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  Subjects -> ENVIRONMENTAL STUDIES (Total: 767 journals)
    - ENVIRONMENTAL STUDIES (704 journals)
    - POLLUTION (21 journals)
    - TOXICOLOGY AND ENVIRONMENTAL SAFETY (34 journals)
    - WASTE MANAGEMENT (8 journals)

ENVIRONMENTAL STUDIES (704 journals)            First | 1 2 3 4 5 6 7 8     

Marine Environmental Research     Hybrid Journal   (Followers: 12)
Marine Pollution Bulletin     Hybrid Journal   (Followers: 11)
Materials for Renewable and Sustainable Energy     Open Access   (Followers: 7)
Mathematical and Computational Forestry & Natural-Resource Sciences     Free  
Mathematical Population Studies: An International Journal of Mathematical Demography     Hybrid Journal   (Followers: 2)
Medio Ambiente y Urbanizacion     Full-text available via subscription  
Membranes     Open Access   (Followers: 4)
Michigan Journal of Sustainability     Open Access  
Midwest Studies In Philosophy     Hybrid Journal   (Followers: 10)
Mine Water and the Environment     Hybrid Journal   (Followers: 6)
Mitigation and Adaptation Strategies for Global Change     Hybrid Journal   (Followers: 12)
Modern Asian Studies     Hybrid Journal   (Followers: 5)
Modern Cartography Series     Full-text available via subscription   (Followers: 6)
Mountain Research and Development     Open Access   (Followers: 3)
Multequina     Open Access  
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis     Hybrid Journal   (Followers: 2)
Mutation Research/Genetic Toxicology and Environmental Mutagenesis     Hybrid Journal   (Followers: 8)
Nativa     Open Access  
Natur und Recht     Hybrid Journal   (Followers: 5)
Natural Areas Journal     Full-text available via subscription   (Followers: 7)
Natural Hazards     Hybrid Journal   (Followers: 204)
Natural Resources     Open Access  
Natural Resources and Environmental Issues     Open Access   (Followers: 5)
Nature and Culture     Full-text available via subscription   (Followers: 9)
NeuroToxicology     Hybrid Journal   (Followers: 1)
Neurotoxicology and Teratology     Hybrid Journal   (Followers: 2)
NEW SOLUTIONS: A Journal of Environmental and Occupational Health Policy     Full-text available via subscription   (Followers: 6)
New Zealand Journal of Environmental Law     Full-text available via subscription   (Followers: 3)
NJAS - Wageningen Journal of Life Sciences     Full-text available via subscription   (Followers: 1)
Noise Notes     Full-text available via subscription   (Followers: 3)
Novos Cadernos NAEA     Open Access  
Observatorio Medioambiental     Open Access  
Occupational and Environmental Medicine     Full-text available via subscription   (Followers: 8)
Ocean Acidification     Open Access  
Oecologia     Hybrid Journal   (Followers: 25)
Oikos     Hybrid Journal   (Followers: 31)
Open Journal of Ecology     Open Access   (Followers: 10)
Open Journal of Marine Science     Open Access   (Followers: 6)
Open Journal of Modern Hydrology     Open Access   (Followers: 1)
Our Nature     Open Access   (Followers: 2)
Oxford Journal of Legal Studies     Hybrid Journal   (Followers: 16)
Pace Environmental Law Review     Open Access   (Followers: 4)
Palaeobiodiversity and Palaeoenvironments     Hybrid Journal   (Followers: 3)
Papers on Global Change IGBP     Open Access   (Followers: 1)
Particle and Fibre Toxicology     Open Access   (Followers: 3)
Pastos y Forrajes     Open Access  
Pesquisa em Educação Ambiental     Open Access  
Pharmacology & Therapeutics     Hybrid Journal   (Followers: 5)
Pharmacology Biochemistry and Behavior     Hybrid Journal   (Followers: 1)
Philosophical Studies     Hybrid Journal   (Followers: 7)
Physio-Géo     Open Access   (Followers: 2)
Pittsburgh Journal of Environmental and Public Health Law     Open Access   (Followers: 1)
Planet     Open Access   (Followers: 1)
Planning & Environmental Law: Issues and decisions that impact the built and natural environments     Hybrid Journal   (Followers: 6)
Plant Ecology & Diversity     Partially Free   (Followers: 11)
Plant Knowledge Journal     Open Access   (Followers: 2)
Plant, Cell & Environment     Hybrid Journal   (Followers: 4)
Polar Journal     Hybrid Journal   (Followers: 1)
Policy Studies     Hybrid Journal   (Followers: 7)
Policy Studies Journal     Hybrid Journal   (Followers: 5)
Polish Polar Research     Open Access   (Followers: 4)
Political Studies     Hybrid Journal   (Followers: 22)
Political Studies Review     Hybrid Journal   (Followers: 14)
Population and Environment     Hybrid Journal   (Followers: 6)
Population Ecology     Hybrid Journal   (Followers: 9)
Population Studies: A Journal of Demography     Hybrid Journal   (Followers: 6)
Postcolonial Studies     Hybrid Journal   (Followers: 6)
Practice Periodical of Hazardous, Toxic, and Radioactive Waste Management     Full-text available via subscription   (Followers: 3)
Presence Teleoperators & Virtual Environments     Hybrid Journal   (Followers: 1)
Presidential Studies Quarterly     Hybrid Journal   (Followers: 4)
Procedia Environmental Sciences     Open Access   (Followers: 2)
Proceedings of ICE, Waste and Resource Management     Hybrid Journal   (Followers: 3)
Proceedings of the Institution of Mechanical Engineers Part M: Journal of Engineering for the Maritime Environment     Hybrid Journal   (Followers: 1)
Proceedings of the International Academy of Ecology and Environmental Sciences     Open Access   (Followers: 4)
Process Safety and Environmental Protection     Hybrid Journal   (Followers: 3)
Progress in Industrial Ecology, An International Journal     Hybrid Journal   (Followers: 4)
Psychological Assessment     Full-text available via subscription   (Followers: 5)
Public Money & Management     Hybrid Journal   (Followers: 4)
Public Works Management & Policy     Hybrid Journal   (Followers: 5)
Qatar Foundation Annual Research Forum Proceedings     Open Access   (Followers: 3)
Radioactivity in the Environment     Full-text available via subscription   (Followers: 4)
Regional Environmental Change     Hybrid Journal   (Followers: 3)
Regional Studies     Hybrid Journal   (Followers: 6)
Religious Studies     Hybrid Journal   (Followers: 11)
RELP - Renewable Energy Law and Policy     Full-text available via subscription   (Followers: 4)
Remediation Journal     Hybrid Journal   (Followers: 5)
Remote Sensing Letters     Hybrid Journal   (Followers: 9)
Renaissance Studies     Hybrid Journal   (Followers: 13)
Rendiconti Lincei     Hybrid Journal  
Renewable Energy Focus     Full-text available via subscription   (Followers: 7)
Research & Reviews : Journal of Ecology     Full-text available via subscription  
Research and Practice for Persons with Severe Disabilities     Full-text available via subscription   (Followers: 4)
Research Journal of Environmental Sciences     Open Access   (Followers: 1)
Research Journal of Environmental Toxicology     Open Access   (Followers: 2)
ReSource     Full-text available via subscription  
Resources     Open Access  
Resources, Conservation and Recycling     Hybrid Journal   (Followers: 9)
Reuse/Recycle Newsletter     Hybrid Journal   (Followers: 1)
Review of English Studies     Hybrid Journal   (Followers: 7)
Review of Environmental Economics and Policy     Hybrid Journal   (Followers: 7)

  First | 1 2 3 4 5 6 7 8     

Journal Cover Toxicology and Applied Pharmacology
   Journal TOC RSS feeds Export to Zotero [14 followers]  Follow    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
     ISSN (Print) 0041-008X - ISSN (Online) 1096-0333
     Published by Elsevier Homepage  [2563 journals]   [SJR: 1.328]   [H-I: 110]
  • Ochratoxin A induces rat renal carcinogenicity with limited induction of
           oxidative stress responses
    • Abstract: Publication date: Available online 8 September 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Xiaozhe Qi , Tao Yu , Liye Zhu , Jing Gao , Xiaoyun He , Kunlun Huang , Yunbo Luo , Wentao Xu
      Ochratoxin A (OTA) has displayed nephrotoxicity and renal carcinogenicity in mammals, however, no clear mechanisms have been identified detailing the relationship between oxidative stress and these toxicities. This study was performed to clarify the relationship between oxidative stress and the renal carcinogenicity induced by OTA. Rats were treated with 70 or 210μg/kg b.w. OTA for 4 or 13weeks. In the rats administrated with OTA for 13weeks, the kidney was damaged seriously. Cytoplasmic vacuolization was observed in the outer stripe of outer medulla. Karyomegaly was prominent in the tubular epithelium. Kidney injury molecule-1 (Kim-1) was detected in the outer stripe of the outer medulla in both low- and high-dose groups. OTA increased the mRNA levels of clusterin in rat kidneys. Interestingly, OTA did not significantly alter oxidative stress level in rat liver and kidney. Yet, some indications related to proliferation and carcinogenicity were observed. A dose-related increase in proliferating cell nuclear antigen (PCNA) was observed at 4weeks in both liver and kidney, but at 13weeks, only in the kidney. OTA down-regulated reactive oxygen species (ROS); and up-regulated vimentin and lipocalin 2 in rat kidney at 13weeks. The p53 gene was decreased in both liver and kidney at 13weeks. These results suggest that OTA caused apparent kidney damage within 13weeks but exerted limited effect on oxidative stress parameters. It implies that cell proliferation is the proposed mode of action for OTA-induced renal carcinogenicity.


      PubDate: 2014-09-13T03:24:34Z
       
  • Atorvastatin ameliorates arsenic-induced hypertension and enhancement of
           vascular redox signaling in rats
    • Abstract: Publication date: Available online 11 September 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Thengumpallil Sasindran Sarath , Prashantkumar Waghe , Priyanka Gupta , Soumen Choudhury , Kandasamy Kannan , Ayyappan Harikrishna Pillai , Sankaran Kutty Harikumar , Santosh Kumar Mishra , Souvendra Nath Sarkar
      Chronic arsenic exposure has been linked to elevated blood pressure and cardiovascular diseases, while statins reduce the incidence of cardiovascular disease predominantly by their low density lipoprotein-lowering effect. Besides, statins have other beneficial effects, including antioxidant and anti-inflammatory activities. We evaluated whether atorvastatin, a widely used statin, can ameliorate arsenic-induced increase in blood pressure and alteration in lipid profile and also whether the amelioration could relate to altered NO and ROS signaling. Rats were exposed to sodium arsenite (100ppm) through drinking water for 90 consecutive days. Atorvastatin (10mg/kg bw, orally) was administered once daily during the last 30days of arsenic exposure. On the 91st day, blood was collected for lipid profile. Western Blot of iNOS and eNOS protein, NO and 3-nitrotyrosine production, Nox-4 and p22Phox mRNA expression, Nox activity, ROS generation, lipid peroxidation and antioxidants were evaluated in thoracic aorta. Arsenic increased systolic, diastolic and mean arterial blood pressure, while it decreased HDL-C and increased LDL-C, total cholesterol and triglycerides in serum. Arsenic down-regulated eNOS and up-regulated iNOS protein expression; increased basal NO and 3-nitrotyrosine level. Arsenic increased aortic Nox-4 and p22Phox mRNA expression, Nox activity, ROS generation and lipid peroxidation. Further, arsenic decreased the activities of superoxide dismutase, catalase, glutathione peroxidase and depleted aortic GSH content. Atorvastatin regularized blood pressure, improved lipid profile and attenuated arsenic-mediated redox alterations. The results demonstrate that atorvastatin has the potential to ameliorate arsenic-induced hypertension by improving lipid profile, aortic NO signaling and restoring vascular redox homeostasis.


      PubDate: 2014-09-13T03:24:34Z
       
  • Up-regulation of cholesterol associated genes as novel resistance
           mechanism in glioblastoma cells in response to archazolid B
    • Abstract: Publication date: Available online 11 September 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Rebecca Hamm , Maen Zeino , Simon Frewert , Thomas Efferth
      Treatment of glioblastoma multiforme (GBM), the most common and aggressive lethal brain tumor, represents a great challenge. Despite decades of research, the survival prognosis of GBM patients is unfavorable and more effective therapeutics are sorely required. Archazolid B, a potent vacuolar H+-ATPase inhibitor influencing cellular pH values, is a promising new compound exerting cytotoxicity in the nanomolar range on wild-type U87MG glioblastoma cells and U87MG.∆EGFR cells transfected with a mutant epidermal growth factor receptor (EGFR) gene. Gene expression profiling using microarray technology showed that archazolid B caused drastic disturbances in cholesterol homeostasis. Cholesterol, a main component of cellular membranes, is known to be essential for GBM growth and cells bearing EGFRvIII mutation are highly dependent on exogenous cholesterol. Archazolid B caused excessive accumulation of free cholesterol within intracellular compartments thus depleting cellular cholesterol and leading to up-regulation of SREBP targeted genes, including LDLR and HMGCR, the key enzyme of cholesterol biosynthesis. This cholesterol response is considered to be a novel resistance mechanism induced by archazolid B. We surmise that re-elevation of cholesterol levels in archazolid B treated cells may be mediated by newly synthesized cholesterol, since the drug leads to endosomal/lysosomal malfunction and cholesterol accumulation.


      PubDate: 2014-09-13T03:24:34Z
       
  • Molecular cloning and functional characterization of a rainbow trout liver
           Oatp
    • Abstract: Publication date: Available online 12 September 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Konstanze Steiner , Bruno Hagenbuch , Daniel R. Dietrich
      Cyanobacterial blooms have an impact on the aquatic ecosystem due to the production of toxins (e.g. microcystins, MCs), which constrain fish health or even cause fish death. However the toxicokinetics of the most abundant toxin, microcystin-LR (MC-LR), are not yet fully understood. To investigate the uptake mechanism, the novel Oatp1d1 in rainbow trout (rtOatp1d1) was cloned, identified and characterized. The cDNA isolated from a clone library consisted of 2772bp containing a 2115bp open reading frame coding for a 705 aa protein with an approximate molecular mass of 80kDa. This fish specific transporter belongs to the OATP1 family and has most likely evolved from a common ancestor of OATP1C1. Real time PCR analysis showed that rtOatp1d1 is predominantly expressed in the liver, followed by the brain while expression in other organs was not detectable. Transient transfection in HEK293 cells was used for further characterization. Like its human homologues OATP1A1, OATP1B1 and OATP1B3, rtOatp1d1 displayed multi-specific transport including endogenous and xenobiotic substrates. Kinetic analyses revealed a Km value of 13.9μM and 13.4μM for estrone-3-sulfate and methotrexate, respectively and a rather low affinity for taurocholate with a Km value of 103μM. Furthermore, it was confirmed that rtOatp1d1 is a MC-LR transporter and therefore most likely plays a key role in the susceptibility of rainbow trout to MC intoxications.


      PubDate: 2014-09-13T03:24:34Z
       
  • Inhibition of Neutral Sphingomyelinase Decreases Elevated Levels of
           Inducible Nitric Oxide Synthase and Apoptotic Cell Death in Ocular
           Hypertensive Rats
    • Abstract: Publication date: Available online 6 September 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Mutay Aslan , Goksun Basaranlar , Mustafa Unal , Akif Ciftcioglu , Narin Derin , Bulent Mutus
      Endoplasmic reticulum (ER) stress and excessive nitric oxide production via induction of inducible nitric oxide synthase (NOS2) have been implicated in the pathogenesis of neuronal retinal cell death in ocular hypertension. Neutral sphingomyelinase (N-SMase)/ceramide pathway can regulate NOS2 expression, hence this study determined the role of selective neutral sphingomyelinase (N-SMase) inhibition on retinal NOS2 levels, ER stress, apoptosis and visual evoked potentials (VEP) in a rat model of elevated intraocular pressure (EIOP). NOS2 expression and retinal protein nitration was significantly greater in EIOP and significantly decreased with N-SMase inhibition. A significant increase was observed in retinal ER stress markers pPERK, CHOP and GRP78 in EIOP, which was not significantly altered by N-SMase inhibition. Retinal TUNEL staining showed increased apoptosis in all EIOP groups; however N-SMase inhibition significantly decreased the percent of apoptotic cells in EIOP. Caspase-3, -8 and -9 activities were significantly increased in EIOP and returned to baseline levels following N-SMase inhibition. Latencies of all VEP components were significantly prolonged in EIOP and shortened following N-SMase inhibition. Data confirm the role of nitrative injury in EIOP and highlight the protective effect of N-SMase inhibition in EIOP via down-regulation of NOS2 levels and nitrative stress.


      PubDate: 2014-09-08T02:26:33Z
       
  • Aldosterone induces fibrosis, oxidative stress and DNA damage in livers of
           male rats independent of blood pressure changes
    • Abstract: Publication date: Available online 7 September 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Nina Queisser , Kathrin Happ , Samuel Link , Daniel Jahn , Anna Zimnol , Andreas Geier , Nicole Schupp
      Mineralocorticoid receptor blockers show antifibrotic potential in hepatic fibrosis. The mechanism of this protective effect is not known yet, although reactive oxygen species seem to play an important role. Here, we investigated the effects of elevated levels of aldosterone (Ald), the primary ligand of the mineralocorticoid receptor, on livers of rats in a hyperaldosteronism model: aldosterone-induced hypertension. Male Sprague–Dawley rats were treated for 4weeks with aldosterone. To distinguish if damage caused in the liver depended on increased blood pressure or on increased Ald levels, the mineralocorticoid receptor antagonist spironolactone was given in a subtherapeutic dose, not normalizing blood pressure. To investigate the impact of oxidative stress, the antioxidant tempol was administered. Aldosterone induced fibrosis, detected histopathologically, and by expression analysis of the fibrosis marker, α-smooth muscle actin. Further, the mRNA amount of the profibrotic cytokine TGF-β was increased significantly. Fibrosis could be reduced by scavenging reactive oxygen species, and also by blocking the mineralocorticoid receptor. Furthermore, aldosterone treatment caused oxidative stress and DNA double strand breaks in livers, as well as the elevation of DNA repair activity. An increase of the transcription factor Nrf2, the main regulator of the antioxidative response could be observed, and of its target genes heme oxygenase-1 and γ-glutamylcysteine synthetase. All these effects of aldosterone were prevented by spironolactone and tempol. Already after 4weeks treatment, aldosterone-infusion induced fibrosis in the liver. This effect was independent of elevated blood pressure. DNA damage caused by aldosterone might contribute to fibrosis progression when aldosterone is chronically increased.


      PubDate: 2014-09-08T02:26:33Z
       
  • Cyanidin-3-glucoside inhibits UVB-induced oxidative damage and
           inflammation by regulating MAP kinase and NF-κB signaling pathways in
           SKH-1 hairless mice skin
    • Abstract: Publication date: 1 October 2014
      Source:Toxicology and Applied Pharmacology, Volume 280, Issue 1
      Author(s): Poyil Pratheeshkumar , Young-Ok Son , Xin Wang , Sasidharan Padmaja Divya , Binoy Joseph , John Andrew Hitron , Lei Wang , Donghern Kim , Yuanqin Yin , Ram Vinod Roy , Jian Lu , Zhuo Zhang , Yitao Wang , Xianglin Shi
      Skin cancer is one of the most commonly diagnosed cancers in the United States. Exposure to ultraviolet-B (UVB) radiation induces inflammation and photocarcinogenesis in mammalian skin. Cyanidin-3-glucoside (C3G), a member of the anthocyanin family, is present in various vegetables and fruits especially in edible berries, and displays potent antioxidant and anticarcinogenic properties. In this study, we have assessed the in vivo effects of C3G on UVB irradiation induced chronic inflammatory responses in SKH-1 hairless mice, a well-established model for UVB-induced skin carcinogenesis. Here, we show that C3G inhibited UVB-induced skin damage and inflammation in SKH-1 hairless mice. Our results indicate that C3G inhibited glutathione depletion, lipid peroxidation and myeloperoxidation in mouse skin by chronic UVB exposure. C3G significantly decreased the production of UVB-induced pro-inflammatory cytokines, such as IL-6 and TNF-α, associated with cutaneous inflammation. Likewise, UVB-induced inflammatory responses were diminished by C3G as observed by a remarkable reduction in the levels of phosphorylated MAP kinases, Erk1/2, p38, JNK1/2 and MKK4. Furthermore, C3G also decreased UVB-induced cyclooxygenase-2 (COX-2), PGE2 and iNOS levels, which are well-known key mediators of inflammation and cancer. Treatment with C3G inhibited UVB-induced nuclear translocation of NF-κB and degradation of IκBα in mice skin. Immunofluorescence assay revealed that topical application of C3G inhibited the expression of 8-hydroxy-2′-deoxyguanosine, proliferating cell nuclear antigen, and cyclin D1 in chronic UVB exposed mouse skin. Collectively, these data indicates that C3G can provide substantial protection against the adverse effects of UVB radiation by modulating UVB-induced MAP kinase and NF-κB signaling pathways.


      PubDate: 2014-09-04T01:51:02Z
       
  • Chronic nandrolone administration promotes oxidative stress, induction of
           pro-inflammatory cytokine and TNF-α mediated apoptosis in the kidneys
           of CD1 treated mice
    • Abstract: Publication date: 1 October 2014
      Source:Toxicology and Applied Pharmacology, Volume 280, Issue 1
      Author(s): Irene Riezzo , Emanuela Turillazzi , Stefania Bello , Santina Cantatore , Daniela Cerretani , Marco Di Paolo , Anna Ida Fiaschi , Paola Frati , Margherita Neri , Monica Pedretti , Vittorio Fineschi
      Nandrolone decanoate administration and strenuous exercise increase the extent of renal damage in response to renal toxic injury. We studied the role played by oxidative stress in the apoptotic response caused by nandrolone decanoate in the kidneys of strength-trained male CD1 mice. To measure cytosolic enzyme activity, glutathione peroxidase (GPx), glutathione reductase (GR) and malondialdehyde (MDA) were determined after nandrolone treatment. An immunohistochemical study and Western blot analysis were performed to evaluate cell apoptosis and to measure the effects of renal expression of inflammatory mediators (IL-1β, TNF-α) on the induction of apoptosis (HSP90, TUNEL). Dose-related oxidative damage in the kidneys of treated mice is shown by an increase in MDA levels and by a reduction of antioxidant enzyme GR and GPx activities, resulting in the kidney's reduced radical scavenging ability. Renal specimens of the treated group showed relevant glomeruli alterations and increased immunostaining and protein expressions, which manifested significant focal segmental glomerulosclerosis. The induction of proinflammatory cytokine expression levels was confirmed by Western blot analysis. Long-term administration of nandrolone promotes oxidative injury in the mouse kidneys. TNF-α mediated injury due to nandrolone in renal cells appears to play a role in the activation of both the intrinsic and extrinsic apoptosis pathways.


      PubDate: 2014-09-04T01:51:02Z
       
  • Atorvastatin restores arsenic-induced vascular dysfunction in rats:
           Modulation of nitric oxide signaling and inflammatory mediators
    • Abstract: Publication date: 1 October 2014
      Source:Toxicology and Applied Pharmacology, Volume 280, Issue 1
      Author(s): Manickam Kesavan , Thengumpallil Sasindran Sarath , Kandasamy Kannan , Subramaniyam Suresh , Priyanka Gupta , Karunakaran Vijayakaran , Palanisamy Sankar , Nitin Pandurang Kurade , Santosh Kumar Mishra , Souvendra Nath Sarkar
      We evaluated whether atorvastatin, an extensively prescribed statin for reducing the risks of cardiovascular diseases, can reduce the risk of arsenic-induced vascular dysfunction and inflammation in rats and whether the modulation could be linked to improvement in vascular NO signaling. Rats were exposed to sodium arsenite (100ppm) through drinking water for 90 consecutive days. Atorvastatin (10mg/kg bw, orally) was administered once daily during the last 30days of arsenic exposure. On the 91st day, blood was collected for measuring serum C-reactive protein. Thoracic aorta was isolated for assessing reactivity to phenylephrine, sodium nitroprusside and acetylcholine; evaluating eNOS and iNOS mRNA expression and measuring NO production, while abdominal aorta was used for ELISA of cytokines, chemokine and vascular cell adhesion molecules. Histopathology was done in aortic arches. Arsenic did not alter phenylephrine-elicited contraction. Atorvastatin inhibited Emax of phenylephrine, but it augmented the contractile response in aortic rings from arsenic-exposed animals. Sodium nitroprusside-induced relaxation was not altered with any treatment. However, arsenic reduced acetylcholine-induced relaxation and affected aortic eNOS at the levels of mRNA expression, protein concentration, phosphorylation and NO production. Further, it increased aortic iNOS mRNA expression, iNOS-derived NO synthesis, production of pro-inflammatory mediators (IL-1β, IL-6, MCP-1, VCAM, sICAM) and serum C-reactive protein and aortic vasculopathic lesions. Atorvastatin attenuated these arsenic-mediated functional, biochemical and structural alterations. Results show that atorvastatin has the potential to ameliorate arsenic-induced vascular dysfunction and inflammation by restoring endothelial function with improvement in NO signaling and attenuating production of pro-inflammatory mediators and cell adhesion molecules.


      PubDate: 2014-09-04T01:51:02Z
       
  • Hydroxychavicol, a betel leaf component, inhibits prostate cancer through
           ROS-driven DNA damage and apoptosis
    • Abstract: Publication date: 1 October 2014
      Source:Toxicology and Applied Pharmacology, Volume 280, Issue 1
      Author(s): Sushma Reddy Gundala , Chunhua Yang , Rao Mukkavilli , Rutugandha Paranjpe , Meera Brahmbhatt , Vaishali Pannu , Alice Cheng , Michelle D. Reid , Ritu Aneja
      Dietary phytochemicals are excellent ROS-modulating agents and have been shown to effectively enhance ROS levels beyond toxic threshold in cancer cells to ensure their selective killing while leaving normal cells unscathed. Here we demonstrate that hydroxychavicol (HC), extracted and purified from Piper betel leaves, significantly inhibits growth and proliferation via ROS generation in human prostate cancer, PC-3 cells. HC perturbed cell-cycle kinetics and progression, reduced clonogenicity and mediated cytotoxicity by ROS-induced DNA damage leading to activation of several pro-apoptotic molecules. In addition, HC treatment elicited a novel autophagic response as evidenced by the appearance of acidic vesicular organelles and increased expression of autophagic markers, LC3-IIb and beclin-1. Interestingly, quenching of ROS with tiron, an antioxidant, offered significant protection against HC-induced inhibition of cell growth and down regulation of caspase-3, suggesting the crucial role of ROS in mediating cell death. The collapse of mitochondrial transmembrane potential by HC further revealed the link between ROS generation and induction of caspase-mediated apoptosis in PC-3 cells. Our data showed remarkable inhibition of prostate tumor xenografts by ~72% upon daily oral administration of 150mg/kg bw HC by quantitative tumor volume measurements and non-invasive real-time bioluminescent imaging. HC was well-tolerated at this dosing level without any observable toxicity. This is the first report to demonstrate the anti-prostate cancer efficacy of HC in vitro and in vivo, which is perhaps attributable to its selective prooxidant activity to eliminate cancer cells thus providing compelling grounds for future preclinical studies to validate its potential usefulness for prostate cancer management.


      PubDate: 2014-09-04T01:51:02Z
       
  • Transcriptional responses in the rat nasal epithelium following subchronic
           inhalation of naphthalene vapor
    • Abstract: Publication date: 1 October 2014
      Source:Toxicology and Applied Pharmacology, Volume 280, Issue 1
      Author(s): H.J. Clewell , A. Efremenko , J.L. Campbell , D.E. Dodd , R.S. Thomas
      Male and female Fischer 344 rats were exposed to naphthalene vapors at 0 (controls), 0.1, 1, 10, and 30ppm for 6h/d, 5 d/wk, over a 90-day period. Following exposure, the respiratory epithelium and olfactory epithelium from the nasal cavity were dissected separately, RNA was isolated, and gene expression microarray analysis was conducted. Only a few significant gene expression changes were observed in the olfactory or respiratory epithelium of either gender at the lowest concentration (0.1ppm). At the 1.0ppm concentration there was limited evidence of an oxidative stress response in the respiratory epithelium, but not in the olfactory epithelium. In contrast, a large number of significantly enriched cellular pathway responses were observed in both tissues at the two highest concentrations (10 and 30ppm, which correspond to tumorigenic concentrations in the NTP bioassay). The nature of these responses supports a mode of action involving oxidative stress, inflammation and proliferation. These results are consistent with a dose-dependent transition in the mode of action for naphthalene toxicity/carcinogenicity between 1.0 and 10ppm in the rat. In the female olfactory epithelium (the gender/site with the highest incidences of neuroblastomas in the NTP bioassay), the lowest concentration at which any signaling pathway was significantly affected, as characterized by the median pathway benchmark dose (BMD) or its 95% lower bound (BMDL) was 6.0 or 3.7ppm, respectively, while the lowest female olfactory BMD values for pathways related to glutathione homeostasis, inflammation, and proliferation were 16.1, 11.1, and 8.4ppm, respectively. In the male respiratory epithelium (the gender/site with the highest incidences of adenomas in the NTP bioassay), the lowest pathway BMD and BMDL were 0.4 and 0.3ppm, respectively, and the lowest male respiratory BMD values for pathways related to glutathione homeostasis, inflammation, and proliferation were 0.5, 0.7, and 0.9ppm, respectively. Using a published physiologically based pharmacokinetic (PBPK) model to estimate target tissue dose relevant to the proposed mode of action (total naphthalene metabolism per gram nasal tissue), the lowest transcriptional BMDLs from this analysis equate to human continuous naphthalene exposure at approximately 0.3ppm. It is unlikely that significant effects of naphthalene or its metabolites will occur at exposures below this concentration.


      PubDate: 2014-09-04T01:51:02Z
       
  • Arsenic methylation capacity is associated with breast cancer in northern
           Mexico
    • Abstract: Publication date: 1 October 2014
      Source:Toxicology and Applied Pharmacology, Volume 280, Issue 1
      Author(s): Lizbeth López-Carrillo , Raúl Ulises Hernández-Ramírez , A. Jay Gandolfi , José Manuel Ornelas-Aguirre , Luisa Torres-Sánchez , Mariano E. Cebrian
      Exposure to environmental contaminants, dietary factors and lifestyles may explain worldwide different breast cancer (BC) incidence. Inorganic arsenic (iAs) in the drinking water is a concern in many regions, such as northern Mexico. Studies in several countries have associated the proportion of urinary monomethylarsenic (%MMA) with increased risks for many As-related diseases, including cancer. To investigate the potential relationships between the risk of BC and the capacity to methylate iAs, a hospital-based case–control study (1016 cases/1028 controls) was performed in northern Mexico. Women were directly interviewed about their reproductive histories. The profile of As metabolites in urine was determined by HPLC-ICP-MS and methylation capacity was assessed by metabolite percentages and indexes. Total urinary As, excluding arsenobetaine (TAs-AsB), ranged from 0.26 to 303.29μg/L. Most women (86%) had TAs-AsB levels below As biological exposure index (35μg/L). Women with higher %MMA and/or primary methylation index (PMI) had an increased BC risk (%MMA ORQ5vs.Q1 =2.63; 95%CI 1.89,3.66; p for trend <0.001; PMI ORQ5vs.Q1 =1.90; 95%CI 1.39,2.59, p for trend <0.001). In contrast, women with higher proportion of urinary dimethylarsenic (%DMA) and/or secondary methylation index (SMI) had a reduced BC risk (%DMA ORQ5vs.Q1 =0.63; 95%CI 0.45,0.87, p for trend 0.006; SMI ORQ5vsQ1 =0.42, 95%CI 0.31,0.59, p for trend <0.001). Neither %iAs nor total methylation index was associated to BC risk. Inter-individual variations in iAs metabolism may play a role in BC carcinogenesis. Women with higher capacity to methylate iAs to MMA and/or a lower capacity to further methylate MMA to DMA were at higher BC risk.


      PubDate: 2014-09-04T01:51:02Z
       
  • Celastrol ameliorates HIV-1 Tat-induced inflammatory responses via
           NF-kappaB and AP-1 inhibition and heme oxygenase-1 induction in astrocytes
           
    • Abstract: Publication date: 1 October 2014
      Source:Toxicology and Applied Pharmacology, Volume 280, Issue 1
      Author(s): Gi Soo Youn , Dong-Joo Kwon , Sung Mi Ju , Hyangshuk Rhim , Yong Soo Bae , Soo Young Choi , Jinseu Park
      HIV-1 Tat causes extensive neuroinflammation that may progress to AIDS-related encephalitis and dementia. Celastrol possesses various biological activities such as anti-oxidant, anti-tumor, and anti-inflammatory activities. In this study, we investigated the modulatory effects of celastrol on HIV-1 Tat-induced inflammatory responses and the molecular mechanisms underlying its action in astrocytes. Pre-treatment of CRT-MG human astroglioma cells with celastrol significantly inhibited HIV-1 Tat-induced expression of ICAM-1/VCAM-1 and subsequent monocyte adhesiveness in CRT-MG cells. In addition, celastrol suppressed HIV-1 Tat-induced expression of pro-inflammatory chemokines, such as CXCL10, IL-8, and MCP-1. Celastrol decreased HIV-1 Tat-induced activation of JNK MAPK, AP-1, and NF-κB. Furthermore, celastrol induced mRNA and protein expression of HO-1 as well as Nrf2 activation. Blockage of HO-1 expression using siRNA reversed the inhibitory effect of celastrol on HIV-1 Tat-induced inflammatory responses. These results suggest that celastrol has regulatory effects on HIV-1 Tat-induced inflammatory responses by blocking the JNK MAPK-AP-1/NF-κB signaling pathways and inducing HO-1 expression in astrocytes.
      Graphical abstract image

      PubDate: 2014-09-04T01:51:02Z
       
  • Ozone (O3) elicits neurotoxicity in spinal cord neurons (SCNs) by inducing
           ER Ca2+ release and activating the CaMKII/MAPK signaling pathway
    • Abstract: Publication date: Available online 2 September 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Yun Li , Xiaowen Lin , XueJun Zhao , Juntian Xie , Wang JunNan , Tao Sun , Zhijian Fu
      Ozone (O3) is widely used in the treatment of spinal cord related diseases. Excess or accumulation of this photochemical air can however be neurotoxic. In this study, in vitro cultured Wister rat spinal cord neurons (SCNs) were used to investigate the detrimental effects and underlying mechanisms of O3. Ozone in a dose-dependent manner inhibited cell viability at a range of 20 to 500μg/ml, with the dose at 40μg/ml resulting in a decrease of cell viability to 75%. The cell death after O3 exposure was related to endoplasmic reticulum (ER) calcium (Ca2+) release. Intracellular Ca2+ chelator, ER stabilizer (Inositol 1,4,5-trisphosphate receptor (IP3R) antagonist and Ryanodine receptor (RyR) antagonist) and calcium/calmodulin-dependent protein kinase II (CaMKII) antagonist could effectively block Ca2+ mobilization and inhibit cell death following 40μg/mL O3 exposure. In addition, ER Ca2+ release due to O3 exposure enhanced phospho-p38 and phospho-JNK levels and apoptosis of SCNs through activating CaMKII. Based on these results, we confirm that ozone elicits neurotoxicity in SCNs via inducing ER Ca2+ release and activating CaMKII/MAPK signaling pathway. Therefore, physicians should get attention to the selection of treatment concentrations of oxygen/ozone. And, approaches, such as chelating intracellular Ca2+ and stabilizing neuronal Ca2+ homeostasis could effectively ameliorate the neurotoxicity of O3.


      PubDate: 2014-09-04T01:51:02Z
       
  • The aryl hydrocarbon receptor suppresses osteoblast proliferation and
           differentiation through the activation of the ERK signaling pathway
    • Abstract: Publication date: Available online 3 September 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Haitao Yu , Yuxuan Du , Xulong Zhang , Ying Sun , Shentao Li , Yunpeng Dou , Zhanguo Li , Huihui Yuan , Wenming Zhao
      Ahr activation is known to be associated with synovitis and exacerbated RA, but its contributions to bone loss have not been completely elucidated. Osteoblast proliferation and differentiation are abnormal at the erosion site in RA. Here, we reported that the expression of Ahr was increased in the hind paws’ bone upon collagen-induced arthritis (CIA) in mice, and the levels of Ahr were negatively correlated with bone mineral density (BMD). In addition, immunofluorescent staining showed that the high expression of Ahr was mainly localized in osteoblasts from the CIA mice compared to normal controls. Moreover, the luciferase intensity of Ahr in the nucleus increased by 12.5% in CIA osteoblasts compared to that in normal controls. In addition, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) activation of the Ahr inhibited pre-osteoblast MC3T3-E1 cellular proliferation and differentiation in a dose-dependent manner. Interestingly, the levels of alkaline phosphatase (ALP) mRNA expression in the osteoblasts of CIA mice were reduced compared to normal controls. In contrast, decreased ALP expression by activated Ahr was completely reversed after pretreatment with an Ahr inhibitor (CH-223191) in MC3T3-E1 cell lines and primary osteoblasts on day 5. Our data further showed that activation of Ahr promoted the phosphorylation of ERK after 5days. Moreover, Ahr-dependent activation of the ERK signaling pathway decreased the levels of proliferation cells and inhibited ALP activity in MC3T3-E1 cells. These results demonstrated that the high expression of Ahr may suppress osteoblast proliferation and differentiation through activation of the ERK signaling pathway, further enabling bone erosion in CIA mice.


      PubDate: 2014-09-04T01:51:02Z
       
  • Additive and synergistic antiandrogenic activities of mixtures of azol
           fungicides and vinclozolin
    • Abstract: Publication date: 15 September 2014
      Source:Toxicology and Applied Pharmacology, Volume 279, Issue 3
      Author(s): Verena Christen , Pierre Crettaz , Karl Fent
      Objective Many pesticides including pyrethroids and azole fungicides are suspected to have an endocrine disrupting property. At present, the joint activity of compound mixtures is only marginally known. Here we tested the hypothesis that the antiandrogenic activity of mixtures of azole fungicides can be predicted by the concentration addition (CA) model. Methods The antiandrogenic activity was assessed in MDA-kb2 cells. Following assessing single compounds activities mixtures of azole fungicides and vinclozolin were investigated. Interactions were analyzed by direct comparison between experimental and estimated dose–response curves assuming CA, followed by an analysis by the isobole method and the toxic unit approach. Results The antiandrogenic activity of pyrethroids deltamethrin, cypermethrin, fenvalerate and permethrin was weak, while the azole fungicides tebuconazole, propiconazole, epoxiconazole, econazole and vinclozolin exhibited strong antiandrogenic activity. Ten binary and one ternary mixture combinations of five antiandrogenic fungicides were assessed at equi-effective concentrations of EC25 and EC50. Isoboles indicated that about 50% of the binary mixtures were additive and 50% synergistic. Synergism was even more frequently indicated by the toxic unit approach. Conclusion Our data lead to the conclusion that interactions in mixtures follow the CA model. However, a surprisingly high percentage of synergistic interactions occurred. Therefore, the mixture activity of antiandrogenic azole fungicides is at least additive. Practice Mixtures should also be considered for additive antiandrogenic activity in hazard and risk assessment. Implications Our evaluation provides an appropriate “proof of concept”, but whether it equally translates to in vivo effects should further be investigated.
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      PubDate: 2014-09-04T01:51:02Z
       
  • Beta-carotene reduces oxidative stress, improves glutathione metabolism
           and modifies antioxidant defense systems in lead-exposed workers
    • Abstract: Publication date: 1 October 2014
      Source:Toxicology and Applied Pharmacology, Volume 280, Issue 1
      Author(s): Sławomir Kasperczyk , Michał Dobrakowski , Janusz Kasperczyk , Alina Ostałowska , Jolanta Zalejska-Fiolka , Ewa Birkner
      The aim of this study was to determine whether beta-carotene administration reduces oxidative stress and influences antioxidant, mainly glutathione-related, defense systems in workers chronically exposed to lead. The population consisted of two randomly divided groups of healthy male volunteers exposed to lead. Workers in the first group (reference group) were not administered any antioxidants, while workers in the second group (CAR group) were treated orally with 10mg of beta-carotene once a day for 12weeks. Biochemical analysis included measuring markers of lead-exposure and oxidative stress in addition to the levels and activities of selected antioxidants. After treatment, levels of malondialdehyde, lipid hydroperoxides and lipofuscin significantly decreased compared with the reference group. However, the level of glutathione significantly increased compared with the baseline. Treatment with beta-carotene also resulted in significantly decreased glutathione peroxidase activity compared with the reference group, while the activities of other glutathione-related enzymes and of superoxide dismutase were not significantly changed. However, the activities of glucose-6-phosphate dehydrogenase and catalase, as well as the level of alpha-tocopherol, were significantly higher after treatment compared with the baseline. Despite controversy over the antioxidant properties of beta-carotene in vivo, our findings showed reduced oxidative stress after beta-carotene supplementation in chronic lead poisoning.


      PubDate: 2014-09-04T01:51:02Z
       
  • Dysregulation of protein degradation pathways may mediate the liver injury
           and phospholipidosis associated with a cationic amphiphilic antibiotic
           drug
    • Abstract: Publication date: 1 October 2014
      Source:Toxicology and Applied Pharmacology, Volume 280, Issue 1
      Author(s): Merrie Mosedale , Hong Wu , C. Lisa Kurtz , Stephen P. Schmidt , Karissa Adkins , Alison H. Harrill
      A large number of antibiotics are known to cause drug-induced liver injury in the clinic; however, interpreting clinical risk is not straightforward owing to a lack of predictivity of the toxicity by standard preclinical species and a poor understanding of the mechanisms of toxicity. An example is PF-04287881, a novel ketolide antibiotic that caused elevations in liver function tests in Phase I clinical studies. In this study, a mouse diversity panel (MDP), comprised of 34 genetically diverse, inbred mouse strains, was utilized to model the toxicity observed with PF-04287881 treatment and investigate potential mechanisms that may mediate the liver response. Significant elevations in serum alanine aminotransferase (ALT) levels in PF-04287881-treated animals relative to vehicle-treated controls were observed in the majority (88%) of strains tested following a seven day exposure. The average fold elevation in ALT varied by genetic background and correlated with microscopic findings of hepatocellular hypertrophy, hepatocellular single cell necrosis, and Kupffer cell vacuolation (confirmed as phospholipidosis) in the liver. Global liver mRNA expression was evaluated in a subset of four strains to identify transcript and pathway differences that distinguish susceptible mice from resistant mice in the context of PF-04287881 treatment. The protein ubiquitination pathway was highly enriched among genes associated with PF-04287881-induced hepatocellular necrosis. Expression changes associated with PF-04287881-induced phospholipidosis included genes involved in drug transport, phospholipid metabolism, and lysosomal function. The findings suggest that perturbations in genes involved in protein degradation leading to accumulation of oxidized proteins may mediate the liver injury induced by this drug.


      PubDate: 2014-09-04T01:51:02Z
       
  • Time- and concentration-dependent genomic responses of the rat airway to
           inhaled nickel subsulfide
    • Abstract: Publication date: 15 September 2014
      Source:Toxicology and Applied Pharmacology, Volume 279, Issue 3
      Author(s): A.Y. Efremenko , J.L. Campbell Jr. , D.E. Dodd , A.R. Oller , H.J. Clewell III.
      Objective To provide insights into the mode of action for Ni3S2 lung carcinogenicity by examining gene expression changes in target cells after inhalation exposure. Methods Gene expression changes were determined in micro-dissected lung broncho-alveolar cells from Fischer 344 rats following inhalation of Ni3S2 at 0.0, 0.04, 0.08, 0.15, and 0.60mg/m3 (0.03, 0.06, 0.11, and 0.44mgNi/m3) for one and four weeks (6h/day, 5days/week). Results Broncho-alveolar lavage fluid evaluation and lung histopathology provided evidence of inflammation only at the two highest concentrations, which were similar to those tested in the 2-year bioassay. The number of statistically significant up- and down-regulated genes decreased markedly from one to four weeks of exposure, suggesting adaptation. Cell signal pathway enrichment at both time-points primarily reflected responses to toxicity, including inflammatory and proliferative signaling. While proliferative signaling was up-regulated at both time points, some inflammatory signaling reversed from down-regulation at 1week to up-regulation at 4weeks. Conclusions These results support a mode of action for Ni3S2 carcinogenicity driven by chronic toxicity, inflammation and proliferation, leading to mis-replication, rather than by direct genotoxicity. Benchmark dose (BMD) analysis identified the lowest pathway transcriptional BMD exposure concentration as 0.026mgNi/m3, for apoptosis/survival signaling. When conducted on the basis of lung Ni concentration the lowest pathway BMD was 0.64μgNi/g lung, for immune/inflammatory signaling. Implications These highly conservative BMDs could be used to derive a point of departure in a nonlinear risk assessment for Ni3S2 toxicity and carcinogenicity.


      PubDate: 2014-09-04T01:51:02Z
       
  • Genotoxicity testing of peptides: Folate deprivation as a marker of
           exaggerated pharmacology
    • Abstract: Publication date: 15 September 2014
      Source:Toxicology and Applied Pharmacology, Volume 279, Issue 3
      Author(s): Melanie Guérard , Andreas Zeller , Matthias Festag , Christine Schubert , Thomas Singer , Lutz Müller
      The incidence of micronucleated-cells is considered to be a marker of a genotoxic event and can be caused by direct- or indirect-DNA reactive mechanisms. In particular, small increases in the incidence of micronuclei, which are not associated with toxicity in the target tissue or any structurally altering properties of the compound, trigger the suspicion that an indirect mechanism could be at play. In a bone marrow micronucleus test of a synthetic peptide (a dual agonist of the GLP-1 and GIP receptors) that had been integrated into a regulatory 13-week repeat-dose toxicity study in the rat, small increases in the incidence of micronuclei had been observed, together with pronounced reductions in food intake and body weight gain. Because it is well established that folate plays a crucial role in maintaining genomic integrity and pronounced reductions in food intake and body weight gain were observed, folate levels were determined from plasma samples initially collected for toxicokinetic analytics. A dose-dependent decrease in plasma folate levels was evident after 4weeks of treatment at the mid and high dose levels, persisted until the end of the treatment duration of 13-weeks and returned to baseline levels during the recovery period of 4weeks. Based on these properties, and the fact that the compound tested (peptide) per se is not expected to reach the nucleus and cause DNA damage, the rationale is supported that the elevated incidence of micronucleated polychromatic erythrocytes is directly linked to the exaggerated pharmacology of the compound resulting in a decreased folate level.


      PubDate: 2014-09-04T01:51:02Z
       
  • Unraveling the mechanism of neuroprotection of curcumin in arsenic induced
           cholinergic dysfunctions in rats
    • Abstract: Publication date: 15 September 2014
      Source:Toxicology and Applied Pharmacology, Volume 279, Issue 3
      Author(s): Pranay Srivastava , Rajesh S. Yadav , Lalit P. Chandravanshi , Rajendra K. Shukla , Yogesh K. Dhuriya , Lalit K.S. Chauhan , Hari N. Dwivedi , Aditiya B. Pant , Vinay K. Khanna
      Earlier, we found that arsenic induced cholinergic deficits in rat brain could be protected by curcumin. In continuation to this, the present study is focused to unravel the molecular mechanisms associated with the protective efficacy of curcumin in arsenic induced cholinergic deficits. Exposure to arsenic (20mg/kg body weight, p.o) for 28days in rats resulted to decrease the expression of CHRM2 receptor gene associated with mitochondrial dysfunctions as evident by decrease in the mitochondrial membrane potential, activity of mitochondrial complexes and enhanced apoptosis both in the frontal cortex and hippocampus in comparison to controls. The ultrastructural images of arsenic exposed rats, assessed by transmission electron microscope, exhibited loss of myelin sheath and distorted cristae in the mitochondria both in the frontal cortex and hippocampus as compared to controls. Simultaneous treatment with arsenic (20mg/kg body weight, p.o) and curcumin (100mg/kg body weight, p.o) for 28days in rats was found to protect arsenic induced changes in the mitochondrial membrane potential and activity of mitochondrial complexes both in frontal cortex and hippocampus. Alterations in the expression of pro- and anti-apoptotic proteins and ultrastructural damage in the frontal cortex and hippocampus following arsenic exposure were also protected in rats simultaneously treated with arsenic and curcumin. The data of the present study reveal that curcumin could protect arsenic induced cholinergic deficits by modulating the expression of pro- and anti-apoptotic proteins in the brain. More interestingly, arsenic induced functional and ultrastructural changes in the brain mitochondria were also protected by curcumin.


      PubDate: 2014-09-04T01:51:02Z
       
  • Expression profiles of genes involved in xenobiotic metabolism and
           disposition in human renal tissues and renal cell models
    • Abstract: Publication date: 15 September 2014
      Source:Toxicology and Applied Pharmacology, Volume 279, Issue 3
      Author(s): Cynthia Van der Hauwaert , Grégoire Savary , David Buob , Xavier Leroy , Sébastien Aubert , Vincent Flamand , Marie-Flore Hennino , Michaël Perrais , Jean-Marc Lo-Guidice , Franck Broly , Christelle Cauffiez , François Glowacki
      Numerous xenobiotics have been shown to be harmful for the kidney. Thus, to improve our knowledge of the cellular processing of these nephrotoxic compounds, we evaluated, by real-time PCR, the mRNA expression level of 377 genes encoding xenobiotic-metabolizing enzymes (XMEs), transporters, as well as nuclear receptors and transcription factors that coordinate their expression in eight normal human renal cortical tissues. Additionally, since several renal in vitro models are commonly used in pharmacological and toxicological studies, we investigated their metabolic capacities and compared them with those of renal tissues. The same set of genes was thus investigated in HEK293 and HK2 immortalized cell lines in commercial primary cultures of epithelial renal cells and in proximal tubular cell primary cultures. Altogether, our data offers a comprehensive description of kidney ability to process xenobiotics. Moreover, by hierarchical clustering, we observed large variations in gene expression profiles between renal cell lines and renal tissues. Primary cultures of proximal tubular epithelial cells exhibited the highest similarities with renal tissue in terms of transcript profiling. Moreover, compared to other renal cell models, Tacrolimus dose dependent toxic effects were lower in proximal tubular cell primary cultures that display the highest metabolism and disposition capacity. Therefore, primary cultures appear to be the most relevant in vitro model for investigating the metabolism and bioactivation of nephrotoxic compounds and for toxicological and pharmacological studies.


      PubDate: 2014-09-04T01:51:02Z
       
  • Methamidophos alters sperm function and DNA at different stages of
           spermatogenesis in mice
    • Abstract: Publication date: 15 September 2014
      Source:Toxicology and Applied Pharmacology, Volume 279, Issue 3
      Author(s): Mayrut Urióstegui-Acosta , Isabel Hernández-Ochoa , Manuel Sánchez-Gutiérrez , Belem Piña-Guzmán , Leticia Rafael-Vázquez , M.J. Solís-Heredia , Gerardo Martínez-Aguilar , Betzabet Quintanilla-Vega
      Methamidophos (MET) is a highly toxic organophosphate (OP) pesticide that is widely used in developing countries. MET has male reproductive effects, including decreased fertility. We evaluated MET effects on sperm quality, fertilization and DNA integrity, exploring the sensitivity of different stages of spermatogenesis. Adult male mice received MET (3.75 or 5mg/kg-bw/ip/day/4days) and were euthanized 1, 28 or 45days post-treatment (dpt) to evaluate MET's effects on epididymal maturation, meiosis or mitosis, respectively. Spermatozoa were obtained from the cauda epididymis–vas deferens and were evaluated for sperm quality, acrosome reaction (AR; Coomassie staining), mitochondrial membrane potential (by JC-1), DNA damage (comet assay), oxidative damage (malondialdehyde (MDA) production), in vitro fertilization and protein phosphorylation (immunodetection), and erythrocyte acetylcholinesterase (AChE) activity. At 1-dpt, MET inhibited AChE (43–57%) and increased abnormal cells (6%). While at 28- and 45-dpt, sperm motility and viability were significantly reduced with an increasing MET dose, and abnormal morphology increased at 5mg/kg/day/4days. MDA and mitochondrial activity were not affected at any dose or time. DNA damage (OTM and %DNA) was observed at 5mg/kg/day/4days in a time-dependent manner, whereas both parameters were altered in cells from mice exposed to 3.75mg/kg/day/4days only at 28-dpt. Depending on the time of collection, initial-, spontaneous- and induced-AR were altered at 5mg/kg/day/4days, and the fertilization capacity also decreased. Sperm phosphorylation (at serine and tyrosine residues) was observed at all time points. Data suggest that meiosis and mitosis are the more sensitive stages of spermatogenesis for MET reproductive toxicity compared to epididymal maturation.


      PubDate: 2014-09-04T01:51:02Z
       
  • Polychlorinated biphenyls (PCB 101, PCB 153 and PCB 180) alter leptin
           signaling and lipid metabolism in differentiated 3T3-L1 adipocytes
    • Abstract: Publication date: 15 September 2014
      Source:Toxicology and Applied Pharmacology, Volume 279, Issue 3
      Author(s): Maria C. Ferrante , Paola Amero , Anna Santoro , Anna Monnolo , Raffaele Simeoli , Francesca Di Guida , Giuseppina Mattace Raso , Rosaria Meli
      Non-dioxin-like polychlorinated biphenyls (NDL-PCBs) are highly lipophilic environmental contaminants that accumulate in lipid-rich tissues, such as adipose tissue. Here, we reported the effects induced by PCBs 101, 153 and 180, three of the six NDL-PCBs defined as indicators, on mature 3T3-L1 adipocytes. We observed an increase in lipid content, in leptin gene expression and a reduction of leptin receptor expression and signaling, when cells were exposed to PCBs, alone or in combination. These modifications were consistent with the occurrence of “leptin-resistance” in adipose tissue, a typical metabolic alteration related to obesity. Therefore, we investigated how PCBs affect the expression of pivotal proteins involved in the signaling of leptin receptor. We evaluated the PCB effect on the intracellular pathway JAK/STAT, determining the phosphorylation of STAT3, a downstream activator of the transcription of leptin gene targets, and the expression of SOCS3 and PTP1B, two important regulators of leptin resistance. In particular, PCBs 153 and 180 or all PCB combinations induced a significant reduction in pSTAT3/STAT3 ratio and an increase in PTP1B and SOCS3, evidencing an additive effect. The impairment of leptin signaling was associated with the reduction of AMPK/ACC pathway activation, leading to the increase in lipid content. These pollutants were also able to increase the transcription of inflammatory cytokines (IL-6 and TNFα). It is worthy to note that the PCB concentrations used are comparable to levels detectable in human adipose tissue. Our data strongly support the hypothesis that NDL-PCBs may interfere with the lipid metabolism contributing to the development of obesity and related diseases.


      PubDate: 2014-09-04T01:51:02Z
       
  • Evaluation of Aroclor 1260 exposure in a mouse model of diet-induced
           obesity and non-alcoholic fatty liver disease
    • Abstract: Publication date: 15 September 2014
      Source:Toxicology and Applied Pharmacology, Volume 279, Issue 3
      Author(s): Banrida Wahlang , Ming Song , Juliane I. Beier , K. Cameron Falkner , Laila Al-Eryani , Heather B. Clair , Russell A. Prough , Tanasa S. Osborne , David E. Malarkey , J. Christopher States , Matthew C. Cave
      Polychlorinated biphenyls (PCBs) are persistent organic pollutants associated with non-alcoholic fatty liver disease (NAFLD) in epidemiologic studies. The purpose of this study was to evaluate the hepatic effects of a PCB mixture, Aroclor 1260, whose composition mimics human bioaccumulation patterns, in a mouse model of diet-induced obesity (DIO). Male C57Bl/6J mice were fed control diet or 42% high fat diet (HFD) and exposed to Aroclor 1260 (20mg/kg or 200mg/kg in corn oil) for 12weeks. A glucose tolerance test was performed; plasma/tissues were obtained at necropsy for measurements of adipocytokine levels, histology, and gene expression. Aroclor 1260 exposure was associated with decreased body fat in HFD-fed mice but had no effect on blood glucose/lipid levels. Paradoxically, Aroclor 1260+HFD co-exposed mice demonstrated increased hepatic inflammatory foci at both doses while the degree of steatosis did not change. Serum cytokines, ALT levels and hepatic expression of IL-6 and TNFα were increased only at 20mg/kg, suggesting an inhibition of pro-inflammatory cytokine production at the 200mg/kg exposure. Aroclor 1260 induced hepatic expression of cytochrome P450s including Cyp3a11 (Pregnane-Xenobiotic Receptor target) and Cyp2b10 (constitutive androstane receptor target) but Cyp2b10 inducibility was diminished with HFD-feeding. Cyp1a2 (aryl hydrocarbon Receptor target) was induced only at 200mg/kg. In summary, Aroclor 1260 worsened hepatic and systemic inflammation in DIO. The results indicated a bimodal response of PCB-diet interactions in the context of inflammation which could potentially be explained by xenobiotic receptor activation. Thus, PCB exposure may be a relevant “second hit” in the transformation of steatosis to steatohepatitis.
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      PubDate: 2014-09-04T01:51:02Z
       
  • XRCC1 Arg194Trp and Arg399Gln polymorphisms and arsenic methylation
           capacity are associated with urothelial carcinoma
    • Abstract: Publication date: 15 September 2014
      Source:Toxicology and Applied Pharmacology, Volume 279, Issue 3
      Author(s): Chien-I Chiang , Ya-Li Huang , Wei-Jen Chen , Horng-Sheng Shiue , Chao-Yuan Huang , Yeong-Shiau Pu , Ying-Chin Lin , Yu-Mei Hsueh
      The association between DNA repair gene polymorphisms and bladder cancer has been widely studied. However, few studies have examined the correlation between urothelial carcinoma (UC) and arsenic or its metabolites. The aim of this study was to examine the association between polymorphisms of the DNA repair genes, XRCC1 Arg194Trp, XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln, with urinary arsenic profiles and UC. To this end, we conducted a hospital-based case–control study with 324 UC patients and 647 age- and gender-matched non-cancer controls. Genomic DNA was used to examine the genotype of XRCC1 Arg194Trp, XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln by PCR-restriction fragment length polymorphism analysis (PCR-RFLP). Urinary arsenic profiles were measured by high performance liquid chromatography (HPLC) linked with hydride generator and atomic absorption spectrometry. The XRCC1 399 Gln/Gln and 194 Arg/Trp and Trp/Trp genotypes were significantly related to UC, and the odds ratio (OR) and 95% confidence interval (95%CI) were 1.68 (1.03–2.75) and 0.66 (0.48–0.90), respectively. Participants with higher total urinary arsenic levels, a higher percentage of inorganic arsenic (InAs%) and a lower percentage of dimethylarsinic acid (DMA%) had a higher OR of UC. Participants carrying XRCC1 risk diplotypes G-C/G-C, A-C/A-C, and A-T/G-T, and who had higher total arsenic levels, higher InAs%, or lower DMA% compared to those with other XRCC1 diplotypes had a higher OR of UC. Our results suggest that the XRCC1 399 Gln/Gln and 194 Arg/Arg DNA repair genes play an important role in poor arsenic methylation capacity, thereby increasing the risk of UC in non-obvious arsenic exposure areas.


      PubDate: 2014-09-04T01:51:02Z
       
  • Taurine protects HK-2 cells from oxidized LDL-induced cytotoxicity via the
           ROS-mediated mitochondrial and p53-related apoptotic pathways
    • Abstract: Publication date: 15 September 2014
      Source:Toxicology and Applied Pharmacology, Volume 279, Issue 3
      Author(s): Chun-Yu Chang , Chao-Yu Shen , Chao-Kai Kang , Yuh-Pyng Sher , Wayne H.-H. Sheu , Chia-Che Chang , Tsung-Han Lee
      Oxidized LDL (oxLDL) induces a pro-oxidative environment and promotes apoptosis, causing the progression of renal diseases in humans. Taurine is a semi-essential amino acid in mammals and has been shown to be a potent endogenous antioxidant. The kidney plays a pivotal role in maintaining the balance of taurine. However, the mechanisms underlying the protective effects of taurine against oxLDL-induced injury in renal epithelial cells have not been clarified. In the present study, we investigated the anti-apoptotic effects of taurine on human proximal tubular epithelial (HK-2) cells exposed to oxLDL and explored the related mechanisms. We observed that oxLDL increased the contents of ROS and of malondialdehyde (MDA), which is a lipid peroxidation by-product that acts as an indicator of the cellular oxidation status. In addition, oxLDL induced cell death and apoptosis in HK-2 cells. Pretreatment with taurine at 100μM significantly attenuated the oxLDL-induced cytotoxicity. We determined that oxLDL triggered the phosphorylation of ERK and, in turn, the activation of p53 and other apoptosis-related events, including calcium accumulation, destabilization of the mitochondrial permeability and disruption of the balance between pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins. The malfunctions induced by oxLDL were effectively blocked by taurine. Thus, our results suggested that taurine exhibits potential therapeutic activity by preventing oxLDL-induced nephrotoxicity. The inhibition of oxLDL-induced epithelial apoptosis by taurine was at least partially due to its anti-oxidant activity and its ability to modulate the ERK and p53 apoptotic pathways.


      PubDate: 2014-09-04T01:51:02Z
       
  • PBPK and population modelling to interpret urine cadmium concentrations of
           the French population
    • Abstract: Publication date: 15 September 2014
      Source:Toxicology and Applied Pharmacology, Volume 279, Issue 3
      Author(s): Camille Béchaux , Laurent Bodin , Stéphan Clémençon , Amélie Crépet
      As cadmium accumulates mainly in kidney, urinary concentrations are considered as relevant data to assess the risk related to cadmium. The French Nutrition and Health Survey (ENNS) recorded the concentration of cadmium in the urine of the French population. However, as with all biomonitoring data, it needs to be linked to external exposure for it to be interpreted in term of sources of exposure and for risk management purposes. The objective of this work is thus to interpret the cadmium biomonitoring data of the French population in terms of dietary and cigarette smoke exposures. Dietary and smoking habits recorded in the ENNS study were combined with contamination levels in food and cigarettes to assess individual exposures. A PBPK model was used in a Bayesian population model to link this external exposure with the measured urinary concentrations. In this model, the level of the past exposure was corrected thanks to a scaling function which account for a trend in the French dietary exposure. It resulted in a modelling which was able to explain the current urinary concentrations measured in the French population through current and past exposure levels. Risk related to cadmium exposure in the general French population was then assessed from external and internal critical values corresponding to kidney effects. The model was also applied to predict the possible urinary concentrations of the French population in 2030 assuming there will be no more changes in the exposures levels. This scenario leads to significantly lower concentrations and consequently lower related risk.


      PubDate: 2014-09-04T01:51:02Z
       
  • Methyl parathion inhibits the nuclear maturation, decreases the
           cytoplasmic quality in oocytes and alters the developmental potential of
           embryos of Swiss albino mice
    • Abstract: Publication date: 15 September 2014
      Source:Toxicology and Applied Pharmacology, Volume 279, Issue 3
      Author(s): Ramya Nair , Vikram Jeet Singh , Sujith Raj Salian , Sneha Guruprasad Kalthur , Antony Sylvan D'Souza , Pallavi K. Shetty , Srinivas Mutalik , Guruprasad Kalthur , Satish Kumar Adiga
      Methyl parathion (MP) is one of the most commonly used and extremely toxic organophosphorous group of pesticide. A large number of studies in the literature suggest that it has adverse effects on the male reproductive system. However, there is limited information about its toxicity to the female reproductive system. In the present study we report the toxic effects of methyl parathion on the female reproductive system using Swiss albino mice as the experimental model. The female mice were administered orally with 5, 10 and 20mg/kg of MP. One week later, the mice were superovulated with pregnant mare serum gonadotrophin (PMSG) and human chorionic gonadotrophin (hCG) to study the quality of the oocytes, spindle organization, developmental potential of early embryos and the DNA integrity in blastocysts. MP exposure resulted in a non-significant decrease in the number of primordial follicles and increased DNA damage in granulosa cells. Though MP did not have any effect on the ovulation it had a significant inhibitory effect on the nuclear maturity of oocytes which was associated with spindle deformity. In addition, the oocytes had higher cytoplasmic abnormalities with depleted glutathione level. Even though it did not have any effect on the fertilization and blastocyst rate at lower doses, at 20 mg/kg MP it resulted in a significant decrease in blastocyst hatching, decrease in cell number and high DNA damage. While low body weight gain was observed in F1 generation from 5mg/kg group, at higher dose, the body weight in F1 generation was marginally higher than control. Post-natal death in F1 generation was observed only in mice treated with 20mg/kg MP. In conclusion, we report that MP has adverse effects on the oocyte quality, developmental potential of the embryo and reproductive outcome.


      PubDate: 2014-09-04T01:51:02Z
       
  • Fenitrothion action at the endocannabinoid system leading to
           spermatotoxicity in Wistar rats
    • Abstract: Publication date: 15 September 2014
      Source:Toxicology and Applied Pharmacology, Volume 279, Issue 3
      Author(s): Yuki Ito , Motohiro Tomizawa , Himiko Suzuki , Ai Okamura , Katsumi Ohtani , Mari Nunome , Yuki Noro , Dong Wang , Tamie Nakajima , Michihiro Kamijima
      Organophosphate (OP) compounds as anticholinesterase agents may secondarily act on diverse serine hydrolase targets, revealing unfavorable physiological effects including male reproductive toxicity. The present investigation proposes that fenitrothion (FNT, a major OP compound) acts on the endocannabinoid signaling system in male reproductive organs, thereby leading to spermatotoxicity (sperm deformity, underdevelopment, and reduced motility) in rats. FNT oxon (bioactive metabolite of FNT) preferentially inhibited the fatty acid amide hydrolase (FAAH), an endocannabinoid anandamide (AEA) hydrolase, in the rat cellular membrane preparation from the testis in vitro. Subsequently, male Wistar rats were treated orally with 5 or 10mg/kg FNT for 9weeks and the subchronic exposure unambiguously deteriorated sperm motility and morphology. The activity-based protein profiling analysis with a phosphonofluoridate fluorescent probe revealed that FAAH was selectively inhibited among the FNT-treated cellular membrane proteome in testis. Intriguingly, testicular AEA (endogenous substrate of FAAH) levels were elevated along with the FAAH inhibition caused by the subchronic exposure. More importantly, linear regression analyses for the FNT-elicited spermatotoxicity reveal a good correlation between the testicular FAAH activity and morphological indices or sperm motility. Accordingly, the present study proposes that the FNT-elicited spermatotoxicity appears to be related to inhibition of FAAH leading to overstimulation of the endocannabinoid signaling system, which plays crucial roles in spermatogenesis and sperm motility acquirement.
      Graphical abstract image

      PubDate: 2014-09-04T01:51:02Z
       
  • Downregulation of glutathione S-transferase M1 protein in
           N-butyl-N-(4-hydroxybutyl)nitrosamine-induced mouse bladder carcinogenesis
           
    • Abstract: Publication date: 15 September 2014
      Source:Toxicology and Applied Pharmacology, Volume 279, Issue 3
      Author(s): Jing-Jing Chuang , Yuan-Chang Dai , Yung-Lun Lin , Yang-Yi Chen , Wei-Han Lin , Hong-Lin Chan , Yi-Wen Liu
      Bladder cancer is highly recurrent following specific transurethral resection and intravesical chemotherapy, which has prompted continuing efforts to develop novel therapeutic agents and early-stage diagnostic tools. Specific changes in protein expression can provide a diagnostic marker. In our present study, we investigated changes in protein expression during urothelial carcinogenesis. The carcinogen BBN was used to induce mouse bladder tumor formation. Mouse bladder mucosa proteins were collected and analyzed by 2D electrophoresis from 6 to 20weeks after commencing continuous BBN treatment. By histological examination, the connective layer of the submucosa showed gradual thickening and the number of submucosal capillaries gradually increased after BBN treatment. At 12-weeks after the start of BBN treatment, the urothelia became moderately dysplastic and tumors arose after 20-weeks of treatment. These induced bladder lesions included carcinoma in situ and connective tissue invasive cancer. In protein 2D analysis, the sequentially downregulated proteins from 6 to 20weeks included GSTM1, L-lactate dehydrogenase B chain, keratin 8, keratin 18 and major urinary proteins 2 and 11/8. In contrast, the sequentially upregulated proteins identified were GSTO1, keratin 15 and myosin light polypeptide 6. Western blotting confirmed that GSTM1 and NQO-1 were decreased, while GSTO1 and Sp1 were increased, after BBN treatment. In human bladder cancer cells, 5-aza-2′-deoxycytidine increased the GSTM1 mRNA and protein expression. These data suggest that the downregulation of GSTM1 in the urothelia is a biomarker of bladder carcinogenesis and that this may be mediated by DNA CpG methylation.


      PubDate: 2014-09-04T01:51:02Z
       
  • Tris(2-butoxyethyl)phosphate and triethyl phosphate alter embryonic
           development, hepatic mRNA expression, thyroid hormone levels, and
           circulating bile acid concentrations in chicken embryos
    • Abstract: Publication date: 15 September 2014
      Source:Toxicology and Applied Pharmacology, Volume 279, Issue 3
      Author(s): Caroline Egloff , Doug Crump , Emily Porter , Kim L. Williams , Robert J. Letcher , Lewis T. Gauthier , Sean W. Kennedy
      The organophosphate flame retardants tris(2-butoxyethyl) phosphate (TBOEP) and triethyl phosphate (TEP) are used in a wide range of applications to suppress or delay the ignition and spread of fire. Both compounds have been detected in the environment and TBOEP was recently measured in free-living avian species. In this study, TBOEP and TEP were injected into the air cell of chicken embryos at concentrations ranging from 0 to 45,400ng/g and 0 to 241,500ng/g egg, respectively. Pipping success, development, hepatic mRNA expression of 9 target genes, thyroid hormone levels, and circulating bile acid concentrations were determined. Exposure to the highest doses of TBOEP and TEP resulted in negligible detection of the parent compounds in embryonic contents at pipping indicating their complete metabolic degradation. TBOEP exposure had limited effects on chicken embryos, with the exception of hepatic CYP3A37 mRNA induction. TEP exposure decreased pipping success to 68%, altered growth, increased liver somatic index (LSI) and plasma bile acids, and modulated genes associated with xenobiotic and lipid metabolism and the thyroid hormone pathway. Plasma thyroxine levels were decreased at all TEP doses, including an environmentally-relevant concentration (8ng/g), and gallbladder hypotrophy was evident at ≥43,200ng/g. Tarsus length and circulating thyroxine concentration emerged as potential phenotypic anchors for the modulation of transthyretin mRNA. The increase in plasma bile acids and LSI, gallbladder hypotrophy, and discoloration of liver tissue represented potential phenotypic outcomes associated with modulation of hepatic genes involved with xenobiotic and lipid metabolism.


      PubDate: 2014-09-04T01:51:02Z
       
  • Isoliquiritigenin, a flavonoid from licorice, blocks M2 macrophage
           polarization in colitis-associated tumorigenesis through downregulating
           PGE2 and IL-6
    • Abstract: Publication date: 15 September 2014
      Source:Toxicology and Applied Pharmacology, Volume 279, Issue 3
      Author(s): Haixia Zhao , Xinhua Zhang , Xuewei Chen , Ying Li , Zunqiong Ke , Tian Tang , Hongyan Chai , Austin M. Guo , Honglei Chen , Jing Yang
      M2 macrophage polarization is implicated in colorectal cancer development. Isoliquiritigenin (ISL), a flavonoid from licorice, has been reported to prevent azoxymethane (AOM) induced colon carcinogenesis in animal models. Here, in a mouse model of colitis-associated tumorigenesis induced by AOM/dextran sodium sulfate (DSS), we investigated the chemopreventive effects of ISL and its mechanisms of action. Mice were treated with AOM/DSS and randomized to receive either vehicle or ISL (3, 15 and 75mg/kg). Tumor load, histology, immunohistochemistry, and gene and protein expressions were determined. Intragastric administration of ISL for 12weeks significantly decreased colon cancer incidence, multiplicity and tumor size by 60%, 55.4% and 42.6%, respectively. Moreover, ISL inhibited M2 macrophage polarization. Such changes were accompanied by downregulation of PGE2 and IL-6 signaling. Importantly, depletion of macrophages by clodronate (Clod) or zoledronic acid (ZA) reversed the effects of ISL. In parallel, in vitro studies also demonstrated that ISL limited the M2 polarization of RAW264.7 cells and mouse peritoneal macrophages with concomitant inactivation of PGE2/PPARδ and IL-6/STAT3 signaling. Conversely, exogenous addition of PGE2 or IL-6, or overexpression of constitutively active STAT3 reversed ISL-mediated inhibition of M2 macrophage polarization. In summary, dietary flavonoid ISL effectively inhibits colitis-associated tumorigenesis through hampering M2 macrophage polarization mediated by the interplay between PGE2 and IL-6. Thus, inhibition of M2 macrophage polarization is likely to represent a promising strategy for chemoprevention of colorectal cancer.
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      PubDate: 2014-09-04T01:51:02Z
       
  • Modeling toxicodynamic effects of trichloroethylene on liver in mouse
           model of autoimmune hepatitis
    • Abstract: Publication date: 15 September 2014
      Source:Toxicology and Applied Pharmacology, Volume 279, Issue 3
      Author(s): Kathleen M. Gilbert , Brad Reisfeld , Todd J. Zurlinden , Meagan N. Kreps , Stephen W. Erickson , Sarah J. Blossom
      Chronic exposure to industrial solvent and water pollutant trichloroethylene (TCE) in female MRL+/+mice generates disease similar to human autoimmune hepatitis. The current study was initiated to investigate why TCE-induced autoimmunity targeted the liver. Compared to other tissues the liver has an unusually robust capacity for repair and regeneration. This investigation examined both time-dependent and dose-dependent effects of TCE on hepatoprotective and pro-inflammatory events in liver and macrophages from female MRL+/+mice. After a 12-week exposure to TCE in drinking water a dose-dependent decrease in macrophage production of IL-6 at both the transcriptional and protein level was observed. A longitudinal study similarly showed that TCE inhibited macrophage IL-6 production. In terms of the liver, TCE had little effect on expression of pro-inflammatory genes (Tnfa, Saa2 or Cscl1) until the end of the 40-week exposure. Instead, TCE suppressed hepatic expression of genes involved in IL-6 signaling (Il6r, gp130, and Egr1). Linear regression analysis confirmed liver histopathology in the TCE-treated mice correlated with decreased expression of Il6r. A toxicodynamic model was developed to estimate the effects of TCE on IL-6 signaling and liver pathology under different levels of exposure and rates of repair. This study underlined the importance of longitudinal studies in mechanistic evaluations of immuntoxicants. It showed that later-occurring liver pathology caused by TCE was associated with early suppression of hepatoprotection rather than an increase in conventional pro-inflammatory events. This information was used to create a novel toxicodynamic model of IL-6-mediated TCE-induced liver inflammation.


      PubDate: 2014-09-04T01:51:02Z
       
  • Magnolol protects neurons against ischemia injury via the downregulation
           of p38/MAPK, CHOP and nitrotyrosine
    • Abstract: Publication date: 15 September 2014
      Source:Toxicology and Applied Pharmacology, Volume 279, Issue 3
      Author(s): Jiann-Hwa Chen , Hsing-Chun Kuo , Kam-Fai Lee , Tung-Hu Tsai
      Magnolol is isolated from the herb Magnolia officinalis, which has been demonstrated to exert pharmacological effects. Our aim was to investigate whether magnolol is able to act as an anti-inflammatory agent that brings about neuroprotection using a global ischemic stroke model and to determine the mechanisms involved. Rats were treated with and without magnolol after ischemia reperfusion brain injury by occlusion of the two common carotid arteries. The inflammatory cytokine production in serum and the volume of infarction in the brain were measured. The proteins present in the brains obtained from the stroke animal model (SAM) and control animal groups with and without magnolol treatment were compared. Magnolol reduces the total infarcted volume by 15% and 30% at dosages of 10 and 30mg/kg, respectively, compared to the untreated SAM group. The levels of acute inflammatory cytokines, including interleukin-1 beta, tumor necrosis factor alpha, and interleukin-6 were attenuated by magnolol. Magnolol was also able to suppress the production of nitrotyrosine, 4-hydroxy-2-nonenal (4-HNE), inducible NO synthase (iNOS), various phosphorylated p38 mitogen-activated protein kinases and various C/EBP homologues. Furthermore, this modulation of ischemia injury factors in the SAM model group treated with magnolol seems to result from a suppression of reactive oxygen species production and the upregulation of p-Akt and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). These findings confirm the anti-oxidative properties of magnolol, including the inhibition of ischemic injury to neurons; this protective effect seems to involve changes in the in vivo activity of Akt, GSK3β and NF-κB.
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      PubDate: 2014-09-04T01:51:02Z
       
  • Structure-dependent binding and activation of perfluorinated compounds on
           human peroxisome proliferator-activated receptor γ
    • Abstract: Publication date: 15 September 2014
      Source:Toxicology and Applied Pharmacology, Volume 279, Issue 3
      Author(s): Lianying Zhang , Xiao-Min Ren , Bin Wan , Liang-Hong Guo
      Perfluorinated compounds (PFCs) have been shown to disrupt lipid metabolism and even induce cancer in rodents through activation of peroxisome proliferator-activated receptors (PPARs). Lines of evidence showed that PPARα was activated by PFCs. However, the information on the binding interactions between PPARγ and PFCs and subsequent alteration of PPARγ activity is still limited and sometimes inconsistent. In the present study, in vitro binding of 16 PFCs to human PPARγ ligand binding domain (hPPARγ-LBD) and their activity on the receptor in cells were investigated. The results showed that the binding affinity was strongly dependent on their carbon number and functional group. For the eleven perfluorinated carboxylic acids (PFCAs), the binding affinity increased with their carbon number from 4 to 11, and then decreased slightly. The binding affinity of the three perfluorinated sulfonic acids (PFSAs) was stronger than their PFCA counterparts. No binding was detected for the two fluorotelomer alcohols (FTOHs). Circular dichroim spectroscopy showed that PFC binding induced distinctive structural change of the receptor. In dual luciferase reporter assays using transiently transfected Hep G2 cells, PFCs acted as hPPARγ agonists, and their potency correlated with their binding affinity with hPPARγ-LBD. Molecular docking showed that PFCs with different chain length bind with the receptor in different geometry, which may contribute to their differences in binding affinity and transcriptional activity.
      Graphical abstract image

      PubDate: 2014-09-04T01:51:02Z
       
  • Mechanisms of acetaminophen-induced cell death in primary human
           hepatocytes
    • Abstract: Publication date: 15 September 2014
      Source:Toxicology and Applied Pharmacology, Volume 279, Issue 3
      Author(s): Yuchao Xie , Mitchell R. McGill , Kenneth Dorko , Sean C. Kumer , Timothy M. Schmitt , Jameson Forster , Hartmut Jaeschke
      Acetaminophen (APAP) overdose is the most prevalent cause of drug-induced liver injury in western countries. Numerous studies have been conducted to investigate the mechanisms of injury after APAP overdose in various animal models; however, the importance of these mechanisms for humans remains unclear. Here we investigated APAP hepatotoxicity using freshly isolated primary human hepatocytes (PHH) from either donor livers or liver resections. PHH were exposed to 5mM, 10mM or 20mM APAP over a period of 48h and multiple parameters were assessed. APAP dose-dependently induced significant hepatocyte necrosis starting from 24h, which correlated with the clinical onset of human liver injury after APAP overdose. Interestingly, cellular glutathione was depleted rapidly during the first 3h. APAP also resulted in early formation of APAP-protein adducts (measured in whole cell lysate and in mitochondria) and mitochondrial dysfunction, indicated by the loss of mitochondrial membrane potential after 12h. Furthermore, APAP time-dependently triggered c-Jun N-terminal kinase (JNK) activation in the cytosol and translocation of phospho-JNK to the mitochondria. Both co-treatment and post-treatment (3h) with the JNK inhibitor SP600125 reduced JNK activation and significantly attenuated cell death at 24h and 48h after APAP. The clinical antidote N-acetylcysteine offered almost complete protection even if administered 6h after APAP and a partial protection when given at 15h. Conclusion: These data highlight important mechanistic events in APAP toxicity in PHH and indicate a critical role of JNK in the progression of injury after APAP in humans. The JNK pathway may represent a therapeutic target in the clinic.


      PubDate: 2014-09-04T01:51:02Z
       
  • Prediction of binding affinity and efficacy of thyroid hormone receptor
           ligands using QSAR and structure-based modeling methods
    • Abstract: Publication date: 1 October 2014
      Source:Toxicology and Applied Pharmacology, Volume 280, Issue 1
      Author(s): Regina Politi , Ivan Rusyn , Alexander Tropsha
      The thyroid hormone receptor (THR) is an important member of the nuclear receptor family that can be activated by endocrine disrupting chemicals (EDC). Quantitative Structure–Activity Relationship (QSAR) models have been developed to facilitate the prioritization of THR-mediated EDC for the experimental validation. The largest database of binding affinities available at the time of the study for ligand binding domain (LBD) of THRβ was assembled to generate both continuous and classification QSAR models with an external accuracy of R 2 =0.55 and CCR=0.76, respectively. In addition, for the first time a QSAR model was developed to predict binding affinities of antagonists inhibiting the interaction of coactivators with the AF-2 domain of THRβ (R 2 =0.70). Furthermore, molecular docking studies were performed for a set of THRβ ligands (57 agonists and 15 antagonists of LBD, 210 antagonists of the AF-2 domain, supplemented by putative decoys/non-binders) using several THRβ structures retrieved from the Protein Data Bank. We found that two agonist-bound THRβ conformations could effectively discriminate their corresponding ligands from presumed non-binders. Moreover, one of the agonist conformations could discriminate agonists from antagonists. Finally, we have conducted virtual screening of a chemical library compiled by the EPA as part of the Tox21 program to identify potential THRβ-mediated EDCs using both QSAR models and docking. We concluded that the library is unlikely to have any EDC that would bind to the THRβ. Models developed in this study can be employed either to identify environmental chemicals interacting with the THR or, conversely, to eliminate the THR-mediated mechanism of action for chemicals of concern.


      PubDate: 2014-09-04T01:51:02Z
       
  • Gingerol sensitizes TRAIL-induced apoptotic cell death of glioblastoma
           cells
    • Abstract: Publication date: 15 September 2014
      Source:Toxicology and Applied Pharmacology, Volume 279, Issue 3
      Author(s): Dae-Hee Lee , Dong-Wook Kim , Chang-Hwa Jung , Yong J. Lee , Daeho Park
      Glioblastoma multiforme (GBM) is the most lethal and aggressive astrocytoma of primary brain tumors in adults. Although there are many clinical trials to induce the cell death of glioblastoma cells, most glioblastoma cells have been reported to be resistant to TRAIL-induced apoptosis. Here, we showed that gingerol as a major component of ginger can induce TRAIL-mediated apoptosis of glioblastoma. Gingerol increased death receptor (DR) 5 levels in a p53-dependent manner. Furthermore, gingerol decreased the expression level of anti-apoptotic proteins (survivin, c-FLIP, Bcl-2, and XIAP) and increased pro-apoptotic protein, Bax and truncate Bid, by generating reactive oxygen species (ROS). We also found that the sensitizing effects of gingerol in TRAIL-induced cell death were blocked by scavenging ROS or overexpressing anti-apoptotic protein (Bcl-2). Therefore, we showed the functions of gingerol as a sensitizing agent to induce cell death of TRAIL-resistant glioblastoma cells. This study gives rise to the possibility of applying gingerol as an anti-tumor agent that can be used for the purpose of combination treatment with TRAIL in TRAIL-resistant glioblastoma tumor therapy.


      PubDate: 2014-09-04T01:51:02Z
       
  • Oral intake of hydrogen-rich water ameliorated chlorpyrifos-induced
           neurotoxicity in rats
    • Abstract: Publication date: 1 October 2014
      Source:Toxicology and Applied Pharmacology, Volume 280, Issue 1
      Author(s): Tingting Wang , Ling Zhao , Mengyu Liu , Fei Xie , Xuemei Ma , Pengxiang Zhao , Yunqi Liu , Jiala Li , Minglian Wang , Zhaona Yang , Yutong Zhang
      Chronic exposure to low-levels of organophosphate (OP) compounds, such as chlorpyrifos (CPF), induces oxidative stress and could be related to neurological disorders. Hydrogen has been identified as a novel antioxidant which could selectively scavenge hydroxyl radicals. We explore whether intake of hydrogen-rich water (HRW) can protect Wistar rats from CPF-induced neurotoxicity. Rats were gavaged daily with 6.75mg/kg body weight (1/20 LD50) of CPF and given HRW by oral intake. Nissl staining and electron microscopy results indicated that HRW intake had protective effects on the CPF-induced damage of hippocampal neurons and neuronal mitochondria. Immunostaining results showed that the increased glial fibrillary acidic protein (GFAP) expression in astrocytes induced by CPF exposure can be ameliorated by HRW intake. Moreover, HRW intake also attenuated CPF-induced oxidative stress as evidenced by enhanced level of MDA, accompanied by an increase in GSH level and SOD and CAT activity. Acetylcholinesterase (AChE) activity tests showed significant decrease in brain AChE activity after CPF exposure, and this effect can be ameliorated by HRW intake. An in vitro study demonstrated that AChE activity was more intense in HRW than in normal water with or without chlorpyrifos-oxon (CPO), the metabolically-activated form of CPF. These observations suggest that HRW intake can protect rats from CPF-induced neurotoxicity, and the protective effects of hydrogen may be mediated by regulating the oxidant and antioxidant status of rats. Furthermore, this work defines a novel mechanism of biological activity of hydrogen by directly increasing the AChE activity.


      PubDate: 2014-09-04T01:51:02Z
       
  • Effect of the combination of metformin hydrochloride and melatonin on
           oxidative stress before and during pregnancy, and biochemical and
           histopathological analysis of the livers of rats after treatment for
           polycystic ovary syndrome
    • Abstract: Publication date: 1 October 2014
      Source:Toxicology and Applied Pharmacology, Volume 280, Issue 1
      Author(s): Ana Janaina Jeanine M. Lemos , Christina A. Peixoto , Álvaro Aguiar C. Teixeira , Rayana Leal A. Luna , Sura Wanessa S. Rocha , Hilda Michelly P. Santos , Amanda Karolina S. Silva , Ana Karolina S. Nunes , Valéria Wanderley-Teixeira
      The aim of the present study was to analyze the effect of a combination of metformin hydrochloride and melatonin on oxidative stress together with a biochemical and histopathological analysis of the livers of Wistar rats induced with PCOS. The results indicated that a combination of the drugs was more effective in the reduction of plasmatic levels of liver enzyme alanine aminotransferase, nitric oxide and total glutathione, and decreased the inflammatory response and histopathological damage, producing results that were significantly similar to animals from the control group. A mixture of the drugs produced more effective results against liver toxicity caused by PCOS, encouraging the normalization of biochemical parameters. During pregnancy, there was reduced oxidative stress compared to monotherapeutic use of these drugs. Interestingly, the combination of the drugs caused a physiological reaction similar to responses identified in healthy rats without induction of the PCOS control group. However, the clinical and physiological effectiveness of the combination should be further explored, especially with respect to the possible side effects on offspring.
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      PubDate: 2014-09-04T01:51:02Z
       
  • Interaction of environmental contaminants with zebrafish organic anion
           transporting polypeptide, Oatp1d1 (Slco1d1)
    • Abstract: Publication date: 1 October 2014
      Source:Toxicology and Applied Pharmacology, Volume 280, Issue 1
      Author(s): Marta Popovic , Roko Zaja , Karl Fent , Tvrtko Smital
      Polyspecific transporters from the organic anion transporting polypeptide (OATP/Oatp) superfamily mediate the uptake of a wide range of compounds. In zebrafish, Oatp1d1 transports conjugated steroid hormones and cortisol. It is predominantly expressed in the liver, brain and testes. In this study we have characterized the transport of xenobiotics by the zebrafish Oatp1d1 transporter. We developed a novel assay for assessing Oatp1d1 interactors using the fluorescent probe Lucifer yellow and transient transfection in HEK293 cells. Our data showed that numerous environmental contaminants interact with zebrafish Oatp1d1. Oatp1d1 mediated the transport of diclofenac with very high affinity, followed by high affinity towards perfluorooctanesulfonic acid (PFOS), nonylphenol, gemfibrozil and 17α-ethinylestradiol; moderate affinity towards carbaryl, diazinon and caffeine; and low affinity towards metolachlor. Importantly, many environmental chemicals acted as strong inhibitors of Oatp1d1. A strong inhibition of Oatp1d1 transport activity was found by perfluorooctanoic acid (PFOA), chlorpyrifos-methyl, estrone (E1) and 17β-estradiol (E2), followed by moderate to low inhibition by diethyl phthalate, bisphenol A, 7-acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4 tetrahydronapthalene and clofibrate. In this study we identified Oatp1d1 as a first Solute Carrier (SLC) transporter involved in the transport of a wide range of xenobiotics in fish. Considering that Oatps in zebrafish have not been characterized before, our work on zebrafish Oatp1d1 offers important new insights on the understanding of uptake processes of environmental contaminants, and contributes to the better characterization of zebrafish as a model species.


      PubDate: 2014-09-04T01:51:02Z
       
  • Evaluation of the usefulness of novel biomarkers for drug-induced acute
           kidney injury in beagle dogs
    • Abstract: Publication date: 1 October 2014
      Source:Toxicology and Applied Pharmacology, Volume 280, Issue 1
      Author(s): Xiaobing Zhou , Ben Ma , Zhi Lin , Zhe Qu , Yan Huo , Jufeng Wang , Bo Li
      As kidney is a major target organ affected by drug toxicity, early detection of renal injury is critical in preclinical drug development. In past decades, a series of novel biomarkers of drug-induced nephrotoxicity were discovered and verified in rats. However, limited data regarding the performance of novel biomarkers in non-rodent species are publicly available. To increase the applicability of these biomarkers, we evaluated the performance of 4 urinary biomarkers including neutrophil gelatinase-associated lipocalin (NGAL), clusterin, total protein, and N-acetyl-β-D-glucosaminidase (NAG), relative to histopathology and traditional clinical chemistry in beagle dogs with acute kidney injury (AKI) induced by gentamicin. The results showed that urinary NGAL and clusterin levels were significantly elevated in dogs on days 1 and 3 after administration of gentamicin, respectively. Gene expression analysis further provided mechanistic evidence to support that NGAL and clusterin are potential biomarkers for the early assessment of drug-induced renal damage. Furthermore, the high area (both AUCs=1.000) under receiver operator characteristics (ROC) curve also indicated that NGAL and clusterin were the most sensitive biomarkers for detection of gentamicin-induced renal proximal tubular toxicity. Our results also suggested that NAG may be used in routine toxicity testing due to its sensitivity and robustness for detection of tissue injury. The present data will provide insights into the preclinical use of these biomarkers for detection of drug-induced AKI in non-rodent species.
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      PubDate: 2014-09-04T01:51:02Z
       
  • Editorial Board
    • Abstract: Publication date: 1 September 2014
      Source:Toxicology and Applied Pharmacology, Volume 279, Issue 2




      PubDate: 2014-08-14T19:47:43Z
       
  • Lysosomal membrane permeabilization: carbon nanohorns-induced reactive
           oxygen species generation and toxicity by this neglected mechanism
    • Abstract: Publication date: Available online 8 August 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Mei Yang , Minfang Zhang , Yoshio Tahara , Svetlana Chechetka , Eijiro Miyako , Sumio Iijima , Masako Yudasaka
      Understanding the molecular mechanisms responsible for the cytotoxic effects of carbon nanomaterials is important for their future biomedical applications. Carbon nanotubular materials induce the generation of reactive oxygen species (ROS), which cause cell death; however, the exact details of this process are still unclear. Here, we identify a mechanism of ROS generation that is involved in the apoptosis of RAW264.7 macrophages caused by excess uptake of carbon nanohorns (CNH), a typical type of carbon nanotubule. CNH accumulated in lysosomes, where they induced lysosomal membrane permeabilization (LMP) and the subsequent release of lysosomal proteases, such as cathepsins, which in turn caused mitochondrial dysfunction and triggered the generation of ROS in mitochondria. The nicotinamide adenine dinucleotide phosphate-oxidase was not directly involved in CNH-related ROS production, and the ROS generation cannot be regulated by mitochondrial electron transport chain. ROS fed back to amplify the mitochondrial dysfunction, leading to the subsequent activation of caspases and cell apoptosis. Carbon nanotubules commonly accumulate in lysosomes after internalization in cells; however, lysosomal dysfunction has not attracted much attention in toxicity studies of these materials. These results suggest that LMP, a neglect mechanism, may be the primary reason for carbon nanotubule toxicity.
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      PubDate: 2014-08-09T19:19:51Z
       
  • Selectivity of natural, synthetic and environmental estrogens for
           zebrafish estrogen receptors
    • Abstract: Publication date: Available online 8 August 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Caroline Pinto , Marina Grimaldi , Abdelhay Boulahtouf , Farzad Pakdel , François Brion , Sélim Aït-Aïssa , Vincent Cavaillès , William Bourguet , Jan-Ake Gustafsson , Maria Bondesson , Patrick Balaguer
      Zebrafish, Danio rerio, is increasingly used as an animal model to study the effects of pharmaceuticals and environmental estrogens. As most of these estrogens have only been tested on human estrogen receptors (ERs), it is necessary to measure their effects on zebrafish ERs. In humans there are two distinct nuclear ERs (hERα and hERβ), whereas the zebrafish genome encodes three ERs, zfERα and two zfERβs (zfERβ1 and zfERβ2). In this study, we established HeLa-based reporter cell lines stably expressing each of the three zfERs. We first reported that estrogens more efficiently activate the zfERs at 28°C as compared to 37°C, thus reflecting the physiological temperature of zebrafish in wildlife. We then showed significant differences in the ability of agonist and antagonist estrogens to modulate activation of the three zfER isotypes in comparison to hERs. Environmental compounds (bisphenol A, alkylphenols, mycoestrogens) which are hER panagonists and hERβ selective agonists displayed greater potency for zfERα as compared to zfERβs. Among hERα selective synthetic agonists, PPT did not activate zfERα while 16α-LE2 was the most zfERα selective compound. Altogether, these results confirm that all hER ligands control in a similar manner the transcriptional activity of zfERs although significant differences in selectivity were observed among subtypes. The zfER subtype selective ligands that we identified thus represent new valuable tools to dissect the physiological roles of the different zfERs. Finally, our work also points out that care has to be taken in transposing the results obtained using the zebrafish as a model for human physiopathology.
      Graphical abstract image

      PubDate: 2014-08-09T19:19:51Z
       
  • Bioavailability of andrographolide and protection against carbon
           tetrachloride-induced oxidative damage in rats
    • Abstract: Publication date: Available online 7 August 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Haw-Wen Chen , Chin-Shiu Huang , Chien-Chun Li , Ai-Hsuan Lin , Yu-Ju Huang , Tsu-Shing Wang , Hsien-Tsung Yao , Chong-Kuei Lii
      Andrographolide, a bioactive diterpenoid, is identified in Andrographis paniculata. In this study, we investigated the pharmacokinetics and bioavailability of andrographolide in rats and studied whether andrographolide enhances antioxidant defense in a variety of tissues and protects against carbon tetrachloride-induced oxidative damage. After a single 50-mg/kg administration, the maximum plasma concentration of andrographolide was 1μM which peaked at 30min. The bioavailability of andrographolide was 1.19%. In a hepatoprotection study, rats were intragastrically dosed with 30 or 50mg/kg andrographolide for 5 consecutive days. The results showed that andrographolide up-regulated glutamate cysteine ligase (GCL) catalytic and modifier subunits, superoxide dismutase (SOD)-1, heme oxygenase (HO)-1, and glutathione (GSH) S-transferase (GST) Ya/Yb protein and mRNA expression in the liver, heart, and kidneys. The activity of SOD, GST, and GSH reductase was also increased in rats dosed with andrographolide (p<0.05). Immunoblot analysis and EMSA revealed that andrographolide increased nuclear Nrf2 contents and Nrf2 binding to DNA, respectively. After the 5-day andrographolide treatment, one group of animals was intraperitoneally injected with carbon tetrachloride (CCl4) at day 6. Andrographolide pretreatment suppressed CCl4-induced plasma aminotransferase activity and hepatic lipid peroxidation (p <0.05). These results suggest that andrographolide is quickly absorbed in the intestinal tract in rats with a bioavailability of 1.19%. Andrographolide protects against chemical-induced oxidative damage by up-regulating the gene transcription and activity of antioxidant enzymes in various tissues.


      PubDate: 2014-08-09T19:19:51Z
       
  • Metformin suppresses CYP1A1 and CYP1B1 expression in breast cancer cells
           by down-regulating aryl hydrocarbon receptor expression
    • Abstract: Publication date: Available online 7 August 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Minh Truong Do , Hyung Gyun Kim , Thi Thu Phuong Tran , Tilak Khanal , Jae Ho Choi , Young Chul Chung , Tae Cheon Jeong , Hye Gwang Jeong
      Induction of cytochrome P450 (CYP) 1A1 and CYP1B1 by environmental xenobiotic chemicals or endogenous ligands through the activation of the aryl hydrocarbon receptor (AhR) has been implicated in a variety of cellular processes related to cancer, such as transformation and tumorigenesis. Here, we investigated the effects of the anti-diabetes drug metformin on expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and inducible conditions. Our results indicated that metformin down-regulated the expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)–induced conditions. Down-regulation of AhR expression was required for metformin-mediated decreases in CYP1A1 and CYP1B1 expression, and the metformin-mediated CYP1A1 and CYP1B1 reduction is irrelevant to estrogen receptor α (ERα) signaling. Furthermore, we found that metformin markedly down-regulated Sp1 protein levels in breast cancer cells. The use of genetic and pharmacological tools revealed that metformin-mediated down-regulation of AhR expression was mediated through the reduction of Sp1 protein. Metformin inhibited endogenous AhR ligand-induced CYP1A1 and CYP1B1 expression by suppressing tryptophan-2,3-dioxygenase (TDO) expression in MCF-7 cells. Finally, metformin inhibits TDO expression through a down-regulation of Sp1 and glucocorticoid receptor (GR) protein levels. Our findings demonstrate that metformin reduces CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating AhR signaling. Metformin would be able to act as a potential chemopreventive agent against CYP1A1 and CYP1B1-mediated carcinogenesis and development of cancer.
      Graphical abstract image

      PubDate: 2014-08-09T19:19:51Z
       
  • Analysis of the safety and pharmacodynamics of human fibrinogen
           concentrate in animals
    • Abstract: Publication date: Available online 4 August 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Andrea Beyerle , Marc W. Nolte , Cristina Solomon , Eva Herzog , Gerhard Dickneite
      Fibrinogen, a soluble 340kDa plasma glycoprotein, is critical in achieving and maintaining hemostasis. Reduced fibrinogen levels are associated with an increased risk of bleeding and recent research has investigated the efficacy of fibrinogen concentrate for controlling perioperative bleeding. European guidelines on the management of perioperative bleeding recommend the use of fibrinogen concentrate if significant bleeding is accompanied by plasma fibrinogen levels less than 1.5–2.0g/l. Plasma-derived human fibrinogen concentrate has been available for therapeutic use since 1956. The overall aim of the comprehensive series of non-clinical investigations presented was to evaluate i) the pharmacodynamic and pharmacokinetic characteristics and ii) the safety and tolerability profile of human fibrinogen concentrate Haemocomplettan P® (RiaSTAP®). Pharmacodynamic characteristics were assessed in rabbits, pharmacokinetic parameters were determined in rabbits and rats and a safety pharmacology study was performed in beagle dogs. Additional toxicology tests included: single-dose toxicity tests in mice and rats; local tolerance tests in rabbits; and neoantigenicity tests in rabbits and guinea pigs following the introduction of pasteurization in the manufacturing process. Human fibrinogen concentrate was shown to be pharmacodynamically active in rabbits and dogs and well tolerated, with no adverse events and no influence on circulation, respiration or hematological parameters in rabbits, mice, rats and dogs. In these non-clinical investigations, human fibrinogen concentrate showed a good safety profile. This data adds to the safety information available to date, strengthening the current body of knowledge regarding this hemostatic agent.


      PubDate: 2014-08-05T19:02:43Z
       
  • Downregulation of COX-2 and CYP 4A signaling by isoliquiritigenin inhibits
           human breast cancer metastasis through preventing anoikis resistance,
           migration and invasion
    • Abstract: Publication date: Available online 2 August 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Hao Zheng , Ying Li , Yuzhong Wang , Haixia Zhao , Jing Zhang , Hongyan Chai , Tian Tang , Jiang Yue , Austin M. Guo , Jing Yang
      Flavonoids exert extensive in vitro anti-invasive and in vivo anti-metastatic activities. Anoikis resistance occurs at multiple key stages of the metastatic cascade. Here, we demonstrate that isoliquiritigenin (ISL), a flavonoid from Glycyrrhiza glabra, inhibits human breast cancer metastasis by preventing anoikis resistance, migration and invasion through downregulating cyclooxygenase (COX)-2 and cytochrome P450 (CYP) 4A signaling. ISL induced anoikis in MDA-MB-231 and BT-549 human breast cancer cells as evidenced by flow cytometry and the detection of caspase cleavage. Moreover, ISL inhibited the mRNA expression of phospholipase A2, COX-2 and CYP 4A and decreased the secretion of prostaglandin E2 (PGE2) and 20-hydroxyeicosatetraenoic acid (20-HETE) in detached MDA-MB-231 cells. In addition, it decreased the levels of phospho-PI3K (Tyr458), phospho-PDK (Ser241) and phospho-Akt (Thr308). Conversely, the exogenous addition of PGE2, WIT003 (a 20-HETE analog) and an EP4 agonist (CAY10580) or overexpression of constitutively active Akt reversed ISL-induced anoikis. ISL exerted the in vitro anti-migratory and anti-invasive activities, whereas the addition of PGE2, WIT003 and CAY10580 or overexpression of constitutively active Akt reversed the in vitro anti-migratory and anti-invasive activities of ISL in MDA-MB-231 cells. Notably, ISL inhibited the in vivo lung metastasis of MDA-MB-231 cells, together with decreased intratumoral levels of PGE2, 20-HETE and phospho-Akt (Thr308). In conclusion, ISL inhibits breast cancer metastasis by preventing anoikis resistance, migration and invasion via downregulating COX-2 and CYP 4A signaling. It suggests that ISL could be a promising multi-target agent for preventing breast cancer metastasis, and anoikis could represent a novel mechanism through which flavonoids may exert the anti-metastatic activities.
      Graphical abstract image

      PubDate: 2014-08-05T19:02:43Z
       
 
 
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