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  Subjects -> ENVIRONMENTAL STUDIES (Total: 766 journals)
    - ENVIRONMENTAL STUDIES (703 journals)
    - POLLUTION (21 journals)
    - TOXICOLOGY AND ENVIRONMENTAL SAFETY (34 journals)
    - WASTE MANAGEMENT (8 journals)

ENVIRONMENTAL STUDIES (703 journals)            First | 1 2 3 4 5 6 7 8     

International Innovation - climate     Open Access  
International innovation. Environment     Open Access  
International Journal of Acarology     Hybrid Journal   (Followers: 1)
International Journal of Advancement in Earth and Enviromental Sciences     Open Access   (Followers: 2)
International Journal of African Renaissance Studies - Multi-, Inter- and Transdisciplinarity     Hybrid Journal   (Followers: 2)
International Journal of Agricultural and Environmental Information Systems     Full-text available via subscription   (Followers: 1)
International Journal of Alternative Propulsion     Hybrid Journal   (Followers: 1)
International Journal of Applied Psychoanalytic Studies     Hybrid Journal   (Followers: 2)
International Journal of Chinese Culture and Management     Hybrid Journal   (Followers: 1)
International Journal of Corrosion     Open Access   (Followers: 10)
International Journal of Critical Infrastructures     Hybrid Journal   (Followers: 3)
International Journal of Disaster Risk Reduction     Hybrid Journal   (Followers: 5)
International Journal of Disaster Risk Science     Open Access   (Followers: 8)
International Journal of Ecological Economics and Statistics     Full-text available via subscription   (Followers: 1)
International Journal of Ecology     Open Access   (Followers: 8)
International Journal of Ecology & Development     Full-text available via subscription   (Followers: 1)
International Journal of Energy and Environmental Engineering     Open Access   (Followers: 2)
International Journal of Environment     Open Access   (Followers: 3)
International Journal of Environment and Health     Hybrid Journal   (Followers: 7)
International Journal of Environment and Pollution     Hybrid Journal   (Followers: 6)
International Journal of Environment and Sustainable Development     Hybrid Journal   (Followers: 14)
International Journal of Environment and Waste Management     Hybrid Journal   (Followers: 5)
International Journal of Environment, Workplace and Employment     Hybrid Journal   (Followers: 3)
International Journal of Environmental Engineering     Hybrid Journal   (Followers: 5)
International Journal of Environmental Health Engineering     Open Access  
International Journal of Environmental Health Research     Hybrid Journal   (Followers: 3)
International Journal of Environmental Policy and Decision Making     Hybrid Journal   (Followers: 10)
International Journal of Environmental Protection     Open Access   (Followers: 12)
International Journal of Environmental Research and Public Health     Open Access   (Followers: 14)
International Journal of Environmental Science and Technology     Hybrid Journal   (Followers: 4)
International Journal of Environmental Studies     Hybrid Journal   (Followers: 11)
International Journal of Exergy     Hybrid Journal   (Followers: 3)
International Journal of Forest, Soil and Erosion     Open Access   (Followers: 3)
International Journal of Global Environmental Issues     Hybrid Journal   (Followers: 4)
International Journal of Global Warming     Hybrid Journal   (Followers: 5)
International Journal of Greenhouse Gas Control     Partially Free   (Followers: 6)
International Journal of Health Planning and Management     Hybrid Journal   (Followers: 6)
International Journal of Hygiene and Environmental Health     Hybrid Journal   (Followers: 6)
International Journal of Logistics Research and Applications : A Leading Journal of Supply Chain Management     Hybrid Journal   (Followers: 9)
International Journal of Philosophical Studies     Hybrid Journal   (Followers: 2)
International Journal of Phytoremediation     Hybrid Journal   (Followers: 1)
International Journal of Process Systems Engineering     Hybrid Journal   (Followers: 1)
International Journal of Recycling of Organic Waste in Agriculture     Open Access   (Followers: 1)
International Journal of Regulation and Governance     Hybrid Journal   (Followers: 2)
International Journal of Reliability and Safety     Hybrid Journal   (Followers: 5)
International Journal of Renewable Energy Development     Open Access   (Followers: 5)
International Journal of Social Sciences and Management     Open Access  
International Journal of Soil, Sediment and Water     Open Access   (Followers: 8)
International Journal of Stress Management     Full-text available via subscription   (Followers: 8)
International Journal of Sustainable Construction Engineering and Technology     Open Access   (Followers: 7)
International Journal of Sustainable Engineering     Hybrid Journal   (Followers: 7)
International Journal of Sustainable Materials and Structural Systems     Hybrid Journal   (Followers: 5)
International Journal of Sustainable Society     Hybrid Journal   (Followers: 7)
International Journal of Testing     Hybrid Journal   (Followers: 1)
International Journal of the Commons     Open Access   (Followers: 2)
International Journal of Toxicology     Hybrid Journal   (Followers: 6)
International Journal of Water Resources and Environmental Engineering     Open Access  
International Review of Environmental and Resource Economics     Full-text available via subscription  
International Studies in the Philosophy of Science     Hybrid Journal   (Followers: 9)
Interventions : International Journal of Postcolonial Studies     Hybrid Journal   (Followers: 5)
IOP Conference Series: Earth and Environmental Science     Open Access   (Followers: 7)
Iranian Journal of Environmental Health Science & Engineering     Open Access   (Followers: 1)
Iranian Studies     Hybrid Journal   (Followers: 8)
Irish Educational Studies     Hybrid Journal   (Followers: 1)
Irish Journal of Earth Sciences     Full-text available via subscription  
Irish Political Studies     Hybrid Journal   (Followers: 7)
ISLE: Interdisciplinary Studies in Literature and Environment     Hybrid Journal   (Followers: 2)
Isotopes in Environmental and Health Studies     Hybrid Journal   (Followers: 2)
Israel Studies     Full-text available via subscription   (Followers: 5)
ISRN Ecology     Open Access  
ISRN Environmental Chemistry     Open Access  
Jahangirnagar University Environmental Bulletin     Open Access  
Journal of Bioremediation & Biodegradation     Open Access   (Followers: 2)
Journal of Earth Science & Climatic Change     Open Access   (Followers: 8)
Journal of Petroleum & Environmental Biotechnology     Open Access   (Followers: 2)
Journal of Advances in Environmental Health Research     Open Access  
Journal of Agricultural and Environmental Ethics     Hybrid Journal   (Followers: 6)
Journal of Agricultural Biotechnology and Sustainable Development     Open Access  
Journal of Agriculture and Environment     Open Access  
Journal of Agriculture and Environment for International Development     Open Access   (Followers: 6)
Journal of Agrobiology     Open Access   (Followers: 2)
Journal of Applied Ecology     Hybrid Journal   (Followers: 149)
Journal of Applied Meteorology and Climatology     Full-text available via subscription   (Followers: 7)
Journal of Applied Psychoanalytic Studies     Hybrid Journal   (Followers: 1)
Journal of Applied Sciences and Environmental Management     Open Access   (Followers: 1)
Journal of Applied Sciences in Environmental Sanitation     Open Access   (Followers: 5)
Journal of Applied Toxicology     Hybrid Journal   (Followers: 9)
Journal of Applied Volcanology     Open Access   (Followers: 6)
Journal of Arid Environments     Hybrid Journal   (Followers: 8)
Journal of Asian Studies     Full-text available via subscription   (Followers: 21)
Journal of Biochemical and Molecular Toxicology     Hybrid Journal   (Followers: 5)
Journal of Black Studies     Hybrid Journal   (Followers: 2)
Journal of Chemical Ecology     Hybrid Journal   (Followers: 1)
Journal of Chemical Health and Safety     Hybrid Journal   (Followers: 2)
Journal of Climate     Full-text available via subscription   (Followers: 22)
Journal of Coastal Research     Full-text available via subscription   (Followers: 11)
Journal of Contaminant Hydrology     Hybrid Journal   (Followers: 9)
Journal of Contemporary European Studies     Hybrid Journal   (Followers: 3)
Journal of East African Natural History     Full-text available via subscription   (Followers: 5)
Journal of Ecology     Hybrid Journal   (Followers: 34)

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Journal Cover Journal of Applied Toxicology
   [11 followers]  Follow    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
     ISSN (Print) 0260-437X - ISSN (Online) 1099-1263
     Published by John Wiley and Sons Homepage  [1603 journals]   [SJR: 0.689]   [H-I: 47]
  • Comparative genotoxicity of nanosilver in human liver HepG2 and colon
           Caco2 cells evaluated by fluorescent microscopy of cytochalasin
           B‐blocked micronucleus formation
    • Authors: Saura C. Sahu; Shambhu Roy, Jiwen Zheng, Jeffrey J. Yourick, Robert L. Sprando
      Abstract: As a consequence of the increased use of silver nanoparticles in food, food contact materials, dietary supplements and cosmetics to prevent fungal and bacterial growth, there is a need for validated rapid screening methods to assess the safety of nanoparticle exposure. This study evaluated two widely used in vitro cell culture models, human liver HepG2 cells and human colon Caco2 cells, as tools for assessing the potential genotoxicity of 20‐nm nanosilver. The average silver nanoparticle size as determined by transmission electron microscopy (TEM) was 20.4 nm. Dynamic light scattering (DLS) analysis showed no large agglomeration of the silver nanoparticles. The silver concentration in a 20‐nm nanosilver solution determined by the inductively coupled plasma–mass spectrometry (ICP‐MS) analysis was 0.962 mg ml−1. Analysis by ICP‐MS and TEM demonstrated the uptake of 20‐nm silver by both HepG2 and Caco2 cells. Genotoxicity was determined by the cytochalasin B‐blocked micronucleus assay with acridine orange staining and fluorescence microscopy. Concentration‐ and time‐dependent increases in the frequency of binucleated cells with micronuclei induced by the nanosilver was observed in the concentration range of 0.5 to 15 µg ml−1 in both HepG2 and Caco2 cells compared with the control. Our results indicated that HepG2 cells were more sensitive than Caco2 cells in terms of micronuclei formation induced by nanosilver exposure. In summary, the results of this study indicate that the widely used in vitro models, HepG2 and Caco2 cells in culture, represent potential screening models for prediction of genotoxicity of silver nanoparticles by in vitro micronucleus assay. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.
      PubDate: 2014-06-06T09:15:06.224268-05:
      DOI: 10.1002/jat.3028
       
  • Time‐dependent bioaccumulation of distinct rod‐type TiO2
           nanoparticles: Comparison by crystalline phase
    • Authors: Eun-Jung Park; Gwang-Hee Lee, Cheolho Yoon, Min-Sung Kang, Soo Nam Kim, Myung-Haing Cho, Jae-Ho Kim, Dong-Wan Kim
      Abstract: A complete understanding of the interaction between nanoparticles and biological systems, including nanoparticle uptake and distribution and the biological responses, could guide the design of safer and more effective nanoparticles than those currently available. In this study, we compared the distribution in mice over time of two rod‐type titanium dioxide nanoparticles (TiNPs) that feature distinct phases, anatase (ATO) and brookite (BTO). Surface areas of BTO and ATO were estimated to be 102 and 268 m2 g–1, respectively, and negative charge on the surface of ATO was higher than that of BTO in deionized water. Both TiNPs were rapidly distributed into tissues after injection. At 4 weeks after injection, both TiNPs were maximally accumulated in the spleen, followed by the liver, but the total accumulation of ATO in tissues measured in this study was more than that of BTO. Moreover, the cellular antioxidant function was similar although the levels of Ti measured in tissues were distinct between the two TiNPs. Based on these results, we suggest that the fate of TiNPs in the body may differ according to the size and surface charge of the TiNPs even when their shape is the same. Copyright © 2014 John Wiley & Sons, Ltd.
      PubDate: 2014-05-29T08:38:10.446352-05:
      DOI: 10.1002/jat.3006
       
  • Vascular endothelial growth factor mRNA levels as a biomarker for
           short‐term N‐butyl‐N‐(4‐hydroxybutyl)
           nitrosamine‐induced rat bladder carcinogenesis bioassay
    • Authors: Shin Wakui; Tomoko Mutou, Hiroyuki Takahashi, Masahiro Ikegami, Hideki Wanibuchi, Shoji Fukushima
      Abstract: Generically, carcinogenic effects of chemicals in bladder carcinogenesis are judged by induction of papillary or nodular (PN) hyperplasia in rats given N‐butyl‐N‐(4‐hydroxybutyl) nitrosamine (BBN) for 4 weeks and the test chemical for 22–28 weeks. However, upregulation of vascular endothelial growth factor (VEGF) begins early in rat BBN bladder carcinogenesis. To establish a short‐term rat bladder carcinogenic bioassay, we analyzed the correlations between VEGF, VEGF mRNA and bladder lesions inductions at 10 and 26 weeks after BBN treatment. Six‐week‐old male Wistar (slc) rats were given 0.05% BBN for 4, 10 or 26 weeks. To avoid individual rat bias, the bladders were investigated by partial cystectomy at 10 weeks and total cystectomy at 26 weeks. After induction, PN hyperplasia and carcinoma in rats increased with the length of BBN treatment and immunohistochemical VEGF expression also increased following carcinogenesis, but the immunoreactivity of individual lesions was quite variable. Moreover, induction of PN hyperplasia at 10 weeks’ BBN treatment was not significantly correlated with that at 26 weeks' treatment; thus, it was not possible to predict the carcinogenic effect due to the induction of PN hyperplasia at 26 weeks' BBN treatment by that at 10 weeks' treatment. However, VEGF mRNA levels of rat bladders at 10 weeks' BBN treatment revealed a strong significant correlation with the incidence of bladder lesions at 26 weeks' treatment. Here, we suggest that quantitative VEGF mRNA levels are a good biomarker for a short‐term BBN‐induced bioassay for rat bladder carcinogenesis. Copyright © 2014 John Wiley & Sons, Ltd.
      PubDate: 2014-05-28T09:25:42.146279-05:
      DOI: 10.1002/jat.3021
       
  • Development of haemostatic decontaminants for the treatment of wounds
           contaminated with chemical warfare agents. 1: Evaluation of in vitro
           clotting efficacy in the presence of certain contaminants
    • Abstract: The treatment of penetrating, haemorrhaging injuries sustained within a hazardous environment may be complicated by contamination with toxic chemicals. There are currently no specific medical countermeasures for such injuries. Haemostats with an absorbent mechanism of action have the potential to simultaneously stop bleeding and decontaminate wounds. However, a primary requirement of a ‘haemostatic decontaminant’ is the retention of clotting function in the presence of chemical contaminants. Thus, the aim of this study was to investigate the haemostatic efficacy of seven commercially available haemostats in the presence of toxic chemicals (soman, VX, sulphur mustard, petrol, aviation fuel and motor oil). Clot viscosity was assessed ex vivo using thrombelastography following treatment of pig blood with: (i) toxic chemical; (ii) haemostat; or (iii) haemostat in combination with toxic chemical. Several contaminants (VX, petrol and GD) were found to be pro‐haemostatic and none had an adverse effect on the rate with which the test products attained haemostasis. However, the total clot strength for blood treated with certain haemostats in the presence of sulphur mustard, soman and petrol was significantly decreased. Three test products failed to demonstrate haemostatic function in this ex vivo (thrombelastography) model; this was tentatively ascribed to the products achieving haemostasis through a tamponade mechanism of action, which can only be replicated using in vivo models. Overall, this study has identified a number of commercial products that may have potential as haemostatic decontaminants and warrant further investigation to establish their decontaminant efficacy. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Cardiolipin profiles as a potential biomarker of mitochondrial health in
           diet‐induced obese mice subjected to exercise,
           diet‐restriction and ephedrine treatment
    • Abstract: Cardiolipin (CL) is crucial for mitochondrial energy metabolism and structural integrity. Alterations in CL quantity or CL species have been associated with mitochondrial dysfunction in several pathological conditions and diseases, including mitochondrial dysfunction‐related compound attrition and post‐market withdrawal of promising drugs. Here we report alterations in the CL profiles in conjunction with morphology of soleus muscle (SM) and brown adipose tissue (BAT) in diet‐induced obese (DIO) mice, subjected to ephedrine treatment (EPH: 200 mg kg–1 day–1 orally), treadmill exercise (EX: 10 meters per min, 1 h per day), or dietary restriction (DR: 25% less of mean food consumed by the EX group) for 7 days. Mice from the DR and EPH groups had a significant decrease in percent body weight and reduced fat mass compared with DIO controls. Morphologic alterations in the BAT included brown adipocytes with reduced cytoplasmic lipid droplets and increased cytoplasmic eosinophilia in the EX, DR and EPH groups. Increased cytoplasmic eosinophilia in the BAT was ultrastructurally manifested by increased mitochondrial cristae, fenestration of mitochondrial cristae, increased electron density of mitochondrial matrix, and increased complexity of shape and elongation of mitochondria. Mitochondrial ultrastructural alterations in the SM of the EX and DR groups included increased mitochondrial cristae, cup‐shaped mitochondria and mitochondrial degeneration. All four CL species (tri‐linoleoyl‐mono‐docosahexaenoyl, tetralinoleoyl, tri‐linoleoyl‐mono‐oleoyl, and di‐linoleoyl‐di‐oleoyl) were increased in the BAT of the DR and EPH groups and in the SM of the EPH and EX groups. In conclusion, cardiolipin profiling supported standard methods for assessing mitochondrial biogenesis and health, and may serve as a potential marker of mitochondrial dysfunction in preclinical toxicity studies. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • In utero and early childhood exposure to arsenic decreases lung function
           in children
    • Abstract: The lung is a target organ for adverse health outcomes following exposure to As. Several studies have reported a high prevalence of respiratory symptoms and diseases in subjects highly exposed to As through drinking water; however, most studies to date has been performed in exposed adults, with little information on respiratory effects in children. The objective of the study was to evaluate the association between urinary levels of As and its metabolites with lung function in children exposed in utero and in early childhood to high As levels through drinking water. A total of 358 healthy children were included in our study. Individual exposure was assessed based on urinary concentration of inorganic As. Lung function was assessed by spirometry. Participants were exposed since pregnancy until early childhood to an average water As concentration of 152.13 µg l–1. The mean urinary As level registered in the studied subjects was 141.2 µg l–1 and only 16.7% had a urinary concentration below the national concern level. Forced vital capacity was significantly decreased in the studied population and it was negatively associated with the percentage of inorganic As. More than 57% of the subjects had a restrictive spirometric pattern. The urinary As level was higher in those children with restrictive lung patterns when compared with the levels registered in subjects with normal spirometric patterns. Exposure to As through drinking water during in utero and early life was associated with a decrease in forced vital capacity and with a restrictive spirometric pattern in the children evaluated. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Protective role of L‐ascorbic acid, N‐acetylcysteine and
           apocynin on neomycin‐induced hair cell loss in Zebrafish
    • Abstract: Hair cells are highly sensitive to environmental insults and other therapeutic drugs. The adverse effects of drugs such as aminoglycosides can cause hair cell death and lead to hearing loss and imbalance. The objective of the present study was to evaluate the protective activity of L‐ascorbic acid, N‐acetylcysteine (NAC) and apocynin on neomycin‐induced hair cell damage in zebrafish (Danio rerio) larvae at 5 days post fertilization (dpf). Results showed that the loss of hair cells within the neuromasts of the lateral lines after neomycin exposure was evidenced by a significantly lower number of neuromasts labeled with fluorescent dye FM1‐43FX observed under a microscope. Co‐administration with L‐ascorbic acid, NAC and apocynin protected neomycin‐induced hair cell loss within the neuromasts. Moreover, these three compounds reduced the production of reactive oxygen species (ROS) in neuromasts exposed to neomycin, indicating that their antioxidant action is involved. In contrast, the neuromasts were labeled with specific fluorescent dye Texas‐red conjugated with neomycin to detect neomycin uptake. Interestingly, the uptake of neomycin into hair cells was not influenced by these three antioxidant compounds. These data imply that prevention of hair cell damage against neomycin by L‐ascorbic acid, NAC and apocynin might be associated with inhibition of excessive ROS production, but not related to modulating neomycin uptake. Our findings conclude that L‐ascorbic acid, NAC and apocynin could be used as therapeutic drugs to protect aminoglycoside‐induced listening impairment after further confirmatory studies. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Analysis of drugs of abuse in human plasma by dispersive
           liquid–liquid microextraction and high‐performance liquid
           chromatography
    • Abstract: Opioids and cocaine are widely used at present, both for recreational purposes and as drugs of abuse. This raises the need to develop new analytical methods specifically designed for the simultaneous detection of several drugs of abuse in biological samples. In this work, dispersive liquid–liquid microextraction (DLLME) was assessed as a new sample treatment for the simultaneous extraction of morphine (MOR), 6‐acetylmorphine (6AM), cocaine (COC), benzoylecgonine (BZE) and methadone (MET) from human plasma. Preliminary assays were done before developing an experimental design based on a Uniform Network Doehlert which allowed the optimum extraction conditions to be identified, namely: a volume of extractant solvent (chloroform) and dispersant solvent (acetonitrile) of 220 µl and 3.2 ml, respectively; 0.2 g of NaCl as a salting‐out additive; pH 10.6 and ultrasound stirring for 3.5 min. The resulting extracts were analyzed by high‐performance liquid chromatography with photodiode array detection (HPLC‐PDA), using an XBridge® RP18 column (250 × 4.6 mm i.d., 5 µm particle size). Calibration graphs were linear over the concentration range 0.1–10 µg ml–1, and detection limits ranged from 13.9 to 28.5 ng ml–1. Precision calculated at three different concentration levels in plasma was included in the range 0.1–6.8% RSD. Recoveries of the five drugs were all higher than 84% on average. Finally the proposed method was successfully applied to 22 plasma samples from heroin, cocaine and/or methadone users, and the most frequently detected drug was benzoylecgonine, followed by methadone, cocaine and morphine. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • The relationship between chemical‐induced kidney weight increases
           and kidney histopathology in rats
    • Abstract: The kidney is a major site of chemical excretion, which results in its propensity to exhibit chemically‐induced toxicological effects at a higher rate than most other organs. Although the kidneys are often weighed in animal toxicity studies, the manner in which these kidney weight measurements are interpreted and the value of this information in predicting renal damage remains controversial. In this study we sought to determine whether a relationship exists between chemically‐induced kidney weight changes and renal histopathological alterations. We also examined the relative utility of absolute and relative (kidney‐to‐body weight ratio) kidney weight in the prediction of renal toxicity. For this, data extracted from oral chemical exposure studies in rats performed by the National Toxicology Program were qualitatively and quantitatively evaluated. Our analysis showed a statistically significant correlation between absolute, but not relative, kidney weight and renal histopathology in chemically‐treated rats. This positive correlation between absolute kidney weight and histopathology was observed even with compounds that statistically decreased terminal body weight. Also, changes in absolute kidney weight, which occurred at subchronic exposures, were able to predict the presence or absence of kidney histopathology at both subchronic and chronic exposures. Furthermore, most increases in absolute kidney weight reaching statistical significance (irrespective of the magnitude of change) were found to be relevant for the prediction of histopathological changes. Hence, our findings demonstrate that the evaluation of absolute kidney weight is a useful method for identifying potential renal toxicants. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Systemic drugs inducing non‐immediate cutaneous adverse reactions
           and contact sensitizers evoke similar responses in THP‐1 cells
    • Abstract: Contact sensitizers induce phenotypic and functional changes in dendritic cells (DC) that enhance their antigen‐presenting capacity and, ultimately, modulate the T cell response. To evaluate if there is a similar effect of drugs causing T‐cell‐mediated cutaneous adverse drug reactions (CADR), we studied the in vitro effect of drugs on THP‐1 cells, a cell line widely used to evaluate the early molecular and cellular events triggered by contact sensitizers. The effect of allopurinol, oxypurinol, ampicillin, amoxicillin, carbamazepine and sodium valproate, at EC30 concentrations, was evaluated on p38 MAPK activation, by Western Blot, and on the expression of genes coding for DC maturation markers, pro‐inflammatory cytokine/chemokines and hemeoxygenase 1 (HMOX1), by real‐time RT‐PCR. Results were compared with lipopolysaccharide (LPS), a DC maturation stimulus, and the strong contact sensitizer, 1‐fluoro‐2,4‐dinitrobenzene (DNFB). All drugs studied significantly upregulated HMOX1 gene transcription and all, except the anticonvulsants, also upregulated IL8. Allopurinol and oxypurinol showed the most intense effect, in a magnitude similar to DNFB and superior to betalactams. Transcription of CD40, IL12B and CXCL10 genes by drugs was more irregular. Moreover, like DNFB, all drugs activated p38 MAPK, although significantly only for oxypurinol. Like contact sensitizers, drugs that cause non‐immediate CADR activate THP‐1 cells in vitro, using different signalling pathways and affecting gene transcription with an intensity that may reflect the frequency and severity of the CADR they cause. Direct activation of antigen‐presenting DC by systemic drugs may be an important early step in the pathophysiology of non‐immediate CADR. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Plasma miR‐208 as a useful biomarker for drug‐induced
           cardiotoxicity in rats
    • Abstract: Cardiotoxicity is one of the major safety concerns in drug development. Therefore, detecting and monitoring cardiotoxicity throughout preclinical and clinical studies is important for pharmaceutical companies. The present study was conducted in order to explore a plasma miRNA biomarker for cardiotoxicity in rats. As organ specificity is an important factor for a biomarker, we analyzed the miRNA microarray dataset in 55 organs/tissues in normal male rats. Based on this analysis, 5 miRNAs consisting of miR‐208 (heart‐specific), miR‐1, miR‐133a, miR‐133b (heart and skeletal muscle‐specific) and miR‐206 (skeletal muscle‐specific) were selected. Next, we evaluated the usefulness of those 5 miRNAs as circulating biomarkers in rats administered with single‐dose isoproterenol or doxorubicin. Plasma miR‐208 was consistently increased through 24 h after dosing in rats administered with isoproterenol, whereas plasma concentrations of cardiac troponin (cTn) showed transient elevation. In contrast, the plasma levels of miR‐1, miR‐133a, miR‐133a and miR‐206 were elevated after treatment with doxorubicin, probably as a result of skeletal muscle toxicity. Additionally, the plasma miR‐208 level was elevated even after repeat‐dose administration (once daily for 7 days) of isoproterenol under which the pathological condition proceeded to the sub‐chronic phase such as fibrosis. Thus, our data suggest that miR‐208 is a promising plasma biomarker for cardiotoxicity in rats. Monitoring of plasma miR‐208 levels in rats may lead to more accurate evaluation of cardiotoxicity in preclinical studies. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Rapid determination of quetiapine in blood by gas
           chromatography–mass spectrometry. Application to post‐mortem
           cases
    • Abstract: A simple, fast and sensitive method for the determination of quetiapine in human blood has been developed and validated. The method involved a basic liquid–liquid extraction procedure and subsequent analysis by gas chromatography–mass spectrometry, previous derivatization with bis(trimethylsilyl)‐trifluoro‐acetamide and chorotrimethylsilane (99 : 1). The methods of validation included linearity with a correlation coefficient > 0.99 over the range 0.02–1 µg ml–1, intra‐ and interday precision (always 
       
  • Borrelidin has limited anti‐cancer effects in bcl‐2
           overexpressing breast cancer and leukemia cells and reveals toxicity in
           non‐malignant breast epithelial cells
    • Abstract: Clinically effective anti‐cancer drugs have to tread a narrow line between selective cytotoxicity on tumor cells and tolerable adverse effects against healthy tissues. This causes the failure of many potential cancer drugs in advanced clinical trials, hence signifying the importance of a comprehensive initial estimate of the cytotoxicity of prospective anti‐cancer drugs in preclinical studies. In this study, the cytotoxicity of borrelidin, a macrolide antibiotic with a high cytotoxic selectivity for proliferating endothelial cells and leukemia cells, was tested on malignant and non‐malignant breast cells. Highly metastatic breast cancer cell lines (MDA‐MB‐231 and MDA‐MB‐435) showed promising results and exhibited good sensitivity to borrelidin at low nanomolar concentrations, but borrelidin was cytotoxic to a non‐malignant breast epithelial cell line (MCF10A) as well. Furthermore, although a high sensitivity of endothelial cells (human umbilical vein endothelial cells; HUVEC) and individual leukemia cell lines (Jurkat and IM9) to borrelidin was confirmed in this study, another leukemia cell line (HL60) and an immortalized endothelial cell line (EA.hy926) displayed a significantly decreased sensitivity. Reduced sensitivity to borrelidin was associated with elevated bcl‐2 expression in these cell lines. In conclusion, the results presented show that borrelidin displays high and selective cytotoxicity against subgroups of cancer cells and endothelial cells, but, owing to its non‐specific toxicity to non‐malignant cells, its clinical application might be restricted because of likely adverse effects and limited efficacy in bcl2‐overexpressing cancer cells. Copyright © 2013 John Wiley & Sons, Ltd.
       
  • Prophylactic administration of non‐organophosphate cholinesterase
           inhibitors before acute exposure to organophosphates: assessment using
           terbufos sulfone
    • Abstract: Poisoning with organophosphorus compounds (OPCs) poses a serious threat worldwide. OPC‐induced mortality can be significantly reduced by prophylactic administration of reversible acetylcholinesterase (AChE) inhibitors. The only American Food and Drug Administration (FDA)‐approved substance for such pre‐treatment (to soman exposure) is presently pyridostigmine, although its efficacy is controversial. In search for more efficacious and broad‐spectrum alternatives, we have assessed in vivo the mortality‐reducing efficacy of a group of five compounds with known AChE inhibitory activity (pyridostigmine, physostigmine, ranitidine, tacrine and K‐27), when given in equitoxic dosage (25% of LD01) 30 min before exposure to the OPC terbufos sulfone. Protection was quantified in rats by determining the relative risk of death (RR) using Cox analysis, with RR = 1 for animals given only terbufos sulfone, but no pre‐treatment. All tested AChE inhibitors reduced terbufos sulfone‐induced mortality significantly (p ≤ 0.05) as compared with the non‐treatment group (RR = 1: terbufos sulfone only). Best in vivo protection from terbufos sulfone‐induced mortality was achieved, when K‐27 was given before terbufos sulfone exposure (RR = 0.06), which was significantly (P ≤ 0.05) superior to the pre‐treatment with all other tested compounds, for example tacrine (RR = 0.21), pyridostigmine (RR = 0.28), physostigmine (RR = 0.29) and ranitidine (RR = 0.33). The differences in efficacy between tacrine, pyridostigmine, physostigmine and ranitidine were not statistically significant. Prophylactic administration of an oxime (such as K‐27) in case of imminent OPC exposure may be a viable option. Copyright © 2013 John Wiley & Sons, Ltd.
       
  • Identification of metabolomic biomarkers for drug‐induced acute
           kidney injury in rats
    • Abstract: Nephrotoxicity is a common side effect observed during both nonclinical and clinical drug development investigations. The present study aimed to identify metabolomic biomarkers that could provide early and sensitive indication of nephrotoxicity in rats. Metabolomic analyses were performed using capillary electrophoresis–time‐of‐flight mass spectrometry on rat plasma collected at 9 and 24 h after a single dose of 2‐bromoethylamine or n‐phenylanthranilic acid and at 24 h after 7 days of repeated doses of gentamicin, cyclosporine A or cisplatin. Among a total of 169 metabolites identified, 3‐methylhistidine (3‐MH), 3‐indoxyl sulfate (3‐IS) and guanidoacetate (GAA) were selected as candidate biomarkers. The biological significance and reproducibility of the observed changes were monitored over time in acute nephrotoxicity model rats treated with a single dose of cisplatin, with the glomerular filtration rate monitored by determination of creatinine clearance. Increased plasma levels of 3‐MH and 3‐IS were related to a decline in glomerular filtration due to a renal failure. In contrast, the decrease in plasma GAA, which is synthesized from arginine and glycine in the kidneys, was considered to reflect decreased production due to renal malfunction. Although definitive validation studies are required to confirm their usefulness and reliability, 3‐MH, 3‐IS and GAA may prove to be valuable plasma biomarkers for monitoring nephrotoxicity in rats. Copyright © 2013 John Wiley & Sons, Ltd.
       
  • Long‐term maintenance of HepaRG cells in serum‐free conditions
           and application in a repeated dose study
    • Abstract: Chronic repeated‐dose toxicity studies are still carried out on animals and often do not correlate with the effects in human beings mainly due to species‐specific differences in biotransformation. The human hepatoma cell line HepaRG has been used for human relevant toxicity assessment. However, HepaRG cells are commonly maintained in serum containing medium which limits their use in ’omics‘‐based toxicology. In this study, we compared the maintenance of HepaRG cells in standard serum‐supplemented and serum‐free conditions. Viability and Cytochrome P450 (CYP) activity during long‐term cultivation were assessed. Liver‐specific albumin and urea production was measured. The extracellular metabolome (amino acids, glucose, lactate and pyruvate) was measured to compare different cultivation conditions using metabolic flux analysis. Although metabolic flux analysis reveals differences in certain parts of the metabolism, e.g. production of urea, the overall metabolism of serum‐free and serum‐supplemented cultured HepaRG cells is similar. We conclude that HepaRG cells can be maintained in optimized serum‐free conditions for 30 days without viability change and with high CYP activity. We also tested the acute (24 h) and long‐term repeated‐dose (7 doses, every second day) toxicity of valproic acid. We calculated an EC50 value of 1.4 mM after repeated exposure which is close to the cmax value for valproic acid. Maintenance of HepaRG cells in serum‐free conditions opens up the opportunity for the use of these cells in human long‐term repeated‐dose hepatotoxicity studies and for application in systems toxicology. Copyright © 2013 John Wiley & Sons, Ltd.
       
  • A proposal to improve clarity and communication in the EU Classification
           process for chemicals for carcinogenicity and reproductive and
           developmental toxicity
    • Abstract: There is an issue in the EU classification of substances for carcinogenicity and for reproductive or developmental toxicity which has brought difficulties to those involved in the process. The issue lies in the inability of the classification system to distinguish between carcinogens and reproductive toxicants with different levels of concern. This has its origins in the early years of toxicology when it was thought that a relatively small number of chemicals would be either carcinogens or reproductive toxicants, but this has turned out not to be the case. This can cause problems in communicating to the users of chemicals, including the public, the nature of the hazard presented by chemicals. Processes have been developed within the classification system for setting specific concentration limits which assess the degree of hazard for carcinogens and reproductive toxicants as high, medium or low. However these categories are not otherwise used in classification. It is proposed that their wider use would bring the advantages of transparency, clarity of communication, certainty of the process and would allow chemicals with a high degree of hazard to be identified and managed in an appropriate way. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Elevated levels of antibodies against xenobiotics in a subgroup of healthy
           subjects
    • Abstract: In spite of numerous research efforts, the exact etiology of autoimmune diseases remains largely unknown. Genetics and environmental factors, including xenobiotics, are believed to be involved in the induction of autoimmune disease. Some environmental chemicals, acting as haptens, can bind to a high‐molecular‐weight carrier protein such as human serum albumin (HSA), causing the immune system to misidentify self‐tissue as an invader and launch an immune response against it, leading to autoimmunity. This study aimed to examine the percentage of blood samples from healthy donors in which chemical agents mounted immune challenges and produced antibodies against HSA‐bound chemicals. The levels of specific antibodies against 12 different chemicals bound to HSA were measured by ELISA in serum from 400 blood donors. We found that 10% (IgG) and 17% (IgM) of tested individuals showed significant antibody elevation against aflatoxin‐HSA adduct. The percentage of elevation against the other 11 chemicals ranged from 8% to 22% (IgG) and 13% to 18% (IgM). Performance of serial dilution and inhibition of the chemical–antibody reaction by specific antigens but not by non‐specific antigens were indicative of the specificity of these antibodies. Although we lack information about chemical exposure in the tested individuals, detection of antibodies against various protein adducts may indicate chronic exposure to these chemical haptens in about 20% of the tested individuals. Currently the pathological significance of these antibodies in human blood is still unclear, and this protein adduct formation could be one of the mechanisms by which environmental chemicals induce autoimmune reactivity in a significant percentage of the population. Copyright © 2014. The
      Authors . Journal of Applied Toxicology Published by John Wiley & Sons Ltd.
       
  • Cytotoxic and apoptotic activities of the plancitoxin I from the venom of
           crown‐of‐thorns starfish (Acanthaster planci) on A375.S2 cells
           
    • Abstract: This study reports on a cytotoxic toxin derived from the venom of the crown‐of‐thorns starfish Acanthaster planci (CAV). The protein toxin was isolated through both ion‐exchange and gel‐filtration chromatography, and characterized by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS–PAGE) and mass spectrum analyzes. The CAV was identified as plancitoxin I protein. The mechanistic role of the CAV toxin was explored in human malignant melanoma A375.S2 cell death. The results indicated that after incubation with CAV toxin, cells significantly decreased in A375.S2 cell viability and increased in the lactate dehydrogenase (LDH) level in a dose‐dependent manner. The assays indicated that CAV toxin promoted reactive oxygen species (ROS) production, induced nitric oxide (NO) formation, lost mitochondrial membrane potential (ΔΨm) and induced inter‐nucleosomal DNA fragmentation in A375.S2 cells. The molecular cytotoxicity of the CAV toxin was tested through evaluation of the apoptosis/necrosis ratio by double staining with annexin V‐FITC and a propidium iodide (PI) assay. The results suggested that CAV toxin induced a cytotoxic effect in A375.S2 cells via the apoptotic procedure, and may be associated with the regulation of the p38 pathways. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Characterization of Oryzias latipes glucocorticoid receptors and their
           unique response to progestins
    • Abstract: Various receptor bioassays, including estrogens, androgens and thyroid hormones, have been developed and applied successfully for assessing hormone function in a wide range of animal species, including fish. In fish, corticosteroids play a pivotal role in physiology as they do in mammals, but far less is known about the corticosteroid receptor system in fish compared with in mammals. Here we established a transient transactivation assay using the Japanese medaka, Oryzias latipes, glucocorticoid receptors (olGRs) and mineralocorticoid receptor to analyse their functional properties in a fish. We found that olGR2 was highly responsive to glucocorticoids, similar to the human GR, whereas the olGR1 subtype was minimally responsive. Thus, olGR2 most likely mediates glucocorticoid signaling in medaka. We further tested crosstalk between GRs and other steroid hormones, and found that progestins could activate or inactivate olGR2‐mediating transcription, depending on the presence or absence of cortisol. The transactivation assays developed for medaka GRs provide tools to gain useful insights into corticosteroid signaling in fish and for in vitro screening of environmental substances activating GRs. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • In vitro evaluation of the effects of perfluorooctanesulfonic acid (PFOS)
           and perfluorooctanoic acid (PFOA) on IL‐2 production in human
           T‐cells
    • Abstract: Perfluorinated compounds, such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), have been shown to alter various immune functions suggesting they are immunotoxic. This study assessed the effects of PFOS and PFOA on interleukin (IL)‐2 production in the human Jurkat T‐cell line and PFOS in healthy human primary T cells. Jurkat cells were stimulated with phytohemagglutinin (PHA)/phorbol myristate acetate (PMA), anti CD‐3/anti CD‐28, or anti CD‐3, and dosed with 0, 0.05, 0.1, 0.5, 1, 5, 10, 50, 75, or 100 µg ml−1 PFOS or 0, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 5, or 10 µg ml−1 PFOA. Jurkat cells stimulated with PHA/PMA or anti CD‐3 exhibited decreased IL‐2 production beginning at 50 µg PFOS ml−1 and 5 µg PFOS ml−1 respectively, but stimulation with anti‐CD3/anti‐CD28 resulted in no changes compared with the control. Addition of the PPAR‐alpha antagonist GW6471 to PFOS‐dosed cells stimulated with PHA/PMA resulted in decreases in IL‐2 production starting at 50 µg PFOS ml−1, which suggests PFOS affected T‐cell IL‐2 production via PPAR‐alpha‐independent mechanisms. Exposure to PFOA, PFOA + GW6471, or PFOS + PFOA in Jurkat cells resulted in no significant differences in IL‐2 production. In vitro dosing studies using healthy primary human CD4+ T cells were consistent with the Jurkat results. These data demonstrated that PFOA did not impact IL‐2 production, but PFOS suppressed IL‐2 production in both a human cell line and human primary cells at dose levels within the high end of the human exposure range. A decrease in IL‐2 production is characteristic of autoimmune diseases such as systemic lupus erythematosus and should be further investigated. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Diisocyanates, occupational asthma and IgE antibody: implications for
           hazard characterization
    • Abstract: Sensitization of the respiratory tract by chemicals resulting in rhinitis and asthma is an important occupational health issue. Occupational asthma is associated with significant morbidity and can be fatal. Tests for the identification and characterization of chemicals with the potential to cause sensitization of the respiratory tract are lacking. In spite of sustained interest there are no validated or widely accepted methods available, and this presents toxicologists with a considerable challenge. One important constraint on the development of appropriate testing strategies has been uncertainty and controversy about the immunological mechanisms through which chemicals may induce sensitization of the respiratory tract. By analogy with protein respiratory allergy it is legitimate to consider that IgE antibody‐dependent mechanisms may play a pivotal role. However, although many aspects of chemical respiratory allergy are consistent with reactions caused by IgE antibody, uncertainty remains because among patients with occupational asthma caused by chemical respiratory allergens there are commonly a proportion, and sometimes a significant proportion, of subjects that lack detectable IgE antibody. Here we consider the relevance of IgE antibody responses for the development of a chemical respiratory allergy to diisocyanates. A case is made that IgE antibody responses are, either directly or indirectly, closely associated with occupational asthma to the diisocyanates (and to other chemical respiratory allergens). As such the argument is advanced here that IgE antibody represents an appropriate readout for the characterization of chemical respiratory allergens, and that uncertainty about mode of action should no longer represent a hurdle in the development of suitable test methods. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Toxicity profiles and solvent–toxicant interference in the planarian
           Schmidtea mediterranea after dimethylsulfoxide (DMSO) exposure
    • Abstract: To investigate hydrophobic test compounds in toxicological studies, solvents like dimethylsulfoxide (DMSO) are inevitable. However, using these solvents, the interpretation of test compound‐induced responses can be biased. DMSO concentration guidelines are available, but are mostly based on acute exposures involving one specific toxicity endpoint. Hence, to avoid solvent–toxicant interference, we use multiple chronic test endpoints for additional interpretation of DMSO concentrations and propose a statistical model to assess possible synergistic, antagonistic or additive effects of test compounds and their solvents. In this study, the effects of both short‐ (1 day) and long‐term (2 weeks) exposures to low DMSO concentrations (up to 1000 µl l−1) were studied in the planarian Schmidtea mediterranea. We measured different biological levels in both fully developed and developing animals. In a long‐term exposure set‐up, a concentration of 500 µl l−1 DMSO interfered with processes on different biological levels, e.g. behaviour, stem cell proliferation and gene expression profiles. After short exposure times, 500 µl l−1 DMSO only affected motility, whereas the most significant changes on different parameters were observed at a concentration of 1000 µl l−1 DMSO. As small sensitivity differences exist between biological levels and developmental stages, we advise the use of this solvent in concentrations below 500 µl l−1 in this organism. In the second part of our study, we propose a statistical approach to account for solvent–toxicant interactions and discuss full‐scale solvent toxicity studies. In conclusion, we reassessed DMSO concentration limits for different experimental endpoints in the planarian S. mediterranea. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Toxicity of new emerging pollutant tris‐(2,3‐dibromopropyl)
           isocyanurate on BALB/c mice
    • Abstract: The emerging heterocyclic brominated flame retardant tris‐(2,3‐dibromopropyl) isocyanurate (TBC), widely used in reinforced plastics, has demonstrated toxicity to fish. However, little is known about its toxicity in rodents. This study aims to determine the effect of TBC on growth, biochemical parameters in serum, organs and related gene expression of both male and female BALB/c mice after gastro‐gavage administration of 0, 2, 10 and 50 mg kg−1 TBC for 28 days. Results indicated that exposure to TBC had no effects on basic growth and food intake of mice, but significantly increased serum alanine aminotransferase levels in male mice. Histopathological analyses showed that focal necrosis (2, 10 and 50 mg kg−1 TBC‐exposed groups) and ballooning degeneration (10 and 50 mg kg−1 TBC‐exposed groups) were found in mouse liver, whereas transmission electron microscopy revealed dose‐dependent hepatocyte apoptosis, mitochondrial degeneration and endoplasmic reticulum dilation. Histopathological and ultrastructural assessments in the lung showed dose‐dependent hyperplasia of pulmonary alveolar epithelium, bronchial congestion, infiltration of inflammatory cells and mitochondrial swelling following TBC exposure. Our results also indicated that mitochondria are one of the major target cytoplasmic organelles for TBC, suggesting that damage in mitochondria is one of the pathways that led to toxic effects in the liver and lung of TBC‐treated groups. Moreover, TBC effectively activated the gene expression of p53 in mice liver. Our findings provide strong evidence that TBC induces significant toxicity in mice organs, especially in liver and lung, which play vital roles in detoxification and gas exchange, respectively. This research will contribute to characterize the toxic effects of TBC, which was introduced as one of the candidates for brominated flame retardant replacement. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Renal cells exposed to cadmium in vitro and in vivo: normalizing gene
           expression data
    • Abstract: Cadmium (Cd) is a toxic metal with a long half‐life in biological systems. This half‐life is partly as a result of metallothioneins (MTs), metal‐binding proteins with a high affinity for Cd. The high retention properties of the kidneys reside in proximal tubular cells that possess transport mechanisms for Cd‐MT uptake, ultimately leading to more Cd accumulation. Researchers have studied MT–metal interactions using various techniques including quantitative real‐time PCR (qPCR), an efficient tool for quantifying gene expression. Often a poor choice of reference genes, which is represented by their instability and condition dependency, leads to inefficient normalization of gene expression data and misinterpretations. This study demonstrates the importance of an efficient normalization strategy in toxicological research. A selection of stable reference genes was proposed in order to acquire reliable and reproducible gene quantification under metal stress using MT expression as an example. Moreover, in vitro and in vivo setups were compared to identify the influence of toxicological compounds in function of the experimental design. This study shows that glyceraldehyde‐3‐phosphate dehydrogenase (Gapdh), tyrosine monooxygenase/tryptophan5‐monooxygenase activation‐protein, zeta polypeptide (Ywhaz) and beta‐actin (Actb) are the most stable reference genes in a kidney proximal tubular cell line exposed to moderate and high Cd concentrations, applied as CdCl2. A slightly different sequence in reference gene stability was found in renal cells isolated from rats in vivo exposed to Cd. It was further shown that three reference genes are required for efficient normalization in this experimental setup. This study demonstrates the importance of an efficient normalization strategy in toxicological research. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Inhibitory effect of apocynin on methylglyoxal‐mediated glycation in
           osteoblastic MC3T3‐E1 cells
    • Abstract: Methylglyoxal (MG), a highly reactive metabolite of hyperglycemia, can enhance protein glycation, oxidative stress or inflammation. The present study investigated the effects of apocynin on the mechanisms associated with MG toxicity in osteoblastic MC3T3‐E1 cells. Pretreatment of MC3T3‐E1 cells with apocynin prevented the MG‐induced protein glycation and formation of intracellular reactive oxygen species and mitochondrial superoxide in MC3T3‐E1 cells. In addition, apocynin increased glutathione levels and restored the activity of glyoxalase I inhibited by MG. These findings suggest that apocynin provide a protective action against MG‐induced cell damage by reducing oxidative stress and by increasing the MG detoxification system. Apocynin treatment decreased the levels of proinflammatory cytokines such as tumor necrosis factor‐α and interleukin‐6 induced by MG. Additionally, the nitric oxide level reduced by MG was significantly increased by apocynin. These findings indicate that apocynin might exert its therapeutic effects via upregulation of glyoxalase system and antioxidant activity. Taken together, apocynin may prove to be an effective treatment for diabetic osteopathy. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Reactive oxygen species‐dependent JNK downregulated
           olaquindox‐induced autophagy in HepG2 cells
    • Abstract: Autophagy plays an important role in response to intracellular and extracellular stress to sustain cell survival. However, dysregulated or excessive autophagy may lead to cell death, known as “type II programmed cell death,” and it is closely associated with apoptosis. In our previous study, we proposed that olaquindox induced apoptosis of HepG2 cells through a caspase‐9 dependent mitochondrial pathway. In this study, we investigated autophagy induced by olaquindox and explored the crosstalk between apoptosis and autophagy in olaquindox‐treated HepG2 cells. Olaquindox‐induced autophagy was demonstrated by the accumulation of monodansylcadervarine, as well as elevated expression of autophagy‐related MAP‐LC3 and Beclin 1 proteins. The autophagy inhibitor 3‐methyladenine significantly increased the apoptotic rate induced by olaquindox, which was correlated with increased ratio of Bax/Bcl‐2. The further studies showed that olaquindox increased the levels of reactive oxygen species (ROS), and antioxidant N‐acetyl‐L‐cysteine (NAC) effectively blocked the accumulation of ROS but failed to block autophagy. Moreover, olaquindox induced the activation of c‐Jun N‐terminal protein kinase (JNK), and JNK inhibitor SP600125 failed to block autophagy. Instead, olaquindox‐induced autophagy was enhanced by NAC or SP600125. Meanwhile, JNK activation was remarkably blocked by NAC, indicating that ROS may be the upstream signaling molecules of JNK activation and involved in the negative regulation of olaquindox‐induced autophagy. These results suggest that olaquindox induces autophagy in HepG2 cells and that olaquindox‐induced apoptosis can be enhanced by 3‐methyladenine. Olaquindox‐induced autophagy in HepG2 cells is upregulated by Beclin 1 but downregulated by ROS‐dependent JNK. Copyright © 2014 John Wiley & Sons, Ltd.
       
 
 
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