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https://www.readbyqxmd.com/read/29329425/comparison-of-hepatic-2d-sandwich-cultures-and-3d-spheroids-for-long-term-toxicity-applications-a-multi-center-study
#1
Catherine C Bell, Anita C A Dankers, Volker M Lauschke, Rowena Sison-Young, Roz Jenkins, Cliff Rowe, Chris Goldring, Kevin Park, Sophie Regan, Tracy Walker, Chris Schofield, Audrey Baze, Alison J Foster, Dominic Williams, Amy W M van de Ven, Frank Jacobs, Jos van Houdt, Tuula Lähteenmäki, Jan Snoeys, Satu Juhila, Lysiane Richert, Magnus Ingelman-Sundberg
Primary human hepatocytes (PHH) are commonly used for in vitro studies of drug-induced liver injury. However, when cultured as 2D monolayers, PHH lose crucial hepatic functions within hours. This dedifferentiation can be ameliorated when PHH are cultured in sandwich configuration (2Dsw), particularly when cultures are regularly re-overlaid with extracellular matrix, or as 3D spheroids. In this study, the six participating laboratories evaluated the robustness of these two model systems made from cryopreserved PHH from the same donors considering both inter-donor and inter-lab variability and compared their suitability for use in repeated-dose toxicity studies using 5 different hepatotoxins with different toxicity mechanisms...
January 10, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29313451/microcystin-lr-degradation-utilizing-a-novel-effective-indigenous-bacterial-community-yfmcd1-from-lake-taihu
#2
Fei Yang, Isaac Yaw Massey, Jian Guo, Shu Yang, Yuepu Pu, Weiming Zeng, Hongzhuan Tan
Microcystins (MC) produced by species of cyanobacteria including Microcystis, Anabaena, and Aphanizomenon are a group of monocyclic hepatotoxins posing serious threat to public health. Microcystin-LR (MC-LR) is the most toxic and frequently encountered microcystin variant in the environment, and thus removal of this toxin using bacteria was shown to be a reliable, efficient, and cost-effective method that avoids utilization of chemicals that may produce potentially harmful by-products. The aim of this study was to determine whether a novel indigenous bacterial community designated YFMCD1 was effective in destroying MC...
January 9, 2018: Journal of Toxicology and Environmental Health. Part A
https://www.readbyqxmd.com/read/29297242/recent-advances-in-three-dimensional-cell-culturing-to-assess-liver-function-and-dysfunction-from-a-drug-biotransformation-and-toxicity-perspective
#3
Carlemi Calitz, Josias H Hamman, Stephen J Fey, Krzysztof Wrzesinski, Chrisna Gouws
The liver is a vital organ fulfilling a central role in over 500 major metabolic functions, including serving as the most essential site for drug biotransformation. Dysfunction of the drug biotransformation processes may result in the exposure of the liver (and other organs) to hepatotoxins, potentially interacting with cellular constituents and causing toxicity and various lesions. Hepatotoxicity can be investigated on a tissue, cellular and molecular level by employing various in vivo and in vitro techniques, including novel three-dimensional (3D) cell culturing methods...
January 3, 2018: Toxicology Mechanisms and Methods
https://www.readbyqxmd.com/read/29248467/protective-capabilities-of-silymarin-and-inulin-nanoparticles-against-hepatic-oxidative-stress-genotoxicity-and-cytotoxicity-of-deoxynivalenol-in-rats
#4
Mosaad A Abdel-Wahhab, Aziza A El-Nekeety, Asmaa S Salman, Sekena H Abdel-Aziem, Fathy M Mehaya, Nabila S Hassan
Deoxynivalenol (DON) is a Fusarium mycotoxin that frequently contaminates cereal and cereal-based food and induces liver injury. This study evaluated the protective role of silymarin nanoparticles (SILNPs) and inulin nanoparticles (INNPs) against DON-induced liver injury in rats. Eleven groups of rats were treated orally for 3 weeks as follows: the control group, DON-treated group (5 mg/kg b.w.); INNPs-treated groups at low (LD) or high (HD) dose (100 or 200 mg/kg b.w.); SILPNs-treated group (50 mg/kg b...
December 14, 2017: Toxicon: Official Journal of the International Society on Toxinology
https://www.readbyqxmd.com/read/29241671/mkp-1-protects-mice-against-toxin-induced-liver-damage-by-promoting-the-nrf2-cytoprotective-response
#5
Lin Luo, Yeru Chen, Hongyan Wang, Shengcun Wang, Kaihua Liu, Xin Li, Xiu Jun Wang, Xiuwen Tang
The present study was undertaken to investigate the possible protective effect of mitogen-activated protein kinase phosphatase 1 (Mkp-1) on toxin-induced hepatic injury. Here, we uncovered a positive feedback loop between Mkp-1, a dual threonine/tyrosine phosphatase, and nuclear factor erythroid 2-related factor 2 (Nrf2), a crucial regulator of the defense system in the liver. Mkp-1-/- mice exhibited decreased protein levels of Nrf2, phase II gene products, and reduced glutathione (GSH) in the liver. Induction of detoxifying enzymes by the Nrf2 activator butylated hydroxyanisole (BHA) or sulforaphane, was attenuated in the liver and small intestines of Mkp-1-/- mice, indicating that the Nrf2 signaling pathway is impaired as a result of Mkp-1 deficiency...
December 11, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/29235390/mir-122-and-other-micrornas-as-potential-circulating-biomarkers-of-drug-induced-liver-injury
#6
Lawrence S Howell, Lucy Ireland, B Kevin Park, Christopher E Goldring
Drug-induced liver injury (DILI) is a severe adverse drug reaction which is of major concern to patients, clinicians and the pharmaceutical industry. Accurate and rapid detection of DILI is important for patient stratification and treatment in the clinic and benefits preclinical drug design and risk assessment. MicroRNAs (miRNAs) offer a potential new and improved class of circulating biomarkers of DILI over the current gold standard biomarkers. Areas covered: This review highlights the shortcomings of the currently used panel of biomarkers and how miRNAs, primarily miR-122, show an improved level of specificity and sensitivity in the prediction of DILI...
December 15, 2017: Expert Review of Molecular Diagnostics
https://www.readbyqxmd.com/read/29195944/fresh-produce-and-their-soils-accumulate-cyanotoxins-from-irrigation-water-implications-for-public-health-and-food-security
#7
Seungjun Lee, Xuewen Jiang, Manjunath Manubolu, Ken Riedl, Stuart A Ludsin, Jay F Martin, Jiyoung Lee
Microcystin (MC), a hepatotoxin that can adversely affect human health, has become more prevalent in freshwater ecosystems worldwide, owing to an increase in toxic cyanobacteria blooms. While consumption of water and fish are well-documented exposure pathways of MCs to humans, less is known about the potential transfer to humans through consumption of vegetables that have been irrigated with MC-contaminated water. Likewise, the impact of MC on the performance of food crops is understudied. To help fill these information gaps, we conducted a controlled laboratory experiment in which we exposed lettuce, carrots, and green beans to environmentally relevant concentrations of MC-LR (0, 1, 5, and 10μg/L) via two irrigation methods (drip and spray)...
December 2017: Food Research International
https://www.readbyqxmd.com/read/29182536/are-we-underestimating-benthic-cyanotoxins-extensive-sampling-results-from-spain
#8
Enrique A Cantoral Uriza, Antonia D Asencio, Marina Aboal
Microcystins (MCs) are potent hepatotoxins, and their presence in water bodies poses a threat to wildlife and human populations. Most of the available information refers to plankton, and much less is known about microcystins in other habitats. To broaden our understanding of the presence and environmental distribution of this group of toxins, we conducted extensive sampling throughout Spain, under a range of conditions and in distinct aquatic and terrestrial habitats. More than half of the tested strains were toxic; concentrations of the hepatotoxin were low compared with planktic communities, and the number of toxic variants identified in each sample of the Spanish strains ranged from 1-3...
November 28, 2017: Toxins
https://www.readbyqxmd.com/read/29167567/real-time-in-vivo-imaging-reveals-localised-nrf2-stress-responses-associated-with-direct-and-metabolism-dependent-drug-toxicity
#9
Shiva S Forootan, Fiona E Mutter, Anja Kipar, Takao Iwawaki, Ben Francis, Christopher E Goldring, B Kevin Park, Ian M Copple
The transcription factor Nrf2 coordinates an adaptive response to chemical and oxidative stress characterised by the upregulated expression of cytoprotective target genes. In order to understand the mechanistic relevance of Nrf2 as a marker of drug-induced stress it is important to know if this adaptive response is truly localised in the context of organ-specific drug toxicity. Here, we address this knowledge gap through real-time bioluminescence imaging of transgenic Nrf2-luciferase (Nrf2-luc) reporter mice following administration of the metabolism-dependent hepatotoxin acetaminophen (APAP) or the direct nephrotoxin cisplatin...
November 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29162699/dnajb1-prkaca-fusion-kinase-interacts-with-%C3%AE-catenin-and-the-liver-regenerative-response-to-drive-fibrolamellar-hepatocellular-carcinoma
#10
Edward R Kastenhuber, Gadi Lalazar, Shauna L Houlihan, Darjus F Tschaharganeh, Timour Baslan, Chi-Chao Chen, David Requena, Sha Tian, Benedikt Bosbach, John E Wilkinson, Sanford M Simon, Scott W Lowe
A segmental deletion resulting in DNAJB1-PRKACA gene fusion is now recognized as the signature genetic event of fibrolamellar hepatocellular carcinoma (FL-HCC), a rare but lethal liver cancer that primarily affects adolescents and young adults. Here we implement CRISPR-Cas9 genome editing and transposon-mediated somatic gene transfer to demonstrate that expression of either the endogenous fusion protein or a chimeric cDNA leads to the formation of indolent liver tumors in mice that closely resemble human FL-HCC...
November 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29154789/biosynthesis-of-microcystin-hepatotoxins-in-the-cyanobacterial-genus-fischerella
#11
Karina Heck, Danillo O Alvarenga, Tania K Shishido, Alessandro M Varani, Felipe A Dörr, Ernani Pinto, Leo Rouhiainen, Jouni Jokela, Kaarina Sivonen, Marli F Fiore
Microcystins (MCs) are serine/threonine phosphatase inhibitors synthesized by several members of the phylum Cyanobacteria. Mining the draft genome sequence of the nostocalean MC-producing Fischerella sp. strain CENA161 led to the identification of three contigs containing mcy genes. Subsequent PCR and Sanger sequencing allowed the assembling of its complete biosynthetic mcy gene cluster with 55,016 bases in length. The cluster encoding ten genes (mcyA-J) with a central bidirectional promoter was organized in a similar manner as found in other genera of nostocalean cyanobacteria...
November 14, 2017: Toxicon: Official Journal of the International Society on Toxinology
https://www.readbyqxmd.com/read/29151689/reabsorption-of-iron-into-acutely-damaged-rat-liver-a-role-for-ferritins
#12
Ihtzaz Ahmed Malik, Jörg Wilting, Giuliano Ramadori, Naila Naz
AIM: To studied iron metabolism in liver, spleen, and serum after acute liver-damage, in relation to surrogate markers for liver-damage and repair. METHODS: Rats received intraperitoneal injection of the hepatotoxin thioacetamide (TAA), and were sacrificed regularly between 1 and 96 h thereafter. Serum levels of transaminases and iron were measured using conventional laboratory assays. Liver tissue was used for conventional histology, immunohistology, and iron staining...
November 7, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/29132031/effects-of-microcystis-on-development-of-early-life-stage-japanese-medaka-oryzias-latipes-comparative-toxicity-of-natural-blooms-cultured-microcystis-and-microcystin-lr
#13
Spencer R Saraf, Amy Frenkel, Matthew J Harke, Jennifer G Jankowiak, Christopher J Gobler, Anne E McElroy
Freshwater cyanobacterial harmful algal blooms (CyanoHABs) caused by algae in the genus Microcystis have been increasing in frequency and severity in recent decades. Microcystis blooms threaten aquatic organisms through effects associated with the rapid increase of biomass and the production of the hepatotoxin microcystin (MC) by toxic strains. Among fish, effects of blooms are likely to be more severe for early life stages, and physiological impacts on this life stage could significantly impact recruitment and fish populations...
November 2, 2017: Aquatic Toxicology
https://www.readbyqxmd.com/read/29062311/production-of-high-amounts-of-hepatotoxin-nodularin-and-new-protease-inhibitors-pseudospumigins-by-the-brazilian-benthic-nostoc-sp-cena543
#14
Jouni Jokela, Lassi M P Heinilä, Tânia K Shishido, Matti Wahlsten, David P Fewer, Marli F Fiore, Hao Wang, Esa Haapaniemi, Perttu Permi, Kaarina Sivonen
Nostoc is a cyanobacterial genus, common in soils and a prolific producer of natural products. This research project aimed to explore and characterize Brazilian cyanobacteria for new bioactive compounds. Here we report the production of hepatotoxins and new protease inhibitors from benthic Nostoc sp. CENA543 isolated from a small, shallow, saline-alkaline lake in the Nhecolândia, Pantanal wetland area in Brazil. Nostoc sp. CENA543 produces exceptionally high amounts of nodularin-R. This is the first free-living Nostoc that produces nodularin at comparable levels as the toxic, bloom-forming, Nodularia spumigena...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/29055933/long-term-low-dose-exposure-to-microcystin-lr-does-not-cause-or-increase-the-severity-of-liver-disease-in-rodents
#15
Meaghan Labine, Yuewen Gong, Gerald Y Minuk
BACKGROUND: Acute exposure to high concentrations of microcystin-LR (MC-LR) can cause significant hepatocyte injury. AIM: To document the effects of long-term, low-dose MC-LR exposure on hepatic inflammation and fibrosis in mice with healthy and diseased livers. MATERIAL AND METHODS: Male CD1 mice (N = 20/group) were exposed to 1.0 μg/L of MC-LR in drinking water; 1.0 μg/L MC-LR plus 300 mg/L of the hepatotoxin thioacetamide (MC-LR/TAA); or 300 mg/L TAA alone for 28 weeks...
October 16, 2017: Annals of Hepatology
https://www.readbyqxmd.com/read/29054145/simple-high-efficiency-detection-of-microcystins-and-nodularin-r-in-water-by-fluorescence-polarization-immunoassay
#16
Huiyan Zhang, Shupeng Yang, Ross C Beier, Natalia V Beloglazova, Hongtao Lei, Xiulan Sun, Yuebin Ke, Suxia Zhang, Zhanhui Wang
This manuscript describes the development of a sensitive, fast and easily-performed fluorescence polarization immunoassay (FPIA) for detection of microcystins (MCs) and nodularin-R (NOD) in water. MCs and NOD, the most widespread cyanobacterial toxin are hepatotoxins and tumor promoters, and their acute exposure may result in severe health problems in animals and humans. The fluorescein-based tracers were synthesized, and for the first time preparative high performance liquid chromatography (HPLC) was employed for their purification...
November 1, 2017: Analytica Chimica Acta
https://www.readbyqxmd.com/read/29024253/prerequisites-of-isopeptide-bond-formation-in-microcystin-biosynthesis
#17
Sabine Meyer, Andi Mainz, Jan-Christoph Kehr, Roderich D Süssmuth, Elke Dittmann
The biosynthesis of the potent cyanobacterial hepatotoxin microcystin involves isopeptide bond formation through the carboxylic acid side chains of d-glutamate and β-methyl d-aspartate. Analysis of the in vitro activation profiles of the two corresponding adenylation domains, McyE-A and McyB-A2 , either in a didomain or a tridomain context with the cognate thiolation domain and the upstream condensation domain revealed that substrate activation of both domains strictly depended on the presence of the condensation domains...
October 11, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28984034/microcystin-lr-disrupts-insulin-signaling-by-hyperphosphorylating-insulin-receptor-substrate-1-and-glycogen-synthase
#18
Jinghui Liu, Chun Xu, Shaofeng Zhang, Haoyan Li, Kele Chen, Pu Huang, Zonglou Guo, Lihong Xu
Microcystin-LR (MC-LR) is a cyanobacteria-derived heptapeptide that has been commonly characterized as a hepatotoxin. Although the liver is a primary organ in glucose homeostasis, the effect of MC-LR on glucose metabolism remains unclear. In this study, the human liver cell line HL7702 and ICR mice were exposed to various concentrations of MC-LR for 24 h, and the proteins involved in insulin signaling were investigated. The results showed that MC-LR treatment induced the hyperphosphorylation of insulin receptor substrate 1 (IRS1) at several serine sites, S307, S323, S636/639, and S1101 in HL7702 cells, and S302, S318, S632/635, and S1097 in mice livers...
October 6, 2017: Environmental Toxicology
https://www.readbyqxmd.com/read/28919358/perfused-human-hepatocyte-microtissues-identify-reactive-metabolite-forming-and-mitochondria-perturbing-hepatotoxins
#19
Cliff Rowe, Mohsen Shaeri, Emma Large, Terri Cornforth, Angela Robinson, Tomasz Kostrzewski, Rowena Sison-Young, Christopher Goldring, Kevin Park, David Hughes
Hepatotoxins cause liver damage via many mechanisms but the formation of reactive metabolites and/or damage to liver mitochondria are commonly implicated. We assess 3D human primary hepatocyte microtissues as a platform for hepatotoxicity studies with reactive metabolite-forming and mitochondria-perturbing compounds. We show that microtissues formed from cryopreserved human hepatocytes had bile canaliculi, transcribed mRNA from genes associated with xenobiotic metabolism and expressed functional cytochrome P450 enzymes...
September 15, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/28899665/toxin-composition-of-the-2016-microcystis-aeruginosa-bloom-in-the-st-lucie-estuary-florida
#20
Stuart Oehrle, Marliette Rodriguez-Matos, Michael Cartamil, Cristian Zavala, Kathleen S Rein
A bloom of the cyanobacteria, Microcystis aeruginosa occurred in the St. Lucie Estuary during the summer of 2016, stimulated by the release of waters from Lake Okeechobee. This cyanobacterium produces the microcystins, a suite of heptapeptide hepatotoxins. The toxin composition of the bloom was analyzed and was compared to an archived bloom sample from 2005. Microcystin-LR was the most abundant toxin with lesser amounts of microcystin variants. Nodularin, cylindrospermopsin and anatoxin-a were not detected.
November 2017: Toxicon: Official Journal of the International Society on Toxinology
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