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https://www.readbyqxmd.com/read/28548833/structure-activity-relationship-for-small-molecule-inhibitors-of-nicotinamide-n-methyltransferase
#1
Harshini Neelakantan, Hua-Yu Wang, Virginia Vance, Jonathan D Hommel, Stanton F McHardy, Stanley J Watowich
Nicotinamide N-methyltransferase (NNMT) is a fundamental cytosolic biotransforming enzyme that catalyzes the N-methylation of endogenous and exogenous xenobiotics. We have identified small molecule inhibitors of NNMT with >1000-fold range of activity and developed comprehensive structure-activity relationships (SARs) for NNMT inhibitors. Screening of N-methylated quinolinium, isoquinolinium, pyrididium, and benzimidazolium/benzothiazolium analogs resulted in the identification of quinoliniums as a promising scaffold with very low micromolar (IC50 ~1 μM) NNMT inhibition...
May 26, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28542880/suicidal-death-of-erythrocytes-in-cancer-and-its-chemotherapy-a-potential-target-in-the-treatment-of-tumor-associated-anemia
#2
REVIEW
Elisabeth Lang, Rosi Bissinger, Syed M Qadri, Florian Lang
In analogy to apoptosis of nucleated cells, erythrocytes may enter eryptosis characterized by cell shrinkage and cell membrane scrambling. Eryptotic erythrocytes are rapidly cleared from circulating blood and may adhere to the vascular wall. Stimulation of eryptosis thus impairs microcirculation and leads to anemia as soon as the loss of erythrocytes cannot be fully compensated by enhanced erythropoiesis. Signaling stimulating eryptosis includes increase of cytosolic Ca(2+) -activity, ceramide, caspases, calpain, p38-kinase, protein-kinase C, Janus-activated kinase 3, casein-kinase 1α, and cyclin-dependent kinase 4...
May 23, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28541669/effects-of-polychlorinated-biphenyls-pcbs-and-their-hydroxylated-metabolites-oh-pcbs-on-arabidopsis-thaliana
#3
Srishty Subramanian, Jerald L Schnoor, Benoit Van Aken
Plants metabolize polychlorinated biphenyls (PCBs) into hydroxylated derivatives (OH-PCBs), which are sometimes more toxic than the parent PCBs. The objective of this research was to compare the toxicity of a suite of PCBs and OH-PCBs toward the model plant, Arabidopsis thaliana. While parent PCBs and higher-chlorinated OH-PCBs exhibited a low or non-detectable toxicity, lower-chlorinated OH-PCBs significantly inhibited the germination rate and plant growth, with IC50 ranging from 1.6 to 12.0 mg L-1. The transcriptomic response of A...
May 25, 2017: Environmental Science & Technology
https://www.readbyqxmd.com/read/28541575/xenobiotic-car-activators-induce-dlk1-dio3-locus-non-coding-rna-expression-in-mouse-liver
#4
Lucie Pouché, Antonio Vitobello, Michael Römer, Milica Glogovac, A Kenneth MacLeod, Heidrun Ellinger-Ziegelbauer, Magdalena Westphal, Valérie Dubost, Daniel Philipp Stiehl, Bérengère Dumotier, Alexander Fekete, Pierre Moulin, Andreas Zell, Michael Schwarz, Rita Moreno, Jeffrey T J Huang, Cliff R Elcombe, Colin J Henderson, C Roland Wolf, Jonathan G Moggs, Rémi Terranova
Derisking xenobiotic-induced non-genotoxic carcinogenesis (NGC) represents a significant challenge during the safety assessment of chemicals and therapeutic drugs. The identification of robust mechanism-based NGC biomarkers has the potential to enhance cancer hazard identification. We previously demonstrated Constitutive Androstane Receptor (CAR) and WNT signaling-dependent up-regulation of the pluripotency associated Dlk1-Dio3 imprinted gene cluster non-coding RNAs (ncRNAs) in the liver of mice treated with tumor-promoting doses of phenobarbital (PB)...
May 25, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28540740/the-incomplete-glutathione-puzzle-just-guessing-at-numbers-and-figures
#5
Marcel Deponte
SIGNIFICANCE: Glutathione metabolism is comparable to a jigsaw puzzle with too many pieces. It supposably comprises (i) the reduction of disulfides, hydroperoxides, sulfenic acids and nitrosothiols, (ii) the detoxification of aldehydes, xenobiotics and heavy metals, and (iii) the synthesis of eicosanoids, steroids and iron-sulfur clusters. Furthermore, glutathione affects oxidative protein folding and redox signaling. Here, I review the relevance of glutathione-dependent pathways with an emphasis on quantitative data...
May 25, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/28536195/discovery-of-a-widespread-metabolic-pathway-within-and-among-phenolic-xenobiotics
#6
Pahriya Ashrap, Guomao Zheng, Yi Wan, Tong Li, Wenxin Hu, Wenjuan Li, Hong Zhang, Zhaobin Zhang, Jianying Hu
Metabolism is an organism's primary defense against xenobiotics, yet it also increases the production of toxic metabolites. It is generally recognized that phenolic xenobiotics, a group of ubiquitous endocrine disruptors, undergo rapid phase II metabolism to generate more water-soluble glucuronide and sulfate conjugates as a detoxification pathway. However, the toxicological effects of the compounds invariably point to the phase I metabolic cytochrome P450 enzymes. Here we show that phenolic xenobiotics undergo an unknown metabolic pathway to form more lipophilic and bioactive products...
May 23, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28535598/antarctic-seals-molecular-biomarkers-as-indicators-for-pollutant-exposure-health-effects-and-diet
#7
K Lehnert, L Weirup, K C Harding, T Härkönen, O Karlsson, J Teilmann
Weddell (Leptonychotes weddellii), Ross (Ommatophoca rossii) and crabeater seals (Lobodon carcinophaga) are phocid seals with a circumpolar distribution around Antarctica. As long-lived and large top predators, they bioaccumulate contaminants and are considered as sentinels of ecosystem health. Antarctic seals are increasingly exposed to climate change, pollution, shipping and fisheries. To reveal and understand possible anthropogenic impacts on their immune and health status, this study investigates sensitive biomarkers of the xenobiotic metabolism and immune system in relation to mercury (Hg) burden...
May 19, 2017: Science of the Total Environment
https://www.readbyqxmd.com/read/28534176/functions-of-pregnane-x-receptor-in-self-detoxification
#8
REVIEW
Liuqin He, Xihong Zhou, Niu Huang, Huan Li, Tiejun Li, Kang Yao, Yanan Tian, Chien-An Andy Hu, Yulong Yin
Pregnane X receptor (PXR, NR1I2), a member of the nuclear receptor superfamily, is a crucial regulator of nutrient metabolism and metabolic detoxification such as metabolic syndrome, xenobiotic metabolism, inflammatory responses, glucose, cholesterol and lipid metabolism, and endocrine homeostasis. Notably, much experimental and clinical evidence show that PXR senses xenobiotics and triggers the detoxification response to prevent diseases such as diabetes, obesity, intestinal inflammatory diseases and liver fibrosis...
May 22, 2017: Amino Acids
https://www.readbyqxmd.com/read/28533019/the-in-vitro-effect-of-nonylphenol-propranolol-and-diethylstilbestrol-on-quality-parameters-and-oxidative-stress-in-sterlet-acipenser-ruthenus-spermatozoa
#9
Olena Shaliutina, Ievgeniia Gazo, Anna Shaliutina-Kolešová, Ievgen Lebeda, Marek Rodina
The sturgeon is a highly endangered fish mostly due to over-fishing, habitat destruction, and water pollution. Nonylphenol (NP), propranolol (PN), and diethylstilbestrol (DES) are multifunctional xenobiotic compounds used in a variety of commercial and industrial products. The mechanism by which these xenobiotic compounds interfere with fish reproduction is not fully elucidated. This study assessed the effect of NP, PN, and DES on motility parameters, membrane integrity, and oxidative/antioxidant status in sterlet Acispenser ruthenus spermatozoa...
May 19, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/28532626/single-nucleotide-polymorphisms-of-abcc2-modulate-renal-secretion-of-endogenous-organic-anions
#10
Kienana Muhrez, Bérenger Largeau, Patrick Emond, Montigny Frédéric, Jean-Michel Halimi, Patrick Trouillas, Chantal Barin-LE Guellec
The ATP-binding cassette family transporter MRP2 (multidrug resistance-associated protein 2), encoded by the ABCC2 gene, is involved in the renal excretion of numerous xenobiotics and it is likely that it also transports many endogenous molecules arising from not only normal essential metabolic processes but also from environmental toxins or food intake. We used a targeted gas chromatography-mass spectrometry metabolomics analysis to study whether endogenous organic anions are differentially excreted in urines of healthy volunteers according to their genotype for three functional single nucleotide polymorphisms (SNPs) in ABCC2...
May 19, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28527150/development-of-in-silico-protocols-to-predict-structural-insights-into-the-metabolic-activation-pathways-of-xenobiotics
#11
M Kalim A Khan, Salman Akhtar, Jamal M Arif
To establish in silico model to predict the structural insight into the metabolic bioactivation pathway of xenobiotics, we considered two specific and one non-specific mammary procarcinogen [e.g., dibenzo[a,l]pyrene (DBP), 7,12-dimethylbenz[a]anthracene (DMBA), and benzo[a]pyrene (BP)]. The CYP1A1, 1B1, 2C9, 1A2 and 2B6 reported in wet-lab studies to actively metabolize DBP also showed strong binding energies (kcal/mol) of -11.50, -10.67, -10.37, -9.76 and -9.72, respectively, with inhibition constants ranging between 0...
May 19, 2017: Interdisciplinary Sciences, Computational Life Sciences
https://www.readbyqxmd.com/read/28527140/effect-of-tannery-effluent-on-oxidative-status-of-brain-structures-and-liver-of-rodents
#12
Felipe Dos Santos Moysés, Karine Bertoldi, Viviane Rostirola Elsner, Laura Reck Cechinel, Carla Basso, Simone Stülp, Marco Antônio Siqueira Rodrigues, Ionara Rodrigues Siqueira
Oxidative stress has been considered as a central mechanism of toxicity induced by xenobiotics. Previously, it was demonstrated that mice exposed to tannery effluent showed an anxiety-like behavior, without any comparable behavioral effects in rats. The aim of the present study was to investigate the impact of tannery wastewater on oxidative status in in vitro and in vivo assays with two mammal species, mice and rats. Specifically, homogenates of two brain areas and the liver were incubated with tannery wastewater; reactive species and lipid peroxidation levels and antioxidant enzyme activities were detected...
May 19, 2017: Environmental Science and Pollution Research International
https://www.readbyqxmd.com/read/28527047/dietary-ascorbic-acid-reduced-micronucleus-and-nuclear-abnormalities-in-clarias-gariepinus-burchell-1822-exposed-to-hospital-effluent
#13
Chibuisi G Alimba, Raphael D Ajiboye, Olakunle S Fagbenro
Hospital effluents contain myriad of mutagens and genotoxins capable of increasing DNA damage in aquatic biota. African mudfish, Clarias gariepinus, are exposed to genotoxins when cultured in swamps and derelict water bodies often contaminated by effluents. Moreover, its DNA is susceptible to xenobiotic-induced lesions since it lacks L-gulonolactone oxidase and hence cannot synthesize L-ascorbic acid. This study investigated 96-h acute toxicity and protective effects of dietary ascorbic acid (AA) against micronucleus (MN) and abnormal nuclear (NAs) formation in C...
May 19, 2017: Fish Physiology and Biochemistry
https://www.readbyqxmd.com/read/28525281/interaction-of-7-alkoxycoumarins-with-the-aryl-hydrocarbon-receptor
#14
Marco Gargaro, Francesco Epifano, Serena Fiorito, Vito Alessandro Taddeo, Salvatore Genovese, Matteo Pirro, Antonella Turco, Paolo Puccetti, Carsten B Schmidt-Weber, Francesca Fallarino
The aryl hydrocarbon receptor (AhR) is a transcription factor activated by a vast array of natural and synthetic ligands. It plays a pivotal role in numerous physiological and pathological responses, such as cell proliferation and differentiation, induction of xenobiotic metabolizing enzymes, response to environmental toxins, and several others. In this study, we investigated the ability of some natural compounds (oxyprenylated ferulic acid and umbelliferone derivatives) and their semisynthetic analogues (e...
May 19, 2017: Journal of Natural Products
https://www.readbyqxmd.com/read/28525266/gliotoxin-biosynthesis-structure-mechanism-and-metal-promiscuity-of-carboxypeptidase-glij
#15
Antoine Marion, Michael Groll, Daniel H Scharf, Kirstin Scherlach, Manuel Glaser, Holger Sievers, Michael Schuster, Christian Hertweck, Axel A Brakhage, Iris Antes, Eva M Huber
The formation of glutathione (GSH) conjugates, best known from the detoxification of xenobiotics, is a widespread strategy to incorporate sulfur into biomolecules. The biosynthesis of gliotoxin, a virulence factor of the human pathogenic fungus Aspergillus fumigatus, involves attachment of two GSH molecules and their sequential decomposition to yield two reactive thiol groups. The degradation of the GSH moieties requires the activity of the Cys-Gly carboxypeptidase GliJ, for which we describe the X-ray structure here...
May 19, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28524356/association-between-yap-expression-in-neoplastic-and-non-neoplastic-breast-tissue-with-arsenic-urinary-levels
#16
Gladis Michel-Ramirez, Rogelio Recio-Vega, Guadalupe Ocampo-Gomez, Eduardo Palacios-Sanchez, Manuel Delgado-Macias, Manuel Delgado-Gaona, Robert Clark Lantz, Jay Gandolfi, Tania Gonzalez-Cortes
The Hippo pathway regulates cell proliferation and apoptosis and it has been noted that loss of critical components of this pathway can lead to uncontrolled cell growth. Yes-associated protein (YAP) is an important component of this Hippo pathway because YAP is the nuclear effector of the Hippo tumor suppressor pathway and it is crucial for the response to oxidative stress induced by cellular process and by different xenobiotics, including arsenic. It has been proposed that YAP dysregulation can contribute to a malignant cellular phenotype acting as both a tumor suppressor and an oncogene...
May 19, 2017: Journal of Applied Toxicology: JAT
https://www.readbyqxmd.com/read/28524082/cellular-repair-of-dna-dna-cross-links-induced-by-1-2-3-4-diepoxybutane
#17
Lisa N Chesner, Amanda Degner, Dewakar Sangaraju, Shira Yomtoubian, Susith Wickramaratne, Bhaskar Malayappan, Natalia Tretyakova, Colin Campbell
Xenobiotic-induced interstrand DNA-DNA cross-links (ICL) interfere with transcription and replication and can be converted to toxic DNA double strand breaks. In this work, we investigated cellular responses to 1,4-bis-(guan-7-yl)-2,3-butanediol (bis-N7G-BD) cross-links induced by 1,2,3,4-diepoxybutane (DEB). High pressure liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI⁺-MS/MS) assays were used to quantify the formation and repair of bis-N7G-BD cross-links in wild-type Chinese hamster lung fibroblasts (V79) and the corresponding isogenic clones V-H1 and V-H4, deficient in the XPD and FANCA genes, respectively...
May 18, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28523395/evaluating-the-association-between-body-weight-and-the-intestinal-microbiota-of-weaned-piglets-via-16s-rrna-sequencing
#18
Geon Goo Han, Jun-Yeong Lee, Gwi-Deuk Jin, Jongbin Park, Yo Han Choi, Byung Jo Chae, Eun Bae Kim, Yun-Jaie Choi
Due to the ban on the use of antimicrobial growth promoters in livestock feeds, understanding the relationship between intestinal microbiota and the physiology of the host has become very important for improving livestock performance. In this study, we investigated the relationship between intestinal microbiota and body weights of weaned piglets. Lighter (n = 9) and heavier (n = 9) 9-week-old weaned piglets were selected from approximately one hundred individuals based on their body weights. Their fecal microbial communities were analyzed by sequencing the V4 region of the 16S rRNA gene...
May 18, 2017: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/28521423/molecular-dysexpression-in-gastric-cancer-revealed-by-integrated-analysis-of-transcriptome-data
#19
Xiaomei Li, Weiwei Dong, Xueling Qu, Huixia Zhao, Shuo Wang, Yixin Hao, Qiuwen Li, Jianhua Zhu, Min Ye, Wenhua Xiao
Gastric cancer (GC) is often diagnosed in the advanced stages and is associated with a poor prognosis. Obtaining an in depth understanding of the molecular mechanisms of GC has lagged behind compared with other cancers. This study aimed to identify candidate biomarkers for GC. An integrated analysis of microarray datasets was performed to identify differentially expressed genes (DEGs) between GC and normal tissues. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were then performed to identify the functions of the DEGs...
May 2017: Oncology Letters
https://www.readbyqxmd.com/read/28521388/non-targeted-high-resolution-mass-spectrometry-strategy-for-simultaneous-monitoring-of-xenobiotics-and-endogenous-compounds-in-green-sea-turtles-on-the-great-barrier-reef
#20
Amy L Heffernan, Maria M Gómez-Ramos, Caroline Gaus, Soumini Vijayasarathy, Ian Bell, Christine Hof, Jochen F Mueller, Maria J Gómez-Ramos
Chemical contamination poses a threat to ecosystem, biota and human health, and identifying these hazards is a complex challenge. Traditional hazard identification relies on a priori-defined targets of limited chemical scope, and is generally inappropriate for exploratory studies such as explaining toxicological effects in environmental systems. Here we present a non-target high resolution mass spectrometry environmental monitoring study with multivariate statistical analysis to simultaneously detect biomarkers of exposure (e...
May 14, 2017: Science of the Total Environment
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