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Journal Cover Toxicology and Applied Pharmacology
  [SJR: 1.593]   [H-I: 135]   [18 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0041-008X - ISSN (Online) 1096-0333
   Published by Elsevier Homepage  [3042 journals]
  • Antitumor effectiveness of a combined therapy with a new cucurbitacin B
           derivative and paclitaxel on a human lung cancer xenograft model
    • Authors: Lucas Lourenço Marostica; André Luís Branco de Barros; Juliana Oliveira; Breno Souza Salgado; Geovanni Dantas Cassali; Elaine Amaral Leite; Valbert Nascimento Cardoso; Karen Luise Lang; Miguel Soriano Balparda Caro; Fernando Javier Durán; Eloir Paulo Schenkel; Mônica Cristina de Oliveira; Cláudia Maria Oliveira Simões
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Lucas Lourenço Marostica, André Luís Branco de Barros, Juliana Oliveira, Breno Souza Salgado, Geovanni Dantas Cassali, Elaine Amaral Leite, Valbert Nascimento Cardoso, Karen Luise Lang, Miguel Soriano Balparda Caro, Fernando Javier Durán, Eloir Paulo Schenkel, Mônica Cristina de Oliveira, Cláudia Maria Oliveira Simões
      Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors, with a high mortality rate due to the elevated risk of resistance. Natural cucurbitacins and their derivatives are recognized as promising antitumor compounds for several types of cancer, including NSCLC. In a recent study published by our research group, DACE (2-deoxy-2-amine-cucurbitacin E), which is a semisynthetic derivative of cucurbitacin B, showed potential in vitro synergistic antiproliferative effects combined with paclitaxel (PTX) in A549 cells. In sequence, the purpose of this study was to evaluate the in vivo antitumor efficacy of this combined therapy as well as with these drugs individually, using a human NSCLC xenograft model. Some indicators of sub chronic toxicity that could be affected by treatments were also assessed. The results obtained in vivo with the combined treatment (1mg/kg+PTX 10mg/kg) showed the most effective reduction of the relative tumor volume and the highest inhibition of tumor growth and proliferation, when compared with those of the single treatments. Furthermore, scintigraphic images, obtained before and after the treatments, showed that the most effective protocol able to reduce the residual viable tumor mass was the combined treatment. All treatment regimens were well tolerated without significant changes in body weight and no histological and functional damage to liver and kidney tissues. These results corroborate our previous in vitro synergistic effects published. Taken together, these insights are novel and highlight the therapeutic potential of DACE and PTX combination scheme for NSCLC.
      Graphical abstract image

      PubDate: 2017-06-21T20:09:14Z
      DOI: 10.1016/j.taap.2017.06.007
      Issue No: Vol. 329 (2017)
       
  • Impact of hepatic P450-mediated biotransformation on the disposition and
           respiratory tract toxicity of inhaled naphthalene
    • Authors: Nataliia Kovalchuk; Jacklyn Kelty; Lei Li; Matthew Hartog; Qing-Yu Zhang; Patricia Edwards; Laura Van Winkle; Xinxin Ding
      Pages: 1 - 8
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Nataliia Kovalchuk, Jacklyn Kelty, Lei Li, Matthew Hartog, Qing-Yu Zhang, Patricia Edwards, Laura Van Winkle, Xinxin Ding
      We determined whether a decrease in hepatic microsomal cytochrome P450 activity would impact lung toxicity induced by inhalation exposure to naphthalene (NA), a ubiquitous environmental pollutant. The liver-Cpr-null (LCN) mouse showed decreases in microsomal metabolism of NA in liver, but not lung, compared to wild-type (WT) mouse. Plasma levels of NA and NA-glutathione conjugates (NA-GSH) were both higher in LCN than in WT mice after a 4-h nose-only NA inhalation exposure at 10ppm. Levels of NA were also higher in lung and liver of LCN, compared to WT, mice, following exposure to NA at 5 or 10ppm. Despite the large increase in circulating and lung tissue NA levels, the level of NA-GSH, a biomarker of NA bioactivation, was either not different, or only slightly higher, in lung and liver tissues of LCN mice, relative to that in WT mice. Furthermore, the extent of NA-induced acute airway injury, judging from high-resolution lung histopathology and morphometry at 20h following NA exposure, was not higher, but lower, in LCN than in WT mice. These results, while confirming the ability of extrahepatic organ to bioactivate inhaled NA and mediate NA's lung toxicity, suggest that liver P450-generated NA metabolites also have a significant, although relatively small, contribution to airway toxicity of inhaled NA. This hepatic contribution to the airway toxicity of inhaled NA may be an important risk factor for individuals with diminished bioactivation activity in the lung.

      PubDate: 2017-06-02T19:24:53Z
      DOI: 10.1016/j.taap.2017.05.015
      Issue No: Vol. 329 (2017)
       
  • Ochratoxin A transport by the human breast cancer resistance protein
           (BCRP), multidrug resistance protein 2 (MRP2), and organic
           anion-transporting polypeptides 1A2, 1B1 and 2B1
    • Authors: Xiaozhe Qi; Els Wagenaar; Wentao Xu; Kunlun Huang; Alfred H. Schinkel
      Pages: 18 - 25
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Xiaozhe Qi, Els Wagenaar, Wentao Xu, Kunlun Huang, Alfred H. Schinkel
      Ochratoxin A (OTA) is a fungal secondary metabolite that can contaminate various foods. OTA has several toxic effects like nephrotoxicity, hepatotoxicity, and neurotoxicity in different animal species, but its mechanisms of toxicity are still unclear. How OTA accumulates in kidney, liver, and brain is as yet unknown, but transmembrane transport proteins are likely involved. We studied transport of OTA in vitro, using polarized MDCKII cells transduced with cDNAs of the efflux transporters mouse (m)Bcrp, human (h)BCRP, mMrp2, or hMRP2, and HEK293 cells overexpressing cDNAs of the human uptake transporters OATP1A2, OATP1B1, OATP1B3, or OATP2B1 at pH7.4 and 6.4. MDCKII-mBcrp cells were more resistant to OTA toxicity than MDCKII parental and hBCRP-transduced cells. Transepithelial transport experiments showed some apically directed transport by MDCKII-mBcrp cells at pH7.4, whereas both mBcrp and hBCRP clearly transported OTA at pH6.4. There was modest transport of OTA by mMrp2 and hMRP2 only at pH6.4. OATP1A2 and OATP2B1 mediated uptake of OTA both at pH7.4 and 6.4, but OATP1B1 only at pH7.4. There was no detectable transport of OTA by OATP1B3. Our data indicate that human BCRP and MRP2 can mediate elimination of OTA from cells, thus reducing OTA toxicity. On the other hand, human OATP1A2, OATP1B1, and OATP2B1 can mediate cellular uptake of OTA, which could aggravate OTA toxicity.

      PubDate: 2017-06-02T19:24:53Z
      DOI: 10.1016/j.taap.2017.05.022
      Issue No: Vol. 329 (2017)
       
  • Impact of chlorpyrifos on human villous trophoblasts and chorionic villi
    • Authors: M.E. Ridano; A.C. Racca; J.B. Flores-Martin; R. Fretes; C.L. Bandeira; L. Reyna; E. Bevilacqua; S. Genti-Raimondi; G.M. Panzetta-Dutari
      Pages: 26 - 39
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): M.E. Ridano, A.C. Racca, J.B. Flores-Martin, R. Fretes, C.L. Bandeira, L. Reyna, E. Bevilacqua, S. Genti-Raimondi, G.M. Panzetta-Dutari
      Placental barrier regulates maternal-fetal interchange protecting the baby from damage caused by substances found in the uterine environment or circulating in the vascular system. Organophosphate (OP) pesticides are a paramount group of environmental pollutants used in intensive agriculture for protection against diseases and pests. While many studies have reported an increased risk of pregnancy alterations in pregnant women exposed to OPs, few have analyzed the effects caused by these pesticides in the placenta. Herein, we evaluated the effects of chlorpyrifos (CPF), one of the most widely used OP insecticides, on human placenta using in vitro and ex vivo exposure models. Villous cytotrophoblast cells isolated from normal human term placentas maintained their cell viability, differentiated into syncytiotrophoblast-like structures, and increased the expression of β-hCG, ABCG2, and P-gp in the presence of CPF at concentrations of 10 to 100μM. The same doses of CPF induced marked changes in chorionic villi samples. Indeed, CPF exposure increased stroma cell apoptosis, altered villi matrix composition, basement membrane thickness, and trophoblastic layer integrity. Histomorphological and ultrastructural alterations are compatible with those found in placentas where maternal-placenta injury is chronic and able to impair the placental barrier function and nutrient transport from mother to the fetus. Our study shows that placental ex vivo exposure to CPF produces tissue alterations and suggest that human placenta is a potential target of CPF toxicity. In addition, it highlights the importance of using different models to assess the effects of a toxic on human placenta.

      PubDate: 2017-06-02T19:24:53Z
      DOI: 10.1016/j.taap.2017.05.026
      Issue No: Vol. 329 (2017)
       
  • Rebamipide ameliorates radiation-induced intestinal injury in a mouse
           model
    • Authors: Sehwan Shim; Hyo-Sun Jang; Hyun-Wook Myung; Jae Kyung Myung; Jin-Kyu Kang; Min-Jung Kim; Seung Bum Lee; Won-Suk Jang; Sun-Joo Lee; Young-Woo Jin; Seung-Sook Lee; Sunhoo Park
      Pages: 40 - 47
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Sehwan Shim, Hyo-Sun Jang, Hyun-Wook Myung, Jae Kyung Myung, Jin-Kyu Kang, Min-Jung Kim, Seung Bum Lee, Won-Suk Jang, Sun-Joo Lee, Young-Woo Jin, Seung-Sook Lee, Sunhoo Park
      Radiation-induced enteritis is a major side effect in cancer patients undergoing abdominopelvic radiotherapy. Radiation exposure produces an uncontrolled inflammatory cascade and epithelial cell loss leading to impaired epithelial barrier function. The goal of this study was to determine the effect of rebamipide on regeneration of the intestinal epithelia after radiation injury. The abdomens of C57BL/6 mice were exposed to 13Gy of irradiation (IR) and then the mice were treated with rebamipide. Upon IR, intestinal epithelia were destroyed structurally at the microscopic level and bacterial translocation was increased. The intestinal damage reached a maximum level on day 6 post-IR and intestinal regeneration occurred thereafter. We found that rebamipide significantly ameliorated radiation-induced intestinal injury. In mice treated with rebamipide after IR, intestinal barrier function recovered and expression of the tight junction components of the intestinal barrier were upregulated. Rebamipide administration reduced radiation-induced intestinal mucosal injury. The levels of proinflammatory cytokines and matrix metallopeptidase 9 (MMP9) were significantly reduced upon rebamipide administration. Intestinal cell proliferation and β-catenin expression also increased upon rebamipide administration. These data demonstrate that rebamipide reverses impairment of the intestinal barrier by increasing intestinal cell proliferation and attenuating the inflammatory response by inhibiting MMP9 and proinflammatory cytokine expression in a murine model of radiation-induced enteritis.

      PubDate: 2017-06-02T19:24:53Z
      DOI: 10.1016/j.taap.2017.05.012
      Issue No: Vol. 329 (2017)
       
  • Methylparaben and butylparaben alter multipotent mesenchymal stem cell
           fates towards adipocyte lineage
    • Authors: Pan Hu; Haley Overby; Emily Heal; Shu Wang; Jiangang Chen; Chwan-li Shen; Ling Zhao
      Pages: 48 - 57
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Pan Hu, Haley Overby, Emily Heal, Shu Wang, Jiangang Chen, Chwan-li Shen, Ling Zhao
      Paraben esters and their salts are widely used as preservatives in cosmetics, personal care products, pharmaceuticals, and foods. We previously reported that parabens promoted adipocyte differentiation in vitro and increased adiposity but suppressed serum marker of bone formation in vivo. Here, we investigated the effects of parabens (methylparaben and butylparaben) on modulating cell fate of multipotent stem cell line C3H10T1/2. Both parabens modulated adipogenic, osteogenic, and chondrogenic differentiation of C3H10T1/2 cells in vitro. Butylparaben markedly promoted adipogenic differentiation, but suppressed osteogenic and chondrogenic differentiation whereas methylparaben showed similar but less pronounced effects. Moreover, butylparaben, but not methylparaben, was shown to activate peroxisome proliferator-activated receptor (PPAR) γ whereas neither of the paraben was shown to activate glucocorticoid receptor (GR) responsive reporter in C3H10T1/2 cells. The adipogenic effects of butylparaben were significantly attenuated by PPARγ knockdown, but not by GR knockdown. In contrast, paraben's effects on osteoblast differentiation were affected by both knockdowns. Collectively, the results demonstrate opposing effects of parabens on adipogenic and osteoblastogenic/chondrogenic differentiation of multipotent stem cells. In light of the recent findings that parabens are detected in human placenta and milk, our studies provide rationales to study paraben exposure during early development of life in the future.

      PubDate: 2017-06-02T19:24:53Z
      DOI: 10.1016/j.taap.2017.05.019
      Issue No: Vol. 329 (2017)
       
  • Brevetoxin-2, is a unique inhibitor of the C-terminal redox center of
           mammalian thioredoxin reductase-1
    • Authors: Wei Chen; Anupama Tuladhar; Shantelle Rolle; Yanhao Lai; Freddy Rodriguez del Rey; Cristian E. Zavala; Yuan Liu; Kathleen S. Rein
      Pages: 58 - 66
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Wei Chen, Anupama Tuladhar, Shantelle Rolle, Yanhao Lai, Freddy Rodriguez del Rey, Cristian E. Zavala, Yuan Liu, Kathleen S. Rein
      Karenia brevis, the Florida red tide dinoflagellate produces a suite of neurotoxins known as the brevetoxins. The most abundant of the brevetoxins PbTx-2, was found to inhibit the thioredoxin-thioredoxin reductase system, whereas the PbTx-3 has no effect on this system. On the other hand, PbTx-2 activates the reduction of small disulfides such as 5,5′-dithio-bis-(2-nitrobenzoic acid) by thioredoxin reductase. PbTx-2 has an α, β-unsaturated aldehyde moiety which functions as an efficient electrophile and selenocysteine conjugates are readily formed. PbTx-2 blocks the inhibition of TrxR by the inhibitor curcumin, whereas curcumin blocks PbTx-2 activation of TrxR. It is proposed that the mechanism of inhibition of thioredoxin reduction is via the formation of a Michael adduct between selenocysteine and the α, β-unsaturated aldehyde moiety of PbTx-2. PbTx-2 had no effect on the rates of reactions catalyzed by related enzymes such as glutathione reductase, glutathione peroxidase or glutaredoxin.
      Graphical abstract image

      PubDate: 2017-06-02T19:24:53Z
      DOI: 10.1016/j.taap.2017.05.027
      Issue No: Vol. 329 (2017)
       
  • Deficiency of long isoforms of Nfe2l1 sensitizes MIN6 pancreatic β cells
           to arsenite-induced cytotoxicity
    • Authors: Qi Cui; Jingqi Fu; Yuxin Hu; Yongfang Li; Bei Yang; Lu Li; Jing Sun; Chengjie Chen; Guifan Sun; Yuanyuan Xu; Qiang Zhang; Jingbo Pi
      Pages: 67 - 74
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Qi Cui, Jingqi Fu, Yuxin Hu, Yongfang Li, Bei Yang, Lu Li, Jing Sun, Chengjie Chen, Guifan Sun, Yuanyuan Xu, Qiang Zhang, Jingbo Pi
      Increasing evidence indicates that chronic inorganic arsenic exposure is associated with type 2 diabetes (T2D), a disease of growing prevalence. Pancreatic β-cells were targeted and damaged by oxidative stress induced by arsenite. We previously showed that nuclear factor erythroid 2 like 2 (Nfe2l2)-deficient pancreatic β-cells were vulnerable to cell damage induced by oxidative stressors including arsenite, due to a muted antioxidant response. Like nuclear factor erythroid 2 like 2 (NFE2L2), NFE2L1 also belongs to the cap ‘n’ collar (CNC) basic-region leucine zipper (bZIP) transcription factor family, and regulates antioxidant response element (ARE) related genes. Our prior work showed NFE2L1 regulates glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells and isolated islets. In the current study, we demonstrated that MIN6 cells with a specific knockdown of long isoforms of Nfe2l1 (L-Nfe2l1) by lentiviral shRNA (Nfe2l1(L)-KD) were vulnerable to arsenite-induced apoptosis and cell damage. The expression levels of antioxidant genes, such as Gclc, Gclm and Ho-1, and intracellular reactive oxygen species (ROS) levels were not different in Scramble and Nfe2l1(L)-KD cells, while the expression of arsenic metabolism related-genes, such as Gsto1, Gstm1 and Nqo1, increased in Nfe2l1(L)-KD cells with or without arsenite treatment. The up-regulation of arsenic biotransformation genes was due to activated NFE2L2 in Nfe2l1(L)-KD MIN6 cells. Furthermore, the level of intracellular monomethylarsenic (MMA) was higher in Nfe2l1(L)-KD MIN6 cells than in Scramble cells. These results showed that deficiency of L-Nfe2l1 in pancreatic β-cells increased susceptibility to acute arsenite-induced cytotoxicity by promoting arsenic biotransformation and intracellular MMA levels.

      PubDate: 2017-06-06T19:41:12Z
      DOI: 10.1016/j.taap.2017.05.013
      Issue No: Vol. 329 (2017)
       
  • Bisphenol A impairs the memory function and glutamatergic homeostasis in a
           sex-dependent manner in mice: Beneficial effects of diphenyl diselenide
    • Authors: Natália S. Jardim; Glaúbia Sartori; Marcel H.M. Sari; Sabrina G. Müller; Cristina W. Nogueira
      Pages: 75 - 84
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Natália S. Jardim, Glaúbia Sartori, Marcel H.M. Sari, Sabrina G. Müller, Cristina W. Nogueira
      Bisphenol A (BPA) is a compound integrated in commodities, which consequently increases the human exposure to this toxicant. The deleterious effects of BPA exposure during periods of brain development have been documented mainly concerning the impairment in memory functions. Diphenyl diselenide (PhSe)2, an organoselenium compound, shows protective/restorative effects against memory deficits in experimental models. Thus, this study investigated the effects of (PhSe)2 on the memory impairments induced by BPA exposure to male and female mice and the possible involvement of glutamatergic system in these effects. Three-week-old male and female Swiss mice received BPA (5mg/kg), intragastrically, from 21st to 60th postnatal day. After, the animals were intragastrically treated with (PhSe)2 (1mg/kg) during seven days. The mice performed the behavioral memory tests and the [3H] glutamate uptake and NMDA receptor subunits (2A and 2B) analyses were carried out in the hippocampus and cerebral cortex of mice. The results demonstrated that the BPA exposure induced impairment of object recognition memory in both sexes. However, it caused impairments in spatial memory in female and in the passive avoidance memory in male mice. Besides, BPA caused a decrease in the [3H] glutamate uptake and NMDA receptor subunit levels in the cortical and hippocampal regions depending on the sex. Treatment with (PhSe)2 reversed in a sex-independent manner the behavioral impairments and molecular alterations. In conclusion, BPA had a negative effect in different memory types as well as in the glutamatergic parameters in a sex-dependent manner and (PhSe)2 treatment was effective against these alterations.
      Graphical abstract image

      PubDate: 2017-06-02T19:24:53Z
      DOI: 10.1016/j.taap.2017.05.035
      Issue No: Vol. 329 (2017)
       
  • Naloxegol, an opioid antagonist with reduced CNS penetration:
           Mode-of-action and human relevance for rat testicular tumours
    • Authors: Håkan Andersson; Terri Mitchard; Nakpangi Johnson; Eike Floettmann
      Pages: 85 - 95
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Håkan Andersson, Terri Mitchard, Nakpangi Johnson, Eike Floettmann
      Naloxegol is an opioid antagonist which has been developed for the treatment of patients with opioid induced constipation. In the nonclinical safety program naloxegol was shown to have a very benign toxicity profile. In the rat, but not the mouse, 2-year carcinogenicity study a change in tumour pattern with an increase in testicular Leydig cell tumours (LCT) was observed after dosing at high (supra-pharmacological) concentrations. To establish the basis of the increase in LCT and to assess its potential relevance to humans, studies to exclude and potentially identify mode-of-action (MoA) were performed. A genotoxic mechanism was ruled out following negative results in the Ames, mouse lymphoma, and micronucleus assays. An effect on androgen metabolism was excluded since the treatment of rats with naloxegol for 14days did not result in any induction of CYP protein levels. It was demonstrated that administration of centrally restricted opioid antagonists naloxegol or methylnaltrexone at high doses induced an increase in LH release with no clear increase in testosterone, in contrast to the centrally acting opioid antagonist naloxone, which showed marked increases in both LH and testosterone. LCT due to increased LH stimulation is common in rats but not documented in humans. Collectively, the lack of genotoxicity signal, the lack of androgen effect, the increase in LH secretion in rats, which is no considered to be relevant for LCT formation in humans, and high margins to clinical exposures, the observed increase in LCT in the rat is not expected to be clinically relevant.

      PubDate: 2017-06-06T19:41:12Z
      DOI: 10.1016/j.taap.2017.05.032
      Issue No: Vol. 329 (2017)
       
  • Nanotechnology in agriculture: Opportunities, toxicological implications,
           and occupational risks
    • Authors: Ivo Iavicoli; Veruscka Leso; Donald H. Beezhold; Anna A. Shvedova
      Pages: 96 - 111
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Ivo Iavicoli, Veruscka Leso, Donald H. Beezhold, Anna A. Shvedova
      Nanotechnology has the potential to make a beneficial impact on several agricultural, forestry, and environmental challenges, such as urbanization, energy constraints, and sustainable use of resources. However, new environmental and human health hazards may emerge from nano-enhanced applications. This raises concerns for agricultural workers who may become primarily exposed to such xenobiotics during their job tasks. The aim of this review is to discuss promising solutions that nanotechnology may provide in agricultural activities, with a specific focus on critical aspects, challenging issues, and research needs for occupational risk assessment and management in this emerging field. Eco-toxicological aspects were not the focus of the review. Nano-fertilizers, (nano-sized nutrients, nano-coated fertilizers, or engineered metal-oxide or carbon-based nanomaterials per se), and nano-pesticides, (nano-formulations of traditional active ingredients or inorganic nanomaterials), may provide a targeted/controlled release of agrochemicals, aimed to obtain their fullest biological efficacy without over-dosage. Nano-sensors and nano-remediation methods may detect and remove environmental contaminants. However, limited knowledge concerning nanomaterial biosafety, adverse effects, fate, and acquired biological reactivity once dispersed into the environment, requires further scientific efforts to assess possible nano-agricultural risks. In this perspective, toxicological research should be aimed to define nanomaterial hazards and levels of exposure along the life-cycle of nano-enabled products, and to assess those physico-chemical features affecting nanomaterial toxicity, possible interactions with agro-system co-formulants, and stressors. Overall, this review highlights the importance to define adequate risk management strategies for workers, occupational safety practices and policies, as well as to develop a responsible regulatory consensus on nanotechnology in agriculture.

      PubDate: 2017-06-06T19:41:12Z
      DOI: 10.1016/j.taap.2017.05.025
      Issue No: Vol. 329 (2017)
       
  • Molecular insights into the differences in anti-inflammatory activities of
           green tea catechins on IL-1β signaling in rheumatoid arthritis synovial
           fibroblasts
    • Authors: Sabrina Fechtner; Anil Singh; Mukesh Chourasia; Salahuddin Ahmed
      Pages: 112 - 120
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Sabrina Fechtner, Anil Singh, Mukesh Chourasia, Salahuddin Ahmed
      In this study, we found that catechins found in green tea (EGCG, EGC, and EC) differentially interfere with the IL-1β signaling pathway which regulates the expression of pro-inflammatory mediators (IL-6 and IL-8) and Cox-2 in primary human rheumatoid arthritis synovial fibroblasts (RASFs). EGCG and EGC inhibited IL-6, IL-8, and MMP-2 production and selectively inhibited Cox-2 expression. EC did not exhibit any inhibitory effects. When we looked at the expression of key signaling proteins in the IL-1β signaling pathway, we found all the tested catechins could inhibit TAK-1 activity. Therefore, the consumption of green tea offers an overall anti-inflammatory effect. Molecular docking analysis confirms that EGCG, EGC, and EC all occupy the active site of the TAK1 kinase domain. However, EGCG occupies the majority of the TAK1 active site. In addition to TAK1 inhibition, EGCG can also inhibit P38 and nuclear NF-κB expression whereas EC and EGC were not effective inhibitors. Our findings suggest one of the main health benefits associated with the consumption of green tea are due to the activity of EGCG and EGC which are both present at higher amounts. Although EGCG is the most effective catechin at inhibiting downstream inflammatory signaling, its effectiveness could be hindered by the presence of EC. Therefore, varying EC content in green tea may reduce the anti-inflammatory effects of other potential catechins in green tea.
      Graphical abstract image

      PubDate: 2017-06-06T19:41:12Z
      DOI: 10.1016/j.taap.2017.05.016
      Issue No: Vol. 329 (2017)
       
  • An impedance-based approach using human iPSC-derived cardiomyocytes
           significantly improves in vitro prediction of in vivo cardiotox
           liabilities
    • Authors: Bryan Koci; Gregory Luerman; Anika Duenbostell; Ralf Kettenhofen; Heribert Bohlen; Luke Coyle; Brian Knight; Warren Ku; Walter Volberg; Joseph R. Woska; Martha P. Brown
      Pages: 121 - 127
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Bryan Koci, Gregory Luerman, Anika Duenbostell, Ralf Kettenhofen, Heribert Bohlen, Luke Coyle, Brian Knight, Warren Ku, Walter Volberg, Joseph R. Woska, Martha P. Brown
      Current in vitro approaches to cardiac safety testing typically focus on mechanistic ion channel testing to predict in vivo proarrhythmic potential. Outside of the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative, structural and functional cardiotoxicity related to chronic dosing effects are of great concern as these effects can impact compound attrition. Development and implementation of an in vitro cardiotoxicity screening platform that effectively identifies these liabilities early in the discovery process should reduce costly attrition and decrease preclinical development time. Impedence platforms have the potential to accurately identify structural and functional cardiotoxicity and have sufficient throughput to be included in a multi-parametric optimization approach. Human induced pluripotent stem cell cardiomyocytes (hIPSC-CMs) have demonstrated utility in cardiac safety and toxicity screening. The work described here leverages these advantages to assess the predictive value of data generated by two impedance platforms. The response of hIPSC-CMs to compounds with known or predicted cardiac functional or structural toxicity was determined. The compounds elicited cardiac activities and/or effects on “macro” impedance often associated with overt structural or cellular toxicity, detachment, or hypertrophy. These assays correctly predicted in vivo cardiotox findings for 81% of the compounds tested and did not identify false positives. In addition, internal or literature Cmax values from in vivo studies correlated within 4 fold of the in vitro observations. The work presented here demonstrates the predictive power of impedance platforms with hIPSC-CMs and provides a means toward accelerating lead candidate selection by assessing preclinical cardiac safety earlier in the drug discovery process.

      PubDate: 2017-06-06T19:41:12Z
      DOI: 10.1016/j.taap.2017.05.023
      Issue No: Vol. 329 (2017)
       
  • Galangin ameliorates cisplatin-induced nephrotoxicity by attenuating
           oxidative stress, inflammation and cell death in mice through inhibition
           of ERK and NF-kappaB signaling
    • Authors: Yu-Ching Huang; Ming-Shiun Tsai; Pei-Chi Hsieh; Jheng-Hong Shih; Tsu-Shing Wang; Yi-Chun Wang; Ting-Hui Lin; Sue-Hong Wang
      Pages: 128 - 139
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Yu-Ching Huang, Ming-Shiun Tsai, Pei-Chi Hsieh, Jheng-Hong Shih, Tsu-Shing Wang, Yi-Chun Wang, Ting-Hui Lin, Sue-Hong Wang
      Cisplatin is a chemotherapeutic agent widely used in the treatment of various cancers. However, cisplatin can induce nephrotoxicity and neurotoxicity, limiting its dosage and usage. Galangin, a natural flavonol, has been found to exhibit anti-oxidant and anti-inflammatory effects in vivo. Here, we investigated the effects of galangin on cisplatin-induced acute kidney injury (AKI) and its molecular mechanisms in mice. Galangin administration reduced the cisplatin-induced oxidative stress by decreasing renal MDA and 3-NT formations. Galangin administration also increased renal anti-oxidative enzyme activities (SOD, GPx, and CAT) and GSH levels depleted by cisplatin. Furthermore, galangin administration inactivated stress-induced Nrf2 protein and its downstream products, HO-1 and GCLC. In terms of the inflammatory response, galangin administration reduced IκBα phosphorylation, NF-κB phosphorylation and nuclear translocation, and then inhibited cisplatin-induced secretions of pro-inflammatory TNF-α, IL-1β and IL-6. In addition, cisplatin-induced ERK and p38 phosphorylations were inhibited by galangin administration. In terms of cell death, galangin administration reduced levels of p53, pro-apoptotic Bax and activated caspase-3 to inhibit the cisplatin-induced apoptosis. Galangin administration also reduced the expression levels of RIP1 and RIP3 to inhibit cisplatin-induced RIP1/RIP3-dependent necroptosis. Therefore, galangin administration significantly ameliorates cisplatin-induced nephrotoxicity by attenuating oxidative stress, inflammation, and cell death through inhibitions of ERK and NF-κB signaling pathways. Galangin might be a potential adjuvant for clinical cisplatin therapy.

      PubDate: 2017-06-06T19:41:12Z
      DOI: 10.1016/j.taap.2017.05.034
      Issue No: Vol. 329 (2017)
       
  • DNA methylation of extracellular matrix remodeling genes in children
           exposed to arsenic
    • Authors: Tania Gonzalez-Cortes; Rogelio Recio-Vega; Robert Clark Lantz; Binh T. Chau
      Pages: 140 - 147
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Tania Gonzalez-Cortes, Rogelio Recio-Vega, Robert Clark Lantz, Binh T. Chau
      Several novel mechanistic findings regarding to arsenic's pathogenesis has been reported and some of them suggest that the etiology of some arsenic induced diseases are due in part to heritable changes to the genome via epigenetic processes such as DNA methylation, histone maintenance, and mRNA expression. Recently, we reported that arsenic exposure during in utero and early life was associated with impairment in the lung function and abnormal receptor for advanced glycation endproducts (RAGE), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) sputum levels. Based on our results and the reported arsenic impacts on DNA methylation, we designed this study in our cohort of children exposed in utero and early childhood to arsenic with the aim to associate DNA methylation of MMP9, TIMP1 and RAGE genes with its protein sputum levels and with urinary and toenail arsenic levels. The results disclosed hypermethylation in MMP9 promotor region in the most exposed children; and an increase in the RAGE sputum levels among children with the mid methylation level; there were also positive associations between MMP9 DNA methylation with arsenic toenail concentrations; RAGE DNA methylation with iAs, and %DMA; and finally between TIMP1 DNA methylation with the first arsenic methylation. A negative correlation between MMP9 sputum levels with its DNA methylation was registered. In conclusion, arsenic levels were positive associated with the DNA methylation of extracellular matrix remodeling genes;, which in turn could modifies the biological process in which they are involved causing or predisposing to lung diseases.

      PubDate: 2017-06-11T19:51:16Z
      DOI: 10.1016/j.taap.2017.06.001
      Issue No: Vol. 329 (2017)
       
  • Transgenerational inheritance of neurobehavioral and physiological
           deficits from developmental exposure to benzo[a]pyrene in zebrafish
    • Authors: Andrea L. Knecht; Lisa Truong; Skylar W. Marvel; David M. Reif; Abraham Garcia; Catherine Lu; Michael T. Simonich; Justin G. Teeguarden; Robert L. Tanguay
      Pages: 148 - 157
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Andrea L. Knecht, Lisa Truong, Skylar W. Marvel, David M. Reif, Abraham Garcia, Catherine Lu, Michael T. Simonich, Justin G. Teeguarden, Robert L. Tanguay
      Benzo[a]pyrene (B[a]P) is a well-known genotoxic polycylic aromatic compound whose toxicity is dependent on signaling via the aryl hydrocarbon receptor (AHR). It is unclear to what extent detrimental effects of B[a]P exposures might impact future generations and whether transgenerational effects might be AHR-dependent. This study examined the effects of developmental B[a]P exposure on 3 generations of zebrafish. Zebrafish embryos were exposed from 6 to 120h post fertilization (hpf) to 5 and 10μM B[a]P and raised in chemical-free water until adulthood (F0). Two generations were raised from F0 fish to evaluate transgenerational inheritance. Morphological, physiological and neurobehavioral parameters were measured at two life stages. Juveniles of the F0 and F2 exhibited hyper locomotor activity, decreased heartbeat and mitochondrial function. B[a]P exposure during development resulted in decreased global DNA methylation levels and generally reduced expression of DNA methyltransferases in wild type zebrafish, with the latter effect largely reversed in an AHR2-null background. Adults from the F0 B[a]P exposed lineage displayed social anxiety-like behavior. Adults in the F2 transgeneration manifested gender-specific increased body mass index (BMI), increased oxygen consumption and hyper-avoidance behavior. Exposure to benzo[a]pyrene during development resulted in transgenerational inheritance of neurobehavioral and physiological deficiencies. Indirect evidence suggested the potential for an AHR2-dependent epigenetic route.
      Graphical abstract image

      PubDate: 2017-06-11T19:51:16Z
      DOI: 10.1016/j.taap.2017.05.033
      Issue No: Vol. 329 (2017)
       
  • Biological implications of selenium in adolescent rats exposed to binge
           drinking: Oxidative, immunologic and apoptotic balance
    • Authors: M. Luisa Ojeda; Olimpia Carreras; Paula Sobrino; M. Luisa Murillo; Fátima Nogales
      Pages: 165 - 172
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): M. Luisa Ojeda, Olimpia Carreras, Paula Sobrino, M. Luisa Murillo, Fátima Nogales
      Alcohol intermittent binge drinking (BD) during adolescence decreases the levels of selenium (Se), a trace element that plays a key biological role against oxidative damage in hepatocytes through different selenoproteins such as the antioxidant enzymes glutathione peroxidases (GPx1 and Gpx4) and selenoprotein P (SelP). In this context, it has been found that GPx4 has an essential antioxidant role in mitochondria modulating the apoptosis and NF-kB activation (a factor intimately related to apoptosis and immune function). To further investigate the effectiveness of selenium supplementation in oxidative balance, inflammation and apoptosis, the present study examined the protective effects of 0.4ppm of dietary selenite administrated to adolescent rats exposed to BD. BD consumption depleted Se deposits in all the tissues studied. In liver, GPx1 activity and expression were decreased leading to protein and lipid hepatic oxidation. Moreover GPx4 and NF-kB expression were also decreased in liver, coinciding with an increase in caspase-3 expression. This hepatic profile caused general liver damage as shown the increased serum transaminases ratio AST/ALT. Proinflammatory serum citokines and chemocines were decreased. Se supplementation therapy used restored all these values, even AST levels. These findings suggest for first time that Se supplementation is a good strategy against BD liver damage during adolescence, since it increases GPx1 and GPx4 expression and avoids NF-kB downregulation and caspase-3 upregulation, leading to a better oxidative, inflammatory and apoptotic liver profile. The therapy proposed could be considered to have a great biological efficacy and to be suitable for BD exposed teenagers in order to avoid future hepatic complications.

      PubDate: 2017-06-16T19:58:14Z
      DOI: 10.1016/j.taap.2017.05.037
      Issue No: Vol. 329 (2017)
       
  • Characterization of xenobiotic metabolizing enzymes of a reconstructed
           human epidermal model from adult hair follicles
    • Authors: Daniel Bacqueville; Carine Jacques; Laure Duprat; Emilien L. Jamin; Beatrice Guiraud; Elisabeth Perdu; Sandrine Bessou-Touya; Daniel Zalko; Hélène Duplan
      Pages: 190 - 201
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Daniel Bacqueville, Carine Jacques, Laure Duprat, Emilien L. Jamin, Beatrice Guiraud, Elisabeth Perdu, Sandrine Bessou-Touya, Daniel Zalko, Hélène Duplan
      In this study, a comprehensive characterization of xenobiotic metabolizing enzymes (XMEs) based on gene expression and enzyme functionality was made in a reconstructed skin epidermal model derived from the outer root sheath (ORS) of hair follicles (ORS-RHE). The ORS-RHE model XME gene profile was consistent with native human skin. Cytochromes P450 (CYPs) consistently reported to be detected in native human skin were also present at the gene level in the ORS-RHE model. The highest Phase I XME gene expression levels were observed for alcohol/aldehyde dehydrogenases and (carboxyl) esterases. The model was responsive to the CYP inducers, 3-methylcholanthrene (3-MC) and β-naphthoflavone (βNF) after topical and systemic applications, evident at the gene and enzyme activity level. Phase II XME levels were generally higher than those of Phase I XMEs, the highest levels were GSTs and transferases, including NAT1. The presence of functional CYPs, UGTs and SULTs was confirmed by incubating the models with 7-ethoxycoumarin, testosterone, benzo(a)pyrene and 3-MC, all of which were rapidly metabolized within 24h after topical application. The extent of metabolism was dependent on saturable and non-saturable metabolism by the XMEs and on the residence time within the model. In conclusion, the ORS-RHE model expresses a number of Phase I and II XMEs, some of which may be induced by AhR ligands. Functional XME activities were also demonstrated using systemic or topical application routes, supporting their use in cutaneous metabolism studies. Such a reproducible model will be of interest when evaluating the cutaneous metabolism and potential toxicity of innovative dermo-cosmetic ingredients.
      Graphical abstract image

      PubDate: 2017-06-16T19:58:14Z
      DOI: 10.1016/j.taap.2017.05.040
      Issue No: Vol. 329 (2017)
       
  • Zingerone reduces HMGB1-mediated septic responses and improves survival in
           septic mice
    • Authors: Wonhwa Lee; Sae-Kwang Ku; Jong-Sup Bae
      Pages: 202 - 211
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Wonhwa Lee, Sae-Kwang Ku, Jong-Sup Bae
      High mobility group box 1 (HMGB1) is considered a late mediator of sepsis and the inhibition of HMGB1-mediated severe inflammatory responses and restoration of endothelial integrity have emerged as attractive therapeutic strategies for the management of sepsis. Zingerone (ZGR), a phenolic alkanone isolated from ginger, has been reported to possess various pharmacological activities. We examined the effects of ZGR on HMGB1-mediated septic responses and survival rate in a mouse model of sepsis. ZGR was administered after HMGB1 challenge. The antiseptic activity of ZGR was determined from the measurements of permeability, leukocyte adhesion and migration, activation of pro-inflammatory proteins, and the production of tissue injury markers in HMGB1-activated HUVECs and mice. ZGR significantly reduced HMGB1 release in LPS-activated HUVECs via the SIRT1-mediated deacetylation of HMGB1. And, ZGR suppressed the production of TNF-α and IL-6 and the activation of NF-κB and ERK 1/2 by HMGB1. ZGR also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with ZGR reduced the CLP-induced release of HMGB1, sepsis-related mortality, and tissue injury in vivo. Our results indicated that ZGR might be useful in the treatment of sepsis by targeting HMGB1.

      PubDate: 2017-06-21T20:09:14Z
      DOI: 10.1016/j.taap.2017.06.006
      Issue No: Vol. 329 (2017)
       
  • Anti-liver cancer activity in vitro and in vivo induced by 2-pyridyl
           2,3-thiazole derivatives
    • Authors: Thiago David dos Santos Silva; Larissa Mendes Bomfim; Ana Carolina Borges da Cruz Rodrigues; Rosane Borges Dias; Caroline Brandi Schlaepfer Sales; Clarissa Araújo Gurgel Rocha; Milena Botelho Pereira Soares; Daniel Pereira Bezerra; Marcos Veríssimo de Oliveira Cardoso; Ana Cristina Lima Leite; Gardenia Carmen Gadelha Militão
      Pages: 212 - 223
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Thiago David dos Santos Silva, Larissa Mendes Bomfim, Ana Carolina Borges da Cruz Rodrigues, Rosane Borges Dias, Caroline Brandi Schlaepfer Sales, Clarissa Araújo Gurgel Rocha, Milena Botelho Pereira Soares, Daniel Pereira Bezerra, Marcos Veríssimo de Oliveira Cardoso, Ana Cristina Lima Leite, Gardenia Carmen Gadelha Militão
      A total of 24 hybrid compounds containing pyridyl and 1,3-thiazole moieties were screened against HL-60 (leukemia), MCF-7 (breast adenocarcinoma), HepG2 (hepatocellular carcinoma), NCI-H292 (lung carcinoma) human tumor cell lines and non-tumor cells (PBMC, human peripheral blood mononuclear cells). Most of them were highly potent in at least one cell line tested (IC50 ≤3μM), being HL-60 the most sensitive and HepG2 the most resistant cell line. Among them, TAP-07 and TP-07 presented cytotoxic activity in all tumor cell lines, including HepG2 (IC50 2.2 and 5.6μM, respectively) without antiproliferative effects to normal cells (PBMC) (IC50 >30μM), making TAP-07 and TP-07, the compounds with the most favorable selectivity index. TAP-07 and TP-07 induced apoptosis in HepG2 cells and presented in vivo antitumor activity in hepatocellular xenograft cancer model in C.B-17 severe combined immunodeficient mice. Systemic toxicological verified by biochemical and histopathological techniques reveled no major signs of toxicity after treatment with TAP-07 and TP-07. Together the results indicated the anti-liver cancer activity of 2-pyridyl 2,3-thiazole derivatives.

      PubDate: 2017-06-21T20:09:14Z
      DOI: 10.1016/j.taap.2017.06.003
      Issue No: Vol. 329 (2017)
       
  • Modulation of TGF-β/Smad and ERK signaling pathways mediates the
           anti-fibrotic effect of mirtazapine in mice
    • Authors: Dalia M. El-Tanbouly; Walaa Wadie; Rabab H. Sayed
      Pages: 224 - 230
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Dalia M. El-Tanbouly, Walaa Wadie, Rabab H. Sayed
      Serotonin (5-HT) has been implicated as a key driver of liver fibrosis, acting via 5-HT2 receptor activation in the hepatic stellate cells. The current study was conducted to investigate the effects of mirtazapine, a 5-HT2A antagonist, in a mouse model of liver fibrosis. Mice received thioacetamide (TAA, 150mg/kg/biweekly, ip) for nine successive weeks for induction of liver fibrosis. Administration of mirtazapine significantly improved the plasma aminotransferases, reduced hepatic 5-HT concentration and ameliorated TAA-induced liver fibrosis, as demonstrated by reduced portal blood pressure, liver procollagen I content and α alpha smooth muscle actin expression. Moreover, hepatic collagen deposition was markedly decreased in mirtazapine-treated mice as evaluated by Masson's trichrome staining. Mirtazapine provided an antifibrotic environment by decreasing the liver content of transforming growth factor-β1 (TGF-β1), and protein kinase C as well as the expression of phosphorylated-Smad3 (p-Smad) and phosphorylated extracellular signal-regulated kinases 1 and 2 (p-ERK1/2). Additionally, oxidative stress was largely mitigated by mirtazapine as manifested by decreased liver lipid peroxidation and NADPH oxidase 1 along with glutathione replenishment. The current study indicates that mirtazapine suppressed 5-HT–mediated TGF-β1/Smad3 and ERK1/2 signaling pathways as well as oxidative stress that contribute to the progression of liver fibrosis.
      Graphical abstract image

      PubDate: 2017-06-21T20:09:14Z
      DOI: 10.1016/j.taap.2017.06.012
      Issue No: Vol. 329 (2017)
       
  • Adrenal-derived stress hormones modulate ozone-induced lung injury and
           inflammation
    • Authors: Andres Henriquez; John House; Desinia B. Miller; Samantha J. Snow; Anna Fisher; Hongzu Ren; Mette C. Schladweiler; Allen D. Ledbetter; Fred Wright; Urmila P. Kodavanti
      Pages: 249 - 258
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Andres Henriquez, John House, Desinia B. Miller, Samantha J. Snow, Anna Fisher, Hongzu Ren, Mette C. Schladweiler, Allen D. Ledbetter, Fred Wright, Urmila P. Kodavanti
      Ozone-induced systemic effects are modulated through activation of the neuro-hormonal stress response pathway. Adrenal demedullation (DEMED) or bilateral total adrenalectomy (ADREX) inhibits systemic and pulmonary effects of acute ozone exposure. To understand the influence of adrenal-derived stress hormones in mediating ozone-induced lung injury/inflammation, we assessed global gene expression (mRNA sequencing) and selected proteins in lung tissues from male Wistar-Kyoto rats that underwent DEMED, ADREX, or sham surgery (SHAM) prior to their exposure to air or ozone (1ppm), 4h/day for 1 or 2days. Ozone exposure significantly changed the expression of over 2300 genes in lungs of SHAM rats, and these changes were markedly reduced in DEMED and ADREX rats. SHAM surgery but not DEMED or ADREX resulted in activation of multiple ozone-responsive pathways, including glucocorticoid, acute phase response, NRF2, and PI3K-AKT. Predicted targets from sequencing data showed a similarity between transcriptional changes induced by ozone and adrenergic and steroidal modulation of effects in SHAM but not ADREX rats. Ozone-induced increases in lung Il6 in SHAM rats coincided with neutrophilic inflammation, but were diminished in DEMED and ADREX rats. Although ozone exposure in SHAM rats did not significantly alter mRNA expression of Ifnγ and Il-4, the IL-4 protein and ratio of IL-4 to IFNγ (IL-4/IFNγ) proteins increased suggesting a tendency for a Th2 response. This did not occur in ADREX and DEMED rats. We demonstrate that ozone-induced lung injury and neutrophilic inflammation require the presence of circulating epinephrine and corticosterone, which transcriptionally regulates signaling mechanisms involved in this response.

      PubDate: 2017-06-21T20:09:14Z
      DOI: 10.1016/j.taap.2017.06.009
      Issue No: Vol. 329 (2017)
       
  • Distribution, lipid-bilayer affinity and kinetics of the metabolic effects
           of dinoseb in the liver
    • Authors: Gabriela Bueno Franco Salla; Lívia Bracht; Anacharis Babeto de Sá-Nakanishi; Angela Valderrama Parizotto; Fabrício Bracht; Rosane Marina Peralta; Adelar Bracht
      Pages: 259 - 271
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Gabriela Bueno Franco Salla, Lívia Bracht, Anacharis Babeto de Sá-Nakanishi, Angela Valderrama Parizotto, Fabrício Bracht, Rosane Marina Peralta, Adelar Bracht
      Dinoseb is a highly toxic pesticide of the dinitrophenol group. Its use has been restricted, but it can still be found in soils and waters in addition to being a component of related pesticides that, after ingestion by humans or animals, can originate the compound by enzymatic hydrolysis. As most dinitrophenols, dinoseb uncouples oxidative phosphorylation. In this study, distribution, lipid bilayer affinity and kinetics of the metabolic effects of dinoseb were investigated, using mainly the isolated perfused rat liver, but also isolated mitochondria and molecular dynamics simulations. Dinoseb presented high affinity for the hydrophobic region of the lipid bilayers, with a partition coefficient of 3.75×104 between the hydrophobic and hydrophilic phases. Due to this high affinity for the cellular membranes dinoseb underwent flow-limited distribution in the liver. Transformation was slow but uptake into the liver space was very pronounced. For an extracellular concentration of 10μM, the equilibrium intracellular concentration was equal to 438.7μM. In general dinoseb stimulated catabolism and inhibited anabolism. Half-maximal stimulation of oxygen uptake in the whole liver occurred at concentrations (2.8–5.8μM) at least ten times above those in isolated mitochondria (0.28μM). Gluconeogenesis and ureagenesis were half-maximally inhibited at concentrations between 3.04 and 5.97μM. The ATP levels were diminished, but differently in livers from fed and fasted rats. Dinoseb disrupts metabolism in a complex way at concentrations well above its uncoupling action in isolated mitochondria, but still at concentrations that are low enough to be dangerous to animals and humans even at sub-lethal doses.
      Graphical abstract image

      PubDate: 2017-06-21T20:09:14Z
      DOI: 10.1016/j.taap.2017.06.013
      Issue No: Vol. 329 (2017)
       
  • Genipin protects the liver from ischemia/reperfusion injury by modulating
           mitochondrial quality control
    • Authors: Jun-Kyu Shin; Sun-Mee Lee
      Pages: 25 - 33
      Abstract: Publication date: 1 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 328
      Author(s): Jun-Kyu Shin, Sun-Mee Lee
      Hepatic ischemia and reperfusion (IR) injury is closely linked to oxidative mitochondrial damage. Since mitochondrial quality control (QC) plays a pivotal role in the recovery of impaired mitochondrial function, mitochondrial QC has emerged as a potential therapeutic target. Genipin, an iridoid compound from Gardenia jasminoides, has been showed antioxidant and anti-inflammatory properties. In this study, we investigated the hepatoprotective mechanism of genipin against IR-induced hepatic injury, particularly focusing on mitochondrial QC. Male C57BL/6 mice underwent liver ischemia for 60min, followed by reperfusion for 6h. Genipin (100mg/kg, i.p.) or vehicle (10% Tween 80 in saline) was administrated to mice 1h before ischemia. Liver and blood samples were collected 6h after reperfusion. Hepatic IR increased hepatocellular oxidative damage and induced mitochondrial dysfunction. These phenomena were ameliorated by genipin. Hepatic IR also increased the level of mitochondrial fission, such as dynamin-related protein 1 and the level of PINK1 protein expression. In contrast, hepatic IR decreased the levels of mitochondrial biogenesis related proteins (e.g., peroxisome proliferator-activated receptor gamma coactivator 1α, nuclear respiratory factor 1, and mitochondrial transcription factor A), mitophagy related proteins (e.g., Parkin), and fusion related protein (e.g., mitofusin 2). Furthermore, hepatic IR decreased the levels of sirtuin1 protein and phosphorylation of AMP-activated protein kinase. Genipin alleviated these IR-induced changes. These data indicate that genipin protects against IR-induced hepatic injury via regulating mitochondrial QC. (225/250).

      PubDate: 2017-05-22T19:08:11Z
      DOI: 10.1016/j.taap.2017.05.002
      Issue No: Vol. 328 (2017)
       
  • HMGA2, a driver of inflammation, is associated with hypermethylation in
           acute liver injury
    • Authors: Huimin Huang; Haidi Li; Xin Chen; Yang Yang; Xiaofeng Li; Wanxia Li; Cheng Huang; Xiaoming Meng; Lei Zhang; Jun Li
      Pages: 34 - 45
      Abstract: Publication date: 1 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 328
      Author(s): Huimin Huang, Haidi Li, Xin Chen, Yang Yang, Xiaofeng Li, Wanxia Li, Cheng Huang, Xiaoming Meng, Lei Zhang, Jun Li
      Acute liver injury (ALI) is characteristic of abrupt hepatic dysfunction and inflammatory response. Activaion of Kupffer cells (KCs) plays a central role in the pathogenesis of ALI. Since the High Mobility Group A protein2 (HMGA2) occurs as a driver at critical stage of hepatocellular carcinoma, herein, we investigated the role of HMGA2 in macrophage activation during ALI. Our study found that the expression of HMGA2 decreased dramatically both in KCs isolated from the liver in mice with ALI and in LPS-induced RAW264.7 cell lines. Moreover, loss- and gain-of-function studies suggested that HMGA2 could enhance the expression of pro-inflammatory cytokines including TNF-α, IL-6 and IL-1β. These results indicated that HMGA2 may play an essential role in macrophage activation during ALI. Additionally, our results showed the expression of HMGA2 was up-regulated when LPS-induced RAW264.7 cells were treated with 5-aza-2-deoxycytidine. Furthermore, silencing of DNMT1, DNMT3a, DNMT3b could respectively prevent the down-expression of HMGA2 in LPS-induced RAW264.7 cells. In conclusion, HMGA2 promotes the release of pro-inflammatory cytokines through NF-κB pathway, and the dysregulation of HMGA2 may involve with hypermethylation.

      PubDate: 2017-05-22T19:08:11Z
      DOI: 10.1016/j.taap.2017.05.005
      Issue No: Vol. 328 (2017)
       
  • Effects of monocrotophos pesticide on cholinergic and dopaminergic
           neurotransmitter systems during early development in the sea urchin
           Hemicentrotus pulcherrimus
    • Authors: Xiaona Zhang; Shuman Li; Cuicui Wang; Hua Tian; Wei Wang; Shaoguo Ru
      Pages: 46 - 53
      Abstract: Publication date: 1 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 328
      Author(s): Xiaona Zhang, Shuman Li, Cuicui Wang, Hua Tian, Wei Wang, Shaoguo Ru
      During early development in sea urchins, classical neurotransmitters, including acetylcholine (ACh), dopamine (DA), and serotonin (5-HT), play important roles in the regulation of morphogenesis and swimming behavior. However, the underlying mechanisms of how organophosphate pesticides cause developmental neurotoxicity by interfering with different neurotransmitter systems are unclear. In this study, we investigated the effects of 0.01, 0.10, and 1.00mg/L monocrotophos (MCP) pesticide on the activity of acetyltransferase (ChAT), acetylcholinesterase (AChE), monoamine oxidase, the concentration of DA, dopamine transporter, and the transcription activity of DA receptor D1 and tyrosine hydroxylase, during critical periods in cholinergic and dopaminergic nervous system development in sea urchin (Hemicentrotus pulcherrimus) embryos and larvae. At the blastula stages, MCP disrupted DA metabolism but not 5-HT metabolism, resulting in abnormal development. High ChAT and AChE activity were observed at the gastrulation-completed stage and the two-armed pluteus stage, respectively, MCP inhibited ChAT activity and AChE activity/distribution and resulted in developmental defects of the plutei. From the gastrula stage to the two-armed pluteus stage, we found ubiquitous disrupting effects of MCP on ACh, DA, and 5-HT metabolism, particularly at critical periods during the development of these neurotransmitter systems. Therefore, we propose that this disruption is one of the main mechanisms of MCP-related developmental neurotoxicity, which would contribute better understanding insight into the mechanism of MCP pesticide's toxic effects.

      PubDate: 2017-05-22T19:08:11Z
      DOI: 10.1016/j.taap.2017.05.003
      Issue No: Vol. 328 (2017)
       
  • Dual effect of silymarin on experimental non-alcoholic steatohepatitis
           induced by irinotecan
    • Authors: Eudmar Marcolino; Anielle Torres Melo; Venúcia Bruna Magalhães Pereira; Deysi Viviana Tenazoa Wong; Nathalia Ribeiro Pinho Sousa; Christiane Mendes Gonçalves Oliveira; Lara Raissa Cavalcante Malveira; Leonardo Silva Moreira; Marcellus Henrique Loiola Ponte Souza; Paulo Roberto Carvalho Almeida; Roberto César Pereira Lima
      Abstract: Publication date: 15 July 2017
      Source:Toxicology and Applied Pharmacology, Volume 327
      Author(s): Eudmar Marcolino Assis-Júnior, Anielle Torres Melo, Venúcia Bruna Magalhães Pereira, Deysi Viviana Tenazoa Wong, Nathalia Ribeiro Pinho Sousa, Christiane Mendes Gonçalves Oliveira, Lara Raissa Cavalcante Malveira, Leonardo Silva Moreira, Marcellus Henrique Loiola Ponte Souza, Paulo Roberto Carvalho Almeida, Roberto César Pereira Lima-Júnior
      Irinotecan-based regimens are commonly used for treatment of colorectal cancer, which is limited by mucositis and non-alcoholic steatohepatitis (NASH). Silymarin (SIL) prevents fatty liver disease in the clinical setting and in models of liver damage induced chemically. This study investigated the possible effect of SIL on irinotecan (IRI)-induced NASH. Swiss female mice were injected with saline (SAL 5ml/kg i.p.), IRI (50mg/kg i.p.), SIL (150mg/kg p.o.) or IRI (50mg/kg i.p.)+(SIL 1.5, 15 or 150mg/kg p.o.) thrice/week/7weeks. On the seventh week, blood samples were collected for transaminases assay and livers were collected for histopathology, measurement of the total lipids, malondyadehyde (MDA), non-protein sulfhydryl groups (NPSH), cytokines (IL-1β, IL 6 and IL-10), 3-nitrotyrosine (N-Tyr) and toll-like receptor 4 (TLR4) immunoexpression, quantification of NF-kB, α-smooth muscle actin (α-SMA), and Escherichia coli 16S rRNA gene (RRS) expression. IRI increased liver transaminases, neutrophil infiltration, lipid accumulation, MDA, IL-1β and IL-6 levels, N-Tyr and TLR4 immunostaining, NF-kB, α-SMA expression and RRS versus the SAL group (p<0.05). Additionally, SIL (1.5mg/kg) improved these parameters (p<0.05), except neutrophil infiltration and RSS versus the IRI group. Furthermore, the SIL (15mg/kg) only improved the inflammatory parameters, the expression of α-SMA and RRS versus the IRI group (p<0.05). The higher dose of SIL (150mg/kg) was even more deleterious than the intermediate dose. Therefore, silymarin showed a dual effect on liver damage induced by IRI. Hepatoprotection seems to involve the inhibition of oxidative stress and protein nitrosylation, preventing activation of hepatic fibrosis mechanisms.
      Graphical abstract image

      PubDate: 2017-05-13T15:29:55Z
      DOI: 10.1016/j.taap.2017.04.023
      Issue No: Vol. 327 (2017)
       
  • Loss of Nrf2 promotes rapid progression to heart failure following
           myocardial infarction
    • Authors: Joshua Strom; Qin M. Chen
      Abstract: Publication date: 15 July 2017
      Source:Toxicology and Applied Pharmacology, Volume 327
      Author(s): Joshua Strom, Qin M. Chen
      Nrf2 gene encodes a transcription factor regulating the expression of antioxidant and detoxification genes. We test here whether Nrf2 plays a role for cardiac protection during ischemic injury in an effort to establish Nrf2 as a target for cardiac protection therapies. Cardiac ischemia induced by the left anterior descending (LAD) coronary artery ligation results in myocardial infarction (MI). Young mice surviving MI show minimal signs of heart failure. Mice lacking Nrf2 experience an accelerated progression to heart failure that occurs within 10days following induction of MI. Nrf2 knockout (Nrf2 KO) mice have a survival rate similar to wild type (WT) mice at 24h after MI, but a significantly higher mortality rate within 10days after MI (50% vs 86%). Morphological examination revealed maladaptive remodeling, including cardiac hypertrophy and dilated left ventricle in Nrf2 KO mice, which were absent in WT mice. Measurements of cardiac function revealed increased left ventricular mass and decreases in cardiac output in Nrf2 KO mice. In addition, Nrf2 KO mice show biomarkers of heart failure, such as elevated levels of β-MHC, ANF, and BNP mRNA in the myocardium. These data support that Nrf2 plays an important role in protecting the myocardium from ischemic injury. Lack of Nrf2 leads to rapid development of heart failure.

      PubDate: 2017-05-07T15:17:34Z
      DOI: 10.1016/j.taap.2017.03.025
      Issue No: Vol. 327 (2017)
       
  • Genetic susceptibility to toxicologic lung responses among inbred mouse
           strains following exposure to carbon nanotubes and profiling of underlying
           gene networks
    • Authors: Evan A. Frank; Vinicius S. Carreira; Kumar Shanmukhappa; Mario Medvedovic; Daniel R. Prows; Jagjit S. Yadav
      Abstract: Publication date: 15 July 2017
      Source:Toxicology and Applied Pharmacology, Volume 327
      Author(s): Evan A. Frank, Vinicius S. Carreira, Kumar Shanmukhappa, Mario Medvedovic, Daniel R. Prows, Jagjit S. Yadav
      The risk of human exposure to fiber nanoparticles has risen in recent years due to increases in the manufacture and utilization of carbon nanotubes (CNTs). CNTs are present as airborne particulates in occupational settings and their hazard potential has been demonstrated in experimental lung exposure studies using inbred mouse strains. However, it is not known whether different inbred strains differ in lung responses to CNTs by virtue of their genetics. In this work, common inbred strains (BALB/c, C57Bl/6, DBA/2, and C3H/He) were exposed to CNTs via oropharyngeal aspiration and lung histology and bronchoalveolar lavage (BAL) samples were evaluated over 28days with the objective of evaluating sensitivity/resistance among strains. C57Bl/6 mice developed significantly more extensive type II pneumocyte (T2P) hyperplasia and alveolar infiltrate compared to DBA/2 mice, which were resistant. Surprisingly, DBA/2 but not C57Bl/6 mice were extremely sensitive to increases in leukocytes recovered in BAL fluid. Underlying global gene expression patterns in the two strains were compared using mRNA sequencing to investigate regulatory networks associated with the different effects. The impact of exposure on gene networks regulating various aspects of immune response and cell survival was limited in DBA/2 mice compared to C57Bl/6. Investigation of B6D2F1 (C57Bl/6×DBA/2 hybrid) mice demonstrated inheritance of sensitivity to CNT exposures in regard to toxicologic lung pathology and BAL leukocyte accumulations. These findings demonstrate a genetic basis of susceptibility to CNT particle exposures and both inform the use of inbred mouse models and suggest the likelihood of differences in genetic susceptibility among humans.

      PubDate: 2017-05-07T15:17:34Z
      DOI: 10.1016/j.taap.2017.04.019
      Issue No: Vol. 327 (2017)
       
  • Pulmonary pathobiology induced by zinc oxide nanoparticles in mice: A
           24-hour and 28-day follow-up study
    • Authors: Hsiao-Chi Chuang; Kai-Jen Chuang; Jen-Kun Chen; His-En Hua; Yen-Ling Shen; Wei-Neng Liao; Chii-Hong Lee; Chih-Hong Pan; Kuan-Yuan Chen; Kang-Yun Lee; Ta-Chih Hsiao; Tsun-Jen Cheng
      Pages: 13 - 22
      Abstract: Publication date: Available online 19 April 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Hsiao-Chi Chuang, Kai-Jen Chuang, Jen-Kun Chen, His-En Hua, Yen-Ling Shen, Wei-Neng Liao, Chii-Hong Lee, Chih-Hong Pan, Kuan-Yuan Chen, Kang-Yun Lee, Ta-Chih Hsiao, Tsun-Jen Cheng
      Inhaled zinc oxide nanoparticles (ZnONPs) have high deposition rates in the alveolar region of the lungs; however, the adverse health effects of ZnONPs on the respiratory system are unclear. Herein, pathobiological responses of the respiratory system of mice that received intratracheal administration of ZnONPs were investigated by a combination of molecular and imaging (SPECT and CT) approaches. Also, normal BEAS-2B and adenocarcinoma A549 cells were used to confirm the results in mice. First, female BALB/c mice were administrated a series of doses of 20-nm ZnONPs and were compared to the phosphate-buffered saline control for 24-h and 28-day follow-up observations. Field emission-scanning electron microscopy and an energy-dispersive X-ray microanalysis were first used to characterize ZnONPs. After 24h, instilled ZnONPs had caused significant increases in lactic dehydrogenase (LDH) in bronchoalveolar lavage fluid (BALF) and 8-hydroxy-2′-deoxyguanosine (8-OHdG), caspase-3, and the p63 tumor marker in lung tissues (p <0.05). Airway inflammation was present in a dose-dependent manner from the upper to the lower airway as analyzed by SPECT. After 28days, p63 had significantly increased due to ZnONP exposure in lung tissues (p <0.05). Pulmonary inflammatory infiltration mainly occurred in the left and right subsegments of the secondary bronchial bifurcation as observed by CT. A significant increase in p63 and decrease in TTF1 levels were observed in BEAS-2B cells by ZnONP (p <0.05), but not in A549 cells. Our results demonstrated that regional lung inflammation occurred with ZnONP exposure. We also showed that p63 was consistently overexpressed due to ZnONP exposure in vivo and in vitro. This work provides unique findings on the p63 response and the pathobiology in response to ZnONPs, which could be important to the study of pulmonary toxicity and repair.

      PubDate: 2017-04-25T14:50:47Z
      DOI: 10.1016/j.taap.2017.04.018
      Issue No: Vol. 327 (2017)
       
  • Mono-2-ethylhexyl phthalate inhibits human extravillous trophoblast
           invasion via the PPARγ pathway
    • Authors: Fumei Gao; Wenxin Hu; Yu Li; Huan Shen; Jianying Hu
      Pages: 23 - 29
      Abstract: Publication date: 15 July 2017
      Source:Toxicology and Applied Pharmacology, Volume 327
      Author(s): Fumei Gao, Wenxin Hu, Yu Li, Huan Shen, Jianying Hu
      Concerns over the adverse reproductive outcomes in human have been raised, more evidence including the underlying mechanism are required. Since extravillous trophoblast (EVT) invasion is an important physiological step during early development, the effects of mono-2-ethylhexyl phthalate (MEHP), the bioactive metabolite of DEHP, on EVT invasion were investigated using Matrigel-coated transwell chambers and cell line HTR-8/SVneo. In the transwell-based invasive assay, MEHP exposure inhibited EVT invasion as judged by decreased invasion index. Further analysis showed that MEHP exposure significantly inhibited the activity of matrix metalloproteinase-9 (MMP-9), which is an important positive regulator of EVT invasion. Meanwhile, the protein levels of tissue inhibitor matrix metalloproteinase-1 (TIMP-1), one key negative regulator of EVT invasion, were upregulated by MEHP treatment. Finally, inactivation of PPARγ pathway by either PPARγ inhibitors or PPARγ shRNA knockdown rescued the MEHP-induced inhibited invasion of HTR-8/SVneo cells, which is accompanied by the recovery of inhibited MMP-9 expression. The present study provides the evidence that MEHP exposure inhibits trophoblast invasion via PPARγ at concentrations comparable to those found in humans, which provides an insight in understanding the mechanisms of DEHP-associated early pregnancy loss.

      PubDate: 2017-05-02T15:07:11Z
      DOI: 10.1016/j.taap.2017.04.014
      Issue No: Vol. 327 (2017)
       
  • Quercetin, a natural product supplement, impairs mitochondrial
           bioenergetics and locomotor behavior in larval zebrafish (Danio rerio)
    • Authors: Ji-Liang Zhang; Christopher Laurence Souders; Nancy D. Denslow; Christopher J. Martyniuk
      Pages: 30 - 38
      Abstract: Publication date: 15 July 2017
      Source:Toxicology and Applied Pharmacology, Volume 327
      Author(s): Ji-Liang Zhang, Christopher Laurence Souders, Nancy D. Denslow, Christopher J. Martyniuk
      Quercetin is a natural product that is sold as a supplement in health food stores. While there are reported benefits for this flavonoid as a dietary supplement due to antioxidant properties, the full scope of its biological interactions has not been fully addressed. To learn more about the mechanisms of action related to quercetin, we exposed zebrafish (Danio rerio) embryos to 1 and 10μg/L quercetin for 96h starting at 3h post fertilization. Quercetin up to 10μg/L did not induce significant mortality in developing fish, but did increase prevalence of an upward-curved dorsal plane in hatched larvae. To determine whether this developmental defect was potentially related to mitochondrial bioenergetics during development, we measured oxygen consumption rate in whole embryos following a 24-hour exposure to quercetin. Basal mitochondrial and ATP-linked respiration were decreased at 1 and 10μg/L quercetin, and maximal respiration was decreased at 10μg/L quercetin, suggesting that quercetin impairs mitochondrial bioenergetics. This is proposed to be related to the deformities observed during development. Due to the fact that ATP production was affected by quercetin, larval behaviors related to locomotion were investigated, as well as transcriptional responses of six myogenesis transcripts. Quercetin at 10μg/L significantly reduced the swimming velocity of zebrafish larvae. The expression levels of both myostatin A (mstna) and myogenic differentiation (myoD) were also altered by quercetin. Mstna, an inhibitory factor for myogenesis, was significantly increased at 1μg/L quercetin exposure, while myoD, a stimulatory factor for myogenesis, was significantly increased at 10μg/L quercetin exposure. There were no changes in transcripts related to apoptosis (bcl2, bax, casp3, casp7), but we did observe a decrease in mRNA levels for catalase (cat) in fish exposed to each dose, supporting an oxidative stress response. Our data support the hypothesis that quercetin may affect locomotion and induce deformities in zebrafish larvae by diminishing ATP production and by altering the expression of transcripts related to muscle formation and activity.

      PubDate: 2017-05-07T15:17:34Z
      DOI: 10.1016/j.taap.2017.04.024
      Issue No: Vol. 327 (2017)
       
  • Altered ion transport in normal human bronchial epithelial cells following
           exposure to chemically distinct metal welding fume particles
    • Authors: Jeffrey S. Fedan; Janet A. Thompson; Terence G. Meighan; Patti C. Zeidler-Erdely; James M. Antonini
      Pages: 1 - 6
      Abstract: Publication date: 1 July 2017
      Source:Toxicology and Applied Pharmacology, Volume 326
      Author(s): Jeffrey S. Fedan, Janet A. Thompson, Terence G. Meighan, Patti C. Zeidler-Erdely, James M. Antonini
      Welding fume inhalation causes pulmonary toxicity, including susceptibility to infection. We hypothesized that airway epithelial ion transport is a target of fume toxicity, and investigated the effects of fume particulates from manual metal arc-stainless steel (MMA-SS) and gas metal arc-mild steel (GMA-MS) on ion transport in normal human bronchial epithelium (NHBE) cultured in air-interface. MMA-SS particles, more soluble than GMA-MS particles, contain Cr, Ni, Fe and Mn; GMA-MS particles contain Fe and Mn. MMA-SS or GMA-MS particles (0.0167–166.7μg/cm2) were applied apically to NHBEs. After 18h transepithelial potential difference (Vt), resistance (Rt), and short circuit current (I sc) were measured. Particle effects on Na+ and Cl¯ channels and the Na+,K+,2Cl¯-cotransporter were evaluated using amiloride (apical), 5-nitro-2-[(3-phenylpropyl)amino]benzoic acid (NPPB, apical), and bumetanide (basolateral), respectively. MMA-SS (0.0167–16.7μg/cm2) increased basal Vt. Only 16.7μg/cm2 GMA-MS increased basal Vt significantly. MMA-SS or GMA-MS exposure potentiated I sc responses (decreases) to amiloride and bumetanide, while not affecting those to NPPB, GMA-MS to a lesser degree than MMA-SS. Variable effects on Rt were observed in response to amiloride, and bumetanide. Generally, MMA-SS was more potent in altering responses to amiloride and bumetanide than GMA-MS. Hyperpolarization occurred in the absence of LDH release, but decreases in Vt, Rt, and I sc at higher fume particulate doses accompanied LDH release, to a greater extent for MMA-SS. Thus, Na+ transport and Na+,K+,2Cl¯-cotransport are affected by fume exposure; MMA-MS is more potent than GMA-MS. Enhanced Na+ absorption and decreased airway surface liquid could compromise defenses against infection.

      PubDate: 2017-04-18T14:35:59Z
      DOI: 10.1016/j.taap.2017.04.008
      Issue No: Vol. 326 (2017)
       
  • Arsenic activates the expression of 3β-HSD in mouse Leydig cells through
           repression of histone H3K9 methylation
    • Authors: Ambreen Alamdar; Guochen Xi; Qingyu Huang; Meiping Tian; Syed Ali Musstjab Akber Shah Eqani; Heqing Shen
      Pages: 7 - 14
      Abstract: Publication date: 1 July 2017
      Source:Toxicology and Applied Pharmacology, Volume 326
      Author(s): Ambreen Alamdar, Guochen Xi, Qingyu Huang, Meiping Tian, Syed Ali Musstjab Akber Shah Eqani, Heqing Shen
      Arsenic exposure has been associated with male reproductive dysfunction by disrupting steroidogenesis; however, the roles of epigenetic drivers, especially histone methylation in arsenic-induced steroidogenic toxicity remain not well documented. In this study, we investigated the role of histone H3 lysine 9 (H3K9) methylation in steroidogenesis disturbance in mouse Leydig cells (MLTC-1) due to arsenic exposure. Our results indicated that mRNA and protein expression levels of 3β-hydroxysteroid dehydrogenase (3β-HSD) were both significantly up-regulated while the rest of key genes involved in steroidogenesis were down-regulated. Moreover, arsenic exposure significantly decreased the histone H3K9 di- and tri-methylation (H3K9me2/3) levels in MLTC-1 cells. Since H3K9 demethylation leads to gene activation, we further investigated whether the induction of 3β-HSD expression was ascribed to reduced H3K9 methylation. The results showed that H3K9me2/3 demethylase (JMJD2A) inhibitor, quercetin (Que) significantly attenuated the decrease of H3K9me2/3 and increase of 3β-HSD expression induced by arsenic. To further elucidate the mechanism for the activation of 3β-HSD, we determined the histone H3K9 methylation levels in Hsd3b gene promoter, which also showed significant decrease of H3K9me2/3 in the investigated region after arsenic exposure. Considering these results, we conclude that arsenic exposure induced 3β-HSD up-regulation by suppressing H3K9me2/3 status, which is suggested as a compensatory mechanism for steroidogenic disturbance in MLTC-1 cells.

      PubDate: 2017-04-18T14:35:59Z
      DOI: 10.1016/j.taap.2017.04.012
      Issue No: Vol. 326 (2017)
       
  • Targeting Oct2 and P53: Formononetin prevents cisplatin-induced acute
           kidney injury
    • Authors: Di Huang; Chuangyuan Wang; Yingjie Duan; Qiang Meng; Zhihao Liu; Xiaokui Huo; Huijun Sun; Xiaodong Ma; Kexin Liu
      Pages: 15 - 24
      Abstract: Publication date: Available online 13 April 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Di Huang, Chuangyuan Wang, Yingjie Duan, Qiang Meng, Zhihao Liu, Xiaokui Huo, Huijun Sun, Xiaodong Ma, Kexin Liu
      Nephrotoxicity is one of major side effects of cisplatin in chemotherapy. Therefore, there is an urgent medical need to develop drugs that may protect kidney from toxicity. In previous study, we found that it showed the protective effects of formononetin against apoptosis by upregulating Nrf2. In this study, we investigated the renoprotective effect of formononetin against cisplatin-induced AKI and tried to elucidate the possible mechanisms. The amelioration of renal function, histopathological changes, and apoptosis in tubular cells was observed after formononetin treatment. Formononetin decreased expression of organic cation transporter 2 (Oct2) and increased the expressions of multidrug resistance-associated proteins (Mrps), which might result in a decrease accumulation of cisplatin in tubular cells after AKI. 5-Bromo-2-deoxyuridine (BrdU) and Ki-67 staining assay indicated that formononetin could promote the renal tubular cells proliferation after cisplatin nephrotoxicity. Moreover, formononetin regulated cyclins and pro-apoptotic proteins to involve the regulation of cell cycle. Furthermore, formononetin decreased p53 expression via promoting the overexpression of murine double minute 2 (MDM2) and MDMX. Taken together, formononetin provided protective effects by promoting proliferation of surviving renal tubular cells and inhibiting apoptosis after cisplatin-induced AKI.

      PubDate: 2017-04-18T14:35:59Z
      DOI: 10.1016/j.taap.2017.04.013
      Issue No: Vol. 326 (2017)
       
  • Licoricidin inhibits the growth of SW480 human colorectal adenocarcinoma
           cells in vitro and in vivo by inducing cycle arrest, apoptosis and
           autophagy
    • Authors: Shuai Ji; Shunan Tang; Kai Li; Ziwei Li; Wenfei Liang; Xue Qiao; Qi Wang; Siwang Yu; Min Ye
      Pages: 25 - 33
      Abstract: Publication date: Available online 14 April 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Shuai Ji, Shunan Tang, Kai Li, Ziwei Li, Wenfei Liang, Xue Qiao, Qi Wang, Siwang Yu, Min Ye
      Licorice (Glycyrrhiza uralensis Fisch.) possesses significant anti-cancer activities, but the active ingredients and underlying mechanisms have not been revealed. By screening the cytotoxic activities of 122 licorice compounds against SW480 human colorectal adenocarcinoma cells, we found that licoricidin (LCD) inhibited SW480 cell viability with an IC50 value of 7.2μM. Further studies indicated that LCD significantly induced G1/S cell cycle arrest and apoptosis in SW480 cells, accompanied by inhibition of cyclins/CDK1 expression and activation of caspase-dependent pro-apoptotic signaling. Meanwhile, LCD promoted autophagy in SW480 cells, and activated AMPK signaling and inhibited Akt/mTOR pathway. Overexpression of a dominant-negative AMPKα2 abolished LCD-induced inhibition of Akt/mTOR, autophagic and pro-apoptotic signaling pathways, and significantly reversed loss of cell viability, suggesting activation of AMPK is essential for the anti-cancer activity of LCD. In vivo anti-tumor experiments indicated that LCD (20mg/kg, i.p.) significantly inhibited the growth of SW480 xenografts in nude mice with an inhibitory rate of 43.5%. In addition, we obtained the glycosylated product LCDG by microbial transformation, and found that glycosylation slightly enhanced the in vivo anti-cancer activities of LCD. This study indicates that LCD could inhibit SW480 cells by inducing cycle arrest, apoptosis and autophagy, and is a potential chemopreventive or chemotherapeutic agent against colorectal cancer.

      PubDate: 2017-04-18T14:35:59Z
      DOI: 10.1016/j.taap.2017.04.015
      Issue No: Vol. 326 (2017)
       
  • Content
    • Abstract: Publication date: 15 July 2017
      Source:Toxicology and Applied Pharmacology, Volume 327


      PubDate: 2017-05-27T19:20:56Z
       
  • The impact of Zearalenone on the meiotic progression and primordial
           follicle assembly during early oogenesis
    • Authors: Ke-Han Liu; Xiao-Feng Sun; Yan-Zhong Feng; Shun-Feng Cheng; Bo Li; Ya-Peng Li; Wei Shen; Lan Li
      Abstract: Publication date: Available online 26 May 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Ke-Han Liu, Xiao-Feng Sun, Yan-Zhong Feng, Shun-Feng Cheng, Bo Li, Ya-Peng Li, Wei Shen, Lan Li
      Zearalenone (ZEA) is a mycotoxin produced by fusarium graminearum. It can cause abnormal reproductive function by acting as an environmental estrogen. Research has traditionally focused on acute and chronic injury on mammalian reproductive capacity after ZEA treatment. Little research has been done studying the effects of ZEA exposure on early oogenesis. In this study, we investigate the effects of ZEA exposure on meiotic entry, DNA double-strand breaks (DSBs), and primordial follicle assembly during murine early oogenesis. The results show that ZEA exposure significantly decreased the percentage of diplotene stage germ cells, and made more germ cells remain at zygotene or pachytene stages. Moreover, the mRNA expression level of meiosis-related genes was significantly reduced after ZEA treatment. ZEA exposure significantly increased DNA-DSBs at the diplotene stage. Meanwhile, DNA damage repair genes such as RAD51 and BRCA1 were activated. Furthermore, maternal exposure to ZEA significantly decreased the number of primordial follicles in newborn mouse ovaries. In conclusion, ZEA exposure impairs mouse female germ cell meiotic progression, DNA-DSBs, and primordial follicle assembly.

      PubDate: 2017-05-27T19:20:56Z
      DOI: 10.1016/j.taap.2017.05.024
       
  • Early life allergen and air pollutant exposures alter longitudinal blood
           immune profiles in infant rhesus monkeys
    • Authors: Candace M. Crowley; Justin H. Fontaine; Joan E. Gerriets; Edward S. Schelegle; Dallas M. Hyde; Lisa A. Miller
      Abstract: Publication date: Available online 18 May 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Candace M. Crowley, Justin H. Fontaine, Joan E. Gerriets, Edward S. Schelegle, Dallas M. Hyde, Lisa A. Miller
      Early life is a critical period for the progressive establishment of immunity in response to environmental stimuli; the impact of airborne challenges on this process is not well defined. In a longitudinal fashion, we determined the effect of episodic house dust mite (HDM) aerosol and ozone inhalation, both separately and combined, on peripheral blood immune cell phenotypes and cytokine expression from 4 to 25weeks of age in an infant rhesus monkey model of childhood development. Immune profiles in peripheral blood were compared with lung lavage at 25weeks of age. Independent of exposure, peripheral blood cell counts fluctuated with chronologic age of animals, while IFNγ and IL-4 mRNA levels increased over time in a linear fashion. At 12weeks of age, total WBC, lymphocyte numbers, FoxP3 mRNA and IL-12 mRNA were dramatically reduced relative to earlier time points, but increased to a steady state with age. Exposure effects were observed for monocyte numbers, as well as CCR3, FoxP3, and IL-12 mRNA levels in peripheral blood. Significant differences in cell surface marker and cytokine expression were detected following in vitro HDM or PMA/ionomycin stimulation of PBMC isolated from animals exposed to either HDM or ozone. Lavage revealed a mixed immune phenotype of FoxP3, IFNγ and eosinophilia in association with combined HDM plus ozone exposure, which was not observed in blood. Collectively, our findings show that airborne challenges during postnatal development elicit measureable cell and cytokine changes in peripheral blood over time, but exposure-induced immune profiles are not mirrored in the lung.

      PubDate: 2017-05-22T19:08:11Z
      DOI: 10.1016/j.taap.2017.05.006
       
  • Cadmium stimulates metastasis-associated phenotype in triple-negative
           breast cancer cells through integrin and β-catenin signaling
    • Authors: Zhengxi Wei; Zahir A. Shaikh
      Abstract: Publication date: Available online 17 May 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Zhengxi Wei, Zahir A. Shaikh
      Cadmium (Cd) is a carcinogenic heavy metal which is implicated in breast cancer development. While the mechanisms of Cd-induced breast cancer initiation and promotion have been studied, the molecular processes involved in breast cancer progression remain to be investigated. The purpose of the present study was to evaluate the influence of Cd on metastasis-associated phenotypes, such as cell adhesion, migration, and invasion in triple-negative breast cancer cells. Treatment of MDA-MB-231 cells with 1μM Cd increased cell spreading and cell migration. This was associated with the activation of integrin β1, FAK, Src, and Rac1. Treatment with Cd also inhibited GSK3β activity and induced T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription, indicating the involvement of β-catenin signaling. Furthermore, treatment with 3μM Cd for 4weeks increased the expression of β-catenin and enhanced TCF/LEF-mediated transcription. Furthermore, enhanced expressions of integrins α5 and β1, paxillin, and vimentin indicated that prolonged Cd treatment reorganized the cytoskeleton, which aided malignancy, as evidenced by enhanced matrix metalloprotease 2/9 (MMP2/9) secretion and cell invasion. Prolonged Cd treatment also caused an increase in cell growth. Together, these results indicate that Cd alters key signaling processes involved in the regulation of cytoskeleton to enhance cancer cell migration, invasion, adhesion, and proliferation.

      PubDate: 2017-05-22T19:08:11Z
      DOI: 10.1016/j.taap.2017.05.017
       
  • Von Willebrand factor deficiency reduces liver fibrosis in mice
    • Authors: Nikita Joshi; Anna K. Kopec; Jessica L. Ray; Holly Cline-Fedewa; Dafna J. Groeneveld; Ton Lisman; James P. Luyendyk
      Abstract: Publication date: Available online 17 May 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Nikita Joshi, Anna K. Kopec, Jessica L. Ray, Holly Cline-Fedewa, Dafna J. Groeneveld, Ton Lisman, James P. Luyendyk
      Liver diseases are associated with complex changes in the hemostatic system and elevated levels of the platelet-adhesive protein Von Willebrand factor (VWF) are reported in patients with acute and chronic liver damage. Although elevated levels of VWF are associated with fibrosis in the general population, the role of VWF in acute and chronic liver injury has not been examined in depth in experimental settings. We tested the hypothesis that VWF deficiency inhibits experimental liver injury and fibrosis. Wild-type (WT) and VWF-deficient mice were challenged with carbon tetrachloride (CCl4) and the impact of VWF deficiency on acute liver injury and chronic liver fibrosis was determined. VWF deficiency did not significantly affect acute CCl4-induced hepatocellular necrosis in mice. Chronic CCl4 challenge, twice weekly for 6weeks, significantly increased hepatic stellate cell activation and collagen deposition in livers of WT mice. Interestingly, hepatic induction of several profibrogenic and stellate cell activation genes was attenuated in VWF-deficient mice. Moreover, birefringent sirius red staining (indicating type I and III collagens) and type I collagen immunofluorescence indicated a reduction in hepatic collagen deposition in CCl4-exposed VWF-deficient mice compared to CCl4-exposed WT mice. The results indicate that VWF deficiency attenuates chronic CCl4-induced liver fibrosis without affecting acute hepatocellular necrosis. The results are the first to demonstrate that VWF deficiency reduces the progression of liver fibrosis, suggesting a mechanistic role of elevated plasma VWF levels in cirrhosis.

      PubDate: 2017-05-22T19:08:11Z
      DOI: 10.1016/j.taap.2017.05.018
       
  • Impact of common clandestine structural modifications on synthetic
           cathinone “bath salt” pharmacokinetics
    • Authors: Gregory G. Grecco; David F. Kisor; Joseph S. Magura; Jon E. Sprague
      Abstract: Publication date: Available online 12 May 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Gregory G. Grecco, David F. Kisor, Joseph S. Magura, Jon E. Sprague
      Since 2009, the synthetic cathinones (“bath salts”) have risen in popularity as drugs of abuse. However, there are a paucity of studies that have determined the impact of functional group modifications in the synthetic cathinone chemical structures on plasma and central nervous system (CNS) pharmacokinetics. In the present study, we investigated the in vivo plasma and CNS pharmacokinetics of three synthetic cathinones whose structures differ by lengthening of the α-alkyl chain: methylone (-CH3), butylone (-CH2CH3), and pentylone (-CH2CH2CH3). Male Sprague-Dawley rats were treated with a 20mg/kg subcutaneous dose of the individual synthetic cathinone. Blood samples were obtained at specific times from a jugular vein cannula over an 8hour period. Over a separate three-hour period, CNS samples were obtained using a microdialysis cannula surgically implanted into the lateral ventricle. In the plasma, pentylone, with the longest α-alkyl chain, displayed the highest Cmax and AUC0–∞, and the longest t1/2. Decreasing the α-alkyl chain length as in butylone and methylone significantly decreased the Cmax, AUC0–∞, and t1/2. The plasma pharmacokinetic values are consistent with the greater lipophilicity associated with α-alkyl side chain lengthening. Conversely, in the CNS, methylone and butylone displayed higher Cmax and AUC0–∞ values than pentylone. These contrary findings in the CNS and plasma demonstrate that lengthening of the α-alkyl chain of methylone, butylone, and pentylone yields differential pharmacokinetic properties in the CNS as compared to the plasma.
      Graphical abstract image

      PubDate: 2017-05-13T15:29:55Z
      DOI: 10.1016/j.taap.2017.05.010
       
  • Safety evaluation of dermal exposure to phthalates: Metabolism-dependent
           percutaneous absorption
    • Authors: Masahiro Sugino; Tomomi Hatanaka; Hiroaki Todo; Yuko Mashimo; Takamasa Suzuki; Miho Kobayashi; Osamu Hosoya; Hideto Jinno; Kazuhiko Juni; Kenji Sugibayashi
      Abstract: Publication date: Available online 12 May 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Masahiro Sugino, Tomomi Hatanaka, Hiroaki Todo, Yuko Mashimo, Takamasa Suzuki, Miho Kobayashi, Osamu Hosoya, Hideto Jinno, Kazuhiko Juni, Kenji Sugibayashi
      Phthalates, known as reproductive toxicants and endocrine disruptors, are widely used as plasticizers in polyvinyl chloride products. The present study was conducted for risk identification of dermal exposure to phthalates. When dibutyl phthalate was applied to the skin of hairless rats and humans, only monobutyl phthalate appeared through the skin, and the permeability of the skin was higher than that after the application of the monoester directly. The inhibition of skin esterases made the skin impermeable to the metabolite following dermal exposure to dibutyl ester, whereas removal of the stratum corneum from the skin did not change the skin permeation behavior. Similar phenomena were observed for benzyl butyl phthalate. The skin permeability of monobenzyl phthalate was higher than that of monobutyl phthalate in humans, although the reverse was observed in rats. Species difference in skin permeation profile corresponded to the esterase activity of the skin homogenate. Di(2-ethylhexyl) phthalate, which was not metabolized by esterases in the skin, was not transported across the skin. These results suggest that highly lipophilic phthalates may be transported easily across the stratum corneum lipids. The water-rich viable layer may become permeable to these phthalates by their metabolism into monoesters, which are relatively hydrophilic. Skin metabolism is essential to the percutaneous absorption of phthalates. Because esterase activity has large inter-individual differences, further study will be needed for individual risk identification of dermal exposure to phthalates.
      Graphical abstract image

      PubDate: 2017-05-13T15:29:55Z
      DOI: 10.1016/j.taap.2017.05.009
       
  • Curcumin improves alcoholic fatty liver by inhibiting fatty acid
           biosynthesis
    • Authors: Chang Guo; Jingfan Ma; Qionghong Zhong; Mengyuan Zhao; Tianxing Hu; Tong Chen; Longxin Qiu; Longping Wen
      Abstract: Publication date: Available online 2 May 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Chang Guo, Jingfan Ma, Qionghong Zhong, Mengyuan Zhao, Tianxing Hu, Tong Chen, Longxin Qiu, Longping Wen
      Alcoholic fatty liver is a threat to human health. It has been long known that abstinence from alcohol is the most effective therapy, other effective therapies are not available for the treatment in humans. Curcumin has a great potential for anti-oxidation and anti-inflammation, but the effect on metabolic reconstruction remains little known. Here we performed metabolomic analysis by gas chromatography/mass spectrometry and explored ethanol pathogenic insight as well as curcumin action pattern. We identified seventy-one metabolites in mouse liver. Carbohydrates and lipids were characteristic categories. Pathway analysis results revealed that ethanol-induced pathways including biosynthesis of unsaturated fatty acids, fatty acid biosynthesis and pentose and glucuronate interconversions were suppressed by curcumin. Additionally, ethanol enhanced galactose metabolism and pentose phosphate pathway. Glyoxylate and dicarboxylate metabolism and pyruvate metabolism were inhibited in mice fed ethanol diet plus curcumin. Stearic acid, oleic acid and linoleic acid were disease biomarkers and therapical biomarkers. These results reflect the landscape of hepatic metabolism regulation. Our findings illustrate ethanol pathological pathway and metabolic mechanism of curcumin therapy.
      Graphical abstract image

      PubDate: 2017-05-07T15:17:34Z
      DOI: 10.1016/j.taap.2017.05.001
       
  • Structure-toxicity relationship of cefoperazone and its impurities to
           developing zebrafish by transcriptome and Raman analysis
    • Authors: Ying Han; Jianqin Qian; Jingpu Zhang; Changqin Hu; Chen Wang
      Abstract: Publication date: Available online 29 April 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Ying Han, Jianqin Qian, Jingpu Zhang, Changqin Hu, Chen Wang
      Cefoperazone (CFP) is a potent antibacterial agent that is widely used for the treatment of bacterial infections. Previously, we found that both the C-7 and C-3 substituents of CFP are toxic functional groups, and two groups could affect gene expression in zebrafish embryos, thereby resulting in variable abnormal phenotypes. (6R, 7S)-cefoperazone (7S-CFP) is the 7-epimer of CFP and 1-methyl-1H-tetrazole-5-thiol (MTT) is the C-3 substituent of CFP. Both molecules are impurities isolated from CFP that can induce adverse effects. Transcriptome analysis was performed in the present study to identify differentially expressed genes (DEGs), coupled with Raman mapping of individual organ regions to detect changes in the biochemical composition of zebrafish embryos, which reflect the differences in distribution of the compounds. CFP, 7S–CFP, and MTT exposure altered the expression of 254, 368, and 1153 genes, respectively. Gene ontology analysis revealed that various processes related to development, growth, and morphology of tissues were significantly enriched with DEGs. We integrated seven co-DEGs with protein-protein interaction networks and identified various developmental processes that were regulated by the three compounds, including vasodilation, eye, brain, melanogenesis, and heart looping. Our findings suggested that Calca and Ptger4a may be potentially utilized as novel biomarkers for CFP, which causes bleeding. Raman analysis indicated that CFP, 7S-CFP, and MTT exhibited abnormal maps in tissues, which coincided with changes in their expression and morphological features. This study may provide bioinformatics and spectral information that may be used in further investigations on the relationship between structure and toxicity of drugs and impurities.
      Graphical abstract image

      PubDate: 2017-05-02T15:07:11Z
      DOI: 10.1016/j.taap.2017.04.025
       
  • In vivo inhibitory activity of andrographolide derivative ADN-9 against
           liver cancer and its mechanisms involved in inhibition of tumor
           angiogenesis
    • Authors: Wei Yang; Jin Zhao; Yake Wang; Haiwei Xu; Zhenwei Wu; Yangyang Hu; Kunkun Jiang; Pengpeng Shen; Cuiyun Ma; Zhenzhen Guan; Yan Zhang; Jiahui Ma; Ning Shang; Guangming Yan; Zhenji Wang; Guifu Dai
      Abstract: Publication date: Available online 22 April 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Wei Yang, Jin Zhao, Yake Wang, Haiwei Xu, Zhenwei Wu, Yangyang Hu, Kunkun Jiang, Pengpeng Shen, Cuiyun Ma, Zhenzhen Guan, Yan Zhang, Jiahui Ma, Ning Shang, Guangming Yan, Zhenji Wang, Guifu Dai
      It is well known that liver cancer is a highly aggressive malignancy with poor prognosis. Andrographolide (AD), a major bioactive component of Andrographis paniculata (Burm. F.), is a potential anti-cancer pharmacophore and the synthesis of AD derivatives with better cytotoxicity to cancer cells has attracted considerable attentions. In the present study, we evaluated the in vivo inhibitory effects of ADN-9, a 15-benzylidene substituted derivative of AD, on the growth and metastasis of murine hepatoma H22 using an orthotopic xenograft model and a subcutaneous xenograft model, and we further studied the anti-angiogenic action and the related mechanisms of ADN-9 in vivo and in vitro. Importantly, ADN-9 remarkably suppressed the growth and metastasis of both orthotopic and subcutaneous xenograft tumors, and the serum AFP level in orthotopic hepatoma-bearing mice treated with 100mg/kg ADN-9 (ig.) was decreased to the normal level. We also found that ADN-9 showed stronger abilities than AD in shrinking tumors, suppressing the invasion and metastasis of H22 cells, decreasing the MVD and promoting tumor cell apoptosis in subcutaneous xenograft of mice. Additionally, ADN-9 exhibited stronger inhibitory activity than AD against the migration and VEGF-induced capillary-like tube formation in HUVECs, which was further proved to be associated with attenuating VEGF/VEGFR2/AKT signaling pathway. The present research provides the first evidence that a 15-substituted AD derivative is more promising than the parent compound in therapeutic treatment of liver cancer.

      PubDate: 2017-04-25T14:50:47Z
      DOI: 10.1016/j.taap.2017.04.022
       
 
 
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