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(Source: Toxicological Sciences)
Source: Toxicological Sciences - June 26, 2016 Category: Toxicology Tags: Standing Material Source Type: research
Safety Evaluation of CNS Administered Biologics--Study Design, Data Interpretation, and Translation to the Clinic
Many central nervous system (CNS) diseases are inadequately treated by systemically administered therapies due to the blood brain barrier (BBB), which prevents achieving adequate drug concentrations at sites of action. Due to the increasing prevalence of neurodegenerative diseases and the inability of most systemically administered therapies to cross the BBB, direct CNS delivery will likely play an increasing role in treatment. Administration of large molecules, cells, viral vectors, oligonucleotides, and other novel therapies directly to the CNS via the subarachnoid space, ventricular system, or parenchyma overcomes this ...
Source: Toxicological Sciences - June 26, 2016 Category: Toxicology Authors: Vuillemenot, B. R., Korte, S., Wright, T. L., Adams, E. L., Boyd, R. B., Butt, M. T. Tags: Contemporary Review: Assessing the Safety of CNS Administered Biologics Source Type: research
Editorial Board
(Source: Toxicological Sciences)
Source: Toxicological Sciences - June 26, 2016 Category: Toxicology Tags: Standing Material Source Type: research
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(Source: Toxicological Sciences)
Source: Toxicological Sciences - June 26, 2016 Category: Toxicology Tags: Cover Source Type: research
From the Editors Desk, Editors Highlights
(Source: Toxicological Sciences)
Source: Toxicological Sciences - June 26, 2016 Category: Toxicology Tags: Look Inside ToxSci Source Type: research
An 8-Month Systems Toxicology Inhalation/Cessation Study in Apoe-/- Mice to Investigate Cardiovascular and Respiratory Exposure Effects of a Candidate Modified Risk Tobacco Product, THS 2.2, Compared With Conventional Cigarettes
(Source: Toxicological Sciences)
Source: Toxicological Sciences - May 24, 2016 Category: Toxicology Authors: Phillips, B., Veljkovic, E., Boue, S., Schlage, W. K., Vuillaume, G., Martin, F., Titz, B., Leroy, P., Buettner, A., Elamin, A., Oviedo, A., Cabanski, M., De Leon, H., Guedj, E., Schneider, T., Talikka, M., Ivanov, N. V., Vanscheeuwijck, P., Peitsch, M. C Tags: Corrigendum Source Type: research
Grouping 34 Chemicals Based on Mode of Action Using Connectivity Mapping
Connectivity mapping is a method used in the pharmaceutical industry to find connections between small molecules, disease states, and genes. The concept can be applied to a predictive toxicology paradigm to find connections between chemicals, adverse events, and genes. In order to assess the applicability of the technique for predictive toxicology purposes, we performed gene array experiments on 34 different chemicals: bisphenol A, genistein, ethinyl-estradiol, tamoxifen, clofibrate, dehydorepiandrosterone, troglitazone, diethylhexyl phthalate, flutamide, trenbolone, phenobarbital, retinoic acid, thyroxine, 1α,25-dih...
Source: Toxicological Sciences - May 24, 2016 Category: Toxicology Authors: De Abrew, K. N., Kainkaryam, R. M., Shan, Y. K., Overmann, G. J., Settivari, R. S., Wang, X., Xu, J., Adams, R. L., Tiesman, J. P., Carney, E. W., Naciff, J. M., Daston, G. P. Tags: Connectivity Mapping to Group Chemicals Using Mode of Action Source Type: research
The G Protein-Coupled Estrogen Receptor Agonist G-1 Inhibits Nuclear Estrogen Receptor Activity and Stimulates Novel Phosphoproteomic Signatures
Estrogen exerts cellular effects through both nuclear (ESR1 and ESR2) and membrane-bound estrogen receptors (G-protein coupled estrogen receptor, GPER); however, it is unclear if they act independently or engage in crosstalk to influence hormonal responses. To investigate each receptor’s role in proliferation, transcriptional activation, and protein phosphorylation in breast cancer cells (MCF-7), we employed selective agonists for ESR1 propyl-pyrazole-triol (PPT), ESR2 diarylpropionitrile (DPN), and GPER (G-1) and also determined the impact of xenoestrogens bisphenol-A (BPA) and genistein on these effects. As anticip...
Source: Toxicological Sciences - May 24, 2016 Category: Toxicology Authors: Smith, L. C., Ralston-Hooper, K. J., Ferguson, P. L., Sabo-Attwood, T. Tags: GPCR-Estrogen Receptor Agonist Acts as Inhibitor at Nuclear Estrogen Receptor Source Type: research
First Morphological and Molecular Evidence of the Negative Impact of Diatom-Derived Hydroxyacids on the Sea Urchin Paracentrotus lividus
Oxylipins (including polyunsaturated aldehydes [PUAs], hydoxyacids, and epoxyalcohols) are the end-products of a lipoxygenase/hydroperoxide lyase metabolic pathway in diatoms. To date, very little information is available on oxylipins other than PUAs, even though they represent the most common oxylipins produced by diatoms. Here, we report, for the first time, on the effects of 2 hydroxyacids, 5- and 15-HEPE, which have never been tested before, using the sea urchin Paracentrotus lividus as a model organism. We show that HEPEs do induce developmental malformations but at concentrations higher when compared with PUAs. Inter...
Source: Toxicological Sciences - May 24, 2016 Category: Toxicology Authors: Varrella, S., Romano, G., Ruocco, N., Ianora, A., Bentley, M. G., Costantini, M. Tags: Hydroxyacids from Diatoms Adversely Affect Sea Urchin Function Source Type: research
Activation of Constitutive Androstane Receptor (CAR) in Mice Results in Maintained Biliary Excretion of Bile Acids Despite a Marked Decrease of Bile Acids in Liver
This study was performed to determine the effect of CAR activation on bile flow, BA profile, as well as expression of BA synthesis and transport genes. Synthetic CAR ligand 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) was administered to mice for 4 days. BAs were quantified by UPLC-MS/MS (ultraperformance liquid chromatography-tandem mass spectrometry). CAR activation decreases total BAs in livers of male (49%) and female mice (26%), largely attributable to decreases of the 12α-hydroxylated BA taurocholic acid (T-CA) (males (M) 65%, females (F) 45%). Bile flow in both sexes was increased by CAR activation, a...
Source: Toxicological Sciences - May 24, 2016 Category: Toxicology Authors: Lickteig, A. J., Csanaky, I. L., Pratt-Hyatt, M., Klaassen, C. D. Tags: The Constitutive Androstane Receptor and Bile Acid Homeostasis Source Type: research
Linking Inflammation and Parkinson Disease: Hypochlorous Acid Generates Parkinsonian Poisons
Inflammation is a common feature of Parkinson Disease and other neurodegenerative disorders. Hypochlorous acid (HOCl) is a reactive oxygen species formed by neutrophils and other myeloperoxidase-containing cells during inflammation. HOCl chlorinates the amine and catechol moieties of dopamine to produce chlorinated derivatives collectively termed chlorodopamine. Here, we report that chlorodopamine is toxic to dopaminergic neurons both in vivo and in vitro. Intrastriatal administration of 90 nmol chlorodopamine to mice resulted in loss of dopaminergic neurons from the substantia nigra and decreased ambulation-results that w...
Source: Toxicological Sciences - May 24, 2016 Category: Toxicology Authors: Jeitner, T. M., Kalogiannis, M., Krasnikov, B. F., Gomlin, I., Peltier, M. R., Moran, G. R. Tags: Chlorodopamine as a Novel Mediator of Dopamine Neuron Injury Source Type: research
Cancer Stem-Like Cells Accumulated in Nickel-Induced Malignant Transformation
This study examines the role of cancer stem cells in nickel-induced cell transformation. The nontransformed human bronchial epithelial cell line (Beas-2B) was chronically exposed to nickel chloride for 12 months to induce cell transformation. Nickel induced Beas-2B cell transformation, and cancer stem-like cells were enriched in nickel-transformed cell (BNiT) population. The BNiT cancer stem-like cells demonstrated enhanced self-renewal and distinctive differentiation properties. In vivo tumorigenesis studies show that BNiT cancer stem-like cells possess a high tumor-initiating capability. It was also demonstrated that sup...
Source: Toxicological Sciences - May 24, 2016 Category: Toxicology Authors: Wang, L., Fan, J., Hitron, J. A., Son, Y.-O., Wise, J. T. F., Roy, R. V., Kim, D., Dai, J., Pratheeshkumar, P., Zhang, Z., Shi, X. Tags: Role of Cancer Stem-Like Cells in Nickel-Related Malignancies Source Type: research
Subtoxic Alterations in Hepatocyte-Derived Exosomes: An Early Step in Drug-Induced Liver Injury?
Drug-induced liver injury (DILI) is a significant clinical and economic problem in the United States, yet the mechanisms that underlie DILI remain poorly understood. Recent evidence suggests that signaling molecules released by stressed hepatocytes can trigger immune responses that may be common across DILI mechanisms. Extracellular vesicles released by hepatocytes, principally hepatocyte-derived exosomes (HDEs), may constitute one such signal. To examine HDE alterations as a function of drug-induced stress, this work utilized prototypical hepatotoxicant acetaminophen (APAP) in male Sprague-Dawley (SD) rats, SD rat hepatoc...
Source: Toxicological Sciences - May 24, 2016 Category: Toxicology Authors: Holman, N. S., Mosedale, M., Wolf, K. K., LeCluyse, E. L., Watkins, P. B. Tags: Extracellular Vesicles and Drug-Induced Liver Injury Source Type: research
Proposed Mode of Action for Acrolein Respiratory Toxicity Associated with Inhaled Tobacco Smoke
This article presents a mode of action (MOA) analysis that identifies key mechanisms in the respiratory toxicity of inhaled acrolein and proposes key acrolein-related toxic events resulting from the inhalation of tobacco smoke. Smoking causes chronic obstructive pulmonary disorder (COPD) and acrolein has been previously linked to the majority of smoking-induced noncancer respiratory toxicity. In contrast to previous MOA analyses for acrolein, this MOA focuses on the toxicity of acrolein in the lower respiratory system, reflecting the exposure that smokers experience upon tobacco smoke inhalation. The key mechanisms of acro...
Source: Toxicological Sciences - May 24, 2016 Category: Toxicology Authors: Yeager, R. P., Kushman, M., Chemerynski, S., Weil, R., Fu, X., White, M., Callahan-Lyon, P., Rosenfeldt, H. Tags: Systematic Review of Acrolein Mode of Action from Tobacco Smoke Source Type: research
Sulfur Dioxide Contributes to the Cardiac and Mitochondrial Dysfunction in Rats
Epidemiological studies have demonstrated an association between sulfur dioxide (SO2) and an increase of morbidity and mortality of cardiovascular diseases, such as ischemic heart disease, heart failure, and arrhythmia. Mitochondrion is the most sensitive organelle in myocardium of animals exposed to SO2. Here we study the molecular characterization of mitochondrial dysfunction in cardiac muscles of rat after SO2 exposure. We found that the cytochrome c oxidase (COX) activity, mitochondrial membrane potential (m), ATP contents, mitochondrial DNA (mtDNA) contents, and mRNA expression of complexes IV and V subunits encoded b...
Source: Toxicological Sciences - May 24, 2016 Category: Toxicology Authors: Qin, G., Wu, M., Wang, J., Xu, Z., Xia, J., Sang, N. Tags: Sulfur Dioxide and Cardiac Dysfunction Source Type: research
