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Guotao Peng, Robbie Martin, Stephen Dearth, Xiaocun Sun, Gregory L Boyer, Shawn Campagna, Sijie Lin, Steven W Wilhelm
Freshwater cyanobacterial blooms are regularly formed by Microcystis spp., which are well-known producers of the hepatotoxin microcystin. The environmental factors that regulate microcystin synthesis remain unclear. We used reverse transcription-quantitative PCR (RT-qPCR), metabolomics, and toxin profiling (both by LC-MS) to measure the response of Microcystis aeruginosa NIES-843 to nitrogen (N) concentration, N chemistry (nitrate vs. urea), and a range of seasonally-relevant temperatures. Growth rates at lower temperatures were slower but resulted in increased cellular microcystin content (quota), and at these lower temperatures, N concentration had no effect on toxin production...
March 9, 2018: Environmental Science & Technology
Shiqing Zhou, Yanghai Yu, Weiqiu Zhang, Xiaoyang Meng, Jinming Luo, Lin Deng, Zhou Shi, John C Crittenden
Advanced oxidation processes (AOPs) have been widely used for the destruction of organic contaminants in the aqueous phase. In this study, we introduce an AOP on activated peroxymonosulfate (PMS) by using ascorbic acid (H2A) to generate sulfate radicals (SO4•-). Sulfate radicals, hydroxyl radicals (HO•) and ascorbyl radicals (A•-) were found using electron spin resonance (ESR). But we found A•- is negligible in the degradation of microcystin-LR (MCLR) due to its low reactivity. We developed a first-principles kinetic model to simulate the MCLR degradation and predict the radical concentrations...
March 7, 2018: Environmental Science & Technology
Gaby Danan, Rolf Teschke
Launched in 1993 and partially based on the results of an international consensus meeting organized under the auspices of the Council of International Organizations of Medical Sciences (CIOMS), the Roussel Uclaf Causality Assessment Method (RUCAM) is the most used causality assessment tool worldwide for the diagnosis of drug-induced liver injury (DILI) and herb-induced liver injury (HILI) in a large number of epidemiological studies, case reports, and case series. The 25-year experience of RUCAM use confirmed that the success was due to its objective, standardized, and liver-injury-specific approach structured with defined key elements derived from a series of DILI cases with positive rechallenge...
March 3, 2018: Drug Safety: An International Journal of Medical Toxicology and Drug Experience
Yujiao Wang, Yanqiu Cao, Hongmei Li, Aijun Gong, Jintao Han, Zhen Qian, Wenran Chao
Microcystins (MCs) is a kind of hepatotoxin, which is the secondary metabolite of cyanobacteria. Bi 2 O 2 CO 3 (BOC) is a kind of cheap and nontoxic semiconductor material. BOC was synthetized by solvothermal method and then microcystin-LR (MC-LR) and microcystin-RR (MC-RR) were removed by BOC, through adsorption and photocatalytic degradation. When the dosage of BOC is 6 g/L, the MC-LR and MC-RR in the natural water sample can be completely adsorbed in 30 min and then after 12 h irradiation, MC-LR and MC-RR were photocatalytically degraded by BOC...
February 14, 2018: Environmental Science and Pollution Research International
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
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
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
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
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...
February 1, 2018: Free Radical Biology & Medicine
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...
January 2018: Expert Review of Molecular Diagnostics
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
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
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
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...
December 12, 2017: Proceedings of the National Academy of Sciences of the United States of America
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...
January 2018: Toxicon: Official Journal of the International Society on Toxinology
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
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
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
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
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
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