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bioRxiv2018

Chemoreception of Meloidogyne incognita and Caenorhabditis elegans on botanical nematicidals

Plant-parasitic nematodes cause serious damage to various agricultural crops worldwide, and their control necessitates environmentally safe measures. Plant secondary metabolites of botanical origin are tested here-in to study their effect in Meloidogyne incognita locomotion, being this an important factor affecting host inoculation inside the soil. We compare the effect to the respective behavioral responses of the model organism Caenorhabditis elegans. The tested botanical nematicidals, all reported of activity against Meloidogyne sp. in our previous works, belong to different chemical groups of small molecular weight molecules encompassing acids, alcohols, aldehydes and ketones. Specifically we report on the attractant or repellent properties of trans-anethole, (E,E)-2,4-decadienal, (E)-2-decenal, fostiazate, and 2-undecanone. The treatments for both nematode species were made at sublethal concentration levels, namely 1mM (<EC50), and the chemical control used for the experiment was the commercial nematicide fosthiazate and oxamyl. According to our results, trans-anethole, decenal, and oxamyl act as C. elegans attractants. 2-undecanone strongly attracts M. incognita. These findings can be of use in the development of nematicidal formulates, contributing to the disruption of nematode chemotaxis to root systems.

pharmacology and toxicology↗

bioRxiv2018

Arsenite exposure inhibits histone acetyltransferase p300 for attenuating H3K27ac at enhancers in low-dose exposed mouse embryonic fibroblast cells

Epidemiological investigations have validated the positive relationships between arsenic in drinking water and several cancers, including skin, liver and lung cancers. Besides genotoxicity, arsenic exposure-related pathogenesis of disease is widely considered through epigenetic mechanisms; however, the underlying mechanistic insight remains elusive. Herein we explore the initial epigenetic changes via acute low-dose arsenite exposures of mouse embryonic fibroblast (MEF) cells and Dot1L knockout MEF (Dot1L-/- for abbreviation) cells. Our RNA-seq and Western blot data demonstrated that, in both cell lines, acute low-dose arsenite exposure abolished histone acetyltransferase p300 at the RNA level and subsequent protein level. Consequently, p300-specific main target histone H3K27ac, a marker separating active from poised enhancers, decreased dramatically as validated by both Western blot and ChIP-seq analyses. Concomitantly, H3K4me1 as another well-known marker for enhancers also showed significant decreases, suggesting an underappreciated crosstalk between H3K4me1 and H3K27ac involved in arsenite exposure. Significantly, arsenite exposure-reduced H3K27ac and H3K4me1 inhibit the expression of genes including EP300 itself and Kruppel Like Factor 4(Klf4), a tumor suppressor gene. Collectively, our investigations identify p300 as an internal bridging factor within cells to sense external environmental arsenite exposure to alter chromatin, thereby changing gene transcription for disease pathogenesis.

pharmacology and toxicology↗

bioRxiv2018

Putative rapid-acting antidepressant nitrous oxide ("laughing gas") evokes rebound emergence of slow EEG oscillations during which TrkB signaling is induced

Electroconvulsive therapy (ECT) remains among the most efficient antidepressants but it seldom brings immediate remedy. However, a subanesthetic dose of NMDA-R (N-methyl-D-aspartate receptor) blocker ketamine ameliorates symptoms of depression already within hours. Glutamatergic excitability and regulation of TrkB neurotrophin receptor and GSK3{beta} (glycogen synthase kinase 3{beta}) signaling are considered as molecular-level determinants for ketamines antidepressant effects. Recent clinical observations suggests that nitrous oxide (N2O, \"laughing gas\"), another NMDA-R blocking dissociative anesthestic, also produces rapid antidepressant effects but the underlying mechanisms remain essentially unstudied. In this animal study we show that N2O, with a clinically relevant dosing regimen, evokes an emergence of rebound slow EEG (electroencephalogram) oscillations, a phenomenon considered to predict the efficacy and onset-of-action ECT. Very similar rebound slow oscillations are induced by subanesthetic ketamine and flurothyl (a treatment analogous to ECT). These responses become best evident upon drug withdrawal, i.e. after the peak of acute pharmacological actions, when their most prominent effects on cortical excitability have subsided. Most importantly, TrkB and GSK3{beta} signaling remain unchanged during N2O administration (ongoing NMDA-R blockade) but emerge gradually upon gas withdrawal along with increased slow EEG oscillations. Collectively these findings reveal that rapid-acting antidepressants produce cortical excitability that triggers \"a brain state\" dominated by ongoing slow oscillations, sedation and drowsiness during which TrkB and GSK3{beta} signaling alterations are induced.

pharmacology and toxicology↗

bioRxiv2018

Molecular Modeling Suggests Homologous 2-APB Binding Sites in Connexins 26 and 32

Connexins are the transmembrane pore forming proteins that participate in gap junctions; connections between cells that certain nutrients and other molecules can pass through. There are several kinds of connexins (Cx) named based on their weight in kilodaltons. 2-aminoethoxydiphenyl borate (2-APB) is a small molecule inhibitor (SMI) of Cx26 and Cx32. Knock out of Cx32 and also blockage of Cx32 by 2-aminoethoxydiphenyl (2-APB) has been suspected to be beneficial in not only, drug induced liver toxicity, but also in blocking the propagation of an inflammatory signal. If the binding site of 2-APB can be determined, virtual screening for additional, perhaps more specific Cx26 and Cx32 blocking SMI can be carried out. Our modeling suggests that 2-APB binds to similar sites inside the pores of Cx26 and Cx32. Here 2-APB interacts with the conserved ILE82 and THR86. These residues hold the same numbering in both CX26 and CX32. This suggests these residues have a high level of conservation and importance Further virtual screening results imply molecules with similar activity on Cx26 and Cx32 as 2-APB can be found.\n\nBackground2-APB has been shown to block Cx26 and Cx32.\n\nResultsDocking of 2-APB to Cx26 and CX32 finds conserved binding site in pore. Suggestive that 2-APB has conserved homologous binding site on Cx26 and Cx32.\n\nConclusionMutational studies of 2APB and ILE82 and THR86 in Cx26 and Cx32 appear warranted. Additional virtual screening could yield 2-APB analogs that act on Cx26 and Cx32.\n\nSignificancePotential for developing gap junction blocking compounds.

pharmacology and toxicology↗

bioRxiv2018

Hydrophobicity drives the systemic distribution of lipid-conjugated siRNAs via lipid transport pathways

Efficient delivery of therapeutic RNA is the fundamental obstacle preventing its clinical utility. Lipid conjugation improves plasma half-life, tissue accumulation, and cellular uptake of small interfering RNAs (siRNAs). However, the impact of conjugate structure and hydrophobicity on siRNA pharmacokinetics is unclear, impeding the design of clinically relevant lipid-siRNAs. Using a panel of biologically-occurring lipids, we show that lipid conjugation modulates siRNA hydrophobicity and governs spontaneous partitioning into distinct plasma lipoprotein classes in vivo. Lipoprotein binding influences siRNA distribution by delaying renal excretion and promoting uptake into lipoprotein receptor-enriched tissues. Lipid-siRNAs elicit mRNA silencing without causing toxicity in a tissue-specific manner. Lipid-siRNA internalization occurs independently of lipoprotein endocytosis, and is mediated by siRNA phosphorothioate modifications. Although biomimetic lipoprotein nanoparticles have been considered for the enhancement of siRNA delivery, our findings suggest that hydrophobic modifications can be leveraged to incorporate therapeutic siRNA into endogenous lipid transport pathways without the requirement for synthetic formulation.

pharmacology and toxicology↗

bioRxiv2018

A Machine Learning Approach Predicts Tissue-Specific Drug Adverse Events

One of the main causes for failure in the drug development pipeline or withdrawal post approval is the unexpected occurrence of severe drug adverse events. Even though such events should be detected by in vitro, in vivo, and human trials, they continue to unexpectedly arise at different stages of drug development causing costly clinical trial failures and market withdrawal. Inspired by the \"moneyball\" approach used in baseball to integrate diverse features to predict player success, we hypothesized that a similar approach could leverage existing adverse event and tissue-specific toxicity data to learn how to predict adverse events. We introduce MAESTER, a data-driven machine learning approach that integrates information on a compounds structure, targets, and phenotypic effects with tissue-wide genomic profiling and our toxic target database to predict the probability of a compound presenting with different types of tissue-specific adverse events. When tested on 6 different types of adverse events MAESTER maintains a high accuracy, sensitivity, and specificity across both the training data and new test sets. Additionally, MAESTER scores could flag a number of drugs that were approved, but later withdrawn due to unknown adverse events - highlighting its potential to identify events missed by traditional methods. MAESTER can also be used to identify toxic targets for each tissue type. Overall MAESTER provides a broadly applicable framework to identify toxic targets and predict specific adverse events and can accelerate the drug development pipeline and drive the design of new safer compounds.

pharmacology and toxicology↗

bioRxiv2018

Chronic environmentally relevant levels of Simvastatin induces non-monotonic responses in Zebrafish (Danio rerio)

Simvastatin (SIM), a hypocholesterolaemic compound, is among the most prescribed pharmaceuticals for cardiovascular disease prevention worldwide. Several studies have shown that acute exposure to SIM is able to produce multiple adverse effects in aquatic organisms. However, uncertainties still remain regarding the chronic effects of SIM in aquatic ecosystems. Therefore, the present study aimed to investigate the effects of SIM in the model freshwater teleost zebrafish (Danio rerio) following a chronic exposure (90 days) to environmentally relevant concentrations ranging from 8 ng/L to 1000 ng/L. This study used a multi-parametric approach integrating distinct ecological-relevant endpoints, i.e. survival, growth, reproduction and embryonic development, with biochemical markers (cholesterol and triglycerides). Furthermore, Real Time PCR was used to analyse the transcription levels of key genes involved in the mevalonate pathway (hmgcra, cyp51, and dhcr7). Globally, SIM induced several non-monotonic dose-responses; embryonic development, biochemical and molecular markers, were significantly impacted in the low-intermediate concentrations, 40 ng/L and 200 ng/L, whereas no effects were recorded for the highest tested SIM levels (1000 ng/L). Taken together, these findings expand our understanding of statins effects in teleosts, demonstrating significant impacts at environmentally relevant concentrations. The findings highlight the importance of addressing the effects of chemicals under chronic low-level concentrations.\n\nGraphical abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC=\"FIGDIR/small/289694v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (17K):\norg.highwire.dtl.DTLVardef@1922156org.highwire.dtl.DTLVardef@caad80org.highwire.dtl.DTLVardef@44c058org.highwire.dtl.DTLVardef@1afe60f_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LISeveral uncertainties exist regarding simvastatin mode of action in non-target organisms\nC_LIO_LIThis work integrates D. rerio multi-level responses after long-term exposure to simvastatin\nC_LIO_LISimvastatin impacted cholesterol/triglycerides levels and transcript levels of genes related to mevalonate pathway.\nC_LIO_LIParental exposure to simvastatin induced offspring embryonic malformations.\nC_LIO_LIEmbryonic abnormalities, biochemical and molecular data did follow a non-monotonic curve.\nC_LI

pharmacology and toxicology↗

bioRxiv2018

ADS-J1 Disaggregates Semen-derived Amyloid Fibrils

Semen-derived amyloid fibrils, composing SEVI (semen-derived enhancer of viral infection) fibrils and SEM1 fibrils, could remarkably enhance HIV-1 sexual transmission and thus, are potential targets for the development of an effective microbicide. Previously, we found that ADS-J1, apart from being an HIV-1 entry inhibitor, could also potently inhibit seminal amyloid fibrillization and block fibril-mediated enhancement of viral infection. However, the remodeling effects of ADS-J1 on mature seminal fibrils were unexplored. Herein, we investigated the capacity of ADS-J1 to disassemble seminal fibrils and the potential mode of action by applying several biophysical and biochemical measurements, combined with molecular dynamic (MD) simulations. We found that ADS-J1 effectively remodeled SEVI, SEM186-107 fibrils and endogenous seminal fibrils. Unlike epi-gallocatechin gallate (EGCG), a universal amyloid fibril breaker, ADS-J1 disaggregated SEVI fibrils into monomeric peptides, which was independent of oxidation reaction. MD simulations revealed that ADS-J1 displayed strong binding potency to the full-length PAP248-286 via electrostatic interactions, hydrophobic interactions and hydrogen bonds. ADS-J1 might initially bind to the fibrillar surface and then occupy the amyloid core, which eventually lead to fibril disassembly. Furthermore, the binding of ADS-J1 with PAP248-286 might induce conformational changes of PAP248-286. Disassembled PAP248-286 might not be favor to re-aggregate into fibrils. ADS-J1 also exerts abilities to remodel a panel of amyloid fibrils, including A{beta}1-42, hIAPP1-37 and EP2 fibrils. ADS-J1 displays promising potential to be a combination microbicide and an effective lead-product to treat amyloidogenic diseases.

pharmacology and toxicology↗

bioRxiv2018

Ref-1/APE1 inhibition with novel small molecules blocks ocular neovascularization

Ocular neovascular diseases like wet age-related macular degeneration are a major cause of blindness. Novel therapies are greatly needed for these diseases. One appealing antiangiogenic target is reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease 1 (Ref-1/APE1). This protein can act as a redox-sensitive transcriptional activator for NF-{kappa}B and other pro-angiogenic transcription factors. An existing inhibitor of Ref-1s function, APX3330, previously showed antiangiogenic effects. Here, we developed improved APX3330 derivatives and assessed their antiangiogenic activity. We synthesized APX2009 and APX2014 and demonstrated enhanced inhibition of Ref-1 function in a DNA-binding assay compared to APX3330. Both compounds were antiproliferative against human retinal microvascular endothelial cells (HRECs; GI50 APX2009: 1.1 M, APX2014: 110 nM) and macaque choroidal endothelial cells (Rf/6a GI50 APX2009: 26 M, APX2014: 5.0 M). Both compounds significantly reduced the ability of HRECs and Rf/6a cells to form tubes at mid nanomolar concentrations compared to control, and both significantly inhibited HREC and Rf/6a cell migration in a scratch wound assay, reducing NF-{kappa}B activation and downstream targets. Ex vivo, both APX2009 and APX2014 inhibited choroidal sprouting at low micromolar and high nanomolar concentrations respectively. In the laser-induced choroidal neovascularization mouse model, intraperitoneal APX2009 treatment significantly decreased lesion volume by 4-fold compared to vehicle (p < 0.0001, ANOVA with Dunnetts post hoc tests), without obvious intraocular or systemic toxicity. Thus, Ref-1 inhibition with APX2009 and APX2014 blocks ocular angiogenesis in vitro and ex vivo, and APX2009 is an effective systemic therapy for CNV in vivo, establishing Ref-1 inhibition as a promising therapeutic approach for ocular neovascularization.

pharmacology and toxicology↗

bioRxiv2018

Combination of tenofovir and emtricitabine with efavirenz does not moderate inhibitory effect of efavirenz on mitochondrial function and cholesterol biosynthesis in human T lymphoblastoid cell line

Efavirenz (EFV), the most popular non-nucleoside reverse transcriptase inhibitor, has been associated with mitochondrial dysfunction in most in vitro studies. However, in real life the prevalence of EFV-induced mitochondrial toxicity is relatively low. We hypothesized that the agents given in combination with EFV might moderate the effect of EFV on mitochondrial function. To test this hypothesis, we cultured human T lymphoblastoid cell line (CEM cells) with EFV alone and in combination with emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) to investigate the effects on mitochondrial respiration and function and cholesterol biosynthesis.\n\nThere was a statistically significant concentration- and time-dependent apoptosis, reduction in mitochondrial membrane potential ({Delta}{Psi}), and increase production of reactive oxygen species (ROS) in cells treated with either EVF alone or in combination with TDF/FTC. EFV treated cells compared to DMSO treated cells had significant reduction in oxygen consumption rate (OCR) contributed by mitochondrial respiration, ATP production-linked respiration, and spare respiratory capacity (SRC). Treatment with EFV resulted in a decrease in mitochondrial DNA content, and perturbation of more coding genes (n=13); among these were 11 genes associated with lipid or cholesterol biosynthesis. Our findings support the growing body of knowledge on the effects of EFV on mitochondrial respiration and function and cholesterol biosynthesis.\n\nInterestingly, combining TDF/FTC with EFV did not alter the effects of EFV on mitochondrial respiration and function and cholesterol biosynthesis. The gap between the prevalence of EFV-induced mitochondrial toxicity in vitro and in vivo studies may be explained by individual differences in the pharmacokinetic of EFV.

pharmacology and toxicology↗

bioRxiv2018

Structure-based drug design and characterization of sulfonyl-piperazine benzothiazinone inhibitors of DprE1 from Mycobacterium tuberculosis

Macozinone (MCZ) is a tuberculosis (TB) drug candidate that specifically targets the essential flavoenzyme DprE1 thereby blocking synthesis of the cell wall precursor decaprenyl phosphoarabinose (DPA) and provoking lysis of Mycobacterium tuberculosis. As part of the MCZ back-up program we exploited structure-guided drug design to produce a new series of sulfone-containing derivatives, 2-sulphonylpiperazin 8-nitro 6-trifluoromethyl 1,3-benzothiazin-4-one, or sPBTZ. These compounds are less active than MCZ but have a better solubility profile and some derivatives display enhanced stability in microsomal assays. DprE1 was efficiently inhibited by sPBTZ and covalent adducts with the active site cysteine residue (C387) were formed. However, despite the H-bonding potential of the sulfone group no additional bonds were seen in the crystal structure of the sPBTZ-DprE1 complex with compound 11326127 as compared to MCZ. Compound 11626091, the most advanced sPBTZ, displayed good antitubercular activity in the murine model of chronic TB but was less effective than MCZ. Nonetheless, further testing of this MCZ backup compound is warranted as part of combination treatment with other TB drugs.

pharmacology and toxicology↗

bioRxiv2018

Early Exposure to Polycyclic Aromatic Hydrocarbons (PAHs) and Cardiac Toxicity in a Species (Xenopus laevis) with Low Aryl Hydrocarbon Receptor (AHR) Responsiveness

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous, persistent environmental contaminants, of which 16 are EPA-designated priority pollutants. Cardiotoxicity is observed in fish with developmental exposures to certain PAHs; however, the mechanism of toxicity can differ. Phenanthrene (PHE) and benzo(a)pyrene (BaP) are both cardiotoxic to fish, but PHE acts independently of aryl hydrocarbon receptor (AHR) activation while BaP-associated cardiotoxicity is AHR-dependent. To further understanding of mechanisms of toxicity, we compared the effects of early exposure to the priority PAHs pyrene (PYR), fluoranthene (FLA), PHE and BaP on cardiac function and cytochrome P450 type 1A (cyp1a) mRNA expression, an indicator of AHR activation, in a model system with lower AHR sensitivity than that of fish, the embryos and larvae of Xenopus laevis. Exposure to PYR, PHE, and FLA (0.25 - 25 M) caused ventricular tachycardia early in heart development, but bradycardia and atrioventricular (AV) block in later stages. Elevated cyp1a mRNA levels indicate that FLA and BaP, but not PHE or PYR, are AHR agonists. The finding of FLA-induced cardiotoxicity and cyp1a expression (35-fold) is particularly surprising as FLA inhibits CYP1A activity in fish and, as a single compound, is not cardiotoxic. Our results suggest that early exposure to PHE, PYR, and FLA, but not to BaP, compromises cardiac function by altering normal pacemaker activity and conduction in Xenopus, effects associated with increased mortality. Our findings also reveal a considerable degree of species specificity between fish and frog regarding cardiac sensitivity to developmental PAH exposures and have implications for the cardiovascular health of PAH-exposed humans and wild amphibians.

pharmacology and toxicology↗

bioRxiv2018

Azithromycin reduces systemic inflammation and provides survival benefit in murine model of polymicrobial sepsis

Sepsis is a life threatening systemic inflammatory condition triggered as a result of excessive host immune response to infection. In the past, drugs modulating immune reactions have demonstrated protective effect in sepsis. Azithromycin (macrolide antibiotic) with immunomodulatory activity was therefore evaluated in combination with ceftriaxone in a more clinically relevant murine model of sepsis induced by caecal ligation and puncture (CLP). First, mice underwent CLP and 3 h later were administered with vehicle, sub-effective dose of ceftriaxone (100 mg/kg, subcutaneous) alone or in combination with immunomodulatory dose of azithromycin (100 mg/kg, intraperitoneal). Survival was then monitored for 5 days. Parameters like body temperature, blood glucose, total white blood cell count, plasma glutathione (GSH), plasma and lung myeloperoxidase (MPO) as well as cytokine (interleukin IL-6, IL-1{beta}, tumor necrosis factor-) levels along with bacterial load in blood, peritoneal fluid and lung homogenate were measured 18 h after CLP challenge. Combination group significantly improved the survival of CLP mice. It attenuated the elevated levels of inflammatory cytokines and MPO in plasma and lung tissue and increased the body temperature, blood glucose and GSH which were otherwise markedly decreased in CLP mice. Ceftriaxone exhibited significant reduction of bacterial count in blood, peritoneal fluid and lung homogenate, while co-administration of azithromycin did not further reduce it. This confirms that survival benefit by azithromycin was due to immunomodulation and not by its antibacterial action. Findings of this study indicate that azithromycin in combination with ceftriaxone could exhibit clinical benefit in sepsis.

pharmacology and toxicology↗

bioRxiv2018

Sapropterin Treatment Prevents Congenital Heart Defects Induced by Pregestational Diabetes in Mice

AimsTetrahydrobiopterin (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(R)), an orally active synthetic form of BH4 on eNOS uncoupling and congenital heart defects (CHDs) induced by pregestational diabetes in mice.\n\nMethodsAdult 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.\n\nResultsPregestational 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. Lineage tracing reveals that pregestational diabetes results in decreased commitment of second heart field progenitors to the outflow tract, endocardial cushions, and ventricular myocardium of the fetal heart. Notably, decreased cell proliferation and cardiac transcription factor expression induced by maternal diabetes were normalized with sapropterin treatment. Furthermore, sapropterin administration in the diabetic dams increased eNOS dimerization and lowered ROS levels in the fetal heart.\n\nConclusionsSapropterin treatment in the diabetic mothers improves eNOS coupling, increases cell proliferation and prevents the development of CHDs in the offspring. Thus, sapropterin may have therapeutic potential in preventing CHDs in pregestational diabetes.

pharmacology and toxicology↗

bioRxiv2018

Identification and Quantification of Paclitaxel and its Metabolites in Human Meconium from Newborns with Gestational Chemotherapeutic Exposure

ObjectiveCancer diagnosis during pregnancy occurs in 1 out of 1000 pregnancies with common malignancies including breast and hematological cancers. Fetal exposure to currently utilized agents is poorly described. We directly assessed fetal exposure by screening meconium from 23 newborns whose mothers had undergone treatment for cancer during pregnancy.\n\nStudy DesignMeconium was collected from newborns whose mothers were diagnosed with cancer during pregnancy and underwent chemotherapy in the second or third trimester as part of the Cancer and Pregnancy Registry. We conducted screening of 23 meconium samples for chemotherapeutics and known metabolites of chemotherapeutics by liquid chromatography-high resolution mass spectrometry (LC-HRMS). Putative identification of paclitaxel and/or its metabolites was made in 8 screened samples. In positively screened samples, we quantified paclitaxel, 3-p-hydroxypaclitaxel, and 6-hydroxypaclitaxel by stable isotope dilution-LC-HRMS.\n\nResultsMean levels of paclitaxel were 399.9 pg/mg in meconium samples from newborn born to mothers that underwent chemotherapy during pregnancy. 3-p-hydroxypaclitaxel and 6-hydroxypaclitaxel mean levels were 105.2 and 113.4 pg/mg meconium, respectively.\n\nConclusionIntact paclitaxel, and at least two of its major metabolites were detected in meconium, providing unambiguous confirmation of human fetal exposure. Variability in meconium levels between individuals may indicate a potential for reducing fetal exposure based on timing, dosing, and individual characteristics. This preliminary study may provide an efficient approach for examining the effects of cancer diagnosis during pregnancy on other outcomes by providing a measure of direct fetal exposure.

pharmacology and toxicology↗

bioRxiv2018

iPSC-derived neurons as a tool for probing molecular pharmacology of antipsychotic action.

BackgroundInduced pluripotent stem cell derived neurons (iPSC-Neurons) provide a potential way to investigate molecular mechanisms of psychotropic drug action in human neurons. Until now such studies have relied on animal models or artificial expression systems in transfected cells.\n\nMethodsInduced pluripotent stem cells were subjected to a dual SMAD inhibition differentiation protocol. Resulting neurons were examined using qPCR, immunocytochemistry, viral transduction, and calcium imaging.\n\nResultsHere we report the presence of target receptors for antipsychotic drugs in human iPSC-neurons. A cortical neuronal differentiation protocol resulted in cells that expressed D2, 5HT2A, and other target receptors. Moreover, stimulation with glutamate, dopamine, or the 5HT2A agonist DOI evoked calcium transients. We analyzed single cell responses, and found cells with signature response profiles to these ligands. In addition, pre-incubation of iPSC-neurons with clozapine altered the proportion of cells that responded to glutamate or DOI in a subpopulation of neurons.\n\nConclusionsOur results support the use of iPSC-neuron single cell pharmacology for studying how psychotropic medications modulate neuronal responses. Because these cells can be derived directly from patients, results derived from using iPSC-neurons have immediate relevance for personalized medicine.\n\nSignificance StatementThe current study examines the feasibility of using induced pluripotent stem cells from patients to generate neurons and study psychopharmacology. This article is broadly intended to inform the readership on the key points of iPSC-derived neurons as a system and how it can be used to understand antipsychotic pharmacology for potential clinical application. The specific advances include 1) demonstrating the presence of receptors targeted by antipsychotics on iPSC-derived neurons; 2) Using single cell analysis to identify human neurons with distinct responses to receptor modulation; and 3) Demonstrating that clozapine modulates glutamatergic and serotonergic responses in distinct human neuronal populations.

pharmacology and toxicology↗

bioRxiv2018

Probing the chemical-biological relationship space with the Drug Target Explorer

Modern phenotypic high-throughput screens (HTS) present several challenges including identifying the target(s) that mediate the effect seen in the screen, characterizing hits with a polypharmacologic target profile, and contextualizing screen data within the large potential space of drugs and biological screening model combinations. To address these challenges, we developed an interactive web application that enables exploration of the chemical-biological interaction space. Compound-target interaction data from public resources were quantified for over 280,000 molecules. Each molecule was annotated with a name and chemical structure, and every target was annotated with gene identifiers. The Drug-Target Explorer allows users to query molecules within this database of experimentally-derived and curated compound-target interactions and identify structurally similar molecules. It also enables network-based visualizations of the compound-target interaction space, and incorporates comparisons to publicly-available in vitro HTS datasets. Users can also identify compounds given one or more targets of interest. The Drug Target Explorer is a multifunctional platform for exploring chemical space as it relates to biological targets, and may be useful at several steps along the drug development pipeline including target discovery, structure-activity relationship, and lead compound identification studies.

pharmacology and toxicology↗

bioRxiv2018

The utility of Saw-scaled viper, Echis pyramidum, and Kenyan sand boa, Eryx colubrinus as bioindicator of heavy metals bioaccumulation in relation to DPTA soil extract and biological consequences.

The present investigation was conducted to compare between the ecotoxocological effects of Ca, Mg, Fe, Cu, Zn, Co, Mo, Mn, B, Al, Sr, Pb, Ni, Cd and Cr on the saw-scaled viper, Echis pyramidum (E. p.) and the Kenyan sand boa, Eryx colubrinus (E.c.) inhabiting Gabal El-Nagar and Kahk Qibliyyah respectively in El-Faiyum desert, Egypt. Accumulation varied significantly among the liver, kidney and muscle. The relationship between concentrations of heavy metals in snakes and those in the soil from the collected sites was established by analyzing metal DPTA in soil. Bioaccumulation factor is calculated to estimate the degree of toxicity within the tissues. Morphometric analysis was recorded. All body morphometric measurements were higher in E. p. than in E. c.. Body, liver, gonad, kidney and heart weight, HSI, GSI, RBCs count, Hb content, PCV, MCV, MCH, MCHC, plasma glucose, total lipids and total proteins showed a significant increase in E. p. Histopathological examination showed damage and alterations of liver, kidney and testes sections. The tissues of E. c. were more destructed than those of E. p..

pharmacology and toxicology↗