread threat to human health. Political and economic forces also came into play when the tourism and seafood industries were adversely impacted by rumors of toxin-laden water in estuaries along the east coast of the United States. Amid this climate of evolving science and public concern, Pfiesteria has emerged as a highly controversial public health issue. In October 2000 Centers for Disease Control and Prevention sponsored the National Conference on Pfiesteria: From Biology to Public Health to bring together Pfiesteria researchers from many disparate disciplines. The goal of this meeting was to describe the state of the science and identify directions for future research. In preparation for the conference an expert peer-review panel was commissioned to review the existing literature and identify research gaps; the summary of their review is published in this monograph. During the meeting primary Pfiesteria researchers presented previously unpublished results. The majority of those presentations are included as peer-reviewed articles in this monograph. The discussion portion of the conference focused upon researcher-identified research gaps. This article details the discussion segments of the conference and makes reference to the presentations as it describes emerging areas of Pfiesteria research. PMID:11677172

  17. STEROLS OF THE HETEROTROPHIC DINOFLAGELLATE, PFIESTERIA PISCICIDA (DINOPHYCEAE): IS THERE A LIPID BIOMARKER?

    EPA Science Inventory

    Within United States waters, blooms of the dinoflagellate, Pfiesteria piscicida, have been recorded on an almost regular basis in the Chesapeake Bay and surrounding mid-Atlantic regions for the last two decades. Despite the apparent significance of such blooms to the environment ...

  18. Screening wastewater for toxicity to activated sludge

    SciTech Connect

    Schneider, C.G.

    1987-01-01

    Several toxicity tests were compared to define their utility for prediction of toxicity to activated sludge. The tests included: (1) oxygen uptake rates in batch tests with activated sludge, (2) adenosine triphosphate (ATP) measurements in the same batch tests, (3) Warburg respirometer studies with activated sludge, and (4) a luminescent bacteria test (Microtox/sup TM/). An evaluation of the toxicity tests was made with several toxicants; nickel (II), mercury (II), 2,4-dichlorophenol (DCP) and 4,6-dinitro-o-cresol (DNOC). Because of differences in toxic mechanism, some of the toxicants produced greater toxic effects in some tests than in other tests. The ATP levels decreased significant when uncouplers of oxidative phosphorylation were studied (DCP and DNOC). Several procedures for measuring ATP were investigated and were found to be unsatisfactory when applied to activated sludge. A new method for extraction of ATP, which incorporated a sonic bath and trichloroacetic acid, was developed. The improved ATP method was used in the toxicity tests and for the additional studies. Current practice in environmental engineering relies on volatile suspended solids (VSS) as a measure of active biomass in activated sludge. After an improved ATP procedure was developed, ATP was investigated for estimation of active biomass. The fate of DCP in the toxicity tests was studied and an adsorptive mechanism was proposed that was based on membrane solubility. This mechanism explained the fate of DCP in the toxicity tests and is useful for understanding the fate of DCP in activated sludge.

  19. Effect of Biotic and Abiotic Factors on In Vitro Proliferation, Encystment, and Excystment of Pfiesteria piscicida▿ †

    PubMed Central

    Saito, Keiko; Drgon, Tomás; Krupatkina, Danara N.; Drgonova, Jana; Terlizzi, Daniel E.; Mercer, Natalia; Vasta, Gerardo R.

    2007-01-01

    Pfiesteria spp. are mixotrophic armored dinoflagellates populating the Atlantic coastal waters of the United States. They have been a focus of intense research due to their reported association with several fish mortality events. We have now used a clonal culture of Pfiesteria piscicida and several new environmental isolates to describe growth characteristics, feeding, and factors contributing to the encystment and germination of the organism in both laboratory and environmental samples. We also discuss applied methods of detection of the different morphological forms of Pfiesteria in environmental samples. In summary, Pfiesteria, when grown with its algal prey, Rhodomonas sp., presents a typical growth curve with lag, exponential, and stationary phases, followed by encystment. The doubling time in exponential phase is about 12 h. The profiles of proliferation under a standard light cycle and in the dark were similar, although the peak cell densities were markedly lower when cells were grown in the dark. The addition of urea, chicken manure, and soil extracts did not enhance Pfiesteria proliferation, but crude unfiltered spent aquarium water did. Under conditions of food deprivation or cold (4°C), Pfiesteria readily formed harvestable cysts that were further analyzed by PCR and scanning electron microscopy. The germination of Pfiesteria cysts in environmental sediment was enhanced by the presence of live fish: dinospores could be detected 13 to 15 days earlier and reached 5- to 10-times-higher peak cell densities with live fish than with artificial seawater or f/2 medium alone. The addition of ammonia, urea, nitrate, phosphate, or surprisingly, spent fish aquarium water had no effect. PMID:17704277

  20. Toxic industrial deposit remediation by ant activity

    NASA Astrophysics Data System (ADS)

    Jilkova, Veronika; Frouz, Jan

    2016-04-01

    Toxic industrial deposits are often contaminated by heavy metals and the substrates have low pH values. In such systems, soil development is thus slowed down by high toxicity and acidic conditions which are unfavourable to soil fauna. Ants (Hymenoptera, Formicidae) are considered tolerant to heavy metal pollution and are known to increase organic matter content and microbial activity in their nests. Here, we focused on soil remediation caused by three ant species (Formica sanguinea, Lasius niger, and Tetramorium sp.) in an ore-washery sedimentation basin near Chvaletice (Czech Republic). Soil samples were taken from the centre of ant nests and from the nest surroundings (>3 m from nests). Samples were then analyzed for microbial activity and biomass and contents of organic matter and nutrients. As a result, ant species that most influenced soil properties was F. sanguinea as there were higher microbial activity and total nitrogen and ammonia contents in ant nests than in the surrounding soil. We expected such a result because F. sanguinea builds conspicuous large nests and is a carnivorous species that brings substantial amounts of nitrogen in insect prey to their nests. Effects of the other two ant species might be lower because of smaller nests and different feeding habits as they rely mainly on honeydew from aphids or on plant seeds that do not contain much nutrients.

  1. Assessment of toxicity using dehydrogenases activity and mathematical modeling.

    PubMed

    Matyja, Konrad; Małachowska-Jutsz, Anna; Mazur, Anna K; Grabas, Kazimierz

    2016-07-01

    Dehydrogenase activity is frequently used to assess the general condition of microorganisms in soil and activated sludge. Many studies have investigated the inhibition of dehydrogenase activity by various compounds, including heavy metal ions. However, the time after which the measurements are carried out is often chosen arbitrarily. Thus, it can be difficult to estimate how the toxic effects of compounds vary during the reaction and when the maximum of the effect would be reached. Hence, the aim of this study was to create simple and useful mathematical model describing changes in dehydrogenase activity during exposure to substances that inactivate enzymes. Our model is based on the Lagergrens pseudo-first-order equation, the rate of chemical reactions, enzyme activity, and inactivation and was created to describe short-term changes in dehydrogenase activity. The main assumption of our model is that toxic substances cause irreversible inactivation of enzyme units. The model is able to predict the maximum direct toxic effect (MDTE) and the time to reach this maximum (TMDTE). In order to validate our model, we present two examples: inactivation of dehydrogenase in microorganisms in soil and activated sludge. The model was applied successfully for cadmium and copper ions. Our results indicate that the predicted MDTE and TMDTE are more appropriate than EC50 and IC50 for toxicity assessments, except for long exposure times. PMID:27021434

  2. Toxic activity of Bacillus sphaericus SSII-1 for mosquito larvae.

    PubMed

    Myers, P; Yousten, A A

    1978-03-01

    Using larvae of the mosquito Culex pipiens var. quinquefasciatus as a bioassay system, we have verified an earlier proposal that pathogenicity of Bacillus sphaericus SSII-1 is a toxin-mediated rather than an infectious process. Chloroform or ultraviolet-light treatments that decreased the viable count of SSII-1 cells by 4 or 5 logs did not significantly alter the ability of the bacterial cells to kill larvae. Three lines of evidence indicated that toxic activity was not related to sporulation: (i) cells grown in either a complex or a defined medium were toxic at all ages; (ii) when supplemental Mn2+ was excluded from a complex medium, the culture yielded few spores but was of equal toxicity to a culture containing many spores; and (iii) several early blocked oligosporogenous mutants were isolated that had toxic activities comparable to that of the parent. The toxin was shown to be relatively unstable because activity was destroyed by heat and decreased by refrigeration, a freeze-thaw cycle, or two methods of cell breakage. Thin sections of SSII-1 cells did not reveal the presence of any inclusion body that might be related to toxicity. PMID:640722

  3. ECVAM's ongoing activities in the area of acute oral toxicity.

    PubMed

    Kinsner-Ovaskainen, Agnieszka; Bulgheroni, Anna; Hartung, Thomas; Prieto, Pilar

    2009-12-01

    The 7th Amendment of the Cosmetics Directive (2003/15/EC) set up timelines for banning animal testing and marketing of cosmetic products and their ingredients tested on animals. For most of the human health effects, including acute toxicity, the deadline for these bans was in March 2009. Moreover, the new Regulation EC 1907/2006 on Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) provided a strong impetus towards the application of alternative approaches to reduce the number of animals used for toxicological testing. Therefore, the European Centre for the Validation of Alternative Methods (ECVAM) is currently putting considerable effort into developing and validating alternative methods in the field of acute toxicity. The main activities in this area include: (1) the Integrated Project ACuteTox, funded by the European Commission's 6th Framework Programme in 2005 with the aim to develop and pre-validate a testing strategy to fully replace acute oral toxicity testing in vivo; (2) a follow-up validation study to assess the predictive capacity of the validated BALB/3T3 Neutral Red Uptake cytotoxicity assay to discriminate between toxic/hazardous (LD(50)<2,000 mg/kg) substances and substances not classified for acute toxicity (LD(50)>2,000 mg/kg); (3) an approach to identify compounds with LD(50)>2,000 mg/kg using information from 28-days repeated dose toxicity studies. PMID:19591916

  4. Propulsion Risk Reduction Activities for Non-Toxic Cryogenic Propulsion

    NASA Technical Reports Server (NTRS)

    Smith, Timothy D.; Klem, Mark D.; Fisher, Kenneth

    2010-01-01

    The Propulsion and Cryogenics Advanced Development (PCAD) Project s primary objective is to develop propulsion system technologies for non-toxic or "green" propellants. The PCAD project focuses on the development of non-toxic propulsion technologies needed to provide necessary data and relevant experience to support informed decisions on implementation of non-toxic propellants for space missions. Implementation of non-toxic propellants in high performance propulsion systems offers NASA an opportunity to consider other options than current hypergolic propellants. The PCAD Project is emphasizing technology efforts in reaction control system (RCS) thruster designs, ascent main engines (AME), and descent main engines (DME). PCAD has a series of tasks and contracts to conduct risk reduction and/or retirement activities to demonstrate that non-toxic cryogenic propellants can be a feasible option for space missions. Work has focused on 1) reducing the risk of liquid oxygen/liquid methane ignition, demonstrating the key enabling technologies, and validating performance levels for reaction control engines for use on descent and ascent stages; 2) demonstrating the key enabling technologies and validating performance levels for liquid oxygen/liquid methane ascent engines; and 3) demonstrating the key enabling technologies and validating performance levels for deep throttling liquid oxygen/liquid hydrogen descent engines. The progress of these risk reduction and/or retirement activities will be presented.

  5. Toxicity and mutagenic activity of some selected Nigerian plants.

    PubMed

    Sowemimo, A A; Fakoya, F A; Awopetu, I; Omobuwajo, O R; Adesanya, S A

    2007-09-25

    The toxicity and mutagenic potential of most African plants implicated in the management of cancer have not been investigated. The ethanolic extracts of selected Nigerian plants were subsequently studied using the brine shrimp lethality tests, inhibition of telomerase activity and induction of chromosomal aberrations in vivo in rat lymphocytes. Morinda lucida root bark, Nymphaea lotus whole plant and Garcinia kola root were active in the three test systems. Bryophyllum calycinum whole plant, Annona senegalensis root, Hymenocardia acida stem bark, Erythrophleum suaveolens leaves and Spondiathus preussii stem bark were toxic to brine shrimps and caused chromosomal damage in rat lymphocytes. Ficus exasperata leaves, Chrysophyllum albidum root bark and Hibiscus sabdariffa leaves were non-toxic to all the three test systems. Chenopodium ambrosioides whole plant was non-toxic to brine shrimps and rat lymphocyte chromosomes but showed inhibition in the conventional telomerase assay indicating a possible selectivity for human chromosomes. The result justified the use of the first eight plants and Chenopodium ambrosioides in the management of cancer in south west Nigeria although they appear to be non-selective and their mode of action may be different from plant to plant. All these plants except Chenopodium ambrosioides are also mutagenic and cytotoxic. PMID:17707603

  6. Iron Metallodrugs: Stability, Redox Activity and Toxicity against Artemia salina

    PubMed Central

    2015-01-01

    Iron metallodrugs comprise mineral supplements, anti-hypertensive agents and, more recently, magnetic nanomaterials, with both therapeutic and diagnostic roles. As biologically-active metal compounds, concern has been raised regarding the impact of these compounds when emitted to the environment and associated ecotoxicological effects for the fauna. In this work we assessed the relative stability of several iron compounds (supplements based on glucoheptonate, dextran or glycinate, as well as 3,5,5-trimethylhexanoyl (TMH) derivatives of ferrocene) against high affinity models of biological binding, calcein and aprotransferrin, via a fluorimetric method. Also, the redox-activity of each compound was determined in a physiologically relevant medium. Toxicity toward Artemia salina at different developmental stages was measured, as well as the amount of lipid peroxidation. Our results show that polymer-coated iron metallodrugs are stable, non-redox-active and non-toxic at the concentrations studied (up to 300 µM). However, TMH derivatives of ferrocene were less stable and more redox-active than the parent compound, and TMH-ferrocene displayed toxicity and lipid peroxidation to A. salina, unlike the other compounds. Our results indicate that iron metallodrugs based on polymer coating do not present direct toxicity at low levels of emission; however other iron species (eg. metallocenes), may be deleterious for aquatic organisms. We suggest that ecotoxicity depends more on metal speciation than on the total amount of metal present in the metallodrugs. Future studies with discarded metallodrugs should consider the chemical speciation of the metal present in the composition of the drug. PMID:25849743

  7. Chronic activation of FXR in transgenic mice caused perinatal toxicity and sensitized mice to cholesterol toxicity.

    PubMed

    Cheng, Qiuqiong; Inaba, Yuka; Lu, Peipei; Xu, Meishu; He, Jinhan; Zhao, Yueshui; Guo, Grace L; Kuruba, Ramalinga; de la Vega, Rona; Evans, Rhobert W; Li, Song; Xie, Wen

    2015-04-01

    The nuclear receptor farnesoid X receptor (FXR) (nuclear receptor subfamily 1, group H, member 4, or NR1H4) is highly expressed in the liver and intestine. Previous reports have suggested beneficial functions of FXR in the homeostasis of bile acids, lipids, and glucose, as well as in promoting liver regeneration and inhibiting carcinogenesis. To investigate the effect of chronic FXR activation in vivo, we generated transgenic mice that conditionally and tissue specifically express the activated form of FXR in the liver and intestine. Unexpectedly, the transgenic mice showed several intriguing phenotypes, including partial neonatal lethality, growth retardation, and spontaneous liver toxicity. The transgenic mice also displayed heightened sensitivity to a high-cholesterol diet-induced hepatotoxicity but resistance to the gallstone formation. The phenotypes were transgene specific, because they were abolished upon treatment with doxycycline to silence the transgene expression. The perinatal toxicity, which can be rescued by a maternal vitamin supplement, may have resulted from vitamin deficiency due to low biliary bile acid output as a consequence of inhibition of bile acid formation. Our results also suggested that the fibroblast growth factor-inducible immediate-early response protein 14 (Fn14), a member of the proinflammatory TNF family, is a FXR-responsive gene. However, the contribution of Fn14 induction in the perinatal toxic phenotype of the transgenic mice remains to be defined. Because FXR is being explored as a therapeutic target, our results suggested that a chronic activation of this nuclear receptor may have an unintended side effect especially during the perinatal stage. PMID:25719402

  8. Chronic Activation of FXR in Transgenic Mice Caused Perinatal Toxicity and Sensitized Mice to Cholesterol Toxicity

    PubMed Central

    Cheng, Qiuqiong; Inaba, Yuka; Lu, Peipei; Xu, Meishu; He, Jinhan; Zhao, Yueshui; Guo, Grace L.; Kuruba, Ramalinga; de la Vega, Rona; Evans, Rhobert W.; Li, Song

    2015-01-01

    The nuclear receptor farnesoid X receptor (FXR) (nuclear receptor subfamily 1, group H, member 4, or NR1H4) is highly expressed in the liver and intestine. Previous reports have suggested beneficial functions of FXR in the homeostasis of bile acids, lipids, and glucose, as well as in promoting liver regeneration and inhibiting carcinogenesis. To investigate the effect of chronic FXR activation in vivo, we generated transgenic mice that conditionally and tissue specifically express the activated form of FXR in the liver and intestine. Unexpectedly, the transgenic mice showed several intriguing phenotypes, including partial neonatal lethality, growth retardation, and spontaneous liver toxicity. The transgenic mice also displayed heightened sensitivity to a high-cholesterol diet-induced hepatotoxicity but resistance to the gallstone formation. The phenotypes were transgene specific, because they were abolished upon treatment with doxycycline to silence the transgene expression. The perinatal toxicity, which can be rescued by a maternal vitamin supplement, may have resulted from vitamin deficiency due to low biliary bile acid output as a consequence of inhibition of bile acid formation. Our results also suggested that the fibroblast growth factor-inducible immediate-early response protein 14 (Fn14), a member of the proinflammatory TNF family, is a FXR-responsive gene. However, the contribution of Fn14 induction in the perinatal toxic phenotype of the transgenic mice remains to be defined. Because FXR is being explored as a therapeutic target, our results suggested that a chronic activation of this nuclear receptor may have an unintended side effect especially during the perinatal stage. PMID:25719402

  9. Intracellular mechanisms of hydroquinone toxicity on endotoxin-activated neutrophils.

    PubMed

    Hebeda, Cristina Bichels; Pinedo, Fernanda Júdice; Bolonheis, Simone Marques; Ferreira, Zulma F; Muscará, Marcelo Nicolas; Teixeira, Simone Aparecida; Farsky, Sandra Helena Poliselli

    2012-11-01

    Circulating neutrophils promptly react to different substances in the blood and orchestrate the beginning of the innate inflammatory response. We have shown that in vivo exposure to hydroquinone (HQ), the most oxidative compound of cigarette smoke and a toxic benzene metabolite, affects circulating neutrophils, making them unresponsive to a subsequent bacterial infection. In order to understand the action of toxic molecular mechanisms on neutrophil functions, in vitro HQ actions on pro-inflammatory mediator secretions evoked by Escherichia coli lipopolysaccharide (LPS) were investigated. Neutrophils from male Wistar rats were cultured with vehicle or HQ (5 or 10 μM; 2 h) and subsequently incubated with LPS (5 μg/ml; 18 h). Hydroquinone treatment impaired LPS-induced nitric oxide (NO), tumour necrosis factor α (TNF-α), interleukin (IL)-1β and IL-6 secretions by neutrophils. The toxic effect was not dependent on cell death, reduced expression of the LPS receptor or toll-like receptor-4 (TLR-4) or cell priming, as HQ did not induce reactive oxygen species generation or β(2)integrin membrane expression. The action of toxic mechanisms on cytokine secretion was dependent on reduced gene synthesis, which may be due to decreased nuclear factor κB (NF-κB) nuclear translocation. Conversely, this intracellular pathway was not involved in impaired NO production because HQ treatments only affected inducible nitric oxide synthase protein expression and activity, suggesting posttranscriptional and/or posttranslational mechanisms of action. Altogether, our data show that HQ alters the action of different LPS-activated pathways on neutrophils, which may contribute to the impaired triggering of the host innate immune reaction detected during in vivo HQ exposure. PMID:22717997

  10. Antiulcerogenic Activity and Toxicity of Bauhinia holophylla Hydroalcoholic Extract

    PubMed Central

    Rozza, A. L.; Cesar, D. A. S.; Pieroni, L. G.; Saldanha, L. L.; Dokkedal, A. L.; De-Faria, F. M.; Souza-Brito, A. R. M.; Vilegas, W.; Takahira, R. K.; Pellizzon, C. H.

    2015-01-01

    Several species of Bauhinia are used in traditional medicine for the treatment of gastrointestinal diseases, diabetes, and inflammation, among other conditions. The aim of this study was to investigate the antiulcer effect of a hydroalcoholic extract from the leaves of B. holophylla. The chemical profile of the extract was determined by HPLC-PAD-ESI-IT-MS. A dose-effect relation was constructed using the ethanol-induced gastric ulcer model in male Wistar rats. Histological analyses and studies of antioxidant and anti-inflammatory activities were performed in stomach samples. The involvement of SH compounds, NO, K+ATP channels, and α2-adrenergic receptors in the gastroprotective effect was evaluated. A toxicity study was performed with a single oral dose of 5000 mg/kg. The extract was composed mainly of cyanoglucoside and flavonol-O-glycosides derivatives of quercetin and myricetin. SH compounds, NO release, K+ATP channel activation, and presynaptic α2-adrenergic receptor stimulation each proved to be involved in the antiulcer effect. The levels of GSH and activity of GR and GPx were increased, and the levels of TNF-α, IL-6 and IL-10 were modulated. There was an antidiarrheal effect and there were no signs of toxicity. B. holophylla presents antiulcer activity mainly by decreasing oxidative stress and attenuating the inflammatory response, without inducing side effects. PMID:25954316

  11. In vivo toxicity and antitumor activity of mangosteen extract.

    PubMed

    Kosem, Nuttavut; Ichikawa, Kazuhiro; Utsumi, Hideo; Moongkarndi, Primchanien

    2013-04-01

    Mangosteen (Garcinia mangostana) has been widely used in the traditional medicine of Thailand to treat various ailments, especially diseases of the digestive system and infections. Many reports show antiproliferation of crude extracts and active constituents from mangosteen against many cancer cell lines. Therefore, the current study is proposed to demonstrate in vivo evidence on the antitumor activity of mangosteen. Crude methanolic extract (CME) from mangosteen pericarp including 25.19 % α-mangostin as an active xanthone was used in this study. The inhibition on tumor cell proliferation of CME was preliminarily evaluated against the murine colon cancer cell line NL-17 with an IC50 value of 17 and 84 μg/ml based on WST-1 and LDH assays, respectively. The safety dose for animal application was assessed by in vivo toxicity studies using female BALB/c mice. Acute toxicity showed an LD50 value and approximate lethal dose at 1,000 mg/kg, whereas the suitable dose for short-term study should be ≤200 mg/kg. The effective dose for antitumor activity of CME was found to be between 100 and 200 mg/kg, with a tumor size reduction of 50-70 %. Histological staining clearly illustrated a decrease of tumor cell density in the footpad in a dose-dependent manner. The median survival time and life span significantly increased in tumor-bearing mice with CME treatment. This study suggests that CME possesses a powerful antitumor activity. Therefore, it is worth undertaking further investigation to identify active compounds and obtain a deeper understanding of their mechanism, in order to acquire novel effective anticancer drugs. PMID:22622784

  12. 4-Alkynylphenylsilatranes: Insecticidal activity, mammalian toxicity, and mode of action

    SciTech Connect

    Horsham, M.A.; Palmer, C.J.; Cole, L.M.; Casida, J.E. )

    1990-08-01

    4-Ethynyl- and 4-(prop-1-ynyl)phenylsilatranes (N(CH{sub 2}CH{sub 2}O){sub 3}SiR, R = C{sub 6}H{sub 4}-4-C{triple bond}CH or C{sub 6}H{sub 4}-4-C{triple bond}CCH{sub 3}) are highly toxic to houseflies (pretreated with piperonyl butoxide) and milkweed bugs (topical LD{sub 50}s 3-14 {mu}g/g) and to mice (intraperitoneal LD{sub 50}s 0.4-0.9 mg/kg), and they are moderately potent inhibitors of the ({sup 35}S)-tert-butylbicyclophosphorothionate or TBPS binding site (GABA-gated chloride channel) of mouse brain membranes. Scatchard analysis indicates noncompetitive interaction of 4-ethynylphenylsilatrane with the TBPS binding site. Phenylsilatrane analogues with 4-substituents of H, CH{sub 3}, Cl, Br, and C{triple bond}CSi(CH{sub 3}){sub 3} are highly toxic to mice but have little or no activity in the insect and receptor assays. Radioligand binding studies with (4-{sup 3}H)phenylsilatrane failed to reveal a specific binding site in mouse brain. Silatranes with R = H, CH{sub 3}, CH{sub 2}Cl, CH{double bond}CH{sub 2}, OCH{sub 2}CH{sub 3}, and C{sub 6}H{sub 4}-4-CH{sub 2}CH{sub 3} are of little or no activity in the insect and mouse toxicity and TBPS binding site assays as are the trithia and monocyclic analogues of phenylsilatrane. 4-Alkynylphenylsilatranes are new probes to examine the GABA receptor-ionophore complex of insects and mammals.

  13. Chemical properties and toxicity of soils contaminated by mining activity.

    PubMed

    Agnieszka, Baran; Tomasz, Czech; Jerzy, Wieczorek

    2014-09-01

    This research is aimed at assessing the total content and soluble forms of metals (zinc, lead and cadmium) and toxicity of soils subjected to strong human pressure associated with mining of zinc and lead ores. The research area lay in the neighbourhood of the Bolesław Mine and Metallurgical Plant in Bukowno (Poland). The study obtained total cadmium concentration between 0.29 and 51.91 mg, zinc between 7.90 and 3,614 mg, and that of lead between 28.4 and 6844 mg kg(-1) of soil d.m. The solubility of the heavy metals in 1 mol dm(-3) NH4NO3 was 1-49% for zinc, 5-45% for cadmium, and <1-10% for lead. In 1 mol HCl dm(-3), the solubility of the studied metals was much higher and obtained values depending on the collection site, from 45 to 92% for zinc, from 74 to 99%, and from 79 to 99% for lead. The lower solubility of the heavy metals in 1 mol dm(-3) NH4NO3 than 1 mol HCl dm(-3) is connected with that, the ammonium nitrate has low extraction power, and it is used in determining the bioavailable (active) form of heavy metals. Toxicity assessment of the soil samples was performed using two tests, Phytotoxkit and Microtox(®). Germination index values were between 22 and 75% for Sinapis alba, between 28 and 100% for Lepidium sativum, and between 10 and 28% for Sorghum saccharatum. Depending on the studied soil sample, Vibrio fischeri luminescence inhibition was 20-96%. The sensitivity of the test organisms formed the following series: S. saccharatum > S. alba = V. fischeri > L. sativum. Significant positive correlations (p ≤ 0.05) of the total and soluble contents of the metals with luminescence inhibition in V. fischeri and root growth inhibition in S. saccharatum were found. The general trend observed was an increase in metal toxicity measured by the biotest with increasing available metal contents in soils. All the soil samples were classified into toxicity class III, which means that they are toxic and present severe danger. Biotest are a good complement to

  14. FISH KILLS, BOTTOM-WATER HYPOXIA, AND THE TOXIC PFIESTERIA COMPLEX IN THE NEUSE RIVER AND ESTUARY. (R825551)

    EPA Science Inventory

    The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

  15. Antibacterial activity and toxicity of silver - nanosilver versus ionic silver

    NASA Astrophysics Data System (ADS)

    Kvitek, L.; Panacek, A.; Prucek, R.; Soukupova, J.; Vanickova, M.; Kolar, M.; Zboril, R.

    2011-07-01

    The in vitro study of antibacterial activity of silver nanoparticles (NPs), prepared via modified Tollens process, revealed high antibacterial activity even at very low concentrations around several units of mg/L. These concentrations are comparable with concentrations of ionic silver revealing same antibacterial effect. However, such low concentrations of silver NPs did not show acute cytotoxicity to mammalian cells - this occurs at concentrations higher than 60 mg/L of silver, while the cytotoxic level of ionic silver is much more lower (approx. 1 mg/L). Moreover, the silver NPs exhibit lower acute ecotoxicity against the eukaryotic organisms such as Paramecium caudatum, Monoraphidium sp. and D. melanogaster. The silver NPs are toxic to these organisms at the concentrations higher than 30 mg/L of silver. On contrary, ionic silver retains its cytoxicity and ecotoxicity even at the concentration equal to 1 mg/L. The performed experiments demonstrate significantly lower toxicity of silver NPs against the eukaryotic organisms than against the prokaryotic organisms.

  16. Mechanism of neutrophil activation and toxicity elicited by engineered nanomaterials.

    PubMed

    Johnston, Helinor; Brown, David M; Kanase, Nilesh; Euston, Matthew; Gaiser, Birgit K; Robb, Calum T; Dyrynda, Elisabeth; Rossi, Adriano G; Brown, Euan R; Stone, Vicki

    2015-08-01

    The effects of nanomaterials (NMs) on biological systems, especially their ability to stimulate inflammatory responses requires urgent investigation. We evaluated the response of the human differentiated HL60 neutrophil-like cell line to NMs. It was hypothesised that NM physico-chemical characteristics would influence cell responsiveness by altering intracellular Ca2+ concentration [Ca2+]i and reactive oxygen species production. Cells were exposed (1.95-125 μg/ml, 24 h) to silver (Ag), zinc oxide (ZnO), titanium dioxide (TiO2), multi-walled carbon nanotubes (MWCNTs) or ultrafine carbon black (ufCB) and cytotoxicity assessed (alamar blue assay). Relatively low (TiO2, MWCNTs, ufCB) or high (Ag, ZnO) cytotoxicity NMs were identified. Sub-lethal impacts of NMs on cell function were investigated for selected NMs only, namely TiO2, Ag and ufCB. Only Ag stimulated cell activation. Within minutes, Ag stimulated an increase in [Ca2+]i (in Fura-2 loaded cells), and a prominent inward ion current (assessed by electrophysiology). Within 2-4 h, Ag increased superoxide anion release and stimulated cytokine production (MCP-1, IL-8) that was diminished by Ca2+ inhibitors or trolox. Light microscopy demonstrated that cells had an activated phenotype. In conclusion NM toxicity was ranked; Ag>ufCB>TiO2, and the battery of tests used provided insight into the mechanism of action of NM toxicity to guide future testing strategies. PMID:25962642

  17. Metal Toxicity Affects Fungal and Bacterial Activities in Soil Differently

    PubMed Central

    Rajapaksha, R. M. C. P.; Tobor-Kapłon, M. A; Bååth, E.

    2004-01-01

    Although the toxic effect of heavy metals on soil microorganism activity is well known, little is known about the effects on different organism groups. The influence of heavy metal addition on total, bacterial, and fungal activities was therefore studied for up to 60 days in a laboratory experiment using forest soil contaminated with different concentrations of Zn or Cu. The effects of the metals differed between the different activity measurements. During the first week after metal addition, the total activity (respiration rate) decreased by 30% at the highest level of contamination and then remained stable during the 60 days of incubation. The bacterial activity (thymidine incorporation rate) decreased during the first days with the level of metal contamination, resulting in a 90% decrease at the highest level of contamination. Bacterial activity then slowly recovered to values similar to those of the control soil. The recovery was faster when soil pH, which had decreased due to metal addition, was restored to control values by liming. Fungal activity (acetate-in-ergosterol incorporation rate) initially increased with the level of metal contamination, being up to 3 and 7 times higher than that in the control samples during the first week at the highest levels of Zn and Cu addition, respectively. The positive effect of metal addition on fungal activity then decreased, but fungal activity was still higher in contaminated than in control soil after 35 days. This is the first direct evidence that fungal and bacterial activities in soil are differently affected by heavy metals. The different responses of bacteria and fungi to heavy metals were reflected in an increase in the relative fungal/bacterial ratio (estimated using phospholipid fatty acid analysis) with increased metal load. PMID:15128558

  18. Metal toxicity affects fungal and bacterial activities in soil differently.

    PubMed

    Rajapaksha, R M C P; Tobor-Kapłon, M A; Bååth, E

    2004-05-01

    Although the toxic effect of heavy metals on soil microorganism activity is well known, little is known about the effects on different organism groups. The influence of heavy metal addition on total, bacterial, and fungal activities was therefore studied for up to 60 days in a laboratory experiment using forest soil contaminated with different concentrations of Zn or Cu. The effects of the metals differed between the different activity measurements. During the first week after metal addition, the total activity (respiration rate) decreased by 30% at the highest level of contamination and then remained stable during the 60 days of incubation. The bacterial activity (thymidine incorporation rate) decreased during the first days with the level of metal contamination, resulting in a 90% decrease at the highest level of contamination. Bacterial activity then slowly recovered to values similar to those of the control soil. The recovery was faster when soil pH, which had decreased due to metal addition, was restored to control values by liming. Fungal activity (acetate-in-ergosterol incorporation rate) initially increased with the level of metal contamination, being up to 3 and 7 times higher than that in the control samples during the first week at the highest levels of Zn and Cu addition, respectively. The positive effect of metal addition on fungal activity then decreased, but fungal activity was still higher in contaminated than in control soil after 35 days. This is the first direct evidence that fungal and bacterial activities in soil are differently affected by heavy metals. The different responses of bacteria and fungi to heavy metals were reflected in an increase in the relative fungal/bacterial ratio (estimated using phospholipid fatty acid analysis) with increased metal load. PMID:15128558

  19. Toxicity of 8-Hydroxyquinoline in Cryprinus carpio Using the Acute Toxicity Test, Hepatase Activity Analysis and the Comet Assay.

    PubMed

    Yan, Shuaiguo; Chen, Lili; Dou, Xiaofei; Qi, Meng; Du, Qiyan; He, Qiaoqiao; Nan, Mingge; Chang, Zhongjie; Nan, Ping

    2015-08-01

    To evaluate the environmental toxicity of 8-hydroxyquinoline (8-HOQ), an important industrial raw material found in China's major ornamental fish, Cryprinus carpio, using the acute toxicity test, hepatase activity analysis and the comet assay. The results indicated that 8-HOQ had significant acute toxicity in adult C. carpio with a 96 h-LC50 of 1.15 and 0.22 mg L(-1) hepatic quinoline residues as assessed by HPLC. 8-HOQ also induced genotoxicity in the form of strand breaks in the DNA of hepatic cells as shown by the comet assay. With regard to physiological toxicity, 8-HOQ induced a decrease in the activities of hepatic GOT and GPT with increased exposure concentration and time. These data suggest that 8-HOQ may be toxic to the health of aquatic organisms when accidentally released into aquatic ecosystems. The data also suggest that the comet assay may be used in biomonitoring to determine 8-HOQ genotoxicity and hepatic GPT and GOT activities may be potential biomarkers of physiological toxicity. PMID:26067700

  20. Hormonal activity, cytotoxicity and developmental toxicity of UV filters.

    PubMed

    Balázs, Adrienn; Krifaton, Csilla; Orosz, Ivett; Szoboszlay, Sándor; Kovács, Róbert; Csenki, Zsolt; Urbányi, Béla; Kriszt, Balázs

    2016-09-01

    Ultraviolet (UV) filters are commonly used compounds in personal care products and polymer based materials, as they can absorb solar energy in the UVA and UVB spectrum. However, they are able to bind to hormone receptors and have several and different types of hormonal activities determined by in vitro assays. One of the aims of this work was to measure the hormonal and cytotoxic activities of four frequently used UV filters using bioluminescence based yeast test organisms. Using Saccharomyces cerevisiae BLYES and BLYAS strains allowed the rapid and reliable detection of agonist and antagonist hormonal activities, whereas BLYR strain served to measure cytotoxicity. Results confirmed that all tested UV filters show multiple hormonal activities. Cytotoxicity is detected only in the case of benzophenone-3. Research data on the toxic effects of benzophenone-3, especially on aquatic organisms are scarce, so further investigations were carried out regarding its cytotoxic and teratogenic effects on bacteria and zebrafish (Danio rerio) embryos, respectively. Results revealed the cytotoxicity of benzophenone-3 not only to yeasts but to bacteria, as well as its ability to influence zebrafish embryo hatching and development. PMID:27208882

  1. Rapid toxicity testing based on yeast respiratory activity

    SciTech Connect

    Haubenstricker, M.E. ); Meier, P.G.; Mancy, K.H. ); Brabec, M.J. )

    1990-05-01

    Rapid and economical techniques are needed to determine the effects of environmental contaminants. At present, the main methods to assess the impact of pollutants are based on chemical analysis of the samples. Invertebrate and vertebrate exposures have been used over the last two decades in assessing acute and chronic toxicities. However, these tests are labor intensive and require several days to complete. An alternative to whole organism exposure is to determine toxic effects in monocellular systems. Another approach for assessing toxicity is to monitor sensitive, nonspecific, subcellular target sites such as mitochondria. Changes in mitochondrial function which could indicate a toxic effect can be demonstrated readily after addition of a foreign substance. In initial assessments of various chemicals, rat liver mitochondria (RLM) were evaluated as a biological sensor of toxicity. False toxicity assessments will result if these ions are present even though they are generally considered nontoxic. Because of these disadvantages, an alternative mitochondrial system, such as found in bakers yeast, was evaluated.

  2. Saving two birds with one stone: using active substance avian acute toxicity data to predict formulated plant protection product toxicity.

    PubMed

    Maynard, Samuel K; Edwards, Peter; Wheeler, James R

    2014-07-01

    Environmental safety assessments for exposure of birds require the provision of acute avian toxicity data for both the pesticidal active substance and formulated products. As an example, testing on the formulated product is waived in Europe using an assessment of data for the constituent active substance(s). This is often not the case globally, because some countries require acute toxicity tests with every formulated product, thereby triggering animal welfare concerns through unnecessary testing. A database of 383 formulated products was compiled from acute toxicity studies conducted with northern bobwhite (Colinus virginianus) or Japanese quail (Coturnix japonica) (unpublished regulatory literature). Of the 383 formulated products studied, 159 contained only active substances considered functionally nontoxic (median lethal dose [LD50] > highest dose tested). Of these, 97% had formulated product LD50 values of >2000 mg formulated product/kg (limit dose), indicating that no new information was obtained in the formulated product study. Furthermore, defined (point estimated) LD50 values for formulated products were compared with LD50 values predicted from toxicity of the active substance(s). This demonstrated that predicted LD50 values were within 2-fold and 5-fold of the measured formulated product LD50 values in 90% and 98% of cases, respectively. This analysis demonstrates that avian acute toxicity testing of formulated products is largely unnecessary and should not be routinely required to assess avian acute toxicity. In particular, when active substances are known to be functionally nontoxic, further formulated product testing adds no further information and unnecessarily increases bird usage in testing. A further analysis highlights the fact that significant reductions (61% in this dataset) could be achieved by using a sequential testing design (Organisation for Economic Co-operation and Development test guideline 223), as opposed to established single

  3. Removal of toxic chemicals from water with activated carbon

    USGS Publications Warehouse

    Dawson, V.K.; Marking, L.L.; Bills, T.D.

    1976-01-01

    Activated carbon was effective in removing fish toxicants and anesthetics from water solutions. Its capacity to adsorb 3-trifluoromethyl-4-nitrophenol (TFM), antimycin, NoxfishA? (5% rotenone), Dibrorms, juglone, MSa??222, and benzocaine ranged from 0.1 to 64 mg per gram of carbon. The adsorptive capacity (end point considered as a significant discharge) of activated carbon for removal of TFM was determined at column depths of 15, 30, and 60 cm; temperatures of 7, 12, 17, and 22 C; pH's of 6.5, 7.5, 8.5, and 9.5; and flow rates of 50, 78, 100, 200, and 940 ml/min. Adsorptive capacity increased when the contact time was increased by reducing the flow rate or increasing the column depth. The adsorptive capacity was not significantly influenced by temperature but was substantially higher at pH 6.5 than at the other pH's tested. A practical and efficient filter for purifying chemically treated water was developed.

  4. Synthesis, characterization, antiamoebic activity and toxicity of novel bisdioxazole derivatives.

    PubMed

    Iqbal, Prince Firdoos; Parveen, Humaira; Bhat, Abdul Roouf; Hayat, Faisal; Azam, Amir

    2009-11-01

    Cyclization of benzene-1,4-dicarbaldehyde dioxime 1 with different aromatic aldehydes in inert atmosphere yielded the corresponding new bisdioxazoles 2-11. The structure of 2-11 was elucidated by spectral data. In vitro antiamoebic activity was performed against HM1:IMSS strain of Entamoeba histolytica. The results showed that the compounds 3 (IC(50)=1.22 microM), 4 (IC(50)=1.41 microM), 7 (IC(50)=1.05 microM) and 10 (IC(50)=1.01 microM) exhibited better antiamoebic activity than the standard drug metronidazole (IC(50)=1.80 microM). The compounds 3, 4, 7 and 10 were tested for toxicity by MTT assay on H9c2 cardiac myoblasts and the results showed that the compounds 3, 4, 7 and 10 offered remarkable viability of 96.2%, 83.5%, 82% and 89%, respectively at a concentration of 12.5 microg/ml. PMID:19589625

  5. STRUCTURE-ACTIVITY RELATIONSHIP STUIDES AND THEIR ROLE IN PREDICTING AND INVESTIGATING CHEMICAL TOXICITY

    EPA Science Inventory

    Structure-Activity Relationship Studies and their Role in Predicting and Investigating Chemical Toxicity

    Structure-activity relationships (SAR) represent attempts to generalize chemical information relative to biological activity for the twin purposes of generating insigh...

  6. Hepatoprotective activity of Moringa oleifera against cadmium toxicity in rats

    PubMed Central

    Toppo, Reetu; Roy, Birendra Kumar; Gora, Ravuri Halley; Baxla, Sushma Lalita; Kumar, Prabhat

    2015-01-01

    Aim: The present investigation has been conducted to evaluate the hepatoprotective activity of Moringa oleifera against cadmium-induced toxicity in rats. Materials and Methods: For this study, 18 Wistar albino rats were taken. Control group, Group I rats were given cadmium chloride @ 200 ppm per kg and Group II rats were treated with M. oleifera extract @ 500 mg/kg along with cadmium chloride @ 200 ppm per kg (daily oral for 28 days). On 29th day, animals were slaughtered and various parameters were determined. Serum biomarkers, oxidative stress parameters, histomorphological examination were carried out with estimation of cadmium concentration in liver tissues. Results: Oral administration of cadmium chloride @ 200 ppm/kg for 28 days resulted in a significant increase in aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), significant (p≤0.01) increase of lipid peroxidation (LPO) and decrease in superoxide dismutase (SOD), and increase in cadmium accumulation in liver. Treatment with M. oleifera @ 500 mg/kg significantly (p<0.01) decreased the elevated ALP, AST, ALT, LPO levels and increase in SOD levels, and as compared to cadmium chloride treated group. However, there was no significant difference in cadmium concentration in liver when compared with cadmium chloride treated group. Conclusion: The study conclude that supplementation of M. oleifera (500 mg/kg), daily oral for 28 days has shown protection against cadmium-induced hepatotoxicity. PMID:27047130

  7. Rapid toxicity testing based on mitochondrial respiratory activity

    SciTech Connect

    Haubenstricker, M.E. ); Holodnick, S.E.; Mancy, K.H. ); Brabec, M.J. )

    1990-05-01

    The need exists for rapid and inexpensive methods to determine the health effects of environmental contaminants on biological systems. One of the current research approaches for assessing cytotoxicity is to monitor the respiratory activity of the mitochondrion, a sensitive, nonspecific subcellular target site. Detected changes in mitochondrial function after the addition of a test chemical could be correlated to toxic effects. Mitochondrial respiration can be characterized by three indices: state 3 and state 4 respiratory rates, and the respiratory control ratio (RCR). State 4, the idle or resting state, results when coupled mitochondrial respire in a medium containing inorganic phosphate and a Kreb's cycle substrate in the absence of a phosphate acceptor such as adenosine diphosphate (ADP). In the presence of ADP the respiration rate increases to a maximum (state 3), accompanied by phosphorylation of ADP to adenosine triphosphate (ATP). The ratio of state 3 to state 4, or RCR, indicates how tightly the oxidative phosphorylation process is coupled. The synthesis of ATP by mitochondria is influenced by a number of compounds, most of which are either uncouplers or inhibitors.

  8. Pharmacological activity and toxicity of some neurotropic agents under conditions of experimental hypodynamia

    NASA Technical Reports Server (NTRS)

    Kirichek, L. T.

    1980-01-01

    The indices of pharmacological range, risk coefficients, ED50, LD50, the size of the area of toxic activity, and maximal tolerated and absolute lethal doses were compared in hypodynamic mice. The pharmacological activity of the test neurotropic agents exhibiting a central action underwent change, but their toxicity remained unchanged.

  9. ACTIVITY PROFILES OF DEVELOPMENTAL TOXICITY: DESIGN CONSIDERATIONS AND PILOT IMPLEMENTATION

    EPA Science Inventory

    The available literature was searched for quantitative test results from both in vitro and in vivo assays for developmental toxicity for five model compounds: yclophosphamid, methotrexate, hydroxyurea, caffeine, and ethylenethiourea. hese compounds were chosen on the basis of the...

  10. Anticancer activities against cholangiocarcinoma, toxicity and pharmacological activities of Thai medicinal plants in animal models

    PubMed Central

    2012-01-01

    Background Chemotherapy of cholangiocarcinoma (CCA), a devastating cancer with increasing worldwide incidence and mortality rates, is largely ineffective. The discovery and development of effective chemotherapeutics is urgently needed. Methods/Design The study aimed at evaluating anticancer activities, toxicity, and pharmacological activities of the curcumin compound (CUR), the crude ethanolic extracts of rhizomes of Zingiber officinale Roscoe (Ginger: ZO) and Atractylodes lancea thung. DC (Khod-Kha-Mao: AL), fruits of Piper chaba Hunt. (De-Plee: PC), and Pra-Sa-Prao-Yhai formulation (a mixture of parts of 18 Thai medicinal plants: PPF) were investigated in animal models. Anti-cholangiocarcinoma (anti-CCA) was assessed using CCA-xenograft nude mouse model. The antihypertensive, analgesic, anti-inflammatory, antipyretic, and anti-ulcer activities and effects on motor coordination were investigated using Rota-rod test, CODA tail-cuff system, writhing and hot plate tests, carrageenan-induced paw edema test, brewer's yeast test, and alcohol-induced gastric ulcer test, respectively. Acute and subacute toxicity tests were performed according to the OECD guideline for testing of chemicals with modification. Results Promising anticancer activity against CCA in nude mouse xenograft model was shown for the ethanolic extract of AL at all oral dose levels (1000, 3000, and 5000 mg/kg body weight) as well as the extracts of ZO, PPF, and CUR compound at the highest dose level (5000, 4000, and 5000 mg/kg body weight, respectively). PC produced no significant anti-CCA activity. Results from acute and subacute toxicity tests both in mice and rats indicate safety profiles of all the test materials in a broad range of dose levels. No significant toxicity except stomach irritation and general CNS depressant signs were observed. Investigation of pharmacological activities of the test materials revealed promising anti-inflammatory (ZO, PPF, and AL), analgesic (CUR and PPF), antipyretic

  11. Estimating Toxicity Pathway Activating Doses for High Throughput Chemical Risk Assessments

    EPA Science Inventory

    Estimating a Toxicity Pathway Activating Dose (TPAD) from in vitro assays as an analog to a reference dose (RfD) derived from in vivo toxicity tests would facilitate high throughput risk assessments of thousands of data-poor environmental chemicals. Estimating a TPAD requires def...

  12. SOME EFFECTS OF AGE, SPECIES DIFFERENCE, ANTIBIOTICS AND TOXICANT EXPOSURE ON INTESTINAL ENZYME ACTIVITY AND GENOTOXICITY

    EPA Science Inventory

    Altered intestinal enzyme activity significantly affects the biotransformation and toxicity of many xenobiotics. his review summarizes research, supported by the Air Force Bioenvironmental Hazards Research Program, that employs a novel gas-liquid chromatographic assay to investig...

  13. Quantitative Structure--Activity Relationship Modeling of Rat Acute Toxicity by Oral Exposure

    EPA Science Inventory

    Background: Few Quantitative Structure-Activity Relationship (QSAR) studies have successfully modeled large, diverse rodent toxicity endpoints. Objective: In this study, a combinatorial QSAR approach has been employed for the creation of robust and predictive models of acute toxi...

  14. [The importance of using biological test objects in studying the toxicity of surface-active substances].

    PubMed

    Mudryĭ, I V; Debrivnaia, I E

    1996-01-01

    The Azotobacter agilis [correction of azobacter agile] culture appeared to be the most sensitive one among the studied test objects. Buckwheat as a test plant can be recommended in studying the toxicity of surface-active substances. PMID:9035856

  15. Activation of AhR-mediated toxicity pathway by emerging pollutants polychlorinated diphenyl sulfides

    EPA Science Inventory

    Polychlorinated diphenyl sulfides (PCDPSs) are a group of environmental pollutants for which limited toxicological information is available. This study tested the hypothesis that PCDPSs could activate the mammalian aryl hydrocarbon receptor (AhR) mediated toxicity pathways. Eight...

  16. Lead Toxicity to the Performance, Viability, And Community Composition of Activated Sludge Microorganisms

    SciTech Connect

    Yuan, L; Zhi, W; Liu, YS; Karyala, S; Vikesland, PJ; Chen, X; Zhang, HS

    2015-01-20

    Lead (Pb) is a prominent toxic metal in natural and engineered systems. Current knowledge on Pb toxicity to the activated sludge has been limited to short-term (<= 24 h) toxicity. The effect of extended Pb exposure on process performance, bacterial viability, and community compositions remains unknown. We quantified the 24-h and 7-day Pb toxicity to chemical oxygen demand (COD) and NH3-N removal, bacterial viability, and community compositions using lab-scale experiments. Our results showed that 7-day toxicity was significantly higher than the short-term 24-h toxicity. Ammonia-oxidizing bacteria were more susceptible than the heterotrophs to Pb toxicity. The specific oxygen uptake rate responded quickly to Pb addition and could serve as a rapid indicator for detecting Pb pollutions. Microbial viability decreased linearly with the amount of added Pb at extended exposure. The bacterial community diversity was markedly reduced with elevated Pb concentrations. Surface analysis suggested that the adsorbed form of Pb could have contributed to its toxicity along with the dissolved form. Our study provides for the first time a systematic investigation of the effect of extended exposure of Pb on the performance and microbiology of aerobic treatment processes, and it indicates that long-term Pb toxicity has been underappreciated by previous studies.

  17. Lead toxicity to the performance, viability, and community composition of activated sludge microorganisms.

    PubMed

    Yuan, Li; Zhi, Wei; Liu, Yangsheng; Karyala, Saikumar; Vikesland, Peter J; Chen, Xi; Zhang, Husen

    2015-01-20

    Lead (Pb) is a prominent toxic metal in natural and engineered systems. Current knowledge on Pb toxicity to the activated sludge has been limited to short-term (≤24 h) toxicity. The effect of extended Pb exposure on process performance, bacterial viability, and community compositions remains unknown. We quantified the 24-h and 7-day Pb toxicity to chemical oxygen demand (COD) and NH3–N removal, bacterial viability, and community compositions using lab-scale experiments. Our results showed that 7-day toxicity was significantly higher than the short-term 24-h toxicity. Ammonia-oxidizing bacteria were more susceptible than the heterotrophs to Pb toxicity. The specific oxygen uptake rate responded quickly to Pb addition and could serve as a rapid indicator for detecting Pb pollutions. Microbial viability decreased linearly with the amount of added Pb at extended exposure. The bacterial community diversity was markedly reduced with elevated Pb concentrations. Surface analysis suggested that the adsorbed form of Pb could have contributed to its toxicity along with the dissolved form. Our study provides for the first time a systematic investigation of the effect of extended exposure of Pb on the performance and microbiology of aerobic treatment processes, and it indicates that long-term Pb toxicity has been underappreciated by previous studies. PMID:25536278

  18. Toxicity of N-substituted aromatics to acetoclastic methanogenic activity in granular sludge.

    PubMed Central

    Donlon, B A; Razo-Flores, E; Field, J A; Lettinga, G

    1995-01-01

    N-substituted aromatics are important priority pollutants entering the environment primarily through anthropogenic activities associated with the industrial production of dyes, explosives, pesticides, and pharmaceuticals. Anaerobic treatment of wastewaters discharged by these industries could potentially be problematical as a result of the high toxicity of N-substituted aromatics. The objective of this study was to examine the structure-toxicity relationships of N-substituted aromatic compounds to acetoclastic methanogenic bacteria. The toxicity was assayed in serum flasks by measuring methane production in granular sludge. Unacclimated cultures were used to minimize the biotransformation of the toxic organic chemicals during the test. The nature and the degree of the aromatic substitution were observed to have a profound effect on the toxicity of the test compound. Nitroaromatic compounds were, on the average, over 500-fold more toxic than their corresponding aromatic amines. Considering the facile reduction of nitro groups by anaerobic microorganisms, a dramatic detoxification of nitroaromatics towards methanogens can be expected to occur during anaerobic wastewater treatment. While the toxicity exerted by the N-substituted aromatic compounds was closely correlated with compound apolarity (log P), it was observed that at any given log P, N-substituted phenols had a toxicity that was 2 orders of magnitude higher than that of chlorophenols and alkylphenols. This indicates that toxicity due to the chemical reactivity of nitroaromatics is much more important than partitioning effects in bacterial membranes. PMID:8526501

  19. Effect of steam activation of biochar produced from a giant Miscanthus on copper sorption and toxicity.

    PubMed

    Shim, Taeyong; Yoo, Jisu; Ryu, Changkook; Park, Yong-Kwon; Jung, Jinho

    2015-12-01

    This study aims to evaluate the physiochemical properties, sorption characteristics, and toxicity effects of biochar (BC) produced from Miscanthus sacchariflorus via slow pyrolysis at 500°C and its steam activation product (ABC). Although BC has a much lower surface area than ABC (181 and 322m(2)g(-1), respectively), the Cu sorption capacities of BC and ABC are not significantly different (p>0.05). A two-compartment model successfully explains the sorption of BC and ABC as being dominated by fast and slow sorption processes, respectively. In addition, both BC and ABC efficiently eliminate the toxicity of Cu towards Daphnia magna. However, ABC itself induced acute toxicity to D. magna, which is possibly due to increased aromaticity upon steam activation. These findings suggest that activation of BC produced from M. sacchariflorus at a pyrolytic temperature of 500°C may not be appropriate in terms of Cu sorption and toxicity reduction. PMID:26318926

  20. A Categorical Structure-Activity Relationship Analysis of the Developmental Toxicity of Antithyroid Drugs

    PubMed Central

    Cunningham, Albert R.; Carrasquer, C. Alex; Mattison, Donald R.

    2009-01-01

    The choice of therapeutic strategies for hyperthyroidism during pregnancy is limited. Surgery and radioiodine are typically avoided, leaving propylthiouracil and methimazole in the US. Carbimazole, a metabolic precursor of methimazole, is available in some countries outside of the US. In the US propylthiouracil is recommended because of concern about developmental toxicity from methimazole and carbimazole. Despite this recommendation, the data on developmental toxicity of all three agents are extremely limited and insufficient to support a policy given the broad use of methimazole and carbimazole around the world. In the absence of new human or animal data we describe the development of a new structure-activity relationship (SAR) model for developmental toxicity using the cat-SAR expert system. The SAR model was developed from data for 323 compounds evaluated for human developmental toxicity with 130 categorized as developmental toxicants and 193 as nontoxicants. Model cross-validation yielded a concordance between observed and predicted results between 79% to 81%. Based on this model, propylthiouracil, methimazole, and carbimazole were observed to share some structural features relating to human developmental toxicity. Thus given the need to treat women with Graves's disease during pregnancy, new molecules with minimized risk for developmental toxicity are needed. To help meet this challenge, the cat-SAR method would be a useful in screening new drug candidates for developmental toxicity as well as for investigating their mechanism of action. PMID:20111734

  1. Major Pesticides Are More Toxic to Human Cells Than Their Declared Active Principles

    PubMed Central

    Spiroux de Vendômois, Joël; Séralini, Gilles-Eric

    2014-01-01

    Pesticides are used throughout the world as mixtures called formulations. They contain adjuvants, which are often kept confidential and are called inerts by the manufacturing companies, plus a declared active principle, which is usually tested alone. We tested the toxicity of 9 pesticides, comparing active principles and their formulations, on three human cell lines (HepG2, HEK293, and JEG3). Glyphosate, isoproturon, fluroxypyr, pirimicarb, imidacloprid, acetamiprid, tebuconazole, epoxiconazole, and prochloraz constitute, respectively, the active principles of 3 major herbicides, 3 insecticides, and 3 fungicides. We measured mitochondrial activities, membrane degradations, and caspases 3/7 activities. Fungicides were the most toxic from concentrations 300–600 times lower than agricultural dilutions, followed by herbicides and then insecticides, with very similar profiles in all cell types. Despite its relatively benign reputation, Roundup was among the most toxic herbicides and insecticides tested. Most importantly, 8 formulations out of 9 were up to one thousand times more toxic than their active principles. Our results challenge the relevance of the acceptable daily intake for pesticides because this norm is calculated from the toxicity of the active principle alone. Chronic tests on pesticides may not reflect relevant environmental exposures if only one ingredient of these mixtures is tested alone. PMID:24719846

  2. Effects of Environmental Toxicants on Metabolic Activity of Natural Microbial Communities

    PubMed Central

    Barnhart, Carole L. H.; Vestal, J. Robie

    1983-01-01

    Two methods of measuring microbial activity were used to study the effects of toxicants on natural microbial communities. The methods were compared for suitability for toxicity testing, sensitivity, and adaptability to field applications. This study included measurements of the incorporation of 14C-labeled acetate into microbial lipids and microbial glucosidase activity. Activities were measured per unit biomass, determined as lipid phosphate. The effects of various organic and inorganic toxicants on various natural microbial communities were studied. Both methods were useful in detecting toxicity, and their comparative sensitivities varied with the system studied. In one system, the methods showed approximately the same sensitivities in testing the effects of metals, but the acetate incorporation method was more sensitive in detecting the toxicity of organic compounds. The incorporation method was used to study the effects of a point source of pollution on the microbiota of a receiving stream. Toxic doses were found to be two orders of magnitude higher in sediments than in water taken from the same site, indicating chelation or adsorption of the toxicant by the sediment. The microbiota taken from below a point source outfall was 2 to 100 times more resistant to the toxicants tested than was that taken from above the outfall. Downstream filtrates in most cases had an inhibitory effect on the natural microbiota taken from above the pollution source. The microbial methods were compared with commonly used bioassay methods, using higher organisms, and were found to be similar in ability to detect comparative toxicities of compounds, but were less sensitive than methods which use standard media because of the influences of environmental factors. PMID:16346432

  3. REGARDING PFIESTERIA. (R827084)

    EPA Science Inventory

    The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

  4. Improved antitumor activity and reduced myocardial toxicity of doxorubicin encapsulated in MPEG-PCL nanoparticles.

    PubMed

    Sun, Chuntang; Zhou, Le; Gou, Maling; Shi, Shuai; Li, Tao; Lang, Jinyi

    2016-06-01

    Doxorubicin (Dox) is a broad-spectrum antitumor drug used for the treatment of many types of malignant tumors. Although it possesses powerful antitumor activity, its clinical application is seriously encumbered by its unselective distribution and systemic toxicities, particularly myocardial toxicity. Thus, it is imperative to modify Dox to decrease its systemic toxicities and improve its therapeutic index. In the present study, we adopted a novel type of monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) micelles to encapsulate Dox to prepare Dox-loaded MPEG-PCL (Dox/MPEG-PCL) nanoparticles by a controllable self-assembly process. The cellular uptake efficiency and cell proliferation inhibition of the Dox/MPEG-PCL nanoparticles were examined. The antitumor activity of the Dox/MPEG-PCL nanoparticles was tested on a multiple pulmonary metastasis model of melanoma on C57BL/6 mice. Systemic toxicities and survival time were compared between the mice treated with the Dox/MPEG-PCL nanoparticles and free Dox. The potential myocardial toxicity of the Dox/MPEG-PCL nanoparticles was investigated using a prolonged observation period. Encapsulation of Dox in MPEG-PCL nanoparticles significantly improved the cellular uptake and cell proliferation inhibition of Dox in vivo. Intravenous injection of Dox/MPEG-PCL nanoparticles obtained significant inhibition of the growth and metastasis of melanoma in the lung and prolonged survival time compared with free Dox (P<0.05). The Dox/MPEG-PCL nanoparticles did not show obvious additional systemic toxicities compared with free Dox during the treatment time. During the prolonged observation period, obvious decreased cardiac toxicity was observed in the Dox/MPEG-PCL nanoparticle-treated mice compared with that observed in the free Dox-treated mice. These results indicated that encapsulating Dox with MPEG-PCL micelles could significantly promote its antitumor activity and reduce its toxicity to the myocardium. PMID

  5. Automated swimming activity monitor for examining temporal patterns of toxicant effects on individual Daphnia magna.

    PubMed

    Bahrndorff, Simon; Michaelsen, Thomas Yssing; Jensen, Anne; Marcussen, Laurits Faarup; Nielsen, Majken Elley; Roslev, Peter

    2016-07-01

    Aquatic pollutants are often biologically active at low concentrations and impact on biota in combination with other abiotic stressors. Traditional toxicity tests may not detect these effects, and there is a need for sensitive high-throughput methods for detecting sublethal effects. We have evaluated an automated infra-red (IR) light-based monitor for recording the swimming activity of Daphnia magna to establish temporal patterns of toxicant effects on an individual level. Activity was recorded for 48 h and the sensitivity of the monitor was evaluated by exposing D. magna to the reference chemicals K2 Cr2 O7 at 15, 20 and 25 °C and 2,4-dichlorophenol at 20 °C. Significant effects (P < 0.001) of toxicant concentrations, exposure time and incubation temperatures were observed. At 15 °C, the swimming activity remained unchanged for 48 h at sublethal concentrations of K2 Cr2 O7 whereas activity at 20 and 25 °C was more biphasic with decreases in activity occurring after 12-18 h. A similar biphasic pattern was observed after 2,4-dichlorophenol exposure at 20 °C. EC50 values for 2,4-dichlorophenol and K2 Cr2 O7 determined from automated recording of swimming activity showed increasing toxicity with time corresponding to decreases in EC50 of 0.03-0.07 mg l(-1) h(-1) . EC50 values determined after 48 h were comparable or lower than EC50 values based on visual inspection according to ISO 6341. The results demonstrated that the swimming activity monitor is capable of detecting sublethal behavioural effects that are toxicant and temperature dependent. The method allows EC values to be established at different time points and can serve as a high-throughput screening tool in toxicity testing. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26198804

  6. Toxicity and immunomodulatory activity of liposomal vectors formulated with cationic lipids toward immune effector cells.

    PubMed

    Filion, M C; Phillips, N C

    1997-10-23

    Liposomal vectors formulated with cationic lipids (cationic liposomes) and fusogenic dioleoylphosphatidylethanolamine (DOPE) have potential for modulating the immune system by delivering gene or antisense oligonucleotide inside immune cells. The toxicity and the immunoadjuvant activity of cationic liposomes containing nucleic acids toward immune effector cells has not been investigated in detail. In this report, we have evaluated the toxicity of liposomes formulated with various cationic lipids towards murine macrophages and T lymphocytes and the human monocyte-like U937 cell line. The effect of these cationic liposomes on the synthesis of two immunomodulators produced by activated macrophages, nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha), has also been determined. We have found that liposomes formulated from DOPE and cationic lipids based on diacyltrimethylammonium propane (dioleoyl-, dimyristoyl-, dipalmitoyl-, disteroyl-: DOTAP, DMTAP, DPTAP, DSTAP) or dimethyldioctadecylammonium bromide (DDAB) are highly toxic in vitro toward phagocytic cells (macrophages and U937 cells), but not towards non-phagocytic T lymphocytes. The rank order of toxicity was DOPE/DDAB > DOPE/DOTAP > DOPE/DMTAP > DOPE/DPTAP > DOPE/DSTAP. The ED50's for macrophage toxicity were < 10 nmol/ml for DOPE/DDAB, 12 nmol/ml for DOPE/DOTAP, 50 nmol/ml for DOPE/DMTAP, 400 nmol/ml for DOPE/DPTAP and > 1000 nmol/ml for DOPE/DSTAP. The incorporation of DNA (antisense oligonucleotide or plasmid vector) into the cationic liposomes marginally reduced their toxicity towards macrophages. Although toxicity was observed with cationic lipids alone, it was clearly enhanced by the presence of DOPE. The replacement of DOPE by dipalmitoylphosphatidylcholine (DPPC) significantly reduced liposome toxicity towards macrophages, and the presence of dipalmitoylphosphatidylethanolamine-PEG2000 (DPPE-PEG2000: 10 mol%) in the liposomes completely abolished this toxicity. Cationic liposomes, irrespective of

  7. Ethoxylated adjuvants of glyphosate-based herbicides are active principles of human cell toxicity.

    PubMed

    Mesnage, R; Bernay, B; Séralini, G-E

    2013-11-16

    Pesticides are always used in formulations as mixtures of an active principle with adjuvants. Glyphosate, the active ingredient of the major pesticide in the world, is an herbicide supposed to be specific on plant metabolism. Its adjuvants are generally considered as inert diluents. Since side effects for all these compounds have been claimed, we studied potential active principles for toxicity on human cells for 9 glyphosate-based formulations. For this we detailed their compositions and toxicities, and as controls we used a major adjuvant (the polyethoxylated tallowamine POE-15), glyphosate alone, and a total formulation without glyphosate. This was performed after 24h exposures on hepatic (HepG2), embryonic (HEK293) and placental (JEG3) cell lines. We measured mitochondrial activities, membrane degradations, and caspases 3/7 activities. The compositions in adjuvants were analyzed by mass spectrometry. Here we demonstrate that all formulations are more toxic than glyphosate, and we separated experimentally three groups of formulations differentially toxic according to their concentrations in ethoxylated adjuvants. Among them, POE-15 clearly appears to be the most toxic principle against human cells, even if others are not excluded. It begins to be active with negative dose-dependent effects on cellular respiration and membrane integrity between 1 and 3ppm, at environmental/occupational doses. We demonstrate in addition that POE-15 induces necrosis when its first micellization process occurs, by contrast to glyphosate which is known to promote endocrine disrupting effects after entering cells. Altogether, these results challenge the establishment of guidance values such as the acceptable daily intake of glyphosate, when these are mostly based on a long term in vivo test of glyphosate alone. Since pesticides are always used with adjuvants that could change their toxicity, the necessity to assess their whole formulations as mixtures becomes obvious. This challenges

  8. A quantitative structure-activity relationship approach for assessing toxicity of mixture of organic compounds.

    PubMed

    Chang, C M; Ou, Y H; Liu, T-C; Lu, S-Y; Wang, M-K

    2016-06-01

    Four types of reactivity indices were employed to construct quantitative structure-activity relationships for the assessment of toxicity of organic chemical mixtures. Results of analysis indicated that the maximum positive charge of the hydrogen atom and the inverse of the apolar surface area are the most important descriptors for the toxicity of mixture of benzene and its derivatives to Vibrio fischeri. The toxicity of mixture of aromatic compounds to green alga Scenedesmus obliquus is mainly affected by the electron flow and electrostatic interactions. The electron-acceptance chemical potential and the maximum positive charge of the hydrogen atom are found to be the most important descriptors for the joint toxicity of aromatic compounds. PMID:27426856

  9. Acute toxicity and anticonvulsant activity of liposomes containing nimodipine on pilocarpine-induced seizures in mice.

    PubMed

    Moreno, Lina Clara Gayoso e Almendra Ibiapina; Cavalcanti, Isabella Macário Ferro; Satyal, Prabodh; Santos-Magalhães, Nereide Stela; Rolim, Hercília Maria Lins; Freitas, Rivelilson Mendes

    2015-01-12

    Nimodipine has been shown to have an inhibitory action on seizures and brain damage in rodents. However, the pharmaceutical applicability of this drug is limited by its low solubility in gastrointestinal fluids and high first-pass effect in the liver, which leads to low bioavailability. These difficulties can be overcome through the use of liposomes. The aim of the present study is to evaluate the toxicity and anticonvulsant activity of liposomes containing nimodipine (NMD-Lipo) on pilocarpine-induced seizures. NMD-Lipo was prepared using the lipid-film hydration method. Central nervous system toxicity of NMD-Lipo was assessed by Hippocratic screening. Systemic toxicity was evaluated by analyses of biochemical and hematological parameters and by observing possible signs of toxicity. The possible anticonvulsant activity was tested by the pilocarpine model. The administration of the NMD-Lipo at doses of 0.1, 1, and 10 mg/kg caused no toxicity in animals. Furthermore, NMD-Lipo prevented the installation of 100% of the pilocarpine-induced seizures and prevented the death of 100% of the mice treated with pilocarpine. These data shown that NMD-Lipo has an anticonvulsant activity significantly superior to free NMD, suggesting that the liposomes promoted a drug controlled release by improving its bioavailability and consequently increasing its pharmacological activity. PMID:25445375

  10. Deglycosylated bleomycin has the antitumor activity of bleomycin without pulmonary toxicity.

    PubMed

    Burgy, Olivier; Wettstein, Guillaume; Bellaye, Pierre S; Decologne, Nathalie; Racoeur, Cindy; Goirand, Françoise; Beltramo, Guillaume; Hernandez, Jean-François; Kenani, Abderraouf; Camus, Philippe; Bettaieb, Ali; Garrido, Carmen; Bonniaud, Philippe

    2016-02-17

    Bleomycin (BLM) is a potent anticancer drug used to treat different malignancies, mainly lymphomas, germ cell tumors, and melanomas. Unfortunately, BLM has major, dose-dependent, pulmonary toxicity that affects 20% of treated individuals. The most severe form of BLM-induced pulmonary toxicity is lung fibrosis. Deglyco-BLM is a molecule derived from BLM in which the sugar residue d-mannosyl-l-glucose disaccharide has been deleted. The objective of this study was to assess the anticancer activity and lung toxicity of deglyco-BLM. We compared the antitumor activity and pulmonary toxicity of intraperitoneally administrated deglyco-BLM and BLM in three rodent models. Pulmonary toxicity was examined in depth after intratracheal administration of both chemotherapeutic agents. The effect of both drugs was further studied in epithelial alveolar cells in vitro. We demonstrated in rodent cancer models, including a human Hodgkin's lymphoma xenograft and a syngeneic melanoma model, that intraperitoneal deglyco-BLM is as effective as BLM in inducing tumor regression. Whereas the antitumor effect of BLM was accompanied by a loss of body weight and the development of pulmonary toxicity, deglyco-BLM did not affect body weight and did not engender lung injury. Both molecules induced lung epithelial cell apoptosis after intratracheal administration, but deglyco-BLM lost the ability to induce caspase-1 activation and the production of ROS (reactive oxygen species), transforming growth factor-β1, and other profibrotic and inflammatory cytokines in the lungs of mice and in vitro. Deglyco-BLM should be considered for clinical testing as a less toxic alternative to BLM in cancer therapy. PMID:26888428

  11. Toxicity and Estrogenic Endocrine Disrupting Activity of Phthalates and Their Mixtures

    PubMed Central

    Chen, Xueping; Xu, Shisan; Tan, Tianfeng; Lee, Sin Ting; Cheng, Shuk Han; Lee, Fred Wang Fat; Xu, Steven Jing Liang; Ho, Kin Chung

    2014-01-01

    Phthalates, widely used in flexible plastics and consumer products, have become ubiquitous contaminants worldwide. This study evaluated the acute toxicity and estrogenic endocrine disrupting activity of butyl benzyl phthalate (BBP), di(n-butyl) phthalate (DBP), bis(2-ethylhexyl) phthalate (DEHP), diisodecyl phthalate (DIDP), diisononyl phthalate (DINP), di-n-octyl phthalate (DNOP) and their mixtures. Using a 72 h zebrafish embryo toxicity test, the LC50 values of BBP, DBP and a mixture of the six phthalates were found to be 0.72, 0.63 and 0.50 ppm, respectively. The other four phthalates did not cause more than 50% exposed embryo mortality even at their highest soluble concentrations. The typical toxicity symptoms caused by phthalates were death, tail curvature, necrosis, cardio edema and no touch response. Using an estrogen-responsive ChgH-EGFP transgenic medaka (Oryzias melastigma) eleutheroembryos based 24 h test, BBP demonstrated estrogenic activity, DBP, DEHP, DINP and the mixture of the six phthalates exhibited enhanced-estrogenic activity and DIDP and DNOP showed no enhanced- or anti-estrogenic activity. These findings highlighted the developmental toxicity of BBP and DBP, and the estrogenic endocrine disrupting activity of BBP, DBP, DEHP and DINP on intact organisms, indicating that the widespread use of these phthalates may cause potential health risks to human beings. PMID:24637910

  12. Indirect aluminum toxicity to the green alga Scenedesmus through increased cupric ion activity

    SciTech Connect

    Rueter, J.G. Jr.; O'Reilly, K.T.; Petersen, R.R.

    1987-05-01

    Additions of aluminum and copper to chemically defined media resulted in inhibition of growth of Scenedesmus and of alkaline phosphatase activity. The alkaline phosphatase activity was assayed both on commercially available purified enzyme from bacteria and on the enzyme present in whole Scenedesmus cells. The effect of metal additions was compared to the total aluminum added and to the computed free ion activities for both copper and aluminum. In all three systems (algal growth, purified enzyme, and algal enzyme) the observed toxicity with increased total aluminum was mostly due to an increase in cupric ion activity. The algal growth response was affected for the range of cupric ion activities from 10/sup -6/ to 10/sup -12/. The toxic dose response of aluminum was largely due to indirect competitive effects of Al in the medium that displaced copper from the chelator. 33 references, 4 figures.

  13. Shape regulated anticancer activities and systematic toxicities of drug nanocrystals in vivo.

    PubMed

    Zhou, Mengjiao; Zhang, Xiujuan; Yu, Caitong; Nan, Xueyan; Chen, Xianfeng; Zhang, Xiaohong

    2016-01-01

    In this paper, shape regulated anticancer activities as well as systematic toxicities of hydroxycamptothecin nanorods and nanoparticles (HCPT NRs and NPs) were systematically studied. In vitro and in vivo therapeutic efficacies were evaluated in cancer cells and tumor-bearing mice, indicating that NRs possessed superior antitumor efficacy over NPs at the equivalent dose, while systematic toxicity of the differently shaped nanodrugs assessed in healthy mice, including the maximum tolerated dose, blood analysis and histology examinations and so on, suggested that the NRs also caused higher toxicities than NPs, and also had a long-term toxicity. These results imply that the balance between anticancer efficiency and systematic toxicity of drug nanocrystals should be fully considered in practice, which will provide new concept in the future design of drug nanocrystals for cancer therapy. From the Clinical Editor: Advances in nanotechnology have enabled the design of novel nanosized drugs for the treatment of cancer. One of the interesting findings thus far is the different biological effects seen with different shaped nanoparticles. In this article, the authors investigated and compared the anticancer activities of hydroxycamptothecin nanorods and nanoparticles. The experimental data would provide a better understanding for future drug design. PMID:26427356

  14. pH-Dependent Metal Ion Toxicity Influences the Antibacterial Activity of Two Natural Mineral Mixtures

    PubMed Central

    Cunningham, Tanya M.; Koehl, Jennifer L.; Summers, Jack S.; Haydel, Shelley E.

    2010-01-01

    Background Recent studies have demonstrated that several mineral products sold for medicinal purposes demonstrate antimicrobial activity, but little is known about the physicochemical properties involved in antibacterial activity. Methodology/Principal Findings Using in vitro mineral suspension testing, we have identified two natural mineral mixtures, arbitrarily designated BY07 and CB07, with antibacterial activity against a broad-spectrum of bacterial pathogens. Mineral-derived aqueous leachates also exhibited antibacterial activity, revealing that chemical, not physical, mineral characteristics were responsible for the observed activity. The chemical properties essential for bactericidal activity against Escherichia coli were probed by testing antibacterial activity in the presence of metal chelators, the hydroxyl radical scavenger, thiourea, and varying pH levels. Chelation of the BY07 minerals with EDTA or desferrioxamine eliminated or reduced BY07 toxicity, respectively, suggesting a role of an acid-soluble metal species, particularly Fe3+ or other sequestered metal cations, in mineral toxicity. This conclusion was supported by NMR relaxation data, which indicated that BY07 and CB07 leachates contained higher concentrations of chemically accessible metal ions than leachates from non-bactericidal mineral samples. Conclusions/Significance We conclude that the acidic environment of the hydrated minerals significantly contributes to antibacterial activity by increasing the availability and toxicity of metal ions. These findings provide impetus for further investigation of the physiological effects of mineral products and their applications in complementary antibacterial therapies. PMID:20209160

  15. Toxicity and biodistribution of activated and non-activated intravenous iron oxide nanoparticles

    NASA Astrophysics Data System (ADS)

    Tate, J. A.; Ogden, J. A.; Strawbridge, R. R.; Pierce, Z. E.; Hoopes, P. J.

    2009-02-01

    The use of nanoparticles in medical treatment has prompted the question of their safety. In this study, the pathophysiology and biodistribution of three different concentrations of intravenously-delivered dextran-coated Fe3O4 iron oxide nanoparticles (IONP) were evaluated in mice. Some groups of mice were exposed to an AC magnetic field (AMF) at levels comparable with those proposed for cancer treatments. Iron biodistribution analysis for both AMF and non-AMF treated mice was performed for all three concentrations used (.6 mg Fe/mouse, 1.8 mg Fe/mouse, and 5.6 mg Fe/mouse). Blood urea nitrogen, alanine transaminase, alkaline phosphatase, total serum protein, and creatinine were also assessed at 4 hours, 7 days, and 14 days post-injection. Histological analysis of lung, spleen, heart, liver, and kidney tissue was conducted at 7 and 14 days post-injection. Prussian blue and H&E stains were used to histomorphometrically assess iron content in the tissues studied. Preliminary results demonstrate small temporary elevation in liver enzymes and hepatocyte vacuolization at all iron concentrations studied. Liver and spleen were the primary sites of IONP deposition. None of the animals demonstrated systemic or local toxicity or illness, with or without AMF activation.

  16. Transcytosis, Antitumor Activity and Toxicity of Staphylococcal Enterotoxin C2 as an Oral Administration Protein Drug

    PubMed Central

    Zhao, Wenbin; Li, Yangyang; Liu, Wenhui; Ding, Ding; Xu, Yingchun; Pan, Liqiang; Chen, Shuqing

    2016-01-01

    Staphylococcal enterotoxin C2 (SEC2) is a classical superantigen (SAg), which can tremendously activate T lymphocytes at very low dosage, thus exerting its powerful antitumor activity. As an intravenous protein drug and a bacterial toxin, SEC2 has some limitations including poor patient compliance and toxic side effects. In this research, we devoted our attention to studying the antitumor activity and toxicity of SEC2 as a potential oral administration protein drug. We proved that His-tagged SEC2 (SEC2-His) could undergo facilitated transcytosis on human colon adenocarcinoma (Caco-2) cells and SEC2-His was detected in the blood of rats after oral administration. Furthermore, oral SEC2-His caused massive cytokine release and immune cell enrichment around tumor tissue, leading to inhibition of tumor growth in vivo. Meanwhile, although SEC2-His was dosed up to 32 mg/kg in mice, no significant toxicity was observed. These data showed that SEC2 can cross the intestinal epithelium in an immunologically integral form, maintaining antitumor activity but with reduced systemic toxicity. Therefore, these results may have implications for developing SEC2 as an oral administration protein drug. PMID:27322320

  17. Transcytosis, Antitumor Activity and Toxicity of Staphylococcal Enterotoxin C2 as an Oral Administration Protein Drug.

    PubMed

    Zhao, Wenbin; Li, Yangyang; Liu, Wenhui; Ding, Ding; Xu, Yingchun; Pan, Liqiang; Chen, Shuqing

    2016-01-01

    Staphylococcal enterotoxin C2 (SEC2) is a classical superantigen (SAg), which can tremendously activate T lymphocytes at very low dosage, thus exerting its powerful antitumor activity. As an intravenous protein drug and a bacterial toxin, SEC2 has some limitations including poor patient compliance and toxic side effects. In this research, we devoted our attention to studying the antitumor activity and toxicity of SEC2 as a potential oral administration protein drug. We proved that His-tagged SEC2 (SEC2-His) could undergo facilitated transcytosis on human colon adenocarcinoma (Caco-2) cells and SEC2-His was detected in the blood of rats after oral administration. Furthermore, oral SEC2-His caused massive cytokine release and immune cell enrichment around tumor tissue, leading to inhibition of tumor growth in vivo. Meanwhile, although SEC2-His was dosed up to 32 mg/kg in mice, no significant toxicity was observed. These data showed that SEC2 can cross the intestinal epithelium in an immunologically integral form, maintaining antitumor activity but with reduced systemic toxicity. Therefore, these results may have implications for developing SEC2 as an oral administration protein drug. PMID:27322320

  18. Teaching about Hazardous and Toxic Materials. Teaching Activities in Environmental Education Series.

    ERIC Educational Resources Information Center

    Disinger, John F.; Lisowski, Marylin

    Designed to assist practitioners of both formal and non-formal settings, this 18th volume of the ERIC Clearinghouse for Science, Mathematics, and Environmental Education's Teaching Activities in Environmental Education series specifically focuses on the theme of hazardous and toxic materials. Initially, basic environmental concepts that deal with…

  19. Functional activity of sphingomyelin cycle in rat liver in chronic toxic hepatitis.

    PubMed

    Serebrov, V Yu; Kuzmenko, D I; Burov, P G; Novitsky, S V

    2008-12-01

    Activities of sphingomyelinase and ceramidase decreased in the liver in chronic toxic hepatitis and the balance between the levels of proapoptotic ceramide and antiapoptotic sphyngosine-1-phosphate shifts towards the latter substance. Pronounced changes in the qualitative and quantitative composition of fatty acids in the sphingomyelin cycle effector molecules were revealed. PMID:19513367

  20. STRUCTURE-ACTIVITY APPROACHES IN THE SCREENING OF ENVIRONMENTAL AGENTS FOR DEVELOPMENTAL TOXICITY

    EPA Science Inventory

    In drug development, SARs are an integral part of the process of finding efficacious and non-toxic analogues, and in vitro test systems which detect the biological activity of a particular chemical class have found an important role in SAR research. n contrast, SARs are not a pri...

  1. Developmental Exposure to a Dopaminergic Toxicant Produces Altered Locomotor Activity in Larval Zebrafish

    EPA Science Inventory

    In an effort to develop a rapid in vivo screen for EPA’s prioritization of toxic chemicals, we are characterizing the locomotor activity of zebrafish (Danio rerio) larvae after developmental exposure to various classes of prototypic drugs that act on the central nervous system. ...

  2. EFFECTIVENESS OF ACTIVATED CARBON FOR REMOVAL OF TOXIC AND/OR CARCINOGENIC COMPOUNDS FROM WATER SUPPLIES

    EPA Science Inventory

    This research addressed quantification of the performance of fixed-bed granular activated carbon processes for treatment of public water supplies. It included evaluation of the adsorption of selected toxic and/or carcinogenic trace compounds of man-related origin, including carbo...

  3. An integrated study of toxicant-induced inhibition of feeding and digestion activity in Daphnia magna

    SciTech Connect

    Coen, W.M. De; Janssen, C.R.; Persoone, G.

    1995-12-31

    Previous studies on D. magna exposed to xenobiotics have demonstrated that feeding inhibition can be used as a general indicator of toxic stress. In order to evaluate the consequences of the reduced food absorption on the energy balance of the organism, the effects of short-term exposure to sublethal toxicant concentrations of 8 chemicals on physiological (ingestion rate) and biochemical aspects (digestive enzyme activity) of the feeding process were investigated. The ingestion activity was assessed using a simple and sensitive method based on the use of fluorescent latex microbeads. The biochemical aspects of feeding were studied by analyzing the activity of 5 digestive enzymes, each responsible for the breakdown of one of the three major macromolecular constituents of the food (3 carbohydrases: amylase, cellulose and {beta}-galactosidase; trypsin and esterase). Using ingestion as an effect criterium, correlation analysis revealed a significant (p < 0.05) and positive (r{sup 2} = 0.89) correlation between the 1.5h EC50 value and the conventional acute toxicity endpoint (24hEC50). For 3 out of 5 enzymes studied a clear concentration-response relationship was observed. The 2h EC 10 value (inhibition) of {beta}-galactosidase activity and 2h EC5 value of trypsin and esterase activity showed a significant linear correlation (r{sup 2} respectively 0.98, 0.96 and 0.95) with the 24hEC50 value. The relationships between the physiological and biochemical effects will be discussed in the context of toxicant-induced homeostatic adjustments in the organism`s metabolism. Finally the potential use of both types of effect criteria as rapid screening tools in aquatic toxicity testing will be reviewed.

  4. Hepatoprotective activity of a new polyherbal formulation against paracetamol and D-galactosamine induced hepatic toxicity

    PubMed Central

    Khan, Mohammad Ahmed; Gupta, Arun; Kumar, Satyendra; Ahmad, Sayeed; Sastry, J. L. N.

    2015-01-01

    Objective: The present study was envisaged to evaluate the protective effect of polyherbal formulation, DRDC/AY/8060, developed by Dabur India Ltd., against paracetamol and D-galactosamine induced hepatic toxicities in Wistar rats. Materials and Methods: The study was carried out in two different experiments of 10 and 14 days against paracetamol and D-galactosamine, respectively. Animals were divided into different treatment groups (n = 6). The control group received normal saline, a toxicant group in two experiments received paracetamol 750 mg/kg p.o. every 72 h for 10 days and D-galactosamine 400 mg/kg i.p. single dose. The test formulation was used at the two dose levels of 120 and 240 mg/kg/day. Treatment groups treated with test formulations were also administered D-galactosamine as given in toxicant group. At the end of the dosing schedule, blood was withdrawn from the retrobulbar plexus of the animals for serum estimation of serum glutamate oxaloacetate transferase (SGOT), serum glutamate pyruvate trasnferase (SGPT), albumin, bilirubin, and alkaline phosphatase (ALP). Following the withdrawal of blood animals was sacrificed, and liver tissue was excised for estimation of thiobarbituric acid reactive substances (lipid peroxidation, malondialdehyde), tissue glutathione (GSH) and histopathological studies. Results: It was evident from the biochemical estimation that both paracetamol and galactosamine caused hepatotoxicity in the toxicant groups. However, treatment with DRDC/AY/8060 significantly (P < 0.001, vs. toxicant) reduced the levels of SGOT, SGPT, serum bilirubin, and ALP, as well as decreased lipid peroxidation. In addition, treatment with test formulation also significantly (P < 0.001, vs. toxicant) elevated serum albumin and GSH levels compared to toxicant groups. Conclusion: On the basis of these studies and comparative evaluation it can be concluded that the formulation DRDC/AY/8060 showed hepatoprotective activity against paracetamol and D

  5. Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities

    SciTech Connect

    Peters, Diane E.; Hoover, Benjamin; Cloud, Loretta Grey; Liu, Shihui; Molinolo, Alfredo A.; Leppla, Stephen H.; Bugge, Thomas H.

    2014-09-01

    We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6 syngraft model of melanoma; mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA-activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32% to 87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5–3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. - Highlights: • Toxicity and anti

  6. Controlling a toxic shock of pentachlorophenol (PCP) to anaerobic digestion using activated carbon addition.

    PubMed

    Xiao, Yeyuan; De Araujo, Cecilia; Sze, Chun Chau; Stuckey, David C

    2015-04-01

    Several powdered and granular activated carbons (PACs and GACs) were tested for adsorption of pentachlorophenol (PCP) in bench-scale anaerobic digestion reactors to control the toxicity of PCP to acetoclastic methanogenesis. Results showed that the adsorption capacities of PAC were reduced by 21-54%, depending on the PAC addition time, in the presence of the methanogenic sludge compared to the controls without sludge. As a preventive measure, PAC at a low dose of 20% (mass ratio to the VSS) added 24 h prior to, or simultaneously with, the addition of PCP could completely eliminate the toxic effects of PCP. At the same dose, PAC also enabled methanogenesis to recover immediately after the sludge had been exposed to PCP for 24h. GAC was not effective in enabling the recovery of methanogenesis due to its slow adsorption kinetics; however, at a dose of 80% it could partially ameliorate the toxic shock of PCP. PMID:25665874

  7. Carlina acaulis Exhibits Antioxidant Activity and Counteracts Aβ Toxicity in Caenorhabditis elegans.

    PubMed

    Link, Pille; Roth, Kevin; Sporer, Frank; Wink, Michael

    2016-01-01

    Carlina acaulis is a medicinal plant that has shown antioxidant activity in in vitro studies, but to date no corresponding in vivo data is available. Therefore, in the present study the antioxidant activity and its impact in counteracting Aβ toxicity were studied in the Caenorhabditis elegans model. A dichloromethane extract of the roots of C. acaulis was prepared and characterised via gas-liquid-chromatography/mass-spectrometry (GLC-MS). The in vitro antioxidant activity was confirmed via 2,2-diphenyl-1-picrylhydracyl assay. The extract was further separated by thin layer chromatography into two fractions, one of which was a fraction of the dichloromethane extract of C. acaulis containing mostly Carlina oxide (CarOx). Different strains of C. elegans were employed to study the expression of hsp-16.2p::GFP as a marker for oxidative stress, delocalisation of the transcription factor DAF-16 as a possible mechanism of antioxidant activity, the effect of the drug under lethal oxidative stress, and the effect against beta-amyloid (Aβ) toxicity in a paralysis assay. The C. acaulis extract and CarOx showed high antioxidant activity (stress reduction by 47% and 64%, respectively) in C. elegans and could activate the transcription factor DAF-16 which directs the expression of anti-stress genes. In paralysis assay, only the total extract was significantly active, delaying paralysis by 1.6 h. In conclusion, in vivo antioxidant activity was shown for C. acaulis for the first time in the C. elegans model. The active antioxidant compound is Carlina oxide. This activity, however, is not sufficient to counteract Aβ toxicity. Other mechanisms and possibly other active compounds are involved in this effect. PMID:27384550

  8. Effects of an aquatic plant and suspended clay on the activity of fish toxicants

    USGS Publications Warehouse

    Gilderhus, P.A.

    1982-01-01

    Rotenone, antimycin, permethrin, pydrin, and Salicylanilide I were tested for their toxicities against fathead minnows (Pimephales promelas) in the presence of Canadian waterweed (Elodea canadensis) or suspended clay. The plants had little effect on the activity of rotenone and antimycin but substantially reduced the activity of permethrin and pydrin (synthetic pyrethroids). Bentonite severely inhibited the activity of all chemicals tested. Salicylanilide I was affected least and pydrin most (27 times as much pydrin was required when I g/liter of bentonite was present in 96-hour tests). The efficacy of the registered fish toxicants rotenone and antimycin is probably not significantly affected by vegetation under field conditions, but is greatly reduced by suspended bentonite clay.

  9. Cardiac myocyte-specific AHR activation phenocopies TCDD-induced toxicity in zebrafish.

    PubMed

    Lanham, Kevin A; Plavicki, Jessica; Peterson, Richard E; Heideman, Warren

    2014-09-01

    Exposure of zebrafish embryos to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) activates the zebrafish aryl hydrocarbon receptor 2 (AHR) to produce developmental and cardiovascular toxicity. AHR is found in the heart; however, AHR activation by TCDD is not confined to the heart and occurs throughout the organism. In order to understand the cause of cardiotoxicity, we constructed a constitutively active AHR (caAHR) based on the zebrafish AHR2 and expressed it specifically in cardiomyocytes. We show that AHR activation within the cardiomyocytes can account for the heart failure induced by TCDD. Expression of the caAHR within the heart produced cardiac malformations, loss of circulation, and pericardial edema. The heart-specific activation of AHR reproduced several other well-characterized endpoints of TCDD toxicity outside of the cardiovascular system, including defects in swim bladder and craniofacial development. This work identifies a single cellular site of TCDD action, the myocardial cell, that can account for the severe cardiovascular collapse observed following early life stage exposure to TCDD, and contributes to other forms of toxicity. PMID:25037585

  10. Cardiac Myocyte-Specific AHR Activation Phenocopies TCDD-Induced Toxicity in Zebrafish

    PubMed Central

    Lanham, Kevin A.; Plavicki, Jessica; Peterson, Richard E.; Heideman, Warren

    2014-01-01

    Exposure of zebrafish embryos to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) activates the zebrafish aryl hydrocarbon receptor 2 (AHR) to produce developmental and cardiovascular toxicity. AHR is found in the heart; however, AHR activation by TCDD is not confined to the heart and occurs throughout the organism. In order to understand the cause of cardiotoxicity, we constructed a constitutively active AHR (caAHR) based on the zebrafish AHR2 and expressed it specifically in cardiomyocytes. We show that AHR activation within the cardiomyocytes can account for the heart failure induced by TCDD. Expression of the caAHR within the heart produced cardiac malformations, loss of circulation, and pericardial edema. The heart-specific activation of AHR reproduced several other well-characterized endpoints of TCDD toxicity outside of the cardiovascular system, including defects in swim bladder and craniofacial development. This work identifies a single cellular site of TCDD action, the myocardial cell, that can account for the severe cardiovascular collapse observed following early life stage exposure to TCDD, and contributes to other forms of toxicity. PMID:25037585

  11. Assessing developmental toxicity and estrogenic activity of halogenated bisphenol A on zebrafish (Danio rerio).

    PubMed

    Song, Maoyong; Liang, Dong; Liang, Yong; Chen, Minjie; Wang, Fengbang; Wang, Hailin; Jiang, Guibin

    2014-10-01

    Halogenated bisphenol A (H-BPAs), widely used in industrial production, have been identified in various environmental matrices and detected in human serum and breast milk. The persistence and prevalence of H-BPAs in the environment underscore the need to in-depth understand their adverse effects to humans and other organisms. In the present study, zebrafish embryos/larvae were used as models to investigate the developmental toxicities of three H-BPAs, namely tetrabromobisphenol A (TBBPA), tetrachlorobisphenol A (TCBPA), and bisphenol AF (BPAF). The half lethal concentration (LC50) values indicated that the rank order of toxicities of the chemicals were TCBPA>TBBPA>BPAF. Three H-BPAs exposure resulted in a variety of developmental lesions in the embryos/larvae, such as a delay in time to hatch, edema, and hemorrhage. The estrogenic activities of H-BPAs were determined by means of in vivo vitellogenin (vtg) assay and in vitro MVLN assay. Here only BPAF specifically shows a stronger estrogenic activity than BPA both in in vivo and in vitro. These data suggest that TCBPA, TBBPA, and BPAF are more potent toxicants than BPA, and indicate that further research of the mechanisms on their toxicities is required. PMID:25048916

  12. Toxicity and mAChRs binding activity of Cassiopea xamachana venom from Puerto Rican coasts.

    PubMed

    Radwan, Faisal F Y; Román, Laura G; Baksi, Krishna; Burnett, Joseph W

    2005-01-01

    A separation of toxic components from the upside down jellyfish Cassiopea xamachana (Cx) was carried out to study their cytotoxic effects and examine whether these effects are combined with a binding activity to cell membrane receptors. Nematocysts containing toxins were isolated from the autolysed tentacles, ruptured by sonication, and the crude venom (CxTX) was separated from the pellets by ultracentrifugation. For identifying its bioactive components, CxTX was fractionated by gel filtration chromatography into six fractions (named fraction I-VI). The toxicity of CxTX and fractions was tested on mice; however, the hemolytic activity was tested on saline washed human erythrocytes. The LD50 of CxTX was 0.75 microg/g of mouse body and for fraction III, IV and VI were 0.28, 0.25 and 0.12 microg/g, respectively. Fractions I, II and V were not lethal at doses equivalent to LD50 1 microg/g. The hemolytic and phospholipase A2 (PLA2) activities of most fractions were well correlated with their mice toxicity. However, fraction VI, which contains the low molecular mass protein components (< or =10 kDa), has shown no PLA2 activity but highest toxicity to mice, highest hemolytic activity, and bound significantly to the acetylcholine muscarinic receptors (mAChRs) isolated from rat brain. The results suggested that fraction VI contains proteinaceous components contributing to most of cytolysis as well as membrane binding events. Meanwhile, fraction IV has shown high PLA2 that may contribute to the venom lethality and paralytic effects. PMID:15581689

  13. Developmental toxicity of thyroid-active compounds in a zebrafish embryotoxicity test.

    PubMed

    Jomaa, Barae; Hermsen, Sanne A B; Kessels, Maurijn Y; van den Berg, Johannes H J; Peijnenburg, Ad A C M; Aarts, Jac M M J G; Piersma, Aldert H; Rietjens, Ivonne M C M

    2014-01-01

    Zebrafish embryos were exposed to concentration ranges of selected thyroid-active model compounds in order to assess the applicability of zebrafish-based developmental scoring systems withinan alternative testing strategy to detect the developmental toxicity ofthyroid-active compounds. Model compounds tested included triiodothyronine (T3), propylthiouracil (PTU), methimazole (MMI), sodium perchlorate (NaClO4) and amiodarone hydrochloride (AMI), selected to represent different modes of action affecting thyroid activity. Tested time windows included 48-120 hours post fertilization (hpf), 0-72 hpf and 0-120 hpf. All tested compounds resulted in developmental changes, with T3 being the most potent. The developmental parameters affected included reflective iridophores, beat and glide swimming, inflated swim bladders, as well as resorbed yolk sacs. These effects are only evident by 120 hpf and therefore an existing General Morphology Score (GMS) system was extended to create a General Developmental Score(GDS) that extends beyond the 72 hpfscoring limit of GMS and includes additional parameters that are affected by exposure to model thyroid-active compounds. Moreover, the GDS is cumulative as it includes not only the scoring of developmental morphologies but also integrates developmental dysmorphologies. Exposures from 48-120 hpf did not provide additional information to exposures from 0-120 hpf. The results indicate that the zebrafish GDS can detect the developmental toxicity of thyroid toxicants and may be of use in an integrated testing strategy to reduce, refine and in certain cases replace animal testing. PMID:24793664

  14. Non-toxic antifouling activity of polymeric 3-alkylpyridinium salts from the Mediterranean sponge Reniera sarai (Pulitzer-Finali).

    PubMed

    Faimali, Marco; Sepcić, Kristina; Turk, Tom; Geraci, Sebastiano

    2003-02-01

    The antifouling activity and toxicity of polymeric 3-alkylpyridinium salts (poly-APS) isolated from the Mediterranean sponge Reniera sarai were studied. The activity of these natural products was compared to that of zinc and copper complexes of pyrithione, two non-persistent booster biocides successfully used in current antifouling coatings. Larvae of Balanus amphitrite (cyprids and nauplii) were used to monitor settlement inhibition and the extent to which inhibition was due to toxicity. The microalga Tetraselmis suecica and larvae of the mussel Mytilus galloprovincialis were used in toxicity bioassays. Compared to the booster biocides, poly-APS were less effective at inhibiting cyprid settlement, but their effects were non toxic and reversible, with very low toxicity against the organisms used in the toxicity bioassays. Although encouraging, these results are not enough to warrant the use of poly-APS as a potential commercial antifoulant. They however justify possible future efforts to chemically synthesize poly-APS analogues for further tests. PMID:14618688

  15. Toxic effects of nanoparticles on bioluminescence activity, seed germination, and gene mutation.

    PubMed

    Ko, Kyung-Seok; Kong, In Chul

    2014-04-01

    The potential environmental toxicities of several metal oxide nanoparticles (NPs; CuO, TiO2, NiO, Fe2O3, ZnO, and Co3O4) were evaluated in the context of bioluminescence activity, seed germination, and bacterial gene mutation. The bioassays exhibited different sensitivities, i.e., each kind of NP exhibited a different level of toxicity in each of the bioassays. However, with a few exceptions, CuO and ZnO NPs had most toxic for germination of Lactuca seed (EC50 0.46 mg CuO/l) and bioluminescence (EC50 1.05 mg ZnO/l). Three NPs (Co3O4, TiO2, and Fe2O3) among all tested concentrations (max. 1,000 mg/l) showed no inhibitory effects on the tested organisms, except for Co3O4 NPs on bioluminescence activity (EC50 62.04 mg/l). The sensitivity of Lactuca seeds was greater than that of Raphanus seeds (EC50 0.46 mg CuO/l versus 26.84 mg CuO /l ). The ranking of metal toxicity levels on bioluminescence was in the order of ZnO > CuO > Co3O4 > NiO > Fe2O3, TiO2, while CuO > ZnO > NiO > Co3O4, Fe2O3, TiO2 on germination. No revertant mutagenic ratio (greater than 2.0) of Salmonella typhimurium TA 98 was observed under any tested condition. These findings demonstrate that several bioassays, as opposed to any single one, are needed for the accurate assessment of NP toxicity on ecosystems. PMID:24297479

  16. Mechanisms of toxic action and structure-activity relationships for organochlorine and synthetic pyrethroid insecticides.

    PubMed Central

    Coats, J R

    1990-01-01

    The mechanisms and sites of action of organochlorine (DDT-types and chlorinated alicyclics) and synthetic pyrethroid insecticides are presented with discussion of symptoms, physiological effects, and selectivity. The structural requirements for toxicity are assessed, and structure-activity relationships are considered for each subclass. Lipophilicity is important for all the groups because it facilitates delivery of these neurotoxicants to the site of action in the nerve. Steric factors including molecular volume, shape, and isomeric configuration greatly influence toxicity. Electronic parameters also have been demonstrated to affect biological activity in some of the groups of insecticides, e.g., Hammett's sigma and Taft's sigma * as indicators of electronegativity. New synthetic pyrethroids continue to be developed, with varied structures and different physicochemical and biological properties. PMID:2176589

  17. The antibacterial activity and toxicity of enrofloxacin are decreased by nanocellulose conjugated with aminobenzyl purin.

    PubMed

    Yasini, Seyed Ali; Zadeh, Mohammad Hossein Balal; Shahdadi, Hossein

    2015-11-01

    The first aim of this study was to synthesize nanocellulose conjugated with aminobenzyl purin (NCABP), and the second aim was to evaluate the effect of NCABP on both toxicity and antibacterial activity of enrofloxacin. Here, the adsorption of enrofloxacin by NCABP was first modeled by molecular dynamic (MD) simulation. In the next step, NCABP was synthesized, and was exposed to enrofloxacin, 1000 μg mL(-1), at various conditions. Then, the quantity of adsorption and release was separately measured. Furthermore, both toxicity and antibacterial activity of NCABP, enrofloxacin, and (NCABP+enrofloxacin) were separately evaluated. In this study, MD simulation clearly showed the adsorption after 50 picoseconds. The adsorption tests revealed that the increase of incubation time and NCABP concentration, at range of 50-200 μg mL(-1), led to increase of adsorption. Moreover, the decrease of pH led to increase of adsorption. Interestingly, NCABP could adsorb enrofloxacin, up to 1000 μg mL(-1), in different types of meat. Moreover, the increase of incubation time and temperature did not release enrofloxacin, but the increase of pH increased release. This study showed that both toxicity and antibacterial activity of enrofloxacin were decreased when exposed together with NCABP. PMID:26295691

  18. Expression of NK cells activation receptors after occupational exposure to toxics: a preliminary study.

    PubMed

    De Celis, Ruth; Feria-Velasco, Alfredo; Bravo-Cuellar, Alejandro; Hicks-Gómez, Juan José; García-Iglesias, Trinidad; Preciado-Martínez, Verónica; Muñoz-Islas, Laura; González-Unzaga, Marco

    2008-06-30

    The expression of NK cells activation receptors was assessed by comparative study of two groups of women workers at a chemical reagents factory, located in Zapopan, Jalisco, Mexico. Twenty of them were exposed to environmental toxics identified and quantified by gas chromatography, and 20 women unexposed to toxic substances. The expression of the surface markers CD56+ and CD3+, and of the activation receptors and co-receptors on NK cells was quantified by flow cytometry. To assess the cellular damage produced by chronic exposure to the toxics, the thiobarbituric acid reacting substances (TBARS) generated and the total plasma antioxidizing capacity (TPAC) were quantified in both groups. The exposed women had been exposed at least to 12 volatile toxic compounds, benzene, benz(a)pyrene, ethylbenzene, dimethylbenz(a)anthracene, xylene, toluene, styrene, chloroform, formaldehyde, iodine, chlorine and fluorine. Significant difference between the two groups was in the proportion of CD3 lymphocytes, 72.7+/-10.3% in the unexposed women versus 66.8+/-7.9% in the exposed group (p<0.05). The density of expression of NKG2D and NKp30 receptors was significantly higher in the unexposed women compared to the exposed group: NKG2D were 31.3+/-6.3 and NKp30 were 9.5+/-5.2 in the unexposed women and 5.14+/-2.9 (p<0.01) and 4.6+/-1.9 (p<0.05), respectively in the exposed women. No statistically significant differences were found in the expression of NKp80, NKp46 and 2B4 receptors. The concentration of TBARS was lower in women from the unexposed group than the corresponding data from women of the exposed group. However, no significant difference was observed in TPAC between the two groups studied. The results of this preliminary study suggest that from the five activation receptors and co-receptors of NK cells evaluated (NKp30, NKp46, NKp80, NKG2D and 2B4), only NKp30 and NKG2D receptor expression was diminished in women exposed to toxics when compared with data from unexposed women

  19. Novel approaches to the use of cytochrome P450 activities in wildlife toxicity studies

    SciTech Connect

    VandenBerg, M.; Bosveld, A.T.C.

    1995-12-31

    Many wildlife toxicity studies, e.g. with avian species, use cytochrome P450 activities as markers for biological activities of environmental contaminants. It has been established that induction of CYP1A1 correlates with Ah-receptor mediated toxicity of dioxin-like compounds in many species. In addition, CYP1A1 plays a significant role in bioactivation of polycyclic aromatics. So far very few studies focused on the natural function of P450 isoenzymes in wildlife species. Besides classical hepatic CYP1A(1) associated activities, like EROD and AHH, several new techniques are available to study the activities of various CYP isoenzymes. Caffeine N-demethylation, testosterone and 17ss-estradiol hydroxylation patterns can provide new insights in the physiological function of P450 isoenzymes and the induction of the basal activities by chemicals. So far little interest was given to processes which occur after the DNA-receptor binding, e.g. changes in steroid hormone metabolism and pathways in environmental toxicology. This in spite of the fact that very subtle changes in steroid hormone levels may have significant physiological implications. This presentation will focus on some P450 activities, besides CYP1A(1), which might be important for development and reproduction. Some experimental approaches, limitations and techniques will be discussed which could lead to elucidation of the possible endocrine function of P450s.

  20. STRUCTURE-ACTIVITY APPROACHES AND DATA EXPLORATION TOOLS FOR PRIORITIZING AND ASSESSING THE TOXICITY OF HAZARDOUS AIR POLLUTANTS

    EPA Science Inventory


    STRUCTURE-ACTIVITY APPROACHES AND DATA EXPLORATION TOOLS FOR PRIORITIZING AND ASSESSING THE TOXICITY OF HAZARDOUS AIR POLLUTANTS

    Hazardous Air Pollutants (HAPs) refers to a set of structurally diverse environmental chemicals, many with limited toxicity data, that have...

  1. Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities.

    PubMed

    Peters, Diane E; Hoover, Benjamin; Cloud, Loretta Grey; Liu, Shihui; Molinolo, Alfredo A; Leppla, Stephen H; Bugge, Thomas H

    2014-09-01

    We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6 syngraft model of melanoma; mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA-activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32% to 87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5-3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. PMID:24971906

  2. Mycorrhizal fungi modulate phytochemical production and antioxidant activity of Cichorium intybus L. (Asteraceae) under metal toxicity.

    PubMed

    Rozpądek, P; Wężowicz, K; Stojakowska, A; Malarz, J; Surówka, E; Sobczyk, Ł; Anielska, T; Ważny, R; Miszalski, Z; Turnau, K

    2014-10-01

    Cichorium intybus (common chicory), a perennial plant, common in anthropogenic sites, has been the object of a multitude of studies in recent years due to its high content of antioxidants utilized in pharmacy and food industry. Here, the role of arbuscular mycorrhizal fungi (AMF) in the biosynthesis of plant secondary metabolites and the activity of enzymatic antioxidants under toxic metal stress was studied. Plants inoculated with Rhizophagus irregularis and non-inoculated were grown on non-polluted and toxic metal enriched substrata. The results presented here indicate that AMF improves chicory fitness. Fresh and dry weight was found to be severely affected by the fungi and heavy metals. The concentration of hydroxycinnamates was increased in the shoots of mycorrhizal plants cultivated on non-polluted substrata, but no differences were found in plants cultivated on metal enriched substrata. The activity of SOD and H2O2 removing enzymes CAT and POX was elevated in the shoots of mycorrhizal plants regardless of the cultivation environment. Photochemical efficiency of inoculated chicory was significantly improved. Our results indicate that R. irregularis inoculation had a beneficial role in sustaining the plants ability to cope with the deleterious effects of metal toxicity. PMID:25048909

  3. Assessment of toxicity and biodegradability on activated sludge of priority and emerging pollutants.

    PubMed

    Tobajas, Montserrat; Verdugo, Verónica; Polo, Alicia M; Rodriguez, Juan J; Mohedano, Angel F

    2016-03-01

    Several methods for evaluating the toxicity and biodegradability of hazardous pollutants (chlorinated compounds, chemical additives and pharmaceuticals) have been studied in this work. Different bioassays using representative bacteria of marine and terrestrial ecosystems such as Vibrio fischeri and Pseudomonas putida have been used to assess the ecotoxicity. Activated sludge was used to analyse the effect of those pollutants in a biological reactor of a sewage treatment plant (STP). The results demonstrate that none of the compounds is toxic to activated sludge, except ofloxacin to P. putida. The additives tested can be considered moderately toxic according to the more sensitive V. fischeri assays, whereas the EC50 values of the pharmaceuticals depend on the specific microorganism used in each test. Regarding the biodegradability, respirometric measurements were carried out for fast biodegradability assessment and the Zahn-Wellens test for inherent biodegradability. The evolution of the specific oxygen uptake rate (SOUR) showed that only diethyl phthalate was easily biodegradable and acetylsalicylic acid was partially biodegradable (98% and 65% degradation, respectively). The persistence of dichloromethane, ofloxacin and hidrochlorothiazide was confirmed along the 28 days of the Zahn-Wellens test whereas 1,1,1-trichloroethane showed inherent biodegradability (74% removal). Most of the chlorinated compounds, pharmaceuticals, bisphenol A and ethylenediaminetetraacetic acid were partially degraded in 28 d with total organic carbon (TOC) reduction ranging from 21% to 51%. Sulphamethoxazole showed certain biodegradation (50% removal) with TOC decrease around 31%, which indicates the formation of non-biodegradable by-products. PMID:26243262

  4. Relative toxicity and residual activity of insecticides used in blueberry pest management: mortality of natural enemies.

    PubMed

    Roubos, Craig R; Rodriguez-Saona, Cesar; Holdcraft, Robert; Mason, Keith S; Isaacs, Rufus

    2014-02-01

    A series of bioassays were conducted to determine the relative toxicities and residual activities of insecticides labeled for use in blueberry (Vaccinium corymbosum L.) on natural enemies, to identify products with low toxicity or short duration effects on biological control agents. In total, 14 insecticides were evaluated using treated petri dishes and four commercially available natural enemies (Aphidius colemani Viereck, Orius insidiosus [Say], Chrysoperla rufilabris [Burmeister], and Hippodamia convergens [Guérin-Menéville]). Dishes were aged under greenhouse conditions for 0, 3, 7, or 14 d before introducing insects to test residual activity. Acute effects (combined mortality and knockdown) varied by insecticide, residue age, and natural enemy species. Broad-spectrum insecticides caused high mortality to all biocontrol agents, whereas products approved for use in organic agriculture had little effect. The reduced-risk insecticide acetamiprid consistently caused significant acute effects, even after aging for 14 d. Methoxyfenozide, novaluron, and chlorantraniliprole, which also are classified as reduced-risk insecticides, had low toxicity, and along with the organic products could be compatible with biological control. This study provides information to guide blueberry growers in their selection of insecticides. Further research will be needed to determine whether adoption of a pest management program based on the use of more selective insecticides will result in higher levels of biological control in blueberry. PMID:24665711

  5. Removal of toxic Cr(VI) by the adsorption of activated carbons prepared from Simarouba shells.

    PubMed

    Neelavathi, A; Sekhar, K B Chandra; Babu, C Ramesh; Jayaveera, K N

    2004-04-01

    Removal of toxic Cr(VI) in aqueous medium was investigated using activated carbon adsorbents prepared from Simarouba glauca seed shells. The pH effect, Cr(VI) concentration, adsorbent dosage and contact time period were studied in batch experiment. The removal of Cr(VI) was in general most effective at pH range 2.0-4.0 and high Cr(VI) concentrations. Activated carbons are prepared at 80050 degrees C temperature. One is non-impregnated and the remaining three are impregnated with zinc chloride in 1:1,1:2,1:3 ratio. Important characteristics of activated carbons are also investigated. The data for all the adsorbents fit well to the Freundlich adsorption isotherm. The removal of Cr(VI) is around 97% was observed with 1:2 impregnated activated carbon at pH 3.0 where as other adsorbents showed much lower activities. PMID:16649604

  6. Antiviral activity and toxicity of fialuridine in the woodchuck model of hepatitis B virus infection.

    PubMed

    Tennant, B C; Baldwin, B H; Graham, L A; Ascenzi, M A; Hornbuckle, W E; Rowland, P H; Tochkov, I A; Yeager, A E; Erb, H N; Colacino, J M; Lopez, C; Engelhardt, J A; Bowsher, R R; Richardson, F C; Lewis, W; Cote, P J; Korba, B E; Gerin, J L

    1998-07-01

    Woodchucks were used to study the antiviral activity and toxicity of fialuridine (FIAU; 1,-2'deoxy-2'fluoro-1-beta-D-arabinofuranosyl-5-iodo-uracil). In an initial experiment, groups of six chronic woodchuck hepatitis virus (WHV) carrier woodchucks received daily doses of FIAU by intraperitoneal injection for 4 weeks. At 0.3 mg/kg/d, the antiviral effect was equivocal, but at 1.5 mg/kg/d, FIAU had significant antiviral activity. No evidence of drug toxicity was observed during the 4-week period of treatment or during posttreatment follow-up. In a second experiment, groups of nine WHV carriers or uninfected woodchucks were given 1.5 mg/kg/d of FIAU orally for 12 weeks, and the results compared with placebo-treated controls. After 4 weeks, the serum WHV-DNA concentration in the FIAU-treated carrier group was two to three logs lower than that in the placebo-treated group. After 12 weeks of FIAU treatment, serum WHV DNA was not detectable by conventional dot-blot analysis, hepatic WHV-DNA replicative intermediates (RI) had decreased 100-fold, and hepatic expression of WHV core antigen was remarkably decreased. No evidence of toxicity was observed after 4 weeks, but, after 6 to 7 weeks, food intake decreased and, after 8 weeks, the mean body weights of woodchucks treated with FIAU were significantly lower than controls. Anorexia, weight loss, muscle wasting, and lethargy became progressively severe, and all FIAU-treated woodchucks died or were euthanized 78 to 111 days after treatment began. Hepatic insufficiency (hyperbilirubinemia, decreased serum fibrinogen, elevated prothrombin time), lactic acidosis, and hepatic steatosis were characteristic findings in the final stages of FIAU toxicity in woodchucks. The syndrome of delayed toxicity in woodchucks was similar to that observed previously in humans treated with FIAU, suggesting that the woodchuck should be valuable in future investigations of the molecular mechanisms of FIAU toxicity in vivo and for preclinical

  7. Redox-Active Selenium Compounds—From Toxicity and Cell Death to Cancer Treatment

    PubMed Central

    Misra, Sougat; Boylan, Mallory; Selvam, Arun; Spallholz, Julian E.; Björnstedt, Mikael

    2015-01-01

    Selenium is generally known as an antioxidant due to its presence in selenoproteins as selenocysteine, but it is also toxic. The toxic effects of selenium are, however, strictly concentration and chemical species dependent. One class of selenium compounds is a potent inhibitor of cell growth with remarkable tumor specificity. These redox active compounds are pro-oxidative and highly cytotoxic to tumor cells and are promising candidates to be used in chemotherapy against cancer. Herein we elaborate upon the major forms of dietary selenium compounds, their metabolic pathways, and their antioxidant and pro-oxidant potentials with emphasis on cytotoxic mechanisms. Relative cytotoxicity of inorganic selenite and organic selenocystine compounds to different cancer cells are presented as evidence to our perspective. Furthermore, new novel classes of selenium compounds specifically designed to target tumor cells are presented and the potential of selenium in modern oncology is extensively discussed. PMID:25984742

  8. Comparative toxicity and structure-activity in Chlorella and Tetrahymena: Monosubstituted phenols

    SciTech Connect

    Jaworska, J.S.; Schultz, T.W. )

    1991-07-01

    The relative toxicity of selected monosubstituted phenols has been assessed by Kramer and Truemper in the Chlorella vulgaris assay. The authors examined population growth inhibition of this simple green algae under short-term static conditions for 33 derivatives. However, efforts to develop a strong predictive quantitative structure-activity relationship (QSAR) met with limited success because they modeled across modes of toxic action or segregated derivatives such as positional isomers (i.e., ortho-, meta-, para-). In an effort to further their understanding of the relationships of ecotoxic effects of phenols, the authors have evaluated the same derivatives reported by Kramer and Truemper in the Tetrahymena pyriformis population growth assay, compared the responses in both systems and developed QSARs for the Chlorella vulgaris data based on mechanisms of action.

  9. Pinelliae rhizoma, a toxic chinese herb, can significantly inhibit CYP3A activity in rats.

    PubMed

    Wu, Jinjun; Cheng, Zaixing; He, Shugui; Shi, Jian; Liu, Shuqiang; Zhang, Guiyu; Zhu, Lijun; Liu, Liang; Liu, Zhongqiu; Lin, Na; Lu, Linlin

    2015-01-01

    Raw Pinelliae Rhizoma (RPR) is a representative toxic herb that is widely used for eliminating phlegm or treating cough and vomiting. Given its irritant toxicity, its processed products, including Pinelliae Rhizoma Praeparatum (PRP) and Pinelliae Rhizoma Praeparatum cum Zingibere et Alumine (PRPZA), are more commonly applied and administered concomitantly with other chemical drugs, such as cough medications. This study aimed to investigate the effects of RPR, PRP, and PRPZA on CYP3A activity. Testosterone (Tes) and buspirone (BP) were used as specific probe substrates ex vivo and in vivo, respectively. CYP3A activity was determined by the metabolite formation ratios from the substrates. Ex vivo results show that the metabolite formation ratios from Tes significantly decreased, indicating that RPR, PRP, and PRPZA could inhibit CYP3A activity in rats. CYP3A protein and mRNA levels were determined to explore the underlying mechanism. These levels showed marked and consistent down-regulation with CYP3A activity. A significant decrease in metabolite formation ratios from BP was also found in PRPZA group in vivo, implying that PRPZA could inhibit CYP3A activity. Conclusively, co-administration of PR with other CYP3A-metabolizing drugs may cause drug-drug interactions. Clinical use of PR-related formulae should be monitored carefully to avoid adverse interactions. PMID:25574821

  10. In silico analysis of Pycnoporus cinnabarinus laccase active site with toxic industrial dyes.

    PubMed

    Prasad, Nirmal K; Vindal, Vaibhav; Narayana, Siva Lakshmi; Ramakrishna, V; Kunal, Swaraj Priyaranjan; Srinivas, M

    2012-05-01

    Laccases belong to multicopper oxidases, a widespread class of enzymes implicated in many oxidative functions in various industrial oxidative processes like production of fine chemicals to bioremediation of contaminated soil and water. In order to understand the mechanisms of substrate binding and interaction between substrates and Pycnoporus cinnabarinus laccase, a homology model was generated. The resulted model was further validated and used for docking studies with toxic industrial dyes- acid blue 74, reactive black 5 and reactive blue 19. Interactions of chemical mediators with the laccase was also examined. The docking analysis showed that the active site always cannot accommodate the dye molecules, due to constricted nature of the active site pocket and steric hindrance of the residues whereas mediators are relatively small and can easily be accommodated into the active site pocket, which, thereafter leads to the productive binding. The binding properties of these compounds along with identification of critical active site residues can be used for further site-directed mutagenesis experiments in order to identify their role in activity and substrate specificity, ultimately leading to improved mutants for degradation of these toxic compounds. PMID:21877154

  11. The chaperone activity and toxicity of ambroxol on Gaucher cells and normal mice.

    PubMed

    Luan, Zhuo; Li, Linjing; Higaki, Katsumi; Nanba, Eiji; Suzuki, Yoshiyuki; Ohno, Kousaku

    2013-04-01

    Gaucher disease (GD), caused by a defect of acid β-glucosidase (β-Glu), is one of the most common sphingolipidoses. Recently, ambroxol, an FDA-approved drug used to treat airway mucus hypersecretion and hyaline membrane disease in newborns, was identified as a chemical chaperone for GD. In the present study, we investigated the chaperone activity and toxicity of ambroxol on both cultured GD patient cells and normal mice. We found that ambroxol treatment significantly increased N370S, F213I, N188S/G193W and R120W mutant β-Glu activities in GD fibroblasts with low cytotoxicity. Additionally, we measured the β-Glu activity in the tissues of normal mice which received water containing increasing concentrations of ambroxol ad libitum for one week. No serious adverse effect was observed during this experiment. Ambroxol significantly increased the β-Glu activity in the spleen, heart and cerebellum of the mice. This result showed its oral availability and wide distribution and chaperone activity in the tissues, including the brain, and its lack of acute toxicity. These characteristics of ambroxol would make it a potential therapeutic chaperone in the treatment of GD with neurological manifestations. PMID:22682976

  12. Electrochemical oxidation of fluoroquinolone antibiotics: Mechanism, residual antibacterial activity and toxicity change.

    PubMed

    Zhu, Linyan; Santiago-Schübel, Beatrix; Xiao, Hongxia; Hollert, Henner; Kueppers, Stephan

    2016-10-01

    In this paper, we studied the electrochemical oxidation mechanisms of three typical fluoroquinolone antibiotics (FQs), and investigated residual antibacterial activity and toxicity changes after oxidation processes. Electrochemistry coupled to mass spectrometry (EC-MS) was used to study the oxidation processes of ciprofloxacin (CIP), norfloxacin (NOR) and ofloxacin (OFL). Eight oxidation products for each parent compound were identified and their chemical structures were elucidated. The transformation trend of each product, with the continuous increase of voltage from 0 to 3000 mV, was recorded by online EC-MS. The oxidation pathways were proposed based on the structural information and transformation trends of oxidation products. We found the oxidation mechanisms of FQs consisted of the hydroxylation and cleavage of piperazinyl ring via reactions with hydroxyl radicals, while the fluoroquinolone core remained intact. The antibacterial activity of the parent compounds and their oxidation mixtures was estimated using zone inhibition tests for gram-negative bacteria Salmonella typhimurium. It was found that the oxidation mixtures of CIP and NOR retained the antibacterial properties with lower activity compared to their parent compounds, while the antibacterial activity of OFL was almost eliminated after oxidation. Furthermore, the toxicity of the three FQs and their oxidation mixtures were evaluated using algal growth inhibition test (Desmodesmus subspicatus). The median effective concentration (EC50) values for the algal inhibition tests were calculated for the end point of growth rate. The toxicity of CIP and NOR to green algae after electrochemical oxidation, remained unchanged, while that of OFL significantly increased. The results presented in this paper contribute to an understanding of the electrochemical oxidation mechanisms of FQs, and highlight the potential environmental risks of FQs after electrochemical oxidation processes. PMID:27318447

  13. A selection assay for haloalkane dehalogenase activity based on toxic substrates.

    PubMed

    Fibinger, Michael P C; Davids, Timo; Böttcher, Dominique; Bornscheuer, Uwe T

    2015-11-01

    Based on natural selection and the survival of the fittest by evolutionary adaption, a smart high-throughput system was developed to select active haloalkane dehalogenase variants from a large mutant library. Only active enzyme variants can hydrolyse toxic halogenated alkanes to promote growth, whereas inactive mutants starve or die due to the toxic compound. With this powerful tool, huge enzyme mutant libraries can be screened within a few days. The selection is done without any artificial substrates that are hard to synthesize and they also resemble typical ones for haloalkane dehalogenases. Three saturation libraries, with a size of more than 10(6) cells, based on inactive variants of the haloalkane dehalogenases DhaA or DhlA were successfully screened to retrieve active enzymes. The enrichment of the active wild-type enzyme in contrast to the inactive variants was about 340-fold. In addition, this selection approach can be applied for continuous directed evolution experiments for the enrichment of cells expressing adapted haloalkane dehalogenases. PMID:25998660

  14. FISH ACUTE TOXICITY SYNDROMES: APPLICATION TO THE DEVELOPMENT OF MECHANISM-SPECIFIC QSARS (QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS)

    EPA Science Inventory

    Predictive models based on quantitative structure activity relationships (QSARs), are used as rapid screening tools to identify potentially hazardous chemicals. Several QSARs are now available that predict the acute toxicity of narcotic-industrial chemicals. Predictions for compo...

  15. FISH ACUTE TOXICITY SYNDROMES AND THEIR USE IN THE QSAR (QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIP) APPROACH TO HAZARD ASSESSMENT

    EPA Science Inventory

    Implementation of the Toxic Substances Control Act of 1977 creates the need to reliably establish testing priorities because laboratory resources are limited and the number of industrial chemicals requiring evaluation is overwhelming. The use of quantitative structure activity re...

  16. Evaluation of the anti-mycobacterium tuberculosis activity and in vivo acute toxicity of Annona sylvatic

    PubMed Central

    2014-01-01

    Background The recent emergence of extensively multidrug-resistant Mycobacterium tuberculosis strains has further complicated the control of tuberculosis. There is an urgent need for the development of new molecular candidates antitubercular drugs. Medicinal plants have been an excellent source of leads for the development of drugs. The aim of this study was to evaluate the in vitro activity of 28 alcoholic extracts and essential oils of native and exotic Brazilian plants against Mycobacterium tuberculosis and to further study these extracts through chemical fractionation, the isolation of their constituents, and an evaluation of the in vivo acute toxicity of the active extracts. To the best of our knowledge this is the first chemical characterization, antituberculosis activity and acute toxicity evaluation of Annona sylvatica. Methods The anti-mycobacterial activity of these extracts and their constituent compounds was evaluated using the resazurin reduction microtiter assay (REMA). To investigate the acute toxicity of these extracts in vivo, female Swiss mice were treated with the extracts at doses of 500, 1000 and 2000 mg · kg-1 of body weight. The extracts were characterized by LC-MS, and the constituents were isolated and identified by chromatographic analysis of spectroscopic data. Results Of the 28 extracts, the methanol extract obtained from the leaves of Annona sylvatica showed anti-mycobacterial activity with an minimal inhibitory concentration (MIC) of 184.33 μg/mL, and the ethyl acetate fraction (EAF) resulting from liquid-liquid partitioning of the A. sylvatica extract showed an MIC of 115.2 μg/mL. The characterization of this extract by LC-MS identified flavonoids and acetogenins as its main constituents. The phytochemical study of the A. sylvatica EAF resulted in the isolation of quercetin, luteolin, and almunequin. Conclusions Among the compounds isolated from the EAF, luteolin and almunequin were the most promising, with MICs of 236.8

  17. Pharmacologically active drug metabolites: therapeutic and toxic activities, plasma and urine data in man, accumulation in renal failure.

    PubMed

    Drayer, D E

    1976-01-01

    Drugs that are administered to man may be biotransformed to yield metabolites that are pharmacologically active. The therapeutic and toxic activities of drug metabolites and the species in which this activity was demonstrated are compiled for the metabolites of 58 drugs. The metabolite to parent drug ratio in the plasma of non-uraemic man and the percentage urinary excretion of the metabolite in non-uraemic man are also tabulated. Those active metabolites with significant pharmacological activity and high plasma levels, both relative to that of the parent drug, will probably contribute substantially to the pharmacological effect ascribed to the parent drug. Active metabolites may accumulate in patients with end stage renal disease if renal excretion is a major elimination pathway for the metabolite. This is true even if the active metabolite is a minor metabolite of the parent drug, as long as the minor metabolite is not further biotransformed and is mainly excreted in the urine. Minor metabolite accumulation may also occur if it is further biotransformed by a pathway inhibited in uraemia. Some clinical examples of the accumulation of active drug metabolites in patients with renal failure are: (a) The abolition of premature ventricular contractions and prevention of paroxysmal atrial tachycardia in some cardiac patients with poor renal function treated with procainamide are associated with high levels of N-acetylprocainamide. (b) The severe irritability and twitching seen in a uraemic patient treated with pethidine (meperidine) are associated with high levels of norpethidine. (c) The severe muscle weakness and tenderness seen in patients with renal failure receiving clofibrate are associated with excessive accumulation of the free acid metabolite of clofibrate. (d) Patients with severe renal insufficiency taking allopurinol appear to experience a higher incidence of side reactions, possibly due to the accumulation of oxipurinol. (e) Accumulation of free and

  18. Identification of alpha-beta unsaturated aldehydes as sources of toxicity to activated sludge biomass in polyester manufacturing wastewater.

    PubMed

    Caffaro-Filho, R A; Wagner, R; Umbuzeiro, G A; Grossman, M J; Durrant, L R

    2010-01-01

    Wastewater generated in industrial production processes are often contaminated by hazardous chemicals. Characterization by means of toxicity-directed analysis is useful for identifying which fractions of a waste stream possess the most toxicity. We applied this approach to evaluate toxic components of a polyester manufacturing wastewater. Using the reduction in oxygen uptake rate of activated sludge as an indicator of toxicity, it was determined that increasing the pH from 3 to 11 followed by air stripping significantly reduced the toxicity of the wastewater. Comparative headspace GC/MS analysis of wastewater at different pHs selected a group of Volatile Organic Compounds (VOCs) associated with the observed effect of air stripping at pH 11. Ten of these compounds were identified as alpha,beta unsaturated aldehydes (acrolein (2-propenal) congeners); these compounds are known to be toxic as well as mutagenic. Confirmation that these compounds were a cause of toxicity was achieved by demonstrating that removal of these compounds by air stripping significantly reduced the wastewater mutagenic potency in a Salmonella mutagenicity assay. Formation of these volatile compounds by base catalyzed aldol condensation at pH 11 may account for the effectiveness of air stripping in reducing toxicity. To date there is no record in the literature about the toxicity and presence of acrolein congeners in polyester manufacturing wastewater. PMID:20418629

  19. Quantitative structure-activity relationships (QSARs) using the novel marine algal toxicity data of phenols.

    PubMed

    Ertürk, M Doğa; Saçan, Melek Türker; Novic, Marjana; Minovski, Nikola

    2012-09-01

    The present study reports for the first time in its entirety the toxicity of 30 phenolic compounds to marine alga Dunaliella tertiolecta. Toxicity of polar narcotics and respiratory uncouplers was strongly correlated to hydrophobicity as described by the logarithm of the octanol/water partition coefficient (Log P). Compounds expected to act by more reactive mechanisms, particularly hydroquinones, were shown to have toxicity in excess of that predicted by Log P. A quality quantitative structure-activity relationship (QSAR) was obtained with Log P and a 2D autocorrelation descriptor weighted by atomic polarizability (MATS3p) only after the removal of hydroquinones from the data set. In an attempt to model the whole data set including hydroquinones, 3D descriptors were included in the modeling process and three quality QSARs were developed using multiple linear regression (MLR). One of the most significant results of the present study was the superior performance of the consensus MLR model, obtained by averaging the predictions from each individual linear model, which provided excellent prediction accuracy for the test set (Q(test)²=0.94). The four-parameter Counter Propagation Artificial Neural Network (CP ANN) model, which was constructed using four out of six descriptors that appeared in the linear models, also provided an excellent external predictivity (Q(test)²=0.93). The proposed algal QSARs were further tested in their predictivity using an external set comprising toxicity data of 44 chemicals on freshwater alga Pseudokirchneriella subcapitata. The two-parameter global model employing a 3D descriptor (Mor24m) and a charge-related descriptor (C(ortho)) not only had high external predictivity (Q(ext)²=0.74), but it also had excellent external data set coverage (%97). PMID:23085159

  20. Fungicidal activity of AKWATON and in vitro assessment of its toxic effects on animal cells.

    PubMed

    Oulé, Mathias Kégnon; Staines, Kenton; Lightly, Tasia; Roberts, Loren; Traoré, Yannick Léandre; Dickman, Michael; Bernier, Anne-Marie; Diop, Lamine

    2015-01-01

    Acquired superficial fungal infections are among the most common infections. It is necessary to create new effective and non-toxic disinfectants. AKWATON is a new disinfectant of the polymeric guanidine family. Its fungicidal activity against Trichophyton mentagrophytes and its in vitro toxicity assessment were determined in this study. The MIC, minimum fungicidal concentration (MFC) and time required for its fungicidal activity at the MFC were evaluated using the official methods of analysis of the Association of Official Analytical Chemists, with modifications as recommended by the Canadian General Standards Board. The toxic effects of AKWATON and of four commercial disinfectants were evaluated on rat pancreatic (C2C12) and muscle (RnM5F) cells, using the trypan blue and MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] methods. The MIC, MFC and time required for the fungicidal activity of AKWATON at the MFC were 0.025 % (w/v), 0.045 % (w/v) and 2.5 min, respectively. Cell cultures and the different tests carried out showed that the AKWATON-based disinfectant killed fewer cells than the commercial disinfectants, sparing 80 % of C2C12 cells and 65 % of RnM5F cells, whilst some of the well-known disinfectants currently on the market killed 85-100 % of cells. This study demonstrates that AKWATON has great potential as an odourless, colourless, non-corrosive and safe disinfectant for use in hospitals, the agriculture industry, farming and household facilities. PMID:25411261

  1. Acute toxicity, antiedematogenic activity, and chemical constituents of Palicourea rigida Kunth.

    PubMed

    Alves, Vanessa G; da Rosa, Elisa A; de Arruda, Laura L M; Rocha, Bruno A; Bersani Amado, Ciomar A; Santin, Silvana M O; Pomini, Armando M; da Silva, Cleuza C

    2016-03-01

    The phytochemical study of the leaves, roots, and flowers of Palicourea rigida led to the isolation of the triterpenes betulinic acid (1) and lupeol (2), the diterpene phytol (3), and the iridoid glycosides sweroside (4) and secoxyloganin (5). These compounds were identified using NMR 1H and 13C and comparing the spectra with published data. We studied the antiedematogenic activity of crude extracts from the organs, and of different fractions, in mice and found that the n-hexane fraction of the leaf extract significantly inhibited the ear edema resulting from croton oil administration. The crude extract from leaves was not acutely toxic to the mice. PMID:26927220

  2. Food preference and foraging activity of ants: recommendations for field applications of low-toxicity baits.

    PubMed

    Nyamukondiwa, Casper; Addison, Pia

    2014-01-01

    Control of ants using baits of low toxicity cannot be effective without knowledge of bait distribution patterns and bait station densities, which are determined by ants' foraging activities. Furthermore, the success of toxic baits also depends upon attractiveness of bait carriers. Here, we assessed ground and vine foraging activity and food preferences for the three ant species ( Linepithema humile (Mayr) (Hymenoptera: Formicidae), Anoplolepis custodiens (F. Smith) and Crematogaster peringueyi Emery) under field conditions. We found that L. humile's vineyard foraging activity was high and that movement of ant bait by C. peringueyi and A. custodiens in the vineyard was relatively low. Consequently, more bait stations need to be dispensed for more effective control of C. peringueyi and A. custodiens than for L. humile. Different bait densities are discussed for the various ant species. Food preference trials indicated that vineyard foraging ants preferred wet bait attractants over dry ones, making liquids the most ideal carriers for baiting these ants. Linepithema humile was attracted to 25% sugar water, while C. peringueyi was attracted to both 25% sugar water and honey. Anoplolepis custodiens was attracted to tuna but was also attracted to 25% sugar water. Thus, future bait formulations should be tailor made to suit these specific food requirements if baits are to be successful in ant pest management. PMID:25373195

  3. Food Preference and Foraging Activity of Ants: Recommendations for Field Applications of Low-Toxicity Baits

    PubMed Central

    Nyamukondiwa, Casper; Addison, Pia

    2014-01-01

    Control of ants using baits of low toxicity cannot be effective without knowledge of bait distribution patterns and bait station densities, which are determined by ants' foraging activities. Furthermore, the success of toxic baits also depends upon attractiveness of bait carriers. Here, we assessed ground and vine foraging activity and food preferences for the three ant species (Linepithema humile (Mayr) (Hymenoptera: Formicidae), Anoplolepis custodiens (F. Smith) and Crematogaster peringueyi Emery) under field conditions. We found that L. humile's vineyard foraging activity was high and that movement of ant bait by C. peringueyi and A. custodiens in the vineyard was relatively low. Consequently, more bait stations need to be dispensed for more effective control of C. peringueyi and A. custodiens than for L. humile. Different bait densities are discussed for the various ant species. Food preference trials indicated that vineyard foraging ants preferred wet bait attractants over dry ones, making liquids the most ideal carriers for baiting these ants. Linepithema humile was attracted to 25% sugar water, while C. peringueyi was attracted to both 25% sugar water and honey. Anoplolepis custodiens was attracted to tuna but was also attracted to 25% sugar water. Thus, future bait formulations should be tailor made to suit these specific food requirements if baits are to be successful in ant pest management. PMID:25373195

  4. Biological screening of some Turkish medicinal plant extracts for antimicrobial and toxicity activities.

    PubMed

    Turker, A U; Usta, C

    2008-01-20

    Screening of antibacterial activity and toxicity of 22 aqueous plant extracts from 17 Turkish plants was conducted. Antibacterial activity was performed with six bacteria including Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Streptococcus pyogenes, Staphylococcus aureus and Staphylococcus epidermidis. Extracts of Tussilago farfara leaves, Helichyrsum plicatum flowers, Solanum dulcamara aerial parts and Urtica dioica leaves gave the best inhibitory activity against S. pyogenes, S. aureus and S. epidermidis. Of the 22 plant extracts, 20 extracts displayed toxicity (LC50 was <1000 mg L(-1)) in the brine shrimp bioassay. For radish seed bioassay, two different determinations (root length and seed germination) were performed with a comparison between two concentrations (50,000 mg L(-1) and 10,000 mg L(-1)). At low concentration (10,000 mg L(-1)), S. dulcamara aerial parts and Primula vulgaris leaf extracts were observed to inhibit the root length more than the other plant extracts. Also, the most inhibitive plant extract for seed germination was obtained with S. dulcamara aerial parts. PMID:18075897

  5. Hepatoprotective activity of white horehound (Marrubium vulgare) extract against cyclophosphamide toxicity in male rats.

    PubMed

    Ettaya, Amani; Dhibi, Sabah; Samout, Noura; Elfeki, Abdelfettah; Hfaiedh, Najla

    2016-04-01

    The hepatoprotective activity of Marrubium vulgare against cyclophosphamide toxicity in Wistar rats was evaluated. Adult male rats were divided into 4 groups of 6 each: a control group, a group injected with cyclophosphamide (150 mg·kg(-1)) for 3 days, a group orally given a M. vulgare aqueous extract ((500 mg of dry leaves)·kg(-1)·day(-1)) for 30 days then treated with cyclophosphamide, and a group receiving only M. vulgare for 30 days. After 33 days of treatment, activities of alanine amino transferase (ALAT), aspartate amino transferase (ASAT), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP) were determined in serum. Moreover, lipid peroxidation level and superoxide dismutase (SOD) activities, catalase (CAT) and glutathione peroxidase (GPx) were measured in liver. Alterations of these hepatic biomarkers and increased lipid peroxidation confirmed cyclophosphamide-induced liver toxicity. Cyclophosphamide also decreased the enzymatic defense system against oxidative stress. However, when this drug was administered in rats given M. vulgare extract, all the biological parameters underwent much less alteration. Administration of M. vulgare extract was found to be beneficial by attenuating cyclophosphamide-induced liver damage. The protective effect of the plant is mainly attributed to its antioxidant properties and the existence of phenolic acids and flavonoids, as highlighted by HPLC-based analysis. PMID:26886858

  6. Assessing estrogenic activity and reproductive toxicity of organic extracts in WWTP effluents.

    PubMed

    Li, Bo; Cao, Jun; Xing, Chuanhong; Wang, Zhijin; Cui, Liuxin

    2015-03-01

    Trace level organic contaminants might not be completely removed from the municipal wastewater and the safety incurred by them had become a concern. These organic pollutants were extracted from water samples and detected by GC-MS. The estrogenic activity of the organic was tested using Yeast Estrogen Screen to detect the transcriptional activation of the estrogen receptor (ER) and immature mouse uterotrophic bioassays to study reproductive toxicity. The results of GC-MS demonstrated the organic extracts in the municipal wastewater and the WWTP effluents Included two major categories, benzenes and Phthalates. The estrogenic activity of organic extracts from the secondary effluent (SE) and tertiary effluent (TE) was below that of the raw wastewater (RW). Results of uterotrophic bioassay demonstrated that SE would bring some potential hazards on animals while TE was relatively safe. PMID:25818108

  7. Cellular interaction and toxicity depend on physicochemical properties and surface modification of redox-active nanomaterials.

    PubMed

    Dowding, Janet M; Das, Soumen; Kumar, Amit; Dosani, Talib; McCormack, Rameech; Gupta, Ankur; Sayle, Thi X T; Sayle, Dean C; von Kalm, Laurence; Seal, Sudipta; Self, William T

    2013-06-25

    The study of the chemical and biological properties of CeO2 nanoparticles (CNPs) has expanded recently due to its therapeutic potential, and the methods used to synthesize these materials are diverse. Moreover, conflicting reports exist regarding the toxicity of CNPs. To help resolve these discrepancies, we must first determine whether CNPs made by different methods are similar or different in their physicochemical and catalytic properties. In this paper, we have synthesized several forms of CNPs using identical precursors through a wet chemical process but using different oxidizer/reducer; H2O2 (CNP1), NH4OH (CNP2), or hexamethylenetetramine (HMT-CNP1). Physicochemical properties of these CNPs were extensively studied and found to be different depending on the preparation methods. Unlike CNP1 and CNP2, HMT-CNP1 was readily taken into endothelial cells and the aggregation can be visualized using light microscopy. Exposure to HMT-CNP1 also reduced cell viability at a 10-fold lower concentration than CNP1 or CNP2. Surprisingly, exposure to HMT-CNP1 led to substantial decreases in ATP levels. Mechanistic studies revealed that HMT-CNP1 exhibited substantial ATPase (phosphatase) activity. Though CNP2 also exhibits ATPase activity, CNP1 lacked ATPase activity. The difference in catalytic (ATPase) activity of different CNPs preparation may be due to differences in their morphology and oxygen extraction energy. These results suggest that the combination of increased uptake and ATPase activity of HMT-CNP1 may underlie the biomechanism of the toxicity of this preparation of CNPs and may suggest that ATPase activity should be considered when synthesizing CNPs for use in biomedical applications. PMID:23668322

  8. Cellular Interaction and Toxicity Depends on Physiochemical Properties and Surface Modification of Redox Active Nanomaterials

    PubMed Central

    Dowding, Janet M.; Das, Soumen; Kumar, Amit; Dosani, Talib; McCormack, Rameech; Gupta, Ankur; Sayle, Thi X. T.; Sayle, Dean C.; von Kalm, Laurence; Seal, Sudipta; Self, William T.

    2013-01-01

    The study of the chemical and biological properties of CeO2 NPs (CNPs) has expanded recently due to its therapeutic potential, and the methods used to synthesize these materials are diverse. Moreover, conflicting reports exists regarding the toxicity of CNP. To help resolve these discrepancies, we must first determine whether CeO2 NPs made by different methods are similar or different in their physiochemical and catalytic properties. In this paper, we have synthesized several forms of CNPs using identical precursors through a wet chemical process but using different oxidizer/reducer H2O2 (CNP1), NH4OH (CNP2) or hexamethylenetetramine (HMT-CNP1). Physiochemical properties of these CeO2 NPs were extensively studied and found to be different depending on the preparation methods. Unlike CNP1 and CNP2, HMT-CNP1 were readily taken into endothelial cells and their aggregation can be visualized using light microscopy. Exposure to HMT-CNP1 also reduced cell viability (MTT) at a 10-fold lower concentration than CNP1 or CNP2. Surprisingly, exposure to HMT-CNP1 led to substantial decreases in the ATP levels. Mechanistic studies revealed that HMT-CNP1 exhibited substantial ATPase (phosphatase) activity. Though CNP2 also exhibits ATPase activity, CNP1 lacked ATPase activity. The difference in catalytic (ATPase) activity of different CeO2 NPs preparation may be due to differences in their morphology and oxygen extraction energy. These results suggest the combination of increased uptake and ATPase activity of HMT-CNP1 may underlie the biomechanism of the toxicity of this preparation of CNPs, and may suggest ATPase activity should be considered when synthesizing CNPs for use in biomedical applications. PMID:23668322

  9. Electrophoretic and densitometric analysis of esterase activity as an indicator of mercury toxicity

    SciTech Connect

    Benton, M.J.; Guttman, S.I.

    1995-12-31

    In an earlier experiment, esterase activity as determined by starch gel electrophoresis was absent in larval caddisflies (Nectopsyche albida) that succumbed to mercury exposure, but was present in control larvae. To test the effects of mercury exposure duration on esterase activity, additional larval N. albida were exposed under conditions identical to those in the earlier experiment, and esterase activity was determined by electrophoresis of several live individuals every 12 hours. To test the effects of mercury concentration on esterase activity, homogenates of unexposed N. albida were electrophoresed, and esterase activity was determined using esterase-specific stains spiked with various concentrations of mercury. Following both experiments, esterase activity was quantified by laser densitometry of stained electrophoresis gels, Results indicate that: (1) inorganic mercury inhibited esterase activity, (2) inhibition increased with exposure time, and (3) inhibition increased with mercury concentration. Esterase inhibition may be a causal factor in mortality related to mercury exposure. Quantification of esterase activity by densitometry of electrophoretic gels may be an alternative method of rapid toxicity assessment.

  10. Aplidine: a paradigm of how to handle the activity and toxicity of a novel marine anticancer poison.

    PubMed

    Le Tourneau, C; Raymond, E; Faivre, S

    2007-01-01

    The marine ecosystem that has contributed to the discovery of cytarabine and its fluorinated derivative gemcitabine is now considered the most productive toll to acquire new natural derived anticancer entities. Few marine anticancer agents have entered clinical development, including bryostatin-1, dolastatin 10, LU103793, ET-743, kahalalide F, didemnin B and aplidine. The marine plitidepsin aplidine derived from the mediterranean tunicate Aplidium albicans is a synthetically produced anticancer agent that is structurally related to didemnins. Aplidine's mechanism of action involves several pathways, including cell cycle arrest, inhibition of protein synthesis and antiangiogenic activity. Phase I studies have been reported for a number of several schedules including 1-hour, 3-hour and 24-hour infusion. Evidences of antitumor activity and clinical benefit of aplidine in several tumor types were noted across phase I trials, particularly in advanced medullar thyroid carcinoma. Phase II studies are underway. Within the entire phase I program, dose-limiting toxicities of aplidine were neuromuscular toxicity, asthenia, skin toxicity, and diarrhea. Interestingly, no hematological toxicity was observed. Aplidine displayed a very peculiar delayed neuromuscular toxicity that was found to be closely related to the symptoms described in the adult form of carnitine palmitoyl transferase deficiency type 2, which is a genetic disease treated with L-carnitine. Consistently, concomitant administration of L-carnitine allowed to improve aplidine-induce neuromuscular toxicity. In summary, aplidine is a novel marine anticancer agent with a very particular delayed neuromuscular toxicity that requires careful follow-up with promising antitumor activity. PMID:18045196

  11. Se-methylselenocysteine offers selective protection against toxicity and potentiates the antitumour activity of anticancer drugs in preclinical animal models

    PubMed Central

    Cao, S; Durrani, F A; Tóth, K; Rustum, Y M

    2014-01-01

    Background: Identification and development of drugs that can effectively modulate the therapeutic efficacy and toxicity of chemotherapy remain an unmet challenge. We evaluated the effects of Se-methylselenocysteine (MSC) on the toxicity and antitumour activity of cyclophosphamide, cisplatin, oxaliplatin, and irinotecan in animal models. Methods: Cyclophosphamide, cisplatin, and oxaliplatin were administered by a single i.v. injection and irinotecan by i.v. weekly × 4 schedules. For the combination, MSC was administered daily via the oral route for 7 days in mice and daily for 14 days in rats before and concurrent with drug administration. Results: Se-methylselenocysteine significantly protected against organ-specific toxicity induced by lethal doses of cyclophosphamide, cisplatin, oxaliplatin, and irinotecan. These include diarrhoea, stomatitis, alopecia, bladder, kidney, and bone marrow toxicities. Protection from lethal toxicity by MSC was associated with enhanced antitumour activity in rats bearing advanced Ward colorectal carcinoma and in nude mice bearing human squamous cell carcinoma of the head and neck, FaDu, and A253 xenografts. Conclusions: Se-methylselenocysteine offers selective protection against organ-specific toxicity induced by clinically active agents and enhances further antitumour activity, resulting in improved therapeutic index. These data provided the rationale for the need to clinically evaluate MSC as selective modulator of the antitumour activity and selectivity of anticancer drugs. PMID:24619073

  12. Chitosan-isoniazid conjugates: Synthesis, evaluation of tuberculostatic activity, biodegradability and toxicity.

    PubMed

    Berezin, Alexander S; Skorik, Yury A

    2015-08-20

    Novel water-soluble chitosan-isoniazid conjugates were synthesized by two methods: (1) the carbodiimide method using isoniazid (INH) and N-(2-carboxyethyl)chitosan (CEC), and (2) the reaction between INH and N-(3-chloro-2-hydroxypropyl)chitosan (CHPC). The solubility of the conjugates under physiological conditions was enhanced by phosphorylation. Method (1) is preferable in terms of obtaining conjugates with a high content of active substance; depending on reaction conditions, the degree of substitution in the INH-CEC conjugates varies from 0.08 to 0.39. Ultrasound treatment increased the reaction rate by a factor of 1.3-1.5, but caused partial degradation of the polymer. Consecutive modification led to a considerable decrease in polymer biodegradability in the following order: chitosan>CEC or CHPC>conjugate. In vitro screening of the antimicrobial activity against Mycobacterium tuberculosis H37Rv demonstrated a comparable or slightly higher minimum inhibitory concentration for conjugates than for INH itself (0.20, 0.25, and 1.05 μg INH/mL for INH, CEC-INH, and CHPC-INH, respectively). A slug mucosal irritation test employing Limax flavus revealed a lower toxicity for the conjugates than for INH by a factor of 3-4; the most noticeable toxicity decrease was observed for the conjugates obtained by method (1). Studies of acute toxicity in mice revealed a 3-4-fold increase in median lethal dose for the conjugates compared with INH (LD50 210, 850, and 650 mg INH/kg for INH, CEC-INH, and CHPC-INH, respectively). PMID:25965488

  13. Daphnia and fish toxicity of (benzo)triazoles: validated QSAR models, and interspecies quantitative activity-activity modelling.

    PubMed

    Cassani, Stefano; Kovarich, Simona; Papa, Ester; Roy, Partha Pratim; van der Wal, Leon; Gramatica, Paola

    2013-08-15

    Due to their chemical properties synthetic triazoles and benzo-triazoles ((B)TAZs) are mainly distributed to the water compartments in the environment, and because of their wide use the potential effects on aquatic organisms are cause of concern. Non testing approaches like those based on quantitative structure-activity relationships (QSARs) are valuable tools to maximize the information contained in existing experimental data and predict missing information while minimizing animal testing. In the present study, externally validated QSAR models for the prediction of acute (B)TAZs toxicity in Daphnia magna and Oncorhynchus mykiss have been developed according to the principles for the validation of QSARs and their acceptability for regulatory purposes, proposed by the Organization for Economic Co-operation and Development (OECD). These models are based on theoretical molecular descriptors, and are statistically robust, externally predictive and characterized by a verifiable structural applicability domain. They have been applied to predict acute toxicity for over 300 (B)TAZs without experimental data, many of which are in the pre-registration list of the REACH regulation. Additionally, a model based on quantitative activity-activity relationships (QAAR) has been developed, which allows for interspecies extrapolation from daphnids to fish. The importance of QSAR/QAAR, especially when dealing with specific chemical classes like (B)TAZs, for screening and prioritization of pollutants under REACH, has been highlighted. PMID:23702385

  14. Antimicrobial activity and brine shrimp toxicity of extracts of Terminalia brownii roots and stem

    PubMed Central

    Mbwambo, Zakaria H; Moshi, Mainen J; Masimba, Pax J; Kapingu, Modest C; Nondo, Ramadhani SO

    2007-01-01

    Background Ternimalia brownii Fresen (Combretaceae) is widely used in traditional medicine to treat bacterial, fungal and viral infections. There is a need to evaluate extracts of this plant in order to provide scientific proof for it's wide application in traditional medicine system. Methods Extraction of stem bark, wood and whole roots of T. brownii using solvents of increasing polarity, namely, Pet ether, dichloromethane, dichloromethane: methanol (1:1), methanol and aqua, respectively, afforded dry extracts. The extracts were tested for antifungal and antibacterial activity and for brine shrimp toxicity test. Results Extracts of the stem bark, wood and whole roots of T. brownii exhibited antibacterial activity against standard strains of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella typhi, and Bacillus anthracis and the fungi, Candida albicans and Cryptococcus neoformans. Aqueous extracts exhibited the strongest activity against both bacteria and fungi. Extracts of the roots and stem bark exhibited relatively mild cytotoxic activity against brine shrimp larvae with LC50 values ranging from 113.75–4356.76 and 36.12–1458.81 μg/ml, respectively. The stem wood extracts exhibited the highest toxicity against the shrimps (LC50 values 2.58–14.88 μg/ml), while that of cyclophosphamide, a standard anticancer drug, was 16.33 (10.60–25.15) μg/ml. Conclusion These test results support traditional medicinal use of, especially, aqueous extracts for the treatment of conditions such as diarrhea, and gonorrhea. The brine shrimp results depict the general trend among plants of the genus Terminalia, which are known to contain cytotoxic compounds such as hydrolysable tannins. These results warrant follow-up through bioassay-directed isolation of the active principles. PMID:17394672

  15. Morphological impact of zinc oxide particles on the antibacterial activity and human epithelia toxicity.

    PubMed

    Čepin, Marjeta; Hribar, Gorazd; Caserman, Simon; Orel, Zorica Crnjak

    2015-01-01

    ZnO nanoparticles are utilized in an ever growing number of products and can, therefore, be readily encountered in our everyday life. Human beings' outermost tissues consist of different epithelia and are, therefore, the most exposed to materials from the environment. In this paper, Caco-2 and Calu-3 cell lines were used, having been previously broadly applied for in vitro modelling of intestinal and respiratory epithelia, respectively. The toxicity of synthesized micro-, submicro- and nanoparticulate ZnO on these epithelia was measured and compared to the efficacy of the same ZnO particles as antibacterial agents. An approximately four-fold excess in antibacterial activity of ZnO nanoparticles over ZnO granulate was observed. The results of this paper reveal a sharp distinction between toxic nanoparticulate ZnO and safe ZnO particles of larger sizes in intestinal and airway in vitro epithelial models. In contrast, ZnO of larger particle sizes had only modestly lower antibacterial activity, which can be compensated for with higher dosing. These results show that nanoparticulate ZnO requires critical in vivo assessment before application. PMID:25953559

  16. Toxicity and antioxidant capacity of Frangula alnus Mill. bark and its active component emodin.

    PubMed

    Brkanac, Sandra Radić; Gerić, Marko; Gajski, Goran; Vujčić, Valerija; Garaj-Vrhovac, Vera; Kremer, Dario; Domijan, Ana-Marija

    2015-12-01

    In the present study toxicity of Frangula alnus Mill. bark, widely used as laxative, was investigated. Human peripheral blood lymphocytes (HPBLs) were treated with F. alnus bark extract or emodin (emodin is bark component with laxative property), and cytotoxicity, genotoxicity and parameters of oxidative stress were assessed. Also, polyphenol content of bark extract and antioxidant activity of the extract and emodin measured by DPPH, ABTS and FRAP methods were examined. The bark extract (500 μg/ml) produced cell death and DNA damage, while level of ROS changed at 250 μg/ml. Emodin induced cell death and DNA damage at 150 μg/ml and 200 μg/ml, respectively, and the increase of ROS was observed at 25 μg/ml. These results suggest that both, bark extract and emodin, are cyto/genotoxic to HPBLs and that oxidative stress is involved in the mechanism of their toxicity. The results on antioxidant activity showed that, unlike emodin, bark extract possess moderate antioxidant capacity (44.6%, 46.8% and 2.25 mmol Fe(2+)/g measured by DPPH, ABTS and FRAP assay, respectively) that can be related to relatively high phenolic content (116.07 mg/g). However, due to toxicological properties use of F. alnus bark as well as emodin-containing preparations should be taken with caution. PMID:26399165

  17. The assessment of inflammatory activity and toxicity of treated sewage using RAW264.7 cells

    PubMed Central

    Makene, Vedastus W.

    2015-01-01

    Abstract Toxicity and inflammatory activity of wastewater samples were evaluated using RAW264.7 cells as a bioassay model. The RAW264.7 cell cultures were exposed to sterile filtered wastewater samples collected from a sewage treatment plant. Cell viability was evaluated using WST‐1 and XTT assays. Inflammatory effects of samples were assessed by determination of nitric oxide (NO) and interleukin 6 (IL‐6). The NO was estimated using the Griess reaction and IL‐6 was measured by enzyme‐linked immunoassay. All samples had no toxicity effects to RAW264.7 cells, however they significantly (P < 0.001) induced NO and IL‐6 production. The highest NO (12.5 ± 0.38 μM) and IL‐6 (25383.84 ± 2327 pg/mL) production was induced by postbiofiltration sample. Final effluent induced the lowest inflammatory response, which indicates effective sewage treatment. In conclusion, wastewater samples can induce inflammatory activities in RAW264.7 cells. The RAW264.7 cells, therefore, can be used as a model for monitoring the quality of treated sewage. PMID:26900395

  18. Subchronic Toxicity Study in Rats of Two New Ethyl-Carbamates with Ixodicidal Activity

    PubMed Central

    Prado-Ochoa, María Guadalupe; Abrego-Reyes, Víctor Hugo; Velázquez-Sánchez, Ana María; Muñoz-Guzmán, Marco Antonio; Ramírez-Noguera, Patricia; Angeles, Enrique; Alba-Hurtado, Fernando

    2014-01-01

    Female and male Wistar rats were used to determine the subchronic oral toxicities of two new ethyl-carbamates with ixodicidal activities (ethyl-4-bromphenyl-carbamate and ethyl-4-chlorphenyl-carbamate). The evaluated carbamates were administered in the drinking water (12.5, 25 and 50 mg/kg/day) for 90 days. Exposure to the evaluated carbamates did not cause mortality or clinical signs and did not affect food consumption or weight gain. However, exposure to these carbamates produced alterations in water consumption, hematocrit, percentages of reticulocytes, plasma proteins, some biochemical parameters (aspartate aminotransferase, gamma-glutamyl transpeptidase, cholinesterase, and creatinine activities), thiobarbituric acid reactive substances, and the relative weight of the spleen. Histologically, slight pathological alterations were found in the liver that were consistent with the observed biochemical alterations. The nonobserved adverse effect levels (NOAELs) of the evaluated carbamates were 12.5 mg/kg/day for both the female and male rats. The low severity and reversibility of the majority of the observed alterations suggest that the evaluated carbamates have low subchronic toxicity. PMID:24818142

  19. A cationic tetrapyrrole inhibits toxic activities of the cellular prion protein

    PubMed Central

    Massignan, Tania; Cimini, Sara; Stincardini, Claudia; Cerovic, Milica; Vanni, Ilaria; Elezgarai, Saioa R.; Moreno, Jorge; Stravalaci, Matteo; Negro, Alessandro; Sangiovanni, Valeria; Restelli, Elena; Riccardi, Geraldina; Gobbi, Marco; Castilla, Joaquín; Borsello, Tiziana; Nonno, Romolo; Biasini, Emiliano

    2016-01-01

    Prion diseases are rare neurodegenerative conditions associated with the conformational conversion of the cellular prion protein (PrPC) into PrPSc, a self-replicating isoform (prion) that accumulates in the central nervous system of affected individuals. The structure of PrPSc is poorly defined, and likely to be heterogeneous, as suggested by the existence of different prion strains. The latter represents a relevant problem for therapy in prion diseases, as some potent anti-prion compounds have shown strain-specificity. Designing therapeutics that target PrPC may provide an opportunity to overcome these problems. PrPC ligands may theoretically inhibit the replication of multiple prion strains, by acting on the common substrate of any prion replication reaction. Here, we characterized the properties of a cationic tetrapyrrole [Fe(III)-TMPyP], which was previously shown to bind PrPC, and inhibit the replication of a mouse prion strain. We report that the compound is active against multiple prion strains in vitro and in cells. Interestingly, we also find that Fe(III)-TMPyP inhibits several PrPC-related toxic activities, including the channel-forming ability of a PrP mutant, and the PrPC-dependent synaptotoxicity of amyloid-β (Aβ) oligomers, which are associated with Alzheimer’s Disease. These results demonstrate that molecules binding to PrPC may produce a dual effect of blocking prion replication and inhibiting PrPC-mediated toxicity. PMID:26976106

  20. Overoxidation of chloroplast 2-Cys peroxiredoxins: balancing toxic and signaling activities of hydrogen peroxide

    PubMed Central

    Puerto-Galán, Leonor; Pérez-Ruiz, Juan M.; Ferrández, Julia; Cano, Beatriz; Naranjo, Belén; Nájera, Victoria A.; González, Maricruz; Lindahl, Anna M.; Cejudo, Francisco J.

    2013-01-01

    Photosynthesis, the primary source of biomass and oxygen into the biosphere, involves the transport of electrons in the presence of oxygen and, therefore, chloroplasts constitute an important source of reactive oxygen species, including hydrogen peroxide. If accumulated at high level, hydrogen peroxide may exert a toxic effect; however, it is as well an important second messenger. In order to balance the toxic and signaling activities of hydrogen peroxide its level has to be tightly controlled. To this end, chloroplasts are equipped with different antioxidant systems such as 2-Cys peroxiredoxins (2-Cys Prxs), thiol-based peroxidases able to reduce hydrogen and organic peroxides. At high peroxide concentrations the peroxidase function of 2-Cys Prxs may become inactivated through a process of overoxidation. This inactivation has been proposed to explain the signaling function of hydrogen peroxide in eukaryotes, whereas in prokaryotes, the 2-Cys Prxs of which were considered to be insensitive to overoxidation, the signaling activity of hydrogen peroxide is less relevant. Here we discuss the current knowledge about the mechanisms controlling 2-Cys Prx overoxidation in chloroplasts, organelles with an important signaling function in plants. Given the prokaryotic origin of chloroplasts, we discuss the occurrence of 2-Cys Prx overoxidation in cyanobacteria with the aim of identifying similarities between chloroplasts and their ancestors regarding their response to hydrogen peroxide. PMID:23967002

  1. Antiulcer activity and subacute toxicity of trans-dehydrocrotonin from Croton cajucara.

    PubMed

    Rodríguez, Jaime A; Hiruma-Lima, Clélia A; Souza Brito, Alba R M

    2004-08-01

    The antiulcerogenic activity of trans-dehydrocrotonin (DHC), a nor-clerodane diterpene isolated from Croton cajucara Benth. (Euphorbiaceae), and its subacute (35 days) toxicity were studied in mice and rats, respectively. For the antiulcerogenic tests, models of gastric ulcers induced in mice by ethanol/HCl or stress were used. In both models, an oral dose of DHC (100 mg/kg) significantly reduced (P < 0.01) the formation of gastric lesions. DHC was also tested for its ability to scavenge free radicals, but no such action was observed in rat liver mitochondria. To assess the subacute toxicity, rats were treated orally with DHC (25, 50 and 100 mg/kg) for 5 weeks. A significant increase in liver weight was observed in male and female rats at highest doses, whereas a significant reduction in plasma alkaline phosphatase and cholesterol levels and an increase in gamma glutamyl transpeptidase were observed only at the highest dose (100 mg/kg) in female rats. DHC caused histopathological alterations in the liver that included a turbid tumefaction, microvacuolar degeneration and nuclear alterations. Despite the beneficial antiulcerogenic activity of DHC, our results suggest that the long-term use of this compound may induce liver damage. PMID:15497821

  2. Antidiarrheal activity and acute oral toxicity of Mentha longifolia L. essential oil

    PubMed Central

    Jalilzadeh-Amin, Ghader; Maham, Massoud

    2015-01-01

    Objectives: Mentha longifolia L. (Lamiaceae) is an annual herb that is used in the Iranian traditional medicine for treating stomach and intestinal disorders. The purpose of this study was to determine the protective effect of M. longifolia on experimental diarrhea in a rat model. Materials and Methods: The antidiarrheal activity of essential oil of M. longifolia (20-80 mg/kg) was investigated against castor oil-induced diarrhea in rats using loperamide as the standard reference drug. In acute toxicity evaluation, rats were orally administrated with single dose of EOML at doses ranging from 10 to 1000 mg/kg. Results: EOML caused a significant (p<0.05) and dose-dependent decrease of gastrointestinal transit, nevertheless, it could not block the inhibitory effect of atropine (0.1 mg/kg). EOML at oral doses of 20 and 80 mg/kg protected the animals against castor oil-induced diarrhea significantly (p<0.05). EOML decreased the intestinal fluid accumulation as indicated by the significantly (p<0.05 to p<0.001) decrease compared to control. The oral LD50 of EOML was found to be 470 mg/kg in rat. Conclusion: Since the inhibition of intestinal hyperactivity and hypersecretory are the bases of the treatment of diarrhea, results obtained in the present study suggest that EOML is endowed with antidiarrheal activity. EOML is moderately toxic for oral medication. PMID:25949954

  3. Prompt gamma neutron activation analysis of toxic elements in radioactive waste packages.

    PubMed

    Ma, J-L; Carasco, C; Perot, B; Mauerhofer, E; Kettler, J; Havenith, A

    2012-07-01

    The French Alternative Energies and Atomic Energy Commission (CEA) and National Radioactive Waste Management Agency (ANDRA) are conducting an R&D program to improve the characterization of long-lived and medium activity (LL-MA) radioactive waste packages. In particular, the amount of toxic elements present in radioactive waste packages must be assessed before they can be accepted in repository facilities in order to avoid pollution of underground water reserves. To this aim, the Nuclear Measurement Laboratory of CEA-Cadarache has started to study the performances of Prompt Gamma Neutron Activation Analysis (PGNAA) for elements showing large capture cross sections such as mercury, cadmium, boron, and chromium. This paper reports a comparison between Monte Carlo calculations performed with the MCNPX computer code using the ENDF/B-VII.0 library and experimental gamma rays measured in the REGAIN PGNAA cell with small samples of nickel, lead, cadmium, arsenic, antimony, chromium, magnesium, zinc, boron, and lithium to verify the validity of a numerical model and gamma-ray production data. The measurement of a ∼20kg test sample of concrete containing toxic elements has also been performed, in collaboration with Forschungszentrum Jülich, to validate the model in view of future performance studies for dense and large LL-MA waste packages. PMID:22406218

  4. Aryl hydrocarbon receptor activation and developmental toxicity in zebrafish in response to soil extracts containing unsubstituted and oxygenated PAHs.

    PubMed

    Wincent, Emma; Jönsson, Maria E; Bottai, Matteo; Lundstedt, Staffan; Dreij, Kristian

    2015-03-17

    Many industrial sites are polluted by complex mixtures of polycyclic aromatic compounds (PACs). Besides polycyclic aromatic hydrocarbons (PAHs), these mixtures often contain significant amounts of more polar PACs including oxygenated PAHs (oxy-PAHs). The effects of oxy-PAHs are, however, poorly known. Here we used zebrafish embryos to examine toxicities and transcriptional changes induced by PAC containing soil extracts from three different industrial sites: a gasworks (GAS), a former wood preservation site (WOOD), and a coke oven (COKE), and to PAH and oxy-PAH containing fractions of these. All extracts induced aryl hydrocarbon receptor (Ahr)-regulated mRNAs, malformations, and mortality. The WOOD extract was most toxic and the GAS extract least toxic. The extracts induced glutathione transferases and heat shock protein 70, suggesting that the toxicity also involved oxidative stress. With all extracts, Ahr2-knock-down reduced the toxicity, indicating a significant Ahr2-dependence on the effects. Ahr2-knock-down was most effective with the PAH fraction of the WOOD extract and with the oxy-PAH fraction of the COKE extract. Our results indicate that oxy-PAH containing mixtures can be as potent Ahr activators and developmental toxicants as PAHs. In addition to Ahr activating potency, the profile of cytochrome P4501 inhibitors may also determine the toxic potency of the extracts. PMID:25715055

  5. Partial in vitro analysis of toxic and antigenic activities of eleven Peruvian pitviper snake venoms.

    PubMed

    Guerra-Duarte, C; Lopes-Peixoto, J; Fonseca-de-Souza, B R; Stransky, S; Oliveira, D; Schneider, F S; Lopes-de-Souza, L; Bonilla, C; Silva, W; Tintaya, B; Yarleque, A; Chávez-Olórtegui, C

    2015-12-15

    This work used eleven Peruvian snake venoms (Bothrops andianus, Bothrops atrox, Bothrops barnetti, Bothrops castelnaudi, Bothriopsis chloromelas, Bothrocophias microphthalmus, Bothrops neuwiedi, Bothriopsis oligolepis, Bothriopsis peruviana, Bothrops pictus and Bothriopsis taeniata) to perform in vitro experimentation and determine its main characteristics. Hyaluronidase (HYAL), phospholipase A2 (PLA2), snake venom metalloproteinase (SVMP), snake venom serine protease (SVSP) and L-amino acid oxidase (LAAO) activities; toxicity by cell viability assays using MGSO3, VERO and HeLa cell lineages; and crossed immunoreactivity with Peruvian (PAV) and Brazilian (BAV) antibothropic polyvalent antivenoms, through ELISA and Western Blotting assays, were determined. Results show that the activities tested in this study were not similar amongst the venoms and each species present their own peculiarities, highlighting the diversity within Bothrops complex. All venoms were capable of reducing cell viability of all tested lineages. It was also demonstrated the crossed recognition of all tested venoms by both antivenoms. PMID:26365916

  6. Metabolic Activation of Rhein: Insights into the Potential Toxicity Induced by Rhein-Containing Herbs.

    PubMed

    Yuan, Yuan; Zheng, Jiyue; Wang, Meiyu; Li, Yuan; Ruan, Jianqing; Zhang, Hongjian

    2016-07-20

    Rhein is a major component of the many medicinal herbs such as rhubarb. Despite wide use, intoxication cases associated with rhein-containing herbs are often reported. The present work aimed to investigate if rhein was subject to metabolic activation leading to toxicity. Upon incubations with different species of liver microsomes, three monoglucuronides were identified, corresponding to two hydroxyl glucuronides and one acyl glucuronide via the carboxyl group, respectively. Further study revealed that rhein acyl glucuronide was chemically reactive, and showed cytotoxicity toward hepatocarcinoma cells. In addition, significant species differences in glucuronidation of rhein were observed between laboratory animals and humans. Reaction phenotyping experiments demonstrated that rhein acyl glucuronide was catalyzed predominantly by uridine 5'-diphospho-glucuronosyltransferase 1A1, 1A9, and 2B7. Taken together, the present study confirmed that rhein could be metabolically activated via the formation of acyl glucuronide, especially in human. PMID:27362917

  7. Relationship of molecular weight to antiviral and antitumor activities and toxic effects of maleic anhydride-divinyl ether (MVE) polyanions.

    PubMed

    Morahan, P S; Barnes, D W; Munson, A E

    1978-11-01

    The molecular weight (MW) and dose dependency of several of the toxic effects and antitumor and antiviral activities of a new series of five maleic anhydride-divinyl ether copolymers (MVE) were established. Each polyanion preparation was relatively homogeneous and exhibited a narrow MW range, from 12,500 (MVE-1) to greater than 52,000 (MVE-5). All of the polyanions were effective as adjuvants to surgery against the metastatic Lewis lung carcinoma, and also exhibited marked antitumor activity against the P815 mastocytoma. MVE-1 retained antitumor activity while losing considerable antiviral activity. This polyanion also exhibited the least toxicity with regard to criteria such as sensitization to the lethal effects of endotoxin, inhibition of reticuloendothelial function, and depression of the microsomal mixed functional oxidase system. The MVE-4 (MW, 32,000) and MVE-5 (MW, 52,600) polyanions exhibited potent antitumor and antiviral activity, but also demonstrated dose-dependent toxic effects. PMID:103618

  8. [Detection of fungal metabolites showing toxic activity through Artemia salina bioassay].

    PubMed

    González, Ana María; Presa, Maximiliano; Latorre, María Gabriela; Lurá, María Cristina

    2007-03-01

    The aim of this study was to detect toxic metabolites from fungi contaminating food and medicinal herbs by applying the toxicity assay to Artemia salina. According to toxicity percentages, the extracts were classified as nontoxic (NT), slightly toxic (ST), toxic (T) and highly toxic (HT). Those classified as T and HT were assayed for mycotoxins. Only 6 out of 71 strains were found to be T (8.5%) for A. salina. Penicillium brevicompactum Dierckx, isolated from sausages, was found to be HT, mainly due to the presence of ochratoxin A and two other unidentified metabolites. PMID:17592895

  9. Levels of toxic arsenic species in native terrestrial plants from soils polluted by former mining activities.

    PubMed

    García-Salgado, Sara; Quijano, M Ángeles

    2014-03-01

    Ten native terrestrial plants from soils polluted by former mining activities (Mónica mine, NW Madrid, Spain), with high total arsenic concentration levels (up to 3500 μg g(-1)), have been studied to determine the fraction of arsenic present as toxic forms (inorganic and methylated species), which present a higher mobility and therefore the potential risk associated with their reintegration into the environment is high. Roots and aboveground parts were analyzed separately to assess possible transformations from translocation processes. Extractions were carried out with deionized water by microwave-assisted extraction at a temperature of 90 °C and three extraction steps of 7.5 min each. Total extracted arsenic concentrations were determined by inductively coupled plasma atomic emission spectrometry, showing extraction percentages from 9 to 39% (calculated as the ratio between total extracted arsenic (Asext) and total arsenic (AsT) concentrations in plants). Speciation studies, performed by high performance liquid chromatography-photo-oxidation-hydride generation-atomic fluorescence spectrometry, showed the main presence of arsenate (As(v)) (up to 350 μg g(-1)), followed by arsenite (As(iii)), in both plant parts. Monomethylarsonic acid (MMA) and trimethylarsine oxide (TMAO) were also found only in some plants. On the other hand, the use of 0.5 mol L(-1) acetic acid as an extractant led to higher extraction percentages (33-87%), but lower column recoveries, probably due to the extraction of arsenic compounds different to the toxic free ions studied, which may come from biotransformation mechanisms carried out by plants to reduce arsenic toxicity. However, As(v) concentrations increased up to 800 μg g(-1) in acid medium, indicating the probable release of As(v) from organoarsenic compounds and therefore a higher potential risk for the environment. PMID:24513726

  10. Quantitative structure-activity analysis of the algae toxicity of nitroaromatic compounds.

    PubMed

    Schmitt, H; Altenburger, R; Jastorff, B; Schüürmann, G

    2000-06-01

    Proliferation toxicity toward the algae Scenedesmus vacuolatus in a 24 h one-generation reproduction assay was determined for nitrobenzene and 18 derivatives, including two phenols. The resultant EC(50) values covering more than 4 orders of magnitude were subjected to a quantitative structure-activity analysis (QSAR) using hydrophobicity in terms of the octanol/water partition coefficient in logarithmic form, log K(ow), and 16 quantum chemical descriptors of molecular reactivity that were calculated with the AM1 scheme. For 13 mononitro derivatives and the highly hydrophobic trifluralin, a narcotic-type mode of action can explain most of the toxicity variation. Correction of log K(ow) for ionization for the phenols and quantification of the molecular susceptibility for one-electron reduction as apparently rate-determining biotransformation step by the energy of the lowest unoccupied molecular orbital, E(LUMO), yields a highly significant QSAR for all 19 compounds (r(adj)(2) = 0.90), which can be further improved when adding the maximum net atomic charge at the nitro nitrogen, q(nitro)(-)(N), as the third descriptor (r(adj)(2) = 0.93). Comparison of the energy of the singly occupied molecular orbital, E(SOMO), of the radical anions as initial metabolites with the E(SOMO) of known redox cyclers suggests that dinitrobenzenes and TFM as well as multiply chlorinated nitrobenzenes may also exert oxidative stress. This is based on an E(SOMO) window of -0.30 to 0. 55 eV as a tentative criterion for molecular structures to have the potential for redox cycling, derived from a set of eight known redox cyclers. The discussion includes a detailed analysis of apparently relevant metabolic pathways and associated modes of toxic action of nitroaromatics. PMID:10858317

  11. Toxicity mitigation and solidification of municipal solid waste incinerator fly ash using alkaline activated coal ash

    SciTech Connect

    Ivan Diaz-Loya, E.; Allouche, Erez N.; Eklund, Sven; Joshi, Anupam R.; Kupwade-Patil, Kunal

    2012-08-15

    Highlights: Black-Right-Pointing-Pointer Incinerator fly ash (IFA) is added to an alkali activated coal fly ash (CFA) matrix. Black-Right-Pointing-Pointer Means of stabilizing the incinerator ash for use in construction applications. Black-Right-Pointing-Pointer Concrete made from IFA, CFA and IFA-CFA mixes was chemically characterized. Black-Right-Pointing-Pointer Environmentally friendly solution to IFA disposal by reducing its toxicity levels. - Abstract: Municipal solid waste (MSW) incineration is a common and effective practice to reduce the volume of solid waste in urban areas. However, the byproduct of this process is a fly ash (IFA), which contains large quantities of toxic contaminants. The purpose of this research study was to analyze the chemical, physical and mechanical behaviors resulting from the gradual introduction of IFA to an alkaline activated coal fly ash (CFA) matrix, as a mean of stabilizing the incinerator ash for use in industrial construction applications, where human exposure potential is limited. IFA and CFA were analyzed via X-ray fluorescence (XRF), X-ray diffraction (XRD) and Inductive coupled plasma (ICP) to obtain a full chemical analysis of the samples, its crystallographic characteristics and a detailed count of the eight heavy metals contemplated in US Title 40 of the Code of Federal Regulations (40 CFR). The particle size distribution of IFA and CFA was also recorded. EPA's Toxicity Characteristic Leaching Procedure (TCLP) was followed to monitor the leachability of the contaminants before and after the activation. Also images obtained via Scanning Electron Microscopy (SEM), before and after the activation, are presented. Concrete made from IFA, CFA and IFA-CFA mixes was subjected to a full mechanical characterization; tests include compressive strength, flexural strength, elastic modulus, Poisson's ratio and setting time. The leachable heavy metal contents (except for Se) were below the maximum allowable limits and in many cases

  12. Gas chromatography-mass spectroscopy analysis of bioactive petalostigma extracts: Toxicity, antibacterial and antiviral activities

    PubMed Central

    Kalt, F. R.; Cock, I. E.

    2014-01-01

    Background: Petalostigma pubescens and Petalostigma triloculare were common components of pharmacopeia's of multiple Australian Aboriginal tribal groupings which traditionally inhabited the areas in which they grow. Among these groups, they had a myriad of medicinal uses in treating a wide variety of bacterial, fungal and viral infections. This study was undertaken to test P. pubescens and P. triloculare leaf and fruit extracts for the ability to inhibit bacterial and viral growth and thus validate Australian Aboriginal usage of these plants in treating bacterial and fungal diseases. Materials and Methods: P. pubescens, and P. triloculare leaves and fruit were extracted and tested for antimicrobial, antiviral activity and toxicity. The bioactive extracts were further examined by RP-HPLC and GC-MS to identify the component compounds. Results: The methanol, water and ethyl acetate leaf and fruit extracts of displayed potent antibacterial activity. The methanol and ethyl acetate extracts displayed the broadest specificity, inhibiting the growth of 10 of the 14 bacteria tested (71%) for the leaf extract and 9 of the 14 bacteria tested (64%) for the fruit extracts. The water extracts also had broad spectrum antibacterial activity, inhibiting the growth of 8 (57%) and 7 (50%) of the 14 bacteria tested, respectively. All antibacterial extracts were approximately equally effective against Gram-positive and Gram-negative bacteria, inhibiting the growth of 50-75% of the bacteria tested. The methanol, water and ethyl acetate extracts also displayed antiviral activity in the MS2 plaque reduction assay. The methanol and water extracts inhibited 26.6-49.0% and 85.4-97.2% of MS2 plaque formation, respectively, with the fruit extracts being more potent inhibitors. All ethyl acetate extracts inhibited 100% of MS2 plaque formation. All extracts were also non-toxic or of low toxicity. Analysis of these extracts by RP-HPLC showed that the P. triloculare ethyl acetate fruit extract was

  13. Toxicity of perfluorooctanoic acid towards earthworm and enzymatic activities in soil.

    PubMed

    He, Wenxiang; Megharaj, Mallavarapu; Naidu, Ravi

    2016-07-01

    Perfluorooctanoic acid (PFOA) is a widespread persistent organic contaminant in the environment that has recently raised much of regulatory and public concern. Therefore, assessment of its ecological risk is a top priority research. Hence, this study investigated the toxicity of PFOA to beneficial microbial processes in the soil such as activities of dehydrogenase, urease and potential nitrification in addition to earthworm survival, weight loss and PFOA bioaccumulation in two contrasting soils. In general, PFOA caused inhibition of all the measured microbial processes in a dose-dependent manner and the inhibition was higher in Williamtown (WT) soil than Edinburgh (EB) soil. Thus, WT soil being sandy in nature with low clay content showed higher PFOA bioavailability and hence showed higher toxicity. There was no mortality in earthworms exposed up to 100 mg PFOA/kilogram soil in both the soils; however, there was a significant weight loss from 25 mg/kg onwards. This study clearly demonstrates that soil contamination of PFOA can lead to adverse effects on soil health. PMID:27329475

  14. The expert system for toxicity prediction of chemicals based on structure-activity relationship.

    PubMed Central

    Nakadate, M; Hayashi, M; Sofuni, T; Kamata, E; Aida, Y; Osada, T; Ishibe, T; Sakamura, Y; Ishidate, M

    1991-01-01

    The prediction systems of chemical toxicity has been developed by means of structure-activity relationship based on the computerized fact database (BL-DB). Numbers and ratio of elements, side chains, bonding, position, and microenvironment of side chains were used as structural factors of the chemical for the prediction. Such information was obtained from the BL-DB database by Wiswesser line-formula chemical notation. In the present study, the Salmonella/microsome assay was chosen as indicative of the target toxicity of chemicals. A set of chemicals specified with mutagenicity data was retrieved, and necessary information was extracted and transferred to the working file. Rules of the relations between characteristics of chemical structure and the assay result are extracted as parameters for rules by experts on the rearranged data set. These were analyzed statistically by the discriminant analysis and the prediction with the rules were evaluated by the elimination method. Eight kinds of rules to predict Salmonella/microsome assay were constructed, and currently results of the assay on aliphatic and heterocyclic compounds can be predicted as accurately as +90%. PMID:1820282

  15. Lipopolysaccharide Sequestrants: Structural Correlates of Activity and Toxicity in Novel Acylhomospermines

    PubMed Central

    Miller, Kelly A.; Kumar, E.V.K. Suresh; Wood, Stewart J.; Cromer, Jens R.; Datta, Apurba; David*, Sunil A.

    2005-01-01

    Lipopolysaccharides (LPS), otherwise termed ‘endotoxins’, are outer-membrane constituents of Gram-negative bacteria. Lipopolysaccharides play a key role in the pathogenesis of ‘Septic Shock’, a major cause of mortality in the critically ill patient. Therapeutic options aimed at limiting downstream systemic inflammatory processes by targeting lipopolysaccharide do not exist at the present time. We have defined the pharmacophore necessary for small molecules to specifically bind and neutralize LPS and, using animal models of sepsis, have shown that the sequestration of circulatory LPS by small molecules is a therapeutically viable strategy. In this paper, the interactions of a series of acylated homologated spermine compounds with lipopolysaccharide (LPS) have been characterized. The optimal acyl chain length for effective sequestration of LPS was identified to be C16 for the mono-acyl compounds. The most promising of these compounds, 4e, binds LPS with an ED50 of 1.37 μM. Nitric oxide production in murine J774A.1 cells, as well as TNF-α in human blood, are inhibited in a dose-dependent manner by 4e at concentrations orders of magnitude lower than toxic doses. Administration of 4e to d-galactosamine-sensitized mice challenged with supralethal doses of LPS provided significant protection against lethality. Potent anti-endotoxic activity, low toxicity, and ease of synthesis render this class of compounds candidate endotoxin-sequestering agents of potential significant therapeutic value. PMID:15801849

  16. Toxicity of phenol and monochlorophenols to growth and metabolic activities of Pseudomonas

    SciTech Connect

    Huang, D.S.; Tseng, I.C.

    1996-07-01

    Phenolic compounds are toxic to many organisms and are often present in the effluents from oil refineries, the petrochemical, pesticide, and color and textile industries. Several authors have demonstrated a characteristic pattern of behavioral responses in fishes during phenol exposure. Others have also evaluated the toxicity of halogenated phenolic compounds by screening for effects on the specific growth rates (SGR) and the dehydrogenase activity (DHA) of Escherichia coli. However, little work has been done to determine the effects on biota from short exposures at relatively high concentrations of phenol or monochlorophenols that might occur following a deliberate or accidental discharge to a receiving water. Microorganisms with phenol-degrading capacity have been studied intensively, including cyanobacteria such as Nostoc linckia, yeast such as Trichosporon cutaneum, bacteria such as Pseudomonas putida, and other unidentified species. Among these Pseudomonas has received the most attention and several mutants have been prepared to degrade substituted phenols. This study investigates the initial response of Pseudomonas upon exposure to high concentrations of phenol and chlorophenols by measuring the oxygen uptake rates. A series growth experiment was also conducted in order to compare the kinetic results with standard microbial tests. 12 refs., 3 figs., 1 tab.

  17. Toxicity and in vitro activity of HIV-1 latency-reversing agents in primary CNS cells.

    PubMed

    Gray, Lachlan R; On, Hung; Roberts, Emma; Lu, Hao K; Moso, Michael A; Raison, Jacqueline A; Papaioannou, Catherine; Cheng, Wan-Jung; Ellett, Anne M; Jacobson, Jonathan C; Purcell, Damian F J; Wesselingh, Steve L; Gorry, Paul R; Lewin, Sharon R; Churchill, Melissa J

    2016-08-01

    Despite the success of combination antiretroviral therapy (cART), HIV persists in long lived latently infected cells in the blood and tissue, and treatment is required lifelong. Recent clinical studies have trialed latency-reversing agents (LRA) as a method to eliminate latently infected cells; however, the effects of LRA on the central nervous system (CNS), a well-known site of virus persistence on cART, are unknown. In this study, we evaluated the toxicity and potency of a panel of commonly used and well-known LRA (panobinostat, romidepsin, vorinostat, chaetocin, disulfiram, hexamethylene bisacetamide [HMBA], and JQ-1) in primary fetal astrocytes (PFA) as well as monocyte-derived macrophages as a cellular model for brain perivascular macrophages. We show that most LRA are non-toxic in these cells at therapeutic concentrations. Additionally, romidepsin, JQ-1, and panobinostat were the most potent at inducing viral transcription, with greater magnitude observed in PFA. In contrast, vorinostat, chaetocin, disulfiram, and HMBA all demonstrated little or no induction of viral transcription. Together, these data suggest that some LRA could potentially activate transcription in latently infected cells in the CNS. We recommend that future trials of LRA also examine the effects of these agents on the CNS via examination of cerebrospinal fluid. PMID:26727904

  18. In vivo monitoring of toxic metals: assessment of neutron activation and x-ray fluorescence techniques

    SciTech Connect

    Ellis, K.J.

    1986-01-01

    To date, cadmium, lead, aluminum, and mercury have been measured in vivo in humans. The possibilities of monitoring other toxic metals have also been demonstrated, but no human studies have been performed. Neutron activation analysis appears to be most suitable for Cd and Al measurements, while x-ray fluorescence is ideally suited for measurement of lead in superficial bone. Filtered neutron beams and polarized x-ray sources are being developed which will improve in vivo detection limits. Even so, several of the current facilities are already suitable for use in epidemiological studies of selected populations with suspected long-term low-level ''environmental'' exposures. Evaluation and diagnosis of patients presenting with general clinical symptoms attributable to possible toxic metal exposure may be assisted by in vivo examination. Continued in vivo monitoring of industrial workers, especially follow-up measurements, will provide the first direct assessment of changes in body burden and a direct measure of the biological life-times of these metals in humans. 50 refs., 4 figs., 2 tabs.

  19. Percutaneous penetration, melanin activation and toxicity evaluation of a phytotherapic formulation for vitiligo therapeutic.

    PubMed

    Truite, Cecília Valente Rodrigues; Philippsen, Gisele Strieder; Ueda-Nakamura, Tânia; Natali, Maria Raquel Marçal; Dias Filho, Benedito Prado; Bento, Antonio Carlos; Baesso, Mauro Luciano; Nakamura, Celso Vataru

    2007-01-01

    The aim of this work was to apply photoacoustic spectroscopy for the ex vivo determination of the penetration rate of a phytotherapic formulation for vitiligo therapeutic, with or without salicylic acid as the promoter agent. In addition, the compound toxicity and morphophysiology effects were evaluated for different concentrations of salicylic acid. The experiments were performed as a function of the period of time of treatment in a well-controlled group of rabbits. Toxic effects were not observed with any of the tested products. All formulations containing salicylic acid induced cutaneous reaction which was dose dependent. The histological analysis showed that the use of the medication was associated with an increased comedogenic effect in relation to the control group, regardless of salicylic acid concentration. Inflammatory reactions and acanthosis were observed only in the animals treated with formulations containing higher concentrations of salicylic acid, while none of these effects were detected with the use of the formulation containing 2.5% (wt/vol) of salicylic acid. Photoacoustic depth monitoring showed that both formulations, with or without salicylic acid, propagated through the skin up to the melanocytes region, suggesting that the transport of the active agent may occur through the epithelial structure without the need of using queratinolitic substances, which are known to induce side effects in the animals. PMID:18028229

  20. Antibacterial activity of neem nanoemulsion and its toxicity assessment on human lymphocytes in vitro.

    PubMed

    Jerobin, Jayakumar; Makwana, Pooja; Suresh Kumar, R S; Sundaramoorthy, Rajiv; Mukherjee, Amitava; Chandrasekaran, Natarajan

    2015-01-01

    Neem (Azadirachta indica) is recognized as a medicinal plant well known for its antibacterial, antimalarial, antiviral, and antifungal properties. Neem nanoemulsion (NE) (O/W) is formulated using neem oil, Tween 20, and water by high-energy ultrasonication. The formulated neem NE showed antibacterial activity against the bacterial pathogen Vibrio vulnificus by disrupting the integrity of the bacterial cell membrane. Despite the use of neem NE in various biomedical applications, the toxicity studies on human cells are still lacking. The neem NE showed a decrease in cellular viability in human lymphocytes after 24 hours of exposure. The neem NE at lower concentration (0.7-1 mg/mL) is found to be nontoxic while it is toxic at higher concentrations (1.2-2 mg/mL). The oxidative stress induced by the neem NE is evidenced by the depletion of catalase, SOD, and GSH levels in human lymphocytes. Neem NE showed a significant increase in DNA damage when compared to control in human lymphocytes (P<0.05). The NE is an effective antibacterial agent against the bacterial pathogen V. vulnificus, and it was found to be nontoxic at lower concentrations to human lymphocytes. PMID:26491309

  1. Antibacterial activity of neem nanoemulsion and its toxicity assessment on human lymphocytes in vitro

    PubMed Central

    Jerobin, Jayakumar; Makwana, Pooja; Suresh Kumar, RS; Sundaramoorthy, Rajiv; Mukherjee, Amitava; Chandrasekaran, Natarajan

    2015-01-01

    Neem (Azadirachta indica) is recognized as a medicinal plant well known for its antibacterial, antimalarial, antiviral, and antifungal properties. Neem nanoemulsion (NE) (O/W) is formulated using neem oil, Tween 20, and water by high-energy ultrasonication. The formulated neem NE showed antibacterial activity against the bacterial pathogen Vibrio vulnificus by disrupting the integrity of the bacterial cell membrane. Despite the use of neem NE in various biomedical applications, the toxicity studies on human cells are still lacking. The neem NE showed a decrease in cellular viability in human lymphocytes after 24 hours of exposure. The neem NE at lower concentration (0.7–1 mg/mL) is found to be nontoxic while it is toxic at higher concentrations (1.2–2 mg/mL). The oxidative stress induced by the neem NE is evidenced by the depletion of catalase, SOD, and GSH levels in human lymphocytes. Neem NE showed a significant increase in DNA damage when compared to control in human lymphocytes (P<0.05). The NE is an effective antibacterial agent against the bacterial pathogen V. vulnificus, and it was found to be nontoxic at lower concentrations to human lymphocytes. PMID:26491309

  2. Anti-Oxidant and Hepatoprotective Activities of Ziziphus mucronata Fruit Extract Against Dimethoate-Induced Toxicity

    PubMed Central

    Kwape, Tebogo Elvis; Chaturvedi, Padmaja; Kamau, Macharia; Majinda, Runner

    2013-01-01

    Objective: The study was carried out to evaluate the hepatoprotective and antioxidant potential of Ziziphus mucronata (ZM) fruit extract. Methods: The different types of fruit extract were prepared by soaking the dry powdered fruit in different solvents followed by rotary evaporation. Each extract was tested for its phenol content and antioxidant activities. An in vivo study was performed in Sprague- Dawley (SD) rats. Thirty adult male SD rats (aged 21 weeks) were divided into six groups of five rats each and treated as follows: The normal control (NC) received distilled water while the dimethoate control (DC) received 6 mg/kg.bw.day-1 dimethoate dissolved in distilled water. The experimental groups E1, E2, E3, and E0 received dimethoate (6 mg/kg.bw) + ZMFM (100 mg/kg.bw-1), dimethoate (6 mg/kg.bw) + ZMFM (200 mg/kg.bw-1), dimethoate (6 mg/kg.bw) + ZMFM (300 mg/kg.bw-1), and ZMFM (300 mg/kg.bw-1) only. Both the normal control and the dimethoate control groups were used to compare the results. After 90 days, rats were sacrificed, blood was collected for biochemical assays, and livers were harvested for histological study. Results: High phenol content was estimated, and 2, 2- diphenyl-1-picryl hydrazyl radical (DPPH) spectrophotometric, thin layer chromatography (TLC) and 2, 2-Azobis-3-ethyl benzothiazoline-6-sulphonic acid (ABTS) assays showed a high antioxidant activity among the extracts. The preventive effects observed in the E1, E2 and E3 groups proved that the extract could prevent dimethoate toxicity by maintaining normal reduced glutathione (GSH), vitamin C and E, superoxide dismutase, catalase, cholineasterase and lipid profiles. The preventive effect was observed to be dose dependent. The EO group showed no extractinduced toxicity. Histological observations agreed with the results obtained in the biochemical studies. Conclusion: The study demonstrated that ZM methanol fruit extract is capable of attenuating dimethoate-induced toxicity because of its high

  3. Active Oxygen Metabolites and Thromboxane in Phorbol Myristate Acetate Toxicity to the Isolated, Perfused Rat Lung.

    NASA Astrophysics Data System (ADS)

    Carpenter, Laurie Jean

    When administered intravenously or intratracheally to rats, rabbits and sheep, phorbol myristate acetate (PMA) produces changes in lung morphology and function are similar to those seen in humans with the adult respiratory distress syndrome (ARDS). Therefore, it is thought that information about the mechanism of ARDS development can be gained from experiments using PMA-treated animals. Currently, the mechanisms by which PMA causes pneumotoxicity are unknown. Results from other studies in rabbits and in isolated, perfused rabbit lungs suggest that PMA-induced lung injury is mediated by active oxygen species from neutrophils (PMN), whereas studies in sheep and rats suggest that PMN are not required for the toxic response. The role of PMN, active oxygen metabolites and thromboxane (TxA_2) in PMA-induced injury to isolated, perfused rat lungs (IPLs) was examined in this thesis. To determine whether PMN were required for PMA to produce toxicity to the IPL, lungs were perfused for 30 min with buffer containing various concentrations of PMA (in the presence or absence of PMN). When concentrations >=q57 ng/ml were added to medium devoid of added PMN, perfusion pressure and lung weight increased. When a concentration of PMA (14-28 ng/ml) that did not by itself cause lungs to accumulate fluid was added to the perfusion medium containing PMN (1 x 10 ^8), perfusion pressure increased, and lungs accumulated fluid. These results indicate that high concentrations of PMA produce lung injury which is independent of PMN, whereas injury induced by lower concentrations is PMN-dependent. To examine whether active oxygen species were involved in mediating lung injury induced by PMA and PMN, lungs were coperfused with the oxygen radical scavengers SOD and/or catalase. Coperfusion with either or both of these enzymes totally protected lungs against injury caused by PMN and PMA. These results suggest that active oxygen species (the hydroxyl radical in particular), mediate lung injury in

  4. Toxicity and Residual Activity of Insecticides Against Tamarixia triozae (Hymenoptera: Eulophidae), a Parasitoid of Bactericera cockerelli (Hemiptera: Triozidae).

    PubMed

    Luna-Cruz, Alfonso; Rodríguez-Leyva, Esteban; Lomeli-Flores, J Refugio; Ortega-Arenas, Laura D; Bautista-Martínez, Néstor; Pineda, Samuel

    2015-10-01

    Bactericera cockerelli (Sulc) (Hemiptera: Triozidae) is one of the most economically important pests of potato, tomato, and peppers in Central America, Mexico, the United States, and New Zealand. Its control is based on the use of insecticides; however, recently, the potential of the eulophid parasitoid Tamarixia triozae (Burks) (Hymenoptera: Eulophidae) for population regulation has been studied. Because T. triozae is likely to be exposed to insecticides on crops, the objective of this study was to explore the compatibility of eight insecticides with this parasitoid. The toxicity and residual activity (persistence) of spirotetramat, spiromesifen, beta-cyfluthrin, pymetrozine, azadirachtin, imidacloprid, abamectin, and spinosad against T. triozae adults were assessed using a method based on the residual contact activity of each insecticide on tomato leaf discs collected from treated plants growing under greenhouse conditions. All eight insecticides were toxic to T. triozae. Following the classification of the International Organization of Biological Control, the most toxic were abamectin and spinosad, which could be placed in toxicity categories 3 and 4, respectively. The least toxic were azadirachtin, pymetrozine, spirotetramat, spiromesifen, imidacloprid, and beta-cyfluthrin, which could be placed in toxicity category 2. In terms of persistence, by day 5, 6, 9, 11, 13, 24, and 41 after application, spirotetramat, azadirachtin, spiromesifen, pymetrozine, imidacloprid, beta-cyfluthrin, abamectin, and spinosad could be considered harmless, that is, placed in toxicity category 1 (<25% mortality of adults). The toxicity and residual activity of some of these insecticides allow them to be considered within integrated pest management programs that include T. triozae. PMID:26453717

  5. Pharmacological assessment of the medicinal potential of Acacia mearnsii De Wild.: antimicrobial and toxicity activities.

    PubMed

    Olajuyigbe, Olufunmiso O; Afolayan, Anthony J

    2012-01-01

    Acacia mearnsii De Wild. (Fabaceae) is a medicinal plant used in the treatment of microbial infections in South Africa without scientific validation of its bioactivity and toxicity. The antimicrobial activity of the crude acetone extract was evaluated by both agar diffusion and macrobroth dilution methods while its cytotoxicity effect was assessed with brine shrimp lethality assay. The study showed that both bacterial and fungal isolates were highly inhibited by the crude extract. The MIC values for the gram-positive bacteria (78.1-312.5) μg/mL, gram-negative bacteria (39.1-625) μg/mL and fungal isolates (625-5000) μg/mL differ significantly. The bacteria were more susceptible than the fungal strains tested. The antibiosis determination showed that the extract was more (75%) bactericidal than bacteriostatic (25%) and more fungicidal (66.67%) than fungistatic (33.33%). The cytotoxic activity of the extract was observed between 31.25 μg/mL and 500 μg/mL and the LC(50) value (112.36 μg/mL) indicates that the extract was nontoxic in the brine shrimp lethality assay (LC(50) > 100 μg/mL). These results support the use of A. mearnsii in traditional medicine for treatment of microbial infections. The extract exhibiting significant broad spectrum antimicrobial activity and nontoxic effects has potential to yield active antimicrobial compounds. PMID:22605976

  6. Pharmacological Assessment of the Medicinal Potential of Acacia mearnsii De Wild.: Antimicrobial and Toxicity Activities

    PubMed Central

    Olajuyigbe, Olufunmiso O.; Afolayan, Anthony J.

    2012-01-01

    Acacia mearnsii De Wild. (Fabaceae) is a medicinal plant used in the treatment of microbial infections in South Africa without scientific validation of its bioactivity and toxicity. The antimicrobial activity of the crude acetone extract was evaluated by both agar diffusion and macrobroth dilution methods while its cytotoxicity effect was assessed with brine shrimp lethality assay. The study showed that both bacterial and fungal isolates were highly inhibited by the crude extract. The MIC values for the gram-positive bacteria (78.1–312.5) μg/mL, gram-negative bacteria (39.1–625) μg/mL and fungal isolates (625–5000) μg/mL differ significantly. The bacteria were more susceptible than the fungal strains tested. The antibiosis determination showed that the extract was more (75%) bactericidal than bacteriostatic (25%) and more fungicidal (66.67%) than fungistatic (33.33%). The cytotoxic activity of the extract was observed between 31.25 μg/mL and 500 μg/mL and the LC50 value (112.36 μg/mL) indicates that the extract was nontoxic in the brine shrimp lethality assay (LC50 > 100 μg/mL). These results support the use of A. mearnsii in traditional medicine for treatment of microbial infections. The extract exhibiting significant broad spectrum antimicrobial activity and nontoxic effects has potential to yield active antimicrobial compounds. PMID:22605976

  7. Evaluation of Antioxidant Activity and Acute Toxicity of Clausena excavata Leaves Extract

    PubMed Central

    Albaayit, Shaymaa Fadhel Abbas; Abdullah, Rasedee

    2014-01-01

    Clausena excavata (Lour.), locally known as “Kemantu hitam,” is a common plant in Malaysian folklore medicine. This study evaluated the antioxidant properties of the solvent extracts of C. excavata leaves and determined the acute toxicity of methanolic extract C. excavata (MECE) leaves in Sprague-Dawley rats. Harvested leaves were dried and subjected to solvent extraction using petroleum ether, chloroform, ethyl acetate and methanol in succession. The antioxidant activity of each extract was determined using the ferric-reducing antioxidant power (FRAP) and 2,2-diphenyl-1-picryl dihydrazyl (DPPH) radical scavenging activity. The total phenolic content (TPC) and total flavonoids content (TFC) were estimated by Folin-Ciocalteu and ethanolic aluminium chloride method, respectively. The chloroform extract was found to be highest in flavonoid content, while the methanolic extract showed the highest TPC and antioxidant activity. There was no mortality in rats treated with MECE leaves even at a high dose of 5000 mg/kg body weight. However, the MECE leaves produced mild to moderate pathological changes in the liver and kidneys, shown by mild degenerative changes and leucocyte infiltration. The extract did not affect the haematological parameters or relative weights of the liver or kidneys. Overall, the MECE leaves have potent antioxidant activity and are presumed safe to be used orally as health-promoting product at low to moderate doses. PMID:25610488

  8. Mitochondrial Dysfunction Is Involved in the Toxic Activity of Boric Acid against Saprolegnia

    PubMed Central

    Ali, Shimaa E.; Thoen, Even; Evensen, Øystein; Wiik-Nielsen, Jannicke; Gamil, Amr A. A.; Skaar, Ida

    2014-01-01

    There has been a significant increase in the incidence of Saprolegnia infections over the past decades, especially after the banning of malachite green. Very often these infections are associated with high economic losses in salmonid farms and hatcheries. The use of boric acid to control the disease has been investigated recently both under in vitro and in vivo conditions, however its possible mode of action against fish pathogenic Saprolegnia is not known. In this study, we have explored the transformation in Saprolegnia spores/hyphae after exposure to boric acid (1 g/L) over a period 4–24 h post treatment. Using transmission electron microscopy (TEM), early changes in Saprolegnia spores were detected. Mitochondrial degeneration was the most obvious sign observed following 4 h treatment in about 20% of randomly selected spores. We also investigated the effect of the treatment on nuclear division, mitochondrial activity and function using confocal laser scanning microscopy (CLSM). Fluorescence microscopy was also used to test the effect of treatment on mitochondrial membrane potential and formation of reactive oxygen species. Additionally, the viability and proliferation of treated spores that correlated to mitochondrial enzymatic activity were tested using an MTS assay. All obtained data pointed towards changes in the mitochondrial structure, membrane potential and enzymatic activity following treatment. We have found that boric acid has no effect on the integrity of membranes of Saprolegnia spores at concentrations tested. It is therefore likely that mitochondrial dysfunction is involved in the toxic activity of boric acid against Saprolegnia spp. PMID:25354209

  9. Synthesis and Evaluation of Chloramphenicol Homodimers: Molecular Target, Antimicrobial Activity, and Toxicity against Human Cells

    PubMed Central

    Kostopoulou, Ourania N.; Magoulas, George E.; Papadopoulos, Georgios E.; Mouzaki, Athanasia; Dinos, George P.; Papaioannou, Dionissios; Kalpaxis, Dimitrios L.

    2015-01-01

    As fight against antibiotic resistance must be strengthened, improving old drugs that have fallen in reduced clinical use because of toxic side effects and/or frequently reported resistance, like chloramphenicol (CAM), is of special interest. Chloramphenicol (CAM), a prototypical wide-spectrum antibiotic has been shown to obstruct protein synthesis via binding to the bacterial ribosome. In this study we sought to identify features intensifying the bacteriostatic action of CAM. Accordingly, we synthesized a series of CAM-dimers with various linker lengths and functionalities and compared their efficiency in inhibiting peptide-bond formation in an Escherichia coli cell-free system. Several CAM-dimers exhibited higher activity, when compared to CAM. The most potent of them, compound 5, containing two CAM bases conjugated via a dicarboxyl aromatic linker of six successive carbon-bonds, was found to simultaneously bind both the ribosomal catalytic center and the exit-tunnel, thus revealing a second, kinetically cryptic binding site for CAM. Compared to CAM, compound 5 exhibited comparable antibacterial activity against MRSA or wild-type strains of Staphylococcus aureus, Enterococcus faecium and E. coli, but intriguingly superior activity against some CAM-resistant E. coli and Pseudomonas aeruginosa strains. Furthermore, it was almost twice as active in inhibiting the growth of T-leukemic cells, without affecting the viability of normal human lymphocytes. The observed effects were rationalized by footprinting tests, crosslinking analysis, and MD-simulations. PMID:26267355

  10. Nephroprotective and antioxidant activities of Salacia oblonga on acetaminophen-induced toxicity in rats.

    PubMed

    Palani, S; Raja, S; Kumar, S Nirmal; Kumar, B Senthil

    2011-11-01

    Salacia oblonga, a woody climbing plant belonging to the family Celastaceae, is widely distributed in India and other southeast Asian countries. The genus Salacia have been used particularly for the treatment of diabetes, obesity, gonorrhoea, rheumatism, pruritus and asthma. Acetaminophen (APAP), used as an analgesic drug, produces liver and kidney necrosis in mammals at high doses. The aim of this study was to investigate the nephroprotective and antioxidant activities of the ethanol extract of Salacia oblonga (EESO) at the two dose levels of 250 and 500 mg/kg bw on APAP-induced toxicity in rats. The results showed that APAP significantly increases the levels of serum urea, creatinine, and reduces levels of uric acid concentration. The EESO reduces these by increasing anti-oxidative responses as assessed by biochemical and histopathological parameters. In conclusion, our results suggest that the EESO possesses nephroprotective and antioxidant effects against APAP-induced nephrotoxicity in rats. PMID:21848492

  11. Activity-guided chemo toxic profiling of Cassia occidentalis (CO) seeds: detection of toxic compounds in body fluids of CO-exposed patients and experimental rats.

    PubMed

    Panigrahi, Gati Krushna; Ch, Ratnasekhar; Mudiam, Mohana K R; Vashishtha, Vipin M; Raisuddin, S; Das, Mukul

    2015-06-15

    Our prior studies have shown an association between the deaths of children and consumption of Cassia occidentalis (CO) seeds. However, the chemicals responsible for the CO poisoning are not known. Therefore, the present study was designed to identify the key moieties in CO seeds and their cytotoxicity in rat primary hepatocytes and HepG2 cells. Activity-guided sequential extraction and fractionation of the seeds followed by GC-MS analysis identified the toxic compounds in the CO seeds. These identified compounds were subsequently detected and quantified in blood and urine samples from CO-exposed rats and CO poisoning human study cases. GC-MS analysis of different fractions of methanol extracts of CO seeds revealed the presence of five anthraquinones (AQs), viz. physcion, emodin, rhein, aloe-emodin, and chrysophanol. Interestingly, these AQs were detected in serum and urine samples from the study cases and CO-exposed rats. Cytotoxicity analysis of the above AQs in rat primary hepatocytes and HepG2 cells revealed that rhein is the most toxic moiety, followed by emodin, aloe-emodin, physcion, and chrysophanol. These studies indicate that AQ aglycones are responsible for producing toxicity, which may be associated with symptoms of hepatomyoencephalopathy in CO poisoning cases. PMID:25915165

  12. Efficacy of activated diatomaceous clay in reducing the toxicity of zearalenone in rats and piglets.

    PubMed

    Denli, M; Blandon, J C; Guynot, M E; Salado, S; Pérez, J F

    2015-02-01

    Two experiments were conducted to evaluate the efficacy of an activated diatomaceous clay (ADC) in reducing the toxic effects of zearalenone (ZEA) in the diet of rats and piglets. In the rat experiment, 90 Sprague-Dawley female weanling rats with an initial BW of 45 ± 1.0 g were assigned to 1 of 6 dietary treatments for 28 d in a completely randomized design (CRD) with a 2 × 3 factorial arrangement (0 or 6 mg ZEA/kg feed and 0, 1, and 5 g ADC/kg feed). In the piglet experiment, 64 female piglets ([Large White × Landrace] × Pietrain with an initial BW of 14.9 ± 1.65 kg) were fed 1 of 8 experimental diets for 26 d in a CRD design with a 2 × 4 factorial arrangement (0 or 0.8 mg ZEA/kg feed and 0, 1, 2, and 5 g ADC/kg feed). The ADFI, ADG, and G:F were determined at the end of each experiment. At the conclusion of studies, serum samples were collected and rats and piglets were euthanized to determine visceral organ weights. The diet contaminated with ZEA did not alter the growth of rats and the relative weight of liver and kidneys. However, ZEA increased ( < 0.05) the relative weight of uterus, ovaries, and spleen and decreased ( < 0.05) the serum activities of alkaline phosphatase and alanine aminotransferase compared to the control group. Supplementation of ADC in the rat diets counteracted ( < 0.05) the observed toxic effects of ZEA on the uterus and ovaries weight. The diet contaminated with ZEA (0.8 mg/kg feed) increased ( < 0.05) the weight of the uterus and ovaries in piglets but did not modify the serum biochemical variables or the relative weight of other visceral organs. The addition of 5 g ADC/kg to the contaminated feed reduced the toxic effects of ZEA on uterus and ovary weights to that of the control group. Zearalenone (10.5 μg/kg bile) and α-zearalenol (5.6 μg/kg bile) residues were detected in the bile of piglets fed the ZEA treatment. Supplementation of ADC to diets contaminated with ZEA reduced ( = 0.001) ZEA content in bile compared to the

  13. Chemical composition, toxicity and larvicidal and antifungal activities of Persea americana (avocado) seed extracts.

    PubMed

    Leite, João Jaime Giffoni; Brito, Erika Helena Salles; Cordeiro, Rossana Aguiar; Brilhante, Raimunda Sâmia Nogueira; Sidrim, José Júlio Costa; Bertini, Luciana Medeiros; Morais, Selene Maia de; Rocha, Marcos Fábio Gadelha

    2009-01-01

    The present study had the aim of testing the hexane and methanol extracts of avocado seeds, in order to determine their toxicity towards Artemia salina, evaluate their larvicidal activity towards Aedes aegypti and investigate their in vitro antifungal potential against strains of Candida spp, Cryptococcus neoformans and Malassezia pachydermatis through the microdilution technique. In toxicity tests on Artemia salina, the hexane and methanol extracts from avocado seeds showed LC50 values of 2.37 and 24.13 mg mL-1 respectively. Against Aedes aegypti larvae, the LC50 results obtained were 16.7 mg mL-1 for hexane extract and 8.87 mg mL-1 for methanol extract from avocado seeds. The extracts tested were also active against all the yeast strains tested in vitro, with differing results such that the minimum inhibitory concentration of the hexane extract ranged from 0.625 to 1.25mg L-(1), from 0.312 to 0.625 mg mL-1 and from 0.031 to 0.625 mg mL-1, for the strains of Candida spp, Cryptococcus neoformans and Malassezia pachydermatis, respectively. The minimal inhibitory concentration for the methanol extract ranged from 0.125 to 0.625 mg mL-1, from 0.08 to 0.156 mg mL-1 and from 0.312 to 0.625 mg mL-1, for the strains of Candida spp., Cryptococcus neoformans and Malassezia pachydermatis, respectively. PMID:19448924

  14. Antimicrobial activity and cellular toxicity of nanoparticle-polymyxin B conjugates

    NASA Astrophysics Data System (ADS)

    Park, Soonhyang; Chibli, Hicham; Wong, Jody; Nadeau, Jay L.

    2011-05-01

    We investigate the antimicrobial activity and cytotoxicity to mammalian cells of conjugates of the peptide antibiotic polymyxin B (PMB) to Au nanoparticles and CdTe quantum dots. Au nanoparticles fully covered with PMB are identical in antimicrobial activity to the free drug alone, whereas partially-conjugated Au particles show decreased effectiveness in proportion to the concentration of Au. CdTe-PMB conjugates are more toxic to Escherichia coli than PMB alone, resulting in a flattening of the steep PMB dose-response curve. The effect is most pronounced at low concentrations of PMB, with a greater effect on the concentration required to reduce growth by half (IC50) than on the concentration needed to inhibit all growth (minimum inhibitory concentration, MIC). The Gram positive organism Staphylococcus aureus is resistant to both PMB and CdTe, showing minimal increased sensitivity when the two are conjugated. Measurement of reactive oxygen species (ROS) generation shows a significant reduction in photo-generated hydroxyl and superoxide radicals with CdTe-PMB as compared with bare CdTe. There is a corresponding reduction in toxicity of QD-PMB versus bare CdTe to mammalian cells, with nearly 100% survival in fibroblasts exposed to bactericidal concentrations of QD-PMB. The situation in bacteria is more complex: photoexcitation of the CdTe particles plays a small role in IC50 but has a significant effect on the MIC, suggesting that at least two different mechanisms are responsible for the antimicrobial action seen. These results show that it is possible to create antimicrobial agents using concentrations of CdTe quantum dots that do not harm mammalian cells.

  15. A cationic tetrapyrrole inhibits toxic activities of the cellular prion protein.

    PubMed

    Massignan, Tania; Cimini, Sara; Stincardini, Claudia; Cerovic, Milica; Vanni, Ilaria; Elezgarai, Saioa R; Moreno, Jorge; Stravalaci, Matteo; Negro, Alessandro; Sangiovanni, Valeria; Restelli, Elena; Riccardi, Geraldina; Gobbi, Marco; Castilla, Joaquín; Borsello, Tiziana; Nonno, Romolo; Biasini, Emiliano

    2016-01-01

    Prion diseases are rare neurodegenerative conditions associated with the conformational conversion of the cellular prion protein (PrP(C)) into PrP(Sc), a self-replicating isoform (prion) that accumulates in the central nervous system of affected individuals. The structure of PrP(Sc) is poorly defined, and likely to be heterogeneous, as suggested by the existence of different prion strains. The latter represents a relevant problem for therapy in prion diseases, as some potent anti-prion compounds have shown strain-specificity. Designing therapeutics that target PrP(C) may provide an opportunity to overcome these problems. PrP(C) ligands may theoretically inhibit the replication of multiple prion strains, by acting on the common substrate of any prion replication reaction. Here, we characterized the properties of a cationic tetrapyrrole [Fe(III)-TMPyP], which was previously shown to bind PrP(C), and inhibit the replication of a mouse prion strain. We report that the compound is active against multiple prion strains in vitro and in cells. Interestingly, we also find that Fe(III)-TMPyP inhibits several PrP(C)-related toxic activities, including the channel-forming ability of a PrP mutant, and the PrP(C)-dependent synaptotoxicity of amyloid-β (Aβ) oligomers, which are associated with Alzheimer's Disease. These results demonstrate that molecules binding to PrP(C) may produce a dual effect of blocking prion replication and inhibiting PrP(C)-mediated toxicity. PMID:26976106

  16. Effect of light intensity on the degree of ammonia toxicity on PSII activity of Arthrospira platensis and Chlorella vulgaris.

    PubMed

    Markou, Giorgos; Muylaert, Koenraad

    2016-09-01

    Herein the effect of increasing light intensity on the degree of ammonia toxicity and its impact on the photosynthetic performance of Arthrospira and Chlorella was investigated using Chl fluorescence as a technique to characterize their photosystem II (PSII) activity. The results revealed that the increase of light intensity amplifies the ammonia toxicity on PSII. Chl fluorescence transients shown that at a given free ammonia (FA) concentration (100mg-N/L), the photochemistry potential decreased by increasing light intensity. The inhibition of the PSII was not reversible either by re-incubating the cells under dark or under decreased FA concentration. Moreover, the decrease of photochemical and non-photochemical quenching (NPQ) of fluorescence suggest that ammonia toxicity decreases the open available PSII centers, as well the inability of PSII to transfer the generated electrons beyond QA. The collapse of NPQ suggests that ammonia toxicity inhibits the photoprotection mechanism(s) and hence renders PSII more sensitive to photoinhibition. PMID:27262720

  17. Mechanistic quantitative structure-activity relationship model for the photoinduced toxicity of polycyclic aromatic hydrocarbons. 2: An empirical model for the toxicity of 16 polycyclic aromatic hydrocarbons to the duckweed Lemna gibba L. G-3

    SciTech Connect

    Huang, X.D.; Krylov, S.N.; Ren, L.; McConkey, B.J.; Dixon, D.G.; Greenberg, B.M.

    1997-11-01

    Photoinduced toxicity of polycyclic aromatic hydrocarbons (PAHs) occurs via photosensitization reactions (e.g., generation of singlet-state oxygen) and by photomodification (photooxidation and/or photolysis) of the chemicals to more toxic species. The quantitative structure-activity relationship (QSAR) described in the companion paper predicted, in theory, that photosensitization and photomodification additively contribute to toxicity. To substantiate this QSAR modeling exercise it was necessary to show that toxicity can be described by empirically derived parameters. The toxicity of 16 PAHs to the duckweed Lemna gibba was measured as inhibition of leaf production in simulated solar radiation (a light source with a spectrum similar to that of sunlight). A predictive model for toxicity was generated based on the theoretical model developed in the companion paper. The photophysical descriptors required of each PAH for modeling were efficiency of photon absorbance, relative uptake, quantum yield for triplet-state formation, and the rate of photomodification. The photomodification rates of the PAHs showed a moderate correlation to toxicity, whereas a derived photosensitization factor (PSF; based on absorbance, triplet-state quantum yield, and uptake) for each PAH showed only a weak, complex correlation to toxicity. However, summing the rate of photomodification and the PSF resulted in a strong correlation to toxicity that had predictive value. When the PSF and a derived photomodification factor (PMF; based on the photomodification rate and toxicity of the photomodified PAHs) were summed, an excellent explanatory model of toxicity was produced, substantiating the additive contributions of the two factors.

  18. Methylmercury-induced toxicity is mediated by enhanced intracellular calcium through activation of phosphatidylcholine-specific phospholipase C

    SciTech Connect

    Kang, Mi Sun; Jeong, Ju Yeon; Seo, Ji Heui; Jeon, Hyung Jun; Jung, Kwang Mook; Chin, Mi-Reyoung; Moon, Chang-Kiu; Bonventre, Joseph V.; Jung, Sung Yun; Kim, Dae Kyong . E-mail: proteinlab@hanmail.net

    2006-10-15

    Methylmercury (MeHg) is a ubiquitous environmental toxicant to which humans can be exposed by ingestion of contaminated food. MeHg has been suggested to exert its toxicity through its high reactivity to thiols, generation of arachidonic acid and reactive oxygen species (ROS), and elevation of free intracellular Ca{sup 2+} levels ([Ca{sup 2+}]{sub i}). However, the precise mechanism has not been fully defined. Here we show that phosphatidylcholine-specific phospholipase C (PC-PLC) is a critical pathway for MeHg-induced toxicity in MDCK cells. D609, an inhibitor of PC-PLC, significantly reversed the toxicity in a time- and dose-dependent manner with concomitant inhibition of the diacylglycerol (DAG) generation and the phosphatidylcholine (PC)-breakdown. MeHg activated the group IV cytosolic phospholipase A{sub 2} (cPLA{sub 2}) and acidic form of sphingomyelinase (A-SMase) downstream of PC-PLC, but these enzymes as well as protein kinase C (PKC) were not linked to the toxicity by MeHg. Furthermore, MeHg produced ROS, which did not affect the toxicity. Addition of EGTA to culture media resulted in partial decrease of [Ca{sup 2+}]{sub i} and partially blocked the toxicity. In contrast, when the cells were treated with MeHg in the presence of Ca{sup 2+} in the culture media, D609 completely prevented cell death with parallel decrease in [Ca{sup 2+}]{sub i}. Our results demonstrated that MeHg-induced toxicity was linked to elevation of [Ca{sup 2+}]{sub i} through activation of PC-PLC, but not attributable to the signaling pathways such as cPLA{sub 2}, A-SMase, and PKC, or to the generation of ROS.

  19. Structurally-diverse, PPARγ-activating environmental toxicants induce adipogenesis and suppress osteogenesis in bone marrow mesenchymal stromal cells

    PubMed Central

    Watt, James; Schlezinger, Jennifer J.

    2015-01-01

    Environmental obesogens are a newly recognized category of endocrine disrupting chemicals that have been implicated in contributing to the rising rates of obesity in the United States. While obesity is typically regarded as an increase in visceral fat, adipocyte accumulation in the bone has been linked to increased fracture risk, lower bone density, and osteoporosis. Exposure to environmental toxicants that activate peroxisome proliferator activated receptor γ (PPARγ), a critical regulator of the balance of differentiation between adipogenesis and osteogenesis, may contribute to the increasing prevalence of osteoporosis. However, induction of adipogenesis and suppression of osteogenesis are separable activities of PPARγ, and ligands may selectively alter these activities. It currently is unknown whether suppression of osteogenesis is a common toxic endpoint of environmental PPARγ ligands. Using a primary mouse bone marrow culture model, we tested the hypothesis that environmental toxicants acting as PPARγ agonists divert the differentiation pathway of bone marrow-derived multipotent mesenchymal stromal cells towards adipogenesis and away from osteogenesis. The toxicants tested included the organotins tributyltin and triphenyltin, a ubiquitous phthalate metabolite (mono-(2-ethylhexyl) phthalate, MEHP), and two brominated flame retardants (tetrabromobisphenol-a, TBBPA, and mono-(2-ethylhexyl) tetrabromophthalate, METBP). All of the compounds activated PPARγ1 and 2. All compounds increased adipogenesis (lipid accumulation, Fabp4 expression) and suppressed osteogenesis (alkaline phosphatase activity, Osx expression) in mouse primary bone marrow cultures, but with different potencies and efficacies. Despite structural dissimilarities, there was a strong negative correlation between efficacies to induce adipogenesis and suppress osteogenesis, with the organotins being distinct in their exceptional ability to suppress osteogenesis. As human exposure to a mixture of

  20. Structurally-diverse, PPARγ-activating environmental toxicants induce adipogenesis and suppress osteogenesis in bone marrow mesenchymal stromal cells.

    PubMed

    Watt, James; Schlezinger, Jennifer J

    2015-05-01

    Environmental obesogens are a newly recognized category of endocrine disrupting chemicals that have been implicated in contributing to the rising rates of obesity in the United States. While obesity is typically regarded as an increase in visceral fat, adipocyte accumulation in the bone has been linked to increased fracture risk, lower bone density, and osteoporosis. Exposure to environmental toxicants that activate peroxisome proliferator activated receptor γ (PPARγ), a critical regulator of the balance of differentiation between adipogenesis and osteogenesis, may contribute to the increasing prevalence of osteoporosis. However, induction of adipogenesis and suppression of osteogenesis are separable activities of PPARγ, and ligands may selectively alter these activities. It currently is unknown whether suppression of osteogenesis is a common toxic endpoint of environmental PPARγ ligands. Using a primary mouse bone marrow culture model, we tested the hypothesis that environmental toxicants acting as PPARγ agonists divert the differentiation pathway of bone marrow-derived multipotent mesenchymal stromal cells towards adipogenesis and away from osteogenesis. The toxicants tested included the organotins tributyltin and triphenyltin, a ubiquitous phthalate metabolite (mono-(2-ethylhexyl) phthalate, MEHP), and two brominated flame retardants (tetrabromobisphenol-a, TBBPA, and mono-(2-ethylhexyl) tetrabromophthalate, METBP). All of the compounds activated PPARγ1 and 2. All compounds increased adipogenesis (lipid accumulation, Fabp4 expression) and suppressed osteogenesis (alkaline phosphatase activity, Osx expression) in mouse primary bone marrow cultures, but with different potencies and efficacies. Despite structural dissimilarities, there was a strong negative correlation between efficacies to induce adipogenesis and suppress osteogenesis, with the organotins being distinct in their exceptional ability to suppress osteogenesis. As human exposure to a mixture of

  1. Sensitive detection of chemical agents and toxic industrial chemicals using active open-path FTIRs

    NASA Astrophysics Data System (ADS)

    Walter, William T.

    2004-03-01

    Active open-path FTIR sensors provide more sensitive detection of chemical agents than passive FTIRs, such as the M21 RSCAAL and JSLSCAD, and at the same time identify and quantify toxic industrial chemicals (TIC). Passive FTIRs are bistatic sensors relying on infrared sources of opportunity. Utilization of earth-based sources of opportunity limits the source temperatures available for passive chemical-agent FTIR sensors to 300° K. Active FTIR chemical-agent sensors utilize silicon carbide sources, which can be operated at 1500° K. The higher source temperature provides more than an 80-times increase in the infrared radiant flux emitted per unit area in the 7 to 14 micron spectral fingerprint region. Minimum detection limits are better than 5 μgm/m3 for GA, GB, GD, GF and VX. Active FTIR sensors can (1) assist first responders and emergency response teams in their assessment of and reaction to a terrorist threat, (2) provide information on the identification of the TIC present and their concentrations and (3) contribute to the understanding and prevention of debilitating disorders analogous to the Gulf War Syndrome for military and civilian personnel.

  2. Structure-activity relationship studies on the mosquito toxicity and biting deterrency of callicarpenal derivatives.

    PubMed

    Cantrell, Charles L; Klun, Jerome A; Pridgeon, Julia; Becnel, James; Green, Solomon; Fronczek, Frank R

    2009-04-01

    Callicarpenal (=13,14,15,16-tetranorclerod-3-en-12-al=[(1S,2R,4aR,8aR)-1,2,3,4,4a,7,8,8a-octahydro-1,2,4a,5-tetramethylnaphthalen-1-yl]acetaldehyde; 1) has previously demonstrated significant mosquito bite-deterring activity against Aedes aegypti and Anopheles stephensi in addition to repellent activity against host-seeking nymphs of the blacklegged tick, Ixodes scapularis. In the present study, structural modifications were performed on callicarpenal (1) in an effort to understand the functional groups necessary for maintaining and/or increasing its activity and to possibly lead to more effective insect control agents. All modifications in this study targeted the C(12) aldehyde or the C(3) alkene functionalities or combinations thereof. Mosquito biting deterrency appeared to be influenced most by C(3) alkene modification as evidenced by catalytic hydrogenation that resulted in a compound having significantly less effectiveness than 1 at a test amount of 25 nmol/cm2. Oxidation and/or reduction of the C(12) aldehyde did not diminish mosquito biting deterrency, but, at the same time, none of the modifications were more effective than 1 in deterring mosquito biting. Toxicities of synthesized compounds towards Ae. aegypti ranged from an LD50 value of 2.36 to 40.11 microg per mosquito. Similarly, LD95 values ranged from a low of 5.59 to a high of 104.9 microg. PMID:19353538

  3. A bioinspired peptide scaffold with high antibiotic activity and low in vivo toxicity

    PubMed Central

    Rabanal, Francesc; Grau-Campistany, Ariadna; Vila-Farrés, Xavier; Gonzalez-Linares, Javier; Borràs, Miquel; Vila, Jordi; Manresa, Angeles; Cajal, Yolanda

    2015-01-01

    Bacterial resistance to almost all available antibiotics is an important public health issue. A major goal in antimicrobial drug discovery is the generation of new chemicals capable of killing pathogens with high selectivity, particularly multi-drug-resistant ones. Here we report the design, preparation and activity of new compounds based on a tunable, chemically accessible and upscalable lipopeptide scaffold amenable to suitable hit-to-lead development. Such compounds could become therapeutic candidates and future antibiotics available on the market. The compounds are cyclic, contain two D-amino acids for in vivo stability and their structures are reminiscent of other cyclic disulfide-containing peptides available on the market. The optimized compounds prove to be highly active against clinically relevant Gram-negative and Gram-positive bacteria. In vitro and in vivo tests show the low toxicity of the compounds. Their antimicrobial activity against resistant and multidrug-resistant bacteria is at the membrane level, although other targets may also be involved depending on the bacterial strain. PMID:26024044

  4. Evaluation of the potential cardioprotective activity of some Saudi plants against doxorubicin toxicity.

    PubMed

    Ashour, Osama M; Abdel-Naim, Ashraf B; Abdallah, Hossam M; Nagy, Ayman A; Mohamadin, Ahmed M; Abdel-Sattar, Essam A

    2012-01-01

    Doxorubicin (DOX) is an anthracycline antibiotic widely used as a chemotherapeutic agent in the treatment of several tumours. However, its cardiac toxicity limits its use at maximum therapeutic doses. Most studies implicated increased oxidative stress as the major determinant of DOX cardiotoxicity. The local Saudi flora is very rich in a variety of plants of quite known folkloric or traditional medicinal uses. Tribulus macropterus Boiss., Olea europaea L. subsp. africana (Mill.) P. S. Green, Tamarix aphylla (L.) H. Karst., Cynomorium coccineum L., Cordia myxa L., Calligonum comosum L' Hér, and Withania somnifera (L.) Dunal are Saudi plants known to have antioxidant activities. The aim of the current study was to explore the potential protective effects of methanolic extracts of these seven Saudi plants against DOX-induced cardiotoxicity in rats. Two plants showed promising cardioprotective potential in the order Calligonum comosum > Cordia myxa. The two plant extracts showed potent in vitro radical scavenging and antioxidant properties. They significantly protected against DOX-induced alterations in cardiac oxidative stress markers (GSH and MDA) and cardiac serum markers (CK-MB and LDH activities). Additionally, histopathological examination indicated a protection against DOX-induced cardiotoxicity. In conclusion, C. comosum and C. myxa exerted protective activity against DOX-induced cardiotoxicity, which is, at least partly, due to their antioxidant effect. PMID:22888535

  5. A bioinspired peptide scaffold with high antibiotic activity and low in vivo toxicity.

    PubMed

    Rabanal, Francesc; Grau-Campistany, Ariadna; Vila-Farrés, Xavier; Gonzalez-Linares, Javier; Borràs, Miquel; Vila, Jordi; Manresa, Angeles; Cajal, Yolanda

    2015-01-01

    Bacterial resistance to almost all available antibiotics is an important public health issue. A major goal in antimicrobial drug discovery is the generation of new chemicals capable of killing pathogens with high selectivity, particularly multi-drug-resistant ones. Here we report the design, preparation and activity of new compounds based on a tunable, chemically accessible and upscalable lipopeptide scaffold amenable to suitable hit-to-lead development. Such compounds could become therapeutic candidates and future antibiotics available on the market. The compounds are cyclic, contain two D-amino acids for in vivo stability and their structures are reminiscent of other cyclic disulfide-containing peptides available on the market. The optimized compounds prove to be highly active against clinically relevant Gram-negative and Gram-positive bacteria. In vitro and in vivo tests show the low toxicity of the compounds. Their antimicrobial activity against resistant and multidrug-resistant bacteria is at the membrane level, although other targets may also be involved depending on the bacterial strain. PMID:26024044

  6. Evaluation of Antimalarial Activity and Toxicity of a New Primaquine Prodrug

    PubMed Central

    Davanço, Marcelo Gomes; Aguiar, Anna Caroline Campos; dos Santos, Leandro Alves; Padilha, Elias Carvalho; Campos, Michel Leandro; de Andrade, Cleverton Roberto; da Fonseca, Luiz Marcos; dos Santos, Jean Leandro; Chin, Chung Man; Krettli, Antoniana Ursine; Peccinini, Rosangela Gonçalves

    2014-01-01

    Plasmodium vivax is the most prevalent of the five species causing malaria in humans. The current available treatment for P. vivax malaria is limited and unsatisfactory due to at least two drawbacks: the undesirable side effects of primaquine (PQ) and drug resistance to chloroquine. Phenylalanine-alanine-PQ (Phe-Ala-PQ) is a PQ prodrug with a more favorable pharmacokinetic profile compared to PQ. The toxicity of this prodrug was evaluated in in vitro assays using a human hepatoma cell line (HepG2), a monkey kidney cell line (BGM), and human red blood cells deficient in the enzyme glucose-6-phosphate-dehydrogenase (G6PD). In addition, in vivo toxicity assays were performed with rats that received multiple doses of Phe-Ala-PQ to evaluate biochemical, hematological, and histopathological parameters. The activity was assessed by the inhibition of the sporogonic cycle using a chicken malaria parasite. Phe-Ala-PQ blocked malaria transmission in Aedes mosquitoes. When compared with PQ, it was less cytotoxic to BGM and HepG2 cells and caused less hemolysis of G6PD-deficient red blood cells at similar concentrations. The prodrug caused less alteration in the biochemical parameters than did PQ. Histopathological analysis of the liver and kidney did show differences between the control and Phe-Ala-PQ-treated groups, but they were not statistically significant. Taken together, the results highlight the prodrug as a novel lead compound candidate for the treatment of P. vivax malaria and as a blocker of malaria transmission. PMID:25133630

  7. Toxicity mitigation and solidification of municipal solid waste incinerator fly ash using alkaline activated coal ash.

    PubMed

    Diaz-Loya, E Ivan; Allouche, Erez N; Eklund, Sven; Joshi, Anupam R; Kupwade-Patil, Kunal

    2012-08-01

    Municipal solid waste (MSW) incineration is a common and effective practice to reduce the volume of solid waste in urban areas. However, the byproduct of this process is a fly ash (IFA), which contains large quantities of toxic contaminants. The purpose of this research study was to analyze the chemical, physical and mechanical behaviors resulting from the gradual introduction of IFA to an alkaline activated coal fly ash (CFA) matrix, as a mean of stabilizing the incinerator ash for use in industrial construction applications, where human exposure potential is limited. IFA and CFA were analyzed via X-ray fluorescence (XRF), X-ray diffraction (XRD) and Inductive coupled plasma (ICP) to obtain a full chemical analysis of the samples, its crystallographic characteristics and a detailed count of the eight heavy metals contemplated in US Title 40 of the Code of Federal Regulations (40 CFR). The particle size distribution of IFA and CFA was also recorded. EPA's Toxicity Characteristic Leaching Procedure (TCLP) was followed to monitor the leachability of the contaminants before and after the activation. Also images obtained via Scanning Electron Microscopy (SEM), before and after the activation, are presented. Concrete made from IFA, CFA and IFA-CFA mixes was subjected to a full mechanical characterization; tests include compressive strength, flexural strength, elastic modulus, Poisson's ratio and setting time. The leachable heavy metal contents (except for Se) were below the maximum allowable limits and in many cases even below the reporting limit. The leachable Chromium was reduced from 0.153 down to 0.0045 mg/L, Arsenic from 0.256 down to 0.132 mg/L, Selenium from 1.05 down to 0.29 mg/L, Silver from 0.011 down to .001 mg/L, Barium from 2.06 down to 0.314 mg/L and Mercury from 0.007 down to 0.001 mg/L. Although the leachable Cd exhibited an increase from 0.49 up to 0.805 mg/L and Pd from 0.002 up to 0.029 mg/L, these were well below the maximum limits of 1.00 and 5

  8. Development of an Antioxidant Phytoextract of Lantana grisebachii with Lymphoprotective Activity against In Vitro Arsenic Toxicity

    PubMed Central

    Soria, Elio A.; Quiroga, Patricia L.; Albrecht, Claudia; Ramos Elizagaray, Sabina I.; Cantero, Juan J.; Bongiovanni, Guillermina A.

    2014-01-01

    Phytochemicals have been presumed to possess prophylactic and curative properties in several pathologies, such as arsenic- (As-) induced immunosuppression. Our aim was to discover a lymphoprotective extract from Lantana grisebachii Stuck. (Verbenaceae) (LG). We assessed its bioactivity and chemical composition using cell-based assays. Fractions produced from a hexane extract acutely induced nitrite formation in T-activated cell cultures (P < 0.0001). Water extraction released a fraction lacking nitrite inducing activity in both lymphocyte types. Aqueous LG was found to be safe in proliferated and proliferating cells. The infusion-derived extract presented better antioxidant capacity in proportion to phenolic amount in lymphocytes (infusive LG-1i at 100 μg/mL), which protected them against in vitro As-induced lymphotoxicity (P < 0.0001). This infusive LG phytoextract contained 10.23 ± 0.43 mg/g of phenolics, with 58.46% being flavonoids. Among the phenolics, the only predominant compound was 0.723 mg of chlorogenic acid per gram of dry plant, in addition to 10 unknown minor compounds. A fatty acid profile was assessed. It contained one-third of saturated fatty acids, one-third of ω9, followed by ω6 (~24%) and ω3 (~4%), and scarce ω7. Summing up, L. grisebachii was a source of bioactive and lymphoprotective compounds, which could counteract As-toxicity. This supports its phytomedical use and research in order to reduce As-related dysfunctions. PMID:25002868

  9. Evaluation of Antidiabetic Activity and Associated Toxicity of Artemisia afra Aqueous Extract in Wistar Rats

    PubMed Central

    Sunmonu, Taofik O.; Afolayan, Anthony J.

    2013-01-01

    Artemisia afra Jacq. ex Willd. is a widely used medicinal plant in South Africa for the treatment of diabetes. This study aimed to evaluate the hypoglycemic activity and possible toxicity effect of aqueous leaf extract of the herb administered at different dosages for 15 days in streptozotocin-induced diabetic rats. Administration of the extract at 50, 100, and 200 mg/kg body weight significantly (P < 0.05) increased body weight, decreased blood glucose levels, increased glucose tolerance, and improved imbalance in lipid metabolism in diabetic rats. These are indications of antidiabetic property of A. afra with 200 mg/kg body weight of the extract showing the best hypoglycemic action by comparing favourably well with glibenclamide, a standard hypoglycemic drug. The extract at all dosages tested also restored liver function indices and haematological parameters to normal control levels in the diabetic rats, whereas the kidney function indices were only normalized in the diabetic animals administered with 50 mg/kg body weight of the extract. This investigation clearly showed that in addition to its hypoglycemic activity, A. afra may also protect the liver and blood against impairment due to diabetes. However, some kidney functions may be compromised at high dosages of the extract. PMID:23861717

  10. A novel mithramycin analogue with high antitumor activity and less toxicity generated by combinatorial biosynthesis.

    PubMed

    Núñez, Luz E; Nybo, Stephen E; González-Sabín, Javier; Pérez, María; Menéndez, Nuria; Braña, Alfredo F; Shaaban, Khaled A; He, Min; Morís, Francisco; Salas, José A; Rohr, Jürgen; Méndez, Carmen

    2012-06-28

    Mithramycin is an antitumor compound produced by Streptomyces argillaceus that has been used for the treatment of several types of tumors and hypercalcaemia processes. However, its use in humans has been limited because of its side effects. Using combinatorial biosynthesis approaches, we have generated seven new mithramycin derivatives, which differ from the parental compound in the sugar profile or in both the sugar profile and the 3-side chain. From these studies three novel derivatives were identified, demycarosyl-3D-β-d-digitoxosylmithramycin SK, demycarosylmithramycin SDK, and demycarosyl-3D-β-d-digitoxosylmithramycin SDK, which show high antitumor activity. The first one, which combines two structural features previously found to improve pharmacological behavior, was generated following two different strategies, and it showed less toxicity than mithramycin. Preliminary in vivo evaluation of its antitumor activity through hollow fiber assays, and in subcutaneous colon and melanoma cancers xenografts models, suggests that demycarosyl-3D-β-d-digitoxosylmithramycin SK could be a promising antitumor agent worthy of further investigation. PMID:22578073

  11. Antioxidant enzymes activities of Burkholderia spp. strains-oxidative responses to Ni toxicity.

    PubMed

    Dourado, M N; Franco, M R; Peters, L P; Martins, P F; Souza, L A; Piotto, F A; Azevedo, R A

    2015-12-01

    Increased agriculture production associated with intense application of herbicides, pesticides, and fungicides leads to soil contamination worldwide. Nickel (Ni), due to its high mobility in soils and groundwater, constitutes one of the greatest problems in terms of environmental pollution. Metals, including Ni, in high concentrations are toxic to cells by imposing a condition of oxidative stress due to the induction of reactive oxygen species (ROS), which damage lipids, proteins, and DNA. This study aimed to characterize the Ni antioxidant response of two tolerant Burkholderia strains (one isolated from noncontaminated soil, SNMS32, and the other from contaminated soil, SCMS54), by measuring superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), and glutathione S-transferase (GST) activities. Ni accumulation and bacterial growth in the presence of the metal were also analyzed. The results showed that both strains exhibited different trends of Ni accumulation and distinct antioxidant enzymes responses. The strain from contaminated soil (SCMS54) exhibited a higher Ni biosorption and exhibited an increase in SOD and GST activities after 5 and 12 h of Ni exposure. The analysis of SOD, CAT, and GR by nondenaturing PAGE revealed the appearance of an extra isoenzyme in strain SCMS54 for each enzyme. The results suggest that the strain SCMS54 isolated from contaminated soil present more plasticity with potential to be used in soil and water bioremediation. PMID:26289332

  12. A fluorescence-based hydrolytic enzyme activity assay for quantifying toxic effects of Roundup® to Daphnia magna.

    PubMed

    Ørsted, Michael; Roslev, Peter

    2015-08-01

    Daphnia magna is a widely used model organism for aquatic toxicity testing. In the present study, the authors investigated the hydrolytic enzyme activity of D. magna after exposure to toxicant stress. In vivo enzyme activity was quantified using 15 fluorogenic enzyme probes based on 4-methylumbelliferyl or 7-amino-4-methylcoumarin. Probing D. magna enzyme activity was evaluated using short-term exposure (24-48 h) to the reference chemical K2 Cr2 O7 or the herbicide formulation Roundup®. Toxicant-induced changes in hydrolytic enzyme activity were compared with changes in mobility (International Organization for Standardization standard 6341). The results showed that hydrolytic enzyme activity was quantifiable as a combination of whole body fluorescence of D. magna and the fluorescence of the surrounding water. Exposure of D. magna to lethal and sublethal concentrations of Roundup resulted in loss of whole body enzyme activity and release of cell constituents, including enzymes and DNA. Roundup caused comparable inhibition of mobility and alkaline phosphatase activity with median effective concentration values at 20 °C of 8.7 mg active ingredient (a.i.)/L to 11.7 mg a.i./L. Inhibition of alkaline phosphatase activity by Roundup was lowest at 14 °C and greater at 20 °C and 26 °C. The results suggest that the fluorescence-based hydrolytic enzyme activity assay (FLEA assay) can be used as an index of D. magna stress. Combining enzyme activity with fluorescence measurements may be applied as a simple and quantitative supplement for toxicity testing with D. magna. PMID:25809520

  13. Analgesic activity and acute toxicity study of Semecarpus anacardium stem bark extracts using mice

    PubMed Central

    Lingaraju, G. M.; Hoskeri, H. Joy; Krishna, V.; Babu, P. Suresh

    2011-01-01

    Background: The analgesic activity of petroleum ether, chloroform and methanol extracts of Semecarpus anacardium was investigated by tail flicking and writhing method using acetyl salicylic acid as the standard reference. Materials and Methods: The staircase method was adopted for the determination of the acute toxicity. LD50 of the petroleum ether extract and the chloroform extract was 700 mg/kg; however, the LD50 for the methanol extract was 500 mg/kg. After 1 h of oral administration of the extracts, 0.6% acetic acid was administered intraperitoneally and the analgesic activity was evaluated. Results: The number of writhing observed in the control group was 73.33 writhes. The methanol extract showed a significant analgesic activity, with 28.33 writhes, than the petroleum ether extract and the chloroform extract. But, all the extracts showed proved to be less potent than the standard drug which showed 2.33 writhes. Animals pretreated with saline did not show a signify cant effect on the latent period of tail-flick response. The analgesic effect of the petroleum ether extract was comparatively less evident. The maximum possible analgesia (MPA) increased up to 9.1% which remained elevated above the basal levels throughout the observation period. The MPA calculated for the chloroform extract increased to 14.03%. However, the analgesic effect of the methanol extract was also observed at 0.5 h following oral administration and the effect remained significant throughout the 3 h observation period, and was increased to 20.43%. Conclusion: Consistent analgesic activity of all the three S. anacardium extracts was observed by both the methods. The methanol extract was more potent than the petroleum ether and chloroform extracts but was less effective than the standard drug. This investigation supported the ethnomedicinal claims of S. anacardium. PMID:21731397

  14. Activated Charcoal Does Not Reduce Duration of Phenytoin Toxicity in Hospitalized Patients.

    PubMed

    Cumpston, Kirk; Stromberg, Paul; Wills, Brandon K; Rose, S Rutherfoord

    2016-01-01

    Phenytoin toxicity frequently results in a prolonged inpatient admission. Several publications avow multidose activated charcoal (MDAC) will enhance the elimination of phenytoin. However, these claims are not consistent, and the mechanism of enhanced eliminaiton is unproven. The aim of this investigation is to compare the time to reach a clinical composite end point in phenytoin overdose patients treated with no activated charcoal (NoAC), single-dose activated charcoal (SDAC), and MDAC. This was a retrospective study using electronic poison center data. Patients treated in a health care facility with phenytoin concentrations >20 mg/L were included. Patients were grouped by use of SDAC, MDAC, and NoAC. The primary end points were either time to resolution of symptoms, hospital discharge, or the case was closed by a toxicologist. After applying inclusion and exclusion criteria, 132 cases were included for analysis. There were 88 NoAC, 13 SDAC, and 31 MDAC cases. The groups were similar in symptomatology, age, and chronicity of expsoure. Mean peak phenytoin concentrations (SD) were 42 mg/L (12), 41 mg/L (11), and 42 mg/L (11) for NoAC, SDAC, and MDAC, respectively. Mean time to reach the study end point was 39 hours [95% confidence interval (CI), 31-48], 52 hours (95% CI, 36-68), and 60 hours (95% CI, 45-75) for NoAC, SDAC, and MDAC, respectively. The groups appeared similar with respect to peak phenytoin concentrations and prevalence of signs and symptoms. In this observational series, the use of activated charcoal was associated with increased time to reach the composite end point of clinical improvement. PMID:24621645

  15. Phospholipase B activity and organophosphorus compound toxicity in cultured neural cells

    SciTech Connect

    Read, David J.; Langford, Lynda; Barbour, Helen R.; Forshaw, Philip J.; Glynn, Paul . E-mail: pg8@le.ac.uk

    2007-03-15

    Organophosphorus compounds (OP) such as phenyl saligenin phosphate (PSP) and mipafox (MPX) which cause delayed neuropathy, inhibit neuropathy target esterase (NTE), while OPs such as paraoxon (PXN) react more readily with acetylcholinesterase. In yeast and mammalian cell lines, NTE has been shown to have phospholipase B (PLB) activity which deacylates intracellular phosphatidylcholine to glycerophosphocholine (GroPCho) and can be detected by metabolic labeling with [{sup 14}C]choline. Here we investigated PLB activity in primary cultures of mouse neural cells. In cortical and cerebellar granule neurons and astrocytes, [{sup 14}C]GroPCho labeling was inhibited by PSP and MPX: phenyl dipentylphosphinate (PDPP), a non-neuropathic NTE inhibitor, was more potent, while PXN, was substantially less so. In all three cell types, conversion of [{sup 14}C]phosphatidylcholine to [{sup 14}C]GroPCho over 24 h was relatively small (2.3-14%). Consequently, even with > 80% inhibition of [{sup 14}C]GroPCho production, increased [{sup 14}C]phosphatidylcholine was not detected. At concentrations of 1-10 {mu}M, only PSP was cytotoxic to cortical and cerebellar granule neurons after 24-h exposure. Moreover, dramatic changes in glial cell morphology were induced by PSP, but not PDPP or MPX, with rapid (2-3 h) rounding up of astrocytes and of Schwann cells in cultures of dissociated mouse dorsal root ganglia. We conclude that PLB activity is present in a variety of cultured mouse neural cell types but that acute loss of this activity is not cytotoxic. Conversely, the rapid toxic effects of PSP in vitro suggest that a serine hydrolase distinct from NTE is required continuously by neurons and glia.

  16. Toxicity of essential oil of Satureja khuzistanica: in vitro cytotoxicity and anti-microbial activity.

    PubMed

    Yousefzadi, Morteza; Riahi-Madvar, Ali; Hadian, Javad; Rezaee, Fatemeh; Rafiee, Roya; Biniaz, Mehdi

    2014-01-01

    In nature, essential oils play an important role in the protection of the plants by exerting anti-bacterial, -viral, -fungal, -oxidative, -genotoxic, and free radical scavenging properties, as well as in some cases acting as insecticides. Several Satureja species are used in traditional medicine due to recognized therapeutic properties, namely anti-microbial and cytotoxic activities. The purpose of the present work was to determine the biologic activity of the essential oil of S. khuzistanica Jamzad (Lamiaceae) against four human cancer cell lines, as well as its inhibitory effects against a wide array (i.e. n = 11) of pathogenic bacteria and fungi. The essential oil was isolated by hydro-distillation and analyzed by GC-FID and GC-MS. Carvacrol (92.87%) and limonene (1.2%) were found to be the main components of the isolated oil. Anti-microbial activity of the essential oil was assessed using a disc diffusion method; an MTT cytotoxicity assay was employed to test effects of the oil on each cancer cell line. The oil exhibited considerable anti-microbial activity against the majority of the tested bacteria and fungi. The test oil also significantly reduced cell viability of Vero, SW480, MCF7, and JET 3 cells in a dose-dependent manner, with the IC50 values calculated for each cell type being, respectively, 31.2, 62.5, 125, and 125 μg/ml. Based on the findings, it is concluded that the essential oil of S. khuzistanica and its major constituents have a potential for further use in anti-bacterial and anti-cancer applications, pending far more extensive testing of toxicities in normal (i.e. primary) cells. PMID:23662744

  17. Activated microglia are less vulnerable to hemin toxicity due to nitric oxide-dependent inhibition of JNK and p38 MAPK activation.

    PubMed

    Cai, Ying; Cho, Geum-Sil; Ju, Chung; Wang, Si-Ling; Ryu, Jong Hoon; Shin, Chan Young; Kim, Hee-Sun; Nam, Kung-Woo; Jalin, Angela M A Anthony; Sun, Woong; Choi, In-Young; Kim, Won-Ki

    2011-08-01

    In intracerebral hemorrhage, microglia become rapidly activated and remove the deposited blood and cellular debris. To survive in a harmful hemorrhagic or posthemorrhagic condition, activated microglia must be equipped with appropriate self-defensive mechanism(s) to resist the toxicity of hemin, a component released from damaged RBCs. In the current study, we found that activation of microglia by pretreatment with LPS markedly reduced their vulnerability to hemin toxicity in vitro. Similarly, intracorpus callosum microinjection of LPS prior to hemin treatment reduced the brain tissue damage caused by hemin and increased microglial density in the penumbra in rats. LPS induced the expressions of inducible NO synthase (iNOS) and heme oxygenase (HO)-1, the rate-limiting enzyme in heme degradation in microglia. The preventive effect by LPS was significantly diminished by an iNOS inhibitor, L-N(6)-(1-iminoethyl)lysine, whereas it was mimicked by a NO donor, diethylamine-NONOate, both suggesting the crucial role of NO in the modulation of hemin-induced toxicity in activated microglia. We further found that NO reduced hemin toxicity via inhibition of hemin-induced activation of JNK and p38 MAPK pathways in microglia. Whereas HO-1 expression in LPS-stimulated microglia was markedly blocked by L-N(6)-(1-iminoethyl)lysine, the HO-1 inhibitor, tin protoporphyrin, increased iNOS expression and decreased the susceptibility of LPS-activated microglia to hemin toxicity. The data indicate that the mutual interaction between NO and HO-1 plays a critical role in modulating the adaptive response of activated microglia to hemin toxicity. Better understanding of the survival mechanism of activated microglia may provide a therapeutic strategy to attenuate the devastating intracerebral hemorrhagic injury. PMID:21709153

  18. Mixture toxicity of the antiviral drug Tamiflu((R)) (oseltamivir ethylester) and its active metabolite oseltamivir acid.

    PubMed

    Escher, Beate I; Bramaz, Nadine; Lienert, Judit; Neuwoehner, Judith; Straub, Jürg Oliver

    2010-02-18

    Tamiflu (oseltamivir ethylester) is an antiviral agent for the treatment of influenza A and B. The pro-drug Tamiflu is converted in the human body to the pharmacologically active metabolite, oseltamivir acid, with a yield of 75%. Oseltamivir acid is indirectly photodegradable and slowly biodegradable in sewage works and sediment/water systems. A previous environmental risk assessment has concluded that there is no bioaccumulation potential of either of the compounds. However, little was known about the ecotoxicity of the metabolite. Ester hydrolysis typically reduces the hydrophobicity and thus the toxicity of a compound. In this case, a zwitterionic, but overall neutral species is formed from the charged parent compound. If the speciation and predicted partitioning into biological membranes is considered, the metabolite may have a relevant contribution to the overall toxicity. These theoretical considerations triggered a study to investigate the toxicity of oseltamivir acid (OA), alone and in binary mixtures with its parent compound oseltamivir ethylester (OE). OE and OA were found to be baseline toxicants in the bioluminescence inhibition test with Vibrio fischeri. Their mixture effect lay between predictions for concentration addition and independent action for the mixture ratio excreted in urine and nine additional mixture ratios of OE and OA. In contrast, OE was an order of magnitude more toxic than OA towards algae, with a more pronounced effect when the direct inhibition of photosystem II was used as toxicity endpoint opposed to the 24h growth rate endpoint. The binary mixtures in this assay yielded experimental mixture effects that agreed with predictions for independent action. This is consistent with the finding that OE exhibits slightly enhanced toxicity, while OA acts as baseline toxicant. Therefore, with respect to mixture classification, the two compounds can be considered as acting according to different modes of toxic action, although there are

  19. Acetylcholinesterase inhibition, antioxidant activity and toxicity of Peumus boldus water extracts on HeLa and Caco-2 cell lines.

    PubMed

    Falé, P L; Amaral, F; Amorim Madeira, P J; Sousa Silva, M; Florêncio, M H; Frazão, F N; Serralheiro, M L M

    2012-08-01

    This work aimed to study the inhibition on acetylcholinesterase activity (AChE), the antioxidant activity and the toxicity towards Caco-2 and HeLa cells of aqueous extracts of Peumus Boldus. An IC(50) value of 0.93 mg/mL, for AChE inhibition, and EC(50) of 18.7 μg/mL, for the antioxidant activity, was determined. This activity can be attributed to glycosylated flavonoid derivatives detected, which were the main compounds, although boldine and other aporphine derivatives were also present. No changes in the chemical composition or the biochemical activities were found after gastrointestinal digestion. Toxicity of P. boldus decoction gave an IC(50) value 0.66 mg/mL for HeLa cells, which caused significant changes in the cell proteome profile. PMID:22617353

  20. Influence of alkylphenols and trace elements in toxic, genotoxic, and endocrine disruption activity of wastewater treatment plants.

    PubMed

    Isidori, Marina; Lavorgna, Margherita; Palumbo, Maria; Piccioli, Veronica; Parrella, Alfredo

    2007-08-01

    Toxicity and endocrine interference of influent and effluent waters from domestic and industrial wastewater treatment plants were determined. In addition, chemical analyses were performed to detect the presence of 17beta-estradiol, 17alpha-ethinyl estradiol, nonylphenol, 4-octylphenol, and p-t-octylphenol as well as lead, copper, and cadmium in these matrices. The results showed that despite low acute toxic potential, most of the samples tested showed both genotoxicity and endocrine interference. Furthermore, to establish whether the observed effects were caused by the alkylphenols and the heavy metals detected, toxic, genotoxic, and endocrine interference tests also were performed on pure chemicals. The acute toxicity was measured on the crustacean Daphnia magna. The estrogenic activity was determined by using the yeast estrogen screen with Saccharomyces cerevisiae RMY326, whereas the SOS Chromotest and Ames test detected the genotoxicity on Escherichia coli PQ37 and Salmonella typhimurium TA98 and TA100, respectively. The results showed that the toxicity found in the matrices did not match the values found for pure chemicals, but a clear correlation was found between alkylphenols and genotoxicity. Both heavy metals and alkylphenols took part in the endocrine interference activity. PMID:17702343

  1. In vitro anti oxidant activity and acute oral toxicity of Terminalia paniculata bark ethanolic extract on Sprague Dawley rats

    PubMed Central

    Mopuri, Ramgopal; Meriga, Balaji

    2014-01-01

    Objective To ensure the safety and evaluate the anti oxidant activity of Terminalia paniculata (T. paniculata) ethanolic extract in Sprague Dawley rats. Methods The solvent extracts (hexane, ethyl acetate and ethanol) of T. paniculata were subjected to phytochemical analysis and their DPPH radical scavenging activity was assayed. The oral acute toxicity was evaluated using ethanolic extract of T. paniculata. Results Ethyl acetate and ethanolic extracts showed more phytochemicals, whereas highest DPPH scavenging activity was found in ethanolic extract. In an acute toxicity study, T. paniculata ethanolic extract was orally administered (1 000 mg/kg body weight) to rats and observed for 72 h for any toxic symptoms and the dose was continued up to 14 d. On the 15th day rats were sacrificed and blood samples were collected from control and test animals and analyzed for some biochemical parameters. We did not observe any behavioral changes in test groups in comparison with their controls. Also, there were no significant alterations in biochemical, hematological (hemoglobin content and blood cells count) and liver function parameters such as serum glutamate pyruvate transaminase, serum glutamate oxaloacetate transaminase, alkaline phosphatase, total proteins, albumin and bilirubin levels between T. paniculata ethanolic extract treated and normal control groups. Conclusions Together our results demonstrated that T. paniculata ethanolic possessed potent antioxidant activity and it was safer and non toxic to rats even at higher doses and therefore could be well considered for further investigation for its medicinal and therapeutic efficacy. PMID:25182554

  2. QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIP (QSAR) MODELS TO PREDICT CHEMICAL TOXICITY FOR VARIOUS HEALTH ENDPOINTS

    EPA Science Inventory

    Although ranking schemes based on exposure and toxicity have been developed to aid in the prioritization of research funds for identifying chemicals of regulatory concern, there are significant gaps in the availability of experimental toxicity data for most health endpoints. Pred...

  3. A mitogen-activated protein kinase kinase inhibitor induced compound skin toxicity with oedema in metastatic malignant melanoma.

    PubMed

    Thomas, C L; Mortimer, P S; Larkin, J M; Basu, T N; Gore, M E; Fearfield, L

    2016-04-01

    We report three cases of skin toxicity associated with oral mitogen-activated protein kinase kinase (MEK) inhibitor treatment for metastatic malignant melanoma (MM). All three patients developed oedema, and a single patient experienced eyelash trichomegaly. This is the first known report of eyelash trichomegaly secondary to MEK inhibitor use. We also discuss possible mechanisms for MEK inhibitor-associated oedema development. This series supports the role of the dermatologist in the screening and management of patients in the rapidly developing oncology setting, as new targeted agents can give rise to marked skin toxicity. PMID:26411345

  4. In vitro antibacterial activity and acute toxicity studies of aqueous-methanol extract of Sida rhombifolia Linn. (Malvaceae)

    PubMed Central

    2010-01-01

    Background Many bacteria among the Enterobacteria family are involved in infectious diseases and diarrhoea. Most of these bacteria become resistant to the most commonly used synthetic drugs in Cameroon. Natural substances seem to be an alternative to this problem. Thus the aim of this research was to investigate the in vitro antibacterial activity of the methanol and aqueous-methanol extracts of Sida rhombifolia Linn (Malvaceae) against seven pathogenic bacteria involved in diarrhoea. Acute toxicity of the most active extract was determined and major bioactive components were screened. Methods The agar disc diffusion and the agar dilution method were used for the determination of inhibition diameters and the Minimum Inhibitory Concentration (MICs) respectively. The acute toxicity study was performed according WHO protocol. Results The aqueous-methanol extract (1v:4v) was the most active with diameters of inhibition zones ranging from 8.7 - 23.6 mm, however at 200 μg/dic this activity was relatively weak compared to gentamycin. The MICs of the aqueous-methanol extract (1v:4v) varied from 49.40 to 78.30 μg/ml. Salmonella dysenteriae was the most sensitive (49.40 μg/ml). For the acute toxicity study, no deaths of rats were recorded. However, significant increase of some biochemical parameters such as aspartate amino-transferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and creatinine (CRT) were found. The phytochemical analysis of the aqueous methanol extract indicated the presence of tannins, polyphenols, alkaloids, glycosides, flavonoids and saponins Conclusion The results showed that the aqueous-methanol extract of S. rhombifolia exhibited moderate antibacterial activity. Some toxic effects were found when rats received more than 8 g/kg bw of extract. Antibacterial; Enterobacteria; Acute toxicity; Phytochemical analysis PMID:20663208

  5. Acute toxicity estimation by calculation--Tubifex assay and quantitative structure-activity relationships.

    PubMed

    Tichý, Milon; Rucki, Marian; Hanzlíková, Iveta; Roth, Zdenek

    2008-11-01

    A quantitative structure-activity relationship (QSAR) model dependent on log P(n - octanol/water), or log P(OW), was developed with acute toxicity index EC50, the median effective concentration measured as inhibition of movement of the oligochaeta Tubifex tubifex with 3 min exposure, EC50(Tt) (mol/L): log EC50(Tt) = -0.809 (+/-0.035) log P(OW) - 0.495 (+/-0.060), n=82, r=0.931, r2=0.867, residual standard deviation of the estimate 0.315. A learning series for the QSAR model with the oligochaete contained alkanols, alkenols, and alkynols; saturated and unsaturated aldehydes; aniline and chlorinated anilines; phenol and chlorinated phenols; and esters. Three cross-validation procedures proved the robustness and stability of QSAR models with respect to the chemical structure of compounds tested within a series of compounds used in the learning series. Predictive ability was described by q2 .801 (cross-validated r2; predicted variation estimated with cross-validation) in LSO (leave-a structurally series-out) cross-validation. PMID:18522479

  6. Insect-gene-activity detection system for chemical and biological warfare agents and toxic industrial chemicals

    NASA Astrophysics Data System (ADS)

    Mackie, Ryan S.; Schilling, Amanda S.; Lopez, Arturo M.; Rayms-Keller, Alfredo

    2002-02-01

    Detection of multiple chemical and biological weapons (CBW) agents and/or complex mixtures of toxic industrial chemicals (TIC) is imperative for both the commercial and military sectors. In a military scenario, a multi-CBW attack would create confusion, thereby delaying decontamination and therapeutic efforts. In the commercial sector, polluted sites invariably contain a mixture of TIC. Novel detection systems capable of detecting CBW and TIC are sorely needed. While it may be impossible to build a detector capable of discriminating all the possible combinations of CBW, a detection system capable of statistically predicting the most likely composition of a given mixture is within the reach of current emerging technologies. Aquatic insect-gene activity may prove to be a sensitive, discriminating, and elegant paradigm for the detection of CBW and TIC. We propose to systematically establish the expression patterns of selected protein markers in insects exposed to specific mixtures of chemical and biological warfare agents to generate a library of biosignatures of exposure. The predicting capabilities of an operational library of biosignatures of exposures will allow the detection of emerging novel or genetically engineered agents, as well as complex mixtures of chemical and biological weapons agents. CBW and TIC are discussed in the context of war, terrorism, and pollution.

  7. Sulforaphane protects Microcystin-LR-induced toxicity through activation of the Nrf2-mediated defensive response

    SciTech Connect

    Gan Nanqin; Mi Lixin; Sun Xiaoyun; Dai Guofei; Chung Funglung; Song Lirong

    2010-09-01

    Microcystins (MCs), a cyclic heptapeptide hepatotoxins, are mainly produced by the bloom-forming cyanobacerium Microcystis, which has become an environmental hazard worldwide. Long term consumption of MC-contaminated water may induce liver damage, liver cancer, and even human death. Therefore, in addition to removal of MCs in drinking water, novel strategies that prevent health damages are urgently needed. Sulforaphane (SFN), a natural-occurring isothiocyanate from cruciferous vegetables, has been reported to reduce and eliminate toxicities from xenobiotics and carcinogens. The purpose of the present study was to provide mechanistic insights into the SFN-induced antioxidative defense system against MC-LR-induced cytotoxicity. We performed cell viability assays, including MTS assay, colony formation assay and apoptotic cell sorting, to study MC-LR-induced cellular damage and the protective effects by SFN. The results showed that SFN protected MC-LR-induced damages at a nontoxic and physiological relevant dose in HepG2, BRL-3A and NIH 3 T3 cells. The protection was Nrf2-mediated as evident by transactivation of Nrf2 and activation of its downstream genes, including NQO1 and HO-1, and elevated intracellular GSH level. Results of our studies indicate that pretreatment of cells with 10 {mu}M SFN for 12 h significantly protected cells from MC-LR-induced damage. SFN-induced protective response was mediated through Nrf2 pathway.

  8. The activated sludge metabolic characteristics changing sole carbon source from readily biodegradable acetate to toxic phenol.

    PubMed

    Wu, Changyong; Zhou, Yuexi; Song, Jiamei

    2016-01-01

    A sequencing batch reactor was used to investigate the effect of carbon sources on the metabolism of activated sludge. Acetate and phenol, with the chemical oxygen demand (COD) of 330-350 mg L(-1), was used as the carbon source in Periods I and II, respectively. Acetate decreased in the initial 120 min with the intracellular storage materials (XSTO), extracellular polymeric substances (EPS), and the soluble microbial products (SMP) accumulating to 131.0 mg L(-1), 347.5 mg L(-1), and 35.5 mg L(-1), respectively. Then, XSTO and EPS decreased to 124.5 mg L(-1) and 340.0 mg L(-1), respectively, in the following 120 min. When acetate was replaced by phenol, it could not be used at the beginning due to its toxicity. The XSTO decreased from 142 mg L(-1) to 54.6 mg L(-1) during the aeration period. The EPS had a significant increase, with the highest value of 618.1 mg L(-1), which then decreased to 245.6 mg L(-1) at 240 min. The phenol was gradually degraded with the acclimation and it can be fully degraded 18 d later. Meanwhile, the usage ratio of the internal carbon source decreased. The effluent SMP in Period II was 1.7 times that in Period I. PMID:27191552

  9. Quantitative structure-activity relationships for the toxicity of nitrobenzenes to Tetrahymena thermophila.

    PubMed

    Xu, Jing-Bo; Jing, Ti-Song; Pauli, W; Berger, S

    2002-01-01

    In this study IGC50 (50% inhibitory growth concentration) values of 26 nitrobenzenes were determined for population growth endpoint of Tetrahymena thermophila. The toxicity order of the observed compounds has been found as follows: dinitro compounds > mono-nitro compounds; dichloronitrobenzenes > monochloronitrobenzenes; and meta-substituted nitrobenzenes > ortho-/para-substituted nitrobenzenes (NT, NPh, NAnis) except for the dinitrobenzenes and nitroanilines (DNB, NAn). Quantitative structure activity relationships (QSARs) were developed using log of the inverse of the IGC50 (logIGC50(-1)) in mole liter as the dependent variable and six molecular descriptors--logP, 1X(V), I, K alpha, sigma sigma- and E(LUMO) as the independent variables. Through multiplicate regression analysis, one best equation was obtained: log IGC50(-1) = 2.93 + 0.830sigma sigma- + 0.350I, n = 26, r = 0.923, r2 = 0.852, s = 0.265, f = 66.4 The equation was used to estimate IGC50 for seven analogues. PMID:12046656

  10. [The effect of altan on the functional activity of the liver mitochondria and microsomes from rats with toxic hepatitis].

    PubMed

    Gordienko, A D; Iakovleva, L V

    1999-01-01

    In in vitro experiments althan had no effect on the respiration of intact mitochondria in state 4 according to Chance and produced a high antioxidant effect in fermentative and ascorbate-dependent lipid peroxidation in intact microsomes isolated from the rat liver. In ethanol-induced toxic hepatitis althan restored the functional activity of mitochondria to the level of that in intact animals and increased microsome hydroxylase activity in CCl4-hepatitis. PMID:10513340

  11. The toxic effects of diethyl phthalate on the activity of glutamine synthetase in greater duckweed (Spirodela polyrhiza L.).

    PubMed

    Cheng, Tai-Sheng

    2012-11-15

    The toxic effects of diethyl phthalate (DEP), a potent allelochemical, on the enzyme activity and polypeptide accumulation of glutamine synthetase (GS) in greater duckweed were investigated. In our previous studies, DEP induced oxidative responses at concentrations from 0.5 to 2 mM in greater duckweed and the antioxidant enzymes played important roles in the defense strategy against DEP stress. In this study, DAB-H(2)O(2) and NBT stain for superoxide radicals (O(2)(·-)), lipid peroxidation, HSP70, and ammonia accumulation in DEP-treated duckweed tissues revealed adverse effect of DEP in plant growth. Biochemical analysis and physiological methods were combined to investigate GS activity and polypeptide accumulation under DEP-induced stress. The results showed that GS activity was reduced with the increasing concentration of DEP, indicative of enhanced toxic effect. Immunoblot analysis with chloroplast soluble fractions indicated that the chloroplastic GS (GS2) polypeptide from greater duckweed was degraded under DEP stress conditions. The response of GS2 to the DEP stress may be modulated by means of redox change in plant tissues, chloroplasts, and chloroplast lysates. The results suggest that DEP is toxic to the greater duckweed by inhibition of the GS isoenzymes in nitrogen assimilation and the GS2 plays important roles in the adaptation strategy against DEP toxicity. PMID:22975440

  12. Microcystin-LR induced developmental toxicity and apoptosis in zebrafish (Danio rerio) larvae by activation of ER stress response.

    PubMed

    Qi, Mei; Dang, Yao; Xu, Qinglong; Yu, Liqin; Liu, Chunsheng; Yuan, Yongchao; Wang, Jianghua

    2016-08-01

    Recent studies have demonstrated that cyanobacteria-derived Microcystin-LR (MC-LR) can cause developmental toxicity and trigger apoptosis in zebrafish (Danio rerio) larvae, but the underlying mechanisms remain largely unknown. In this study, we tested the hypothesis that the mechanism by which MC-LR induces developmental toxicity is through activation of endoplasmic reticulum (ER) stress. MC-LR (4.0 μM) exposure through submersion caused serious developmental toxicity, such as malformation, growth delay and decreased heart rates in zebrafish larvae, which could be inhibited by ER stress blocker, tauroursodeoxycholic acid (TUDCA, 20 μM). Meanwhile, acridine orange (AO) staining showed TUDCA could rescue cell apoptosis in heart area in zebrafish larvae resulted by MC-LR exposure. Real-time polymerase chain reaction (real-time PCR) analysis demonstrated that MC-LR induced activation of ER stress which consequently triggered apoptosis in zebrafish larvae. Protein expression examined by western blot indicated that MC-LR could activate MAPK8/Bcl-2/Bax pathway and caspase-dependent apoptotic pathway in zebrafish larva and the effects were mitigated by inhibition of ER stress. Taken together, the results observed in this study suggested that ER stress plays a critical role in developmental toxicity and apoptosis in zebrafish embryos exposed to MC-LR. PMID:27219292

  13. Toxicity of granular activated carbon treated coal gasification water as determined by the Microtox test and Escherichia coli.

    PubMed

    Makino, Y; Adams, J C; McTernan, W F

    1986-01-01

    The Microtox assay and various parameters (growth, ATP concentration and electrochemical detection) of Escherichia coli were used to assess the toxicity of various levels of granular activated carbon treated coal gasification process water. The generation time of E. coli was statistically significantly slower at the level of 50 percent treatment than any other level of treatment. No differences were seen for ATP concentration per cell or in the electrochemical detection methods for any level treatment. There was a very high correlation between total organic carbon removal by GAC treatment and reduction in toxicity as measured by the Microtox system. However, even the treated water which had 91 percent of the TOC removed was still highly toxic. PMID:3512964

  14. Rate of biodegradiation of toxic organic compounds while in contact with organics which are actively composting. Final report

    SciTech Connect

    Not Available

    1982-03-01

    Results are presented of a study to biodegrade toxic organic wastes and to determine the degree of breakdown of compounds while in contact with high-rate composting. An artificial compost mixture consisting of shredded newspaper, manure, wastewater treatment plant sludge, sawdust, peat moss, soil, powdered milk, and fertilizer was prepared. Toxic organic chemicals were mixed with this actively composting mixture to obtain a concentration of about 500 mg/kg. Samples were analyzed after seven days of composting and again after 30 days. Thirty-two of the 59 chemicals tested were found to be moderately to highly susceptible to biodegradation. The potential for success is shown to be very high for using high-rate composting to degrade organic wastes. The possibility of accelerating the decomposition of toxic wastes in soils is suggested.

  15. In vivo toxicity, pharmacokinetics, and anticancer activity of Genistein linked to recombinant human epidermal growth factor.

    PubMed

    Uckun, F M; Narla, R K; Zeren, T; Yanishevski, Y; Myers, D E; Waurzyniak, B; Ek, O; Schneider, E; Messinger, Y; Chelstrom, L M; Gunther, R; Evans, W

    1998-05-01

    Epidermal growth factor receptor (EGFR)-associated protein tyrosine kinase (PTK) complexes have vital anti-apoptotic functions in human breast cancer cells. We have shown previously that targeting the naturally occurring PTK inhibitor genistein to the EGFR-associated PTK complexes using the EGF-Genistein (Gen) conjugate triggers rapid apoptotic cell death in human breast cancer cells and abrogates their in vitro clonogenic growth. In the present study, we examined the in vivo toxicity profile, pharmacokinetics, and anticancer activity of EGF-Gen. No toxicities were observed in mice treated with EGF-Gen at dose levels as high as 40 mg/kg administered i.p. as a single dose or 140 mg/kg administered i.p. over 28 consecutive days. EGF-Gen significantly improved tumor-free survival in a severe combined immune deficiency (SCID) mouse xenograft model of human breast cancer, when it was administered 24 h after inoculation of tumor cells. At 100 microg/kg/day x 10 days (1 mg/kg total dose), which is >100-fold less than the highest tested and nontoxic cumulative dose (ie., 140 mg/kg) in mice, EGF-Gen was more effective than cyclophosphamide (50 mg/kg/day x 2 days), Adriamycin (2.5 mg/kg x 1 day), or methotrexate (0.5 mg/kg x 1 day), the most widely used standard chemotherapeutic drugs for breast cancer, and resulted in 60% long-term tumor-free survival. Furthermore, treating SCID mice with established s.c. human breast cancer xenografts of 0.5-cm diameter with EGF-Gen at this dose level resulted in disappearance of the tumors in two of five mice and >50% shrinkage in three of five mice within 10 days, whereas all of the control tumors in five PBS-treated mice as well as five mice treated with unconjugated Gen (1 mg/kg/day x 10 days) showed >200% increase in diameter during the same observation period. EGF-Gen treatment reduced the growth rate of breast cancer xenografts of 1.0-cm diameter, but unlike with tumors of 0.5-cm diameter, it failed to cause shrinkage or

  16. Ecotoxicity quantitative structure-activity relationships for alcohol ethoxylate mixtures based on substance-specific toxicity predictions.

    PubMed

    Boeije, G M; Cano, M L; Marshall, S J; Belanger, S E; Van Compernolle, R; Dorn, P B; Gümbel, H; Toy, R; Wind, T

    2006-05-01

    Traditionally, ecotoxicity quantitative structure-activity relationships (QSARs) for alcohol ethoxylate (AE) surfactants have been developed by assigning the measured ecotoxicity for commercial products to the average structures (alkyl chain length and ethoxylate chain length) of these materials. Acute Daphnia magna toxicity tests for binary mixtures indicate that mixtures are more toxic than the individual AE substances corresponding with their average structures (due to the nonlinear relation of toxicity with structure). Consequently, the ecotoxicity value (expressed as effects concentration) attributed to the average structures that are used to develop the existing QSARs is expected to be too low. A new QSAR technique for complex substances, which interprets the mixture toxicity with regard to the "ethoxymers" distribution (i.e., the individual AE components) rather than the average structure, was developed. This new technique was then applied to develop new AE ecotoxicity QSARs for invertebrates, fish, and mesocosms. Despite the higher complexity, the fit and accuracy of the new QSARs are at least as good as those for the existing QSARs based on the same data set. As expected from typical ethoxymer distributions of commercial AEs, the new QSAR generally predicts less toxicity than the QSARs based on average structure. PMID:16256196

  17. Chemically Diverse Group I p21-Activated Kinase (PAK) Inhibitors Impart Acute Cardiovascular Toxicity with a Narrow Therapeutic Window.

    PubMed

    Rudolph, Joachim; Murray, Lesley J; Ndubaku, Chudi O; O'Brien, Thomas; Blackwood, Elizabeth; Wang, Weiru; Aliagas, Ignacio; Gazzard, Lewis; Crawford, James J; Drobnick, Joy; Lee, Wendy; Zhao, Xianrui; Hoeflich, Klaus P; Favor, David A; Dong, Ping; Zhang, Haiming; Heise, Christopher E; Oh, Angela; Ong, Christy C; La, Hank; Chakravarty, Paroma; Chan, Connie; Jakubiak, Diana; Epler, Jennifer; Ramaswamy, Sreemathy; Vega, Roxanne; Cain, Gary; Diaz, Dolores; Zhong, Yu

    2016-06-01

    p21-activated kinase 1 (PAK1) has an important role in transducing signals in several oncogenic pathways. The concept of inhibiting this kinase has garnered significant interest over the past decade, particularly for targeting cancers associated with PAK1 amplification. Animal studies with the selective group I PAK (pan-PAK1, 2, 3) inhibitor G-5555 from the pyrido[2,3-d]pyrimidin-7-one class uncovered acute toxicity with a narrow therapeutic window. To attempt mitigating the toxicity, we introduced significant structural changes, culminating in the discovery of the potent pyridone side chain analogue G-9791. Mouse tolerability studies with this compound, other members of this series, and compounds from two structurally distinct classes revealed persistent toxicity and a correlation of minimum toxic concentrations and PAK1/2 mediated cellular potencies. Broad screening of selected PAK inhibitors revealed PAK1, 2, and 3 as the only overlapping targets. Our data suggest acute cardiovascular toxicity resulting from the inhibition of PAK2, which may be enhanced by PAK1 inhibition, and cautions against continued pursuit of pan-group I PAK inhibitors in drug discovery. PMID:27167326

  18. Pharmacokinetics and dose-range finding toxicity of a novel anti-HIV active integrase inhibitor.

    PubMed

    Nair, Vasu; Okello, Maurice; Mishra, Sanjay; Mirsalis, Jon; O'Loughlin, Kathleen; Zhong, Yu

    2014-08-01

    Integration of viral DNA into human chromosomal DNA catalyzed by HIV integrase represents the "point of no return" in HIV infection. For this reason, HIV integrase is considered a crucial target in the development of new anti-HIV therapeutic agents. We have discovered a novel HIV integrase inhibitor 1, that exhibits potent antiviral activity and a favorable metabolism profile. This paper reports on the pharmacokinetics and toxicokinetics of compound 1 and the relevance of these findings with respect to further development of this integrase-targeted antiviral agent. Oral administration of compound 1 in Sprague Dawley rats revealed rapid absorption. Drug exposure increased with increasing drug concentration, indicative of appropriate dose-dependence correlation. Compound 1 exhibited suitable plasma half-life, extensive extravascular distribution and acceptable bioavailability. Toxicity studies revealed no compound-related clinical pathology findings. There were no changes in erythropoietic, white blood cell or platelet parameters in male and female rats. There was no test-article related change in other clinical chemistry parameters. In addition, there were no detectable levels of bilirubin in the urine and there were no treatment-related effects on urobilinogen or other urinalysis parameters. The preclinical studies also revealed that the no observed adverse effect level and the maximum tolerated dose were both high (>500mg/kg/day). The broad and significant antiviral activity and favorable metabolism profile of this integrase inhibitor, when combined with the in vivo pharmacokinetic and toxicokinetic data and their pharmacological relevance, provide compelling and critical support for its further development as an anti-HIV therapeutic agent. PMID:24821255

  19. Toxic and chemopreventive ligands preferentially activate distinct aryl hydrocarbon receptor pathways: implications for cancer prevention.

    PubMed

    Okino, Steven T; Pookot, Deepa; Basak, Shashwati; Dahiya, Rajvir

    2009-03-01

    The aryl hydrocarbon receptor (AhR) is a ligand-activated regulatory protein that controls estrogen action through two distinct pathways. In one pathway, AhR acts as a transcription factor that induces the expression of the CYP1 family of estrogen-metabolizing genes; in the other pathway, AhR initiates the degradation of the estrogen receptor and suppresses estrogen signaling. The AhR ligand 3,3'-diindolylmethane (DIM) is a beneficial dietary constituent that prevents breast tumors in rodents and is associated with decreased breast cancer risk in humans. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a toxic AhR ligand that is implicated in birth defects, infertility, and cancer. We analyzed MCF-7 cells to gain insight into how two AhR ligands can exert such fundamentally different health effects. We find that DIM and TCDD have differing abilities to activate the distinct AhR-controlled pathways. TCDD strongly induces AhR-dependent CYP1 gene expression, whereas DIM is a relatively weak CYP1 inducer. DIM strongly inhibits estrogen receptor-alpha expression and estrogen signaling, whereas TCDD has a notably weaker effect on these processes. Small interfering RNA knockdown of AhR confirms that the effects of DIM and TCDD are indeed AhR dependent. Our findings reveal that DIM and TCDD each elicit a unique pattern of change in pathways that control estrogen action; such patterns may determine if an AhR ligand has beneficial or adverse health effects. PMID:19223575

  20. Quantifying the toxic and mutagenic activity of complex mixtures with Salmonella typhimurium

    SciTech Connect

    Somani, S.M.; Schaeffer, D.J.; Mack, J.O.

    1981-03-01

    The toxicity and mutagenicity of 11 compounds individually and in mixtures were quantified in Salmonella typhimurium strains TA98, TA100, and TA1537 by a modification of the Ames spot test. The distance (millimeters) from the center of the petri dish to the bacterial growth front represented the toxic response. When mutagenicity occurred, the distance from the inner radius to the outer radius of the mutagenic growth represented the mutagenic response. Multiple regression analysis was used to quantify the toxicity and mutagenicity of individual compounds in the mixtures. The results indicate that the effects of compounds in mixtures are generally additive.

  1. Aquatic toxicity of acrylates and methacrylates: quantitative structure-activity relationships based on Kow and LC50

    SciTech Connect

    Reinert, K.H.

    1987-12-01

    Recent EPA scrutiny of acrylate and methacrylate monomers has resulted in restrictive consent orders and Significant New Use Rules under the Toxic Substances Control Act, based on structure-activity relationships using mouse skin painting studies. The concern is centered on human health issues regarding worker and consumer exposure. Environmental issues, such as aquatic toxicity, are still of concern. Understanding the relationships and environmental risks to aquatic organisms may improve the understanding of the potential risks to human health. This study evaluates the quantitative structure-activity relationships from measured log Kow's and log LC50's for Pimephales promelas (fathead minnow) and Carassius auratus (goldfish). Scientific support of the current regulations is also addressed. Two monomer classes were designated: acrylates and methacrylates. Spearman rank correlation and linear regression were run. Based on this study, an ecotoxicological difference exists between acrylates and methacrylates. Regulatory activities and scientific study should reflect this difference.

  2. Understanding Toxicities of Targeted Agents: Implications for Anti-tumor Activity and Management.

    PubMed

    Liu, Sariah; Kurzrock, Razelle

    2015-12-01

    Targeted treatments have distinctive side effects: dermatologic problems (rash, hand-food skin reaction, skin/hair whitening), endocrine dysfunction (hyperglycemia, hypothyroidism, dyslipidemia), as well as hypertension, diarrhea, liver problems, ocular toxicity and proteinuria. Toxicities can be classified as: (1) on-target, mechanism-driven toxicities that are either related or unrelated to response; and (2) off-target side effects. Off-target toxicities may be specific to the class of agent, eg, small molecule tyrosine kinase inhibitor versus antibody versus cytotoxic; alternatively, they may also be mediated by metabolites or immune reactions. Both on- and off-target toxicities can be amplified or attenuated by drug concentrations or end-organ sensitivity, which in turn can be attributable to genetic polymorphisms regulating metabolism or tissue responsiveness. On-target side effects are important to identify as some are associated with response and, therefore, controlling these side effects is preferable to dose reduction or treatment discontinuation. Side effects caused by relevant target impact may be recognized when different types of agents, eg, small molecule inhibitors and antibodies, with the same target have the same side effect. These on-target effects may also correlate with better outcomes. We discuss toxicity of targeted agents in the context of understanding target impact, drug-drug interactions, and implications for optimized management. PMID:26615131

  3. Novel Nystatin A₁ derivatives exhibiting low host cell toxicity and antifungal activity in an in vitro model of oral candidosis.

    PubMed

    Boros-Majewska, Joanna; Salewska, Natalia; Borowski, Edward; Milewski, Sławomir; Malic, Sladjana; Wei, Xiao-Qing; Hayes, Anthony J; Wilson, Melanie J; Williams, David W

    2014-10-01

    Opportunistic oral infections caused by Candida albicans are frequent problems in immunocompromised patients. Management of such infections is limited due to the low number of antifungal drugs available, their relatively high toxicity and the emergence of antifungal resistance. Given these issues, our investigations have focused on novel derivatives of the antifungal antibiotic Nystatin A1, generated by modifications at the amino group of this molecule. The aims of this study were to evaluate the antifungal effectiveness and host cell toxicity of these new compounds using an in vitro model of oral candidosis based on a reconstituted human oral epithelium (RHOE). Initial studies employing broth microdilution, revealed that against planktonic C. albicans, Nystatin A1 had lower minimal inhibitory concentration than novel derivatives. However, Nystatin A1 was also markedly more toxic against human keratinocyte cells. Interestingly, using live/dead staining to assess C. albicans and tissue cell viability after RHOE infection, Nystatin A1 derivatives were more active against Candida with lower toxicity to epithelial cells than the parent drug. Lactate dehydrogenase activity released by the RHOE indicated a fourfold reduction in tissue damage when certain Nystatin derivatives were used compared with Nystatin A1. Furthermore, compared with Nystatin A1, colonisation of the oral epithelium by C. albicans was notably reduced by the new polyenes. In the absence of antifungal agents, confocal laser scanning microscopy showed that C. albicans extensively invaded the RHOE. However, the presence of the novel derivatives greatly reduced or totally prevented this fungal invasion. PMID:24924305

  4. Essential Oil from Flowers and Leaves of Elaeagnus Angustifolia (Elaeagnaceae): Composition, Radical Scavenging and General Toxicity Activities

    PubMed Central

    Torbati, Mohammadali; Asnaashari, Solmaz; Heshmati Afshar, Fariba

    2016-01-01

    Purpose: The aim of this work was to identify the chemical composition of the essential oils obtained from the flowers and leaves of Elaeagnus angostifolia (Elaeagnaceae) along with evaluate the radical scavenging and general toxicity activities. Methods: A combination of GC-MS and GC-FID were utilized for analyzing the chemical profile of the essential oils extracted by hydro-distillation from the leaves and flowers of E. angustifolia. The essential oils were subjected to general toxicity and radical scavenging assays using brine shrimp lethality test and DPPH method, respectively. Results: In total, 53 and 25 components were identified and quantified in the essential oils of flowers and leaves, accounting for 96.59% and 98.97% of the oil, respectively. The both oils were observed to be rich in ester compounds. The most abundant components of the oil from flowers were E-ethyl cinnamate (60.00%), hexahydrofarnesyl acetone (9.99%), palmitic acid (5.20%) and phytol (3.29%). The major constituents of the oil from leaves were E-ethyl cinnamate (37.27%), phytol (12.08%), nonanal (10.74%) and Z-3-hexenyl benzoate (7.65%). Both oils showed moderate activity in DPPH assay; however, they exhibited potent tocixity in brine shrimp lethality test. Conclusion: The remarkable toxicity effects of the oils are worthy to further investigation to find the probable mechanisms of action accountable for the noticeable toxic effect of these essential oils. PMID:27478777

  5. Aberrant Activation of p38 MAP Kinase-Dependent Innate Immune Responses Is Toxic to Caenorhabditis elegans.

    PubMed

    Cheesman, Hilary K; Feinbaum, Rhonda L; Thekkiniath, Jose; Dowen, Robert H; Conery, Annie L; Pukkila-Worley, Read

    2016-03-01

    Inappropriate activation of innate immune responses in intestinal epithelial cells underlies the pathophysiology of inflammatory disorders of the intestine. Here we examine the physiological effects of immune hyperactivation in the intestine of the nematode Caenorhabditis elegans. We previously identified an immunostimulatory xenobiotic that protects C. elegans from bacterial infection by inducing immune effector expression via the conserved p38 MAP kinase pathway, but was toxic to nematodes developing in the absence of pathogen. To investigate a possible connection between the toxicity and immunostimulatory properties of this xenobiotic, we conducted a forward genetic screen for C. elegans mutants that are resistant to the deleterious effects of the compound, and identified five toxicity suppressors. These strains contained hypomorphic mutations in each of the known components of the p38 MAP kinase cassette (tir-1, nsy-1, sek-1, and pmk-1), demonstrating that hyperstimulation of the p38 MAPK pathway is toxic to animals. To explore mechanisms of immune pathway regulation in C. elegans, we conducted another genetic screen for dominant activators of the p38 MAPK pathway, and identified a single allele that had a gain-of-function (gf) mutation in nsy-1, the MAP kinase kinase kinase that acts upstream of p38 MAPK pmk-1. The nsy-1(gf) allele caused hyperinduction of p38 MAPK PMK-1-dependent immune effectors, had greater levels of phosphorylated p38 MAPK, and was more resistant to killing by the bacterial pathogen Pseudomonas aeruginosa compared to wild-type controls. In addition, the nsy-1(gf) mutation was toxic to developing animals. Together, these data suggest that the activity of the MAPKKK NSY-1 is tightly regulated as part of a physiological mechanism to control p38 MAPK-mediated innate immune hyperactivation, and ensure cellular homeostasis in C. elegans. PMID:26818074

  6. Acute, sub-chronic oral toxicity studies and evaluation of antiulcer activity of Sooktyn in experimental animals

    PubMed Central

    Chandra, Phool; Sachan, Neetu; Kishore, Kamal; Ghosh, Ashoke Kumar

    2012-01-01

    Sooktyn (SKN), mineralo-herbal drug which is being used largely by the patients for its extremely good therapeutic value to treat the gastric ulcers. The present study was undertaken to evaluate the toxicity studies and antiulcer activity of SKN. Acute and sub-chronic toxicities were studied in male and female Wistar rats. A single acute SKN of 2 000 mg/kg was administered by oral gavage for acute toxicity. Sub-chronic doses were 400 and 800 mg/kg/day. The major toxicological end points examined included animal body weight and food intake, selected tissue weights, and detailed gross necropsy. In addition, we examined blood elements: hematocrit, hemoglobin concentration, erythrocyte count, total leukocyte count and MCH, MCHC and platelets as well as biochemical parameters: urea, sugar, alanine transaminase, aspartate transaminase, alkaline phosphatase, total proteins, and creatinine. Also, anti-ulcer activity was carried out by employing indomethacin, ethanol, pylorus ligation, and hypothermic-stress-induced ulcer models. LD50 may be greater than 2 000 mg/kg (orally) for SKN and there were no signs of toxicity on 28 days sub-chronic oral administration of 400 and 800 mg/kg of SKN in rats on the basis of blood elements and biochemical parameters. The ulcer indices decrease in all ulcer models with 66.62%, 61.24%, 80.18%, and 74.76% in indomethacin, ethanol, pylorus ligation, and hypothermic-stress-induced ulcer models, respectively. The results suggest that SKN has no signs of toxicity at 2 000 mg/kg body weight of rats orally; sub-chronically. The drug is safe and has antiulcer activity. PMID:22837960

  7. Aberrant Activation of p38 MAP Kinase-Dependent Innate Immune Responses Is Toxic to Caenorhabditis elegans

    PubMed Central

    Cheesman, Hilary K.; Feinbaum, Rhonda L.; Thekkiniath, Jose; Dowen, Robert H.; Conery, Annie L.; Pukkila-Worley, Read

    2016-01-01

    Inappropriate activation of innate immune responses in intestinal epithelial cells underlies the pathophysiology of inflammatory disorders of the intestine. Here we examine the physiological effects of immune hyperactivation in the intestine of the nematode Caenorhabditis elegans. We previously identified an immunostimulatory xenobiotic that protects C. elegans from bacterial infection by inducing immune effector expression via the conserved p38 MAP kinase pathway, but was toxic to nematodes developing in the absence of pathogen. To investigate a possible connection between the toxicity and immunostimulatory properties of this xenobiotic, we conducted a forward genetic screen for C. elegans mutants that are resistant to the deleterious effects of the compound, and identified five toxicity suppressors. These strains contained hypomorphic mutations in each of the known components of the p38 MAP kinase cassette (tir-1, nsy-1, sek-1, and pmk-1), demonstrating that hyperstimulation of the p38 MAPK pathway is toxic to animals. To explore mechanisms of immune pathway regulation in C. elegans, we conducted another genetic screen for dominant activators of the p38 MAPK pathway, and identified a single allele that had a gain-of-function (gf) mutation in nsy-1, the MAP kinase kinase kinase that acts upstream of p38 MAPK pmk-1. The nsy-1(gf) allele caused hyperinduction of p38 MAPK PMK-1-dependent immune effectors, had greater levels of phosphorylated p38 MAPK, and was more resistant to killing by the bacterial pathogen Pseudomonas aeruginosa compared to wild-type controls. In addition, the nsy-1(gf) mutation was toxic to developing animals. Together, these data suggest that the activity of the MAPKKK NSY-1 is tightly regulated as part of a physiological mechanism to control p38 MAPK-mediated innate immune hyperactivation, and ensure cellular homeostasis in C. elegans. PMID:26818074

  8. Cytokine gene expression and activation of NF-{kappa}B in aniline-induced splenic toxicity

    SciTech Connect

    Wang Jianling; Kannan, Subburaj; Li Hui; Firoze Khan, M. . E-mail: mfkhan@utmb.edu

    2005-02-15

    Exposure to aniline results in selective toxicity to the spleen, leading to a variety of sarcomas on chronic exposure in rats, and fibrosis appears to be an important initiating preneoplastic lesion of the spleen. However, the molecular mechanism(s) by which aniline leads to fibrogenic response is not well understood. Previously, we have shown that aniline exposure leads to iron overload and induction of oxidative stress in the spleen. We hypothesized that aniline-induced oxidative stress in the spleen causes transcriptional up-regulation of fibrogenic cytokines via activation of redox-sensitive transcription factor, nuclear factor-kappa B (NF-{kappa}B). To test this hypothesis, male SD rats were treated with 0.5 mmol/kg/day aniline hydrochloride via drinking water for 30 days. Cytokine mRNAs were measured by real-time quantitative PCR, while cytokine release was determined in the supernatants of the cultured splenocytes using specific ELISAs. IL-1{alpha}, IL-6, and TNF-{alpha} mRNA levels showed 6.9-, 2.9-, and 2.6-fold increases, respectively, in the spleens of aniline-treated rats in comparison to the controls. The increases in mRNA levels were associated with enhanced secretion of these cytokines in the splenocyte culture supernatants. NF-{kappa}B p65 level in the nuclear extracts of cultured splenocytes of aniline-treated rats showed a 2-fold increase in comparison to the controls as quantitated by NF-{kappa}B p65-specific ELISA. The binding activity of NF-{kappa}B, determined by electrophoretic mobility shift assay (EMSA), also showed an increase in NF-{kappa}B binding in the nuclear extracts of the splenocytes from aniline-treated rats. The specificity of NF-{kappa}B binding was further confirmed by supershift assays. The results indicate that aniline exposure causes enhanced expression of IL-1{alpha}, IL-6, and TNF-{alpha}, both at mRNA and protein levels, suggesting their role in splenic fibrosis. Also, the increased NF-{kappa}B binding activity suggests

  9. Deciphering the Nongenomic, Mitochondrial Toxicity of Tamoxifens As Determined by Cell Metabolism and Redox Activity.

    PubMed

    Theodossiou, Theodossis Athanassios; Wälchli, Sébastien; Olsen, Cathrine Elisabeth; Skarpen, Ellen; Berg, Kristian

    2016-01-15

    Tamoxifen is not only considered a very potent chemotherapeutic adjuvant for estrogen receptor positive breast cancers but also a very good chemo-preventive drug. Recently, there has been a rising amount of evidence for a nongenomic cytotoxicity of tamoxifen, even in estrogen receptor negative cells, which has greatly confounded researchers. Clinically, the side effects of tamoxifen can be very serious, ranging from liver steatosis to cirrhosis, tumorigenesis, or onset of porphyrias. Herein, we deciphered the nongenomic, mitochondrial cytotoxicity of tamoxifen in estrogen receptor positive MCF7 versus triple-negative MDA-MB-231 cells, employing the mitochondrial complex III quinoloxidizing-center inhibitor myxothiazol. We showed a role for hydroxyl-radical-mediated lipid peroxidation, catalyzed by iron, stemming from the redox interactions of tamoxifen quinoid metabolites with complex III, resulting in Fenton-capable reduced quinones. The role of tamoxifen semiquinone species in mitochondrial toxicity was also shown together with evidence of mitochondrial DNA damage. Tamoxifen caused an overall metabolic (respiratory and glycolytic) rate decrease in the Pasteur type MCF cells, while in the Warburg type MDA-MB-231 cells the respiratory rate was not significantly affected and the glycolytiv rate was significantly boosted. The nongenomic cytotoxicity of tamoxifens was hence associated with the metabolic phenotype and redox activity of the cells, as in the present paradigm of Pasteur MCF7s versus Warburg MDA-MB-231 cells. Our present findings call for caution in the use of the drugs, especially as a chemopreventive and/or in cases of iron overload diseases. PMID:26569462

  10. Active foraging for toxic prey during gestation in a snake with maternal provisioning of sequestered chemical defences.

    PubMed

    Kojima, Yosuke; Mori, Akira

    2015-01-01

    Many animals sequester dietary defensive compounds and incorporate them into the offspring, which protects the young against predation. One possible but poorly investigated question is whether females of such species actively prey upon toxic diets. The snake Rhabdophis tigrinus sequesters defensive steroids from toads consumed as prey; it also feeds on other amphibians. Females produce chemically armed offspring in direct proportion to their own level of toad-derived toxins by provisioning the toxins to their eggs. Our field observations of movements and stomach contents of radio-tracked R. tigrinus showed that gravid snakes preyed upon toads by actively foraging in the habitat of toads, even though toads were a scarce resource and toad-searching may incur potential costs. Our Y-maze experiments demonstrated that gravid females were more likely to trail the chemical cues of toads than were males or non-gravid females. These results showed behavioural switching in females and active foraging for scarce, toxic prey during gestation. Because exploitation of toads by gravid females results in their offspring being more richly endowed with prey-derived toxins, active foraging for toxic prey is expected to be an adaptive antipredator trait, which may enhance chemical defence in offspring. PMID:25392472

  11. Induction of lcc2 expression and activity by Agaricus bisporus provides defence against Trichoderma aggressivum toxic extracts.

    PubMed

    Sjaarda, Calvin P; Abubaker, Kamal S; Castle, Alan J

    2015-11-01

    Laccases are used by fungi for several functions including defence responses to stresses associated with attack by other fungi. Laccase activity changes and the induction of two laccase genes, lcc1 and lcc2, in Agaricus bisporus were measured in response to toxic extracts of medium in which Trichoderma aggressivum, the cause of green mould disease, was grown. A strain of A. bisporus that shows resistance to the extracts showed higher basal levels and greater enzymatic activity after extract exposure than did a sensitive strain. Furthermore, pre-incubation of T. aggressivum extract with laccases reduced toxicity. Faster induction and greater numbers of lcc2 transcripts in response to the extract were noted in the resistant strain than in the sensitive strain. The timing and increase in lcc2 transcript abundance mirrored changes in total laccase activity. No correlation between resistance and lcc1 transcription was apparent. Transcript abundance in transformants with a siRNA construct homologous to both genes varied widely. A strong negative correlation between transcript abundance and sensitivity of the transformant to toxic extract was observed in plate assays. These results indicated that laccase activity and in particular that encoded by lcc2 contributes to toxin metabolism and by extension green mould disease resistance. PMID:25824278

  12. Active foraging for toxic prey during gestation in a snake with maternal provisioning of sequestered chemical defences

    PubMed Central

    Kojima, Yosuke; Mori, Akira

    2015-01-01

    Many animals sequester dietary defensive compounds and incorporate them into the offspring, which protects the young against predation. One possible but poorly investigated question is whether females of such species actively prey upon toxic diets. The snake Rhabdophis tigrinus sequesters defensive steroids from toads consumed as prey; it also feeds on other amphibians. Females produce chemically armed offspring in direct proportion to their own level of toad-derived toxins by provisioning the toxins to their eggs. Our field observations of movements and stomach contents of radio-tracked R. tigrinus showed that gravid snakes preyed upon toads by actively foraging in the habitat of toads, even though toads were a scarce resource and toad-searching may incur potential costs. Our Y-maze experiments demonstrated that gravid females were more likely to trail the chemical cues of toads than were males or non-gravid females. These results showed behavioural switching in females and active foraging for scarce, toxic prey during gestation. Because exploitation of toads by gravid females results in their offspring being more richly endowed with prey-derived toxins, active foraging for toxic prey is expected to be an adaptive antipredator trait, which may enhance chemical defence in offspring. PMID:25392472

  13. Induction of lcc2 expression and activity by Agaricus bisporus provides defence against Trichoderma aggressivum toxic extracts

    PubMed Central

    Sjaarda, Calvin P; Abubaker, Kamal S; Castle, Alan J

    2015-01-01

    Laccases are used by fungi for several functions including defence responses to stresses associated with attack by other fungi. Laccase activity changes and the induction of two laccase genes, lcc1 and lcc2, in Agaricus bisporus were measured in response to toxic extracts of medium in which Trichoderma aggressivum, the cause of green mould disease, was grown. A strain of A. bisporus that shows resistance to the extracts showed higher basal levels and greater enzymatic activity after extract exposure than did a sensitive strain. Furthermore, pre-incubation of T. aggressivum extract with laccases reduced toxicity. Faster induction and greater numbers of lcc2 transcripts in response to the extract were noted in the resistant strain than in the sensitive strain. The timing and increase in lcc2 transcript abundance mirrored changes in total laccase activity. No correlation between resistance and lcc1 transcription was apparent. Transcript abundance in transformants with a siRNA construct homologous to both genes varied widely. A strong negative correlation between transcript abundance and sensitivity of the transformant to toxic extract was observed in plate assays. These results indicated that laccase activity and in particular that encoded by lcc2 contributes to toxin metabolism and by extension green mould disease resistance. PMID:25824278

  14. Effect of H+ ion activity and Ca2+ on the toxicity of metals in the environment.

    PubMed Central

    Hutchinson, T C; Collins, F W

    1978-01-01

    The role of acidity in determining and restricting plant distribution and performance is discussed. In soils especially, a key effect of H+ ion concentration is on the solubility of potentially toxic heavy metals such as aluminum, managenese, zinc, iron, copper, and nickel. Al has been reported from many studies since the 1920's as the key determining toxic factor in acid soils. Some acid-tolerant species have been shown to be especially tolerant of Al, and mechanisms of tolerance have been suggested. Mn is also a commonly toxic factor at soil pH less than 5.0. Calcium has been shown to alleviate Mn toxicity. Low pH soils are also generally low in Ca, K, Na, and P; all essential major elements for plant growth. In lakes and marine situations acidic waters are uncommon as the waters are buffered. Calcium is again ameliorative of metal toxicities. The pH, redox, and valency state are critical in determining nutrient availability and metal speciation. Recent increases in the H+ ion content of precipitation have caused increased acidities of freshwater lakes in Scandinavia and eastern North America, which have depleted biota, including fish populations. PMID:31277

  15. Reproductive and developmental toxicity of the herbicide Betanal® Expert and corresponding active ingredients to Daphnia spp.

    PubMed

    Vidal, Tânia; Pereira, Joana Luísa; Abrantes, Nelson; Soares, Amadeu M V M; Gonçalves, Fernando

    2016-07-01

    The commercial herbicide formulation Betanal® Expert and its active ingredients (a.i.s) ethofumesate, phenmedipham and desmedipham were focused in this study. Following questions yielding from a previous study, an in-depth analysis of the reproductive toxicity of the pesticide was made. Long-term exposures of Daphnia magna and Daphnia longispina to Betanal® Expert, to each a.i. and to a customised mixture matching the a.i.s ratio within the commercial formulation were carried out, and deleterious effects in the offspring were recorded. This intended to clarify whether (1) the tested compounds induce reproductive injury; (2) there is interspecific variation in daphnids tolerance to the compounds; (3) there is an interaction between chemicals in combined treatments; and (4) the so-called inert ingredients added to the commercial formulation contribute to the toxicity of the herbicide. Generally, developmental impair was observed in both species (egg abortion and release of undeveloped embryos or dead offspring) at concentrations of any of the a.i.s below 1 mg L(-1). Ethofumesate was invariably the least toxic pesticide, and D. magna tended to be of slightly higher sensitivity to the exposures compared to D. longispina. Joint exposures indicated that the a.i.s can interact, inducing more than and less than additive effects for Betanal® Expert and the customised a.i. mixture, respectively. This indicates that inert ingredients co-formulating the commercial pesticide (which are absent from the customised a.i. mixture) actually contribute to its overall toxicity. This study constitutes an add-on to the discussion on the ecotoxicological framework required for authorisation of pesticide trade and usage. The results support the need to consider test species, long-term hazardous potential and toxicity of commercial formulations rather than solely that of active ingredients, as relevant variables in pesticide regulation. PMID:27023815

  16. Fumigant Toxicity and Repellence Activity of Camphor Essential Oil from Cinnamonum camphora Siebold Against Solenopsis invicta Workers (Hymenoptera:Formicidae).

    PubMed

    Fu, J T; Tang, L; Li, W S; Wang, K; Cheng, D M; Zhang, Z X

    2015-01-01

    The red imported fire ant (RIFA) Solenopsis invicta Buren causes severe damage to humans and animals as well as the environment. Chemical treatment is the main strategy of RIFA management, which also is potentially toxic to the environment. Plant essential oils (EOs) are considered as potential substance that can be used to control insects. This study aimed to identify the chemical composition of camphor EO and investigate the insecticidal activity on RIFAs. The chemical composition of the EO was analyzed by gas chromatography/mass spectrometry and gas chromatography with flame ionization detection. Results revealed that 36.61% camphor and 30.05% cineole were the major components. The insecticidal activity of camphor EO was assessed against RIFA workers by conducting two different bioassays: fumigant toxicity and repellence. Fumigant toxicity assay results showed that the lethal dose (LC50) of the EO at 24 h was 1.67 and 4.28 μg/ml for minor and major workers, respectively; knockdown time (KT50) was 10.82 and 14.73 h. At 2.55 μg/ml, the highest average mortality of the ants was 84.89% after 72 h. Camphor EO exhibited fumigant toxicity against minor and major workers as indicated by the effects on attacking, feeding, and climbing behaviors. This EO was also strongly repellent to the two size workers of the colony as observed in their behavior against Tenebrio molitor treated with 5 µl EO. The fumigant toxicity and repellence of camphor EO against RIFA indicated that this substance could be a potential alternative for the development of eco-friendly products used to control pests. PMID:26392574

  17. Fumigant Toxicity and Repellence Activity of Camphor Essential Oil from Cinnamonum camphora Siebold Against Solenopsis invicta Workers (Hymenoptera:Formicidae)

    PubMed Central

    Fu, J. T.; Tang, L.; Li, W. S.; Wang, K.; Cheng, D. M.; Zhang, Z. X.

    2015-01-01

    The red imported fire ant (RIFA) Solenopsis invicta Buren causes severe damage to humans and animals as well as the environment. Chemical treatment is the main strategy of RIFA management, which also is potentially toxic to the environment. Plant essential oils (EOs) are considered as potential substance that can be used to control insects. This study aimed to identify the chemical composition of camphor EO and investigate the insecticidal activity on RIFAs. The chemical composition of the EO was analyzed by gas chromatography/mass spectrometry and gas chromatography with flame ionization detection. Results revealed that 36.61% camphor and 30.05% cineole were the major components. The insecticidal activity of camphor EO was assessed against RIFA workers by conducting two different bioassays: fumigant toxicity and repellence. Fumigant toxicity assay results showed that the lethal dose (LC50) of the EO at 24 h was 1.67 and 4.28 μg/ml for minor and major workers, respectively; knockdown time (KT50) was 10.82 and 14.73 h. At 2.55 μg/ml, the highest average mortality of the ants was 84.89% after 72 h. Camphor EO exhibited fumigant toxicity against minor and major workers as indicated by the effects on attacking, feeding, and climbing behaviors. This EO was also strongly repellent to the two size workers of the colony as observed in their behavior against Tenebrio molitor treated with 5 µl EO. The fumigant toxicity and repellence of camphor EO against RIFA indicated that this substance could be a potential alternative for the development of eco-friendly products used to control pests. PMID:26392574

  18. Toxicity and Antiviral Activity of the Extracts of Submerged Mycelium of Nematophagous Duddingtonia flagrans Fungus in Vero Cell Culture.

    PubMed

    Ibragimova, Zh B; Anan'ko, G G; Kostina, N E; Teplyakova, T V; Mazurkova, N A

    2015-12-01

    We studied toxicity and antiviral activity of aqueous and ethanol extracts of bioactive substances from the biomass of nematophagous fungus Duddingtonia flagrans prepared by submerged culturing of the mycelium. It is found that both extracts were characterized by low toxicity for cultured Vero cells and inhibited reproduction of DNA-viruses in this cell line. Ethanol extract of the fungus exhibited higher in vitro antiviral activity against Herpes simplex virus type 2, ectromelia virus, and vaccinia virus than water extract, which can be due to higher content of proteins, polysaccharides, flavonols, catechins, or carotenes or more effective their combination. The extracts of cultured mycelium of Duddingtonia flagrans fungus containing a complex of bioactive substances can be used for creation of broad-spectrum antiviral drugs against DNA-viruses. PMID:26621278

  19. Effect of metals and other inorganic ions on soil microbial activity: soil dehydrogenase assay as a simple toxicity test

    SciTech Connect

    Rogers, J.E.; Li, S.W.

    1985-06-01

    The purpose of this report is to illustrate the utility of the soil dehydrogenase assay as an effective primary test for assessing the potential toxicity of chemicals to soil microbial activity. In this manuscript the authors describe their use of the soil dehydrogenase assay in determining the effects of a number of potential toxic inorganic ions on soil microbial activity. The ions include Cu/sup 2 +/, Mg/sup 2 +/, Ni/sup 2 +/, Zn/sup 2 +/, NH/sub 4//sup +/, Cd/sup 2 +/, Cr/sup 32/, F/sup -/, AsO/sub 4//sup 3 -/, BO/sub 3//sup 3 -/, and SO/sub 4//sup 2 -/.

  20. Removal potential of toxic 2378-substituted PCDD/F from incinerator flue gases by waste-derived activated carbons.

    PubMed

    Hajizadeh, Yaghoub; Onwudili, Jude A; Williams, Paul T

    2011-06-01

    The application of activated carbons has become a commonly used emission control protocol for the removal or adsorption of persistent organic pollutants from the flue gas streams of waste incinerators. In this study, the 2378-substituted PCDD/F removal efficiency of three types of activated carbons derived from the pyrolysis of refuse derived fuel, textile waste and scrap tyre was investigated and compared with that of a commercial carbon. Experiments were carried out in a laboratory scale fixed-bed reactor under a simulated flue gas at 275°C with a reaction period of four days. The PCDD/F in the solid matrices and exhaust gas, were analyzed using gas chromatography coupled with a triple quadrupole mass spectrometer. In the absence of activated carbon adsorbent, there was a significant increase in the concentration of toxic PCDD/F produced in the reacted flyash, reaching up to 6.6 times higher than in the raw flyash. In addition, there was a substantial release of PCDD/F into the gas phase, which was found in the flue gas trapping system. By application of the different commercial, refuse derived fuel, textile and tyre activated carbons the total PCDD/F toxic equivalent removal efficiencies in the exhaust gas stream were 58%, 57%, 64% and 52%, respectively. In general, the removal of the PCDDs was much higher with an average of 85% compared to PCDFs at 41%. Analysis of the reacted activated carbons showed that there was some formation of PCDD/F, for instance, a total of 60.6 μg I-TEQ kg(-1) toxic PCDD/F was formed in the refuse derived fuel activated carbon compared to 34 μg I-TEQ kg(-1) in the commercial activated carbon. The activated carbons derived from the pyrolysis of waste, therefore, showed good potential as a control material for PCDD/F emissions in waste incinerator flue gases. PMID:21334872

  1. Removal potential of toxic 2378-substituted PCDD/F from incinerator flue gases by waste-derived activated carbons

    SciTech Connect

    Hajizadeh, Yaghoub; Onwudili, Jude A.; Williams, Paul T.

    2011-06-15

    The application of activated carbons has become a commonly used emission control protocol for the removal or adsorption of persistent organic pollutants from the flue gas streams of waste incinerators. In this study, the 2378-substituted PCDD/F removal efficiency of three types of activated carbons derived from the pyrolysis of refuse derived fuel, textile waste and scrap tyre was investigated and compared with that of a commercial carbon. Experiments were carried out in a laboratory scale fixed-bed reactor under a simulated flue gas at 275 deg. C with a reaction period of four days. The PCDD/F in the solid matrices and exhaust gas, were analyzed using gas chromatography coupled with a triple quadrupole mass spectrometer. In the absence of activated carbon adsorbent, there was a significant increase in the concentration of toxic PCDD/F produced in the reacted flyash, reaching up to 6.6 times higher than in the raw flyash. In addition, there was a substantial release of PCDD/F into the gas phase, which was found in the flue gas trapping system. By application of the different commercial, refuse derived fuel, textile and tyre activated carbons the total PCDD/F toxic equivalent removal efficiencies in the exhaust gas stream were 58%, 57%, 64% and 52%, respectively. In general, the removal of the PCDDs was much higher with an average of 85% compared to PCDFs at 41%. Analysis of the reacted activated carbons showed that there was some formation of PCDD/F, for instance, a total of 60.6 {mu}g I-TEQ kg{sup -1} toxic PCDD/F was formed in the refuse derived fuel activated carbon compared to 34 {mu}g I-TEQ kg{sup -1} in the commercial activated carbon. The activated carbons derived from the pyrolysis of waste, therefore, showed good potential as a control material for PCDD/F emissions in waste incinerator flue gases.

  2. Granular activated carbon for simultaneous adsorption and biodegradation of toxic oil sands process-affected water organic compounds.

    PubMed

    Islam, Md Shahinoor; Zhang, Yanyan; McPhedran, Kerry N; Liu, Yang; Gamal El-Din, Mohamed

    2015-04-01

    Naphthenic acids (NAs) released into oil sands process-affected water (OSPW) during bitumen processing in Northern Alberta are problematic for oil sands industries due to their toxicity in the environment and resistance to degradation during conventional wastewater treatment processes. Granular activated carbon (GAC) has shown to be an effective media in removing biopersistent organics from wastewater using a combination of adsorption and biodegradation removal mechanisms. A simultaneous GAC (0.4 g GAC/L) adsorption and biodegradation (combined treatment) study was used for the treatment of raw and ozonated OSPW. After 28 days of batch treatment, classical and oxidized NAs removals for raw OSPW were 93.3% and 73.7%, and for ozonated OSPW were 96.2% and 77.1%, respectively. Synergetic effects of the combined treatment process were observed in removals of COD, the acid extractable fraction, and oxidized NAs, which indicated enhanced biodegradation and bioregeneration in GAC biofilms. A bacteria copy number >10(8) copies/g GAC on GAC surfaces was found using quantitative real time polymerase chain reaction after treatment for both raw and ozonated OSPW. A Microtox(®) acute toxicity test (Vibrio fischeri) showed effective toxicity removal (>95.3%) for the combined treatments. Therefore, the simultaneous GAC adsorption and biodegradation treatment process is a promising technology for the elimination of toxic OSPW NAs. PMID:25617868

  3. Reduction of gas phase air toxics from combustion and incineration sources using the GE-Mitsui-BG activated coke process

    SciTech Connect

    Olson, D.G.; Tsuji, K.; Shiraishi, I.

    1998-04-01

    The dry desulfurization, denitification and air toxics removal process using activated coke (AC) was originally researched and developed during the 1960`s by Bergbau Forschung (BF), now called Deutsche Montan Technologies. Mitsui Mining Company (MMC) signed a licensing agreement with BF in 1982 to investigate, test and adapt the system to facilities in Japan. Japanese regulations are stricter than in the United States toward SOx/NOx pollutants, as well as flyash emissions from the utility industry, oil refineries and other industries. This process is installed on four coal-fired boilers and Fluidized Catalytic Cracker (FCC) units. These plants were constructed by MMC in Japan and Uhde GmbH in Germany. General Electric Environmental Services, Inc. (GEESI) signed a license agreement in 1992 with MMC and Mitsui and Company, Ltd. of Tokyo. Under this agreement, GEESI will market, design, fabricate and install the Mitsui-BF process for flue gas cleaning applications in North America. MMC also developed a technology to produce AC used in the dry DeSOx/DeNOx/Air Toxics removal process based on their own metallurgical coke manufacturing technology. This paper provides information on the details of MMC`s AC used in the dry DeSOx/DeNOx/Air Toxics removal process and of the DeSOx/DeNOx/Air Toxics removal process itself.

  4. Toxicant content, physical properties and biological activity of waterpipe tobacco smoke and its tobacco-free alternatives

    PubMed Central

    Shihadeh, Alan; Schubert, Jens; Klaiany, Joanne; El Sabban, Marwan; Luch, Andreas; Saliba, Najat A

    2015-01-01

    Objectives Waterpipe smoking using sweetened, flavoured tobacco products has become a widespread global phenomenon. In this paper, we review chemical, physical and biological properties of waterpipe smoke. Data sources Peer-reviewed publications indexed in major databases between 1991 and 2014. Search keywords included a combination of: waterpipe, narghile, hookah, shisha along with names of chemical compounds and classes of compounds, in addition to terms commonly used in cellular biology and aerosol sizing. Study selection The search was limited to articles published in English which reported novel data on waterpipe tobacco smoke (WTS) toxicant content, biological activity or particle size and which met various criteria for analytical rigour including: method specificity and selectivity, precision, accuracy and recovery, linearity, range, and stability. Data extraction Multiple researchers reviewed the reports and collectively agreed on which data were pertinent for inclusion. Data synthesis Waterpipe smoke contains significant concentrations of toxicants thought to cause dependence, heart disease, lung disease and cancer in cigarette smokers, and includes 27 known or suspected carcinogens. Waterpipe smoke is a respirable aerosol that induces cellular responses associated with pulmonary and arterial diseases. Except nicotine, smoke generated using tobacco-free preparations marketed for ‘health conscious’ users contains the same or greater doses of toxicants, with the same cellular effects as conventional products. Toxicant yield data from the analytical laboratory are consistent with studies of exposure biomarkers in waterpipe users. Conclusions A sufficient evidence base exists to support public health interventions that highlight the fact that WTS presents a serious inhalation hazard. PMID:25666550

  5. The effect-enhancing and toxicity-reducing activity of Hypericum japonicum Thunb. extract in murine liver cancer chemotherapy.

    PubMed

    Zhang, Hong-Bo; Lu, Ping; Cao, Wen-Bo; Zhang, Zhen-Hua; Meng, Xiang-Lei

    2013-03-01

    Chinese herbs are potential sources of antitumor drugs with immunoregulatory activity and few adverse effects. In the present study, we investigated whether the Hypericum japonicum Thunb. (HJT) extract enhanced the efficacy of 5-fluorouracil (5-FU) treatment in murine liver tumor xenografts and reduced toxicity of chemotherapy in hepatoma H22-bearing mice. Tumor weight and inhibition rate, thymus and spleen indices, as well as white blood cell (WBC) count were calculated. The phagocytic function of macrophages was assessed by observing peritoneal macrophages phagocytized chicken red blood cells (RBC). Body weight and toxic reactions of the chemotherapeutic and life prolongation rate were investigated in the mice. Results demonstrated that the HJT extract significantly enhanced the tumor inhibition rate of 5-FU, improved the immune function, reduced the toxic effects and prolonged the survival time in the tumor-bearing mice. Taken together, these results indicated that the HJT extract has a synergistic tumor-inhibiting effect with 5-FU, is able to reduce the toxic side effects and is likely to be safe and efficacious for use in antitumor therapy. PMID:24649182

  6. Recombinant murine toxin from Yersinia pestis shows high toxicity and β-adrenergic blocking activity in mice.

    PubMed

    Fan, Yanxiao; Zhou, Yazhou; Feng, Na; Wang, Qiong; Tian, Guang; Wu, Xiaohong; Liu, Zizhong; Bi, Yujing; Yang, Ruifu; Wang, Xiaoyi

    2016-05-01

    Yersinia pestis murine toxin (Ymt) encoded on pMT1 is a 61-kDa protein, a member of the phospholipase D superfamily, which is found in all the domains of life. It is considered to be an intracellular protein required for the survival of Y. pestis in the midgut of the flea, but the exact role of Ymt in the pathogenesis of Y. pestis has not been clarified. Purified Ymt is highly toxic to mice and rats, but the exact mechanism of the animals' death is unclear. Here, we prepared a recombinant Ymt in Escherichia coli BL21 cells, and determined its toxicity and activity. We demonstrated that recombinant Ymt was as toxic to mice as the native protein when administered via the intraperitoneal or intravenous route, and inhibited the elevation of blood sugar caused by adrenaline. We also demonstrated that recombinant Ymt was highly toxic to mice when administered via the muscular or subcutaneous route. We also show that the multiple organ congestion or hemorrhage caused by Ymt poisoning may explain the death of the mice. PMID:26774329

  7. Toxicity of Vertimec® 18 EC (active ingredient abamectin) to the neotropical cladoceran Ceriodaphnia silvestrii.

    PubMed

    Casali-Pereira, Maressa P; Daam, Michiel A; de Resende, Juliana C; Vasconcelos, Ana M; Espíndola, Evaldo L G; Botta, Clarice M R

    2015-11-01

    The aim of the present study was to evaluate the toxicity of abamectin to the neotropical cladoceran Ceriodaphnia silvestrii. To this end, acute and chronic bioassays were conducted with the commercial formulation Vertimec® 18 EC. In addition, the toxicity of water samples taken from a microcosm experiment evaluating the effects of a single application (144μga.i./L) and two applications (2×36μga.i./L) of Vertimec® 18 EC, in the presence or absence of a tadpole species (Lithobates catesbeianus), was also assessed. The acute LC50-48h for immobilization was 1.47μga.i./L and chronic NOEC-8d for survival and fertility (number of neonates per female) were 169 and 84nga.i./L, respectively. Irrespective of the presence of tadpoles, water samples from the microcosms applied with the single concentration of 144μga.i./L remained toxic until the end of the experiment, even when samples were diluted 32 times with culture medium. Water in the repeated pesticide treatment showed a similar toxic response after both applications. Toxicity of water samples from the microcosms was lower than that expected based on the generated LC50 values, which is explained by a potential reduced bioavailability of the test compound resulting from absorbance to organic material. Potential side-effects on C. silvestrii related with the use of Vertimec® 18 EC in Brazil and the suitability of this species for tropical toxicity testing are discussed. PMID:26318118

  8. Antiproliferative Activity and in Vivo Toxicity of Double-Point Modified Analogs of 1,25-Dihydroxyergocalciferol

    PubMed Central

    Trynda, Justyna; Turlej, Eliza; Milczarek, Magdalena; Pietraszek, Anita; Chodyński, Michał; Kutner, Andrzej; Wietrzyk, Joanna

    2015-01-01

    Analogs of 1,25-dihydroxyergocalciferol, modified in the side-chain and in the A-ring, were tested for their antiproliferative activity against a series of human cancer cell lines in vitro and in vivo toxicity. The proliferation inhibition caused by the analogs was higher than that of the parent compounds, while the toxicity, measured as the serum calcium level, was lower. All analogs were able to induce, in HL-60 and MV4-11 leukemic cells, G0/G1 cell cycle arrest and differentiation expressed as morphological signs typical for monocytes. The analogs also induced the expression of CD11b and/or CD14 cell-differentiation markers. The most potent analogs, PRI-5105, PRI-5106, PRI-5201 and PRI-5202, were also able to induce vitamin D receptor (VDR) protein expression, mainly in the cytoplasmic fraction of HL-60 or MV4-11 cells. The most active analogs were the 19-nor ones with an extended and rigidified side-chain (PRI-5201 and PRI-5202), as in the former analogs PRI-1906 and PRI-1907. Epimerization at C-24 (PRI-5101) or introduction of an additional hydroxyl at C-23 (PRI-5104) reduced the toxicity of the analog with retained antiproliferative activity. PMID:26492238

  9. Evaluation of Toxicity and Antimicrobial Activity of an Ethanolic Extract from Leaves of Morus alba L. (Moraceae)

    PubMed Central

    de Oliveira, Alisson Macário; Mesquita, Matheus da Silva; da Silva, Gabriela Cavalcante; de Oliveira Lima, Edeltrudes; de Medeiros, Paloma Lys; Paiva, Patrícia Maria Guedes; de Souza, Ivone Antônia; Napoleão, Thiago Henrique

    2015-01-01

    This work evaluated an ethanolic extract from Morus alba leaves for toxicity to Artemia salina, oral toxicity to mice, and antimicrobial activity. Phytochemical analysis revealed the presence of coumarins, flavonoids, tannins, and triterpenes in the extract, which did not show toxicity to A. salina nauplii. No mortality and behavioral alterations were detected for mice treated with the extract (300 and 2000 mg/kg b.w.) for 14 days. However, animals that received the highest dose showed reduced MCV and MCHC as well as increased serum alkaline phosphatase activity. In treatments with the extract at both 300 and 2000 mg/kg, there was a reduction in number of leukocytes, with decrease in percentage of lymphocytes and increase in proportion of segmented cells. Histopathological analysis of organs from mice treated with the extract at 2000 mg/kg revealed turgidity of contorted tubules in kidneys, presence of leukocyte infiltration around the liver centrilobular vein, and high dispersion of the spleen white pulp. The extract showed antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, Candida krusei, Candida tropicalis, and Aspergillus flavus. In conclusion, the extract contains antimicrobial agents and was not lethal for mice when ingested; however, its use requires caution because it promoted biochemical, hematological, and histopathological alterations. PMID:26246840

  10. Effect of Environmental Conditions and Toxic Compounds on the Locomotor Activity of Pediculus humanus capitis (Phthiraptera: Pediculidae).

    PubMed

    Ortega-Insaurralde, I; Toloza, A C; Gonzalez-Audino, P; Mougabure-Cueto, G A; Alvarez-Costa, A; Roca-Acevedo, G; Picollo, M I

    2015-09-01

    In this work, we evaluated the effect of environmental variables such as temperature, humidity, and light on the locomotor activity of Pediculus humanus capitis. In addition, we used selected conditions of temperature, humidity, and light to study the effects of cypermethrin and N,N-diethyl-3-methylbenzamide (DEET) on the locomotor activity of head lice. Head lice increased their locomotor activity in an arena at 30°C compared with activity at 20°C. When we tested the influence of the humidity level, the locomotor activity of head lice showed no significant differences related to humidity level, both at 30°C and 20°C. Concerning light influence, we observed that the higher the intensity of light, the slower the movement of head lice. We also demonstrated that sublethal doses of toxics may alter locomotor activity in adults of head lice. Sublethal doses of cypermethrin induced hyperactivated responses in adult head lice. Sublethal doses of DEET evocated hypoactivated responses in head lice. The observation of stereotyped behavior in head lice elicited by toxic compounds proved that measuring locomotor activity in an experimental set-up where environmental conditions are controlled would be appropriate to evaluate compounds of biological importance, such as molecules involved in the host-parasite interaction and intraspecific relationships. PMID:26336260

  11. Reevaluating the free-ion activity model of trace metal toxicity toward higher plants: experimental evidence with copper and zinc.

    PubMed

    Parker, D R; Pedler, J F; Ahnstrom, Z A; Resketo, M

    2001-04-01

    Across a diverse spectrum of organisms, the absorption and toxicity of trace elements are usually correlated with the activity of the free metal ion, but reported exceptions to this generalization are increasing. For the first time, we tested the validity of the free-ion activity model (FIAM) in the case of terrestrial plants and organic acids that may be abundant in the soil solution and rhizosphere. Short-term (48-h) root elongation of wheat (Triticum aestitvum L.) in a simple medium (2 mM CaCl2, pH 6.0) was used to probe the toxicity of Cu and Zn in the presence of malonate, malate, and citrate. Precautions were taken to prevent biodegradation of the organic acids, and its absence was confirmed by ion chromatography. Copper speciation was verified using a Cu-selective ion electrode, and published stability constants were modified to improve agreement between measured and calculated Cu2+ activities. With additions of both malonate and malate, Cu toxicity was alleviated but not to the extent predicted by the FIAM; the Cu-ligand complexes seemingly contributed to the toxicity. No such departures were observed with citrate and Cu nor with any of the three ligands in combination with Zn. Thus, exceptions to the FIAM occur with higher plants as well as with aquatic biota but do not seem to occur in a predictable or systematic fashion with respect to metal or organic acid under investigation. Several possible explanations for the observed departures from the FIAM are discussed, including the possibility of accidental cotransport of metal and ligand into the cytoplasm. PMID:11345467

  12. Mechanisms of perfluoroalkyl acid (PFAA) toxicity: Involvement of peroxisome proliferator activator receptor alpha (PPAR) molecular signals.

    EPA Science Inventory

    Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are members of a family of environmentally persistent perfluorinated compounds and are found in the serum of wildlife and humans. PFOS and PFOA are developmentally toxic in rats and mice. Exposure in utero reduces...

  13. INVERSE QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIP ANALYSIS FOR IMPROVING PREDICTIONS OF CHEMICAL TOXICITY

    EPA Science Inventory

    The toxic outcomes associated with environmental contaminants are often not due to the chemical form that was originally introduced into the environment, but rather to the chemical having undergone a transformation prior to reaching the vulnerable species. More importantly, the c...

  14. In-silico structure activity relationship study of toxicity endpoints by QSAR modeling (SOT)

    EPA Science Inventory

    Several thousand chemicals were tested in 700 toxicity-related in-vitro HTS bioassays through the EPA’s ToxCast and Tox21 projects. This chemical set only covers a portion of the chemical space of interest for environmental exposure, leading to a need to fill data gaps with alter...

  15. Co-Formulants in Glyphosate-Based Herbicides Disrupt Aromatase Activity in Human Cells below Toxic Levels

    PubMed Central

    Defarge, Nicolas; Takács, Eszter; Lozano, Verónica Laura; Mesnage, Robin; Spiroux de Vendômois, Joël; Séralini, Gilles-Eric; Székács, András

    2016-01-01

    Pesticide formulations contain declared active ingredients and co-formulants presented as inert and confidential compounds. We tested the endocrine disruption of co-formulants in six glyphosate-based herbicides (GBH), the most used pesticides worldwide. All co-formulants and formulations were comparably cytotoxic well below the agricultural dilution of 1% (18–2000 times for co-formulants, 8–141 times for formulations), and not the declared active ingredient glyphosate (G) alone. The endocrine-disrupting effects of all these compounds were measured on aromatase activity, a key enzyme in the balance of sex hormones, below the toxicity threshold. Aromatase activity was decreased both by the co-formulants alone (polyethoxylated tallow amine—POEA and alkyl polyglucoside—APG) and by the formulations, from concentrations 800 times lower than the agricultural dilutions; while G exerted an effect only at 1/3 of the agricultural dilution. It was demonstrated for the first time that endocrine disruption by GBH could not only be due to the declared active ingredient but also to co-formulants. These results could explain numerous in vivo results with GBHs not seen with G alone; moreover, they challenge the relevance of the acceptable daily intake (ADI) value for GBHs exposures, currently calculated from toxicity tests of the declared active ingredient alone. PMID:26927151

  16. Co-Formulants in Glyphosate-Based Herbicides Disrupt Aromatase Activity in Human Cells below Toxic Levels.

    PubMed

    Defarge, Nicolas; Takács, Eszter; Lozano, Verónica Laura; Mesnage, Robin; Spiroux de Vendômois, Joël; Séralini, Gilles-Eric; Székács, András

    2016-03-01

    Pesticide formulations contain declared active ingredients and co-formulants presented as inert and confidential compounds. We tested the endocrine disruption of co-formulants in six glyphosate-based herbicides (GBH), the most used pesticides worldwide. All co-formulants and formulations were comparably cytotoxic well below the agricultural dilution of 1% (18-2000 times for co-formulants, 8-141 times for formulations), and not the declared active ingredient glyphosate (G) alone. The endocrine-disrupting effects of all these compounds were measured on aromatase activity, a key enzyme in the balance of sex hormones, below the toxicity threshold. Aromatase activity was decreased both by the co-formulants alone (polyethoxylated tallow amine-POEA and alkyl polyglucoside-APG) and by the formulations, from concentrations 800 times lower than the agricultural dilutions; while G exerted an effect only at 1/3 of the agricultural dilution. It was demonstrated for the first time that endocrine disruption by GBH could not only be due to the declared active ingredient but also to co-formulants. These results could explain numerous in vivo results with GBHs not seen with G alone; moreover, they challenge the relevance of the acceptable daily intake (ADI) value for GBHs exposures, currently calculated from toxicity tests of the declared active ingredient alone. PMID:26927151

  17. Assessment of quantitative structure-activity relationship of toxicity prediction models for Korean chemical substance control legislation

    PubMed Central

    Kim, Kwang-Yon; Shin, Seong Eun; No, Kyoung Tai

    2015-01-01

    Objectives For successful adoption of legislation controlling registration and assessment of chemical substances, it is important to obtain sufficient toxicological experimental evidence and other related information. It is also essential to obtain a sufficient number of predicted risk and toxicity results. Particularly, methods used in predicting toxicities of chemical substances during acquisition of required data, ultimately become an economic method for future dealings with new substances. Although the need for such methods is gradually increasing, the-required information about reliability and applicability range has not been systematically provided. Methods There are various representative environmental and human toxicity models based on quantitative structure-activity relationships (QSAR). Here, we secured the 10 representative QSAR-based prediction models and its information that can make predictions about substances that are expected to be regulated. We used models that predict and confirm usability of the information expected to be collected and submitted according to the legislation. After collecting and evaluating each predictive model and relevant data, we prepared methods quantifying the scientific validity and reliability, which are essential conditions for using predictive models. Results We calculated predicted values for the models. Furthermore, we deduced and compared adequacies of the models using the Alternative non-testing method assessed for Registration, Evaluation, Authorization, and Restriction of Chemicals Substances scoring system, and deduced the applicability domains for each model. Additionally, we calculated and compared inclusion rates of substances expected to be regulated, to confirm the applicability. Conclusions We evaluated and compared the data, adequacy, and applicability of our selected QSAR-based toxicity prediction models, and included them in a database. Based on this data, we aimed to construct a system that can be used

  18. Mechanistic toxicodynamic model for receptor-mediated toxicity of diazoxon, the active metabolite of diazinon, in Daphnia magna.

    PubMed

    Kretschmann, Andreas; Ashauer, Roman; Hitzfeld, Kristina; Spaak, Piet; Hollender, Juliane; Escher, Beate I

    2011-06-01

    The organothiophosphate diazinon inhibits the target site acetylcholinesterase only after activation to its metabolite diazoxon. Commonly, the toxicity of xenobiotics toward aquatic organisms is expressed as a function of the external concentration and the resulting effect on the individual level after fixed exposure times. This approach does not account for the time dependency of internal processes such as uptake, metabolism, and interaction of the toxicant with the target site. Here, we develop a mechanistic toxicodynamic model for Daphnia magna and diazoxon, which accounts for the inhibition of the internal target site acetylcholinesterase and its link to the observable effect, immobilization, and mortality. The model was parametrized by experiments performed in vitro with the active metabolite diazoxon on enzyme extracts and in vivo with the parent compound diazinon. The mechanism of acetylcholinesterase inhibition was shown to occur irreversibly in two steps via formation of a reversible enzyme-inhibitor complex. The corresponding kinetic parameters revealed a very high sensitivity of acetylcholinesterase from D. magna toward diazoxon, which corresponds well with the high toxicity of diazinon toward this species. Recovery of enzyme activity but no recovery from immobilization was observed after in vivo exposure to diazinon. The toxicodynamic model combining all in vitro and in vivo parameters was successfully applied to describe the time course of immobilization in dependence of acetylcholinesterase activity during exposure to diazinon. The threshold value for enzyme activity below which immobilization set in amounted to 40% of the control activity. Furthermore, the model enabled the prediction of the time-dependent diazoxon concentration directly present at the target site. PMID:21539304

  19. A Comparison of the Antimicrobial Activity and Toxicity of Six Combretum and Two Terminalia Species from Southern Africa

    PubMed Central

    Cock, I. E.; Van Vuuren, S.F.

    2015-01-01

    Background: Plants of the family Combretaceae are amongst the most widely used plants for traditional medicinal purposes in southern Africa. In particular, many species of Combretum and Terminalia are used for their antibacterial, antifungal, antiprotozoal, antiviral, antidiarrhoeal, analgesic, antimalarial, antioxidant, anti-inflammatory and anticancer activities, yet their antimicrobial potential has not been rigorously studied and compared. Materials and Methods: A survey of antimicrobial activity was undertaken on selected South African Combretum and Terminalia species. Sixteen extracts from 6 Combretum and 2 Terminalia plant species with a history of medicinal usage were investigated by disc diffusion assay against a panel of bacteria and fungi and their MIC values were determined. Toxicity was determined using the Artemia franciscana nauplii bioassay. Results: All extracts tested displayed broad spectrum antibacterial activity, inhibiting the growth of 12-16 (75-100%) of the bacteria tested, with Gram-positive and Gram-negative bacteria being approximately equally susceptible. Potent antibacterial activities (generally in the range 200-5000 μg/ml) were evident for all Combretaceae extracts against both Gram-positive and Gram-negative bacteria. Similarly, the extracts also displayed good antifungal activity, inhibiting the growth of 2-3 (66.7-100%) of the fungal species tested, with fungal growth inhibition activities generally in the range 200–4000 μg/ml. In general, the Terminalia extracts had better efficacies than the Combretum extracts. Furthermore, the methanol extracts were generally better antimicrobial agents than the water extracts. All extracts were also shown to be non-toxic in the Artemia nauplii bioassay. Conclusion: The lack of toxicity of these extracts and their inhibitory bioactivity against a panel of bacteria and fungi indicate their potential as medicinal agents and partially validate their usage in multiple South African traditional

  20. The fate and toxicity of Raman-active silica-gold nanoparticles in mice.

    PubMed

    Thakor, Avnesh S; Luong, Richard; Paulmurugan, Ramasamy; Lin, Frank I; Kempen, Paul; Zavaleta, Cristina; Chu, Pauline; Massoud, Tarik F; Sinclair, Robert; Gambhir, Sanjiv S

    2011-04-20

    Raman spectroscopy is an optical imaging method that is based on the Raman effect, the inelastic scattering of a photon when energy is absorbed from light by a surface. Although Raman spectroscopy is widely used for chemical and molecular analysis, its clinical application has been hindered by the inherently weak nature of the Raman effect. Raman-silica-gold-nanoparticles (R-Si-Au-NPs) overcome this limitation by producing larger Raman signals through surface-enhanced Raman scattering. Because we are developing these particles for use as targeted molecular imaging agents, we examined the acute toxicity and biodistribution of core polyethylene glycol (PEG)-ylated R-Si-Au-NPs after different routes of administration in mice. After intravenous administration, PEG-R-Si-Au-NPs were removed from the circulation by macrophages in the liver and spleen (that is, the reticuloendothelial system). At 24 hours, PEG-R-Si-Au-NPs elicited a mild inflammatory response and an increase in oxidative stress in the liver, which subsided by 2 weeks after administration. No evidence of significant toxicity was observed by measuring clinical, histological, biochemical, or cardiovascular parameters for 2 weeks. Because we are designing targeted PEG-R-Si-Au-NPs (for example, PEG-R-Si-Au-NPs labeled with an affibody that binds specifically to the epidermal growth factor receptor) to detect colorectal cancer after administration into the bowel lumen, we tested the toxicity of the core nanoparticle after administration per rectum. We observed no significant bowel or systemic toxicity, and no PEG-R-Si-Au-NPs were detected systemically. Although additional studies are required to investigate the long-term effects of PEG-R-Si-Au-NPs and their toxicity when carrying the targeting moiety, the results presented here support the idea that PEG-R-Si-Au-NPs can be safely used in living subjects, especially when administered rectally. PMID:21508310

  1. A conjugate of the lytic peptide Hecate and gallic acid: structure, activity against cervical cancer, and toxicity.

    PubMed

    Sanches, Paulo R S; Carneiro, Bruno M; Batista, Mariana N; Braga, Ana Cláudia S; Lorenzón, Esteban N; Rahal, Paula; Cilli, Eduardo Maffud

    2015-07-01

    Conjugate compounds constitute a new class of molecules of important biological interest mainly for the treatment of diseases such as cancer. The N-terminus region of cationic peptides has been described as important for their biological activity. The aim of this study was to evaluate the lytic peptide Hecate (FALALKALKKALKKLKKALKKAL) and the effect of conjugating this macromolecule with gallic acid (C7H6O5) in terms of structure, anti-cancer activity, and toxicity. An N-terminus GA-Hecate peptide conjugate was synthesized to provide information regarding the relationship between the amino-terminal region and its charge and the secondary structure and biological activity of the peptide; and the effects of gallic acid on these parameters. Peptide secondary structure was confirmed using circular dichroism (CD). The CD measurements showed that the peptide has a high incidence of α-helical structures in the presence of SDS and LPC, while GA-Hecate presented lower incidence of α-helical structures in the same chemical environment. An evaluation of the anti-cancer activity in HeLa cancer cells indicated that both peptides are active, but that coupling gallic acid at the N-terminus decreased the activity of the free peptide. GA-Hecate showed lower activity in non-tumor keratinocyte cells but higher hemolytic activity. Our findings suggest that the N-terminus of Hecate plays an important role in its activity against cervical cancer by affecting it secondary structure, toxicity, and hemolytic activity. This study highlights the importance of the N-terminus in antitumor activity and could provide an important tool for developing new anti-cancer drugs. PMID:25868656

  2. Protective activity of andrographolide and arabinogalactan proteins from Andrographis paniculata Nees. against ethanol-induced toxicity in mice.

    PubMed

    Singha, Prajjal K; Roy, Somenath; Dey, Satyahari

    2007-04-20

    To find out the active principles against ethanol-induced toxicity in mice, Andrographis paniculata Nees. (Ap) was chosen and isolated andrographolide (ANDRO) and arabinogalactan proteins (AGPs). ANDRO was detected by HPTLC, FTIR and quantified by HPLC (10mg/g of Ap powder). AGPs was detected by beta-glucosyl Yariv staining of SDS-PAGE gel, FTIR and quantified by single radial gel diffusion assay with beta-glucosyl Yariv reagent (0.5mg/g Ap powder). The mice are pretreated intra-peritoneally (i.p.) with different doses (62.5, 125, 250, and 500mg/kg) of body weight of mice] of ANDRO and AGPs for 7 days and then ethanol (7.5g/kg of body weight) was injected, i.p. Besides, silymarin was used as standard hepatoprotective agent for comparative study with ANDRO and AGPs. The ameliorative activity of ANDRO and AGP against hepatic renal alcohol toxicity was measured by assessing GOT, GPT, ACP, ALP and LP levels in liver and kidney. It has been observed that pretreatment of mice with ANDRO and AGPs at 500mg/kg of body weight and 125mg/kg of body weight respectively could able to minimize the toxicity in compare to ethanol treated group as revealed by the different enzymatic assay in liver and kidney tissues and the results were comparable with silymarin. Hence, out of several ill-defined compounds present in Ap, ANDRO and AGPs are the potential bioactive compounds responsible for protection against ethanol-induced toxicity. PMID:17127022

  3. Mechanisms of olfactory toxicity of the herbicide 2,6-dichlorobenzonitrile: Essential roles of CYP2A5 and target-tissue metabolic activation

    SciTech Connect

    Xie Fang; Zhou Xin; Behr, Melissa; Fang Cheng; Horii, Yuichi; Gu Jun; Kannan, Kurunthachalam; Ding Xinxin

    2010-11-15

    The herbicide 2,6-dichlorobenzonitril (DCBN) is a potent and tissue-specific toxicant to the olfactory mucosa (OM). The toxicity of DCBN is mediated by cytochrome P450 (P450)-catalyzed bioactivation; however, it is not known whether target-tissue metabolic activation is essential for toxicity. CYP2A5, expressed abundantly in both liver and OM, was previously found to be one of the P450 enzymes active in DCBN bioactivation in vitro. The aims of this study were to determine the role of CYP2A5 in DCBN toxicity in vivo, by comparing the extents of DCBN toxicity between Cyp2a5-null and wild-type (WT) mice, and to determine whether hepatic microsomal P450 enzymes (including CYP2A5) are essential for the DCBN toxicity, by comparing the extents of DCBN toxicity between liver-Cpr-null (LCN) mice, which have little P450 activity in hepatocytes, and WT mice. We show that the loss of CYP2A5 expression did not alter systemic clearance of DCBN (at 25 mg/kg); but it did inhibit DCBN-induced non-protein thiol depletion and cytotoxicity in the OM. Thus, CYP2A5 plays an essential role in mediating DCBN toxicity in the OM. In contrast to the results seen in the Cyp2a5-null mice, the rates of systemic DCBN clearance were substantially reduced, while the extents of DCBN-induced nasal toxicity were increased, rather than decreased, in the LCN mice, compared to WT mice. Therefore, hepatic P450 enzymes, although essential for DCBN clearance, are not necessary for DCBN-induced OM toxicity. Our findings form the basis for a mechanism-based approach to assessing the potential risks of DCBN nasal toxicity in humans.

  4. Mimic of superoxide dismutase activity protects Chlorella sorokiniana against the toxicity of sulfite

    SciTech Connect

    Rabinowitch, H.D.; Rosen, G.M.; Fridovich, I.

    1989-01-01

    The spin-trapping agent 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) has been used to demonstrate the light-dependent production of O/sub 2/- by Chlorella sorokiniana. In the presence of SO/sub 3/= a light-dependent production of the sulfur trioxy anion radical (SO/sub 3/-.) could also be seen. A complex prepared by reacting desferrioxamine with MnO/sub 2/, which catalyzes the dismutation of O/sub 2/-, protected the alga against the toxicity of sulfite. The data suggest that SO/sub 2/ toxicity is at least partially due to the effects of sulfoxy-free radicals generated by the oxidation of SO3= by O/sub 2/-.

  5. Cisplatin-loaded core cross-linked micelles: comparative pharmacokinetics, antitumor activity, and toxicity in mice

    PubMed Central

    Oberoi, Hardeep S; Nukolova, Natalia V; Laquer, Frederic C; Poluektova, Larisa Y; Huang, Jiangeng; Alnouti, Yazen; Yokohira, Masanao; Arnold, Lora L; Kabanov, Alexander V; Cohen, Samuel M; Bronich, Tatiana K

    2012-01-01

    Polymer micelles with cross-linked ionic cores are shown here to improve the therapeutic performance of the platinum-containing anticancer compound cisplatin. Biodistribution, antitumor efficacy, and toxicity of cisplatin-loaded core cross-linked micelles of poly(ethylene glycol)-b-poly(methacrylic acid) were evaluated in a mouse ovarian cancer xenograft model. Cisplatin-loaded micelles demonstrated prolonged blood circulation, increased tumor accumulation, and reduced renal exposure. Improved antitumor response relative to free drug was seen in a mouse model. Toxicity studies with cisplatin-loaded micelles indicate a significantly improved safety profile and lack of renal abnormalities typical of free cisplatin treatment. Overall, the study supports the fundamental possibility of improving the potential of platinum therapy using polymer micelle-based drug delivery. PMID:22745537

  6. Reproductive activities of Heliotropium indicum isolate against Helopeltis theivora and toxicity evaluation in mice.

    PubMed

    Dolui, A K; Debnath, Manabendra; De, B; Kumar, Atul

    2012-05-01

    A new compound E was isolated from the methanolic extract of the leaves of Heliotropium indicum by chromatographic fractionation. In the present study, the effect of the compound E on reproduction of Helopeltis theivora has been evaluated. The acute toxicity study (LD50) and sub-acute toxicity studies (haematological, biochemical and histopathological parameters) in albino Swiss mice were carried out to evaluate the safety aspect of the compound E. The compound showed significant inhibitory effect on the reproductive life of H. theivora. The oviposition period, fecundity and hatching percentage of H. theivora were found to be 15.67 days, 39.33 and 28.00% respectively after treatment with 2% compound E, whereas the control value were found to be 20.33 days, 77.67 and 77.33% respectively. The LD50 of the compound was found to be 780 mg kg(-1) in Swiss albino female mice. The compound did not show any toxicity in mice at sub-lethal dose treatment (78 mg kg(-1) b. wt., once daily) for 21 days as evident from different haematological, biochemical and histopathological parameters in compound E treated group when compared with control. PMID:23029910

  7. The antioxidant, general toxicity and insecticidal activities of Nepeta scrophularioides Rech. f. extracts in different developmental stages.

    PubMed

    Gharbani, Parvin; Javazi, Hamideh

    2015-09-01

    The essence of the present study is to focus on the antioxidant, general toxicity and insecticidal properties of the extracts of Nepeta scrophularioides Rech.f. during different developmental (vegetative, flowering, post-flowering) stages. The samples were subjected to screening for their possible antioxidant activities by using 2, 2-diphenyl-1-picrylhydrazyl (DPPH) assay. The extracts of the flowering and the post-flowering stages showed higher antioxidant activity than those from the vegetative stage. The MeOH extracts of N. scrophularioides in different development stages were tested for cytotoxicity by brine shrimp toxicity assay. The result obtained for the bio assay was found to be significantly lethality. Among the samples, the extracts of flowering stage were found to be the most active with a LC50 value of 0.078 mg/mL. All three extracts showed significant insecticidal activity at the concentration of 20 mg/mL dose of test sample after 24 h. The extracts of vegetative and post-flowering were the most potent samples. PMID:26525034

  8. Identification of phototransformation products of thalidomide and mixture toxicity assessment: an experimental and quantitative structural activity relationships (QSAR) approach.

    PubMed

    Mahmoud, Waleed M M; Toolaram, Anju P; Menz, Jakob; Leder, Christoph; Schneider, Mandy; Kümmerer, Klaus

    2014-02-01

    The fate of thalidomide (TD) was investigated after irradiation with a medium-pressure Hg-lamp. The primary elimination of TD was monitored and structures of phototransformation products (PTPs) were assessed by LC-UV-FL-MS/MS. Environmentally relevant properties of TD and its PTPs as well as hydrolysis products (HTPs) were predicted using in silico QSAR models. Mutagenicity of TD and its PTPs was investigated in the Ames microplate format (MPF) aqua assay (Xenometrix, AG). Furthermore, a modified luminescent bacteria test (kinetic luminescent bacteria test (kinetic LBT)), using the luminescent bacteria species Vibrio fischeri, was applied for the initial screening of environmental toxicity. Additionally, toxicity of phthalimide, one of the identified PTPs, was investigated separately in the kinetic LBT. The UV irradiation eliminated TD itself without complete mineralization and led to the formation of several PTPs. TD and its PTPs did not exhibit mutagenic response in the Salmonella typhimurium strains TA 98, and TA 100 with and without metabolic activation. In contrast, QSAR analysis of PTPs and HTPs provided evidence for mutagenicity, genotoxicity and carcinogenicity using additional endpoints in silico software. QSAR analysis of different ecotoxicological endpoints, such as acute toxicity towards V. fischeri, provided positive alerts for several identified PTPs and HTPs. This was partially confirmed by the results of the kinetic LBT, in which a steady increase of acute and chronic toxicity during the UV-treatment procedure was observed for the photolytic mixtures at the highest tested concentration. Moreover, the number of PTPs within the reaction mixture that might be responsible for the toxification of TD during UV-treatment was successfully narrowed down by correlating the formation kinetics of PTPs with QSAR predictions and experimental toxicity data. Beyond that, further analysis of the commercially available PTP phthalimide indicated that transformation of

  9. Structure-activity relationship studies on derivatives of eudesmanolides from Inula helenium as toxicants against Aedes aegypti larvae and adults.

    PubMed

    Cantrell, Charles L; Pridgeon, Julia W; Fronczek, Frank R; Becnel, James J

    2010-07-01

    An Aedes aegypti larval toxicity bioassay was performed on compounds representing many classes of natural compounds including polyacetylenes, phytosterols, flavonoids, sesquiterpenoids, and triterpenoids. Among these compounds, two eudesmanolides, alantolactone, and isoalantolactone showed larvicidal activities against Ae. aegypti and, therefore, were chosen for further structure-activity relationship study. In this study, structural modifications were performed on both alantolactone and isoalantolactone in an effort to understand the functional groups necessary for maintaining and/or increasing its activity, and to possibly lead to more effective insect-control agents. All parent compounds and synthetic modification reaction products were evaluated for their toxic activities against Ae. aegypti larvae and adults. Structure modifications included epoxidations, reductions, catalytic hydrogenations, and Michael additions to the alpha,beta-unsaturated lactones. None of the synthetic isomers synthesized and screened against Ae. aegypti larvae were more active than isoalantolactone itself which had an LC(50) value of 10.0 microg/ml. This was not the case for analogs of alantolactone for which many of the analogs had larvicidal activities ranging from 12.4 to 69.9 microg/ml. In general, activity trends observed from Ae. aegypti larval screening were not consistent with observations from adulticidal screening. The propylamine Michael addition analog of alantolactone was the most active adulticide synthesized with an LC(50) value of 1.07 microg/mosquito. In addition, the crystal structures of both alantolactone and isoalantolactone were determined using CuK(alpha) radiation, which allowed their absolute configurations to be determined based on resonant scattering of the light atoms. PMID:20658657

  10. Evaluation of antimicrobial activity of glycerol monolaurate nanocapsules against American foulbrood disease agent and toxicity on bees.

    PubMed

    Lopes, Leonardo Q S; Santos, Cayane G; de Almeida Vaucher, Rodrigo; Gende, Liesel; Raffin, Renata P; Santos, Roberto C V

    2016-08-01

    The American Foulbrood Disease (AFB) is a fatal larval bee infection. The etiologic agent is the bacterium Paenibacillus larvae. The treatment involves incineration of all contaminated materials, leading to high losses. The Glycerol Monolaurate (GML) is a known antimicrobial potential compound, however its use is reduced due to its low solubility in water and high melting point. The nanoencapsulation of some drugs offers several advantages like improved stability and solubility in water. The present study aimed to evaluate the antimicrobial activity against P. larvae and the toxicity in bees of GML nanoparticles. The nanocapsules were produced and presented mean diameter of 210 nm, polydispersity index of 0.044, and zeta potential of -23.4 mV demonstrating the acceptable values to predict a stable system. The microdilution assay showed that it is necessary 142 and 285 μg/mL of GML nanocapsules to obtain a bacteriostatic and bactericidal effect respectively. The time-kill curve showed the controlled release of compound, exterminating the microorganism after 24 h. The GML nanocapsules were able to kill the spore form of Paenibacillus larvae while the GML do not cause any effect. The assay in bees showed that the GML has a high toxicity while the GML nanoparticles showed a decrease on toxic effects. Concluding, the formulation shows positive results in the action to combat AFB besides not causing damage to bees. PMID:27216238

  11. Estimating the Potential Toxicity of Chemicals Associated with Hydraulic Fracturing Operations Using Quantitative Structure-Activity Relationship Modeling.

    PubMed

    Yost, Erin E; Stanek, John; DeWoskin, Robert S; Burgoon, Lyle D

    2016-07-19

    The United States Environmental Protection Agency (EPA) identified 1173 chemicals associated with hydraulic fracturing fluids, flowback, or produced water, of which 1026 (87%) lack chronic oral toxicity values for human health assessments. To facilitate the ranking and prioritization of chemicals that lack toxicity values, it may be useful to employ toxicity estimates from quantitative structure-activity relationship (QSAR) models. Here we describe an approach for applying the results of a QSAR model from the TOPKAT program suite, which provides estimates of the rat chronic oral lowest-observed-adverse-effect level (LOAEL). Of the 1173 chemicals, TOPKAT was able to generate LOAEL estimates for 515 (44%). To address the uncertainty associated with these estimates, we assigned qualitative confidence scores (high, medium, or low) to each TOPKAT LOAEL estimate, and found 481 to be high-confidence. For 48 chemicals that had both a high-confidence TOPKAT LOAEL estimate and a chronic oral reference dose from EPA's Integrated Risk Information System (IRIS) database, Spearman rank correlation identified 68% agreement between the two values (permutation p-value =1 × 10(-11)). These results provide support for the use of TOPKAT LOAEL estimates in identifying and prioritizing potentially hazardous chemicals. High-confidence TOPKAT LOAEL estimates were available for 389 of 1026 hydraulic fracturing-related chemicals that lack chronic oral RfVs and OSFs from EPA-identified sources, including a subset of chemicals that are frequently used in hydraulic fracturing fluids. PMID:27172125

  12. Sorption and toxicity reduction of pharmaceutically active compounds and endocrine disrupting chemicals in the presence of colloidal humic acid.

    PubMed

    Kim, Injeong; Kim, Hyo-Dong; Jeong, Tae-Yong; Kim, Sang Don

    2016-01-01

    This study investigated the toxicity changes and sorption of pharmaceuticals and endocrine disrupters in the presence of humic acid (HA). For the sorption experiment, a dead end filtration (DEF) system was used to separate bound and free-form target compounds. An algae growth inhibition test and E-screen assay were conducted to estimate the toxic effect of pharmaceutically active compounds (PhACs) and endocrine disrupting chemicals (EDCs), respectively. The permeate concentration was confirmed using liquid chromatography-mass spectrometry. In the sorption test, we observed significant sorption of PhACs and EDCs on colloidal HA, except for sulfamethoxazole (SMX). The values of log KCOC derived from DEF determinations ranged from 4.40 to 5.03. The removal efficiency varied with the HA concentration and the target chemical properties. Tetracycline and 4-octylphenol showed the highest sorption or removal efficiency (≈50%), even at 5 mg C/L HA. The algal growth inhibition of PhACs and the estrogenic effects of EDCs were significantly decreased in proportion to HA concentrations, except for SMX. In addition, the chemical analysis results showed a positive relationship with the bioassay results. Consequently, the sorption of PhACs and EDCs onto colloidal HA should be emphasized in natural environments because it significantly reduces bioavailable concentrations and toxicity to aquatic organisms. PMID:27533865

  13. Toxicity evaluation of cordycepin and its delivery system for sustained in vitro anti-lung cancer activity

    NASA Astrophysics Data System (ADS)

    Aramwit, Pornanong; Porasuphatana, Supatra; Srichana, Teerapol; Nakpheng, Titpawan

    2015-03-01

    In the previous study, we have found that the cordycepin which was extracted from Cordyceps mycelia produced by growing Cordyceps militaris on the dead larva of Bombyx mori silkworms showed the anti-proliferative effect toward lung cancer cells without toxicity to non-cancer cells. In this work, the cordycepin was tested for its in vitro mutagenicity and in vivo toxicity. From the Ames test and subacute toxicity test using oral administration in a rat model, the cordycepin was proved to be a non-mutagenic and non-toxic compound. The hematology and blood chemistry as well as the microanatomical characteristic of the tissues of rats fed with cordycepin every day for consecutive 30 days were comparable to those of the normal ones. Then, the cordycepin was incorporated in gelatin type A (GA) and gelatin type B (GB) nanoparticles aimed to sustain its release and activity. The cordycepin incorporated in both GA and GB nanoparticles showed the sustained release profiles. GA nanoparticles could encapsulate cordycepin at higher encapsulation efficiency due to the attractive electrostatic interaction between the positive-charged GA and the negative-charged cordycepin. However, GA nanoparticles released cordycepin at the higher amount possibly because of the large surface area of small size nanoparticles. Comparing to GB nanoparticles, the higher amount of cordycepin released from GA nanoparticles showed the higher anti-proliferative and anti-migratory effects on A549 lung cancer cells. In conclusion, GA nanoparticles were suggested as a suitable carrier for the sustained release of cordycepin. The GA nanoparticles releasing cordycepin could be an effective and non-invasive material for the treatment of lung cancer cells.

  14. Thresholds of arsenic toxicity to Eisenia fetida in field-collected agricultural soils exposed to copper mining activities in Chile.

    PubMed

    Bustos, Víctor; Mondaca, Pedro; Verdejo, José; Sauvé, Sébastien; Gaete, Hernán; Celis-Diez, Juan L; Neaman, Alexander

    2015-12-01

    Several previous studies highlighted the importance of using field-collected soils-and not artificially-contaminated soils-for ecotoxicity tests. However, the use of field-collected soils presents several difficulties for interpretation of results, due to the presence of various contaminants and unavoidable differences in the physicochemical properties of the tested soils. The objective of this study was to estimate thresholds of metal toxicity in topsoils of 24 agricultural areas historically contaminated by mining activities in Chile. We performed standardized earthworm reproduction tests (OECD 222 and ISO 11268-2) with Eisenia fetida. Total soil concentrations of Cu, As, Zn, and Pb were in the ranges of 82-1295 mg kg(-1), 7-41 mg kg(-1), 86-345 mg kg(-1), and 25-97 mg kg(-1), respectively. In order to differentiate between the effects of different metals, we used regression analysis between soil metal concentrations and earthworm responses, as well as between metal concentrations in earthworm tissues and earthworm responses. Based on regression analysis, we concluded that As was a metal of prime concern for Eisenia fetida in soils affected by Cu mining activities, while Cu exhibited a secondary effect. In contrast, the effects of Zn and Pb were not significant. Soil electrical conductivity was another significant contributor to reproduction toxicity in the studied soils, forcing its integration in the interpretation of the results. By using soils with electrical conductivity ≤ 0.29 dS m(-1) (which corresponds to EC50 of salt toxicity to Eisenia fetida), it was possible to isolate the effect of soil salinity on earthworm reproduction. Despite the confounding effects of Cu, it was possible to determine EC10, EC25 and EC50 values for total soil As at 8 mg kg(-1), 14 mg kg(-1) and 22 mg kg(-1), respectively, for the response of the cocoon production. However, it was not possible to determine these threshold values for juvenile production. Likewise, we were able to

  15. Life stage toxicity and residual activity of insecticides to codling moth and oriental fruit moth (Lepidoptera: Tortricidae).

    PubMed

    Magalhaes, Leonardo C; Walgenbach, James F

    2011-12-01

    The codling moth, Cydia pomonella (L.), and oriental fruit moth, Grapholita molesta (Busck), are two key pests of apple (Malus domestica Borkh.) in North Carolina. Growers extensively relied on organophosphate insecticides, primarily azinphosmethyl, for > 40 yr to manage these pests. Because of organophosphate resistance development and regulatory actions, growers are transitioning to management programs that use new, reduced-risk, and OP-replacement insecticides. This study evaluated the toxicity of a diversity of replacement insecticides to eggs, larvae, and adults, as well as an assessment of their residual activity, to codling moth and oriental fruit moth. Laboratory-susceptible strains of both species were used for all bioassays. Fresh field-harvested apples were used as a media for assessing the ovicidal activity of insecticides. For larval studies, insecticides were topically applied to the surface of lima bean-based diet, onto which neonates were placed. Toxicity was based on two measures of mortality; 5-d mortality and development to adult stage. Ovicidal bioassays showed that oriental fruit moth eggs were generally more tolerant than codling moth eggs to insecticides, with novaluron, acetamiprid, and azinphoshmethyl having the highest levels of toxicity to eggs of both species. In contrast, codling moth larvae generally were more tolerant than oriental fruit moth to most insecticides. Methoxyfenozide and pyriproxyfen were the only insecticides with lower LC50 values against codling moth than oriental fruit moth neonates. Moreover, a number of insecticides, particularly the IGRs methoxyfenozide and novaluron, the anthranilic diamide chlorantriliprole, and the spinosyn spinetoram, provided equal or longer residual activity against codling moth compared with azinphosmethyl in field studies. Results are discussed in relation to their use in devising field use patterns of insecticides and for insecticide resistance monitoring programs. PMID:22299357

  16. Metabolites from Aspergillus fumigatus, an endophytic fungus associated with Melia azedarach, and their antifungal, antifeedant, and toxic activities.

    PubMed

    Li, Xiao-Jun; Zhang, Qiang; Zhang, An-Ling; Gao, Jin-Ming

    2012-04-01

    Thirty-nine fungal metabolites 1-39, including two new alkaloids, 12β-hydroxy-13α-methoxyverruculogen TR-2 (6) and 3-hydroxyfumiquinazoline A (16), were isolated from the fermentation broth of Aspergillus fumigatus LN-4, an endophytic fungus isolated from the stem bark of Melia azedarach. Their structures were elucidated on the basis of detailed spectroscopic analysis (mass spectrometry and one- and two-dimensional NMR experiments) and by comparison of their NMR data with those reported in the literature. These isolated compounds were evaluated for in vitro antifungal activities against some phytopathogenic fungi, toxicity against brine shrimps, and antifeedant activities against armyworm larvae (Mythimna separata Walker). Among them, sixteen compounds showed potent antifungal activities against phytopathogenic fungi (Botrytis cinerea, Alternaria solani, Alternaria alternata, Colletotrichum gloeosporioides, Fusarium solani, Fusarium oxysporum f. sp. niveum, Fusarium oxysporum f. sp. vasinfectum, and Gibberella saubinettii), and four of them, 12β-hydroxy-13α-methoxyverruculogen TR-2 (6), fumitremorgin B (7), verruculogen (8), and helvolic acid (39), exhibited antifungal activities with MIC values of 6.25-50 μg/mL, which were comparable to the two positive controls carbendazim and hymexazol. In addition, of eighteen that exerted moderate lethality toward brine shrimps, compounds 7 and 8 both showed significant toxicities with median lethal concentration (LC(50)) values of 13.6 and 15.8 μg/mL, respectively. Furthermore, among nine metabolites that were found to possess antifeedant activity against armyworm larvae, compounds 7 and 8 gave the best activity with antifeedant indexes (AFI) of 50.0% and 55.0%, respectively. Structure-activity relationships of the metabolites were also discussed. PMID:22409377

  17. Toxic action/toxicity.

    PubMed

    Hathway, D E

    2000-02-01

    Some six or so physiological systems, essential to normal mammalian life, are involved in poisoning; an intoxication that causes severe injury to any one of them could be life threatening. Reversible chemical reactions showing Scatchard-type binding are exemplified by CO, CN- and cyclodiene neurotoxin insecticide intoxications, and by antigen-antibody complex formation. Haemoglobin (Hb) molecular biology accounts for the allosteric co-operativity and other characteristics of CO poisoning, CN- acts as a powerful cytochrome oxidase inhibitor, and antigen binding in a deep antibody cleft between two domains equipped with epitopes for antigen-binding groups explains hapten-specific immune reactions. Covalent chemical reactions with second-order (SN2) kinetics characterize Hg and Cd poisonings, the reactions of organophosphates and phosphonates with acetylcholinesterase and neurotoxic esterase and the reaction sequence whereby Paraquat accepts electrons and generates superoxide under aerobic conditions. Indirect carcinogens require cytochrome P450 activation to form DNA adducts in target-organ DNA and cause cancer, but a battery of detoxifying enzymes clustered with the P450 system must be overcome. Thus, S-metabolism competes ineffectively with target DNA for reactive vinyl chloride (VC) metabolites, epoxide hydrolase is important to the metabolism and carcinogenicity of alfatoxins and polycyclic aromatic hydrocarbons (benzo[a]pyrene, etc.), and the non-toxic 2-naphthylhydroxylamine N-glucuronide acts as a transport form in 2-naphthylamine bladder cancer. VC liver-cancer pathogenesis is explicable in terms of the presence of the glutathione S-transferase detoxifying system in hepatocytes and its absence from the fibroblastic elements, and of the VC concentrations reaching the liver by different administrative routes. In VC carcinogenicity, chemical reactions give imidazo-cyclization products with nucleoside residues of target DNA, and in benzene leukaemia, Z

  18. THE FATE AND TOXICITY OF RAMAN ACTIVE SILICA-GOLD NANOPARTICLES IN MICE

    PubMed Central

    THAKOR, AVNESH S; LUONG, RICHARD; PAULMURUGAN, RAMASAMY; LIN, FRANK I; KEMPEN, PAUL; ZAVALETA, CRISTINA; CHU, PAULINE; MASSOUD, TARIK F; SINCLAIR, ROBERT; GAMBHIR, SANJIV S

    2013-01-01

    Raman spectroscopy is an optical imaging modality which analyses the Raman effect in which energy is exchanged between light and matter. Although Raman spectroscopy has been widely used for chemical and molecular analysis, its use in clinical applications has been hindered by the inherently weak nature of the Raman effect. Raman-silica-gold-nanoparticles (R-Si-Au-NPs) overcome this limitation by producing high Raman signals via Surface Enhanced Raman Scattering. Targeted polyethylene glycol (PEG)-ylated R-Si-Au-NPs (e.g. PEG-R-Si-Au-NPs labeled with an affibody which binds specifically to the epidermal growth factor receptor) are currently being designed to detect colorectal cancer after administration into the bowel lumen. With this approach, PEG-R-Si-Au-NPs are not expected to enter the systemic circulation and would be removed from the body via defecation. We examined the acute toxicity and biodistribution of core PEG-R-Si-Au-NPs after different routes of administration in mice. After intravenous administration, PEG-R-Si-Au-NPs were removed from the circulation by marcophages in the liver and spleen (i.e. the reticuloendothelial system). At 24 hours, PEG-R-Si-Au-NPs elicited a mild inflammatory response and an increase in oxidative stress in the liver, which subsided by 2 weeks. No evidence of significant toxicity was observed by measuring clinical, histological, biochemical or cardiovascular parameters for 2 weeks. Notably, after administration per rectum, we observed no significant bowel or systemic toxicity and no PEG-R-Si-Au-NPs were detected systemically. Although additional studies are required to investigate the long-term effects of PEG-R-Si-Au-NPs, these initial results support the idea that they can be safely used in living subjects, especially when administered rectally. PMID:21508310

  19. T cell activation and cytokine release in streptococcal toxic shock-like syndrome.

    PubMed

    Nadal, D; Lauener, R P; Braegger, C P; Kaufhold, A; Simma, B; Lütticken, R; Seger, R A

    1993-05-01

    A 5-year-old girl with streptococcal toxic shock-like syndrome during varicella infection had high levels of tumor necrosis factor alpha and interleukin-6 but no interleukin-1 or interleukin-2 in the serum. Intravenous administration of gamma-globulin coincided with clinical improvement and with reduction of the levels of tumor necrosis factor alpha and interleukin-6. The data suggest that streptococcal pyrogenic exotoxins trigger synthesis of tumor necrosis factor alpha and interleukin-6 in vivo; intravenously administered gamma-globulin may down-regulate the cytokine response. PMID:8496751

  20. Oxidative Stress and Mitochondrial Activation as the Main Mechanisms Underlying Graphene Toxicity against Human Cancer Cells

    PubMed Central

    Jarosz, Anna; Skoda, Marta; Dudek, Ilona; Szukiewicz, Dariusz

    2016-01-01

    Due to the development of nanotechnology graphene and graphene-based nanomaterials have attracted the most attention owing to their unique physical, chemical, and mechanical properties. Graphene can be applied in many fields among which biomedical applications especially diagnostics, cancer therapy, and drug delivery have been arousing a lot of interest. Therefore it is essential to understand better the graphene-cell interactions, especially toxicity and underlying mechanisms for proper use and development. This review presents the recent knowledge concerning graphene cytotoxicity and influence on different cancer cell lines. PMID:26649139

  1. Lunar Dust and Lunar Simulant Activation, Monitoring, Solution and Cellular Toxicity Properties

    NASA Technical Reports Server (NTRS)

    Jeevarajan, A.S.; Wallace, W.T.

    2009-01-01

    During the Apollo missions, many undesirable situations were encountered that must be mitigated prior to returning humans to the moon. Lunar dust (that part of the lunar regolith less than 20 m in diameter) was found to produce several problems with astronaut s suits and helmets, mechanical seals and equipment, and could have conceivably produced harmful physiological effects for the astronauts. For instance, the abrasive nature of the dust was found to cause malfunctions of various joints and seals of the spacecraft and suits. Additionally, though efforts were made to exclude lunar dust from the cabin of the lunar module, a significant amount of material nonetheless found its way inside. With the loss of gravity correlated with ascent of the lunar module from the lunar surface to rendezvous with the command module, much of the major portions of the contaminating soil and dust began to float, irritating the astronaut s eyes and being inhaled into their lungs. Our goal has been to understand some of the properties of lunar dust that could lead to possible hazards for humans. Due to the lack of an atmosphere, there is nothing to protect the lunar soil from ultraviolet radiation, solar wind, and meteorite impacts. These processes could all serve to activate the soil, or produce reactive surface species. In order to understand the possible toxic effects of the reactive dust, it is necessary to reactivate the dust, as samples returned during the Apollo missions were exposed to the atmosphere of the Earth. We have used grinding and UV exposure to mimic some of the processes occurring on the Moon. The level of activation has been monitored using two methods: fluorescence spectroscopy and electron paramagnetic resonance spectroscopy (EPR). These techniques allow the monitoring of hydroxyl radical production in solution. We have found that grinding of lunar dust produces 2-3 times the concentration of hydroxyl radicals as lunar simulant and 10 times that of quartz. Exposure

  2. Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2 activation, leading to neurodegeneration

    PubMed Central

    Chen, Kuchuan; Lin, Guang; Haelterman, Nele A; Ho, Tammy Szu-Yu; Li, Tongchao; Li, Zhihong; Duraine, Lita; Graham, Brett H; Jaiswal, Manish; Yamamoto, Shinya; Rasband, Matthew N; Bellen, Hugo J

    2016-01-01

    Mutations in Frataxin (FXN) cause Friedreich’s ataxia (FRDA), a recessive neurodegenerative disorder. Previous studies have proposed that loss of FXN causes mitochondrial dysfunction, which triggers elevated reactive oxygen species (ROS) and leads to the demise of neurons. Here we describe a ROS independent mechanism that contributes to neurodegeneration in fly FXN mutants. We show that loss of frataxin homolog (fh) in Drosophila leads to iron toxicity, which in turn induces sphingolipid synthesis and ectopically activates 3-phosphoinositide dependent protein kinase-1 (Pdk1) and myocyte enhancer factor-2 (Mef2). Dampening iron toxicity, inhibiting sphingolipid synthesis by Myriocin, or reducing Pdk1 or Mef2 levels, all effectively suppress neurodegeneration in fh mutants. Moreover, increasing dihydrosphingosine activates Mef2 activity through PDK1 in mammalian neuronal cell line suggesting that the mechanisms are evolutionarily conserved. Our results indicate that an iron/sphingolipid/Pdk1/Mef2 pathway may play a role in FRDA. DOI: http://dx.doi.org/10.7554/eLife.16043.001 PMID:27343351

  3. Toxic essential oils. Part III: identification and biological activity of new allylmethoxyphenyl esters from a Chamomile species (Anthemis segetalis Ten.).

    PubMed

    Radulović, Niko S; Mladenović, Marko Z; Blagojević, Polina D; Stojanović-Radić, Zorica Z; Ilic-Tomic, Tatjana; Senerovic, Lidija; Nikodinovic-Runic, Jasmina

    2013-12-01

    To determine the exact structure of previously tentatively identified minor essential-oil constituents of a Chamomile species (Antemis segetalis Ten. (Asteraceae)), we have synthesized a small combinatorial library of 54 regioisomeric allylmethoxyphenyl pentanoates and 2-pentenoates (49 completely new compounds). GC-MS in combination with 1D- and 2D-NMR analyses of the library compounds provided unambiguous data that led to a straightforward identification of the mentioned A. segetalis constituents as eugenyl angelate, 2-methylbutanoate and 3-methylbutanoate (0.21, 0.22, and 0.13 mg/100 g of fresh plant material, respectively). To assess the safety and potential beneficial pharmacological uses of these naturally occurring esters and several other library compounds (these were tested to provide relevant data for a SAR (structure-activity relationship) analysis), we have studied the effect of these compounds in several models of toxicity (acute toxicity against Artemia salina, cytotoxicity against two cell lines (fibroblast and melanoma)), as well as their acetylcholinesterase inhibitory and antibacterial activities. Anthemis segetalis constituents showed low to moderate activity in all tests. The obtained results suggest that the intake of these compounds in naturally available amounts, on their own, would probably not represent a risk to human health but the possible adverse interactions with the plant matrix should not be neglected. PMID:24055768

  4. Assessment of antidiabetic activity and acute toxicity of leaf extracts from Physalis peruviana L. in guinea-pig

    PubMed Central

    Kasali, Félicien Mushagalusa; Kadima, Justin Ntokamunda; Mpiana, Pius Tshimankinda; Ngbolua, Koto-te-Nyiwa; Tshibangu, Damien Sha-Tshibey

    2013-01-01

    Objective To verify the antidiabetic activity of leaf extracts from Physalis peruviana L. popularly used in the Eastern part of the Democratic Republic of the Congo and to point out the possible toxicity. Method Aqueous decoctions prepared from dried leaves powder were administrated to guinea pigs at the dose range of 100 mg/kg to 3.2 g/kg of body weight. The hypoglycemic activity was evaluated by glucose tolerance test, loading animals with glucose 4 g/kg and measuring blood glucose concentrations at various times. The effect was compared to the control and glibenclamide as antidiabetic reference drug. Acute toxicity was evaluated by recording mortality rate, changes on blood biomarkers and damage caused to vital organs. Results At a dose of 100 mg/kg, the aqueous extract induced a significant reduction of peak concentration at 30 min after glucose loading as compared with control or reference (P<0.05). At doses greater than 400 mg, some alterations on blood, kidney and liver markers were observed. Upper 800 mg/kg, mortality was observed with LD50 estimated at about 1 280 mg/kg. At the autopsy, vital organs were in haemorrhage and swelling state. Conclusion The crude aqueous extracts from the leaves of Physalis peruviana L. present hypoglycemic activity in animal model, but at high doses the plant may cause severe intoxication.

  5. Toxicity Profiles In Vivo in Mice and Antitumour Activity in Tumour-Bearing Mice of Di- and Triorganotin Compounds

    PubMed Central

    Willem, R.; Dalil, H.; de Vos, D.; Kuiper, C. M.; Peters, G. J.

    1998-01-01

    The in vivo toxicity profiles in mice and the antitumour activity in tumour bearing mice were screened for four di-n-butyltin and five triorganotin carboxylates, di-n-butyltin diterebate (5), bis(phenylacetate) (6), bis(deoxycholate) (7), bis(lithocholate) (8), tri-n-butyltin terebate (9), cinnamate (10), and triphenyltin terebate (11). At their maximum tolerated dosis (MTD), no antitumour effect (T/C ~1) was observed for the compounds 5, 7, 9, 10 and 11. The compounds 6 (T/C = 0.51) and 8 (T/C = 0.42) showed clear antitumour activity after single dose administration and might therefore be of interest for further antitumour activity studies. PMID:18475827

  6. Hepatoprotective activity of picroliv, curcumin and ellagic acid compared to silymarin on paracetamol induced liver toxicity in mice.

    PubMed

    Girish, C; Koner, Bidhan Chandra; Jayanthi, S; Ramachandra Rao, K; Rajesh, B; Pradhan, Suresh Chandra

    2009-12-01

    Oxidative stress is implicated as a common pathologic mechanism contributing to the initiation and progression of hepatic damage in a variety of liver disorders. Present study attempts to evaluate the hepatoprotective activity of picroliv, curcumin and ellagic acid in comparison to silymarin using paracetamol (PCM) induced acute liver damage. Hepatotoxicity was induced by administering a single oral dose of PCM (500 mg/kg) and was assessed by quantifying the serum enzyme activities, phenobarbitone induced sleeping time and histopathological analysis of liver tissues. The antioxidant parameters, malondialdehyde (MDA), reduced glutathione (GSH) and catalase of the liver tissue were also assessed. The herbal drugs were administered for 7 days by oral route at 50 and 100 mg/kg. PCM induced hepatic damage was manifested by a significant increase in the activities of marker enzymes (alanine transaminase, aspartate transaminase and alkaline phosphatase) in serum and MDA level in liver. There was also a significant decrease in activity of GSH and catalase levels. The histopathological examination on toxic models revealed centrizonal necrosis and fatty changes. Pretreatment of mice with picroliv, curcumin and ellagic acid reversed these altered parameters towards normal values, which were compared with silymarin. The normalization of phenobarbitone induced sleeping time suggests the restoration of liver cytochrome P450 enzymes. This study supports the use of these active phytochemicals against toxic liver injury, which may act by preventing the lipid peroxidation and augmenting the antioxidant defense system or regeneration of hepatocytes. These active phytochemicals may be developed as drugs for the treatment of liver diseases. PMID:19656205

  7. Anti-inflammatory, Antioxidant and Antimicrobial Activity Characterization and Toxicity Studies of Flowers of "Jarilla", a Medicinal Shrub from Argentina.

    PubMed

    Moreno, Alejandra; Nuño, Gabriela; Cuello, Soledad; Sayago, Jorge E; Alberto, María Rosa; Zampini, Catiana; Isla, María Inés

    2015-06-01

    Zuccagnia punctata Cav. (Fabaceae) is an Argentine medicinal aromatic shrub (jarilla pispito, puspus, lata and jarilla macho). The chalcones were identified as pigments responsible for the yellow color of the flowers. Hydroethanolic extracts were obtained both from fresh flowers and from flowers dried by lyophilization. The extracts were standardized by their phenolic and flavonoids content. Their fingerprints by HPLC-DAD indicated the presence of two chalcones as major compounds (2',4'-dihydroxychalcone and 2',4'-dihydroxy-3'-methoxychalcone). Both extracts showed the same total phenolic, non-flavonoid phenolic and flavonoid phenolic content and their phenolic profiles were similar. The polyphenolic extracts exhibited antioxidant (free radical scavenging and inhibitory activity on lipoperoxidation) and anti-inflammatory (inhibition of lipoxygenase and cyclooxygenase enzymes) activities. The flower extracts were active against six Candida species with MIC values between 60 and 120 μg GAE x mL(-1) and were also active on methicillin-resistant Staphylococcus aureus (MIC: 250 μg GAE x mL(-1)) and Enterococcus faecalis (MIC: 500 μg GAE x mL(-1)). The extracts were neither toxic (Artemia salina test) nor mutagenic (Ames test). Jarilla flowers could be considered as a new dietary supplement that could help to prevent pathologies associated with oxidative stress and the polyphenolic extract obtained from them could be considered as a standardized phytotherapeutic product with antimicrobial, antioxidant and anti-inflammatory activities. The aim of this work was to determine the pigments responsible for the yellow color of the flowers of Z. punctata and to evaluate the functional properties of the polyphenolic extract of the flowers. The toxicity (Artemia salina) and mutagenic activity (Ames test) of the extract were also evaluated. PMID:26197533

  8. Acute toxicity and mutagenic activity of Mexican plants used in traditional medicine.

    PubMed

    Déciga-Campos, Myrna; Rivero-Cruz, Isabel; Arriaga-Alba, Myriam; Castañeda-Corral, Gabriela; Angeles-López, Guadalupe E; Navarrete, Andrés; Mata, Rachel

    2007-03-21

    The present work was undertaken to determine safety parameters of selected Mexican medicinal plants chosen on the basis of their frequency of medicinal use and commercial importance. The medicinal herbs included Amphipteryngium adstringens, Hintonia standleyana, Hintonia latiflora, Piper sanctum, Haemathoxylon brasiletto, Iostephane heterophylla, Valeriana procera, Arracacia tolucensis, Brickellia veronicaefolia, Scaphyglottis livida, Exostema caribaeum, Hippocratea excelsa, Ligusticum porteri, Poliomintha longiflora and Gnaphalium sp. In the acute toxicity studies in mice performed according to the Lorke procedure, Exostema caribaeum, Hippocratea excelsa, Ligusticum porteri and Poliomintha longiflora were the most toxic with LD(50) values between 1085 and 2mg/kg. The Ames test revealed that Gnaphalium sp. and Valeriana procera extracts induced mutations of S. typhimurium TA98 with or without the S9 microsomal fraction, and TA100 in the presence of the enzymatic fraction, respectively. The tincture of Valeriana procera, however, was non-mutagenic. Finally, in the Artemia salina lethality test Brickellia veronicaefolia, Arracacia tolucensis, Poliomintha longiflora and Piper sanctum caused significant mortality of the crustacean larvae with LC(50) in the range of 37-227 microg/mL. PMID:17101253

  9. Induction of nitric oxide synthase activity by toxic shock syndrome toxin 1 in a macrophage-monocyte cell line.

    PubMed Central

    Zembowicz, A; Vane, J R

    1992-01-01

    Toxic shock syndrome toxin 1 (TSST-1) is a Mr 22,000 protein produced by Staphylococcus aureus. It is thought to be the cause of toxic shock syndrome. We investigated the hypothesis that TSST-1 induces nitric oxide (NO) synthase and that the NO formed may be involved in the pathogenesis of toxic shock syndrome. We used the murine monocyte-macrophage cell line J744.2 that responds to TSST-1 and also expresses NO synthase activity upon immunological stimulation. J774.2 macrophages stimulated with TSST-1 (10-100 nM) generated nitrite, a breakdown product of NO, and induced concentration-dependent elevations of cGMP in the pig kidney epithelial cell line (LLC-PK1). This latter effect was due to the generation of L-arginine-derived NO for it was (i) abolished by oxyhemoglobin (10 microM), a scavenger of NO, or by methylene blue (10 microM), an inhibitor of NO-activated guanylate cyclase; (ii) potentiated by superoxide dismutase (100 units/ml), which prolongs the life of NO; (iii) inhibited by NG-monomethyl-L-arginine (0.3 mM), an inhibitor of NO synthase; (iv) significantly decreased when L-arginine (0.4 mM) in the medium was replaced by D-arginine (0.4 mM). Moreover, TSST-1 (100 nM) enhanced the activity of cytosolic NO synthase in J774.2 cells. Hydrocortisone (1 microM) but not indomethacin (5 micrograms/ml) or salicylic acid (5 micrograms/ml) prevented the generation of NO2- and the increases in cGMP levels in LLC-PK1 cells induced by J774.2 cells stimulated with TSST-1. The effects of hydrocortisone were partially reversed by coincubation with RU 486 (1 microM), an antagonist of glucocorticoid receptors. Thus, TSST-1 and perhaps other exotoxins produced by Gram-positive bacteria induce NO synthase and the increased NO formation may contribute to toxic shock syndrome and possibly to changes in the immune responses that accompany infection. PMID:1372433

  10. Tacrine-Trolox Hybrids: A Novel Class of Centrally Active, Nonhepatotoxic Multi-Target-Directed Ligands Exerting Anticholinesterase and Antioxidant Activities with Low In Vivo Toxicity.

    PubMed

    Nepovimova, Eugenie; Korabecny, Jan; Dolezal, Rafael; Babkova, Katerina; Ondrejicek, Ales; Jun, Daniel; Sepsova, Vendula; Horova, Anna; Hrabinova, Martina; Soukup, Ondrej; Bukum, Neslihan; Jost, Petr; Muckova, Lubica; Kassa, Jiri; Malinak, David; Andrs, Martin; Kuca, Kamil

    2015-11-25

    Coupling of two distinct pharmacophores, tacrine and trolox, endowed with different biological properties, afforded 21 hybrid compounds as novel multifunctional candidates against Alzheimer's disease. Several of them showed improved inhibitory properties toward acetylcholinesterase (AChE) in relation to tacrine. These hybrids also scavenged free radicals. Molecular modeling studies in tandem with kinetic analysis exhibited that these hybrids target both catalytic active site as well as peripheral anionic site of AChE. In addition, incorporation of the moiety bearing antioxidant abilities displayed negligible toxicity on human hepatic cells. This striking effect was explained by formation of nontoxic metabolites after 1 h incubation in human liver microsomes system. Finally, tacrine-trolox hybrids exhibited low in vivo toxicity after im administration in rats and potential to penetrate across blood-brain barrier. All of these outstanding in vitro results in combination with promising in vivo outcomes highlighted derivative 7u as the lead structure worthy of further investigation. PMID:26503905

  11. Analytical applications of microbial fuel cells. Part II: Toxicity, microbial activity and quantification, single analyte detection and other uses.

    PubMed

    Abrevaya, Ximena C; Sacco, Natalia J; Bonetto, Maria C; Hilding-Ohlsson, Astrid; Cortón, Eduardo

    2015-01-15

    Microbial fuel cells were rediscovered twenty years ago and now are a very active research area. The reasons behind this new activity are the relatively recent discovery of electrogenic or electroactive bacteria and the vision of two important practical applications, as wastewater treatment coupled with clean energy production and power supply systems for isolated low-power sensor devices. Although some analytical applications of MFCs were proposed earlier (as biochemical oxygen demand sensing) only lately a myriad of new uses of this technology are being presented by research groups around the world, which combine both biological-microbiological and electroanalytical expertises. This is the second part of a review of MFC applications in the area of analytical sciences. In Part I a general introduction to biological-based analytical methods including bioassays, biosensors, MFCs design, operating principles, as well as, perhaps the main and earlier presented application, the use as a BOD sensor was reviewed. In Part II, other proposed uses are presented and discussed. As other microbially based analytical systems, MFCs are satisfactory systems to measure and integrate complex parameters that are difficult or impossible to measure otherwise, such as water toxicity (where the toxic effect to aquatic organisms needed to be integrated). We explore here the methods proposed to measure toxicity, microbial metabolism, and, being of special interest to space exploration, life sensors. Also, some methods with higher specificity, proposed to detect a single analyte, are presented. Different possibilities to increase selectivity and sensitivity, by using molecular biology or other modern techniques are also discussed here. PMID:24906984

  12. Activated carbon from leather shaving wastes and its application in removal of toxic materials.

    PubMed

    Kantarli, Ismail Cem; Yanik, Jale

    2010-07-15

    In this study, utilization of a solid waste as raw material for activated carbon production was investigated. For this purpose, activated carbons were produced from chromium and vegetable tanned leather shaving wastes by physical and chemical activation methods. A detailed analysis of the surface properties of the activated carbons including acidity, total surface area, extent of microporosity and mesoporosity was presented. The activated carbon produced from vegetable tanned leather shaving waste produced has a higher surface area and micropore volume than the activated carbon produced from chromium tanned leather shaving waste. The potential application of activated carbons obtained from vegetable tanned shavings as adsorbent for removal of water pollutants have been checked for phenol, methylene blue, and Cr(VI). Adsorption capacities of activated carbons were found to be comparable to that of activated carbons derived from biomass. PMID:20382474

  13. A novel natural Nrf2 activator with PPARγ-agonist (monascin) attenuates the toxicity of methylglyoxal and hyperglycemia.

    PubMed

    Hsu, Wei-Hsuan; Lee, Bao-Hong; Chang, Yu-Ying; Hsu, Ya-Wen; Pan, Tzu-Ming

    2013-11-01

    Methylglyoxal (MG) is a toxic-glucose metabolite and a major precursor of advanced glycation endproducts (AGEs). MG has been reported to result in inflammation by activating receptor for AGEs (RAGE). We recently found that Monascus-fermented metabolite monascin acts as a novel natural peroxisome proliferator-activated receptor-γ (PPARγ) agonist that improves insulin sensitivity. We investigated the metabolic, biochemical, and molecular abnormalities characteristic of type 2 diabetes in MG-treated Wistar rats treated with oral administration of monascin or rosiglitazone. Monascin (a novel PPARγ agonist) activated nuclear factor-erythroid 2-related factor 2 (Nrf2) and down-regulated hyperinsulinmia in oral glucose tolerance test (OGTT). Monascin was able to elevate glyoxalase-1 expression via activation of hepatic Nrf2, hence, resulting in MG metabolism to d-lactic acid and protected from AGEs production in MG-treated rats. Rosiglitazone did not activate Nrf2 nor glyoxalase expression to lower serum and hepatic AGEs levels. Monascin acts as a novel natural Nrf2 activator with PPARγ-agonist activity were confirmed by Nrf2 and PPARγ reporter assays in Hep G2 cells. These findings suggest that monascin acts as an anti-diabetic and anti-oxidative stress agent to a greater degree than rosiglitazone and thus may have therapeutic potential for the prevention of diabetes. PMID:23954466

  14. Phenylalanine-24 in the N-terminal region of ammodytoxins is important for both enzymic activity and presynaptic toxicity.

    PubMed Central

    Petan, Toni; Krizaj, Igor; Gubensek, Franc; Pungercar, Joze

    2002-01-01

    Ammodytoxins (Atxs) are group II phospholipases A(2) (PLA(2)s) with presynaptic toxicity from venom of the snake Vipera ammodytes ammodytes. The molecular basis of their neurotoxicity, and that of similar PLA(2) toxins, is still to be explained. To address this problem, a surface-exposed aromatic residue, Phe(24), in the N-terminal region of the most potent Atx, AtxA, was replaced by other aromatic (tyrosine, tryptophan), hydrophobic (alanine) and polar uncharged (serine, asparagine) residues. The mutants were produced in the bacterial expression system, refolded in vitro and purified to homogeneity. All but the Trp(24) mutant, whose activity was similar to that of the wild type, showed a considerable decrease (40-80%) in enzymic activity on a micellar phosphatidylcholine substrate. This result indicates an important role for the aromatic side chains of phenylalanine or tryptophan, but not tyrosine, in PLA(2) activity, very likely at a stage of interfacial adsorption of the enzyme to zwitterionic aggregated substrates. The substitutions of Phe(24) also significantly decreased toxicity in mice, with the most prominent decrease, of 130-fold, observed in the case of the Asn(24) mutant. The results with the mutants show that there is no correlation between enzymic activity, lethality and binding affinity for three AtxA neuronal receptors (R180, R25 and calmodulin). Our results suggest a critical involvement of Phe(24) in the neurotoxicity of AtxA, apparently at a stage which does not involve the interaction with the known Atx-binding neuronal proteins and catalytic activity. PMID:11931665

  15. Study of antisickling and vasorelaxant activities and acute toxicity assessment of crude extracts of leaves of Ficus sycomorus L. (Moraceae).

    PubMed

    Ramdé-Tiendrébéogo, Alphonsine; Tibiri, André; Ouedraogo, Moussa; Ouédraogo, Sylvin; Nacoulma, Odile Germaine; Guissou, Innocent Pierre

    2014-06-01

    The leaves of Ficus sycomorus are used in Burkina Faso folk medicine for the treatment of sickle cell disease. The present comparative study of crude extracts of leaves (decoction, macerated extract and a 95% ethanol extract) was performed with the aim to assess the efficiency of this traditional use and to determine the most active of the three extracts. Antisickling activity was assessed by the Emmel's test. Vasorelaxant effect on rat aortic rings precontracted by phenylephrine with and without N-nitro-L-arginine methyl ester chloride (L-NAME) was also evaluated. The 95% ethanol extract (20 mg mL(-1)) showed the most antisickling activity on sickle erythrocytes, by inhibiting completely sickling of double heterozygote SC cells in 60 min and that of homozygote SS cells in 90 min. On the aorta this extract exhibited a significant (p<0.05) vasorelaxant activity, better than that of the other extracts, with an IC50 value of 6.86±0.13 mg mL(-1) against 18.78±0.38 and 28.56±1.27 mg mL(-1), respectively for the macerated extract and the decoction. When the aortic rings were pretreated with L-NAME, only the ethanolic extract conserved its vasorelaxant activity, up to 73% of relaxation. The acute toxicity of the decoction, assessed by intraperitoneal route and using the Litchfield and Wilcoxon method, led to an LD50 value of 1553.61 mg kg(-1) b.wt. This places the drug among those with low toxicity according to the WHO scale. These results confirm those previously obtained and provide a scientific basis supporting the use of this plant in folk medicine against sickle cell disease. They indicate the importance of Ficus sycomorus in the research of new antisickling molecules. PMID:26035956

  16. Antioxidant activity, delayed aging, and reduced amyloid-β toxicity of methanol extracts of tea seed pomace from Camellia tenuifolia.

    PubMed

    Wei, Chia-Cheng; Yu, Chan-Wei; Yen, Pei-Ling; Lin, Huan-You; Chang, Shang-Tzen; Hsu, Fu-Lan; Liao, Vivian Hsiu-Chuan

    2014-11-01

    There is a growing interest in the exploitation of the residues generated by plants. This study explored the potential beneficial health effects from the main biowaste, tea seed pomace, produced when tea seed is processed. DPPH radical scavenging and total phenolic content assays were performed to evaluate the in vitro activities of the extracts. Caenorhabditis elegans was used as in vivo model to evaluate the beneficial health effects, including antioxidant activity, delayed aging, and reduced amyloid-β toxicity. Among all soluble fractions obtained from the extracts of tea seed pomace from Camellia tenuifolia, the methanol (MeOH)-soluble fraction has the best in vivo antioxidant activities. The MeOH-soluble extraction was further divided into six fractions by chromatography with a Diaion HP-20 column eluted with water/MeOH, and fraction 3 showed the best in vitro and in vivo antioxidant activities. Further analysis in C. elegans showed that the MeOH extract (fraction 3) of tea seed pomace significantly decreased intracellular reactive oxygen species, prolonged C. elegans lifespan, and reduced amyloid-β (Aβ) toxicity in transgenic C. elegans expressing human Aβ. Moreover, bioactivity-guided fractionation yielded two potent constituents from fraction 3 of the MeOH extract, namely, kaempferol 3-O-(2″-glucopyranosyl)-rutinoside and kaempferol 3-O-(2″-xylopyranosyl)-rutinoside, and both compounds exhibited excellent in vivo antioxidant activity. Taken together, MeOH extracts of tea seed pomace from C. tenuifolia have multiple beneficial health effects, suggesting that biowaste might be valuable to be explored for further development as nutraceutical products. Furthermore, the reuse of agricultural byproduct tea seed pomace also fulfills the environmental perspective. PMID:25295856

  17. Sitophilus granarius L. (Coleoptera) Toxicity and Biological Activities of the Essential Oils of Tanacetum macrophyllum (Waldst. & Kit.) Schultz Bip.

    PubMed

    Polatoğlu, Kaan; Karakoç, Ömer Cem; Demirci, Betül; Gören, Nezhun; Can Başer, Kemal Hüsnü

    2015-01-01

    Insecticides of the natural origin are an important alternative to the synthetic insecticides that are being employed for the preserving stored products. The volatiles obtained from T. cinerariifolium (=Pyrethrum cinerariifolium) is being used for many types of insecticidal applications; however there is a very little information on the insecticidal activity of the essential oils of other Tanacetum species. The main purpose of the present study is to determine the chemical composition of T. macrophyllum (Waldst. & Kit.) Schultz Bip. essential oils and evaluate their insecticidal activity against S. granarius as well as its other beneficial biological activities. Highest contact toxicity was observed in the leaf oil of (88.93%) against S. granarius. The flower oil showed considerable fumigant toxicity against L. minor at 10 mg/mL application concentration (61.86 %) when compared with other samples at the same concentration. The highest DPPH (2,2-Diphenyl-1-picrylhydrazyl) scavenging activity (47.7%) and phosphomolybdenum reducing activity was observed also for the flower oil of T. macrophyllum at 10 mg/mL concentration. The essential oils were analyzed by GC, GC/MS. The flower and leaf oils were characterized with γ-eudesmol 21.5%, (E)-sesquilavandulol 20.3%, copaborneol 8.5% and copaborneol 14.1%, 1,8-cineole 11%, bornyl acetate 9.6%, borneol 6.3% respectively. AHC analysis of the qualitative and quantitative data obtained from the essential oil composition of the T. macrophyllum essential oil from the present research and previous reports pointed out that two different chemotypes could be proposed with current findings which are p-methyl benzyl alcohol/ cadinene and eudesmane chemotypes. PMID:26179008

  18. Mutant LRRK2 Toxicity in Neurons Depends on LRRK2 Levels and Synuclein But Not Kinase Activity or Inclusion Bodies

    PubMed Central

    Skibinski, Gaia; Nakamura, Ken; Cookson, Mark R.

    2014-01-01

    By combining experimental neuron models and mathematical tools, we developed a “systems” approach to deconvolve cellular mechanisms of neurodegeneration underlying the most common known cause of Parkinson's disease (PD), mutations in leucine-rich repeat kinase 2 (LRRK2). Neurons ectopically expressing mutant LRRK2 formed inclusion bodies (IBs), retracted neurites, accumulated synuclein, and died prematurely, recapitulating key features of PD. Degeneration was predicted from the levels of diffuse mutant LRRK2 that each neuron contained, but IB formation was neither necessary nor sufficient for death. Genetic or pharmacological blockade of its kinase activity destabilized LRRK2 and lowered its levels enough to account for the moderate reduction in LRRK2 toxicity that ensued. By contrast, targeting synuclein, including neurons made from PD patient-derived induced pluripotent cells, dramatically reduced LRRK2-dependent neurodegeneration and LRRK2 levels. These findings suggest that LRRK2 levels are more important than kinase activity per se in predicting toxicity and implicate synuclein as a major mediator of LRRK2-induced neurodegeneration. PMID:24403142

  19. Larvicidal activity of Myrtaceae essential oils and their components against Aedes aegypti, acute toxicity on Daphnia magna, and aqueous residue.

    PubMed

    Park, Hye-Mi; Kim, Junheon; Chang, Kyu-Sik; Kim, Byung-Seok; Yang, Yu-Jung; Kim, Gil-Hah; Shin, Sang-Chul; Park, Il-Kwon

    2011-03-01

    The larvicidal activity of 11 Myrtaceae essential oils and their constituents was evaluated against Aedes aegypti L. Of the 11, Melaleuca linariifolia Sm., Melaleuca dissitiflora F. Muell., Melaleuca quinquenervia (Cav.) S. T. Blake, and Eucalyptus globulus Labill oils at 0.1 mg/ml exhibited > or = 80% larval mortality. At this same concentration, the individual constituents tested, allyl isothiocyanate, alpha-terpinene, p-cymene, (+)-limonene, (-)-limonene, gamma-terpinene, and (E)-nerolidol, resulted in > or = 95% mortality. We also tested the acute toxicity of these four active oils earlier mentioned and their constituents against Daphnia magna Straus. M. linariifolia and allyl isothiocyanate was the most toxic to D. magna. Twodays after treatment, residues of M. dissitiflora, M. linariifolia, M. quinquenervia, and E. globulus oils in water were 55.4, 46.6, 32.4, and 14.8%, respectively. Less than 10% of allyl isothiocyanate, alpha-terpinene, p-cymene, (-)-limonene, (+)-limonene, and gamma-terpinene was detected in the water at 2 d after treatment. Our results indicated that oils and their constituents could easily volatilize in water within a few days after application, thus minimizing their effect on the aqueous ecosystem. Therefore, Myrtaceae essential oils and their constituents could be developed as control agents against mosquito larvae. PMID:21485381

  20. Metabolic activation and toxicity of acetaminophen and related analogs. A theoretical study.

    PubMed

    Loew, G H; Goldblum, A

    1985-03-01

    Reaction thermodynamics have been calculated for an oxene model for cytochrome P-450 oxidations of four related arylamines: aniline, p-hydroxyaniline, acetanilide, and acetaminophen, by both radical and nonradical mechanisms, using a semiempirical molecular orbital method (modified neglect of differential overlap). The results indicate that for both p-hydroxyaniline and acetaminophen, a recently proposed peroxidase-like mechanism leading directly to p-benzoquinoneimines via radical intermediates is thermodynamically favored over N-hydroxylamine formation by H abstraction or addition rearrangement. These studies also provide a detailed characterization of three candidate species for the toxic reactive intermediate of acetaminophen: 1) p-benzoquinoneimines, 2) the radical intermediate formed by H abstraction from the nitrogen, and 3) the radical intermediate formed by H abstraction from the phenol. Calculated electron and spin densities indicate that the radical formed by H abstraction from the phenol oxygen does not remain localized on the oxygen, but is primarily a semiquinone aryl radical with significant unpaired spin density on the ring carbon atoms, particularly on C-3 and C-5. This result is consistent with the hyperfine splitting pattern observed for a transient radical species in a hydroxyl radical-mediated chemical oxidation of acetaminophen. The radical formed by H abstraction from the nitrogen also delocalizes on the ring carbons, but to a lesser extent and at the 2- and 4-positions. A closed shell mechanism of N oxidation of arylamines appears to lead directly to the hydroxylamines with less likelihood of precursor reactive intermediates. Toxic species could then be formed by loss of H2O from the hydroxylamines. PMID:2983185

  1. Venom of the Brazilian Spider Sicarius ornatus (Araneae, Sicariidae) Contains Active Sphingomyelinase D: Potential for Toxicity after Envenomation

    PubMed Central

    Lopes, Priscila Hess; Bertani, Rogério; Gonçalves-de-Andrade, Rute M.; Nagahama, Roberto H.; van den Berg, Carmen W.; Tambourgi, Denise V.

    2013-01-01

    Background The spider family Sicariidae includes two genera, Sicarius and Loxosceles. Bites by Sicarius are uncommon in humans and, in Brazil, a single report is known of a 17-year old man bitten by a Sicarius species that developed a necrotic lesion similar to that caused by Loxosceles. Envenomation by Loxosceles spiders can result in dermonecrosis and severe ulceration. Sicarius and Loxosceles spider venoms share a common characteristic, i.e., the presence of Sphingomyelinases D (SMase D). We have previously shown that Loxosceles SMase D is the enzyme responsible for the main pathological effects of the venom. Recently, it was demonstrated that Sicarius species from Africa, like Loxosceles spiders from the Americas, present high venom SMase D activity. However, despite the presence of SMase D like proteins in venoms of several New World Sicarius species, they had reduced or no detectable SMase D activity. In order to contribute to a better understanding about the toxicity of New World Sicarius venoms, the aim of this study was to characterize the toxic properties of male and female venoms from the Brazilian Sicarius ornatus spider and compare these with venoms from Loxosceles species of medical importance in Brazil. Methodology/Principal Findings SDS-PAGE analysis showed variations in the composition of Loxosceles spp. and Sicarius ornatus venoms. Differences in the electrophoretic profiles of male and female venoms were also observed, indicating a possible intraspecific variation in the composition of the venom of Sicarius spider. The major component in all tested venoms had a Mr of 32–35 kDa, which was recognized by antiserum raised against Loxosceles SMases D. Moreover, male and female Sicarius ornatus spiders' venoms were able to hydrolyze sphingomyelin, thus showing an enzymatic activity similar to that determined for Loxosceles venoms. Sicarius ornatus venoms, as well as Loxosceles venoms, were able to render erythrocytes susceptible to lysis by

  2. Toxic Hazards Research Unit

    NASA Technical Reports Server (NTRS)

    Macewen, J. D.; Vernot, E. H.

    1971-01-01

    The activities of the Toxic Hazards Research Unit (THRU) for the period of June 1970 through May 1971 reviewed. Modification of the animal exposure facilities primarily for improved human safety but also for experimental integrity and continuity are discussed. Acute toxicity experiments were conducted on hydrogen fluoride (HF), hydrogen chloride (HCl), nitrogen dioxide (NO2), and hydrogen cyanide (HCN) both singly and in combination with carbon dioxide (CO). Additional acute toxicity experiments were conducted on oxygen difluoride (OF2) and chlorine pentafluoride (ClF5). Subacute toxicity studies were conducted on methylisobutylketone and dichloromethane (methylene dichloride). The interim results of further chronic toxicity experiments on monomethylhydrazine (MMH) are also described.

  3. Fumigant toxicity of Oriental sweetgum (Liquidambar orientalis) and valerian (Valeriana wallichii) essential oils and their components, including their acetylcholinesterase inhibitory activity, against Japanese termites (Reticulitermes speratus).

    PubMed

    Park, Il-Kwon

    2014-01-01

    This study investigated the fumigant toxicity of oriental sweetgum (Liquidambar orientalis) and valerian (Valeriana wallichii) essential oils and their components against the Japanese termite (Reticulitermes speratus). The fumigant toxicity of oriental sweetgum and valerian oil differed significantly according to exposure time. Oriental sweetgum showed toxicity at short exposure times (2 days), and the toxicity of valerian oil was high 7 days after treatment. The main constituents of oriental sweetgum and valerian oils were tested individually for their fumigant toxicity against Japanese termites. Among the test compounds, benzyl alcohol, acetophenone, 1-phenyl-1-ethanol, hydrocinnamyl alcohol, trans-cinnamyl aldehyde, trans-cinnamyl alcohol, cis-asarone, styrene, and cis-ocimene showed toxicity against Japanese termites 7 days after treatment. Hydrocinnamyl alcohol and trans-cinnamyl alcohol were found to be the major contributors to the fumigant antitermitic toxicity of oriental sweetgum oil. The acetylcholinesterase (AChE) inhibition activity of two oils and their constituents was tested to determine their mode of action. Only cis-ocimene showed strong AChE inhibition activity with an IC50 value of 0.131 mg/mL. Further studies are warranted to determine the potential of these essential oils and their constituents as fumigants for termite control. PMID:25153870

  4. First Evidence of Altererythrobacter sp. LY02 with Indirect Algicidal Activity on the Toxic Dinoflagellate, Alexandrium tamarense.

    PubMed

    Li, Yi; Liu, Lei; Xu, Yanting; Guan, Chengwei; Lei, Xueqian; Zheng, Wei; Wang, Hailei; Zheng, Tianling

    2016-10-01

    Alexandrium tamarense is a toxic harmful algal blooms (HABs) causing species, which poses great threat to human health and marine economy. In this study, we isolated an algicidal bacterium Altererythrobacter sp. LY02 towards to A. tamarense and later investigated the algicidal activity, algicidal mode, characteristics of algicidal active substance and algicidal procedure. The results indicated that the cell-free filtrate of strain LY02 showed high algicidal effect on algal growth, however, bacterial cells almost lost algicidal activity. The algicidal active substance was temperature- and pH-stability, and its molecular weight was less than 1000 Da, and was a non-proteinaceous material or non-polysaccharide, mid-polar substance. Under the algicidal effect of active substance, the morphology and structure of A. tamarense cells were seriously damaged as well as organelles. Our study confirmed that the algicidal active substance could be used as an excellent bio-agent for controlling HABs caused by A. tamarense. PMID:27422436

  5. Study on the toxic effects of diphenol compounds on soil microbial activity by a combination of methods.

    PubMed

    Chen, Huilun; Yao, Jun; Wang, Fei; Choi, Martin M F; Bramanti, Emilia; Zaray, Gyula

    2009-08-15

    Microcalorimetric technique based on heat-output measurement, direct microorganism counting and enzymatic activity determination, have been explored to evaluate the toxic effects of diphenol species (catechol, resorcinol, and hydroquinone) on soil microbial activity. The thermokinetic parameters including growth rate constant (k), inhibitory ratio, half inhibitory concentration and total thermal effect (Q(total)), were calculated and compared using the data obtained from the power-time curves of the microcalorimeter. It was found that addition of high concentrations of diphenol compounds to the soil samples resulted in low microorganism counts. The trend of the number of cultivable microorganisms with increasing concentration of diphenols was similar to specific growth rate k. It appeared that the higher the water soluble carbon (WSC) content, the higher the Q(total) value. The low dehydrogenase and beta-glucosidase found in the soils treated by catechol and hydroquinone was possibly due to their low WSC concentration and high inhibitory effects, respectively. The results reveal the toxicity of the three diphenols in a descending sequence: hydroquinone, resorcinol and catechol. The combination of the three methods is a more comprehensive toxicological investigation of a complex microbiological system. Microcalorimetry is for studying the metabolic growth of microorganisms, the plate counting method is for quantifying the real microbial growth, and the soil enzyme activity is for assessing the intracellular and extracellular activity of microbial biomass. Our proposed methods can provide toxicological information of diphenols to soil microbes from the metabolic, microbial and biochemical point of views which are consistent with and correlated to each other. PMID:19223121

  6. Activation of SIRT3 attenuates triptolide-induced toxicity through closing mitochondrial permeability transition pore in cardiomyocytes.

    PubMed

    Yang, Yanqin; Wang, Wenwen; Xiong, Zhewen; Kong, Jiamin; Qiu, Yuwen; Shen, Feihai; Huang, Zhiying

    2016-08-01

    Triptolide (TP), an active component of the traditional Chinese herb Tripterygium wilfordii Hook f. (TWHF), has multiple pharmacological effects. However, the severe toxicity of TP greatly restricts its clinical applications. Although TP exposure causes serious heart injury, the mechanism underlying TP-induced cardiotoxicity has rarely been investigated. In previous studies, we found that TP-induced oxidative stress was involved in the mitochondria-dependent apoptosis of cardiomyocytes. Opening of the mitochondrial permeability transition pore (mPTP) is the key to the mitochondrial dysfunction in cardiac toxicity. The aim of this study was to investigate the potential cardioprotective effects of sirtuin 3 (SIRT3) on the mPTP. In the present study, the cytotoxicity of TP was accompanied by the up-regulation of the SIRT3 protein level and its rapid aggregation in nuclei and mitochondria. The SIRT3-FOXO3 signaling pathway was activated simultaneously, resulting in increased transcription of manganese superoxide dismutase (MnSOD) and catalase (CAT) for the elimination of reactive oxygen species (ROS). In addition, augmentation of the SIRT3 level via the overexpression plasmid SIRT3-Flag provided resistance to TP-induced cellular damage, whereas knocking down the SIRT3 level via siRNA accelerated the damage. Because it is an activator of SIRT3, the protective effect of resveratrol was also evaluated in H9c2 cells. In conclusion, the current results suggest that activation of SIRT3 substantially ameliorates the detrimental effects of TP by closing the mPTP. PMID:27064125

  7. Target Organ Specific Activity of Drosophila MRP (ABCC1) Moderates Developmental Toxicity of Methylmercury

    PubMed Central

    Prince, Lisa; Korbas, Malgorzata; Davidson, Philip; Broberg, Karin; Rand, Matthew Dearborn

    2014-01-01

    Methylmercury (MeHg) is a ubiquitous and persistent neurotoxin that poses a risk to human health. Although the mechanisms of MeHg toxicity are not fully understood, factors that contribute to susceptibility are even less well known. Studies of human gene polymorphisms have identified a potential role for the multidrug resistance-like protein (MRP/ABCC) family, ATP-dependent transporters, in MeHg susceptibility. MRP transporters have been shown to be important for MeHg excretion in adult mouse models, but their role in moderating MeHg toxicity during development has not been explored. We therefore investigated effects of manipulating expression levels of MRP using a Drosophila development assay. Drosophila MRP (dMRP) is homologous to human MRP1–4 (ABCC1–4), sharing 50% identity and 67% similarity with MRP1. A greater susceptibility to MeHg is seen in dMRP mutant flies, demonstrated by reduced rates of eclosion on MeHg-containing food. Furthermore, targeted knockdown of dMRP expression using GAL4>UAS RNAi methods demonstrates a tissue-specific function for dMRP in gut, Malpighian tubules, and the nervous system in moderating developmental susceptibility to MeHg. Using X-ray synchrotron fluorescence imaging, these same tissues were also identified as the highest Hg-accumulating tissues in fly larvae. Moreover, higher levels of Hg are seen in dMRP mutant larvae compared with a control strain fed an equivalent dose of MeHg. In sum, these data demonstrate that dMRP expression, both globally and within Hg-targeted organs, has a profound effect on susceptibility to MeHg in developing flies. Our findings point to a potentially novel and specific role for dMRP in neurons in the protection against MeHg. Finally, this experimental system provides a tractable model to evaluate human polymorphic variants of MRP and other gene variants relevant to genetic studies of mercury-exposed populations. PMID:24863968

  8. Target organ specific activity of drosophila MRP (ABCC1) moderates developmental toxicity of methylmercury.

    PubMed

    Prince, Lisa; Korbas, Malgorzata; Davidson, Philip; Broberg, Karin; Rand, Matthew Dearborn

    2014-08-01

    Methylmercury (MeHg) is a ubiquitous and persistent neurotoxin that poses a risk to human health. Although the mechanisms of MeHg toxicity are not fully understood, factors that contribute to susceptibility are even less well known. Studies of human gene polymorphisms have identified a potential role for the multidrug resistance-like protein (MRP/ABCC) family, ATP-dependent transporters, in MeHg susceptibility. MRP transporters have been shown to be important for MeHg excretion in adult mouse models, but their role in moderating MeHg toxicity during development has not been explored. We therefore investigated effects of manipulating expression levels of MRP using a Drosophila development assay. Drosophila MRP (dMRP) is homologous to human MRP1-4 (ABCC1-4), sharing 50% identity and 67% similarity with MRP1. A greater susceptibility to MeHg is seen in dMRP mutant flies, demonstrated by reduced rates of eclosion on MeHg-containing food. Furthermore, targeted knockdown of dMRP expression using GAL4>UAS RNAi methods demonstrates a tissue-specific function for dMRP in gut, Malpighian tubules, and the nervous system in moderating developmental susceptibility to MeHg. Using X-ray synchrotron fluorescence imaging, these same tissues were also identified as the highest Hg-accumulating tissues in fly larvae. Moreover, higher levels of Hg are seen in dMRP mutant larvae compared with a control strain fed an equivalent dose of MeHg. In sum, these data demonstrate that dMRP expression, both globally and within Hg-targeted organs, has a profound effect on susceptibility to MeHg in developing flies. Our findings point to a potentially novel and specific role for dMRP in neurons in the protection against MeHg. Finally, this experimental system provides a tractable model to evaluate human polymorphic variants of MRP and other gene variants relevant to genetic studies of mercury-exposed populations. PMID:24863968

  9. Antimicrobial activity against oral pathogens and immunomodulatory effects and toxicity of geopropolis produced by the stingless bee Melipona fasciculata Smith

    PubMed Central

    2011-01-01

    Background Native bees of the tribe Meliponini produce a distinct kind of propolis called geopropolis. Although many pharmacological activities of propolis have already been demonstrated, little is known about geopropolis, particularly regarding its antimicrobial activity against oral pathogens. The present study aimed at investigating the antimicrobial activity of M. fasciculata geopropolis against oral pathogens, its effects on S. mutans biofilms, and the chemical contents of the extracts. A gel prepared with a geopropolis extract was also analyzed for its activity on S. mutans and its immunotoxicological potential. Methods Antimicrobial activities of three hydroalcoholic extracts (HAEs) of geopropolis, and hexane and chloroform fractions of one extract, were evaluated using the agar diffusion method and the broth dilution technique. Ethanol (70%, v/v) and chlorhexidine (0.12%, w/w) were used as negative and positive controls, respectively. Total phenol and flavonoid concentrations were assayed by spectrophotometry. Immunotoxicity was evaluated in mice by topical application in the oral cavity followed by quantification of biochemical and immunological parameters, and macro-microscopic analysis of animal organs. Results Two extracts, HAE-2 and HAE-3, showed inhibition zones ranging from 9 to 13 mm in diameter for S. mutans and C. albicans, but presented no activity against L. acidophilus. The MBCs for HAE-2 and HAE-3 against S. mutans were 6.25 mg/mL and 12.5 mg/mL, respectively. HAE-2 was fractionated, and its chloroform fraction had an MBC of 14.57 mg/mL. HAE-2 also exhibited bactericidal effects on S. mutans biofilms after 3 h of treatment. Significant differences (p < 0.05) in total phenol and flavonoid concentrations were observed among the samples. Signs toxic effects were not observed after application of the geopropolis-based gel, but an increase in the production of IL-4 and IL-10, anti-inflammatory cytokines, was detected. Conclusions In summary

  10. Modulators of γ-Secretase Activity Can Facilitate the Toxic Side-Effects and Pathogenesis of Alzheimer's Disease

    PubMed Central

    Svedružić, Željko M.; Popović, Katarina; Šendula-Jengić, Vesna

    2013-01-01

    Background Selective modulation of different Aβ products of an intramembrane protease γ-secretase, could be the most promising strategy for development of effective therapies for Alzheimer's disease. We describe how different drug-candidates can modulate γ-secretase activity in cells, by studying how DAPT affects changes in γ-secretase activity caused by gradual increase in Aβ metabolism. Results Aβ 1–40 secretion in the presence of DAPT shows biphasic activation-inhibition dose-response curves. The biphasic mechanism is a result of modulation of γ-secretase activity by multiple substrate and inhibitor molecules that can bind to the enzyme simultaneously. The activation is due to an increase in γ-secretase's kinetic affinity for its substrate, which can make the enzyme increasingly more saturated with otherwise sub-saturating substrate. The noncompetitive inhibition that prevails at the saturating substrate can decrease the maximal activity. The synergistic activation-inhibition effects can drastically reduce γ-secretase's capacity to process its physiological substrates. This reduction makes the biphasic inhibitors exceptionally prone to the toxic side-effects and potentially pathogenic. Without the modulation, γ-secretase activity on it physiological substrate in cells is only 14% of its maximal activity, and far below the saturation. Significance Presented mechanism can explain why moderate inhibition of γ-secretase cannot lead to effective therapies, the pharmacodynamics of Aβ-rebound phenomenon, and recent failures of the major drug-candidates such as semagacestat. Novel improved drug-candidates can be prepared from competitive inhibitors that can bind to different sites on γ-secretase simultaneously. Our quantitative analysis of the catalytic capacity can facilitate the future studies of the therapeutic potential of γ-secretase and the pathogenic changes in Aβ metabolism. PMID:23308095

  11. Minding the Calcium Store: Ryanodine Receptor Activation as a Convergent Mechanism of PCB Toxicity

    PubMed Central

    Pessah, Isaac N.; Cherednichenko, Gennady; Lein, Pamela J.

    2009-01-01

    Chronic low level polychlorinated biphenyls (PCB) exposures remain a significant public health concern since results from epidemiological studies indicate PCB burden is associated with immune system dysfunction, cardiovascular disease, and impairment of the developing nervous system. Of these various adverse health effects, developmental neurotoxicity has emerged as a particularly vulnerable endpoint in PCB toxicity. Arguably the most pervasive biological effects of PCBs could be mediated by their ability to alter the spatial and temporal fidelity of Ca2+ signals through one or more receptor mediated processes. This review will focus on our current knowledge of the structure and function of ryanodine receptors (RyRs) in muscle and nerve cells and how PCBs and related non-coplanar structures alter these functions. The molecular and cellular mechanisms by which non-coplanar PCBs and related structures alter local and global Ca2+ signaling properties and the possible short and long-term consequences of these perturbations on neurodevelopment and neurodegeneration are reviewed. PMID:19931307

  12. Using Quantitative Structure-Activity Relationship Modeling to Quantitatively Predict the Developmental Toxicity of Halogenated Azole compounds

    EPA Science Inventory

    Developmental toxicity is a relevant endpoint for the comprehensive assessment of human health risk from chemical exposure. However, animal developmental toxicity studies remain unavailable for many environmental contaminants due to the complexity and cost of these types of analy...

  13. Assessment of acute oral and dermal toxicity of 2 ethyl-carbamates with activity against Rhipicephalus microplus in rats.

    PubMed

    Prado-Ochoa, María Guadalupe; Gutiérrez-Amezquita, Ricardo Alfonso; Abrego-Reyes, Víctor Hugo; Velázquez-Sánchez, Ana María; Muñoz-Guzmán, Marco Antonio; Ramírez-Noguera, Patricia; Angeles, Enrique; Alba-Hurtado, Fernando

    2014-01-01

    The acute oral and dermal toxicity of two new ethyl-carbamates (ethyl-4-bromophenyl-carbamate and ethyl-4-chlorophenyl-carbamate) with ixodicide activity was determined in rats. The oral LD50 of each carbamate was 300 to 2000 mg/kg, and the dermal LD50 of each carbamate was >5000 mg/kg. Clinically, the surviving rats that had received oral doses of each carbamate showed decreased weight gain (P < 0.05) and had slight nervous system manifestations. These clinical signs were evident from the 300 mg/kg dose and were reversible, whereas the 2000 mg/kg dose caused severe damage and either caused their death or was motive for euthanasia. At necropsy, these rats had dilated stomachs and cecums with diffuse congestion, as well as moderate congestion of the liver. Histologically, the liver showed slight degenerative lesions, binucleated hepatocytes, focal coagulative necrosis, and congestion areas; the severity of the lesions increased with dosage. Furthermore, an slight increase in gamma-glutamyltransferase, lactate dehydrogenase, and creatinine was observed in the plasma. The dermal application of the maximum dose (5000 mg/kg) of each carbamate did not cause clinical manifestations or liver and skin alterations. This finding demonstrates that the carbamates under study have a low oral hazard and low acute dermal toxicity. PMID:24883331

  14. Glycosaminoglycans from aged human hippocampus have altered capacities to regulate trophic factors activities but not Aβ42 peptide toxicity.

    PubMed

    Huynh, Minh Bao; Villares, Joao; Díaz, Julia Elisa Sepúlveda; Christiaans, Stephy; Carpentier, Gilles; Ouidja, Mohand Ouidir; Sissoeff, Ludmilla; Raisman-Vozari, Rita; Papy-Garcia, Dulce

    2012-05-01

    Glycosaminoglycans (GAGs) are major extracellular matrix components known to tightly regulate cell behavior by interacting with tissue effectors as trophic factors and other heparin binding proteins. Alterations of GAGs structures might thus modify the nature and extent of these interactions and alter tissue integrity. Here, we studied levels and composition of GAGs isolated from adult and aged human hippocampus and investigated if their changes can influence the function of important trophic factors and the Aβ42 peptide toxicity. Biochemical analyses showed that heparan sulfates are increased in the aged hippocampus. Moreover, GAGs from aged hippocampus showed altered capacities to regulate trophic factor activities without changing their capacities to protect cells from Aβ42 toxicity, compared to adult hippocampus GAGs. Structural alterations in GAGs from elderly were suggested by differential transcripts levels of key biosynthetic enzymes. C5-epimerase and 2-OST expressions were decreased while NDST-2 and 3-OST-4 were increased; in contrast, heparanase expression was unchanged. Results suggest that alteration of GAGs in hippocampus of aged subjects could participate to tissue impairment during aging. PMID:22035591

  15. Toxicity of petroleum crude oils and their effect on xenobiotic metabolizing enzyme activities in the chicken embryo in ovo

    SciTech Connect

    Lee, Y.Z.; O'Brien, P.J.; Payne, J.F.; Rahimtula, A.D.

    1986-01-01

    Microliter quantities of a Prudhoe Bay crude oil (PBCO) applied to the shell of fertile chick eggs during various stages of development induced cytochrome P-450 levels and mixed-function oxidase activities within the liver of the embryo. PBCO (5 ..mu..l) applied on Day 11 of incubation was found to maximally induce within 24 hr embryo hepatic cytochrome P-450 levels (fourfold), naphthalene hydroxylase (sixfold), benzo(a)pyrene 3-hyroxylase (14-fold), and 7-ethoxyresorufin O-deethylase (24-fold). Glutathione S-transferase was not induced. Crude oils are known to be highly toxic to avian embryos, especially during the early stages of development. The LD/sub 50/ of PBCO and Hibernia crude oil applied to the egg shell on Day 8 of incubation was found to be 1.3 and 2.2 ..mu..l, respectively. Mixed-function oxidase-dependent metabolism of crude oil components may be required for toxicity since administration of 20 ..mu..g of disulfiram in dioxane 1 hr prior to application of 1.3 ..mu..l of PBCO reduced embryo mortality from 60 to 20%.

  16. A fully human chimeric antigen receptor with potent activity against cancer cells but reduced risk for off-tumor toxicity

    PubMed Central

    Song, De-Gang; Ye, Qunrui; Poussin, Mathilde; Liu, Lin; Figini, Mariangela; Powell, Daniel J.

    2015-01-01

    Chimeric antigen receptors (CARs) can redirect T cells against antigen-expressing tumors in an HLA-independent manner. To date, various CARs have been constructed using mouse single chain antibody variable fragments (scFvs) of high affinity that are immunogenic in humans and have the potential to mediate “on-target” toxicity. Here, we developed and evaluated a fully human CAR comprised of the human C4 folate receptor-alpha (αFR)-specific scFv coupled to intracellular T cell signaling domains. Human T cells transduced to express the C4 CAR specifically secreted proinflammatory cytokine and exerted cytolytic functions when cultured with αFR-expressing tumors in vitro. Adoptive transfer of C4 CAR T cells mediated the regression of large, established human ovarian cancer in a xenogeneic mouse model. Relative to a murine MOv19 scFv-based αFR CAR, C4 CAR T cells mediated comparable cytotoxic tumor activity in vitro and in vivo but had lower affinity for αFR protein and exhibited reduced recognition of normal cells expressing low levels of αFR. Thus, T cells expressing a fully human CAR of intermediate affinity can efficiently kill antigen-expressing tumors in vitro and in vivo and may overcome issues of transgene immunogenicity and “on-target off-tumor” toxicity that plague trials utilizing CARs containing mouse-derived, high affinity scFvs. PMID:26101914

  17. Assessment of Acute Oral and Dermal Toxicity of 2 Ethyl-Carbamates with Activity against Rhipicephalus microplus in Rats

    PubMed Central

    Prado-Ochoa, María Guadalupe; Gutiérrez-Amezquita, Ricardo Alfonso; Abrego-Reyes, Víctor Hugo; Velázquez-Sánchez, Ana María; Muñoz-Guzmán, Marco Antonio; Ramírez-Noguera, Patricia; Angeles, Enrique; Alba-Hurtado, Fernando

    2014-01-01

    The acute oral and dermal toxicity of two new ethyl-carbamates (ethyl-4-bromophenyl-carbamate and ethyl-4-chlorophenyl-carbamate) with ixodicide activity was determined in rats. The oral LD50 of each carbamate was 300 to 2000 mg/kg, and the dermal LD50 of each carbamate was >5000 mg/kg. Clinically, the surviving rats that had received oral doses of each carbamate showed decreased weight gain (P < 0.05) and had slight nervous system manifestations. These clinical signs were evident from the 300 mg/kg dose and were reversible, whereas the 2000 mg/kg dose caused severe damage and either caused their death or was motive for euthanasia. At necropsy, these rats had dilated stomachs and cecums with diffuse congestion, as well as moderate congestion of the liver. Histologically, the liver showed slight degenerative lesions, binucleated hepatocytes, focal coagulative necrosis, and congestion areas; the severity of the lesions increased with dosage. Furthermore, an slight increase in gamma-glutamyltransferase, lactate dehydrogenase, and creatinine was observed in the plasma. The dermal application of the maximum dose (5000 mg/kg) of each carbamate did not cause clinical manifestations or liver and skin alterations. This finding demonstrates that the carbamates under study have a low oral hazard and low acute dermal toxicity. PMID:24883331

  18. A Quantitative Structure Activity Relationship for acute oral toxicity of pesticides on rats: Validation, domain of application and prediction.

    PubMed

    Hamadache, Mabrouk; Benkortbi, Othmane; Hanini, Salah; Amrane, Abdeltif; Khaouane, Latifa; Si Moussa, Cherif

    2016-02-13

    Quantitative Structure Activity Relationship (QSAR) models are expected to play an important role in the risk assessment of chemicals on humans and the environment. In this study, we developed a validated QSAR model to predict acute oral toxicity of 329 pesticides to rats because a few QSAR models have been devoted to predict the Lethal Dose 50 (LD50) of pesticides on rats. This QSAR model is based on 17 molecular descriptors, and is robust, externally predictive and characterized by a good applicability domain. The best results were obtained with a 17/9/1 Artificial Neural Network model trained with the Quasi Newton back propagation (BFGS) algorithm. The prediction accuracy for the external validation set was estimated by the Q(2)ext and the root mean square error (RMS) which are equal to 0.948 and 0.201, respectively. 98.6% of external validation set is correctly predicted and the present model proved to be superior to models previously published. Accordingly, the model developed in this study provides excellent predictions and can be used to predict the acute oral toxicity of pesticides, particularly for those that have not been tested as well as new pesticides. PMID:26513561

  19. Quantitative structure-activity relationships and mixture toxicity of organic chemicals in Photobacterium phosphoreum: the Microtox test

    SciTech Connect

    Hermens, J.; Busser, F.; Leeuwangh, P.; Musch, A.

    1985-02-01

    Quantitative structure-activity relationships were calculated for the inhibition of bioluminescence of Photobacterium phosphoreum by 22 nonreactive organic chemicals. The inhibition was measured using the Microtox test and correlated with the partition coefficient between n-octanol and water (Poct), molar refractivity (MR), and molar volume (MW/d). At log Poct less than 1 and greater than 3, deviations from linearity were observed. Introduction of MR and MW/d improved the quality of the relationships. The influences of MR or MW/d may be related with an interaction of the tested chemicals to the enzyme system which produces the light emission. The sensitivity of the Microtox test to the 22 tested compounds is comparable to a 14-day acute mortality test with guppies for chemicals with log Poct less than 4. The inhibition of bioluminescence by a mixture of the tested compounds was slightly less than was expected in case of concentration addition. The Microtox test can give a good estimate of the total aspecific minimum toxicity of polluted waters. When rather lipophilic compounds or pollutants with more specific modes of action are present, this test will underestimate the toxicity to other aquatic life.

  20. Inhibition of histone deacetylase activity by trichostatin A modulates gene expression during mouse embryogenesis without apparent toxicity.

    PubMed

    Nervi, C; Borello, U; Fazi, F; Buffa, V; Pelicci, P G; Cossu, G

    2001-02-15

    Remodeling of the chromatin template by inhibition of histone deacetylase (HDAC) activities represents a major goal for transcriptional therapy in neoplastic diseases. Recently, a number of specific and potent HDAC-inhibitors that modulate in vitro cell growth and differentiation have been developed. In this study we analyzed the effect of trichostatin A (TSA), a specific and potent HDAC-inhibitor, on mouse embryos developing in vivo. When administered i.p. to pregnant mice (at a concentration of 0.5-1 mg/kg) at postimplantation stages (embryonic day 8 to embryonic day 10), TSA was not toxic for the mother and did not cause any obvious malformation during somitogenesis or at later stages of development. Treated embryos were born at similar frequency and were indistinguishable from control animals, developed normally, and were fertile. Interestingly, embryos from TSA-treated mice killed during somitogenesis were modestly but consistently larger than control embryos and presented an increased (+2 to +6) number of somites. This correlated with an increased acetylation of histone H4, the number of somites expressing the myogenic factor Myf-5, and the expression of Notch, RARalpha2, and RARbeta2 mRNAs. These data indicate that the effects of TSA on transcription: (a) are not toxic for the mother; (b) transiently accelerated growth in mouse embryos without perturbing embryogenesis; and (c) do not result in teratogenesis, at least in rodents. Thus, TSA might represent a nontoxic and effective agent for the transcriptional therapy of neoplasia. PMID:11245412

  1. Structure-Activity Relationship Studies on the Mosquito Toxicity and Biting Deterrency of Callicarpenal Derivatives

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Callicarpenal (13,14,15,16-tetranor-3-cleroden-12-al) has previously demonstrated significant mosquito bite-deterring activity against Aedes aegypti and Anopheles stephensi in addition to repellent activity against host-seeking nymphs of the blacklegged tick, Ixodes scapularis. In the present study...

  2. Developmental toxicity of perfluorononanoic acid is dependent on peroxisome proliferator activated receptor-alpha.

    EPA Science Inventory

    Perfluorononanoic acid (PFNA) is one of the predominant perfluoroalkyl acids in the environment and in tissues of humans and wildlife. PFNA strongly activates the mouse and human peroxisome proliferator-activated receptor-alpha (PPARα) in vitro and negatively impacts development ...

  3. Stability and toxicity of tris-tolyl bismuth(V) dicarboxylates and their biological activity towards Leishmania major.

    PubMed

    Ong, Yih Ching; Blair, Victoria L; Kedzierski, Lukasz; Tuck, Kellie L; Andrews, Philip C

    2015-11-01

    A series of 29 tris-tolyl bismuth(v) di-carboxylato complexes of composition [Bi(Tol)3(O2CR)2] involving either ortho, meta or para substituted tolyl ligands have been synthesized and characterised. Of these 15 were assessed for their toxicity towards Leishmania promastigotes and human fibroblast cells, with ten then being subsequently assessed against parasite amastigotes. The carboxylate ligands are drawn from a series of substituted and biologically relevant benzoic acids which allow a comparison with earlier studies on [BiPh3(O2CR)2] and analogous Sb(v) [SbAr3(O2CR)2] (Ar = Ph and Tol) complexes. Twelve complexes have been structurally characterized by single crystal X-ray diffraction and shown to adopt a typical trigonal bipyramidal geometry in which the three tolyl ligands occupy the equatorial plane. NMR studies on two illustrative examples indicate that the complexes are stable in D2O and DMSO but only have a half-life of 1.2 hours in culture medium, with glucose being a contributing factor in decomposition and reduction to Bi(Tol)3. Despite their short lifetime many complexes show significant toxicity towards promastigotes at low concentration (<6 μM) and at that concentration provide for good selectivity indices (parasite vs. mammalian cells), for example 114 for [Bi(o-Tol)3(O2CC6H3(2-OH,5-C6H3(2,4-F2)))2] and 838 for [Bi(m-Tol)3(O2CC6H4(2-OAc))2]. Best activity and selectivity is observed with complexes containing o- and m-tolyl ligands, and it appears the primary influence on fibroblast toxicity is the Ar ligand while the carboxylate influences promastigote toxicity. The complexes are less effective in vitro against the parasite amastigotes, where longer incubation times and harsher chemical and biological environments are encountered in the assay. Nevertheless, there were some statistically relevant differences at 1 μM against the positive controls with the best performing complexes being [Bi(o-Tol)3(O2CC6H4(2-EtO))2] and [Bi(m-Tol)3(O2CC6H4(2-OAc))2

  4. A novel natural Nrf2 activator with PPARγ-agonist (monascin) attenuates the toxicity of methylglyoxal and hyperglycemia

    SciTech Connect

    Hsu, Wei-Hsuan; Lee, Bao-Hong; Chang, Yu-Ying; Hsu, Ya-Wen; Pan, Tzu-Ming

    2013-11-01

    Methylglyoxal (MG) is a toxic-glucose metabolite and a major precursor of advanced glycation endproducts (AGEs). MG has been reported to result in inflammation by activating receptor for AGEs (RAGE). We recently found that Monascus-fermented metabolite monascin acts as a novel natural peroxisome proliferator-activated receptor-γ (PPARγ) agonist that improves insulin sensitivity. We investigated the metabolic, biochemical, and molecular abnormalities characteristic of type 2 diabetes in MG-treated Wistar rats treated with oral administration of monascin or rosiglitazone. Monascin (a novel PPARγ agonist) activated nuclear factor-erythroid 2-related factor 2 (Nrf2) and down-regulated hyperinsulinmia in oral glucose tolerance test (OGTT). Monascin was able to elevate glyoxalase-1 expression via activation of hepatic Nrf2, hence, resulting in MG metabolism to D-lactic acid and protected from AGEs production in MG-treated rats. Rosiglitazone did not activate Nrf2 nor glyoxalase expression to lower serum and hepatic AGEs levels. Monascin acts as a novel natural Nrf2 activator with PPARγ-agonist activity were confirmed by Nrf2 and PPARγ reporter assays in Hep G2 cells. These findings suggest that monascin acts as an anti-diabetic and anti-oxidative stress agent to a greater degree than rosiglitazone and thus may have therapeutic potential for the prevention of diabetes. - Highlights: • Monascin acts as a PPARgamma agonist. • Monascin activates Nrf2 and AMPK. • Monascin promotes MG metabolism into D-lactic acid. • Monascin attenuates inflammation and diabetes in vivo.

  5. Effect of Kaempferia parviflora Wall. ex. Baker on sexual activity of male rats and its toxicity.

    PubMed

    Sudwan, Paiwan; Saenphet, Kanokporn; Saenphet, Supap; Suwansirikul, Songkiet

    2006-01-01

    Kaempferia parviflora Wall. Ex. Baker (Krachaidum) has long been used among Thai men for sexual enhancement. The aim of this study was to determine the effect of K. parviflora ethanolic extract on the sexual behavior of male rats and its toxicity. The experiment was divided into three groups of rats given K. parviflora extract at doses of 60, 120, and 240 mg/kg BW for 60 days, whilst a control group received distilled water at 1 ml/day per oral. The results showed that all groups of male rats had significantly higher courtship behavior during the first 10-minute period of observation than in the 2nd and 3rd 10-minute periods, except those receiving the highest dose of K. parviflora. They revealed the same amount of courtship behavior throughout a whole 30-minute period, which was significantly lower than the control group. There was no significant difference between treated and control groups in other sexual behaviors; mount frequency (MF), intromission frequency (IF), mount latency (ML), or intromission latency (IL). Toxicological study revealed no significant difference of hemoglobin, WBC or differential cell count. All dosages had no effect on kidney and liver function, according to the normal values of blood urea nitrogen (BUN), creatinine (Crea), aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Nevertheless, the histopathological study showed a morphological change in the liver. It was concluded that K. parviflora extract at 240 mg/kg BW reduced the time in the first 10 mintues of rat courtship behavior and the use of high and chronic doses of K. parviflora in humans should be considered inadvisable. PMID:17547083

  6. Effects of zinc, copper, and lead toxicity on. cap alpha. -aminolevulinic acid dehydratase activity. [Rats

    SciTech Connect

    Shafiq-ur-Rehman

    1984-07-01

    The distribution of lead, zinc and copper in the human environment has been recognized as a major toxicological factor. Lead ions have been shown to inhibit the activity of delta-aminolevulinic acid dehydratase (delta-ALAD), which is involved in the biosynthesis of heme. Copper also has its inhibitory effect on delta-ALAD activity. A study has shown that the delta-ALAD was activated by zinc ions at physiological concentrations. In view of these reports, it was considered worthwhile to study the poisoning effects of lead, zinc and copper on delta-ALAD activity along with the concentrations of these metal ions in the blood. A possible role of Zn/sup + +/, Cu/sup + +/, and Pb/sup + +/ interaction and their influence on delta-ALAD has been explored in the present paper.

  7. Discovery and Canine Preclinical Assessment of a Non-Toxic Procaspase-3-Activating Compound

    PubMed Central

    Peterson, Quinn P.; Hsu, Danny C.; Novotny, Chris J.; West, Diana C.; Kim, Dewey; Schmit, Joanna M.; Dirikolu, Levent; Hergenrother, Paul J.; Fan, Timothy M.

    2010-01-01

    A critical event in the apoptotic cascade is the proteolytic activation of procaspases to active caspases. The caspase auto-activating compound PAC-1 induces cancer cell apoptosis and exhibits antitumor activity in murine xenograft models when administered orally as a lipid-based formulation or implanted subcutaneously as a cholesterol pellet. However, high doses of PAC-1 were found to induce neurotoxicity, prompting us to design and assess a novel PAC-1 derivative called S-PAC-1. Similar to PAC-1, S-PAC-1 activated procaspase-3 and induced cancer cell apoptosis. However, S-PAC-1 did not induce neurotoxicity in mice or dogs. Continuous intravenous infusion of S-PAC-1 in dogs led to a steady state plasma concentration of ~10 µM for 24–72 hours. In a small efficacy trial of S-PAC-1, evaluation of six pet dogs with lymphoma revealed that S-PAC-1 was well-tolerated and that the treatments induced partial tumor regression or stable diseasein 4 / 6 subjects. Our results support this canine setting for further evaluation of small molecule procaspase-3 activators, including S-PAC-1, a compound that is an excellent candidate for further clinical evaluation as a novel cancer chemotherapeutic. PMID:20823163

  8. Toxic responses and antioxidative enzymes activity of Scenedesmus obliquus exposed to fenhexamid and atrazine, alone and in mixture.

    PubMed

    Mofeed, Jelan; Mosleh, Yahia Y

    2013-09-01

    Laboratory studies were conducted to determine the effects of different concentrations of fenhexamid and atrazine (25, 50 and 100 µg L(-1)) on growth and oxidative stress on Scenedesmus obliquus (microalgae) after exposure for 24, 48, and 96 h. In addition, residues of fenhexamid and atrazine were determined in the culture medium after 96 h; 52%, 44% and 43% of fenhexamid remained in the medium for the lowest, middle and highest concentrations, respectively. Atrazine concentration decreased significantly in the medium with time. The reduction was faster with the lowest concentration (-53%), than in the highest concentration (-46%), while it was intermediate with 50 µg L(-1) (-47%). The antioxidative enzyme activities were used as biomarkers to evaluate the toxic effects of fenhexamid and atrazine on the microalgae. Enzymatic activities were measured in the presence of each compound alone after 24, 48 and 96 h and also in mixture after 24h exposure. The results showed that fenhexamid and atrazine induced antioxidative enzyme activities (GST, CAT and GR) at different concentrations. Catalase activities (CAT) in both pesticides treated-algae were significantly increased. Additionally, an increase in gulathione-S-transferase (GST) was observed in algae after 24, 48 and 96 h of exposure to both fenhexamid and atrazine. Antioxidative enzymes in fenhexamid and atrazine mixture treatment showed an antagonistic interaction after 24h of exposure in algae. PMID:23796667

  9. Evaluation of the Toxicity, AChE Activity and DNA Damage Caused by Imidacloprid on Earthworms, Eisenia fetida.

    PubMed

    Wang, Kai; Qi, Suzhen; Mu, Xiyan; Chai, Tingting; Yang, Yang; Wang, Dandan; Li, Dongzhi; Che, Wunan; Wang, Chengju

    2015-10-01

    Imidacloprid is a well-known pesticide and it is timely to evaluate its toxicity to earthworms (Eisenia fetida). In the present study, the effect of imidacloprid on reproduction, growth, acetylcholinesterase (AChE) and DNA damage in earthworms was assessed using an artificial soil medium. The median lethal concentration (LC50) and the median number of hatched cocoons (EC50) of imidacloprid to earthworms was 3.05 and 0.92 mg/kg respectively, the lowest observed effect concentration of imidacloprid about hatchability, growth, AChE activity and DNA damage was 0.02, 0.5, 0.1 and 0.5 mg/kg, respectively. PMID:26293707

  10. Inhibition by oxonic acid of gastrointestinal toxicity of 5-fluorouracil without loss of its antitumor activity in rats.

    PubMed

    Shirasaka, T; Shimamoto, Y; Fukushima, M

    1993-09-01

    The possibility of decreasing the gastrointestinal (GI) toxic effects of 5-fluorouracil (5-FU) on the digestive tract such as its injury of cells and induction of diarrhea, without reducing its antitumor activity, was investigated in rats. Oxonic acid was found to inhibit the phosphorylation of 5-FU to 5-fluorouridine-5'-monophosphate catalyzed by pyrimidine phosphoribosyl-transferase in a different manner from allopurinol in cell-free extracts and intact cells in vitro. On p.o. administration of 5-FU (2 mg/kg) and a potent inhibitor of 5-FU degradation to Yoshida sarcoma-bearing rats, oxonic acid (10 mg/kg) was found to inhibit the formation of 5-fluorouridine-5'-monophosphate from 5-FU and its subsequent incorporation into the RNA fractions of small and large intestine but not of tumor and bone marrow tissues. This selective inhibition of 5-FU phosphorylation in the GI tract was due to the much higher concentrations of oxonic acid in GI tissues than in other tissues and the blood. On p.o. administration with the 5-FU derivative, UFT, which is a combined form of 1 M tegafur and 4 M uracil and usually administered p.o. to cancer patients in Japan, oxonic acid (10-50 mg/kg) markedly reduced injury of GI tissues and/or severe diarrhea without influencing the antitumor effect of UFT. These findings suggest that coadministration of oxonic acid suppresses the GI toxicity of 5-FU and its derivatives without affecting their antitumor activity and thus prolongs the life span of cancer-bearing rats. PMID:7689420

  11. Toxic influence of silver and uranium salts on activated sludge of wastewater treatment plants and synthetic activated sludge associates modeled on its pure cultures.

    PubMed

    Tyupa, Dmitry V; Kalenov, Sergei V; Skladnev, Dmitry A; Khokhlachev, Nikolay S; Baurina, Marina M; Kuznetsov, Alexander Ye

    2015-01-01

    Toxic impact of silver and uranium salts on activated sludge of wastewater treatment facilities has been studied. Some dominating cultures (an active nitrogen fixer Agrobacterium tumifaciens (A.t) and micromyces such as Fusarium nivale, Fusarium oxysporum, and Penicillium glabrum) have been isolated and identified as a result of selection of the activated sludge microorganisms being steadiest under stressful conditions. For these cultures, the lethal doses of silver amounted 1, 600, 50, and 300 µg/l and the lethal doses of uranium were 120, 1,500, 1,000, and 1,000 mg/l, respectively. A.tumifaciens is shown to be more sensitive to heavy metals than micromyces. Synthetic granular activated sludge was formed on the basis of three cultures of the isolated micromyces steadiest against stress. Its granules were much more resistant to silver than the whole native activated sludge was. The concentration of silver causing 50 % inhibition of synthetic granular activated sludge growth reached 160-170 μg/l as far as for the native activated sludge it came only to 100-110 μg/l. PMID:25027236

  12. Hepatoprotective activity of bacoside A against N-nitrosodiethylamine-induced liver toxicity in adult rats.

    PubMed

    Janani, Panneerselvam; Sivakumari, Kanakarajan; Parthasarathy, Chandrakesan

    2009-10-01

    N-Nitrosodiethylamine (DEN) is a notorious carcinogen, present in many environmental factors. DEN induces oxidative stress and cellular injury due to enhanced generation of reactive oxygen species; free radical scavengers protect the membranes from DEN-induced damage. The present study was designed to evaluate the protective effect of bacoside A (the active principle isolated from Bacopa monniera Linn.) on carcinogen-induced damage in rat liver. Adult male albino rats were pretreated with 15 mg/kg body weight/day of bacoside A orally (for 14 days) and then intoxicated with single necrogenic dose of N-nitrosodiethylamine (200 mg/kg bodyweight, intraperitonially) and maintained for 7 days. The liver weight, lipid peroxidation (LPO), and activity of serum marker enzymes (aspartate transaminases, alanine transaminases, lactate dehydrogenase, alkaline phosphatase, and gamma-glutamyl transpeptidase) were markedly increased in carcinogen-administered rats, whereas the activities of marker enzymes were near normal in bacoside A-pretreated rats. Activities of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutatione-S-transferase, and reduced glutathione) in liver also decreased in carcinogen-administered rats, which were significantly elevated in bacoside A-pretreated rats. It is concluded that pretreatment of bacoside A prevents the elevation of LPO and activity of serum marker enzymes and maintains the antioxidant system and thus protects the rats from DEN-induced hepatotoxicity. PMID:18679812

  13. Toxicity of aryl- and benzylhalides to Daphnia magna and classification of their mode of action based on quantitative structure-activity relationship

    SciTech Connect

    Marchini, S.; Passerini, L.; Hoglund, M.D.; Pino, A.; Nendza, M.

    1999-12-01

    The acute toxicity of aryl- and benzylhalides to Daphnia magna was investigated to test the validity of existing classification schemes for chemicals by mode of action, mainly based on fish studies, and the applicability of predictive quantitative structure-activity relationship (QSAR) models. Halobenzenes and halotoluenes are generally agreed to be unambiguous baseline toxicants (class 1) with the major exception of the benzylic structures, which are reactive in fish tests (class 3). Eighty-nine percent of the arylhalides tested in this study match a log P{sub ow}-dependent QSAR, including fluorinated, chlorinated, brominated, and iodinated derivatives, thereby confirming the validity of the baseline models also for variously halogenated compounds (other than only-chloro compounds). The toxicities of the benzylhalides relative to baseline QSARs clearly indicate that these compounds belong to two classes of mode of action, i.e., they either act as narcotic toxicants (class 1) or reveal excess toxicity due to unspecific reactivity (class 3). On some occasions, the assignment to the two classes of F. magna deviates from the structural rules derived from fish, i.e., iodinated compounds as well as {alpha},{alpha}-Cl{sub 2}-toluene's lack reactive excess toxicity but behave as nonpolar nonspecific toxicants. The QSARs derived during this study reveal lower slopes and higher intercepts than typical baseline models and, together with the analysis of mixture toxicity studies, behavioral studies, and critical body burden, advocate the hypothesis that there are several different ways to produce baseline toxicity. Most halobenzenes and halotoluenes are actually baseline chemicals with some extra reactivity and as such form a subgroup, whose limits still have to be defined. Different primary sites of action could explain why the chemicals are discriminated by different classification systems, but still they must have some rate-limiting interaction in common as they fit the

  14. Hepatoprotective and Antioxidant Activity of Dunaliella salina in Paracetamol-induced Acute Toxicity in Rats

    PubMed Central

    Madkour, Fedekar F.; Abdel-Daim, M. M.

    2013-01-01

    Paracetamol has a reasonable safety profile when taken in therapeutic doses. However, it could induce hepatotoxicity and even more severe fatal acute hepatic damage when taken in an overdose. The green alga, Dunaliella salina was investigated for hepatoprotective and antioxidant activity against paracetamol-induced liver damage in rats. Male albino Wistar rats overdosed with paracetamol showed liver damage and oxidative stress as indicated by significantly (P<0.05) increased serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total and direct bilirubin, malondialdehyde, cholesterol and nitric oxide. At the same time, there were decreased activities of serum superoxide dismutase and total antioxidant capacity compared with the control group. Treatment with D. salina methanol extract at doses of 500 and 1000 mg/kg body weight or silymarin could significantly (P<0.05) decrease the liver damage marker enzymes, total and direct bilirubin, malondialdehyde, cholesterol and nitric oxide levels and increase the activities of superoxide dismutase and total antioxidant capacity in serum when compared with paracetamol intoxicated group. Liver histopathology also showed that D. salina reduced the centrilobular necrosis, congestion and inflammatory cell infiltration evoked by paracetamol overdose. These results suggest that D. salina exhibits a potent hepatoprotective effect on paracetamol-induced liver damage in rats, which may be due to both the increase of antioxidant enzymes activity and inhibition of lipid peroxidation. PMID:24591738

  15. LINKING EXPOSURE AND DOSIMETRY TO RISK FROM PHOTO-ACTIVATED TOXICITY OF PAHS

    EPA Science Inventory

    Hazard from photo-activation of PAHs has been well documented in aquatic organisms. Far less certain is the degree to which risk actually occurs in the field. One of the key difficulties in understanding this risk lies in quantifying exposure/dosimetry for both PAHs and UV radiat...

  16. Surface Water Impacted by Rural Activities Induces Genetic Toxicity Related to Recombinagenic Events in Vivo.

    PubMed

    Soares Neto, José Lopes; de Carli, Raíne Fogliati; Kotzal, Queila Susana Gambim; Latroni, Francine Bolico; Lehmann, Mauricio; Dias, Johnny Ferraz; de Souza, Cláudia Telles; Niekraszewicz, Liana Appel Boufleur; da Silva, Fernanda Rabaioli; da Silva, Juliana; Dihl, Rafael Rodrigues

    2016-01-01

    This investigation assessed the interaction of surface water samples with DNA to quantitatively and qualitatively characterize their mutagenic and/or recombinagenic activity. Samples were obtained at three different sites along the Tocantins River (Tocantins State, Brazil). The area has withstood the impact mainly of rural activities, which release different chemical compounds in the environment. The Drosophila melanogaster Somatic Mutation and Recombination Test (SMART) was performed in standard (ST) and high bioactivation (HB) crosses. SMART is useful for the detection of mutational and recombinational events induced by genotoxins of direct and indirect action. Results demonstrated that samples collected in both seasons were able to induce increments on the mutant spot frequencies in the larvae of the HB cross. Genotoxicity was related to a massive recombinagenic activity. The positive responses ascribed to only the HB cross means that it is linked to pro-genotoxins requiring metabolic activation. The SMART wing test in Drosophila melanogaster was shown to be highly sensitive to detect genotoxic agents present in the aquatic environment impacted by agriculture. PMID:27537904

  17. Surface Water Impacted by Rural Activities Induces Genetic Toxicity Related to Recombinagenic Events in Vivo

    PubMed Central

    Soares Neto, José Lopes; de Carli, Raíne Fogliati; Kotzal, Queila Susana Gambim; Latroni, Francine Bolico; Lehmann, Mauricio; Dias, Johnny Ferraz; de Souza, Cláudia Telles; Niekraszewicz, Liana Appel Boufleur; da Silva, Fernanda Rabaioli; da Silva, Juliana; Dihl, Rafael Rodrigues

    2016-01-01

    This investigation assessed the interaction of surface water samples with DNA to quantitatively and qualitatively characterize their mutagenic and/or recombinagenic activity. Samples were obtained at three different sites along the Tocantins River (Tocantins State, Brazil). The area has withstood the impact mainly of rural activities, which release different chemical compounds in the environment. The Drosophila melanogaster Somatic Mutation and Recombination Test (SMART) was performed in standard (ST) and high bioactivation (HB) crosses. SMART is useful for the detection of mutational and recombinational events induced by genotoxins of direct and indirect action. Results demonstrated that samples collected in both seasons were able to induce increments on the mutant spot frequencies in the larvae of the HB cross. Genotoxicity was related to a massive recombinagenic activity. The positive responses ascribed to only the HB cross means that it is linked to pro-genotoxins requiring metabolic activation. The SMART wing test in Drosophila melanogaster was shown to be highly sensitive to detect genotoxic agents present in the aquatic environment impacted by agriculture. PMID:27537904

  18. In vitro anticancer activity, toxicity and structure-activity relationships of phyllostictine A, a natural oxazatricycloalkenone produced by the fungus Phyllosticta cirsii

    SciTech Connect

    Le Calve, Benjamin; Lallemand, Benjamin; Perrone, Carmen; Lenglet, Gaelle; Depauw, Sabine; Van Goietsenoven, Gwendoline; Bury, Marina; Vurro, Maurizio; Herphelin, Francoise; Andolfi, Anna; Zonno, Maria Chiara; Mathieu, Veronique; Dufrasne, Francois; Van Antwerpen, Pierre; Poumay, Yves

    2011-07-01

    The in vitro anticancer activity and toxicity of phyllostictine A, a novel oxazatricycloalkenone recently isolated from a plant-pathogenic fungus (Phyllosticta cirsii) was characterized in six normal and five cancer cell lines. Phyllostictine A displays in vitro growth-inhibitory activity both in normal and cancer cells without actual bioselectivity, while proliferating cells appear significantly more sensitive to phyllostictine A than non-proliferating ones. The main mechanism of action by which phyllostictine displays cytotoxic effects in cancer cells does not seem to relate to a direct activation of apoptosis. In the same manner, phyllostictine A seems not to bind or bond with DNA as part of its mechanism of action. In contrast, phyllostictine A strongly reacts with GSH, which is a bionucleophile. The experimental data from the present study are in favor of a bonding process between GSH and phyllostictine A to form a complex though Michael attack at C=C bond at the acrylamide-like system. Considering the data obtained, two new hemisynthesized phyllostictine A derivatives together with three other natural phyllostictines (B, C and D) were also tested in vitro in five cancer cell lines. Compared to phyllostictine A, the two derivatives displayed a higher, phyllostictines B and D a lower, and phyllostictine C an almost equal, growth-inhibitory activity, respectively. These results led us to propose preliminary conclusions in terms of the structure-activity relationship (SAR) analyses for the anticancer activity of phyllostictine A and its related compounds, at least in vitro.

  19. In vitro anticancer activity, toxicity and structure-activity relationships of phyllostictine A, a natural oxazatricycloalkenone produced by the fungus Phyllosticta cirsii.

    PubMed

    Le Calvé, Benjamin; Lallemand, Benjamin; Perrone, Carmen; Lenglet, Gaëlle; Depauw, Sabine; Van Goietsenoven, Gwendoline; Bury, Marina; Vurro, Maurizio; Herphelin, Françoise; Andolfi, Anna; Zonno, Maria Chiara; Mathieu, Véronique; Dufrasne, François; Van Antwerpen, Pierre; Poumay, Yves; David-Cordonnier, Marie-Hélène; Evidente, Antonio; Kiss, Robert

    2011-07-01

    The in vitro anticancer activity and toxicity of phyllostictine A, a novel oxazatricycloalkenone recently isolated from a plant-pathogenic fungus (Phyllosticta cirsii) was characterized in six normal and five cancer cell lines. Phyllostictine A displays in vitro growth-inhibitory activity both in normal and cancer cells without actual bioselectivity, while proliferating cells appear significantly more sensitive to phyllostictine A than non-proliferating ones. The main mechanism of action by which phyllostictine displays cytotoxic effects in cancer cells does not seem to relate to a direct activation of apoptosis. In the same manner, phyllostictine A seems not to bind or bond with DNA as part of its mechanism of action. In contrast, phyllostictine A strongly reacts with GSH, which is a bionucleophile. The experimental data from the present study are in favor of a bonding process between GSH and phyllostictine A to form a complex though Michael attack at C=C bond at the acrylamide-like system. Considering the data obtained, two new hemisynthesized phyllostictine A derivatives together with three other natural phyllostictines (B, C and D) were also tested in vitro in five cancer cell lines. Compared to phyllostictine A, the two derivatives displayed a higher, phyllostictines B and D a lower, and phyllostictine C an almost equal, growth-inhibitory activity, respectively. These results led us to propose preliminary conclusions in terms of the structure-activity relationship (SAR) analyses for the anticancer activity of phyllostictine A and its related compounds, at least in vitro. PMID:21504755

  20. Evidence for Classical Cholinergic Toxicity Associated with Selective Activation of M1 Muscarinic Receptors.

    PubMed

    Alt, Andrew; Pendri, Annapurna; Bertekap, Robert L; Li, Guo; Benitex, Yulia; Nophsker, Michelle; Rockwell, Kristin L; Burford, Neil T; Sum, Chi Shing; Chen, Jing; Herbst, John J; Ferrante, Meredith; Hendricson, Adam; Cvijic, Mary Ellen; Westphal, Ryan S; O'Connell, Jonathan; Banks, Martyn; Zhang, Litao; Gentles, Robert G; Jenkins, Susan; Loy, James; Macor, John E

    2016-02-01

    The muscarinic acetylcholine receptor subtype 1 (M1) receptors play an important role in cognition and memory, and are considered to be attractive targets for the development of novel medications to treat cognitive impairments seen in schizophrenia and Alzheimer's disease. Indeed, the M1 agonist xanomeline has been shown to produce beneficial cognitive effects in both Alzheimer's disease and schizophrenia patients. Unfortunately, the therapeutic utility of xanomeline was limited by cholinergic side effects (sweating, salivation, gastrointestinal distress), which are believed to result from nonselective activation of other muscarinic receptor subtypes such as M2 and M3. Therefore, drug discovery efforts targeting the M1 receptor have focused on the discovery of compounds with improved selectivity profiles. Recently, allosteric M1 receptor ligands have been described, which exhibit excellent selectivity for M1 over other muscarinic receptor subtypes. In the current study, the following three compounds with mixed agonist/positive allosteric modulator activities that are highly functionally selective for the M1 receptor were tested in rats, dogs, and cynomologous monkeys: (3-((1S,2S)-2-hydrocyclohexyl)-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)benzo[h]quinazolin-4(3H)-one; 1-((4-cyano-4-(pyridin-2-yl)piperidin-1-yl)methyl)-4-oxo-4H-quinolizine-3-carboxylic acid; and (R)-ethyl 3-(2-methylbenzamido)-[1,4'-bipiperidine]-1'-carboxylate). Despite their selectivity for the M1 receptor, all three compounds elicited cholinergic side effects such as salivation, diarrhea, and emesis. These effects could not be explained by activity at other muscarinic receptor subtypes, or by activity at other receptors tested. Together, these results suggest that activation of M1 receptors alone is sufficient to produce unwanted cholinergic side effects such as those seen with xanomeline. This has important implications for the development of M1 receptor-targeted therapeutics since it

  1. Activation of transcription factor AP-1 and mitogen-activated protein kinases in aniline-induced splenic toxicity

    SciTech Connect

    Khan, M. Firoze . E-mail: mfkhan@utmb.edu; Kannan, Subburaj; Wang Jianling

    2006-01-15

    Signaling mechanisms in aniline-induced fibrogenic and/or tumorigenic response in the spleen are not known. Previous studies have shown that aniline exposure leads to iron accumulation and oxidative stress in the spleen, which may cause activation of redox-sensitive transcription factors and regulate the transcription of genes involved in fibrosis and/or tumorigenesis. To test this, male SD rats were treated with 0.5 mmol/kg/day aniline via drinking water for 30 days, and activation of transcription factor AP-1 was determined in the splenocyte nuclear extracts (NEs). AP-1 DNA-binding activity in the NEs of freshly isolated splenocytes from aniline-treated rats increased in comparison to the controls, as determined by electrophoretic mobility shift assay (EMSA). AP-1 binding was also determined in the NEs of cultured splenocytes (2 h and 24 h), which showed even a greater increase in binding activity at 2 h. The specificity of AP-1 binding for relevant DNA motifs was confirmed by competition EMSA and by supershift EMSA using antibodies specific to c-Jun and c-Fos. To further explore the signaling mechanisms in the AP-1 activation, phosphorylation patterns of mitogen-activated protein kinases (MAPKs) were pursued. Aniline exposure induced increases in the phosphorylation of the three classes of MAPKs: extracellular-signal-regulated kinase (ERK 1/2), c-Jun N-terminal kinase (JNK 1/2), and p38 MAPKs. Furthermore, TGF-{beta}1 mRNA expression showed a 3-fold increase in the spleens of aniline-treated rats. These observations suggest a strong association among MAPK phosphorylation, AP-1 activation, and enhanced TGF-{beta}1 gene expression. The observed sequence of events subsequent to aniline exposure could regulate genes that lead to fibrogenic and/or tumorigenic response in the spleen.

  2. Effects of Croton rhamnifolioides essential oil on Aedes aegypti oviposition, larval toxicity and trypsin activity.

    PubMed

    Santos, Geanne K N; Dutra, Kamilla A; Lira, Camila S; Lima, Bheatriz N; Napoleão, Thiago H; Paiva, Patrícia M G; Maranhão, Claudia A; Brandão, Sofia S F; Navarro, Daniela M A F

    2014-01-01

    Although numerous reports are available concerning the larvicidal potential of essential oils, very few investigations have focused on their mechanisms of action. In the present study, we have investigated the chemical composition of the leaf oil of Croton rhamnifolioides during storage and its effects on oviposition and survival of larvae of the dengue fever mosquito Aedes aegypti. In addition, we have established a possible mechanism of action for the larvicidal activity of the essential oil. GC-MS analyses revealed marked differences in the composition of oil that had been freshly isolated and that of a sample that had been stored in a sealed amber-glass vial under refrigeration for three years. However, both fresh and stored oil exhibited substantial larvicidal activities with LC50 values of 122.35 and 89.03 ppm, respectively, and oviposition deterrent effects against gravid females at concentrations of 50 and 100 µg·mL-1. These results demonstrate that the larvicidal effect of the essential oil was unchanged during three years of storage even though its chemical composition altered. Hence, the essential oil could be used in the preparation of commercial products. In addition, we observed that the trypsin-like activity of mosquito larvae was inhibited in vitro by the essential oil of C. rhamnifolioides, suggesting that the larvicidal effect may be associated with inhibition of this enzyme. PMID:25317582

  3. Protease susceptibility and toxicity of heat-labile enterotoxins with a mutation in the active site or in the protease-sensitive loop.

    PubMed Central

    Giannelli, V; Fontana, M R; Giuliani, M M; Guangcai, D; Rappuoli, R; Pizza, M

    1997-01-01

    To generate nontoxic derivatives of Escherichia coli heat-labile enterotoxin (LT), site-directed mutagenesis has been used to change either the amino acid residues located in the catalytic site (M. Pizza, M. Domenighini, W. Hol, V. Giannelli, M. R. Fontana, M. M. Giuliani, C. Magagnoli, S. Peppoloni, R. Manetti, and R. Rappuoli, Mol. Microbiol. 14:51-60, 1994) or those located in the proteolytically sensitive loop that joins the A1 and A2 moieties of the A subunit (C. C. R. Grant, R. J. Messer, and W. J. Cieplack, Infect. Immun. 62:4270-4278, 1994; B. L. Dickinson and J. D. Clements, Infect. Immun. 63:1617-1623, 1995). In this work, we compared the in vitro and in vivo toxic properties and the resistance to protease digestion of the prototype molecules obtained by both approaches (LT-K63 and LT-R192G, respectively). As expected, LT-K63 was normally processed by proteases, while LT-R192G showed increased resistance to trypsin in vitro and was digested by trypsin only under denaturing conditions (3.5 M urea) or by intestinal proteases. No toxicity was detected with the LT-K63 mutant, even when 40 micrograms and 1 mg were used in the in vitro and in vivo assays, respectively. In marked contrast, LT-R192G showed only a modest (10-fold) reduction in toxicity in Y1 cells with a delay in the appearance of the toxic activity and had toxicity comparable to that of wild-type LT in the rabbit ileal loop assay. We conclude that mutagenesis of the active site generates molecules that are fully devoid of toxicity, while mutagenesis of the A1-A2 loop generates molecules that are resistant to trypsin in vitro but still susceptible to proteolytic activation by proteases other than trypsin, and therefore they may still be toxic in tissue culture and in vivo. PMID:8975934

  4. Development of acute toxicity quantitative structure activity relationships (QSAR) and their use in linear alkylbenzene sulfonate species sensitivity distributions.

    PubMed

    Belanger, Scott E; Brill, Jessica L; Rawlings, Jane M; Price, Brad B

    2016-07-01

    Linear Alkylbenzene Sulfonate (LAS) is high tonnage and widely dispersed anionic surfactant used by the consumer products sector. A range of homologous structures are used in laundry applications that differ primarily on the length of the hydrophobic alkyl chain. This research summarizes the development of a set of acute toxicity QSARs (Quantitative Structure Activity Relationships) for fathead minnows (Pimephales promelas) and daphnids (Daphnia magna, Ceriodaphnia dubia) using accepted test guideline approaches. A series of studies on pure chain length LAS from C10 to C14 were used to develop the QSARs and the robustness of the QSARs was tested by evaluation of two technical mixtures of differing compositions. All QSARs were high quality (R(2) were 0.965-0.997, p < 0.0001). Toxicity normalization employing QSARs is used to interpret a broader array of tests on LAS chain length materials to a diverse group of test organisms with the objective of developing Species Sensitivity Distributions (SSDs) for various chain lengths of interest. Mixtures include environmental distributions measured from exposure monitoring surveys of wastewater effluents, various commercial mixtures, or specific chain lengths. SSD 5th percentile hazardous concentrations (HC5s) ranged from 0.129 to 0.254 mg/L for wastewater effluents containing an average of 11.26-12 alkyl carbons. The SSDs are considered highly robust given the breadth of species (n = 19), use of most sensitive endpoints from true chronic studies and the quality of the underlying statistical properties of the SSD itself. The data continue to indicate a low hazard to the environment relative to expected environmental concentrations. PMID:27105149

  5. Modified GFAP promoter auto-regulates tet-activator expression for increased transactivation and reduced tTA-associated toxicity.

    PubMed

    Barton, Michael D; Dunlop, J W; Psaltis, G; Kulik, J; DeGennaro, L; Kwak, Seung P

    2002-05-30

    Transactivator tTA is a necessary component of the tetracycline-regulated inducible gene system. While several transgenic animals have been described that express tTA in the central nervous system (CNS), their tTA levels are often limited, presumably due to toxic effects. We evaluated methods for auto-regulating tTA levels in astrocytes by modifying the transgenic promoter human GFAP (hGFAP). The hGFAP promoter carrying a single copy of the tet-operon in place of a native enhancer element (GFAPtetO1) drove expression of tTA at low levels during un-stimulated, basal condition. However the same promoter auto-induced expression of tTA to significant levels after tetracycline withdrawal. Glial cell-specificity of the promoter remained uncompromised during both basal and induced conditions. Transgenic rats were developed using the auto-inducible GFAPtetO1 promoter that expressed tTA mRNA to high levels in the brain. Expression was widespread within the CNS but enriched in astrocyte-rich regions including the cerebellum. Primary cerebellar astrocytes from GFAPtetO1 rats transfected with 07LacZ produced substantially greater inducibility of reporter gene compared to GFAP-tTA transgenic rats. Finally, GFAPtetO1 rats exhibited severe motor/gait deficit when bred to homozygosity. This phenotype was attributable to developmental abnormalities of the cerebellum and was completely abrogated by doxycycline administration. These results suggest that developmental toxicity resulting from tTA expression can be circumvented and tTA transgenics with high transactivation potential can be developed using the auto-activation strategy. Promoter modification presented here may be useful in developing highly inducible transgenic strategies without loss in tissue-specificity. PMID:12007834

  6. Methylene blue counteracts H2S toxicity-induced cardiac depression by restoring L-type Ca channel activity.

    PubMed

    Judenherc-Haouzi, Annick; Zhang, Xue-Qian; Sonobe, Takashi; Song, Jianliang; Rannals, Matthew D; Wang, JuFang; Tubbs, Nicole; Cheung, Joseph Y; Haouzi, Philippe

    2016-06-01

    We have previously reported that methylene blue (MB) can counteract hydrogen sulfide (H2S) intoxication-induced circulatory failure. Because of the multifarious effects of high concentrations of H2S on cardiac function, as well as the numerous properties of MB, the nature of this interaction, if any, remains uncertain. The aim of this study was to clarify 1) the effects of MB on H2S-induced cardiac toxicity and 2) whether L-type Ca(2+) channels, one of the targets of H2S, could transduce some of the counteracting effects of MB. In sedated rats, H2S infused at a rate that would be lethal within 5 min (24 μM·kg(-1)·min(-1)), produced a rapid fall in left ventricle ejection fraction, determined by echocardiography, leading to a pulseless electrical activity. Blood concentrations of gaseous H2S reached 7.09 ± 3.53 μM when cardiac contractility started to decrease. Two to three injections of MB (4 mg/kg) transiently restored cardiac contractility, blood pressure, and V̇o2, allowing the animals to stay alive until the end of H2S infusion. MB also delayed PEA by several minutes following H2S-induced coma and shock in unsedated rats. Applying a solution containing lethal levels of H2S (100 μM) on isolated mouse cardiomyocytes significantly reduced cell contractility, intracellular calcium concentration ([Ca(2+)]i) transient amplitudes, and L-type Ca(2+) currents (ICa) within 3 min of exposure. MB (20 mg/l) restored the cardiomyocyte function, ([Ca(2+)]i) transient, and ICa The present results offer a new approach for counteracting H2S toxicity and potentially other conditions associated with acute inhibition of L-type Ca(2+) channels. PMID:26962024

  7. Acute toxicity and genotoxic activity of avocado seed extract (Persea americana Mill., c.v. Hass).

    PubMed

    Padilla-Camberos, Eduardo; Martínez-Velázquez, Moisés; Flores-Fernández, José Miguel; Villanueva-Rodríguez, Socorro

    2013-01-01

    The use of vegetal extracts requires toxicological and genotoxic evaluations to establish and verify safety before being added to human cosmetic, pharmaceutical medicine, or alimentary products. Persea americana seeds have been used in traditional medicine as treatment for several diseases. In this work, the ethanolic seed extract of Persea americana was evaluated with respect to its genotoxic potential through micronucleus assay in rodents. The frequency of micronuclei in groups of animals treated with avocado seed extract showed no differences compared to the negative control (vehicle); therefore, it is considered that the avocado seed extract showed no genotoxic activity in the micronucleus test. PMID:24298206

  8. Acute Toxicity and Genotoxic Activity of Avocado Seed Extract (Persea americana Mill., c.v. Hass)

    PubMed Central

    Padilla-Camberos, Eduardo; Martínez-Velázquez, Moisés; Flores-Fernández, José Miguel; Villanueva-Rodríguez, Socorro

    2013-01-01

    The use of vegetal extracts requires toxicological and genotoxic evaluations to establish and verify safety before being added to human cosmetic, pharmaceutical medicine, or alimentary products. Persea americana seeds have been used in traditional medicine as treatment for several diseases. In this work, the ethanolic seed extract of Persea americana was evaluated with respect to its genotoxic potential through micronucleus assay in rodents. The frequency of micronuclei in groups of animals treated with avocado seed extract showed no differences compared to the negative control (vehicle); therefore, it is considered that the avocado seed extract showed no genotoxic activity in the micronucleus test. PMID:24298206

  9. The adjuvant activity of a non-toxic, water-soluble glycopeptide present in large quantities in the culture filtrate of Mycobacterium tuberculosis strain DT.

    PubMed Central

    Stewart-Tull, D E; Shimono, T; Kotani, S; Kato, M; Ogawa, Y; Yamamura, Y; Koga, T; Pearson, C M

    1975-01-01

    A water-soluble mycobacterial glycopeptide was obtained in large quantities from the culture supernatant fluid of M. tuberculosis strain DT. This glycopeptide was strongly adjuvant-active when injected, in a water-in-oil emulsion contianing ovalbumin, into guinea-pigs. In addition, it was devoid of cord factor toxicity in mice, polyarthritogenic activity in rats and cavity stimulating activity in rabbit lungs. Images FIG. 2 FIG. 3 FIG. 4 FIG. 5 FIG. 6 FIG. 8 PMID:806515

  10. Effect of activated carbon or biochars on toxicity of different soils contaminated by mixture of native polycyclic aromatic hydrocarbons and heavy metals.

    PubMed

    Kołtowski, Michał; Oleszczuk, Patryk

    2016-05-01

    Activated carbon (AC), biochar from wheat straw (BCS), and biochar from willow (BCW) were added to the soils sampled from areas of strong anthropogenic influence at doses of 0.5%, 1%, 2.5%, or 5% (w/w) and incubated for 2 mo. At the end of this period, the toxicity of the soils was measured. The effect of AC and biochars on the toxicity of the soils varied based on soil, type of amendment, dose, and test organism. For most of the parameters tested, the highest effectiveness of AC in terms of reduction of toxicity was observed in soil POPI (from bitumen processing plant area). In the case of the remaining soils, after the addition of AC varied results were observed, in which a reduction or an increase of toxicity, relative to the control soil, occurred. As in the case of AC, biochars also caused a significant reduction of phytotoxicity of soil POPI. In soils KB (from coking plant area, industrial waste deposit) and KOK (from coking plant area, coking battery), the reduction or increase of toxicity depended on biochar dose. Compared with the biochars, the effectiveness of AC in the reduction of toxicity depended also on soil, type of amendment, dose, and test organism. Generally, the AC was more effective than biochars in relation to mortality and reproduction of Folsomia candida (in all soils) and for reduction of luminescence inhibition of Vibrio fischeri (in POPI soil). Environ Toxicol Chem 2016;35:1321-1328. © 2015 SETAC. PMID:26378767

  11. Olomoucine inhibits cathepsin L nuclear translocation, activates autophagy and attenuates toxicity of 6-hydroxydopamine.

    PubMed

    Fei, Xi-Feng; Qin, Zheng-Hong; Xiang, Bei; Li, Ling-Yun; Han, Feng; Fukunaga, Kohji; Liang, Zhong-Qin

    2009-04-01

    The finding of nuclear translocation of cathepsin L and its ability to process the CDP/Cux transcription factor uncovers an important role of cathepsin L in control of cell cycle progression. As the expression of certain cell cycle regulators is associated with nigral neuronal death, the present study was sought to investigate if nuclear translocation of cathepsin L and expression of certain cyclins were induced in DA neurons by 6-hydroxydopamine (6-OHDA). The neuroprotective effects of the cell cycle inhibitor olomoucine against 6-OHDA-induced death of nigral neurons were examined. Using immunocytochemistry and real-time PCR we demonstrated that cyclin D1, cyclin B1 and proliferating cell nuclear antigen (PCNA) were aberrantly expressed in some dopaminergic neurons after 6-OHDA infusion. The nuclear translocation of cathepsin L and up-regulation of LC3, a protein involved in autophagy, were observed in nigral DA neurons. Olomoucine, a cyclin dependent kinase (CDK) inhibitor, reduced contralateral rotations and the loss of TH-positive neurons in substantia nigra induced by lesion with 6-OHDA. Pretreatment of rats or primary DA neurons with olomoucine resulted in a partial blockade of nuclear translocation of cathepsin L. Olomoucine also increased the expression of punctate LC3 immunoreactivity, indicating activation of autophagy. These findings suggest that olomoucine may exert neuroprotective effects through inhibiting cathepsin L nuclear translocation and activating autophagy. PMID:19368812

  12. A study of antioxidant activity, enzymatic inhibition and in vitro toxicity of selected traditional sudanese plants with anti-diabetic potential

    PubMed Central

    2014-01-01

    Background Diabetes mellitus is a chronic metabolic disease with life-threatening complications. Despite the enormous progress in conventional medicine and pharmaceutical industry, herbal-based medicines are still a common practice for the treatment of diabetes. This study evaluated ethanolic and aqueous extracts of selected Sudanese plants that are traditionally used to treat diabetes. Methods Extraction was carried out according to method described by Sukhdev et. al. and the extracts were tested for their glycogen phosphorylase inhibition, Brine shrimp lethality and antioxidant activity using (DPPH) radical scavenging activity and iron chelating activity. Extracts prepared from the leaves of Ambrosia maritima, fruits of Foeniculum vulgare and Ammi visnaga, exudates of Acacia Senegal, and seeds of Sesamum indicum and Nigella sativa. Results Nigella sativa ethanolic extract showed no toxicity on Brine shrimp Lethality Test, while its aqueous extract was toxic. All other extracts were highly toxic and ethanolic extracts of Foeniculum vulgare exhibited the highest toxicity. All plant extracts with exception of Acacia senegal revealed significant antioxidant activity in DPPH free radical scavenging assay. Conclusions These results highly agree with the ethnobotanical uses of these plants as antidiabetic. This study endorses further studies on plants investigated, to determine their potential for type 2 diabetes management. Moreover isolation and identification of active compounds are highly recommended. PMID:24885334

  13. Adaptive response of trivial activated sludge towards toxic effect of oNP, PCP and combination oNP/PCP

    SciTech Connect

    Topalova, Y.; Dimkov, R. . Faculty of Biology); Kozuharov, D. )

    1999-01-01

    The reaction of the real aerobic activated sludge taken from the Sofia Waste Water Treatment Plant (SWWTP) and treated with the xenobiotics pentachlorphenol (PCP) (0.16 mMol), ortho-nitrophenol (oNP) (0.58 mMol) and with a combination of PCP (0.08 mMol), oNP (0.29 mMol) has been investigated in a model detoxification process. The adaptive changes are studied in the microbial structure level and at the level of changes in the qualitative and quantitative parameters of the macro-organisms in the activated sludge (consuments of 1 and 2 level). The presence of several different taxonomic groups has been shown by other researchers to be essential in the detoxification process. The quantitative changes in these taxonomic and physiological groups of micro-organisms are studied. The number of micro-organisms from Pseudomonas, Acinetobacter and the bacteria from the xenobiotic-catabolizing complex considerably increased with the individual and the combined effect of the xenobiotics oNP, PCP and oNP PCP. At the same time the toxic shock leads to a remarkable reduction of NH[sub 3] releasing, nitrifying bacteria and those from family Enterobacteriaceae. It is ascertained that the number of Ciliata, Flagellata apochromata, Oligochaeta and Rotatoria is strongly decreased in the series of samples treated with xenobiotics. The leading role of micro-organisms in the real detoxification of hazardous pollutants was experimentally confirmed by research.

  14. Sorption and modeling of mass transfer of toxic chemical vapors in activated-carbon fiber-cloth adsorbers

    USGS Publications Warehouse

    Lordgooei, M.; Sagen, J.; Rood, M.J.; Rostam-Abadi, M.

    1998-01-01

    A new activated-carbon fiber-cloth (ACFC) adsorber coupled with an electrothermal regenerator and a cryogenic condenser was designed and developed to efficiently capture and recover toxic chemical vapors (TCVs) from simulated industrial gas streams. The system was characterized for adsorption by ACFC, electrothermal desorption, and cryogenic condensation to separate acetone and methyl ethyl ketone from gas streams. Adsorption dynamics are numerically modeled to predict system characteristics during scale-up and optimization of the process in the future. The model requires diffusivities of TCVs into an activated-carbon fiber (ACF) as an input. Effective diffusivities of TCVs into ACFs were modeled as a function of temperature, concentration, and pore size distribution. Effective diffusivities for acetone at 65 ??C and 30-60 ppmv were measured using a chromatography method. The energy factor for surface diffusion was determined from comparison between the experimental and modeled effective diffusivities. The modeled effective diffusivities were used in a dispersive computational model to predict mass transfer zones of TCVs in fixed beds of ACFC under realistic conditions for industrial applications.

  15. Hepatoprotective activity of Tribulus terrestris extract against acetaminophen-induced toxicity in a freshwater fish (Oreochromis mossambicus).

    PubMed

    Kavitha, P; Ramesh, R; Bupesh, G; Stalin, A; Subramanian, P

    2011-12-01

    The potential protective role of Tribulus terrestris in acetaminophen-induced hepatotoxicity in Oreochromis mossambicus was investigated. The effect of oral exposure of acetaminophen (500 mg/kg) in O. mossambicus at 24-h duration was evaluated. The plant extract (250 mg/kg) showed a remarkable hepatoprotective activity against acetaminophen-induced hepatotoxicity. It was judged from the tissue-damaging level and antioxidant levels in liver, gill, muscle and kidney tissues. Further acetaminophen impact induced a significant rise in the tissue-damaging level, and the antioxidant level was discernible from the enzyme activity modulations such as glutamate oxaloacetic transaminase, glutamate pyruvic transaminase, alkaline phosphatase, acid phosphatase, glucose-6-phosphate dehydrogenase, lactate dehydrogenase, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione S-transferase, lipid peroxidase and reduced glutathione. The levels of all these enzymes have significantly (p < 0.05) increased in acetaminophen-treated fish tissues. The elevated levels of these enzymes were significantly controlled by the treatment of T. terrestris extract (250 kg/mg). Histopathological changes of liver, gill and muscle samples were compared with respective controls. The results of the present study specify the hepatoprotective and antioxidant properties of T. terrestris against acetaminophen-induced toxicity in freshwater fish, O. mossambicus. PMID:21975853

  16. Different toxic mechanisms are activated by emission PM depending on combustion efficiency

    NASA Astrophysics Data System (ADS)

    Uski, O.; Jalava, P. I.; Happo, M. S.; Leskinen, J.; Sippula, O.; Tissari, J.; Mäki-Paakkanen, J.; Jokiniemi, J.; Hirvonen, M.-R.

    2014-06-01

    Ambient air levels of fine particulate matter (PM ≤ 2.5 μm) are associated with mortality and morbidity. In addition to traffic, large quantities of fine and ultrafine particles (UFPs ≤ 100 nm) are emitted by residential wood combustion. Polycyclic aromatic hydrocarbon (PAH) and soot-rich emissions from small scale heating appliances have been linked with a plethora of toxicological effects. Recently, new technology appliances have been introduced into use although there are several uncertainties related to the toxicological properties of those emissions. In this study, PM1 (PM ≤ 1 μm) emissions from three different biomass combustion situations were compared. PM samples were produced in a novel adjustable biomass combustion reactor to avoid the problems encountered if one uses different appliances to generate the desired combustion conditions. The combustion conditions represented efficient, intermediate and smoldering situations. The concentration related effects of the particles (15, 50,150 and 300 μg ml-1) were investigated in a RAW264.7 macrophage cell line after 24 h' exposure. We analyzed cellular metabolic activity, cell cycle, and indicators of genotoxicty, oxidative stress and proinflammatory responses. Interestingly, the particles collected from smoldering and intermediate combustion conditions decreased cellular metabolic activity less than those from efficient combustion (10-fold difference). However, the samples from intermediate and smoldering combustion evoked greater DNA damage in the comet assay (2.5-fold difference). In contrast, only the particulate samples from efficient combustion triggered G2-cell cycle arrest and oxidative stress in the macrophages. These results indicate that ash rich PM emissions from appliances with almost complete combustion may still exert health impacts. However, particulate emissions from efficient combustion were small when compared to the two other situations. Thus, even with their faults and the obvious

  17. Developmental Toxicity

    EPA Science Inventory

    This chapter provides an overview the developmental toxicity resulting from exposure to perfluorinated alkyl acids (PFAAs). The majority of studies of PFAA-induced developmental toxicity have examined effects of perfluorooctane sulfonate (PFOS) or perfluorooctanoic acid (PFOA) a...

  18. TFP5, a peptide derived from p35, a Cdk5 neuronal activator, rescues cortical neurons from glucose toxicity.

    PubMed

    Binukumar, B K; Zheng, Ya-Li; Shukla, Varsha; Amin, Niranjana D; Grant, Philip; Pant, Harish C

    2014-01-01

    Multiple lines of evidence link the incidence of diabetes to the development of Alzheimer's disease (AD). Patients with diabetes have a 50 to 75% increased risk of developing AD. Cyclin dependent kinase 5 (Cdk5) is a serine/threonine protein kinase, which forms active complexes with p35 or p39, found principally in neurons and in pancreatic β cells. Recent studies suggest that Cdk5 hyperactivity is a possible link between neuropathology seen in AD and diabetes. Previously, we identified P5, a truncated 24-aa peptide derived from the Cdk5 activator p35, later modified as TFP5, so as to penetrate the blood-brain barrier after intraperitoneal injections in AD model mice. This treatment inhibited abnormal Cdk5 hyperactivity and significantly rescued AD pathology in these mice. The present study explores the potential of TFP5 peptide to rescue high glucose (HG)-mediated toxicity in rat embryonic cortical neurons. HG exposure leads to Cdk5-p25 hyperactivity and oxidative stress marked by increased reactive oxygen species production, and decreased glutathione levels and superoxide dismutase activity. It also induces hyperphosphorylation of tau, neuroinflammation as evident from the increased expression of inflammatory cytokines like TNF-α, IL-1β, and IL-6, and apoptosis. Pretreatment of cortical neurons with TFP5 before HG exposure inhibited Cdk5-p25 hyperactivity and significantly attenuated oxidative stress by decreasing reactive oxygen species levels, while increasing superoxide dismutase activity and glutathione. Tau hyperphosphorylation, inflammation, and apoptosis induced by HG were also considerably reduced by pretreatment with TFP5. These results suggest that TFP5 peptide may be a novel candidate for type 2 diabetes therapy. PMID:24326517

  19. Toxicity Studies.

    PubMed

    2016-01-01

    Toxicity studies in the animal models are done to determine the dose level recommended for the treatment of disease as drug. This guideline enables the characterization of adverse effects following repeated daily inhalation exposure to a test. This chapter includes oral and dermal toxicity studies which are discussed as per OECD guidelines. Both acute and subacute toxicity studies are given special emphasis. PMID:26939270

  20. Quantitative structure-activity relationship models for prediction of the toxicity of polybrominated diphenyl ether congeners.

    PubMed

    Wang, Yawei; Liu, Huanxiang; Zhao, Chunyan; Liu, Hanxia; Cai, Zongwei; Jiang, Guibin

    2005-07-01

    Levels of polybrominated diphenyl ethers (PBDEs) are increasing in the environment and may cause long-term health problems in humans. The similarity in the chemical structures of PBDEs and other halogenated aromatic pollutants hints on the possibility that they might share similar toxicological effects. In this work, three-dimensional quantitative structure activity relationships (3-D-QSAR) models, using comparative molecular field analysis (CoMFA) and comparative similarity indices analysis (CoMSIA), were built based on calculated structural indices and a reported experimental toxicology index (aryl hydrocarbon receptor relative binding affinities, RBA) of 18 PBDEs congeners, to determine the factors required for the RBA of these PBDEs. After performing leave-one-out cross-validation, satisfactory results were obtained with cross-validation O2 and R2 values of 0.580 and 0.995 by the CoMFA model and 0.680 and 0.982 by the CoMSIA model, respectively. The results showed clearly that the nonplanar conformations of PBDEs result in the lowest energy level and that the electrostatic index was the main factor reflecting the RBA of PBDEs. The two QSAR models were then used to predict the RBA value of 46 PBDEs for which experimental values are unavailable at present. PMID:16053097

  1. Integrative rodent models for assessing male reproductive toxicity of environmental endocrine active substances

    PubMed Central

    Auger, Jacques; Eustache, Florence; Rouiller-Fabre, Virginie; Canivenc-Lavier, Marie Chantal; Livera, Gabriel

    2014-01-01

    In the present review, we first summarize the main benefits, limitations and pitfalls of conventional in vivo approaches to assessing male reproductive structures and functions in rodents in cases of endocrine active substance (EAS) exposure from the postulate that they may provide data that can be extrapolated to humans. Then, we briefly present some integrated approaches in rodents we have recently developed at the organism level. We particularly focus on the possible effects and modes of action (MOA) of these substances at low doses and in mixtures, real-life conditions and at the organ level, deciphering the precise effects and MOA on the fetal testis. It can be considered that the in vivo experimental EAS exposure of rodents remains the first choice for studies and is a necessary tool (together with the epidemiological approach) for understanding the reproductive effects and MOA of EASs, provided the pitfalls and limitations of the rodent models are known and considered. We also provide some evidence that classical rodent models may be refined for studying the multiple consequences of EAS exposure, not only on the reproductive axis but also on various hormonally regulated organs and tissues, among which several are implicated in the complex process of mammalian reproduction. Such models constitute an interesting way of approaching human exposure conditions. Finally, we show that organotypic culture models are powerful complementary tools, especially when focusing on the MOA. All these approaches have contributed in a combinatorial manner to a better understanding of the impact of EAS exposure on human reproduction. PMID:24369134

  2. Biosorption of toxic lead (II) ions using tomato waste (Solanum lycopersicum) activated by NaOH

    NASA Astrophysics Data System (ADS)

    Permatasari, Diah; Heraldy, Eddy; Lestari, Witri Wahyu

    2016-02-01

    This research present to uptake lead (II) ion from aqueous solutions by activated tomato waste. Biosorbent were characterized by applying Fourier Transform Infrared Spectroscopy (FTIR) and Surface Area Analyzer (SAA). The biosorption investigated with parameters including the concentration of NaOH, effects of solution pH, biosorbent dosage, contact time,and initial metal concentration. Experimental data were analyzed in terms of two kinetic model such us the pseudo-first order and pseudo-second order. Langmuir and Freundlich isotherm models were applied todescribe the biosorption process. According to the experiment, the optimum concentration of NaOH was achieved at 0.1 M. The maximum % lead (II) removal was achieved at pH 4 with 94.5%. Optimum biosorbentdosage were found as 0.1 g/25 mL solution while optimum contact time were found at 75 minutes. The results showed that the biosorption processes of Lead (II) followed pseudo-second order kinetics. Langmuir adsorption isotherm was found fit the adsorption data with amaximum capacity of 24.079 mg/g with anadsorption energy of 28.046 kJ/mol.

  3. Antidotal activity of Averrhoa carambola (Star fruit) on fluoride induced toxicity in rats

    PubMed Central

    Vasant, Rupal A.

    2014-01-01

    Consumption of fluoride leads to several physiological disturbances in carbohydrate, lipid and antioxidant metabolisms. Averrhoa carambola L. fruit (Star fruit) is a commonly consumed fruit in tropical countries and is an ingredient in folklore medicines. As the fruits have high polyphenolic and antioxidant contents, the present study was undertaken to investigate the potential of star fruit as a dietary supplement in attenuating the fluoride induced hyperglycemia, hypercholesterolemia and oxidative stress in laboratory rats. A four-week exposure to fluoride caused sustained hyperglycemia, hyperlipidemia and oxidative stress and, when the diet was supplemented with star fruit powder, carbohydrate, lipid and antioxidant profiles were restored significantly. It is surmised that the antihyperglycemic, antihypercholesterolemic and antioxidant activities of star fruit in fluoride exposed rats could be due to the presence of polyphenols, flavonoids, saponins, phytosterols, ascorbic acid and fibers in the fruit, which are all well known regulators of carbohydrate, lipid and antioxidant metabolisms. These findings suggest that star fruit can be used as a dietary supplement in fluoride endemic regions to contain fluoride induced hyperglycemia, hyperlipidemia and oxidative stress. PMID:26109886

  4. A low-cost non-toxic post-growth activation step for CdTe solar cells

    NASA Astrophysics Data System (ADS)

    Major, J. D.; Treharne, R. E.; Phillips, L. J.; Durose, K.

    2014-07-01

    Cadmium telluride, CdTe, is now firmly established as the basis for the market-leading thin-film solar-cell technology. With laboratory efficiencies approaching 20 per cent, the research and development targets for CdTe are to reduce the cost of power generation further to less than half a US dollar per watt (ref. 2) and to minimize the environmental impact. A central part of the manufacturing process involves doping the polycrystalline thin-film CdTe with CdCl2. This acts to form the photovoltaic junction at the CdTe/CdS interface and to passivate the grain boundaries, making it essential in achieving high device efficiencies. However, although such doping has been almost ubiquitous since the development of this processing route over 25 years ago, CdCl2 has two severe disadvantages; it is both expensive (about 30 cents per gram) and a water-soluble source of toxic cadmium ions, presenting a risk to both operators and the environment during manufacture. Here we demonstrate that solar cells prepared using MgCl2, which is non-toxic and costs less than a cent per gram, have efficiencies (around 13%) identical to those of a CdCl2-processed control group. They have similar hole densities in the active layer (9 × 1014 cm-3) and comparable impurity profiles for Cl and O, these elements being important p-type dopants for CdTe thin films. Contrary to expectation, CdCl2-processed and MgCl2-processed solar cells contain similar concentrations of Mg; this is because of Mg out-diffusion from the soda-lime glass substrates and is not disadvantageous to device performance. However, treatment with other low-cost chlorides such as NaCl, KCl and MnCl2 leads to the introduction of electrically active impurities that do compromise device performance. Our results demonstrate that CdCl2 may simply be replaced directly with MgCl2 in the existing fabrication process, thus both minimizing the environmental risk and reducing the cost of CdTe solar-cell production.

  5. A low-cost non-toxic post-growth activation step for CdTe solar cells.

    PubMed

    Major, J D; Treharne, R E; Phillips, L J; Durose, K

    2014-07-17

    Cadmium telluride, CdTe, is now firmly established as the basis for the market-leading thin-film solar-cell technology. With laboratory efficiencies approaching 20 per cent, the research and development targets for CdTe are to reduce the cost of power generation further to less than half a US dollar per watt (ref. 2) and to minimize the environmental impact. A central part of the manufacturing process involves doping the polycrystalline thin-film CdTe with CdCl2. This acts to form the photovoltaic junction at the CdTe/CdS interface and to passivate the grain boundaries, making it essential in achieving high device efficiencies. However, although such doping has been almost ubiquitous since the development of this processing route over 25 years ago, CdCl2 has two severe disadvantages; it is both expensive (about 30 cents per gram) and a water-soluble source of toxic cadmium ions, presenting a risk to both operators and the environment during manufacture. Here we demonstrate that solar cells prepared using MgCl2, which is non-toxic and costs less than a cent per gram, have efficiencies (around 13%) identical to those of a CdCl2-processed control group. They have similar hole densities in the active layer (9 × 10(14) cm(-3)) and comparable impurity profiles for Cl and O, these elements being important p-type dopants for CdTe thin films. Contrary to expectation, CdCl2-processed and MgCl2-processed solar cells contain similar concentrations of Mg; this is because of Mg out-diffusion from the soda-lime glass substrates and is not disadvantageous to device performance. However, treatment with other low-cost chlorides such as NaCl, KCl and MnCl2 leads to the introduction of electrically active impurities that do compromise device performance. Our results demonstrate that CdCl2 may simply be replaced directly with MgCl2 in the existing fabrication process, thus both minimizing the environmental risk and reducing the cost of CdTe solar-cell production. PMID:25030171

  6. Antiviral activity of Quercus persica L.: High efficacy and low toxicity

    PubMed Central

    Karimi, Ali; Moradi, Mohammad-Taghi; Saeedi, Mojtaba; Asgari, Sedigheh; Rafieian-kopaei, Mahmoud

    2013-01-01

    Background: Drug-resistant strain of Herpes simplex virus type 1 (HSV-I) has increased the interest in the use of natural substances. Aims: This study was aimed to determine minimum inhibitory concentration of hydroalchoholic extract of a traditionally used herbal plant, Quercus persica L., on HSV-1 replication on baby hamster kidney (BHK) cells. Setting: The study was conducted in Shahrekord University of Medical Sciences, Iran. Design: This was an experimental study. Materials and Methods: BHK cells were grown in monolayer culture with Dulbecco's modified Eagle's medium (DMEM) supplemented with 5% fetal calf serum and plated onto 48-well culture plates. Fifty percent cytotoxic concentration (CC50%) of Q. persica L. on BHK cells was determined. Subsequently, 50% inhibitory concentration (IC50%) of the extract on replication of HSV-1 both in interacellular and exteracellular cases was assessed. Statistical Analysis: Statistic Probit model was used for statistical analysis. The dose-dependent effect of antiviral activity of the extracts was determined by linear regression. Results: Q. persica L. had no cytotoxic effect on this cell line. There was significant relationship between the concentration of the extract and cell death (P<0.01). IC50s of Q. persica L. on HSV-1, before and after attachment to BHK cells were 1.02 and 0.257 μg/mL, respectively. There was significant relationship between the concentration of this extract and inhibition of cytopathic effect (CPE) (P<0.05). Antioxidant capacity of the extract was 67.5%. Conclusions: The hydroalchoholic extract of Q. persica L. is potentially an appropriate and promising anti herpetic herbal medicine. PMID:24516836

  7. Lunar Dust and Lunar Simulant Activation, Monitoring, Solution and Cellular Toxicity Properties

    NASA Technical Reports Server (NTRS)

    Wallace, William; Jeevarajan, A. S.

    2009-01-01

    During the Apollo missions, many undesirable situations were encountered that must be mitigated prior to returning humans to the moon. Lunar dust (that part of the lunar regolith less than 20 microns in diameter) was found to produce several problems with mechanical equipment and could have conceivably produced harmful physiological effects for the astronauts. For instance, the abrasive nature of the dust was found to cause malfunctions of various joints and seals of the spacecraft and suits. Additionally, though efforts were made to exclude lunar dust from the cabin of the lunar module, a significant amount of material nonetheless found its way inside. With the loss of gravity correlated with ascent from the lunar surface, much of the finer fraction of this dust began to float and was inhaled by the astronauts. The short visits tothe Moon during Apollo lessened exposure to the dust, but the plan for future lunar stays of up to six months demands that methods be developed to minimize the risk of dust inhalation. The guidelines for what constitutes "safe" exposure will guide the development of engineering controls aimed at preventing the presence of dust in the lunar habitat. This work has shown the effects of grinding on the activation level of lunar dust, the changes in dissolution properties of lunar simulant, and the production of cytokines by cellular systems. Grinding of lunar dust leads to the production of radicals in solution and increased dissolution of lunar simulant in buffers of different pH. Additionally, ground lunar simulant has been shown to promote the production of IL-6 and IL-8, pro-inflammatory cytokines, by alveolar epithelial cells. These results provide evidence of the need for further studies on these materials prior to returning to the lunar surface.

  8. Blood acylpeptide hydrolase activity is a sensitive marker for exposure to some organophosphate toxicants.

    PubMed

    Quistad, Gary B; Klintenberg, Rebecka; Casida, John E

    2005-08-01

    Acylpeptide hydrolase (APH) unblocks N-acetyl peptides. It is a major serine hydrolase in rat blood, brain, and liver detected by derivatization with (3)H-diisopropyl fluorophosphate (DFP) or a biotinylated fluorophosphonate. Although APH does not appear to be a primary target of acute poisoning by organophosphorus (OP) compounds, the inhibitor specificity of this secondary target is largely unknown. This study fills the gap and emphasizes blood APH as a potential marker of OP exposure. The most potent in vitro inhibitors for human erythrocyte and mouse brain APH are DFP (IC(50) 11-17 nM), chlorpyrifos oxon (IC(50) 21-71 nM), dichlorvos (IC(50) 230-560 nM), naled (IC(50) 370-870 nM), and their analogs with modified alkyl substituents. (3)H-diisopropyl fluorophosphate is a potent inhibitor of mouse blood and brain APH in vivo (ED(50) 0.09-0.2 mg/kg and 0.02-0.03 mg/l for ip and vapor exposure, respectively). Mouse blood and brain APH and blood butyrylcholinesterase (BChE) are of similar sensitivity to DFP in vitro and in vivo (ip and vapor exposure), but APH inhibition is much more persistent in vivo (still >80% inhibition after 4 days). The inhibitory potency of OP pesticides in vivo in mice varies from APH selective (dichlorvos, naled, and trichlorfon), to APH and BChE selective (profenofos and tribufos), to ChE selective or nonselective (many commercial insecticides). Sarin administered ip at a lethal dose to guinea pigs inhibits blood acetylcholinesterase and BChE completely but erythrocyte APH only partially. Blood APH activity is therefore a sensitive marker for exposure to some but not all OP pesticides and chemical warfare agents. PMID:15888665

  9. Molecular-orbital analysis of the electronic structure and determination of quantitative structure-activity and structure-toxicity relationships for water-soluble ionol derivatives

    SciTech Connect

    Bushelev, S.N.

    1985-08-01

    In this paper the authors attempt to establish a quantitative relationship between experimental data on antitumor activity and the toxicity of ionol and its derivatives on the one hand, and on the other hand the electronic structure parameters of the compounds obtained as a result of the quantum chemical calculation.

  10. Activity of sphingomyelinase in rat liver in acute and chronic toxic hepatitis: proportion between peroxidative and phospholipase pathways of lipid bilayer modification.

    PubMed

    Serebrov, V Yu; Kuzmenko, D I; Burov, P G; Novitsky, S V

    2009-01-01

    We showed that sphingomyelinase activity in the liver increased only during the acute phase of toxic hepatitis. Peroxidative modification of hepatocyte membrane bilayer prevailed during the acute phase, while after transformation of the process to the chronic phase phospholipase pathway predominated. PMID:19526125

  11. Efficacy of attractive toxic sugar baits (ATSB) against Aedes albopictus with garlic oil encapsulated in beta-Cyclodextrin as the active ingredient

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We tested the efficacy of attractive toxic sugar bait (ATSB) with garlic oil microencapsulated in beta-cyclodextrin as active ingredient against Aedes albopictus in suburban Haifa, Israel. Two three-acre gardens with high numbers of Ae. albopictus were chosen for perimeter spray treatment with ATSB ...

  12. Balance between herbicidal activity and toxicity effect: a case study of the joint effects of triazine and phenylurea herbicides on Selenastrum capricornutum and Photobacterium phosphoreum.

    PubMed

    Ge, Hongming; Lin, Zhifen; Yao, Zhifeng; Gao, Ya; Cong, Yongping; Yu, Hongxia

    2014-05-01

    The use of herbicide mixtures has become a cost-effective strategy against the evolution of herbicide resistance to protect global food production. Much research has focused on investigating either the herbicidal activities or the toxicity effects of herbicides; however, few of them have investigated both factors. This study investigates the balance between herbicidal activity for Selenastrum capricornutum and toxicity effect toward Photobacterium phosphoreum by determining the joint effects of triazine (simetryn, atrazine, prometon and prometryn) and phenylurea (fenuron, monuron, monolinuron and diuron) herbicides. The results showed that among the four triazines, only simetryn exhibited a unique effect (formation of a pi-sigma bond with the D1 microalga protein and an H-bond with the Luc photobacterial protein); and among 16 triazine-phenylurea binary mixtures, only the mixtures containing simetryn resulted in TU1 values (herbicidal activities of mixtures on S. capricornutum) >TU2 values (toxicity effects of mixtures on P. phosphoreum). However, the other 12 mixtures, which did not contain simetryn, showed the opposite result (TU1activity and toxicity effect, which will encourage thoughtful efforts for how to best combine herbicides in a sustainable way. PMID:24681700

  13. Corrigendum to "PAHs in the Great Barrier Reef Lagoon reach potentially toxic levels from coal port activities" [Estuar. Coast. Shelf Sci. 144, 39-45

    NASA Astrophysics Data System (ADS)

    Burns, Kathryn A.

    2014-08-01

    Erratum with respect to the paper: Burns, K A, 2014 PAHs in the Great Barrier Reef Lagoon reach potentially toxic levels from coal port activities. Estuarine Coastal and Shelf Science 144, 39-45. DOI 10.1016/j.ecss.2014.04.001.

  14. DEVELOPMENT OF QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS (QSARS) TO PREDICT TOXICITY FOR A VARIETY OF HUMAN AND ECOLOGICAL ENDPOINTS

    EPA Science Inventory

    In general, the accuracy of a predicted toxicity value increases with increase in similarity between the query chemical and the chemicals used to develop a QSAR model. A toxicity estimation methodology employing this finding has been developed. A hierarchical based clustering t...

  15. DEVELOPMENT OF QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS (QSARS) TO PREDICT TOXICITY FOR A VARIETY OF HUMAN AND ECOLOGICAL ENDPOINTS

    EPA Science Inventory

    A web accessible software tool is being developed to predict the toxicity of unknown chemicals for a wide variety of endpoints. The tool will enable a user to easily predict the toxicity of a query compound by simply entering its structure in a 2-dimensional (2-D) chemical sketc...

  16. Toxic effects of heavy metals (Cd, Cr and Pb) on seed germination and growth and DPPH-scavenging activity in Brassica rapa var. turnip.

    PubMed

    Siddiqui, Maryam Mehmood; Abbasi, Bilal Haider; Ahmad, Nisar; Ali, Mohammad; Mahmood, Tariq

    2014-04-01

    Toxicity of heavy metal is a wide spread environmental problem affecting all life forms including plants. In the present study the toxic effects of heavy metals, cadmium (Cd), chromium (Cr) and lead (Pb) on seed germination rate (%), germination index (G-index) and growth (mm) of Brassica rapa var. turnip have been investigated. The seeds were soaked either in distilled water (control) or in aqueous solutions of Cd, Cr and Pb (1 g/l, 2.5 g/l and 5 g/l) at 4°C in dark for 24 hours. Prior to inoculation onto MS0 medium, the soaked seeds were either washed with sterile distilled water or inoculated without washing on solidified MS0 medium at 25 ± 2°C with 16/8-hour photoperiod in a growth chamber to germinate in vitro. Such stress conditions revealed that by increasing the concentration of heavy metals, the germination rate (%), G-index value and growth (mm) decreased significantly, suggesting their toxic effect on B. rapa var. turnip. This study further revealed that experiment with seed washing resulted in less toxicity of selected heavy metals on germination and growth of B. rapa var. turnip, as compared to experiment without washing. However, the resulting toxicity order of the selected heavy metals remained the same (Cd > Cr > Pb). Significant decrease has been observed in seed viability and germination potential and finally heavy metals completely ceased further growth and development of plants. The 2, 2-diphenyl-1-picrylhydrazyl (DPPH)-scavenging activity revealed that significantly higher activity was observed in control plants without heavy metals treatment. Furthermore, the Cd-treated plants showed decreased antioxidant activity. Cr and Pb were less toxic as compared to Cd (control > Pb > Cr > Cd). This study revealed that selected heavy metals not only affected plant development but also disturbed plant metabolic pathways. PMID:22872632

  17. [The therapeutic activity of synthetic peptides, analogs of the renal natural peptide complex, in the late periods of a toxic lesion by ethylene glycol].

    PubMed

    Gaĭko, O A; Kaĭdashev, I P

    1999-01-01

    The purpose of the work was study of the therapeutic activity of synthetic peptides, analogs of the natural renal peptide complexes, in late-term sequelae of a toxic affection caused by oral administration of ethylene glycol. Quite moderate disorders of renal function were encountered in the late-term periods after affection of the hepatic parenchyma. Under such conditions all the peptides under study produced a therapeutic effect, but of a different degree. It is thus obvious that study of these synthetic peptides, analogs of the natural renal complex, as potential drugs for the prevention of late-term toxic disorders of renal function is promising. PMID:10572753

  18. Organic Anion Transporting Polypeptide (OATP)2B1 Contributes to Gastrointestinal Toxicity of Anticancer Drug SN-38, Active Metabolite of Irinotecan Hydrochloride.

    PubMed

    Fujita, Daichi; Saito, Yoshimasa; Nakanishi, Takeo; Tamai, Ikumi

    2016-01-01

    Gastrointestinal toxicity, such as late-onset diarrhea, is a significant concern in irinotecan hydrochloride (CPT-11)-containing regimens. Prophylaxis of late-onset diarrhea has been reported with use of Japanese traditional (Kampo) medicine containing baicalin and with the antibiotic cefixime, and this has been explained in terms of inhibition of bacterial deconjugation of SN-38-glucuronide since unconjugated SN-38 (active metabolite of CPT-11) is responsible for the gastrointestinal toxicity. It is also prerequisite for SN-38 to be accumulated in intestinal tissues to exert toxicity. Based on the fact that liver-specific organic anion transporting polypeptide (OATP)1B1, a member of the same family as OATP2B1, is known to be involved in hepatic transport of SN-38, we hypothesized that intestinal transporter OATP2B1 contributes to the accumulation of SN-38 in gastrointestinal tissues, and its inhibition would help prevent associated toxicity. We found that uptake of SN-38 by OATP2B1-expressing Xenopus oocytes was significantly higher than that by control oocytes. OATP2B1-mediated uptake of SN-38 was saturable, pH dependent, and decreased in the presence of baicalin, cefixime, or fruit juices such as apple juice. In vivo gastrointestinal toxicity of SN-38 in mice caused by oral administration for consecutive 5 days was prevented by coingestion of apple juice. Thus, OATP2B1 contributes to the uptake of SN-38 by intestinal tissues, triggering gastrointestinal toxicity. So, in addition to the reported inhibition of bacterial β-glucuronidase by cefixime or baicalin, inhibition of OATP2B1 may also contribute to prevention of gastrointestinal toxicity. Apple juice may be helpful for prophylaxis of late-onset diarrhea observed in CPT-11 therapy without disturbance of the intestinal microflora. PMID:26526067

  19. Phenotyping of UGT1A1 Activity Using Raltegravir Predicts Pharmacokinetics and Toxicity of Irinotecan in FOLFIRI

    PubMed Central

    Lee, Lawrence Soon-U; Seng, Kok-Yong; Wang, Ling-Zhi; Yong, Wei-Peng; Hee, Kim-Hor; Soh, Thomas I.; Wong, Andrea; Cheong, Pei F.; Soong, Richie; Sapari, Nur S.; Soo, Ross; Fan, Lu; Lee, Soo-Chin; Goh, Boon C.

    2016-01-01

    Background Irinotecan toxicity correlates with UGT1A1 activity. We explored whether phenotyping UGT1A1 using a probe approach works better than current genotyping methods. Methods Twenty-four Asian cancer patients received irinotecan as part of the FOLFIRI regimen. Subjects took raltegravir 400 mg orally and intravenous midazolam 1 mg. Pharmacokinetic analyses were performed using WinNonLin and NONMEM. Genomic DNA was isolated and screened for the known genetic variants in UGT1A1 and CYP3A4/5. Results SN-38G/SN-38 AUC ratio correlated well with Raltegravir glucuronide/ Raltegravir AUC ratio (r = 0.784 p<0.01). Midazolam clearance correlated well with irinotecan clearance (r = 0.563 p<0.01). SN-38 AUC correlated well with Log10Nadir Absolute Neutrophil Count (ANC) (r = -0.397 p<0.05). Significant correlation was found between nadir ANC and formation rate constant of raltegravir glucuronide (r = 0.598, P<0.005), but not UGT1A1 genotype. Conclusion Raltegravir glucuronide formation is a good predictor of nadir ANC, and can predict neutropenia in East Asian patients. Prospective studies with dose adjustments should be done to develop raltegravir as a probe to optimize irinotecan therapy. Trial Registration Clinicaltrials.gov NCT00808184 PMID:26808671

  20. Antioxidant and antiapoptotic activities of Calotropis procera latex on Catfish (Clarias gariepinus) exposed to toxic 4-nonylphenol.

    PubMed

    Sayed, Alaa El-Din H; Mohamed, Nadia H; Ismail, Mady A; Abdel-Mageed, Wael M; Shoreit, Ahmed A M

    2016-06-01

    Calotropis procera L. is known as medicinal plant. The Phytochemical analyzes of its latex revealed that it possessed antioxidants, namely terpenes, phenolic compounds and cardenolides, flavonoids and saponins, while tannins, alkaloids and resin were absent in moderate to high concentration. In the present study, the role of latex of Calotropis procera as antioxidant and antiapoptotic was reported. To carry out this aim, fishes were exposed to 100 µg l(-1) 4-nonylphenol as chemical pollutant. The enzymes, superoxidase dismutase, catalase, acetlycholinstrase (AchE), glutathione s-transferase, cortisol, G6PDH) and apoptotic cells increased significantly (p<0.05) accompanied by irregular disturbance of (Na(+), K(+)) ions in the presence of 4-nonylphenol. On the other hand, these enzymes, ions, and apoptotic cells decreased normally and significantly (p<0.05) in the presence of latex. Total phenol content, total capacity antioxidant, reducing power decrease significantly (p<0.05) in the presence of 4-nonylphenol and increase normally in the presence of latex. Latex was used for the first time to protect catfish after 4-nonylphenol exposure. Our study confirms that crude latex of Calotropis procera possessed antioxidant and antiapoptotic activities against the toxicity of 4-Nonylphenol. PMID:26946283

  1. Antifungal activity and acute toxicity of stem bark extracts of Drypetes gossweileri S. Moore-euphorbiaceae from Cameroon.

    PubMed

    Ngouana, Vincent; Fokou, Patrick Valère Tsouh; Foudjo, Brice Ulrich Saha; Ngouela, Silvère Augustin; Boyom, Fabrice Fekam; Zollo, Paul Henri Amvam

    2011-01-01

    Drypetes gossweilleri S. Moore is a plant used in traditional medicine in Cameroon. The antifungal properties of its stem-bark crude extract and fractions DG(1), DG(2), DG(3), DG(4), DG(5), DG(6), DG(7), DG(8) and DG(9) were assayed by agar and broth dilution methods on solid and liquid media against C. Krusei, C. albicans, C. glabrata, T. mentagerophytes, M. langeroinii, M. gypeum, M. audouini, T. rubrum, T. soudanense, T. terrestre, A. flavus and A. niger. The results revealed a substantial antifungal effect with minimal inhibitory concentrations ranging respectively from 24.11µg/ml to 1562µg/ml for yeasts and from 3125µg/ml to 12500µg/ml for filamentous fungi. Among the fractions, fraction DG4 exerted the highest antifungal activity. Moreover, no toxic effect was noticed in male and female albinos Wistar rats treated per os with the crude stem bark's extract of Drypetes gossweileri at a dose up to 12g/kg of body weight. The phytochemical screening of the crude extract and fractions showed the presence of alkaloids, phenols, flavonoids, saponins, anthocyanines, anthraquinones, sterols, lipids and essential oils. Therefore, Drypetes gossweileri may be safe as phytomedecine for the treatment of fungal infections. PMID:22468013

  2. Effect of lipid composition and liposome size on toxicity and in vitro fungicidal activity of liposome-intercalated amphotericin B.

    PubMed Central

    Szoka, F C; Milholland, D; Barza, M

    1987-01-01

    Intercalation of amphotericin B into liposomes at a 10 mol% drug/lipid ratio decreased its cytotoxicity by 3- to 90-fold in cultured murine cells and reduced its lethality by 2- to 8-fold in a median lethal dose (LD50) test in mice when compared with the commercial deoxycholate-solubilized drug (LD50 = 2.3 mg/kg). The cytotoxicity and lethality of the liposomal preparations were a function of their lipid composition and diameter. There was no correlation between the reduction of toxicity in the tissue culture assay and the reduction of lethality in the LD50 test. The rank order of reduction of lethality was sterol-containing liposomes greater than solid liposomes greater than fluid liposomes. In general, small sterol-containing vesicles were less lethal than large vesicles of the same composition. Intercalation of amphotericin B in sterol or solid liposomes increased not only the LD50 but also the time to death. The organ distribution of amphotericin B 24 h after intravenous administration was similar whether the drug was given as the commercial deoxycholate preparation or in liposomes. Finally, there were no differences among any of the formulations in their fungicidal activity against Candida tropicalis and Saccharomyces cerevisiae in vitro. The lesser and slower lethality of the liposomal and detergent-solubilized drug suggests that the mechanism by which liposomes reduce the lethality of amphotericin B is by slowing its rate of transfer to a sensitive cellular target. PMID:3579259

  3. Immobilized nickel hexacyanoferrate on activated carbons for efficient attenuation of radio toxic Cs(I) from aqueous solutions

    NASA Astrophysics Data System (ADS)

    Lalhmunsiama; Lalhriatpuia, C.; Tiwari, Diwakar; Lee, Seung-Mok

    2014-12-01

    The aim of this study is to immobilize nickel hexacyanoferrate onto the large surface of activated carbons (ACs) precursor to rice hulls and areca nut waste materials. These nickel hexacyanoferrate immobilized materials are then assessed in the effective attenuation of radio logically important cesium ions from aqueous solutions. The solid samples are characterized by the XRD analytical method and surface morphology is obtained from the SEM images. The batch reactor experiments show that an increase in sorptive pH (2.0-10.0) apparently not affecting the high percent uptake of Cs(I). Equilibrium modeling studies suggest that the data are reasonably and relatively fitted well to the Langmuir adsorption isotherm. Kinetic studies show that sorption process is fairly rapid and the kinetic data are fitted well to the pseudo-second order rate model. Increasing the background electrolyte concentration from 0.001 to 0.1 mol/L NaCl causes insignificant decrease in Cs(I) removal which infers the higher selectivity of these materials for Cs(I) from aqueous solutions. Further, the column reactor operations enable to obtain the breakthrough data which are then fitted to the Thomas non-linear equation as to obtain the loading capacity of column for Cs(I). The results show that the modified materials show potential applicability in the attenuation of radio toxic cesium from aqueous solution.

  4. Lowering the isoelectric point of the Fv portion of recombinant immunotoxins leads to decreased nonspecific animal toxicity without affecting antitumor activity.

    PubMed

    Onda, M; Nagata, S; Tsutsumi, Y; Vincent, J J; Wang, Q; Kreitman, R J; Lee, B; Pastan, I

    2001-07-01

    Recombinant immunotoxins are genetically engineered proteins in which the Fv portion of an antibody is fused to a toxin. Our laboratory uses a 38-kDa form of Pseudomonas exotoxin A termed PE38 for this purpose. Clinical studies with immunotoxins targeting CD25 and CD22 have shown that dose-limiting side effects are attributable to liver damage and other inflammatory toxicities. We recently showed that mutating exposed surface neutral residues to acidic residues in the framework region of the Fv portion of an immunotoxin targeting CD25 [anti-Tac(scFv)-PE38] lowered its isoelectric point (pI) and decreased its toxicity in mice without impairing its cytotoxic or antitumor activities. We have now extended these studies and made mutations that change basic residues to neutral or acidic residues. Initially the pI of the mutant Fv (M1) of anti-Tac(scFv)-PE38 was decreased further. Subsequently, mutations were made in two other immunotoxins, SS1(dsFv)-PE38 targeting ovarian cancer and B3(dsFv)-PE38 targeting colon and breast cancers. We have found that all these mutant molecules fully retained specific target cell cytotoxicity and antitumor activity but were considerably less toxic to mice. Therefore, lowering the pI of the Fv may be a general approach to diminish the nonspecific toxicity of recombinant immunotoxins and other Fv fusion proteins without losing antitumor activity. PMID:11431343

  5. Evidence for effects on the in vivo activity of ribulose-bisphosphate carboxylase/oxygenase during development of Mn toxicity in tobacco. [Nicotiana tabacum L. cv KY14

    SciTech Connect

    Houtz, R.L.; Nable, R.O.; Cheniae, G.M. )

    1988-04-01

    The progressive decrease in net photosynthesis accompanying development of Mn toxicity in young leaves of burley tobacco (Nicotiana tabacum L. cv KY 14) is a result of effects on in vivo activity of ribulose-1,5-bisphosphate (RuBP) carboxylase/oxygenase (rubisco, EC 4.1.1.39). This conclusion is supported by: (a) decrease in rates of CO{sub 2} depletion during measurements of CO{sub 2} compensation, (b) increase in leaf RuBP concentrations, (c) progressive decreases in rate-constants of RuBP loss (light to dark transition analyses) with progressive increases of leaf Mn concentrations, and (d) restoration of diminished rates of net photosynthesis to control rates by elevated CO{sub 2} (5%). Moreover, elevated CO{sub 2} (1100 microliters per liter) during culture of Mn-treated plants decreased elevated RuBP concentrations to control levels and alleviated foliar symptoms of Mn toxicity. These effects of Mn toxicity on in vivo activity of rubisco were not expressed by in vitro kinetic analyses of rubisco prepared under conditions to sequester Mn or to adsorb polyphenols or their oxidation products. Similarly, the in vitro activity of fructose bisphosphatase (EC 3.1.3.11) was unaffected by Mn toxicity.

  6. Effect of dumping and cleaning activities on the aquatic ecosystems of the Guadiamar River following a toxic flood.

    PubMed

    Prat, N; Toja, J; Solà, C; Burgos, M D; Plans, M; Rieradevall, M

    1999-12-01

    The main aim of the study was to document the recovery of the aquatic ecosystem after the release of toxic mining waste in the Guadiamar River Basin (Sevilla, SW Spain) in April 1998. Samples of water, plankton, periphyton and macroinvertebrates were taken once a month at nine sampling stations (six affected by the toxic release and three for control). Water hardness and pH recovered in a few weeks and did not change significantly thereafter in the river or in the marsh stations. Only the Agrio River (the tributary that received the initial waste dump) had a low pH (3-5) throughout the study period. High ammonia contents (up to 300 microM) were measured at two sampling stations due to sewage and oil mill pollution. Eutrophication was also common at most of the stations, including one reference site. The planktonic community did not differ substantially between reference and affected stations. On all occasions the small phytoplankton and zooplankton (rotifers) were dominant. Compared with the reference station, chlorophyll a in the riverine area increased, especially in the sewage-affected stations, while in the marsh area, no significant differences were found between affected and reference stations. After 6 months of cleaning operations, in November 1998 the macroinvertebrate community of the river was composed mainly of species of short life cycles typical of ponds (Heteroptera, Coleoptera and Odonata), while typical riverine species found at the upstream control station had not recolonized the river due to the transformation of the river into a series of artificial ponds constructed as sediment traps. An analysis of variance showed significantly higher values (P < 0.05) for all heavy metals analysed (Zn, Cu, Pb, As, Cd, Sb, Tl) in plankton and macroinvertebrate communities from impacted sites. Values found in invertebrates were highly variable, with a mean concentration of the most abundant metals, Zn and Cu, between two and three times those found in unpolluted

  7. Perfluorinated chemicals: Differential toxicity, inhibition of aromatase activity and alteration of cellular lipids in human placental cells

    SciTech Connect

    Gorrochategui, Eva; Pérez-Albaladejo, Elisabet; Casas, Josefina; Lacorte, Sílvia; Porte, Cinta

    2014-06-01

    The cytotoxicity of eight perfluorinated chemicals (PFCs), namely, perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorododecanoic acid (PFDoA), perfluorobutanesulfonate (PFBS), perfluorohexanesulfonate (PFHxS) and perfluorooctanesulfonate (PFOS) was assessed in the human placental choriocarcinoma cell line JEG-3. Only the long chain PFCs – PFOS, PFDoA, PFNA, PFOA – showed significant cytotoxicity in JEG-3 cells with EC50 values in the range of 107 to 647 μM. The observed cytotoxicity was to some extent related to a higher uptake of the longer chain PFCs by cells (PFDoA > PFOS ≫ PFNA > PFOA > PFHxA). Moreover, this work evidences a high potential of PFOS, PFOA and PFBS to act as aromatase inhibitors in placental cells with IC50s in the range of 57–80 μM, the inhibitory effect of PFBS being particularly important despite the rather low uptake of the compound by cells. Finally, exposure of JEG-3 cells to a mixture of the eight PFCs (0.6 μM each) led to a relative increase (up to 3.4-fold) of several lipid classes, including phosphatidylcholines (PCs), plasmalogen PC and lyso plasmalogen PC, which suggests an interference of PFCs with membrane lipids. Overall, this work highlights the ability of the PFC mixture to alter cellular lipid pattern at concentrations well below those that generate toxicity, and the potential of the short chain PFBS, often considered a safe substitute of PFOS, to significantly inhibit aromatase activity in placental cells. - Highlights: • Eight perfluorinated chemicals of different chain lengths have been selected. • Long chain ones – PFOS, PFDoA, PFNA, PFOA – were cytotoxic in placenta cells. • The uptake of long chain perfluorinated chemicals by cells was comparatively higher. • PFOS, PFOA and the short chain PFBS significantly inhibited aromatase activity. • A mixture of perfluorinated chemicals significantly altered placenta cell

  8. Combinatorial QSAR Modeling of Rat Acute Toxicity by Oral Exposure

    EPA Science Inventory

    Quantitative Structure-Activity Relationship (QSAR) toxicity models have become popular tools for identifying potential toxic compounds and prioritizing candidates for animal toxicity tests. However, few QSAR studies have successfully modeled large, diverse mammalian toxicity end...

  9. Jasmonic Acid Modulates the Physio-Biochemical Attributes, Antioxidant Enzyme Activity, and Gene Expression in Glycine max under Nickel Toxicity

    PubMed Central

    Sirhindi, Geetika; Mir, Mudaser Ahmad; Abd-Allah, Elsayed Fathi; Ahmad, Parvaiz; Gucel, Salih

    2016-01-01

    In present study, we evaluated the effects of Jasmonic acid (JA) on physio-biochemical attributes, antioxidant enzyme activity, and gene expression in soybean (Glycine max L.) plants subjected to nickel (Ni) stress. Ni stress decreases the shoot and root length and chlorophyll content by 37.23, 38.31, and 39.21%, respectively, over the control. However, application of JA was found to improve the chlorophyll content and length of shoot and root of Ni-fed seedlings. Plants supplemented with JA restores the chlorophyll fluorescence, which was disturbed by Ni stress. The present study demonstrated increase in proline, glycinebetaine, total protein, and total soluble sugar (TSS) by 33.09, 51.26, 22.58, and 49.15%, respectively, under Ni toxicity over the control. Addition of JA to Ni stressed plants further enhanced the above parameters. Ni stress increases hydrogen peroxide (H2O2) by 68.49%, lipid peroxidation (MDA) by 50.57% and NADPH oxidase by 50.92% over the control. Supplementation of JA minimizes the accumulation of H2O2, MDA, and NADPH oxidase, which helps in stabilization of biomolecules. The activities of superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and ascorbate peroxidase (APX) increases by 40.04, 28.22, 48.53, and 56.79%, respectively, over the control in Ni treated seedlings and further enhancement in the antioxidant activity was observed by the application of JA. Ni treated soybean seedlings showed increase in expression of Fe-SOD by 77.62, CAT by 15.25, POD by 58.33, and APX by 80.58% over the control. Nevertheless, application of JA further enhanced the expression of the above genes in the present study. Our results signified that Ni stress caused negative impacts on soybean seedlings, but, co-application of JA facilitate the seedlings to combat the detrimental effects of Ni through enhanced osmolytes, activity of antioxidant enzymes and gene expression. PMID:27242811

  10. Jasmonic Acid Modulates the Physio-Biochemical Attributes, Antioxidant Enzyme Activity, and Gene Expression in Glycine max under Nickel Toxicity.

    PubMed

    Sirhindi, Geetika; Mir, Mudaser Ahmad; Abd-Allah, Elsayed Fathi; Ahmad, Parvaiz; Gucel, Salih

    2016-01-01

    In present study, we evaluated the effects of Jasmonic acid (JA) on physio-biochemical attributes, antioxidant enzyme activity, and gene expression in soybean (Glycine max L.) plants subjected to nickel (Ni) stress. Ni stress decreases the shoot and root length and chlorophyll content by 37.23, 38.31, and 39.21%, respectively, over the control. However, application of JA was found to improve the chlorophyll content and length of shoot and root of Ni-fed seedlings. Plants supplemented with JA restores the chlorophyll fluorescence, which was disturbed by Ni stress. The present study demonstrated increase in proline, glycinebetaine, total protein, and total soluble sugar (TSS) by 33.09, 51.26, 22.58, and 49.15%, respectively, under Ni toxicity over the control. Addition of JA to Ni stressed plants further enhanced the above parameters. Ni stress increases hydrogen peroxide (H2O2) by 68.49%, lipid peroxidation (MDA) by 50.57% and NADPH oxidase by 50.92% over the control. Supplementation of JA minimizes the accumulation of H2O2, MDA, and NADPH oxidase, which helps in stabilization of biomolecules. The activities of superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and ascorbate peroxidase (APX) increases by 40.04, 28.22, 48.53, and 56.79%, respectively, over the control in Ni treated seedlings and further enhancement in the antioxidant activity was observed by the application of JA. Ni treated soybean seedlings showed increase in expression of Fe-SOD by 77.62, CAT by 15.25, POD by 58.33, and APX by 80.58% over the control. Nevertheless, application of JA further enhanced the expression of the above genes in the present study. Our results signified that Ni stress caused negative impacts on soybean seedlings, but, co-application of JA facilitate the seedlings to combat the detrimental effects of Ni through enhanced osmolytes, activity of antioxidant enzymes and gene expression. PMID:27242811

  11. Structure-Activity Relationship Studies on Natural Eremophilanes from Inula helenium as Toxicants Against Aedes aegypti Larvae and Adults

    Technology Transfer Automated Retrieval System (TEKTRAN)

    An Aedes aegypti larval toxicity bioassay was performed on compounds representing many classes of natural compounds including polyacetylenes, phytosterols, flavonoids, sesquiterpenoids, and triterpenoids. Among these compounds studies, two eudesmanolides, alantolactone and isoalantolactone, showed l...

  12. Toxic and antifeedant activities of prenylated flavonoids isolated from Tephrosia apollinea L. against three major coleopteran pests of stored grains with reference to their structure-activity relationship.

    PubMed

    Nenaah, Gomah E

    2014-01-01

    Four prenylated flavonoids, isoglabratephrin, (+)-glabratephrin, tephroapollin-F and lanceolatin-A, were isolated from Tephrosia apollinea L. and tested against three stored grain insects. Using the filter paper bioassay, compounds showed adulticidal activity against Sitophilus oryzae (L), Rhyzopertha dominica (F) and Tribolium castaneum (Herbst) at concentrations of 0.875, 1.75 and 3.5 mg mL(- 1). At 3.5 mg mL(- 1), tephroapollin-F was the most toxic (78.6%, 64.6% and 60.7% mortality was recorded after 10 days exposure of S. oryzae, R. dominica and T. castaneum, respectively). The F1 progeny production of insects was affected after parental exposure to flavonoids, where S. oryzae was the most susceptible. A nutritional bioassay, employing a flour disc and test concentrations of 0.65, 1.3 and 2.6 mg g(- 1), revealed a significant reduction in the relative growth rate, relative consumption rate and efficiency of conversion of ingested food by all insects. The structure-activity relationship among the tested flavonoids was discussed. PMID:24980754

  13. Quantitative structure-activity relationship (QSAR) prediction of (eco)toxicity of short aliphatic protic ionic liquids.

    PubMed

    Peric, Brezana; Sierra, Jordi; Martí, Esther; Cruañas, Robert; Garau, Maria Antonia

    2015-05-01

    Ionic liquids (ILs) are considered as a group of very promising compounds due to their excellent properties (practical non-volatility, high thermal stability and very good and diverse solving capacity). The ILs have a good prospect of replacing traditional organic solvents in vast variety of applications. However, the complete information on their environmental impact is still not available. There is also an enormous number of possible combinations of anions and cations which can form ILs, the fact that requires a method allowing the prediction of toxicity of existing and potential ILs. In this study, a group contribution QSAR model has been used in order to predict the (eco)toxicity of protic and aprotic ILs for five tests (Microtox®, Pseudokirchneriella subcapitata and Lemna minor growth inhibition test, and Acetylcholinestherase inhibition and Cell viability assay with IPC-81 cells). The predicted and experimental toxicity are well correlated. A prediction of EC50 for these (eco)toxicity tests has also been made for eight representatives of the new family of short aliphatic protic ILs, whose toxicity has not been determined experimentally to date. The QSAR model applied in this study can allow the selection of potentially less toxic ILs amongst the existing ones (e.g. in the case of aprotic ILs), but it can also be very helpful in directing the synthesis efforts toward developing new "greener" ILs respectful with the environment (e.g. short aliphatic protic ILs). PMID:25728357

  14. Determination of Toxic Activities in Bothrops spp. Snake Venoms Using Animal-Free Approaches: Correlation Between In Vitro Versus In Vivo Assays.

    PubMed

    de Souza, Letícia Lopes; Stransky, Stephanie; Guerra-Duarte, Clara; Flor-Sá, Ana; Schneider, Francisco Santos; Kalapothakis, Evanguedes; Chávez-Olórtegui, Carlos

    2015-10-01

    The main purpose of this study is to investigate the in vitro toxic effects of 5 Bothrops spp. snake venoms, which are part of the antigenic mixture used for the production of Brazilian antivenom, and evaluate their correlation with the in vivo toxic activities of Bothrops spp. venoms. The correlation analysis could be helpful for the replacement of living animals experimentation for in vitro bioassay. Cytotoxicity, L-amino acid oxidase (LAAO), proteolitic (serine and metalloproteinase), hyaluronidase (Hyal), and phospholipase A2 (PLA2) activities were estimated and the correlation coefficient was determined for each activity in relation to lethality, edema, hemorrhage and necrosis induced in live animals by B. jararaca, B. alternatus, B. jararacussu, B. neuwiedi, and B. moojeni venoms. The lethal activity in mice was highly related to Hyal activity (r = 0.94, p < .05), edema related to PLA2 activity (r = 0.94, p < .05), whereas the necrotizing activity showed high correlation with LAAO activity (r = 0.83, p < .05). A very significant correlation between in vitro cytotoxicity and LAAO activities was also observed (r = 0.97, p < .05). PMID:26160116

  15. Activation of DNA damage repair pathways in response to nitrogen mustard-induced DNA damage and toxicity in skin keratinocytes

    PubMed Central

    Inturi, Swetha; Tewari-Singh, Neera; Agarwal, Chapla; White, Carl W.; Agarwal, Rajesh

    2014-01-01

    Nitrogen mustard (NM), a structural analog of chemical warfare agent sulfur mustard (SM), forms adducts and crosslinks with DNA, RNA and proteins. Here we studied the mechanism of NM-induced skin toxicity in response to double strand breaks (DSBs) resulting in cell cycle arrest to facilitate DNA repair, as a model for developing countermeasures against vesicant-induced skin injuries. NM exposure of mouse epidermal JB6 cells decreased cell growth and caused S-phase arrest. Consistent with these biological outcomes, NM exposure also increased comet tail extent moment and the levels of DNA DSB repair molecules phospho H2A.X Ser139 and p53 Ser15 indicating NM-induced DNA DSBs. Since DNA DSB repair occurs via non homologous end joining pathway (NHEJ) or homologous recombination repair (HRR) pathways, next we studied these two pathways and noted their activation as defined by an increase in phospho- and total DNA-PK levels, and the formation of Rad51 foci, respectively. To further analyze the role of these pathways in the cellular response to NM-induced cytotoxicity, NHEJ and HRR were inhibited by DNA-PK inhibitor NU7026 and Rad51 inhibitor BO2, respectively. Inhibition of NHEJ did not sensitize cells to NM-induced decrease in cell growth and cell cycle arrest. However, inhibition of the HRR pathway caused a significant increase in cell death, and prolonged G2M arrest following NM exposure. Together, our findings, indicating that HRR is the key pathway involved in the repair of NM-induced DNA DSBs, could be useful in developing new therapeutic strategies against vesicant-induced skin injury. PMID:24732344

  16. Activation of DNA damage repair pathways in response to nitrogen mustard-induced DNA damage and toxicity in skin keratinocytes.

    PubMed

    Inturi, Swetha; Tewari-Singh, Neera; Agarwal, Chapla; White, Carl W; Agarwal, Rajesh

    2014-01-01

    Nitrogen mustard (NM), a structural analog of chemical warfare agent sulfur mustard (SM), forms adducts and crosslinks with DNA, RNA and proteins. Here we studied the mechanism of NM-induced skin toxicity in response to double strand breaks (DSBs) resulting in cell cycle arrest to facilitate DNA repair, as a model for developing countermeasures against vesicant-induced skin injuries. NM exposure of mouse epidermal JB6 cells decreased cell growth and caused S-phase arrest. Consistent with these biological outcomes, NM exposure also increased comet tail extent moment and the levels of DNA DSB repair molecules phospho H2A.X Ser139 and p53 Ser15 indicating NM-induced DNA DSBs. Since DNA DSB repair occurs via non homologous end joining pathway (NHEJ) or homologous recombination repair (HRR) pathways, next we studied these two pathways and noted their activation as defined by an increase in phospho- and total DNA-PK levels, and the formation of Rad51 foci, respectively. To further analyze the role of these pathways in the cellular response to NM-induced cytotoxicity, NHEJ and HRR were inhibited by DNA-PK inhibitor NU7026 and Rad51 inhibitor BO2, respectively. Inhibition of NHEJ did not sensitize cells to NM-induced decrease in cell growth and cell cycle arrest. However, inhibition of the HRR pathway caused a significant increase in cell death, and prolonged G2M arrest following NM exposure. Together, our findings, indicating that HRR is the key pathway involved in the repair of NM-induced DNA DSBs, could be useful in developing new therapeutic strategies against vesicant-induced skin injury. PMID:24732344

  17. Therapeutic Antibody-Induced Vascular Toxicity Due to Off-Target Activation of Nitric Oxide in Cynomolgus Monkeys.

    PubMed

    Pai, Rama; Ma, Ning; Connor, Anu V; Danilenko, Dimitry M; Tarrant, Jacqueline M; Salvail, Dany; Wong, Lisa; Hartley, Dylan P; Misner, Dinah; Stefanich, Eric; Wu, Yan; Chen, Yongmei; Wang, Hong; Dambach, Donna M

    2016-06-01

    PRO304186, a humanized monoclonal antibody targeting soluble interleukin-17 A and F, was developed for autoimmune and inflammatory disease indications. When administered to cynomolgus monkeys PRO304186 induced unexpected adverse effects characterized by clinical signs of hematemesis, hematochezia, and moribundity. Pathology findings included hemorrhage throughout the gastrointestinal tract without any evidence of vascular wall damage or inflammatory cellular infiltration. Mechanistic investigation of these effects revealed mild elevations of serum MCP-1 and IL-12/23 but without a classical proinflammatory profile in PRO304186-treated animals. In vitro studies demonstrated off-target effects on vascular endothelial cells including activation of nitric oxide synthase leading to production of nitric oxide (NO) accompanied by increased mitochondrial membrane depolarization, glutathione depletion, and increased paracellular permeability. Additionally, endothelial cell-PRO304186-conditioned medium reduced myosin light chain phosphorylation in vascular smooth muscle cells. Furthermore, an ex vivo study utilizing segments from cynomolgus aorta and femoral artery confirmed PRO304186-induced endothelium-dependent smooth muscle relaxation and vasodilation mediated via NO. Finally, a single dose of PRO304186 in cynomolgus monkeys induced a rapid and pronounced increase in NO in the portal circulation that preceded a milder elevation of NO in the systemic circulation and corresponded temporally with systemic hypotension; findings consistent with NO-mediated vasodilation leading to hypotension. These changes were associated with non-inflammatory, localized hemorrhage in the gastrointestinal tract consistent with hemodynamic vascular injury associated with intense local vasodilation. Together, these data demonstrate that PRO304186-associated toxicity in monkeys was due to an off-target effect on endothelium that involved regional NO release resulting in severe systemic

  18. Mechanistic quantitative structure-activity relationship model for the photoinduced toxicity of polycyclic aromatic hydrocarbons. 1: Physical model based on chemical kinetics in a two-compartment system

    SciTech Connect

    Krylov, S.N.; Huang, X.D.; Zeiler, L.F.; Dixon, D.G.; Greenberg, B.M.

    1997-11-01

    A quantitative structure-activity relationship model for the photoinduced toxicity of 16 polycyclic aromatic hydrocarbons (PAHs) to duckweed (Lemna gibba) in simulated solar radiation (SSR) was developed. Lemna gibba was chosen for this study because toxicity could be considered in two compartments: water column and leaf tissue. Modeling of photoinduced toxicity was described by photochemical reactions between PAHs and a hypothetical group of endogenous biomolecules (G) required for normal growth, with damage to G by PAHs and/or photomodified PAHs in SSR resulting in impaired growth. The reaction scheme includes photomodification of PAHs, uptake of PAHs into leaves, triplet-state formation of intact PAHs, photosensitization reactions that damage G, and reactions between photomodified PAHs and G. The assumptions used were: the PAH photomodification rate is slower than uptake of chemicals into leaves, the PAH concentration in aqueous solution is nearly constant during a toxicity test, the fluence rate of actinic radiation is lower within leaves than in the aqueous phase, and the toxicity of intact PAHs in the dark is negligible. A series of differential equations describing the reaction kinetics of intact and photomodifed PAHs with G was derived. The resulting equation for PAH toxicity was a function of treatment period, initial PAH concentration, relative absorbance of SSR by each PAH, quantum yield for formation of triplet-state PAH, and rate of PAH photomodification. Data for growth in the presence of intact and photomodified PAHs were used to empirically solve for a photosensitization constant (PSC) and a photomodification constant (PMC) for each of the 16 PAHs tested. For 9 PAHs the PMC dominates and for 7 PAHs the PSC dominates.

  19. Application of mass balance models and the chemical activity concept to facilitate the use of in vitro toxicity data for risk assessment.

    PubMed

    Armitage, James M; Wania, Frank; Arnot, Jon A

    2014-08-19

    Practical, financial, and ethical considerations related to conducting extensive animal testing have resulted in various initiatives to promote and expand the use of in vitro testing data for chemical evaluations. Nominal concentrations in the aqueous phase corresponding to an effect (or biological activity) are commonly reported and used to characterize toxicity (or biological response). However, the true concentration in the aqueous phase can be substantially different from the nominal. To support in vitro test design and aid the interpretation of in vitro toxicity data, we developed a mass balance model that can be parametrized and applied to represent typical in vitro test systems. The model calculates the mass distribution, freely dissolved concentrations, and cell/tissue concentrations corresponding to the initial nominal concentration and experimental conditions specified by the user. Chemical activity, a metric which can be used to assess the potential for baseline toxicity to occur, is also calculated. The model is first applied to a set of hypothetical chemicals to illustrate the degree to which test conditions (e.g., presence or absence of serum) influence the distribution of the chemical in the test system. The model is then applied to set of 1194 real substances (predominantly from the ToxCast chemical database) to calculate the potential range of concentrations and chemical activities under assumed test conditions. The model demonstrates how both concentrations and chemical activities can vary by orders of magnitude for the same nominal concentration. PMID:25014875

  20. Microplastic Size-Dependent Toxicity, Oxidative Stress Induction, and p-JNK and p-p38 Activation in the Monogonont Rotifer (Brachionus koreanus).

    PubMed

    Jeong, Chang-Bum; Won, Eun-Ji; Kang, Hye-Min; Lee, Min-Chul; Hwang, Dae-Sik; Hwang, Un-Ki; Zhou, Bingsheng; Souissi, Sami; Lee, Su-Jae; Lee, Jae-Seong

    2016-08-16

    In this study, we evaluated accumulation and adverse effects of ingestion of microplastics in the monogonont rotifer (Brachionus koreanus). The dependence of microplastic toxicity on particle size was investigated by measuring several in vivo end points and studying the ingestion and egestion using 0.05-, 0.5-, and 6-μm nonfunctionalized polystyrene microbeads. To identify the defense mechanisms activated in response to microplastic exposure, the activities of several antioxidant-related enzymes and the phosphorylation status of mitogen-activated protein kinases (MAPKs) were determined. Exposure to polystyrene microbeads of all sizes led to significant size-dependent effects, including reduced growth rate, reduced fecundity, decreased lifespan and longer reproduction time. Rotifers exposed to 6-μm fluorescently labeled microbeads exhibited almost no fluorescence after 24 h, while rotifers exposed to 0.05- and 0.5-μm fluorescently labeled microbeads displayed fluorescence until 48 h, suggesting that 6-μm microbeads are more effectively egested from B. koreanus than 0.05- or 0.5-μm microbeads. This observation provides a potential explanation for our findings that microbead toxicity was size-dependent and smaller microbeads were more toxic. In vitro tests revealed that antioxidant-related enzymes and MAPK signaling pathways were significantly activated in response to microplastic exposure in a size-dependent manner. PMID:27438693

  1. Toxic Encephalopathy

    PubMed Central

    Kim, Jae Woo

    2012-01-01

    This article schematically reviews the clinical features, diagnostic approaches to, and toxicological implications of toxic encephalopathy. The review will focus on the most significant occupational causes of toxic encephalopathy. Chronic toxic encephalopathy, cerebellar syndrome, parkinsonism, and vascular encephalopathy are commonly encountered clinical syndromes of toxic encephalopathy. Few neurotoxins cause patients to present with pathognomonic neurological syndromes. The symptoms and signs of toxic encephalopathy may be mimicked by many psychiatric, metabolic, inflammatory, neoplastic, and degenerative diseases of the nervous system. Thus, the importance of good history-taking that considers exposure and a comprehensive neurological examination cannot be overemphasized in the diagnosis of toxic encephalopathy. Neuropsychological testing and neuroimaging typically play ancillary roles. The recognition of toxic encephalopathy is important because the correct diagnosis of occupational disease can prevent others (e.g., workers at the same worksite) from further harm by reducing their exposure to the toxin, and also often provides some indication of prognosis. Physicians must therefore be aware of the typical signs and symptoms of toxic encephalopathy, and close collaborations between neurologists and occupational physicians are needed to determine whether neurological disorders are related to occupational neurotoxin exposure. PMID:23251840

  2. Development of Quantitative Structure-Activity Relationship Models for Predicting Chronic Toxicity of Substituted Benzenes to Daphnia Magna.

    PubMed

    Fan, Deling; Liu, Jining; Wang, Lei; Yang, Xianhai; Zhang, Shenghu; Zhang, Yan; Shi, Lili

    2016-05-01

    The chronic toxicity of anthropogenic molecules such as substituted benzenes to Daphnia magna is a basic eco-toxicity parameter employed to assess their environmental risk. As the experimental methods are laborious, costly, and time-consuming, development in silico models for predicting the chronic toxicity is vitally important. In this study, on the basis of five molecular descriptors and 48 compounds, a quantitative structure-property relationship model that can predict the chronic toxicity of substituted benzenes were developed by employing multiple linear regressions. The correlation coefficient (R (2)) and root-mean square error (RMSE) for the training set were 0.836 and 0.390, respectively. The developed model was validated by employing 10 compounds tested in our lab. The R EXT (2) and RMSE EXT for the validation set were 0.736 and 0.490, respectively. To further characterizing the toxicity mechanism of anthropogenic molecules to Daphnia, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models were developed. PMID:27016939

  3. Enhancement of bioreductive drug toxicity in murine tumours by inhibition of the activity of nitric oxide synthase.

    PubMed Central

    Butler, S. A.; Wood, P. J.; Cole, S.; Williams, C.; Adams, G. E.; Stratford, I. J.

    1997-01-01

    Nitro-L-arginine inhibits the production of nitric oxide and can thereby cause vasoconstriction in vivo. One consequence of this is that nitro-L-arginine can increase hypoxia in a range of transplantable and spontaneous murine solid tumours. Bioreductive drugs such as RB6145 are more active under hypoxic conditions, and the combination of RB6145 with nitro-L-arginine in vivo shows greater anti-tumour activity than either agent individually. In mice given nitro-L-arginine at 10 mg kg(-1) i.p. up to 1 h before or after 300 mg kg(-1) i.p. RB6145, survival of KHT tumour cells was reduced by 3-4 logs when assessed by clonogenic assay 24 h after treatment. RB6145 or nitro-L-arginine alone caused no more than 20% cell kill. Similar effects were found in SCCVII tumours. The tumour response to the drug combination was tumour size dependent, with increased tumour cell sensitivity occurring when the tumour volume at the time of treatment was increased. Further, the response of KHT tumours to the combination of RB6145 and nitro-L-arginine was also dependent on the time interval between treatment and on when tumours were excised for determination of survival in vitro. The relative surviving fraction was about 0.3 for intervals less than 4 h but was reduced to 0.01 at 12 h and 0.001 at 24 h. These results were supported by histological examination of tumours, when necrosis at 2 h after treatment was less than 5% but increased to greater than 90% at 24 h. RB6145-induced normal tissue damage, as measured by CFU-A survival, was not altered by combining with nitro-L-arginine. Hence, this drug combination may provide therapeutic benefit. It is likely that the substantial anti-tumour effects are due to enhancement of bioreductive toxicity through increased tumour hypoxia, although additional mechanism(s) may also contribute to the overall response. Images Figure 4 PMID:9275019

  4. [Toxic polyneuropathies].

    PubMed

    Neundörfer, B

    1992-08-01

    Toxic factors may have damaging effects on the peripheral nerves at different sites: on the axon, on the myelin sheath, on the cell bodies and on the vasa nervorum. The toxic neuropathies can be divided up into polyneuropathies induced by drugs, by industrial, environmental and stimulant poisons. Mostly symmetrical sensory symptoms and signs are the first disturbances, often followed by symmetrical motor pareses. Some polyneuropathies induced by amiodarone, benzene, lead, cimetidine, chloroquine, dapsone, gentamycin, gold, imipramine, hexacarbons, nialamide, penicillin, triorthocresylphosphate and vincristine are primarily dominated by motory losses. Polyneuropathies induced by amitriptyline, ethylene, oxide, lead, chlorprothixene, heroin, hydralazine, methaqualone, nialamide and penicillin show an asymmetrical distribution pattern of the neural losses. In some types of toxic polyneuropathies the cranial nerves and the autonomic nerves are particularly involved. The clinical symptomatology of the most important types of toxic neuropathies are described shortly. The best therapy is, of course, termination of exposure to the toxic substance concerned. PMID:1509644

  5. TiO2 nanoparticles tested in a novel screening whole human blood model of toxicity trigger adverse activation of the kallikrein system at low concentrations.

    PubMed

    Ekstrand-Hammarström, Barbro; Hong, Jaan; Davoodpour, Padideh; Sandholm, Kerstin; Ekdahl, Kristina N; Bucht, Anders; Nilsson, Bo

    2015-05-01

    There is a compelling need to understand and assess the toxicity of industrially produced nanoparticles (NPs). In order to appreciate the long-term effects of NPs, sensitive human-based screening tests that comprehensively map the NP properties are needed to detect possible toxic mechanisms. Animal models can only be used in a limited number of test applications and are subject to ethical concerns, and the interpretation of experiments in animals is also distorted by the species differences. Here, we present a novel easy-to-perform highly sensitive whole-blood model using fresh non-anticoagulated human blood, which most justly reflects complex biological cross talks in a human system. As a demonstrator of the tests versatility, we evaluated the toxicity of TiO2 NPs that are widely used in various applications and otherwise considered to have relatively low toxic properties. We show that TiO2 NPs at very low concentrations (50 ng/mL) induce strong activation of the contact system, which in this model elicits thromboinflammation. These data are in line with the finding of components of the contact system in the protein corona of the TiO2 NPs after exposure to blood. The contact system activation may lead to both thrombotic reactions and generation of bradykinin, thereby representing fuel for chronic inflammation in vivo and potentially long-term risk of autoimmunity, arteriosclerosis and cancer. These results support the notion that this novel whole-blood model represents an important contribution to testing of NP toxicity. PMID:25770998

  6. Cytochrome P4501A induction in avian hepatocyte cultures exposed to polychlorinated biphenyls: Comparisons with AHR1-mediated reporter gene activity and in ovo toxicity

    SciTech Connect

    Manning, Gillian E.; Mundy, Lukas J.; Crump, Doug; Jones, Stephanie P.; Chiu, Suzanne; Klein, Jeff; Konstantinov, Alex; Potter, Dave; Kennedy, Sean W.

    2013-01-01

    Avian-specific toxic equivalency factors (TEFs) were developed by the World Health Organization to simplify environmental risk assessments of dioxin-like compounds (DLCs), but TEFs do not account for differences in the toxic and biochemical potencies of DLCs among species of birds. Such variability may be due to differences in species sensitivity to individual DLCs. The sensitivity of avian species to DLCs was recently associated with the identity of amino acids 324 and 380 in the aryl hydrocarbon receptor 1 (AHR1) ligand binding domain. A luciferase reporter gene (LRG) assay, measuring AHR1-mediated induction of a cytochrome P450 1A5 (CYP1A5) reporter gene, in combination with a species' AHR1 ligand binding domain sequence, were also shown to predict avian species sensitivity to polychlorinated biphenyls (PCBs) and PCB relative potency in a given species. The goals of the present study were to (1) characterize the concentration-dependent effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and PCBs 126, 77, 105 and 118 on induction of ethoxyresorufin O-deethylase (EROD) activity and CYP1A4/5 mRNA in chicken, ring-necked pheasant and Japanese quail embryo hepatocytes and (2) compare these in vitro results to those previously generated by the LRG assay and in ovo toxicity studies. EROD activity and CYP1A4/5 mRNA expression data support and complement the findings of the LRG assay. CYP1A enzyme activity and mRNA expression were significantly correlated both with luciferase activity and in ovo toxicity induced by PCBs. Relative potency values were generally similar between the LRG and EROD assays and indicate that the relative potency of some PCBs may differ among species. -- Highlights: ► The chicken isn't the most sensitive species to CYP1A induction by PCB 105 and 118. ► The relative potency of PCBs differs between avian species. ► EROD activity was correlated with luciferase activity from the LRG assay. ► EROD activity was a better predictor of toxicity than CYP

  7. Multihydroxylated [Gd@C82(OH)22]n nanoparticles: antineoplastic activity of high efficiency and low toxicity.

    PubMed

    Chen, Chunying; Xing, Gengmei; Wang, Jiangxue; Zhao, Yuliang; Li, Bai; Tang, Jun; Jia, Guang; Wang, Tiancheng; Sun, Jin; Xing, Li; Yuan, Hui; Gao, Yuxi; Meng, Huan; Chen, Zhen; Zhao, Feng; Chai, Zhifang; Fang, Xiaohong

    2005-10-01

    [Gd@C82(OH)22]n particles (22 nm in a saline solution) of a dose level as low as 10(-7) mol/kg exhibit a very high antineoplastic efficiency ( approximately 60%) in mice. A dose increment of 1 x 10(-7) mol/kg increases the tumor inhibition rate 26%. [Gd@C82(OH)22]n particles have a strong capacity to improve immunity and interfere with tumor invasion in normal muscle cells, nearly without toxicity in vivo and in vitro. Unlike conventional antineoplastic chemicals, the high antitumor efficiency of nanoparticles is not due to toxic effects to cells because they do not kill the tumor cells directly and only about 0.05% of the used dose is found in the tumor tissues. Results suggest that fullerene derivatives with proper surface modifications and sizes may help realize the dream of tumor chemotherapeutics of high-efficacy and low-toxicity. PMID:16218736

  8. Assessing Aromatic-Hydrocarbon Toxicity to Fish Early Life Stages Using Passive-Dosing Methods and Target-Lipid and Chemical-Activity Models.

    PubMed

    Butler, Josh D; Parkerton, Thomas F; Redman, Aaron D; Letinski, Daniel J; Cooper, Keith R

    2016-08-01

    Aromatic hydrocarbons (AH) are known to impair fish early life stages (ELS). However, poorly defined exposures often confound ELS-test interpretation. Passive dosing (PD) overcomes these challenges by delivering consistent, controlled exposures. The objectives of this study were to apply PD to obtain 5 d acute embryo lethality and developmental data and 30 d chronic embryo-larval survival and growth-effects data using zebrafish with different AHs; to analyze study and literature toxicity data using target-lipid (TLM) and chemical-activity (CA) models; and to extend PD to a mixture and test the assumption of AH additivity. PD maintained targeted exposures over a concentration range of 6 orders of magnitude. AH toxicity increased with log Kow up to pyrene (5.2). Pericardial edema was the most sensitive sublethal effect that often preceded embryo mortality, although some AHs did not produce developmental effects at concentrations causing mortality. Cumulative embryo-larval mortality was more sensitive than larval growth, with acute-to-chronic ratios of <10. More-hydrophobic AHs did not exhibit toxicity at aqueous saturation. The relationship and utility of the TLM-CA models for characterizing fish ELS toxicity is discussed. Application of these models indicated that concentration addition provided a conservative basis for predicting ELS effects for the mixture investigated. PMID:27398931

  9. The reduction of gas phase air toxics from combustion and incineration sources using the GE-Mitsui-BF activated coke process

    SciTech Connect

    Olson, D.G.; Tsuji, K.; Shiraishi, I.

    1998-07-01

    The dry desulfurization, denitrification and air toxics removal process using activated coke (AC) was originally researched and developed during the 1960's by Bergbau Forschung (BF), now called Deutsche Montan Technologies. Mitsui Mining Company (MMC) signed a licensing agreement with BF in 1982 to investigate, test and adapt the system to facilities in Japan. Japanese regulations are stricter than in the US toward SOx/NOx pollutants, as well as flyash emissions from the utility industry, oil refineries and other industries. This process is installed on four coal-fired boilers and Fluidized Catalytic Cracker (FCC) units. These plants were constructed by MMC in Japan and Uhde GmbH in Germany. General Electric Environmental Services, Inc. (GEESI) signed a license agreement in 1992 with MMC and Mitsui and Company, Ltd. Of Tokyo. Under this agreement, GEESI will market, design, fabricate and install the Mitsui-BF process for flue gas cleaning applications in North America. MMC also developed a technology to produce AC used in the dry DeSOx/DeNOx/Air Toxics removal process based on their own metallurgical coke manufacturing technology. This paper provides information on the details of MMC's AC used in the dry DeSOx/DeNOx/Air Toxics removal process and of the DeSOx/DeNOx/Air Toxics removal process itself.

  10. Amendment in phosphorus levels moderate the chromium toxicity in Raphanus sativus L. as assayed by antioxidant enzymes activities.

    PubMed

    Sayantan, D; Shardendu

    2013-09-01

    Chromium (Z=24), a d-block element, is a potent carcinogen, whereas phosphorus is an essential and limiting nutrient for the plant growth and development. This study undertakes the role of phosphorus in moderating the chromium toxicity in Raphanus sativus L., as both of them compete with each other during the uptake process. Two-factor complete randomized experiment (5 chromium × 5 phosphorus concentrations) was conducted for twenty eight days in green house. The individuals of R. sativus were grown in pots supplied with all essential nutrients. The toxic effects of chromium and the moderation of toxicity due to phosphorus amendment were determined as accumulation of chromium, nitrogen, phosphorus in root tissues and their effects were also examined in the changes in biomass, chlorophyll and antioxidant enzyme levels. Cr and N accumulation were almost doubled at the highest concentration of Cr supply, without any P amendment, whereas at the highest P concentration (125 mM), the accumulation was reduced to almost half. A significant reduction in toxic effects of Cr was determined as there was three-fold increase in total chlorophyll and biomass at the highest P amendment. Antioxidant enzymes like superoxide dismutase, catalase, peroxidase and lipid peroxidation were analyzed at various levels of Cr each amended with five levels of P. It was observed that at highest level of P amendment, the reduction percentage in toxicity was 33, 44, 39 and 44, correspondingly. Conclusively, the phosphorus amendment moderates the toxicity caused by the supplied chromium in R. sativus. This finding can be utilized to develop a novel technology for the amelioration of chromium stressed fields. PMID:23810367

  11. DEVELOPMENT OF QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS TO PREDICT TOXICITY FOR A VARIETY OF HUMAN AND ECOLOGICAL ENDPOINTS

    EPA Science Inventory

    The number of chemicals released into the environment has significantly increased over the past few years, leading to increased risk of human exposure through inhalation, ingestion, or dermal uptake. In addition, the risk also increases with increasing toxicity of the chemical. ...

  12. The apoptosis-inducing activity towards leukemia and lymphoma cells in a cyanobacterial culture collection is not associated with mouse bioassay toxicity.

    PubMed

    Oftedal, Linn; Skjærven, Kaja H; Coyne, Rosie T; Edvardsen, Bente; Rohrlack, Thomas; Skulberg, Olav M; Døskeland, Stein Ove; Herfindal, Lars

    2011-04-01

    Cyanobacteria (83 strains and seven natural populations) were screened for content of apoptosis (cell death)-inducing activity towards neoplastic cells of the immune (jurkat acute T-cell lymphoma) and hematopoetic (acute myelogenic leukemia) lineage. Apoptogenic activity was frequent, even in strains cultured for decades, and was unrelated to whether the cyanobacteria had been collected from polar, temperate, or tropic environments. The activity was more abundant in the genera Anabaena and Microcystis compared to Nostoc, Phormidium, Planktothrix, and Pseudanabaena. Whereas the T-cell lymphoma apoptogens were frequent in organic extracts, the cell death-inducing activity towards leukemia cells resided mainly in aqueous extracts. The cyanobacteria were from a culture collection established for public health purposes to detect toxic cyanobacterial blooms, and 54 of them were tested for toxicity by the mouse bioassay. We found no correlation between the apoptogenic activity in the cyanobacterial isolates with their content of microcystin, nor with their ability to elicit a positive standard mouse bioassay. Several strains produced more than one apoptogen, differing in biophysical or biological activity. In fact, two strains contained microcystin in addition to one apoptogen specific for the AML cells, and one apoptogen specific for the T-cell lymphoma. This study shows the potential of cyanobacterial culture collections as libraries for bioactive compounds, since strains kept in cultures for decades produced apoptogens unrelated to the mouse bioassay detectable bloom-associated toxins. PMID:20689978

  13. Reduced Activity of Double-Strand Break Repair Genes in Prostate Cancer Patients With Late Normal Tissue Radiation Toxicity

    SciTech Connect

    Oorschot, Bregje van; Hovingh, Suzanne E.; Moerland, Perry D.; Medema, Jan Paul; Stalpers, Lukas J.A.; Vrieling, Harry; Franken, Nicolaas A.P.

    2014-03-01

    Purpose: To investigate clinical parameters and DNA damage response as possible risk factors for radiation toxicity in the setting of prostate cancer. Methods and Materials: Clinical parameters of 61 prostate cancer patients, 34 with (overresponding, OR) and 27 without (non-responding, NR) severe late radiation toxicity were assembled. In addition, for a matched subset the DNA damage repair kinetics (γ-H2AX assay) and expression profiles of DNA repair genes were determined in ex vivo irradiated lymphocytes. Results: Examination of clinical data indicated none of the considered clinical parameters to be correlated with the susceptibility of patients to develop late radiation toxicity. Although frequencies of γ-H2AX foci induced immediately after irradiation were similar (P=.32), significantly higher numbers of γ-H2AX foci were found 24 hours after irradiation in OR compared with NR patients (P=.03). Patient-specific γ-H2AX foci decay ratios were significantly higher in NR patients than in OR patients (P<.0001). Consequently, NR patients seem to repair DNA double-strand breaks (DSBs) more efficiently than OR patients. Moreover, gene expression analysis indicated several genes of the homologous recombination pathway to be stronger induced in NR compared with OR patients (P<.05). A similar trend was observed in genes of the nonhomologous end-joining repair pathway (P=.09). This is congruent with more proficient repair of DNA DSBs in patients without late radiation toxicity. Conclusions: Both gene expression profiling and DNA DSB repair kinetics data imply that less-efficient repair of radiation-induced DSBs may contribute to the development of late normal tissue damage. Induction levels of DSB repair genes (eg, RAD51) may potentially be used to assess the risk for late radiation toxicity.

  14. Toxic trauma.

    PubMed

    Moles, T M; Baker, D J

    2001-01-01

    Hazardous materials (HAZMAT) carry many inherent dangers. Such materials are distributed widely in industrial and military sites. Toxic trauma (TT) denotes the complex of systemic and organ injury caused by toxic agents. Often, TT is associated with other injuries that also require the application of life-support techniques. Rapid onset of acute respiratory failure and consequent cardiovascular failure are of primary concern. Management of TT casualties is dependent upon the characteristics of the toxic agents involved and on the demographics surrounding the HAZMAT incident. Agents that can produce TT possess two pairs of salient characteristics: (1) causality (toxicity and latency), and (2) EMS system (persistency and transmissibility). Two characteristics of presentations are important: (1) incident presentation, and (2) casualty presentation. In addition, many of these agents complicate the processes associated with anaesthesia and must be dealt with. Failure of recognition of these factors may result in the development of respiratory distress syndromes and multiorgan system failure, or even death. PMID:11513285

  15. Digitalis toxicity

    MedlinePlus

    These are symptoms of digitalis toxicity: Confusion Irregular pulse Loss of appetite Nausea , vomiting , diarrhea Fast heartbeat Vision changes (unusual), including blind spots, blurred vision, changes in how colors look, or ...

  16. Antimony Toxicity

    PubMed Central

    Sundar, Shyam; Chakravarty, Jaya

    2010-01-01

    Antimony toxicity occurs either due to occupational exposure or during therapy. Occupational exposure may cause respiratory irritation, pneumoconiosis, antimony spots on the skin and gastrointestinal symptoms. In addition antimony trioxide is possibly carcinogenic to humans. Improvements in working conditions have remarkably decreased the incidence of antimony toxicity in the workplace. As a therapeutic, antimony has been mostly used for the treatment of leishmaniasis and schistosomiasis. The major toxic side-effects of antimonials as a result of therapy are cardiotoxicity (~9% of patients) and pancreatitis, which is seen commonly in HIV and visceral leishmaniasis co-infections. Quality control of each batch of drugs produced and regular monitoring for toxicity is required when antimonials are used therapeutically. PMID:21318007

  17. A study of antimicrobial activity, acute toxicity and cytoprotective effect of a polyherbal extract in a rat ethanol-HCl gastric ulcer model

    PubMed Central

    2012-01-01

    Background The decoction of the aerial parts of Rhynchosia recinosa (A.Rich.) Bak. [Fabaceae] is used in combination with the stem barks of Ozoroa insignis Del. (Anacardiaceae), Maytenus senegalensis (Lam.) Excell. [Celastraceae] Entada abyssinica Steud. ex A.Rich [Fabaceae] and Lannea schimperi (Hochst.)Engl. [Anacardiaceae] as a traditional remedy for managing peptic ulcers. However, the safety and efficacy of this polyherbal preparation has not been evaluated. This study reports on the phytochemical profile and some biological activities of the individual plant extracts and a combination of extracts of the five plants. Methods A mixture of 80% ethanol extracts of R. recinosa, O. insignis, M. senegalensis, E. abyssinica and L. schimperi at doses of 100, 200, 400 and 800 mg/kg body wt were evaluated for ability to protect Sprague Dawley rats from gastric ulceration by an ethanol-HCl mixture. Cytoprotective effect was assessed by comparison with a negative control group given 1% tween 80 in normal saline and a positive control group given 40 mg/kg body wt pantoprazole. The individual extracts and their combinations were also tested for antibacterial activity against four Gram negative bacteria; Escherichia coli (ATCC 25922), Salmonella typhi (NCTC 8385), Vibrio cholerae (clinical isolate), and Klebsiella pneumoniae (clinical isolate) using the microdilution method. In addition the extracts were evaluated for brine shrimp toxicity and acute toxicity in mice. Phytochemical tests were done using standard methods to determine the presence of tannins, saponins, steroids, cardiac glycosides, flavonoids, alkaloids and terpenoids in the individual plant extracts and in the mixed extract of the five plants. Results The combined ethanolic extracts of the 5 plants caused a dose-dependent protection against ethanol/HCl induced ulceration of rat gastric mucosa, reaching 81.7% mean protection as compared to 87.5% protection by 40 mg/kg body wt pantoprazole. Both the individual

  18. Evaluation of acute and subacute toxicity and mutagenic activity of the aqueous extract of pecan shells [Carya illinoinensis (Wangenh.) K. Koch].

    PubMed

    Porto, Luiz Carlos Santos; da Silva, Juliana; Ferraz, Alexandre de Barros Falcão; Corrêa, Dione Silva; dos Santos, Marcela Silva; Porto, Caroline Dalla Lana; Picada, Jaqueline Nascimento

    2013-09-01

    The infusion of pecan shells has been used to prevent and control hypercholesterolemia, diabetes and toxicological diseases. The aim of the present study was to evaluate toxicity and mutagenic effects of pecan shells aqueous extract (PSAE). Wistar rats were treated with a single dose of 300 or 2000 mg/kg of PSAE in the acute toxicity test. For the subacute test, the animals received 10 or 100 mg/kg of PSAE for 28 days. The mutagenicity was evaluated using Salmonella/microsome assay in TA1535, TA1537, TA98, TA100 and TA102 S. typhimurium strains in the presence and absence of metabolic activation (S9 mix) and micronucleus test in bone marrow. HPLC analyses indicated the presence of tannins, flavonoids, gallic and ellagic acids. Except for triglycerides, all treated groups presented normal hematological and biochemical parameters. Lower levels of triglycerides and weight loss were observed in the 100 mg/kg group. Mutagenic activities were not detected in S. typhimurium strains and by the micronucleus test. Based on these results, PSAE was not able to induce chromosomal or point mutations, under the conditions tested. The 100mg/kg dose showed significant antihyperlipidemic action, with no severe toxic effects. PMID:23831307

  19. Separations chemistry of toxic metals

    SciTech Connect

    Smith, P.; Barr, M.; Barrans, R.

    1996-04-01

    Sequestering and removing toxic metal ions from their surroundings is an increasingly active area of research and is gaining importance in light of current environmental contamination problems both within the DOE complex and externally. One method of separating metal ions is to complex them to a molecule (a ligand or chelator) which exhibits specific binding affinity for a toxic metal, even in the presence of other more benign metals. This approach makes use of the sometimes subtle differences between toxic and non-toxic metals resulting from variations in size, charge and shape. For example, toxic metals such as chromium, arsenic, and technetium exist in the environment as oxyanions, negatively charged species with a characteristic tetrahedral shape. Other toxic metals such as actinides and heavy metals are positively charged spheres with specific affinities for particular donor atoms such as oxygen (for actinides) and nitrogen (for heavy metals). In most cases the toxic metals are found in the presence of much larger quantities of less toxic metals such as sodium, calcium and iron. The selectivity of the chelators is critical to the goal of removing the toxic metals from their less toxic counterparts. The approach was to build a ligand framework that complements the unique characteristics of the toxic metal (size, charge and shape) while minimizing interactions with non-toxic metals. The authors have designed ligands exhibiting specificity for the target metals; they have synthesized, characterized and tested these ligands; and they have shown that they exhibit the proposed selectivity and cooperative binding effects.

  20. Acute toxicity and sublethal effects of the mixture glyphosate (Roundup Active) and Cosmo-Flux 411F to anuran embryos and tadpoles of four Colombian species.

    PubMed

    Henao Muñoz, Liliana Marcela; Montes Rojas, Claudia Marsela; Bernal Bautista, Manuel Hernando

    2015-03-01

    Glyphosate is the most widely used herbicide in the world with application in agriculture, forestry, industrial weed control, garden and aquatic environments. However, its use is highly controversial for the possible impact on not-target organisms, such as amphibians, which are vanishing at an alarming and rapid rate. Due to the high solubility in water and ionic nature, the glyphosate requires of surfactants to increase activity. In addition, for the control of coca (Erythroxylum coca) and agricultural weeds in Colombia, formulated glyphosate is mixed and sprayed with the adjuvant Cosmo-Flux 411F to increase the penetration and activity of the herbicide. This study evaluates the acute toxic and sublethal effects (embryonic development, tadpole body size, tadpole swimming performance) of the mixture of the formulated glyphosate Roundup Active and Cosmo-Flux 411F to anuran embryos and tadpoles of four Colombian species under 96h laboratory standard tests and microcosms, which are more similar to field conditions as they include soil, sand and macrophytes. In the laboratory, embryos and tadpoles of Engystomops pustulosus were the most tolerant (LC50 = 3904 microg a.e./L; LC50=2 799 pg a.e./L, respectively), while embryos and tadpoles of Hypsiboas crepitans (LC50=2 203 microg a.e./L; LC50=1424 microgg a.e./L, respectively) were the most sensitive. R. humboldti and R. marina presented an intermediate toxicity. Embryos were significantly more tolerant to the mixture than tadpoles, which could be likely attributed to the exclusion of chemicals by the embryonic membranes and the lack of organs, such as gills, which are sensitive to surfactants. Sublethal effects were observed for the tadpole body size, but not for the embryonic development and tadpole swimming performance. In microcosms, no toxicity (LC50 could not be estimated), or sublethal responses were observed at concentrations up to fourfold (14.76 kg glyphosate a.e./ha) the highest field application rate of 3

  1. Role of IgG(T) and IgGa isotypes obtained from arachnidic antivenom to neutralize toxic activities of Loxosceles gaucho, Phoneutria nigriventer and Tityus serrulatus venoms.

    PubMed

    Toro, Ana Flávia; Malta, Marília Brinati; Soares, Sabrina Lucio; Da Rocha, Guilherme Casoni; da Silva Lira, Marcela; De Oliveira, Thais Abbate; Takehara, Harumi Ando; Lopes-Ferreira, Mônica; Santoro, Marcelo Larami; Guidolin, Rosalvo; Gondo Higashi, Hisako; Fernandes, Irene; Barbaro, Katia Cristina

    2006-11-01

    The ability of IgG(T) and IgGa subclasses--isolated by liquid chromatography from equine arachnidic antivenom (AAV)-to neutralize toxic activities of Loxosceles gaucho, Phoneutria nigriventer and Tityus serrulatus venoms as well as to remove venom toxins from circulation was investigated. These subclasses showed similar antibody titers against L. gaucho, P. nigriventer and T. serrulatus venoms, and by immunoblotting few differences were observed in the recognition pattern of venom antigens. IgG(T) and IgGa neutralized 100% lethality induced by L. gaucho and 50% of P. nigriventer venom, but IgGa failed to neutralize T. serrulatus venom, in contrast to IgG(T). Both subclasses neutralized local reactions and dermonecrosis induced by L. gaucho venom in rabbits. In mice, IgG(T) and IgGa partially neutralized the edematogenic activity induced by P. nigriventer and T. serrulatus venoms, but only IgG(T) neutralized (ca. 81%) the nociceptive activity induced by T. serrulatus venom. Both subclasses failed to neutralize nociceptive activity induced by P. nigriventer venom. IgG(T) reduced the serum venom levels of animals injected with L. gaucho, P. nigriventer or T. serrulatus venoms, while IgGa solely reduced L. gaucho and P. nigriventer venoms levels. Our results demostrate that IgG(T) and IgGa subclasses neutralize toxic activities induced by P. nigriventer, T. serrulatus and L. gaucho venoms with different efficacies, as well as depurate these venoms from circulation. PMID:16979205

  2. Fabrication of novel vesicles of triptolide for antirheumatoid activity with reduced toxicity in vitro and in vivo

    PubMed Central

    Zhang, Li; Wang, Tengteng; Li, Qiang; Huang, Jing; Xu, Hao; Li, Jinlong; Wang, Yongjun; Liang, Qianqian

    2016-01-01

    Triptolide (TP) displays a strong immunosuppression function in immune-mediated diseases, especially in the treatment of rheumatoid arthritis. However, in addition to its medical and health-related functions, TP also exhibits diverse pharmacological side effects, for instance, liver and kidney toxicity and myelosuppression. In order to reduce the side effects, a nano drug carrier system (γ-PGA-l-PAE-TP [PPT]), in which TP was loaded by a poly-γ-glutamic acid-grafted l-phenylalanine ethylester copolymer, was developed. PPT was characterized by photon scattering correlation spectroscopy and transmission electron microscopy, which demonstrated that the average diameter of the drug carrier system is 98±15 nm, the polydispersity index is 0.18, the zeta potential is −35 mV, and the TP encapsulation efficiency is 48.6% with a controlled release manner. The methylthiazolyldiphenyl-tetrazolium bromide assay and flow cytometry revealed that PPT could decrease toxicity and apoptosis induced by free TP on RAW264.7 cells, respectively. The detection of reactive oxygen species showed that PPT could decrease the cellular reactive oxygen species induced by TP. Compared with the free TP-treated group, PPT improved the survival rate of the mice (P<0.01) and had no side effects or toxic effects on the thymus index (P>0.05) and spleen index (P>0.05). The blood biochemical indexes revealed that PPT did not cause much damage to the kidney (blood urea nitrogen and creatinine), liver (serum alanine aminotransferase and aspartate aminotransferase), or blood cells (P>0.05). Meanwhile, hematoxylin and eosin staining and terminal-deoxynucleotidyl transferase dUTP nick-end labeling staining indicated that PPT reduced the damage of free TP on the liver, kidney, and spleen. Our results demonstrated that PPT reduced free TP toxicity in vitro and in vivo and that it is a promising fundamental drug delivery system for rheumatoid arthritis treatment. PMID:27354796

  3. Emulsifying Activity and Stability of a Non-Toxic Bioemulsifier Synthesized by Microbacterium sp. MC3B-10

    PubMed Central

    Camacho-Chab, Juan Carlos; Guézennec, Jean; Chan-Bacab, Manuel Jesús; Ríos-Leal, Elvira; Sinquin, Corinne; Muñiz-Salazar, Raquel; De la Rosa-García, Susana del C.; Reyes-Estebanez, Manuela; Ortega-Morales, Benjamín Otto

    2013-01-01

    A previously reported bacterial bioemulsifier, here termed microbactan, was further analyzed to characterize its lipid component, molecular weight, ionic character and toxicity, along with its bioemulsifying potential for hydrophobic substrates at a range of temperatures, salinities and pH values. Analyses showed that microbactan is a high molecular weight (700 kDa), non-ionic molecule. Gas chromatography of the lipid fraction revealed the presence of palmitic, stearic, and oleic acids; thus microbactan may be considered a glycolipoprotein. Microbactan emulsified aromatic hydrocarbons and oils to various extents; the highest emulsification index was recorded against motor oil (96%). The stability of the microbactan-motor oil emulsion model reached its highest level (94%) at 50 °C, pH 10 and 3.5% NaCl content. It was not toxic to Artemia salina nauplii. Microbactan is, therefore, a non-toxic and non-ionic bioemulsifier of high molecular weight with affinity for a range of oily substrates. Comparative phylogenetic assessment of the 16S rDNA gene of Microbacterium sp. MC3B-10 with genes derived from other marine Microbacterium species suggested that this genus is well represented in coastal zones. The chemical nature and stability of the bioemulsifier suggest its potential application in bioremediation of marine environments and in cosmetics. PMID:24065097

  4. A best​ comprehension about the toxicity of phenylsulfonyl carboxylates in Vibrio fischeri using quantitative structure activity/property relationship methods.

    PubMed

    de Melo, Eduardo Borges; Martins, João Paulo Athaíde; Miranda, Eduardo Hösel; Ferreira, Márcia Miguel Castro

    2016-03-01

    Aromatic sulfones comprise a class of chemicals used in agrochemical and pharmaceutical industries and as floatation and extractant agents in petrochemical and metallurgy industries. In this study, new QSA(P)R studies were carried out to predict the toxicity against Vibrio fischeri of a set of 52 aromatic sulfones. The same approach was used to evaluate the relationship between these endpoint and the water solubility, another important environmental endpoint. The study resulted in models of good statistical quality and mechanistic interpretation with a possible correlation between the two endpoints, but the toxic effect is also likely to depend on other physicochemical properties. The use of the PLS2, a method not commonly used in QSA(P)R studies, also produced models of greater reliability, and the relationship between the two endpoints was reinforced to some degree. These results are useful for better understanding the process by which these compounds exert their environmental toxicity, thus aiding in the development of industrially useful compounds with less potential environmental damage. PMID:26551227

  5. Synergistic enhancement of parasiticidal activity of amphotericin B using copaiba oil in nanoemulsified carrier for oral delivery: an approach for non-toxic chemotherapy

    PubMed Central

    Gupta, Pramod K; Jaiswal, Anil K; Asthana, Shalini; Teja B, Venkatesh; Shukla, Prashant; Shukla, Minakshi; Sagar, Neeti; Dube, Anuradha; Rath, Srikanta K; Mishra, Prabhat R

    2015-01-01

    Background and Purpose The aim of this study was to devise a nanoemulsified carrier system (CopNEC) to improve the oral delivery of amphotericin B (AmB) by increasing its oral bioavailability and synergistically enhance its antileishmanial activity with copaiba oil (Cop). Experimental Approach The AmB encapsulated NEC (CopNEC-AmB) comprised of Cop, d-α-tocopheryl polyethylene glycol 1000 succinate and phosphatidylcholine was prepared by high-pressure homogenization method. Stability study of CopNEC-AmB was carried out in simulated gastric fluid and simulated intestinal fluid. The CopNEC-AmB and plain AmB were compared as regards their in vitro antileishmanial activity, pharmacokinetics, organ distribution and toxicity. Key Results The optimal CopNEC-AmB had a small globule size, low polydispersity index, high ζ potential and encapsulation efficiency. The high resolution transmission electron microscopy illustrated spherical particle geometry with homogeny in their sizes. The optimal CopNEC-AmB was found to be stable in gastrointestinal fluids showing insignificant changes in globule size and encapsulation efficiency. The AUC0–48 value of CopNEC-AmB in rats was significantly improved showing 7.2-fold higher oral bioavailability than free drug. The in vitro antileishmanial activity of CopNEC-AmB was significantly higher than that of the free drug as Cop synergistically enhanced the antileishmanial effect of AmB by causing drastic changes in the morphology of Leishmania parasite and rupturing its plasma membrane. The CopNEC-AmB showed significantly less haemolytic toxicity and cytotoxicity and did not change the histopathology of kidney tissues as compared with AmB alone. Conclusions and Implications This prototype CopNEC formulation showed improved bioavailability and had a non-toxic synergistic effect on the antileishmanial activity of AmB. PMID:25825339

  6. Binding of nickel and copper to fish gills predicts toxicity when water hardness varies, but free-ion activity does not

    SciTech Connect

    Meyer, J.S.; Bobbitt, J.P.; Debrey, L.D.; Boese, C.J.; Bergman, H.L.; Santore, R.C.; Paquin, P.R.; Ditoro, D.M.; Allen, H.E.

    1999-03-15

    Based on a biotic-ligand model (BLM), the authors hypothesized that the concentration of a transition metal bound to fish gills ([M{sub gill}]) will be a constant predictor of mortality, whereas a free-ion activity model is generally interpreted to imply that the chemical activity of the aquo (free) ion of the metal will be a constant predictor of mortality. In laboratory tests, measured [Ni{sub gill}] and calculated [Cu{sub gill}] were constant predictors of acute toxicity of Ni and Cu to fathead minnows (Pimephales promelas) when water hardness varied up to 10-fold, whereas total aqueous concentrations and free-ion activities of Ni and Cu were not. Thus, the BLM, which simultaneously accounts for (a) metal speciation in the exposure water and (b) competitive binding of transition-metal ions and other cations to biotic ligands predicts acute toxicity better than does free-ion activity of Ni or Cu. Adopting a biotic-ligand modeling approach could help establish a more defensible, mechanistic basis for regulating aqueous discharges of metals.

  7. Functional characterizations of venom phenotypes in the eastern diamondback rattlesnake (Crotalus adamanteus) and evidence for expression-driven divergence in toxic activities among populations.

    PubMed

    Margres, Mark J; Walls, Robert; Suntravat, Montamas; Lucena, Sara; Sánchez, Elda E; Rokyta, Darin R

    2016-09-01

    Phenotypes frequently vary across and within species. The connection between specific phenotypic effects and function, however, is less understood despite being essential to our understanding of the adaptive process. Snake venoms are ideal for identifying functionally important phenotypic variation because venom variation is common, and venoms can be functionally characterized through simple assays and toxicity measurements. Previous work with the eastern diamondback rattlesnake (Crotalus adamanteus) used multivariate statistical approaches to identify six unique venom phenotypes. We functionally characterized hemolytic, gelatinase, fibrinogenolytic, and coagulant activity for all six phenotypes, as well as one additional venom, to determine if the statistically significant differences in toxin expression levels previously documented corresponded to differences in venom activity. In general, statistical differences in toxin expression predicted the identified functional differences, or lack thereof, in toxic activity, demonstrating that the statistical approach used to characterize C. adamanteus venoms was a fair representation of biologically meaningful differences. Minor differences in activity not accounted for by the statistical model may be the result of amino-acid differences and/or post-translational modifications, but overall we were able to link variation in protein expression levels to variation in function as predicted by multivariate statistical approaches. PMID:27179420

  8. Toxic effects of the joint exposure of decabromodiphenyl ether (BDE209) and tetrabromobisphenol A (TBBPA) on soil microorganism and enzyme activity.

    PubMed

    Zhang, Wei; Chen, Lei; An, Shuai; Liu, Kou; Lin, Kuangfei; Zhao, Li

    2014-09-01

    Decabromodiphenyl ether (BDE209) and tetrabromobisphenol A (TBBPA) are the main contaminants at e-waste recycling sites, and their potential toxicological effects have received extensive attention. However, the impact on soil culturable microbial population and enzyme activity of joint exposure to the two chemicals remains almost unknown. Therefore, indoor incubation tests were performed on control and contaminated soil samples to determine the eco-toxicological response in the joint presence of BDE209 and TBBPA for the first time. The results have demonstrated some notable toxic effects due to long-term exposure to either or both contaminants. The inhibition ratios of microbial populations increased with incubation time and increasing concentrations of BDE209 or TBBPA following certain dose-response relationships and time-effect trends. The response sensitivity sequence was fungi>bacteria>actinomycete. The influence of the two chemicals on soil enzymes reached peak values on day 7, and highly significant differences (P<0.01) were observed compared to the controls. Urease was more susceptive to the two chemicals than catalase and saccharase activities. Generally, the joint toxicity of both contaminants on soil microbes, catalase or saccharase activities indicated antagonistic effects, while, as for urease activity, addition role was dominant. Such observations have provided the useful information of potential ecological effects of brominated flame retardants contamination in the environment. PMID:25195096

  9. Antimicrobial activity, acute toxicity and cytoprotective effect of Crassocephalum vitellinum (Benth.) S. Moore extract in a rat ethanol-HCl gastric ulcer model

    PubMed Central

    2014-01-01

    Background A decoction of Crassocephallum vitellinum (Benth.) S. Moore (Asteraceae) is used in Kagera Region to treat peptic ulcers. This study seeks to evaluate an aqueous ethanol extract of aerial parts of the plant for safety and efficacy. Methods An 80% ethanolic extract of C. vitellinum at doses of 100, 200, 400 and 800 mg/kg body wt was evaluated for ability to protect Sprague Dawley rats from acidified ethanol gastric ulceration in comparison with 40 mg/kg body wt pantoprazole. The extract and its dichloromethane, ethyl acetate, and aqueous fractions were also evaluated for acute toxicity in mice, brine shrimp toxicity, and antibacterial activity against four Gram negative bacteria; Escherichia coli (ATCC 25922), Salmonella typhi (NCTC 8385), Vibrio cholera (clinical isolate), and Streptococcus faecalis (clinical isolate). The groups of phytochemicals present in the extract were also determined. Results The ethanolic extract of C. vitellinum dose-dependently protected rat gastric mucosa against ethanol/HCl insult to a maximum of 88.3% at 800 mg/kg body wt, affording the same level of protection as by 40 mg/kg body wt pantoprazole. The extract also exhibited weak antibacterial activity against S. typhi and E. coli, while its ethyl acetate, dichloromethane and aqueous fractions showed weak activity against K. pneumonia, S.typhi, E. coli and V. cholera. The extract was non-toxic to mice up to 5000 mg/kg body wt, and the total extract (LC50 = 37.49 μg/ml) and the aqueous (LC50 = 87.92 μg/ml), ethyl acetate (LC50 = 119.45 μg/ml) and dichloromethane fractions (88.79 μg/ml) showed low toxicity against brine shrimps. Phytochemical screening showed that the extract contains tannins, saponins, flavonoids, and terpenoids. Conclusion The results support the claims by traditional healers that a decoction of C.vitellinum has antiulcer activity. The mechanism of cytoprotection is yet to be determined but the phenolic compounds present in the

  10. The reduction of gas phase air toxics from combustion and incineration sources using the GE-MITSUI-BE activated coke process

    SciTech Connect

    Olson, D.G.

    1995-12-31

    The dry desulfurization, denitrification and air toxics removal process using activated coke (AC) was originally researched and developed during the 1960s by Bergbau Forschung (BF), now called Deutsche Montan Technologies. Mitsui Mining Company (MMC) signed a licensing agreement with BF in 1982 to investigate, test and adapt the system to the facilities in Japan. Japanese regulations are stricter than in the U.S. toward SO{sub x}/NO{sub x} pollutants, as well as flyash emissions from the utility industry, oil refineries and other industries. This process is installed on flour coal-fired boilers and Fluidized Catalytic Cracker (FCC) units. These plants were constructed by MCC in Japan and Uhde GmbH in Germany. General Electric Environmental Systems, Inc. (GEESI) signed a license agreement in 1992 with MMC and Mitsui and Company, Ltd. of Tokyo. Under this agreement, GEESI will market, design, fabricate and install the Mitsui-BF press for flue gas cleaning applications in North America. MMC also developed a technology to produce AC used in the dry DeSO{sub x}/DeNO{sub x}/Air Toxics removal process based on their own metallurgical coke manufacturing technology. This paper provides information on the details of MMC`s AC used in the dry DeSO{sub x}/DeNO{sub x}/Air Toxics removal process.

  11. Toxicity in relation to mode of action for the nematode Caenorhabditis elegans: Acute-to-chronic ratios and quantitative structure-activity relationships.

    PubMed

    Ristau, Kai; Akgül, Yeliz; Bartel, Anna Sophie; Fremming, Jana; Müller, Marie-Theres; Reiher, Luise; Stapela, Frederike; Splett, Jan-Paul; Spann, Nicole

    2015-10-01

    Acute-to-chronic ratios (ACRs) and quantitative structure-activity relationships (QSARs) are of particular interest in chemical risk assessment. Previous studies focusing on the relationship between the size or variation of ACRs to substance classes and QSAR models were often based on data for standard test organisms, such as daphnids and fish. In the present study, acute and chronic toxicity tests were performed with the nematode Caenorhabditis elegans for a total of 11 chemicals covering 3 substance classes (nonpolar narcotics: 1-propanol, ethanol, methanol, 2-butoxyethanol; metals: copper, cadmium, zinc; and carbamates: methomyl, oxamyl, aldicarb, dioxacarb). The ACRs were variable, especially for the carbamates and metals, although there was a trend toward small and less variable ACRs for nonpolar narcotic substances. The octanol-water partition coefficient was a good predictor for explaining acute and chronic toxicity of nonpolar narcotic substances to C. elegans, but not for carbamates. Metal toxicity could be related to the covalent index χm2r. Overall, the results support earlier results from ACR and QSAR studies with standard freshwater test animals. As such C. elegans as a representative of small soil/sediment invertebrates would probably be protected by risk assessment strategies already in use. To increase the predictive power of ACRs and QSARs, further research should be expanded to other species and compounds and should also consider the target sites and toxicokinetics of chemicals. PMID:25994998

  12. JANEX-1, a JAK3 inhibitor, protects pancreatic islets from cytokine toxicity through downregulation of NF-{kappa}B activation and the JAK/STAT pathway

    SciTech Connect

    Lv, Na; Kim, Eun-Kyung; Song, Mi-Young; Choi, Ha-Na; Moon, Woo Sung; Park, Sung-Joo; Park, Jin-Woo; Kwon, Kang-Beom; Park, Byung-Hyun

    2009-07-15

    JANEX-1/WHI-P131, a selective Janus kinase 3 (JAK3) inhibitor, has been shown to delay the onset of diabetes in the NOD mouse model. However, the molecular mechanism by which JANEX-1 protects pancreatic {beta}-cells is unknown. In the current study, we investigated the role of JANEX-1 on interleukin (IL)-1{beta} and interferon (IFN)-{gamma}-induced {beta}-cell damage using isolated islets. JANEX-1-pretreated islets showed resistance to cytokine toxicity, namely suppressed nitric oxide (NO) production, reduced inducible form of NO synthase (iNOS) expression, and decreased islet destruction. The molecular mechanism by which JANEX-1 inhibits iNOS expression was mediated through suppression of the nuclear factor {kappa}B (NF-{kappa}B) and JAK/signal transducer and activator of transcription (STAT) pathways. Islets treated with the cytokines downregulated the protein levels of suppressor of cytokine signaling (SOCS)-1 and SOCS-3, but pretreatment with JANEX-1 attenuated these decreases. Additionally, islets from JAK3{sup -/-} mice were more resistant to cytokine toxicity than islets from control mice. These results demonstrate that JANEX-1 protects {beta}-cells from cytokine toxicity through suppression of the NF-{kappa}B and JAK/STAT pathways and upregulation of SOCS proteins, suggesting that JANEX-1 may be used to preserve functional {beta}-cell mass.

  13. Toxic Myopathies

    PubMed Central

    Pasnoor, Mamatha; Barohn, Richard J.; Dimachkie, Mazen M.

    2014-01-01

    Muscle tissue is highly sensitive to many substances. Early recognition of toxic myopathies is important, as they potentially are reversible on removal of the offending drug or toxin, with greater likelihood of complete resolution the sooner this is achieved. Clinical features range from mild muscle pain and cramps to severe weakness with rhabdomyolysis, renal failure, and even death. The pathogenic bases can be multifactorial. This article reviews some of the common toxic myopathies and their clinical presentation, histopathologic features and possible underlying cellular mechanisms. PMID:25037083

  14. Huperzine A Alleviates Oxidative Glutamate Toxicity in Hippocampal HT22 Cells via Activating BDNF/TrkB-Dependent PI3K/Akt/mTOR Signaling Pathway.

    PubMed

    Mao, Xiao-Yuan; Zhou, Hong-Hao; Li, Xi; Liu, Zhao-Qian

    2016-08-01

    Oxidative glutamate toxicity is involved in diverse neurological disorders including epilepsy and ischemic stroke. Our present work aimed to assess protective effects of huperzine A (HupA) against oxidative glutamate toxicity in a mouse-derived hippocampal HT22 cells and explore its potential mechanisms. Cell survival and cell injury were analyzed by MTT method and LDH release assay, respectively. The production of ROS was measured by detection kits. Protein expressions of BDNF, phosphor-TrkB (p-TrkB), TrkB, phosphor-Akt (p-Akt), Akt, phosphor-mTOR (p-mTOR), mTOR, phosphor-p70s6 (p-p70s6) kinase, p70s6 kinase, Bcl-2, Bax, and β-actin were assayed via Western blot analysis. Enzyme-linked immunosorbent assay was employed to measure the contents of nerve growth factor, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). Our findings illustrated 10 μM HupA for 24 h significantly protected HT22 from cellular damage and suppressed the generation of ROS. Additionally, after treating with LY294002 or wortmannin [the selective inhibitors of phosphatidylinositol 3 kinase (PI3K)], HupA dramatically prevented the down-regulations of p-Akt, p-mTOR, and p-p70s6 kinase in HT22 cells under oxidative toxicity. Furthermore, it was observed that the protein levels of BDNF and p-TrkB were evidently enhanced after co-treatment with HupA and glutamate in HT22 cells. The elevations of p-Akt and p-mTOR were abrogated under toxic conditions after blockade of TrkB by TrkB IgG. Cellular apoptosis was significantly suppressed (decreased caspase-3 activity and enhanced Bcl-2 protein level) after HupA treatment. It was concluded that HupA attenuated oxidative glutamate toxicity in murine hippocampal HT22 cells via activating BDNF/TrkB-dependent PI3K/Akt/mTOR signaling pathway. PMID:26440805

  15. Different design of enzyme-triggered CO-releasing molecules (ET-CORMs) reveals quantitative differences in biological activities in terms of toxicity and inflammation.

    PubMed

    Stamellou, E; Storz, D; Botov, S; Ntasis, E; Wedel, J; Sollazzo, S; Krämer, B K; van Son, W; Seelen, M; Schmalz, H G; Schmidt, A; Hafner, M; Yard, B A

    2014-01-01

    Acyloxydiene-Fe(CO)3 complexes can act as enzyme-triggered CO-releasing molecules (ET-CORMs). Their biological activity strongly depends on the mother compound from which they are derived, i.e. cyclohexenone or cyclohexanedione, and on the position of the ester functionality they harbour. The present study addresses if the latter characteristic affects CO release, if cytotoxicity of ET-CORMs is mediated through iron release or inhibition of cell respiration and to what extent cyclohexenone and cyclohexanedione derived ET-CORMs differ in their ability to counteract TNF-α mediated inflammation. Irrespective of the formulation (DMSO or cyclodextrin), toxicity in HUVEC was significantly higher for ET-CORMs bearing the ester functionality at the outer (rac-4), as compared to the inner (rac-1) position of the cyclohexenone moiety. This was paralleled by an increased CO release from the former ET-CORM. Toxicity was not mediated via iron as EC50 values for rac-4 were significantly lower than for FeCl2 or FeCl3 and were not influenced by iron chelation. ATP depletion preceded toxicity suggesting impaired cell respiration as putative cause for cell death. In long-term HUVEC cultures inhibition of VCAM-1 expression by rac-1 waned in time, while for the cyclohexanedione derived rac-8 inhibition seems to increase. NFκB was inhibited by both rac-1 and rac-8 independent of IκBα degradation. Both ET-CORMs activated Nrf-2 and consequently induced the expression of HO-1. This study further provides a rational framework for designing acyloxydiene-Fe(CO)3 complexes as ET-CORMs with differential CO release and biological activities. We also provide a better understanding of how these complexes affect cell-biology in mechanistic terms. PMID:25009775

  16. Antidiabetic effect, antioxidant activity, and toxicity of 3',4'-Di-O-acetyl-cis-khellactone in Streptozotocin-induced diabetic rats.

    PubMed

    Domínguez-Mendoza, Elix Alberto; Cornejo-Garrido, Jorge; Burgueño-Tapia, Eleuterio; Ordaz-Pichardo, Cynthia

    2016-08-15

    Pyranocoumarins are compounds with an important pharmacological profile, such as anti-inflammatory, antioxidant, cytotoxic, antiviral, antibacterial, and hypoglycemic effects. These molecules have a widespread presence as secondary metabolites in medicinal plants used to treat Diabetes Mellitus (DM). The aim of this work was to evaluate antidiabetic activity in Streptozotocin (STZ)-induced diabetic rats and the antioxidant effects of 3',4'-Di-O-acetyl-cis-khellactone (DOAcK), as well as its toxic potential. We obtained DOAcK with an enantiomeric excess of 70% by chemical synthesis. Our results showed that this compound exerts an important antidiabetic effect: blood glucose decreased in groups treated with DOAcK by 60.9% at dose of 15mg/kg (p<0.05) compared with the diabetic control group, and demonstrated a statistically significant increase in weight gain (45.7±9.7 in the group treated with DOAcK vs. -23.0±33.1 in the group with diabetes). In a biochemical profile, DOAcK did not modify lipid metabolism and did not cause damage at the renal level. DOAcK administration increased the activities of Catalase (CAT), Glutathione Peroxidase (GPx), and Super Oxide Dismutase (SOD) to levels near those of the healthy group. Histopathological analysis exhibited morphology similar to that of the healthy group and the group treated with DOAcK. DOAcK is not mutagenic by Ames test for Salmonella typhimurium strains TA98, TA100, or TA102, and is not genotoxic by Micronucleus assay; median lethal dose (LD50) >2000mg/kg and, at this dose, no signs of toxicity or death were reported after 14days of observation. These results indicate that DOAcK can improve glucose metabolism, which may be due to the increased antioxidant activity of CAT, GPx and SOD. In addition, DOAcK is not toxic in the studies tested. PMID:27397496

  17. Different design of enzyme-triggered CO-releasing molecules (ET-CORMs) reveals quantitative differences in biological activities in terms of toxicity and inflammation

    PubMed Central

    Stamellou, E.; Storz, D.; Botov, S.; Ntasis, E.; Wedel, J.; Sollazzo, S.; Krämer, B.K.; van Son, W.; Seelen, M.; Schmalz, H.G.; Schmidt, A.; Hafner, M.; Yard, B.A.

    2014-01-01

    Acyloxydiene–Fe(CO)3 complexes can act as enzyme-triggered CO-releasing molecules (ET-CORMs). Their biological activity strongly depends on the mother compound from which they are derived, i.e. cyclohexenone or cyclohexanedione, and on the position of the ester functionality they harbour. The present study addresses if the latter characteristic affects CO release, if cytotoxicity of ET-CORMs is mediated through iron release or inhibition of cell respiration and to what extent cyclohexenone and cyclohexanedione derived ET-CORMs differ in their ability to counteract TNF-α mediated inflammation. Irrespective of the formulation (DMSO or cyclodextrin), toxicity in HUVEC was significantly higher for ET-CORMs bearing the ester functionality at the outer (rac-4), as compared to the inner (rac-1) position of the cyclohexenone moiety. This was paralleled by an increased CO release from the former ET-CORM. Toxicity was not mediated via iron as EC50 values for rac-4 were significantly lower than for FeCl2 or FeCl3 and were not influenced by iron chelation. ATP depletion preceded toxicity suggesting impaired cell respiration as putative cause for cell death. In long-term HUVEC cultures inhibition of VCAM-1 expression by rac-1 waned in time, while for the cyclohexanedione derived rac-8 inhibition seems to increase. NFκB was inhibited by both rac-1 and rac-8 independent of IκBα degradation. Both ET-CORMs activated Nrf-2 and consequently induced the expression of HO-1. This study further provides a rational framework for designing acyloxydiene–Fe(CO)3 complexes as ET-CORMs with differential CO release and biological activities. We also provide a better understanding of how these complexes affect cell-biology in mechanistic terms. PMID:25009775

  18. [Ammonia release and binding processes and the activity of acid proteinase and glycolysis enzymes in the dynamics of experimental toxic adrenal encephalopathy].

    PubMed

    Kovalenko, V M; Trapezontseva, R A; Vilkov, G A

    1988-01-01

    The content of ammonium, glutamine, glutamate, aspartate and GABA, glutamine synthetase activity, acid proteinase, hexonase, phosphohexoisomerase and dehydrogenase glucose-6-phosphate were studied in dog brain homogenates after individual injections of Bacillus coli endotoxin (10 micrograms/kg) and adrenaline (75 micrograms/kg) into veins and their combined injections into the carotid artery. Isolated injections of endotoxin and adrenaline were shown to cause transient metabolic compensatory changes. Combined injections caused stable progressing brain metabolic disorders. It is suggested that neurochemical changes influence endogenous development of toxic adrenal encephalopathy. PMID:3276357

  19. [Activity of the sphingomyelin cycle enzymes and concentration of products of sphingomyelin degradation in the rat liver in the course of acute toxic hepatitis].

    PubMed

    Serebrov, V Iu; Kuz'menko, D I; Burov, P G; Sapugol'tseva, O B

    2010-01-01

    Activity of key enzymes of a sphingomyelin cycle and the maintenance of its components (sphingomyelin, ceramide and sphingosine-1-phosphate) have been studied in livers of rats in dynamics of the acute toxic hepatitis caused by hypodermic introduction of an oil solution of CCl4. Sphingomyelinase activity significally increased already on early terms and remained increased over the whole period of observation. Activity of ceramidase insignificantly differed from the control level. The levels of sphingomyelin and sphingosine-1-phosphate did not undergo marked changes while ceramide content significally increased. Thus, balance between liver content of ceramide (proapoptotic) and the sphingosine-1-phosphate, being the antiapoptotic factor, was shifted towards ceramide. In sphingomyelin molecules there was a significant decrease in the content of fatty acids C18: and C22:2, while in ceramide molecules and sphingosine-1-phosphate only fatty acid C22:2 changed. In spite of significant decrease in content of some unsaturated fatty acids, calculated unsaturation coefficients of the fatty acid component of the sphingomyelin cycle metabolites. Thus, our results together with literature data suggests involvement of ceramide-mediated apoptosis in the pathogenesis of acute toxic hepatitis. Elimination of damaged hepatocytes facilitates realization of repair processes and optimization of cellular community of a liver. PMID:21341516

  20. ZnO Nanoparticles Impose a Panmetabolic Toxic Effect Along with Strong Necrosis, Inducing Activation of the Envelope Stress Response in Salmonella enterica Serovar Enteritidis

    PubMed Central

    Vidovic, Sinisa; Elder, Jeff; Medihala, Prabhakara; Lawrence, John R.; Predicala, Bernardo; Zhang, Haixia

    2015-01-01

    In this study, we tested the antimicrobial activity of three metal nanoparticles (NPs), ZnO, MgO, and CaO NPs, against Salmonella enterica serovar Enteritidis in liquid medium and on solid surfaces. Out of the three tested metal NPs, ZnO NPs exhibited the most significant antimicrobial effect both in liquid medium and when embedded on solid surfaces. Therefore, we focused on revealing the mechanisms of surface-associated ZnO biocidal activity. Using the global proteome approach, we report that a great majority (79%) of the altered proteins in biofilms formed by Salmonella enterica serovar Enteritidis were downregulated, whereas a much smaller fraction (21%) of proteins were upregulated. Intriguingly, all downregulated proteins were enzymes involved in a wide range of the central metabolic pathways, including translation; amino acid biosynthetic pathways; nucleobase, nucleoside, and nucleotide biosynthetic processes; ATP synthesis-coupled proton transport; the pentose phosphate shunt; and carboxylic acid metabolic processes, indicating that ZnO NPs exert a panmetabolic toxic effect on this prokaryotic organism. In addition to their panmetabolic toxicity, ZnO NPs induced profound changes in cell envelope morphology, imposing additional necrotic effects and triggering the envelope stress response of Salmonella serovar Enteritidis. The envelope stress response effect activated periplasmic chaperones and proteases, transenvelope complexes, and regulators, thereby facilitating protection of this prokaryotic organism against ZnO NPs. PMID:25801570

  1. Evaluation of General Toxicity, Anti-Oxidant Activity and Effects of Ficus Carica Leaves Extract on Ischemia/Reperfusion Injuries in Isolated Heart of Rat

    PubMed Central

    Allahyari, Saeideh; Delazar, Abbas; Najafi, Moslem

    2014-01-01

    Purpose: This study was aimed to evaluate general toxicity, anti-oxidant activity and effects of Ficus carica leaves extract on ischemia/reperfusion injuries. Methods: Antioxidant activity, total phenolic and flavonoid compounds of 70% methanolic extract of Ficus carica leaves were measured. The general toxicity test was carried out by brine shrimp lethality assay. Isolated hearts of male rats were mounted on a Langendorff apparatus and perfused with modified Krebs-Henseleit solution. In control group, the hearts were perfused with normal Krebs solution, however, treatment groups received enriched solution with the extract (0.04, 0.2 and 1 mg/ml) during stabilization and reperfusion (after 30 min global ischemia), respectively. Cardiac arrhythmias were analyzed and TTC method was used for infarct size determination. Results: The extract displayed antioxidant activity in the DPPH assay (RC50=0.06666 mg/ml). Total phenolic content was 12.29 mg GAE/100 g dry sample and the amount of flavonoids was calculated 40.729 mg/g. LD50 value by brine shrimp test was 0.158 mg/ml. The extract decreased number of VEBs, incidence and duration of Rev VF with clear reduction in infarct size and infarct volume (P<0.001). Conclusion: Ficus carica decreased ischemia/reperfusion-induced injuries. These protections are probably due to antioxidant capacity and the existence of flavonoid and phenolic compounds in the extract. PMID:25671192

  2. ZnO nanoparticles impose a panmetabolic toxic effect along with strong necrosis, inducing activation of the envelope stress response in Salmonella enterica serovar Enteritidis.

    PubMed

    Vidovic, Sinisa; Elder, Jeff; Medihala, Prabhakara; Lawrence, John R; Predicala, Bernardo; Zhang, Haixia; Korber, Darren R

    2015-01-01

    In this study, we tested the antimicrobial activity of three metal nanoparticles (NPs), ZnO, MgO, and CaO NPs, against Salmonella enterica serovar Enteritidis in liquid medium and on solid surfaces. Out of the three tested metal NPs, ZnO NPs exhibited the most significant antimicrobial effect both in liquid medium and when embedded on solid surfaces. Therefore, we focused on revealing the mechanisms of surface-associated ZnO biocidal activity. Using the global proteome approach, we report that a great majority (79%) of the altered proteins in biofilms formed by Salmonella enterica serovar Enteritidis were downregulated, whereas a much smaller fraction (21%) of proteins were upregulated. Intriguingly, all downregulated proteins were enzymes involved in a wide range of the central metabolic pathways, including translation; amino acid biosynthetic pathways; nucleobase, nucleoside, and nucleotide biosynthetic processes; ATP synthesis-coupled proton transport; the pentose phosphate shunt; and carboxylic acid metabolic processes, indicating that ZnO NPs exert a panmetabolic toxic effect on this prokaryotic organism. In addition to their panmetabolic toxicity, ZnO NPs induced profound changes in cell envelope morphology, imposing additional necrotic effects and triggering the envelope stress response of Salmonella serovar Enteritidis. The envelope stress response effect activated periplasmic chaperones and proteases, transenvelope complexes, and regulators, thereby facilitating protection of this prokaryotic organism against ZnO NPs. PMID:25801570

  3. A large-scale chemical modification screen identifies design rules to generate siRNAs with high activity, high stability and low toxicity

    PubMed Central

    Bramsen, Jesper B.; Laursen, Maria B.; Nielsen, Anne F.; Hansen, Thomas B.; Bus, Claus; Langkjær, Niels; Babu, B. Ravindra; Højland, Torben; Abramov, Mikhail; Van Aerschot, Arthur; Odadzic, Dalibor; Smicius, Romualdas; Haas, Jens; Andree, Cordula; Barman, Jharna; Wenska, Malgorzata; Srivastava, Puneet; Zhou, Chuanzheng; Honcharenko, Dmytro; Hess, Simone; Müller, Elke; Bobkov, Georgii V.; Mikhailov, Sergey N.; Fava, Eugenio; Meyer, Thomas F.; Chattopadhyaya, Jyoti; Zerial, Marino; Engels, Joachim W.; Herdewijn, Piet; Wengel, Jesper; Kjems, Jørgen

    2009-01-01

    The use of chemically synthesized short interfering RNAs (siRNAs) is currently the method of choice to manipulate gene expression in mammalian cell culture, yet improvements of siRNA design is expectably required for successful application in vivo. Several studies have aimed at improving siRNA performance through the introduction of chemical modifications but a direct comparison of these results is difficult. We have directly compared the effect of 21 types of chemical modifications on siRNA activity and toxicity in a total of 2160 siRNA duplexes. We demonstrate that siRNA activity is primarily enhanced by favouring the incorporation of the intended antisense strand during RNA-induced silencing complex (RISC) loading by modulation of siRNA thermodynamic asymmetry and engineering of siRNA 3′-overhangs. Collectively, our results provide unique insights into the tolerance for chemical modifications and provide a simple guide to successful chemical modification of siRNAs with improved activity, stability and low toxicity. PMID:19282453

  4. Toxic remediation

    DOEpatents

    Matthews, Stephen M.; Schonberg, Russell G.; Fadness, David R.

    1994-01-01

    What is disclosed is a novel toxic waste remediation system designed to provide on-site destruction of a wide variety of hazardous organic volatile hydrocarbons, including but not limited to halogenated and aromatic hydrocarbons in the vapor phase. This invention utilizes a detoxification plenum and radiation treatment which transforms hazardous organic compounds into non-hazardous substances.

  5. Toxic effects of mercury on PSI and PSII activities, membrane potential and transthylakoid proton gradient in Microsorium pteropus.

    PubMed

    Deng, Chunnuan; Zhang, Daoyong; Pan, Xiangliang; Chang, Fengqin; Wang, Shuzhi

    2013-10-01

    Mercury (Hg) is one of the top toxic metals in environment and it poses a great risk to organisms. This study aimed to elucidate the toxic effects of Hg(2+) on energy conversion of photosystem I (PSI) and photosystem II (PSII), membrane potential and proton gradient of Microsorium pteropus (an aquatic plant species). Contents of chlorophyll a, chlorophyll b and carotenoids, quantum yield and electron transfer of PSI and PSII of M. pteropus exposed to various concentrations of Hg(2+) were measured. With increasing Hg(2+) concentration, quantum yield and electron transport of PSI [Y(I) and ETR(I)] and PSII [Y(II) and ETR(II)] decreased whereas limitation of donor side of PSI [Y(ND)] increased. At ⩾165μgL(-1) Hg(2+), quantum yield of non-light-induced non-photochemical fluorescence quenching in PSII [Y(NO)] significantly increased but quantum yield of light-induced non-photochemical fluorescence quenching [Y(NPQ)] decreased. Membrane potential (Δψ) and proton gradient (ΔpH) of M. pteropus were reduced significantly at 330μg L(-1) Hg(2+) compared to control. Mercury exposure affected multiple sites in PSII and PSI of M. pteropus. PMID:23920143

  6. An evaluation of fish early life stage tests for predicting reproductive and longer-term toxicity from plant protection product active substances.

    PubMed

    Wheeler, James R; Maynard, Samuel K; Crane, Mark

    2014-08-01

    The chronic toxicity of chemicals to fish is routinely assessed by using fish early life stage (ELS) test results. Fish full life cycle (FLC) tests are generally required only when toxicity, bioaccumulation, and persistence triggers are met or when there is a suspicion of potential endocrine-disrupting properties. This regulatory approach is based on a relationship between the results of fish ELS and FLC studies first established more than 35 yrs ago. Recently, this relationship has been challenged by some regulatory authorities, and it has been recommended that more substances should undergo FLC testing. In addition, a project proposal has been submitted to the Organisation for Economic Cooperation and Development (OECD) to develop a fish partial life cycle (PLC) test including a reproductive assessment. Both FLC and PLC tests are animal- and resource-intensive and technically challenging and should therefore be undertaken only if there is clear evidence that they are necessary for coming to a regulatory decision. The present study reports on an analysis of a database of paired fish ELS and FLC endpoints for plant protection product active substances from European Union draft assessment reports and the US Environmental Protection Agency Office of Pesticide Programs Pesticide Ecotoxicity Database. Analysis of this database shows a clear relationship between ELS and FLC responses, with similar median sensitivity across substances when no-observed-effect concentrations (NOECs) are compared. There was also no indication that classification of a substance as a mammalian reproductive toxicant leads to more sensitive effects in fish FLC tests than in ELS tests. Indeed, the response of the ELS tests was generally more sensitive than the most sensitive reproduction NOEC from a FLC test. This analysis indicates that current testing strategies and guidelines are fit for purpose and that there is no need for fish full or partial life cycle tests for most plant protection

  7. Thunbergia laurifolia extract minimizes the adverse effects of toxicants by regulating P-glycoprotein activity, CYP450, and lipid metabolism gene expression in HepG2 cells.

    PubMed

    Rocejanasaroj, A; Tencomnao, T; Sangkitikomol, W

    2014-01-01

    Thunbergia laurifolia (TL) is widely used as an antidote in Thai traditional medicine against toxic substances such as alcohol, pesticides, arsenic, and strychnine. We found that the lyophilized form of TL in 80% ethanol possessed the antioxidant levels within the range 23,163.9 ± 1457.4 Trolox equivalents mM/kg dry mass and 899.8 ± 14.5 gallic acid equivalents mM/kg dry mass using the oxygen radical absorbance capacity assay and the Folin Ciocalteu phenol assay, respectively. TL extract (TLE) at a high dose (3000 mg/L) induced cytotoxicity according to the neutral red assay and the MTT assay. However, TLE doses of 800-3000 mg/L could reduce intracellular oxidative stress in a dose-dependent manner (P < 0.05) using the dichlorodihydrofluorescein diacetate assay. TLE significantly enhanced the mRNA expression of CYP1A1, CYP1A2, CYP2B6, CYP3A4, and PPARg, but it significantly inhibited the mRNA expression of CYP3A7, CYP2D6, and CYP2E1 (P < 0.05) by reverse transcription-polymerase chain reaction. Moreover, TLE could increase the activity of a multidrug transporter, P-glycoprotein, which accelerated the excretion of toxic substances from HepG2 cells. It is suggested that TLE may be beneficial for detoxification by reducing oxidative stress, minimizing toxicity by regulating the expression CYP450 mRNAs for suitable production of CYP450 isoenzymes, and increasing PPARγ mRNA expression and P-glycoprotein activity in HepG2 cells, thereby maintaining xenobiotic biotransformation balance. PMID:24446304

  8. Efficacy of attractive toxic sugar baits (ATSB) against Aedes albopictus with garlic oil encapsulated in beta-cyclodextrin as the active ingredient

    PubMed Central

    Junnila, Amy; Revay, Edita E.; Müller, Gunter C.; Kravchenko, Vasiliy; Qualls, Whitney A.; Xue, Rui-de; Allen, Sandra A.; Beier, John C.; Schlein, Yosef

    2016-01-01

    We tested the efficacy of attractive toxic sugar bait (ATSB) with garlic oil microencapsulated in beta-cyclodextrin as active ingredient against Aedes albopictus in suburban Haifa, Israel. Two three-acre gardens with high numbers of Ae. albopictus were selected for perimeter spray treatment with ATSB and ASB (bait containing no active ingredient). Baits were colored with food dye to verify feeding of the mosquitoes. The mosquito population was monitored by human landing catches and sweep net catches in the surrounding vegetation. Experiments lasted for 44 days. Treatment occurred on day 13. The mosquito population collapsed about 4 days after treatment and continued to drop steadily for 27 days until the end of the study. At the experimental site the average pre-treatment landing rate was 17.2 per 5 mins. Two days post-treatment, the landing rate dropped to 11.4, and continued to drop to an average of 2.6 during the following 26 days. During the same period, the control population was stable. Few sugar fed females (8–10%) approached a human bait and anthrone tests showed relatively small amounts of sugar within their crop/gut. Around 60–70 % of males caught near our human bait were sugar positive which may indicate that the males were feeding on sugar for mating related behavior. From the vegetation treated with the toxic bait, we recovered significantly fewer (about 10–14%) males and females stained by ATSB than at the ASB-treated control. This may indicate that the toxic baits alter the resting behavior of the poisoned mosquitoes within the vegetation. Almost no Ae. albopictus females (5.2 ± 1.4) approached human bait after treatment with ATSB. It therefore appears that microencapsulated garlic oil is an effective pesticide against Ae. albopictus when used in an ATSB system. PMID:26403337

  9. Efficacy of attractive toxic sugar baits (ATSB) against Aedes albopictus with garlic oil encapsulated in beta-cyclodextrin as the active ingredient.

    PubMed

    Junnila, Amy; Revay, Edita E; Müller, Gunter C; Kravchenko, Vasiliy; Qualls, Whitney A; Xue, Rui-de; Allen, Sandra A; Beier, John C; Schlein, Yosef

    2015-12-01

    We tested the efficacy of attractive toxic sugar bait (ATSB) with garlic oil microencapsulated in beta-cyclodextrin as active ingredient against Aedes albopictus in suburban Haifa, Israel. Two three-acre gardens with high numbers of Ae. albopictus were selected for perimeter spray treatment with ATSB and ASB (bait containing no active ingredient). Baits were colored with food dye to verify feeding of the mosquitoes. The mosquito population was monitored by human landing catches and sweep net catches in the surrounding vegetation. Experiments lasted for 44 days. Treatment occurred on day 13. The mosquito population collapsed about 4 days after treatment and continued to drop steadily for 27 days until the end of the study. At the experimental site the average pre-treatment landing rate was 17.2 per 5mins. Two days post-treatment, the landing rate dropped to 11.4, and continued to drop to an average of 2.6 during the following 26 days. During the same period, the control population was stable. Few sugar fed females (8-10%) approached a human bait and anthrone tests showed relatively small amounts of sugar within their crop/gut. Around 60-70 % of males caught near our human bait were sugar positive which may indicate that the males were feeding on sugar for mating related behavior. From the vegetation treated with the toxic bait, we recovered significantly fewer (about 10-14%) males and females stained by ATSB than at the ASB-treated control. This may indicate that the toxic baits alter the resting behavior of the poisoned mosquitoes within the vegetation. Almost no Ae. albopictus females (5.2±1.4) approached human bait after treatment with ATSB. It therefore appears that microencapsulated garlic oil is an effective pesticide against Ae. albopictus when used in an ATSB system. PMID:26403337

  10. BEHAVIORAL TOXICITY OF TRIALKYLTIN COMPOUNDS: A REVIEW

    EPA Science Inventory

    Triethyltin (TET) and trimethyltin (TMT) are neurotoxic organotin compounds which produce different patterns of toxicity in adult animals. Exposure to TET produces behavioral toxicity (decreased motor activity, grip strength, operant response rate and startle response amplitude) ...

  11. Dual effects of N-acetyl-L-cysteine dependent on NQO1 activity: Suppressive or promotive of 9,10-phenanthrenequinone-induced toxicity

    SciTech Connect

    Toyooka, Tatsushi; Shinmen, Takuya; Aarts, Jac M.M.J.G.; Ibuki, Yuko

    2012-11-01

    A typical antioxidant, N-acetyl-L-cysteine (NAC) generally protects cells from oxidative damage induced by reactive oxygen species (ROS). 9,10-Phenanthrenequinone (9,10-PQ), a major quinone in diesel exhaust particles, produces ROS in redox cycling following two-electron reduction by NAD(P)H:quinone oxidoreductase 1 (NQO1), which has been considered as a cause of its cyto- and genotoxicity. In this study, we show that NAC unexpectedly augments the toxicity of 9,10-PQ in cells with low NQO1 activity. In four human skin cell lines, the expression and the activity of NQO1 were lower than in human adenocarcinoma cell lines, A549 and MCF7. In the skin cells, the cytotoxicity of 9,10-PQ was significantly enhanced by addition of NAC. The formation of DNA double strand breaks accompanying phosphorylation of histone H2AX, was also remarkably augmented. On the other hand, the cyto- and genotoxicity were suppressed by addition of NAC in the adenocarcinoma cells. Two contrasting experiments: overexpression of NQO1 in CHO-K1 cells which originally expressed low NQO1 levels, and knock‐down of NQO1 in the adenocarcinoma cell line A549 by transfection of RNAi, also showed that NAC suppressed 9,10-PQ-induced toxicity in cell lines expressing high NQO1 activity and enhanced it in cell lines with low NQO1 activity. The results suggested that dual effects of NAC on the cyto- and genotoxicity of 9,10-PQ were dependent on tissue-specific NQO1 activity. -- Highlights: ► NAC augmented the cytotoxicity of 9,10-PQ in skin cell lines. ► 9,10-PQ-induced DSBs accompanying γ-H2AX were also augmented by NAC. ► NAC suppressed the cyto- and genotoxicity of 9,10-PQ in adenocarcinoma cell lines. ► The dual effects of NAC on toxicity of 9,10-PQ were dependent on NQO1 activity.

  12. Toxic Substances in the Environment.

    ERIC Educational Resources Information Center

    Clearing: Nature and Learning in the Pacific Northwest, 1984

    1984-01-01

    Discusses the nature of toxic substances, examining pesticides and herbicides, heavy metals, industrial chemicals, and household substances. Includes a list of major toxic substances (indicating what they are, where they are found, and health concerns) and a student activity on how pesticides enter the food chain. (JN)