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  Subjects -> ENVIRONMENTAL STUDIES (Total: 755 journals)
    - ENVIRONMENTAL STUDIES (690 journals)
    - POLLUTION (22 journals)
    - TOXICOLOGY AND ENVIRONMENTAL SAFETY (34 journals)
    - WASTE MANAGEMENT (9 journals)

ENVIRONMENTAL STUDIES (690 journals)            First | 1 2 3 4 5 6 7     

Membranes     Open Access   (4 followers)
Midwest Studies In Philosophy     Hybrid Journal   (11 followers)
Mine Water and the Environment     Hybrid Journal   (6 followers)
Mitigation and Adaptation Strategies for Global Change     Hybrid Journal   (12 followers)
Modern Asian Studies     Hybrid Journal   (4 followers)
Modern Cartography Series     Full-text available via subscription   (6 followers)
Mountain Research and Development     Open Access   (3 followers)
Multequina     Open Access  
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis     Hybrid Journal   (2 followers)
Mutation Research/Genetic Toxicology and Environmental Mutagenesis     Hybrid Journal   (7 followers)
Natur und Recht     Hybrid Journal   (5 followers)
Natural Areas Journal     Full-text available via subscription   (7 followers)
Natural Hazards     Hybrid Journal   (97 followers)
Natural Resources     Open Access  
Natural Resources and Environmental Issues     Open Access   (5 followers)
Nature and Culture     Full-text available via subscription   (9 followers)
NeuroToxicology     Hybrid Journal   (1 follower)
Neurotoxicology and Teratology     Hybrid Journal   (2 followers)
NEW SOLUTIONS: A Journal of Environmental and Occupational Health Policy     Full-text available via subscription   (6 followers)
New Zealand Journal of Environmental Law     Full-text available via subscription   (2 followers)
NJAS - Wageningen Journal of Life Sciences     Full-text available via subscription   (1 follower)
Noise Notes     Full-text available via subscription   (3 followers)
Observatorio Medioambiental     Open Access  
Occupational and Environmental Medicine     Full-text available via subscription   (8 followers)
Ocean Acidification     Open Access  
Oecologia     Hybrid Journal   (24 followers)
Oikos     Hybrid Journal   (26 followers)
Open Journal of Ecology     Open Access   (10 followers)
Open Journal of Marine Science     Open Access   (6 followers)
Open Journal of Modern Hydrology     Open Access   (1 follower)
Our Nature     Open Access   (2 followers)
Oxford Journal of Legal Studies     Hybrid Journal   (14 followers)
Pace Environmental Law Review     Open Access   (4 followers)
Packaging, Transport, Storage and Security of Radioactive Material     Hybrid Journal   (2 followers)
Palaeobiodiversity and Palaeoenvironments     Hybrid Journal   (3 followers)
Papers on Global Change IGBP     Open Access   (1 follower)
Particle and Fibre Toxicology     Open Access   (3 followers)
Pastos y Forrajes     Open Access  
Pesquisa em Educação Ambiental     Open Access  
Pharmacology & Therapeutics     Hybrid Journal   (5 followers)
Pharmacology Biochemistry and Behavior     Hybrid Journal   (1 follower)
Philosophical Studies     Hybrid Journal   (6 followers)
Physio-Géo     Open Access   (2 followers)
Pittsburgh Journal of Environmental and Public Health Law     Open Access   (1 follower)
Planet     Open Access  
Planning & Environmental Law: Issues and decisions that impact the built and natural environments     Hybrid Journal   (5 followers)
Plant Ecology & Diversity     Partially Free   (9 followers)
Plant Knowledge Journal     Open Access   (2 followers)
Plant, Cell & Environment     Hybrid Journal   (4 followers)
Polar Journal     Hybrid Journal   (1 follower)
Policy Studies     Hybrid Journal   (6 followers)
Policy Studies Journal     Hybrid Journal   (5 followers)
Polish Polar Research     Open Access   (4 followers)
Political Studies     Hybrid Journal   (21 followers)
Political Studies Review     Hybrid Journal   (14 followers)
Population and Environment     Hybrid Journal   (6 followers)
Population Ecology     Hybrid Journal   (9 followers)
Population Studies: A Journal of Demography     Hybrid Journal   (4 followers)
Postcolonial Studies     Hybrid Journal   (5 followers)
Practice Periodical of Hazardous, Toxic, and Radioactive Waste Management     Full-text available via subscription   (3 followers)
Presence Teleoperators & Virtual Environments     Hybrid Journal   (1 follower)
Presidential Studies Quarterly     Hybrid Journal   (3 followers)
Procedia Environmental Sciences     Open Access   (2 followers)
Proceedings of ICE, Waste and Resource Management     Hybrid Journal   (3 followers)
Proceedings of the Institution of Mechanical Engineers Part M: Journal of Engineering for the Maritime Environment     Hybrid Journal   (1 follower)
Proceedings of the International Academy of Ecology and Environmental Sciences     Open Access   (4 followers)
Process Safety and Environmental Protection     Hybrid Journal   (3 followers)
Progress in Industrial Ecology, An International Journal     Hybrid Journal   (4 followers)
Psychological Assessment     Full-text available via subscription   (5 followers)
Public Money & Management     Hybrid Journal   (4 followers)
Public Works Management & Policy     Hybrid Journal   (5 followers)
Qatar Foundation Annual Research Forum Proceedings     Open Access   (3 followers)
Radioactivity in the Environment     Full-text available via subscription   (4 followers)
Regional Environmental Change     Hybrid Journal   (3 followers)
Regional Studies     Hybrid Journal   (6 followers)
Religious Studies     Hybrid Journal   (9 followers)
RELP - Renewable Energy Law and Policy     Full-text available via subscription   (4 followers)
Remediation Journal     Hybrid Journal   (5 followers)
Remote Sensing Letters     Hybrid Journal   (8 followers)
Renaissance Studies     Hybrid Journal   (11 followers)
Rendiconti Lincei     Hybrid Journal  
Renewable Energy Focus     Full-text available via subscription   (7 followers)
Research and Practice for Persons with Severe Disabilities     Full-text available via subscription   (3 followers)
Research Journal of Environmental Sciences     Open Access   (1 follower)
Research Journal of Environmental Toxicology     Open Access   (2 followers)
ReSource     Full-text available via subscription  
Resources     Open Access  
Resources, Conservation and Recycling     Hybrid Journal   (9 followers)
Reuse/Recycle Newsletter     Hybrid Journal   (2 followers)
Review of English Studies     Hybrid Journal   (7 followers)
Review of Environmental Economics and Policy     Hybrid Journal   (7 followers)
Revista AIDIS de Ingeniería y Ciencias Ambientales. Investigación, desarrollo y práctica     Open Access   (2 followers)
Revista Brasileira de Engenharia Agrícola e Ambiental     Open Access   (1 follower)
Revista Capital Científico     Open Access  
Revista Chapingo. Serie Ciencias Forestales y del Ambiente     Open Access   (2 followers)
Revista de Ciências Ambientais     Open Access  
Revista de Gestão Ambiental e Sustentabilidade - GeAS     Open Access  
Revista de Salud Ambiental     Open Access  
Revista Eletrônica em Gestão, Educação e Tecnologia Ambiental     Open Access   (1 follower)
Revista Hábitat Sustenable     Open Access   (3 followers)

  First | 1 2 3 4 5 6 7     

Toxicology and Applied Pharmacology    [12 followers]  Follow    
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
     ISSN (Print) 0041-008X - ISSN (Online) 1096-0333
     Published by Elsevier Homepage  [2556 journals]   [SJR: 1.328]   [H-I: 110]
  • Bleomycin-induced epithelial–mesenchymal transition in sclerotic
           skin of mi Possible role of oxidative stress in the pathogenesis
    • Abstract: Publication date: Available online 12 April 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Cheng-Fan Zhou , Deng-Chuan Zhou , Jia-Xiang Zhang , Feng Wang , Wan-Sheng Cha , Chang-Hao Wu , Qi-Xing Zhu
      Epithelial–mesenchymal transition (EMT) derived myofibroblasts are partly responsible for the increased collagen synthesis and deposition that occur in tissue fibrosis; however EMT occurrence in skin fibrosis and its mechanism remain unknown. The aim of this study was to investigate whether epithelial cells undergo EMT and determine the role of oxidative stress in this process. BALB/c mice were subcutaneously injected with bleomycin (BLM) or phosphate buffer saline (PBS) into the shaved back daily for 2, 3, and 4weeks. Skin collagen deposition was evaluated by histopathology and Western blotting. EMT characteristics in the skin were determined by histopathology and immunofluorescent staining for E-cadherin and vimentin, which were further evaluated by Western blotting and reverse transcriptase polymerase chain reaction (RT-PCR). To investigate the role of oxidative stress in EMT, the antioxidant N-acetylcysteine (NAC) was intraperitoneally (100mg/kg body weight/day) injected daily for 3weeks. The epithelial suprabasal cells were detached from the basement membrane zone (BMZ) in the sclerotic skin treated with BLM. Immunofluorescent staining indicated vimentin-positive epithelial cells frequently occurring in the thickened epidermis of BLM-treated mice. Western blotting and RT-PCR showed that the expression of E-cadherin was significantly decreased but that of vimentin significantly increased in the skin treated with BLM. NAC attenuated BLM induced oxidative damage, changes in E-cadherin and vimentin expressions and collagen deposition in the sclerotic skin of mice. This study provides the first evidence that BLM induces the EMT of the epithelial cells superficial to the basement membrane zone in the skin fibrosis. Oxidative stress may contribute, at least in part, to BLM induced EMT and skin fibrosis in mice.


      PubDate: 2014-04-16T16:21:31Z
       
  • Coactivation of the PI3K/Akt and ERK signaling pathways in PCB153-induced
           NF-κB activation and caspase inhibition
    • Abstract: Publication date: Available online 12 April 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Changjiang Liu , Jixin Yang , Wenjuan Fu , Suqin Qi , Chenmin Wang , Chao Quan , Kedi Yang
      Polychlorinated biphenyls (PCBs) are a group of persistent and widely distributed environmental pollutants that have various deleterious effects, e.g., neurotoxicity, endocrine disruption and reproductive abnormalities. In order to verify the hypothesis that the PI3K/Akt and MAPK pathways play important roles in hepatotoxicity induced by PCBs, Sprague–Dawley (SD) rats were dosed with PCB153 intraperitoneally at 0, 4, 16 and 32mg/kg for five consecutive days; BRL cells (rat liver cell line) were treated with PCB153 (0, 1, 5, and 10μM) for 24h. Results indicated that the PI3K/Akt and ERK pathways were activated in vivo and in vitro after exposure to PCB153, and protein levels of phospho-Akt and phospho-ERK were significantly increased. Nuclear factor-κB (NF-κB) activation and caspase-3, -8 and -9 inhibition caused by PCB153 were also observed. Inhibiting the ERK pathway significantly attenuated PCB153-induced NF-κB activation, whereas inhibiting the PI3K/Akt pathway hardly influenced phospho-NF-κB level. However, inhibiting the PI3K/Akt pathway significantly elevated caspase-3, -8 and -9 activities, while the ERK pathway only synergistically regulated caspase-9. Proliferating cell nuclear antigen (PCNA), a reliable indicator of cell proliferation, was also induced. Moreover, PCB153 led to hepatocellular hypertrophy and elevated liver weight. Taken together, PCB153 leads to aberrant proliferation and apoptosis of hepatocytes through NF-κB activation and caspase inhibition, and coactivated PI3K/Akt and ERK pathways play critical roles in PCB153-induced hepatotoxicity.


      PubDate: 2014-04-16T16:21:31Z
       
  • The effect of doxycycline treatment on the postvaccinal immune response in
           pigs
    • Abstract: Publication date: Available online 13 April 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Małgorzata Pomorska-Mól , Krzysztof Kwit , Iwona Markowska-Daniel , Zygmunt Pejsak
      The effect of a seven-day antibiotic therapy with doxycycline was investigated on the postvaccinal humoral and cellular immune response in pigs. The selected parameters of non-specific immunity were also studied. Fifty pigs were used (control not vaccinated (C, n=10), control vaccinated (CV, n=20), and experimental - received doxycycline (DOXY, n=20). For vaccination live-attenuated vaccine against pseudorabies (PR) was used. From day -1 to day 5 pigs from DOXY group received doxycycline orally with drinking water, at the recommended dose. Pigs from DOXY and CV groups were vaccinated at 8 and 10week of age. The results of present study showed that cell-mediated postvaccinal immune response can be modulated by oral treatment with doxycycline. Significantly lower values of stimulation index were observed after PRV restimulation in doxycycline-treated pigs. Moreover, in DOXY group a significant decrease in IFN-γ production after PRV restimulation was noted. The significantly lower number of CD4+CD8+ cells were also observed in doxy-treated, vaccinated pigs, 2weeks after final vaccination. Simultaneously, specific humoral response was not disturbed. This study demonstrated the importance of defining the immune modulatory activity of doxycycline because it may alter the immune responses to vaccines. The exact mechanism of T-cell response suppression by doxycycline remains to be elucidated, however the influence of doxycycline on the secretion of various cytokines, including IFN-γ, may be considered as a possible causes. The present observations should prompt further studies on the practical significance of such phenomena in terms of clinical implications.


      PubDate: 2014-04-16T16:21:31Z
       
  • DNA damage in internal organs after cutaneous exposure to sulphur mustard
    • Abstract: Publication date: Available online 13 April 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Mohamed Batal , Isabelle Boudry , Stéphane Mouret , Cécile Cléry-Barraud , Julien Wartelle , Izabel Bérard , Thierry Douki
      Sulphur mustard (SM) is a chemical warfare agent that attacks mainly skin, eye and lungs. Due to its lipophilic properties, SM is also able to diffuse through the skin and reach internal organs. DNA represents one of the most critical molecular targets of this powerful alkylating agent which modifies DNA structure by forming monoadducts and biadducts. These DNA lesions are involved in the acute toxicity of SM as well as its long-term carcinogenicity. In the present work we studied the formation and persistence of guanine and adenine monoadducts and guanine biadducts in the DNA of brain, lungs, kidneys, spleen, and liver of SKH-1 mice cutaneously exposed to 2, 6 and 60mg/kg of SM. SM-DNA adducts were detected in all studied organs, except in liver at the two lowest doses. Brain and lungs were the organs with the highest level of SM-DNA adducts, followed by kidney, spleen and liver. Monitoring the level of adducts for three weeks after cutaneous exposure showed that the lifetime of adducts were not the same in all organs, lungs being the organ with the longest persistence. Diffusion from skin to internal organs was much more efficient at the highest compared to the lowest dose investigated as the result of the loss of the skin barrier function. These data provide novel information on the distribution of SM in tissues following cutaneous exposures and indicate that brain is an important target.
      Graphical abstract image

      PubDate: 2014-04-16T16:21:31Z
       
  • Fetal bovine serum and human constitutive androstane receptor: Evidence
           for activation of the SV23 splice variant by artemisinin, artemether, and
           arteether in a serum-free cell culture system
    • Abstract: Publication date: Available online 12 April 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Aik Jiang Lau , Thomas K.H. Chang
      The naturally occurring SV23 splice variant of human constitutive androstane receptor (hCAR-SV23) is activated by di-(2-ethylhexyl)phthalate (DEHP), which is detected as a contaminant in fetal bovine serum (FBS). In our initial experiment, we compared the effect of dialyzed FBS, charcoal-stripped, dextran-treated FBS (CS-FBS), and regular FBS on the basal activity and ligand-activation of hCAR-SV23 in a cell-based reporter gene assay. In transfected HepG2 cells cultured in medium supplemented with 10% FBS, basal hCAR-SV23 activity varied with the type of FBS (regular>dialyzed>CS). DEHP increased hCAR-SV23 activity when 10% CS-FBS, but not regular FBS or dialyzed FBS, was used. With increasing concentrations (1–10%) of regular FBS or CS-FBS, hCAR-SV23 basal activity increased, whereas in DEHP-treated cells, hCAR-SV23 activity remained similar (regular FBS) or slightly increased (CS-FBS). Subsequent experiments identified a serum-free culture condition to detect DEHP activation of hCAR-SV23. Under this condition, artemisinin, artemether, and arteether increased hCAR-SV23 activity, whereas they decreased it in cells cultured in medium supplemented with 10% regular FBS. By comparison, FBS increased the basal activity of the wild-type isoform of hCAR (hCAR-WT), whereas it did not affect the basal activity of the SV24 splice variant (hCAR-SV24) or ligand activation of hCAR-SV24 and hCAR-WT by 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO). The use of serum-free culture condition was suitable for detecting CITCO activation of hCAR-WT and hCAR-SV24. In conclusion, FBS leads to erroneous classification of pharmacological ligands of hCAR-SV23 in cell-based assays, but investigations on functional ligands of hCAR isoforms can be conducted in serum-free culture condition.


      PubDate: 2014-04-16T16:21:31Z
       
  • Zinc oxide nanoparticles induce migration and adhesion of monocytes to
           endothelial cells and accelerate foam cell formation
    • Abstract: Publication date: Available online 16 April 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Yuka Suzuki , Saeko Tada-Oikawa , Gaku Ichihara , Masayuki Yabata , Kiyora Izuoka , Masako Suzuki , Kiyoshi Sakai , Sahoko Ichihara
      Metal oxide nanoparticles are widely used in industry, cosmetics, and biomedicine. However, the effects of exposure to these nanoparticles on the cardiovascular system remain unknown. The present study investigated the effects of nanosized TiO2 and ZnO particles on the migration and adhesion of monocytes, which are essential processes in atherosclerogenesis, using an in vitro set-up of human umbilical vein endothelial cells (HUVECs) and human monocytic leukemia cells (THP-1). We also examined the effects of exposure to nanosized metal oxide particles on macrophage cholesterol uptake and foam cell formation. The 16-hour exposure to ZnO particles increased the level of monocyte chemotactic protein-1 (MCP-1) and induced migration of THP-1 monocyte mediated by increased MCP-1. Exposure to ZnO particles also induced adhesion of THP-1 cells to HUVECs. Moreover, exposure to ZnO particles, but not TiO2 particles, upregulated the expression of membrane scavenger receptors of modified LDL and increased cholesterol uptake in THP-1 monocytes/macrophages. In the present study, we found that exposure to ZnO particles increased macrophage cholesterol uptake, which was mediated by upregulation of membrane scavenger receptors of modified LDL. These results suggest that nanosized ZnO particles could potentially enhance atherosclerogenesis and accelerate foam cell formation.


      PubDate: 2014-04-16T16:21:31Z
       
  • Exploring the potential role of tungsten carbide cobalt (WC-Co)
           nanoparticle internalization in observed toxicity toward lung epithelial
           cells in vitro
    • Abstract: Publication date: Available online 16 April 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Andrea L. Armstead , Christopher B. Arena , Bingyun Li
      Tungsten carbide cobalt (WC-Co) has been recognized as a workplace inhalation hazard in the manufacturing, mining and drilling industries by the National Institute of Occupational Safety and Health. Exposure to WC-Co is known to cause “hard metal lung disease” but the relationship between exposure, toxicity and development of disease remain poorly understood. To better understand this relationship, the present study examined the role of WC-Co particle size and internalization on toxicity using lung epithelial cells. We demonstrated that nano- and micro-WC-Co particles exerted toxicity in a dose- and time-dependent manner and that nano-WC-Co particles caused significantly greater toxicity at lower concentrations and shorter exposure times compared to micro-WC-Co particles. WC-Co particles in the nano-size range (not micron-sized) were internalized by lung epithelial cells, which suggested that internalization may play a key role in the enhanced toxicity of nano-WC-Co particles over micro-WC-Co particles. Further exploration of the internalization process indicated that there may be multiple mechanisms involved in WC-Co internalization such as actin and microtubule based cytoskeletal rearrangements. These findings support our hypothesis that WC-Co particle internalization contributes to cellular toxicity and suggests that therapeutic treatments inhibiting particle internalization may serve as prophylactic approaches for those at risk of WC-Co particle exposure.


      PubDate: 2014-04-16T16:21:31Z
       
  • Involvement of a volatile metabolite during phosphoramide mustard-induced
           ovotoxicity
    • Abstract: Publication date: 15 May 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 1
      Author(s): Jill A. Madden , Patricia B. Hoyer , Patrick J. Devine , Aileen F. Keating
      The finite ovarian follicle reserve can be negatively impacted by exposure to chemicals including the anti-neoplastic agent, cyclophosphamide (CPA). CPA requires bioactivation to phosphoramide mustard (PM) to elicit its therapeutic effects however; in addition to being the tumor-targeting metabolite, PM is also ovotoxic. In addition, PM can break down to a cytotoxic, volatile metabolite, chloroethylaziridine (CEZ). The aim of this study was initially to characterize PM-induced ovotoxicity in growing follicles. Using PND4 Fisher 344 rats, ovaries were cultured for 4days before being exposed once to PM (10 or 30μM). Following eight additional days in culture, relative to control (1% DMSO), PM had no impact on primordial, small primary or large primary follicle number, but both PM concentrations induced secondary follicle depletion (P <0.05). Interestingly, a reduction in follicle number in the control-treated ovaries was observed. Thus, the involvement of a volatile, cytotoxic PM metabolite (VC) in PM-induced ovotoxicity was explored in cultured rat ovaries, with control ovaries physically separated from PM-treated ovaries during culture. Direct PM (60μM) exposure destroyed all stage follicles after 4days (P <0.05). VC from nearby wells depleted primordial follicles after 4days (P <0.05), temporarily reduced secondary follicle number after 2days, and did not impact other stage follicles at any other time point. VC was determined to spontaneously liberate from PM, which could contribute to degradation of PM during storage. Taken together, this study demonstrates that PM and VC are ovotoxicants, with different follicular targets, and that the VC may be a major player during PM-induced ovotoxicity observed in cancer survivors.


      PubDate: 2014-04-16T16:21:31Z
       
  • Short-term effects of electronic and tobacco cigarettes on exhaled nitric
           oxide
    • Abstract: Publication date: Available online 13 April 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Sara Marini , Giorgio Buonanno , Luca Stabile , Giorgio Ficco
      The objective of this study was to compare the short-term respiratory effects due to the inhalation of electronic and conventional tobacco cigarette-generated mainstream aerosols through the measurement of the exhaled nitric oxide (eNO). To this purpose, twenty-five smokers were asked to smoke a conventional cigarette and to vape an electronic cigarette (with and without nicotine), and an electronic cigarette without liquid (control session). Electronic and tobacco cigarette mainstream aerosols were characterized in terms of total particle number concentrations and size distributions. On the basis of the measured total particle number concentrations and size distributions, the average particle doses deposited in alveolar and tracheobronchial regions of the lungs for a single 2-s puff were also estimated considering a subject performing resting (sitting) activity. Total particle number concentrations in the mainstream resulted equal to 3.5±0.4×109, 5.1±0.1×109, and 3.1±0.6×109 part. cm−3 for electronic cigarettes without nicotine, with nicotine, and for conventional cigarettes, respectively. The corresponding alveolar doses for a resting subject were estimated equal to 3.8×1010, 5.2×1010 and 2.3×1010 particles. The mean eNO variations measured after each smoking/vaping session were equal to 3.2ppb, 2.7ppb and 2.8ppb for electronic cigarettes without nicotine, with nicotine, and for conventional cigarettes, respectively; whereas, negligible eNO changes were measured in the control session. Statistical tests performed on eNO data showed statistically significant differences between smoking/vaping sessions and the control session, thus confirming a similar effect on human airways whatever the cigarette smoked/vaped, the nicotine content, and the particle dose received.


      PubDate: 2014-04-16T16:21:31Z
       
  • Availability of human induced pluripotent stem cell-derived cardiomyocytes
           in assessment of drugs potential for QT prolongation
    • Abstract: Publication date: Available online 15 April 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Yumiko Nozaki , Yayoi Honda , Shinji Tsujimoto , Hitoshi Watanabe , Takeshi Kunimatsu , Hitoshi Funabashi
      Field potential duration (FPD) in human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), which can express QT interval in electrocardiogram, is reported to be a useful tool to predict K+ channel and Ca2+ channel blockers effects on QT interval. However, there is no report showing that this technique can be used to predict multichannel blockers potential for QT prolongation. The aim of this study is to show that FPD from MEA (Multielectrode array) of hiPS-CMs can detect QT prolongation induced by multichannel blockers. hiPS-CMs were seeded onto MEA and FPD was measured for 2min every 10min for 30min after drug exposure for the vehicle and each drug concentration. IKr and IKs blockers concentration-dependently prolonged corrected FPD (FPDc), whereas Ca2+ channel blockers concentration-dependently shortened FPDc. Also, the multichannel blockers Amiodarone, Paroxetine, Terfenadine and Citalopram prolonged FPDc in a concentration dependent manner. Finally, the IKr blockers, Terfenadine and Citalopram, which are reported to cause Torsade de Pointes (TdP) in clinical practice, produced early afterdepolarization (EAD). hiPS-CMs using MEA system and FPDc can predict the effects of drug candidates on QT interval. This study also shows that this assay can help detect EAD for drugs with TdP potential.


      PubDate: 2014-04-16T16:21:31Z
       
  • Persistent modification of Nav1.9 following chronic exposure to
           insecticides and pyridostigmine bromide
    • Abstract: Publication date: Available online 13 April 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Thomas J. Nutter , Brian Y. Cooper
      Many veterans of the 1991 Gulf War (GW) returned from that conflict with a widespread chronic pain affecting deep tissues. Recently, we have shown that a 60day exposure to the insecticides permethrin, chlorpyrifos, and pyridostigmine bromide (NTPB) had little influence on nociceptor action potential forming Nav1.8, but increased Kv7 mediated inhibitory currents 8weeks after treatment. Using the same exposure regimen, we used whole cell patch methods to examine whether the influences of NTPB could be observed on Nav1.9 expressed in muscle and vascular nociceptors. During a 60day exposure to NTPB, rats exhibited lowered muscle pain thresholds and increased rest periods, but these measures subsequently returned to normal levels. Eight and 12weeks after treatments ceased, DRG neurons were excised from sensory ganglia. Whole cell patch studies revealed little change in voltage dependent activation and deactivation of Nav1.9, but significant increases in the amplitude of Nav1.9 were observed 8weeks after exposure. Cellular studies, at the 8week delay, revealed that NTPB also significantly prolonged action potential duration and afterhyperpolarization (22° C). Acute application of permethrin (10μM) also increased the amplitude of Nav1.9 in skin, muscle and vascular nociceptors. In conclusion, chronic exposure to Gulf War agents produced long term changes in the amplitude of Nav1.9 expressed in muscle and vascular nociceptors. Reported increases in Kv7 amplitude may have been an adaptive response to increased Nav1.9, and effectively suppressed behavioral pain measures in the post treatment period. Factors that alter the balance between Nav1.9 and Kv7 could release spontaneous discharge and produce chronic deep tissue pain.


      PubDate: 2014-04-16T16:21:31Z
       
  • Herb–drug interaction prediction based on the high specific
           inhibition of andrographolide derivatives towards
           UDP-glucuronosyltransferase (UGT) 2B7
    • Abstract: Publication date: 15 May 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 1
      Author(s): Hai-Ying Ma , Dong-Xue Sun , Yun-Feng Cao , Chun-Zhi Ai , Yan-Qing Qu , Cui-Min Hu , Changtao Jiang , Pei-Pei Dong , Xiao-Yu Sun , Mo Hong , Naoki Tanaka , Frank J. Gonzalez , Xiao-Chi Ma , Zhong-Ze Fang
      Herb–drug interaction strongly limits the clinical application of herbs and drugs, and the inhibition of herbal components towards important drug-metabolizing enzymes (DMEs) has been regarded as one of the most important reasons. The present study aims to investigate the inhibition potential of andrographolide derivatives towards one of the most important phase II DMEs UDP-glucuronosyltransferases (UGTs). Recombinant UGT isoforms (except UGT1A4)-catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction and UGT1A4-catalyzed trifluoperazine (TFP) glucuronidation were employed to firstly screen the andrographolide derivatives' inhibition potential. High specific inhibition of andrographolide derivatives towards UGT2B7 was observed. The inhibition type and parameters (Ki) were determined for the compounds exhibiting strong inhibition capability towards UGT2B7, and human liver microsome (HLMs)-catalyzed zidovudine (AZT) glucuronidation probe reaction was used to furtherly confirm the inhibition behavior. In combination of inhibition parameters (Ki) and in vivo concentration of andrographolide and dehydroandrographolide, the potential in vivo inhibition magnitude was predicted. Additionally, both the in vitro inhibition data and computational modeling results provide important information for the modification of andrographolide derivatives as selective inhibitors of UGT2B7. Taken together, data obtained from the present study indicated the potential herb–drug interaction between Andrographis paniculata and the drugs mainly undergoing UGT2B7-catalyzed metabolic elimination, and the andrographolide derivatives as potential candidates for the selective inhibitors of UGT2B7.
      Graphical abstract image

      PubDate: 2014-04-16T16:21:31Z
       
  • Anti-inflammatory effect of tricin
           4′-O-(threo-β-guaiacylglyceryl) ether, a novel flavonolignan
           
    • Abstract: Publication date: 15 May 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 1
      Author(s): Young-Suk Jung , Dae Hwan Kim , Jae Yeon Hwang , Na Young Yun , Yun-Hee Lee , Sang Bae Han , Bang Yeon Hwang , Moon Soon Lee , Heon-Sang Jeong , Jin Tae Hong
      Although recent study has shown tricin 4′-O-(threo-β-guaiacylglyceryl) ether (TTGE), an isolated compound from Njavara rice, to have the most potent anti-inflammatory effects, the action mechanism has not been fully understood. Here, we examined the effect of TTGE on the inflammation and elucidated the potential mechanism. We demonstrated that TTGE significantly inhibited LPS-induced NO and ROS generation in RAW264.7 cells, which was correlated with the down-regulating effect of TTGE on the iNOS and COX-2 expression via NF-κB and STAT3. TPA-induced ear edema was also efficiently inhibited by the TTGE treatment. TTGE blocked the induction of iNOS and COX-2 through the regulation of NF-κB and STAT3, which could explain the reduced TPA-induced edema symptoms. Moreover, the introduction of ERK inhibitor abrogated the anti-inflammatory effect of TTGE via the recovery of NF-κB and STAT3 signalings. Taken together, these results suggest that TTGE has anti-inflammatory properties through down-regulation of NF-κB and STAT3 pathways.


      PubDate: 2014-04-16T16:21:31Z
       
  • The effect of acetaminophen on the expression of BCRP in trophoblast cells
           impairs the placental barrier to bile acids during maternal cholestasis
    • Abstract: Publication date: 15 May 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 1
      Author(s): Alba G. Blazquez , Oscar Briz , Ester Gonzalez-Sanchez , Maria J. Perez , Carolina I. Ghanem , Jose J.G. Marin
      Acetaminophen is used as first-choice drug for pain relief during pregnancy. Here we have investigated the effect of acetaminophen at subtoxic doses on the expression of ABC export pumps in trophoblast cells and its functional repercussion on the placental barrier during maternal cholestasis. The incubation of human choriocarcinoma cells (JAr, JEG-3 and BeWo) with acetaminophen for 48h resulted in no significant changes in the expression and/or activity of MDR1 and MRPs. In contrast, in JEG-3 cells, BCRP mRNA, protein, and transport activity were reduced. In rat placenta, collected at term, acetaminophen administration for the last three days of pregnancy resulted in enhanced mRNA, but not protein, levels of Mrp1 and Bcrp. In fact, a decrease in Bcrp protein was found. Using in situ perfused rat placenta, a reduction in the Bcrp-dependent fetal-to-maternal bile acid transport after treating the dams with acetaminophen was found. Complete biliary obstruction in pregnant rats induced a significant bile acid accumulation in fetal serum and tissues, which was further enhanced when the mothers were treated with acetaminophen. This drug induced increased ROS production in JEG-3 cells and decreased the total glutathione content in rat placenta. Moreover, the NRF2 pathway was activated in JEG-3 cells as shown by an increase in nuclear NRF2 levels and an up-regulation of NRF2 target genes, NQO1 and HMOX-1, which was not observed in rat placenta. In conclusion, acetaminophen induces in placenta oxidative stress and a down-regulation of BCRP/Bcrp, which may impair the placental barrier to bile acids during maternal cholestasis.
      Graphical abstract image

      PubDate: 2014-04-16T16:21:31Z
       
  • Leptin induces CYP1B1 expression in MCF-7 cells through ligand-independent
           activation of the ERα pathway
    • Abstract: Publication date: 15 May 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 1
      Author(s): Tilak Khanal , Hyung Gyun Kim , Minh Truong Do , Jae Ho Choi , Seong Su Won , Wonku Kang , Young Chul Chung , Tae Cheon Jeong , Hye Gwang Jeong
      Leptin, a hormone with multiple biological actions, is produced predominantly by adipose tissue. Among its functions, leptin can stimulate tumour cell growth. Oestrogen receptor α (ERα), which plays an essential role in breast cancer development, can be transcriptionally activated in a ligand-independent manner. In this study, we investigated the effect of leptin on CYP1B1 expression and its mechanism in breast cancer cells. Leptin induced CYP1B1 protein, messenger RNA expression and promoter activity in ERα-positive MCF-7 cells but not in ERα-negative MDA-MB-231 cells. Additionally, leptin increased 4-hydroxyoestradiol in MCF-7 cells. Also, ERα knockdown by siRNA significantly blocked the induction of CYP1B1 expression by leptin, indicating that leptin induced CYP1B1 expression via an ERα-dependent mechanism. Transient transfection with CYP1B1 deletion promoter constructs revealed that the oestrogen response element (ERE) plays important role in the up-regulation of CYP1B1 by leptin. Furthermore, leptin stimulated phosphorylation of ERα at serine residues 118 and 167 and increased ERE-luciferase activity, indicating that leptin induced CYP1B1 expression by ERα activation. Finally, we found that leptin activated ERK and Akt signalling pathways, which are upstream kinases related to ERα phosphorylation induced by leptin. Taken together, our results indicate that leptin-induced CYP1B1 expression is mediated by ligand-independent activation of the ERα pathway as a result of the activation of ERK and Akt in MCF-7 cells.


      PubDate: 2014-04-16T16:21:31Z
       
  • Generation, characterization and in vivo biological activity of two
           distinct monoclonal anti-PEG IgMs
    • Abstract: Publication date: 15 May 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 1
      Author(s): Yosuke Hashimoto , Taro Shimizu , Yu Mima , Amr S. Abu Lila , Tatsuhiro Ishida , Hiroshi Kiwada
      PEGylation, the attachment of polyethylene glycol (PEG) to nanocarriers and proteins, is a widely accepted approach to improving the in vivo efficacy of the non-PEGylated products. However, both PEGylated liposomes and PEGylated proteins reportedly trigger the production of specific antibodies, mainly IgM, against the PEG moiety, which possibly leads to a reduction in safety and therapeutic efficacy of the PEGylated products. In the present study, two monoclonal anti-PEG IgMs — HIK-M09 via immunization with an intravenous injection of PEGylated liposomes (SLs) and HIK-M11 via immunization with a subcutaneous administration of PEGylated ovalbumin (PEG-OVA) were successfully generated. The generated IgMs showed efficient reactivity to mPEG2000 conjugated to 1,2-distearoyl-sn-glycero-3-phospho-ethanolamine (DSPE), PEGylated liposome (SL) and PEG-OVA. It appears that HIK-M09 recognizes ethoxy (OCH2CH2) repeat units along with a terminal motif of PEG, while HIK-M11 recognizes only ethoxy repeat units of PEG. Such unique properties allow HIK-M09 to bind with dense PEG. In addition, their impact on the in vivo clearance of the PEGylated products was investigated. It was found that the generated ant-PEG IgMs induced a clearance of SL as they were intravenously administered with SL. Interestingly, the HIK-M11, generated by PEG-OVA, induced the clearance of both SL and PEG-OVA, while the HIK-M09, generated by SL, induced the clearance of SL only. We here revealed that the presence of serum anti-PEG IgM and the subsequent binding of anti-PEG IgM to the PEGylated products are not necessarily related to the enhanced clearance of the products. It appears that subsequent complement activation following anti-PEG IgM binding is the most important step in dictating the in vivo fate of PEGylated products. This study may have implications for the design, development and clinical application of PEGylated products and therapeutics.
      Graphical abstract image

      PubDate: 2014-04-16T16:21:31Z
       
  • Monomethylarsonous acid inhibited endogenous cholesterol biosynthesis in
           human skin fibroblasts
    • Abstract: Publication date: 15 May 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 1
      Author(s): Lei Guo , Yongsheng Xiao , Yinsheng Wang
      Human exposure to arsenic in drinking water is a widespread public health concern, and such exposure is known to be associated with many human diseases. The detailed molecular mechanisms about how arsenic species contribute to the adverse human health effects, however, remain incompletely understood. Monomethylarsonous acid [MMA(III)] is a highly toxic and stable metabolite of inorganic arsenic. To exploit the mechanisms through which MMA(III) exerts its cytotoxic effect, we adopted a quantitative proteomic approach, by coupling stable isotope labeling by amino acids in cell culture (SILAC) with LC-MS/MS analysis, to examine the variation in the entire proteome of GM00637 human skin fibroblasts following acute MMA(III) exposure. Among the ~6500 unique proteins quantified, ~300 displayed significant changes in expression after exposure with 2μM MMA(III) for 24h. Subsequent analysis revealed the perturbation of de novo cholesterol biosynthesis, selenoprotein synthesis and Nrf2 pathways evoked by MMA(III) exposure. Particularly, MMA(III) treatment resulted in considerable down-regulation of several enzymes involved in cholesterol biosynthesis. In addition, real-time PCR analysis showed reduced mRNA levels of select genes in this pathway. Furthermore, MMA(III) exposure contributed to a distinct decline in cellular cholesterol content and significant growth inhibition of multiple cell lines, both of which could be restored by supplementation of cholesterol to the culture media. Collectively, the present study demonstrated that the cytotoxicity of MMA(III) may arise, at least in part, from the down-regulation of cholesterol biosynthesis enzymes and the resultant decrease of cellular cholesterol content.


      PubDate: 2014-04-16T16:21:31Z
       
  • Naringin ameliorates gentamicin-induced nephrotoxicity and associated
           mitochondrial dysfunction, apoptosis and inflammation in rats: Possible
           mechanism of nephroprotection
    • Abstract: Publication date: 15 May 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 1
      Author(s): Bidya Dhar Sahu , Srujana Tatireddy , Meghana Koneru , Roshan M. Borkar , Jerald Mahesh Kumar , Madhusudana Kuncha , Srinivas R. , Shyam Sunder R. , Ramakrishna Sistla
      Gentamicin-induced nephrotoxicity has been well documented, although its underlying mechanisms and preventive strategies remain to be investigated. The present study was designed to investigate the protective effect of naringin, a bioflavonoid, on gentamicin-induced nephrotoxicity and to elucidate the potential mechanism. Serum specific renal function parameters (blood urea nitrogen and creatinine) and histopathology of kidney tissues were evaluated to assess the gentamicin-induced nephrotoxicity. Renal oxidative stress (lipid peroxidation, protein carbonylation, enzymatic and non-enzymatic antioxidants), inflammatory (NF-kB [p65], TNF-α, IL-6 and MPO) and apoptotic (caspase 3, caspase 9, Bax, Bcl-2, p53 and DNA fragmentation) markers were also evaluated. Significant decrease in mitochondrial NADH dehydrogenase, succinate dehydrogenase, cytochrome c oxidase and mitochondrial redox activity indicated the gentamicin-induced mitochondrial dysfunction. Naringin (100mg/kg) treatment along with gentamicin restored the mitochondrial function and increased the renal endogenous antioxidant status. Gentamicin induced increased renal inflammatory cytokines (TNF-α and IL-6), nuclear protein expression of NF-κB (p65) and NF-κB-DNA binding activity and myeloperoxidase (MPO) activity were significantly decreased upon naringin treatment. In addition, naringin treatment significantly decreased the amount of cleaved caspase 3, Bax, and p53 protein expression and increased the Bcl-2 protein expression. Naringin treatment also ameliorated the extent of histologic injury and reduced inflammatory infiltration in renal tubules. U-HPLS-MS data revealed that naringin co-administration along with gentamicin did not alter the renal uptake and/or accumulation of gentamicin in kidney tissues. These findings suggest that naringin treatment attenuates renal dysfunction and structural damage through the reduction of oxidative stress, mitochondrial dysfunction, inflammation and apoptosis in the kidney.


      PubDate: 2014-04-16T16:21:31Z
       
  • Attenuation of Aβ25–35-induced parallel autophagic and
           apoptotic cell death by gypenoside XVII through the estrogen
           receptor-dependent activation of Nrf2/ARE pathways
    • Abstract: Publication date: Available online 12 April 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Xiangbao Meng , Min Wang , Guibo Sun , Jingxue Ye , Yanhui Zhou , Xi Dong , Tingting Wang , Shan Lu , Xiaobo Sun
      Amyloid-beta (Aβ) has a pivotal function in the pathogenesis of Alzheimer's disease. To investigate Aβ neurotoxicity, we used an in vitro model that involves Aβ25–35-induced cell death in the nerve growth factor-induced differentiation of PC12 cells. Aβ25–35 (20μM) treatment for 24h caused apoptotic cell death, as evidenced by significant cell viability reduction, LDH release, phosphatidylserine externalization, mitochondrial membrane potential disruption, cytochrome c release, caspase-3 activation, PARP cleavage, and DNA fragmentation in PC12 cells. Aβ25–35 treatment led to autophagic cell death, as evidenced by augmented GFP-LC3 puncta, conversion of LC3-I to LC3-II, and increased LC3-II/LC3-I ratio. Aβ25–35 treatment induced oxidative stress, as evidenced by intracellular ROS accumulation and increased production of mitochondrial superoxide, malondialdehyde, protein carbonyl, and 8-OHdG. Phytoestrogens have been proved to be protective against Aβ-induced neurotoxicity and regarded as relatively safe targets for AD drug development. Gypenoside XVII (GP-17) is a novel phytoestrogen isolated from Gynostemma pentaphyllum or Panax notoginseng. Pretreatment with GP-17 (10μM) for 12h increased estrogen response element reporter activity, activated PI3K/Akt pathways, inhibited GSK-3β, induced Nrf2 nuclear translocation, augmented antioxidant responsive element enhancer activity, upregulated heme oxygenase 1 (HO-1) expression and activity, and provided protective effects against Aβ25–35-induced neurotoxicity, including oxidative stress, apoptosis, and autophagic cell death. In conclusion, GP-17 conferred protection against Aβ25–35-induced neurotoxicity through estrogen receptor-dependent activation of PI3K/Akt pathways, inactivation of GSK-3β and activation of Nrf2/ARE/HO-1 pathways. This finding might provide novel insights into understanding the mechanism for neuroprotective effects of phytoestrogens or gypenosides.
      Graphical abstract image

      PubDate: 2014-04-16T16:21:31Z
       
  • Recombinant human tripeptidyl peptidase-1 infusion to the monkey CNS:
           Safety, pharmacokinetics, and distribution
    • Abstract: Publication date: 15 May 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 1
      Author(s): Brian R. Vuillemenot , Derek Kennedy , Randall P. Reed , Robert B. Boyd , Mark T. Butt , Donald G. Musson , Steve Keve , Rhea Cahayag , Laurie S. Tsuruda , Charles A. O'Neill
      CLN2 disease is caused by deficiency in tripeptidyl peptidase-1 (TPP1), leading to neurodegeneration and death. The safety, pharmacokinetics (PK), and CNS distribution of recombinant human TPP1 (rhTPP1) were characterized following a single intracerebroventricular (ICV) or intrathecal-lumbar (IT-L) infusion to cynomolgus monkeys. Animals received 0, 5, 14, or 20mg rhTPP1, ICV, or 14mg IT-L, in artificial cerebrospinal fluid (aCSF) vehicle. Plasma and CSF were collected for PK analysis. Necropsies occurred at 3, 7, and 14days post-infusion. CNS tissues were sampled for rhTPP1 distribution. TPP1 infusion was well tolerated and without effect on clinical observations or ECG. A mild increase in CSF white blood cells (WBCs) was detected transiently after ICV infusion. Isolated histological changes related to catheter placement and infusion were observed in ICV treated animals, including vehicle controls. The CSF and plasma exposure profiles were equivalent between animals that received an ICV or IT-L infusion. TPP1 levels peaked at the end of infusion, at which point the enzyme was present in plasma at 0.3% to 0.5% of CSF levels. TPP1 was detected in brain tissues with half-lives of 3–14days. CNS distribution between ICV and IT-L administration was similar, although ICV resulted in distribution to deep brain structures including the thalamus, midbrain, and striatum. Direct CNS infusion of rhTPP1 was well tolerated with no drug related safety findings. The favorable nonclinical profile of ICV rhTPP1 supports the treatment of CLN2 by direct administration to the CNS.


      PubDate: 2014-04-16T16:21:31Z
       
  • 1,2-Dibromo-4-(1,2-dibromoethyl)-cyclohexane and tris(methylphenyl)
           phosphate cause significant effects on development, mRNA expression, and
           circulating bile acid concentrations in chicken embryos
    • Abstract: Publication date: Available online 12 April 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Doug Crump , Emily Porter , Caroline Egloff , Kim L. Williams , Robert J. Letcher , Lewis T. Gauthier , Sean W. Kennedy
      1,2-Dibromo-4-(1,2-dibromoethyl)-cyclohexane (DBE-DBCH; formerly abbreviated as TBECH) and tris(methylphenyl) phosphate (TMPP; formerly abbreviated as TCP) are additive flame retardants that are detected in the environment and biota. A recent avian in vitro screening study of 16 flame retardants identified DBE-DBCH and TMPP as important chemicals for follow-up in ovo evaluation based on their effects on cytotoxicity and mRNA expression in avian hepatocytes. In this study, technical mixtures of DBE-DBCH and TMPP were injected into the air cell of chicken embryos at concentrations ranging from 0 to 54,900ng/g and from 0 to 261,400ng/g, respectively, to determine effects on pipping success, development, hepatic mRNA expression, thyroid hormone levels, and circulating bile acid concentrations. Both compounds were detectable in embryos at pipping and the β-DBE-DBCH isomer was depleted more rapidly than the α-isomer in tissue samples. DBE-DBCH had limited effects on the endpoints measured, with the exception of the up-regulation of two phase I metabolizing enzymes, CYP3A37 and CYP2H1. TMPP exposure caused embryonic deformities, altered growth, increased liver somatic index (LSI) and plasma bile acid concentrations, and altered mRNA expression levels of genes associated with xenobiotic and lipid metabolism and the thyroid hormone pathway. Overall, TMPP elicited more adverse molecular and phenotypic effects than DBE-DBCH albeit at concentrations several orders of magnitude greater than those detected in the environment. The increase in plasma bile acid concentrations was a useful phenotypic anchor as it was associated with a concomitant increase in LSI, discoloration of the liver tissue, and modulation of hepatic genes involved with xenobiotic and lipid metabolism.


      PubDate: 2014-04-16T16:21:31Z
       
  • SIRT1 inhibition restores apoptotic sensitivity in p53-mutated human
           keratinocytes
    • Abstract: Publication date: Available online 12 April 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Katharine J. Herbert , Anthony L. Cook , Elizabeth T. Snow
      Mutations to the p53 gene are common in UV-exposed keratinocytes and contribute to apoptotic resistance in skin cancer. P53-dependent activity is modulated, in part, by a complex, self-limiting feedback loop imposed by miR-34a-mediated regulation of the lysine deacetylase, SIRT1. Expression of numerous microRNAs is dysregulated in squamous and basal cell carcinomas; however the contribution of specific microRNAs to the pathogenesis of skin cancer remains untested. Through use of RNAi, miRNA target site blocking oligonucleotides and small molecule inhibitors, this study explored the influence of p53 mutational status, SIRT1 activity and miR-34a levels on apoptotic sensitivity in primary (NHEK) and p53-mutated (HaCaT) keratinocyte cell lines. SIRT1 and p53 are overexpressed in p53-mutated keratinocytes, whilst miR-34a levels are 90% less in HaCaT cells. HaCaTs have impaired responses to p53/SIRT1/miR-34a axis manipulation which enhanced survival during exposure to the chemotherapeutic agent, camptothecin. Inhibition of SIRT1 activity in this cell line increased p53 acetylation and doubled camptothecin-induced cell death. Our results demonstrate that p53 mutations increase apoptotic resistance in keratinocytes by interfering with miR-34a-mediated regulation of SIRT1 expression. Thus, SIRT1 inhibitors may have a therapeutic potential for overcoming apoptotic resistance during skin cancer treatment.
      Graphical abstract image

      PubDate: 2014-04-16T16:21:31Z
       
  • 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-d-pyranoside confers
           neuroprotection in cell and animal models of ischemic stroke through
           calpain1/PKA/CREB-mediated induction of neuronal glucose transporter 3
    • Abstract: Publication date: Available online 12 April 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Shu Yu , Qiong Chen , Lu Li , Mei Liu , Yumin Yang , Fei Ding
      Salidroside is proven to be a neuroprotective agent of natural origin, and its analog, 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-d-pyranoside (named SalA-4g), has been synthesized in our lab. In this study, we showed that SalA-4g promoted neuronal survival and inhibited neuronal apoptosis in primary hippocampal neurons exposed to oxygen and glucose deprivation (OGD) and in rats subjected to ischemia by transient middle cerebral artery occlusion (MCAO), respectively, and that SalA-4g was more neuroprotective than salidroside. We further found that SalA-4g elevated glucose uptake in OGD-injured primary hippocampal neurons and increased the expression and recruitment of glucose transporter 3 (GLUT3) in ischemic brain. Signaling analysis revealed that SalA-4g triggered the phosphorylation of CREB, and increased the expression of PKA RII in primary hippocampal neurons exposed to OGD injury, while inhibition of PKA/CREB by H-89 alleviated the elevation in glucose uptake and GLUT3 expression, and blocked the protective effects of SalA-4g. Moreover, SalA-4g was noted to inhibit intracellular Ca2+ influx and calpain1 activation in OGD-injured primary hippocampal neurons. Our results suggest that SalA-4g neuroprotection might be mediated by increased glucose uptake and elevated GLUT3 expression through calpain1/PKA/CREB pathway.
      Graphical abstract image

      PubDate: 2014-04-16T16:21:31Z
       
  • Flavin-containing monooxygenase S-oxygenation of a series of thioureas and
           thiones
    • Abstract: Publication date: Available online 12 April 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Marilyn C. Henderson , Lisbeth K. Siddens , Sharon K. Krueger , J. Fred Stevens , Karen Kedzie , Ken Fang , Todd Heidelbaugh , Phong Nguyen , Ken Chow , Michael Garst , Daniel Gil , David E. Williams
      Mammalian flavin-containing monooxygenase (FMO) is active towards many drugs with a heteroatom having the properties of a soft nucleophile. Thiocarbamides and thiones are S-oxygenated to the sulfenic acid which can either react with glutathione and initiate a redox-cycle or be oxygenated a second time to the unstable sulfinic acid. In this study, we utilized LC–MS/MS to demonstrate that the oxygenation by hFMO of the thioureas under test terminated at the sulfenic acid. With thiones, hFMO catalyzed the second reaction and the sulfinic acid rapidly lost sulfite to form the corresponding imidazole. Thioureas are often pulmonary toxicants in mammals and, as previously reported by our laboratory, are excellent substrates for hFMO2. This isoform is expressed at high levels in the lung of most mammals, including non-human primates. Genotyping to date indicates that individuals of African (up to 49%) or Hispanic (2–7%) ancestry have at least one allele for functional hFMO2 in lung, but not Caucasians nor Asians. In this study the major metabolite formed by hFMO2 with thioureas from Allergan, Inc. was the sulfenic acid that reacted with glutathione. The majority of thiones were poor substrates for hFMO3, the major form in adult human liver. However, hFMO1, the major isoform expressed in infant and neonatal liver and adult kidney and intestine, readily S-oxygenated thiones under test, with K m s ranging from 7 to 160μM and turnover numbers of 30–40min−1. The product formed was identified by LC–MS/MS as the imidazole. The activities of the mouse and human FMO1 and FMO3 orthologs were in good agreement with the exception of some thiones for which activity was much greater with hFMO1 than mFMO1.


      PubDate: 2014-04-16T16:21:31Z
       
  • Editorial Board
    • Abstract: Publication date: 1 May 2014
      Source:Toxicology and Applied Pharmacology, Volume 276, Issue 3




      PubDate: 2014-04-11T14:31:54Z
       
  • Translational research into species differences of endocrine toxicity via
           steroidogenesis inhibition by SMP-028 — For human safety in clinical
           study
    • Abstract: Publication date: 1 May 2014
      Source:Toxicology and Applied Pharmacology, Volume 276, Issue 3
      Author(s): Yohei Nishizato , Satoki Imai , Noriko Okahashi , Atsushi Yabunaka , Takeshi Kunimatsu , Kaoru Kikuchi , Masashi Yabuki
      SMP-028 is a drug candidate developed for the treatment of asthma. In a 13-week repeated dose toxicity study of SMP-028 in rats and monkeys, differences of endocrine toxicological events between rats and monkeys were observed. In rats, these toxicological events mainly consisted of pathological changes in the adrenal, testis, ovary, and the other endocrine-related organs. On the other hand, in monkeys, no toxicological events were observed. The goal of this study is to try to understand the reason why only rats, but not monkeys, showed toxicological events following treatment with SMP-028 and to eventually predict the possible toxicological effect of this compound on human endocrine organs. Our results show that SMP-028 inhibits neutral cholesterol esterase more strongly than other steroidogenic enzymes in rats. Although SMP-028 also inhibits monkeys and human neutral cholesterol esterase, this inhibition is much weaker than that of rat neutral cholesterol esterase. These results indicate (1) that the difference in endocrine toxicological events between rats and monkeys is mainly due to inhibition of steroidogenesis by SMP-028 in rats, not in monkeys, and (2) that SMP-028 may not affect steroidogenesis in humans and therefore might cause no endocrine toxicological events in clinical studies.


      PubDate: 2014-04-11T14:31:54Z
       
  • Cigarette smoking during pregnancy regulates the expression of specific
           nicotinic acetylcholine receptor (nAChR) subunits in the human placenta
    • Abstract: Publication date: 1 May 2014
      Source:Toxicology and Applied Pharmacology, Volume 276, Issue 3
      Author(s): R. Machaalani , E. Ghazavi , T. Hinton , K.A. Waters , A. Hennessy
      Smoking during pregnancy is associated with low birth weight, premature delivery, and neonatal morbidity and mortality. Nicotine, a major pathogenic compound of cigarette smoke, binds to the nicotinic acetylcholine receptors (nAChRs). A total of 16 nAChR subunits have been identified in mammals (9 α, 4 β, and 1 δ, γ and ε subunits). The effect of cigarette smoking on the expression of these subunits in the placenta has not yet been determined, thus constituting the aim of this study. Using RT-qPCR and western blotting, this study investigated all 16 mammalian nAChR subunits in the normal healthy human placenta, and compared mRNA and protein expressions in the placentas from smokers (n=8) to controls (n=8). Our data show that all 16 subunit mRNAs are expressed in the normal, non-diseased human placenta and that the expression of α2, α3, α4, α9, β2 and β4 subunits is greater than the other subunits. For mRNA, cigarette smoke exposure was associated with increased expression of the α9 subunit, and decreased expression of the δ subunit. At the protein level, expression of both α9 and δ was increased. Thus, cigarette smoking in pregnancy is sufficient to regulate nAChR subunits in the placenta, specifically α9 and δ subunits, and could contribute to the adverse effects of vasoconstriction and decreased re-epithelialisation (α9), and increased calcification and apoptosis (δ), seen in the placentas of smoking women.


      PubDate: 2014-04-11T14:31:54Z
       
  • Acute 7,12-dimethylbenz[a]anthracene exposure causes differential
           concentration-dependent follicle depletion and gene expression in neonatal
           rat ovaries
    • Abstract: Publication date: 1 May 2014
      Source:Toxicology and Applied Pharmacology, Volume 276, Issue 3
      Author(s): Jill A. Madden , Patricia B. Hoyer , Patrick J. Devine , Aileen F. Keating
      Chronic exposure to the polycyclic aromatic hydrocarbon 7,12-dimethylbenz[a]anthracene (DMBA), generated during combustion of organic matter including cigarette smoke, depletes all ovarian follicle types in the mouse and rat, and in vitro models mimic this effect. To investigate the mechanisms involved in follicular depletion during acute DMBA exposure, two concentrations of DMBA at which follicle depletion has (75nM) and has not (12.5nM) been observed were investigated. Postnatal day four F344 rat ovaries were maintained in culture for four days before a single exposure to vehicle control (1% DMSO; CT) or DMBA (12nM; low-concentration or 75nM; high-concentration). After four or eight additional days of culture, DMBA-induced follicle depletion was evaluated via follicle enumeration. Relative to control, DMBA did not affect follicle numbers after 4days of exposure, but induced large primary follicle loss at both concentrations after 8days; while, the low-concentration DMBA also caused secondary follicle depletion. Neither concentration affected primordial or small primary follicle number. RNA was isolated and quantitative RT-PCR performed prior to follicle loss to measure mRNA levels of genes involved in xenobiotic metabolism (Cyp2e1, Gstmu, Gstpi, Ephx1), autophagy (Atg7, Becn1), oxidative stress response (Sod1, Sod2) and the phosphatidylinositol 3-kinase (PI3K) pathway (Kitlg, cKit, Akt1) 1, 2 and 4days after exposure. With the exception of Atg7 and cKit, DMBA increased (P <0.05) expression of all genes investigated. Also, BECN1 and pAKTThr308 protein levels were increased while cKIT was decreased by DMBA exposure. Taken together, these results suggest an increase in DMBA bioactivation, add to the mechanistic understanding of DMBA-induced ovotoxicity and raise concern regarding female low concentration DMBA exposures.


      PubDate: 2014-04-11T14:31:54Z
       
  • TCDD induces dermal accumulation of keratinocyte-derived matrix
           metalloproteinase-10 in an organotypic model of human skin
    • Abstract: Publication date: 1 May 2014
      Source:Toxicology and Applied Pharmacology, Volume 276, Issue 3
      Author(s): K. Nadira De Abrew , Christina L. Thomas-Virnig , Cathy A. Rasmussen , Elyse A. Bolterstein , Sandy J. Schlosser , B. Lynn Allen-Hoffmann
      The epidermis of skin is the first line of defense against the environment. A three dimensional model of human skin was used to investigate tissue-specific phenotypes induced by the environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Continuous treatment of organotypic cultures of human keratinocytes with TCDD resulted in intracellular spaces between keratinocytes of the basal and immediately suprabasal layers as well as thinning of the basement membrane, in addition to the previously reported hyperkeratinization. These tissue remodeling events were preceded temporally by changes in expression of the extracellular matrix degrading enzyme, matrix metalloproteinase-10 (MMP-10). In organotypic cultures MMP-10 mRNA and protein were highly induced following TCDD treatment. Q-PCR and immunoblot results from TCDD-treated monolayer cultures, as well as indirect immunofluorescence and immunoblot analysis of TCDD-treated organotypic cultures, showed that MMP-10 was specifically contributed by the epidermal keratinocytes but not the dermal fibroblasts. Keratinocyte-derived MMP-10 protein accumulated over time in the dermal compartment of organotypic cultures. TCDD-induced epidermal phenotypes in organotypic cultures were attenuated by the keratinocyte-specific expression of tissue inhibitor of metalloproteinase-1, a known inhibitor of MMP-10. These studies suggest that MMP-10 and possibly other MMP-10-activated MMPs are responsible for the phenotypes exhibited in the basement membrane, the basal keratinocyte layer, and the cornified layer of TCDD-treated organotypic cultures. Our studies reveal a novel mechanism by which the epithelial–stromal microenvironment is altered in a tissue-specific manner thereby inducing structural and functional pathology in the interfollicular epidermis of human skin.
      Graphical abstract image

      PubDate: 2014-04-11T14:31:54Z
       
  • Reactive oxygen species contribute to arsenic-induced EZH2 phosphorylation
           in human bronchial epithelial cells and lung cancer cells
    • Abstract: Publication date: 1 May 2014
      Source:Toxicology and Applied Pharmacology, Volume 276, Issue 3
      Author(s): Lingzhi Li , Ping Qiu , Bailing Chen , Yongju Lu , Kai Wu , Chitra Thakur , Qingshan Chang , Jiaying Sun , Fei Chen
      Our previous studies suggested that arsenic is able to induce serine 21 phosphorylation of the EZH2 protein through activation of JNK, STAT3, and Akt signaling pathways in the bronchial epithelial cell line, BEAS-2B. In the present report, we further demonstrated that reactive oxygen species (ROS) were involved in the arsenic-induced protein kinase activation that leads to EZH2 phosphorylation. Several lines of evidence supported this notion. First, the pretreatment of the cells with N-acetyl-l-cysteine (NAC), a potent antioxidant, abolishes arsenic-induced EZH2 phosphorylation along with the inhibition of JNK, STAT3, and Akt. Second, H2O2, the most important form of ROS in the cells in response to extracellular stress signals, can induce phosphorylation of the EZH2 protein and the activation of JNK, STAT3, and Akt. By ectopic expression of the myc-tagged EZH2, we additionally identified direct interaction and phosphorylation of the EZH2 protein by Akt in response to arsenic and H2O2. Furthermore, both arsenic and H2O2 were able to induce the translocation of ectopically expressed or endogenous EZH2 from nucleus to cytoplasm. In summary, the data presented in this report indicate that oxidative stress due to ROS generation plays an important role in the arsenic-induced EZH2 phosphorylation.


      PubDate: 2014-04-11T14:31:54Z
       
  • Contents
    • Abstract: Publication date: 1 May 2014
      Source:Toxicology and Applied Pharmacology, Volume 276, Issue 3




      PubDate: 2014-04-11T14:31:54Z
       
  • Placental oxidative stress and decreased global DNA methylation are
           corrected by copper in the Cohen diabetic rat
    • Abstract: Publication date: 1 May 2014
      Source:Toxicology and Applied Pharmacology, Volume 276, Issue 3
      Author(s): Zivanit Ergaz , Claire Guillemin , Meytal Neeman-azulay , Liza Weinstein-Fudim , Christopher J. Stodgell , Richard K. Miller , Moshe Szyf , Asher Ornoy
      Fetal Growth Restriction (FGR) is a leading cause for long term morbidity. The Cohen diabetic sensitive rats (CDs), originating from Wistar, develop overt diabetes when fed high sucrose low copper diet (HSD) while the original outbred Sabra strain do not. HSD induced FGR and fetal oxidative stress, more prominent in the CDs, that was alleviated more effectively by copper than by the anti-oxidant vitamins C and E. Our aim was to evaluate the impact of copper or the anti-oxidant Tempol on placental size, protein content, oxidative stress, apoptosis and total DNA methylation. Animals were mated following one month of HSD or regular chow diet and supplemented throughout pregnancy with either 0, 1 or 2ppm of copper sulfate or Tempol in their drinking water. Placental weight on the 21st day of pregnancy decreased in dams fed HSD and improved upon copper supplementation. Placental/fetal weight ratio increased among the CDs. Protein content decreased in Sabra but increased in CDs fed HSD. Oxidative stress biochemical markers improved upon copper supplementation; immunohistochemistry for oxidative stress markers was similar between strains and diets. Caspase 3 was positive in more placentae of dams fed HSD than those fed RD. Placental global DNA methylation was decreased only among the CDs dams fed HSD. We conclude that FGR in this model is associated with smaller placentae, reduced DNA placental methylation, and increased oxidative stress that normalized with copper supplementation. DNA hypomethylation makes our model a unique method for investigating genes associated with growth, oxidative stress, hypoxia and copper.


      PubDate: 2014-04-11T14:31:54Z
       
  • Repeated Nrf2 stimulation using sulforaphane protects fibroblasts from
           ionizing radiation
    • Abstract: Publication date: 1 May 2014
      Source:Toxicology and Applied Pharmacology, Volume 276, Issue 3
      Author(s): Sherin T. Mathew , Petra Bergström , Ola Hammarsten
      Most of the cytotoxicity induced by ionizing radiation is mediated by radical-induced DNA double-strand breaks. Cellular protection from free radicals can be stimulated several fold by sulforaphane-mediated activation of the transcription factor Nrf2 that regulates more than 50 genes involved in the detoxification of reactive substances and radicals. Here, we report that repeated sulforaphane treatment increases radioresistance in primary human skin fibroblasts. Cells were either treated with sulforaphane for four hours once or with four-hour treatments repeatedly for three consecutive days prior to radiation exposure. Fibroblasts exposed to repeated-sulforaphane treatment showed a more pronounced dose-dependent induction of Nrf2-regulated mRNA and reduced amount of radiation-induced free radicals compared with cells treated once with sulforaphane. In addition, radiation- induced DNA double-strand breaks measured by gamma-H2AX foci were attenuated following repeated sulforaphane treatment. As a result, cellular protection from ionizing radiation measured by the 5-ethynyl-2′-deoxyuridine (EdU) assay was increased, specifically in cells exposed to repeated sulforaphane treatment. Sulforaphane treatment was unable to protect Nrf2 knockout mouse embryonic fibroblasts, indicating that the sulforaphane-induced radioprotection was Nrf2-dependent. Moreover, radioprotection by repeated sulforaphane treatment was dose-dependent with an optimal effect at 10 uM, whereas both lower and higher concentrations resulted in lower levels of radioprotection. Our data indicate that the Nrf2 system can be trained to provide further protection from radical damage.


      PubDate: 2014-04-11T14:31:54Z
       
  • Interaction between arsenic exposure from drinking water and genetic
           susceptibility in carotid intima–media thickness in Bangladesh
    • Abstract: Publication date: 1 May 2014
      Source:Toxicology and Applied Pharmacology, Volume 276, Issue 3
      Author(s): Fen Wu , Farzana Jasmine , Muhammad G. Kibriya , Mengling Liu , Xin Cheng , Faruque Parvez , Rachelle Paul-Brutus , Tariqul Islam , Rina Rani Paul , Golam Sarwar , Alauddin Ahmed , Jieying Jiang , Tariqul Islam , Vesna Slavkovich , Tatjana Rundek , Ryan T. Demmer , Moise Desvarieux , Habibul Ahsan , Yu Chen
      Epidemiologic studies that evaluated genetic susceptibility for the effects of arsenic exposure from drinking water on subclinical atherosclerosis are limited. We conducted a cross-sectional study of 1078 participants randomly selected from the Health Effects of Arsenic Longitudinal Study in Bangladesh to evaluate whether the association between arsenic exposure and carotid artery intima–media thickness (cIMT) differs by 207 single-nucleotide polymorphisms (SNPs) in 18 genes related to arsenic metabolism, oxidative stress, inflammation, and endothelial dysfunction. Although not statistically significant after correcting for multiple testing, nine SNPs in APOE, AS3MT, PNP, and TNF genes had a nominally statistically significant interaction with well-water arsenic in cIMT. For instance, the joint presence of a higher level of well-water arsenic (≥40.4μg/L) and the GG genotype of AS3MT rs3740392 was associated with a difference of 40.9μm (95% CI=14.4, 67.5) in cIMT, much greater than the difference of cIMT associated with the genotype alone (β=−5.1μm, 95% CI=−31.6, 21.3) or arsenic exposure alone (β=7.2μm, 95% CI=−3.1, 17.5). The pattern and magnitude of the interactions were similar when urinary arsenic was used as the exposure variable. Additionally, the at-risk genotypes of the AS3MT SNPs were positively related to the proportion of monomethylarsonic acid (MMA) in urine, which is indicative of arsenic methylation capacity. The findings provide novel evidence that genetic variants related to arsenic metabolism may play an important role in arsenic-induced subclinical atherosclerosis. Future replication studies in diverse populations are needed to confirm the findings.


      PubDate: 2014-04-11T14:31:54Z
       
  • Augmented atherogenesis in ApoE-null mice co-exposed to polychlorinated
           biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin
    • Abstract: Publication date: 15 April 2014
      Source:Toxicology and Applied Pharmacology, Volume 276, Issue 2
      Author(s): Qiuli Shan , Jing Wang , Fengchen Huang , Xiaowen Lv , Min Ma , Yuguo Du
      2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyls (PCBs) are persistent organic pollutants found as complex mixtures in the environment throughout the world. Therefore, humans are ubiquitously and simultaneously exposed to TCDD and PCBs. TCDD and PCBs alone have been linked to atherosclerosis. However, the effects of interactions or synergism between TCDD and PCBs on atherogenesis are unknown. We investigated the possible enhanced atherogenesis by co-exposure to TCDD and PCBs and the potential mechanism(s) involved in this enhancement. Male ApoE−/− mice were exposed to TCDD (15μg/kg) and Aroclor1254 (55mg/kg, a representative mixture of PCBs) alone or in combination by intraperitoneal injection four times over six weeks of duration. Our results showed that mice exposed to TCDD alone, but not Aroclor1254 alone, developed atherosclerotic lesions. Moreover, we found that atherosclerotic disease was exacerbated to the greatest extent in mice co-exposed to TCDD and Aroclor1254. The enhanced lesions correlated with several pro-atherogenic changes, including a marked increase in the accumulation of the platelet-derived chemokine PF4, and the expression of the proinflammatory cytokine MCP-1 and the critical immunity gene-RIG-I. Our data demonstrated that co-exposure to TCDD and Aroclor1254 markedly enhanced atherogenesis in ApoE−/− mice. Significantly, our observations suggest that combined exposure to TCDD and PCBs may be a greater cardiovascular health risk than previously anticipated from individual studies.


      PubDate: 2014-04-07T16:09:14Z
       
  • The chemopreventive activity of the histone deacetylase inhibitor
           tributyrin in colon carcinogenesis involves the induction of apoptosis and
           reduction of DNA damage
    • Abstract: Publication date: 15 April 2014
      Source:Toxicology and Applied Pharmacology, Volume 276, Issue 2
      Author(s): Renato Heidor , Kelly Silva Furtado , Juliana Festa Ortega , Tiago Franco de Oliveira , Paulo Eduardo Latorre Martins Tavares , Alessandra Vieira , Mayara Lilian Paulino Miranda , Eduardo Purgatto , Fernando Salvador Moreno
      The chemopreventive activity of the histone deacetylase inhibitor (HDACi) tributyrin (TB), a prodrug of butyric acid (BA), was evaluated in a rat model of colon carcinogenesis. The animals were treated with TB (TB group: 200mg/100g of body weight, b.w.) or maltodextrin (MD isocaloric control group: 300mg/100g b.w.) daily for 9 consecutive weeks. In the 3rd and 4th weeks of treatment, the rats in the TB and MD groups were given DMH (40mg/kg b.w.) twice a week. After 9weeks, the animals were euthanized, and the distal colon was examined. Compared with the control group (MD group), TB treatment reduced the total number of aberrant crypt foci (ACF; p<0.05) as well as the ACF with ≥4 crypts (p<0.05), which are considered more aggressive, but not inhibited the formation of DMH-induced O6-methyldeoxyguanosine DNA adducts. The TB group also showed a higher apoptotic index (p<0.05) and reduced DNA damage (p<0.05) compared with MD group. TB acted as a HDACi, as rats treated with the prodrug of BA had higher levels of histone H3K9 acetylation compared with the MD group (p<0.05). TB administration resulted in increased colonic tissue concentrations of BA (p<0.05) compared with the control animals. These results suggest that TB can be considered a promising chemopreventive agent for colon carcinogenesis because it reduced the number of ACF, including those that were more aggressive. Induction of apoptosis and reduction of DNA damage are cellular mechanisms that appear to be involved in the chemopreventive activity of TB.


      PubDate: 2014-04-07T16:09:14Z
       
  • TNF/TNFR1 pathway and endoplasmic reticulum stress are involved in
           ofloxacin-induced apoptosis of juvenile canine chondrocytes
    • Abstract: Publication date: 15 April 2014
      Source:Toxicology and Applied Pharmacology, Volume 276, Issue 2
      Author(s): Fu-Tao Zhang , Yi Ding , Zahir Shah , Dan Xing , Yuan Gao , Dong Ming Liu , Ming-Xing Ding
      Background and purpose Quinolones cause obvious cartilaginous lesions in juvenile animals by chondrocyte apoptosis, which results in the restriction of their use in pediatric and adolescent patients. Studies showed that chondrocytes can be induced to produce TNFα, and the cisternae of the endoplasmic reticulum in quinolone-treated chondrocytes become dilated. We investigated whether TNF/TNFR1 pathway and endoplasmic reticulum stress (ERs) are involved in ofloxacin (a typical quinolone)-induced apoptosis of juvenile canine chondrocytes. Experimental approach Canine juvenile chondrocytes were treated with ofloxacin. Cell survival and apoptosis rates were determined with MTT method and flow cytometry, respectively. The gene expression levels of the related signaling molecules (TNFα, TNFR1, TRADD, FADD and caspase-8) in death receptor pathways and main apoptosis-related molecules (calpain, caspase-12, GADD153 and GRP78) in ERs were measured by qRT-PCR. The gene expression of TNFR1 was suppressed with its siRNA. The protein levels of TNFα, TNFR1 and caspase-12 were assayed using Western blotting. Key results The survival rates decreased while apoptosis rates increased after the chondrocytes were treated with ofloxacin. The mRNA levels of the measured apoptosis-related molecules in death receptor pathways and ERs, and the protein levels of TNFα, TNFR1 and caspase-12 increased after the chondrocytes were exposed to ofloxacin. The downregulated mRNA expressions of TNFR1, Caspase-8 and TRADD, and the decreased apoptosis rates of the ofloxacin-treated chondrocytes occurred after TNFR1–siRNA interference. Conclusions and implications Ofloxacin-induced chondrocyte apoptosis in a time- and concentration-dependent fashion. TNF/TNFR1 pathway and ERs are involved in ofloxacin-induced apoptosis of juvenile canine chondrocytes in the early stage.


      PubDate: 2014-04-07T16:09:14Z
       
  • Subneurotoxic copper(II)-induced NF-κB-dependent microglial
           activation is associated with mitochondrial ROS
    • Abstract: Publication date: 15 April 2014
      Source:Toxicology and Applied Pharmacology, Volume 276, Issue 2
      Author(s): Zhuqin Hu , Fengxiang Yu , Ping Gong , Yu Qiu , Wei Zhou , Yongyao Cui , Juan Li , Hongzhuan Chen
      Microglia-mediated neuroinflammation and the associated neuronal damage play critical roles in the pathogenesis of neurodegenerative disorders. Evidence shows an elevated concentration of extracellular copper(II) in the brains of these disorders, which may contribute to neuronal death through direct neurotoxicity. Here we explored whether extracellular copper(II) triggers microglial activation. Primary rat microglia and murine microglial cell line BV-2 cells were cultured and treated with copper(II). The content of tumor necrosis factor-α (TNF-α) and nitric oxide in the medium was determined. Extracellular hydrogen peroxide was quantified by a fluorometric assay with Amplex Red. Mitochondrial superoxide was measured by MitoSOX oxidation. At subneurotoxic concentrations, copper(II) treatment induced a dose- and time-dependent release of TNF-α and nitric oxide from microglial cells, and caused an indirect, microglia-mediated neurotoxicity that was blocked by inhibition of TNF-α and nitric oxide production. Copper(II)-initiated microglial activation was accompanied with reduced IкB-α expression as well as phosphorylation and translocation of nuclear factor-κB (NF-κB) p65 and was blocked by NF-κB inhibitors (BAY11-7082 and SC-514). Moreover, copper(II) treatment evoked a rapid release of hydrogen peroxide from microglial cells, an effect that was not affected by NADPH oxidase inhibitors. N-acetyl-cysteine, a scavenger of reactive oxygen species (ROS), abrogated copper(II)-elicited microglial release of TNF-α and nitric oxide and subsequent neurotoxicity. Importantly, mitochondrial production of superoxide, paralleled to extracellular release of hydrogen peroxide, was induced after copper(II) stimulation. Our findings suggest that extracellular copper(II) at subneurotoxic concentrations could trigger NF-κB-dependent microglial activation and subsequent neurotoxicity. NADPH oxidase-independent, mitochondria-derived ROS may be involved in this activation.


      PubDate: 2014-04-07T16:09:14Z
       
  • High fat diet and GLP-1 drugs induce pancreatic injury in mice
    • Abstract: Publication date: 15 April 2014
      Source:Toxicology and Applied Pharmacology, Volume 276, Issue 2
      Author(s): Rodney Rouse , Lin Xu , Sharron Stewart , Jun Zhang
      Glucagon Like Peptide-1 (GLP-1) drugs are currently used to treat type-2 diabetes. Safety concerns for increased risk of pancreatitis and pancreatic ductal metaplasia have accompanied these drugs. High fat diet (HFD) is a type-2 diabetes risk factor that may affect the response to GLP-1 drug treatment. The objective of the present study was to investigate the effects of diet and GLP-1 based drugs on the exocrine pancreas in mice. Experiments were designed in a mouse model of insulin resistance created by feeding a HFD or standard diet (STD) for 6weeks. The GLP-1 drugs, sitagliptin (SIT) and exenatide (EXE) were administered once daily for additional 6weeks in both mice fed HFD or STD. The results showed that body weight, blood glucose levels, and serum levels of pro-inflammatory cytokines (TNFα, IL-1β, and KC) were significantly greater in HFD mice than in STD mice regardless of GLP-1 drug treatment. The semi-quantitative grading showed that pancreatic changes were significantly greater in EXE and SIT-treated mice compared to control and that HFD exacerbated spontaneous exocrine pancreatic changes seen in saline-treated mice on a standard diet. Exocrine pancreatic changes identified in this study included acinar cell injury (hypertrophy, autophagy, apoptosis, necrosis, and atrophy), vascular injury, interstitial edema and inflammation, fat necrosis, and duct changes. These findings support HFD as a risk factor to increased susceptibility/severity for acute pancreatitis and indicate that GLP-1 drugs cause pancreatic injury that can be exacerbated in a HFD environment.


      PubDate: 2014-04-07T16:09:14Z
       
  • Inhibition of reactive oxygen species in hypothalamic paraventricular
           nucleus attenuates the renin–angiotensin system and proinflammatory
           cytokines in hypertension
    • Abstract: Publication date: 15 April 2014
      Source:Toxicology and Applied Pharmacology, Volume 276, Issue 2
      Author(s): Qing Su , Da-Nian Qin , Fu-Xin Wang , Jun Ren , Hong-Bao Li , Meng Zhang , Qing Yang , Yu-Wang Miao , Xiao-Jing Yu , Jie Qi , Zhiming Zhu , Guo-Qing Zhu , Yu-Ming Kang
      Aims To explore whether reactive oxygen species (ROS) scavenger (tempol) in the hypothalamic paraventricular nucleus (PVN) attenuates renin–angiotensin system (RAS) and proinflammatory cytokines (PICs), and decreases the blood pressure and sympathetic activity in angiotensin II (ANG II)-induced hypertension. Methods and results Male Sprague–Dawley rats were infused intravenously with ANG II (10ng/kg per min) or normal saline (NS) for 4weeks. These rats were treated with bilateral PVN infusion of oxygen free radical scavenger tempol (TEMP, 20μg/h) or vehicle (artificial cerebrospinal fluid, aCSF) for 4weeks. ANG II infusion resulted in increased mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). These ANG II-infused rats also had higher levels of gp91phox (a subunit of NAD(P)H oxidase), angiotensin-converting enzyme (ACE), and interleukin-1beta (IL-1β) in the PVN than the control animals. Treatment with PVN infusion of TEMP attenuated the overexpression of gp91phox, ACE and IL-1β within the PVN, and decreased sympathetic activity and MAP in ANG II-infused rats. Conclusion These findings suggest that ANG II infusion induces elevated PICs and oxidative stress in the PVN, which contribute to the sympathoexcitation in hypertension. Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system, proinflammatory cytokines and oxidative stress in ANG II-induced hypertension.


      PubDate: 2014-04-07T16:09:14Z
       
  • Current understandings and perspectives on non-cancer health effects of
           benzene: A global concern
    • Abstract: Publication date: 15 April 2014
      Source:Toxicology and Applied Pharmacology, Volume 276, Issue 2
      Author(s): Haji Bahadar , Sara Mostafalou , Mohammad Abdollahi
      Objective Benzene, as a volatile organic compound, is known as one of the main air pollutants in the environment. The aim of this review is to summarize all available evidences on non-cancerous health effects of benzene providing an overview of possible association of exposure to benzene with human chronic diseases, specially, in those regions of the world where benzene concentration is being poorly monitored. Methodology A bibliographic search of scientific databases including PubMed, Google Scholar, and Scirus was conducted with key words of “benzene toxic health effects”, “environmental volatile organic compounds”, “diabetes mellitus and environmental pollutants”, “breast cancer and environmental pollution”, “prevalence of lung cancer”, and “diabetes prevalence”. More than 300 peer reviewed papers were examined. Experimental and epidemiologic studies reporting health effects of benzene and volatile organic compounds were included in the study. Results Epidemiologic and experimental studies suggest that benzene exposure can lead to numerous non-cancerous health effects associated with functional aberration of vital systems in the body like reproductive, immune, nervous, endocrine, cardiovascular, and respiratory. Conclusion Chronic diseases have become a health burden of global dimension with special emphasis in regions with poor monitoring over contents of benzene in petrochemicals. Benzene is a well known carcinogen of blood and its components, but the concern of benzene exposure is more than carcinogenicity of blood components and should be evaluated in both epidemiologic and experimental studies. Aspect of interactions and mechanism of toxicity in relation to human general health problems especially endocrine disturbances with particular reference to diabetes, breast and lung cancers should be followed up.


      PubDate: 2014-04-07T16:09:14Z
       
  • Environmentally Persistent Free Radicals Inhibit Cytochromes P450 Activity
           in Rat Liver Microsomes
    • Abstract: Publication date: Available online 5 April 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): James R. Reed , George F. Cawley , Taylor G. Ardoin , Barry Dellinger , Slawomir M. Lomnicki , Farhana Hasan , Lucy W. Kiruri , Wayne L. Backes
      Combustion processes generate particulate matter that affects human health. When incineration fuels include components that are highly enriched in aromatic hydrocarbons (especially halogenated varieties) and redox-active metals, ultrafine particulate matter containing air-stable, environmentally persistent free radicals (EPFRs) are generated. The exposure to fine EPFRs (less than 2.5 μm in diameter) has been shown to negatively influence pulmonary and cardiovascular functions in living organisms. The goal of this study was to determine if these EPFRs have a direct affect on cytochrome P450 function. This was accomplished by direct addition of the EPFRs to rat liver microsomal preparations and measurement of several P450 activities using form-selective substrates. The EPFRs used in this study were formed by heating vapors from an organic compound (either monochlorophenol (MCP230) or 1,2- dichlorobenzene (DCB230)) and 5% copper oxide supported on silica (approximately 0.2 μm in diameter) to 230°C under vacuum. Both types of EPFRs (but not silica, physisorbed silica, or silica impregnated with copper oxide) dramatically inhibited the activities of CYP1A, CYP2B, CYP2E1, CYP2D2 and CYP3A when incubated at concentrations less than 0.1 mg/ml with microsomes and NADPH. Interestingly, at the same concentrations, the EPFRs did not inhibit HO-1 activity or the reduction of cytochrome c by NADPH-cytochrome P450 reductase. CYP2D2-selective metabolism by rat liver microsomes was examined in more detail. The inhibition of CYP2D2-selective metabolism by both DCB230- and MCP230-EPFRs appeared to be largely noncompetitive and was attenuated in the presence of catalase suggesting that reactive oxygen species may be involved in the mechanism of inhibition.


      PubDate: 2014-04-07T16:09:14Z
       
  • Metabolism and Physiologically Based Pharmacokinetic Modeling of
           Flumioxazin in Pregnant Animals
    • Abstract: Publication date: Available online 6 April 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Tomoyuki Takaku , Hirohisa Nagahori , Yoshihisa Sogame
      A physiologically based pharmacokinetic (PBPK) model was developed to predict the concentration of flumioxazin, in the blood and fetus of pregnant humans during a theoretical accidental intake (1000mg/kg). The data on flumioxazin concentration in pregnant rats (30mg/kg po) was used to develop the PBPK model in pregnant rats using physiological parameters and chemical specific parameters. The rat PBPK model developed was extrapolated to a human model. Liver microsomes of female rats and a mixed gender of humans were used for the in vitro metabolism study. To determine the % of flumioxazin absorbed after administration at a dose of 1000mg/kg assuming maximum accidental intake, the biliary excretion study of [phenyl-U-14C]flumioxazin was conducted in bile duct-cannulated female rats (Crl:CD (SD)) to collect and analyze the bile, urine, feces, gastrointestinal tract, and residual carcass. The % of flumioxazin absorbed at a dose of 1000mg/kg in rats was low (12.3%) by summing up 14C of the urine, bile, and residual carcass. The pregnant human model that was developed demonstrated that the maximum flumioxazin concentration in the blood and fetus of a pregnant human at a dose of 1000mg/kg po was 0.86μg/mL and 0.68μg/mL, respectively, which is much lower than Km (202.4μg/mL). Because the metabolism was not saturated and the absorption rate was low at a dose of 1000mg/kg, the calculated flumioxazin concentration in pregnant humans was thought to be relatively low, considering the flumioxazin concentration in pregnant rats at a dose of 30mg/kg. For the safety assessment of flumioxazin, these results would be useful for further in vitro toxicology experiments.


      PubDate: 2014-04-07T16:09:14Z
       
  • Prenatal nicotinic exposure suppresses fetal adrenal steroidogenesis via
           steroidogenic factor 1 (SF-1) deacetylation
    • Abstract: Publication date: Available online 5 April 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): You-e Yan , Lian Liu , Jian-fei Wang , Fang Liu , Xiao-hai Li , Hai-quan Qin , Hui Wang
      This study aimed to investigate the suppressive effect of nicotine on fetal adrenal steroidogenesis and to explore the potential role of epigenetic modification of steroidogenic factor-1 (SF-1) transcriptional activity in this process. Nicotine was intragastrically administered to pregnant rats and NCI-H295A cells were treated with nicotine or trichostatin A (TSA). The pathomorphology of fetal adrenals, steroid hormones levels, the expression of SF-1 and its target genes, histone deacetylases (HDACs) mRNA were analyzed. Histone modification and DNA methylation of the SF-1 promoter region were assessed using chromatin immunoprecipitation (ChIP) and bisulfite sequencing PCR. The interaction between SF1 and its target genes were observed. Prenatal nicotinic exposure decreased fetal body weight, increased the IUGR rate and caused detrimental changes in fetal adrenal. In addition, the levels of corticosterone, the expression of SF-1 and its target genes were decreased while HDAC2 expression was enhanced. Nicotine treatment decreased histone H3K9 and H3K14 acetylation levels while there was no nicotinic effect on the methylation frequency on the SF-1 promoter region. Furthermore, in nicotine-treated NCI-H295A cells, lower levels of steroidogenic synthesis, lower expression of SF-1 and its target genes were observed while the expression of HDACs was enhanced. The interaction between SF1 and StAR decreased with nicotine treatment. Nicotine treatment decreased histone H3K9 and H3K14 acetylation levels, and addition of TSA reversed the inhibition of nicotine-mediated SF-1 and its partial target genes. Thus, nicotine-mediated reduction of SF-1 expression resulted in an inhibitory effect on the expression of its target genes and steroid production via histone deacetylation.


      PubDate: 2014-04-07T16:09:14Z
       
  • A metabonomic evaluation of the monocrotaline-induced sinusoidal
           obstruction syndrome (SOS) in rats
    • Abstract: Publication date: 15 April 2014
      Source:Toxicology and Applied Pharmacology, Volume 276, Issue 2
      Author(s): R. Conotte , J.-M. Colet
      The main curative treatment of colorectal cancer remains the surgery. However, when metastases are suspected, surgery is followed by a preventive chemotherapy using oxaliplatin which, unfortunately, may cause liver sinusoidal obstruction syndrome (SOS). Such hepatic damage is barely detected during or after chemotherapy due to a lack of effective diagnostic procedures, but liver biopsy. The primary objective of the present study was to identify potential early diagnosis biomarkers of SOS using a metabonomic approach. SOS was induced in rats by monocrotaline, a prototypical toxic substance. 1H NMR spectroscopy analysis of urine samples collected from rats treated with monocrotaline showed significant metabolic changes as compared to controls. During a first phase, cellular protective mechanisms such as an increased synthesis of GSH (reduced taurine) and the recruitment of cell osmolytes in the liver (betaine) were seen. In the second phase, the disturbance of the urea cycle (increased ornithine and urea reduction) leading to the depletion of NO, the alteration in the GSH synthesis (increased creatine and GSH precursors (glutamate, dimethylglycine and sarcosine)), and the liver necrosis (decrease taurine and increase creatine) all indicate the development of SOS.


      PubDate: 2014-04-07T16:09:14Z
       
  • In utero bisphenol A exposure disrupts germ cell nest breakdown and
           reduces fertility with age in the mouse
    • Abstract: Publication date: 15 April 2014
      Source:Toxicology and Applied Pharmacology, Volume 276, Issue 2
      Author(s): Wei Wang , Katlyn S. Hafner , Jodi A. Flaws
      Bisphenol A (BPA) is a known reproductive toxicant in rodents. However, the effects of in utero BPA exposure on early ovarian development and the consequences of such exposure on female reproduction in later reproductive life are unclear. Thus, we determined the effects of in utero BPA exposure during a critical developmental window on germ cell nest breakdown, a process required for establishment of the finite primordial follicle pool, and on female reproduction. Pregnant FVB mice (F0) were orally dosed daily with tocopherol-striped corn oil (vehicle), diethylstilbestrol (DES; 0.05μg/kg, positive control), or BPA (0.5, 20, and 50μg/kg) from gestational day 11 until birth. Ovarian morphology and gene expression profiles then were examined in F1 female offspring on postnatal day (PND) 4 and estrous cyclicity was examined daily after weaning for 30days. F1 females were also subjected to breeding studies with untreated males at three to nine months. The results indicate that BPA inhibits germ cell nest breakdown via altering expression of selected apoptotic factors. BPA also significantly advances the age of first estrus, shortens the time that the females remain in estrus, and increases the time that the females remain in metestrus and diestrus compared to controls. Further, F1 females exposed to low doses of BPA exhibit various fertility problems and have a significantly higher percentage of dead pups compared to controls. These results indicate that in utero exposure to low doses of BPA during a critical ovarian developmental window interferes with early ovarian development and reduces fertility with age.


      PubDate: 2014-04-07T16:09:14Z
       
  • Contents
    • Abstract: Publication date: 15 April 2014
      Source:Toxicology and Applied Pharmacology, Volume 276, Issue 2




      PubDate: 2014-04-07T16:09:14Z
       
  • Editorial Board
    • Abstract: Publication date: 15 April 2014
      Source:Toxicology and Applied Pharmacology, Volume 276, Issue 2




      PubDate: 2014-04-07T16:09:14Z
       
  • α-dihydroxychalcone-glycoside (α-DHC) isolated from the
           heartwood of Pterocarpus marsupium inhibits LPS induced MAPKs activation
           and up regulates HO-1 expression in murine RAW 264.7 macrophage
    • Abstract: Publication date: Available online 25 March 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Prarthana Chakraborty , Ghungroo Saraswat , Syed N. Kabir
      Three phenolic glycosides isolated from the heartwood of Pterocarpus marsupium showed significant free radical and superoxide ion scavenging activity and antioxidant potential that were comparable to, or several folds higher than those of standard antioxidants, trolox and ascorbic acid. The effective concentrations of these compounds were far below their cytotoxic levels. Compound 3, which was characterized to be α-dihydroxychalcone-glycoside (α-DHC), was the most potent one. Subsequent studies demonstrated that α-DHC effectively reduced nitric oxide and cytokine production by the LPS stimulated RAW 264.7 mouse macrophage cell line. The compound effectively attenuated the expression of inflammation-mediating enzymes COX-2 and iNOS at the mRNA as well as protein levels in a concentration dependent manner. It prevented phosphorylation of all the three MAPKs (JNK, ERK, p38) and eventually blocked the activation of downstream elements contributing to inflammation. Phosphorylation of IκB-α and subsequent translocation of NF-κB into the nucleus were restricted, while the expression of stress responsive gene HO-1 was up-regulated. α-DHC targeted Keap-1 by modifying its cysteine thiols, dissociating it from Nrf-2 and facilitating nuclear entry of the latter; and this in turn induced HO-1 expression. Thus α-DHC exerts its anti-inflammatory activity in a dual manner: by down regulating MAPKs and restricting nuclear stabilization of NF-κB at one end, and by disrupting Nrf-2-Keap-1complex on the other. In conclusion, the anti-inflammatory potential together with its high therapeutic index envisages α-DHC as a prospective candidate molecule for the development of therapeutic strategy against inflammatory disorders.
      Graphical abstract image

      PubDate: 2014-03-27T12:19:31Z
       
  • Metallothionein as a compensatory component prevents intermittent
           hypoxia-induced cardiomyopathy in mice
    • Abstract: Publication date: Available online 18 March 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Xia Yin , Shanshan Zhou , Yang Zheng , Yi Tan , Maiying Kong , Bo Wang , Wenke Feng , Paul N. Epstein , Jun Cai , Lu Cai
      Obstructive sleep apnea (OSA) causes chronic intermittent hypoxia (IH) to induce cardiovascular disease, which may be related to oxidative damage. Metallothionein (MT) has been extensively proved to be an endogenous and highly inducible antioxidant protein expressed in the heart. Therefore, we tested the hypotheses that oxidative stress plays a critical role in OSA induced cardiac damage and MT protects the heart from OSA-induced cardiomyopathy. To mimic hypoxia/reoxygenation events that occur in adult OSA patients, mice were exposed to IH for 3days to 8weeks. The IH paradigm consisted of alternating cycles of 20.9% O2/8% O2 FIO2 (30 episodes per hour) with 20s at the nadir FIO2 for 12h a day during daylight. IH significantly increased the ratio of heart weight to tibia length at 4weeks with a decrease in cardiac function from 4 to 8weeks. Cardiac oxidative damage and fibrosis were observed after 4 and 8weeks of IH exposures. Endogenous MT expression was up-regulated in response to 3-day IH, but significantly decreased at 4 and 8weeks of IH. In support of MT as a major compensatory component, mice with cardiac overexpression of MT gene and mice with global MT gene deletion were completely resistant, and highly sensitive, respectively, to chronic IH induced cardiac effects. These findings suggest that chronic IH induces cardiomyopathy characterized by oxidative stress-mediated cardiac damage and the antioxidant MT protects the heart from such pathological and functional changes.
      Graphical abstract image

      PubDate: 2014-03-22T08:27:09Z
       
 
 
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