for Journals by Title or ISSN
for Articles by Keywords
help
  Subjects -> ENVIRONMENTAL STUDIES (Total: 771 journals)
    - ENVIRONMENTAL STUDIES (697 journals)
    - POLLUTION (23 journals)
    - TOXICOLOGY AND ENVIRONMENTAL SAFETY (40 journals)
    - WASTE MANAGEMENT (11 journals)

ENVIRONMENTAL STUDIES (697 journals)

The end of the list has been reached or no journals were found for your choice.
Journal Cover Toxicology and Applied Pharmacology
  [SJR: 1.593]   [H-I: 135]   [19 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0041-008X - ISSN (Online) 1096-0333
   Published by Elsevier Homepage  [3043 journals]
  • Melatonin as an angiogenesis inhibitor to combat cancer: Mechanistic
           evidence
    • Authors: Nasser Hashemi Goradel; Mohammad Hossein Asghari; Milad Moloudizargari; Babak Negahdari; Hamed Haghi-Aminjan; Mohammad Abdollahi
      Abstract: Publication date: 15 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 335
      Author(s): Nasser Hashemi Goradel, Mohammad Hossein Asghari, Milad Moloudizargari, Babak Negahdari, Hamed Haghi-Aminjan, Mohammad Abdollahi
      Melatonin, a pineal indolamine, participates in different body functions and is shown to possess diverse biological activities such as anti-tumor action. Angiogenesis inhibition is one of the mechanisms by which melatonin exerts its oncostatic effects. Increased angiogenesis is a major feature of tumor progression, thus angiogenesis inhibition is a critical step in cancer therapy. Melatonin employs a variety of mechanisms to target nutrients and oxygen supply to cancer cells. At the transcriptional level, hypoxia induced factor-1α (HIF-1α) and the genes under its control, such as vascular endothelial growth factor (VEGF) are the main targets of melatonin for inhibition of angiogenesis. Melatonin prevents translocation of HIF-1α into the nucleus thereby hindering VEGF expression and also prevents the formation of HIF-1α, phospho-STAT3 and CBP/p300 complex which is involved in the expression of angiogenesis-related genes. Angiostatic properties of melatonin could be also due to its ability to inhibit VEGFR2’s activation and expression. Other angiostatic mechanisms of melatonin include the inhibition of endothelial cell migration, invasion, and tube formation. In the present study, we have reviewed the molecular anti-angiogenesis pathways mediated by melatonin and the responsible mechanisms in various types of cancers both in vitro and in vivo.

      PubDate: 2017-10-08T11:22:08Z
      DOI: 10.1016/j.taap.2017.09.022
      Issue No: Vol. 335 (2017)
       
  • Sildenafil protects against bile duct ligation induced hepatic fibrosis in
           rats: Potential role for silent information regulator 1 (SIRT1)
    • Authors: Dalia M. Abd El Motteleb; Islam A.A.E.-H. Ibrahim; Shimaa M. Elshazly
      Abstract: Publication date: 15 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 335
      Author(s): Dalia M. Abd El Motteleb, Islam A.A.E.-H. Ibrahim, Shimaa M. Elshazly
      Hepatic fibrosis is a potential health problem that may end with life-threatening cirrhosis and primary liver cancer. Recent studies point out to the protective effects of silent information regulator1 (SIRT1), against different models of organs fibrosis. This work aimed to investigate the possible protective effect of sildenafil (SIRT1 activator) against hepatic fibrosis induced by bile duct ligation (BDL). Firstly, three different doses of sildenafil (5, 10, 20mg/kg/day) were investigated; to detect the most protective one against BDL induced liver dysfunction and hepatic fibrosis. The most protective dose is then used; to study its effect on BDL induced SIRT1 downregulation, imbalance of oxidant/antioxidant status, increased inflammatory cytokines and fibrosis. Sildenafil (20mg/kg/day) was the most protective one, it caused upregulation of SIRT1, reduction of hepatic malondialdehyde (MDA) content, increase in expression of nuclear factor erythroid 2-related factor 2 (Nrf2), hemeoxygenease (HO)-1, reduced glutathione (GSH) content and superoxide dismutase (SOD) activity. Hepatic content of tumor necrosis factor-α (TNF-α) and nuclear factor κB (NFκB) expression & content displayed significant reductions with sildenafil treatment, Furthermore, sildenafil caused marked reductions of transforming growth factor (TGF)-β content, expression of plasminogen activator inhibitor-1 (PAI-1), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), α-smooth muscle actin (α-SMA), fibronectin, collagen I (α1) and hydroxyproline content. However, sildenafil protective effects were significantly reduced by co-administration of EX527 (SIRT1 inhibitor). Our work showed, for the first time that, sildenafil has promising protective effects against BDL induced liver dysfunction and hepatic fibrosis. These effects may be, in part, mediated by up regulation of SIRT1.

      PubDate: 2017-10-08T11:22:08Z
      DOI: 10.1016/j.taap.2017.09.021
      Issue No: Vol. 335 (2017)
       
  • Inhalation exposure to three-dimensional printer emissions stimulates
           acute hypertension and microvascular dysfunction
    • Authors: A.B. Stefaniak; R.F. LeBouf; M.G. Duling; J. Yi; A.B. Abukabda; C.R. McBride; T.R. Nurkiewicz
      Pages: 1 - 5
      Abstract: Publication date: 15 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 335
      Author(s): A.B. Stefaniak, R.F. LeBouf, M.G. Duling, J. Yi, A.B. Abukabda, C.R. McBride, T.R. Nurkiewicz
      Fused deposition modeling (FDM™), or three-dimensional (3D) printing has become routine in industrial, occupational and domestic environments. We have recently reported that 3D printing emissions (3DPE) are complex mixtures, with a large ultrafine particulate matter component. Additionally, we and others have reported that inhalation of xenobiotic particles in this size range is associated with an array of cardiovascular dysfunctions. Sprague-Dawley rats were exposed to 3DPE aerosols via nose-only exposure for ~3h. Twenty-four hours later, intravital microscopy was performed to assess microvascular function in the spinotrapezius muscle. Endothelium-dependent and -independent arteriolar dilation were stimulated by local microiontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP). At the time of experiments, animals exposed to 3DPE inhalation presented with a mean arterial pressure of 125±4mmHg, and this was significantly higher than that for the sham-control group (94±3mmHg). Consistent with this pressor response in the 3DPE group, was an elevation of ~12% in resting arteriolar tone. Endothelium-dependent arteriolar dilation was significantly impaired after 3DPE inhalation across all iontophoretic ejection currents (0–27±15%, compared to sham-control: 15–120±21%). Endothelium-independent dilation was not affected by 3DPE inhalation. These alterations in peripheral microvascular resistance and reactivity are consistent with elevations in arterial pressure that follow 3DPE inhalation. Future studies must identify the specific toxicants generated by FDM™ that drive this acute pressor response.

      PubDate: 2017-09-30T10:53:07Z
      DOI: 10.1016/j.taap.2017.09.016
      Issue No: Vol. 335 (2017)
       
  • Cytogenetic effects of Jacareubin from Calophyllum brasiliense on human
           peripheral blood mononucleated cells in vitro and on mouse polychromatic
           erythrocytes in vivo
    • Authors: W.R. García-Niño; E. Estrada-Muñiz; M. Valverde; R. Reyes-Chilpa; L. Vega
      Pages: 6 - 15
      Abstract: Publication date: 15 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 335
      Author(s): W.R. García-Niño, E. Estrada-Muñiz, M. Valverde, R. Reyes-Chilpa, L. Vega
      Jacareubin is a xanthone isolated from the heartwood of Calophyllum brasiliense with antibacterial and gastroprotective properties and the intention for clinical use as an anti-cancer treatment (due to the similar chemical structure to other anti-neoplastic drugs) requires an investigation of whether this compound can generate adverse effects on non-transformed cells. Jacareubin (0.5–1000μM in DMSO) was more cytotoxic on phytohemagglutinin (PHA)-stimulated normal human peripheral blood mononuclear cells (PBMCs; IC50 at 72h by MTT: 85.9μM) than on G0 phase-PBMCs (IC50 315.6μM) using trypan blue exclusion and formazan metabolism assays. Jacareubin had lower toxicity on PBMCs than Taxol (1μM). Jacareubin presented cytostatic activity because it inhibited PHA-stimulated PBMCs proliferation (from 2.5μM; CFSE dilution and replication index). Jacareubin induced PBMCs arrest in G0/G1 phase of the cell cycle (from 5μM) as evaluated by DNA content. Moreover, Jacareubin generated genotoxicity by breaking DNA strands selectively in PHA-stimulated PBMCs (from 5μM) rather than on resting PBMCs using the single-cell gel electrophoresis assay and increasing the frequency of micronucleated (MN) PBMCs in vitro (from 5μM) and frequency of hypodiploid cells (from 10μM). When 100mg/kg Jacareubin was injected i.p. into mice (a fifth of the LD50; 0.548g/kg. Approximately to 300μM in vitro), we observe no increase in the MN level in bone marrow cells. Jacareubin can be consider for further anti-tumoural activity due to its preferential genotoxic, cytotoxic and cytostatic actions on proliferating cells rather than on resting cells and the lack of in vivo genotoxicity.

      PubDate: 2017-09-30T10:53:07Z
      DOI: 10.1016/j.taap.2017.09.018
      Issue No: Vol. 335 (2017)
       
  • Leptomycin B reduces primary and acquired resistance of gefitinib in lung
           cancer cells
    • Authors: Zhongwei Liu; Weimin Gao
      Pages: 16 - 27
      Abstract: Publication date: 15 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 335
      Author(s): Zhongwei Liu, Weimin Gao
      Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) gefitinib has demonstrated dramatic clinical efficacy in non-small cell lung cancer (NSCLC) patients. However, its therapeutic efficacy is ultimately limited by the development of acquired drug resistance. The aim of this study was to explore the potential utility of chromosome region maintenance 1 (CRM1) inhibitor leptomycin B (LMB) in combination with gefitinib to overcome primary and acquired gefitinib resistance in NSCLC cells. The combinative effects of gefitinib and LMB were evaluated by MTT and its underlining mechanism was assessed by flow cytometry and Western blot. LMB displayed a synergistic effect on gefitinib-induced cytotoxicity in A549 (IC50: 25.0±2.1μM of gefitinib+LMB vs. 32.0±2.5μM of gefitinib alone, p <0.05). Gefitinib+LMB caused a significantly different cell cycle distribution and signaling pathways involved in EGFR/survivin/p21 compared with gefitinib. A549 cells then were treated with progressively increased concentrations of gefitinib (A549GR) or in combination with LMB (A549GLR) over 10months to generate gefitinib resistance. IC50 of gefitinib in A549GLR (37.0±2.8μM) was significantly lower than that in A549GR (53.0±3.0μM, p <0.05), which indicates that LMB could reverse gefitinib-induced resistance in A549. Further mechanism investigation revealed that the expression patterns of EGFR pathway and epithelial-mesenchymal transition (EMT) markers in A549, A549GR, and A549GLR were significantly different. In conclusion, LMB at a very low concentration (0.5nM) combined with gefitinib showed synergistic therapeutic effects and ameliorated the development of gefitinib-induced resistance in lung cancer cells.
      Graphical abstract image

      PubDate: 2017-09-30T10:53:07Z
      DOI: 10.1016/j.taap.2017.09.017
      Issue No: Vol. 335 (2017)
       
  • Assessing molecular initiating events (MIEs), key events (KEs) and
           modulating factors (MFs) for styrene responses in mouse lungs using whole
           
    • Authors: Melvin E. Andersen; George Cruzan; Michael B. Black; Salil N. Pendse; Darol Dodd; James S. Bus; Satinder S. Sarang; Marcy I. Banton; Robbie Waites; Patrick D. McMullen
      Pages: 28 - 40
      Abstract: Publication date: 15 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 335
      Author(s): Melvin E. Andersen, George Cruzan, Michael B. Black, Salil N. Pendse, Darol Dodd, James S. Bus, Satinder S. Sarang, Marcy I. Banton, Robbie Waites, Patrick D. McMullen
      Styrene increased lung tumors in mice at chronic inhalation exposures of 20ppm and greater. MIEs, KEs and MFs were examined using gene expression in three strains of male mice (the parental C57BL/6 strain, a CYP2F2(−/−) knock out and a CYP2F2(−/−) transgenic containing human CYP2F1, 2A13 and 2B6). Exposures were for 1-day and 1, 4 and 26weeks. After 1-day exposures at 1, 5, 10, 20, 40 and 120ppm significant increases in differentially expressed genes (DEGs) occurred only in parental strain lungs where there was already an increase in DEGs at 5ppm and then many thousands of DEGs by 120ppm. Enrichment for 1-day and 1-week exposures included cell cycle, mitotic M-M/G1 phases, DNA-synthesis and metabolism of lipids and lipoproteins pathways. The numbers of DEGs decreased steadily over time with no DEGs meeting both statistical significance and fold-change criteria at 26weeks. At 4 and 26weeks, some key transcription factors (TFs) - Nr1d1, Nr1d2, Dbp, Tef, Hlf, Per3, Per2 and Bhlhe40 - were upregulated ( FC >1.5), while others - Npas, Arntl, Nfil3, Nr4a1, Nr4a2, and Nr4a3 - were down-regulated. At all times, consistent changes in gene expression only occurred in the parental strain. Our results support a MIE for styrene of direct mitogenicity from mouse-specific CYP2F2-mediated metabolites activating Nr4a signaling. Longer-term MFs include down-regulation of Nr4a genes and shifts in both circadian clock TFs and other TFs, linking circadian clock to cellular metabolism. We found no gene expression changes indicative of cytotoxicity or activation of p53-mediated DNA-damage pathways.

      PubDate: 2017-10-14T02:12:11Z
      DOI: 10.1016/j.taap.2017.09.015
      Issue No: Vol. 335 (2017)
       
  • Perfluorooctanoic acid exposure disturbs glucose metabolism in mouse liver
    • Authors: Fei Zheng; Nan Sheng; Hongxia Zhang; Shengmin Yan; Jianhai Zhang; Jianshe Wang
      Pages: 41 - 48
      Abstract: Publication date: 15 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 335
      Author(s): Fei Zheng, Nan Sheng, Hongxia Zhang, Shengmin Yan, Jianhai Zhang, Jianshe Wang
      Environmental pollutants such as perfluorooctanoic acid (PFOA) can influence human metabolism processes and are associated with certain metabolic diseases. To investigate the effect of PFOA on liver glucose homeostasis, adult male Balb/c mice were orally administered 1.25mg/kg of PFOA for 28d consecutively. Compared with the control mice, the body weights of the PFOA-treated mice were unchanged following exposure. However, PFOA exposure increased fasting blood glucose levels and decreased glycogen and glucose content in the liver of treated mice, but did not influence blood insulin significantly. The increased blood glucagon might contribute to the hyperglycemia observed in the PFOA-treated group compared with the control group. In addition, pyruvate tolerance tests supported enhanced glucose production ability in PFOA-exposed mice. Consistent with the increase in blood glucose and decrease in hepatic glucose and glycogen, PFOA exposure decreased the protein level of glycogen synthase in the mouse liver, but increased the level of glucokinase. Furthermore, liver pyruvate, as well as mRNA levels of enzymes involved in the Krebs cycle, such as citrate synthase, isocitrate dehydrogenase, and alpha-ketoglutarate dehydrogenase, increased in the PFOA-treated group. PFOA exposure did not affect muscle glucose or glycogen levels. Indirect calorimetry showed higher VO2 consumption and respiratory quotient values in the PFOA-treated group compared with the control group, implying that PFOA treatment might promote energy consumption in mice, with a reliance on carbohydrates as a primary source of energy. Thus, our findings indicate that subacute exposure to PFOA might enhance glycogenolysis and gluconeogenesis and promote carbohydrate consumption.

      PubDate: 2017-10-14T02:12:11Z
      DOI: 10.1016/j.taap.2017.09.019
      Issue No: Vol. 335 (2017)
       
  • Gut satiety hormones cholecystokinin and glucagon-like Peptide-17-36 amide
           mediate anorexia induction by trichothecenes T-2 toxin, HT-2 toxin,
           diacetoxyscirpenol and neosolaniol
    • Authors: Jie Zhang; Shengli Liu; Hua Zhang; Yuanyuan Li; Wenda Wu; Haibin Zhang
      Pages: 49 - 55
      Abstract: Publication date: 15 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 335
      Author(s): Jie Zhang, Shengli Liu, Hua Zhang, Yuanyuan Li, Wenda Wu, Haibin Zhang
      The food-borne trichothecene mycotoxins have been documented to cause human and animal food poisoning. Anorexia is a hallmark of the trichothecene mycotoxins-induced adverse effects. Type B trichothecenes have been previously demonstrated to elicit robust anorectic responses, and this response has been directly linked to secretion of the gut satiety hormones cholecystokinin (CCK) and glucagon-like peptide-17–36 amide (GLP-1). However, less is known about the anorectic effects and underlying mechanisms of the type A trichothecenes, including T-2 toxin (T-2), HT-2 toxin (HT-2), diacetoxyscirpenol (DAS), neosolaniol (NEO). The purpose of this study was to relate type A trichothecenes T-2, HT-2, DAS and NEO-induced anorectic response to changes plasma concentrations of CCK and GLP-1. Following both oral gavage and intraperitoneal (IP) administration of 1mg/kg bw T-2, HT-2, DAS and NEO evoked robust anorectic response and secretion of CCK and GLP-1. Elevations of plasma CCK markedly corresponded to anorexia induction by T-2, HT-2, DAS and NEO. Following oral exposure, plasma CCK was peaked at 6h, 6h, 2h, 2h and lasted up to 24h, 24h, > 6h, > 6h for T-2, HT-2, DAS and NEO, respectively. IP exposed to four toxins all induced elevation of CCK with peak point and duration at 6h and >24h, respectively. In contrast to CCK, GLP-1 was moderately elevated by these toxins. Following both oral and IP exposure, T-2 and HT-2 evoked plasma GLP-1 elevation with peak point and duration at 2h and 6h, respectively. Plasma GLP-1 was peaked at 2h and still increased at 6h for IP and oral administration with DAS and NEO, respectively. In conclusion, CCK plays a contributory role in anorexia induction but GLP-1 might play a lesser role in this response.

      PubDate: 2017-10-08T11:22:08Z
      DOI: 10.1016/j.taap.2017.09.020
      Issue No: Vol. 335 (2017)
       
  • Effects of diosmetin on nine cytochrome P450 isoforms, UGTs and three drug
           transporters in vitro
    • Authors: Jun-Jun Chen; Jing-Xian Zhang; Xiang-Qi Zhang; Mei-Juan Qi; Mei-Zhi Shi; Jiao Yang; Ke-Zhi Zhang; Cheng Guo; Yong-Long Han
      Pages: 1 - 7
      Abstract: Publication date: 1 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 334
      Author(s): Jun-Jun Chen, Jing-Xian Zhang, Xiang-Qi Zhang, Mei-Juan Qi, Mei-Zhi Shi, Jiao Yang, Ke-Zhi Zhang, Cheng Guo, Yong-Long Han
      Diosmetin (3′, 5, 7-trihydroxy-4′-methoxyflavone), a natural flavonoid from traditional Chinese herbs, has been used in various medicinal products because of its anticancer, antimicrobial, antioxidant, estrogenic and anti-inflammatory activity. However, flavonoids could affect the metabolic enzymes and cause drug-drug interactions (DDI), reducing the efficacy of co-administered drugs and potentially resulting in serious adverse reactions. To evaluate its potential to interact with co-administered drugs, the IC50 value of phase I cytochrome P450 enzymes (CYPs), phase II UDP-glucuronyltransferases (UGTs) and hepatic uptake transporters (organic cation transporters (OCTs), organic anion transporter polypeptides (OATPs) and Na+-taurocholate cotransporting polypeptides (NTCPs)) were examined in vitro by LC-MS/MS. Diosmetin showed strong inhibition of CYP1A2 in a concentration-dependent manner. The intensity of the inhibitory effect was followed by CYP2C8, CYP2C9, CYP2C19 and CYP2E1. For CYP2A6, CYP2B6, CYP2D6 and CYP3A4, diosmetin was found to have no significant inhibitory effects, and the induction effect on CYPs was not significant. For UGTs, diosmetin had a minimal inhibitory effect. In addition, the inhibitory effects of diosmetin on OATP and OCT1 were weak, and it had little effect on NTCP. This finding indicated that drug-drug interactions induced by diosmetin may occur through co-administration of drugs metabolized by CYP1A2.

      PubDate: 2017-09-11T20:05:04Z
      DOI: 10.1016/j.taap.2017.08.020
      Issue No: Vol. 334 (2017)
       
  • Neuromuscular paralysis by the basic phospholipase A2 subunit of crotoxin
           from Crotalus durissus terrificus snake venom needs its acid chaperone to
           concurrently inhibit acetylcholine release and produce muscle blockage
    • Authors: Walter L.G. Cavalcante; José B. Noronha-Matos; Maria A. Timóteo; Marcos R.M. Fontes; Márcia Gallacci; Paulo Correia-de-Sá
      Pages: 8 - 17
      Abstract: Publication date: 1 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 334
      Author(s): Walter L.G. Cavalcante, José B. Noronha-Matos, Maria A. Timóteo, Marcos R.M. Fontes, Márcia Gallacci, Paulo Correia-de-Sá
      Background and purpose Crotoxin (CTX), a heterodimeric phospholipase A2 (PLA2) neurotoxin from Crotalus durissus terrificus snake venom, promotes irreversible blockade of neuromuscular transmission. Indirect electrophysiological evidence suggests that CTX exerts a primary inhibitory action on transmitter exocytosis, yet contribution of a postsynaptic action of the toxin resulting from nicotinic receptor desensitization cannot be excluded. Here, we examined the blocking effect of CTX on nerve-evoked transmitter release measured directly using radioisotope neurochemistry and video microscopy with the FM4-64 fluorescent dye. Experimental approach Experiments were conducted using mice phrenic-diaphragm preparations. Real-time fluorescence video microscopy and liquid scintillation spectrometry techniques were used to detect transmitter exocytosis and nerve-evoked [3H]-acetylcholine ([3H]ACh) release, respectively. Nerve-evoked myographic recordings were also carried out for comparison purposes. Key results Both CTX (5μg/mL) and its basic PLA2 subunit (CB, 20μg/mL) had biphasic effects on nerve-evoked transmitter exocytosis characterized by a transient initial facilitation followed by a sustained decay. CTX and CB reduced nerve-evoked [3H]ACh release by 60% and 69%, respectively, but only the heterodimer, CTX, decreased the amplitude of nerve-evoked muscle twitches. Conclusion and implications Data show that CTX exerts a presynaptic inhibitory action on ACh release that is highly dependent on its intrinsic PLA2 activity. Given the high safety margin of the neuromuscular transmission, one may argue that the presynaptic block caused by the toxin is not enough to produce muscle paralysis unless a concurrent postsynaptic inhibitory action is also exerted by the CTX heterodimer.

      PubDate: 2017-09-11T20:05:04Z
      DOI: 10.1016/j.taap.2017.08.021
      Issue No: Vol. 334 (2017)
       
  • A cell impedance-based real-time in vitro assay to assess the toxicity of
           amphotericin B formulations
    • Authors: Jean Menotti; Alexandre Alanio; Aude Sturny-Leclère; Sandrine Vitry; Félix Sauvage; Gillian Barratt; Stéphane Bretagne
      Pages: 18 - 23
      Abstract: Publication date: 1 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 334
      Author(s): Jean Menotti, Alexandre Alanio, Aude Sturny-Leclère, Sandrine Vitry, Félix Sauvage, Gillian Barratt, Stéphane Bretagne
      Aerosolized liposomal amphotericin B (L-AmB) has been investigated as prophylaxis against invasive aspergillosis. However, the clinical results are controversial and some trials suggest that toxicity could be a limitation for wider use. Our aim was to assess the dynamics of cell toxicity induced in a human alveolar epithelial cell line (A549) after exposure to L-AmB (50 to 400μg/ml) or amphotericin B deoxycholate (D-AmB; 50 to 200μg/ml) by monitoring real-time A549 cell viability using an impedance-based technology. Results were expressed as cell index values integrating cell adhesion, proliferation, and survival. In parallel, the gene expression of proinflammatory cytokines was quantified at 6 and 24h after drug addition by real-time RT-PCR on cell lysates. No sustained reduction of cell indexes was observed with L-AmB or empty liposomes, even at 400μg/ml. Only the highest concentration tested of L-AmB (400μg/ml) yielded transient significant 6-fold and 4-fold induction of TNF-α and IL-8 mRNAs, respectively. In contrast, D-AmB induced a decrease in cell indexes and only the 50μg/ml concentration of D-AmB was followed by cell recovery, higher concentrations leading to cell death. Significant 4-fold, 7-fold and 3-fold inductions of TNF-α, IL-8 and IL-33 mRNAs were also observed at 6h with 50μg/ml of D-AmB. In conclusion, continuous cell impedance measurement showed no toxicity on overall cellular behavior although a slight proinflammatory cytokine expression is possible after L-AmB challenge. Real-time kinetics of cell impedance is an interesting tool for initial screening of cell toxicity.
      Graphical abstract image

      PubDate: 2017-09-11T20:05:04Z
      DOI: 10.1016/j.taap.2017.08.017
      Issue No: Vol. 334 (2017)
       
  • Comparative health effects in mice of Libby amphibole asbestos and a
           fibrous amphibole from Arizona
    • Authors: Jean C. Pfau; Brenda Buck; Rodney V. Metcalf; Zoie Kaupish; Caleb Stair; Maria Rodriguez; Deborah E. Keil
      Pages: 24 - 34
      Abstract: Publication date: 1 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 334
      Author(s): Jean C. Pfau, Brenda Buck, Rodney V. Metcalf, Zoie Kaupish, Caleb Stair, Maria Rodriguez, Deborah E. Keil
      This project developed from studies demonstrating that Libby Amphibole Asbestos (LAA) causes a non-typical set of health outcomes not generally reported for asbestos, including systemic autoimmunity and an unusual and devastating lamellar pleural thickening that progresses to severe pulmonary dysfunction and death. Further, mineral fiber mixtures with some similarities to LAA have recently been discovered in southern Nevada and northwestern Arizona, where the material exists in extensive recreational areas and is present in yards, roads, parking lots and school yards. The objective was to compare the health outcomes in mice exposed to either LAA or the fibrous amphiboles collected in Arizona at the Lake Mead National Recreational Area at very low doses to represent environmental exposures. In this study, the fibrous amphibole asbestos sample from Arizona (AzA) is composed of winchite (69%), actinolite (22%), and non-amphibole minerals (9%) and has a mean aspect ratio of 16.7±0.9. Fibrous amphibole asbestos from Libby (LAA) is composed of winchite (70%), richterite (9%), tremolite (5%), and non-amphibole minerals (16%) with a mean aspect ratio of 8.4±0.7. C57BL/6 mice were exposed by oropharyngeal aspiration to fiber suspensions at a very low dose of 3μg/mouse. After seven months, both LAA- and AzA-exposed mice had indices of chronic immune dysfunction related to a TH17 cytokine profile, with B cell activation, autoantibody production and proteinuria, suggesting kidney involvement. In addition, both exposures led to significant lung and pleural fibrosis. These data suggest that there is risk of pulmonary disease and autoimmune outcomes with environmental exposure to amphibole asbestos, and that this is not limited to Libby, Montana.

      PubDate: 2017-09-11T20:05:04Z
      DOI: 10.1016/j.taap.2017.08.022
      Issue No: Vol. 334 (2017)
       
  • Quinacrine induces the apoptosis of human leukemia U937 cells through
           FOXP3/miR-183/β-TrCP/SP1 axis-mediated BAX upregulation
    • Authors: Chia-Hui Huang; Yuan-Chin Lee; Ying-Jung Chen; Liang-Jun Wang; Yi-Jun Shi; Long-Sen Chang
      Pages: 35 - 46
      Abstract: Publication date: 1 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 334
      Author(s): Chia-Hui Huang, Yuan-Chin Lee, Ying-Jung Chen, Liang-Jun Wang, Yi-Jun Shi, Long-Sen Chang
      Quinacrine, which is clinically used as an antimalarial drug, has anti-cancer activity. However, mechanism underlying its cytotoxic effect remains to be completely elucidated. In the present study, we investigated the cytotoxic effect of quinacrine on human leukemia U937 cells. Quinacrine-induced apoptosis of U937 cells was accompanied with ROS generation, mitochondrial depolarization, and BAX upregulation. Quinacrine-treated U937 cells showed ROS-mediated p38 MAPK activation and ERK inactivation, which in turn upregulated FOXP3 transcription. FOXP3-mediated miR-183 expression decreased β-TrCP mRNA stability and suppressed β-TrCP-mediated SP1 degradation, thus increasing SP1 expression in U937 cells. Upregulated SP1 expression further increased BAX expression. BAX knock-down attenuated quinacrine-induced mitochondrial depolarization and increased the viability of quinacrine-treated cells. Together, our data indicate that quinacrine-induced apoptosis of U937 cells is mediated by mitochondrial alterations triggered by FOXP3/miR-183/β-TrCP/SP1 axis-mediated BAX upregulation.

      PubDate: 2017-09-11T20:05:04Z
      DOI: 10.1016/j.taap.2017.08.019
      Issue No: Vol. 334 (2017)
       
  • A two-step model of TiO2 nanoparticle toxicity in human liver tissue
    • Authors: T. Laomettachit; I.K. Puri; M. Liangruksa
      Pages: 47 - 54
      Abstract: Publication date: 1 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 334
      Author(s): T. Laomettachit, I.K. Puri, M. Liangruksa
      We examine the toxicity of titanium dioxide (TiO2) nanoparticles on human liver through a two-step approach, including a physiologically-based pharmacokinetic (PBPK) model and a cell-response model. The PBPK model predicts the bio-distribution of nanoparticles that remain in the human body after exposure, with special attention to their accumulation in liver tissue. The cell-response model predicts liver cell death as a consequence of the accumulated TiO2 nanoparticles by considering cell fate dynamics through the interplay between cellular uptake of the nanoparticles and their dilution due to cell division. The results suggest that tissue damage from a low nanoparticle dose is negligible due to renewal cell division, but for higher doses larger fractions of cells must participate in the cell cycle to recover the original tissue mass. By combining the two models, it becomes possible to explain the liver cell viability and cell death after TiO2 nanoparticle exposure.
      Graphical abstract image

      PubDate: 2017-09-30T10:53:07Z
      DOI: 10.1016/j.taap.2017.08.018
      Issue No: Vol. 334 (2017)
       
  • Prostacyclin mimetics afford protection against
           lipopolysaccharide/d-galactosamine-induced acute liver injury in mice
    • Authors: Hiroki Misawa; Wakana Ohashi; Kengo Tomita; Kohshi Hattori; Yutaka Shimada; Yuichi Hattori
      Pages: 55 - 65
      Abstract: Publication date: 1 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 334
      Author(s): Hiroki Misawa, Wakana Ohashi, Kengo Tomita, Kohshi Hattori, Yutaka Shimada, Yuichi Hattori
      Prostacyclin (PGI2) serves as a protective, anti-inflammatory mediator and PGI2 mimetics may be useful as a hepatoprotective agent. We examined whether two PGI2 mimetics, ONO-1301 and beraprost, are beneficial in acute liver injury and attempted to delineate the possible mechanism underlying the hepatoprotective effect. Acute liver injury was induced by lipopolysaccharide/d-galactosamine (LPS/GalN) in mice. Mice were given an intraperitoneal injection of PGI2 mimetics 1h before LPS/GalN challenge. Both ONO-1301 and beraprost significantly declined the LPS/GalN-induced increase in serum aminotransferase activity. ONO-1301 and, to a lesser extent, beraprost inhibited hepatic gene expression levels of pro-inflammatory cytokines, which were sharply elevated by LPS/GalN. The hepatoprotective effects of ONO-1301, to a lesser extent, of beraprost were also supported by liver histopathological examinations. The PGI2 receptor antagonist CAY10441 abrogated their hepatoprotective effects. The mechanisms behind the benefit of PGI2 mimetics in reducing LPS/GalN-induced liver injury involved, in part, their suppressive effects on increased generation of reactive oxygen species (ROS), since their ability to prevent LPS/GalN-induced hepatic apoptosis was mimicked by the antioxidant N-acetyl-l-cysteine. They significantly diminished LPS/GalN-induced activation of signal transducers and activators of transcription 3 (STAT3) in liver tissues, an effect which was highly associated with their hepatoprotective effects. We indicate that IP receptor activation with PGI2 mimetics can rescue the damage in the liver induced by LPS/GalN by undermining activation of STAT3 and leading to a lower production of ROS. Our findings point to PGI2 mimetics, especially ONO-1301, as a potential novel therapeutic modality for the treatment of acute liver injury.

      PubDate: 2017-09-30T10:53:07Z
      DOI: 10.1016/j.taap.2017.09.003
      Issue No: Vol. 334 (2017)
       
  • Gender-specific impairment of in vitro sinoatrial node chronotropic
           responses and of myocardial ischemia tolerance in rats exposed prenatally
           to betamethasone
    • Authors: L.R.A. Kiguti; C.S. Borges; A. Mueller; K.P. Silva; C.M. Polo; J.L. Rosa; P.V. Silva; G. Missassi; L. Valencise; W.G. Kempinas; A.S. Pupo
      Pages: 66 - 74
      Abstract: Publication date: 1 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 334
      Author(s): L.R.A. Kiguti, C.S. Borges, A. Mueller, K.P. Silva, C.M. Polo, J.L. Rosa, P.V. Silva, G. Missassi, L. Valencise, W.G. Kempinas, A.S. Pupo
      Excessive fetal glucocorticoid exposure has been linked to increased susceptibility to hypertension and cardiac diseases in the adult life, a process called fetal programming. The cardiac contribution to the hypertensive phenotype of glucocorticoid-programmed progeny is less known, therefore, we investigated in vitro cardiac functional parameters from rats exposed in utero to betamethasone. Pregnant Wistar rats received vehicle (VEH) or betamethasone (BET, 0.1mg/kg, i.m.) at gestational days 12, 13, 18 and 19. Male and female offspring were killed at post-natal day 30 and the right atrium (RA) was isolated to in vitro evaluation of drug-induced chronotropic responses. Additionally, whole hearts were retrograde-perfused in a Langendorff apparatus and infarct size in response to in vitro ischemia/reperfusion (I/R) protocol was evaluated. Male and female progeny from BET-exposed pregnant rats had reduced birth weight, a hallmark of fetal programming. Male BET-progeny had increased basal RA rate, impaired chronotropic responses to noradrenaline and adenosine, and increased myocardial damage to I/R. Though a 12-fold reduction in the negative chronotropic responses to adenosine, the effects of non-metabolisable adenosine receptor agonists 5′-(N-ethylcarboxamido)adenosine or 2-Chloro-adenosine were not different between VEH- and BET-exposed male rats. BET-exposed female offspring presented no cardiac dysfunction. Prenatal BET exposure engenders male-specific impairment of sinoatrial node function and on myocardial ischemia tolerance resulting, at least in part, from an increased adenosine metabolism in the heart. In light of the importance of adenosine in the cardiac physiology our results suggest a link between reduced adenosinergic signaling and the cardiac dysfunctions observed in glucocorticoid-induced fetal programming.
      Graphical abstract image

      PubDate: 2017-09-30T10:53:07Z
      DOI: 10.1016/j.taap.2017.09.002
      Issue No: Vol. 334 (2017)
       
  • Impaired autophagic flux and p62-mediated EMT are involved in
           arsenite-induced transformation of L-02 cells
    • Authors: Xinlu Liu; Min Ling; Chao Chen; Fei Luo; Ping Yang; Dapeng Wang; Xiong Chen; Hui Xu; Junchao Xue; Qianlei Yang; Lu Lu; Jiachun Lu; Qian Bian; Aihua Zhang; Qizhan Liu
      Pages: 75 - 87
      Abstract: Publication date: 1 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 334
      Author(s): Xinlu Liu, Min Ling, Chao Chen, Fei Luo, Ping Yang, Dapeng Wang, Xiong Chen, Hui Xu, Junchao Xue, Qianlei Yang, Lu Lu, Jiachun Lu, Qian Bian, Aihua Zhang, Qizhan Liu
      Autophagy is a catabolic process essential for preserving cellular homeostasis, and the epithelial-to-mesenchymal transition (EMT) is involved during tissue development and cancer progression. In arsenite-treated human hepatic epithelial (L-02) cells, arsenite reduced the autophagic flux, which caused accumulation of p62, an adaptor and receptor of autophagy. Further, in arsenite-transformed L-02 cells, the levels of E-cadherin were attenuated, but the levels of vimentin, which is expressed in mesenchymal cells, and Snail, a transcription regulator of the EMT, were up-regulated. Thus, after chronic exposure of L-02 cells to arsenite, the impaired autophagic flux induced the accumulation of p62, which up-regulated the expression of Snail, a protein involved in arsenite-induced EMT of these cells. Knockdown of p62 by siRNA reversed the arsenite-induced EMT and decreased the capacities of arsenite-transformed L-02 cells for colony formation and invasion and migration. Therefore, in arsenite-induced transformation of L-02 cells, the accumulation of p62, by impairing autophagic flux, mediates the EMT via Snail. These results provide a previously unknown mechanism underlying arsenic toxicity and carcinogenicity.

      PubDate: 2017-09-30T10:53:07Z
      DOI: 10.1016/j.taap.2017.09.004
      Issue No: Vol. 334 (2017)
       
  • Zinc chloride rapidly stimulates efflux transporters in renal proximal
           tubules of killifish (Fundulus heteroclitus)
    • Authors: Alexander Zaremba; David S. Miller; Gert Fricker
      Pages: 88 - 99
      Abstract: Publication date: 1 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 334
      Author(s): Alexander Zaremba, David S. Miller, Gert Fricker
      Multidrug resistance-related protein 2 (Mrp2) is an ATP-driven efflux pump at the luminal membrane in renal proximal tubules. It acts as detoxification mechanism by transporting xenobiotics and metabolic products into urine. The trace element zinc is essential for cellular growth, differentiation and survival. It modulates immune response and is used as dietary supplement. Here, we found that 0.1–10μM ZnCl2 rapidly stimulated transport of the Mrp2 probe substrate Texas Red (TR) in isolated killifish renal proximal tubules, which provide an established model system to measure efflux transporter activity by using fluorescent probe substrates, confocal microscopy and image analysis. This stimulation was insensitive to the translation inhibitor cycloheximide (CHX), but it was quickly reversed by removing ZnCl2 from the incubation medium. ZnCl2-induced transport stimulation was abolished by inhibitors and antagonists of the endothelin receptor type B (ETB)/nitric oxide synthase (NOS)/protein kinase C (PKC) pathway. Moreover, ZnCl2-induced effects were blocked by inhibition of PKCα using Gö6976 and PKCα inhibitor peptide C2-4. Both the phosphatidylinositol 3-kinase (PI3K) inhibitor LY 294002 and the mammalian target of rapamycin (mTOR) inhibitor rapamycin abolished ZnCl2-induced transport stimulation. Furthermore, the stimulating effects of ZnCl2 were blocked by GSK650394, an inhibitor of the downstream target serum- and glucocorticoid-inducible kinase 1 (SGK1). ZnCl2 also stimulated transport mediated by P-glycoprotein (P-gp) and Breast cancer resistance protein (Bcrp). This is the first report about zinc affecting efflux transporter activity and demonstrates that ZnCl2 triggers a suite of signaling events to evoke a rapid stimulation of ABC transporter-mediated efflux in killifish proximal tubules.

      PubDate: 2017-09-18T10:36:04Z
      DOI: 10.1016/j.taap.2017.09.001
      Issue No: Vol. 334 (2017)
       
  • Current nonclinical testing paradigm enables safe entry to First-In-Human
           clinical trials: The IQ consortium nonclinical to clinical translational
           database
    • Authors: Thomas M. Monticello; Thomas W. Jones; Donna M. Dambach; David M. Potter; Michael W. Bolt; Maggie Liu; Douglas A. Keller; Timothy K. Hart; Vivek J. Kadambi
      Pages: 100 - 109
      Abstract: Publication date: 1 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 334
      Author(s): Thomas M. Monticello, Thomas W. Jones, Donna M. Dambach, David M. Potter, Michael W. Bolt, Maggie Liu, Douglas A. Keller, Timothy K. Hart, Vivek J. Kadambi
      The contribution of animal testing in drug development has been widely debated and challenged. An industry-wide nonclinical to clinical translational database was created to determine how safety assessments in animal models translate to First-In-Human clinical risk. The blinded database was composed of 182 molecules and contained animal toxicology data coupled with clinical observations from phase I human studies. Animal and clinical data were categorized by organ system and correlations determined. The 2×2 contingency table (true positive, false positive, true negative, false negative) was used for statistical analysis. Sensitivity was 48% with a 43% positive predictive value (PPV). The nonhuman primate had the strongest performance in predicting adverse effects, especially for gastrointestinal and nervous system categories. When the same target organ was identified in both the rodent and nonrodent, the PPV increased. Specificity was 84% with an 86% negative predictive value (NPV). The beagle dog had the strongest performance in predicting an absence of clinical adverse effects. If no target organ toxicity was observed in either test species, the NPV increased. While nonclinical studies can demonstrate great value in the PPV for certain species and organ categories, the NPV was the stronger predictive performance measure across test species and target organs indicating that an absence of toxicity in animal studies strongly predicts a similar outcome in the clinic. These results support the current regulatory paradigm of animal testing in supporting safe entry to clinical trials and provide context for emerging alternate models.

      PubDate: 2017-09-18T10:36:04Z
      DOI: 10.1016/j.taap.2017.09.006
      Issue No: Vol. 334 (2017)
       
  • CYP4A/CYP2C modulation of the interaction of calcium channel blockers with
           cyclosporine on EDHF-mediated renal vasodilations in rats
    • Authors: Safaa H. Hammoud; Amal G. Omar; Assaad A. Eid; Mahmoud M. El-Mas
      Pages: 110 - 119
      Abstract: Publication date: 1 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 334
      Author(s): Safaa H. Hammoud, Amal G. Omar, Assaad A. Eid, Mahmoud M. El-Mas
      The endothelium-derived hyperpolarizing factor (EDHF) serves as a back-up mechanism that compensates for reduced nitric oxide (NO)/prostanoids bioavailability. Here we investigated whether (i) under conditions of vascular endothelium dysfunction, the immunosuppressant drug cyclosporine (CSA) upregulates EDHF-dependent renal vasodilations through altering CYP4A/CYP2C signaling, and (ii) calcium channel blockers modulate the CSA/EDHF/CYP interaction. Rats were treated with CSA, verapamil, nifedipine, or their combinations for 7days. Blood pressure (BP) was measured by tail-cuff plethysmography. Kidneys were then isolated, perfused with physiological solution containing L-NAME (NOS inhibitor) and diclofenac (cyclooxygenase inhibitor, DIC), and preconstricted with phenylephrine. CSA (25mgkg−1 day−1 for 7days) increased BP and augmented carbachol renal vasodilations. The co-treatment with verapamil (2mgkg−1 day−1) or nifedipine (3mgkg−1 day−1) abolished CSA hypertension and conversely affected carbachol vasodilations (increases vs. decreases). Infusion of MSPPOH (epoxyeicosatrienoic acids, EETs, inhibitor) reduced carbachol vasodilations in kidneys of all rat groups, suggesting the importance of EETs in these responses. By contrast, 20-Hydroxyeicosatetraenoic Acid (20-HETE) inhibition by HET0016 increased carbachol vasodilations in control rats, an effect that disappeared by CSA treatment, and reappeared in rats treated with CSA/verapamil or CSA/nifedipine. Renal protein expression of CYP2C and CYP4A as well as their vasoactive products (EETs/20-HETE) were increased in CSA-treated rats. Whereas the CYP2C/EETs effects of CSA were abolished by verapamil and intensified by nifedipine, the CYP4A/20-HETE effects were reduced by either CCB. Overall, nifedipine and verapamil blunts CSA hypertension but variably affected concomitantly enhanced EDHF-dependent renal vasodilations and alterations in CYP2C/CYP4A signaling.

      PubDate: 2017-09-18T10:36:04Z
      DOI: 10.1016/j.taap.2017.09.007
      Issue No: Vol. 334 (2017)
       
  • Effects of diisononyl phthalate on osteopenia in intact mice
    • Authors: Yun-Ho Hwang; Young-Jin Son; Man-Jeong Paik; Sung-Tae Yee
      Pages: 120 - 128
      Abstract: Publication date: 1 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 334
      Author(s): Yun-Ho Hwang, Young-Jin Son, Man-Jeong Paik, Sung-Tae Yee
      Osteopenia is characterized by bone loss and deterioration of trabecular bone, which leads to osteoporotic fractures. This disease is highly prevalent in industrialized areas and is associated with exposure to endocrine disrupting chemicals (EDCs). Diisononyl phthalate (DINP) is one of these EDCs and is mainly used as a plasticizer in flexible polyvinyl chloride (PVC) products. Although it is well known that exposure to DINP is harmful to humans, no studies have been reported concerning its contribution to osteopenia. Therefore, in this study, we injected DINP (2, 20, and 200mg/kg) into C3H/HeN mice for 6weeks and found that the uterus weight, bone (femur and tibia) weight, and bone length of the DINP-exposed mice were reduced compared to those of the SHAM group. On the other hand, body weight, the serum alkaline phosphatase (ALP) and inorganic phosphorus (IP) levels in the DINP treated mice were increased compared with those of the SHAM group. The tartrate-resistant acid phosphatase (TRAP) activity (bone resorption marker) was increased and the bone alkaline phosphatase (BALP) activity was lowered by the treatment with DINP as compared with the SHAM group. Furthermore, the microarchitecture of the femur and tibia in the intact mice was destroyed by the DINP injection. The tissue volume (TV), bone volume (BV), BV/TV, bone surface (BS), BS/TV, trabecular thickness (Tb.Th), and trabecular number (Tb.N) were reduced and the trabecular pattern factor (Tb.Pf), structure model index (SMI), and trabecular separation (Tb.Sp) were increased by the DINP injection. The bone mineral density (BMD) of the femur and tibia was lower in the DINP group than in the SHAM group. These results indicate that DINP contributes to an increased risk of osteopenia via destruction of the microarchitecture and enhancement of osteoclast activity.
      Graphical abstract image

      PubDate: 2017-09-18T10:36:04Z
      DOI: 10.1016/j.taap.2017.08.016
      Issue No: Vol. 334 (2017)
       
  • Nano-sized titanium dioxide toxicity in rat prostate and testis: Possible
           ameliorative effect of morin
    • Authors: Nancy N. Shahin; Maha M. Mohamed
      Pages: 129 - 141
      Abstract: Publication date: 1 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 334
      Author(s): Nancy N. Shahin, Maha M. Mohamed
      This study investigated the effect of short-term oral exposure to nano-sized titanium dioxide (nTiO2) on Wistar rat prostate and testis, and the associating reproductive-related alterations. The study also evaluated the potential ameliorative effect of the natural flavonoid, morin, on nTiO2-induced aberrations. Intragastric administration of nTiO2 (50mg/kg/day for 1, 2 and 3weeks) increased testicular gamma-glutamyltransferase (γ-GT) activity and decreased testicular steroidogenic acute regulatory protein (StAR) and c-kit gene expression, serum testosterone level and sperm count. nTiO2-treated rats also exhibited prostatic and testicular altered glutathione levels, elevated TNF-α levels, up-regulated Fas, Bax and caspase-3 gene expression, down-regulated Bcl-2 gene expression and enhanced prostatic lipid peroxidation. Sperm malformation and elevated testicular acid phosphatase (ACP) activity and malondialdehyde level, serum prostatic acid phosphatase activity, prostate specific antigen (PSA), gonadotrophin and estradiol levels occurred after the 2 and 3week regimens. Morin (30mg/kg/day administered intragastrically for 5weeks) mitigated nTiO2-induced prostatic and testicular injury as evidenced by lowering serum PSA level, testicular γ-GT and ACP activities and TNF-α level, along with hampering both intrinsic and extrinsic apoptotic pathways. Moreover, morin alleviated prostatic lipid peroxidation, raised prostatic glutathione level, and relieved testicular reductive stress. Additionally, morin increased testicular StAR and c-kit mRNA expression, raised the sperm count, reduced sperm deformities and modified the altered hormone profile. Histopathological evaluation supported the biochemical findings. In conclusion, morin could ameliorate nTiO2-induced prostatic and testicular injury and the corresponding reproductive-related aberrations via redox regulatory, anti-inflammatory and anti-apoptotic mechanisms, promoting steroidogenesis and spermatogenesis, and improving sperm count and morphology.

      PubDate: 2017-09-23T10:42:23Z
      DOI: 10.1016/j.taap.2017.08.014
      Issue No: Vol. 334 (2017)
       
  • Sex-specific effects of developmental lead exposure on the
           immune-neuroendocrine network
    • Authors: Jane Kasten-Jolly; David A. Lawrence
      Pages: 142 - 157
      Abstract: Publication date: 1 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 334
      Author(s): Jane Kasten-Jolly, David A. Lawrence
      The environmental toxicant lead (Pb) has long been known to induce neurological deficits. The 1st century Greek physician Pedanius Dioscorides noted that “lead makes the mind give way”. Current studies are suggesting the effects of Pb on behaviors may involve the immune system and conversely some immunomodulatory changes may be due to Pb effects in the central nervous system. Although Pb-induced disorders do not appear to discriminate among females and males, this report discusses the differences observed in human and animal studies regarding differential gender effects on gene expression after Pb exposure. The overall ill health outcomes are apparent with variant levels of Pb exposure and exposures at different times in development. However, the consensus is that doses leading to blood lead levels>5μg/dl and prenatal exposures are most pathogenic. Although the general detriments induced by Pb may be similar in females and males, there are sex specific outcomes on health and behavior. It is suggested that Pb induces more oxidative stress in females and more upregulation of genes responding to oxidative stress, while males have more proteolytic destruction; but in both cases, there is generation of altered/denatured self-constituents causing inflammation and loss of homeostasis of neuronal and immune functions. The higher estrogen levels of females are indicated as the reason for more Pb-induced reactive oxygen species in females. This review describes some of the different genes involved in female and male responses to Pb exposure and involved pathways.

      PubDate: 2017-09-23T10:42:23Z
      DOI: 10.1016/j.taap.2017.09.009
      Issue No: Vol. 334 (2017)
       
  • MK-801, but not naloxone, attenuates high-dose dextromethorphan-induced
           convulsive behavior: Possible involvement of the GluN2B receptor
    • Authors: Hai-Quyen Tran; Yoon Hee Chung; Eun-Joo Shin; The-Vinh Tran; Ji Hoon Jeong; Choon-Gon Jang; Seung-Yeol Nah; Kiyofumi Yamada; Toshitaka Nabeshima; Hyoung-Chun Kim
      Pages: 158 - 166
      Abstract: Publication date: 1 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 334
      Author(s): Hai-Quyen Tran, Yoon Hee Chung, Eun-Joo Shin, The-Vinh Tran, Ji Hoon Jeong, Choon-Gon Jang, Seung-Yeol Nah, Kiyofumi Yamada, Toshitaka Nabeshima, Hyoung-Chun Kim
      Dextromethorphan (DM) is a dextrorotatory isomer of levorphanol, a typical morphine-like opioid. When administered at supra-antitussive doses, DM produces psychotoxic and neurotoxic effects in humans. Although DM abuse has been well-documented, few studies have examined the effects of high-dose DM. The present study aimed to explore the effects of a single high dose of DM on mortality and seizure occurrence. After intraperitoneal administration with a high dose of DM (80mg/kg), Sprague–Dawley rats showed increased seizure occurrence and intensity. Hippocampal expression levels of N-methyl-d-aspartate (NMDA) receptor subunits (GluN1<GluN2A<GluN2B), c-Fos and pro-apoptotic factors (Bax and cleaved caspase-3) were upregulated by DM treatment; while levels of anti-apoptotic factors (Bcl-2 and Bcl-xL) were downregulated. Consistently, DM also induced ultrastructural degeneration in the hippocampus. A non-competitive NMDA receptor antagonist, MK-801, attenuated these effects of high-dose DM, whereas an opioid antagonist, naloxone, did not affect DM-induced neurotoxicity. Moreover, pretreatment with a highly specific GluN2B subunit inhibitor, traxoprodil, was selectively effective in preventing DM-induced c-Fos expression and apoptotic changes. These results suggest that high-dose DM produces convulsive behaviors by activating GluN2B/NMDA signaling that leads to pro-apoptotic changes.

      PubDate: 2017-09-23T10:42:23Z
      DOI: 10.1016/j.taap.2017.09.010
      Issue No: Vol. 334 (2017)
       
  • Novel oxolane derivative DMTD mitigates high glucose-induced erythrocyte
           apoptosis by regulating oxidative stress
    • Authors: Swamy Jagadish; Mahadevappa Hemshekhar; Somanathapura K. NaveenKumar; Kothanahally S. Sharath Kumar; Mahalingam S. Sundaram; Basappa; Kesturu S. Girish; Kanchugarakoppal S. Rangappa
      Pages: 167 - 179
      Abstract: Publication date: 1 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 334
      Author(s): Swamy Jagadish, Mahadevappa Hemshekhar, Somanathapura K. NaveenKumar, Kothanahally S. Sharath Kumar, Mahalingam S. Sundaram, Basappa, Kesturu S. Girish, Kanchugarakoppal S. Rangappa
      Chronic hyperglycemia is one of the characteristic conditions associated with Diabetes Mellitus (DM), which often exerts deleterious effects on erythrocyte morphology and hemodynamic properties leading to anemia and diabetes-associated vascular complications. High glucose-induced over production of reactive oxygen species (ROS) can alter the blood cell metabolism and biochemical functions subsequently causing eryptosis (red blood cell death), yet another complication of concern in DM. Therefore, blocking high glucose-induced oxidative damage and subsequent eryptosis is of high importance in the better management of DM and associated vascular complications. In this study, we synthesized an oxolane derivative 1-(2,2-dimethyltetrahydrofuro[2,3][1,3]dioxol-5-yl)ethane-1,2-diol (DMTD), and demonstrated its efficacy to mitigate hyperglycemia-induced ROS generation and subsequent eryptosis. We showed that DMTD effectively inhibits high glucose-induced ROS generation, intracellular calcium levels, phosphaditylserine (PS) scrambling, calpain and band 3 activation, LDH leakage, protein glycation and lipid peroxidation, meanwhile enhances the antioxidant indices, osmotic fragility and Na+/K+-ATPase activity in erythrocytes. DMTD dose dependently decreased the glycated hemoglobin level and enhances the glucose utilization by erythrocytes in vitro. Further, DMTD alleviated the increase in ROS production, intracellular Ca2+ level and PS externalization in the erythrocytes of human diabetic subjects and enhanced the Na+/K+-ATPase activity. Taken together, the synthesized oxolane derivative DMTD could be a novel synthetic inhibitor of high glucose-induced oxidative stress and eryptosis. Considering the present results DMTD could be a potential therapeutic to treat DM and associated complications and open new avenues in developing synthetic therapeutic targeting of DM-associated complications.
      Graphical abstract image

      PubDate: 2017-09-23T10:42:23Z
      DOI: 10.1016/j.taap.2017.09.008
      Issue No: Vol. 334 (2017)
       
  • HZ-6d targeted HERC5 to regulate p53 ISGylation in human hepatocellular
           carcinoma
    • Authors: Yang Wang; Qi Ding; Tao Xu; Chang-yao Li; Dan-dan Zhou; Lei Zhang
      Pages: 180 - 191
      Abstract: Publication date: 1 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 334
      Author(s): Yang Wang, Qi Ding, Tao Xu, Chang-yao Li, Dan-dan Zhou, Lei Zhang
      Manipulating the posttranslational modulator of p53 is central in the regulation of its activity and function. ISGylated p53 can be degraded by the 20S proteasome. During this process, HERC5/Ceb1, an IFN-induced HECT-type E3 ligase, mediated p53 ISGylation. In this study, we indicated that HERC5 was over-expressed in both HCC tissue samples and cell lines. Knockdown of HERC5 significantly induced the expression of p53, p21 and Bax/Bcl-2 in HCC cells, resulting in apoptosis augment. Whereas, opposite results were obtained by using HERC5 over-expression. On this basis, we screened a 7, 11-disubstituted quinazoline derivative HZ-6d that could bind to the HERC5 G-rich sequence in vitro. Interestingly, HZ-6d injection effectively delayed the growth of xenografts in nude mice. In vitro, HZ-6d significantly inhibited cell growth, suppressed cell migration, induced apoptosis in HCC cells. Further studies demonstrated the anti-cancer effect of HZ-6d was associated with down-regulation of HERC5 and accumulation of p53. Collectively, we demonstrated that HZ6d is a HERC5 G-quadruplex ligand with anti-tumor properties, an action that may offer an attractive idea for restoration of p53 function in cancers.

      PubDate: 2017-09-23T10:42:23Z
      DOI: 10.1016/j.taap.2017.09.011
      Issue No: Vol. 334 (2017)
       
  • A dioxin-like compound induces hyperplasia and branching morphogenesis in
           mouse mammary gland, through alterations in TGF-β1 and aryl hydrocarbon
           receptor signaling
    • Authors: Noelia Miret; Eva Rico-Leo; Carolina Pontillo; Elsa Zotta; Pedro Fernández-Salguero; Andrea Randi
      Pages: 192 - 206
      Abstract: Publication date: 1 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 334
      Author(s): Noelia Miret, Eva Rico-Leo, Carolina Pontillo, Elsa Zotta, Pedro Fernández-Salguero, Andrea Randi
      Hexachlorobenzene (HCB) is a widespread environmental pollutant and a dioxin-like compound that binds weakly to the aryl hydrocarbon receptor (AhR). Because AhR and transforming growth factor β1 (TGF-β1) converge to regulate common signaling pathways, alterations in this crosstalk might contribute to developing preneoplastic lesions. The aim of this study was to evaluate HCB action on TGF-β1 and AhR signaling in mouse mammary gland, through AhR+/+ and AhR−/− models. Results showed a differential effect in mouse mammary epithelial cells (NMuMG), depending on the dose: 0.05μM HCB induced cell migration and TGF-β1 signaling, whereas 5μM HCB reduced cell migration, promoted cell cycle arrest and stimulated the dioxin response element (DRE) -dependent pathway. HCB (5μM) enhanced α-smooth muscle actin expression and decreased TGF-β receptor II mRNA levels in immortalized mouse mammary fibroblasts AhR+/+, resembling the phenotype of transformed cells. Accordingly, their conditioned medium was able to enhance NMuMG cell migration. Assays in C57/Bl6 mice showed HCB (3mg/kg body weight) to enhance ductal hyperplasia, cell proliferation, estrogen receptor α nuclear localization, branch density, and the number of terminal end buds in mammary gland from AhR+/+ mice. Primary culture of mammary epithelial cells from AhR+/+ mice showed reduced AhR mRNA levels after HCB exposure (0.05 and 5μM). Interestingly, AhR−/− mice exhibited an increase in ductal hyperplasia and mammary growth in the absence of HCB treatment, thus revealing the importance of AhR in mammary development. Our findings show that environmental HCB concentrations modulate AhR and TGF-β1 signaling, which could contribute to altered mammary branching morphogenesis, likely leading to preneoplastic lesions and retaining terminal end buds.

      PubDate: 2017-09-23T10:42:23Z
      DOI: 10.1016/j.taap.2017.09.012
      Issue No: Vol. 334 (2017)
       
  • Downregulation of UBE2E2 in rat liver cells after hepatocarcinogen
           treatment facilitates cell proliferation and slowing down of DNA damage
           response in GST-P-expressing preneoplastic lesions
    • Authors: Sayaka Mizukami; Yousuke Watanabe; Yukie Saegusa; Kota Nakajima; Yuko Ito; Yasunori Masubuchi; Toshinori Yoshida; Makoto Shibutani
      Pages: 207 - 216
      Abstract: Publication date: 1 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 334
      Author(s): Sayaka Mizukami, Yousuke Watanabe, Yukie Saegusa, Kota Nakajima, Yuko Ito, Yasunori Masubuchi, Toshinori Yoshida, Makoto Shibutani
      We previously found downregulation of ubiquitin-conjugating enzyme E2E 2 (UBE2E2) in GST-P-positive (+) proliferative lesions produced by tumor promotion from early hepatocarcinogenesis stages in rats. Here we investigated the role of UBE2E2 downregulation in preneoplastic lesions of the liver and other target organs produced by tumor promotion in rats. Increased number of UBE2E2-related ubiquitination target proteins, phosphorylated c-MYC, KDM4A and KMT5A, was found in the UBE2E2-downregulated GST-P+ foci, compared with GST-P+ foci expressing UBE2E2. However, p21WAF1/CIP1, another UBE2E2 target protein, did not increase in the positive cells. Furthermore, the numbers of PCNA+ cells and γH2AX+ cells were increased in UBE2E2-downregulated foci. These results suggest sustained activation of c-MYC and stabilization of KMT5A to result in c-MYC-mediated transcript upregulation and following KMT5A-mediated protein stabilization of PCNA in GST-P+ foci, as well as KDM4A stabilization resulting in slowing down of DNA damage response in these lesions. Similar results were also observed in GST-P+ foci produced by repeated treatment of rats with a hepatocarcinogen, thioacetamide, for 90days. Hepatocarcinogen treatment for 28 or 90days also increased the numbers of liver cells expressing UBE2E2-related ubiquitination target proteins, as well as PCNA+ or γH2AX+ cells. Conversely, UBE2E2 downregulation was lacking in PPARα agonist-induced hepatocarcinogenesis, as well as in carcinogenic processes targeting other organs, suggestive of the loss of UBE2E2-related ubiquitination limited to hepatocarcinogenesis producing GST-P+ proliferative lesions. Our results suggest that repeated hepatocarcinogen treatment of rats causes stabilization of UBE2E2-related ubiquitination target proteins in liver cells to promote carcinogenesis.

      PubDate: 2017-09-23T10:42:23Z
      DOI: 10.1016/j.taap.2017.09.005
      Issue No: Vol. 334 (2017)
       
  • DMARD use is associated with a higher risk of dementia in patients with
           rheumatoid arthritis: A propensity score-matched case–control study
    • Authors: Ming-Hsien Chou; Jong-Yi Wang; Cheng-Li Lin; Wei-Sheng Chung
      Pages: 217 - 222
      Abstract: Publication date: 1 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 334
      Author(s): Ming-Hsien Chou, Jong-Yi Wang, Cheng-Li Lin, Wei-Sheng Chung
      Background Patients with rheumatoid arthritis (RA) exhibit an increased risk of dementia. Disease-modifying antirheumatic drugs (DMARDs) are commonly used to slow RA progression, but studies investigating the relationship between DMARDs and dementia in patients with RA are lacking. We investigated the relationship between DMARDs and dementia in patients with RA. Methods Using the National Health Insurance Research Database, patients aged ≥20years, who were newly diagnosed with RA between 2000 and 2011 were identified. Patients with RA who had dementia comprised the dementia group, and patients with RA who did not have dementia comprised the control group. The groups were matched at a 1:1 ratio by the propensity score. DMARDs were categorized into conventional synthetic DMARDs (csDMARDs) and biological DMARDs (bDMARDs). Logistic regression models were used to calculate the odds ratio and 95% confidence interval (CI) to evaluate the association between DMARD use and the risk of dementia in patients with RA. Results A total of 957 patients with RA and dementia, and 957 patients with RA but not dementia, were enrolled. The risk of dementia was determined to be 1.63-fold higher in patients with RA with csDMARD use than in those without csDMARD use (95% CI=1.33–2.00). No significant risk of dementia was observed in patients with RA who used bDMARDs compared with their counterparts. However, patients with RA who used hydroxychloroquine, methotrexate, and sulfasalazine exhibited significant risks of dementia, irrespective of cumulative exposure days. Conclusion Patients with RA who used csDMARDs exhibit significant association with dementia.

      PubDate: 2017-09-30T10:53:07Z
      DOI: 10.1016/j.taap.2017.09.014
      Issue No: Vol. 334 (2017)
       
  • High doses of baicalin induces kidney injury and fibrosis through
           regulating TGF-β/Smad signaling pathway
    • Authors: Yi Cai; Wanqing Ma; Yichuan Xiao; Bo Wu; Xiaobing Li; Fengrong Liu; Jianhua Qiu; Genshui Zhang
      Pages: 1 - 9
      Abstract: Publication date: 15 October 2017
      Source:Toxicology and Applied Pharmacology, Volume 333
      Author(s): Yi Cai, Wanqing Ma, Yichuan Xiao, Bo Wu, Xiaobing Li, Fengrong Liu, Jianhua Qiu, Genshui Zhang
      Baicalin is a major flavonoid compound purified from Scutellariae radix, which has been described as an herb in the Chinese Pharmacopoeia. Previous studies have suggested baicalin possessed extensive anti-inflammatory, anti-cancer, anti-viral properties. However, up to known, there have been no reports of safety and toxicity in the rats following oral administration of baicalin. In this present study, we showed the first evidence that treatment of baicalin (400, 800 and 1600mg/kg/day) induced significantly kidney injury and fibrosis. The collagen synthesis and fibrosis-related protein expression were increased in the kidney of Sprague-Dawley (SD) rats after treatment with high doses of baicalin. We further investigated the potential molecular mechanism of baicalin-mediated renal fibrosis and revealed that baicalin activated the transforming growth factor-β (TGF-β)/Smad signaling pathway in a dose-dependent manner. Moreover, we also observed that baicalin induced Smad3 interaction with transcriptional coactivator p300 accompanying with increment of Smad3 acetylation. Our results may contribute to better understanding of the future pharmacological and toxicological studies of Scutellaria baicalensis Georgi and its active compounds on the human disease.
      Graphical abstract image

      PubDate: 2017-08-26T19:46:24Z
      DOI: 10.1016/j.taap.2017.08.003
      Issue No: Vol. 333 (2017)
       
  • Effects of 2,2′,4,4′-tetrabromodiphenyl ether on neurobehavior and
           memory change and bcl-2, c-fos, grin1b and lingo1b gene expression in male
           zebrafish (Danio rerio)
    • Authors: Shukai Zheng; Caixia Liu; Yanhong Huang; Mian Bao; Yuanni Huang; Kusheng Wu
      Pages: 10 - 16
      Abstract: Publication date: 15 October 2017
      Source:Toxicology and Applied Pharmacology, Volume 333
      Author(s): Shukai Zheng, Caixia Liu, Yanhong Huang, Mian Bao, Yuanni Huang, Kusheng Wu
      Polybrominated diphenyl ethers (PBDEs) are persistent organic pollutants in various environmental matrices and organisms and pose a threat to neural systems of organisms. However, though quite a few studies have explored the effect of PBDEs on neural behaviors such as learning and memory abilities in animals, their mechanisms are less known. We used the zebrafish model to evaluate neurotoxicity of PBDEs and observe changes in behavior and related gene expression. In behavioral testing, 50 zebrafish were divided into five groups treated with different concentrations of BDE-47. T-maze exploration was used for learning and memory testing, which was recorded by camera every 7days. After 21days, all fish were killed, and the gene expression of c-fos, bcl-2, lingo1b and grin1b in brain tissue was analyzed by RT-qPCR. The behavioral changes (latency to leave the start zone, reach the reward zone, and stay in the reward zone; accuracy in choosing the right maze arm, accumulation of freezing bouts, etc.) were related to BDE-47 concentration and had a time–effect relation with increasing exposure days, especially with 500μg/L BDE-47. BDE-47 elevated brain bcl-2, grin1b and lingo1b expression. The expression of c-fos showed an increase with 50 and 100μg/L BDE-47 exposure. The PBDE BDE-47 had a negative impact on the neurobehaviors of zebrafish and affected the expression of c-fos, bcl-2, lingo1b and grin1b in zebrafish brain tissue.
      Graphical abstract image

      PubDate: 2017-08-26T19:46:24Z
      DOI: 10.1016/j.taap.2017.08.004
      Issue No: Vol. 333 (2017)
       
  • Effects of low-dose irradiation on mice with Escherichia coli-induced
           sepsis
    • Authors: Kyung-Hee Song; Seung-Youn Jung; Seong-Ho Kho; Sang-Gu Hwang; Hunjoo Ha; Seon Young Nam; Jie-Young Song
      Pages: 17 - 25
      Abstract: Publication date: 15 October 2017
      Source:Toxicology and Applied Pharmacology, Volume 333
      Author(s): Kyung-Hee Song, Seung-Youn Jung, Seong-Ho Kho, Sang-Gu Hwang, Hunjoo Ha, Seon Young Nam, Jie-Young Song
      Although favorable immune responses to low-dose irradiation (LDI) have been observed in normal mice, i.e., a hormesis effect, little is known about the effects of LDI in infectious diseases. In this study, we examined the effects of LDI on mice with sepsis, a severe and often lethal hyperinflammatory response to bacteria. Female C57BL/6 mice were whole-body irradiated with 10cGy 48h before Escherichia coli infection, and survival, bacterial clearance, cytokines, and antioxidants were quantified. LDI pretreatment significantly increased survival from 46.7% in control mice to 75% in mice with sepsis. The bacterial burden was significantly lower in the blood, spleen, and kidney of LDI-treated mice than in those of control septic mice. The levels of pro-inflammatory cytokines, e.g., IL-1β and IL-6, as well as anti-inflammatory IL-10 were markedly reduced in pre-LDI septic mice. Nitric oxide production by peritoneal macrophages was also reduced in pre-LDI septic mice. Immune cells in the spleen increased and Nrf2 and HO-1 were induced in pre-LDI septic mice. LDI stimulates the immune response and minimizes lethality in septic mice via enhanced bacterial clearance and reduced initial proinflammatory responses.
      Graphical abstract image

      PubDate: 2017-08-26T19:46:24Z
      DOI: 10.1016/j.taap.2017.08.008
      Issue No: Vol. 333 (2017)
       
  • DHEA increases epithelial markers and decreases mesenchymal proteins in
           breast cancer cells and reduces xenograft growth
    • Authors: Zaira Colín-Val; Viridiana Yazmín González-Puertos; Criselda Mendoza-Milla; Erika Olivia Gómez; Claudia Huesca-Gómez; Rebeca López-Marure
      Pages: 26 - 34
      Abstract: Publication date: 15 October 2017
      Source:Toxicology and Applied Pharmacology, Volume 333
      Author(s): Zaira Colín-Val, Viridiana Yazmín González-Puertos, Criselda Mendoza-Milla, Erika Olivia Gómez, Claudia Huesca-Gómez, Rebeca López-Marure
      Breast cancer is one of the most common neoplasias and the leading cause of cancer death in women worldwide. Its high mortality rate is linked to a great metastatic capacity associated with the epithelial-mesenchymal transition (EMT). During this process, a decrease in epithelial proteins expression and an increase of mesenchymal proteins are observed. On the other hand, it has been shown that dehydroepiandrosterone (DHEA), the most abundant steroid in human plasma, inhibits migration of breast cancer cells; however, the underlying mechanisms have not been elucidated. In this study, the in vitro effect of DHEA on the expression pattern of some EMT-related proteins, such as E-cadherin (epithelial), N-cadherin, vimentin and Snail (mesenchymal) was measured by Western blot and immunofluorescence in MDA-MB-231 breast cancer cells with invasive, metastatic and mesenchymal phenotype. Also, the in vivo effect of DHEA on xenograft tumor growth in nude mice (nu−/nu−) and on expression of the same epithelial and mesenchymal proteins in generated tumors was evaluated. We found that DHEA increased expression of E-cadherin and decreased N-cadherin, vimentin and Snail expression both in MD-MB-231 cells and in the formed tumors, possibly by DHEA-induced reversion of mesenchymal phenotype. These results were correlated with a tumor size reduction in mouse xenografts following DHEA administration either a week earlier or concurrent with breast cancer cells inoculation. In conclusion, DHEA could be useful in the treatment of breast cancer with mesenchymal phenotype.

      PubDate: 2017-08-26T19:46:24Z
      DOI: 10.1016/j.taap.2017.08.002
      Issue No: Vol. 333 (2017)
       
  • Integrative analysis of hepatic microRNA and mRNA to identify potential
           biological pathways associated with monocrotaline-induced liver injury in
           mice
    • Authors: Zhenlin Huang; Minwei Chen; Jiaqi Zhang; Yuchen Sheng; Lili Ji
      Pages: 35 - 42
      Abstract: Publication date: 15 October 2017
      Source:Toxicology and Applied Pharmacology, Volume 333
      Author(s): Zhenlin Huang, Minwei Chen, Jiaqi Zhang, Yuchen Sheng, Lili Ji
      Pyrrolizidine alkaloids (PAs) are a type of natural hepatotoxic compounds. Monocrotaline (MCT), belongs to PAs, is a main compound distributed in medicinal herb Crotalaria ferruginea Grah. ex Benth. This study aims to identify the potential biological signaling pathway associated with MCT-induced liver injury by analyzing the integrative altered hepatic microRNA (miRNA) and mRNA expression profile. C57BL/6 mice were orally given with MCT (270, 330mg/kg). Serum alanine/aspartate aminotransferase (ALT/AST) activity, total bilirubin (TBil) amount and liver histological evaluation showed the liver injury induced by MCT. Results of miRNA chip analysis showed that the hepatic expression of 15 miRNAs (whose signal intensity>200) was significantly altered in MCT-treated mice, and among them total 11 miRNAs passed further validation by using Real-time PCR assay. Results of mRNA chip analysis demonstrated that the hepatic expression of 569 genes was up-regulated and of other 417 genes was down-regulated in MCT-treated mice. There are total 426 predicted target genes of those above altered 11 miRNAs, and among them total 10 genes were also altered in mice treated with both MCT (270mg/kg) and MCT (330mg/kg) from the results of mRNA chip. Among these above 10 genes, total 8 genes passed further validation by using Real-time PCR assay. Only 1 biological signaling pathway was annotated by using those above 8 genes, which is phagosome. In conclusion, this study demonstrated the integrative altered expression profile of liver miRNA and mRNA, and identified that innate immunity may be critically involved in MCT-induced liver injury in mice.

      PubDate: 2017-08-26T19:46:24Z
      DOI: 10.1016/j.taap.2017.08.007
      Issue No: Vol. 333 (2017)
       
  • SGLT2-inhibitor and DPP-4 inhibitor improve brain function via attenuating
           mitochondrial dysfunction, insulin resistance, inflammation, and apoptosis
           in HFD-induced obese rats
    • Authors: Piangkwan Sa-nguanmoo; Pongpan Tanajak; Sasiwan Kerdphoo; Thidarat Jaiwongkam; Wasana Pratchayasakul; Nipon Chattipakorn; Siriporn C. Chattipakorn
      Pages: 43 - 50
      Abstract: Publication date: 15 October 2017
      Source:Toxicology and Applied Pharmacology, Volume 333
      Author(s): Piangkwan Sa-nguanmoo, Pongpan Tanajak, Sasiwan Kerdphoo, Thidarat Jaiwongkam, Wasana Pratchayasakul, Nipon Chattipakorn, Siriporn C. Chattipakorn
      Dipeptidyl peptidase-4 inhibitor (vildagliptin) has been shown to exert beneficial effects on insulin sensitivity and neuroprotection in obese-insulin resistance. Recent studies demonstrated the neuroprotection of the sodium-glucose co-transporter 2 inhibitor (dapagliflozin) in diabetes. However, the comparative effects of both drugs and a combination of two drugs on metabolic dysfunction and brain dysfunction impaired by the obese-insulin resistance have never been investigated. Forty male Wistar rats were divided into two groups, and received either a normal-diet (ND, n=8) or a high-fat diet (HFD, n=32) for 16weeks. At week 13, the HFD-fed rats were divided into four subgroups (n=8/subgroup) to receive either a vehicle, vildagliptin (3mg/kg/day) dapagliflozin (1mg/kg/day) or combined drugs for four weeks. ND rats were given a vehicle for four weeks. Metabolic parameters and brain function were investigated. The results demonstrated that HFD rats developed obese-insulin resistance and cognitive decline. Dapagliflozin had greater efficacy on improved peripheral insulin sensitivity and reduced weight gain than vildagliptin. Single therapy resulted in equally improved brain mitochondrial function, insulin signaling, apoptosis and prevented cognitive decline. However, only dapagliflozin improved hippocampal synaptic plasticity. A combination of the drugs had greater efficacy in improving brain insulin sensitivity and reducing brain oxidative stress than the single drug therapy. These findings suggested that dapagliflozin and vildagliptin equally prevented cognitive decline in the obese-insulin resistance, possibly through some similar mechanisms. Dapagliflozin had greater efficacy than vildagliptin for preserving synaptic plasticity, thus combined drugs could be the best therapeutic approach for neuroprotection in the obese-insulin resistance.

      PubDate: 2017-08-26T19:46:24Z
      DOI: 10.1016/j.taap.2017.08.005
      Issue No: Vol. 333 (2017)
       
  • Staphylococcal enterotoxin C2 mutant drives T lymphocyte activation
           through PI3K/mTOR and NF-ĸB signaling pathways
    • Authors: Xuanhe Fu; Mingkai Xu; Songyuan Yao; Huiwen Zhang; Chenggang Zhang; Jinghai Zhang
      Pages: 51 - 59
      Abstract: Publication date: 15 October 2017
      Source:Toxicology and Applied Pharmacology, Volume 333
      Author(s): Xuanhe Fu, Mingkai Xu, Songyuan Yao, Huiwen Zhang, Chenggang Zhang, Jinghai Zhang
      Staphylococcal enterotoxin C2 (SEC2), a superantigen, causes rapid clonal expansion of lymphocytes and secretion of T cell growth factors, leading to a severe inflammatory response within tissues. Although previous studies have shown that ST-4, a SEC2 mutant with enhanced recognition of Vβ regions of T-cell receptors (TCRVβ), can activate an increased number of T cells and produce more cytokines than SEC2. However, the signaling mechanisms of SEC2/ST-4-mediated immune activation have not been addressed. In this study, we showed that the phosphatidylinositide-3-kinase (PI-3K) inhibitor LY294002, mammalian target of rapamycin (mTOR) inhibitor rapamycin, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inhibitor Bay11-7085 could suppress SEC2/ST-4-induced proliferation, CD69/CD25 expression, cell-cycle progression, and IL-2 production in BALB/c mouse splenocytes. In addition, we observed significantly upregulated expression of p70S6K, cyclin E, cyclin D3, and NF-ĸB/p65, but downregulated expression of p27kip during SEC2/ST-4-driven T cells activation. However, SEC2/ST-4-induced changes in cell cycle and PI3K/mTOR signaling were significantly relieved by either LY294002 or rapamycin, and the induction of NF-ĸB/p65 induced was significantly downregulated by Bay11-7085. Moreover, we found that IL-2 secretion was positively associated with p65 expression in a time- and dose-dependent manner. Taken together, our findings demonstrate the involvement of PI3K/mTOR and NF-κB signaling pathways in SEC2/ST-4-induced T cell activation. ST-4 intensifies PI3K/mTOR and NF-ĸB signaling transduction, ultimately leading to enhance T cell activation. These results provide a theoretical mechanism for future immunotherapy using ST-4.
      Graphical abstract image

      PubDate: 2017-08-26T19:46:24Z
      DOI: 10.1016/j.taap.2017.08.006
      Issue No: Vol. 333 (2017)
       
  • Effect of low-dose zearalenone exposure on reproductive capacity of male
           mice
    • Authors: Jian Pang; Qingsong Zhou; Xiaofeng Sun; Lan Li; Bo Zhou; Fanchun Zeng; Yong Zhao; Wei Shen; Zhongyi Sun
      Pages: 60 - 67
      Abstract: Publication date: 15 October 2017
      Source:Toxicology and Applied Pharmacology, Volume 333
      Author(s): Jian Pang, Qingsong Zhou, Xiaofeng Sun, Lan Li, Bo Zhou, Fanchun Zeng, Yong Zhao, Wei Shen, Zhongyi Sun
      Zearalenone (ZEA), a kind of nonsteroidal mycotoxin with estrogenic effects, can influence animal reproductive capacity through interfering with estrogen signaling pathway. Previous studies have shown exposure to ZEA at high doses (higher than No-Observed Effect Level, NOEL) had a significant impact on mouse sperm quality and pregnant rate, but little is known about the effect of exposure to ZEA at low doses (lower than NOEL) on mouse reproductive capacity. This study evaluated the effects of exposure to low-dose ZEA on mouse spermatogenesis and semen quality. Male mice (CD-1) of 21days were exposed to ZEA at 20, or 40μg/kg body weight for 14, 28 or 42days. After exposure to ZEA for 14days, the spermatogenic cells in seminiferous tubules were declined dose-independently; however in groups treated by ZEA for 28days, the spermatogenic cells were declined dose-dependently. Moreover, after treatment for 28days or 42days, the DNA double stand break (DSB) in spermatogenic cells were increased in a dose-dependent manner in treated groups. Compared with the control group, the sperm concentration, viability, motility, and hyperactive rate in treated groups were decreased dose-dependently and time-dependently. Meanwhile, deformity and mortality rate of sperm in treated groups were increased remarkably dose-dependently too. In conclusion, low dose ZEA impaired male reproductive capacity especially in spermatogenesis and semen quality of mouse.
      Graphical abstract image

      PubDate: 2017-09-05T20:00:25Z
      DOI: 10.1016/j.taap.2017.08.011
      Issue No: Vol. 333 (2017)
       
  • Toxicity evaluation of two polyoxotungstates with
           anti-acetylcholinesterase activity
    • Authors: Mirjana B. Čolović; Branislava Medić; Mila Ćetković; Tamara Kravić Stevović; Marko Stojanović; Wassim W. Ayass; Ali S. Mougharbel; Miroslav Radenković; Milica Prostran; Ulrich Kortz; Danijela Z. Krstić
      Pages: 68 - 75
      Abstract: Publication date: 15 October 2017
      Source:Toxicology and Applied Pharmacology, Volume 333
      Author(s): Mirjana B. Čolović, Branislava Medić, Mila Ćetković, Tamara Kravić Stevović, Marko Stojanović, Wassim W. Ayass, Ali S. Mougharbel, Miroslav Radenković, Milica Prostran, Ulrich Kortz, Danijela Z. Krstić
      A toxicity evaluation of two Keggin-type heteropolytungstates, K7[Ti2PW10O40]·6H2O and K6H[SiV3W9O40]·3H2O, with different inhibitory potencies toward acetylcholinesterase activity (IC50 values of 1.04×10−6 and 4.80×10−4 mol/L, respectively) was performed. Wistar albino rats were orally treated with single doses (5 and 50mg/kg) of both investigated compounds. The biochemical parameters of renal (serum urea and creatinine) and liver function (direct and total bilirubin, alanine transaminase, and aspartate aminotransferase) were determined after 24h and 14days. A histopathological analysis of liver tissue was carried out 14days after the polyoxotungstate administration. Both applied doses of the investigated compounds did not induce statistically significant alterations of the renal function markers. However, the polyoxotungstate treatment caused an increase in the activities of serum alanine transaminase and aspartate aminotransferase in a time- and concentration-dependent manner, although statistically significant changes in bilirubin concentrations were not observed. Furthermore, the detected hepatotoxic effect was confirmed by histhopathological analysis that suggested some reversible liver tissue damage two weeks after the treatment, especially in the case of K6H[SiV3W9O40]·3H2O. Accordingly, the toxicity of these two polyoxotungstates with anti-acetylcholinesterase effect cannot be considered as a severe one, but their potential clinical application would require a more complex toxicological study.

      PubDate: 2017-09-05T20:00:25Z
      DOI: 10.1016/j.taap.2017.08.010
      Issue No: Vol. 333 (2017)
       
  • Autoimmune potential of perchloroethylene: Role of lipid-derived aldehydes
    • Authors: Gangduo Wang; Jianling Wang; G.A. Shakeel Ansari; M. Firoze Khan
      Pages: 76 - 83
      Abstract: Publication date: 15 October 2017
      Source:Toxicology and Applied Pharmacology, Volume 333
      Author(s): Gangduo Wang, Jianling Wang, G.A. Shakeel Ansari, M. Firoze Khan
      Tetrachloroethene (perchloroethylene, PCE), an ubiquitous environmental contaminant, has been implicated in inducing autoimmunity/autoimmune diseases (ADs), including systemic lupus erythematosus (SLE) and scleroderma in humans. However, experimental evidence suggesting the potential of PCE in mediating autoimmunity is lacking. This study was, therefore, undertaken to explore PCE's potential in inducing/exacerbating an autoimmune response. Six-week old female MRL+/+ mice, in groups of 6 each, were treated with PCE (0.5mg/ml) via drinking water for 12, 18 and 24weeks and markers of autoimmunity and oxidative stress were evaluated. PCE exposure led to significant increases in serum anti-nuclear antibodies (ANA), anti-dsDNA and anti-scleroderma-70 (anti-Scl-70) antibodies at 18weeks and, to a greater extent at 24weeks, suggesting that PCE exposure exacerbated autoimmunity in our animal model. The increases in autoantibodies were associated with time-dependent increases in malondialdehyde (MDA)-protein adducts and their antibodies, as well as significantly decreased levels of antioxidants GSH and SOD. The splenocytes isolated from mice treated with PCE for 18 and 24weeks showed greater Th17 cell proliferation and increased release of IL-17 in culture supernatants following stimulation with MDA-mouse serum albumin adducts, suggesting that MDA-modified proteins may act as an immunologic trigger by activating Th17 cells and contribute to PCE-mediated autoimmunity. Our studies thus provide an experimental evidence that PCE induces/exacerbates an autoimmune response and lipid-derived aldehydes (such as MDA) contribute to this response.

      PubDate: 2017-09-05T20:00:25Z
      DOI: 10.1016/j.taap.2017.08.009
      Issue No: Vol. 333 (2017)
       
  • Diethylcarbamazine: A potential treatment drug for pulmonary
           hypertension'
    • Authors: Edlene Lima Ribeiro; Ingrid Tavares Fragoso; Fabiana Oliveira dos Santos Gomes; Amanda Costa Oliveira; Amanda Karoline Soares e Silva; Patrícia Martins e Silva; Bianca Torres Ciambarella; Isalira Peroba Rezende Ramos; Christina Alves Peixoto
      Pages: 92 - 99
      Abstract: Publication date: 15 October 2017
      Source:Toxicology and Applied Pharmacology, Volume 333
      Author(s): Edlene Lima Ribeiro, Ingrid Tavares Fragoso, Fabiana Oliveira dos Santos Gomes, Amanda Costa Oliveira, Amanda Karoline Soares e Silva, Patrícia Martins e Silva, Bianca Torres Ciambarella, Isalira Peroba Rezende Ramos, Christina Alves Peixoto
      The present study demonstrated the potential effects of diethylcarbamazine (DEC) on monocrotaline (MCT)-induced pulmonary hypertension. MCT solution (600mg/kg) was administered once per week, and 50mg/kg body weight of DEC for 28days. Three C57Bl/6 male mice groups (n=10) were studied: Control; MCT28, and MCT28/DEC. Echocardiography analysis was performed and lung tissues were collected for light microscopy (hematoxylin-eosin and Masson's trichrome staining), immunohistochemistry (αSMA, FADD, caspase 8, caspase 3, BAX, BCL2, cytochrome C and caspase 9) western blot (FADD, caspase 8, caspase 3, BAX, BCL2, cytochrome C and caspase 9) and qRt-PCR (COL-1α and αSMA). Echocardiography analysis demonstrated an increase in the pulmonary arterial blood flow gradient and velocity in the systole and RV area in the MCT28 group, while treatment with DEC resulted in a significant reduction in these parameters. Deposition of collagen fibers and αSMA staining around the pulmonary arteries was evident in the MCT28 group, while treatment with DEC reduced both. Western blot analysis revealed a decrease in BMPR2 in the MCT28 group, in contrast DEC treatment resulted in a significant increase in the level of BMPR2. DEC also significantly reduced the level of VEGF compared to the MCT28 group. Apoptosis extrinsic and intrinsic pathway markers were reduced in the MCT28 group. After treatment with DEC these levels returned to baseline. The results of this study indicate that DEC attenuates PH in an experimental monocrotaline-induced model by inhibiting a series of markers involved in cell proliferation/death.

      PubDate: 2017-09-05T20:00:25Z
      DOI: 10.1016/j.taap.2017.08.015
      Issue No: Vol. 333 (2017)
       
  • Central administration of tert-butylhydroquinone attenuates hypertension
           via regulating Nrf2 signaling in the hypothalamic paraventricular nucleus
           of hypertensive rats
    • Authors: Juan Bai; Xiao-Jing Yu; Kai-Li Liu; Fang-Fang Wang; Gui-Xia Jing; Hong-Bao Li; Yan Zhang; Chan-Juan Huo; Xiang Li; Hong-Li Gao; Jie Qi; Yu-Ming Kang
      Pages: 100 - 109
      Abstract: Publication date: 15 October 2017
      Source:Toxicology and Applied Pharmacology, Volume 333
      Author(s): Juan Bai, Xiao-Jing Yu, Kai-Li Liu, Fang-Fang Wang, Gui-Xia Jing, Hong-Bao Li, Yan Zhang, Chan-Juan Huo, Xiang Li, Hong-Li Gao, Jie Qi, Yu-Ming Kang
      Reactive oxygen species (ROS) in the paraventricular nucleus (PVN) play a pivotal role in the pathogenesis of hypertension. Nuclear factor E2-related factor-2 (Nrf2) is an important transcription factor that modulates cell antioxidant defense response against oxidative stress. The present study aimed to explore the efficacy of PVN administration of tert-butylhydroquinone (tBHQ), a selective Nrf2 activator, in hypertensive rats. 16-week-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were used in this study. These rats were chronic bilateral PVN infusion of tBHQ (0.8μg/day), or oxygen free radical scavenger tempol (20μg/h), or vehicle for 2weeks. SHR rats had higher mean arterial pressure (MAP), plasma norepinephrine (NE) levels, and sympathetic nerve activity (RSNA) and lower PVN levels of Nrf2, hemeoxygenase-1 (HO-1), superoxide dismutase-1 (SOD1) and catalase (CAT) as compared with those in the WKY group. Bilateral PVN infusion of tBHQ or tempol significantly reduced MAP, RSNA, plasma NE levels in SHR rats. In addition, tBHQ treatment enhanced the nuclear accumulation of Nrf2 and increased the expression of HO-1, CAT and SOD1 in SHR rats. Furthermore, tBHQ attenuated PVN levels of ROS, the expression of proinflammatory cytokines and restored the imbalance of neurotransmitters in PVN. Knockdown of Nrf2 in the PVN by adeno-associated virus mediated small interfering RNA abrogated the protective effects of tBHQ on hypertension. These findings suggest that PVN administration of tBHQ can attenuate hypertension by activation of the Nrf2-mediated signaling pathway.

      PubDate: 2017-09-11T20:05:04Z
      DOI: 10.1016/j.taap.2017.08.012
      Issue No: Vol. 333 (2017)
       
  • Cover 2--Ed Board
    • Abstract: Publication date: 15 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 335


      PubDate: 2017-10-14T02:12:11Z
       
  • Cover 4--TOC
    • Abstract: Publication date: 15 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 335


      PubDate: 2017-10-14T02:12:11Z
       
  • 6-Hydroxy-3-O-methyl-kaempferol 6-O-glucopyranoside potentiates the
           anti-proliferative effect of interferon α/β by promoting activation of
           the JAK/STAT signaling by inhibiting SOCS3 in hepatocellular carcinoma
           cells
    • Authors: Orawan Wonganan; Yu-jiao He; Xiao-fei Shen; Kanjana Wongkrajang; Apichart Suksamrarn; Guo-lin Zhang; Fei Wang
      Abstract: Publication date: Available online 12 October 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Orawan Wonganan, Yu-jiao He, Xiao-fei Shen, Kanjana Wongkrajang, Apichart Suksamrarn, Guo-lin Zhang, Fei Wang
      Suppressor of cytokine signaling 3 (SOCS3) is a key negative regulator of type I interferon (IFN α/β) signaling. Inhibition of SOCS3 by small molecules may be a new strategy to enhance the efficacy of type I IFN and reduce its side effects. We established a cell-based screening assay using human hepatoma HepG2 cells stably transfected with a plasmid wherein the luciferase reporter activity was propelled by interferon α-stimulated response element (ISRE), which is a motif specifically recognized by type I IFN-induced activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. After screening our chemical library, 6-hydroxy-3-O-methyl-kaempferol 6-O-glucopyranoside (K6G) was identified to be a potent activator of type I IFN with EC50 value of 3.33±0.04μM. K6G enhanced the phosphorylation of JAK1, Tyk2, and STAT1/2 but decreased the phosphorylation of STAT3. K6G also promoted endogenous IFN-α-regulated genes expression. More interestingly, K6G significantly decreased the expression of SOCS3 without affecting the expression of SOCS1. Furthermore, K6G enhanced the anti-proliferative effect of IFN-α on hepatocellular carcinoma (HCC) cells. These results suggested that K6G potentiated the inhibitory effect of IFN-α on HCC cell proliferation through activation of the JAK/STAT signaling pathway by inhibiting SOCS3 expression. K6G warrants further investigation as a novel therapeutic method to enhance the efficacy of IFN-α/β.

      PubDate: 2017-10-14T02:12:11Z
      DOI: 10.1016/j.taap.2017.10.004
       
  • Arginine methyltransferase inhibitor 1 inhibits gastric cancer by
           downregulating eIF4E and targeting PRMT5
    • Authors: Baolai Zhang; Zhang Lijuan Zhu Xue Chen Yunfeng Zhao Chao
      Abstract: Publication date: Available online 4 October 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Baolai Zhang, Su Zhang, Lijuan Zhu, Xue Chen, Yunfeng Zhao, Li Chao, Juanping Zhou, Xing Wang, Xinyang Zhang, Nengqian Ma
      Arginine methylation is carried out by protein arginine methyltransferase (PRMTs) family. Arginine methyltransferase inhibitor 1 (AMI-1) is mainly used to inhibit type I PRMT activity in vitro. However, the effects of AMI-1 on type II PRMT5 activity and gastric cancer (GC) remain unclear. In this study, we provided the first evidence that AMI-1 significantly inhibited GC cell proliferation and migration while induced GC cell apoptosis, and reduced the expression of PRMT5, eukaryotic translation initiation factor 4E (eIF4E), symmetric dimethylation of histone 3 (H3R8me2s) and histone 4 (H4R3me2s). In addition, AMI-1 inhibited tumor growth, downregulated eIF4E, H4R3me2s and H3R8me2s expression in mice xenografts model of GC. Collectively, our results suggest that AMI-1 inhibits GC by downregulating eIF4E and targeting type II PRMT5.

      PubDate: 2017-10-08T11:22:08Z
       
  • Cover 2--Ed Board
    • Abstract: Publication date: 1 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 334


      PubDate: 2017-09-30T10:53:07Z
       
  • Cover 4--TOC
    • Abstract: Publication date: 1 November 2017
      Source:Toxicology and Applied Pharmacology, Volume 334


      PubDate: 2017-09-30T10:53:07Z
       
  • Cover 2--Ed Board
    • Abstract: Publication date: 15 October 2017
      Source:Toxicology and Applied Pharmacology, Volume 333


      PubDate: 2017-09-11T20:05:04Z
       
  • Cover 4--TOC
    • Abstract: Publication date: 15 October 2017
      Source:Toxicology and Applied Pharmacology, Volume 333


      PubDate: 2017-09-11T20:05:04Z
       
  • Chronic alcohol consumption regulates the expression of poly
           immunoglobulin receptor (pIgR) and secretory IgA in the gut
    • Abstract: Publication date: 15 October 2017
      Source:Toxicology and Applied Pharmacology, Volume 333
      Author(s): María C. López
      The effect of ethanol (EtOH) on the gut immune system was analyzed using an experimental model previously described, where EtOH was provided ad libitum in the drinking water in a 20% w/v concentration for up to 12weeks. Dendritic cells, T cells and macrophages were analyzed in Peyer's patches and the small intestines using flow cytometry. Cytokine and immunoglobulin levels were analyzed in sera, feces, and homogenates from small and large intestines and lungs. Decreases in the proportion of T cells and alterations in dendritic cells and macrophages were observed after EtOH treatment. Levels of immunoglobulin A (IgA) increased in tissue homogenates but decreased in small intestine fecal contents. Meanwhile poly-immunoglobulin receptor (pIgR) levels decreased in tissue homogenates and fecal contents. Levels of cytokines associated with the regulation of pIgR expression decreased for IL-10 and TGF-β, and increased for IFN-γ and IL-17 in the small intestine. The data indicate that chronic EtOH consumption disrupts the homeostasis of the mucosal immune system by altering the phenotype and functionality of multiple immune cell types, leading to a diminished secretion of SIgA, due to pIgR expression decreased.

      PubDate: 2017-09-05T20:00:25Z
       
 
 
JournalTOCs
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Email: journaltocs@hw.ac.uk
Tel: +00 44 (0)131 4513762
Fax: +00 44 (0)131 4513327
 
Home (Search)
Subjects A-Z
Publishers A-Z
Customise
APIs
Your IP address: 54.167.202.184
 
About JournalTOCs
API
Help
News (blog, publications)
JournalTOCs on Twitter   JournalTOCs on Facebook

JournalTOCs © 2009-2016