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ENVIRONMENTAL STUDIES (686 journals)

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Journal Cover Toxicology and Applied Pharmacology
  [SJR: 1.593]   [H-I: 135]   [17 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0041-008X - ISSN (Online) 1096-0333
   Published by Elsevier Homepage  [3040 journals]
  • Myeloid differentiation protein 2-dependent mechanisms in retinal
           ischemia-reperfusion injury
    • Authors: Luqing Ren; Jianjian Tao; Huaicheng Chen; Yang Bian; Xi Yang; Gaozhi Chen; Xin Zhang; Guang Liang; Wencan Wu; Zongming Song; Yi Wang
      Pages: 1 - 11
      Abstract: Publication date: 15 February 2017
      Source:Toxicology and Applied Pharmacology, Volume 317
      Author(s): Luqing Ren, Jianjian Tao, Huaicheng Chen, Yang Bian, Xi Yang, Gaozhi Chen, Xin Zhang, Guang Liang, Wencan Wu, Zongming Song, Yi Wang
      Retinal ischemia-reperfusion (I/R) injury is a common pathological process in many eye disorders. Oxidative stress and inflammation play a role in retinal I/R injury. Recent studies show that toll-like receptor 4 (TLR4) is involved in initiating sterile inflammatory response in retinal I/R. However, the molecular mechanism by which TLR4 is activated is not known. In this study, we show that retinal I/R injury involves a co-receptor of TLR4, myeloid differentiation 2 (MD2). Inhibition of MD2 prevented cell death and preserved retinal function following retinal I/R injury. We confirmed these findings using MD2 knockout mice. Furthermore, we utilized human retinal pigment epithelial cells (ARPE-19 cells) to show that oxidative stress-induced cell death as well as inflammatory response are mediated through MD2. Inhibition of MD2 through a chemical inhibitor or knockdown prevented oxidative stress-induced cell death and expression of inflammatory cytokines. Oxidative stress was found to activate TLR4 in a MD2-dependent manner via increasing the expression of high mobility group box 1. In summary, our study shows that oxidative stress in retinal I/R injury can activate TLR4 signaling via MD2, resulting in induction of inflammatory genes and retinal damage. MD2 may represent an attractive therapeutic target for retinal I/R injury.

      PubDate: 2017-01-08T13:51:22Z
      DOI: 10.1016/j.taap.2017.01.001
      Issue No: Vol. 317 (2017)
       
  • Cutaneous exposure to vesicant phosgene oxime: Acute effects on the skin
           and systemic toxicity
    • Authors: Neera Tewari-Singh; Dinesh G Goswami; Rama Kant; Claire R Croutch; Robert P Casillas; David J Orlicky; Rajesh Agarwal
      Pages: 25 - 32
      Abstract: Publication date: 15 February 2017
      Source:Toxicology and Applied Pharmacology, Volume 317
      Author(s): Neera Tewari-Singh, Dinesh G Goswami, Rama Kant, Claire R Croutch, Robert P Casillas, David J Orlicky, Rajesh Agarwal
      Phosgene Oxime (CX), an urticant or nettle agent categorized as a vesicant, is a potential chemical warfare and terrorist weapon. Its exposure can result in widespread and devastating effects including high mortality due to its fast penetration and ability to cause immediate severe cutaneous injury. It is one of the least studied chemical warfare agents with no effective therapy available. Thus, our goal was to examine the acute effects of CX following its cutaneous exposure in SKH-1 hairless mice to help establish a relevant injury model. Results from our study show that topical cutaneous exposure to CX vapor causes blanching of exposed skin with an erythematous ring, necrosis, edema, mild urticaria and erythema within minutes after exposure out to 8h post-exposure. These clinical skin manifestations were accompanied with increases in skin thickness, apoptotic cell death, mast cell degranulation, myeloperoxidase activity indicating neutrophil infiltration, p53 phosphorylation and accumulation, and an increase in COX-2 and TNFα levels. Topical CX-exposure also resulted in the dilatation of the peripheral vessels with a robust increase in RBCs in vessels of the liver, spleen, kidney, lungs and heart tissues. These events could cause a drop in blood pressure leading to shock, hypoxia and death. Together, this is the first report on effects of CX cutaneous exposure, which could help design further comprehensive studies evaluating the acute and chronic skin injuries from CX topical exposure and elucidate the related mechanism of action to aid in the identification of therapeutic targets and mitigation of injury.

      PubDate: 2017-01-15T14:10:49Z
      DOI: 10.1016/j.taap.2017.01.003
      Issue No: Vol. 317 (2017)
       
  • In vitro neuroprotective potential of lichen metabolite fumarprotocetraric
           acid via intracellular redox modulation
    • Authors: Carlos Fernández-Moriano; Pradeep Kumar Divakar; Ana Crespo; M. Pilar Gómez-Serranillos
      Pages: 83 - 94
      Abstract: Publication date: 1 February 2017
      Source:Toxicology and Applied Pharmacology, Volume 316
      Author(s): Carlos Fernández-Moriano, Pradeep Kumar Divakar, Ana Crespo, M. Pilar Gómez-Serranillos
      The lichen-forming fungi Cetraria islandica has been largely used in folk medicines, and it has recently showed promising in vitro antioxidant effects in glial-like cells. Current work aimed at investigating the neuroprotective potential of its major isolated secondary metabolite: the depsidone fumarprotocetraric acid (FUM). H2O2 was used herein to induce oxidative stress (OS)-mediated cytotoxicity in two models of neurons and astrocytes cells (SH-SY5Y and U373-MG cell lines). We found that a pre-treatment with FUM significantly enhanced cell viability compared to H2O2-treated cells, and we selected the optimal concentrations in each model (1 and 25μg/ml, respectively) for assessing its cytoprotective mechanisms. FUM, which exerted effective peroxyl radical scavenging effect in the chemical oxygen radical antioxidant capacity (ORAC) assay, alleviated the alterations in OS markers provoked by H2O2. It attenuated intracellular ROS formation, lipid peroxidation and GSH depletion. At mitochondrial level, FUM prevented from the dissipation of mitochondrial membrane potential and the increase in mitochondrial calcium, implying a protective role against oxidative damage in mitochondrial membrane. Similarly, FUM pre-treatment diminished H2O2-induced apoptosis, as evidenced by the reduction in caspase-3 activity and expression; inmunoblot analysis also revealed a decrease in Bax and an increase in Bcl-2 proteins levels. Furthermore, FUM up-regulated the expression of the antioxidant enzymes catalase, superoxide dismutase-1, and hemeoxigenase-1. These findings and the activation of Nrf2 binding activity in nuclear extracts suggest a plausible involvement of Nrf2 signaling pathway in the cytoprotection by FUM. In conclusion, FUM emerges as a potential drug candidate in the therapy of OS-related diseases, such as the neurodegenerative disorders.

      PubDate: 2017-01-08T13:51:22Z
      DOI: 10.1016/j.taap.2016.12.020
      Issue No: Vol. 316 (2017)
       
  • Comparative analysis of TCDD-induced AhR-mediated gene expression in
           human, mouse and rat primary B cells
    • Authors: Natalia Kovalova; Rance Nault; Robert Crawford; Timothy R. Zacharewski; Norbert E. Kaminski
      Pages: 95 - 106
      Abstract: Publication date: 1 February 2017
      Source:Toxicology and Applied Pharmacology, Volume 316
      Author(s): Natalia Kovalova, Rance Nault, Robert Crawford, Timothy R. Zacharewski, Norbert E. Kaminski
      2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental pollutant that activates the aryl hydrocarbon receptor (AhR) resulting in altered gene expression. In vivo, in vitro, and ex vivo studies have demonstrated that B cells are directly impaired by TCDD, and are a sensitive target as evidenced by suppression of antibody responses. The window of sensitivity to TCDD-induced suppression of IgM secretion among mouse, rat and human B cells is similar. Specifically, TCDD must be present within the initial 12h post B cell stimulation, indicating that TCDD disrupts early signaling network(s) necessary for B lymphocyte activation and differentiation. Therefore, we hypothesized that TCDD treatment across three different species (mouse, rat and human) triggers a conserved, B cell-specific mechanism that is involved in TCDD-induced immunosuppression. RNA sequencing (RNA-Seq) was used to identify B cell-specific orthologous genes that are differentially expressed in response to TCDD in primary mouse, rat and human B cells. Time course studies identified TCDD-elicited differential expression of 515 human, 2371 mouse and 712 rat orthologous genes over the 24-h period. 28 orthologs were differentially expressed in response to TCDD in all three species. Overrepresented pathways enriched in all three species included cytokine-cytokine receptor interaction, ECM-receptor interaction, focal adhesion, regulation of actin cytoskeleton and pathways in cancer. Differentially expressed genes functionally associated with cell-cell signaling in humans, immune response in mice, and oxidation reduction in rats. Overall, these results suggest that despite the conservation of the AhR and its signaling mechanism, TCDD elicits species-specific gene expression changes.

      PubDate: 2017-01-08T13:51:22Z
      DOI: 10.1016/j.taap.2016.11.009
      Issue No: Vol. 316 (2017)
       
  • The role of PTEN in regulation of hepatic macrophages activation and
           function in progression and reversal of liver fibrosis
    • Authors: Yahui Cheng; Yuanyao Tian; Jialu Xia; Xiaoqin Wu; Yang Yang; Xiaofeng Li; Cheng Huang; Xiaoming Meng; Taotao Ma; Jun Li
      Abstract: Publication date: Available online 14 January 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Yahui Cheng, Yuanyao Tian, Jialu Xia, Xiaoqin Wu, Yang Yang, Xiaofeng Li, Cheng Huang, Xiaoming Meng, Taotao Ma, Jun Li
      Activation of Kupffer cells (KCs) plays a pivotal role in the pathogenesis of liver fibrosis. The progression and reversal of CCl4-induced mouse liver fibrosis showed a mixed induction of hepatic classical (M1) and alternative (M2) macrophage markers. Although the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in modulating myeloid cell activation has recently been identified, its function in macrophage activation during hepatic fibrosis remains to be fully appreciated. In our study, PTEN expression of KCs was remarkably decreased in CCl4-induced mice but increased to a near-normal level in reversed mice. Moreover, PTEN was significantly decreased in IL4-induced RAW 264.7 cells in vitro and lower expression of PTEN was observed in M2 macrophages in vivo. In addition, loss- and gain-of-function studies suggested that PTEN regulates M2 macrophages polarization via activation of PI3K/Akt/STAT6 signaling, but had a limited effect on M1 macrophages polarization in vitro. Additionally, Ly294002, a chemical inhibitor of PI3K/Akt, could dramatically down-regulate the hallmarks of M2 macrophages. In conclusion, PTEN mediates macrophages activation by PI3K/Akt/STAT6 signaling pathway, which provides novel compelling evidences on the potential of PTEN in liver injury and opens new cellular target for the pharmacological therapy of liver fibrosis.
      Graphical abstract image

      PubDate: 2017-01-15T14:10:49Z
      DOI: 10.1016/j.taap.2017.01.005
       
  • Zearalenone exposure impairs ovarian primordial follicle formation via
           down-regulation of Lhx8 expression in vitro
    • Authors: Guo-Liang Zhang; Xiao-Feng Sun; Yan-Zhong Feng; Bo Li; Ya-Peng Li; Fan Yang; Charles Martin Nyachoti; Wei Shen; Shi-Duo Sun; Lan Li
      Abstract: Publication date: Available online 12 January 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Guo-Liang Zhang, Xiao-Feng Sun, Yan-Zhong Feng, Bo Li, Ya-Peng Li, Fan Yang, Charles Martin Nyachoti, Wei Shen, Shi-Duo Sun, Lan Li
      Zearalenone (ZEA) is an estrogenic mycotoxin mainly produced as a secondary metabolite by numerous species of Fusarium. Previous work showed that ZEA had a negative impact on domestic animals with regard to reproduction. The adverse effects and the mechanisms of ZEA on mammalian ovarian folliculogenesis remain largely unknown, particularly its effect on primordial follicle formation. Thus, we investigated the biological effects of ZEA exposure on murine ovarian germ cell cyst breakdown and primordial follicle assembly. Our results demonstrated that newborn mouse ovaries exposed to 10 or 30μM ZEA in vitro had significantly less germ cell numbers compared to the control group. Moreover, the presence of ZEA in vitro increased the numbers of TUNEL and γH2AX positive cells within mouse ovaries and the ratio of mRNA levels of the apoptotic genes Bax/Bcl-2. Furthermore, ZEA exposure reduced the mRNA of oocyte specific genes such as LIM homeobox 8 (Lhx8), newborn ovary homeobox (Nobox), spermatogenesis and oogenesis helix-loop-helix (Sohlh2), and factor in the germline alpha (Figlα) in a dose dependent manner. Exposure to ZEA led to remarkable changes in the Lhx8 3′-UTR DNA methylation dynamics in oocytes and severely impaired folliculogenesis in ovaries after transplantation under the kidney capsules of immunodeficient mice. In conclusion, ZEA exposure impairs mouse primordial follicle formation in vitro.

      PubDate: 2017-01-15T14:10:49Z
      DOI: 10.1016/j.taap.2017.01.004
       
  • Iron oxide nanoparticles modulate heat shock proteins and organ specific
           markers expression in mice male accessory organs
    • Authors: Kiruthika Sundarraj; Azhwar Raghunath; Lakshmikanthan Panneerselvam; Ekambaram Perumal
      Abstract: Publication date: Available online 7 January 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Kiruthika Sundarraj, Azhwar Raghunath, Lakshmikanthan Panneerselvam, Ekambaram Perumal
      With increased industrial utilization of iron oxide nanoparticles (Fe2O3-NPs), concerns on adverse reproductive health effects following exposure have been immensely raised. In the present study, the effects of Fe2O3-NPs exposure in the seminal vesicle and prostate gland were studied in mice. Mice were exposed to two different doses (25 and 50 mg/kg) of Fe2O3-NPs along with the control and analyzed the expressions of heat shock proteins (HSP60, HSP70 and HSP90) and organ specific markers (Caltrin, PSP94, and SSLP1). Fe2O3-NPs decreased food consumption, water intake, and organo-somatic index in mice with elevated iron levels in serum, urine, fecal matter, seminal vesicle and prostate gland. FTIR spectra revealed alterations in the functional groups of biomolecules on Fe2O3-NPs treatment. These changes are accompanied by increased lactate dehydrogenase levels with decreased total protein and fructose levels. The investigation of oxidative stress biomarkers demonstrated a significant increase in reactive oxygen species, nitric oxide, lipid peroxidation, protein carbonyl content and glutathione peroxidase with a concomitant decrement in the glutathione and ascorbic acid in the male accessory organs which confirmed the induction of oxidative stress. An increase in NADPH-oxidase-4 with a decrease in glutathione-S-transferase was observed in the seminal vesicle and prostate gland of the treated groups. An alteration in HSP60, HSP70, HSP90, Caltrin, PSP94, and SSLP1 expression was also observed. Moreover, accumulation of Fe2O3-NPs brought pathological changes in the seminal vesicle and prostate gland of treated mice. These findings provide evidence that Fe2O3-NPs could be an environmental risk factor for reproductive disease.

      PubDate: 2017-01-08T13:51:22Z
      DOI: 10.1016/j.taap.2017.01.002
       
  • Gemcitabine: Selective cytotoxicity, induction of inflammation and effects
           on urothelial function
    • Authors: Stefanie E Farr; Russ Chess-Williams; Catherine M McDermott
      Pages: 1 - 9
      Abstract: Publication date: 1 February 2017
      Source:Toxicology and Applied Pharmacology, Volume 316
      Author(s): Stefanie E Farr, Russ Chess-Williams, Catherine M McDermott
      Intravesical gemcitabine has recently been introduced for the treatment of superficial bladder cancer and has a favourable efficacy and toxicity profile in comparison to mitomycin c (MMC), the most commonly used chemotherapeutic agent. The aim of this study was to assess the cytotoxic potency of gemcitabine in comparison to MMC in urothelial cell lines derived from non-malignant (UROtsa) and malignant (RT4 and T24) tissues to assess selectivity. Cells were treated with gemcitabine or mitomycin C at concentrations up to the clinical doses for 1 or 2h respectively (clinical duration). Treatment combined with hyperthermia was also examined. Cell viability, ROS formation, urothelial function (ATP, acetylcholine and PGE2 release) and secretion of inflammatory cytokines were assessed. Gemcitabine displayed a high cytotoxic selectivity for the two malignant cell lines (RT4, T24) compared to the non-malignant urothelial cells (UROtsa, proliferative and non-proliferative). In contrast, the cytotoxic effects of MMC were non-selective with equivalent potency in each of the cell lines. The cytotoxic effect of gemcitabine in the malignant cell lines was associated with an elevation in free radical formation and was significantly decreased in the presence of an equilibrative nucleoside transporter inhibitor. Transient changes in urothelial ATP and PGE2 release were observed, with significant increase in release of interleukin-6, interleukin-8 and interleukin-1β from urothelial cells treated with gemcitabine. The selectivity of gemcitabine for malignant urothelial cells may account for the less frequent adverse urological effects with comparison to other commonly used chemotherapeutic agents.

      PubDate: 2016-12-23T08:56:00Z
      DOI: 10.1016/j.taap.2016.12.011
      Issue No: Vol. 316 (2016)
       
  • Di-(2-ethylhexyl) phthalate could disrupt the insulin signaling pathway in
           liver of SD rats and L02 cells via PPARγ
    • Authors: Wang Zhang; Xin -yue Shen; Wen-wen Zhang; Hao Chen; Wei-ping Xu; Wei Wei
      Pages: 17 - 26
      Abstract: Publication date: 1 February 2017
      Source:Toxicology and Applied Pharmacology, Volume 316
      Author(s): Wang Zhang, Xin -yue Shen, Wen-wen Zhang, Hao Chen, Wei-ping Xu, Wei Wei
      Di-(2-ethylhexyl)-phthalate (DEHP), a ubiquitous industrial pollutant in our daily life, has been reported to cause adverse effects on glucose homeostasis and insulin sensitivity in epidemiological studies previously. Recently, it has been reported to be an endocrine disrupter and ligand to peroxisome proliferator activated receptor, which could influence the homeostasis of liver metabolic systems and contribute to the development of type-2 diabetes. However, the potential mechanisms are not known yet. This study was designed to solve these problems with male SD rats and normal human hepatocyte line, L02 cells, exposed to DEHP for toxicological experiments. Adult male SD rats were divided into four groups, normal group fed with regular diets and three DEHP-treated groups (dissolved in olive oil at doses of 0.05, 5 and 500mg/kg body weight, respectively, once daily through gastric intubations for 15weeks). L02 cells were divided into 6 groups, normal group with 5, 10, 25, 50, and 100μmol/l DEHP groups. DEHP-exposed rats exhibited significant liver damage, glucose tolerance, and insulin tolerance along with reduced expression of insulin receptor and GLUT4 proteins in the liver tissues. The results of in vitro experiments could determine that the DEHP-induced activation of peroxisome proliferator activated receptor γ (PPARγ) played a key role in the production of oxidative stress and down-regulated expression of insulin receptor and GLUT4 proteins in L02 cells. This conclusion could be supported by the results of in vitro experiments, in which the cells were exposed to DEHP with GW9662 (PPARγ inhibitor). In general, these results highlight the key role of PPARγ in the process of insulin resistance induced by DEHP.

      PubDate: 2016-12-29T13:33:08Z
      DOI: 10.1016/j.taap.2016.12.010
      Issue No: Vol. 316 (2016)
       
  • Dihydroartemisinin protects against alcoholic liver injury through
           alleviating hepatocyte steatosis in a farnesoid X receptor-dependent
           manner
    • Authors: Wenxuan Xu; Chunfeng Lu; Lu Yao; Feng Zhang; Jiangjuan Shao; Shizhong Zheng
      Pages: 23 - 34
      Abstract: Publication date: 15 January 2017
      Source:Toxicology and Applied Pharmacology, Volume 315
      Author(s): Wenxuan Xu, Chunfeng Lu, Lu Yao, Feng Zhang, Jiangjuan Shao, Shizhong Zheng
      Alcoholic liver disease (ALD) is a common etiology of liver diseases, characterized by hepatic steatosis. We previously identified farnesoid X receptor (FXR) as a potential therapeutic target for ALD. Dihydroartemisinin (DHA) has been recently identified to possess potent pharmacological activities on liver diseases. This study was aimed to explore the impact of DHA on ALD and further elaborate the underlying mechanisms. Gain- or loss-of-function analyses of FXR were applied in both in vivo and in vitro studies. Results demonstrated that DHA rescued FXR expression and activity in alcoholic rat livers. DHA also reduced serodiagnostic markers of liver injury, including aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase. DHA improved alcohol-induced liver histological lesions, expression of inflammation genes, and inflammatory cell infiltration. In addition, DHA not only attenuated hyperlipidemia but also reduced hepatic steatosis through regulating lipogenesis and lipolysis genes. In vitro experiments further consolidated the concept that DHA ameliorated ethanol-caused hepatocyte injury and steatosis. Noteworthily, DHA effects were reinforced by FXR agonist obeticholic acid or FXR expression plasmids but abrogated by FXR antagonist Z-guggulsterone or FXR siRNA. In summary, DHA significantly improved alcoholic liver injury by inhibiting hepatic steatosis, which was dependent on its activation of FXR in hepatocytes.
      Graphical abstract image

      PubDate: 2016-12-08T08:42:16Z
      DOI: 10.1016/j.taap.2016.12.001
      Issue No: Vol. 315 (2016)
       
  • Sub-chronic 90-day toxicity of neamine in SD rats and its anti-liver
           cancer activity in vitro and in vivo
    • Authors: Yanli Wu; Yongdong Feng; Yanling Li; Yiping Xu; Nian Shi; Guo-fu Hu; Yunxia Wu
      Pages: 50 - 59
      Abstract: Publication date: 15 January 2017
      Source:Toxicology and Applied Pharmacology, Volume 315
      Author(s): Yanli Wu, Yongdong Feng, Yanling Li, Yiping Xu, Nian Shi, Guo-fu Hu, Yunxia Wu
      Neamine, an inhibitor of angiogenin (ANG), is a new investigative anticancer drug currently in preclinical stage. Here we report the 90-day sub-chronic toxicity of neamine in SD rats and its anti-liver cancer activity in vitro and in vivo. Neamine has a No Observed Adverse Effect Level (NOAEL) of 12 and 16mg·kg−1·d−1 for female and male rats, respectively. No mortality was found. The adverse effects included increased organ coefficients of spleen and kidney, increased BUN in both female and male rats at high dose, increased CR and decreased organ coefficients of heart and liver in male rats at high dose. All of which, except the kidney coefficient and BUN in males, returned to normal levels after 28-day recovery. Histopathological examination revealed vacuolar degeneration of glomerulus, degeneration of renal tubules and cast in the kidneys, which were also recovered except in males of high-dosing group. These results indicate that kidney is the most susceptible organ for neamine toxicity. Tissue microarray analysis validated that ANG is up-regulated in hepatocellular carcinoma accompanied by increased nuclear translocation, suggesting that ANG is a possible target for drug development in liver cancer treatment. Neamine blocked nuclear translocation of ANG in HUVEC and HepG2 cells, and inhibited ANG-stimulated cell proliferation without affecting basal level cell proliferation. Neamine also inhibited progression of HepG2 xenografts in athymic mice accompanied by decreased angiogenesis and cancer cell proliferation. These results suggest that neamine is a specific ANG inhibitor with low toxicity and high anti-liver cancer efficacy.

      PubDate: 2016-12-14T08:48:51Z
      DOI: 10.1016/j.taap.2016.12.006
      Issue No: Vol. 315 (2016)
       
  • A silk peptide fraction restores cognitive function in AF64A-induced
           Alzheimer disease model rats by increasing expression of choline
           acetyltransferase gene
    • Authors: Yeseul Cha; Sang Hoon Lee; Su Kil Jang; Haiyu Guo; Young-Hwan Ban; Dongsun Park; Gwi Yeong Jang; Sungho Yeon; Jeong-Yong Lee; Ehn-Kyoung Choi; Seong Soo Joo; Heon-Sang Jeong; Yun-Bae Kim
      Pages: 48 - 54
      Abstract: Publication date: 1 January 2017
      Source:Toxicology and Applied Pharmacology, Volume 314
      Author(s): Yeseul Cha, Sang Hoon Lee, Su Kil Jang, Haiyu Guo, Young-Hwan Ban, Dongsun Park, Gwi Yeong Jang, Sungho Yeon, Jeong-Yong Lee, Ehn-Kyoung Choi, Seong Soo Joo, Heon-Sang Jeong, Yun-Bae Kim
      This study investigated the effects of a silk peptide fraction obtained by incubating silk proteins with Protease N and Neutrase (SP-NN) on cognitive dysfunction of Alzheimer disease model rats. In order to elucidate underlying mechanisms, the effect of SP-NN on the expression of choline acetyltransferase (ChAT) mRNA was assessed in F3.ChAT neural stem cells and Neuro2a neuroblastoma cells; active amino acid sequence was identified using HPLC-MS. The expression of ChAT mRNA in F3.ChAT cells increased by 3.79-fold of the control level by treatment with SP-NN fraction. The active peptide in SP-NN was identified as tyrosine-glycine with 238.1 of molecular weight. Male rats were orally administered with SP-NN (50 or 300mg/kg) and challenged with a cholinotoxin AF64A. As a result of brain injury and decreased brain acetylcholine level, AF64A induced astrocytic activation, resulting in impairment of learning and memory function. Treatment with SP-NN exerted recovering activities on acetylcholine depletion and brain injury, as well as cognitive deficit induced by AF64A. The results indicate that, in addition to a neuroprotective activity, the SP-NN preparation restores cognitive function of Alzheimer disease model rats by increasing the release of acetylcholine.
      Graphical abstract image

      PubDate: 2016-11-24T14:37:19Z
      DOI: 10.1016/j.taap.2016.11.008
      Issue No: Vol. 314 (2016)
       
  • Multidrug and toxin extrusion proteins mediate cellular transport of
           cadmium
    • Authors: Hong Yang; Dong Guo; Obinna N. Obianom; Tong Su; James E. Polli; Yan Shu
      Pages: 55 - 62
      Abstract: Publication date: 1 January 2017
      Source:Toxicology and Applied Pharmacology, Volume 314
      Author(s): Hong Yang, Dong Guo, Obinna N. Obianom, Tong Su, James E. Polli, Yan Shu
      Cadmium (Cd) is an environmentally prevalent toxicant posing increasing risk to human health worldwide. As compared to the extensive research in Cd tissue accumulation, little was known about the elimination of Cd, particularly its toxic form, Cd ion (Cd2+). In this study, we aimed to examine whether Cd2+ is a substrate of multidrug and toxin extrusion proteins (MATEs) that are important in renal xenobiotic elimination. HEK-293 cells overexpressing the human MATE1 (HEK-hMATE1), human MATE2-K (HEK-hMATE2-K) and mouse Mate1 (HEK-mMate1) were used to study the cellular transport and toxicity of Cd2+. The cells overexpressing MATEs showed a 2–4 fold increase of Cd2+ uptake that could be blocked by the MATE inhibitor cimetidine. A saturable transport profile was observed with the Michaelis-Menten constant (K m ) of 130±15.8μM for HEK-hMATE1; 139±21.3μM for HEK-hMATE2-K; and 88.7±13.5μM for HEK-mMate1, respectively. Cd2+ could inhibit the uptake of metformin, a substrate of MATE transporters, with the half maximal inhibitory concentration (IC50) of 97.5±6.0μM, 20.2±2.6μM, and 49.9±6.9μM in HEK-hMATE1, HEK-hMATE2-K, and HEK-mMate1 cells, respectively. In addition, hMATE1 could transport preloaded Cd2+ out of the HEK-hMATE1 cells, thus resulting in a significant decrease of Cd2+-induced cytotoxicity. The present study has provided the first evidence supporting that MATEs transport Cd2+ and may function as cellular elimination machinery in Cd intoxication.

      PubDate: 2016-11-24T14:37:19Z
      DOI: 10.1016/j.taap.2016.11.007
      Issue No: Vol. 314 (2016)
       
  • The unexpected teratogenicity of RXR antagonist UVI3003 via activation of
           PPARγ in Xenopus tropicalis
    • Authors: Jingmin Zhu; Amanda Janesick; Lijiao Wu; Lingling Hu; Weiyi Tang; Bruce Blumberg; Huahong Shi
      Pages: 91 - 97
      Abstract: Publication date: 1 January 2017
      Source:Toxicology and Applied Pharmacology, Volume 314
      Author(s): Jingmin Zhu, Amanda Janesick, Lijiao Wu, Lingling Hu, Weiyi Tang, Bruce Blumberg, Huahong Shi
      The RXR agonist (triphenyltin, TPT) and the RXR antagonist (UVI3003) both show teratogenicity and, unexpectedly, induce similar malformations in Xenopus tropicalis embryos. In the present study, we exposed X. tropicalis embryos to UVI3003 in seven specific developmental windows and identified changes in gene expression. We further measured the ability of UVI3003 to activate Xenopus RXRα (xRXRα) and PPARγ (xPPARγ) in vitro and in vivo. We found that UVI3003 activated xPPARγ either in Cos7 cells (in vitro) or Xenopus embryos (in vivo). UVI3003 did not significantly activate human or mouse PPARγ in vitro; therefore, the activation of Xenopus PPARγ by UVI3003 is novel. The ability of UVI3003 to activate xPPARγ explains why UVI3003 and TPT yield similar phenotypes in Xenopus embryos. Our results indicate that activating PPARγ leads to teratogenic effects in Xenopus embryos. More generally, we infer that chemicals known to specifically modulate mammalian nuclear hormone receptors cannot be assumed to have the same activity in non-mammalian species, such as Xenopus. Rather they must be tested for activity and specificity on receptors of the species in question to avoid making inappropriate conclusions.

      PubDate: 2016-12-01T08:25:54Z
      DOI: 10.1016/j.taap.2016.11.014
      Issue No: Vol. 314 (2016)
       
  • Corrigendum to “Low doses of arsenic, via perturbing p53, promotes
           tumorigenesis” [Toxicol. Appl. Pharmacol. (2016) 98–104]
    • Authors: Suthakar Ganapathy; Ping Li; Johan Fagman; Tianqi Yu; Jean Lafontant; Guojun Zhang; Changyan Chen
      First page: 118
      Abstract: Publication date: 1 January 2017
      Source:Toxicology and Applied Pharmacology, Volume 314
      Author(s): Suthakar Ganapathy, Ping Li, Johan Fagman, Tianqi Yu, Jean Lafontant, Guojun Zhang, Changyan Chen


      PubDate: 2016-12-23T08:56:00Z
      DOI: 10.1016/j.taap.2016.11.005
      Issue No: Vol. 314 (2016)
       
  • Up-regulation of granzyme B and perforin by staphylococcal enterotoxin C2
           mutant induces enhanced cytotoxicity in Hepa1–6 cells
    • Authors: Guojun Zhang; Mingkai Xu; Huiwen Zhang; Yubo Song; Jian Wang; Chenggang Zhang
      Pages: 1 - 9
      Abstract: Publication date: 15 December 2016
      Source:Toxicology and Applied Pharmacology, Volume 313
      Author(s): Guojun Zhang, Mingkai Xu, Huiwen Zhang, Yubo Song, Jian Wang, Chenggang Zhang
      Staphylococcal enterotoxin C2 (SEC2), a member of bacterial superantigen, is one of the most potent known activators of T lymphocytes. With this property, SEC2 has already been used in clinic as a tumor immunotherapy agent in China. To increase the antitumor activity, a SEC2 mutant named ST-4 (GKVTG102-106WWH) with amino acid substitutions in T cell receptor (TCR)-binding domain was generated by site-directed mutagenesis, and the molecular mechanism of the enhanced antitumor activity was investigated. Results showed that ST-4 could activate much more Vβ 8.2 and 8.3 T cells and NK cells compared with SEC2, and exhibited significantly enhanced immunocyte stimulation and antitumor activity in vitro. The synthetic peptide sequencing the residues of mutant TCR-binding domain could competitively inhibit the immunocyte stimulation activity of ST-4. Most importantly, ST-4 up-regulated granzyme B and perforin at both mRNA and protein levels. We also found that expression of proapoptotic proteins cytochrome c, BAX and activation of caspase-3, 9 was up-regulated, and antiapoptotic protein Bcl-xL was down-regulated in the treatment with either ST-4 or SEC2. When granzyme B inhibitor or perforin inhibitor is presented, tumor cell viability was significantly rescued. Taken together, we demonstrate that increased ST-4-TCR recognition contributed to massive T cells and NK cells activation. These activated cells released up-regulated granzyme B and perforin, which induced the enhanced tumor cells apoptosis by mitochondrial apoptotic pathway, and ultimately led to enhanced tumor cell growth inhibition. ST-4 may be a promising candidate for antitumor clinic usage in future.

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.10.009
      Issue No: Vol. 313 (2016)
       
  • High risks of lung disease associated with early-life and moderate
           lifetime arsenic exposure in northern Chile
    • Authors: Craig Steinmaus; Catterina Ferreccio; Johanna Acevedo; John R Balmes; Jane Liaw; Patricia Troncoso; David C Dauphiné; Anthony Nardone; Allan H Smith
      Pages: 10 - 15
      Abstract: Publication date: 15 December 2016
      Source:Toxicology and Applied Pharmacology, Volume 313
      Author(s): Craig Steinmaus, Catterina Ferreccio, Johanna Acevedo, John R Balmes, Jane Liaw, Patricia Troncoso, David C Dauphiné, Anthony Nardone, Allan H Smith
      Background Arsenic in drinking water has been associated with increases in lung disease, but information on the long-term impacts of early-life exposure or moderate exposure levels are limited. Methods We investigated pulmonary disease and lung function in 795 subjects from three socio-demographically similar areas in northern Chile: Antofagasta, which had a well-described period of high arsenic water concentrations (860μg/L) from 1958 to 1970; Iquique, which had long-term arsenic water concentrations near 60μg/L; and Arica, with long-term water concentrations ≤10μg/L. Results Compared to adults never exposed >10μg/L, adults born in Antofagasta during the high exposure period had elevated odds ratios (OR) of respiratory symptoms (e.g., OR for shortness of breath=5.56, 90% confidence interval (CI): 2.68–11.5), and decreases in pulmonary function (e.g., 224mL decrease in forced vital capacity in nonsmokers, 90% CI: 97–351mL). Subjects with long-term exposure to arsenic water concentrations near 60μg/L also had increases in some pulmonary symptoms and reduced lung function. Conclusions Overall, these findings provide new evidence that in utero or childhood arsenic exposure is associated with non-malignant pulmonary disease in adults. They also provide preliminary new evidence that long-term exposures to moderate levels of arsenic may be associated with lung toxicity, although the magnitude of these latter findings were greater than expected and should be confirmed.

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.10.006
      Issue No: Vol. 313 (2016)
       
  • Nerve cell-mimicking liposomes as biosensor for botulinum neurotoxin
           complete physiological activity
    • Authors: Oliver G. Weingart; Martin J. Loessner
      Pages: 16 - 23
      Abstract: Publication date: 15 December 2016
      Source:Toxicology and Applied Pharmacology, Volume 313
      Author(s): Oliver G. Weingart, Martin J. Loessner
      Botulinum neurotoxins (BoNT) are the most toxic substances known, and their neurotoxic properties and paralysing effects are exploited for medical treatment of a wide spectrum of disorders. To accurately quantify the potency of a pharmaceutical BoNT preparation, its physiological key activities (binding to membrane receptor, translocation, and proteolytic degradation of SNARE proteins) need to be determined. To date, this was only possible using animal models, or, to a limited extent, cell-based assays. We here report a novel in vitro system for BoNT/B analysis, based on nerve-cell mimicking liposomes presenting motoneuronal membrane receptors required for BoNT binding. Following triggered membrane translocation of the toxin's Light Chain, the endopeptidase activity can be quantitatively monitored employing a FRET-based reporter assay within the functionalized liposomes. We were able to detect BoNT/B physiological activity at picomolar concentrations in short time, opening the possibility for future replacement of animal experimentation in pharmaceutical BoNT testing.

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.10.010
      Issue No: Vol. 313 (2016)
       
  • DNA damage response in nephrotoxic and ischemic kidney injury
    • Authors: Mingjuan Yan; Chengyuan Tang; Zhengwei Ma; Shuang Huang; Zheng Dong
      Pages: 104 - 108
      Abstract: Publication date: 15 December 2016
      Source:Toxicology and Applied Pharmacology, Volume 313
      Author(s): Mingjuan Yan, Chengyuan Tang, Zhengwei Ma, Shuang Huang, Zheng Dong
      DNA damage activates specific cell signaling cascades for DNA repair, cell cycle arrest, senescence, and/or cell death. Recent studies have demonstrated DNA damage response (DDR) in experimental models of acute kidney injury (AKI). In cisplatin-induced AKI or nephrotoxicity, the DDR pathway of ATR/Chk2/p53 is activated and contributes to renal tubular cell apoptosis. In ischemic AKI, DDR seems more complex and involves at least the ataxia telangiectasia mutated (ATM), a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, and p53; however, while ATM may promote DNA repair, p53 may trigger cell death. Targeting DDR for kidney protection in AKI therefore relies on a thorough elucidation of the DDR pathways in various forms of AKI.

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.10.022
      Issue No: Vol. 313 (2016)
       
  • DEET Potentiates the Development and Persistence of Anticholinesterase
           Dependent Chronic Pain Signs in a Rat Model of Gulf War Illness Pain
    • Authors: L.K. Flunker; T.J. Nutter R.D. Johnson B.Y. Cooper
      Abstract: Publication date: Available online 23 December 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): L.K. Flunker, T.J. Nutter, R.D. Johnson, B.Y. Cooper
      Exposure to DEET (N,N-diethyl-meta-toluamide) may have influenced the pattern of symptoms observed in soldiers with GWI (Gulf War Illness; Haley and Kurt, 1997). We examined how the addition of DEET (400mg/kg; 50% topical) to an exposure protocol of permethrin (2.6mg/kg; topical), chlorpyrifos (CP; 120mg/kg), and pyridostigmine bromide (PB;13mg/kg) altered the emergence and pattern of pain signs in an animal model of GWI pain (Nutter et al., 2015). Rats underwent behavioral testing before, during and after a 4week exposure: 1) hindlimb pressure withdrawal threshold; 2) ambulation (movement distance and rate); and 3) resting duration. Additional studies were conducted to assess the influence of acute DEET (10–100μM) on muscle and vascular nociceptor Kv7, KDR, Nav1.8 and Nav1.9. We report that a 50% concentration of DEET enhanced the development and persistence of pain-signs. Rats exposed to all 4 compounds exhibited ambulation deficits that appeared 5–12weeks post-exposure and persisted through weeks 21–24. Rats exposed to only three agents (CP or PB excluded), did not fully develop ambulation deficits. When PB was excluded, rats also developed rest duration pain signs, in addition to ambulation deficits. There was no evidence that physiological doses of DEET acutely modified nociceptor Kv7, KDR, Nav1.8 or Nav1.9 activities. Nevertheless, DEET augmented protocols decreased the conductance of Kv7 expressed in vascular nociceptors harvested from chronically exposed rats. We concluded that DEET enhanced the development and persistence of pain behaviors, but the anticholinesterases CP and PB played a determinant role.

      PubDate: 2016-12-29T13:33:08Z
       
  • Hypomethylation of inflammatory genes (COX2, EGR1, and SOCS3) and
           
    • Authors: Preeyaphan Phookphan; Panida Navasumrit Somchamai Waraprasit Jeerawan Promvijit Krittinee Chaisatra
      Abstract: Publication date: Available online 23 December 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Preeyaphan Phookphan, Panida Navasumrit, Somchamai Waraprasit, Jeerawan Promvijit, Krittinee Chaisatra, Thitirat Ngaotepprutaram, Mathuros Ruchirawat
      Early-life exposure to arsenic increases risk of developing a variety of non-malignant and malignant diseases. Arsenic-induced carcinogenesis may be mediated through epigenetic mechanisms and pathways leading to inflammation. Our previous study reported that prenatal arsenic exposure leads to increased mRNA expression of several genes related to inflammation, including COX2, EGR1, and SOCS3. This study aimed to investigate the effects of arsenic exposure on promoter DNA methylation and mRNA expression of these inflammatory genes (COX2, EGR1, and SOCS3), as well as the generation of 8-nitroguanine, which is a mutagenic DNA lesion involved in inflammation-related carcinogenesis. Prenatally arsenic-exposed newborns had promoter hypomethylation of COX2, EGR1, and SOCS3 in cord blood lymphocytes (p<0.01). A follow-up study in these prenatally arsenic-exposed children showed a significant hypomethylation of these genes in salivary DNA (p<0.01). In vitro experiments confirmed that arsenite treatment at short-term high doses (10–100μM) and long-term low doses (0.5–1μM) in human lymphoblasts (RPMI 1788) caused promoter hypomethylation of these genes, which was in concordance with an increase in their mRNA expression. Additionally, the level of urinary 8-nitroguanine was significantly higher (p<0.01) in exposed newborns and children, by 1.4- and 1.8-fold, respectively. Arsenic accumulation in toenails was negatively correlated with hypomethylation of these genes and positively correlated with levels of 8-nitroguanine. These results indicated that early-life exposure to arsenic causes hypomethylation of COX2, EGR1, and SOCS3, increases mRNA expression of these genes, and increases 8-nitroguanine formation. These effects may be linked to mechanisms of arsenic-induced inflammation and cancer development later in life.

      PubDate: 2016-12-29T13:33:08Z
       
  • Apigenin potentiates the antitumor activity of 5-FU on solid Ehrlich
           Carcinoma: Crosstalk between apoptotic and JNK-mediated autophagic cell
           death platforms
    • Authors: Hanaa Gaballah; Rasha Gaber Darin Mohamed
      Abstract: Publication date: Available online 23 December 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Hanaa H. Gaballah, Rasha A. Gaber, Darin A. Mohamed
      Background Although 5- Fluorouracil (5-FU) has exhibited effectiveness against cancer, novel therapeutic strategies are needed to enhance its antitumor efficiency and modulate its cytotoxity. Apigenin, a flavonoid present in fruits and vegetables, is a potent dietary phytochemical effective in cancer chemoprevention. Aim This study was undertaken to investigate the potential synergistic antitumor activity of apigenin and 5-FU on Solid Ehrlich carcinoma (SEC). Methods Eighty Swiss albino male mice were divided into four equal groups: vehicle treated control SEC, SEC+5-FU, SEC+apigenin, SEC+ 5-FU+apigenin. Beclin-1 and caspases 3, 9 and JNK activities were estimated by ELISA; mRNA expression levels of the antiapoptotic gene Mcl-1 were estimated using quantitative real-time RT-PCR, while tissue malondialdehyde (MDA), glutathione peroxidase and total antioxidant capacity were evaluated spectrophotometrically. A part of the tumor was examined for histopathological and Ki-67 immunohistochemistry analysis. Results 5-FU and/or apigenin caused significant increase in tissue levels of Beclin-1, caspases 3, 9 and JNK activities, MDA with significant decrease in tumor volume, Mcl-1expression, tissue glutathione peroxidase and total antioxidant capacity and alleviated the histopathological changes with significant decrease of Ki-67 proliferation index compared to vehicle treated SEC control group. In conclusion The combination of 5-FU and apigenin had a greater effect than each of 5-FU or apigenin alone against solid Ehrlich carcinoma in mice.

      PubDate: 2016-12-29T13:33:08Z
       
  • Activation of AMPK by berberine induces hepatic lipid accumulation by
           upregulation of fatty acid translocase CD36 in mice
    • Authors: You-Jin Choi; Kang-Yo Lee; Seung-Hwan Jung; Hyung Sik Kim; Gayong Shim; Mi-Gyeong Kim; Yu-Kyoung Oh; Seon-Hee Oh; Dae Won Jun; Byung-Hoon Lee
      Abstract: Publication date: Available online 28 December 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): You-Jin Choi, Kang-Yo Lee, Seung-Hwan Jung, Hyung Sik Kim, Gayong Shim, Mi-Gyeong Kim, Yu-Kyoung Oh, Seon-Hee Oh, Dae Won Jun, Byung-Hoon Lee
      Emerging evidence has shown that berberine has a protective effect against metabolic syndrome such as obesity and type II diabetes mellitus by activating AMP-activated protein kinase (AMPK). AMPK induces CD36 trafficking to the sarcolemma for fatty acid uptake and oxidation in contracting muscle. However, little is known about the effects of AMPK on CD36 regulation in the liver. We investigated whether AMPK activation by berberine affects CD36 expression and fatty acid uptake in hepatocytes and whether it is linked to hepatic lipid accumulation. Activation of AMPK by berberine or transduction with adenoviral vectors encoding constitutively active AMPK in HepG2 and mouse primary hepatocytes increased the expression and membrane translocation of CD36, resulting in enhanced fatty acid uptake and lipid accumulation as determined by BODIPY-C16 and Nile red fluorescence, respectively. Activation of AMPK by berberine induced the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) and subsequently induced CCAAT/enhancer-binding protein β (C/EBPβ) binding to the C/EBP-response element in the CD36 promoter in hepatocytes. In addition, hepatic CD36 expression and triglyceride levels were increased in normal diet-fed mice treated with berberine, but completely prevented when hepatic CD36 was silenced with adenovirus containing CD36-specific shRNA. Taken together, prolonged activation of AMPK by berberine increased CD36 expression in hepatocytes, resulting in fatty acid uptake via processes linked to hepatocellular lipid accumulation and fatty liver.

      PubDate: 2016-12-29T13:33:08Z
      DOI: 10.1016/j.taap.2016.12.019
       
  • Relationships among DNA hypomethylation, Cd, and Pb exposure and risk of
           cigarette smoking-related urothelial carcinoma
    • Authors: Chi-Jung Chung; Chao-Hsiang Chang; Saou-Hsing Liou; Chiu-Shong Liu; Huei-Ju Liu; Li-Ching Hsu; Jhih-Sheng Chen; Hui-Ling Lee
      Abstract: Publication date: Available online 24 December 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Chi-Jung Chung, Chao-Hsiang Chang, Saou-Hsing Liou, Chiu-Shong Liu, Huei-Ju Liu, Li-Ching Hsu, Jhih-Sheng Chen, Hui-Ling Lee
      Cigarette smoking and environmental exposure to heavy metals are important global health issues, especially for urothelial carcinoma (UC). However, the effects of cadmium and lead exposure, as well as the levels of DNA hypomethylation, on UC risk are limited. We evaluated the possible exposure sources of Cd and Pb and the relationship among DNA hypomethylation, urinary Cd and Pb levels, and UC risk. We recruited 209 patients with UC and 417 control patients for a hospital-based case–control study between June 2011 and August 2014. We collected environmental exposure-related information with questionnaires. Blood and urine samples were analyzed to measure the Cd and Pb exposure and 5-methyl-2′-deoxycytidine levels as a proxy for DNA methylation. Multivariate logistic regression and 95% confidence intervals were applied to estimate the risk for UC. Study participants with high Cd and Pb exposure in blood or urine had significantly increased risk of UC, especially among the smokers. After adjusting for age and gender, the possible connections of individual cumulative cigarette smoking or herb medicine exposure with the increased levels of Cd and Pb were observed in the controls. Participants with 8.66%–12.39% of DNA hypomethylation had significantly increased risk of UC compared with those with ≥12.39% of DNA hypomethylation. Environmental factors including cigarette smoking and herb medicine may contribute to the internal dose of heavy metals levels. Repeat measurements of heavy metals with different study design, detailed dietary information, and types of herb medicine should be recommended for exploring UC carcinogenesis in future studies.

      PubDate: 2016-12-29T13:33:08Z
      DOI: 10.1016/j.taap.2016.12.016
       
  • Carbonic anhydrase inhibition boosts the antitumor effects of imatinib
           mesylate via potentiating the antiangiogenic and antimetastatic
           machineries
    • Authors: Amal A. Abd-El Fattah; Hebatallah A. Darwish; Nevine Fathy; Samia A. Shouman
      Abstract: Publication date: Available online 28 December 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Amal A. Abd-El Fattah, Hebatallah A. Darwish, Nevine Fathy, Samia A. Shouman
      Carbonic anhydrase inhibitors have emerged in the past few years as an interesting candidate for the development of novel unconventional strategies. Despite their effect in tumor regression via inhibition of tumor acidification, their potential role is not yet fully elucidated. Herein, we investigated whether acetazolamide (AZ) could modulate imatinib (IM) anticancer activity, both in breast cancer cells (T47D) and in isolated tumor specimens of Ehrlich ascites carcinoma (EAC). The impact of this combination on angiogenesis was evidenced by decreasing PDGF-A expression and enhancing that of TSP-1. In the meantime, AZ significantly suppressed IM-induced attenuation of VEGF secretion in T47D cells, most probably due to NO inhibition. The combination also dramatically decreased the metastatic activity of T47D cells by mitigating the protein levels of MMP-2 and -9 and phosphorylation of p38 MAPK, while increasing the expression of TIMP-1 and -2. In addition, a strong proapoptotic effect was observed in T47D cells after combining AZ and IM in terms of increased caspase-9 and -3 activities. Interestingly, these results were confirmed by the reduction in the isolated tumor volume, MVD, Ki-67 and VEGF expression. Eventually, the study provides a new therapeutic strategy for treating cancer.
      Graphical abstract image

      PubDate: 2016-12-29T13:33:08Z
      DOI: 10.1016/j.taap.2016.12.017
       
  • A semi-quantitative translational pharmacology analysis to understand the
           relationship between in vitro ENT1 inhibition and the clinical incidence
           of dyspnoea and bronchospasm
    • Authors: Lyn Rosenbrier Ribeiro; R. Ian Storer
      Abstract: Publication date: Available online 29 December 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Lyn Rosenbrier Ribeiro, R. Ian Storer
      Adenosine contributes to the pathophysiology of respiratory disease, and adenosine challenge leads to bronchospasm and dyspnoea in patients. The equilibrative nucleoside transporter 1 (ENT1) terminates the action of adenosine by removal from the extracellular environment. Therefore, it is proposed that inhibition of ENT1 in respiratory disease patients leads to increased adenosine concentrations, triggering bronchospasm and dyspnoea. This study aims to assess the translation of in vitro ENT1 inhibition to the clinical incidence of bronchospasm and dyspnoea in respiratory disease, cardiovascular disease and healthy volunteer populations. Four marketed drugs with ENT1 activity were assessed; dipyridamole, ticagrelor, draflazine, cilostazol. For each patient population, the relationship between in vitro ENT1 [3H]-NBTI binding affinity (Ki) and [3H]-adenosine uptake (IC50) to the incidence of: (1) bronchospasm/severe dyspnoea; (2) tolerated dyspnoea and; (3) no adverse effects, was evaluated. A high degree of ENT1 inhibition (≥13.3x Ki, ≥4x IC50) associated with increased incidence of bronchospasm/severe dyspnoea for patients with respiratory disease only, whereas a lower degree of ENT1 inhibition (≥0.1x Ki, ≥0.05x IC50) associated with a tolerable level of dyspnoea in both respiratory and cardiovascular disease patients. ENT1 inhibition had no effect in healthy volunteers. Furthermore, physicochemical properties correlative with ENT1 binding were assessed using a set of 1625 diverse molecules. Binding to ENT1 was relatively promiscuous (22% compounds Ki <1 μM) especially for neutral or basic molecules, and greater incidence tracked with higher lipophilicity (clogP >5). This study rationalises inclusion of an assessment of ENT1 activity during early safety profiling for programs targeting respiratory disorders.

      PubDate: 2016-12-29T13:33:08Z
      DOI: 10.1016/j.taap.2016.12.021
       
  • Moving into advanced nanomaterials. Toxicity of rutile TiO2 nanoparticles
           immobilized in nanokaolin nanocomposites on HepG2 cell line
    • Authors: Maria João Bessa; Carla Costa; Julian Reinosa; Cristiana Pereira; Sónia Fraga; José Fernández; Miguel A. Bañares; João Paulo Teixeira
      Abstract: Publication date: Available online 28 December 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Maria João Bessa, Carla Costa, Julian Reinosa, Cristiana Pereira, Sónia Fraga, José Fernández, Miguel A. Bañares, João Paulo Teixeira
      Immobilization of nanoparticles on inorganic supports has been recently developed, resulting in the creation of nanocomposites. Concerning titanium dioxide nanoparticles (TiO2 NPs 1 1 TiO2 NPs: Titanium dioxide nanoparticles ), these have already been developed in conjugation with clays, but so far there are no available toxicological studies on these nanocomposites. The present work intended to evaluate the hepatic toxicity of nanocomposites (C-TiO2 2 2 C-TiO2: Rutile TiO2 NPs immobilized in nanokaolin clay substrates ), constituted by rutile TiO2 NPs immobilized in nanokaolin (NK 3 3 NK: Nanokaolin clay ) clay, and its individual components. These nanomaterials were analysed by means of FE-SEM 4 4 FE-SEM: Field Emission Scanning Electron Microscopy and DLS 5 5 DLS: Dynamic Light Scattering analysis for physicochemical characterization. HepG2 cells were exposed to rutile TiO2 NPs, NK clay and C-TiO2 nanocomposite, in the presence and absence of serum for different exposure periods. Possible interferences with the methodological procedures were determined for MTT, 6 6 MTT: 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide assay neutral red uptake, alamar blue (AB), LDH, 7 7 LDH: Lactate dehydrogenase assay and comet assays, for all studied nanomaterials. Results showed that MTT, AB and alkaline comet assay were suitable for toxicity analysis of the present materials after slight modifications to the protocol. Significant decreases in cell viability were observed after exposure to all studied nanomaterials. Furthermore, an increase in HepG2 DNA damage was observed after shorter periods of exposure in the absence of serum proteins and longer periods of exposure in their presence. Although the immobilization of nanoparticles in micron-sized supports could, in theory, decrease the toxicity of single nanoparticles, the selection of a suitable support is essential. The present results suggest that NK clay is not the appropriate substrate to decrease TiO2 NPs toxicity. Therefore, for future studies, it is critical to select a more appropriate substrate for the immobilization of TiO2 NPs.

      PubDate: 2016-12-29T13:33:08Z
      DOI: 10.1016/j.taap.2016.12.018
       
  • Cover 4--TOC
    • Abstract: Publication date: 1 January 2017
      Source:Toxicology and Applied Pharmacology, Volume 314


      PubDate: 2016-12-23T08:56:00Z
       
  • Pharmacological activation of aldehyde dehydrogenase 2 promotes osteoblast
           differentiation via bone morphogenetic protein-2 and induces bone anabolic
           effect
    • Authors: Monika Mittal; Subhashis Pal Shyamsundar Pal China Konica Porwal Kapil
      Abstract: Publication date: Available online 23 December 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Monika Mittal, Subhashis Pal, Shyamsundar Pal China, Konica Porwal, Kapil Dev, Richa Shrivastava, Kanumuri Siva Rama Raju, Mamunur Rashid, Arun Kumar Trivedi, Sabyasachi Sanyal, Muhammad Wahajuddin, Smrati Bhaduria, Rakesh Maurya, Naibedya Chattopadhyay
      Aldehyde dehydrogenases (ALDHs) are a family of enzymes involved in detoxifying aldehydes. Previously, we reported that an ALDH inhibitor, disulfiram caused bone loss in rats and among ALDHs osteoblast expressed only ALDH2. Loss-of-function mutation in ALDH2 gene is reported to cause bone loss in humans which suggested its importance in skeletal homeostasis. We thus studied whether activating ALDH2 by N-(1, 3-benzodioxol-5-ylmethyl)-2, 6-dichlorobenzamide (alda-1) had osteogenic effect. We found that alda-1 increased and acetaldehyde decreased the differentiation of rat primary osteoblasts and expressions of ALDH2 and bone morphogenetic protein-2 (BMP-2). Silencing ALDH2 in osteoblasts abolished the alda-1 effects. Further, alda-1 attenuated the acetaldehyde-induced lipid-peroxidation and oxidative stress. BMP-2 is essential for bone regeneration and alda-1 increased its expression in osteoblasts. We then showed that alda-1 (40mg/kg dose) augmented bone regeneration at the fracture site with concomitant increase in BMP-2 protein compared with control. The osteogenic dose (40mg/kg) of alda-1 attained a bone marrow concentration that was stimulatory for osteoblast differentiation, suggesting that the tissue concentration of alda-1 matched its pharmacological effect. In addition, alda-1 promoted modelling-directed bone growth and peak bone mass achievement, and increased bone mass in adult rats which reiterated its osteogenic effect. In osteopenic ovariectomized (OVX) rats, alda-1 reversed trabecular osteopenia with attendant increase in serum osteogenic marker (procollagen type I N-terminal peptide) and decrease in oxidative stress. Alda-1 has no effect on liver and kidney function. We conclude that activating ALDH2 by alda-1 had an osteoanabolic effect involving increased osteoblastic BMP-2 production and decreased OVX-induced oxidative stress.

      PubDate: 2016-12-23T08:56:00Z
       
  • Ilexgenin A exerts anti-inflammation and anti-angiogenesis effects through
           inhibition of STAT3 and PI3K pathways and exhibits synergistic effects
           with Sorafenib on hepatoma growth
    • Authors: Hao Yang; Juan Wang; Jin-hong Fan; Ya-qi Zhang; Jun-xian Zhao; Xiao-jun Dai; Qi Liu; Yan-jun Shen; Chang Liu; Wei-dong Sun; Yun Sun
      Abstract: Publication date: Available online 14 December 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Hao Yang, Juan Wang, Jin-hong Fan, Ya-qi Zhang, Jun-xian Zhao, Xiao-jun Dai, Qi Liu, Yan-jun Shen, Chang Liu, Wei-dong Sun, Yun Sun
      Recently, we reported that Ilexgenin A exhibits anti-cancer activities and induces cell arrest. Here, we investigated the effect of Ilexgenin A on the inflammation, angiogenesis and tumor growth of hepatocellular carcinoma (HCC). Our current study revealed that Ilexgenin A significantly inhibited the inflammatory cytokines TNF-α and IL-6 levels and downregulated pro-angiogenic factor VEGF production and transcription in HepG2 cells. The underlying mechanism for Ilexgenin A effects appears to be through inhibiting STAT3 and PI3K pathways. Furthermore, we found that not only Ilexgenin A inhibited STAT3 and PI3K pathways in HepG2 cells but also blocked these signaling pathways in HUVECs. Most importantly, by employing two HCC xenografts models - HepG2 and H22, we showed that Ilexgenin A reduced tumor growth and exhibited synergy effect with Sorafenib. ELISA assay, histological analysis and immunohistochemistry examination revealed that the expression of VEGF and MVD was significantly decreased after the treatment with Ilexgenin A and the combination. Moreover, Ilexgenin A could enhance caspase-3/7 activity in vitro and transmission electron microscope indicated that the combination induced evident apoptosis of tumor cells and caused the structural changes of mitochondria in vivo. Although no apparent adverse effects occurred during the treatment period, Sorafenib monotherapy elicited hepatotoxicity for specific expression in the increased level of AST and the ratio of AST/ALT. However, the combination could remedy this adverse effect. In conclusion, the results described in the present study identifies Ilexgenin A as a promising therapeutic candidate that modulates inflammation, angiogenesis, and HCC growth.

      PubDate: 2016-12-14T08:48:51Z
      DOI: 10.1016/j.taap.2016.12.008
       
  • Physiologically Based Pharmacokinetic Toolkit to Evaluate Environmental
           Exposures: Applications of the Dioxin Model to Study Real Life Exposures
    • Authors: Claude Emond; Patricia Ruiz; Moiz Mumtaz
      Abstract: Publication date: Available online 10 December 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Claude Emond, Patricia Ruiz, Moiz Mumtaz
      Chlorinated dibenzo-p-dioxins (CDDs) are a series of mono- to octa-chlorinated homologous chemicals commonly referred to as polychlorinated dioxins. One of the most potent, well-known, and persistent member of this family is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). As part of translational research to make computerized models accessible to health risk assessors, we present a Berkeley Madonna recoded version of the human physiologically based pharmacokinetic (PBPK) model used by the U.S. Environmental Protection Agency (EPA) in the recent dioxin assessment. This model incorporates CYP1A2 induction, which is an important metabolic vector that drives dioxin distribution in the human body, and it uses a variable elimination half-life that is body burden dependent. To evaluate the model accuracy, the recoded model predictions were compared with those of the original published model. The simulations performed with the recoded model matched well with those of the original model. The recoded model was then applied to available data sets of real life exposure studies. The recoded model can describe acute and chronic exposures and can be useful for interpreting human biomonitoring data as part of an overall dioxin and/or dioxin-like compounds risk assessment.

      PubDate: 2016-12-14T08:48:51Z
      DOI: 10.1016/j.taap.2016.12.007
       
  • Clozapine-induced agranulocytosis: Evidence for an immune-mediated
           mechanism from a patient-specific in-vitro approach
    • Authors: Francesca Regen; Irmelin Herzog; Eric Hahn; Claudia Ruehl; Nathalie Le Bret; Michael Dettling; Isabella Heuser; Julian Hellmann-Regen
      Abstract: Publication date: Available online 6 December 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Francesca Regen, Irmelin Herzog, Eric Hahn, Claudia Ruehl, Nathalie Le Bret, Michael Dettling, Isabella Heuser, Julian Hellmann-Regen
      Use of the atypical antipsychotic clozapine (CZP) is compromised by the risk of potentially fatal agranulocytosis/granulocytopenia (CIAG). To address this, we have established a simple, personalized cell culture-based strategy to identify CIAG-susceptible patients, hypothesizing that an immunogenic and possibly haptene-based mechanism underlies CIAG pathophysiology. To detect a putative haptene-induced response to CZP in vitro exposure, a traditional lymphocyte stimulation assay was adapted and applied to patient-specific peripheral blood-derived mononuclear cells (PBMC). 6 patients with a history of CIAG, 6 patients under CZP treatment (without CIAG) and 12 matched healthy controls were studied. In vitro CZP exposure, even at strikingly low levels, resulted in significantly increased proliferation rates only in CIAG patients' PBMC. Other parameters including cell viability and mitogen-induced proliferation were also affected by in vitro CZP exposure, yet there was no significant difference between the groups. This personalized approach is a starting point for further investigations into a putative haptene-based mechanism underlying CIAG development, and may facilitate the future development of predictive testing.

      PubDate: 2016-12-08T08:42:16Z
      DOI: 10.1016/j.taap.2016.12.003
       
  • Methylation of Septin9 Mediated by DNMT3a Enhances Hepatic Stellate Cells
           Activation and Liver Fibrogenesis
    • Authors: Yuting Wu; Fangtian Bu; Haixia Yu; Wanxia Li; Cheng Huang; Xiaoming Meng; Lei Zhang; Taotao Ma; Jun Li
      Abstract: Publication date: Available online 6 December 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Yuting Wu, Fangtian Bu, Haixia Yu, Wanxia Li, Cheng Huang, Xiaoming Meng, Lei Zhang, Taotao Ma, Jun Li
      Liver fibrosis, resulting from chronic and persistent injury to the liver, is a worldwide health problem. Advanced liver fibrosis results in cirrhosis, liver failure and even hepatocellular cancer (HCC), often eventually requiring liver transplantation, poses a huge health burden on the global community. However, the specific pathogenesis of liver fibrosis remains not fully understood. Numerous basic and clinical studies have provided evidence that epigenetic modifications, especially DNA methylation, might contribute to the activation of hepatic stellate cells (HSCs), the pivotal cell type responsible for the fibrous scar in liver. Here, reduced representation bisulfite sequencing (RRBS) and bisulfite pyrosequencing PCR (BSP) analysis identified hypermethylation status of Septin9 (Sept9) gene in liver fibrogenesis. Sept9 protein was dramatically decreased in livers of CCl4-treated mice and immortalized HSC-T6 cells exposed to TGF-β1. Nevertheless, the suppression of Sept9 could be blocked by DNMT3a-siRNA and DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine (5-azadC). Overexpressed Sept9 attenuated TGF-β1-induced expression of myofibroblast markers α-SMA and Col1a1, accompanied by up-regulation of cell apoptosis-related proteins. Conversely, RNAi-mediated silencing of Sept9 enhanced accumulation of extracellular matrix. These observations suggested that Sept9 contributed to alleviate liver fibrosis might partially through promoting activated HSCs apoptosis and this anti-fibrogenesis effect might be blocked by DNMT-3a mediated methylation of Sept9. Therefore, pharmacological agents that inhibit Sept9 methylation and increase its expression could be considered as valuable treatments for liver fibrosis.

      PubDate: 2016-12-08T08:42:16Z
      DOI: 10.1016/j.taap.2016.12.002
       
  • EX4 stabilizes and activates Nrf2 via PKCδ, contributing to the
           prevention of oxidative stress-induced pancreatic beta cell damage
    • Authors: Mi-Hwi Kim; Eung-Hwi Kim; Hye Seung Jung; Dongki Yang; Eun-Young Park; Hee-Sook Jun
      Abstract: Publication date: Available online 7 December 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Mi-Hwi Kim, Eung-Hwi Kim, Hye Seung Jung, Dongki Yang, Eun-Young Park, Hee-Sook Jun
      Oxidative stress in pancreatic beta cells can inhibit insulin secretion and promote apoptotic cell death. Exendin-4 (EX4), a glucagon-like peptide-1 receptor agonist, can suppress beta cell apoptosis, improve beta cell function and protect against oxidative damage. In this study, we investigated the molecular mechanisms for antioxidative effects of EX4 in pancreatic beta cells. INS-1 cells, a rat insulinoma cell line, were pretreated with EX4 and exposed to palmitate or H2O2. Reactive oxygen species (ROS) production, and glutathione and insulin secretion were measured. The mRNA and protein expression levels of antioxidant genes were examined. The level of nuclear factor erythroid 2-related factor 2 (Nrf2), its binding to antioxidant response element (ARE), and its ubiquination in the presence of EX4 were determined. The Nrf2 signaling pathway was determined using rottlerin (protein kinase [PK]Cδ inhibitor), H89 (PKA inhibitor) and LY294002 (phosphatidylinositide 3-kinase [PI3K] inhibitor). EX4 treatment decreased ROS production, recovered cellular glutathione levels and insulin secretion in the presence of oxidative stress in INS-1 cells. The expression levels of glutamate-cysteine ligase catalytic subunit and heme oxygenase-1 were increased by EX4 treatment. EX4 promoted Nrf2 translocation, ARE binding activity and enhanced stabilization of Nrf2 by inhibition of ubiquitination. Knockdown of Nrf2 abolished the effect of EX4 on increased insulin secretion. Inhibition of PKCδ attenuated Nrf2 translocation and antioxidative gene expression by EX4 treatment. We suggest that EX4 activates and stabilizes Nrf2 through PKCδ activation, contributing to the increase of antioxidant gene expression and consequently improving beta cell function in the presence of oxidative stress.

      PubDate: 2016-12-08T08:42:16Z
      DOI: 10.1016/j.taap.2016.12.005
       
  • The anti-ALS drug riluzole attenuates pericyte loss in the diabetic
           retinopathy of streptozotocin-treated mice
    • Authors: Jeong A. Choi; Yoo-Ri Chung; Hyae-Ran Byun; Hwangseo Park; Jae-Young Koh; Young Hee Yoon
      Abstract: Publication date: Available online 8 December 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Jeong A. Choi, Yoo-Ri Chung, Hyae-Ran Byun, Hwangseo Park, Jae-Young Koh, Young Hee Yoon
      Loss of pericytes, considered an early hallmark of diabetic retinopathy, is thought to involve abnormal activation of protein kinase C (PKC). We previously showed that the anti-amyotrophic lateral sclerosis (ALS) drug riluzole functions as a PKC inhibitor. Here, we examined the effects of riluzole on pathological changes in diabetic retinopathy. Pathological endpoints examined in vivo included the number of pericytes and integrity of retinal vessels in streptozotocin (STZ)-induced diabetic mice. In addition, PKC activation and the induction of monocyte chemotactic protein (MCP1) were assessed in diabetic mice and in human retinal pericytes exposed to advanced glycation end product (AGE) or modified low-density lipoprotein (mLDL). The diameter of retinal vessels and the number of pericytes were severely reduced, and the levels of MCP1 and PKC were increased in STZ-induced diabetic mice. Administration of riluzole reversed all of these changes. Furthermore, the increased expression of MCP1 in AGE- or mLDL-treated cultured retinal pericytes was inhibited by treatment with riluzole or the PKC inhibitor GF109203X. In silico modeling showed that riluzole fits well within the catalytic pocket of PKC. Taken together, our results demonstrate that riluzole attenuates both MCP1 induction and pericyte loss in diabetic retinopathy, likely through its direct inhibitory effect on PKC.

      PubDate: 2016-12-08T08:42:16Z
      DOI: 10.1016/j.taap.2016.12.004
       
  • Acute lung injury and persistent small airway disease in a rabbit model of
           chlorine inhalation
    • Authors: Sadiatu Musah; Connie F. Schlueter; David M. Humphrey; Karen S. Powell; Andrew M. Roberts; Gary W. Hoyle
      Abstract: Publication date: Available online 30 November 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Sadiatu Musah, Connie F. Schlueter, David M. Humphrey, Karen S. Powell, Andrew M. Roberts, Gary W. Hoyle
      Chlorine is a pulmonary toxicant to which humans can be exposed through accidents or intentional releases. Acute effects of chlorine inhalation in humans and animal models have been well characterized, but less is known about persistent effects of acute, high-level chlorine exposures. In particular, animal models that reproduce the long-term effects suggested to occur in humans are lacking. Here, we report the development of a rabbit model in which both acute and persistent effects of chlorine inhalation can be assessed. Male New Zealand White rabbits were exposed to chlorine while the lungs were mechanically ventilated. After chlorine exposure, the rabbits were extubated and were allowed to survive for up to 24h after exposure to 800ppm chlorine for 4min to study acute effects or up to 7days after exposure to 400ppm for 8min to study longer term effects. Acute effects observed 6 or 24h after inhalation of 800ppm chlorine for 4min included hypoxemia, pulmonary edema, airway epithelial injury, inflammation, altered baseline lung mechanics, and airway hyperreactivity to inhaled methacholine. Seven days after recovery from inhalation of 400ppm chlorine for 8min, rabbits exhibited mild hypoxemia, increased area of pressure–volume loops, and airway hyperreactivity. Lung histology 7days after chlorine exposure revealed abnormalities in the small airways, including inflammation and sporadic bronchiolitis obliterans lesions. Immunostaining showed a paucity of club and ciliated cells in the epithelium at these sites. These results suggest that small airway disease may be an important component of persistent respiratory abnormalities that occur following acute chlorine exposure. This non-rodent chlorine exposure model should prove useful for studying persistent effects of acute chlorine exposure and for assessing efficacy of countermeasures for chlorine-induced lung injury.

      PubDate: 2016-12-01T08:25:54Z
      DOI: 10.1016/j.taap.2016.11.017
       
  • Benznidazole, the trypanocidal drug used for Chagas disease, induces
           hepatic NRF2 activation and attenuates the inflammatory response in a
           murine model of sepsis
    • Authors: Flavia Lambertucci; Omar Motiño; Silvina Villar; Juan Pablo Rigalli; María de Luján Alvarez; Viviana Catania; Paloma Martín-Sanz; Cristina Ester Carnovale; Ariel Darío Quiroga; Daniel Eleazar Francés; María Teresa Ronco
      Abstract: Publication date: Available online 27 November 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Flavia Lambertucci, Omar Motiño, Silvina Villar, Juan Pablo Rigalli, María de Luján Alvarez, Viviana Catania, Paloma Martín-Sanz, Cristina Ester Carnovale, Ariel Darío Quiroga, Daniel Eleazar Francés, María Teresa Ronco
      Molecular mechanisms on sepsis progression are linked to the imbalance between reactive oxygen species (ROS) production and cellular antioxidant capacity. Previous studies demonstrated that benznidazole (BZL), known for its antiparasitic action on Trypanosoma cruzi, has immunomodulatory effects, increasing survival in C57BL/6 mice in a model of polymicrobial sepsis induced by cecal ligation puncture (CLP). The mechanism by which BZL inhibits inflammatory response in sepsis is poorly understood. Also, our group recently reported that BZL is able to activate the nuclear erythroid 2-related factor 2 (NRF2) in vitro. The aim of the present work was to delineate the beneficial role of BZL during sepsis, analyzing its effects on the cellular redox status and the possible link to the innate immunity receptor TLR4. Specifically, we analyzed the effect of BZL on Nrf2 regulation and TLR4 expression in liver of mice 24hours post-CLP. BZL was able to induce NRF2 nuclear protein localization in CLP mice. Also, we found that protein kinase C (PKC) is involved in the NRF2 nuclear accumulation and induction of its target genes. In addition, BZL prompted a reduction in hepatic CLP-induced TLR4 protein membrane localization, evidencing its immunomodulatory effects. Together, our results demonstrate that BZL induces hepatic NRF2 activation with the concomitant increase in the antioxidant defenses, and the attenuation of inflammatory response, in part, by inhibiting TLR4 expression in a murine model of sepsis.
      Graphical abstract image

      PubDate: 2016-12-01T08:25:54Z
      DOI: 10.1016/j.taap.2016.11.015
       
  • Protective role of hypoxia-inducible factor-1α-dependent CD39 and CD73 in
           fulminant acute liver failure
    • Authors: Eunyoung Tak; Dong-Hwan Jung; Seok-Hwan Kim; Gil-Chun Park; Dae Young Jun; Jooyoung Lee; Bo-hyun Jung; Varvara A. Kirchner; Shin Hwang; Gi-Won Song; Sung-Gyu Lee
      Abstract: Publication date: Available online 27 November 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Eunyoung Tak, Dong-Hwan Jung, Seok-Hwan Kim, Gil-Chun Park, Dae Young Jun, Jooyoung Lee, Bo-hyun Jung, Varvara A. Kirchner, Shin Hwang, Gi-Won Song, Sung-Gyu Lee
      Acute liver failure (ALF) is a severe life-threatening disease which usually arises in patients with-irreversible liver illnesses. Although human ectonucleotide triphosphate diphosphohydrolase-1, E-NTPDase1 (CD39) and ecto-5′-nucleotidase, Ecto5′NTase (CD73) are known to protect tissues from ALF, the expression and function of CD39 and CD73 during ALF are currently not fully investigated. We tested whether CD39 and CD73 are upregulated by hypoxia inducible factor (HIF)-1α, and improve ischemic tolerance to ALF. To test our hypothesis, liver biopsies were obtained and we found that CD39 and CD73 mRNA and proteins from human specimens were dramatically elevated in ALF. We investigated that induction of CD39 and CD73 in ALF-related with wild type mice. In contrast, deletion of cd39 and cd73 mice has severe ALF. In this study, we concluded that CD39 and CD73 are molecular targets for the development of drugs for ALF patients care.
      Graphical abstract image

      PubDate: 2016-12-01T08:25:54Z
      DOI: 10.1016/j.taap.2016.11.016
       
  • The regulation of cellular apoptosis by the ROS-triggered PERK/EIF2α/chop
           pathway plays a vital role in bisphenol A-induced male reproductive
           toxicity
    • Authors: Yin Yanlin; Dai Zhihong Cui Xiao Jiang Wenbin Liu Fei
      Abstract: Publication date: 1 January 2017
      Source:Toxicology and Applied Pharmacology, Volume 314
      Author(s): Li Yin, Yanlin Dai, Zhihong Cui, Xiao Jiang, Wenbin Liu, Fei Han, Ao Lin, Jia Cao, Jinyi Liu
      Bisphenol A (2,2-bis(4-hydroxyphenyl)propane, BPA) is ubiquitous in the environment, wildlife, and humans. Evidence from past studies suggests that BPA is associated with decreased semen quality. However, the molecular basis for the adverse effect of BPA on male reproductive toxicity remains unclear. We evaluated the effect of BPA on mouse spermatocytes GC-2 cells and adult mice, and we explored the potential mechanism of its action. The results showed that BPA inhibited cell proliferation and increased the apoptosis rate. The testes from BPA-treated mice showed fewer spermatogenic cells and sperm in the seminiferous tubules. In addition, BPA caused reactive oxygen species (ROS) accumulation. Previous study has verified that mitochondrion was the organelle affected by the BPA-triggered ROS accumulation. We found that BPA induced damage to the endoplasmic reticulum (ER) in addition to mitochondria, and most ER stress-related proteins were activated in cellular and animal models. Knocking down of the PERK/EIF2α/chop pathway, one of the ER stress pathways, partially recovered the BPA-induced cell apoptosis. In addition, an ROS scavenger attenuated the expression of the PERK/EIF2α/chop pathway-related proteins. Taken together, these data suggested that the ROS regulated PERK/EIF2α/chop pathway played a vital role in BPA-induced male reproductive toxicity.
      Graphical abstract image

      PubDate: 2016-12-01T08:25:54Z
       
  • Secretory function of ovarian cells and myometrial contractions in cow are
           affected by chlorinated insecticides (chlordane, heptachlor, mirex) in
           vitro
    • Authors: Michael Hubert Wrobel; Jaroslaw Mlynarczuk
      Abstract: Publication date: Available online 22 November 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Michael Hubert Wrobel, Jaroslaw Mlynarczuk
      The aim of the study was to investigate the effect of chlordane, heptachlor and mirex, on hormonal regulation of the force of myometrial contractions. Myometrial, endometrial, granulosa and luteal cells as well as strips of myometrium from non-pregnant cows were incubated with three insecticides at environmentally relevant doses (0.1, 1 or 10ng/ml). None of the insecticides affected the viability of studied cells. Chlordane stimulated, while heptachlor and mirex inhibited, secretion of testosterone and estradiol from granulosa cells as well as secretion of progesterone from luteal cells, respectively. Secretion of oxytocin (OT) from granulosa cells was increased after incubation with all studied insecticides. Only mirex stimulated OT secretion from luteal cells, while heptachlor inhibited this effect. None of them affected synthesis of OT in luteal cells and prostaglandins (PGF2 and PGE2) secretion from uterine cells, except PGE2 secretion from endometrial cells was decreased when the cells were incubated with 0.1ng/ml of chlordane. Basal and OT-stimulated myometrial contractions were increased by mirex and decreased by heptachlor. The data show that the insecticides altered secretory function of ovarian cells. Heptachlor and mirex affected also myometrial contractions in vitro, but uterine secretion of prostaglandins were not involved in the mechanism of that adverse effect of insecticides. The data indicate on potential of these insecticides to disturb fertilisation, blastocyst implantation or even the length of gestation.

      PubDate: 2016-11-24T14:37:19Z
      DOI: 10.1016/j.taap.2016.11.011
       
  • A data-driven weighting scheme for multivariate phenotypic endpoints
           recapitulates zebrafish developmental cascades
    • Authors: Guozhu Zhang; Kyle R. Roell; Lisa Truong; Robert L. Tanguay; David M. Reif
      Abstract: Publication date: Available online 22 November 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Guozhu Zhang, Kyle R. Roell, Lisa Truong, Robert L. Tanguay, David M. Reif
      Zebrafish have become a key alternative model for studying health effects of environmental stressors, partly due to their genetic similarity to humans, fast generation time, and the efficiency of generating high-dimensional systematic data. Studies aiming to characterize adverse health effects in zebrafish typically include several phenotypic measurements (endpoints). While there is a solid biomedical basis for capturing a comprehensive set of endpoints, making summary judgments regarding health effects requires thoughtful integration across endpoints. Here, we introduce a Bayesian method to quantify the informativeness of 17 distinct zebrafish endpoints as a data-driven weighting scheme for a multi-endpoint summary measure, called weighted Aggregate Entropy (wAggE). We implement wAggE using high-throughput screening (HTS) data from zebrafish exposed to five concentrations of all 1060 ToxCast chemicals. Our results show that our empirical weighting scheme provides better performance in terms of the Receiver Operating Characteristic (ROC) curve for identifying significant morphological effects and improves robustness over traditional curve-fitting approaches. From a biological perspective, our results suggest that developmental cascade effects triggered by chemical exposure can be recapitulated by analyzing the relationships among endpoints. Thus, wAggE offers a powerful approach for analysis of multivariate phenotypes that can reveal underlying etiological processes.

      PubDate: 2016-11-24T14:37:19Z
      DOI: 10.1016/j.taap.2016.11.010
       
  • SIRT1 protects cardiac cells against apoptosis induced by zearalenone or
           its metabolites α- and β-zearalenol through an autophagy-dependent
           pathway
    • Authors: Intidhar Ben Salem; Manel Boussabbeh; Julie Pires Da Silva; Arnaud Guilbert; Hassen Bacha; Salwa Abid-Essefi; Christophe Lemaire
      Abstract: Publication date: Available online 23 November 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Intidhar Ben Salem, Manel Boussabbeh, Julie Pires Da Silva, Arnaud Guilbert, Hassen Bacha, Salwa Abid-Essefi, Christophe Lemaire
      Zearalenone (ZEN) is a non-steroidal estrogenic mycotoxin produced by several species of Fusarium in cereals and agricultural products. The major ZEN metabolites are α-zearalenol (α-ZOL) and β-zearalenol (β-ZOL). In the present study, we investigated the underlying mechanism of the toxicity induced by ZEN, α-ZOL and β-ZOL in cardiac cells (H9c2). We show that treatment with ZEN or its metabolites induces the activation of the mitochondrial pathway of apoptosis as characterized by an increase in ROS generation, a loss of mitochondrial transmembrane potential (ΔΨm) and an activation of caspases. Besides, we demonstrate that these mycotoxins promote the activation of autophagy before the onset of apoptosis. Indeed, we observed that a short-time (6h) treatment with ZEN, α-ZOL or β-ZOL, increased the level of Beclin-1 and LC3-II and induced the accumulation of the CytoID® autophagy detection probe. Moreover, the inhibition of autophagy by Chloroquine significantly increased cell death induced by ZEN, α-ZOL or β-ZOL, suggesting that the activation of autophagy serves as a cardioprotective mechanism against these mycotoxins. In addition, we found that the inhibition (EX527) or the knockdown of SIRT1 (siRNA) significantly increased apoptosis induced by ZEN or its derivatives whereas SIRT1 activation with RSV greatly prevents the cytotoxic effects of these mycotoxins. By contrast, when autophagy was inhibited by CQ, the activation of SIRT1 by RSV had no protection against the cardiotoxicity of ZEN or its metabolites, suggesting that SIRT1 protects cardiac cells by an autophagy-dependent pathway.

      PubDate: 2016-11-24T14:37:19Z
      DOI: 10.1016/j.taap.2016.11.012
       
  • Single toxin dose-response models revisited
    • Authors: Eugene Demidenko; Glaholt Kyker-Snowman Shaw Chen
      Abstract: Publication date: Available online 12 November 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Eugene Demidenko, SP Glaholt, E Kyker-Snowman, JR Shaw, CY Chen
      The goal of this paper is to offer a rigorous analysis of the sigmoid shape single toxin dose-response relationship. The toxin efficacy function is introduced and four special points, including maximum toxin efficacy and inflection points, on the dose-response curve are defined. The special points define three phases of the toxin effect on mortality: (1) toxin concentrations smaller than the first inflection point or (2) larger then the second inflection point imply low mortality rate, and (3) concentrations between the first and the second inflection points imply high mortality rate. Probabilistic interpretation and mathematical analysis for each of the four models, Hill, logit, probit, and Weibull is provided. Two general model extensions are introduced: (1) the multi-target hit model that accounts for the existence of several vital receptors affected by the toxin, and (2) model with a nonzero mortality at zero concentration to account for natural mortality. Special attention is given to statistical estimation in the framework of the generalized linear model with the binomial dependent variable as the mortality count in each experiment, contrary to the widespread nonlinear regression treating the mortality rate as continuous variable. The models are illustrated using standard EPA Daphnia acute (48h) toxicity tests with mortality as a function of NiCl or CuSO4 toxin.

      PubDate: 2016-11-17T04:55:33Z
       
  • Obeticholic acid protects against carbon tetrachloride-induced acute liver
           injury and inflammation
    • Authors: Da-Gang Zhang; Cheng Zhang; Jun-Xian Wang; Bi-Wei Wang; Hua Wang; Zhi-Hui Zhang; Yuan-Hua Chen; Yan Lu; Li Tao; Jian-Qing Wang; Xi Chen; De-Xiang Xu
      Abstract: Publication date: Available online 16 November 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Da-Gang Zhang, Cheng Zhang, Jun-Xian Wang, Bi-Wei Wang, Hua Wang, Zhi-Hui Zhang, Yuan-Hua Chen, Yan Lu, Li Tao, Jian-Qing Wang, Xi Chen, De-Xiang Xu
      The farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays important roles in regulating bile acid homeostasis. The aim of the present study was to investigate the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, carbon tetrachloride (CCl4)-induced acute liver injury. Mice were intraperitoneally injected with CCl4 (0.15ml/kg). In CCl4 +OCA group, mice were orally with OCA (5mg/kg) 48, 24 and 1h before CCl4. As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl4-induced elevation of serum ALT and hepatic necrosis. Moreover, OCA pretreatment inhibited CCl4-induced hepatocyte apoptosis. Additional experiment showed that OCA inhibits CCl4-induced hepatic chemokine gene Mcp-1, Mip-2 and Kc. Moreover, OCA inhibits CCl4-induced hepatic pro-inflammatory gene Tnf-α and Il-1β. By contrast, OCA pretreatment elevated hepatic anti-inflammatory gene Il-4. Further analysis showed that OCA pretreatment inhibited hepatic IκB phosphorylation and blocked nuclear translocation of NF-κB p65 and p50 subunits during CCl4-induced acute liver injury. In addition, OCA pretreatment inhibited hepatic Akt, ERK and p38 phosphorylation in CCl4-induced acute liver injury. These results suggest that OCA protects against CCl4-induced acute liver injury and inflammation. Synthetic FXR agonists may be effective antidotes for hepatic inflammation during acute liver injury.

      PubDate: 2016-11-17T04:55:33Z
      DOI: 10.1016/j.taap.2016.11.006
       
  • Sibutramine provokes apoptosis of aortic endothelial cells through altered
           production of reactive oxygen and nitrogen species
    • Authors: Yoshifumi Morikawa; Akinobu Shibata; Naoko Okumura; Akira Ikari; Yasuhide Sasajima; Koichi Suenami; Kiyohito Sato; Yuji Takekoshi; Ossama El-Kabbani; Toshiyuki Matsunaga
      Abstract: Publication date: Available online 9 November 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Yoshifumi Morikawa, Akinobu Shibata, Naoko Okumura, Akira Ikari, Yasuhide Sasajima, Koichi Suenami, Kiyohito Sato, Yuji Takekoshi, Ossama El-Kabbani, Toshiyuki Matsunaga
      Overdose administration of sibutramine, a serotonin-noradrenalin reuptake inhibitor, is considered to elicit severe side effects including hypertension, whose pathogenic mechanism remains unclear. Here, we found that 48-h incubation with >10μM sibutramine provokes apoptosis of human aortic endothelial (HAE) cells. Treatment with the lethal concentration of sibutramine facilitated production of reactive oxygen species (ROS), altered expression of endoplasmic reticulum stress response genes (heat shock protein 70 and C/EBP homologous protein), and inactivated 26S proteasome-based proteolysis. The treatment also decreased cellular level of nitric oxide (NO) through lowering of expression and activity of endothelial NO synthase. These results suggest that ROS production and depletion of NO are crucial events in the apoptotic mechanism and may be linked to the pathogenesis of vasoconstriction elicited by the drug. Compared to sibutramine, its metabolites (N-desmethylsibutramine and N-didesmethylsibutramine) were much less cytotoxic to HAE cells, which hardly metabolized sibutramine. In contrast, both the drug and metabolites showed low cytotoxicity to hepatic HepG2 cells with high metabolic potency and expression of cytochrome P450 (CYP) 3A4. The cytotoxicity of sibutramine to HepG2 cells was remarkably augmented by inhibition and knockdown of CYP3A4. This study also suggests an inverse relationship between sibutramine cytotoxicity and CYP3A4-mediated metabolism into the N-desmethyl metabolites.
      Graphical abstract image

      PubDate: 2016-11-10T14:09:26Z
      DOI: 10.1016/j.taap.2016.11.003
       
  • Estimation of iodine nutrition and thyroid function status in
           late-gestation pregnant women in the United States: Development and
           application of a population-based pregnancy model
    • Authors: A. Lumen; N.I. George
      Abstract: Publication date: Available online 3 November 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): A. Lumen, N.I. George
      Previously, a deterministic biologically-based dose-response (BBDR) pregnancy model was developed to evaluate moderate thyroid axis disturbances with and without thyroid-active chemical exposure in a near-term pregnant woman and fetus.In the current study, the existing BBDR model was adapted to include a wider functional range of iodine nutrition, including more severe iodine deficiency conditions, and to incorporate empirically the effects of homeostatic mechanisms. The extended model was further developed into a population-based model and was constructed using a Monte Carlo-based probabilistic framework. In order to characterize total (T4) and free (fT4) thyroxine levels for a given iodine status at the population-level, the distribution of iodine intake for late-gestation pregnant women in the U.S was reconstructed using various reverse dosimetry methods and available biomonitoring data. The range of median (mean) iodine intake values resulting from three different methods of reverse dosimetry tested was 196.5–219.9μg of iodine/day (228.2–392.9μg of iodine/day). There was minimal variation in model-predicted maternal serum T4 and ft4 thyroxine levels from use of the three reconstructed distributions of iodine intake; the range of geometric mean for T4 and fT4, was 138–151.7nmol/L and 7.9–8.7pmol/L, respectively. The average value of the ratio of the 97.5th percentile to the 2.5th percentile equaled 3.1 and agreed well with similar estimates from recent observations in third-trimester pregnant women in the U.S. In addition, the reconstructed distributions of iodine intake allowed us to estimate nutrient inadequacy for late-gestation pregnant women in the U.S. via the probability approach. The prevalence of iodine inadequacy for third-trimester pregnant women in the U.S. was estimated to be between 21% and 44%. Taken together, the current work provides an improved tool for evaluating iodine nutritional status and the corresponding thyroid function status in pregnant women in the U.S. This model enables future assessments of the relevant risk of thyroid hormone level perturbations due to exposure to thyroid-active chemicals at the population-level.

      PubDate: 2016-11-03T14:00:06Z
      DOI: 10.1016/j.taap.2016.10.026
       
 
 
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