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Chemical Communications (Cambridge,... Apr 2019Correction for 'MOF@activated carbon: a new material for adsorption of aldicarb in biological systems' by Carlos Alberto Fernandes de Oliveira et al., Chem. Commun.,...
Correction for 'MOF@activated carbon: a new material for adsorption of aldicarb in biological systems' by Carlos Alberto Fernandes de Oliveira et al., Chem. Commun., 2013, 49, 6486-6488.
PubMed: 30924822
DOI: 10.1039/c9cc90125f -
The Journal of Biological Chemistry Apr 2019Inhibitory GABAergic transmission is required for proper circuit function in the nervous system. However, our understanding of molecular mechanisms that preferentially...
Inhibitory GABAergic transmission is required for proper circuit function in the nervous system. However, our understanding of molecular mechanisms that preferentially influence GABAergic transmission, particularly presynaptic mechanisms, remains limited. We previously reported that the ubiquitin ligase EEL-1 preferentially regulates GABAergic presynaptic transmission. To further explore how EEL-1 functions, here we performed affinity purification proteomics using and identified the -GlcNAc transferase OGT-1 as an EEL-1 binding protein. This observation was intriguing, as we know little about how OGT-1 affects neuron function. Using biochemistry, we confirmed that the OGT-1/EEL-1 complex forms in neurons and showed that the human orthologs, OGT and HUWE1, also bind in cell culture. We observed that, like EEL-1, OGT-1 is expressed in GABAergic motor neurons, localizes to GABAergic presynaptic terminals, and functions cell-autonomously to regulate GABA neuron function. Results with catalytically inactive point mutants indicated that OGT-1 glycosyltransferase activity is dispensable for GABA neuron function. Consistent with OGT-1 and EEL-1 forming a complex, genetic results using automated, behavioral pharmacology assays showed that and act in parallel to regulate GABA neuron function. These findings demonstrate that OGT-1 and EEL-1 form a conserved signaling complex and function together to affect GABA neuron function.
Topics: Aldicarb; Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Chromatography, Affinity; GABAergic Neurons; N-Acetylglucosaminyltransferases; Presynaptic Terminals; Protein Binding; Proteomics; Signal Transduction; Synaptic Transmission; Ubiquitin-Protein Ligases
PubMed: 30858176
DOI: 10.1074/jbc.RA119.007406 -
Genetics Apr 2019The transcription factor Nrf2 plays a critical role in the organism-wide regulation of the antioxidant stress response. The Nrf2 homolog SKN-1 functions in the...
The transcription factor Nrf2 plays a critical role in the organism-wide regulation of the antioxidant stress response. The Nrf2 homolog SKN-1 functions in the intestinal cells nonautonomously to negatively regulate neuromuscular junction (NMJ) function in To identify additional molecules that mediate SKN-1 signaling to the NMJ, we performed a candidate screen for suppressors of aldicarb resistance caused by acute treatment with the SKN-1 activator arsenite. We identified two receptor tyrosine kinases, EGL-15 (fibroblast growth factor receptor, FGFR) and DAF-2 (insulin-like peptide receptor), that are required for NMJ regulation in response to stress. Through double-mutant analysis, we found that EGL-15 functions downstream of, or parallel to, SKN-1 and SPHK-1 (sphingosine kinase), and that the EGL-15 ligand EGL-17 FGF and canonical EGL-15 effectors are required for oxidative stress-mediated regulation of NMJ function. DAF-2 also functions downstream of or parallel to SKN-1 to regulate NMJ function. Through tissue-specific rescue experiments, we found that FGFR signaling functions primarily in the hypodermis, whereas insulin-like peptide receptor signaling is required in multiple tissues. Our results support the idea that the regulation of NMJ function by SKN-1 occurs via a complex organism-wide signaling network involving receptor tyrosine kinase signaling in multiple tissues.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; DNA-Binding Proteins; Intercellular Signaling Peptides and Proteins; Neuromuscular Junction; Oxidative Stress; Phosphotransferases (Alcohol Group Acceptor); Receptor, Insulin; Receptors, Fibroblast Growth Factor; Signal Transduction; Transcription Factors
PubMed: 30782598
DOI: 10.1534/genetics.119.302026 -
Cell Reports Nov 2018The aberrant regulation of Wnt secretion is implicated in various neurological diseases. However, the mechanisms of Wnt release are still largely unknown. Here we...
The aberrant regulation of Wnt secretion is implicated in various neurological diseases. However, the mechanisms of Wnt release are still largely unknown. Here we describe the role of a C. elegans tetraspan protein, HIC-1, in maintaining normal Wnt release. We show that HIC-1 is expressed in cholinergic synapses and that mutants in hic-1 show increased levels of the acetylcholine receptor AChR/ACR-16. Our results suggest that HIC-1 maintains normal AChR/ACR-16 levels by regulating normal Wnt release from presynaptic neurons, as hic-1 mutants show an increase in secreted Wnt from cholinergic neurons. We further show that HIC-1 affects Wnt secretion by modulating the actin cytoskeleton through its interaction with the actin-binding protein NAB-1. In summary, we describe a protein, HIC-1, that functions as a neuromodulator by affecting postsynaptic AChR/ACR-16 levels by regulating presynaptic Wnt release from cholinergic motor neurons.
Topics: Actin Cytoskeleton; Aldicarb; Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cholinergic Neurons; Membrane Proteins; Microfilament Proteins; Muscles; Mutant Proteins; Mutation; Nerve Tissue Proteins; Neuromuscular Junction; Protein Binding; Signal Transduction; Synapses; Wnt Proteins
PubMed: 30428353
DOI: 10.1016/j.celrep.2018.10.053 -
Aquatic Toxicology (Amsterdam,... Dec 2018Acetylcholinesterase (AChE; EC 3.1.1.7) is a serine hydrolase, whose main function is to modulate neurotransmission at cholinergic synapses. It is, therefore, the...
Acetylcholinesterase (AChE; EC 3.1.1.7) is a serine hydrolase, whose main function is to modulate neurotransmission at cholinergic synapses. It is, therefore, the primary target of some pesticides and heavy metals. Its inhibition in aquatic organisms has been used as an indicator of the presence of these pollutants in water bodies. The present study aimed to characterize physicochemical and kinetic parameters of brain AChE in the benthic fish Hoplosternum littorale and to analyze the in vitro effects of pesticides (dichlorvos, diazinon, chlorpyrifos, parathion-methyl, temephos, carbaryl, carbofuran, aldicarb, diflubenzuron, novaluron and pyriproxyfen) and metal ions (As, Cd, Cu, Fe, Mn, Mg, K, Pb, Hg, Zn) investigating the potential of this enzyme as environmental biomarker based on current regulations. Specific substrates and inhibitors have indicated AChE to be the predominant cholinesterase (ChE) in the brain of H. littorale. Peak activity was observed at pH 8.0 and 30 °C. The enzymatic activity is otherwise moderately thermostable (≈ 50% activity at 45 °C). The enzyme can reduce the activation energy of acetylthiocholine hydrolysis reaction to 8.34 kcal mol while reaching a rate enhancement of 10. Among the pesticides under study, dichlorvos presented an IC value below the maximum concentrations allowed by legislation. This study presents the first report on the inhibition of brain AChE activity from Siluriformes by the pesticides novaluron and pyriproxyfen. Mercury ion also exerted a strong inhibitory effect on its enzymatic activity. The H. littorale enzyme thus has the potential to function as an in vitro biomarker for the presence of the pesticide dichlorvos as well as mercury in areas of mining and industrial discharge.
Topics: Acetylcholinesterase; Animals; Brain; Catfishes; Environmental Monitoring; Enzyme Activation; Ions; Metals, Heavy; Pesticides; Water Pollutants, Chemical
PubMed: 30408655
DOI: 10.1016/j.aquatox.2018.10.017 -
Chemical Research in Toxicology Jan 2019The gut microbiome is highly involved in numerous aspects of host physiology, from energy harvest to stress response, and can confer many benefits to the host. The gut...
The gut microbiome is highly involved in numerous aspects of host physiology, from energy harvest to stress response, and can confer many benefits to the host. The gut microbiome development could be affected by genetic and environmental factors, including pesticides. The carbamate insecticide aldicarb has been extensively used in agriculture, which raises serious public health concerns. However, the impact of aldicarb on the gut microbiome, host metabolome, and lipidome has not been well studied yet. Herein, we use multiomics approaches, including16S rRNA sequencing, shotgun metagenomics sequencing, metabolomics, and lipidomics, to elucidate aldicarb-induced toxicity in the gut microbiome and the host metabolic homeostasis. We demonstrated that aldicarb perturbed the gut microbiome development trajectory, enhanced gut bacterial pathogenicity, altered complex lipid profile, and induced oxidative stress, protein degradation, and DNA damage. The brain metabolism was also disturbed by the aldicarb exposure. These findings may provide a novel understanding of the toxicity of carbamate insecticides.
Topics: Administration, Oral; Aldicarb; Animals; DNA Damage; Gastrointestinal Microbiome; Insecticides; Lipidomics; Lipids; Male; Metabolome; Mice; Mice, Inbred C57BL; Molecular Structure; Oxidative Stress
PubMed: 30406643
DOI: 10.1021/acs.chemrestox.8b00179 -
Medicina Clinica Apr 2019
Topics: Adult; Aldicarb; Atropine; Humans; Insecticides; Male; Muscarinic Antagonists; Myoclonus; Poisoning; Suicide, Attempted
PubMed: 30224173
DOI: 10.1016/j.medcli.2018.07.005 -
Journal of Hazardous Materials Feb 2018Carbamate hydrolase is the initial and key enzyme for degradation of carbamate pesticides. In the present study, we report the isolation of a carbaryl-degrading strain...
Carbamate hydrolase is the initial and key enzyme for degradation of carbamate pesticides. In the present study, we report the isolation of a carbaryl-degrading strain Pseudomonas sp. XWY-1, the cloning of its carbaryl hydrolase gene (mcbA) and the characterization of McbA. Strain XWY-1 was able to utilize carbaryl as a sole carbon source and degrade it using 1-naphthol as an intermediate. Transposon mutagenesis identified a mutant of XWY-1M that was unable to hydrolyze carbaryl. The transposon-disrupted gene mcbA was cloned by self-formed adaptor PCR, then expressed in Escherichia coli BL21(DE3) and purified. McbA was able to hydrolyze carbamate pesticides including carbaryl, isoprocarb, fenobucarb, carbofuran efficiently, while it hydrolyzed aldicarb, and propoxur poorly. The optimal pH of McbA was 7.0 and the optimal temperature was 40°C. The apparent K and k values of McbA for carbaryl were 77.67±12.31μM and 2.12±0.10s, respectively. Three amino acid residues (His467, His477 and His504) in the predicted polymerase/histidinol phosphatase-like domain were shown to be closely related to the activity of McbA, with His504 being the most important, as a replacement of His504 led to the complete loss of activity. This is the first study to identify key amino acids in McbA.
Topics: Amidohydrolases; Amino Acids; Carbaryl; Cloning, Molecular; Electrophoresis, Polyacrylamide Gel; Hydrolysis; Substrate Specificity
PubMed: 30216972
DOI: 10.1016/j.jhazmat.2017.12.006 -
Analytical Chemistry Oct 2018To improve the G-quadruplex specificity of Ir(III) complexes, a novel dinuclear Ir(III) complex (Din Ir(III)-1) was designed and synthesized through connecting two...
To improve the G-quadruplex specificity of Ir(III) complexes, a novel dinuclear Ir(III) complex (Din Ir(III)-1) was designed and synthesized through connecting two mononuclear Ir(III) complexes via a diphenyl bridge. Din Ir(III)-1 presents 3.4-4.1-fold enhancements for G-quadruplex relative to ssDNA and 4.3-5.3-fold enhancements relative to dsDNA in luminescence intensity, respectively, demonstrating an excellent G-quadruplex selectivity. Ascribed to its superior specificity to G-quadruplex, Din Ir(III)-1 was employed to construct a highly sensitive luminescent pesticides' detection platform. The detection is based on acetylcholinesterase (AChE)-catalyzed hydrolysis product-induced DNA conformational transformation and subsequent terminal deoxynucleotidyl transferase (TdT) directed G-quadruplex formation. The assay exhibited a linear response between the emission intensity of Din Ir(III)-1 and the pesticide concentration in the range of 0.5-25 μg/L ( R = 0.994), and the limit of detection for the pesticide was as low as 0.37 μg/L when using aldicarb as the model pesticide. Moreover, this strategy demonstrates good applicability for the pesticide detection in real samples. It is also versatile for the detection of other organophosphate or carbamate pesticides, which have the inhibition ability toward AChE. Therefore, the proposed approach is scalable for practical application in food safety and environmental monitoring fields and will provide promising solutions for the assay of pesticide residues.
PubMed: 30192517
DOI: 10.1021/acs.analchem.8b03687 -
Drug Metabolism Letters 2018The use of polypharmacy in the present day clinical therapy has made the identification of clinical drug-drug interaction risk an important aspect of drug development... (Comparative Study)
Comparative Study
BACKGROUND
The use of polypharmacy in the present day clinical therapy has made the identification of clinical drug-drug interaction risk an important aspect of drug development process. Although many drugs can be metabolized to sulfoxide and/or sulfone metabolites, seldom is known on the CYP inhibition potential and/or the metabolic fate for such metabolites.
OBJECTIVE
The key objectives were: a) to evaluate the in vitro CYP inhibition potential of selected parent drugs with sulfoxide/sulfone metabolites; b) to assess the in vitro metabolic fate of the same panel of parent drugs and metabolites.
METHODS
In vitro drug-drug interaction potential of test compounds was investigated in two stages; 1) assessment of CYP450 inhibition potential of test compounds using human liver microsomes (HLM); and 2) assessment of test compounds as substrate of Phase I enzymes; including CYP450, FMO, AO and MAO using HLM, recombinant human CYP enzymes (rhCYP), Human Liver Cytosol (HLC) and Human Liver Mitochondrial (HLMit). All samples were analysed by LC-MS-MS method.
RESULTS
CYP1A2 was inhibited by methiocarb, triclabendazole, triclabendazole sulfoxide, and ziprasidone sulfone with IC50 of 0.71 µM, 1.07 µM, 4.19 µM, and 17.14 µM, respectively. CYP2C8 was inhibited by montelukast, montelukast sulfoxide, montelukast sulfone, tribendazole, triclabendazole sulfoxide, and triclabendazole sulfone with IC50 of 0.08 µM, 0.05 µM, 0.02 µM, 3.31 µM, 8.95 µM, and 1.05 µM, respectively. CYP2C9 was inhibited by triclabendazole, triclabendazole sulfoxide, triclabendazole sulfone, montelukast, montelukast sulfoxide and montelukast sulfone with IC50 of 1.17 µM, 1.95 µM, 0.69 µM, 1.34 µM, 3.61 µM and 2.15 µM, respectively. CYP2C19 was inhibited by triclabendazole and triclabendazole sulfoxide with IC50 of 0.25 and 0.22, respectively. CYP3A4 was inhibited by montelukast sulfoxide and triclabendazole with IC50 of 9.33 and 15.11, respectively. Amongst the studied sulfoxide/sulfone substrates, the propensity of involvement of CY2C9 and CYP3A4 enzyme was high (approximately 56% of total) in the metabolic fate experiments.
CONCLUSION
Based on the findings, a proper risk assessment strategy needs to be factored (i.e., perpetrator and/or victim drug) to overcome any imminent risk of potential clinical drug-drug interaction when sulfoxide/sulfone metabolite(s) generating drugs are coadministered in therapy.
Topics: Acetates; Albendazole; Aldicarb; Biotransformation; Cyclopropanes; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Drug Interactions; Humans; Isoenzymes; Methiocarb; Microsomes, Liver; Piperazines; Quinolines; Risk Assessment; Sulfides; Sulfones; Sulfoxides; Thiazoles; Triclabendazole
PubMed: 30117405
DOI: 10.2174/1872312812666180816164626