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Toxicology and Applied Pharmacology

Ellen V S Hessel, Yvonne C M Staal, Aldert H Piersma
Developmental neurotoxicity entails one of the most complex areas in toxicology. Animal studies provide only limited information as to human relevance. A multitude of alternative models have been developed over the years, providing insights into mechanisms of action. We give an overview of fundamental processes in neural tube formation, brain development and neural specification, aiming at illustrating complexity rather than comprehensiveness. We also give a flavor of the wealth of alternative methods in this area...
March 12, 2018: Toxicology and Applied Pharmacology
Charles V Vorhees, Jenna N Sprowles, Samantha L Regan, Michael T Williams
High throughput screens for developmental neurotoxicity (DN) will facilitate evaluation of chemicals and can be used to prioritize those designated for follow-up. DN is evaluated under different guidelines. Those for drugs generally include peri- and postnatal studies and juvenile toxicity studies. For pesticides and commercial chemicals, when triggered, include developmental neurotoxicity studies (DNT) and extended one-generation reproductive toxicity studies. Raffaele et al. (2010) reviewed 69 pesticide DNT studies and found two of the four behavioral tests underperformed...
March 12, 2018: Toxicology and Applied Pharmacology
D Hernandez-Cortes, I Alvarado-Cruz, M J Solís-Heredia, B Quintanilla-Vega
Methyl parathion (Me-Pa) is an oxidizing organophosphate (OP) pesticide that generates reactive oxygen species (ROS) through its biotransformation. Some studies have also suggested that OP pesticides have the capacity to alkylate biomolecules, including DNA. In general, DNA methylation in gene promoters represses transcription. NRF2 is a key transcription factor that regulates the expression of antioxidant, metabolic and detoxifying genes through the antioxidant response element (ARE) situated in promoters of regulated genes...
March 11, 2018: Toxicology and Applied Pharmacology
Jan Raska, Lucie Ctverackova, Aneta Dydowiczova, Iva Sovadinova, Ludek Blaha, Pavel Babica
HL1-hT1 cell line represents adult human liver stem cells (LSCs) immortalized with human telomerase reverse transcriptase. In this study, HL1-hT1 cells were found to express mesenchymal markers (vimentin, CD73, CD90/THY-1 and CD105) and an early hepatic endoderm marker FOXA2, while not expressing hepatic progenitor (HNF4A, LGR5, α-fetoprotein) or differentiated hepatocyte markers (albumin, transthyretin, connexin 32). In response to microcystin-LR (MC-LR), a time- and concentration-dependent formation of MC-positive protein bands in HL1-hT1 cells was observed...
March 10, 2018: Toxicology and Applied Pharmacology
Mara Fiorani, Andrea Guidarelli, Valentina Capellacci, Liana Cerioni, Rita Crinelli, Orazio Cantoni
Arsenite toxicity is in numerous cellular systems dependent on the formation of reactive oxygen and or nitrogen species. This is also true in U937 cells in which the metalloid selectively promotes the formation of mitochondrial superoxide (mitoO2 - ) rapidly converted to diffusible H2 O2 . We tested the hypothesis that, under the same conditions, mitoO2 - also mediates the triggering of a parallel survival signaling. We found that a low concentration of the metalloid causes an early activation of nuclear factor erythroid 2 p45-related factor 2 (Nrf2), and a downstream signaling leading to enhanced GSH biosynthesis, via a mechanism sensitive to various treatments/strategies selectively preventing mitoO2 - formation...
March 8, 2018: Toxicology and Applied Pharmacology
Marycarmen Cruz-Hurtado, Ma de Lourdes López-González, Derly Constanza Escobar-Wilches, Adolfo Sierra-Santoyo
Vinclozolin (V) is a fungicide with anti-androgenic properties whose metabolism is not fully understood, and data on urinary elimination of either V or its metabolites are limited. Therefore the kinetics of urinary elimination of V and its metabolites, after an oral dose in adult male rats were investigated. A single oral dose of V (100 mg/kg) suspended in corn oil was administered to male adult Wistar rats, and urine was collected at different times after dosing. V and its metabolites were extracted from urine, then enzymatically hydrolyzed using β-glucuronidase/sulfatase of H...
March 8, 2018: Toxicology and Applied Pharmacology
Fang Qiu, Changjiang Dong, Yanxin Liu, Xiaoqi Shao, Di Huang, Yanna Han, Bing Wang, Yanli Liu, Rong Huo, Petro Paulo, Zhiren Zhang, Dan Zhao, Wen-Feng Chu
BACKGROUND AND PURPOSE: Protein modification by small ubiquitin-like modifier (SUMO) plays a critical role in the pathogenesis of heart diseases. The present study was designed to determine whether ginkgolic acid (GA) as a SUMO-1 inhibitor exerts an inhibitory effect on cardiac fibrosis induced by myocardial infarction (MI). EXPERIMENTAL APPROACH: GA was delivered by osmotic pumps in MI mice. Masson staining, electron microscopy (EM) and echocardiography were used to assess cardiac fibrosis, ultrastructure and function...
March 7, 2018: Toxicology and Applied Pharmacology
Hegui Huang, Lian Liu, Jing Li, Chunyan Zhu, Xiaoyu Xie, Ying Ao, Hui Wang
Autophagy plays a vital role in embryonic development and cell differentiation. Our previous study demonstrated that prenatal ethanol exposure (PEE) resulted in intrauterine growth retardation (IUGR) and adrenal developmental toxicities in rat offspring. The present study focused on PEE-induced autophagy as an underlying mechanism and its biological significance in female fetal rats. Female fetuses in the PEE group exhibited lower body weights and suffered adrenal structural abnormalities compared to the controls...
March 7, 2018: Toxicology and Applied Pharmacology
Masaru Nakagawa, Sigeyuki Uno, Noriyoshi Iriyama, Manabu Matsunawa, Makoto Makishima, Jin Takeuchi, Isao Tsuboi, Yoshihiro Hatta, Masami Takei
Benzo[a]pyrene (BaP) is an environmental pollutant found in cigarette smoke and is implicated as a causative agent of tobacco-related diseases, such as arteriosclerosis. In contrast, vitamin D signaling, which is principally mediated by conversion of vitamin D to the active form, 1α,25-dihydroxyvitamin D3 [1,25(OH)2 D3 ], decreases cardiovascular disease risk. However, combined treatment with BaP and 1,25(OH)2 D3 enhances BaP toxicity, including BaP-DNA adduct formation. We further investigated the cross-talk between BaP and 1,25(OH)2 D3 signaling pathways, and found that combined treatment with these compounds induces mRNA and protein expression of plasminogen activator inhibitor 1 (PAI-1) in monocyte/macrophage-derived THP-1 and U937 cells...
March 7, 2018: Toxicology and Applied Pharmacology
Magdalini Sachana, Alexandra Rolaki, Anna Bal-Price
The Adverse Outcome Pathways (AOPs) are designed to provide mechanistic understanding of complex biological systems and pathways of toxicity that result in adverse outcomes (AOs) relevant to regulatory endpoints. AOP concept captures in a structured way the causal relationships resulting from initial chemical interaction with biological target(s) (molecular initiating event) to an AO manifested in individual organisms and/or populations through a sequential series of key events (KEs), which are cellular, anatomical and/or functional changes in biological processes...
March 7, 2018: Toxicology and Applied Pharmacology
A J McFarland, A K Davey, C M McDermott, G D Grant, J Lewohl, S Anoopkumar-Dukie
3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have been associated with conflicting effects within the central nervous system (CNS), with underlying mechanisms remaining unclear. Although differences between individual statins' CNS effects have been reported clinically, few studies to date have compared multiple statins' neuroprotective effects. This study aimed to compare six statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin; 0-100 μM) using an in vitro model of lipopolysaccharide (LPS)-induced neuroinflammation and subsequent neurodegeneration...
March 6, 2018: Toxicology and Applied Pharmacology
Teemu T Turunen, Ari Koskelainen
Cyclic nucleotide phosphodiesterases (PDEs) hydrolyze the second messengers cAMP and cGMP. PDEs control numerous cellular processes making them promising targets for the development of therapeutic agents. Unfortunately, many PDE inhibitor molecules are non-selective among PDE classes and efficient methods for quantitative studies on the isoform-specificity of PDE inhibitors in the natural environments of PDEs are unavailable. The PDE in photoreceptors, PDE6, mediates the conversion of photon information into electrical signals making the retina an exceptional model system for examinations of the pharmacological effects of PDE inhibitors on PDE6...
March 5, 2018: Toxicology and Applied Pharmacology
Wasila Mansouri, Samuel B Fordyce, Matthew Wu, David Jones, Douglas Cohn, Qishan Lin, Paul Feustel, Tanuj Sharma, James A Bennett, Thomas T Andersen
PURPOSE: The purpose of this study is to assess the efficacy and safety profile of AFPep, a 9-amino acid cyclic peptide prior to its entry into pre-clinical toxicology analyses en route to clinical trials. METHODS: AFPep was assessed for anti-estrogenic activity in a mouse uterine growth assay and for breast cancer therapeutic efficacy in a human tumor xenograft model in mice. AFPep was assessed for tolerability in a variety of in vivo models, notably including assessment for effects on rat liver and human hepatocellular carcinoma cell lines and xenografts...
March 5, 2018: Toxicology and Applied Pharmacology
Rakesh Kumar, Neetika Lal, Vishal Nemaysh, Pratibha Mehta Luthra
Earlier, we reported that Demethoxycurcumin suppressed the growth of human glioma U87 MG cells by downregulation of Bcl-2 expression. In the present work, we investigated the DMC induced reactive oxygen species (ROS) mediated anti-proliferative and apoptotic effects in U87 MG cells. Exposure of U87 MG cells to growth-suppressive concentrations of DMC (0-50 μg/ml) resulted in ROS generation and concomitant increase in apoptosis. The major oxidative species induced by DMC was superoxide anion radical (O2 - )...
March 3, 2018: Toxicology and Applied Pharmacology
K A Fader, R Nault, M P Kirby, G Markous, J Matthews, T R Zacharewski
No abstract text is available yet for this article.
March 1, 2018: Toxicology and Applied Pharmacology
Zhengxi Wei, Zhongguo Shan, Zahir A Shaikh
Epidemiological and experimental studies have implicated cadmium (Cd) with breast cancer. In breast cancer-derived cells, Cd has been shown to promote MCF10A and MDA-MB-231 cell growth. The present study examined whether Cd also causes epithelial-mesenchymal transition (EMT), a hallmark of cancer progression. Human breast epithelial cells consisting of non-cancerous MCF10A, non-metastatic HCC 1937 and HCC 38, and metastatic MDA-MB-231 were treated with 1 or 3 μM Cd for 4 weeks. The MCF10A epithelial cells switched to a more mesenchymal-like morphology, which was accompanied by a decrease in the epithelial marker E-cadherin and an increase in the mesenchymal markers N-cadherin and vimentin...
February 28, 2018: Toxicology and Applied Pharmacology
Amin S M Salehi, Seung-Ook Yang, Conner C Earl, Miriam J Shakalli Tang, J Porter Hunt, Mark T Smith, David W Wood, Bradley C Bundy
Many diseases and disorders are linked to exposure to endocrine disrupting chemicals (EDCs) that mimic the function of natural estrogen hormones. Here we present a Rapid Adaptable Portable In-vitro Detection biosensor platform (RAPID) for detecting chemicals that interact with the human estrogen receptor β (hERβ). This biosensor consists of an allosteric fusion protein, which is expressed using cell-free protein synthesis technology and is directly assayed by a colorimetric response. The resultant biosensor successfully detected known EDCs of hERβ (BPA, E2, and DPN) at similar or better detection range than an analogous cell-based biosensor, but in a fraction of time...
February 27, 2018: Toxicology and Applied Pharmacology
S Spulber, M Raciti, B Dulko-Smith, D Lupu, J Rüegg, K Nam, S Ceccatelli
Methylmercury (MeHg) is a widespread environmental contaminant with established developmental neurotoxic effects. Computational models have identified glucocorticoid receptor (GR) signaling to be a key mediator behind the birth defects induced by Hg, but the mechanisms were not elucidated. Using molecular dynamics simulations, we found that MeHg can bind to the GR protein at Cys736 (located close to the ligand binding site) and distort the conformation of the ligand binging site. To assess the functional consequences of MeHg interaction with GR, we used a human cell line expressing a luciferase reporter system (HeLa AZ-GR)...
February 27, 2018: Toxicology and Applied Pharmacology
Sean M Bugel, Robert L Tanguay
The comparative analysis of complex behavioral phenotypes is valuable as a reductionist tool for both drug discovery and defining chemical bioactivity. Flavonoids are a diverse class of chemicals that elicit robust neuroactive and hormonal actions, though bioactivity information is limited for many, particularly for neurobehavioral endpoints. Here, we used a zebrafish larval chemomotor response (LCR) bioassay to comparatively evaluate a suite of 24 flavonoids, and in addition a panel of 30 model neuroactive compounds representing diverse modes of action (e...
February 27, 2018: Toxicology and Applied Pharmacology
Yanling Guo, Xiaxia Wu, Qin Wu, Yuanfu Lu, Jingshan Shi, Xiuping Chen
Ulcerative colitis (UC) is a chronic and relapsing inflammatory disorder of the colon and rectum with increasing morbidity in recent years. 15,16-dihydrotanshinone Ӏ (DHT) is a natural product with multiple bioactivities. In this study, we aimed to investigate the protective effect and potential mechanisms of DHT on UC. Dextran sulfate sodium salt (DSS) was administrated in drinking water for 7 days to induce UC in mice. DHT (10 and 25 mg/kg) significantly alleviated DSS-induced body weight loss, disease activity index (DAI) scores, and improved histological alterations of colon tissues...
February 26, 2018: Toxicology and Applied Pharmacology
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