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Association of Paraoxonase-1 Genotype and Phenotype with Angiogram Positive Coronary Artery Disease.Arquivos Brasileiros de Cardiologia Oct 2022It has been shown that increased serum PON1 levels are protective against several disorders. Several single nucleotide polymorphisms (SNPs) of the PON1 gene have been...
BACKGROUND
It has been shown that increased serum PON1 levels are protective against several disorders. Several single nucleotide polymorphisms (SNPs) of the PON1 gene have been reported to be associated with serum enzyme protein levels and activity.
OBJECTIVE
To investigate the association of SNPs of PON1 and serum paraoxonase activity with coronary artery disease (CAD).
METHODS
A total of 601 unrelated patients who underwent coronary angiography including those who had >50% stenosis (N=266) and those with <30% stenosis (N=335) were studied. The Paraoxonase gene rs662 and rs840560 SNPs were determined using the ARMS-PCR method and the rs705379 SNP was genotyped using PCR-RFLP analysis. Serum paraoxonase activity was measured using paraoxon as a substrate. A p value of p<0.05 was considered as significant.
RESULTS
Serum paraoxonase activity was not significantly different between the study groups. After adjustment for age, sex, hypertension, diabetes mellitus and dyslipidemia, the GG genotype and co-dominant model of rs662 was positively associated with a positive angiogram (respectively, OR=2.424, 95%CI [1.123-5.233], p<0.05, OR=1.663, 95%CI [1.086-2.547]). Serum paraoxonase activity was significantly higher in the G allele and GG variant of rs662, A allele and AA variant of rs854560 and C allele and CC variant of rs705379. The haplotype analysis has shown that the ATC haplotype was significantly more prevalent among the angiogram negative group. The analysis between groups indicated that the A allele of rs662 was significantly associated with lower paraoxonase activity in the positive angiogram group (p=0.019).
CONCLUSIONS
The presence of the G allele of the rs662 single nucleotide polymorphism is independently associated to increased risk of CAD.
Topics: Humans; Aryldialkylphosphatase; Coronary Artery Disease; Paraoxon; Constriction, Pathologic; Genotype; Polymorphism, Single Nucleotide; Phenotype; Coronary Angiography
PubMed: 36074479
DOI: 10.36660/abc.20210422 -
Langmuir : the ACS Journal of Surfaces... Feb 2017Understanding the molecular interactions between small molecules and double-stranded DNA has important implications on the design and development of DNA and DNA-protein...
Understanding the molecular interactions between small molecules and double-stranded DNA has important implications on the design and development of DNA and DNA-protein nanomaterials. Such materials can be assembled into a vast array of 1-, 2-, and 3D structures that contain a range of chemical and physical features where small molecules can bind via intercalation, groove binding, and electrostatics. In this work, we use a series of simulation-guided binding assays and spectroscopy techniques to investigate the binding of selected organophosphtates, methyl parathion, paraoxon, their common enzyme hydrolysis product p-nitrophenol, and double-stranded DNA fragments and DNA DX tiles, a basic building block of DNA-based materials. Docking simulations suggested that the binding strength of each compound was DNA sequence-dependent, with dissociation constants in the micromolar range. Microscale thermophoresis and fluorescence binding assays confirmed sequence-dependent binding and that paraoxon bound to DNA with K's between ∼10 and 300 μM, while methyl parathion bound with K's between ∼10 and 100 μM. p-Nitrophenol also bound to DNA but with affinities up to 650 μM. Changes in biding affinity were due to changes in binding mode as revealed by circular dichroism spectroscopy. Based on these results, two DNA DX tiles were constructed and analyzed, revealing tighter binding to the studied compounds. Taken together, the results presented here add to our fundamental understanding of the molecular interactions of these compounds with biological materials and opens new possibilities in DNA-based sensors, DNA-based matrices for organophosphate extraction, and enzyme-DNA technologies for organophosphate hydrolysis.
Topics: Circular Dichroism; DNA; Nanostructures; Organophosphates; Paraoxon
PubMed: 28165751
DOI: 10.1021/acs.langmuir.6b03131 -
Polish Journal of Veterinary Sciences 2016Paraoxonase 1 (PON1) is an arylesterase associated with serum high density lipoprotein particles. Its name is derived from hydrolyzing one of several organophosphate... (Review)
Review
Paraoxonase 1 (PON1) is an arylesterase associated with serum high density lipoprotein particles. Its name is derived from hydrolyzing one of several organophosphate compounds, namely paraoxon. Recent studies have shown that PON1 plays a protective role in diseases associated with oxidative stress such as atherosclerosis and diabetes mellitus. Studies have demonstrated reduction-oxidative state changes involving PON1 in humans and laboratory animal models. Although there is less information about the role of this enzyme in veterinary medicine, new data suggest that PON1 might be a new oxidative stress marker in animal patients, similarly to humans.
Topics: Animals; Aryldialkylphosphatase; Gene Expression Regulation, Enzymologic; Humans; Mammals; Polymorphism, Genetic
PubMed: 27096809
DOI: 10.1515/pjvs-2016-0028 -
Ecotoxicology and Environmental Safety Jul 2022Exogenous pollution of Chinese medicinal materials by pesticide residues and heavy metal ions has attracted great attention. Relying on the rapid development of...
Exogenous pollution of Chinese medicinal materials by pesticide residues and heavy metal ions has attracted great attention. Relying on the rapid development of nanotechnology and multidisciplinary fields, fluorescent techniques have been widely applied in contaminant detection and pollution monitoring due to their advantages of simple preparation, low cost, high throughput and others. Most importantly, synchronous detection of multi-targets has always been pursued as one of the major goals in the design of fluorescent probes. Herein, we firstly develop a simultaneous sensing method for methyl-paraoxon (MP) and Nickel ion (Ni, Ⅱ) by using carbon based fluorescent nanocomposite with ratiometric signal readout and nanozyme. Notably, the designed system showed excellent effectiveness even when the two pollutants co-exist. Under the optimum conditions, this method provides low limits of detection of 1.25 µM for methyl-paraoxon and 0.01 µM for Ni (Ⅱ). To further verify the reliability, recovery studies of these two analytes were performed on ginseng radix et rhizoma, nelumbinis semen, and water samples. In addition, smartphone-based visual analysis has been introduced to expand its applicability in point of care detection. This work not only expands the application of the dual-mode approach to pollutant detection, but also provides insights into the analysis of multiple pollutants in a single assay.
Topics: Environmental Pollutants; Fluorescent Dyes; Limit of Detection; Paraoxon; Pesticide Residues; Reproducibility of Results
PubMed: 35623151
DOI: 10.1016/j.ecoenv.2022.113668 -
Neurotoxicology and Teratology 2019Exposure to organophosphate (OP) compounds leads to behavioral alterations. To determine whether paraoxon has effects on anxiety, anxiety-like behaviors were assessed in...
Exposure to organophosphate (OP) compounds leads to behavioral alterations. To determine whether paraoxon has effects on anxiety, anxiety-like behaviors were assessed in paraoxon-exposed rats. Protein expression of glutamate transporters has also been measured in hippocampus and prefrontal cortex. Three doses of paraoxon (0.3, 0.7, or 1 mg/kg) or corn oil (vehicle) were intraperitoneally injected to adult male rats. At 14 or 28 days after exposure, behavioral tests were done using elevated plus-maze (EPM) or open field tests. Thereafter, animals were sacrificed and both hippocampi and prefrontal cortices were extracted for cholinesterase assay and western blotting. Animals treated with convulsive doses of paraoxon (0.7 and 1 mg/kg) showed an increase in percentage of time spent in open arms and percentage of open arm entries in the EPM. In the open field test, an increase in the time spent in central area was observed in rats treated with the same doses of paraoxon. These effects of paraoxon were independent of any changes in locomotor activity. There was an increase in both astrocytic glutamate transporter proteins (GLAST and GLT-1) in the hippocampus of animals treated with 0.7 and 1 mg/kg of paraoxon. In the prefrontal cortex, protein levels of the GLAST and GLT-1 increased in 0.7 and decreased in 1 mg/kg groups. Only a significant decrease in EAAC1 protein was observed in the prefrontal cortex at 14 days following exposure to 1 mg/kg of paraoxon. Collectively, this study showed that exposure to convulsive doses of paraoxon induced anxiolytic-like behaviors in both behavioral tests. This effect may be attributed to alterations of glutamate transporter proteins in the rat hippocampus and prefrontal cortex.
Topics: Animals; Anxiety; Behavior, Animal; Brain; Cholinesterases; Dose-Response Relationship, Drug; Excitatory Amino Acid Transporter 1; Excitatory Amino Acid Transporter 2; Glutamate Plasma Membrane Transport Proteins; Hippocampus; Male; Maze Learning; Motor Activity; Paraoxon; Prefrontal Cortex; Rats
PubMed: 30576762
DOI: 10.1016/j.ntt.2018.12.001 -
Journal of Molecular Neuroscience : MN Feb 2019Organophosphates (OP) are a major threat to the health of soldiers and civilians due to their use as chemical weapons in war and in terror attacks. Among the acute...
Organophosphates (OP) are a major threat to the health of soldiers and civilians due to their use as chemical weapons in war and in terror attacks. Among the acute manifestations of OP poisoning, status epilepticus (SE) is bearing the highest potential for long-term damages. Current therapies do not prevent brain damage and seizure-related brain injuries in OP-exposed humans. Thrombin is a serine protease known to have a fundamental function in the clotting cascade. It is highly expressed in the brain where we have previously found that it regulates synaptic transmission and plasticity. In addition, we have found that an excess of thrombin in the brain leads to hyperexcitability and therefore seizures through a glutamate-dependent mechanism. In the current study, we carried out in vitro, ex vivo, and in vivo experiments in order to determine the role of thrombin and its receptor PAR-1 in paraoxon-induced SE. Elevated thrombin activity was found in the brain slices from mice that were treated (in vitro and in vivo) with paraoxon. Increased levels of PAR-1 and pERK proteins and decreased prothrombin mRNA were found in the brains of paraoxon-treated mice. Furthermore, ex vivo and in vivo electrophysiological experiments showed that exposure to paraoxon causes elevated electrical activity in CA1 and CA3 regions of the hippocampus. Moreover, a specific PAR-1 antagonist (SCH79797) reduced this activity. Altogether, these results reveal the importance of thrombin and PAR-1 in paraoxon poisoning. In addition, the results indicate that thrombin and PAR-1 may be a possible target for the treatment of paraoxon-induced status epilepticus.
Topics: Animals; Cholinesterase Inhibitors; Hippocampus; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 1; Paraoxon; Prothrombin; Receptors, Thrombin; Status Epilepticus
PubMed: 30515700
DOI: 10.1007/s12031-018-1228-6 -
Journal of Hazardous Materials Mar 2019Organophosphates (OPs) are highly toxic compounds used as pesticides and nerve agents. The devastating effects, reported in different studies, on the environment and...
Organophosphates (OPs) are highly toxic compounds used as pesticides and nerve agents. The devastating effects, reported in different studies, on the environment and human health indicate a serious scenario for both instantaneous and long terms effects. Bio-based strategies for OPs degradation seem the most promising solutions, particularly when extremophiles enzymes are used. These systems permit OPs degradation with high efficiency and specificity under mild conditions. However, as frequently observed, enzymes can easily lose activity in batch systems, so that a strategy to improve biocatalyst stability is highly needed, in order to develop continuous systems. In this work, for the first time, a continuous biocatalytic system for organophosphates (OPs) detoxification has been proposed by using a triple mutant of the thermostable phosphotriesterase (named SsoPox) isolated from the hyperthermophilic archaeon Sulfolobus solfataricus. The enzyme was covalently immobilized on polymeric membranes to develop a biocatalytic membrane reactor (BMR) able to hydrolyse a pesticide (paraoxon) contained in water. High paraoxon degradation (about 90%) and long term stability (1 year) were obtained when the enzyme was covalently immobilized on hydrophilic membranes. On the contrary, the enzyme in batch system completely loses its activity within few months after its solubilisation in buffer.
Topics: Biocatalysis; Bioreactors; Hydrolysis; Organophosphates; Phosphoric Triester Hydrolases
PubMed: 30476802
DOI: 10.1016/j.jhazmat.2018.11.063 -
Nanomaterials (Basel, Switzerland) Apr 2022Selective and sensitive identification of paraoxon residue in agricultural products is greatly significant for food safety but remains a challenging task. Herein, a...
Selective and sensitive identification of paraoxon residue in agricultural products is greatly significant for food safety but remains a challenging task. Herein, a detection platform was developed by integrating Cu nanoclusters (Cu NCs) with MnO nanosheets, where the fluorescence of Cu NCs was effectively quenched. Upon introducing butyrylcholinesterase and butyrylcholine into the system, their hydrolysate, thiocholine, leads to the decomposition of the platform through a reaction between the MnO nanosheets and thiol groups on thiocholine. The electron-rich groups on thiocholine can further promote the fluorescence intensity of Cu NCs through host-guest interactions. Adding paraoxon results in the failure of fluorescence recovery and further promotion, which could be utilized for the quantitative detection of paraoxon, and a limit of detection as low as 0.22 ng/mL can be achieved. The detection platform shows strong tolerance to common interference species, which endows its applications for the detection of paraoxon in vegetables and fruit. These presented results not only open a new door for the functionalization of metal nanoclusters but also offer an inspiring strategy for analytic techniques in nanomedicine and environmental science.
PubMed: 35564138
DOI: 10.3390/nano12091429 -
Chemico-biological Interactions Aug 2019Carbamates are esters of substituted carbamic acids that react with acetylcholinesterase (AChE) by initially transferring the carbamoyl group to a serine residue in the... (Review)
Review
Carbamates are esters of substituted carbamic acids that react with acetylcholinesterase (AChE) by initially transferring the carbamoyl group to a serine residue in the enzyme active site accompanied by loss of the carbamate leaving group followed by hydrolysis of the carbamoyl enzyme. This hydrolysis, or decarbamoylation, is relatively slow, and half-lives of carbamoylated AChEs range from 4 min to more than 30 days. Therefore, carbamates are effective AChE inhibitors that have been developed as insecticides and as therapeutic agents. In this report, we review recent data showing that decarbamoylation rate constants are independent of the ester leaving group for a series of carbamic acid esters with the same carbamoyl group and that decarbamoylation rate constants decreased by 800-fold when the alkyl substituents on the carbamoyl group increased in size from N-monomethyl- to N,N-diethyl-. We also review data showing that solvent deuterium oxide isotope effects for decarbamoylation decreased from 2.8 for N-monomethylcarbamoyl AChE to 1.1 for N,N-diethylcarbamoyl AChE, indicating a shift in the rate-limiting step from general acid-base catalysis to a likely conformational change in the distorted active site in N,N-diethylcarbamoyl AChE. The nature of such a conformational change is suggested from X-ray crystal structures of AChE phosphorylated by paraoxon.
Topics: Acetylcholinesterase; Carbamates; Catalytic Domain; Crystallography, X-Ray; Kinetics; Paraoxon
PubMed: 31175846
DOI: 10.1016/j.cbi.2019.06.004 -
Annals of the New York Academy of... Jun 2016Organophosphate (OP) chemicals include nerve agents and pesticides, and there is a growing concern of OP-based chemical attacks against civilians. Current antidotes are... (Review)
Review
Organophosphate (OP) chemicals include nerve agents and pesticides, and there is a growing concern of OP-based chemical attacks against civilians. Current antidotes are essential in limiting immediate mortality associated with OP exposure. However, further research is needed to identify the molecular mechanisms underlying long-term neurological deficits following survival of OP toxicity in order to develop effective therapeutics. We have developed rat survival models of OP-induced status epilepticus (SE) that mimic chronic mortality and morbidity following OP intoxication. We have observed significant elevations in hippocampal calcium levels after OP SE that persisted for weeks following initial survival. Drugs inhibiting intracellular calcium-induced calcium release, such as dantrolene, levetiracetam, and carisbamate, lowered OP SE-mediated protracted calcium elevations. Given the critical role of calcium signaling in modulating behavior and cell death mechanisms, drugs targeted at preventing the development of the calcium plateau could enhance neuroprotection, help reduce morbidity, and improve outcomes following survival of OP SE.
Topics: Animals; Behavior, Animal; Calcium; Disease Models, Animal; Humans; Neurons; Organophosphorus Compounds; Risk Factors; Status Epilepticus
PubMed: 27327161
DOI: 10.1111/nyas.13122