Top 10 Biorxiv Papers Today in Pharmacology And Toxicology


1.998 Mikeys
#1. Black sea cucumber (Holothuria atra Jaeger, 1833) protects Caenorhabditis elegans against Pseudomonas aeruginosa infection
Wan-Ting Lee, Boon-Khai Tan, Su-Anne Eng, Gan Chee Yuen, Kit Lam Chan, Yee Kwang Sim, Shaida Fariza Sulaiman, Alexander Shu-Chien Chong
The capacity of crustaceans to biosynthesise long-chain polyunsaturated fatty acids has yet to be fully defined, due to the lack of evidence on the functional activities of enzymes involved in desaturation or elongation of fatty acid substrates. We report here the cloning and in vitro functional analysis of an elongase from the orange mud crab, Scylla olivacea. Sequence and phylogenetic analysis placed the elovl close to the vertebrate Elovl1 and Elovl7 clade, which is distinct from the other remaining five Elovl families. The elongase was also clustered together with several elongases from crustaceans and insects. This elongase showed activities towards 16:1n-7, and at lower rate, linoleic acid (18:2n-6) and linolenic acid (18:3n-3). To our knowledge this is the first description of a functional enzyme involved in biosynthesis of long-chained polyunsaturated fatty acids in a crustacean species. Expression of the S. olivacea elovl7-like mRNA was prominent in stomach, intestine and gill tissues, due to the need to regulate the...
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Authors: 8
Total Words: 8820
Unqiue Words: 3378

1.993 Mikeys
#2. Scavenging of reactive dicarbonyls with 2-hydroxybenzylamine reduces atherosclerosis in hypercholesterolemic Ldlr-/- mice
Huan Tao, Jiansheng Huang, Patricia G Yancey, Lei Ding, Youmin Zhang, John L Blakemore, Venkataraman Amarnath, John A Oates, L Jackson Roberts, Sean S Davies, MacRae F Linton
The pathogenesis of atherosclerosis is accelerated by oxidative stress, which produces lipid peroxidation. Among the products of lipid peroxidation are highly reactive dicarbonyls that covalently modify proteins. We investigated the impact of treatment with the dicarbonyl scavenger, 2-hydroxybenzylamine (2-HOBA) on HDL function and atherosclerosis in hyperlipidemic Ldlr-/- mice, a model of familial hypercholesterolemia (FH). Compared to mice treated with vehicle, 2-HOBA significantly decreased atherosclerosis in hypercholesterolemic Ldlr-/- mice by 31% in the proximal aortas and 60% in en face aortas, in the absence of changes in blood lipid levels. 2-HOBA reduced malondialdehyde (MDA) content in HDL, LDL, and in the atherosclerotic lesions. Consuming a Western diet increased plasma MDA-apoAI adduct levels in Ldlr-/- mice. 2-HOBA inhibited MDA-apoAI formation and increased the capacity of the mouse HDL to reduce macrophage cholesterol stores. Furthermore, 2-HOBA diminished oxidative stress-induced inflammatory responses in...
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Authors: 11
Total Words: 9380
Unqiue Words: 2570

0.0 Mikeys
#3. Preclinical Modeling of Exposure to a Global Marine Bio Contaminant: Effects of In Utero Domoic Acid Exposure on Neonatal Behavior and Infant Memory
Kimbery S Grant, Brenda Crouthamel, Caroline Kenney, Noelle McKain, Rebekah Petroff, Sara Shum, Jing Jing, Nina Isoherranen, Thomas M Burbacher
Domoic Acid (DA) is a naturally-occurring marine neurotoxin that is increasingly recognized as an important public health issue. Prenatal DA exposure occurs through the maternal consumption of contaminated shellfish/finfish. To better understand the fetal risks associated with DA, we initiated a longitudinal, preclinical study focused on the reproductive and developmental effects of chronic, low-dose oral DA exposure. To this end, 32 adult female Macaca fascicularis monkeys were orally dosed with 0, 0.075 or 0.15 mg/kg/day DA on a daily basis throughout breeding and pregnancy. The doses included the proposed human Tolerable Daily Intake (TDI) (0.075 mg/kg/day) for DA. Adult females were bred to nonexposed males. To evaluate behavioral development during early infancy, offspring were administered a neonatal exam modeled after the human Neonatal Behavior Assessment Scale and a series of visual recognition memory problems. Results indicated that DA does not impact early survival reflexes or responsivity to the environment during the...
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Sample Sizes : [10, 11, 11, 9, 9, 10, 8]
Authors: 9
Total Words: 8196
Unqiue Words: 2785

0.0 Mikeys
#4. The pyriproxyfen metabolite 4'OH- pyriproxyfen disrupts thyroid hormone signaling and enhances Musashi-1 levels in neuroprogenitors.
Petra Spirhanzlova, Sebastien Le Mevel, Karn Wejaphikul, Bilal Mughal, Jean-David Gothie, Anthony Sebillot, Lucille Butruille, Michelle Leemans, Theo Visser, Sylvie Remaud, Jean-Baptiste Fini, Barbara Demeneix
Epidemiological and experimental studies have raised questions as to whether the insecticide pyriproxyfen (PPF) could be implicated in the increased incidence of microcephaly associated with ZIKA infection during pregnancy. This pesticide is documented as a thyroid hormone (TH) disrupting chemical. We investigated whether environmentally relevant amounts of its main metabolite, 4'-OH-pyriproxyfen (4'-OH-PPF), modified TH signaling and early neuronal development. First, an in silico study revealed strong affinity of 4-OH-PPF to fit the ligand binding pocket of TH receptors (TRs). Further, in vitro assays on human cell lines showed 4'OH-PPF (> 3 mg/L ) to act as a TRα antagonist. Next, using a transgenic Xenopus TH-sensitive reporter system, Tg(thibz:GFP) tadpoles showed that 4'OH-PPF (> 10-7 mg/L) displayed TH-disruptive activity and reduced tadpole mobility (> 10-1 mg/L). Exposure to 4'OH-PPF significantly reduced Xenopus head size at levels equivalent to the maximum recommended daily intake of PPF (3x 10-1 mg/L). Most strikingly,...
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biorxivpreprint: The pyriproxyfen metabolite 4'OH- pyriproxyfen disrupts thyroid hormone signaling and enhances Musashi-1 levels in neuroprogenitors. https://t.co/f0Vf2raTLE #bioRxiv
outbreaksci: Read it? Rate it. If you read "The pyriproxyfen metabolite 4'OH- pyriproxyfen disrupts thyroid hormone signaling and enhances Musashi-1 levels in neuroproge..." (https://t.co/rQ8uYluXf0), provide an @outbreaksci rapid review here [prototype]: https://t.co/acDeHAyHI3
outbreaksci: New #Zika preprint: The pyriproxyfen metabolite 4'OH- pyriproxyfen disrupts thyroid hormone signaling and enhances Musashi-1 levels in neuroprogenitors. https://t.co/rQ8uYluXf0
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Sample Sizes : None.
Authors: 12
Total Words: 8836
Unqiue Words: 3441

0.0 Mikeys
#5. The Utilization of Pharmacophore-based 3D QSAR Modeling and Virtual Screening in Safety Profiling: a Case Study to Identify Antagonistic Activities against Adenosince Receptor, A2aR, using 1,897 known drugs
Fan Fan, Hisham Hamadeh, Dora Toledo Warshaviak, Robert Dunn
Safety pharmacology screening against a wide range of unintended vital targets using in vitro assays is crucial to understand off-target interactions with drug candidates. With the increasing demand for in vitro assays, ligand- and structure-based virtual screening approaches have been evaluated for potential utilization in safety profiling. Although ligand based ap-proaches have been actively applied in retrospective analysis or prospectively within well-defined chemical space during the early discovery stage (i.e., HTS screening and lead optimization), virtual screening is rarely implemented in later stage of drug discovery (i.e., safety). Here we present a case study to evaluate ligand-based 3D QSAR models built based on in vitro antagonistic activity data against adenosine receptor 2A (A2aR). The resulting models, obtained from 268 chemically diverse compounds, were used to test a set of 1,897 chemically distinct drugs, simulating the real-world challenge of safety screening when presented with novel chemistry and a limited...
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Authors: 4
Total Words: 11091
Unqiue Words: 3145

0.0 Mikeys
#6. Sapropterin Treatment Prevents Congenital Heart Defects Induced by Pregestational Diabetes in Mice
Anish Engineer, Tana Saiyin, Xiangru Lu, Andrew S. Kucey, Brad L. Urquhart, Thomas A. Drysdale, Kambiz Norozi, Qingping Feng
Aims: Tetrahydrobiopterin (BH4) is a co-factor of endothelial nitric oxide synthase (eNOS), which is critical to embryonic heart development. We aimed to study the effects of sapropterin (Kuvan), an orally active synthetic form of BH4 on eNOS uncoupling and congenital heart defects (CHDs) induced by pregestational diabetes in mice. Methods: Adult female mice were induced to pregestational diabetes by streptozotocin and bred with normal males to produce offspring. Pregnant mice were treated with sapropterin or vehicle during gestation. CHDs were identified by histological analysis. Cell proliferation, eNOS dimerization and reactive oxygen species (ROS) production were assessed in the fetal heart. Results: Pregestational diabetes results in a spectrum of CHDs in their offspring. Oral treatment with sapropterin in the diabetic dams significantly decreased the incidence of CHDs from 59% to 27% and major abnormalities, such as atrioventricular septal defect and double outlet right ventricle were absent in the sapropterin treated group....
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Sample Sizes : [37, 19, 3]
Authors: 8
Total Words: 9129
Unqiue Words: 2687

0.0 Mikeys
#7. Transcriptional regulatory mechanisms of fibrosis development in mouse lung tissue exposed to carbon nanotubes
Vadim Zhernovkov, Tapesh Santra, Hilary Cassidy, Oleksii Rukhlenko, David Matallanas, Aleksandar Krstic, Walter Kolch, Vladimir Lobaskin, Boris N Kholodenko
Carbon nanotubes (CNTs) usage has rapidly increased in the last few decades due to their unique properties, exploited in various industrial and commercial products. Certain types of CNTs cause adverse health effects, including chronic inflammation and fibrosis. Despite the large number of in vitro and in vivo studies evaluating these effects, many important questions remain unanswered due to a lack of mechanistic understanding of how CNTs induce cellular stress responses. In order to predict CNT toxicity, it is important to understand which transcriptional programs are specifically activated in response to CNTs, and what similarities and differences exist in relation to other toxic inducers exerting similar adverse effects. A systems biology approach was applied to reveal complex interactions at the molecular level in mouse lung tissue in response to different fibrosis inducers: two types of multi-walled CNTs, NM-401 and NRCWE-26, and bleomycin (BLM). Based on mRNA gene expression profiles, we inferred gene regulatory networks...
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biorxivpreprint: Transcriptional regulatory mechanisms of fibrosis development in mouse lung tissue exposed to carbon nanotubes https://t.co/AnDtpv3fUO #bioRxiv
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Authors: 9
Total Words: 9885
Unqiue Words: 2936

0.0 Mikeys
#8. Identification of Kinase Inhibitors that Regulate Nuclear Receptor Nurr1 (NR4A2) Cellular Activity
Kenya L. Williams, Carrow I. Wells, John T. Moore
The ability to regulate the activity NR4A subfamily of nuclear receptors would be potentially useful in the treatment of multiple diseases, but to date, few regulators have been reported. This is likely due to the fact that the NR4A subfamily does not have a typical unoccupied nuclear receptor ligand binding pocket, but rather a pocket that is occupied with hydrophobic side chains of adjacent amino acids. It follows that traditional nuclear receptor assays that seek to identify ligands that bind within the ligand binding pocket would not be successful. We have thus focused on an alternate assay to identify NR4A regulators based on the fact that regulation of NR4A, at least partially, results from phosphorylation/dephosphorylation of the amino terminal region of the protein. We developed a medium throughput cellular assay using a fusion of the amino terminus of Nurr1 (NR4A2) with luciferase reporter and used the assay to screen a large and diverse protein kinase inhibitor set (PKIS). We identified multiple kinase inhibitor...
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ScienceofPD: Nuclear receptor related 1 protein (NURR1) is a protein that appears to be critical for dopamine neuron survival. New @biorxivpreprint manuscript identifies kinase inhibitors that regulate (increase or decrease) NURR1 activity. Implications 4 #Parkinsons? https://t.co/aUzMgSBIK5 https://t.co/Qhae38z6rv
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Authors: 3
Total Words: 4312
Unqiue Words: 1608

0.0 Mikeys
#9. Drug prescription pattern in European neonatal units
Inge Mesek, Georgi Nellis, Jana Lass, Tuuli Metsvaht, Heili Varendi, Helle Visk, Mark A. Turner, Anthony J. Nunn, Jennifer Duncan, Irja Lutsar
Background: Hospitalized neonates receive the highest number of drugs compared to all other age groups, but consumption rates vary between studies depending on patient characteristics and local practices. There are no large scale international studies on drug use in neonatal units. We aimed to describe drug use in European neonatal units and characterize its associations with geographic region and gestational age (GA). Methods: A one-day point prevalence study (PPS) was performed as part of the European Study of Neonatal Exposure to Excipients (ESNEE) from January to June 2012. All neonatal prescriptions and demographic data were registered in a web-based database. The impact of GA and region on prescription rate were analyzed with logistic regression. Results: In total, 21 European countries with 89 neonatal units participated. Altogether 2173 prescriptions given to 726 neonates were registered. The 10 drugs with the highest prescription rate were multivitamins, vitamin D, caffeine, gentamicin, amino acids for parenteral...
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biorxivpreprint: Drug prescription pattern in European neonatal units https://t.co/kdi1q7RH9P #bioRxiv
irjalu: Drug prescription pattern in European neonatal units https://t.co/RNz0cTRDBo
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Sample Sizes : [477]
Authors: 10
Total Words: 7213
Unqiue Words: 2540

0.0 Mikeys
#10. A Data-Driven Transcriptional Taxonomy of Adipogenic Chemicals to Identify Emerging Metabolic Health Threats
Stephanie Kim, Eric Reed, Stefano Monti, Jennifer Schlezinger
Background: Growing evidence suggests that chemicals in disparate structural classes activate specific subsets of PPARγ's transcriptional programs to generate adipocytes with distinct phenotypes. Objectives: Our objectives were to 1) establish a novel classification method to predict PPARγ interacting and modifying chemicals, and 2) create a taxonomy to group chemicals based on their effects on PPARγ's transcriptome and downstream metabolic functions. We tested the hypothesis that environmental ligands highly ranked by the taxonomy, but that segregated from the therapeutic ligands, would induce white but not brite adipogenesis. Methods: 3T3-L1 cells were differentiated in the presence of 76 chemicals (negative controls, synthetic nuclear receptor ligands known to influence adipocyte biology, suspected environmental PPARγ ligands). Differentiation was assessed by measuring lipid accumulation. mRNA expression was determined by highly multiplexed RNA-Seq and validated by RT-qPCR. A novel classification model was developed using an...
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biorxivpreprint: A Data-Driven Transcriptional Taxonomy of Adipogenic Chemicals to Identify Emerging Metabolic Health Threats https://t.co/tEE05t2jeT #bioRxiv
tonygill3: A Data-Driven Transcriptional Taxonomy of Adipogenic Chemicals to Identify Emerging Metabolic Health Threats https://t.co/RKjo0SxKaw focus on environmental chemicals that interact or modify PPARγ, the "master regulator of obesity" Interactive dendrograms: https://t.co/WbBWvSQ8uI
MontiLab: #EnvironmentalToxicants not only bad for #Cancer: "A Data-Driven Transcriptional Taxonomy of Adipogenic Chemicals to Identify Emerging Metabolic Health Threats" https://t.co/R9dkKZ8K2v #bioRxiv @BUbioinfo @BU_CBM @BUSPH
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Authors: 4
Total Words: 11112
Unqiue Words: 3304

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