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Toxicology Research

Rosa Chan, Leslie Z Benet
Drug-induced liver injury (DILI) is a major safety concern; it occurs frequently; it is idiosyncratic; it cannot be adequately predicted; and a multitude of underlying mechanisms has been postulated. A number of experimental approaches to predict human DILI have been proposed utilizing in vitro screening such as inhibition of mitochondrial function, hepatobiliary transporter inhibition, reactive metabolite formation with and without covalent binding, and cellular health, but they have achieved only minimal success...
May 8, 2018: Toxicology Research
Beth McMillan, David J Gavaghan, Gary R Mirams
Drug-induced Torsades de Pointes (TdP) arrhythmia is of major interest in predictive toxicology. Drugs which cause TdP block the hERG cardiac potassium channel. However, not all drugs that block hERG cause TdP. As such, further understanding of the mechanistic route to TdP is needed. Early afterdepolarisations (EADs) are a cell-level phenomenon in which the membrane of a cardiac cell depolarises a second time before repolarisation, and EADs are seen in hearts during TdP. Therefore, we propose a method of predicting TdP using induced EADs combined with multiple ion channel block in simulations using biophysically-based mathematical models of human ventricular cell electrophysiology...
November 1, 2017: Toxicology Research
Lakshmanan Jagannathan, Cynthia C Jose, Vinay Singh Tanwar, Sudin Bhattacharya, Suresh Cuddapah
Mercury (Hg) and 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) are major environmental contaminants that commonly co-occur in the environment. Both Hg and TCDD are associated with a number of human diseases including cancers. While the individual toxicological effects of Hg and TCDD have been extensively investigated, studies on co-exposure are limited to a few genes and pathways. Therefore, a significant knowledge gap exists in the understanding of the deleterious effects of co-exposure to Hg and TCDD. Due to the prevalence of Hg and TCDD co-contamination in the environment and the major human health hazards they pose, it is important to obtain a fuller understanding of genome-wide effects of Hg and TCDD co-exposure...
May 1, 2017: Toxicology Research
Trevor M Penning
o -Quinones are formed metabolically from natural and synthetic estrogens as well as upon exposure to polycyclic aromatic hydrocarbons (PAH) and contribute to estrogen and PAH carcinogenesis by genotoxic mechanisms. These mechanisms include the production of reactive oxygen species to produce DNA strand breaks and oxidatively damaged nucleobases; and the formation of covalent depurinating and stable DNA adducts. Unrepaired DNA-lesions can lead to mutation in critical growth control genes and cellular transformation...
2017: Toxicology Research
Jessica H Hartman, Grover P Miller, Joel N Meyer
Cytochrome P450 2E1 (CYP2E1) metabolizes an extensive array of pollutants, drugs, and other small molecules, often resulting in bioactivation to reactive metabolites. Therefore, it is unsurprising that it has been the subject of decades of research publications and reviews. However, while CYP2E1 has historically been studied in the endoplasmic reticulum (erCYP2E1), active CYP2E1 is also present in mitochondria (mtCYP2E1). Relatively few studies have specifically focused on mtCYP2E1, but there is growing interest in this form of the enzyme as a driver in toxicological mechanisms given its activity and location...
2017: Toxicology Research
Pritesh Mistry, Daniel Neagu, Antonio Sanchez-Ruiz, Paul R Trundle, Jonathan D Vessey, John Paul Gosling
Two approaches for the prediction of which of two vehicles will result in lower toxicity for anticancer agents are presented. Machine-learning models are developed using decision tree, random forest and partial least squares methodologies and statistical evidence is presented to demonstrate that they represent valid models. Separately, a clustering method is presented that allows the ordering of vehicles by the toxicity they show for chemically-related compounds.
January 1, 2017: Toxicology Research
P A Bommarito, R C Fry
Globally, millions of people are exposed to elevated levels of inorganic arsenic (iAs) via drinking water. Exposure to iAs is associated with a wide range of negative health outcomes, including cancers, skin lesions, neurological impairment, cardiovascular diseases, and an increased susceptibility to infection. Among those exposed to iAs, the developing fetus and young children represent particularly sensitive subpopulations. Specifically, it has been noted in animal models and human populations that prenatal and early life iAs exposures are associated with diseases occurring during childhood and later in life...
November 1, 2016: Toxicology Research
Leticia Priscilla Arantes, Tanara Vieira Peres, Pam Chen, Samuel Caito, Michael Aschner, Félix Alexandre Antunes Soares
The influence of routine guarana (Paullinia cupana) consumption on apparent tolerance to mercury intoxication has been proposed. The present study investigated this hypothesis in Caenorhabditis elegans, a suitable experimental model for studies in toxicology. Wild type (WT) and skn-1 (ok2315) worm strains were pretreated with guarana ethanolic extract (GEE) from larvae 1 (L1) to L4 stage and then exposed for 6 hours to methylmercury (MeHg). The analyses included evaluation of GEE's effects on lethality, developmental delay, feeding, locomotion, gene expression (sod-3, gst-4, sir-2...
November 1, 2016: Toxicology Research
Harriet Gaskell, Parveen Sharma, Helen E Colley, Craig Murdoch, Dominic P Williams, Steven D Webb
More predictive in vitro liver models are a critical requirement for preclinical screening of compounds demonstrating hepatotoxic liability. 3D liver spheroids have been shown to have an enhanced functional lifespan compared to 2D monocultures; however a detailed characterisation of spatiotemporal function and structure of spheroids still needs further attention before widespread use in industry. We have developed and characterized the structure and function of a 3D liver spheroid model formed from C3A hepatoma cells...
June 1, 2016: Toxicology Research
Crystal S Lewis, Luisa Torres, Jeremy T Miyauchi, Cyrus Rastegar, Jonathan M Patete, Jacqueline M Smith, Stanislaus S Wong, Stella E Tsirka
Understanding the nature of interactions between nanomaterials, such as commercially ubiquitous hematite (α-Fe2O3) Nanorhombohedra (N-Rhomb) and biological systems is of critical importance for gaining insight into the practical applicability of nanomaterials. Microglia represent the first line of defense in the central nervous system (CNS) during severe injury or disease such as Parkinson's and Alzheimer's disease as illustrative examples. Hence, to analyze the potential cytotoxic effect of nanorhombohedra exposure in the presence of microglia, we have synthesized Rhodamine B (RhB) labeled-α-Fe2O3 N-Rhomb, with lengths of 47 ± 10 nm and widths of 35 ± 8 nm...
May 1, 2016: Toxicology Research
Ashley J Broom, Jeffrey Ambroso, Gino Brunori, Angie K Burns, James R Armitage, Ian Francis, Mitul Gandhi, Richard A Peterson, Timothy W Gant, Alan R Boobis, Jonathan J Lyon
Relating the in vitro mitochondrial effects of drug candidates to likely in vivo outcomes remains challenging. Better understanding of this relationship, alongside improved methods to assess mitochondrial dysfunction in vivo , would both guide safer drug candidate selection and better support discovery programmes targeting mitochondria for pharmacological intervention. The aim of this study was to profile the in vivo effects of a compound with suspected complex III electron transport chain (ETC) inhibitory activity (GSK932121A) at doses associated with clinical signs, and relate findings back to in vitro data with the same compound...
January 1, 2016: Toxicology Research
Yi Cui, Samrat Roy Choudhury, Joseph Irudayaraj
The volatile, water soluble trichloroethylene (TCE) is a hazardous industrial waste and could lead to various health problems, including cancer, neuropathy, cardiovascular defects, and immune diseases. Toxicological studies taking use of in vitro and in vivo models have been conducted to understand the biological impacts of TCE at the genetic, transcriptomic, metabolomic, and signaling levels. The epigenetic aberrations induced by TCE have also been reported in a number of model organisms, while a detailed mechanistic elucidation is lacking...
2016: Toxicology Research
Xiaoren Tang, Salomon Amar
Kavain, an extract from the shrub Piper Methysticum, was recently reported to modulate TNF-α expression in both human and mouse cells via regulation of LPS-Induced TNF-Alpha Factor (LITAF). The purpose of the present study was to define the molecular pathway(s) associated with Kavain effects on TNF modulation. In vitro studies using WT mouse primary macrophages showed that Kavain significantly reduced E.coli LPS-induced TNF-α production but this effect was almost abrogated in LITAF(-/-) and ERK2(-/-) cells...
January 1, 2016: Toxicology Research
Patricia Erebi Tawari, Zhipeng Wang, Mohammad Najlah, Chi Wai Tsang, Vinodh Kannappan, Peng Liu, Christopher McConville, Bin He, Angel L Armesilla, Weiguang Wang
The anticancer activity of disulfiram (DS) is copper(ii) (Cu)-dependent. This study investigated the anticancer mechanisms of DS/Cu using in vitro cytotoxicity and metabolic kinetic analysis. Our study indicates that DS/Cu targets cancer cells by the combination of two types of actions: (1) instant killing executed by DS/Cu reaction generated reactive oxygen species; (2) delayed cytotoxicity introduced by the end product, DDC-Cu. Nanoencapsulation of DS might shed light on repositioning of DS into cancer treatment...
November 19, 2015: Toxicology Research
S AlGhamdi, V Leoncikas, K E Plant, N J Plant
There has been a dramatic increase in the number of clinically obese individuals in the last twenty years. This has resulted in an increasingly common scenario where obese individuals are treated for other diseases, including cancer. Here, we examine interactions between lipid-induced steatosis and doxorubicin treatment in the human hepatoma cell line Huh7. The response of cells to either doxorubicin, lipid-loading or a combination were examined at the global level by DNA microarray, and for specific endpoints of cytotoxicity, lipid-loading, reactive oxygen species, anti-oxidant response systems, and apoptosis...
November 19, 2015: Toxicology Research
S Meyer, G Raber, F Ebert, L Leffers, S M Müller, M S Taleshi, K A Francesconi, T Schwerdtle
Arsenic-containing fatty acids are a group of fat-soluble arsenic species (arsenolipids) which are present in marine fish and other seafood. Recently, it has been shown that arsenic-containing hydrocarbons, another group of arsenolipids, exert toxicity in similar concentrations comparable to arsenite although the toxic modes of action differ. Hence, a risk assessment of arsenolipids is urgently needed. In this study the cellular toxicity of a saturated (AsFA 362) and an unsaturated (AsFA 388) arsenic-containing fatty acid and three of their proposed metabolites (DMA(V), DMAPr and thio-DMAPr) were investigated in human liver cells (HepG2)...
September 18, 2015: Toxicology Research
D P Jackson, A D Joshi, C J Elferink
The Ah receptor is a transcription factor that modulates gene expression via interactions with multiple protein partners; these are reviewed, including the novel NC-XRE pathway involving KLF6.
September 1, 2015: Toxicology Research
Byeong Hwa Yun, Viktoriya S Sidorenko, Thomas A Rosenquist, Kathleen G Dickman, Arthur P Grollman, Robert J Turesky
Aristolochic acids (AA) are found in all Aristolochia herbaceous plants, many of which have been used worldwide for medicinal purposes for centuries. AA are causal agents of the chronic kidney disease entity termed aristolochic acid nephropathy (AAN) and potent upper urinary tract carcinogens in humans. AAN and upper urinary tract cancers are endemic in rural areas of Croatia and other Balkan countries where exposure to AA occurs through the ingestion of home-baked bread contaminated with Aristolochia seeds...
July 1, 2015: Toxicology Research
Jingcheng Xiao, Qi Wang, Kristin M Bircsak, Xia Wen, Lauren M Aleksunes
The BCRP (ABCG2) transporter is responsible for the efflux of chemicals from the placenta to the maternal circulation. Inhibition of BCRP activity could enhance exposure of offspring to environmental chemicals leading to altered reproductive, endocrine, and metabolic development. The purpose of this study was to characterize environmental chemicals as potential substrates and inhibitors of the human placental BCRP transporter. The interaction of BCRP with a panel of environmental chemicals was assessed using the ATPase and inverted plasma membrane vesicle assays as well as a cell-based fluorescent substrate competition assay...
May 1, 2015: Toxicology Research
Patrick Allard
Toxicology has seen a recent influx of new talents from other fields attracted by the application of their expertise to pressing questions of toxicological and environmental relevance. This transition has opened the door to innovative and exciting scientific opportunities but has also generated a new set of questions and challenges. In this viewpoint article, I will highlight some of the drivers and hurdles encountered by the recent new breeds of toxicologists.
May 1, 2015: Toxicology Research
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